An extracellular matrix coating similar to articular cartilage inhibits the differentiation of myofibroblasts and limits the development of implant-induced fibrosis

Abstract Fibrosis is involved in 45% of deaths in the United States, with no treatment options to reverse progression of the disease. Implantable devices (such as joint replacements, chips, stents, artificial organs, biosensors, catheters, heart valves, scaffolds for tissue engineering, etc.) can trigger a foreign body response, in which fibrotic tissue covers the implant and impedes its function. Myofibroblast are a key cellular component of scar tissue. To explore the relationship between extracellular matrix-based coatings and fibrosis, we coated tissue-culture surfaces using a library of extracellular matrix (ECM) proteins and then performed an in-vitro screen for myofibroblast differentiation on the coated surfaces as an indicator of fibrotic potential. The protein and proteoglycan components of cartilage (collagen II, biglycan, decorin, and chondroitin sulfate) were individually anti-fibrotic. Further, mixtures of collagen II, biglycan, decorin, and chondroitin sulfate inhibited myofibroblast differentiation to a greater degree than collagen II, biglycan, decorin, or chondroitin sulfate as individual coatings. Next, we performed an in-vivo model of a foreign-body response. Implanting an uncoated implant subcutaneously into mice resulted in a thicker layer of fibrotic scar tissue than implants coated with a cartilage-like ECM mixture. Our results indicate that the ECM microenvironment is key to the initiation, progression, and maintenance of fibrosis. Competing Interest Statement The authors have declared no competing interest. Abbreviations - (αSMA) - alpha-smooth muscle actin - (RGD) - arginine-glycine-aspartate domain - (CCL22) - C-C Motif Chemokine Ligand 22 - (CCL17) - C-C Motif Chemokine Ligand 17 - (CXCL1) - chemokine ligand 1 - (ELISA) - enzyme-linked immunoassay - (ECM) - extracellular matrix - (FPLC) - fast protein liquid chromatography - (GAG) - glycosaminoglycan - (MRC-5) Interleukin 6 (IL6) - Human fibroblasts - (IL-12p70) - Interleukin 12 subunit p70 - (IL13) - Interleukin 13 - (M-CSF) - Macrophage colony-stimulating factor - (NIH-3T3) - mouse fibroblasts - (PBMC) - peripheral blood mononuclear cells - (PBS) - phosphate buffered saline - (PDMS) serum-free media (SFM) - Polydimethylsiloxane - (SLRP) - small leucine-rich proteoglycan - (TGFβ) - Transforming growth factor β - (TLR2) - toll-like receptors 2 - (TLR4) - toll-like receptors 4 - (TNFα) - Tumor necrosis factor α - (EDAC) - 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride