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Biomedical subjects

Farshid Guilak

Publications and source records attributed to Farshid Guilak.

At least 37 records · Page 2Linked to original sources
PubMed2005

Selective Runx2-II deficiency leads to low-turnover osteopenia in adult mice.

Runx2 transcribes Runx2-II and Runx2-I isoforms with distinct N-termini. Deletion of both isoforms results in complete arrest of bone development, whereas selective loss of Runx2-II is sufficient to form a grossly intact skeleton with impaired endochondral bone development. To elucidate the role of Runx2-II in osteoblast function in adult mice, we examined heterozygous Runx2-II (Runx2-II(+/-)) and homozygous Runx2-II (Runx2-II(-/-))-deficient mice, which, respectively, lack one or both copies of Runx2-II but intact Runx2-I expression. Compared to wild-type mice, 6-week-old Runx2-II(+/-) had reduced trabecular bone volume (BV/TV%), cortical thickness (Ct.Th), and bone mineral density (BMD), decreased osteoblastic and osteoclastic markers, lower bone formation rates, impaired osteoblast maturation of BMSCs in vitro, and significant reductions in mechanical properties. Homozygous Runx2-II(-/-) mice had a more severe reduction in BMD, BV/TV%, and Ct.Th, and greater suppression of osteoblastic and osteoclastic markers than Runx2-II(+/-) mice. Non-selective Runx2(+/-) mice, which have an equivalent reduction in Runx2 expression due to the lack one copy of Runx2-I and II, however, had an intermediate reduction in BMD. Thus, selective Runx2-II mutation causes diminished osteoblastic function in an adult mouse leading to low-turnover osteopenia and suggest that Runx2-I and II have distinct functions imparted by their different N-termini.

Animals↗
PubMed2005

The influence of oxygen tension on the induction of nitric oxide and prostaglandin E2 by mechanical stress in articular cartilage.

OBJECTIVES: Articular cartilage is an avascular tissue that exists at low oxygen tension. Oxygen tension can influence the production of the pro-inflammatory mediators nitric oxide (NO) and prostaglandin E2 (PGE(2)) in cartilage, which are increased in osteoarthritis (OA). The synthesis of these molecules can be stimulated by mechanical stress, which is an important risk factor for OA. The objective of this study was to determine the influence of oxygen tension on the induction of NO and PGE(2) production in articular cartilage in response to mechanical stress. DESIGN: Intermittent mechanical compression (0.05MPa, 0.5Hz for 24h) was applied to full thickness skeletally mature porcine articular cartilage explants at either 20%, 5%, or 1% O(2). NO, PGE(2) and peroxynitrite formation were measured, and the effect of the selective nitric oxide synthase 2 inhibitor 1400W was tested. RESULTS: Incubating articular cartilage at 5% O(2) significantly increased (P<0.001) baseline NO production, as compared with 1% or 20% O(2). Peroxynitrite formation was lower at reduced oxygen tension. Mechanical compression significantly increased (P<0.001) NO production at 20% O(2) but not at 5% or 1% O(2), and significantly increased (P<0.001) PGE(2) production at 20% O(2) (50 fold) and 5% O(2) (4 fold) but not at 1% O(2). 1400W blocked mechanically induced NO production and further increased PGE(2) production at 5% O(2) (P<0.05). CONCLUSIONS: Oxygen tension influences the endogenous production of NO and PGE(2) in cartilage and can have a significant effect on the induction of these inflammatory mediators in response to mechanical compression.

Animals↗
PubMed2005

Role of matrix extracellular phosphoglycoprotein in the pathogenesis of X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH), a disorder characterized by hypophosphatemia, impaired skeletal mineralization, and aberrant regulation of 1, 25(OH)(2)D(3), is caused by inactivating mutations of Phex, which results in the accumulation of putative phosphaturic factors, called phosphatonins. Matrix extracellular phosphoglycoprotein (Mepe) is a proposed candidate for phosphatonin. The authors found that Hyp mice had increased expression of the MEPE and another phosphaturic factor, Fgf23. To establish MEPE's role in the pathogenesis of the XLH, Mepe-deficient mice were back-crossed onto the Hyp mouse homologue of XLH and phenotypes of wild-type, Mepe(-/-), Hyp, and Mepe(-/-)/Hyp mice were examined. Transfer of Mepe deficiency onto the Phex-deficient Hyp mouse background failed to correct hypophosphatemia and aberrant serum 1,25(OH)(2)D(3) levels. Increased Fgf23 levels in Hyp mice were not affected by superimposed Mepe deficiency. In addition, Mepe-deficient Hyp mice retained bone mineralization defects in vivo, characterized by decreased bone mineral density, reduced mineralized trabecular bone volume, lower flexural strength, and histologic evidence of osteomalacia; however, cultures of Hyp-derived bone marrow stromal cells in the absence of Mepe showed improved mineralization and normalization of osteoblast gene expression profiles observed in cells derived from Mepe-null mice. These results demonstrate that MEPE elevation in Hyp mice does not contribute to the hypophosphatemia associated with inactivating Phex mutations and is therefore not phosphatonin.

