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ABSTRACT: Tumor metastases and epithelial to mesenchymal transition (EMT) involve tumor cell invasion and migration through the dense collagen-rich extracellular matrix surrounding the tumor. Little is neither known about the mechanobiological mechanisms involved in this process, nor the role of the mechanical forces generated by the cells in their effort to invade and migrate through the stroma. In this paper we propose a new fundamental mechanobiological mechanism involved in cancer growth and metastasis, which can be both protective or destructive depending on the magnitude of the forces generated by the cells. This new mechanobiological mechanism directly challenges current paradigms that are focused mainly on biological and biochemical mechanisms associated with tumor metastasis. Our new mechanobiological mechanism describes how tumor expansion generates mechanical forces within the stroma to not only resist tumor expansion but also inhibit or enhance tumor invasion by, respectively, inhibiting or enhancing matrix metalloproteinase (MMP) degradation of the tensed interstitial collagen. While this mechanobiological mechanism has not been previously applied to the study of tumor metastasis and EMT, it may have the potential to broaden our understanding of the tumor invasive process and assist in developing new strategies for preventing or treating cancer metastasis.
Seminars in Cancer Biology 05/2012; 22(5-6):385-95. · 6.47 Impact Factor
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ABSTRACT: Focal cartilage defects reduce the ability of articular cartilage to resist mechanical loading and provide lubrication during joint motion. The limitations in current surgical treatments have motivated the use of biocompatible scaffolds as a future treatment option. Here we describe a second generation macroporous, polyvinyl alcohol (PVA) scaffold with independently tunable morphological and mechanical properties. The compressive moduli of the PVA scaffold increased with increasing polymer concentration and applied compressive strain, with values in the range for human articular cartilage (H(A) > 1000 kPa, E(Y) > 500 kPa). Scaffolds also possessed strain-dependent permeability and Poisson's ratio. The interconnected macroporous network was found to facilitate chondrocyte seeding and proliferation through the scaffold over one week in culture. Overall, these promising characteristics demonstrate the potential of this macroporous scaffold for future studies in focal cartilage defect repair. Copyright © 2012 John Wiley & Sons, Ltd.
Journal of Tissue Engineering and Regenerative Medicine 05/2012; · 3.28 Impact Factor
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ABSTRACT: Scaffold-cartilage integration is critical for the clinical success of a scaffold used for the repair of a focal cartilage defect. In this study, a macroporous polyvinyl alcohol (PVA) scaffold was found to facilitate chondrocyte infiltration and interfacial matrix formation in a juvenile bovine in vitro cartilage defect model. These results were found to depend on the press-fit between the scaffold and the cartilage, pretreatment of the cartilage with collagenase prior to scaffold insertion, and chondrocyte preseeding of the scaffold. Infiltrated and preseeded chondrocytes in the scaffold survived for 6 weeks in culture and resulted in sufficient matrix at the interface to significantly increase the interface shear strength 30-fold that compared favorably with the interface shear strength of cartilage-cartilage constructs. The ability of this macroporous PVA scaffold to form a stable interface with articular cartilage demonstrates the potential use of this scaffold design for focal cartilage defect repair.
Tissue Engineering Part A 03/2012; 18(11-12):1273-81. · 4.64 Impact Factor
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ABSTRACT: Gamma irradiation is a proven sterilization method, but is not widely used on allografts for anterior cruciate ligament reconstruction (e.g., patella tendon) due to radiation-induced decreases in mechanical strength. Addressing this drawback would improve the safety and supply of allografts to meet current and future demand. It was hypothesized that genipin-induced collagen cross-linking would increase the tensile modulus of patella tendon tissue such that 5 MRad gamma irradiation would not reduce the tissue mechanical strength below the original untreated values. Optimized genipin treatment increased the tensile modulus of bovine tendons by ~2.4-fold. After irradiation, genipin treated tissue did not significantly differ from native tissue, proving the hypothesis. Optimized genipin treatment of human tendons increased the tensile modulus by ~1.3-fold. After irradiation, both control and genipin-treated tissues possessed ~50-60% of their native tendon modulus, disproving the hypothesis. These results highlight possible age- and species- dependent effects of genipin cross-linking on tendon tissue. Cross-linking of human allografts may be beneficial only in younger donor tissues. Future research is warranted to better understand the mechanisms and applications of collagen cross-linking for clinical use.
