Acellular Spinal Cord Scaffold Implantation Promotes Vascular Remodeling with Sustained Delivery of VEGF in a Rat Spinal Cord Hemisection Model.

Abstract

Promoting angiogenesis provides a possible therapeutic approach in treating spinal cord injury (SCI). Vascular endothelial growth factor (VEGF) is a pro-angiogenic substance that is involved in endothelial cell (EC) proliferation, migration, and survival. Exogenous administration of VEGF to the lesion epicenter of the spinal cord has been recently revealed as a potential method for promoting the blood vessel sprouting. Spinal cord hemisection in a rat model was established and angiogenesis was studied through implant of an acellular spinal cord scaffold (ASCS) with sustained delivery of VEGF<sub>165</sub>. The poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) encapsulating VEGF<sub>165</sub> were fabricated on basis of an emulsion and solvent evaporation method and conjugated to ASCS by a Genipin (GP) crosslinking technology. The resultant scaffolds were marked as V-ASCS. VEGF<sub>165</sub> entrapment efficiency (EE) and released kinetics were determined by an ultraviolet absorption measurement. Angiogenesis and vascular remodeling were observed via a high-resolution micro-CT and analyzed quantitatively by vascular morphometric parameters. Spinal cord histology and Basso, Beattie, and Bresnahan (BBB) locomotor rating scale were further studied. VEGF<sub>165</sub> was entrapped with high efficiency (90.8±3.1) %. In vitro VEGF<sub>165</sub> release kinetics study showed an initial burst of 1.966 μg mg NPs-1 and 1.045μg mg V-ASCS-1 respectively in the first 24 hours. In the phase of sustained release, approximately 0.040μg mg NPs-1 and 0.022μg mg V-ASCS-1 per day was on-going until 720h. In the rat spinal cord hemisection model, implant of V-ASCS at the injured site showed a promotion of angiogenesis and vascular remodeling following SCI. A better outcome can be confirmed histologically. However, functional improvement is limited in the animal model. The results indicate that progress of vascular reconstruction is accelerated in the V-ASCS implanted SCI rats.