Local Delivery Of FTY720 In PCL Membrane Promotes Functional Recovery After Spinal Cord Injury

Background:Spinal cord injury (SCI) is one of the most devastating traum atic injuries that are associated with limited functional recovery. Todate, the repai r of SCI remains a major clinical challenge. There are no universally acceptable and effective therapeutic modalities toaddress the dead-weight issue, mainly due t o the limited endoge-nous regeneration capacity of spinal cord tissue.SCI results in neuronal death, reactive astrogliosis and inflammation. Previous studies demons trated that inflammatory responses were positively correlated to the level of sphi ngosine-l-phosphate(S1P) which attributing to accumulating microglia and reactive astrocytes surrounding the lesion site after SCI. Polycaprolactone (PCL) is a co mmonly used biomaterial due its biodegradability,biocompatibility and not giving rise to an acidic microenvironment upon degradation.Hence, we aim to assess the therapeutic efficacy of Fingolimod(FTY720) in animal models of SCI, hypothesi ze that local delivery FTY720 with PCL membrane can promote SCI targeting th e S1P/S1PR signaling pathway.Methods:Firstly, we detected the effect of SIP on proliferation and migrati on capability of astrocytes in vitro. We also assessed the proliferation and migrat ion capability of astrocytes when co-cultured with SIP and FTY720 in vitro. The n we developed the biodegradable PCL membranes to encapsulate FTY720 for s ustained release and established a rat and dog model of the injury, which were t reated with FTY720 incorporated within PCL scaffold. Behavioral performance w as assessed using the BBB locomotor rating scale and grid-walking test at weekl y intervals for up to 4 weeks.Injured spinal cord were collected 4 weeks after s urgery for immunofluorescence, histology, MRI and behavioral analysis.Results:We found that (1) FTY720-P was proved to inhibit astrocyte proliferation and migration induced by S1P/FBS in vitro. (2) PCL membrane incorporated with FTY720 was manufactured and demonstrated to be cytotoxic free and possess sustainable release kinetics. (3) Local administration of FTY720 reduces cavity formation, astrocyte accumulation and protects the surrounding neurons at the injury site in vivo, eventually leading to improved functional recovery in rat and dog SCI models.Conclusion:Our results indicated that local delivery of FTY720 can pave the way for innovative therapy of SCI by reducing reactive astrogliosis.