Cross-Reactive Alginate Derivatives for the Production of Dual Ionic–Covalent Hydrogel Microspheres Presenting Tunable Properties for Cell Microencapsulation

The production of hydrogel micropsheres (MS) presenting physical, mechanical, and biological properties which can be modulated by their chemical composition is required to enlarge the panel of biomaterials for cell transplantation therapies. Functionalization of sodium alginate (Na-alg) with cross-reactive poly­(ethylene glycol) (PEG) derivatives presenting terminal thiol and carbon electrophile functionalities provided novel polymers which upon simple one-step protocol formed hydrogel MS assembled by combination of Ca-alg interactions and sulfur–carbon covalent bonds. Several parameters such as the grafting degree on the alg backbone and the viscosity of the polymer solutions can be adjusted to provide optimal formulation for the capsule formation technology. Compared with pure Ca-alg MS, dual ionic–covalent MS displayed improved mechanical resistance and shape recovery performance. Importantly, under conditions which resulted in complete liquefaction of Ca-alg MS, chemically cross-linked Alg-PEG MS maintained stable spherical morphology. In addition, these hydrogels allowed excellent viability and functionality of microencapsulated Huh7 cells. After transplantation in the peritoneal cavity of immune competent mice, the dual ionic–covalent MS remained free-floating and maintained their integrity over 30 days.