Cell and Tissue Banking 02/2012; · 0.96 Impact Factor
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ABSTRACT: This study sought to determine the role of the coracoacromial ligament and related arch structures in glenohumeral joint stabilization. Eight fresh-frozen cadaver specimens were tested at multiple angles of glenohumeral abduction and rotation for translations (in the direction of and perpendicular to a 50-N force) in intact, vented shoulders and after three interventions: coracoacromial veil release, coracoacromial ligament release, and anterior acromioplasty. After releasing the veil, an inferior force significantly increased inferior translation at lower angles of abduction with no additional increase after coracoacromial ligament section or acromioplasty. After ligament release or acromioplasty, a superior force increased superior translation at all angles. Few increases in anterior or posterior translations were observed. The coracoacromial veil interacts with the structures of the coracoacromial arch and glenohumeral capsule to limit inferior humeral translation. Likewise, the coracoacromial ligament and the acromian serve to limit superior translation. Attempts to preserve these structures may help improve surgical outcomes.
Journal of surgical orthopaedic advances 01/2012; 21(4):210-217.
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ABSTRACT: Collagen cross-linking mechanically strengthens tissues during development and aging, but there is limited data describing how force transmitted across cross-links affects molecular conformation. We used Steered Molecular Dynamics (SMD) to model perpendicular force through a side chain. Results predicted that collagen peptides have negligible bending resistance and that mechanical force causes helix disruption below covalent bond failure strength, suggesting alternative molecular conformations precede cross-link rupture and macroscopic damage during mechanical loading.
Matrix biology: journal of the International Society for Matrix Biology 05/2011; 30(5-6):356-60. · 3.56 Impact Factor
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ABSTRACT: Few options exist to replace or repair damaged articular cartilage. The optimal solution that has been suggested is a scaffold that can carry load and integrate with surrounding tissues; but such a construct has thus far been elusive. The objectives of this study were to manufacture and characterize a nondegradable hydrated scaffold. Our hypothesis was that the polymer content of the scaffold can be used to control its mechanical properties, while an internal porous network augmented with biological agents can facilitate integration with the host tissue. Using a two-step water-in-oil emulsion process a porous polyvinyl alcohol (PVA) hydrogel scaffold combined with alginate microspheres was manufactured. The scaffold had a porosity of 11-30% with pore diameters of 107-187 μm, which readily allowed for movement of cells through the scaffold. Alginate microparticles were evenly distributed through the scaffold and allowed for the slow release of biological factors. The elastic modulus (E(s) ) and Poisson's ratio (υ), Aggregate modulus (H(a) ) and dynamic modulus (E(D) ) of the scaffold were significantly affected by % PVA, as it varied from 10 to 20% wt/vol. E(s) and υ were similar to that of articular cartilage for both polymer concentrations, while H(a) and E(D) were similar to that of cartilage only at 20% PVA. The ability to control scaffold mechanical properties, while facilitating cellular migration suggest that this scaffold is a potentially viable candidate for the functional replacement of cartilage defects. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2011.
Journal of Biomedical Materials Research Part A 02/2011; · 2.63 Impact Factor
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ABSTRACT: Collagen is a key structural protein in the extracellular matrix of many tissues. It provides biological tissues with tensile mechanical strength and is enzymatically cleaved by a class of matrix metalloproteinases known as collagenases. Collagen enzymatic kinetics has been well characterized in solubilized, gel, and reconstituted forms. However, limited information exists on enzyme degradation of structurally intact collagen fibers and, more importantly, on the effect of mechanical deformation on collagen cleavage. We studied the degradation of native rat tail tendon fibers by collagenase after the fibers were mechanically elongated to strains of epsilon=1-10%. After the fibers were elongated and the stress was allowed to relax, the fiber was immersed in Clostridium histolyticum collagenase and the decrease in stress (sigma) was monitored as a means of calculating the rate of enzyme cleavage of the fiber. An enzyme mechanokinetic (EMK) relaxation function T(E)(epsilon) in s(-1) was calculated from the linear stress-time response during fiber cleavage, where T(E)(epsilon) corresponds to the zero order Michaelis-Menten enzyme-substrate kinetic response. The EMK relaxation function T(E)(epsilon) was found to decrease with applied strain at a rate of approximately 9% per percent strain, with complete inhibition of collagen cleavage predicted to occur at a strain of approximately 11%. However, comparison of the EMK response (T(E) versus epsilon) to collagen's stress-strain response (sigma versus epsilon) suggested the possibility of three different EMK responses: (1) constant T(E)(epsilon) within the toe region (epsilon<3%), (2) a rapid decrease ( approximately 50%) in the transition of the toe-to-heel region (epsilon congruent with3%) followed by (3) a constant value throughout the heel (epsilon=3-5%) and linear (epsilon=5-10%) regions. This observation suggests that the mechanism for the strain-dependent inhibition of enzyme cleavage of the collagen triple helix may be by a conformational change in the triple helix since the decrease in T(E)(epsilon) appeared concomitant with stretching of the collagen molecule.
