Designing Amphiphilic Gelatin Hydrogels through Control of Polyester and Polycarbonate Graft Length

Abstract

Both natural and synthetic polymers offer distinct advantages in regenerative medicine, yet their properties are often orthogonal, requiring trade-offs when used individually. Gelatin, the gold standard, exhibits cell adhesivity and is biodegradable but suffers from low mechanical tunability, a UCST around physiological conditions, and inferior porosity following hydrogel production. In contrast, poly(l-lactic acid) (PLA) and poly(trimethylene carbonate) (PTMC) often display mechanical tunability and low batch-to-batch variability, but lack bioactivity. Herein, PLA and PTMC were grafted onto gelatin through thiol-ene coupling, producing hybrid grafted constructs with either semicrystalline or amorphous grafts. These constructs can form physical gels through hydrophobic interactions, which can be covalently cross-linked into porous hydrogels. Graft lengths between 2000 and 10000 g mol were studied, combined with a successful translation to continuous flow ring-opening polymerization. Mass Determination Diffusion Ordered Spectroscopy (MaDDOSY) using a benchtop NMR was employed to measure molar masses, in which good agreements (Δ = 0.02 ± 0.09) were found with conventional techniques. After thiolation (>93%), no influence of graft length on thiol-ene coupling yields was observed. By varying graft length and graft type (PLA vs PTMC), a high tunability of physical hydrogels’ mechanical properties (4–50 kPa), transparency (25–97%), swelling capacity (500–2500%), and pore areas (10–100 000 μm2) upon cross-linking was achieved. These hybrid systems highlight the strong synergy between natural and synthetic polymers for regenerative materials design.