Effect of chronic inflammation and immune response on regeneration induced by decellularized bovine pericardium

Abstract

Decellularised tissue produces a variety of host responses ranging from constructive remodeling to scarring on account of its differences in the source of tissue, processing or sterilization methods. In this study, in vivo regeneration induced by decellularised bovine pericardium with or without mild glutaraldehyde crosslinking was studied in relation to its immune and inflammatory response using rat abdominal regeneration model. Mild glutaraldehyde crosslinking was done to subdue inflammatory and immune response without compromising host cell incorporation and graft remodeling. Evaluations were done at both 21 and 90 days. Un-crosslinked decellularised bovine pericardium showed more intense macrophage response predominantly of M2 phenotype at 90 days indicating chronic inflammatory response compared to mildly crosslinked group. This group also showed significant increase in plasma cell and lymphocyte count indicating immune stimulation. Lymphocyte transformation test detected presence of bovine pericardial antigen sensitized lymphocytes at both periods in un-crosslinked group. Lymphocytes from mildly crosslinked group failed to respond in this test at both periods. Significantly higher antibody response was also noted at both periods in un-crosslinked group. However, abdominal wall regeneration was observed only in animals implanted with un-crosslinked decellularised bovine pericardium at 90 days. From the above findings, it is inferred that un-crosslinked decellularised bovine pericardium produced significant chronic inflammatory response at 90 days and stimulated both humoral and cell mediated immune response in comparison to mildly crosslinked decellularised bovine pericardium. Yet this group produced skeletal muscle formation within graft at 90 days.

To Cross-Link or Not to Cross-Link? Cross-Linking Associated Foreign Body Response of Collagen-Based Devices

“…Commercially available GTA cross-linked tissue grafts (Table 3) (Peri-Guard ® Repair Patch, Synovis, denaturation temperature 83 °C 139 ) have been shown to elicit chronic inflammation and typical foreign reaction, as evidenced by the early dense accumulation of mononuclear cells and the prolonged presence of macrophages, FBGCs and fibrous encapsulation surrounding the implant 149,157,158 . GTA cross-linked bovine pericardium grafts reduced M2/M1 macrophage ratio during inflammation phase, as compared to non-cross-linked grafts 159 . Moreover, non-commercial GTA cross-linked sheep collagen disks induced a massive infiltration of neutrophils that secreted a high amount of MIP-1, MCP-1 and IFN-γ, recruiting and activating macrophages.…”

Immunogenicity in xenogeneic scaffold generation: Antigen removal vs. decellularization

“…Finally, Bayrak et al [78] found that decellularized porcine pulmonary heart valves promote T cell proliferation and activation. Recent work in macrophage polarization has described two macrophage phenotypes in host response: M1 macrophages which are effectors of the pro-inflammatory degenerative response and M2 macrophages which have been linked to a regenerative response following tissue damage [44, 85–87]. Identification of M2 macrophages suggests the possibility of a benefit to the inflammatory response in tissue regeneration, an area under much investigation.…”

Long-term healing of mildly cross-linked decellularized bovine pericardial aortic patch

“…Among the infiltrated macrophages, M1 phenotype is reported to be proinflammatory cytotoxic macrophage, which is associated with classic signs of inflammation, whereas the anti‐inflammatory macrophage M2 promotes immunoregulation, tissue repair, and constructive remodeling . Uncross‐linked decellularised bovine pericardium was shown to elicit M2 macrophage response in rat abdominal implantation, whereas mildly cross‐linked bovine pericardium used in this study elicited M2 macrophage response only at shorter duration . Monocyte infiltration into the graft has also been shown to promote VEGF expression within the scaffold throughout the duration of macrophage infiltration, which was beneficial to healing .…”

“…Decellularized tissue was shown to promote remodeling of the prosthesis by neovascularization and recellularization by the host . Decellularized bovine pericardium was also shown to elicit M2 macrophage response favorable for regeneration besides causing significantly reduced humoral and cell mediated immune response . Decellularization is a critical process, and inadequate procedure may lead to undesirable results, such as calcification and immune reaction on account of removal of tightly bound proteoglycans causing loss of collagen–proteoglycan interactions .…”

“…8 Decellularized bovine pericardium was also shown to elicit M2 macrophage response favorable for regeneration besides causing significantly reduced humoral and cell mediated immune response. 9 Decellularization is a critical process, and inadequate procedure may lead to undesirable results, such as calcification and immune reaction on account of removal of tightly bound proteoglycans causing loss of collagen-proteoglycan interactions. 10,11 The immune response against incompletely decellularized xenografts was also seen much more prominent compared to isografts or even allografts.…”