Traumatic spinal cord injury (SCI) causes partial or complete loss of sensory, motor, and autonomic functions below the injury site. The lost neurons need to be replaced and axons of the remaining neurons need to regenerate across or around the lesion site and re-establish functional neural connections. However, neurons usually cannot renew themselves, and axon regeneration is restricted by the lack of intrinsic regeneration capacity and extrinsic inhibitory environment in the injured spinal cord. Neural stem/progenior cell (NSPCs) transplantation is a promising therapeutic strategy to replace the lost neurons and establish neuronal relays for reconnecting neurons rostral and caudal to the injury site, to rebuild the damaged neural circuitry. However, astroglial-fibrotic scar formation inhibits axon growth and grafted NSPC-host integration. Following SCI, reactive astrocytes produce excessive chondroitin sulfate proteoglycans (CSPGs), a repulsive factor for neural growth, to form glial scars. In addition, infiltrating fibroblasts secrete a large amount of collagen, which is the major component of fibrotic scars. Collagen and CSPGs create a network of tough matrix in astroglial-fibrotic scars, exhibiting a chemical and physical barrier hampering axon growth and graft-host tissue fusion, which led to insufficient signal transmission across the lesion for functional recovery. The overall goal of this study is to develop an effective and clinically applicable approach to promote grafted NSPCs-host integration and reconstruction of neural circuit after SCI. Toward this goal, we will develop and test a novel biomaterial-based approaches to (1) inhibit astroglial-fibrotic scar formation and (2) promote both host and graft axonal growth across the scar, via local delivery of hepatocyte growth factor (HGF). HGF has been shown to promote a normal wound healing process by promoting tissue regeneration and inhibiting fibrosis/collagen deposition in various peripheral tissues outside of the central nervous system (CNS). Moreover, it has been shown to inhibit astrocytic scar formation and CSPG deposition after SCI. We have developed polysaccharide-based complexes (particles) self-assembled through electrostatic interactions for sustained delivery of HGF. The particles can be encapsulated into agarose hydrogel and implanted into the intrathecal space of spinal cord for sustained local delivery of HGF. Using a clinically relevant cervical contusion injury model, we found that local HGF treatment significantly reduced collagen and fibrosis after SCI. Moreover, local HGF treatment also significantly reduced astroglial scar and CSPGs. In this study, we aim to (1) determine the timing of NSPC transplantation following cervical contusion SCI; and (2) determine if local delivery of HGF will promote graft-host integration and functional recovery after SCI. Successful completion of these Aims will facilitate future clinical application of stem therapy in spinal cord inj...