Development of functionalized alginate-based hydrogels to reduce fibrosis in the transplantation of microencapsulated cells

Nowadays, the development of cell therapy relies mainly on the advances made toward cell microencapsulation which allows to evade the need for immunosuppression during cell transplantation. Among the materials considered for cell encapsulation, hydrogels distinguish themselves by their exceptional properties. Due to its gelling properties in contact with divalent cations, the biopolymer sodium alginate (Na-alg), has been widely studied for the microencapsulation and transplantation of cells. However, several defects notably in permselectivity and durability in vivo is limiting the translation of alginate-based hydrogels in clinical applications. In addition, the transplantation of cells without immunosuppressive treatment have to face adverse host responses such as inflammation and fibrosis. At the moment, several approaches have been considered for the development of an ideal material for cell encapsulation; however many challenges still remain in this domain. Hence, this research project focused on the development of hydrogels in order to improve their properties toward cell encapsulation.

The first part of this research focused on the development of new types of one-component hybrid alginate-based hydrogels. These hydrogels combine the gelling properties of Na-alg with covalent crosslinking within the same polymeric structure. In order to do so, a new synthetic approach was developed allowing the functionalization on the hydroxyl position of alginate with heterobifunctional poly(ethylene glycol) (PEG) linkers through carbamate bond. This allowed to maintain the carboxyl moieties available for the formation of electrostatic interactions. Two types of one-component hybrid hydrogel were developed with this method adding either thiols or lipoyl moieties on alginate leading to an improvement of mechanical properties while preserving a good biocompatibility.

Yet, transplantation of encapsulated cells in a foreign host body have to face immune response, in particular inflammation and pericapsular fibrosis overgrowth (PFO) which ultimately leads to necrosis of the encapsulated cells and loss of graft functionality. Therefore, the second part of this research project focused on tuning the composition of the polymeric components of the hydrogels with anti-inflammatory agents which would reduce PFO in vivo. Different anti-inflammatory agents were considered for this purpose. The best candidate (ketoprofen) was then PEGylated via either ester or amide bond and grafted on the backbone of alginate to ensure a controlled release at the site of transplantation. By analyzing the fibrotic tissue around the microspheres, it was observed that the incorporation of ketopreofen on the structure of the hydrogel significantly reduced PFO 30 days after transplantation. In summary, Na-alg was functionalized with a new synthetic methodology allowing the incorporation of either functionalities reinforcing the mechanical resistance of the hydrogel or anti-inflammatory compounds improving the biocompatibility of the graft.