Animals↗
PubMed2005

Cartilage degeneration in post-collapse cases of osteonecrosis of the human femoral head: altered mechanical properties in tension, compression, and shear.

Osteonecrosis, or avascular necrosis, is a painful and debilitating condition characterized by progressive joint degeneration subsequent to collapse of necrotic regions of trabecular bone. A clear understanding of the mechanism of cartilage degeneration in osteonecrosis is critical to the development of treatment strategies aimed at sparing the femoral head. An analysis of 13 post-collapse osteonecrotic (ON) human femoral heads was performed relative to 24 non-ON controls to determine quantitatively the biomechanical and histological properties of post-collapse osteonecrotic cartilage. Cartilage mechanical properties were measured in tension, compression, and shear at different sites on the femoral head and correlated to histologic measures of cartilage degeneration using a semi-quantitative grading scale. Decreasing cartilage tensile strength correlated with histologic evidence of degeneration in the ON group; however, less correlation was noted with shear and compressive properties. After statistical correction for the more severe histologic degeneration in the ON group, the non-ON samples were found to exhibit significantly smaller loss angles during shear testing, while samples from the ON group were found to have greater tensile strength. Similarly, the ON group was found to exhibit significantly greater proteoglycan loss while the non-ON group showed significantly increased surface fibrillation. This study provides evidence that the changes occurring in post-collapse cases of osteonecrosis may involve mechanisms other than those typically attributed to osteoarthritic degeneration. One potential explanation is that decreased loading of cartilage overlying collapsed ON lesions leads to proteoglycan loss similar to that occurring with cartilage disuse. Unlike degenerative changes, some articular cartilage changes caused by disuse may be reversible. The presence of reversible changes would likely increase the chances of success of head sparing treatment strategies that rely on the viability and mechanical integrity of the articular cartilage.

Adult↗
PubMed2005

The biomechanical role of the chondrocyte pericellular matrix in articular cartilage.

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 approximately 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.

Biomechanical Phenomena↗
PubMed2005

Determination of the Poisson's ratio of the cell: recovery properties of chondrocytes after release from complete micropipette aspiration.

Chondrocytes in articular cartilage are regularly subjected to compression and recovery due to dynamic loading of the joint. Previous studies have investigated the elastic and viscoelastic properties of chondrocytes using micropipette aspiration techniques, but in order to calculate cell properties, these studies have generally assumed that cells are incompressible with a Poisson's ratio of 0.5. The goal of this study was to measure the Poisson's ratio and recovery properties of the chondrocyte by combining theoretical modeling with experimental measures of complete cellular aspiration and release from a micropipette. Chondrocytes isolated from non-osteoarthritic and osteoarthritic cartilage were fully aspirated into a micropipette and allowed to reach mechanical equilibrium. Cells were then extruded from the micropipette and cell volume and morphology were measured throughout the experiment. This experimental procedure was simulated with finite element analysis, modeling the chondrocyte as either a compressible two-mode viscoelastic solid, or as a biphasic viscoelastic material. By fitting the experimental data to the theoretically predicted cell response, the Poisson's ratio and the viscoelastic recovery properties of the cell were determined. The Poisson's ratio of chondrocytes was found to be 0.38 for non-osteoarthritic cartilage and 0.36 for osteoarthritic chondrocytes (no significant difference). Osteoarthritic chondrocytes showed an increased recovery time following full aspiration. In contrast to previous assumptions, these findings suggest that chondrocytes are compressible, consistent with previous studies showing cell volume changes with compression of the extracellular matrix.

Capillary Action↗
PubMed2005

Influence of oxygen on the proliferation and metabolism of adipose derived adult stem cells.

