Programmable Gelatin Hydrogels via Ionic Modulation and Structural Design for Mechanical Properties, and Tissue Regeneration

Abstract

This thesis presents the rational design and systematic development of multifunctional gelatin-based hydrogels for applications in mechanical protection and tissue regeneration. This work integrates ionic modulation, structural anisotropy, and supramolecular assembly to fabricate a series of hydrogels. These materials exhibit tunable mechanical and functional properties. These efforts establish gelatin (GE) as a versatile matrix for creating high-performance, sustainable soft materials. In the first study (Chapter 3), inspired by beaver teeth, we report isotropic gelatin–ferric sulfate (GE-FS) hydrogels with anion-mediated hydrogen bonding that exhibit high strength, toughness, and impact resistance. Despite containing over 60% water, GE–FS hydrogels achieve a fracture strength of 20.5 MPa, toughness of 32 MJ/m³, and compressive strength of 114.7 MPa. Notably, they demonstrate a ballistic energy absorption capacity of 4.35 kJ/m², exceeding values reported for most hydrogels and approaching those of lightweight commercial protective materials. These hydrogels are biodegradable, recyclable, and retain high mechanical performance even after dehydration, surpassing conventional plastics and biopolymers. This scalable, low-cost ionic strategy enables the design of tough, sustainable hydrogels for protective and high-performance applications. Motivated by the ion-network synergy observed in GE-FS hydrogels, we next explored whether such design principles could be extended to enable precise and programmable mechanical properties tailored for biological applications. In the subsequent study (Chapter 4), we developed a biocompatible GE hydrogel system by integrating ice-separation-induced self-assembly with the spatiotemporal modulation of diverse inorganic and organic salts. By systematically varying salt species and concentrations, we achieved tunable control over the hydrogel’s network architecture and mechanical performance, encompassing a broad spectrum of tissue-relevant properties, including water content (70–90%), pore size (0.5–11 µm), Young’s modulus (9.7 kPa to 3.6 MPa), and toughness (up to 28.9 MJ/m³). This versatile design framework offers a generalizable strategy for constructing mechanically programmable hydrogels suitable for diverse biomedical applications. Building on this platform, the next study (Chapter 5) focused specifically on tendon regeneration using an optimized citrate-modified GE hydrogel (AGE-SC). This hydrogel benefits from citrate-induced modulation, the AGE-SC hydrogel demonstrated favorable physical properties and excellent cytocompatibility with tendon stem/progenitor cells (TSPCs). When applied in a rat Achilles tendon defect model, the AGE-SC hydrogel effectively restored biomechanical function and promoted tissue integration, underscoring its translational potential for multiscale tendon repair. Collectively, this thesis demonstrates a material and mechanism driven approach to hydrogel innovation, enabling multifunctional applications through hierarchical control of structure, ion interactions, and macroscopic performance.