Tissue response, macrophage phenotype, and intrinsic calcification induced by cardiovascular biomaterials: Can clinical regenerative potential be predicted in a rat subcutaneous implant model?

Abstract

The host immune response to an implanted biomaterial, particularly the phenotype of infiltrating macrophages, is a key determinant of biocompatibility and downstream remodeling outcome. The present study used a subcutaneous rat model to compare the tissue response, including macrophage phenotype, remodeling potential, and calcification propensity of a biologic scaffold composed of glutaraldehyde‐fixed bovine pericardium (GF‐BP), the standard of care for heart valve replacement, with those of an electrospun polycarbonate‐based supramolecular polymer scaffold (ePC‐UPy), urinary bladder extracellular matrix (UBM‐ECM), and a polypropylene mesh (PP). The ePC‐UPy and UBM‐ECM materials induced infiltration of mononuclear cells throughout the thickness of the scaffold within 2 days and neovascularization at 14 days. GF‐BP and PP elicited a balance of pro‐inflammatory (M1‐like) and anti‐inflammatory (M2‐like) macrophages, while UBM‐ECM and ePC‐UPy supported a dominant M2‐like macrophage phenotype at all timepoints. Relative to GF‐BP, ePC‐UPy was markedly less susceptible to calcification for the 180 day duration of the study. UBM‐ECM induced an archetypical constructive remodeling response dominated by M2‐like macrophages and the PP caused a typical foreign body reaction dominated by M1‐like macrophages. The results of this study highlight the divergent macrophage and host remodeling response to biomaterials with distinct physical and chemical properties and suggest that the rat subcutaneous implantation model can be used to predict in vivo biocompatibility and regenerative potential for clinical application of cardiovascular biomaterials.

Subcutaneously Engineered Decalcified Bone Matrix Xenografts Promote Bone Repair by Regulating the Immune Microenvironment, Prevascularization, and Stem Cell Homing

“…24−29 Subcutaneously implanted scaffolds recruit a large number of macrophages to induce an inflammatory response during the initial phase; however, with time, the inflammation within the site subsides and then progresses toward the anti-inflammatory immune response stage. 30 This subcutaneous implantation pretreatment does not affect the immune response in vivo after grafting. 25 In addition to immune regulation, angiogenesis also plays a key role in bone healing.…”

“…The use of host autologous cells to enhance the properties of the scaffolds has become the latest promising approach to tissue engineering. , To further improve the performance of a scaffold, subcutaneous tissue has been utilized as a “bioreactor” since it is easily accessible, has a large anatomical site, and requires a simple operation, which has a low complication rate. − Subcutaneously implanted scaffolds recruit a large number of macrophages to induce an inflammatory response during the initial phase; however, with time, the inflammation within the site subsides and then progresses toward the anti-inflammatory immune response stage . This subcutaneous implantation pretreatment does not affect the immune response in vivo after grafting .…”

Electrospun fiber‐based immune engineering in regenerative medicine

“…63 When juxtaposed with clinically utilized materials like polypropylene mesh, glutaraldehyde-treated bovine pericardium, and porcine bladder ECM (UBM-ECM), polycarbonate electrospun fibers offer advantages, including a higher M2:M1 ratio, reduced propensity for calcification, and facilitation of neovascularization (Figure 4D). 64 In addition, macrophages harbor the ability to engulf extraneous entities, positioning a pivotal role as the predominant cellular mediator in host rejection responses, thereby substantially impacting the tissue repair outcomes of implanted electrospun fibers. 68 After implantation, an array of adhesive proteins adsorbs onto the surface, conferring its identification as a foreign entity by the organism, thereby promptly recruiting and activating macrophages.…”

Pediatric pulmonary valve replacements: Clinical challenges and emerging technologies

“…Another concern is the significantly heterogeneous remodeling rates both within and between valves, 232,234 which bars certainty regarding the composition and quality of the remodeled valve. Consequently, recent work has explored strategies to better predict and control the quality of the remodeled valve, whether through optimizing the design and fabrication process, 39,235 or better understanding the underlying cellular processes 232,236 . For example, computational simulations have been employed to predict leaflet shortening in TEHVs, allowing for the design of a geometry that anticipated these structural changes 39 .…”