Combined effects of growth factors and static mechanical compression on meniscus explant biosynthesis

Imler, Stacy M.; Doshi, Ashish N.; Levenston, Marc E.

doi:10.1016/j.joca.2004.05.007

Cited by 89 publications

(74 citation statements)

References 41 publications

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“…Work from Lima et al (2007) with agarose encapsulated chondrocytes showed that varying the dosing regimen of TGF-b3 was more beneficial than continuous dosing, suggesting a direction for future work with TGF-b1 and the co-cultures. The expected increase in proteoglycan synthesis was, however, borne out in the FC groups: both GAG and collagen production was increased, and this is well corroborated with prior work using fibrochondrocytes in both monolayer, explant, and 3D culture (Collier and Ghosh, 1995;Imler et al, 2004;Lietman et al, 2003;Mauck et al, 2007;Pangborn and Athanasiou, 2005a,b). It is notable that the FC-FM þ T group also had fourfold greater collagen II production over FC-FM, and there was also greater cell proliferation.…”

Section: Discussionsupporting

confidence: 82%

Creating a spectrum of fibrocartilages through different cell sources and biochemical stimuli

Hoben

Athanasiou

2007

Biotech & Bioengineering

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In this study a scaffoldless approach was employed with two different cell sources and biochemical stimuli to engineer a spectrum of fibrocartilages representative of the different regions of the knee meniscus. Constructs composed of 100% fibrochondrocytes (FC) or a 50:50 co-culture of fibrochondrocytes and chondrocytes (CC) were cultured in 10% fetal bovine serum medium or serum-free "chondrogenic" medium, each +/-10 ng/mL TGF-beta1 (+T). Constructs from these two cell groups and four culture conditions were cultured for 6 weeks. By varying the cell type and presence of the growth factor, GAG per dry weight of the constructs spanned that of native tissue, ranging 16-45% and 1-7% in the CC and FC groups, respectively. Collagen density was most dependent on cell type and was significantly lower than tissue values. The collagen I/II ratio could be manipulated by cell type and serum presence to span the native range, from 3.5 in the serum-free CC group to over 1,000 in the FC groups treated with serum-containing medium. Using the CC cell group in the presence of serum-free medium dramatically increased the compressive stiffness to 128 +/- 34 kPa, similar to native tissue. Similarly, serum-free medium or TGF-beta1 treatment enhanced the tensile modulus by an order of magnitude, up to 3,000 kPa. Using two cell sources and manipulating biochemical stimuli, a range of fibrocartilaginous neotissues was engineered. Fibrocartilages such as the knee meniscus are characterized by heterogeneity in matrix and functional properties, and this work demonstrates a strategy for recreating these heterogeneous tissues.

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Section: Discussionsupporting

confidence: 82%

Creating a spectrum of fibrocartilages through different cell sources and biochemical stimuli

Hoben

Athanasiou

2007

Biotech & Bioengineering

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“…Alternatively, mechanical loading regimens may help integrative meniscal repair. In meniscal explants, static loading decreases biosynthesis of matrix components [30] and increases expression of MMPs [52]. Conversely, dynamic compression or stretch increase matrix biosynthesis [20,51] and can decrease the inflammatory effects of IL-1 on isolated meniscal cells by blocking MMP-13 mRNA upregulation [21].…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Matrix Metalloproteinases Enhances In Vitro Repair of the Meniscus

McNulty

Weinberg

Guilak

2008

Clin Orthop Relat Res

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Damage or injury of the meniscus is associated with onset and progression of knee osteoarthritis (OA). The intrinsic repair capacity of the meniscus is inhibited by inflammatory cytokines, such as interleukin-1 (IL-1). Using an in vitro meniscal repair model system, we examined the hypothesis that inhibition of matrix metalloproteinases (MMPs) in the presence of IL-1 will enhance repair of meniscal lesions. Integrative repair of the meniscus was examined between two concentric explants cultured with IL-1 and various MMP inhibitors for 14 days. Throughout the culture period, we assessed total specific MMP activity in the media. At harvest, biomechanical testing to assess the strength of repair and histologic staining were performed. IL-1 decreased the shear strength of repair, as compared with control explants. In the presence of IL-1, the broad-spectrum MMP inhibitor GM 6001 decreased the MMP activity in the media, increased the shear strength of repair, and enhanced tissue repair in the interface. However, individual MMP inhibitors did not alter the shear strength of repair in either the presence or absence of IL-1. These findings suggest IL-1 may inhibit meniscal repair through upregulation of MMPs, but inhibition of multiple MMPs may be necessary to promote integrative meniscal repair.

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“…In addition, it may be possible to enhance meniscal repair by intraarticular injection of synoviocytes or stem cells expressing IL-1Ra complementary DNA. Other cytokines, such as IL-17, may provide additional targets for anticytokine therapies (26), or alternatively, proanabolic growth factors may provide a means of enhancing matrix biosynthesis (52)(53)(54)(55)(56) to accelerate meniscal repair. The in vitro model presented in this study provides a novel and quantitative means of studying the influence of specific pharmacologic inhibitors and their mechanisms of action on integrative repair of the meniscus.…”

Section: Discussionmentioning

confidence: 99%

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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Combined effects of growth factors and static mechanical compression on meniscus explant biosynthesis

Cited by 89 publications

References 41 publications

Creating a spectrum of fibrocartilages through different cell sources and biochemical stimuli

Creating a spectrum of fibrocartilages through different cell sources and biochemical stimuli

Inhibition of Matrix Metalloproteinases Enhances In Vitro Repair of the Meniscus

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

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