Injectable, macroporous scaffolds for delivery of therapeutic genes to the injured spinal cord

Biomaterials are being developed as therapeutics for spinal cord injury (SCI) that can stabilize and bridge acute lesions and mediate the delivery of transgenes, providing a localized and sustained reservoir of regenerative factors. For clinical use, direct injection of biomaterial scaffolds is preferred to enable conformation to unique lesions and minimize tissue damage. While an interconnected network of cell-sized macropores is necessary for rapid host cell infiltration into-and thus integration of host tissue with-implanted scaffolds, injectable biomaterials have generally suffered from a lack of control over the macrostructure. As genetic vectors have short lifetimes in vivo, rapid host cell infiltration into scaffolds is a prerequisite for efficient biomaterial-mediated delivery of transgenes. We present scaffolds that can be injected and assembled in situ from hyaluronic acid (HA)-based, spherical microparticles to form scaffolds with a network of macropores (similar to 10 mu m). The results demonstrate that addition of regularly sized macropores to traditional hydrogel scaffolds, which have nanopores (similar to 10 nm), significantly increases the expression of locally delivered transgene to the spinal cord after a thoracic injury. Maximal cell and axon infiltration into scaffolds was observed in scaffolds with more regularly sized macropores. The delivery of lentiviral vectors encoding the brain-derived neurotrophic factor (BDNF), but not neurotrophin-3, from these scaffolds further increased total numbers and myelination of infiltrating axons. Modest improvements to the hindlimb function were observed with BDNF delivery. The results demonstrate the utility of macroporous and injectable HA scaffolds as a platform for localized gene therapies after SCI.

Automated summary

This study demonstrates the utility of macroporous and injectable HA scaffolds as a platform for localized gene therapies after SCI. Adding regularly sized macropores to traditional hydrogel scaffolds significantly increases the expression of locally delivered transgenes in the spinal cord and enhances cell and axon infiltration. Delivery of lentiviral vectors encoding BDNF from these scaffolds further increases axon infiltration and myelination, leading to modest improvements in hindlimb function.