Macrophage Phenotype as a Determinant of Biologic Scaffold Remodeling

TLDR

Macrophage phenotype can be characterized as proinflammatory (M1) or immunomodulatory and tissue remodeling (M2). The study used a rat model to compare macrophage phenotypes at the implantation sites of two porcine SIS‑derived scaffolds processed differently: the Restore device and the CuffPatch carbodiimide‑crosslinked form. An autologous tissue graft served as control, and immunohistochemistry identified macrophage markers CD68, CD80, CCR7, and CD163 to track M1/M2 profiles during remodeling. All implants showed dense CD68+ cells in the first 4 weeks, but the SIS device induced a predominantly CD163+ (M2) response with constructive remodeling at 16 weeks, whereas the CDI‑SIS device elicited a mainly CD80+/CCR7+ (M1) response and chronic inflammation, and the autologous graft displayed an early CD163+ response followed by a mixed M1/M2 profile and organized tissue, demonstrating that scaffold processing profoundly affects macrophage phenotype and remodeling and that routine histology alone cannot determine cell phenotype.

Abstract

Macrophage phenotype can be characterized as proinflammatory (M1) or immunomodulatory and tissue remodeling (M2). The present study used a rat model to determine the macrophage phenotype at the site of implantation of two biologic scaffolds that were derived from porcine small intestinal submucosa (SIS) and that differed mainly according to their method of processing: the Restore device (SIS) and the CuffPatch device (carbodiimide crosslinked form of porcine-derived SIS (CDI-SIS)). An autologous tissue graft was used as a control implant. Immunohistologic methods were used to identify macrophage surface markers CD68 (pan macrophages), CD80 and CCR7 (M1 profile), and CD163 (M2 profile) during the remodeling process. All graft sites were characterized by the dense population of CD68+ mononuclear cells present during the first 4 weeks. The SIS device elicited a predominantly CD163+ response (M2 profile, p < 0.001) and showed constructive remodeling at 16 weeks. The CDI-SIS device showed a predominately CD80+ and CCR7+ response (M1 profile, p < 0.03), and at 16 weeks was characterized by chronic inflammation. The autologous tissue graft showed a predominately CD163+ response (M2) at 1 week, with a dual M1/M2 population (CD80+, CCR7+, and CD163+) by 2 and 4 weeks and moderately well organized connective tissue by 16 weeks. The processing methods used during the manufacturing of a biologic scaffold can have a profound influence upon the macrophage phenotype profile and downstream remodeling events. Routine histologic examination alone is inadequate to determine the phenotype of mononuclear cells that participate in the host response to the scaffold.