Constructive Tissue Remodeling of Biologic Scaffolds: A Phenomenon Associated with Scaffold Characteristics and Distinctive Macrophage Phenotypes

Scaffolds composed of extracellular matrix (ECM) have been shown to promote the formation of site-specific, functional host tissue following implantation in a number of preclinical and clinical settings. However, the exact mechanisms by which ECM scaffolds are able to promote this type of "constructive tissue remodeling" are unknown. Further, the ability of ECM scaffolds to successfully promote constructive tissue remodeling appears to be dependent on the methods used in their production and the applications in which they are utilized. Therefore, a comprehensive understanding of ECM scaffold characteristics and their effects upon the host response and subsequent tissue remodeling outcome is essential to the design of intelligent scaffolds for specific clinical applications.The present work investigated the effects of tissue source and chemical cross-linking upon the resulting ECM scaffolds, showing that ECM scaffold materials have distinct ultrastructural and compositional characteristics which are dependant on both the anatomic location from which the scaffolds are derived and the methods used in their production. These characteristics were also associated with distinct patterns of cell behavior in vitro. Distinct tissue remodeling outcomes were observed following implantation of a subset of these scaffold materials in a rat abdominal wall musculature reconstruction model. Acellular, non-cross-linked ECM was associated with constructive tissue remodeling while scaffolds that contained cellular components or were chemically cross-linked resulted in dense connective tissue deposition or encapsulation, respectively. Despite differences in the tissue remodeling outcome, a histologically similar population of macrophages was observed following implantation in each of these cases. Therefore, the phenotype of the macrophage population participating in the host response was investigated. It was shown that scaffolds which resulted in constructive tissue remodeling were associated with an increase in the M2 (regulatory, pro-wound healing) macrophage population, while scaffolds which resulted in the deposition of dense collagenous connective tissue or encapsulation were associated with an increase in the M1 (pro-inflammatory) macrophage population, suggesting that different macrophage populations are associated with different tissue remodeling outcomes following ECM scaffold implantation. In vitro work showed that M1 and M2 macrophages had distinct paracrine effects upon other cell populations, further suggesting distinct roles for M1 and M2 macrophages in tissue remodeling