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Pratt School of Engineering
Duke University

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Publications of Lori A. Setton    :chronological  alphabetical  combined listing:

%% Papers Published   
@article{070810438044,
   Author = {Gilchrist, Christopher L. and Witvoet-Braam, Sietske W. and Guilak, Farshid and Setton, Lori A.},
   Title = {Measurement of intracellular strain on deformable substrates
             with texture correlation},
   Journal = {Journal of Biomechanics},
   Volume = {40},
   Number = {4},
   Pages = {786 - 794},
   Year = {2007},
   url = {http://dx.doi.org/10.1016/j.jbiomech.2006.03.013},
   Keywords = {Biocommunications;Deformation;Metabolism;Microscopic
             examination;Stiffness;Strain measurement;},
   Abstract = {Mechanical stimuli are important factors that regulate cell
             proliferation, survival, metabolism and motility in a
             variety of cell types. The relationship between mechanical
             deformation of the extracellular matrix and intracellular
             deformation of cellular sub-regions and organelles has not
             been fully elucidated, but may provide new insight into the
             mechanisms involved in transducing mechanical stimuli to
             biological responses. In this study, a novel fluorescence
             microscopy and image analysis method was applied to examine
             the hypothesis that mechanical strains are fully transferred
             from a planar, deformable substrate to cytoplasmic and
             intranuclear regions within attached cells. Intracellular
             strains were measured in cells derived from the anulus
             fibrosus of the intervertebral disc when attached to an
             elastic silicone membrane that was subjected to tensile
             stretch. Measurements indicated cytoplasmic strains were
             similar to those of the underlying substrate, with a strain
             transfer ratio (STR) of 0.79. In contrast, nuclear strains
             were much smaller than those of the substrate, with an STR
             of 0.17. These findings are consistent with previous studies
             indicating nuclear stiffness is significantly greater than
             cytoplasmic stiffness, as measured using other methods. This
             study provides a novel method for the study of cellular
             mechanics, including a new technique for measuring
             intranuclear deformations, with evidence of differential
             magnitudes and patterns of strain transferred from the
             substrate to cell cytoplasm and nucleus. © 2006
             Elsevier Ltd. All rights reserved.},
   Key = {070810438044}
}

@article{9108356,
   Author = {Li Cao and Youn, I. and Guilak, F. and Setton,
             L.A.},
   Title = {Compressive properties of mouse articular cartilage
             determined in a novel micro-indentation test method and
             biphasic finite element model},
   Journal = {Trans. ASME, J. Biomech. Eng. (USA)},
   Volume = {128},
   Number = {5},
   Pages = {766 - 71},
   Year = {2006},
   url = {http://dx.doi.org/10.1115/1.2246237},
   Keywords = {biological tissues;biomechanics;creep;diseases;finite
             element analysis;genetic algorithms;indentation;parameter
             estimation;permeability;physiological models;Poisson
             ratio;Young's modulus;},
   Abstract = {The mechanical properties of articular cartilage serve as
             important measures of tissue function or degeneration, and
             are known to change significantly with osteoarthritis.
             Interest in small animal and mouse models of osteoarthritis
             has increased as studies reveal the importance of genetic
             background in determining predisposition to osteoarthritis.
             While indentation testing provides a method of determining
             cartilage mechanical properties in situ, it has been of
             limited value in studying mouse joints due to the relatively
             small size of the joint and thickness of the cartilage
             layer. In this study, we developed a micro-indentation
             testing system to determine the compressive and biphasic
             mechanical properties of cartilage in the small joints of
             the mouse. A nonlinear optimization program employing a
             genetic algorithm for parameter estimation, combined with a
             biphasic finite element model of the micro-indentation test,
             was developed to obtain the biphasic, compressive material
             properties of articular cartilage. The creep response and
             material properties of lateral tibial plateau cartilage were
             obtained for wild-type mouse knee joints, by the
             micro-indentation testing and optimization algorithm. The
             newly developed genetic algorithm was found to be efficient
             and accurate when used with the finite element simulations
             for nonlinear optimization to the experimental creep data.
             The biphasic mechanical properties of mouse cartilage in
             compression (average values: Young's modulus, 2.0 MPa;
             Poisson's ratio, 0.20; and hydraulic permeability,
             1.1&times;10<sup>-16</sup> m<sup>4</sup>/N-s) were found to
             be of similar orders of magnitude as previous findings for
             other animal cartilages, including human, bovine, rat, and
             rabbit and demonstrate the utility of the new test methods.
             This study provides the first available data for biphasic
             compressive properties in mouse cartilage and suggests a
             promising method for detecting altered cartilage mechanics
             in small animal models of osteoarthritis},
   Key = {9108356}
}

@article{06059678393,
   Author = {Sontjens, Serge H.M. and Nettles, Dana L. and Carnahan,
             Michael A. and Setton, Lori A. and Grinstaff, Mark
             W.},
   Title = {Biodendrimer-based hydrogel scaffolds for cartilage tissue
             repair},
   Journal = {Biomacromolecules},
   Volume = {7},
   Number = {1},
   Pages = {310 - 316},
   Year = {2006},
   url = {http://dx.doi.org/10.1021/bm050663e},
   Keywords = {Dendrimers;Biological materials;Macromolecules;Tissue;Synthesis
             (chemical);Block copolymers;Acrylic monomers;Biocompatibility;Crosslinking;Biodegradation;Mechanical
             properties;Encapsulation;},
   Abstract = {Photo-crosslinkable dendritic macromolecules are attractive
             materials for the preparation of cartilage tissue
             engineering scaffolds that may be optimized for in situ
             formation of hydrated, mechanically stable, and
             well-integrated hydrogel scaffolds supporting chondrocytes
             and chondrogenesis. We designed and synthesized a novel
             hydrogel scaffold for cartilage repair, based on a
             multivalent and water-soluble tri-block copolymer consisting
             of a poly(ethylene glycol) core and methacrylated
             poly(glycerol succinic acid) dendrimer terminal blocks. The
             terminal methacrylates allow mild and biocompatible
             photo-crosslinking with a visible light, facilitating in
             vivo filling of irregularly shaped defects with the
             dendrimer-based scaffold. The multivalent dendrimer
             constituents allow high crosslink densities that inhibit
             swelling after crosslinking while simultaneously introducing
             biodegradation sites. The mechanical properties and water
             content of the hydrogel can easily be tuned by changing the
             biodendrimer concentration. In vitro chondrocyte
             encapsulation studies demonstrate significant synthesis of
             neocartilaginous material, containing proteoglycans and type
             II collagen. &copy; 2006 American Chemical
             Society.},
   Key = {06059678393}
}

@article{064210174605,
   Author = {Betre, Helawe and Liu, Wenge and Zalutsky, Michael R. and Chilkoti, Ashutosh and Kraus, Virginia B. and Setton, Lori
             A.},
   Title = {A thermally responsive biopolymer for intra-articular drug
             delivery},
   Journal = {Journal of Controlled Release},
   Volume = {115},
   Number = {2},
   Pages = {175 - 182},
   Year = {2006},
   url = {http://dx.doi.org/10.1016/j.jconrel.2006.07.022},
   Keywords = {Controlled drug delivery;Pharmacokinetics;Polypeptides;Phase
             transitions;Joints (anatomy);Diseases;},
   Abstract = {Intra-articular drug delivery is the preferred standard for
             targeting pharmacologic treatment directly to joints to
             reduce undesirable side effects associated with systemic
             drug delivery. In this study, a biologically based drug
             delivery vehicle was designed for intra-articular drug
             delivery using elastin-like polypeptides (ELPs), a
             biopolymer composed of repeating pentapeptides that undergo
             a phase transition to form aggregates above their transition
             temperature. The ELP drug delivery vehicle was designed to
             aggregate upon intra-articular injection at 37 &deg;C, and
             form a drug 'depot' that could slowly disaggregate and be
             cleared from the joint space over time. We evaluated the in
             vivo biodistribution and joint half-life of radiolabeled
             ELPs, with and without the ability to aggregate, at
             physiological temperatures encountered after intra-articular
             injection in a rat knee. Biodistribution studies revealed
             that the aggregating ELP had a 25-fold longer half-life in
             the injected joint than a similar molecular weight protein
             that remained soluble and did not aggregate. These results
             suggest that the intra-articular joint delivery of ELP-based
             fusion proteins may be a viable strategy for the prolonged
             release of disease-modifying protein drugs for
             osteoarthritis and other arthritides. &copy; 2006 Elsevier
             B.V. All rights reserved.},
   Key = {064210174605}
}

@article{9160417,
   Author = {Upton, M.L. and Guilak, F. and Laursen, T.A. and Setton,
             L.A.},
   Title = {Finite element modeling predictions of region-specific
             cell-matrix mechanics in the meniscus},
   Journal = {Biomech. Modeling Mechanobiol. (Germany)},
   Volume = {5},
   Number = {2-3},
   Pages = {140 - 9},
   Year = {2006},
   url = {http://dx.doi.org/10.1007/s10237-006-0031-4},
   Keywords = {biochemistry;biological tissues;biomechanics;cellular
             biophysics;finite element analysis;molecular
             biophysics;physiological models;proteins;},
   Abstract = {The knee meniscus exhibits significant spatial variations in
             biochemical composition and cell morphology that reflect
             distinct phenotypes of cells located in the radial inner and
             outer regions. Associated with these cell phenotypes is a
             spatially heterogeneous microstructure and mechanical
             environment with the innermost regions experiencing higher
             fluid pressures and lower tensile strains than the outer
             regions. It is presently unknown, however, how meniscus
             tissue mechanics correlate with the local micromechanical
             environment of cells. In this study, theoretical models were
             developed to study mechanics of inner and outer meniscus
             cells with varying geometries. The results for an applied
             biaxial strain predict significant regional differences in
             the cellular mechanical environment with evidence of tensile
             strains along the collagen fiber direction of ~0.07 for the
             rounded inner cells, as compared to levels of 0.02-0.04 for
             the elongated outer meniscus cells. The results demonstrate
             an important mechanical role of extracellular matrix
             anisotropy and cell morphology in regulating the
             region-specific micromechanics of meniscus cells, that may
             further play a role in modulating cellular responses to
             mechanical stimuli},
   Key = {9160417}
}

@article{9150369,
   Author = {Haider, M.A. and Schugart, R.C. and Setton, L.A. and Guilak,
             F.},
   Title = {A mechano-chemical model for the passive swelling response
             of an isolated chondron under osmotic loading},
   Journal = {Biomech. Modeling Mechanobiol. (Germany)},
   Volume = {5},
   Number = {2-3},
   Pages = {160 - 71},
   Year = {2006},
   url = {http://dx.doi.org/10.1007/s10237-006-0026-1},
   Keywords = {biochemistry;biodiffusion;bioelectric phenomena;biomechanics;biomembranes;biorheology;deformation;molecular
             biophysics;osmosis;physiological models;proteins;},
   Abstract = {The chondron is a distinct structure in articular cartilage
             that consists of the chondrocyte and its pericellular matrix
             (PCM), a narrow tissue region surrounding the cell that is
             distinguished by type VI collagen and a high
             glycosaminoglycan concentration relative to the
             extracellular matrix. We present a theoretical
             mechano-chemical model for the passive volumetric response
             of an isolated chondron under osmotic loading in a simple
             salt solution at equilibrium. The chondrocyte is modeled as
             an ideal osmometer and the PCM model is formulated using
             triphasic mixture theory. A mechano-chemical chondron model
             is obtained assuming that the chondron boundary is permeable
             to both water and ions, while the chondrocyte membrane is
             selectively permeable to only water. For the case of a
             neo-Hookean PCM constitutive law, the model is used to
             conduct a parametric analysis of cell and chondron
             deformation under hyper- and hypo-osmotic loading. In
             combination with osmotic loading experiments on isolated
             chondrons, model predictions will aid in determination of
             pericellular fixed charge density and its relative
             contribution to PCM mechanical properties},
   Key = {9150369}
}

@article{8837010,
   Author = {Jinho Hyun and Jun Chen and Setton, L.A. and Chilkoti,
             A.},
   Title = {Patterning cells in highly deformable microstructures:
             Effect of plastic deformation of substrate on cellular
             phenotype and gene expression},
   Journal = {Biomaterials (UK)},
   Volume = {27},
   Number = {8},
   Pages = {1444 - 51},
   Year = {2006},
   url = {http://dx.doi.org/10.1016/j.biomaterials.2005.08.018},
   Keywords = {biomechanics;cellular biophysics;deformation;elastomers;embossing;plasticity;proteins;silicon;tissue
             engineering;},
   Abstract = {We describe the fabrication of deformable microstructures by
             low-pressure-soft-microembossing (&mu;SEmb) that provides in
             vitro experimental "test-beds" to investigate the interplay
             of mechanical and chemical stimuli on cell behavior in a
             highly controlled environment. Soft microembossing exploits
             the softness and plasticity of parafilm to fabricate
             microstructures by pressing a silicon master or an
             elastomeric poly(dimethylsiloxane) stamp into the parafilm.
             We demonstrate that a protein-resistant comb polymer can be
             printed into the raised features of the embossed
             microstructures, which imparts protein, and hence cell
             resistance to those regions of the microstructures. These
             two features of our fabrication methodology-microembossing
             followed by spatially selective transfer of a nonfouling
             polymer-forms the core of our strategy to pattern cells
             within the parafilm microstructures, such that the cells are
             confined within bottoms of the microstructures. Cell culture
             experiments demonstrated the preferential cell attachment of
             NIH 3T3 fibroblasts to the fibronectin (FN) micropatterns by
             immunofluorescence microscopy. The actin cytoskeleton
             realigned along the axis of applied mechanical stress, and
             stretched cells showed altered gene expression of
             cytoskeletal and matrix proteins in response to mechanical
             deformation. The use of parafilm as a substrate and &mu;SEmb
             as a fabrication method provides a simple and widely
             accessible methodology to investigate cellular behavior
             under well-defined conditions of plastic deformation and
             surface ligand density. [All rights reserved
             Elsevier]},
   Key = {8837010}
}

@article{8827248,
   Author = {Setton, L.A. and Ong, S.R. and Trabbic-Carlson, K.A. and Nettles, D.L. and Lim, D.W. and Chilkoti,
             A.},
   Title = {Epitope tagging for tracking elastin-like
             polypeptides},
   Journal = {Biomaterials (UK)},
   Volume = {27},
   Number = {9},
   Pages = {1930 - 5},
   Year = {2006},
   url = {http://dx.doi.org/10.1016/j.biomaterials.2005.10.018},
   Keywords = {biological tissues;biomedical materials;DNA;enzymes;patient
             treatment;polymer gels;tissue engineering;},
   Abstract = {Elastin-like polypeptides (ELPs) are a class of
             biocompatible, non-immunogenic and crosslinkable
             biomaterials that offer promise for use as an injectable
             scaffold for cartilage repair. In this study, an
             oligohistidine (His<sub>6</sub>) epitope tag was
             incorporated at the N-terminus of an ELP using recombinant
             DNA techniques to permit tracking without compromising on
             material biocompatibility. His<sub>6</sub>-tagged ELPs were
             successfully detected by Western blot analysis and
             quantified by ELISAs following digestion with trypsin. The
             mass of His<sub>6</sub> tagged ELP fragments freed from a
             crosslinked ELP hydrogel after digestion with trypsin
             correlated highly with hydrogel weight loss, providing
             evidence of the tag's capability to enable tracking of
             enzymatic degradation of the ELP hydrogel. The
             His<sub>6</sub> tag also facilitated recognition of
             crosslinked ELPs from background staining of articular
             cartilage. These results suggest that the His<sub>6</sub>
             epitope tag has the potential to track ELP scaffold loss
             independently of newly formed tissue mass for evaluating
             matrix remodeling in vivo. [All rights reserved
             Elsevier]},
   Key = {8827248}
}

@article{8776598,
   Author = {Setton, L.A. and Betre, H. and Ong, S.R. and Guilak, F. and Chilkoti, A. and Fermor, B.},
   Title = {Chondrocytic differentiation of human adipose-derived adult
             stem cells in elastin-like polypeptide},
   Journal = {Biomaterials (UK)},
   Volume = {27},
   Number = {1},
   Pages = {91 - 9},
   Year = {2006},
   url = {http://dx.doi.org/10.1016/j.biomaterials.2005.05.071},
   Keywords = {biomedical materials;cellular biophysics;gels;genetic
             engineering;molecular biophysics;proteins;},
   Abstract = {Human adipose derived adult stem (<i>h</i>ADAS) cells have
             the ability to differentiate into a chondrogenic phenotype
             in three-dimensional culture and media containing
             dexamethasone and TGF-<i>&beta;</i>. The current study
             examined the potential of a genetically engineered
             elastin-like polypeptide (ELP) to promote the chondrocytic
             differentiation of <i>h</i>ADAS cells without exogenous
             chondrogenic supplements. <i>h</i>ADAS cells were cultured
             in ELP hydrogels in either chondrogenic or standard medium
             at 5% O<sub>2</sub> for up to 2 weeks. By day 14, constructs
             cultured in either medium exhibited significant increases in
             sulfated glycosaminoglycan (up to 100%) and collagen
             contents (up to 420%). Immunolabeling confirmed that the
             matrix formed consisted mainly of type II and not type I
             collagen. The composition of the constructs cultured in
             either medium did not differ significantly. To assess the
             effect of oxygen tension on the differentiation of the above
             constructs, samples were cultured in standard medium at
             either 5% or 20% O<sub>2</sub> for 7 days and their gene
             expression profile was evaluated using real time RT-PCR. In
             both cases, the <i>h</i>ADAS-ELP constructs upregulated SOX9
             and type II collagen gene expression, while type I collagen
             was downregulated. However, constructs cultured in 20%
             O<sub>2</sub> highly upregulated type X collagen, which was
             not detected in the 5% O<sub>2</sub> cultures. The study
             suggests that ELP can promote chondrogenesis for
             <i>h</i>ADAS cells in the absence of exogenous
             TGF-<i>&beta;</i>1 and dexamethasone, especially under low
             oxygen tension conditions. [All rights reserved
             Elsevier]},
   Key = {8776598}
}

@article{06049665755,
   Author = {McHale, Melissa K. and Setton, Lori A. and Chilkoti,
             Ashutosh},
   Title = {Synthesis and in vitro evaluation of enzymatically
             cross-linked elastin-like polypeptide gels for cartilaginous
             tissue repair},
   Journal = {Tissue Engineering},
   Volume = {11},
   Number = {11-12},
   Pages = {1768 - 1779},
   Year = {2005},
   url = {http://dx.doi.org/10.1089/ten.2005.11.1768},
   Keywords = {Hydrogels;Biosynthesis;Tissue;Enzyme immobilization;Cartilage;Mechanical
             properties;Gelation;Biocompatibility;Histology;Elastic
             moduli;},
   Abstract = {Genetically engineered elastin-Iike polypeptide (ELP)
             hydrogels offer unique promise as scaffolds for cartilage
             tissue engineering because of the potential to promote
             chondrogenesis and to control mechanical properties. In this
             study, we designed and synthesized ELPs capable of
             undergoing enzyme-initiated gelation via tissue
             transglutaminase, with the ultimate goal of creating an
             injectable, in situ cross-linking scaffold to promote
             functional cartilage repair. Addition of the enzyme promoted
             ELP gel formation and chondrocyte encapsulation in a
             biocompatible process, which resulted in cartilage matrix
             synthesis in vitro and the potential to contribute to
             cartilage mechanical function in vivo. A significant
             increase in the accumulation of sulfated glycosaminoglycans
             was observed, and histological sections revealed the
             accumulation of a cartilaginous matrix rich in type II
             collagen and lacking in type I collagen, indicative of
             hyaline cartilage formation. These results provide evidence
             of chondrocytic phenotype maintenance for cells in the ELP
             hydrogels in vitro. In addition, the dynamic shear moduli of
             ELP hydrogels seeded with chondrocytes increased from 0.28
             to 1.7 kPa during a 4-week culture period. This increase in
             the mechanical integrity of cross-linked ELP hydrogels
             suggests restructuring of the ELP matrix by deposition of
             functional cartilage extracellular matrix components. &copy;
             Mary Ann Liebert, Inc.},
   Key = {06049665755}
}

@article{06219888998,
   Author = {Haider, Mansoor A. and Schugart, Richard C. and Setton, Lori
             A. and Guilak, Farshid},
   Title = {A mechano-chemical model for osmotic loading of an isolated
             chondron},
   Journal = {Proceedings of the 2005 Summer Bioengineering
             Conference},
   Volume = {2005},
   Pages = {613 - 614},
   Address = {Vail, CO, United States},
   Year = {2005},
   Key = {06219888998}
}

@article{06219889008,
   Author = {Haider, Mansoor A. and Nettles, Dana L. and Trabbic-Carlson,
             Kimberly and Chilkoti, Ashutosh and Setton, Lori
             A.},
   Title = {Predictive modeling of polypeptide hydrogel mechanical
             properties for cartilage repair using artificial neural
             networks},
   Journal = {Proceedings of the 2005 Summer Bioengineering
             Conference},
   Volume = {2005},
   Pages = {633 - 634},
   Address = {Vail, CO, United States},
   Year = {2005},
   Key = {06219889008}
}

@article{05449455291,
   Author = {Guilak, Farshid and Alexopoulos, Leonidas G. and Haider,
             Mansoor A. and Ting-Beall, H. Ping and Setton, Lori
             A.},
   Title = {Zonal uniformity in mechanical properties of the chondrocyte
             pericellular matrix: Micropipette aspiration of canine
             chondrons isolated by cartilage homogenization},
   Journal = {Annals of Biomedical Engineering},
   Volume = {33},
   Number = {10},
   Pages = {1312 - 1318},
   Year = {2005},
   url = {http://dx.doi.org/10.1007/s10439-005-4479-7},
   Keywords = {Tissue;Mechanical properties;Cells;Flow of fluids;Matrix
             algebra;Biomechanics;Collagen;},
   Abstract = {The pericellular matrix (PCM) is a region of tissue that
             surrounds chondrocytes in articular cartilage and together
             with the enclosed cells is termed the chondron. Previous
             studies suggest that the mechanical properties of the PCM,
             relative to those of the chondrocyte and the extracellular
             matrix (ECM), may significantly influence the stress-strain,
             physicochemical, and fluid-flow environments of the cell.
             The aim of this study was to measure the biomechanical
             properties of the PCM of mechanically isolated chondrons and
             to test the hypothesis that the Young's modulus of the PCM
             varies with zone of origin in articular cartilage (surface
             vs. middle/deep). Chondrons were extracted from articular
             cartilage of the canine knee using mechanical
             homogenization, and the elastic properties of the PCM were
             determined using micropipette aspiration in combination with
             theoretical models of the chondron as an elastic
             incompressible half-space, an elastic compressible bilayer,
             or an elastic compressible shell. The Young's modulus of the
             PCM was significantly higher than that reported for isolated
             chondrocytes but over an order of magnitude lower than that
             of the cartilage ECM. No significant differences were
             observed in the Young's modulus of the PCM between surface
             zone (24.0 &plusmn; 8.9 kPa) and middle/deep zone cartilage
             (23.2 &plusmn; 7.1 kPa). In combination with previous
             theoretical biomechanical models of the chondron, these
             findings suggest that the PCM significantly influences the
             mechanical environment of the chondrocyte in articular
             cartilage and therefore may play a role in modulating
             cellular responses to micromechanical factors. &copy; 2005
             Biomedical Engineering Society.},
   Key = {05449455291}
}

