A human tissue-specific ex vivo model of biological scaffold integration: Understanding the interface

Tissue-derived decellularised biological scaffolds have application in regenerative medicine as biomaterials, with the aim of restoring tissue function lost due to damage or disease. Following surgical intervention, it is axiomatic that cells of the immune system respond to the implantation. In vivo animal implantation studies have highlighted that macrophages can surround biomaterials during an encapsulation-type response and infiltrate into biological scaffolds during an integration-type response. Despite the clinical application of tissue-derived biological scaffolds, little is known about the human tissue response to these biomaterials. The aim of this study was to develop and examine an ex vivo biomaterial-human tissue interface in order to identify potential factors and immune mechanisms that govern the tissue response to a biological scaffold, with focus on the macrophage phenotype at the ex vivo interface. An organotypic culture model was established in which human urinary tract tissue was maintained in close apposition with a porcine urinary bladder-derived decellularised biological scaffold. Immunolabelling of histological sections from the tissue constructs using a panel of functional markers identified a striking and significant up-regulation of the macrophage-associated marker, CD163. Mechanistic investigations into CD163 expression in human peripheral blood-monocyte-derived macrophages identified that a subpopulation of monocyte-derived macrophages had a greater propensity towards expression of CD163 and the population of CD163+ macrophages could be increased following activation of the nuclear receptor, PPARγ. Pharmacological inhibition of PPARγ abated the CD163+ subpopulation and inhibited the glucocorticoid-dependent induction of CD163, indicating that CD163 expression was dependent on PPARγ function. Immunolabelling of PPARγ in the biomaterial-tissue constructs showed intense nuclear localisation of the PPARγ in cells at the biomaterial-tissue interface and in cells, with a macrophage-like morphology, present within the biological scaffold. CD163 expression and PPARγ function are associated with the resolution phase of inflammation. It is proposed that factors that govern inflammation resolution are involved in determining the phenotype of macrophages at a biomaterial-tissue interface.