Amphiphilic Brush-Type Hybrid Gelatin-Based Materials Using Thiol–Ene Coupling: A Platform for Polyester or Polycarbonate Grafting

Gelatin has long been considered the gold standard in tissue engineering (TE) due to its biocompatibility, cell-adhesive properties, and low cost. However, its application is constrained by inferior porosity and an upper critical solution temperature (UCST) around physiological temperature. The latter leads to a need for processing, including cell encapsulation, at low temperatures exerting stress on cells. Herein, an efficient pathway was developed for the grafting of polyesters and polycarbonates onto gelatin using thiol–ene coupling, creating a library of amphiphilic brush-type polymers. After in-depth analysis of the synthesized grafts, in terms of graft lengths, coupling efficiencies (>90%) and grafting densities (30–100% of amines in gelatin), the self-assembly, driven by hydrophobic interactions, into nanoparticles and physical gelation potential was investigated. The tunable grafting densities led to a wide range of mechanical properties (E′: 1–50 kPa), showing applicability for soft to medium-soft tissues. Dual cross-linking enabled rapid covalent gelation (1.7–2.3 s) after physical assembly. The hydrophobic associations yielded enhanced porosities (>200 μm), which correlated to graft identity and mechanical properties. Finally, the materials revealed high biocompatibility, as evidenced by the cell viabilities during cytotoxicity (>90%), without loss of cell interactivity.