Articular cartilage is an avascular connective tissue that exhibits little intrinsic capacity for repair. Articular cartilage exists in a reduced oxygen ( approximately 5%) environment in vivo; therefore, oxygen tension may be an important factor that regulates the metabolism of chondrocyte progenitors. A number of recent studies have developed tissue engineering approaches for promoting cartilage repair using undifferentiated progenitor cells seeded on biomaterial scaffolds, but little is known about how oxygen might influence these engineered tissues. Human adipose-derived adult stem (hADAS) cells isolated from the stroma of subcutaneous fat were suspended in alginate beads and cultured in control or chondrogenic media in either low oxygen (5%) or atmospheric oxygen tension (20%) for up to 14 days. Under chondrogenic conditions, low oxygen tension significantly inhibited the proliferation of hADAS cells, but induced a two-fold increase in the rate of protein synthesis and a three-fold increase in total collagen synthesis. Low oxygen tension also increased glycosaminoglycan synthesis at certain timepoints. Immunohistochemical analysis showed significant production of cartilage-associated matrix molecules, including collagen type II and chondroitin-4-sulfate. These findings suggest oxygen tension may play an important role in regulating the proliferation and metabolism of hADAS cells as they undergo chondrogenesis, and the exogenous control of oxygen tension may provide a means of increasing the overall accumulation of matrix macromolecules in tissue-engineered cartilage.

Adipose Tissue↗
PubMed2005

Large deformation finite element analysis of micropipette aspiration to determine the mechanical properties of the chondrocyte.

Chondrocytes, the cells in articular cartilage, exhibit solid-like viscoelastic behavior in response to mechanical stress. In modeling the creep response of these cells during micropipette aspiration, previous studies have attributed the viscoelastic behavior of chondrocytes to either intrinsic viscoelasticity of the cytoplasm or to biphasic effects arising from fluid-solid interactions within the cell. However, the mechanisms responsible for the viscoelastic behavior of chondrocytes are not fully understood and may involve one or both of these phenomena. In this study, the micropipette aspiration experiment was modeled using a large strain finite element simulation that incorporated contact boundary conditions. The cell was modeled using finite strain incompressible and compressible elastic models, a two-mode compressible viscoelastic model, or a biphasic elastic or viscoelastic model. Comparison of the model to the experimentally measured response of chondrocytes to a step increase in aspiration pressure showed that a two-mode compressible viscoelastic formulation accurately captured the creep response of chondrocytes during micropipette aspiration. Similarly, a biphasic two-mode viscoelastic analysis could predict all aspects of the cell's creep response to a step aspiration. In contrast, a biphasic elastic formulation was not capable of predicting the complete creep response, suggesting that the creep response of the chondrocytes under micropipette aspiration is predominantly due to intrinsic viscoelastic phenomena and is not due to the biphasic behavior.

Animals↗
PubMed2005

Zonal uniformity in mechanical properties of the chondrocyte pericellular matrix: micropipette aspiration of canine chondrons isolated by cartilage homogenization.

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.

Animals↗
PubMed2005

Osteoarthritic changes in the biphasic mechanical properties of the chondrocyte pericellular matrix in articular cartilage.

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+/-16.2 kPa vs. 23.5+/-12.9 kPa, p < 0.001), and the permeability was significantly elevated (4.19+/-3.78 x10(-17) m(4)/Ns vs. 10.2+/-9.38 x 10(-17) m(4)/Ns, p < 0.01). 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.

Biomechanical Phenomena↗
PubMed2005

The role of mechanical loading in the onset and progression of osteoarthritis.

Osteoarthritis is a progressive joint disease characterized by an imbalance of articular cartilage biosynthesis and degradation attributed to both inflammatory and biomechanical factors. Whereas moderate mechanical loading appears necessary for maintaining healthy cartilage, abnormal joint loading increases the risk of osteoarthritis. Obesity-induced osteoarthritis and the benefits of physical activity may be mediated by systemic levels of proinflammatory mediators as well as local biomechanical factors in the joint.

Cartilage, Articular↗
PubMed2005

The effect of intermittent pneumatic compression on fracture healing.

