Extracellular matrix mimicking dynamic interpenetrating network hydrogel for skin tissue engineering

Tissue engineering scaffolds with tunable viscoelasticity and adaptability for cell behavior and fate regulation are highly desired. Here a dynamic interpenetrating polymer network (IPN) hydrogel was fabricated via photopolymerization and oxidation of methacryloyl gelatin (GelMA) and hyaluronic acid (HASH). The permanent GelMA network formed by CC bonds provides stable support for cells while the dynamic HASH network formed by disulfide bonds provides an adaptable microenvironment for cell growth. The proposed IPN hydrogel exhibits extensive and tunable porosity, swelling, degradation, and mechanical properties. Remarkably, the dynamic IPN hydrogel mimics the viscoelasticity and adaptability of the extracellular matrix (ECM), which can regulate cellular behaviors such as morphogenesis, alignment, proliferation, migration while offering resistance to cell mediated shrinkage and enzymatic digestion, maintaining the structural integrity of the scaffold. Our results suggest that dynamic IPN 3/7 (HASH/GelMA) hydrogels had more similar physical properties to human skin and were more favorable for human skin fibroblasts (HSF) and human immortalized keratinocytes (HaCaT) growth. Moreover, bilayer tissue-engineered skin prepared using the dynamic IPN hydrogel exhibited satisfactory mechanical stability, dermal-epidermal stratification, matrix secretion, structural differentiation, and barrier functions. In addition, the bilayer tissue-engineered skin can significantly promote healing of full-thickness skin defects through accelerated wound re-epithelialization, collagen deposition, and angiogenesis, without causing non-specific or specific immune rejection. This work based on the novel dynamic IPN hydrogel with biomimetic viscoelasticity and adaptability demonstrates the promising application in tissue engineering.