Commercially available human acellular dermal matrix (HADM), AlloDerm((R)), was implanted as an interpositional graft in the abdominal wall of adult vervet monkeys. Host response to implanted HADM was evaluated and compared with a human cellular dermal matrix (HCDM) and a primate acellular dermal matrix (PADM). Clinical acceptance of the acellular grafts (HADM and PADM) and graft remodeling were evidenced by fibroblast repopulation and neoangiogenesis. A mild inflammatory response marked predominantly by macrophages and T-cells was present in both HADM and PADM during the first month but was absent by 3 months. Similarly, antibody and complement deposition into the grafts as well as in the serum was evident only at the early time points. Interleukin-6 (IL-6) or IL-10 was induced in some acellular graft-implanted monkeys at the early time points, but tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), or IL-2 was not detected over the study period. In contrast, significant inflammation was observed in HCDM-implanted animals, as evidenced by immune cell infiltration (p
Three commercially available porcine-derived biologic meshes were implanted in an Old World primate abdominal wall resection repair model to compare biological outcome as a predictor of clinical efficacy. Tissues were explanted over a 6-month period and evaluated for gross pathology, wound healing strength, mesenchymal cellular repopulation, vascularity, and immune response. In vivo functional outcomes were correlated with in vitro profile for each material. Small intestinal submucosa-based implants demonstrated scar tissue formation and contraction, coincident with mesh pleating, and were characterized by immediate and significant cellular and humoral inflammatory responses. Porcine dermal-based grafts demonstrated significant graft pleating, minimal integration, and an absence of cellular repopulation and vascularization. However, a significant cellular immune response surrounded the grafts, coincident with poor initial wound healing strengths. In vivo observations for the three porcine-derived mesh products correlated with individual in vitro profiles, indicating an absence of characteristic biochemical markers and structural integrity. This correlation suggests that in vivo results observed for these mesh products are a direct consequence of specific manufacturing processes that yield modified collagen matrices. The resulting loss of biological and structural integrity elicits a foreign body response while hindering normal healing and tissue integration.
Sub-optimal clinical outcomes after implantation of animal-derived tissue matrices may be attributed to the nature of the processing of the material or to an immune response elicited in response to xenogeneic epitopes. The ability to produce a porcine-derived graft that retains the structural integrity of the extracellular matrix and minimizes potential antigenic response to galactose-alpha-(1,3)-galactose terminal disaccharide (alpha-Gal) may allow the scaffold to support regeneration of native tissue. Dermal tissue from wild-type (WT-porcine-derived acellular dermal matrix [PADM]) or Gal-deficient (Gal(-/-) PADM) pigs was processed to remove cells and DNA while preserving the structural integrity of the extracellular matrix. In addition, the WT tissue was subjected to an enzymatic treatment to minimize the presence of alpha-Gal (Gal-reduced PADM). Extracellular matrix composition and integrity was assessed by histological, immunohistochemical (IHC), and ultrastructural analysis. In vivo performance was evaluated by implantation into the abdominal wall of Old World primates in an exisional repair model. Anti-alpha-Gal activity in the serum of monkeys implanted subcutaneously was assessed by ELISA. Minimal modification to the extracellular matrix was assessed by evaluation of intact structure as demonstrated by staining patterns for type I and type VII collagens, laminin, and fibronectin similar to native porcine skin tissues. Explants from the abdominal wall showed evidence of remodeling, notably fibroblast cell repopulation and revascularization, as early as 1 month. Serum ELISA revealed an initial anti-alpha-Gal induction that decreased to baseline levels over time in the primates implanted with WT-PADM, whereas no or minimal anti-Gal activity was detected in the primates implanted with Gal(-/-) PADM or Gal-reduced PADM. The combination of a nondamaging process, successful removal of cells, and reduction of xenogeneic alpha-Gal antigens from the porcine dermal matrix are critical for producing a material with the ability to remodel and integrate into host tissue and ultimately support soft tissue regeneration.
Fetal-pig fibroblasts homozygous for the knockout of the alpha1-3 galactosyltransferase gene appear to express low but detectable levels of the gal antigen.
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