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Robert M. Nerem - One of the best experts on this subject based on the ideXlab platform.
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human mesenchymal stem cells form multicellular structures in response to applied Cyclic Strain
Annals of Biomedical Engineering, 2009Co-Authors: Robert M. Nerem, Adele M Doyle, Tabassum AhsanAbstract:Mesenchymal stem cells (MSCs) are a component of many cardiovascular cell-based regenerative medicine therapies. There is little understanding, however, of the response of MSCs to mechanical cues present in cardiovascular tissues. The objectives of these studies were to identify a model system to study the effect of well-defined applied Cyclic Strain on MSCs and to use this system to determine the effect of Cyclic equibiaxial Strain on the cellular and cytoskeletal organization of MSCs. When exposed to 10%, 1 Hz Cyclic equibiaxial Strain for 48 h, MSCs remained viable, retained characteristic gene and protein markers, and rearranged to form multicellular structures defined as clusters and knobs. This novel observation of cluster (overlapping cells surrounded by radial cellular projections) and knob (more dome-like structure containing significantly more cells than a cluster) formation did not involve changes in cytoskeletal proteins and resulted from cellular rearrangements initiated within 8 h of applied Strain. Observed cellular responses were found to be dependent on substrate coating, but not on cell density for the 8-fold ranges tested. This system can thus be used to study the mechanoresponse over hours to days of MSCs exposed to applied Cyclic Strain in the context of cell–cell and cell–matrix interactions.
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The Role of Matrix Metalloproteinase-2 in the Remodeling of Cell-Seeded Vascular Constructs Subjected to Cyclic Strain
Annals of Biomedical Engineering, 2001Co-Authors: Dror Seliktar, Robert M. Nerem, Zorina S GalisAbstract:Tissue engineering offers the opportunity to develop vascular substitutes that mimic the responsive nature of native arteries. A good blood vessel substitute should be able to remodel its matrix in response to mechanical stimulation, as imposed by the hemodynamic environment. We have developed a novel method of studying the influence of mechanical Strain on the remodeling of cell-seeded collagen gel blood vessel analogs. We assessed the remodeling capacity by examining the effect of mechanical conditioning upon the expression of enzymes which remodel the extracellular matrix, called matrix metalloproteinases (MMPs), and upon the mechanical properties of the constructs. We found that subjecting collagen constructs to a 10% Cyclic radial distention, over a course of 4 days, resulted in an overall increase in the production of MMP-2. Cyclic mechanical Strain also stimulated enzymatic activation of latent MMP-2. We found that Cyclic Strain also significantly increased the mechanical strength and material modulus, as indicated by an increase in circumferential tensile properties of the constructs. These observations suggested that MMP-2-dependent remodeling affects the material properties of vascular tissue analogs. To further investigate this possible connection we examined the effects of dynamic conditioning in the presence of two nonspecific inhibitors of MMP activity. Interestingly, we found that nonspecific inhibition of MMP ablated the benefits of mechanical conditioning upon mechanical properties. Our observations suggest that a better understanding of the complex relation between mechanical stimulation and construct remodeling is key for the proper design of tissue-engineered blood vessel substitutes. © 2001 Biomedical Engineering Society. PAC01: 8719Rr, 8714Ee, 8717-d
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the role of matrix metalloproteinase 2 in the remodeling of cell seeded vascular constructs subjected to Cyclic Strain
Annals of Biomedical Engineering, 2001Co-Authors: Dror Seliktar, Robert M. Nerem, Zorina S GalisAbstract:Tissue engineering offers the opportunity to develop vascular substitutes that mimic the responsive nature of native arteries. A good blood vessel substitute should be able to remodel its matrix in response to mechanical stimulation, as imposed by the hemodynamic environment. We have developed a novel method of studying the influence of mechanical Strain on the remodeling of cell-seeded collagen gel blood vessel analogs. We assessed the remodeling capacity by examining the effect of mechanical conditioning upon the expression of enzymes which remodel the extracellular matrix, called matrix metalloproteinases (MMPs), and upon the mechanical properties of the constructs. We found that subjecting collagen constructs to a 10% Cyclic radial distention, over a course of 4 days, resulted in an overall increase in the production of MMP-2. Cyclic mechanical Strain also stimulated enzymatic activation of latent MMP-2. We found that Cyclic Strain also significantly increased the mechanical strength and material modulus, as indicated by an increase in circumferential tensile properties of the constructs. These observations suggested that MMP-2-dependent remodeling affects the material properties of vascular tissue analogs. To further investigate this possible connection we examined the effects of dynamic conditioning in the presence of two nonspecific inhibitors of MMP activity. Interestingly, we found that nonspecific inhibition of MMP ablated the benefits of mechanical conditioning upon mechanical properties. Our observations suggest that a better understanding of the complex relation between mechanical stimulation and construct remodeling is key for the proper design of tissue-engineered blood vessel substitutes. © 2001 Biomedical Engineering Society.
