Combined local delivery of tacrolimus and stem cells in hydrogel for enhancing peripheral nerve regeneration

Abstract

The application of scaffold-based stem cell transplantation to enhance peripheral nerve regeneration has great potential. Recently, the neuroregenerative potential of tacrolimus (a U.S. Food and Drug Administration-approved immunosuppressant) has been explored. In this study, a fibrin gel-based drug delivery system for sustained and localized tacrolimus release was combined with rat adipose-derived mesenchymal stem cells (MSC) to investigate cell viability in vitro. Tacrolimus was encapsulated in poly(lactic-co-glycolic) acid (PLGA) microspheres and suspended in fibrin hydrogel, using concentrations of 0.01 and 100 ng/ml. Drug release over time was measured. MSCs were cultured in drug-released media collected at various days to mimic systemic exposure. MSCs were combined with (i) hydrogel only, (ii) empty PLGA microspheres in the hydrogel, (iii) 0.01, and (iv) 100 ng/ml of tacrolimus PLGA microspheres in the hydrogel. Stem cell presence and viability were evaluated. A sustained release of 100 ng/ml tacrolimus microspheres was observed for up to 35 days. Stem cell presence was confirmed and cell viability was observed up to 7 days, with no significant differences between groups. This study suggests that combined delivery of 100 ng/ml tacrolimus and MSCs in fibrin hydrogel does not result in cytotoxic effects and could be used to enhance peripheral nerve regeneration.

The role of the immune microenvironment in bone, cartilage, and soft tissue regeneration: from mechanism to therapeutic opportunity

“…Hydrogel-based codelivery of MSCs and bioactive factors has also been applied for the treatment of nerve injuries. Fibrin hydrogels loaded with ADSCs and microspheres containing tacrolimus have been reported to enhance peripheral nerve regeneration via immunomodulatory actions [ 297 ]. In another study, on the basis of the acidic microenvironment at injury sites, pH-responsive IL-4 plasmid-loaded liposomes have been incorporated into PLA electrospun fibers to treat acute spinal cord injury (SCI) [ 292 ] (Fig.…”

Recent progresses in neural tissue engineering using topographic scaffolds

“…Early work showed polytetrafluoroethylene conduit, poly(lactide-co-caprolactone) film, fibrin gel and PLGA microspheres scaffold encapsulated small molecule drug of tacrolimus have been used to promote local nerve regeneration [74][75][76][77]. A conductive hydrogel scaffold composed of chitosan-aniline oligomers and agarose as local delivery system was developed to enhance the growth and proliferation of nerve cells by applying electrical stimulation to control drug release [78].…”

Engineered hydrogels for peripheral nerve repair

“…Moreover, researchers are gradually paying attention to the low survival rate of transplanted stem cells due to immune rejection, and are trying to use immunosuppressive agents in synergy with delivery platforms to improve the survival rate of transplanted stem cells and achieve therapeutic effects. Saffari and colleagues [ 106 ] designed a fibrin gel-based drug delivery platform. Tacrolimus was packed into poly (lactic-co-glycolic acid) (PLGA) microspheres and co-delivered with ADSCs in a hydrogel to the site of peripheral nerve injury for synergistic treatment.…”