Journal of Biomechanical Engineering 06/2009; 131(5):051004. · 1.90 Impact Factor
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ABSTRACT: Existing technologies have not met the challenge of designing a construct for the repair of focal cartilage defects such that it mimics the mechanical properties of and can integrate with native cartilage. Herein we describe a novel construct consisting of a non-degradable poly-vinyl alcohol (PVA) scaffold to provide long-term mechanical stability, interconnected pores to allow for the infiltration of chondrocytes, and poly-lactic glycolic acid (PLGA) microspheres for the incorporation of growth factors to enhance cellular migration. The objective of this study was to characterize the morphological features and mechanical properties of our porous PVA-PLGA construct as a function of PLGA content. Varying the PLGA content was found to have a significant effect on the morphological features of the construct. As PLGA content increased from 10% to 75%, samples exhibited a 6-fold increase in average percentage porosity, an increase in average microsphere diameter from 8 to 34 microm and an increase in average pore diameter from 29 to 111 microm. The effect of PLGA content on aggregate modulus and permeability was less profound. Our findings suggest that that morphology of the construct can be tailored to optimize cellular infiltration and the dynamic mechanical response. The experiments herein presented were conducted at the Hospital for Special Surgery.
Tissue Engineering Part A 02/2008; 14(1):207-13. · 4.64 Impact Factor
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ABSTRACT: The coracoacromial (CA) ligament plays an important role in the stability of the shoulder joint by limiting superior translation of the glenohumeral joint. This ligament is further divided into anterolateral and posteromedial bands. Attached to the CA ligament, a supportive structure was noted in some previous studies. The purpose of this study was to learn more about the anatomy of this structure. Twenty-eight shoulders were obtained. Deltoid and trapezius muscles were removed without damaging the rotator cuff and coracoacromial arch. The CA ligament was dissected further to reveal two constituent bands, an anterolateral and a posteromedial band. A connective tissue structure was noted between the posteromedial band, CA ligament, and rotator interval capsule. This structure was oriented as an L-shaped curtain, which the authors termed the "coracoacromial veil." Anatomical position of this veil provides a stabilizing link between the CA ligament and the rotator interval capsule. This structure potentially limits inferior translation of the glenohumeral joint.
Journal of surgical orthopaedic advances 02/2008; 17(2):69-73.
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ABSTRACT: To examine whether differences in chondrocytes from skeletally immature versus adult individuals are important in cartilage healing, repair, or tissue engineering, superficial zone chondrocytes (SZC, from within 100 microm of the articular surface) and deep zone chondrocytes (DZC, from 30%-45% of the deepest un-mineralized part of articular cartilage) were harvested from immature (1-4 months) and young adult (18-36 months) steers and compared. Cell size, matrix gene expression and protein levels, integrin levels, and chemotactic ability were measured in cells maintained in micromass culture for up to 7 days. Regardless of age, SZC were smaller, had a lower type II to type I collagen gene expression ratio, and higher gene expression of SZ proteins than their DZC counterparts. Regardless of zone, chondrocytes from immature steers had higher levels of Sox 9 and type II collagen gene expression. Over 7 days in culture, the SZC of immature steers had the highest rate of proliferation. Phenotypically, the SZC of immature and adult steers were more stable than their respective DZC. Cell surface alpha5 and alpha2 integrin subunit levels were higher in the SZC of immature than of adult steers, whereas beta1 integrin subunit levels were similar. Both immature and adult SZC were capable of chemotaxis in response to fetal bovine serum or basic fibroblast growth factor. Our data indicate that articular chondrocytes vary in the different zones of cartilage and with the age of the donor. These differences may be important for cartilage growth, tissue engineering, and/or repair.
Cell and Tissue Research 02/2006; 323(1):127-35. · 3.11 Impact Factor
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ABSTRACT: This study was designed to evaluate the postimpact response of the articular cartilage in the rabbit knee after a single traumatic episode.
