Fabrication And Study Of Novel Immune Evasive Alg/PEI Hydrogel Materials And Their Applications In Islet Transplantation

Cell transplantation therapy is a promising treatment for a variety of incurable diseases and brings new hope to many patients.However,the long-term clinical application and therapeutic efficacy of this strategy are still seriously limited by the host immune responses after transplantation.Therefore,it is important to develop novel materials that can protect the cells and achieve immune evasion in vivo.In this work,inspired by the anti-biofouling zwitterionic materials,we successfully developed a new type of immune evasive hydrogel materials and used them to encapsulate islets for the treatment of type 1 diabetes mellitus(T1DM).Alginate is a type of negatively charged polyelectrolyte and is one of the most favorable cell encapsulation materials,because it can be easily crosslinked with divalent cations(such as Ca2+ or Ba2+)to form hydrogels at room/body temperature.However,its immunogenicity and inability to evade the foreign body reaction(FBR)restrict its long-term application.Therefore,in this work,inspired by the excellent anti-biofouling properties of zwitterionic materials,we first demonstrated that the divalent cation concentrations could notably influence the net charge and the anti-biofouling behaviors of alginate hydrogels.This is because the balanced charged surface could effectively eliminate the electrostatic interaction between proteins and surfaces.It could be found that at the optimal concentrations(Ca2+ concentration was 0.54 mM or the Ba2+concentration was 0.9 mM),where the net charge of alginate hydrogel was close to 0,the corresponding alginate hydrogel exhibited the best anti-biofouling performances,similar to the zwitterionic materials.Further,based on the balanced charge strategy,we successfully developed a novel anti-biofouling alginate-polyethyleneimine(Alg/PEI)hydrogel by balancing oppositely charged polyelectrolytes alginate and PEI.The results showed that at the optimal ratio where mass ratio of the two polymers was 1:0.045,the hydrogel could effectively resist the adhesion of protein,cell and bacteria.It could also effectively mitigate the FBR and inhibit the capsule formation for at least 3 months after subcutaneous implantation in a mouse model.Next,400 islets were encapsulated for each mouse using the balanced charged immune evasive Alg/PEI hydrogels for the treatment of T1DM.The viability and insulin secretive function of islets in hydrogels could be well maintained.Moreover,compared to the traditional alginate hydrogel,the diabetic mice could achieve a rapid(2 days),stable and long-term(>150 days)regulation of blood glucose after intraperitoneal transplantation in diabetic the mice.Lastly,heparin loaded proangiogenic and immune evasive Alg/PEI microspheres were successfully developed to promote islet revascularization and improve the therapeutic efficacy of T1DM.Rat islets were encapsulated in the 2%heparin loaded Alg/PEI(HEP2-Alg/PEI)microspheres and their viability and function could be well maintained.Moreover,the results showed that the HEP-Alg/PEI microspheres encapsulated 1000 rat islets could promote subcutaneous angiogenesis and stably regulate blood glucose after subcutaneous xenotransplantation in diabetic mouse for at least 180 days.In summary,we successfully developed a type of novel immune evasive hydrogel materials to overcome the immune response to implant materials.Moreover,the hydrogel materials could serve as an ideal matrix in the field of islet transplantation for the treatment of T1DM.These findings hold a great promise for the development of novel immune evasive materials and the long-term cell transplantation therapy.