Mechanisms of biomaterial mediated fibrotic responses and strategies to improve tissue reactions to biomaterial implants

Despite considerable advancements in biomaterial synthesis and modification techniques, most tissue engineering scaffolds elicit fibrotic reactions resulting in implant encapsulation, secluding cells and/or therapeutic agents within a thick collagenous matrix. Therefore, strategies to minimize these responses while improving the functionality of recruited/transplanted cells are required. This work set out to improve the host response to biomaterials and identify what cellular responses were attributed to biomaterial-mediated fibrosis. Two strategies were investigated involving two different targets. In the first approach, PLGA scaffolds were RFGD modified to bear -NH2 (amine), -COOH (carboxyl), and -OH (hydroxyl) groups altering surface wettability and charge properties. Surface modified scaffolds altered fibrinogen adsorption and RAW 264.7 (macrophage) cytokine secretion in vitro, subsequently effecting macrophage chemotaxis to preconditioned media from different modified scaffolds. In vivo scaffolds were able to slightly alter inflammatory cell influx while increasing cell infiltration density and matrix production. However surface modification exerted only minor influence over the thickness of the fibrotic capsule.;In the second approach, SDF-1alpha was incorporated with scaffolds to increase recruitment of host-derived stem cells while reducing fibrotic responses. Increased stem cell recruitment was able to significantly alter interface collagen deposition, in addition to increasing angiogenic progenitor recruitment thus improving angiogenesis and altering the local cytokine environment. By varying cytokine delivery onset and duration, the effects of SDF-1alpha were linked with a stabilized mast cell response upstream. This led us to consider whether the mast cell responses were primarily regulating the biomaterial-mediated fibrotic response, and specifically what cells where responsible for collagen production at the biomaterial interface.;Fibrocytes and fibrocyte-derived myofibroblasts were identified as primary contributors to collagen deposition. Fibrocytes recovered from the biomaterial implantation site predominantly migrated in response to SDF-1alpha. Targeting this link with the anti-inflammatory drug dexamethasone did not alter fibrocyte responses; however SDF-1alpha neutralization significantly reduced the influx of fibrocytes and generation of fibrocyte-derived myofibroblasts. This led to significant reduction in fibrotic responses. Since mast cells influence the acute inflammatory response to biomaterial implants, we hypothesized that creating different degrees of mast cell responses would result in differential stimulation of SDF-1alpha producing cells while reducing inflammatory stimuli. Stabilizing mast cells with Cromolyn was able to significantly reduce macrophage influx along with fibrocyte and fibrocyte-derived myofibroblast influx. This led to significant reduction in fibrotic encapsulation and collagen I structure at the biomaterial interface, implicating mast cells as the initiator of the biomaterial-mediated fibrotic response. Based on these results, we propose a hypothetical sequence of events leading to the formation of fibrotic tissue around biomaterial implants, which depends upon the degree of mast cell activation and subsequent fibrocyte responses. Therefore, this study has identified the critical involvement of the mast cell response in biomaterial-mediated fibrosis, as well as identifies a strategy to reduce mast cell activation while improving host-derived stem cell responses to improve the response to biomaterial scaffolds in the subcutaneous space.