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Cyclic Strain induces an oxidative stress in endothelial cells
American Journal of Physiology-cell Physiology, 1997Co-Authors: A B Howard, Robert M. Nerem, R W Alexander, Kathy K Griendling, W R TaylorAbstract:Hypertension imposes an oxidant stress on the aorta and also causes mechanical deformation of the aortic wall. To assess whether deformation causes an oxidative stress, isolated porcine aortic endothelial cells (PAEC) were subjected to Cyclic Strain, and the cumulative amount of thiobarbituric acid reactive substances (TBARS, an index of lipid peroxidation) and H2O2 (a reactive oxygen species) was measured in the eluent at 2, 6, and 24 h. TBARS were increased by 40.5 +/- 9.2% after 24 h in cells exposed to Cyclic Strain vs. static controls (P < 0.05). No difference was seen at 2 and 6 h. H2O2 release was increased after 6 and 24 h of Cyclic Strain by 22.0 +/- 8.0 and 57.6 +/- 11.1 nmol H2O2/mg, respectively (P < 0.005), but was not increased after 2 h of Strain. In vascular smooth muscle cells, TBARS were not observed and H2O2 release was not increased by Cyclic Strain. To investigate a potential source of H2O2 induced by Strain, the activity of NADH/NADPH oxidase, a superoxide-generating enzyme, was measured by chemiluminescence. After 2 h, cells exposed to Cyclic Strain had greater activity than static controls (531.0 +/- 68.4 vs. 448.3 +/- 54.2 pmol O2- x mg(-1) x s(-1), respectively, when incubated with NADH, P < 0.005; 85.8 +/- 8.9 vs. 71.6 +/- 3.8 pmol O2- x mg(-1) x s(-1) when incubated with NADPH, P < 0.05). No effect on NADH/NADPH oxidase activity was seen after 6 or 24 h. The following conclusions were made: 1) Cyclic Strain induces an oxidant stress in PAEC monolayers as measured by TBARS formation and H2O2 release, 2) NADH/NADPH oxidase is a potential source of H2O2 release in Cyclically Strained cells, and 3) mechanical deformation of endothelial cells may play a critical role in the generation of oxidative stress within the vessel wall.
Zorina S Galis - One of the best experts on this subject based on the ideXlab platform.
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The Role of Matrix Metalloproteinase-2 in the Remodeling of Cell-Seeded Vascular Constructs Subjected to Cyclic Strain
Annals of Biomedical Engineering, 2001Co-Authors: Dror Seliktar, Robert M. Nerem, Zorina S GalisAbstract:Tissue engineering offers the opportunity to develop vascular substitutes that mimic the responsive nature of native arteries. A good blood vessel substitute should be able to remodel its matrix in response to mechanical stimulation, as imposed by the hemodynamic environment. We have developed a novel method of studying the influence of mechanical Strain on the remodeling of cell-seeded collagen gel blood vessel analogs. We assessed the remodeling capacity by examining the effect of mechanical conditioning upon the expression of enzymes which remodel the extracellular matrix, called matrix metalloproteinases (MMPs), and upon the mechanical properties of the constructs. We found that subjecting collagen constructs to a 10% Cyclic radial distention, over a course of 4 days, resulted in an overall increase in the production of MMP-2. Cyclic mechanical Strain also stimulated enzymatic activation of latent MMP-2. We found that Cyclic Strain also significantly increased the mechanical strength and material modulus, as indicated by an increase in circumferential tensile properties of the constructs. These observations suggested that MMP-2-dependent remodeling affects the material properties of vascular tissue analogs. To further investigate this possible connection we examined the effects of dynamic conditioning in the presence of two nonspecific inhibitors of MMP activity. Interestingly, we found that nonspecific inhibition of MMP ablated the benefits of mechanical conditioning upon mechanical properties. Our observations suggest that a better understanding of the complex relation between mechanical stimulation and construct remodeling is key for the proper design of tissue-engineered blood vessel substitutes. © 2001 Biomedical Engineering Society. PAC01: 8719Rr, 8714Ee, 8717-d
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the role of matrix metalloproteinase 2 in the remodeling of cell seeded vascular constructs subjected to Cyclic Strain