OBJECTIVES: Continuously increased venous pressure has been shown to enhance bone growth, stimulate fracture healing, and prevent bone loss, but also causes soft-tissue breakdown as a result of chronic edema. This study was designed to test the hypothesis that intermittently increased venous pressure improves fracture healing without injuring soft tissue. DESIGN: An ostectomy was created in the right radius of 30 skeletally mature male beagles. On postoperative day 7, a pneumatic cuff was placed around the forelimb of each dog. In experimental animals (n = 13), the cuff compressed for 5 minutes followed by no compression for 2.5 minutes. This cycle was repeated 100 times per day for 8 weeks. Control animals (n = 15) wore a nonfunctional cuff. Fracture healing was assessed with dual-energy x-ray absorptiometry, histologic analysis, and biomechanical testing. RESULTS: No soft-tissue complications were noted. Bone mineral content at the ostectomy increased significantly more in the experimental group than in the control group (P < 0.05). Histology revealed that the bone defects in the experimental group were significantly more healed than those in the control group (P < 0.005). No differences were noted between groups in the biomechanical properties of the healing bones. CONCLUSIONS: Intermittently increased venous pressure proximal to a bone defect seems to enhance the formation of new bone without soft-tissue complications. These findings can potentially be applied to the clinical treatment of "difficult to heal" fractures. Further work is necessary to determine the most effective ratio of the presence and absence of pneumatic compression.

Absorptiometry, Photon↗
PubMed2005

Articular cartilage degeneration in post-collapse osteonecrosis of the femoral head. Radiographic staging, macroscopic grading, and histologic changes.

BACKGROUND: Osteonecrosis of the femoral head is a debilitating condition characterized by progressive degeneration of bone that eventually leads to collapse of the femoral head in the majority of patients. Femoral head-sparing procedures have been more successful in pre-collapse stages of osteonecrosis than in post-collapse stages, although some patients with early post-collapse disease have had no additional progression of the disorder. Nevertheless, the effects of collapse on the articular cartilage are not well understood, and radiographic staging of femoral head collapse does not address the condition of the articular cartilage. METHODS: In the current study, we investigated the relationship between the mechanical properties of post-collapse articular cartilage and the histologic findings and macroscopic grades of the articular cartilage from hips with stage-IV osteonecrosis, those with stage-V osteonecrosis, and those without osteonecrosis. RESULTS: The cartilage from both stage-IV and stage-V hips showed significant degeneration compared with the normal control cartilage, but there was no significant difference between the two stages. There was significant variability in the histologic and mechanical properties of these samples that correlated strongly with the gross appearance of the cartilage surface but not with the lesion size. CONCLUSIONS: These results suggest that articular cartilage that appears macroscopically normal may remain mechanically functional even in patients with large osteonecrotic lesions or a late radiographic stage of the disease.

Biomechanical Phenomena↗
PubMed2004

Molecular diffusion in tissue-engineered cartilage constructs: effects of scaffold material, time, and culture conditions.

Diffusion is likely to be the primary mechanism for macromolecular transport in tissue-engineered cartilage, and providing an adequate nutrient supply via diffusion may be necessary for cell proliferation and extracellular matrix production. The goal of this study was to measure the diffusivity of tissue-engineered cartilage constructs as a function of scaffold material, culture conditions, and time in culture. Diffusion coefficients of four different-sized fluorescent dextrans were measured by fluorescence recovery after photobleaching in tissue-engineered cartilage constructs seeded with human adipose-derived stem cells or acellular constructs on scaffolds of alginate, agarose, gelatin, or fibrin that were cultured for 1 or 28 days in either chondrogenic or control conditions. Diffusivities in the constructs were much greater than those of native cartilage. The diffusivity of acellular constructs increased 62% from Day 1 to Day 28, whereas diffusivity of cellular constructs decreased 42% and 27% in chondrogenic and control cultures, respectively. The decrease in diffusivity in cellular constructs is likely due to new matrix synthesis, which may be enhanced with chondrogenic media, and matrix contraction by the cells in the fibrin and gelatin scaffolds. The increase in diffusivity in the acellular constructs is probably due to scaffold degradation and swelling.

Adipocytes↗
PubMed2004

Chondrogenic differentiation of adipose-derived adult stem cells in agarose, alginate, and gelatin scaffolds.

