Recently, macrophages have been characterized as having an M1 or M2 phenotype based on receptor expression, cytokine and effector molecule production, and function. The effects of macrophage phenotype upon tissue remodeling following the implantation of a biomaterial are largely unknown. The objectives of this study were to determine the effects of a cellular component within an implanted extracellular matrix (ECM) scaffold upon macrophage phenotype, and to determine the relationship between macrophage phenotype and tissue remodeling. Partial-thickness defects in the abdominal wall musculature of Sprague–Dawley rats were repaired with autologous body wall tissue, acellular allogeneic rat body wall ECM, xenogeneic pig urinary bladder tissue, or acellular xenogeneic pig urinary bladder ECM. At 3, 7, 14, and 28 days the host tissue response was characterized using histologic, immunohistochemical, and RT-PCR methods. The acellular test articles were shown to elicit a predominantly M2 type response and resulted in constructive remodeling, while those containing a cellular component, even an autologous cellular component, elicited a predominantly M1 type response and resulted in deposition of dense connective tissue and/or scarring. We conclude that the presence of cellular material within an ECM scaffold modulates the phenotype of the macrophages participating in the host response following implantation, and that the phenotype of the macrophages participating in the host response appears to be related to tissue remodeling outcome.

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.

Biologic scaffolds composed of extracellular matrix (ECM) are widely used to facilitate remodeling and reconstruction of a variety of tissues in both preclinical animal studies and human clinical applications. The mechanisms by which such scaffolds influence the host tissue response are only partially understood, but it is logical that the mononuclear macrophage cell population plays a central role. The present study evaluated the role of macrophages that derive from peripheral blood in the degradation of ECM scaffolds. An established rat body wall reconstruction model was used to evaluate the degradation of carbodiimide (CDI)-crosslinked scaffolds composed of porcine small intestinal submucosa (SIS), noncrosslinked SIS, and autologous body wall. To assess the role of circulating macrophages in the degradation process, the degradation of each scaffold was assessed with and without macrophage depletion caused by administration of clodronate-containing liposomes. Results showed that peripheral blood monocytes are required for the early and rapid degradation of both SIS scaffolds and autologous body wall, and that CDI crosslinked SIS is resistant to macrophage-mediated degradation.

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The Galalpha1,3Galbeta1,4GlcNAc-R (Gal) epitope is a major factor in the hyperacute rejection of pig organ transplants in primates. Biologic scaffold materials used for tissue reconstruction and composed of xenogeneic extracellular matrix (ECM) may contain the Gal epitope. However, the effect of this epitope upon the host response is controversial. The present study investigated the effect of the Gal epitope upon the host response to a porcine-derived ECM in an African Green monkey (Cholrocaebus aethiops) abdominal wall resection model. Histologic methods, serology, complement-dependent cytotoxicity, and gene expression profiling were used to evaluate the host response to allogeneic and both wild-type and Gal-deficient xenogeneic scaffold materials. Although expression of the Gal epitope induced an increase in serum anti-Gal antibodies in recipients, no other differences were noted in the host response between test articles. All ECM scaffolds were well tolerated and showed constructive remodeling during the study period. Recipients of all test articles showed no histologic or humoral evidence of sensitization when a second scaffold was implanted 45 days after the original surgery. The findings of the present study show that the presence of the Gal epitope within a porcine-derived ECM scaffold material elicits a serum antibody response, but no adverse effect upon tissue remodeling.

Biologic scaffolds composed of naturally occurring extracellular matrix (ECM) have been utilized as templates for the constructive remodeling of numerous tissues in preclinical studies and human clinical applications. The mechanisms by which ECM induces constructive remodeling are not well understood, but it appears that the degradation products of ECM scaffolds may play key roles in cell recruitment and constructive remodeling. The objective of the present study was to investigate the effects of age and species of the tissue from which ECM is harvested on the chemoattractant activity of degradation products of ECM for human keratinocyte stem and progenitor cells. Adult human skin ECM, fetal human skin ECM, and adult porcine skin ECM were prepared, enzymatically digested, characterized by SDS-PAGE, and evaluated for in vitro chemoattractant activity for human keratinocyte progenitor and stem cells (HEKn). Degradation products of human fetal skin ECM showed greater chemoattractant activity than human adult skin ECM degradation products for the HEKn. Degradation products of porcine adult skin ECM showed greater chemoattractant activity than human adult skin ECM. The human fetal skin ECM degradation products showed the strongest chemoattractant activity for the HEKn. The findings of this study support the concept that the mechanism of ECM scaffold remodeling involves the recruitment of lineage-directed progenitor cells by scaffold degradation products and that both the age and species of the tissue from which the ECM is harvested have an effect upon this chemoattractant potential.

Small intestinal submucosa extracellular matrix is rapidly degraded after implantation for the repair of a musculotendinous tissue in this canine Achilles tendon repair model and is replaced by the deposition and organization of host tissue that is histologically similar to that of normal tissue.