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| Publications of Lori A. Setton :chronological 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,
1.1×10<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. © 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 °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. © 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 (μSEmb) 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 μSEmb
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>β</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>β</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. ©
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 ± 8.9 kPa) and middle/deep zone cartilage
(23.2 ± 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. © 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±16.2kPa vs. 23.5±12.9kPa,
p<0.001), and the permeability was significantly elevated
(4.19±3.78×10<sup>-17</sup>m<sup>4</sup>/Ns vs.
10.2±9.38×10<sup>-17</sup>m<sup>4</sup>/Ns,
p<0.001). The Poisson's ratio was similar for both
non-degenerate and OA PCM (0.044±0.063 vs.
0.030±0.068, p>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 μm<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 °C temperature range. Gels ranged in
stiffness from 0.24 to 3.7 kPa at 7 °C and from 1.6 to
15 kPa at 37 °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. © 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. © 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. © 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
(ν<sub>12</sub>=2.13, ν<sub>21</sub>=1.50,
ν<sub>23</sub>=1.02). However, a significant effect of
anisotropy on permeability was not detected
(k<sub>1</sub>=0.09×10<sup>-16</sup> m<sup>4</sup>/Ns,
k<sub>2</sub>=0.10×10<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 (ν), 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±1.11, p<0.01) than in the
middle zone (0.62±0.23), with no significant
correlation of ν 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±2.78
MPa, n=8) compared to the middle zone (2.51±1.93 MPa,
n=10). In addition, the linear-region modulus (E) in the
surface zone, but not middle zone (3.42±2.17 MPa,
n=10), was found to correlate with age (R=0.97, p<0.02)
with values of surface zone E equal to 23.92±12.29
MPa (n=5) for subjects under 70 yr of age, and
4.27±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, ν 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±1.80 MPa for
subjects under 70 yr old and 0.96±0.69 MPa for
subjects over 70 yr old, and were significantly higher in
the surface zone than in the middle zone (1.10±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. © 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±14.3 MPa versus 5.6±4.7 MPa, outer
versus inner sites) and the Poisson's ratio
ν<sub>21</sub> (0.67±0.22 versus 1.6±0.7,
outer versus inner), but not in the axial modulus
(0.8±0.9 MPa) or the Poisson's ratios
ν<sub>12</sub> (1.8±1.4) or ν<sub>13</sub>
(0.6±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 “matrix,”
“fiber,” “fiber-matrix,” and
“fiber-fiber,” 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°. 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±7.7 to
15.3±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, σ<sub>offset</sub>, and
parameters describing the compressive stiffness (i.e.,
reference aggregate modulus, H<sub>A0</sub>, and nonlinear
stiffening coefficient, β). Average values were
0.13±0.06 and 0.05±0.05 MPa for
σ<sub>offset</sub>, 0.56±0.21 and
1.10±0.53 MPa for H<sub>A0</sub> and 2.13±1.48
and 0.44±0.61 for β 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±0.10×10<sup>-15</sup>
m<sup>4</sup>/N-s and 1.18±1.30 for k<sub>0</sub> and
M, respectively. The loss of σ<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 β 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
“curl” 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 (δ) ranging from 23 to
30° 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 τ<sub>1</sub>≪t≪τ<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
± 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 tanδ 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 tanδ 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° and -30°
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°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
(β).},
Key = {95092853061}
}
@article{4900283,
Author = {McCutchen, C.W. and Setton, L.A. and Zhu, W. and Mow,
V.C.},
Title = {Comment on the `Biphasic poroviscoelastic behavior of
articular cartilage: role of the surface zone in governing
the compressive behavior'},
Journal = {J. Biomech. (UK)},
Volume = {28},
Number = {4},
Pages = {479, 481 -},
Year = {1995},
url = {http://dx.doi.org/10.1016/0021-9290(94)00095-L},
Keywords = {biomechanics;permeability;},
Abstract = {McCutchen comments on an article by Setton et al. (see
ibid., vol. 26 p. 581-92, 1993). McCutchen says that the
permeability values given by Setton et al. are much bigger
than previously measured values. In reply Setton et al. say
that there are no discrepancies in their permeability
values},
Key = {4900283}
}
@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° 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,
τ<sub>1</sub>, and τ<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 14.3×10<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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