@article{06219888808,
   Author = {Upton, Maureen L. and Laursen, Tod A. and Guilak, Farshid and Setton, Lori A.},
   Title = {Finite element modeling of region-specific cell-matrix
             interactions in the meniscus},
   Journal = {Proceedings of the 2005 Summer Bioengineering
             Conference},
   Volume = {2005},
   Pages = {229 - 230},
   Address = {Vail, CO, United States},
   Year = {2005},
   Key = {06219888808}
}

@article{06219888810,
   Author = {Cao, Li and Youn, Inchan and Li, Yefu and Guilak, Farshid and Olsen, Bjorn R. and Setton, Lori A.},
   Title = {Biphasic micro-indentation testing of mouse articular
             cartilage reveals functional changes in a type IX collagen
             knockout model of osteoarthritis},
   Journal = {Proceedings of the 2005 Summer Bioengineering
             Conference},
   Volume = {2005},
   Pages = {233 - 234},
   Address = {Vail, CO, United States},
   Year = {2005},
   Key = {06219888810}
}

@article{8999809,
   Author = {Boyd, L.M. and Richardson, W.J. and Chen, J. and Kraus, V.B. and Tewari, A. and Setton, L.A.},
   Title = {Osmolarity regulates gene expression in intervertebral disc
             cells determined by gene array and real-time quantitative
             RT-PCR},
   Journal = {Ann. Biomed. Eng. (USA)},
   Volume = {33},
   Number = {8},
   Pages = {1071 - 7},
   Year = {2005},
   url = {http://dx.doi.org/10.1007/s10439-005-5775-y},
   Keywords = {biochemistry;biodiffusion;biomembrane transport;genetics;molecular
             biophysics;neurophysiology;osmosis;proteins;},
   Abstract = {Intervertebral disc (IVD) cells experience a broad range of
             physicochemical stimuli under physiologic conditions,
             including alterations in their osmotic environment. Cellular
             responses to altered osmolarity have been documented at the
             transcriptional and post-translational level, but mainly for
             extracellular matrix proteins. In this study, the gene
             expression profile of human IVD cells was quantified with
             gene array technology following exposure to increased
             osmolarity in order to capture the biological responses for
             a broad set of targets. A total of 42 genes were identified
             in IVD cells as significantly changed following culture
             under hyper-osmotic conditions. Gene expression patterns
             were verified using RT-PCR. Genes identified in this study
             include those related to cytoskeleton remodeling and
             stabilization (ephrin-B2, muskelin), as well as membrane
             transport (ion transporter SLC21A12, osmolyte transporter
             SLC5A3, monocarboxylic acid SLC16A6). An unexpected finding
             was the differential regulation of the gene for the
             neurotrophin, brain-derived neurotrophic factor, by
             hyper-osmotic stimuli that suggests a capability of IVD
             cells to respond to physicochemical stimuli with factors
             that may regulate discogenic pain},
   Key = {8999809}
}

@article{8841799,
   Author = {Guilak, F. and Alexopoulos, L.G. and Setton,
             L.A.},
   Title = {The biomechanical role of the chondrocyte pericellular
             matrix in articular cartilage},
   Journal = {Acta Biomat. (UK)},
   Volume = {1},
   Number = {3},
   Pages = {317 - 25},
   Year = {2005},
   url = {http://dx.doi.org/10.1016/j.actbio.2005.02.001},
   Keywords = {biological tissues;biomechanics;cellular transport;finite
             element analysis;permeability;physiological
             models;stress-strain relations;Young's modulus;},
   Abstract = {The pericellular matrix (PCM) is a narrow tissue region that
             surrounds chondrocytes in articular cartilage. Previous
             parametric studies of cell-matrix interactions suggest that
             the mechanical properties of the PCM relative to those of
             the extracellular matrix (ECM) can significantly affect the
             micromechanical environment of the chondrocyte. The goal of
             this study was to use recently quantified mechanical
             properties of the PCM in a biphasic finite element model of
             the cell-PCM-ECM structure to determine the potential
             influence of the PCM on the mechanical environment of the
             chondrocyte under normal and osteoarthritic conditions. Our
             findings suggest that the mismatch between the Young's
             moduli of PCM and ECM amplifies chondrocyte compressive
             strains and exhibits a significant stress shielding effect
             in a zone-dependent manner. Furthermore, the lower
             permeability of PCM relative to the ECM inhibits fluid flux
             near the cell by a factor of 30, and thus may have a
             significant effect on convective transport to and from the
             chondrocyte. Osteoarthritic changes in the PCM and ECM
             properties significantly altered the mechanical environment
             of the chondrocyte, leading to ~66% higher compressive
             strains and higher fluid flux near the cell. These findings
             provide further support for a potential biomechanical role
             for the chondrocyte PCM, and suggest that changes in the
             properties of the PCM with osteoarthritis may alter the
             stress-strain and fluid flow environment of the
             chondrocytes. [All rights reserved Elsevier]},
   Key = {8841799}
}

@article{8419741,
   Author = {Alexopoulos, L.G. and Williams, G.M. and Upton, M.L. and Setton, L.A. and Guilak, F.},
   Title = {Osteoarthritic changes in the biphasic mechanical properties
             of the chondrocyte pericellular matrix in articular
             cartilage},
   Journal = {J. Biomech. (UK)},
   Volume = {38},
   Number = {3},
   Pages = {509 - 17},
   Year = {2005},
   url = {http://dx.doi.org/10.1016/j.jbiomech.2004.04.012},
   Keywords = {biomechanics;biorheology;bone;cellular biophysics;diseases;finite
             element analysis;orthopaedics;physiological models;Poisson
             ratio;viscoelasticity;Young's modulus;},
   Abstract = {The pericellular matrix (PCM) is a narrow region of
             cartilaginous tissue that surrounds chondrocytes in
             articular cartilage. Previous modeling studies indicate that
             the mechanical properties of the PCM relative to those of
             the extracellular matrix (ECM) can significantly affect the
             stress-strain, fluid flow, and physicochemical environments
             of the chondrocyte, suggesting that the PCM plays a
             biomechanical role in articular cartilage. The goals of this
             study were to measure the mechanical properties of the PCM
             using micropipette aspiration coupled with a linear biphasic
             finite element model, and to determine the alterations in
             the mechanical properties of the PCM with osteoarthritis
             (OA). Using a recently developed isolation technique,
             chondrons (the chondrocyte and its PCM) were mechanically
             extracted from non-degenerate and osteoarthritic human
             cartilage. The transient mechanical behavior of the PCM was
             well-described by a biphasic model, suggesting that the
             viscoelastic response of the PCM is attributable to
             flow-dependent effects, similar to that of the ECM. With OA,
             the mean Young's modulus of the PCM was significantly
             decreased (38.7&plusmn;16.2kPa vs. 23.5&plusmn;12.9kPa,
             p&lt;0.001), and the permeability was significantly elevated
             (4.19&plusmn;3.78&times;10<sup>-17</sup>m<sup>4</sup>/Ns vs.
             10.2&plusmn;9.38&times;10<sup>-17</sup>m<sup>4</sup>/Ns,
             p&lt;0.001). The Poisson's ratio was similar for both
             non-degenerate and OA PCM (0.044&plusmn;0.063 vs.
             0.030&plusmn;0.068, p&gt;0.6). These findings suggest that
             the PCM may undergo degenerative processes with OA, similar
             to those occurring in the ECM. In combination with previous
             theoretical models of cell-matrix interactions in cartilage,
             our findings suggest that changes in the properties of the
             PCM with OA may have an important influence on the
             biomechanical environment of the chondrocyte. [All rights
             reserved Elsevier]},
   Key = {8419741}
}

@article{7956034,
   Author = {Gilchrist, C.L. and Xia, J.Q. and Setton, L.A. and Hsu,
             E.W.},
   Title = {High-resolution determination of soft tissue deformations
             using MRI and first-order texture correlation},
   Journal = {IEEE Trans. Med. Imaging (USA)},
   Volume = {23},
   Number = {5},
   Pages = {546 - 53},
   Year = {2004},
   url = {http://dx.doi.org/10.1109/TMI.2004.825616},
   Keywords = {biological tissues;biomechanics;biomedical
             MRI;deformation;image texture;medical image
             processing;strain measurement;},
   Abstract = {Mechanical factors such as deformation and strain are
             thought to play important roles in the maintenance, repair,
             and degeneration of soft tissues. Determination of soft
             tissue static deformation has traditionally only been
             possible at a tissue's surface, utilizing external markers
             or instrumentation. Texture correlation is a displacement
             field measurement technique which relies on unique image
             patterns within a pair of digital images to track
             displacement. The technique has recently been applied to MR
             images, indicating the possibility of high-resolution
             displacement and strain field determination within the
             mid-substance of soft tissues. However, the utility of MR
             texture correlation analysis may vary amongst tissue types
             depending on their underlying structure, composition, and
             contrast mechanism, which give rise to variations in texture
             with MRI. In this study, we investigate the utility of a
             texture correlation algorithm with first-order displacement
             mapping terms for use with MR images, and suggest a novel
             index of image "roughness" as a way to decrease errors
             associated with the use of texture correlation for
             intra-tissue strain measurement with MRI. We find that a
             first-order algorithm can significantly reduce strain
             measurement error, and that an image "roughness" index
             correlates with displacement measurement error for a variety
             of imaging conditions and tissue types},
   Key = {7956034}
}

@article{8184668,
   Author = {Nettles, D.L. and Vail, T.P. and Morgan, M.T. and Grinstaff,
             M.W. and Setton, L.A.},
   Title = {Photocrosslinkable hyaluronan as a scaffold for articular
             cartilage repair},
   Journal = {Ann. Biomed. Eng. (USA)},
   Volume = {32},
   Number = {3},
   Pages = {391 - 7},
   Year = {2004},
   url = {http://dx.doi.org/10.1023/B:ABME.0000017552.65260.94},
   Keywords = {biochemistry;biodiffusion;biomechanics;biomedical
             materials;bone;cellular biophysics;diseases;gels;molecular
             biophysics;organic compounds;shear modulus;tissue
             engineering;},
   Abstract = {Hyaluronan-based scaffolds are of interest for
             tissue-engineered cartilage repair due to an important role
             for hyaluronan in cartilage development and function. In
             this study, an in situ photocrosslinkable hyaluronan (HA-MA)
             was developed and evaluated as a scaffold for articular
             cartilage repair. Chondrocytes were encapsulated in
             crosslinked HA-MA and evaluated for their ability to
             synthesize cartilaginous matrix in vitro. The mechanical and
             physical properties of the crosslinked HA-MA hydrogels were
             similar to that of other hydrogels, with compressive and
             dynamic shear moduli of 0.6 and 0.3 kPa, respectively, and
             diffusion coefficients of 600-8000 &mu;m<sup>2</sup>/s
             depending on molecular weight. Chondrocytes remained rounded
             in the HA-MA hydrogels in vitro, and accumulated significant
             amounts of cartilaginous matrix. Osteochondral defects
             filled with HA-MA were infiltrated with cells, appeared to
             integrate well with native tissue, and also accumulated
             substantial cartilaginous matrix by 2 weeks after surgery.
             In summary, photocrosslinkable HA-MA promoted the retention
             of the chondrocytic phenotype and cartilage matrix synthesis
             for encapsulated chondrocytes in vitro and accelerated
             healing in an in vivo osteochondral defect
             model},
   Key = {8184668}
}

@article{03267515018,
   Author = {Trabbic-Carlson, Kimberly and Setton, Lori A. and Chilkoti,
             Ashutosch},
   Title = {Swelling and mechanical behaviors of chemically cross-linked
             hydrogels of elastin-like polypeptides},
   Journal = {Biomacromolecules},
   Volume = {4},
   Number = {3},
   Pages = {572 - 580},
   Year = {2003},
   url = {http://dx.doi.org/10.1021/bm025671z},
   Keywords = {Hydrogels;Crosslinking;Synthesis (chemical);Stiffness;Molecular
             weight;},
   Abstract = {Genetically engineered elastin-like polypeptides consisting
             of Val-Pro-Gly-X-Gly repeats, where X was chosen to be Lys
             every 7 or 17 pentapeptides (otherwise X was Val), were
             synthesized and expressed in E. coli, purified, and
             chemically cross-linked using tris-succinimidyl
             aminotriacetate to produce hydrogels. Swelling experiments
             indicate hydrogel mass decreases by 80-90% gradually over an
             approximate 50 &deg;C temperature range. Gels ranged in
             stiffness from 0.24 to 3.7 kPa at 7 &deg;C and from 1.6 to
             15 kPa at 37 &deg;C depending on protein concentration,
             lysine content, and molecular weight. Changes in gel
             stiffness and loss angle with cross-linking formulation
             suggest a low-temperature gel structure that is nearly
             completely elastic, where force is transmitted almost
             exclusively through fully extended polypeptide chains and
             chemical crosslinks, and a high-temperature gel structure,
             where ELP chains are contracted and force is transmitted
             through chemical cross-links as well as frictional contact
             between polypeptide chains.},
   Key = {03267515018}
}

@article{03457714515,
   Author = {Upton, Maureen L. and Chen, Jun and Guilak, Farshid and Setton, Lori A.},
   Title = {Differential effects of static and dynamic compression on
             meniscal cell gene expression},
   Journal = {Journal of Orthopaedic Research},
   Volume = {21},
   Number = {6},
   Pages = {963 - 969},
   Year = {2003},
   url = {http://dx.doi.org/10.1016/S0736-0266(03)00063-9},
   Keywords = {Cell culture;Genetic engineering;Metabolism;Proteins;Compressive
             stress;Biosynthesis;},
   Abstract = {Cells of the meniscus are exposed to a wide range of
             time-varying mechanical stimuli that may regulate their
             metabolic activity in vivo. In this study, the biological
             response of the meniscus to compressive stimuli was
             evaluated in vitro, using a well-controlled explant culture
             system. Gene expression for relevant extracellular matrix
             proteins was quantified using real-time RT-PCR following a
             24 h period of applied static (0.1 MPa compressive stress)
             or dynamic compression (0.08-0.16 MPa). Static and dynamic
             compression were found to differentially regulate mRNA
             levels for specific proteins of the extracellular matrix.
             Decreased mRNA levels were observed for decorin ( [similar
             to] 2.1 fold-difference) and type II collagen ( [similar to]
             4.0 fold-difference) following 24 h of dynamic compression.
             Decorin mRNA levels also decreased following static
             compression ( [similar to] 4.5 fold-difference), as did mRNA
             levels for both types I ( [similar to] 3.3 fold-difference)
             and II collagen ( [similar to] 4.0 fold-difference).
             Following either static or dynamic compression, mRNA levels
             for aggrecan, biglycan and cytoskeletal proteins were
             unchanged. It is noteworthy that static compression was
             associated with a 2.6 fold-increase in mRNA levels for
             collagenase, or MMP-1, suggesting that the homeostatic
             balance between collagen biosynthesis and catabolism was
             altered by the mechanical stimuli. These findings
             demonstrate that the biosynthetic response of the meniscus
             to compression is regulated, in part, at the transcriptional
             level and that transcription of types I and II collagen as
             well as decorin may be regulated by common mechanical
             stimuli. &copy; 2003 Orthopaedic Research Society. Published
             by Elsevier Ltd. All rights reserved.},
   Key = {03457714515}
}

@article{7590479,
   Author = {Baer, A.E. and Laursen, T.A. and Guilak, F. and Setton,
             L.A.},
   Title = {The micromechanical environment of intervertebral disc cells
             determined by a finite deformation, anisotropic, and
             biphasic finite element model},
   Journal = {Trans. ASME, J. Biomech. Eng. (USA)},
   Volume = {125},
   Number = {1},
   Pages = {1 - 11},
   Year = {2003},
   url = {http://dx.doi.org/10.1115/1.1532790},
   Keywords = {biomechanics;cellular biophysics;finite element
             analysis;micromechanics;physiological models;viscoelasticity;},
   Abstract = {Cellular response to mechanical loading varies between the
             anatomic zones of the intervertebral disc. This difference
             may be related to differences in the structure and mechanics
             of both cells and extracellular matrix, which are expected
             to cause differences in the physical stimuli (such as
             pressure, stress, and strain) in the cellular
             micromechanical environment. In this study, a finite element
             model was developed that was capable of describing the cell
             micromechanical environment in the intervertebral disc. The
             model was capable of describing a number of important
             mechanical phenomena: flow-dependent viscoelasticity using
             the biphasic theory for soft tissues; finite deformation
             effects using a hyperelastic constitutive law for the solid
             phase; and material anisotropy by including a
             fiber-reinforced continuum law in the hyperelastic strain
             energy function. To construct accurate finite element
             meshes, the in situ geometry of IVD cells were measured
             experimentally using laser scanning confocal microscopy and
             three-dimensional reconstruction techniques. The model
             predicted that the cellular micromechanical environment
             varies dramatically between the anatomic zones, with larger
             cellular strains predicted in the anisotropic anulus
             fibrosus and transition zone compared to the isotropic
             nucleus pulposus. These results suggest that deformation
             related stimuli may dominate for anulus fibrosus and
             transition zone cells, while hydrostatic pressurization may
             dominate in the nucleus pulposus. Furthermore, the model
             predicted that micromechanical environment is strongly
             influenced by cell geometry, suggesting that the geometry of
             IVD cells in situ may be an adaptation to reduce cellular
             strains during tissue loading},
   Key = {7590479}
}

@article{7614356,
   Author = {Upton, M.L. and Chen, J. and Guilak, F. and Setton,
             L.A.},
   Title = {Static compression inhibits matrix protein gene expression
             and increases collagenase gene expression in the
             meniscus},
   Journal = {Conference Proceedings. Second Joint EMBS-BMES Conference
             2002. 24th Annual International Conference of the
             Engineering in Medicine and Biology Society. Annual Fall
             Meeting of the Biomedical Engineering Society (Cat.
             No.02CH37392)},
   Volume = {vol.1},
   Pages = {438 - 9},
   Address = {Houston, TX, USA},
   Year = {2002},
   url = {http://dx.doi.org/10.1109/IEMBS.2002.1136884},
   Keywords = {biological tissues;biomechanics;genetics;orthopaedics;proteins;},
   Abstract = {The biological response of the meniscus to static
             compression was quantified as changes in gene expression
             levels for relevant extracellular matrix proteins. Decreased
             mRNA levels for decorin and type I collagen were observed,
             as well as increased mRNA levels for the matrix
             metalloproteinase MMP-1. These findings demonstrate that the
             response of the meniscus to mechanical stimuli may be
             regulated in part at the transcriptional
             level},
   Key = {7614356}
}

@article{7626542,
   Author = {Betre, H. and Chilkoti, A. and Setton, L.A.},
   Title = {A two-step chondrocyte recovery system based on thermally
             sensitive elastin-like polypeptide scaffolds for cartilage
             tissue engineering},
   Journal = {Conference Proceedings. Second Joint EMBS-BMES Conference
             2002. 24th Annual International Conference of the
             Engineering in Medicine and Biology Society. Annual Fall
             Meeting of the Biomedical Engineering Society (Cat.
             No.02CH37392)},
   Volume = {vol.1},
   Pages = {829 - 30},
   Address = {Houston, TX, USA},
   Year = {2002},
   url = {http://dx.doi.org/10.1109/IEMBS.2002.1137096},
   Keywords = {biological tissues;biomedical materials;biothermics;cellular
             biophysics;monolayers;proteins;},
   Abstract = {A "two step" tissue engineering strategy was developed to
             promote rapid matrix accumulation in cartilage constructs in
             vitro. Chondrocytes expanded in monolayer were encapsulated
             and cultured in a genetically engineered, thermally
             sensitive elastin-like polypeptide (ELP) for ten days. The
             resulting cell-matrix pellets were recovered from the ELP
             and cultured on inserts for up to four weeks, where nutrient
             diffusion was not impeded by the presence of the scaffold.
             Approximately two-milligram (dry weight) tissue was
             generated that resembles native articular cartilage in
             histological appearance and biochemical composition. These
             results suggest that rapid and large cartilage construct
             formation is possible in vitro, following a period of early
             incubation and recovery from the thermally responsive
             ELP},
   Key = {7626542}
}

@article{02407118389,
   Author = {Wyland, Douglas J. and Guilak, Farshid and Elliott, Dawn M. and Setton, Lori A. and Vail, Thomas P.},
   Title = {Chondropathy after meniscal tear or partial meniscectomy in
             a canine model},
   Journal = {Journal of Orthopaedic Research},
   Volume = {20},
   Number = {5},
   Pages = {996 - 1002},
   Year = {2002},
   url = {http://dx.doi.org/10.1016/S0736-0266(02)00022-0},
   Keywords = {Cartilage;Tensile strength;},
   Abstract = {A primary goal in considering treatment for meniscal
             injuries is the preservation of the health of the articular
             cartilage. However, the chondroprotective effects of various
             techniques for meniscal injury treatments are unknown. We
             used a canine model to quantify articular cartilage
             degeneration in the medial compartment of the canine knee,
             resulting from a surgically created tear or a partial
             meniscectomy (PM) of the posterior region of the medial
             meniscus (each group, n = 10). After sacrifice at 12 weeks,
             the development of gross chondropathy and the changes in
             cartilage tensile stiffness were quantified, and
             correlations between these measurements were examined. Both
             treatment surgical treatment groups caused significantly
             greater gross chondropathy as compared to the unoperated
             contralateral controls. Cartilage tensile stiffness was
             significantly lower than unoperated controls by nearly 28%
             in both experimental groups. However, there were no
             significant differences observed between the gross
             chondropathy or the cartilage mechanical property changes
             between the experimental groups. Importantly, the severity
             of gross chondropathy was found to significantly correlate
             with the decrement in tensile stiffness properties of the
             articular cartilage. These findings indicate that
             significant degeneration of canine articular cartilage
             develops to a similar degree in the presence of a partially
             healed meniscus tear or a PM of the knee. &copy; 2002
             Orthopaedic Research Society. Published by Elsevier Science
             Ltd. All rights reserved.},
   Key = {02407118389}
}

@article{02056841813,
   Author = {Narmoneva, Daria A. and Cheung, Herman S. and Wang, Jean Y. and Howell, David S. and Setton, Lori A.},
   Title = {Altered swelling behavior of femoral cartilage following
             joint immbolization in a canine model},
   Journal = {Journal of Orthopaedic Research},
   Volume = {20},
   Number = {1},
   Pages = {83 - 91},
   Year = {2002},
   url = {http://dx.doi.org/10.1016/S0736-0266(01)00076-6},
   Keywords = {Bone;Collagen;Sodium chloride;Biomechanics;Swelling;Metabolism;Volume
             fraction;Physiological models;},
   Abstract = {Periods of reduced joint loading have been shown to induce
             changes in the biochemical composition, metabolism and
             mechanics of articular cartilage. In this study, changes in
             cartilage swelling behavior were studied following a 4-week
             period of joint immobilization, using a recently developed
             osmotic loading technique [J. Biomech. 32 (1999) 401-408].
             The magnitude and distribution of swelling strains were
             measured in cartilage-bone samples equilibrated in
             physiological and hypotonic saline, relative to a hypertonic
             reference NaCl solution. Physicochemical parameters
             (glycosaminoglycan fixed charge density and water volume
             fraction) were determined in site-matched cartilage samples.
             The experimental data for swelling strains, fixed charge
             density and water volume fraction were used with a triphasic
             mechano-chemical theory [J. Biomech. Eng. 113 (1991)
             245-258] to determine the effect of joint immobilization on
             the tensile modulus of the cartilage solid matrix. Four
             weeks of immobilization resulted in a significant increase
             in the magnitude of swelling-induced strains, and a
             significant decrease in fixed charge density in cartilage,
             as compared with the contralateral controls. Joint
             immobilization also resulted in decreases in values for the
             modulus of cartilage, as compared with the contralateral
             controls. Our results suggest that 4 weeks of joint
             immobilization had a significant effect on cartilage
             mechanical function that may be linked to collagen changes
             in the cartilage extracellular matrix. &copy; 2002
             Orthopaedic Research Society. Published by Elsevier Science
             Ltd. All rights reserved.},
   Key = {02056841813}
}

