Bioactivity of small intestinal submucosa and oxidized regenerated cellulose/collagen.

OBJECTIVE: This study examined the bioactivity of porcine small intestinal submucosa (SIS Wound Matrix [SISWM], USP) and oxidized regenerated cellulose/collagen (ORC). DESIGN: Bioactivity was assessed in vitro as the ability to stimulate neurite outgrowth in rat pheochromocytoma (PC12) cells, proliferation of human fibroblasts, secretion of vascular endothelial growth factor (VEGF) from human fibroblasts, and in an in vivo angiogenesis model. In the angiogenesis model, SISWM and ORC were implanted subcutaneously into the mice, and vessel ingrowth was assessed at day 21 after implantation using fluorescence microangiography and histology. MAIN OUTCOME MEASURES: The change in cellular differentiation, proliferation, growth factor secretion, and angiogenesis over the negative control was measured after exposure to SISWM or ORC. MAIN RESULTS: SISWM increased neurite outgrowth in PC12 cells by approximately 22% over negative controls and induced proliferation in 50.8% of human fibroblasts. These increases were comparable to positive controls. ORC was not active in either of these assays. SISWM also stimulated fibroblast VEGF secretion to a greater extent (422.4 pg/mL) than ORC (4.2 pg/mL) (P < .001). At 21 days, fluorescence microangiography showed dense infiltration of blood vessels in the SISWM that extended approximately 3 mm from the edge of the disc. In contrast, the ORC implant showed blood vessel incursion less than 1 mm from the edge of the disc, and it dissolved in the site. CONCLUSIONS: SISWM shows much greater bioactivity than ORC. This is likely related to its close structural and biochemical approximation to natural dermal extracellular matrix and may help explain the strong clinical successes of SISWM.

Extracellular matrix as a strategy for treating chronic wounds.

The dermis normally directs all phases of skin wound healing following tissue trauma or disease. However, in chronic wounds, the dermal matrix is insufficient to stimulate healing and assistance by external factors is needed for wound closure. Although the concept of the extracellular matrix directing wound healing is not new, ideas about how best to provide the extracellular matrix components required to 'jump-start' the healing process are still evolving. Historically, these strategies have included use of enzyme-inhibiting dressing materials, which bind matrix metalloproteinases and remove them from the chronic wound environment, or direct application of purified growth factors to stimulate fibroblast activity and deposition of neo-matrix. More recently, the application of a structurally intact, biochemically complex extracellular matrix, designed to provide the critical extracellular components of the dermis in a single application, has allowed for the reconstruction of new, healthy tissue and restoration of tissue integrity in the previously chronic wound. This review focuses on this third mechanism as an emerging tactic in effective wound repair. Intact extracellular matrix can quickly, easily, and effectively provide key extracellular components of the dermis necessary to direct the healing response and allow for the proliferation of new, healthy tissue. Its application may promote the healing of wounds that have been refractory to other, more conventional treatment strategies, and may eventually show utility when used earlier in wound healing treatment with the goal of preventing wounds from reaching a truly chronic, nonresponsive state.

Matrix metalloproteinase 9 facilitates collagen remodeling and angiogenesis for vascular constructs.

Degradation of the extracellular matrix, facilitated by matrix metalloproteinases (MMPs), can lead to mechanical failure of vascular constructs, suggesting that MMP inhibition could improve survival of constructs. Therefore, we investigated the role of MMP-9 in collagen remodeling in vitro, focusing on the three major steps of production, degradation, and organization. Because an adequate blood supply is essential for survival of tissue-engineered constructs, we also evaluated the influence of MMP-9 deficiency on angiogenesis in vivo by implantation of thin biodegradable polymer scaffolds. Using aortic smooth muscle cells (SMCs) from wild-type and genetically deficient (9KO) mice, we examined the role of MMP-9 in collagen mRNA expression and protein accumulation, both with and without ascorbic acid treatment. We measured collagen assembly in a fibrillogenesis assay. We investigated in vivo angiogenesis and cell invasion, using fluorescence microangiography and histology. MMP-9 deficiency did not affect collagen mRNA production or polymer scaffold degradation, but collagen accumulation was greater in cultures of 9KO SMCs than in wild-type SMCs. Both MMP-9 deficiency and chemical inhibition impaired collagen degradation. Ascorbic acid treatment enhanced collagen production by 9KO SMCs compared with wild-type SMCs at 3 days, but by 7 days this effect was reversed. MMP-9 improved fibrillogenesis of collagen, significantly more on ascorbic acid treatment. MMP-9 deficiency dramatically decreased inflammatory cell invasion, but also capillary formation within biodegradable polymer scaffolds in vivo. Our data suggest that MMP inhibition, by impairing collagen organization and angiogenesis, might have detrimental effects on the survival of vascular constructs.