A novel servo-controlled Rabbit Impact Test System (RITS) was developed to apply a well-defined trauma to the femoral condyle in the rabbit knee. The RITS was first used in an in vitro study to determine an appropriate stress to cause cartilage damage without bone fracture. Viable rabbit knees (n = 18) were impacted with stresses of 15 to 50 MPa at a stress rate of 420 MPa/s, the latter corresponding to joint impact rates commonly seen in sports injuries and vehicular accidents. Based on the in vitro study, we performed an in vivo study by impacting the knees of rabbits (n = 9) with a 35 MPa peak stress at a stress rate of 420 MPa/s. The articular cartilage in these knees was analyzed at 0 and 3 weeks after impaction.
Center for Laboratory Animal Services, Hospital for Special Surgery.
A total of 27 New Zealand White rabbits were used in this study.
A rabbit's knee was rigidly immobilized in the adjustable frame of the RITS. A small incision on the knee exposed the lateral condyle and the impactor was positioned perpendicular to the surface of the condyle. The lateral femoral condyle of the left knee was impacted, whereas the right knee was sham operated and used as a control.
Visual matrix damage, cell viability, and microscopic matrix damage was assessed.
In the in vitro study, matrix damage was observed at stress magnitudes > or =30 MPa. However, cell death was initiated at approximately 20 MPa at the articular surface and increased in depth with increasing stress magnitude (2.8 +/- 2% thickness/MPa,). In the in vivo study, visible surface damage was observed immediately after impaction but not at 3 weeks after impaction. At 3 weeks, the articular cartilage showed significant arthritic changes (matrix damage, chondrocyte death, and proteoglycan loss) typical of late-stage osteoarthritis.
Our novel impact test system was able to accurately apply a quantifiable stress magnitude at a constant stress rate to rabbit femoral condyles in the in vitro and in vivo settings. At the time of impaction, the extent of cell death depended with the intensity of trauma (stress magnitude) in which complete cell death was observed in the impacted site at >40 MPa. Under in vivo conditions, the test system was able to consistently produce superficial matrix damage and cell death at 35 MPa stress magnitude at the time of impaction. This resulted in cartilage "arthritic" changes by 3 weeks postinjury.
Journal of Orthopaedic Trauma 09/2005; 19(7):466-73. · 2.13 Impact Factor
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ABSTRACT: During joint maturation, articular cartilage undergoes compositional, structural, and biomechanical changes, which could affect how the chondrocytes within the cartilage matrix respond to load-induced injury. The objective of this study was to determine the effects of tissue maturity on chondrocyte viability when explanted cartilage was subjected to load-induced injury.
Cartilage explants from immature (4-8-week-old) and mature (1.5-2-year-old) bovine humeral heads were cyclically loaded at 0.5 hertz in confined compression with a stress of 1 or 5 megapascals for 0.5, 1, 3, 6 and 16 h. Cell death was assessed at 0, 24 and 48 h after load removal using cell viability dyes and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. The organization of pericellular matrix (PCM), biochemical composition and biomechanical properties of the cartilage were also determined.
For the immature and mature cartilage, cell death began at the articular surface and increased in depth with loading time up to 6h. No increase of cell death was found after load removal for up to 48 h. In both groups, cell death increased at a faster rate with the increase of stress level. The depth of cell death in the immature cartilage was greater than the mature cartilage, despite the immature cartilage having a higher bulk aggregate modulus. A less organized PCM in immature cartilage was found as indicated by the weak staining of type VI collagen.
Cells in the mature cartilage are less vulnerable to load-induced injury than those in immature cartilage.
Osteoarthritis and Cartilage 07/2005; 13(6):488-96. · 3.90 Impact Factor
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ABSTRACT: The biomechanical response of articular cartilage to a wide range of impact loading rates was investigated for stress magnitudes that exist during joint trauma. Viable, intact bovine cartilage explants were impacted in confined compression with stress rates of 25, 50, 130 and 1000 MPa/s and stress magnitudes of 10, 20, 30 and 40 MPa. Water loss, cell viability, dynamic impact modulus (DIM) and matrix deformation were measured. Under all loading conditions the water loss was small (approximately 15%); water loss increased linearly with increasing peak stress and decreased exponentially with increasing stress rate. Cell death was localized within the superficial zone (< or =12% of total tissue thickness); the depth of cell death from the articular surface increased with peak stress and decreased with increasing stress rate. The DIM increased (200-700 MPa) and matrix deformation decreased with increasing stress rate. Initial water and proteoglycan (PG) content had a weak, yet significant influence on water loss, cell death and DIM. However, the significance of the inhomogeneous structure and composition of the cartilage matrix was accentuated when explants impacted on the deep zone had less water loss and matrix deformation, higher DIM, and no cell death compared to explants impacted on the articular surface. The mechano-biological response of articular cartilage depended on magnitude and rate of impact loading.