@article{7281970,
   Author = {LeRoux, M.A. and Setton, L.A.},
   Title = {Experimental and biphasic FEM determinations of the material
             properties and hydraulic permeability of the meniscus in
             tension},
   Journal = {Trans. ASME, J. Biomech. Eng. (USA)},
   Volume = {124},
   Number = {3},
   Pages = {315 - 21},
   Year = {2002},
   url = {http://dx.doi.org/10.1115/1.1468868},
   Keywords = {biological tissues;biomechanics;finite element
             analysis;orthopaedics;permeability;physiological
             models;Poisson ratio;stress relaxation;stress-strain
             relations;Young's modulus;},
   Abstract = {Tensile tests and biphasic finite element modeling were used
             to determine a set of transversely isotropic properties for
             the meniscus, including the hydraulic permeability
             coefficients and solid matrix properties. Stress-relaxation
             tests were conducted on planar samples of canine meniscus
             samples of different orientations, and the solid matrix
             properties were determined from equilibrium data. A 3-D
             linear biphasic and tranversely isotropic finite element
             model was developed to model the stress-relaxation behavior
             of the samples in tension, and optimization was used to
             determine the permeability coefficients, k<sub>1</sub> and
             k<sub>2</sub>, governing fluid flow parallel and
             perpendicular to the collagen fibers, respectively. The
             collagen fibrillar orientation was observed to have an
             effect on the Young's moduli (E<sub>1</sub>=67.8 MPa,
             E<sub>2</sub>=11.1 MPa) and Poisson's ratios
             (&nu;<sub>12</sub>=2.13, &nu;<sub>21</sub>=1.50,
             &nu;<sub>23</sub>=1.02). However, a significant effect of
             anisotropy on permeability was not detected
             (k<sub>1</sub>=0.09&times;10<sup>-16</sup> m<sup>4</sup>/Ns,
             k<sub>2</sub>=0.10&times;10<sup>-16</sup> m<sup>4</sup>/Ns).
             The low permeability values determined in this study provide
             insight into the extent of fluid pressurization in the
             meniscus and will impact modeling predictions of load
             support in the meniscus},
   Key = {7281970}
}

@article{7237377,
   Author = {Elliott, D.M. and Narmoneva, D.A. and Setton,
             L.A.},
   Title = {Direct measurement of the Poisson's ratio of human patella
             cartilage in tension},
   Journal = {Trans. ASME, J. Biomech. Eng. (USA)},
   Volume = {124},
   Number = {2},
   Pages = {223 - 8},
   Year = {2002},
   url = {http://dx.doi.org/10.1115/1.1449905},
   Keywords = {biological tissues;biomechanics;biomedical
             measurement;Poisson ratio;proteins;},
   Abstract = {Articular cartilage has been shown to exhibit large
             transverse contractions when loaded in tension, suggesting
             the existence of large values for the Poisson's ratio.
             Previous studies have suggested that this effect is
             dependent on amplitude of applied strain, so that a single
             Poisson's ratio may not be sufficient to describe cartilage
             behavior. In this study, the Poisson's ratio (&nu;), toe
             region modulus (E<sub>o</sub>), and linear region modulus
             (E) of human patellar articular cartilage were calculated in
             simple tension tests from optical analysis of the
             two-dimensional strain fields at equilibrium. The Poisson's
             ratio was found to be independent of strain due to the
             absence of viscoelastic effects during testing. The
             Poisson's ratio was found to be significantly higher in the
             surface zone (1.87&plusmn;1.11, p&lt;0.01) than in the
             middle zone (0.62&plusmn;0.23), with no significant
             correlation of &nu; with age of the cartilage. In general,
             values for Poisson's ratio were greater than 0.5, suggesting
             cartilage behavior in tension deviates from isotropy.
             Reported values for the Poisson's ratio of cartilage in
             compression have been much lower than values measured here
             in tension, reflecting a mechanical contribution of the
             collagen fibers to anisotropy in tension but not
             compression. The toe-region modulus (E<sub>o</sub>) was
             significantly higher in the surface zone (4.51&plusmn;2.78
             MPa, n=8) compared to the middle zone (2.51&plusmn;1.93 MPa,
             n=10). In addition, the linear-region modulus (E) in the
             surface zone, but not middle zone (3.42&plusmn;2.17 MPa,
             n=10), was found to correlate with age (R=0.97, p&lt;0.02)
             with values of surface zone E equal to 23.92&plusmn;12.29
             MPa (n=5) for subjects under 70 yr of age, and
             4.27&plusmn;2.89 MPa (n=3) for subjects over 70 yr. Moduli
             values and trends with depth were consistent with previous
             studies of human and animal cartilage. From direct measures
             of two independent material properties, &nu; and E, we
             calculated a shear modulus, G, which had not been previously
             reported for cartilage from tensile testing. Calculated
             values for surface zone G were 3.64&plusmn;1.80 MPa for
             subjects under 70 yr old and 0.96&plusmn;0.69 MPa for
             subjects over 70 yr old, and were significantly higher in
             the surface zone than in the middle zone (1.10&plusmn;0.78
             MPa). This study provides an intrinsic measure for the
             Poisson's ratio of articular cartilage and its dependence on
             depth which will be important in understanding the nonlinear
             tension-compression and anisotropic behaviors of articular
             cartilage},
   Key = {7237377}
}

@article{7265233,
   Author = {Meng, X.N. and LeRoux, M.A. and Laursen, T.A. and Setton,
             L.A.},
   Title = {A nonlinear finite element formulation for axisymmetric
             torsion of biphasic materials},
   Journal = {Int. J. Solids Struct. (UK)},
   Volume = {39},
   Number = {4},
   Pages = {879 - 95},
   Year = {2002},
   url = {http://dx.doi.org/10.1016/S0020-7683(01)00249-9},
   Keywords = {biological tissues;biomechanics;biorheology;deformation;finite
             element analysis;torsion;viscoelasticity;},
   Abstract = {Presents a finite element formulation for describing the
             large deformation torsional response of biphasic materials,
             with specific application to prediction of nonlinear
             coupling between torsional deformation and fluid
             pressurization in articular cartilage. Due to the use of a
             cylindrical coordinate system, a particular challenge arises
             in the linearization of the weak form. The torsional
             axisymmetric case considered gives rise to additional
             geometric terms, which are important for the robustness of
             the numerical implementation and that would not be present
             in a Cartesian formulation. A detailed derivation of this
             linearization process is given, couched in the context of a
             variational formulation suitable for finite element
             implementation. A series of numerical parametric studies are
             presented and compared to experimental measurements of the
             time dependent response of cartilage},
   Key = {7265233}
}

@article{7155395,
   Author = {Narmoneva, D.A. and Wang, J.Y. and Setton,
             L.A.},
   Title = {A noncontacting method for material property determination
             for articular cartilage from osmotic loading},
   Journal = {Biophys. J. (USA)},
   Volume = {81},
   Number = {6},
   Pages = {3066 - 76},
   Year = {2001},
   Keywords = {biological techniques;biological tissues;biomechanics;optimisation;osmosis;physiological
             models;swelling;},
   Abstract = {Articular cartilage is one of several biological tissues in
             which swelling effects are important in tissue mechanics and
             function, and may serve as an indicator of degenerative
             joint disease. This work presents a new approach to quantify
             swelling effects in articular cartilage, as well as to
             determine the material properties of cartilage from a simple
             free-swelling test. Samples of nondegenerate and degenerate
             human patellar cartilage were subjected to osmotic loading
             by equilibrating the tissue in solutions of varying
             osmolarity. The resulting swelling-induced strains were
             measured using a noncontacting optical method. A theoretical
             formulation of articular cartilage in a free-swelling
             configuration was developed based on an inhomogeneous,
             triphasic mechano-chemical model. Optimization of the model
             predictions to the experimental data was performed to
             determine two parameters descriptive of material stiffness
             at the surface and deeper cartilage layers, and a third
             parameter descriptive of thickness of the cartilage surface
             layer. These parameters were used to determine the
             thickness-averaged uniaxial modulus of cartilage,
             H<sub>A</sub>. The obtained values for H<sub>A</sub> were
             similar to those for the tensile modulus of human cartilage
             reported in the literature. Degeneration resulted in an
             increase in thickness of the region of "apparent cartilage
             softening," and a decrease in the value for uniaxial modulus
             at this layer. These findings provide important evidence
             that collagen matrix disruption starts at the articular
             surface and progresses into the deeper layers with continued
             degeneration. These results suggest that the method provides
             a means to quantify the severity and depth of degenerative
             changes in articular cartilage. This method may also be used
             to determine material properties of cartilage in small
             joints in which conventional testing methods are difficult
             to apply},
   Key = {7155395}
}

@article{01216510489,
   Author = {Baer, A.E. and Wang, J.Y. and Kraus, V.B. and Setton,
             L.A.},
   Title = {Collagen gene expression and mechanical properties of
             intervertebral disc cell-alginate cultures},
   Journal = {Journal of Orthopaedic Research},
   Volume = {19},
   Number = {1},
   Pages = {2 - 10},
   Year = {2001},
   url = {http://dx.doi.org/10.1016/S0736-0266(00)00003-6},
   Keywords = {Tissue culture;Genes;RNA;Shear stress;},
   Abstract = {Cells of the intervertebral disc have a limited capacity for
             matrix repair that may contribute to the onset and
             progression of degenerative disc changes. In this study, the
             biosynthetic capacity of cells isolated from specific
             regions of the porcine intervertebral disc was evaluated in
             vitro. Using a competitive reverse transcription-polymerase
             chain reaction technique, gene expression levels for types I
             and II collagen were quantified in cells cultured for up to
             21 d in a three-dimensional alginate culture system and
             compared to levels obtained for cells in vivo. The
             mechanical properties of cell-alginate constructs were
             measured in compression and shear after periods of culture
             up to 16 weeks. Cells from the anulus fibrosus expressed the
             most type I collagen mRNA in vivo and in vitro, while cells
             from the transition zone expressed the most type II collagen
             mRNA in vivo and in vitro. Mechanical testing results
             indicate that a mechanically functional matrix did not form
             at any time during the culture period; rather, decreases of
             up to 50% were observed in the compressive and shear moduli
             of the cell-alginate constructs compared to alginate with no
             cells. Together with results of prior studies, these results
             suggest that intervertebral disc cells maintain
             characteristics of their phenotype when cultured in
             alginate, but the molecules they synthesize are not able to
             form a mechanically functional matrix in vitro. &copy; 2001
             Orthopaedic Research Society. Published by Elsevier Science
             Ltd. All rights reserved.},
   Key = {01216510489}
}

@article{03477739774,
   Author = {Baer, Anthony E. and Grinstaff, Mark W. and Smeds, Kimberly
             A. and Boyd, Lawrence M. and Setton, Lori
             A.},
   Title = {Nonlinear finite element modeling of cell mechanical
             environment in hyorogels for intervertebral disc
             repair},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {50},
   Pages = {113 - 114},
   Address = {Snowbird, UT, United States},
   Year = {2001},
   Keywords = {Cell culture;Tissue;Hydrogels;Finite element
             method;Mathematical models;},
   Abstract = {The nonlinear finite element modeling of cell mechanical
             environment in hydrogels for intervertebral disc (IVD)
             repair was studied. Two hydrogels were studied for
             tissue-engineered IVD repair. The results demonstrated that
             the micromechanical environment of an IVD cell embedded in a
             three-dimensional hydrogel is different from that of a cell
             in its native matrix.},
   Key = {03477739774}
}

@article{03477740103,
   Author = {Baer, Anthony E. and Laursen, Tod A. and Setton, Lori
             A.},
   Title = {A finite-deformation, anisotropic, biphasic finite element
             model of cell-matrix interactions in the intervertebral
             disc},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {50},
   Pages = {799 - 800},
   Address = {Snowbird, UT, United States},
   Year = {2001},
   Keywords = {Deformation;Anisotropy;Strain;Stress relaxation;Computational
             complexity;Finite element method;},
   Abstract = {The finite deformation, anisotropic, biphasic finite element
             model of cell matrix interactions in the intervertebral disc
             was discussed. The model was used as a reference for
             validation of the nonlinear FEM predictions at equilibrium.
             The results suggested that zonal differences in cell
             micromechanical environment play a role in known differences
             in the biosynthetic response of the disc
             cells.},
   Key = {03477740103}
}

@article{03477739982,
   Author = {Meng, X.N. and LeRoux, M.A. and Setton, L.A. and Laursen,
             T.A.},
   Title = {Biphasic finite element formulation for modeling nonlinear
             response of articular cartilage to torsion},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {50},
   Pages = {549 - 550},
   Address = {Snowbird, UT, United States},
   Year = {2001},
   Keywords = {Torsional stress;Shear stress;Stress relaxation;Pressure
             effects;Elasticity;Elastic moduli;Mechanical
             permeability;Finite element method;Tensors;Nonlinear
             equations;Linearization;Computer simulation;},
   Abstract = {A biphasic finite element formulation for predicting the
             coupling between pure torsion and normal stress effects in
             articular cartilage was presented. Both the computational
             and experimental data showed a transient normal stress
             effect arising from torsion that was lower in magnitude that
             the shear stress. Finite element results demonstrated that
             the normal stress during stress-relaxation arose from fluid
             pressurization.},
   Key = {03477739982}
}

@article{03477740126,
   Author = {LeRoux, Michelle A. and Upton, Maureen L. and Laursen, Tod
             A. and Setton, Lori A.},
   Title = {Biphasic finite element modeling of tear effects on the
             mechanics of the meniscus},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {50},
   Pages = {851 - 852},
   Address = {Snowbird, UT, United States},
   Year = {2001},
   Keywords = {Blood;Stress analysis;Strain;Anisotropy;Finite element
             method;Galerkin methods;Mathematical models;},
   Abstract = {The biphasic finite element (FE) modeling of tear effects on
             the mechanics of the meniscus was studied. FE studied of the
             normal meniscus were used to predict the spatially varying
             stress-strain rate within the meniscus. These studies also
             demonstrate the importance of fluid-solid interactions in
             governing load-support and function of the meniscus was also
             demonstrated.},
   Key = {03477740126}
}

@article{6998102,
   Author = {Elliott, D.M. and Setton, L.A.},
   Title = {Anisotropic and inhomogeneous tensile behavior of the human
             anulus fibrosus: experimental measurement and material model
             predictions},
   Journal = {Trans. ASME, J. Biomech. Eng. (USA)},
   Volume = {123},
   Number = {3},
   Pages = {256 - 63},
   Year = {2001},
   url = {http://dx.doi.org/10.1115/1.1374202},
   Keywords = {biological tissues;biomechanics;elastic moduli;physiological
             models;Poisson ratio;proteins;},
   Abstract = {The anulus fibrosus (AF) of the intervertebral disc exhibits
             spatial variations in structure and composition that give
             rise to both anisotropy and inhomogeneity in its material
             behaviors in tension. In this study, the tensile moduli and
             Poisson's ratios were measured in samples of human AF along
             circumferential, axial, and radial directions at inner and
             outer sites. There was evidence of significant inhomogeneity
             in the linear-region circumferential tensile modulus
             (17.4&plusmn;14.3 MPa versus 5.6&plusmn;4.7 MPa, outer
             versus inner sites) and the Poisson's ratio
             &nu;<sub>21</sub> (0.67&plusmn;0.22 versus 1.6&plusmn;0.7,
             outer versus inner), but not in the axial modulus
             (0.8&plusmn;0.9 MPa) or the Poisson's ratios
             &nu;<sub>12</sub> (1.8&plusmn;1.4) or &nu;<sub>13</sub>
             (0.6&plusmn;0.7). These properties were implemented in a
             linear anisotropic material model of the AF to determine a
             complete set of model properties and to predict material
             behaviors for the AF under idealized kinematic states. These
             predictions demonstrate that interactions between fiber
             populations in the multilamellae AF significantly contribute
             to the material behavior, suggesting that a model for the AF
             as concentric and physically isolated lamellae may not be
             appropriate},
   Key = {6998102}
}

@article{00065216862,
   Author = {Lindhorst, E. and Vail, T.P. and Guilak, F. and Wang, H. and Setton, L.A. and Vilim, V. and Kraus, V.B.},
   Title = {Longitudinal characterization of synovial fluid biomarkers
             in the canine meniscectomy model of osteoarthritis},
   Journal = {Journal of Orthopaedic Research},
   Volume = {18},
   Number = {2},
   Pages = {269 - 280},
   Year = {2000},
   Keywords = {Tissue;Diseases;Joints (anatomy);Surgery;Proteins;Blood
             vessels;},
   Abstract = {Damage to the meniscus can lead to posttraumatic
             osteoarthritis. Early markers of joint injury and tissue
             disease may be useful in developing and administering
             clinical treatment. We investigated the effects of total
             medial meniscectomy on biomarkers measured serially in
             synovial lavage fluid each month for 3 months. Following
             meniscectomy in dogs, four biomarkers were evaluated:
             cartilage oligomeric matrix protein, keratan sulfate epitope
             (5D4), the 3B3(-) neoepitope of chondroitin-6-sulfate, and
             the 3B3(+) chondroitinase-generated epitope of
             chondroitin-6-sulfate. Meniscectomy led to statistically
             significant elevations of all four biomarkers, with levels
             peaking at 4 weeks. By 12 weeks, the level of the 5D4
             epitope returned to the preoperative baseline level whereas
             that of cartilage oligomeric matrix protein, 3B3(-), and
             3B3(+) remained above the baseline. Concentrations of these
             biomarkers in the knees not operated on did not change
             significantly from the baseline. The levels of cartilage
             oligomeric matrix protein and 3B3(-) relative to 3B3(+)
             remained constant in all knees. In contrast, the level of
             5D4 relative to 3B3(+) declined over time in the knee
             operated on but remained constant in the knee not operated
             on. These results demonstrate a quantitative change in the
             molecular components of synovial fluid after meniscectomy,
             as well as qualitative change evinced by an alteration in
             the relative proportions of these epitopes. Extensive
             analyses showed a strong correlation between serum levels of
             3B3(-) from the femoral and cephalic veins; however, serum
             3B3(-) was not correlated with synovial fluid 3B3(-). These
             findings support the hypothesis that the concentrations of
             select cartilage biomarkers in synovial fluid are altered
             following meniscectomy and are promising tools for
             objectively monitoring the induction of osteoarthritis in
             this model system.},
   Key = {00065216862}
}

@article{00095320395,
   Author = {LeRoux, Michelle A. and Arokoski, Jari and Vail, T. Parker and Guilak, Farshid and Hyttinen, Mika M. and Kiviranta,
             Ilkka and Setton, Lori A.},
   Title = {Simultaneous changes in the mechanical properties,
             quantitative collagen organization, and proteoglycan
             concentration of articular cartilage following canine
             meniscectomy},
   Journal = {Journal of Orthopaedic Research},
   Volume = {18},
   Number = {3},
   Pages = {383 - 392},
   Year = {2000},
   Keywords = {Orthopedics;Living systems studies;Collagen;Densitometers;Light
             polarization;Optical microscopy;Microstructure;Molecular
             structure;Biomechanics;},
   Abstract = {The mechanical properties and microstructure of articular
             cartilage from the canine tibial plateau were studied 12
             weeks after total medial meniscectomy. The organization of
             the birefringent collagen network was measured with
             quantitative polarized light microscopy to determine the
             thickness and the degree of organization of the superficial
             and deep zones. The zonal concentration of sulfated
             glycosaminoglycan was quantified with digital densitometry
             of safranin-O staining. Equilibrium compressive and shear
             properties, as well as dynamic shear properties, were
             measured at sites adjacent to those of microstructural
             analysis. The results evinced significant loss of cartilage
             function following meniscectomy, with decreases of 20-50% in
             the compressive and shear moduli. There was no evidence of
             alterations in the degree of collagen fibrillar
             organization, although a complete loss of the surface zone
             was seen in 60% of the samples that underwent meniscectomy.
             Meniscectomy resulted in a decreased concentration of
             sulfated glycosaminoglycan, and significant positive
             correlations were found between the equilibrium compressive
             modulus and the glycosaminoglycan content. Furthermore, the
             shear properties of cartilage correlated directly with
             collagen fibrillar organization measured at the superficial
             zone of corresponding sites. These findings demonstrate that
             meniscectomy leads to impaired mechanical function of
             articular cartilage, with significant evidence of
             quantitative correlations between cartilage microstructure
             and mechanics.},
   Key = {00095320395}
}

@article{6676926,
   Author = {Baer, A.E. and Setton, L.A.},
   Title = {The micromechanical environment of intervertebral disc
             cells: effect of matrix anisotropy and cell geometry
             predicted by a linear model},
   Journal = {Trans. ASME, J. Biomech. Eng. (USA)},
   Volume = {122},
   Number = {3},
   Pages = {245 - 51},
   Year = {2000},
   url = {http://dx.doi.org/10.1115/1.429655},
   Keywords = {biomechanics;cellular biophysics;physiological
             models;},
   Abstract = {Cells of the intervertebral disc exhibit spatial variations
             in phenotype and morphology that may be related to
             differences in their local mechanical environments. In this
             study, the stresses, strains, and dilatations in and around
             cells of the intervertebral disc were studied with an
             analytical model of the cell as a mechanical inclusion
             embedded in a transversely isotropic matrix. In response to
             tensile loading of the matrix, the local mechanical
             environment of the cell differed among the anatomic regions
             of the disc and was strongly influenced by changes in both
             matrix anisotropy and parameters of cell geometry. The
             results of this study suggest that the local cellular
             mechanical environment may play a role in determining both
             cell morphology <i>in</i> <i>situ</i> and the inhomogeneous
             response to mechanical loading observed in cells of the
             disc},
   Key = {6676926}
}

@article{6608606,
   Author = {Elliott, D.M. and Setton, L.A.},
   Title = {A linear material model for fiber-induced anisotropy of the
             anulus fibrosus},
   Journal = {Trans. ASME, J. Biomech. Eng. (USA)},
   Volume = {122},
   Number = {2},
   Pages = {173 - 9},
   Year = {2000},
   url = {http://dx.doi.org/10.1115/1.429639},
   Keywords = {biological tissues;biomechanics;fibres;physiological
             models;},
   Abstract = {The anulus fibrosus (AF) is a lamellar, fibrocartilaginous
             component of the intervertebral disc, which exhibits highly
             anisotropic behaviors in tension. These behaviors arise from
             the material's unique collagen structure. We have
             investigated the use of a linear, fiber-induced anisotropic
             model for the AF using a quadratic strain energy density
             formulation with an explicit representation of the collagen
             fiber populations. We have proposed a representative set of
             intrinsic material properties using independent datasets of
             the AF from the literature and appropriate thermodynamic
             constraints. The model was validated by comparing
             predictions with previous experimental data for AF behavior
             and its dependence on fiber angle. The model predicts that
             compressible effects may exist for the AF, and suggests that
             physical effects of the equivalent &ldquo;matrix,&rdquo;
             &ldquo;fiber,&rdquo; &ldquo;fiber-matrix,&rdquo; and
             &ldquo;fiber-fiber,&rdquo; interactions may be important
             contributors to the mechanical behavior of the
             AF},
   Key = {6608606}
}

