Abstract
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 (∼10 μm). The results demonstrate that addition of regularly sized macropores to traditional hydrogel scaffolds, which have nanopores (∼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.
Highlights
As of 2020, spinal cord injury (SCI) is estimated to have an average annual incidence of 54 cases per million people in the United States, and the consequences to those affected are tremendous, often resulting in mild to severe paraplegia, bladder dysfunction, sexual dysfunction, and/or spasticity.[1]
While an interconnected network of cell-sized macropores is necessary for rapid host cell infiltration into—and integration of host tissue with—implanted scaffolds, injectable biomaterials have generally suffered from a lack of control over the macrostructure
The results demonstrate that addition of regularly sized macropores to traditional hydrogel scaffolds, which have nanopores ($10 nm), significantly increases the expression of locally delivered transgene to the spinal cord after a thoracic injury
Summary
As of 2020, spinal cord injury (SCI) is estimated to have an average annual incidence of 54 cases per million people in the United States (roughly 17 800 annually), and the consequences to those affected are tremendous, often resulting in mild to severe paraplegia, bladder dysfunction, sexual dysfunction, and/or spasticity.[1]. A substantial portion of neurological damage caused by SCI has been attributed to the secondary injury response that occurs after the primary traumatic insult, where an ischemic and inflammatory microenvironment propagates cell death, axon retraction, and axon demyelination.[3,4,5] Immediately after SCI, immune cells, which include macrophages and neutrophils from the peripheral blood supply and microglia from surrounding tissue, infiltrate the lesion. Activated immune cells produce reactive oxygen species and cytokines that cause extensive death of cells required for the neurological function, in particular conducting neurons and myelinating oligodendrocytes.[3] While some level of an immune response is necessary to initiate wound
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