The differentiation and growth of adult stem cells within engineered tissue constructs are hypothesized to be influenced by cell-biomaterial interactions. In this study, we compared the chondrogenic differentiation of human adipose-derived adult stem (hADAS) cells seeded in alginate and agarose hydrogels, and porous gelatin scaffolds (Surgifoam), as well as the functional properties of tissue engineered cartilage constructs. Chondrogenic media containing transforming growth factor beta 1 significantly increased the rates of protein and proteoglycan synthesis as well as the content of DNA, sulfated glycosaminoglycans, and hydroxyproline of engineered constructs as compared to control conditions. Furthermore, chondrogenic culture conditions resulted in 86%, and 160% increases ( p < 0.05 ) in the equilibrium compressive and shear moduli of the gelatin scaffolds, although they did not affect the mechanical properties of the hydrogels over 28 days in culture. Cells encapsulated in the hydrogels exhibited a spherical cellular morphology, while cells in the gelatin scaffolds showed a more polygonal shape; however, this difference did not appear to hinder the chondrogenic differentiation of the cells. Furthermore, the equilibrium compressive and shear moduli of the gelatin scaffolds were comparable to agarose by day 28. Our results also indicated that increases in the shear moduli were significantly associated with increases in S-GAG content ( R2 = 0.36, p < 0.05 ) and with the interaction between S-GAG and hydroxyproline ( R2 = 0.34, p < 0.05 ). The findings of this study suggest that various biomaterials support the chondrogenic differentiation of hADAS cells, and that manipulating the composition of these tissue engineered constructs may have significant effects on their mechanical properties.

Adipose Tissue↗
PubMed2004

The effects of cyclic mechanical strain and tumor necrosis factor alpha on the response of cells of the meniscus.

OBJECTIVES: Cells of the knee meniscus respond to changes in their biochemical and biomechanical environments with alterations in the biosynthesis of matrix constituents and inflammatory mediators. Tumor necrosis factor alpha (TNF-alpha) is a pro-inflammatory cytokine that is involved in the pathogenesis of both osteoarthritis and rheumatoid arthritis, but its influence on meniscal physiology or mechanobiology is not fully understood. The objectives of this study were to examine the hypothesis that cyclic mechanical strain of meniscal cells modulates the biosynthesis of matrix macromolecules and pro-inflammatory mediators, and to determine if this response is altered by TNF-alpha. METHODS: Cells were isolated from the inner two-thirds of porcine medial menisci and subjected to biaxial tensile strain of 5-15% at a frequency of 0.5Hz. The synthesis of proteoglycan, protein, nitric oxide (NO), and prostaglandin E(2) were determined. RESULTS: Cyclic tensile strain increased the production of nitric oxide through the upregulation of nitric oxide synthase 2 (NOS2) and also increased synthesis rates of prostaglandin E(2), proteoglycan, and total protein in a manner that depended on strain magnitude. TNF-alpha increased the production of NO and total protein, but inhibited proteoglycan synthesis rates. TNF-alpha prevented the mechanical stimulation of proteoglycan synthesis, and this effect was not dependent on NOS2. CONCLUSIONS: These findings indicate that pro-inflammatory cytokines can modulate the responses of meniscal cells to mechanical signals, suggesting that both biomechanical and inflammatory factors could contribute to the progression of joint disease as a consequence of altered loading of the meniscus.

Animals↗
PubMed2004

Mechanical signals as regulators of stem cell fate.

In recent years, stem cells have shown significant promise for their potential to provide a source of undifferentiated progenitor cells for therapeutic applications in tissue or organ repair. Significant questions still remain, however, as to the genetic and epigenetic signals that regulate the fate of stem cells. It is now well accepted that the micro-environment of the stem cell can have a significant influence on its differentiation and phenotypic expression. Although emphasis has been placed in previous work on the role of soluble mediators such as growth factors and cytokines on stem cell differentiation, there is now significant evidence, both direct and indirect, that mechanical signals may also regulate stem cell fate. We review a number of in vivo and in vitro studies that have provided evidence that mechanical factors have the ability to influence the differentiation of a number of cells that have been classified as either precursor, progenitor, or stem cells. Taken together, these studies show that specific mechanical signals may promote cell differentiation into a particular phenotype, potentially having an effect on embryonic development. The use of such mechanical signals in vitro in specially designed "bioreactors" may provide important adjuncts to standard biochemical signaling pathways for promoting engineered tissue growth. A further understanding of the biomechanical and biochemical pathways involved in mechanical signal transduction by stem cells will hopefully provide new insight for the improvement of stem-cell based therapies.

Animals↗