Repair Response of the Inner and Outer Regions of the Porcine Meniscus in Vitro

Hennerbichler, Alfred; Moutos, Franklin T.; Hennerbichler, Diana; Weinberg, J. Brice; Guilak, Farshid

doi:10.1177/0363546506296416

Cited by 73 publications

(86 citation statements)

References 54 publications

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“…Samples were cultured for 21 d with chondrogenic differentiation medium containing 10 ng/mL TGF-β3 and 100 nM dexamethasone. After 21 d, samples were processed for histology (n = 2 per group) or used to assess the mechanical strength of the defect repair (n ≥ 5 per group) by measuring the peak shear stress during a push-out test in a size-adjusted version of a described method (49).…”

Section: Methodsmentioning

confidence: 99%

Cartilage tissue engineering using differentiated and purified induced pluripotent stem cells

Diekman

Christoforou

Willard

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The development of regenerative therapies for cartilage injury has been greatly aided by recent advances in stem cell biology. Induced pluripotent stem cells (iPSCs) have the potential to provide an abundant cell source for tissue engineering, as well as generating patient-matched in vitro models to study genetic and environmental factors in cartilage repair and osteoarthritis. However, both cell therapy and modeling approaches require a purified and uniformly differentiated cell population to predictably recapitulate the physiological characteristics of cartilage. Here, iPSCs derived from adult mouse fibroblasts were chondrogenically differentiated and purified by type II collagen (Col2)-driven green fluorescent protein (GFP) expression. Col2 and aggrecan gene expression levels were significantly up-regulated in GFP+ cells compared with GFP− cells and decreased with monolayer expansion. An in vitro cartilage defect model was used to demonstrate integrative repair by GFP+ cells seeded in agarose, supporting their potential use in cartilage therapies. In chondrogenic pellet culture, cells synthesized cartilagespecific matrix as indicated by high levels of glycosaminoglycans and type II collagen and low levels of type I and type X collagen. The feasibility of cell expansion after initial differentiation was illustrated by homogenous matrix deposition in pellets from twicepassaged GFP+ cells. Finally, atomic force microscopy analysis showed increased microscale elastic moduli associated with collagen alignment at the periphery of pellets, mimicking zonal variation in native cartilage. This study demonstrates the potential use of iPSCs for cartilage defect repair and for creating tissue models of cartilage that can be matched to specific genetic backgrounds.chondrocyte | bone morphogenetic proteins | transforming growth factor-beta | cartilage micromechanics | cartilage regeneration

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Section: Methodsmentioning

confidence: 99%

Cartilage tissue engineering using differentiated and purified induced pluripotent stem cells

Diekman

Christoforou

Willard

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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234

250

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“…We used an explant model system described previously (19,34) to study integrative repair of the meniscus. Medial menisci were harvested from the knees of 2-3-year-old skeletally mature female pigs; tissues were obtained from a local abattoir.…”

Section: Methodsmentioning

confidence: 99%

“…The interfacial shear strength of repair between the inner core and outer ring was determined using a push-out test as described previously (19). Cultured specimens (8-mm outer ring with integrated 4-mm inner core) were placed into a custom-built testing fixture that consisted of a suspended cup with a central 5-mm hole in the base.…”

Section: Methodsmentioning

confidence: 99%

“…This difference in repair potential between the inner and outer regions of the meniscus is related to the vascular supply. Furthermore, explants from both the inner and outer zones of the meniscus have the same intrinsic repair capacity in vitro (19), suggesting that meniscal lesions could be repaired if provided with the appropriate intraarticular conditions. Inflammatory cytokines, particularly interleukin-1 (IL-1) and tumor necrosis factor ␣ (TNF␣), are up-regulated in injured and degenerated joints.…”

mentioning

confidence: 99%

“…We hypothesized that inflammatory cytokines prevent the repair of meniscal lesions in a dose-dependent manner, and that inhibition of these cytokines will enhance meniscal repair. We used an in vitro model of meniscal repair (19) to examine the effects of a range of physiologic concentrations of IL-1 and TNF␣ on the healing of explants from the outer region of the meniscus. Explants were cultured for 14, 28, or 42 days, and meniscus healing was investigated using mechanical testing to determine the shear strength, histologic features, and fluorescence confocal microscopic characteristics of the tissue interface.…”

