Plasmid Releasing Multiple Channel Bridges for Transgene Expression After Spinal Cord Injury

Abstract

The regeneration of tissues with complex architectures requires strategies that promote the appropriate cellular processes, and can direct their organization. Plasmid-loaded multiple channel bridges were engineered for spinal cord regeneration with the ability to support and direct cellular processes and promote gene transfer at the injury site. The bridges were manufactured with a gas foaming technique, and had multiple channels with controllable diameter and encapsulated plasmid. Initial studies investigating bridge implantation subcutaneously (SC) indicated transgene expression in vivo for 44 days, with gene expression dependent upon the pore size of the bridge. In the rat spinal cord, bridges implanted into a lateral hemisection supported substantial cell infiltration, aligned cells within the channels, axon growth across the channels, and high levels of transgene expression at the implant site with decreasing levels rostral and caudal. Immunohistochemistry revealed that the transfected cells at the implant site were present in both the pores and channels of the bridge and were mainly identified as Schwann cells, fibroblasts, and macrophages, in descending order of transfection. This synergy between gene delivery and the scaffold architecture may enable the engineering of tissues with complex architectures.

Sonic hedgehog and neurotrophin-3 increase oligodendrocyte numbers and myelination after spinal cord injury

“…Bridges were implanted into a lateral hemisection model at T9-T10 ( Fig. 1a, b ), with extensive cell infiltration and integration with the host tissue 1–4 . Additionally, delivery of lentivirus from these bridges has promoted transgene expression that exceeded 60 days 36 .…”

“…Previously, we fabricated multiple channel bridges from biodegradable poly(lactide-co-glycolide) (PLG) containing a high density of linear channels that enabled the guidance of regenerating axons across the injury site when implanted into a lateral hemisection lesion in the mouse spinal cord 2,36 . In addition, the bridge contains a network of interconnected pores that permitted the rapid infiltration of multiple cell types from the adjacent tissue 1–4 . Functionalization of these bridges with lentivirus provided robust, sustained transgene expression after SCI 5,36,37 .…”

Holistic Approach to Axonal Regeneration in Cases of Spinal Cord Injury

“…It was discovered that the use of multiple channel bridges in the treatment of SCI can direct the growth of neural fibers and facilitate spinal cord regeneration. In a similar study, plasmid-loaded multiple channel bridges were engineered to induce the growth of axons across the injury site [89,94]. Tuinstra et al further established a multichannel bridge coating which was capable of delivering neurotrophin encoding lentiviruses to promote axonal regeneration following SCI [90].…”

Processing and Templating of Bioactive-Loaded Polymeric Neural Architectures: Challenges and Innovative Strategies

“…The authors postulated that the "local delivery of lipoplexes from a biomaterial may have the ability to maintain lipoplex stability, and therefore increase the number of transfected cells and transgene expression". Based on their previous study, multiple linear guidance channels were able to support cell infiltration and integrate effectively into the spinal cord wherein the channels induced cell orientation along its major axis and supported and directed axon elongation across the channels [32]. Strategically, lipoplexes were immobilized to the surface of the bridges as follows:…”