@article{00275178035,
   Author = {Baer, Anthony E. and Wang, Jean Y. and Setton, Lori
             A.},
   Title = {Mechanical properties of matrix synthesized by
             intervertebral disc cells in an alginate culture
             system},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {42},
   Pages = {119 - 120},
   Address = {Big Sky, MT, USA},
   Year = {1999},
   Keywords = {Cells;Cell culture;Mechanical properties;Synthesis
             (chemical);Morphology;Genes;Structure (composition);Growth
             kinetics;Mechanical testing;Statistical methods;},
   Abstract = {The mechanical function of matrix synthesized by
             intervertebral disc (IVD) cells in alginate was examined by
             measuring material properties in both compression and shear
             testing of configurations. Samples were evaluated for
             mechanical function after 1, 4, 8, and 16 weeks in culture.
             The main results is that while IVD cells exhibit significant
             biosynthetic activity at both transcriptional and
             translational stages when cultured in alginate, they are not
             able to form a functional matrix.},
   Key = {00275178035}
}

@article{00275178011,
   Author = {Setton, Lori A. and Perry, Charles H. and LeRoux, Michelle
             A. and Wang, Jean Y. and Howell, David S. and Cheung, Herman
             S.},
   Title = {Altered mechanics of tibial cartilage following joint
             immobilization in a canine model},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {42},
   Pages = {71 - 72},
   Address = {Big Sky, MT, USA},
   Year = {1999},
   Keywords = {Cartilage;Joints (anatomy);Mathematical models;Biosynthesis;Enzymes;Collagen;},
   Abstract = {To study the effect of immobilization, the compressive and
             shear properties of articular cartilage were quantified at
             sites corresponding to those of elevated MMP staining on the
             tibial plateau of mongrel dogs. Cartilage samples were
             tested in compression and torsion on a displacement-controlled
             rheometer. The samples were weighed after testing and again
             after lyophilization to determine water content as the
             percentage of tissue wet weight. The results support the
             hypothesis that knee joint immobilization will produce
             deleterious changes in cartilage function at the tibial
             plateau.},
   Key = {00275178011}
}

@article{00275178144,
   Author = {Guilak, Farshid and Ting-Beall, H. Ping and Baer, Anthony E. and Erickson, Geoffrey R. and Jones, Wendy R. and Pearsall,
             Richard L. and Setton, Lori A.},
   Title = {Identification of two biomechanically distinct cell
             populations in the intervertebral disc},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {42},
   Pages = {337 - 338},
   Address = {Big Sky, MT, USA},
   Year = {1999},
   Keywords = {Biomechanics;Bone;Cell culture;Proteins;Microscopic
             examination;Mathematical models;Regression
             analysis;},
   Abstract = {A study was carried out to quantify the morphology and the
             viscoelastic mechanical properties of isolated cells from
             the anulus fibrosus (AF), transition zone (TZ), and nucleus
             pulposus (NP) and to examine the hypothesis that cellular
             properties may influence the biophysical environment of the
             cells. Pronounced differences were observed in the
             morphology of the NP cells as compared to the AF and TZ
             cells. Evidence was obtained concerning the existence of two
             biomechanically distinct cell populations in the
             intervertebral disc (IVD).},
   Key = {00275178144}
}

@article{00275178590,
   Author = {Narmoneva, Daria A. and Wang, Jean Y. and Setton, Lori
             A.},
   Title = {New method for determination of the tensile modulus of
             articular cartilage in situ in a free-swelling
             configuration},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {43},
   Pages = {31 - 32},
   Address = {Nashville, TN, USA},
   Year = {1999},
   Keywords = {Mechanical properties;Diseases;Swelling;Mechanical
             testing;Computer simulation;Numerical methods;Boundary
             conditions;Body fluids;Pressure;},
   Abstract = {Using a triphasic mechanochemical theory, an attempt was
             made to quantify the material properties of canine and human
             cartilage studied in the free-swelling test and to compare
             them with site-matched values measured in uniaxial tensile
             testing. Values for the tensile modulus were found to
             compare well using the free-swelling and uniaxial testing
             methods. The results demonstrate the potential of this new
             methodology for quantifying cartilage properties in small
             cartilage samples.},
   Key = {00275178590}
}

@article{00275178013,
   Author = {Elliott, Dawn M. and Setton, Lori A.},
   Title = {Direct measurement of a complete set of orthotropic material
             properties for the human anulus fibrosus in
             tension},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {42},
   Pages = {75 - 76},
   Address = {Big Sky, MT, USA},
   Year = {1999},
   Keywords = {Neurology;Biochemical engineering;Swelling;Poisson
             ratio;Image analysis;},
   Abstract = {In this study, an attempt was made to directly measure a
             complete set of Poisson's ratios and tensile moduli required
             for a description of the anulus fibrosus (AF) as an
             orthotropic material. Using a new method for surface strain
             measurement, it was demonstrated that the surface strain is
             nearly uniform under uniaxial tension for all orientations
             and all strain magnitudes. While the determined material
             coefficients form a complete set, the measured values did
             not correspond with the predicted relations between material
             coefficients for an orthotropic linear material.},
   Key = {00275178013}
}

@article{00275178012,
   Author = {Setton, Lori A. and Perry, Charles H. and Elliott, Dawn M. and Wyland, Douglas J. and LeRoux, Michelle A. and Guilak,
             Farshid and Vail, Parker T.},
   Title = {Anisotropic properties of the healing meniscus in
             tension},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {42},
   Pages = {73 - 74},
   Address = {Big Sky, MT, USA},
   Year = {1999},
   Keywords = {Musculoskeletal system;Blood vessels;Cells;Tissue;Mathematical
             models;Surgery;Poisson ratio;},
   Abstract = {A study was carried out to quantify the anisotropic
             properties of the meniscus in tension. Skeletally-mature
             dogs underwent open surgery to create a meniscal tear in the
             right stifle joint. Tensile test samples were
             pre-equilibrated in 0.15M NaCl and width and thickness were
             measured. Samples were tested in uniaxial tension using a
             custom-built material test system. The resultant data
             provide evidence of highly anisotropic behaviors for the
             solid matrix of both the native and healing meniscal
             tissue.},
   Key = {00275178012}
}

@article{6529438,
   Author = {Setton, L.A. and Baer, A.E. and Wang, J.Y. and Kraus,
             V.B.},
   Title = {Biosynthesis of intervertebral disc matrix in
             vitro},
   Journal = {Proceedings of the First Joint BMES/EMBS Conference. 1999
             IEEE Engineering in Medicine and Biology 21st Annual
             Conference and the 1999 Annual Fall Meeting of the
             Biomedical Engineering Society (Cat. No.99CH37015)},
   Volume = {vol.2},
   Pages = {1325 vol.2 -},
   Address = {Atlanta, GA, USA},
   Year = {1999},
   url = {http://dx.doi.org/10.1109/IEMBS.1999.804494},
   Keywords = {bone;cellular biophysics;genetics;molecular
             biophysics;proteins;},
   Abstract = {Cells of the intervertebral disc are shown to express genes
             for aggrecan and collagen in an in vitro alginate culture
             system. Despite evidence for significant biosynthesis, the
             cells appear unable to assemble a mechanically functional
             matrix in this in vitro system},
   Key = {6529438}
}

@article{99094779171,
   Author = {LeRoux, Michelle A. and Guilak, Farshid and Setton, Lori
             A.},
   Title = {Compressive and shear properties of alginate gel: Effects of
             sodium ions and alginate concentration},
   Journal = {Journal of Biomedical Materials Research},
   Volume = {47},
   Number = {1},
   Pages = {46 - 53},
   Year = {1999},
   url = {http://dx.doi.org/10.1002/(SICI)1097-4636(199910)47:1<46::AID-JBM6>3.0.CO;2-N},
   Keywords = {Hydrogels;Biopolymers;Tissue culture;Sodium
             chloride;Physiology;Compression testing;Stress
             relaxation;Elastic moduli;Composition effects;Stress
             analysis;Stiffness;Calcium compounds;},
   Abstract = {The equilibrium and viscoelastic properties of alginate gel
             crosslinked with Ca<sup>2+</sup> were determined as a
             function of alginate concentration and duration of exposure
             to physiologic concentrations of NaCl. Compressive and shear
             stress relaxation tests and oscillatory shear tests were
             performed to measure the material properties at two time
             periods after storage in NaCl compared to no NaCl exposure.
             The effect of concentration was determined by testing 1-3%
             alginate gel in a bath of physiological NaCl and
             CaCl<sub>2</sub>. After 15 h of exposure to NaCl, the
             compressive, equilibrium shear, and dynamic shear moduli
             decreased by 63, 84, and 90% of control values,
             respectively. The material properties exhibited no further
             changes after 7 days of exposure to NaCl. The loss angle and
             amplitude of the relaxation function in the shear also
             decreased, indicating less viscous behaviors in both dynamic
             and transient configurations. All moduli, but not the loss
             angle, significantly increased with increasing alginate
             concentration. The observed decrease in compressive and
             shear stiffness for alginate gel after exposure to
             Na<sup>+</sup> was significant and indicated that
             physiological conditions will soften the gel over a time
             period of up to 7 days after gelation. The alginate gel
             retains significant solidlike behaviors, however, as
             measured by a loss angle of approximately 3&deg;. This study
             provides the first available data for material properties of
             alginate gel tested in physiological saline.},
   Key = {99094779171}
}

@article{99094778983,
   Author = {Elliott, Dawn M. and Guilak, Farshid and Vail, T. Parker and Wang, Jean Y. and Setton, Lori A.},
   Title = {Tensile properties of articular cartilage are altered by
             meniscectomy in a canine model of osteoarthritis},
   Journal = {Journal of Orthopaedic Research},
   Volume = {17},
   Number = {4},
   Pages = {503 - 508},
   Year = {1999},
   Keywords = {Tensile properties;Joints (anatomy);Physiological
             models;Biomechanics;Elastic moduli;Stress
             relaxation;Morphology;Tensile testing;Surgery;},
   Abstract = {Loss of or damage to the meniscus alters the pattern of
             loading in the knee joint and frequent leads to cartilage
             degeneration and osteoarthritis. The mechanical properties
             of articular cartilage have been shown to reflect the extent
             of cartilage degeneration in human osteoarthritis and in
             experimental models of joint disease, but there is little
             experimental data documenting changes in cartilage mechanics
             following meniscectomy. We hypothesized that the tensile
             properties of the surface zone of articular cartilage are
             altered following total medial meniscectomy. Twelve mongrel
             dogs underwent complete resection of the medial meniscus in
             the right knee, and the femoral cartilage was studied 12
             weeks after the operation. We performed uniaxial, tensile
             stress-relaxation tests to determine the equilibrium tensile
             modulus of surface-zone cartilage. Water and
             glycosaminoglycan content were also measured at site-matched
             locations. The tensile moduli of the cartilage decreased
             significantly following meniscectomy. The linear region
             modulus decrease by 40%, from 25.5&plusmn;7.7 to
             15.3&plusmn;7.2 MPa. There was a weak (r = -0.45), but
             significant, correlation between the linear region modulus
             and the gross morphological grade for cartilage damage.
             Water and glycosaminoglycan content did not change following
             meniscectomy. Composition was not correlated with mechanic
             properties or morphological grade, suggesting that cartilage
             structure may play a more important role than composition in
             determining the mechanical properties. The observed decrease
             in cartilage material properties provides a quantitative
             measure of the loss of cartilage function following
             meniscectomy and reflects a pattern of change that is
             consistent with damage to the collagen-proteoglycan solid
             network.},
   Key = {99094778983}
}

@article{6279880,
   Author = {Hsu, E.W. and Setton, L.A.},
   Title = {Diffusion tensor microscopy of the intervertebral disc
             anulus fibrosus},
   Journal = {Magn. Reson. Med. (USA)},
   Volume = {41},
   Number = {5},
   Pages = {992 - 9},
   Year = {1999},
   url = {http://dx.doi.org/10.1002/(SICI)1522-2594(199905)41:5<992::AID-MRM19>3.0.CO;2-Y},
   Keywords = {biodiffusion;biomedical MRI;microscopy;tensors;},
   Abstract = {Morphologically accurate biomechanical models of the
             intervertebral disc anulus fibrosus (AF) require precise
             knowledge of its lamellar architecture; however, available
             methods of assessment are limited by poor spatial resolution
             or the destructive nature of the technique. In a novel
             approach, diffusion tensor microscopy was used in this study
             to characterize the microstructure of excised porcine AF
             samples. Results show diffusion in the AF to be anisotropic.
             The orientations of anisotropy exhibit a layered morphology
             that agrees with light micrographs of the corresponding
             samples, and the behavior of the orientation angles is
             consistent with the known AF collagen fiber architecture. A
             static magnetic field-dependent relaxation anisotropy was
             observed in the AF, which has methodological implications
             for magnetic resonance (MR) imaging of ordered collageneous
             tissues. These findings present MR diffusion tensor
             microscopy as a potentially valuable tool to assess
             quantitatively and nondestructively water diffusion
             anisotropy and lamellar structure of the intervertebral disc
             AF},
   Key = {6279880}
}

@article{6230291,
   Author = {Narmoneva, D.A. and Wang, J.Y. and Setton,
             L.A.},
   Title = {Nonuniform swelling-induced residual strains in articular
             cartilage},
   Journal = {J. Biomech. (UK)},
   Volume = {32},
   Number = {4},
   Pages = {401 - 8},
   Year = {1999},
   url = {http://dx.doi.org/10.1016/S0021-9290(98)00184-5},
   Keywords = {biological tissues;biomechanics;osmosis;swelling;},
   Abstract = {Swelling effects in cartilage originate from an interstitial
             osmotic pressure generated by the presence of negatively
             charged proteoglycans in the tissue. This swelling pressure
             gives rise to a non-zero residual strain in the cartilage
             solid matrix in the absence of externally applied loads.
             Previous studies have quantified swelling effects in
             cartilage as volumetric or dimensional change of excised
             samples in varying osmotically active solutions. This study
             presents a new optical technique for measuring
             two-dimensional swelling-induced residual strain fields in
             planar samples of articular cartilage attached to the bone
             (i.e., in situ). Osmotic loading was applied to canine
             cartilage-bone samples by equilibration in external baths of
             varying NaCl concentration. Non-zero swelling-induced
             strains were measured in physiological saline, giving
             evidence of the existence of residual strains in articular
             cartilage. Only one component of planar strain (i.e., in
             thickness direction) was found to be non-zero. This strain
             was found to be highly non-uniform in the thickness
             direction, with evidence of compressive strain in the deep
             zone of cartilage and tensile strain in the middle and
             surface zones. The obtained results can be used to
             characterize the material properties of the articular
             cartilage solid matrix, with estimated values of 26 MPa for
             the tensile modulus for middle zone cartilage. The method
             provides the basis to obtain material properties of the
             cartilage solid matrix from a simple, free-swelling test and
             may be useful for quantifying changes in cartilage
             properties with injury, degeneration and
             repair},
   Key = {6230291}
}

@article{6058555,
   Author = {Iatridis, J.C. and Setton, L.A. and Foster, R.J. and Rawlins, B.A. and Weidenbaum, M. and Mow,
             V.C.},
   Title = {Degeneration affects the anisotropic and nonlinear behaviors
             of human anulus fibrosus in compression},
   Journal = {J. Biomech. (UK)},
   Volume = {31},
   Number = {6},
   Pages = {535 - 44},
   Year = {1998},
   url = {http://dx.doi.org/10.1016/S0021-9290(98)00046-3},
   Keywords = {biomechanics;elastic moduli;permeability;stress
             relaxation;swelling;},
   Abstract = {Axial and radial specimens of non-degenerate and degenerate
             human anulus fibrosus (AF) were tested in confined
             compression to test the hypothesis that degeneration
             significantly affects the compressive properties of AF. Due
             to the highly oriented structure of AF, a secondary
             objective was to investigate anisotropic behaviors of AF in
             compression. Uniaxial swelling and stress-relaxation
             experiments were performed on site-matched samples of anulus
             from the anterior outer region of L2-3 intervertebral discs.
             The experimental stress-relaxation behavior was modeled
             using the finite deformation biphasic theory and a
             finite-difference approximation scheme. Significant effects
             of degeneration but not orientation were detected for the
             reference stress offset, &sigma;<sub>offset</sub>, and
             parameters describing the compressive stiffness (i.e.,
             reference aggregate modulus, H<sub>A0</sub>, and nonlinear
             stiffening coefficient, &beta;). Average values were
             0.13&plusmn;0.06 and 0.05&plusmn;0.05 MPa for
             &sigma;<sub>offset</sub>, 0.56&plusmn;0.21 and
             1.10&plusmn;0.53 MPa for H<sub>A0</sub> and 2.13&plusmn;1.48
             and 0.44&plusmn;0.61 for &beta; for all normal and
             degenerate specimens, respectively. No significant effect of
             degeneration or orientation were detected for either of the
             parameters describing the strain-dependent permeability
             (i.e. reference permeability, k<sub>0</sub>, and
             strain-dependent permeability coefficient M) with average
             values for all specimens of 0.20&plusmn;0.10&times;10<sup>-15</sup>
             m<sup>4</sup>/N-s and 1.18&plusmn;1.30 for k<sub>0</sub> and
             M, respectively. The loss of &sigma;<sub>offset</sub> was
             compensated with an elastic stiffening and change in the
             shape of the equilibrium stress-strain curve with
             H<sub>A0</sub> for degenerate tissues almost twice that of
             normal tissues and &beta; less than one sixth. The increase
             in reference elastic modulus with degeneration is likely
             related to an increase in tissue density resulting from the
             loss of water content. The significant effects of
             degeneration reported in this study suggested a shift in
             load carriage from fluid pressurization and swelling
             pressure to deformation of the solid matrix of the AF. The
             results also suggest that the highly organized and layered
             network of the anulus fibrosus, which gives rise to
             significant anisotropic effects in tension, does not play a
             major role in contributing to the magnitude of compressive
             stiffness or the mechanisms of fluid flow of the anulus in
             the confined compression configuration},
   Key = {6058555}
}

@article{6004116,
   Author = {Setton, L.A. and Tohyama, H. and Mow, V.C.},
   Title = {Swelling and curling behaviors of articular
             cartilage},
   Journal = {Trans. ASME, J. Biomech. Eng. (USA)},
   Volume = {120},
   Number = {3},
   Pages = {355 - 61},
   Year = {1998},
   Keywords = {biomechanics;swelling;},
   Abstract = {A new experimental method was developed to quantify
             parameters of swelling-induced shape change in articular
             cartilage. Full-thickness strips of cartilage were studied
             in free-swelling tests and the swelling-induced stretch,
             curvature, and areal change were measured. In general,
             swelling-induced stretch and curvature were found to
             increase in cartilage with decreasing ion concentration,
             reflecting an increasing tendency to swell and
             &ldquo;curl&rdquo; at higher swelling pressures. An
             exception was observed at the articular surface, which was
             inextensible for all ionic conditions. The swelling induced
             residual strain at physiological ionic conditions was
             estimated from the swelling-induced stretch and found to be
             tensile and from 3-15 percent. Parameters of swelling were
             found to vary with sample orientation, reflecting a role for
             matrix anisotropy in controlling the swelling-induced
             residual strains. In addition, the surface zone was found to
             be a structurally important element, which greatly limits
             swelling of the entire cartilage layer. The findings of this
             study provide the first quantitative measures of
             swelling-induced residual strain in cartilage ex situ, and
             may be readily adapted to studies of cartilage swelling in
             situ},
   Key = {6004116}
}

@article{5777661,
   Author = {Iatridis, J.C. and Setton, L.A. and Weidenbaum, M. and Mow,
             V.C.},
   Title = {The viscoelastic behavior of the non-degenerate human lumbar
             nucleus pulposus in shear},
   Journal = {J. Biomech. (UK)},
   Volume = {30},
   Number = {10},
   Pages = {1005 - 13},
   Year = {1997},
   url = {http://dx.doi.org/10.1016/S0021-9290(97)00069-9},
   Keywords = {biomechanics;biorheology;bone;stress relaxation;viscoelasticity;},
   Abstract = {The viscoelastic behavior of the nucleus pulposus was
             determined in shear under transient and dynamic conditions
             and was modeled using a linear viscoelastic model with a
             variable amplitude relaxation spectrum. During
             stress-relaxation tests, the shear stress of the nucleus
             pulposus relaxed nearly to zero indicative of the fluid
             nature of the tissue. Under dynamic conditions, however, the
             nucleus pulposus exhibited predominantly `solid-like'
             behavior with values for dynamic modulus (|G*|) ranging from
             7 to 20 kPa and loss angle (&delta;) ranging from 23 to
             30&deg; over the range of angular frequencies tested (1-100
             rad s<sup>-1</sup>). This frequency-sensitive viscoelastic
             behavior is likely to be related to the highly polydisperse
             populations of nucleus pulposus molecular constituents. The
             stress-relaxation behavior, which was not linear on a
             semi-log plot (in the range &tau;<sub>1</sub>&Lt;t&Lt;&tau;<sub>2</sub>),
             required a variable amplitude relaxation spectrum capable of
             describing this frequency sensitive behavior. The
             stress-relaxation behavior was well described by this linear
             viscoelastic model with variable amplitude relaxation
             spectrum; however, the dynamic moduli were underpredicted by
             the model which may be related to non-linearities in the
             material behavior},
   Key = {5777661}
}

@article{98054187915,
   Author = {Narmoneva, D.A. and Wang, J.Y. and Patel, S.S. and Howell,
             D.S. and Setton, L.A.},
   Title = {Altered swelling-induced strain fields in articular
             cartilage following periods of immobilization},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {36},
   Pages = {125 - 126},
   Address = {Dallas, TX, USA},
   Year = {1997},
   Keywords = {Cartilage;Swelling;Volume fraction;Strain;Statistical
             tests;},
   Abstract = {An experimental technique was developed for measuring the
             swelling-induced strains in articular cartilage while
             attached to the subchondral bone, a configuration more
             representative of the in vivo state than excised cartilage.
             The cartilage attachment to the bone greatly limits the free
             swelling effect in which the strains observed were much
             smaller than those for excised tissue samples. The
             components of swelling strain varies from compressive at the
             deep zone to tensile at the middle-surface zones. Periods of
             immobilization produced an increase in strains which was not
             related to a change in either water volume fraction or fixed
             charge density.},
   Key = {98054187915}
}

@article{97063692025,
   Author = {Iatridis, James C. and Setton, Lori A. and Weidenbaum, Mark and Mow, Van C.},
   Title = {Alterations in the mechanical behavior of the human lumbar
             nucleus pulposus with degeneration and aging},
   Journal = {Journal of Orthopaedic Research},
   Volume = {15},
   Number = {2},
   Pages = {318 - 322},
   Year = {1997},
   Keywords = {Musculoskeletal system;Biomechanics;Morphology;Composition;},
   Abstract = {This study tested the hypothesis that changes in the
             morphology and composition of the nucleus pulposus with age
             and degeneration have associated changes in its mechanical
             properties. A torsional shear experiment was used to
             determine viscoelastic shear properties of cylindrical
             samples of human nucleus pulposus with large ranges of
             grades of morphological degeneration (normal to severely
             degenerated) and ages (range: 16-88 years; average: 57
             &plusmn 21.5 years). Viscoelastic shear properties were
             determined from stress-relaxation and dynamic sinusoidal
             tests. A linear viscoelastic law with a variable-amplitude
             relaxation spectrum was used to model experimental behaviors
             of nucleus pulposus specimens. A statistically significant
             increase in the instantaneous and dynamic shear moduli was
             found with increasing age and grade of degeneration; the
             values for moduli ranged from 5.0 to 60 kPa. A significant
             decrease in tan&delta; was also detected; the values ranged
             from 0.43 to 0.33, indicating a decreased capacity for the
             nucleus pulposus to dissipate energy. The dynamic modulus
             and tan&delta; were also significantly affected by
             frequency. It was generally concluded that the nucleus
             pulposus undergoes a transition from 'fluid-like' behavior
             to more 'solid-like' behavior with aging and
             degeneration.},
   Key = {97063692025}
}