Annals of Biomedical Engineering, 2001Co-Authors: Dror Seliktar, Robert M. Nerem, Zorina S GalisAbstract:Tissue engineering offers the opportunity to develop vascular substitutes that mimic the responsive nature of native arteries. A good blood vessel substitute should be able to remodel its matrix in response to mechanical stimulation, as imposed by the hemodynamic environment. We have developed a novel method of studying the influence of mechanical Strain on the remodeling of cell-seeded collagen gel blood vessel analogs. We assessed the remodeling capacity by examining the effect of mechanical conditioning upon the expression of enzymes which remodel the extracellular matrix, called matrix metalloproteinases (MMPs), and upon the mechanical properties of the constructs. We found that subjecting collagen constructs to a 10% Cyclic radial distention, over a course of 4 days, resulted in an overall increase in the production of MMP-2. Cyclic mechanical Strain also stimulated enzymatic activation of latent MMP-2. We found that Cyclic Strain also significantly increased the mechanical strength and material modulus, as indicated by an increase in circumferential tensile properties of the constructs. These observations suggested that MMP-2-dependent remodeling affects the material properties of vascular tissue analogs. To further investigate this possible connection we examined the effects of dynamic conditioning in the presence of two nonspecific inhibitors of MMP activity. Interestingly, we found that nonspecific inhibition of MMP ablated the benefits of mechanical conditioning upon mechanical properties. Our observations suggest that a better understanding of the complex relation between mechanical stimulation and construct remodeling is key for the proper design of tissue-engineered blood vessel substitutes. © 2001 Biomedical Engineering Society.
David J Mooney - One of the best experts on this subject based on the ideXlab platform.
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Cyclic Strain enhances matrix mineralization by adult human mesenchymal stem cells via the extracellular signal regulated kinase erk1 2 signaling pathway
Journal of Biomechanics, 2003Co-Authors: Craig A Simmons, Sean Matlis, Amanda J Thornton, Shaoqiong Chen, Cun Yu Wang, David J MooneyAbstract:Physical stimuli play critical roles in the development, regeneration, and pathology of many mesenchymal tissues, most notably bone. While mature bone cells, such as osteoblasts and osteocytes, are clearly involved in these processes, the role of their progenitors in mechanically mediated tissue responses is unknown. In this study, we investigated the effect of Cyclic substrate deformation on the proliferation and osteogenic differentiation of human mesenchymal stem cells (hMSCs). Application of equibiaxial Cyclic Strain (3%, 0.25Hz) to hMSCs cultured in osteogenic media inhibited proliferation and stimulated a 2.3-fold increase in matrix mineralization over unStrained cells. The Strain stimulus activated the extracellular signal-regulated kinase (ERK1/2) and p38 mitogen-activated protein kinase pathways, but had no effect on c-Jun N-terminal kinase phosphorylation or activity. Strain-induced mineralization was largely mediated by ERK1/2 signaling, as inhibition of ERK1/2 attenuated calcium deposition by 55%. Inhibition of the p38 pathway resulted in a more mature osteogenic phenotype, suggesting an inhibitory role for p38 signaling in the modulation of Strain-induced osteogenic differentiation. These results demonstrate that mechanical signals regulate hMSC function, suggesting a critical role for physical stimulation of this specific cell population in mesenchymal tissue formation.
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Cyclic Strain inhibits switching of smooth muscle cells to an osteoblast like phenotype
The FASEB Journal, 2003Co-Authors: Janeta Nikolovski, Byungsoo Kim, David J MooneyAbstract:Ectopic calcification is commonly associated with cardiovascular disease, injury, aging, and biomaterial implantation. We hypothesized that the normal mechanical environment of smooth muscle cells (SMCs) inhibits a phenotypic switch to a pattern of gene expression more typical for bone and inducive for calcification. This hypothesis was tested using a 3-D engineered smooth muscle tissue model subjected to Cyclic mechanical Strain. This simplified model maintained a 3-D tissue architecture while eliminating systemic effects as can be seen with in vivo models. All engineered tissues were found to express bone-associated genes (osteopontin, matrix gla protein, alkaline phosphatase, and the transcription factor CBFA-1). Strikingly, however, expression of these genes was down-regulated in tissues exposed to Cyclic Strain at all time points ranging from 5 to 150 days. Furthermore, long-term Strain played a protective role in regard to calcification, as unStrained tissues exhibited increased calcium deposition with respect to Strained tissues. The results of this study suggest that without an appropriate mechanical environment, SMCs in 3-D culture undergo a phenotypic conversion to an osteoblast-like pattern of gene expression. This finding has significant implications for the mechanisms underlying a variety of cardiovascular diseases and indicates the broad utility of engineered tissue models in basic biology studies.
