Tunable Microfibers Suppress Fibrotic Encapsulation via Inhibition of TGFβ Signaling

Abstract

Fibrotic encapsulation limits the efficacy and lifetime of implantable biomedical devices. Microtopography has shown promise in the regulation of myofibroblast differentiation, a key driver of fibrotic encapsulation. However, existing studies have not systematically isolated the requisite geometric parameters for suppression of myofibroblast differentiation via microtopography, and there has not been in vivo validation of this technology to date. To address these issues, a novel lamination method was developed to afford more control over topography dimensions. Specifically, in this study we focus on fiber length and its effect on myofibroblast differentiation. Fibroblasts cultured on films with microfibers exceeding 16 mm in length lost the characteristic morphology associated with myofibroblast differentiation, while shorter microfibers of 6 mm length failed to produce this phenotype. This increase in length corresponded to a 50% decrease in fiber stiffness, which acts as a mechanical cue to influence myofibroblast differentiation. Longer microfiber films suppressed expression of myofibroblast-specific genes (aSMA, Col1a2, and Col3a1) and TGFb signaling components (TGFb1, TbR2, and Smad3). About 16 mm long microfiber films subcutaneously implanted in a mouse wound-healing model generated a substantially thinner fibrotic capsule and less deposition of collagen in the wound bed. Together, these results identify a critical feature length threshold for microscale topography-mediated repression of fibrotic encapsulation. This study also demonstrates a simple and powerful strategy to improve surface biocompatibility and reduce fibrotic encapsulation around implanted materials.

Local delivery of decorin via hyaluronic acid microrods improves cardiac performance and ventricular remodeling after myocardial infarction.

“…51 Our lab has previously shown the utility of high aspect ratio microstructures made from polypropylene and polyethylene glycol (PEG) to discourage myo broblast transition. 11,12 However, developing therapeutic strategies should aim to employ materials that have biocompatibility, exhibit biodegradation, and possess tunable properties for facile translation to the clinic. As such, next generation microrods were fabricated from HA, a naturally occurring polysaccharide that is implicated in wound healing responses.…”

“…9 We have previously demonstrated the ability to modulate broblast morphology and function using polymeric microstructural cues to achieve less brotic phenotypes, which could have tremendous implications in heart failure therapy. [10][11][12][13] Recent work showed that in vitro treatment with polymeric microrods (15 x 15 x 100 µm) decreased broblast proliferation and that microrod injections in preclinical rodent models of heart failure cause reductions in scar tissue and improvements in cardiac function by in uencing the cardiac microenvironment. 12,13 Bene ts of using hydrogel microstructure strategies with mechanobiological mechanisms of action as therapeutic approaches include being injectable, cell-free, and highly tunable in terms of geometry, stiffness, and material.…”

Local decorin delivery via hyaluronic acid microrods improves cardiac performance, ventricular remodeling after myocardial infarction

“…The ability to reliably dictate cellular responses to elicit specific phenotypes can be a powerful tool in addressing conditions that result from cardiovascular diseases, such as HF 7 . Our lab has previously shown the utility of high aspect ratio microstructures made from polypropylene and polyethylene glycol (PEG) to mitigate fibroblast transition to myofibroblasts 11 , 12 . However, developing therapeutic strategies should aim to employ materials that have biocompatibility, demonstrate favorable bioactive properties, exhibit biodegradation, and possess tunable properties for facile translation to the clinic.…”

Chemical Strategies for Improving Islet Transplant Outcomes

“…Inorganic membranes have the advantages of smaller distribution in pore size and more easily controlled membrane thickness. However, studies have shown that unmodified, rigid materials such as these are more prone to fibrotic encapsulation [173,174], and thus may be more prone to an inflammatory response. In comparison, both PTFE and PCL have demonstrated limited induction of fibrosis, while allowing for revascularization and improved cell viability [170,171].…”