@article{98054187935,
   Author = {Elliott, Dawn M. and LeRoux, Michelle A. and Laursen, Tod A. and Setton, Lori A.},
   Title = {Formulation of a continuum anisotropic model for the anulus
             fibrosus in tension},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {36},
   Pages = {165 - 166},
   Address = {Dallas, TX, USA},
   Year = {1997},
   Keywords = {Tissue;Anisotropy;Aspect ratio;Strain;Stresses;Mathematical
             models;Finite element method;Elastic moduli;},
   Abstract = {The anulus fibrosus (AF) of the intervertebral disc is a
             highly structured material made up of alternating tissue
             layers with collagen fibers oriented +30&deg; and -30&deg;
             to the circumferential axis. Special organization of the AF
             gives rise to strongly anisotropic behaviors which may
             contribute to its mechanical function. A continuum
             formulation for the AF as a linear orthotropic material with
             a complete set of material properties is proposed. Finite
             element implementation of the model is also developed to
             further compare model predictions with experimental findings
             for the AF in tension.},
   Key = {98054187935}
}

@article{97023540093,
   Author = {Elliott, Dawn M. and Setton, Lori A. and Shah, Maulin P. and Vail, T. Parker and Guilak, Farshid},
   Title = {Effects of meniscectomy on the tensile properties of
             articular cartilage},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {33},
   Pages = {247 - 248},
   Address = {Atlanta, GA, USA},
   Year = {1996},
   Keywords = {Cartilage;Tensile properties;Surgery;Joints
             (anatomy);Biomedical engineering;Models;Stiffness;Proteins;Collagen;Composition;Biosynthesis;Hydration;},
   Abstract = {A study was conducted to quantify the tensile properties of
             articular cartilage in an experimental model of
             meniscectomy. The meniscus was completely resected in the
             right knees of 4 skeletally mature mongrel dogs. The left
             knee was used as an unoperated control. Animals were
             sacrificed 12 weeks after surgery and both legs stored at
             -20&deg;C until testing. Successive tensile
             stress-relaxation tests were performed using a screw driven
             uniaxial testing system. All tests were performed in a 0.15M
             NaCl bath at room temperature. The findings were then
             compared with those of both human osteoarthritis (OA) and
             experimental models of joint instability.},
   Key = {97023540093}
}

@article{95092853089,
   Author = {Setton, Lori A. and Mow, Van C.},
   Title = {Contributions of flow-dependent and flow-independent
             viscoelasticity to the behavior of articular cartilage in
             oscillatory compression},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {29},
   Pages = {307 - 308},
   Address = {Beever Creek, CO, USA},
   Year = {1995},
   Keywords = {Cartilage;Viscoelasticity;Oscillations;Mathematical
             models;Tensors;Strain;Relaxation processes;Deformation;Mechanical
             permeability;Stresses;Hysteresis;},
   Abstract = {While flow-dependent viscoelasticity can explain much of the
             observed dependence of cellular response to amplitude and
             frequency of loading, as well as spatial position in the
             explant, contributions of the flow-independent viscoelastic
             mechanism may also be considered to be significant,
             particularly in tissues with large values of hydraulic
             permeability. In this study, a model incorporating both
             flow-dependent and flow-independent viscoelastic mechanisms,
             the biphasic poroviscoelastic theory, is used to predict the
             mechanical environment of the extracellular matrix within a
             cartilage explant in response to a forced oscillatory
             displacement.},
   Key = {95092853089}
}

@article{95102886799,
   Author = {Setton, L.A. and Mow, V.C. and Howell, D.S.},
   Title = {Mechanical behavior of articular cartilage in shear is
             altered by transection of the anterior cruciate
             ligament},
   Journal = {Journal of Orthopaedic Research},
   Volume = {13},
   Number = {4},
   Pages = {473 -},
   Year = {1995},
   Key = {95102886799}
}

@article{95092853061,
   Author = {Iatridis, James C. and Setton, Lori A. and Foster, Robert J. and Rawlins, Bernard A. and Weidenbaum, Mark and Mow, Van
             C.},
   Title = {Human anulus fibrosus behaves nonlinearly and isotropically
             in finite deformation confined compression},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {29},
   Pages = {251 - 252},
   Address = {Beever Creek, CO, USA},
   Year = {1995},
   Keywords = {Biomechanics;Compressive strength;Deformation;Anisotropy;Compression
             testing;Stresses;Relaxation processes;Curve
             fitting;Calculations;Strain;Mathematical models;Pressure
             effects;},
   Abstract = {Human anulus fibrosus (AF) of the intervertebral disk
             exhibits nonlinear and anisotropic behavior in tension. This
             paper investigates both anisotropic and nonlinear behaviors
             of the AF in the confined compression testing configuration
             under conditions of finite deformation. The finite
             deformation formulation of the biphasic theory is used to
             described the experimental stress-relaxation behavior of AF
             under conditions of large deformation. In this formulation,
             the equilibrium elastic behavior is described by two
             material parameters: the aggregate modulus at zero strain
             (H<sub>Ao</sub>) and the nonlinear stiffening coefficient
             (&beta;).},
   Key = {95092853061}
}

@article{95012532254,
   Author = {Setton, L.A. and Tohyama, H. and Lai, W.M. and Guilak, F. and Mow, V.C.},
   Title = {Experimental measurement of the in vitro curling behavior of
             articular cartilage},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {28},
   Pages = {135 - 136},
   Address = {Chicago, IL, USA},
   Year = {1994},
   Keywords = {Swelling;Residual stresses;Strain;Image analysis;Computer
             aided analysis;Measurement errors;Sodium
             chloride;Polynomials;Least squares approximations;Mathematical
             models;Collagen;},
   Abstract = {The objective of this study was to develop a non-contacting
             optical method to quantify the shape changes in cartilage in
             vitro, as a first step toward determining a potential
             mechanical role for the swelling-induced residual stresses
             and strain in cartilage in situ. Rectangular strips of
             articular cartilage prepared from the lateral facet of
             skeletally-mature bovine patella were placed in a glass dish
             and allowed to equilibrate in NaCl solution. A calibration
             cylinder was affixed within each glass dish. Both the
             cylinder and the strips were photographed. The images were
             analyzed for dimensional changes. All the samples
             demonstrated the characteristic curling and swelling
             behaviors after removal from the subchondral bone, and in
             response to changes in the concentration of the external
             bath.},
   Key = {95012532254}
}

@article{95012532345,
   Author = {Iatridis, James C. and Setton, Lori A. and Weidenbaum, Mark and Mow, Van C.},
   Title = {Determination of a relaxation spectrum to evaluate the
             viscoelastic behavior of the nucleus pulposus in
             shear},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {28},
   Pages = {317 - 318},
   Address = {Chicago, IL, USA},
   Year = {1994},
   Keywords = {Cartilage;Pressurization;Viscoelasticity;Stress
             relaxation;Spectrometers;Shear stress;Torque;Mathematical
             models;Integral equations;},
   Abstract = {This study was designed to determine the intrinsic
             viscoelastic behaviour of NP in torsional shear, and to
             obtain a relaxation spectrum capable of describing this
             behaviour. Several relaxation functions based on both
             discrete and continuous relaxation spectra were investigated
             to describe the intrinsic viscoelastic effects for the NP.
             It was observed that the shear behavior of the NP exhibits
             pronounced viscoelastic effects, as demonstrated by a
             considerable stress-relaxation effect.},
   Key = {95012532345}
}

@article{94091407745,
   Author = {Mueller, F.J. and Setton, L.A. and Manicourt, D.H. and Mow,
             V.C. and Howell, D.S. and Pita, J.C.},
   Title = {Centrifugal and biochemical comparison of proteoglycan
             aggregates from articular cartilage in experimental joint
             disuse and joint instability},
   Journal = {Journal of Orthopaedic Research},
   Volume = {12},
   Number = {4},
   Pages = {498 - 508},
   Year = {1994},
   Keywords = {Biological materials;Biochemistry;Joints
             (anatomy);Models;Orthopedics;},
   Abstract = {Two models involving altered joint loading were compared
             with regard to their effects on the biochemical composition
             and proteoglycan aggregate structure of articular cartilage.
             Disuse atrophy was created in greyhound dogs by nonrigid
             immobilization of the right knee in 90&deg; of flexion, and
             joint instability was created by transection of the anterior
             cruciate ligament. Similarities and differences between the
             two experimental groups at two different time periods were
             examined to investigate why joint instability induces
             progressive and irreversible changes to the articular
             cartilage, whereas joint disuse induces changes that may be
             reversible when the joint is remobilized. The following
             studies were performed on the cartilage from all
             experimental and control groups: (a) compositional analyses
             to determine water, uronate, and hydroxyproline contents;
             (b) high performance liquid chromatography for detection of
             hyaluronan and chondroitin sulfates; and (c)
             centrifuguration analyses of nondissociatively extracted and
             purified proteoglycans to isolate and quantify the
             populations of monomers and slow and fast-sedimenting
             families of aggregates. In general, all cartilage was found
             to have a decreased ratio of proteoglycan to collagen after
             4 weeks of disuse, and this ratio returned to control values
             at 8 weeks. In contrast, cartilage had an elevated ratio of
             proteoglycan to collagen as well as increased hydration at
             12 weeks after transection of the anterior cruciate
             ligament. The most striking contrast between the two models
             was the finding of an approximately 80% decrease in the
             content of hyaluronan at both time periods after transection
             of the anterior cruciate ligament, with no evidence of a
             change after disuse. The results of centrifugation analyses
             indicated a significant decrease in the quantity of
             proteoglycan aggregates in both models.},
   Key = {94091407745}
}

@article{94091407741,
   Author = {Setton, L.A. and Mow, V.C. and Muller, F.J. and Pita, J.C. and Howell, D.S.},
   Title = {Mechanical properties of canine articular cartilage are
             significantly altered following transection of the anterior
             cruciate ligament},
   Journal = {Journal of Orthopaedic Research},
   Volume = {12},
   Number = {4},
   Pages = {451 - 463},
   Year = {1994},
   Keywords = {Mechanical properties;Ligaments;Network protocols;Orthopedics;Biomedical
             engineering;},
   Abstract = {The compressive, tensile, and swelling properties of
             articular cartilage were studied at two time periods
             following transection of the anterior cruciate ligament in
             the knee of greyhound dogs. An experimental protocol was
             designed to quantify the essential equilibrium and biphasic
             material properties of cartilage in tension compression and
             shear, as well as the parameters of isometric swelling
             behavior. All properties were measured at several sites to
             elicit differences between sites of frequent and less
             frequent contact. Hydration was determined at each site and
             was compared with the material properties of cartilage from
             corresponding sites. There were extensive changes in all
             compressive, tensile, and swelling properties of cartilage
             after transection of the anterior cruciate ligament. Twelve
             weeks after surgery, the intrinsic moduli were reduced
             significantly in compression (approximately 24 % of control
             values), tension (approximately 64%), and shear
             (approximately 24 %), and the hydraulic was elevated
             significantly (approximately 48 %). Significant-increases in
             hydration (approximately 9 %) also were observed, as well as
             a strong correlation of hydration with hydraulic
             permeability. The pattern of these changes was not found to
             differ with site in the joint, but significant differences
             were observed in the magnitude of change for cartilage from
             the femoral groove and the femoral condyle. The pattern and
             extent of changes in the material properties following
             transection of the anterior cruciate ligament indicate that
             altered loading of the joint severely compromises the
             overall mechanical behavior of articular cartilage. The
             observed loss of matrix stiffness in compression, tension,
             and shear is associated with increase in the deformation of
             the solid matrix, a diminished ability to resit swelling,
             and the increase in hydration observed in this
             study.},
   Key = {94091407741}
}

@article{93061004853,
   Author = {Setton, Lori A. and Zhu, Wenbo and Weidenbaum, Mark and Ratcliffe, Anthony and Mow, Van C.},
   Title = {Compressive properties of the cartilaginous end-plate of the
             baboon lumbar spine},
   Journal = {Journal of Orthopaedic Research},
   Volume = {11},
   Number = {2},
   Pages = {228 - 239},
   Year = {1993},
   Keywords = {Cartilage;Body fluids;Viscoelasticity;Compressibility of
             liquids;Compression testing;Flow of fluids;Mechanical
             properties;Composition;Mathematical models;Curve
             fitting;},
   Abstract = {The viscoelastic behavior of the cartilaginous end-plate of
             the baboon (Papio anubis) was studied in an experiment on
             compressive creep. Data were analyzed with the biphasic
             poroviscoelastic constitutive theory to assess the relative
             contributions of flow-dependent and flow-independent
             viscoelastic mechanisms to the observed creep behavior.
             Material coefficients describing the equilibrium compressive
             behavior (H<sub>A</sub>) and both flow-independent (c,
             &tau;<sub>1</sub>, and &tau;<sub>2</sub>) and flow-dependent
             (k) viscoelastic effects were determined for the end-plate
             by the curve-fitting of the theoretical solution to the
             experimental creep data. Biochemical analyses were performed
             to test for potential relationships between material
             properties and composition which may give rise to the
             viscoelastic behavior of the end-plate. The results indicate
             that the cartilaginous end-plate has a hydraulic
             permeability of 14.3&times;10<sup>-14</sup>
             m<sup>4</sup>/N-s, which is associated with rapid transport
             and pressurization of the interstitial fluid in response to
             loading and an increased emphasis on flow-independent
             viscoelastic effects. Biochemical analyses for water,
             sulfated glycosaminoglycan content, and hydroxyproline
             indicate that the end-plate of the baboon is compositionally
             similar to the cartilaginous end-plate in humans.
             Interpretation of the mechanical and compositional data
             suggests that fluid pressurization in the cartilaginous
             end-plate may be important in the maintenance of a uniform
             stress distribution across the boundary between vertebral
             body and intervertebral disc.},
   Key = {93061004853}
}

@article{94031231322,
   Author = {Setton, L.A. and Lai, W.M. and Mow, V.C.},
   Title = {Swelling-induced residual stress and the mechanism of
             curling in articular cartilage in vitro},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {26},
   Pages = {59 - 62},
   Address = {New Orleans, LA, USA},
   Year = {1993},
   Keywords = {Residual stresses;Swelling;Mathematical models;Physical
             properties;Biomedical engineering;Biological
             materials;},
   Abstract = {The triphasic theory has been used to analyze the in vitro
             free-swelling behavior of two-dimensional strips of
             articular cartilage with an inhomogeneous distribution of
             negative fixed charge density. The results indicate that the
             model can predict the characteristic curling behavior of
             cartilage strips. The free swelling geometry demonstrated a
             dependence on aspect ratio of the strip length thickness, so
             that the curling or cartilage strips increased with
             decreasing cartilage thickness. It was concluded that a
             physiological variation in fixed charge density gives rise
             to a non-uniform distribution of residual stress and strain,
             and is thus responsible for the curling of excised samples
             in vitro. The mathematical solution presented in this study
             provides a means for calculating the residual strains,
             stresses and swelling pressures in the equilibrium
             free-swelling configuration and may prove useful in the
             development of an experimental protocol for measurement of
             the residual strains in vitro and in situ.},
   Key = {94031231322}
}

@article{4410101,
   Author = {Setton, L.A. and Zhu, W. and Mow, V.C.},
   Title = {The biphasic poroviscoelastic behavior of articular
             cartilage: role of the surface zone in governing the
             compressive behavior},
   Journal = {J. Biomech. (UK)},
   Volume = {26},
   Number = {4-5},
   Pages = {581 - 92},
   Year = {1993},
   Keywords = {biorheology;creep;viscoelasticity;},
   Abstract = {To assess the influence of the surface zone on the
             viscoelastic properties of cartilage under compressive
             loading, the authors prepared osteochondral plugs from
             skeletally mature steers, with and without the surface zone
             of articular cartilage, for study in the confined
             compression creep experiment. The relative contributions of
             two viscoelastic mechanisms, i.e. a flow-independent
             mechanism (Hayes and Bodine, ibid., vol.11, p407-19, 1978),
             and a flow-dependent mechanism (Mow et al., J. Biomech.
             Engng. ibid., vol.102, p.73-84, 1980), to the compressive
             creep response of these two types of specimens were
             determined using the biphasic poroviscoelastic theory
             proposed by (Mak., ibid., vol.20, p.703-14, 1986). From the
             experimental results and the biphasic poroviscoelastic
             theory, the authors found that frictional drag associated
             with interstitial fluid flow and fluid pressurization are
             the dominant mechanisms of load support in the intact
             specimens, i.e. the flow-dependent mechanisms alone with
             sufficient to describe normal articular cartilage
             compressive creep behavior. For specimens with the surface
             removed, the authors found an increased creep rate which was
             derived from an increased tissue permeability, as well as
             significant changes in the flow-independent parameters of
             the viscoelastic solid matrix},
   Key = {4410101}
}

@article{93020709999,
   Author = {Setton, L.A. and Gu, W.Y. and Lai, W.M. and Mow,
             V.C.},
   Title = {Pre-stress in articular cartilage due to internal swelling
             pressure},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {22},
   Pages = {485 - 488},
   Address = {Anaheim, CA, USA},
   Year = {1992},
   Keywords = {Stress analysis;Elasticity;Dynamic loads;Structural
             analysis;Pressure effects;Mathematical models;},
   Abstract = {The triphasic theory has been used to calculate the
             pre-stress in spherical and cylindrical layer models of
             articular cartilage. In the present study, cartilage was
             assumed to be homogeneous with a uniform fixed charge
             density. The tissue is attached to subchondral bone of a
             given radius of curvature. It has been determined that: 1)
             the maximum radial elastic stress occurs at the
             cartilage-bone junction and the maximum circumferential
             elastic stress occurs at the cartilage surface; 2) radial
             elastic stress is generally larger than the tangential
             elastic stress; 3) the maximum elastic stress increases with
             decreasing radius of curvature for cartilage layers of fixed
             thickness. The existence of pre-stresses may serve to reduce
             collagen tension resulting from joint loading, and may also
             be an important factor in determining the collagen
             ultrastructure within the cartilage solid
             matrix.},
   Key = {93020709999}
}

@article{93020710026,
   Author = {Setton, L.A. and Mow, V.C.},
   Title = {Generalized biphasic poroviscoelastic model for articular
             cartilage: Theory and experiments},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {22},
   Pages = {589 - 592},
   Address = {Anaheim, CA, USA},
   Year = {1992},
   Keywords = {Viscoelasticity;Porosity;Strength of materials;Shear
             stress;Deformation;Anelastic relaxation;Loads
             (forces);Mechanical testing;Joints (anatomy);Mathematical
             models;},
   Abstract = {The shear and bulk deformation viscoelastic spectrums of the
             solid matrix of articular cartilage has been determined
             using the biphasic poroviscoelastic theory in combination
             with data from two independent stress-relaxation experiments
             in compression and pure shear. The results show that
             viscoelasticity of the solid matrix in bulk deformation
             exerts a strong influence on the compressive behavior of
             cartilage for short times after rapid loading. For long time
             periods, shear and bulk viscoelasticity contribute almost
             equally to the deformational response of the tissue. Results
             indicate that the model for studying cartilage behavior
             should reflect the particular time scales and configuration
             of the specific test. The method presented in this study
             should allow investigators to choose the appropriate
             biphasic model to represent cartilage deformational behavior
             in studying diarthrodial joint biomechanics.},
   Key = {93020710026}
}

@article{93020704622,
   Author = {Lai, W. Michael and Gu, Weiyong and Setton, Lori A. and Mow,
             Van C.},
   Title = {Conditional equivalence of chemical loading and mechanical
             loading on articular cartilage},
   Journal = {American Society of Mechanical Engineers, Bioengineering
             Division (Publication) BED},
   Volume = {20},
   Pages = {481 - 484},
   Address = {Atlanta, GA, USA},
   Year = {1991},
   Keywords = {Stresses;Chemical reactions;Sodium chloride;Solutions;Joints
             (anatomy);},
   Abstract = {The objective of this paper is to ascertain the conditions
             for equivalence between chemical or osmotic loading and
             mechanical loading on articular cartilage. Constitutive
             equations for a charged-hydrated-soft tissue are given and
             chemical potentials are derived. Equivalence between
             chemical vs. mechanical load is discussed. Using the
             triphasic constitutive equations, it is shown that for every
             chemical load generated by a given concentration of
             polyethylene glycol (PEG) in a NaCl solution there
             corresponds an isotropic mechanical load, P<sub>A</sub>,
             which imparts to the tissue an identical equilibrium
             deformation. However, the mechanical load must be delivered
             in an isotropic manner via rigid-porous, free-draining
             loading platens.},
   Key = {93020704622}
}

@article{7435933,
   Author = {Flahiff, C.M. and Narmoneva, D.A. and Huebner, J.L. and Kraus, V.B. and Guilak, F. and Setton, L.A.},
   Title = {Osmotic loading to determine the intrinsic material
             properties of guinea pig knee cartilage},
   Journal = {J. Biomech. (UK)},
   Volume = {35},
   Number = {9},
   Pages = {1285 - 90},
   url = {http://dx.doi.org/10.1016/S0021-9290(02)00079-9},
   Keywords = {biochemistry;biological techniques;biological
             tissues;biomechanics;elastic moduli;fluorescence;optical
             microscopy;osmosis;swelling;},
   Abstract = {Few methods exist to study cartilage mechanics in small
             animal joints due to the difficulties associated with
             handling small tissue samples. In this study, we apply an
             osmotic loading method to quantify the intrinsic material
             properties of articular cartilage in small animal joints.
             Cartilage samples were studied from the femoral condyle and
             tibial plateau of two-month old guinea pigs. Swelling
             strains were measured using confocal fluorescence scanning
             microscopy in samples subjected to osmotic loading. A
             histochemical staining method was developed and calibrated
             for quantification of negative fixed charge density in
             guinea pig cartilage. Site-matched swelling strain data and
             fixed charge density values were then used with a triphasic
             theoretical model for cartilage swelling to determine the
             uniaxial modulus of the cartilage solid matrix. Moduli
             obtained in this study (7.2 MPa femoral condyle; 10.8 MPa,
             tibial plateau) compare well with previously reported values
             for the tensile moduli of human and other animal cartilages
             determined from uniaxial tension experiments. This study
             provides the first available data for material properties
             and fixed charge density in cartilage from the guinea pig
             knee and suggests a promising method for tracking changes in
             cartilage mechanics in small animal models of
             degeneration},
   Key = {7435933}
}