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scaffolds for engineering smooth muscle under Cyclic mechanical Strain conditions
Journal of Biomechanical Engineering-transactions of The Asme, 2000Co-Authors: Byungsoo Kim, David J MooneyAbstract:Cyclic mechanical Strain has been demonstrated to enhance the development and function of engineered smooth muscle (SM) tissues, but appropriate scaffolds for engineering tissues under conditions of Cyclic Strain are currently lacking. These scaffolds must display elastic behavior, and be capable of inducing an appropriate smooth muscle cell (SMC) phenotype in response to mechanical signals. In this study, we have characterized several scaffold types commonly utilized in tissue engineering applications in order to select scaffolds that exhibit elastic properties under appropriate Cyclic Strain conditions. The ability of the scaffolds to promote an appropriate SMC phenotype in engineered SM tissues under Cyclic Strain conditions was subsequently analyzed. Poly(L-lactic acid)-bonded polyglycolide fiber-based scaffolds and type I collagen sponges exhibited partially elastic mechanical properties under Cyclic Strain conditions, although the synthetic polymer scaffolds demonstrated significant permanent deformation after extended times of Cyclic Strain application. SM tissues engineered with type I collagen sponges subjected to Cyclic Strain were found to contain more elastin than control tissues, and the SMCs in these tissues exhibited a contractile phenotype. In contrast, SMCs in control tissues exhibited a structure more consistent with the nondifferentiated, synthetic phenotype. These studies indicate the appropriate choice of a scaffold for engineering tissues in a mechanically dynamic environment is dependent on the time frame of the mechanical stimulation, and elastic scaffolds allow for mechanically directed control of cell phenotype in engineered tissues.
Dror Seliktar - One of the best experts on this subject based on the ideXlab platform.
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The Role of Matrix Metalloproteinase-2 in the Remodeling of Cell-Seeded Vascular Constructs Subjected to Cyclic Strain
Annals of Biomedical Engineering, 2001Co-Authors: Dror Seliktar, Robert M. Nerem, Zorina S GalisAbstract:Tissue engineering offers the opportunity to develop vascular substitutes that mimic the responsive nature of native arteries. A good blood vessel substitute should be able to remodel its matrix in response to mechanical stimulation, as imposed by the hemodynamic environment. We have developed a novel method of studying the influence of mechanical Strain on the remodeling of cell-seeded collagen gel blood vessel analogs. We assessed the remodeling capacity by examining the effect of mechanical conditioning upon the expression of enzymes which remodel the extracellular matrix, called matrix metalloproteinases (MMPs), and upon the mechanical properties of the constructs. We found that subjecting collagen constructs to a 10% Cyclic radial distention, over a course of 4 days, resulted in an overall increase in the production of MMP-2. Cyclic mechanical Strain also stimulated enzymatic activation of latent MMP-2. We found that Cyclic Strain also significantly increased the mechanical strength and material modulus, as indicated by an increase in circumferential tensile properties of the constructs. These observations suggested that MMP-2-dependent remodeling affects the material properties of vascular tissue analogs. To further investigate this possible connection we examined the effects of dynamic conditioning in the presence of two nonspecific inhibitors of MMP activity. Interestingly, we found that nonspecific inhibition of MMP ablated the benefits of mechanical conditioning upon mechanical properties. Our observations suggest that a better understanding of the complex relation between mechanical stimulation and construct remodeling is key for the proper design of tissue-engineered blood vessel substitutes. © 2001 Biomedical Engineering Society. PAC01: 8719Rr, 8714Ee, 8717-d
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the role of matrix metalloproteinase 2 in the remodeling of cell seeded vascular constructs subjected to Cyclic Strain
Annals of Biomedical Engineering, 2001Co-Authors: Dror Seliktar, Robert M. Nerem, Zorina S GalisAbstract:Tissue engineering offers the opportunity to develop vascular substitutes that mimic the responsive nature of native arteries. A good blood vessel substitute should be able to remodel its matrix in response to mechanical stimulation, as imposed by the hemodynamic environment. We have developed a novel method of studying the influence of mechanical Strain on the remodeling of cell-seeded collagen gel blood vessel analogs. We assessed the remodeling capacity by examining the effect of mechanical conditioning upon the expression of enzymes which remodel the extracellular matrix, called matrix metalloproteinases (MMPs), and upon the mechanical properties of the constructs. We found that subjecting collagen constructs to a 10% Cyclic radial distention, over a course of 4 days, resulted in an overall increase in the production of MMP-2. Cyclic mechanical Strain also stimulated enzymatic activation of latent MMP-2. We found that Cyclic Strain also significantly increased the mechanical strength and material modulus, as indicated by an increase in circumferential tensile properties of the constructs. These observations suggested that MMP-2-dependent remodeling affects the material properties of vascular tissue analogs. To further investigate this possible connection we examined the effects of dynamic conditioning in the presence of two nonspecific inhibitors of MMP activity. Interestingly, we found that nonspecific inhibition of MMP ablated the benefits of mechanical conditioning upon mechanical properties. Our observations suggest that a better understanding of the complex relation between mechanical stimulation and construct remodeling is key for the proper design of tissue-engineered blood vessel substitutes. © 2001 Biomedical Engineering Society.