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confidence: 99%

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Enhanced integrative repair of the porcine meniscus in vitro by inhibition of interleukin‐1 or tumor necrosis factor α

McNulty

Moutos

Weinberg

et al. 2007

Arthritis & Rheumatism

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Objective. To examine the hypotheses that increasing concentrations of interleukin-1 (IL-1) or tumor necrosis factor ␣ (TNF␣) inhibit the integrative repair of the knee meniscus in an in vitro model system, and that inhibitors of these cytokines will enhance repair.Methods. Explants (8 mm in diameter) were harvested from porcine medial menisci. To simulate a full-thickness defect, a 4-mm-diameter core was removed and reinserted. Explants were cultured for 14, 28, or 42 days in the presence of 0-1,000 pg/ml of IL-1 or TNF␣. Explants were also cultured in the presence of IL-1 or TNF␣ with IL-1 receptor antagonist (IL-1Ra) or TNF monoclonal antibody (mAb). At the end of the culture period, biomechanical testing, cell viability, and histologic analyses were performed to quantify the extent of repair.Results. Mechanical testing revealed increased repair strength, cell accumulation, and tissue formation at the interface over time under control conditions. Pathophysiologic concentrations of both IL-1 and TNF␣ significantly decreased repair strength, cell migration, and tissue formation at the interface. The addition of IL-1Ra or TNF mAb to explants prevented the effects of IL-1 or TNF␣, respectively. Conclusion. Our findings document that physiologically relevant concentrations of IL-1 and TNF␣ inhibit meniscal repair in vitro and therefore may also inhibit meniscal repair during arthritis or following joint injury. The finding that IL-1Ra and TNF mAb promoted integrative meniscal repair in an inflammatory microenvironment suggests that intraarticular delivery of IL-1Ra and/or TNF mAb may be useful clinically to promote meniscal healing following injury.

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Regional and Zonal Histo‐Morphological Characteristics of the Lapine Menisci

Killian

Lepinski

Haut

et al. 2010

The Anatomical Record

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The menisci have crucial weight-bearing roles in the knee. Regional variations in structure and cellularity of the meniscus have only been minimally investigated. Therefore, the goal of this study was to illustrate the regional cell density, tissue area, and structure of healthy lapine menisci. Skeletally mature Flemish Giant rabbits were used for this study. Upon sacrifice, menisci were removed, fixed in formalin, and cryosectioned. Histological analysis was performed for the detection of sulfated glycosaminoglycans (GAG), collagen Types I and II, cellular density, and tissue area. ANOVA and paired t tests were used for testing of statistical significance. Glycosaminoglycan coverage of the medial meniscus significantly varied between regions, with the anterior region demonstrating significantly more GAG coverage than the posterior region. Inter- and intra-meniscal comparisons revealed variations between zones, with trends that outer zones of the medial menisci had less GAG coverage. Collagen Types I and II had marked characteristics and varying degrees of coverage across regions. Tissue area varied between regions for both medial and lateral menisci. Cellular density was dependent on region in the lateral meniscus. This is the first study to illustrate regional and zonal variation in glycosaminoglycan coverage, size, and cellular density for healthy lapine meniscal tissue. This data provides baseline information for future investigations in meniscal injury models in rabbits.

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Repair Response of the Inner and Outer Regions of the Porcine Meniscus in Vitro

Abstract: These findings support the hypothesis that the regional differences in meniscal repair observed clinically are owed to the additional vascular supply of the outer meniscus rather than intrinsic differences between the extracellular matrix and cells from these 2 areas.

Cited by 73 publications

References 54 publications

Cartilage tissue engineering using differentiated and purified induced pluripotent stem cells

Cartilage tissue engineering using differentiated and purified induced pluripotent stem cells

Enhanced integrative repair of the porcine meniscus in vitro by inhibition of interleukin‐1 or tumor necrosis factor α

Regional and Zonal Histo‐Morphological Characteristics of the Lapine Menisci

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