Journal of Biomechanics 04/2005; 38(3):493-502. · 2.43 Impact Factor
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ABSTRACT: To determine whether load-induced injury causes alterations in proteoglycan (PG), stromelysin-1 (MMP-3) and collagen in articular cartilage.
Mature bovine cartilage was cyclically loaded at 0.5 Hz with 1 and 5 MPa for 1, 6 and 24h. Immediately after loading explants were evaluated for cell viability. Alterations in matrix integrity were determined by measuring PG content, PG degradation using 7D4 and 3B3(-) antibodies, broken collagen using COL2-3/4m antibody, and stromelysin-1 content using a MMP-3 antibody.
Mechanical load caused cell death and PG loss starting from the articular surface and increasing in depth with loading time. There was a decrease in the 7D4 epitope (native chondroitin sulfate) in the superficial zone of cartilage loaded for longer than 1h, but an increase around chondrocytes in the deep zone. The 3B3(-) staining for degraded/abnormal chondroitin-4-sulfate neoepitope appeared only in cartilage loaded under the most severe condition (5 MPa, 24 h). The elevation of stromelysin-1 was co-localized with broken collagen (COL2-3/4m) at the articular surface in explants loaded with 1 and 5 MPa for 24 h.
Cell death and PG loss occurred within 6h of cyclic loading. The elevation of MMP-3 following cell death was consistently found in the superficial zone of loaded cartilage. Since MMP-3 can degrade PG and super-activate procollagenase, the increase of MMP-3 can therefore induce matrix degradation and PG depletion in mechanically injured articular cartilage, both of which are important to the development of osteoarthritis.
Osteoarthritis and Cartilage 07/2004; 12(6):485-96. · 3.90 Impact Factor
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ABSTRACT: Articular cartilage is subjected to cyclic compressive stresses during joint loading. There is increasing experimental evidence that this loading is essential for the chondrocytes to maintain the functionality of the cartilage extracellular matrix (ECM) and that members of the integrin family of transmembrane receptors may play an important role in signal mechanotransduction between the ECM and chondrocytes. Of particular interest are the integrin subunits alpha5 and beta1, which are known to form the receptor for fibronectin, an important ECM protein, and to be involved in mechanotransduction as well as in the regulation of cytokine production. In this study, we measured the amounts of the integrin subunits alpha5 and beta1 in chondrocytes from young (immature) and adult (mature) bovine articular cartilage explants which were subjected to a continuously applied cyclic compressive stress of 1 MPa for 6 and 24 h. The integrin content per chondrocyte was measured immediately after load cessation by flow cytometry following matrix digestion to release the cells. We found that a mechanical stress induced an increase in the number of integrin subunit alpha5 in immature and mature cartilage but not in the integrin subunit beta1 content. The integrin contents were greatest after 6 h of loading and returned to control levels after 24 h of unloading. The results of this study supply further experimental evidence that chondrocytes respond to changes in their mechanical environment and that the integrin alpha5beta1 may act as a mechanical signal transducer between the chondrocyte and the ECM for the modulation of cellular physiology.
Cell and Tissue Research 04/2004; 315(3):385-91. · 3.11 Impact Factor
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ABSTRACT: The objective of this study was to assess mechano-biological response of articular cartilage when subjected to a single impact stress. Mature bovine cartilage explants were impacted with peak stresses ranging from 10 to 60 MPa at a stress rate of 350 MPa/s. Water loss, matrix axial deformation, dynamic impact modulus (DIM), and cell viability were measured immediately after impaction. The water loss through the articular surface (AS) was small and ranged from 1% to 6% with increasing peak stress. The corresponding axial strains ranged from 2.5% to 25%, respectively, while the DIM was 455.9 +/- 111.9 MPa. Chondrocyte death started at the articular surface and increased in depth to a maximum of 6% (70 microns) of the cartilage thickness at the highest stress. We found that the volumetric (axial) strain was more than twice the amount of water loss at the highest peak stress. Furthermore, specimens impacted such that the interstitial water was forced through the deep zone (DZ) had less water loss, a higher DIM, and no cell death. These findings appear to be due to matrix compaction in the superficial region causing higher compressive strains to occur at the surface rather than in the deeper zones.