Jonathan Riboh - One of the best experts on this subject based on the ideXlab platform.
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flexor tendon tissue engineering bioreactor Cyclic Strain increases construct strength
Tissue Engineering Part A, 2010Co-Authors: Jonathan Riboh, Hung Pham, Derek P. Lindsey, Sepideh Saber, Andrew Y Zhang, R L Smith, James ChangAbstract:Mutilating injuries of the hand and upper extremity result in tendon losses too great to be replaced by autologous grafts. The goal of this study was to use tissue engineering techniques to produce additional tendon material. We used a custom bioreactor to apply Cyclic mechanical loading onto tissue-engineered tendon constructs to study ultimate tensile stress (UTS) and elastic modulus (E). Constructs used were acellularized rabbit hindpaw flexor digitorum profundus equivalents reseeded with tenocytes or left unseeded. Tendon constructs were subjected to a stretch force of 1.25 N over a 5-day course. Seeded tendon constructs that were exposed to bioreactor loading had a significantly increased UTS (71.17 +/- 14.15 N) compared to nonloaded controls (35.69 +/- 5.62 N) (p = 0.001). Similarly, seeded constructs exposed to bioreactor loading also had a significantly higher E (1091 +/- 169 MPa) compared to nonloaded controls (632 +/- 86 MPa) (p = 0.001). This study shows that Cyclic loading of tendon constructs increases the UTS and elastic modulus of seeded constructs. The use of the bioreactor may therefore accelerate the in vitro production of strong, nonimmunogenic tendon material that can potentially be used clinically to reconstruct significant tendon losses.
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Optimization of Flexor Tendon Tissue Engineering With a Cyclic Strain Bioreactor
The Journal of hand surgery, 2008Co-Authors: Jonathan Riboh, Hung Pham, Michael T. Longaker, Christopher R. JacobsAbstract:Purpose Mechanical manipulation of cultured tendon cells can enhance cell proliferation and matrix production. This study aims to determine the bioreactor Strain patterns (amplitude, frequency, and on/off ratio) that favor cellular proliferation, promote collagen production, and maintain morphology in candidate cell lines cultured for flexor tendon tissue engineering, including multipotent stromal cells. Methods We studied epitenon tenocytes (Es), sheath fibroblasts (Ss), bone marrow-derived mesenchymal stem cells (BMSCs), and adipoderived stem cells (ASCs). We examined the effects of 3 patterns of Cyclic uniaxial Strain on cell proliferation, collagen I production, and cell morphology. Results Adipoderived stem cells (33% adhesion) and Ss (29%) adhered more strongly to bioreactor membranes than did Es (15%) and BMSCs (7%), p=.04. Continuous Cyclic Strain (CCS, 8%, 1 Hz) inhibited cell proliferation (p=.01) and increased per-cell collagen production (p=.04) in all cell types. Intermittent Cyclic Strain (4%, 0.1 Hz, 1 hour on/5 hours off) increased proliferation in ASCs (p=.06) and Ss (p=.04). Intermittent Cyclic Strain (4%, 0.1 Hz, 1 hour on/2 hours off) increased total collagen production by 25% in ASCs (p=.004) and 20% in Ss (p=.05). Cyclic Strain resulted in cell alignment perpendicular to the Strain axis, cytoskeletal alignment, and nuclear elongation. These morphological characteristics are similar to those of tenocytes. Conclusions These results demonstrate that intermittent Cyclic Strain can increase cell proliferation, promote collagen I production, and maintain tenocyte morphology in vitro. Use of a cell bioreactor might accelerate the in vitro stage of tendon tissue engineering.