%% Papers Published   
@booklet{Nettles09,
   Author = {D. L. Nettles and A. Chilkoti and L. A. Setton},
   Title = {Early Metabolite Levels Predict Long-Term Matrix
             Accumulation for Chondrocytes in Elastin-like Polypeptide
             Biopolymer Scaffolds},
   Journal = {Tissue Engineering Part A},
   Volume = {15},
   Number = {8},
   Pages = {2113 -- 2121},
   Year = {2009},
   Month = {August},
   ISSN = {1937-3341},
   Abstract = {The development of cartilage tissue engineering scaffolds
             could greatly benefit from methods to evaluate the
             interactions of cells with scaffolds that are rapid, are
             nondestructive, and can be carried out at early culture
             times. Motivated by this rationale, the objective of the
             current study was to evaluate whether the concentration of
             metabolites in scaffold-cell cultures at early culture times
             could predict matrix synthesis in the same samples at longer
             culture times. Metabolite and matrix synthesis were measured
             for 16 different formulations of cell-laden elastin-like
             polypeptide hydrogels. Metabolites were measured at days 4
             and 7 of culture, while matrix accumulation was evaluated at
             day 28. Four of the 16 formulations resulted in molar ratios
             of lactate: glucose near 2, indicating anaerobic metabolism
             of glucose, which resulted in collagen: glycosaminoglycan
             accumulation ratios near those of native tissue. Lactate and
             pyruvate concentrations were found to significantly
             correlate with both sulfated glycosaminoglycan and
             hydroxyproline accumulation, with better fits for the
             latter. Lactate was found to be the strongest predictor of
             both matrix components, suggesting that measuring this
             metabolite at very early culture times may be useful for
             evaluating the status of tissue engineering constructs in a
             rapid and nondestructive manner.},
   Key = {Nettles09}
}

@booklet{Christensen09,
   Author = {T. Christensen and M. Amiram and S. Dagher and K.
             Trabbic-carlson and M. F. Shamji and L. A. Setton and A.
             Chilkoti},
   Title = {Fusion order controls expression level and activity of
             elastin-like polypeptide fusion proteins},
   Journal = {Protein Science},
   Volume = {18},
   Number = {7},
   Pages = {1377 -- 1387},
   Year = {2009},
   Month = {July},
   ISSN = {0961-8368},
   Abstract = {We have previously developed a method to purify recombinant
             proteins, termed inverse transition cycling (ITC) that
             eliminates the need for column chromatography. ITC exploits
             the inverse solubility phase transition of an elastin-like
             polypeptide (ELP) that is fused to a protein of interest. In
             ITC, a recombinant ELP fusion protein is cycled through its
             phase transition, resulting in separation of the ELP fusion
             protein from other Escherichia coli contaminants. Herein, we
             examine the role of the position of the ELP in the fusion
             protein on the expression levels and yields of purified
             protein for four recombinant ELP fusion proteins. Placing
             the ELP at the C-terminus of the target protein
             (protein-ELP) results in a higher expression level for the
             four ELP fusion proteins, which also translates to a greater
             yield of purified protein. The position of the fusion
             protein also has a significant impact on its specific
             activity, as ELP-protein constructs have a lower specific
             activity than protein-ELP constructs for three out of the
             four proteins. Our results show no difference in mRNA levels
             between protein-ELP and ELP-protein fusion constructs.
             Instead, we suggest two possible explanations for these
             results: first, the translational efficiency of mRNA may
             differ between the fusion protein in the two orientations
             and second, the lower level of protein expression and lower
             specific activity is consistent with a scenario that
             placement of the ELP at the N-terminus of the fusion protein
             increases the fraction of misfolded, and less active
             conformers, which are also preferentially degraded compared
             to fusion proteins in which the ELP is present at the
             C-terminal end of the protein.},
   Key = {Christensen09}
}

@booklet{Adams09,
   Author = {S. B. Adams and M. F. Shamji and D. L. Nettles and P. Hwang and L. A. Setton},
   Title = {Sustained Release of Antibiotics From Injectable and
             Thermally Responsive Polypeptide Depots},
   Journal = {Journal Of Biomedical Materials Research Part B-applied
             Biomaterials},
   Volume = {90B},
   Number = {1},
   Pages = {67 -- 74},
   Year = {2009},
   Month = {July},
   ISSN = {1552-4973},
   Abstract = {Biodegradable polymeric scaffolds are of interest for
             delivering antibiotics to local sites of infection in
             orthopaedic applications, such as bone and diarthrodial
             joints. The objective of this study was to develop a
             biodegradable scaffold with ease of drug loading in aqueous
             solution, while providing for drug depot delivery via
             syringe injection. Elastin-like polypeptides (ELPs) were
             used for this application, biopolymers of repeating
             pentapeptide sequences that were thermally triggered to
             undergo in situ depot formation at body temperature. ELPs
             were modified to enable loading with the antibiotics,
             cefazolin, and vancomycin, followed by induction of the
             phase transition in vitro. Cefazolin and vancomycin
             concentrations were monitored, as well as bioactivity of the
             released antibiotics, to test an ability of the ELP depot to
             provide for prolonged release of bioactive drugs. Further
             tests of formulation viscosity were conducted to test
             suitability as an injectable drug carrier. Results
             demonstrate sustained release of therapeutic concentrations
             of bioactive antibiotics by the ELP, with first-order time
             constants for drug release of similar to 25 h for cefazolin
             and similar to 500 h for vancomycin. These findings
             illustrate that an injectable, in situ forming ELP depot can
             provide for sustained release of antibiotics with an effect
             that varies across antibiotic formulation. ELPs have
             important advantages for drug delivery, as they are known to
             be biocompatible, biodegradable, and elicit no known immune
             response. These benefits suggest distinct advantages over
             currently used carriers for antibiotic drug delivery in
             orthopedic applications. (C) 2008 Wiley Periodicals, Inc. J
             Biomed Mater Res Part B: Appl Biomater 90B: 67-74,
             2009},
   Key = {Adams09}
}

@booklet{Shamji09,
   Author = {M. F. Shamji and P. Hwang and R. W. Bullock and S. B. Adams and D. L. Nettles and L. A. Setton},
   Title = {Release and Activity of Anti-TNF alpha Therapeutics From
             Injectable Chitosan Preparations for Local Drug
             Delivery},
   Journal = {Journal Of Biomedical Materials Research Part B-applied
             Biomaterials},
   Volume = {90B},
   Number = {1},
   Pages = {319 -- 326},
   Year = {2009},
   Month = {July},
   ISSN = {1552-4973},
   Abstract = {Background: Tumor necrosis factor alpha (TNF alpha) is a
             cytokine that regulates immune and inflammatory
             overactivation in various pathological states. Protein
             therapeutics may antagonize this cytokine, but may also have
             systemic toxicities. Small molecule natural products are
             also efficacious, but can suffer from poor oral
             bioavailability. A drug delivery vehicle is needed to
             sustain release of active therapeutics and address localized
             inflammation. Materials: Chitosan is a biocompatible
             aminopolysaccharide that undergoes thermally-initiated
             gelation in cosolutions with glycerophosphate (GP.), and may
             entrap and sustain release of additive therapeutics.
             Gelation time and temperature of chitosan/GP were evaluated
             by turbidity (OD350), as was the kinetic effect of bovine
             serum albumin (BSA) entrapment. We investigated in vitro
             release of BSA and various anti-TNF agents (curcumin,
             sTNFRII, anti-TNF antibody) and confirmed in vitro activity
             of the released drugs using an established bioassay.
             Results: Turbidity results show that chitosan/GP thermogel
             achieves gelation at 37 degrees C within 10 min, even with
             significant protein loading. Sustained BSA release occurred
             with 50\% retained at 7 days. All anti-TNF therapeutics
             exhibited sustained release, with 10\% of sTNFRII and
             anti-TNF antibody remaining after 7 days and 10\% of
             curcumin remaining after 20 days. After release, each
             compound antagonized TNF alpha-cytotoxicity in murine
             fibrosarcoma cells. Conclusions: This study demonstrates
             that thermogelling chitosan/GP entraps and sustains release
             of a broad range of anti-TNF agents. Such delivery of
             disease-modifying therapy could establish a drug depot to
             treat local inflammation. The breadth of molecular sizes
             demonstrates significant versatility, and slow release could
             protect against toxicities of systemic delivery. (C) 2008
             Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl
             Biomater 90B: 319-326, 2009},
   Key = {Shamji09}
}

@booklet{Shamji09a,
   Author = {M. F. Shamji and K. D. Allen and S. So and L. F. Jing and S.
             B. Adams and R. Schuh and J. Huebner and V. B. Kraus and A.
             H. Friedman and L. A. Setton and W. J. Richardson},
   Title = {Gait Abnormalities and Inflammatory Cytokines in an
             Autologous Nucleus Pulposus Model of Radiculopathy},
   Journal = {Spine},
   Volume = {34},
   Number = {7},
   Pages = {648 -- 654},
   Year = {2009},
   Month = {April},
   ISSN = {0362-2436},
   Abstract = {Study Design. The authors investigated gait abnormalities
             and mechanical hypersensitivity associated with invertebral
             disc herniation in a rat model of radiculopathy. Further
             evaluation involved assessing how nucleus pulposus (NP)
             injury affected systemic cytokine expression and molecular
             changes at the dorsal root ganglion (DRG). Objective. The
             objective of this work was to describe the gait and
             behavioral changes in an animal model of discherniation
             induced radiculopathy. A second objective included examining
             how these functional changes correlated with
             neuroinflammation and autoreactive lymphocyte immune
             activation. Summary of Background Data. Animal models of
             radiculopathy describe demyelination, slowed nerve
             conduction, and heightened pain sensitivity after
             application of autologous NP to the DRG. The quantitative
             impact of disc herniation on animal locomotion has not been
             investigated. Further, while local inflammation occurs at
             the injury site, the role of autoimmune cytokines reactive
             against previously immune-sequestered NP requires
             investigation. Methods. NP-treated animals (n = 16) received
             autologous tail NP placed onto the L5 DRG exposed by
             unilateral facetectomy, and control animals (n = 16)
             underwent exposure only. At weekly time points, animals were
             evaluated for mechanical allodynia, thermal hyperalgesia,
             and gait characteristics through digitized video analysis.
             Serum cytokine content was measured after animal sacrifice,
             and immunohistochemistry tested DRG tissue for mediators of
             inflammation and immune activation. Results. Sensory testing
             revealed mechanical allodynia in the affected limb of
             NP-treated rats compared with sham animals (P $<$ 0.01) at
             all time points. Gait analysis reflected functional
             locomotive consequences of marked asymmetry (P = 0.048) and
             preference to bear weight on the contralateral limb (duty
             factor imbalance, P $<$ 0.01) at early time points.
             Equivalent serum cytokine expression occurred in both
             groups, confirming the local inflammatory nature of this
             disease model. Immunohistochemistry of the sectioned DRGs
             revealed equivalent postsurgical inflammatory activation
             (interleukin 23, P = 0.47) but substantial early immune
             activation in the NP-treated group (interleukin 17, P =
             0.01). Conclusion. This model of radiculopathy provides
             evidence of altered gait in a model of noncompressive disc
             herniation. Systemic inflammation was absent, but mechanical
             allodynia, local inflammation, and autoreactive immune
             activation were observed. Future work will involve
             therapeutic interventions to rescue animals from the
             phenotype of inflammatory radiculopathy.},
   Key = {Shamji09a}
}

@booklet{Shamji08,
   Author = {M. F. Shamji and J. Chen and A. H. Friedman and W. J.
             Richardson and A. Chilkoti and L. A. Setton},
   Title = {Synthesis and characterization of a thermally-responsive
             tumor necrosis factor antagonist},
   Journal = {Journal Of Controlled Release},
   Volume = {129},
   Number = {3},
   Pages = {179 -- 186},
   Year = {2008},
   Month = {August},
   ISSN = {0168-3659},
   Abstract = {Numerous antagonists of tumor necrosis factor alpha (TNF
             alpha) have been developed to attenuate inflammation and
             accompanying pain in many disease processes. Soluble TNF
             receptor type II (sTNFRII) is one such antagonist that
             sequesters TNF alpha away from target receptors and
             attenuates its activity. Systemic delivery of soluble TNF
             receptors or other antagonists may have deleterious side
             effects associated with immune suppression, so that
             strategies for locally targeted drug delivery are of
             interest. Elastin-like polypeptides (ELPs) are biopolymers
             capable of in situ drug depot formation through
             thermally-driven supramolecular complexes at physiological
             temperatures. A recombinant fusion protein between ELP and
             sTNFRII was designed and evaluated for retention of bivalent
             functionality. Thermal sensitivity was observed by formation
             of supramolecular submicron-sized particles at 32 degrees C,
             with gradual resolubilization from the depot observed at
             physiological temperatures. In vitro refolding of the
             sTNFRII domain was required and the purified product
             exhibited an equilibrium dissociation constant for
             interacting with TNF alpha that was seven-fold higher than
             free sTNFRII Furthermore, anti-TNF activity was observed in
             inhibiting TNR alpha-mediated cytotoxicity in the murine
             L929 fibrosarcoma assay. Potential advantages of this
             ELP-sTNFRII fusion protein as an anti-TNFa drug depot
             include facility of injection, in situ depot formation, low
             endotoxin content, and functionality against TNF alpha. (C)
             2008 Elsevier B.V. All rights reserved.},
   Key = {Shamji08}
}

@booklet{Shamji08a,
   Author = {M. F. Shamji and L. F. Jing and J. Chen and P. Hwang and O.
             Ghodsizadeh and A. H. Friedman and W. J. Richardson and L.
             A. Setton},
   Title = {Treatment of neuroinflammation by soluble tumor necrosis
             factor receptor Type II fused to a thermally responsive
             carrier},
   Journal = {Journal Of Neurosurgery-spine},
   Volume = {9},
   Number = {2},
   Pages = {221 -- 228},
   Year = {2008},
   Month = {August},
   ISSN = {1547-5654},
   Abstract = {Object. Biochemical irritation of the dorsal root ganglion
             (DRG) after intervertebral disc herniation contributes to
             radiculopathy through tumor necrosis factor-alpha (TNF
             alpha)-mediated inflammation. Soluble TNF receptor Type II
             (sTNFRII) sequesters this cytokine, providing clinical
             benefit. Previous work involving conjugation of sTNFRII with
             thermally responsive elastin-like polypeptide (ELP) yielded
             a chimeric protein (ELP-sTNFRII) with in vitro anti-TNF
             alpha bioactivity. Furthermore, temperature-triggered ELP
             aggregation into a "depot" prolongs protein residence time
             following perineural injection. In this study the authors
             evaluated the inflammatory phenotype of DRG explants after
             TNF alpha stimulation, and assessed the abilities of sTNFRII
             or ELP-sTNFRII to attenuate these neuroinflammatory changes.
             Methods. Rat lumbar DRGs (35 animals) were treated in 6
             groups, as follows: control; TNFa (25 ng/ml); TNFa with low-
             (0.2 mu g/ml) or high-dose (1 mu g/ml) sTNFRII; and TNFa
             with low- (52.5 mu g/ml) or high-dose (262.5 mu g/ml)
             ELP-sTNFRII. After 24 hours, supernatant was evaluated for
             inflammatory cytokines (interleukin [IL]-1, IL-6, and
             IL-10); prostaglandin E-2; and metabolites (glutamate,
             lactate, and pyruvate). Single-factor analysis of variance
             with post hoc Dunn analysis (alpha = 0.05) was used to
             assess treatment differences. Results. Incubation of
             explants with TNFa caused metabolic stress reflected by an
             increased lactate/pyruvate ratio (1.8 +/- 0.5-fold) and
             extracellular glutamate (79 +/- 8\% increase). Inflammatory
             activation was observed with heightened IL-6 release (5.2
             +/- 1.4-fold) and prostaglandin E-2 production (14 +/-
             3-fold). An autoregulatory response occurred with an 11.8
             +/- 0.6-fold increase in sTNFRI shedding. Treatment with
             high doses of sTNFRII or ELP-sTNFRII reversed all changes.
             Values are expressed as the mean +/- standard deviation.
             Conclusions. These results demonstrate that TNFa stimulation
             of DRG explants yields a phenotype of neurotoxic metabolite
             release and inflammatory mediator expression. Coincubation
             with either sTNFRII or ELP-sTNFRII antagonizes TNFa activity
             to abrogate these changes, suggesting potential for
             therapeutic intervention to treat peripheral nerve
             inflammatory disease.},
   Key = {Shamji08a}
}

@booklet{Upton08,
   Author = {M. L. Upton and C. L. Gilchrist and F. Guilak and L. A.
             Setton},
   Title = {Transfer of macroscale tissue strain to microscale cell
             regions in the deformed meniscus},
   Journal = {Biophysical Journal},
   Volume = {95},
   Number = {4},
   Pages = {2116 -- 2124},
   Year = {2008},
   Month = {August},
   ISSN = {0006-3495},
   Abstract = {Cells within fibrocartilaginous tissues, including
             chondrocytes and fibroblasts of the meniscus, ligament, and
             tendon, regulate cell biosynthesis in response to local
             mechanical stimuli. The processes by which an applied
             mechanical load is transferred through the extracellular
             matrix to the environment of a cell are not fully
             understood. To better understand the role of mechanics in
             controlling cell phenotype and biosynthetic activity, this
             study was conducted to measure strain at different length
             scales in tissue of the fibrocartilaginous meniscus of the
             knee joint, and to de. ne a quantitative parameter that
             describes the strain transferred from the far-field tissue
             to a microenvironment surrounding a cell. Experiments were
             performed to apply a controlled uniaxial tensile deformation
             to explants of porcine meniscus containing live cells. Using
             texture correlation analyses of confocal microscopy images,
             two-dimensional Lagrangian and principal strains were
             measured at length scales representative of the tissue
             (macroscale) and microenvironment in the region of a cell
             (microscale) to yield a strain transfer ratio as a measure
             of median microscale to macroscale strain. The data
             demonstrate that principal strains at the microscale are
             coupled to and amplified from macroscale principal strains
             for a majority of cell microenvironments located across
             diverse microstructural regions, with average strain
             transfer ratios of 1.6 and 2.9 for the maximum and minimum
             principal strains, respectively. Lagrangian strain
             components calculated along the experimental axes of applied
             deformations exhibited considerable spatial heterogeneity
             and intersample variability, and suggest the existence of
             both strain amplification and attenuation. This feature is
             consistent with an in- plane rotation of the principal
             strain axes relative to the experimental axes at the
             microscale that may result from fiber sliding, fiber
             twisting, and fiber-matrix interactions that are believed to
             be important for regulating deformation in other
             fibrocartilaginous tissues. The findings for consistent
             amplification of macroscale to microscale principal strains
             suggest a coordinated pattern of strain transfer from
             applied deformation to the microscale environment of a cell
             that is largely independent of these microstructural
             features in the fibrocartilaginous meniscus.},
   Key = {Upton08}
}

@booklet{Nettles08,
   Author = {D. L. Nettles and K. Kitaoka and N. A. Hanson and C. M.
             Flahiff and B. A. Mata and E. W. Hsu and A. Chilkoti and L.
             A. Setton},
   Title = {In situ crosslinking elastin-like polypeptide gels for
             application to articular cartilage repair in a goat
             osteochondral defect model},
   Journal = {Tissue Engineering Part A},
   Volume = {14},
   Number = {7},
   Pages = {1133 -- 1140},
   Year = {2008},
   Month = {July},
   ISSN = {1937-3341},
   Abstract = {The objective of this study was to evaluate an injectable,
             in situ crosslinkable elastin-like polypeptide (ELP) gel for
             application to cartilage matrix repair in critically sized
             defects in goat knees. One cylindrical, osteochondral defect
             in each of seven animals was filled with an aqueous solution
             of ELP and a biocompatible, chemical crosslinker, while the
             contralateral defect remained unfilled and served as an
             internal control. Joints were sacrificed at 3 (n=3) or 6
             (n=4) months for MRI, histological, and gross evaluation of
             features of biomaterial performance, including integration,
             cellular infiltration, surrounding matrix quality, and new
             matrix in the defect. At 3 months, ELP-filled defects scored
             significantly higher for integration by histological and
             gross grading compared to unfilled defects. ELP did not
             impede cell infiltration but appeared to be partly degraded.
             At 6 months, new matrix in unfilled defects outpaced that in
             ELP-filled defects and scored significantly better for MRI
             evidence of adverse changes, as well as integration and
             proteoglycan-containing matrix via gross and histological
             grading. The ELP-crosslinker solution was easily delivered
             and formed stable, well-integrated gels that supported cell
             infiltration and matrix synthesis; however, rapid
             degradation suggests that ELP formulation modifications
             should be optimized for longer-term benefits in cartilage
             repair applications.},
   Key = {Nettles08}
}

@booklet{Shamji08b,
   Author = {M. F. Shamji and L. Whitlatch and A. H. Friedman and W. J.
             Richardson and A. Chilkoti and L. A. Setton},
   Title = {An injectable and in situ-gelling biopolymer for sustained
             drug release following perineural administration},
   Journal = {Spine},
   Volume = {33},
   Number = {7},
   Pages = {748 -- 754},
   Year = {2008},
   Month = {April},
   ISSN = {0362-2436},
   Abstract = {Study Design. This study evaluated whether the aggregation
             behavior of a thermally responsive elastin-like polypeptide
             (ELP) prolongs protein residence time at the dorsal root
             ganglion (DRG). This work involves development of a
             sustained-release drug delivery vehicle to provide high and
             sustained levels of biologic therapeutics to the dorsal root
             ganglion while minimizing systemic exposure. Objective. To
             study the potential of the ELP biopolymer to sustain release
             and lower systemic exposure of bioactive peptides following
             perineural administration. Summary of Background Data.
             Anticytokine treatment for lumbar radiculopathy may offer
             clinical improvement, but exposes patients to systemic
             toxicities of immunosuppression. ELPs are environmentally
             responsive polypeptides that undergo a phase transition on
             heating to form an insoluble aggregate. Drug conjugates with
             ELP exhibit both temperature-sensitivity and in vitro
             bioactivity. Monomer resolubilization yields solution-phase
             molecules, and this reversible aggregation behavior may
             create a perineural drug depot to sustain drug delivery to
             an inflamed nerve. Methods. This experiment involved 48 rats
             in which radiolabeled ELPs (aggregating or soluble) were
             injected overlying the L5 dorsal root ganglion. Animals were
             killed at 6 different time points, and radioactivity
             associated with the injected segment, serum, and other
             tissues was evaluated. Results. The aggregating ELP
             demonstrated a 7-fold longer perineural half-life compared
             with the soluble ELP. This supports the hypothesis that the
             aggregating ELP forms a depot from which slow
             resolubilization and clearance provides sustained, local
             protein release. Furthermore, serum radioactivity reached a
             lower peak for the aggregating group, demonstrating slower
             absorption of the aggregating protein into the systemic
             circulation. Conclusion. These results suggest that ELP
             aggregation confer the benefit of perineural compartment
             longevity for bioactive therapeutics delivered fused with
             this carrier. This may sustain release of potent
             immunomodulator therapeutics to treat local
             neuroinflammation. Desirable features include delivery of
             high local doses and protection against systemic exposure
             and associated toxicity.},
   Key = {Shamji08b}
}