Journal of Biomechanical Engineering 11/2003; 125(5):594-601. · 1.90 Impact Factor
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ABSTRACT: We investigated the effect of light (0.1 MPa), moderate (1 MPa) or heavy (5 MPa) cyclical stresses applied continuously or intermittently for 0 to 72 h on cell death and collagen damage in adult bovine cartilage explants. No increase in cell death was observed in the cartilage loaded with a continuous cyclic stress at 0.1 MPa for up to 72 h. Cell death occurred in the uppermost superficial tangential zone (STZ) of explants after loading for 1 h at 1 MPa, and reached a maximum depth of 61+/-23 micro m by 6 h (at the rate of 9+/-6 micro m/h). At 5 MPa, cell death occurred in the STZ after as little as 1 min (30 cycles) of loading, and reached a maximum depth of 70+/-2 micro m by 60 min (47+/-8 micro m/h). When an intermittent (with 2 s on, 2 s off) stress of 5 MPa was applied, cell death appeared in the STZ after 2 min (30 cycles) and increased to a depth of 63+/-2 micro m at 60 min (45+/-11 micro m/h). No significant differences were observed between the continuous and intermittent loading conditions. Both collagenase-cleaved and denatured collagen fibers were found in the STZ of explants loaded at 1 and 5 MPa. We concluded that load-induced cell death depends on load duration and magnitude, and that the chondrocytes in the STZ are more vulnerable to load-induced injury than those in the middle and deep zones.
Journal of Orthopaedic Research 10/2003; 21(5):888-98. · 2.81 Impact Factor
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ABSTRACT: To use noninvasive magnetic resonance imaging (MRI), biochemical analyses, and mechanical testing of engineered neocartilage grown in a hollow- fiber bioreactor (HFBR) to establish tissue properties, and to test the hypothesis that MRI can be used to monitor biochemical and biomechanical properties of neocartilage.
Chondrocytes from day 16 embryonic chick sterna were inoculated into an HFBR and maintained for up to 4 weeks with and without exposure to chondroitinase ABC. The fixed-charge density (FCD) of the cartilage was determined using the MRI gadolinium exclusion method. The sulfated glycosaminoglycan (S-GAG), hydroxyproline, and DNA contents were determined using biochemical procedures, while dynamic and equilibrium moduli were determined from mechanical indentation tests.
S-GAG content, tissue cross-sectional area, and equilibrium modulus of the neocartilage increased with development time. There was a gradient of S-GAG content across the length of control neocartilage at the 4-week time point, with higher values being found toward the inflow region. Exposure to chondroitinase ABC resulted in a decrease in tissue area, negative FCD, proteoglycan content, and equilibrium and dynamic moduli. The treated bioreactors displayed a lengthwise variation in S-GAG content, with higher values toward the outflow end. Linear correlations were established among FCD, proteoglycan content, and biomechanical properties.
HFBR-derived neocartilage showed regional variation in S-GAG content under control conditions, and in the decrease of S-GAG in response to enzyme treatment. In addition, the results support the hypothesis that tissue parameters derived from MRI can be used to noninvasively monitor focal neocartilage formation and biochemical and biomechanical properties.
Arthritis & Rheumatism 05/2003; 48(4):1047-56. · 7.87 Impact Factor
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ABSTRACT: Ingrowth of host blood vessels into engineered tissues has potential benefits for successful transplantation of engineered tissues as well as healing of surrounding host tissues. In particular, the use of a vascularized bioengineered tissue could be beneficial for treating injuries to the meniscus, a structure in the knee where the lack of a vascular supply is associated with an inadequate healing response. In this study, gene transfer using an adenovirus vector encoding the hepatocyte growth factor gene (AdHGF) was used to induce blood vessel formation in tissue-engineered meniscus. Bovine meniscal cells were treated with AdHGF, a vector encoding a marker gene E. coli beta-galactosidase (Adbetagal), or no virus. Cells were seeded onto poly-glycolic acid felt scaffolds and then transplanted into the subcutaneous pouch of athymic nude mice for 8 weeks. Expression of the marker gene and HGF was detectable for several weeks after gene transfer. Ink injection studies showed that AdHGF-treated meniscal cells formed tissue which contained fourfold more blood vessels at 2 weeks (p < 0.02) and 2.5-fold more blood vessels at 8 weeks (p < 0.001) posttransplantation than controls. This study demonstrates the feasibility of using adenovirus-mediated gene transfer to engineer a blood supply in the bioengineered meniscal tissue.
Tissue Engineering 02/2002; 8(1):93-105. · 4.02 Impact Factor
