Biomaterials and scaffolds that promote regenerative rather than fibrotic healing

Wound healing after dermal wounding is a major clinical problem and for adult skin, healing reverts to fibrotic repair, which involves an excess of collagen deposition and an activation of myofibroblasts. Embryonic skin, on the other hand, quickly regenerates without scarring, with tightly regulated immune responses and balanced cytokine signaling. The biomaterial scaffolds have been developed to become active therapeutic platforms that can alter the course of the wound from fibrosis to regeneration by mimicking essential microenvironmental signals. Scaffold design principles (architecture, porosity, stiffness, and surface topography) are discussed and natural and synthetic biomaterials are reviewed for their ability to induce regeneration associated phenotypes. We highlight immune-modulatory strategies which switch macrophages to pro-resolving phenotypes and inhibit fibrotic cascade. In addition to state of the art fabrication technologies like 3D bioprinting and electrospinning, advanced biofunctionalization strategies like sustained delivery of anti-fibrotic growth factors, miRNA therapeutics and cell-seeded constructs are also critically evaluated. Preliminary data have shown that strategically designed scaffolds can markedly decrease scar index and restore skin appendages. Lastly, we discuss translational issues and trends for personalized, phase-dependent responsive scaffolds. This analysis emphasizes that biomaterial-directed regeneration is a pedagogic therapeutic model that can revolutionize scar management in the clinical practice.