@booklet{Boyd08,
   Author = {L. M. Boyd and W. J. Richardson and K. D. Allen and C.
             Flahiff and L. Jing and Y. Li and J. Chen and L. A.
             Setton},
   Title = {Early-onset degeneration of the intervertebral disc and
             vertebral end plate in mice deficient in type IX
             collagen},
   Journal = {Arthritis And Rheumatism},
   Volume = {58},
   Number = {1},
   Pages = {164 -- 171},
   Year = {2008},
   Month = {January},
   ISSN = {0004-3591},
   Abstract = {Objective. Type IX collagen is an important component of the
             intervertebral disc extracellular matrix. Mutations in type
             IX collagen are associated with premature disc degeneration
             in mice and a predisposition to disc disorders in humans.
             The aim of this study was to assess the prevalence and
             timeline of intervertebral disc degeneration in mice
             homozygous for an inactivated Col9a1 gene. Methods. Intact
             spine segments were harvested from wild-type (WT) and type
             IX collagen-knockout (Col9a1(-/-)) mice at 3, 6, and 12
             months of age. Sagittal spine sections were evaluated for
             evidence of histologic changes, by 2 blinded graders, using
             a semiquantitative grading method. Results. There was
             evidence of more degeneration of the disc and end plate in
             the spines of Col9a1(-/-) mice compared. with those of WT
             controls, at most time points. These findings were
             significant for the disc region at 3 and 6 months (P $<$
             0.01) and at 12 months (P $<$ 0.10) and for the end plate
             region only at 6 months (P $<$ 0.10). Degenerative changes
             in the disc consisted of cellular changes and mucous
             degeneration. Degeneration in the end plates was associated
             with more cell proliferation, cartilage disorganization, and
             new bone formation. Conclusion. A deletion mutation for type
             IX collagen is associated with connective tissue changes
             characteristic of musculoskeletal degeneration in bony and
             cartilaginous tissue regions. Some of the observed changes
             were similar to cartilage changes in osteoarthritis, while
             others were more similar to disc degenerative changes in
             humans. The finding of premature onset of intervertebral
             disc degeneration in this mouse model may be useful in
             studies of the pathology and treatment of human disc
             degeneration.},
   Key = {Boyd08}
}

@booklet{Lim08,
   Author = {D. W. Lim and D. L. Nettles and L. A. Setton and A.
             Chilkoti},
   Title = {In situ cross-linkinig of elastin-like polypeptide block
             copolymers for tissue repair},
   Journal = {Biomacromolecules},
   Volume = {9},
   Number = {1},
   Pages = {222 -- 230},
   Year = {2008},
   Month = {January},
   ISSN = {1525-7797},
   Abstract = {Rapid cross-linking of elastin-like polypeptides (ELPs) with
             hydroxymethylphosphines (HMPs) in aqueous solution is
             attractive for minimally invasive in vivo implantation of
             biomaterials and tissue engineering scaffolds. In order to
             examine the independent effect of the location and number of
             reactive sites on the chemical cross-linking kinetics of
             ELPs and the mechanical properties of the resulting
             hydrogels, we have designed ELP block copolymers comprised
             of cross-linkable, hydrophobic ELP blocks with periodic Lys
             residues (A block) and aliphatic, hydrophilic ELP blocks
             with no cross-linking sites (B block); three different block
             architectures, A, ABA, and BABA were synthesized in this
             study. All ELP block copolymers were rapidly cross-linked
             with HMPs within several minutes under physiological
             conditions. The inclusion of the un-cross-linked hydrophilic
             block, its length relative to the cross-linkable hydrophobic
             block, and the block copolymer architecture all had a
             significant effect on swelling ratios of the cross-linked
             hydrogels, their microstructure, and mechanical properties.
             Fibroblasts embedded in the ELP hydrogels survived the
             cross-linking process and remained viable for at least 3
             days in vitro when the gels were formed from an equimolar
             ratio of HMPs and Lys residues of ELPs. DNA quantification
             of the embedded cells indicated that the cell viability
             within triblock ELP hydrogels was statistically greater than
             that in the monoblock gels at day 3. These results suggest
             that the mechanical properties of ELP hydrogels and the
             microenvironment that they present to cells can be tuned by
             the design of the block copolymer architecture.},
   Key = {Lim08}
}

@booklet{Shamji07,
   Author = {M. F. Shamji and H. Betre and V. B. Kraus and J. Chen and A.
             Chilkoti and R. Pichika and K. Masuda and L. A.
             Setton},
   Title = {Development and characterization of a fusion protein between
             thermally responsive elastin-like polypeptide and
             interleukin-1 receptor antagonist - Sustained release of a
             local antiinflammatory therapeutic},
   Journal = {Arthritis And Rheumatism},
   Volume = {56},
   Number = {11},
   Pages = {3650 -- 3661},
   Year = {2007},
   Month = {November},
   ISSN = {0004-3591},
   Abstract = {Objective. Interleukin-1 receptor antagonist (IL-1Ra) has
             been evaluated for the intraarticular treatment of
             osteoarthritis. Such administration of proteins may have
             limited utility because of their rapid clearance and short
             half-life in the joint. The fusion of a drug to elastin-like
             polypeptides (ELPs) promotes the formation of aggregating
             particles that form a "drug depot" at physiologic
             temperatures, a phenomenon intended to prolong the presence
             of the drug. The purpose of this study was to develop an
             injectable drug depot composed of IL-1Ra and ELP domains and
             to evaluate the properties and bioactivity of the
             recombinant ELP-IL-1Ra fusion protein. Methods. Fusion
             proteins between IL-1Ra and 2 distinct sequences and
             molecular weights of ELP were overexpressed in Escherichia
             coli. Environmental sensitivity was demonstrated by
             turbidity and dynamic light scattering as a function of
             temperature. IL-1Ra domain activity was evaluated by surface
             plasmon resonance, and in vitro antagonism of IL-1-mediated
             lymphocyte and thymocyte proliferation, as well as
             IL-1-induced tumor necrosis factor alpha (TNF alpha)
             expression and matrix metalloproteinase 3 (MMP-3) and
             ADAMTS-4 messenger RNA expression in human intervertebral
             disc fibrochondrocytes. IL-1Ra immunoreactivity was assessed
             before and after proteolytic degradation of the ELP partner.
             Results. Both fusion proteins underwent supramolecular
             aggregation at subphysiologic temperatures and slowly
             resolubilized at 37 degrees C. Interaction with IL-1
             receptor was slower in association but equivalent in
             dissociation as compared with the commercial antagonist.
             Anti-IL-1 activity was demonstrated by inhibition of
             lymphocyte and thymocyte proliferation and by decreased TNFa
             expression and ADAMTS-4 and MMP-3 transcription by
             fibrochondrocytes. ELP domain proteolysis liberated a
             peptide of comparable size and immunoreactivity as the
             commercial IL-1Ra. This peptide was more bioactive against
             lymphocyte proliferation, nearly equivalent to the
             commercial antagonist. Conclusion. The ELP-IL-1Ra fusion
             protein proved to retain the characteristic ELP inverse
             phase-transitioning behavior as well as the bioactivity of
             the IL-1Ra domain. This technology represents a novel drug
             carrier designed to prolong the presence of bioactive
             peptides following intraarticular delivery.},
   Key = {Shamji07}
}

@booklet{Cao07,
   Author = {L. Cao and F. Guilak and L. A. Setton},
   Title = {Three-dimensional morphology of the pericellular matrix of
             intervertebral disc cells in the rat},
   Journal = {Journal Of Anatomy},
   Volume = {211},
   Number = {4},
   Pages = {444 -- 452},
   Year = {2007},
   Month = {October},
   ISSN = {0021-8782},
   Abstract = {Intervertebral disc cells are surrounded by a pericellular
             matrix that is biochemically and morphologically distinct
             from other extracellular matrix regions. Although the
             function of the pericellular matrix is not fully understood,
             prior studies of pericellular matrix-chondrocyte regions in
             articular cartilage (termed 'chondrons') suggest that the
             size, shape, and mechanical properties of the pericellular
             matrix significantly influence the micromechanical
             environment of the contained cells. A first step in
             understanding the role of the pericellular matrix in the
             intervertebral disc is to quantify the three-dimensional
             morphology and zonal variations of these regions across the
             disc. In this study, three-dimensional reconstructions and
             morphometric measurements of pericellular matrix-cell
             regions were obtained in situ using fluorescence confocal
             microscopy of en bloc sections of nucleus pulposus and
             anulus fibrosus of the rat disc immunolabeled for type VI
             collagen. The morphology of the pericellular matrix and
             cells varied significantly across regions, with distinct
             pericellular matrix aspect ratios (largest/smallest
             diameter) showing shapes that were generally large and
             rounded in the nucleus pulposus (average of 1.9), and
             ellipsoidal and discoidal in the inner (2.4) and outer
             anulus fibrosus (2.8). The average pericellular matrix
             volume per cell was found to be significantly larger in the
             nucleus (6424 mu m(3)) than that of inner (1903 mu m(3)) and
             outer (1433 mu m(3)) anulus. Pericellular matrix regions
             containing 1 or 2 cells were the dominant subgroup in the
             rat intervertebral disc at both 1 and 12 months of age.
             Multicellular pericellular matrix regions were present more
             often in the younger nucleus pulposus and outer anulus
             fibrosus. The orientation of the pericellular matrix regions
             further varied significantly across the disc, reflecting
             local collagen matrix architecture. These studies provide
             new information on the organization and shape of
             intervertebral disc cells and their surrounding pericellular
             matrix, which may provide new insights into the mechanisms
             that regulate cell-matrix interactions.},
   Key = {Cao07}
}

@booklet{Roberts07,
   Author = {S. K. Roberts and A. Chilkoti and L. A. Setton},
   Title = {Multifunctional thermally transitioning oligopeptides
             prepared by ring-opening metathesis polymerization},
   Journal = {Biomacromolecules},
   Volume = {8},
   Number = {8},
   Pages = {2618 -- 2621},
   Year = {2007},
   Month = {August},
   ISSN = {1525-7797},
   Key = {Roberts07}
}

@booklet{Gilchrist07,
   Author = {C. L. Gilchrist and J. Chen and W. J. Richardson and R. F.
             Loeser and L. A. Setton},
   Title = {Functional integrin subunits regulating cell-matrix
             interactions in the intervertebral disc},
   Journal = {Journal Of Orthopaedic Research},
   Volume = {25},
   Number = {6},
   Pages = {829 -- 840},
   Year = {2007},
   Month = {June},
   ISSN = {0736-0266},
   Abstract = {Cellular interactions with the extracellular matrix are key
             factors regulating cell survival, differentiation, and
             response to environmental stimuli in cartilagenous tissues.
             Much is known about the extracellular matrix proteins in the
             intervertebral disc (IVD) and their variations with region,
             age, or degenerative state of the tissue. In contrast,
             little is known of the integrin cell surface receptors that
             directly bind to and interact with these matrix proteins in
             the IVD. In almost all tissues, these integrin-mediated
             cell-matrix interactions are important for transducing
             environmental cues arising from mechanical stimuli, matrix
             degradation fragments, and cytokines into intracellular
             signals. In this study, cells from the nucleus pulposus and
             anulus fibrosus regions of porcine IVDs were analyzed via
             flow cytometry to quantify integrin expression levels upon
             isolation and after monolayer culture. Assays of cell
             attachment to collagens, fibronectin, and laminin were
             performed after functional blocking of select integrin
             subunits to evaluate the role of specific integrins in cell
             attachment. In situ distribution and co-localization of
             integrins and laminin were also characterized. Results
             identify integrin receptors critical for IVD cell
             interactions with collagens (alpha 1 beta 1) and fibronectin
             (alpha 5 beta 1). Additionally, dramatic differences in
             cell-laminin interactions were observed between cells of the
             nucleus and anulus regions, including differences in alpha 6
             integrin expression, cell adhesion to laminin, and in situ
             pericellular environments. These findings suggest
             laminin-cell interactions may be important and unique to the
             nucleus pulposus region of the IVD. The results of this
             study provide new information on functional cell-matrix
             interactions in tissues of the IVD. (C) 2007 Orthopaedic
             Research Society. Published by Wiley Periodicals,
             Inc.},
   Key = {Gilchrist07}
}

@booklet{Lim07,
   Author = {D. W. Lim and D. L. Nettles and L. A. Setton and A.
             Chilkoti},
   Title = {Rapid cross-linking of elastin-like polypeptides with
             (hydroxymethyl)phosphines in aqueous solution},
   Journal = {Biomacromolecules},
   Volume = {8},
   Number = {5},
   Pages = {1463 -- 1470},
   Year = {2007},
   Month = {May},
   ISSN = {1525-7797},
   Abstract = {In situ gelation of injectable polypeptide-based materials
             is attractive for minimally invasive in vivo implantation of
             biomaterials and tissue engineering scaffolds. We
             demonstrate that chemically cross-linked elastin-like
             polypeptide (ELP) hydrogels can be rapidly formed in aqueous
             solution by reacting lysine-containing ELPs with an
             organophosphorous cross-linker, beta-[tris(hydroxymethyl)phosphino]propionic
             acid (THPP) under physiological conditions. The mechanical
             properties of the cross-linked ELP hydrogels were largely
             modulated by the molar concentration of lysine residues in
             the ELP and the pH at which the cross-linking reaction was
             carried out. Fibroblasts embedded in ELP hydrogels survived
             the cross-linking process and were viable after in vitro
             culture for 3 days. DNA quantification of ELP hydrogels with
             encapsulated fibroblasts indicated that there was no
             significant difference in DNA content between day 0 and day
             3 when ELP hydrogels were formed with an equimolar ratio of
             THPP and lysine residues of the ELPs. These results suggest
             that THPP cross-linking may be a biocompatible strategy for
             the in situ formation of cross-linked hydrogels.},
   Key = {Lim07}
}

@booklet{Choi07,
   Author = {J. B. Choi and I. Youn and L. Cao and H. A. Leddy and C. L.
             Gilchrist and L. A. Setton and F. Guilak},
   Title = {Zonal changes in the three-dimensional morphology of the
             chondron under compression: The relationship among cellular,
             pericellular, and extracellular deformation in articular
             cartilage},
   Journal = {Journal Of Biomechanics},
   Volume = {40},
   Number = {12},
   Pages = {2596 -- 2603},
   Year = {2007},
   ISSN = {0021-9290},
   Abstract = {The pericellular matrix (PCM) is a narrow region of tissue
             that completely surrounds chondrocytes in articular
             cartilage. Previous theoretical models of the "chondron"
             (the PCM with enclosed cells) suggest that the structure and
             properties of the PCM may significantly influence the
             mechanical environment of the chondrocyte. The objective of
             this study was to quantify changes in the three-dimensional
             (31) morphology of the chondron in situ at different
             magnitudes of compression applied to the cartilage
             extracellular matrix. Fluorescence immunolabeling for
             type-VI collagen was used to identify the boundaries of the
             cell and PCM, and confocal microscopy was used to form 3D
             images of chondrons from superficial, middle, and deep zone
             cartilage in explants compressed to 0\%, 10\%, 30\%, and
             50\% surface-to-surface strain. Lagrangian tissue strain,
             determined locally using texture correlation, was highly
             inhomogeneous and revealed depth-dependent compressive
             stiffness and Poisson's ratio of the extracellular matrix.
             Compression significantly decreased cell and chondron height
             and volume, depending on the zone and magnitude of
             compression. In the superficial zone, cellular-level strains
             were always lower than tissue-level strains. In the middle
             and deep zones, however, tissue strains below 25\% were
             amplified at the cellular level, while tissue strains above
             25\% were decreased at the cellular level. These findings
             are consistent with previous theoretical models of the
             chondron, suggesting that the PCM can serve as either a
             protective layer for the chondrocyte or a transducer that
             amplifies strain, such that cellular-level strains are more
             homogenous throughout the tissue depth despite large
             inhomogeneities in local ECM strains. (c) 2007 Elsevier Ltd.
             All rights reserved.},
   Key = {Choi07}
}

@booklet{Gilchrist07a,
   Author = {C. L. Gilchrist and S. W. Witvoet-braam and F. Guilak and L.
             A. Setton},
   Title = {Measurement of intracellular strain on deformable substrates
             with texture correlation},
   Journal = {Journal Of Biomechanics},
   Volume = {40},
   Number = {4},
   Pages = {786 -- 794},
   Year = {2007},
   ISSN = {0021-9290},
   Abstract = {Mechanical stimuli are important factors that regulate cell
             proliferation, survival, metabolism and motility in a
             variety of cell types. The relationship between mechanical
             deformation of the extracellular matrix and intracellular
             deformation of cellular sub-regions and organelles has not
             been fully elucidated, but may provide new insight into the
             mechanisms involved in transducing mechanical stimuli to
             biological responses. In this study, a novel fluorescence
             microscopy and image analysis method was applied to examine
             the hypothesis that mechanical strains are fully transferred
             from a planar, deformable substrate to cytoplasmic and
             intranuclear regions within attached cells. Intracellular
             strains were measured in cells derived from the anulus
             fibrosus of the intervertebral disc when attached to an
             elastic silicone membrane that was subjected to tensile
             stretch. Measurements indicated cytoplasmic strains were
             similar to those of the underlying substrate, with a strain
             transfer ratio (STR) of 0.79. In contrast, nuclear strains
             were much smaller than those of the substrate, with an STR
             of 0.17. These findings are consistent with previous studies
             indicating nuclear stiffness is significantly greater than
             cytoplasmic stiffness, as measured using other methods. This
             study provides a novel method for the study of cellular
             mechanics, including a new technique for measuring
             intranuclear deformations, with evidence of differential
             magnitudes and patterns of strain transferred from the
             substrate to cell cytoplasm and nucleus. (c) 2006 Elsevier
             Ltd. All rights reserved.},
   Key = {Gilchrist07a}
}

@booklet{Betre06,
   Author = {H. Betre and W. Liu and M. R. Zalutsky and A. Chilkoti and V. B. Kraus and L. A. Setton},
   Title = {A thermally responsive biopolymer for intra-articular drug
             delivery},
   Journal = {Journal Of Controlled Release},
   Volume = {115},
   Number = {2},
   Pages = {175 -- 182},
   Year = {2006},
   Month = {October},
   ISSN = {0168-3659},
   Abstract = {Intra-articular drug delivery is the preferred standard for
             targeting pharmacologic treatment directly to joints to
             reduce undesirable side effects associated with systemic
             drug delivery. In this study, a biologically based drug
             delivery vehicle was designed for intra-articular drug
             delivery using elastin-like polypeptides (ELPs), a
             biopolymer composed of repeating pentapeptides that undergo
             a phase transition to form aggregates above their transition
             temperature. The ELP drug delivery vehicle was designed to
             aggregate upon intra-articular injection at 37 degrees C,
             and form a drug 'depot' that could slowly disaggregate and
             be cleared from the joint space over time. We evaluated the
             in vivo biodistribution and joint half-life of radiolabeled
             ELPs, with and without the ability to aggregate, at
             physiological temperatures encountered after intra-articular
             injection in a rat knee. Biodistribution studies revealed
             that the aggregating ELP had a 25-fold longer half-life in
             the injected joint than a similar molecular weight protein
             that remained soluble and did not aggregate. These results
             suggest that the intra-articular joint delivery of ELP-based
             fusion proteins may be a viable strategy for the prolonged
             release of disease-modifying protein drugs for
             ostcoarthritis and other arthritides. (c) 2006 Elsevier B.V.
             All rights reserved.},
   Key = {Betre06}
}

@booklet{Cao06,
   Author = {L. Cao and I. Youn and F. Guilak and L. A.
             Setton},
   Title = {Compressive properties of mouse articular cartilage
             determined in a novel micro-indentation test method and
             biphasic finite element model},
   Journal = {Journal Of Biomechanical Engineering-transactions Of The
             Asme},
   Volume = {128},
   Number = {5},
   Pages = {766 -- 771},
   Year = {2006},
   Month = {October},
   ISSN = {0148-0731},
   Abstract = {The mechanical Properties of articular cartilage serve as
             important measures of tissue function or degeneration, and
             are known to change significantly with osteoarthritis.
             Interest in small animal and mouse models of osteoarthritis
             has increased as studies reveal the importance of genetic
             background in determining predisposition to osteoarthritis.
             While indentation testing provides a method of determining
             cartilage mechanical properties in situ, it has been of
             limited value in studying mouse joints due to the relatively
             small size of the joint and thickness of the cartilage layer
             In this study, we developed a micro-indentation testing
             system to determine the compressive and biphasic mechanical
             properties of cartilage in the small joints of the mouse. A
             nonlinear optimization program employing a genetic algorithm
             for parameter estimation, combined with a biphasic finite
             element model of the micro-indentation test, was developed
             to obtain the biphasic, compressive material properties of
             articular cartilage. The creep response and material
             properties of lateral tibial plateau cartilage were obtained
             for wild-type mouse knee joints, by the micro-indentation
             testing and optimization algorithm. The newly developed
             genetic algorithm was found to be efficient and accurate
             when used with the finite element simulations for nonlinear
             optimization to the experimental creep data. The biphasic
             mechanical properties of mouse cartilage in compression
             (average values: Young's modulus, 2.0 MPa; Poisson's ratio,
             0.20; and hydraulic permeability, 1.1 X 10(-16) m(4) /N-s)
             were found to be of similar orders of magnitude as previous
             findings for other animal cartilages, including human,
             bovine, rat, and rabbit and demonstrate the utility of the
             new test methods. This study provides the first available
             data for biphasic compressive properties in mouse cartilage
             and suggests a promising method for detecting altered
             cartilage mechanics in small animal models of
             osteoarthritis.},
   Key = {Cao06}
}

@booklet{Youn06,
   Author = {I. Youn and J. B. Choi and L. Cao and L. A. Setton and F.
             Guilak},
   Title = {Zonal variations in the three-dimensional morphology of the
             chondron measured in situ using confocal
             microscopy},
   Journal = {Osteoarthritis And Cartilage},
   Volume = {14},
   Number = {9},
   Pages = {889 -- 897},
   Year = {2006},
   Month = {September},
   ISSN = {1063-4584},
   Abstract = {Objective: Chondrocytes in articular cartilage are
             surrounded by a narrow pericellular matrix (PCM), which
             together with the enclosed cell(s) are termed the
             "chondron". Although the precise function of this tissue
             region is unknown, previous studies provide indirect
             evidence that the PCM plays an important role in governing
             the local mechanical environment of chondrocytes. In
             particular, theoretical models of the chondron under
             mechanical loading suggest that the shape, size, and
             biomechanical properties of the PCM significantly influence
             the stress-strain and fluid flow environment of the cell.
             The goal of this study was to quantify the three-dimensional
             morphology of chondron in situ using en bloc immunolabeling
             of type VI collagen coupled with fluorescence confocal
             microscopy. Methods: Three-dimensional reconstructions of
             intact, fluorescently labeled chondrons were made from
             stacks of confocal images recorded in situ from the
             superficial, middle, and deep zones of porcine articular
             cartilage of the medial femoral condyle. Results:
             Significant variations in the shape, size, and orientation
             of chondrocytes and chondrons were observed with depth from
             the tissue surface, revealing flattened discoidal chondrons
             in the superficial zone, rounded chondrons in the middle
             zone, and elongated, multicellular chondrons in the deep
             zone. Conclusions: The shape and orientation of the chondron
             appear to reflect the local collagen architecture of the
             interterritorial matrix, which varies significantly with
             depth. Quantitative measurements of morphology of the
             chondron and its variation with site, disease, or aging may
             provide new insights into the influence of this structure on
             physiology and the pathology of articular cartilage. (C)
             2006 OsteoArthritis Research Society International.
             Published by Elsevier Ltd. All rights reserved.},
   Key = {Youn06}
}

