Synthesis strategies to extend the variety of alginate-based hybrid hydrogels for cell microencapsulation

The production of hydrogel microspheres (MS) for cell immobilization, maintaining the favorable properties of alginate gels but presenting enhanced performance in terms of in vivo durability and physical properties, is desirable to extend the therapeutic potential of cell transplantation. A novel type of hydrogel MS was produced by straightforward functionalization of sodium alginate (Na-alg) with heterotelechelic poly(ethylene glycol) (PEG) derivatives equipped with either end thiol or 1,2-dithiolane moieties. Activation of the hydroxyl moieties of the alginate backbone in the form of imidazolide intermediate allowed for fast conjugation to PEG oligomers through a covalent carbamate linkage. Evaluation of the modified alginates for the preparation of MS combining fast ionic gelation ability of the alginate carboxylate groups and slow covalentcross-linking provided by the PEG-end functionalities highlighted the influence of the chemical composition of the PEG-grafting units on the physical characteristics of the MS. The mechanical properties of the MS (resistance and shape recovery) and durability of PEG-grafted alginates in physiological environment can be adjusted by varying the nature of the end functionalities and the length of the PEG chains. In vitro cell microencapsulation studies and preliminary in vivo assessment suggested the potential of these hydrogels for cell transplantation applications

Multicomponent Alginate-Derived Hydrogel Microspheres Presenting Hybrid Ionic-Covalent Network and Drug Eluting Properties

The development of multifunctional encapsulation biomaterials could help the translation of cell‐based therapies into standard medical care. One of the major hurdles in the field of encapsulated cell transplantation is the current lack of materials presenting optimal properties, including long term stability, mechanical durability and non‐immunogenic character. Modification of sodium alginate (Na‐alg) with polyethylene glycol (PEG) derivatives, without restricting its gelling abilities, appeared as an efficient strategy to produce dual ionic‐covalent spherical hydrogels with enhanced mechanical performance as well as drug‐eluting microspheres (MS) for the mitigation of inflammatory response after transplantation. In this study, the combination of PEGylated alginates equipped with cross‐reactive functionalities and the anti‐inflammatory drug ketoprofen (KET) resulted in the assembly of multifunctional (MF) hybrid MS, merging the advantages of ionic‐covalent hydrogels with the ability for controlled drug delivery. Physical characterization confirmed their improved mechanical resistance, their higher shape recovery performance and increased stability toward non‐gelling ions, as compared to pure Ca‐alg hydrogels. In vitro release kinetics revealed the controlled and sustained delivery of KET for over two weeks

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