Yang Yang1, Laura De Laporte1, Marina L. Zelivyanskaya1, Aileen J. Anderson2, and Lonnie D. Shea1. (1) Chemical and Biological Engineering, Northwestern University, 2145 Sheridan Road, Tech Building E136, Evanston, IL 60208-3120, (2) Anatomy and Neurobiology, University of California, Irvine, 1107 Gillespie Neuroscience, Reeve-Irvine Research Center, Irvine, CA 92697-4540
Spinal cord injury leads to a permanent loss of motor and sensory function below the point of injury, for which there are minimal therapies available. Although regeneration is possible, axonal regrowth is limited by the local extracellular environment, which contains a limited supply of neurotrophins, inflammatory cells, and inhibitory factors, such as chondroitin sulfate proteoglycans. Strategies to modify this local environment have focused on the design of a biomaterial bridge that can be implanted at the injury site. Our approach utilizes a bridge design that aim to investigate i) the bridge architecture for modulating cellular infiltration from the surrounding tissue, ii) the releasing of neurotrophin-3 (NT-3) to provide growth promoting signals for the axons, and iii) the delivery of chondroitinase to degrade the elements that blocks the regrowing axons. The biodegradable polymer bridges are fabricated with a mixture of microspheres, composed of copolymers of lactide and glycolide (PLG), and salt particles assembled into a custom built aluminum mold. The interconnected, three-dimensional, porous bridge is produced from a gas foaming/particulate leaching process. The bridges have multiple parallel channels, which have been proposed to serve as reconstructed pathways for the growing axons, and to provide uniform drug delivery. Bridges with channels of 150 Ám and 250 Ám diameters were implanted into a rat hemisection spinal cord model. Cresyl violet staining revealed that the bridge retained its position at the implantation site and maintained good apposition with the surrounding tissue up to 4 weeks. Our ability to manipulate bridge design parameters (i.e. porogen size, porosity, channel diameter) allows for modulating cellular infiltration. Initial studies have identified the presence of macrophages within the bridge. Interestingly, astrocytes, an important glial cell type that is responsible for astroglyosis, had a scarce presence within the bridge, but accumulated in the surrounding tissue. NT-3 released from bridges has shown to enhance axonal extensions into the channels. Furthermore, bridges delivering chondroitinase ABC reduce chondrotin sulfate at the bridge/tissue interface up to 4 weeks of implantation. A bridge that targets multiple barriers to regeneration (inflammatory response, axonal guidance, neurotrophin delivery, and removal of growth inhibition) has the potential to promote the growth of axons into and across the bridge, and to facilitate re-entry into the distal cord as a first step towards functional recovery.