@booklet{Hu06,
   Author = {K. Hu and L. Xu and L. Cao and C. M. Flahiff and J. Brussiau and K. Ho and L. A. Setton and I. Youn and F. Guilak and B.
             R. Olsen and Y. Li},
   Title = {Pathogenesis of osteoarthritis-like changes in the joints of
             mice deficient in type IX collagen},
   Journal = {Arthritis And Rheumatism},
   Volume = {54},
   Number = {9},
   Pages = {2891 -- 2900},
   Year = {2006},
   Month = {September},
   ISSN = {0004-3591},
   Abstract = {Objective. To examine the pathogenetic mechanisms of
             osteoarthritis (OA)-like changes in Col9a1(-/-) mice, which
             are deficient in type IX collagen. Methods. Knee joints and
             temporomandibular joints (TMJs) from Col9a1(-/-) mice and
             their wild-type (Col9a1(+/+)) littermates were examined by
             light microscopy. Immunohistochemical staining was performed
             to examine the expression of matrix metalloproteinase 3
             (MMP-3) and MMP-13, degraded type II collagen, and the
             discoidin domain receptor 2 (DDR-2) in knee joints.
             Cartilage mechanics were also evaluated for compressive
             properties by microindentation testing of the tibial plateau
             and for tensile properties by osmotic loading of the femoral
             condyle. Results. Histologic analysis showed age-dependent
             OA-like changes in the knee and TMJs of Col9a1(-/-) mice
             starting at the age of 3 months. At the age of 6 months,
             enhanced proteoglycan degradation was observed in the
             articular cartilage of the knee and TMJs of the mutant mice.
             The expression of MMP-13 and DDR-2 protein and the amount of
             degraded type II collagen were higher in the knee joints of
             Col9a1(-/-) mice than in their wild-type littermates at the
             age of 6 months. Changes in cartilage mechanics were
             observed in the femoral and tibial plateaus of Col9a1(-/-)
             mice at 6 months, including a decrease in the compressive
             modulus and uniaxial modulus. At 3 and 6 months of age,
             tibial cartilage in Col9a1(-/-) mice was found to be more
             permeable to fluid flow, with an associated compromise in
             the fluid pressurization mechanism of load support. All of
             these changes occurred only at medial sites. Conclusion.
             Lack of type IX collagen in Col9a1(-/-) mice results in
             age-dependent OA-like changes in the knee joints and
             TMJs.},
   Key = {Hu06}
}

@booklet{Chen06,
   Author = {J. Chen and W. Yan and L. A. Setton},
   Title = {Molecular phenotypes of notochordal cells purified from
             immature nucleus pulposus},
   Journal = {European Spine Journal},
   Volume = {15},
   Pages = {S303 -- S311},
   Year = {2006},
   Month = {August},
   ISSN = {0940-6719},
   Abstract = {The immature nucleus pulposus (NP) is populated by cells of
             notochordal-origin that are larger and contain an extensive
             cytoskeletal network and numerous vacuoles. The
             disappearance of these cells with age is believed important
             in regulating metabolic shifts that may contribute to
             age-related disc degeneration. The precise biological
             function of these notochordal cells in the immature NP
             remains unclear, however, because of challenges in studying
             the mixed cell population in the NP. In this study,
             notochordal-like cells were purified from immature NP cells
             using a new fluorescence-activated cell sorting (FACS)
             protocol with auto-fluorescence and size analysis. The
             unique molecular phenotypes of sorted notochordal-like cells
             were characterized by the mRNA expression pattern for key
             matrix proteins and modulators, and by the expression of
             cell matrix receptor integrin subunits. An FACS analysis
             showed that the immature NP contained a majority of cells
             that were larger than anulus fibrosus (AF) cells and with
             fluorescence higher than AF cells. In comparison with the
             small NP cells separated by the FACS protocol, sorted
             notochordal-like cells expressed lower mRNA levels of type I
             collagen, biglycan, TIMP1, HSP70 and c-fos, and did not
             express detectable mRNA levels of decorin, lumican, multiple
             MMPs or IL-1 beta via real-time quantitative RT-PCR. A
             greater number of these notochordal-like cells also
             expressed the higher levels of alpha 6, alpha 1 and beta 1
             integrin subunits as compared to small NP cells. Together,
             our results point towards a unique molecular phenotype for
             these notochordal-like cells of NP, characterized by the
             absence of gene expression for specific small proteoglycans
             and higher protein expression of integrin subunits that
             regulate interactions with collagens and laminin. Future
             studies will be important for revealing if this unique
             molecular profile is coordinated with functional differences
             in pericellular matrix regions and/or tritegrin-mediated
             cell-matrix interactions for these notochordal-like cells
             within the NP.},
   Key = {Chen06}
}

@booklet{Upton06a,
   Author = {M. L. Upton and J. Chen and L. A. Setton},
   Title = {Region-specific constitutive gene expression in the adult
             porcine meniscus},
   Journal = {Journal Of Orthopaedic Research},
   Volume = {24},
   Number = {7},
   Pages = {1562 -- 1570},
   Year = {2006},
   Month = {July},
   ISSN = {0736-0266},
   Abstract = {The knee meniscus exhibits extensive spatial variations in
             native healing capacity, biochemical composition, and cell
             morphology that suggest the existence of distinct phenotypes
             for meniscus cells. Constitutive gene expression levels of
             appropriate extracellular matrix proteins may serve as
             useful molecular markers of cellular phenotypes; however,
             relatively little is known of variations in the gene
             expression for meniscus cells of different regions of the
             tissue. The objective of the present study was to evaluate
             constitutive differences between radial inner and outer
             regions in gene expression for extracellular matrix proteins
             relevant to the meniscus. A secondary objective was to
             determine if these region-specific differences in gene
             expression are maintained after periods of monolayer
             culture. The innermost regions of the meniscus were found to
             constitutively express higher mRNA levels for proteins
             highly expressed in articular cartilage, including aggrecan,
             type 11 collagen, and NOS2. In contrast, the outer meniscus
             was found to contain higher gene expression for proteins
             associated with fibrous tissues including type I collagen,
             and the proteases MMP2 and MMP3. Isolated inner and outer
             meniscus cells maintained these region-specific gene
             expression patterns for collagens and proteoglycans during
             short-term monolayer culture. The results provide new
             information that suggests the utility of constitutive gene
             expression levels as molecular markers to distinguish tissue
             and cells of the inner and outer meniscus. (c) 2006
             Orthopaedic Research Society. Published by Wiley
             Periodicals, Inc.},
   Key = {Upton06a}
}

@booklet{Upton06b,
   Author = {M. L. Upton and F. Guilak and T. A. Laursen and L. A.
             Setton},
   Title = {Finite element modeling predictions of region-specific
             cell-matrix mechanics in the meniscus},
   Journal = {Biomechanics And Modeling In Mechanobiology},
   Volume = {5},
   Number = {2-3},
   Pages = {140 -- 149},
   Year = {2006},
   Month = {June},
   ISSN = {1617-7959},
   Abstract = {The knee meniscus exhibits significant spatial variations in
             biochemical composition and cell morphology that reflect
             distinct phenotypes of cells located in the radial inner and
             outer regions. Associated with these cell phenotypes is a
             spatially heterogeneous microstructure and mechanical
             environment with the innermost regions experiencing higher
             fluid pressures and lower tensile strains than the outer
             regions. It is presently unknown, however, how meniscus
             tissue mechanics correlate with the local micromechanical
             environment of cells. In this study, theoretical models were
             developed to study mechanics of inner and outer meniscus
             cells with varying geometries. The results for an applied
             biaxial strain predict significant regional differences in
             the cellular mechanical environment with evidence of tensile
             strains along the collagen fiber direction of similar to
             0.07 for the rounded inner cells, as compared to levels of
             0.02-0.04 for the elongated outer meniscus cells. The
             results demonstrate an important mechanical role of
             extracellular matrix anisotropy and cell morphology in
             regulating the region-specific micromechanics of meniscus
             cells, that may further play a role in modulating cellular
             responses to mechanical stimuli.},
   Key = {Upton06b}
}

@booklet{Haider06,
   Author = {M. A. Haider and R. C. Schugart and L. A. Setton and F.
             Guilak},
   Title = {A mechano-chemical model for the passive swelling response
             of an isolated chondron under osmotic loading},
   Journal = {Biomechanics And Modeling In Mechanobiology},
   Volume = {5},
   Number = {2-3},
   Pages = {160 -- 171},
   Year = {2006},
   Month = {June},
   ISSN = {1617-7959},
   Abstract = {The chondron is a distinct structure in articular cartilage
             that consists of the chondrocyte and its pericellular matrix
             (PCM), a narrow tissue region surrounding the cell that is
             distinguished by type VI collagen and a high
             glycosaminoglycan concentration relative to the
             extracellular matrix. We present a theoretical
             mechano-chemical model for the passive volumetric response
             of an isolated chondron under osmotic loading in a simple
             salt solution at equilibrium. The chondrocyte is modeled as
             an ideal osmometer and the PCM model is formulated using
             triphasic mixture theory. A mechano-chemical chondron model
             is obtained assuming that the chondron boundary is permeable
             to both water and ions, while the chondrocyte membrane is
             selectively permeable to only water. For the case of a
             neo-Hookean PCM constitutive law, the model is used to
             conduct a parametric analysis of cell and chondron
             deformation under hyper- and hypo-osmotic loading. In
             combination with osmotic loading experiments on isolated
             chondrons, model predictions will aid in determination of
             pericellular fixed charge density and its relative
             contribution to PCM mechanical properties.},
   Key = {Haider06}
}

@booklet{Andersson06,
   Author = {G. B. J. Andersson and H. S. An and T. R. Oegema and L. A.
             Setton},
   Title = {Intervertebral disc degeneration - Summary of an
             AAOS/NIH/ORS Workshop, September 2005},
   Journal = {Journal Of Bone And Joint Surgery-american
             Volume},
   Volume = {88A},
   Number = {4},
   Pages = {895 -- 899},
   Year = {2006},
   Month = {April},
   ISSN = {0021-9355},
   Key = {Andersson06}
}

@booklet{Ong06,
   Author = {S. R. Ong and K. A. Trabbic-carlson and D. L. Nettles and D.
             W. Lim and A. Chilkoti and L. A. Setton},
   Title = {Epitope tagging for tracking elastin-like
             polypeptides},
   Journal = {Biomaterials},
   Volume = {27},
   Number = {9},
   Pages = {1930 -- 1935},
   Year = {2006},
   Month = {March},
   ISSN = {0142-9612},
   Abstract = {Elastin-like polypeptides (ELPs) are a class of
             biocompatible, non-immunogenic and crosslinkable
             biomaterials that offer promise for use as an injectable
             scaffold for cartilage repair. In this study, an
             oligohistidine (His(6)) epitope tag was incorporated at the
             N-terminus of an ELP using recombinant DNA techniques to
             permit tracking without compromising on material
             biocompatibility. His(6)-tagged ELPs were successfully
             detected by Western blot analysis and quantified by ELISAs
             following digestion with trypsin. The mass of His(6) tagged
             ELP fragments freed from a crosslinked ELP hydrogel after
             digestion with trypsin correlated highly with hydrogel
             weight loss, providing evidence of the tag's capability to
             enable tracking of enzymatic degradation of the ELP
             hydrogel. The His(6) tag also facilitated recognition of
             crosslinked ELPs from background staining of articular
             cartilage. These results suggest that the His(6) epitope tag
             has the potential to track ELP scaffold loss independently
             of newly formed tissue mass for evaluating matrix remodeling
             in vivo. (C) 2005 Elsevier Ltd. All rights
             reserved.},
   Key = {Ong06}
}

@booklet{Hyun06,
   Author = {J. H. Hyun and J. Chen and L. A. Setton and A.
             Chilkoti},
   Title = {Patterning cells in highly deformable micro structures:
             Effect of plastic deformation of substrate on cellular
             phenotype and gene expression},
   Journal = {Biomaterials},
   Volume = {27},
   Number = {8},
   Pages = {1444 -- 1451},
   Year = {2006},
   Month = {March},
   ISSN = {0142-9612},
   Abstract = {We describe the fabrication of deformable microstructures by
             low-pressure-soft-microembossing (mu SEmb) that provides in
             vitro experimental "test-beds" to investigate the interplay
             of mechanical and chemical stimuli on cell behavior in a
             highly controlled environment. Soft microembossing exploits
             the softness and plasticity of parafilm to fabricate
             microstructures by pressing a silicon master or an
             elastomeric poly(dimethylsiloxane) stamp into the parafilm.
             We demonstrate that a protein-resistant comb polymer can be
             printed into the raised features of the embossed micro
             structures, which imparts protein, and hence cell resistance
             to those regions of the microstructures. These two features
             of our fabrication methodology-microembossing followed by
             spatially selective transfer of a nonfouling polymer-forms
             the core of our strategy to pattern cells within the
             parafilm microstructures, such that the cells are confined
             within bottoms of the microstructures. Cell culture
             experiments demonstrated the preferential cell attachment of
             NIH 3T3 fibroblasts to the fibronectin (FN) micropatterns by
             immunofluorescence microscopy. The actin cytoskeleton
             realigned along the axis of applied mechanical stress, and
             stretched cells showed altered gene expression of
             cytoskeletal and matrix proteins in response to mechanical
             deformation. The use of parafilm as a substrate and mu SEmb
             as a fabrication method provides a simple and widely
             accessible methodology to investigate cellular behavior
             tinder well-defined conditions of plastic deformation and
             surface ligand density. (c) 2005 Elsevier Ltd. All rights
             reserved.},
   Key = {Hyun06}
}

@booklet{Sontjens06,
   Author = {S. H. M. Sontjens and D. L. Nettles and M. A. Carnahan and L. A. Setton and M. W. Grinstaff},
   Title = {Biodendrimer-based hydrogel scaffolds for cartilage tissue
             repair},
   Journal = {Biomacromolecules},
   Volume = {7},
   Number = {1},
   Pages = {310 -- 316},
   Year = {2006},
   Month = {January},
   ISSN = {1525-7797},
   Abstract = {Photo-crosslinkable dendritic macromolecules are attractive
             materials for the preparation of cartilage tissue
             engineering scaffolds that may be optimized for in situ
             formation of hydrated, mechanically stable, and
             wellintegrated hydrogel scaffolds supporting chondrocytes
             and chondrogenesis. We designed and synthesized a novel
             hydrogel scaffold for cartilage repair, based on a
             multivalent and water-soluble tri-block copolymer consisting
             of a poly(ethylene glycol) core and methacrylated
             poly(glycerol succinic acid) dendrimer terminal blocks. The
             terminal methacrylates allow mild and biocompatible
             photo-crosslinking with a visible light, facilitating in
             vivo filling of irregularly shaped defects with the
             dendrimer-based scaffold. The multivalent dendrimer
             constituents allow high crosslink densities that inhibit
             swelling after crosslinking while simultaneously introducing
             biodegradation sites. The mechanical properties and water
             content of the hydrogel can easily be tuned by changing the
             biodendrimer concentration. In vitro chondrocyte
             encapsulation studies demonstrate significant synthesis of
             neocartilaginous material, containing proteoglycans and type
             11 collagen.},
   Key = {Sontjens06}
}

@booklet{Setton06,
   Author = {L. A. Setton and J. Chen},
   Title = {Mechanobiology of the intervertebral disc and relevance to
             disc degeneration},
   Journal = {Journal Of Bone And Joint Surgery-american
             Volume},
   Volume = {88A},
   Pages = {52 -- 57},
   Year = {2006},
   ISSN = {0021-9355},
   Abstract = {Mechanical loading of the intervertebral disc may contribute
             to disc degeneration by initiating degeneration or by
             regulating cell-mediated remodeling events that occur in
             response to the mechanical stimuli of daily activity. This
             article is a review of the current knowledge of the role of
             mechanical stimuli in regulating intervertebral disc
             cellular responses to loading and the cellular changes that
             occur with degeneration. Intervertebral disc cells exhibit
             diverse biologic responses to mechanical stimuli, depending
             on the loading type, magnitude, duration, and anatomic zone
             of cell origin. The innermost cells respond to
             low-to-moderate magnitudes of static compression, osmotic
             pressure, or hydrostatic pressure with increases in anabolic
             cell responses. Higher magnitudes of loading may give rise
             to catabolic responses marked by elevated protease gene or
             protein expression or activity. The key regulators of these
             mechanobiologic responses for intervertebral disc cells will
             be the micromechanical stimuli experienced at the cellular
             level, which are predicted to differ from that measured for
             the extracellular matrix. Large hydrostatic pressures, but
             little volume change, are predicted to occur for cells of
             the nucleus pulposus during compression, while the highly
             oriented cells of the anulus fibrosus may experience
             deformations in tension or compression during matrix
             deformations. In general, the pattern of biologic response
             to applied loads suggests that the cells of the nucleus
             pulposus and inner portion of the anulus fibrosus experience
             comparable micromechanical stimuli in situ and may respond
             more similarly than cells of the outer portion of the anulus
             fibrosus. Changes in these features with degeneration are
             critically understudied, particularly degeneration-associated
             changes in cell-level mechanical stimuli and the associated
             mechanobiology. Little is known of the mechanisms that
             regulate cellular responses to intervertebral
             mechanobiology, nor is much known with regard to the precise
             mechanical stimuli experienced by cells during loading.
             Mechanical factors appear to regulate responses of the
             intervertebral disc cells through mechanisms involving
             intracellular Ca2+ transients and cytoskeletal remodeling
             that may regulate downstream effects such as gene expression
             and posttranslational biosynthesis. Future studies should
             address the broader biologic responses to mechanical stimuli
             in intervertebral disc mechanobiology, the involved
             signaling mechanisms, and the apparently important
             interactions among mechanical factors, genetic factors,
             cytokines, and inflammatory mediators that may be critical
             in the regulation of intervertebral disc
             degeneration.},
   Key = {Setton06}
}

@booklet{Guilak06,
   Author = {F. Guilak and L. G. Alexopoulos and M. L. Upton and I. Youn and J. B. Choi and L. Cao and L. A. Setton and M. A.
             Haider},
   Title = {The pericellular matrix as a transducer of biomechanical and
             biochemical signals in articular cartilage},
   Journal = {Skeletal Development And Remodeling In Health, Disease, And
             Aging},
   Volume = {1068},
   Series = {ANNALS OF THE NEW YORK ACADEMY OF SCIENCES},
   Pages = {498 -- 512},
   Year = {2006},
   ISSN = {0077-8923},
   Abstract = {The pericellular matrix (PCM) is a narrow tissue region
             surrounding chondrocytes in articular cartilage, which
             together with the enclosed cell(s) has been termed the
             "chondron." While the function of this region is not fully
             understood, it is hypothesized to have important biological
             and biomechanical functions. In this article, we review a
             number of studies that have investigated the structure,
             composition, mechanical properties, and biomechanical role
             of the chondrocyte PCM. This region has been shown to be
             rich in proteoglycans (e.g., aggrecan, hyaluronan, and
             decorin), collagen (types II, VI, and IX), and fibronectin,
             but is defined primarily by the presence of type VI collagen
             as compared to the extracellular matrix (ECM). Direct
             measures of PCM properties via micropipette aspiration of
             isolated chondrons have shown that the PCM has distinct
             mechanical properties as compared to the cell or ECM. A
             number of theoretical and experimental studies suggest that
             the PCM plays an important role in regulating the
             microenvironment of the chondrocyte. Parametric studies of
             cell-matrix interactions suggest that the presence of the
             PCM significantly affects the micromechanical environment of
             the chondrocyte in a zone-dependent manner. These findings
             provide support for a potential biomechanical function of
             the chondrocyte PCM, and furthermore, suggest that changes
             in the PCM and ECM properties that occur with osteoarthritis
             may significantly alter the stress-strain and fluid
             environments of the chondrocytes. An improved understanding
             of the structure and function of the PCM may provide new
             insights into the mechanisms that regulate chondrocyte
             physiology in health and disease.},
   Key = {Guilak06}
}

@booklet{Upton06,
   Author = {M. L. Upton and A. Hennerbichler and B. Fermor and F. Guilak and J. B. Weinberg and L. A. Setton},
   Title = {Biaxial strain effects on cells from the inner and outer
             regions of the meniscus},
   Journal = {Connective Tissue Research},
   Volume = {47},
   Number = {4},
   Pages = {207 -- 214},
   Year = {2006},
   ISSN = {0300-8207},
   Abstract = {During knee joint loading, the fibrocartilaginous menisci
             experience significant spatial variations in mechanical
             stimuli. Meniscus cells also exhibit significant variations
             in biosynthesis and gene expression depending on their
             location within the tissue. These metabolic patterns are
             consistent with a more chondrocytic phenotype for cells
             located within the avascular inner two-thirds compared with
             a more fibroblastic phenotype for cells within the
             vascularized outer periphery. The spatial distribution of
             cell biosynthesis and gene expression patterns within the
             meniscus suggest that cells may exhibit intrinsically
             different responses to mechanical stimuli. The objective of
             our study was to test for intrinsic differences in the
             responsiveness of these meniscus cell populations to an
             equivalent mechanical stimulus. Cellular biosynthesis and
             gene expression for extracellular matrix proteins in
             isolated inner and outer meniscus cells in monolayer were
             quantified following cyclic biaxial stretch. The results
             demonstrate that inner and outer meniscus cells exhibit
             significant differences in matrix biosynthesis and gene
             expression regardless of stretching condition. Both inner
             and outer meniscus cells responded to stretch with increased
             nitric oxide production and total protein synthesis. The
             results suggest that inner and outer meniscus cells may
             respond similarly to biaxial stretch in vitro with measures
             of biosynthesis and gene expression.},
   Key = {Upton06}
}

@booklet{Mchale05,
   Author = {M. K. Mchale and L. A. Setton and A. Chilkoti},
   Title = {Synthesis and in vitro evaluation of enzymatically
             cross-linked elastin-like polypeptide gels for cartilaginous
             tissue repair},
   Journal = {Tissue Engineering},
   Volume = {11},
   Number = {11-12},
   Pages = {1768 -- 1779},
   Year = {2005},
   Month = {November},
   ISSN = {1076-3279},
   Abstract = {Genetically engineered elastin-like polypeptide (ELP)
             hydrogels offer unique promise as scaffolds for cartilage
             tissue engineering because of the potential to promote
             chondrogenesis and to control mechanical properties. In this
             study, we designed and synthesized ELPs capable of
             undergoing enzyme-initiated gelation via tissue
             transglutaminase, with the ultimate goal of creating an
             injectable, in situ cross-linking scaffold to promote
             functional cartilage repair. Addition of the enzyme promoted
             ELP gel formation and chondrocyte encapsulation in a
             biocompatible process, which resulted in cartilage matrix
             synthesis in vitro and the potential to contribute to
             cartilage mechanical function in vivo. A significant
             increase in the accumulation of sulfated glycosaminoglycans
             was observed, and histological sections revealed the
             accumulation of a cartilaginous matrix rich in type II
             collagen and lacking in type I collagen, indicative of
             hyaline cartilage formation. These results provide evidence
             of chondrocytic phenotype maintenance for cells in the ELP
             hydrogels in vitro. In addition, the dynamic shear moduli of
             ELP hydrogels seeded with chondrocytes increased from 0.28
             to 1.7 kPa during a 4-week culture period. This increase in
             the mechanical integrity of cross-linked ELP hydrogels
             suggests restructuring of the ELP matrix by deposition of
             functional cartilage extracellular matrix
             components.},
   Key = {Mchale05}
}

@booklet{Alexopoulos05,
   Author = {L. G. Alexopoulos and L. A. Setton and F.
             Guilak},
   Title = {The biomechanical role of the chondrocyte pericellular
             matrix in articular cartilage},
   Journal = {Acta Biomaterialia},
   Volume = {1},
   Number = {3},
   Pages = {317 -- 325},
   Year = {2005},
   Month = {May},
   ISSN = {1742-7061},
   Key = {Alexopoulos05}
}


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