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 covalent cross-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.
■ INTRODUCTIONProgress in therapies relying on the allo-or xenotransplantation of immobilized cells and tissue strongly depends on the quality of the immobilizing material. Currently, the translation of related therapies to the clinics, for example to treat end-stage organ failure and end-stage diseases such as cancer, diabetes mellitus, and acute liver failure, 1,2 is hindered by the lack of materials having the perfect properties. Hydrogels prepared from the biopolymer sodium alginate (Na-alg) or derivatives of it have been reported in abundant papers as particularly advantageous because they fulfill general requirements such as the spontaneous formations of hydrogels in the presence of divalent cations (e.g., Ca 2+ , Ba 2+ ) under mild conditions of temperature and pH, and high biocompatibility. 3−6 Maintaining these advantages but overcoming several drawbacks, including the lack of in vivo mechanical resistance and stability, and defects in permselectivity, 7,8 are the focus of current research. There are additional limitations caused by the dimension of the targeted final application. This calls in particular for therapies which intend the transplantation of allo-or xenogeneic cells immobilized in microspheres (MS) in order to allow for miniinvasive surgery. 9,10 The stabilization of alginate gel beads by coating the MS with polycations such as (poly(L-lysine), poly(L-ornithine), and poly(L-guanidine) was investigated, but impaired cell graft function in vivo. 11 Another strategy to improve the performance of alginate MS relies on the combination with other polymers such as poly(ethylene glycol) (P...