The wound healing process that occurs after spinal cord injury is critical for maintaining tissue homeostasis and limiting tissue damage, but eventually results in a scar-like environment that is not conducive to regeneration and repair. A better understanding of this dichotomy is critical to developing effective therapeutics that target the appropriate pathobiology, but a major challenge has been the large cellular heterogeneity that results in immensely complex cellular interactions. In this study, we used single-cell RNA sequencing to assess virtually all cell types that comprise the mouse spinal cord injury site. In addition to discovering novel subpopulations, we used expression values of receptor–ligand pairs to identify signaling pathways that are predicted to regulate specific cellular interactions during angiogenesis, gliosis, and fibrosis. Our dataset is a valuable resource that provides novel mechanistic insight into the pathobiology of not only spinal cord injury but also other traumatic disorders of the CNS.

The control and manipulation of cells that trigger secondary mechanisms following spinal cord injury (SCI) is one of the first opportunities to minimize its highly detrimental outcomes. Herein, the ability of surface-engineered carboxymethylchitosan/polyamidoamine (CMCht/PAMAM) dendrimer nanoparticles to intracellularly deliver methylprednisolone (MP) to glial cells, allowing a controlled and sustained release of this corticosteroid in the injury site, is investigated. The negatively charged MP-loaded CMCht/PAMAM dendrimer nanoparticles with sizes of 109 nm enable a MP sustained release, which is detected for a period of 14 days by HPLC. In vitro studies in glial primary cultures show that incubation with 200 μg mL(-1) nanoparticles do not affect the cells' viability or proliferation, while allowing the entire population to internalize the nanoparticles. At higher concentrations, microglial cell viability is proven to be affected in response to the MP amount released. Following lateral hemisection lesions in rats, nanoparticle uptake by the spinal tissue is observed 3 h after administration. Moreover, significant differences in the locomotor output between the controls and the MP-loaded nanoparticle-treated animals one month after the lesion are observed. Therefore, MP-loaded CMCht/PAMAM dendrimer nanoparticles may prove to be useful in the reduction of the secondary injury following SCI.

Schwann cell (SC) transplantation has been comprehensively studied as a strategy for spinal cord injury (SCI) repair. SCs are neuroprotective and promote axon regeneration and myelination. Nonetheless, substantial SC death occurs post-implantation, which limits therapeutic efficacy. The use of extracellular matrix (ECM)-derived matrices, such as Matrigel, supports transplanted SC survival and axon growth, resulting in improved motor function. Because appropriate matrices are needed for clinical translation, we test here the use of an acellular injectable peripheral nerve (iPN) matrix. Implantation of SCs in iPN into a contusion lesion did not alter immune cell infiltration compared to injury only controls. iPN implants were larger and contained twice as many SC-myelinated axons as Matrigel grafts. SC/iPN animals performed as well as the SC/Matrigel group in the BBB locomotor test, and made fewer errors on the grid walk at 4 weeks, equalizing at 8 weeks. The fact that this clinically relevant iPN matrix is immunologically tolerated and supports SC survival and axon growth within the graft offers a highly translational possibility for improving efficacy of SC treatment after SCI. To our knowledge, it is the first time that an injectable PN matrix is being evaluated to improve the efficacy of SC transplantation in SCI repair.

Central nervous system (CNS) injuries are often debilitating, and most currently have no cure. This is due to the formation of a neuroinhibitory microenvironment at injury sites, which includes neuroinflammatory signaling and non‐permissive extracellular matrix (ECM) components. To address this challenge, a viscous interfacial self‐assembly approach, to generate a bioinspired hybrid 3D porous nanoscaffold platform for delivering anti‐inflammatory molecules and establish a favorable 3D‐ECM environment for the effective suppression of the neuroinhibitory microenvironment, is developed. By tailoring the structural and biochemical properties of the 3D porous nanoscaffold, enhanced axonal growth from the dual‐targeting therapeutic strategy in a human induced pluripotent stem cell (hiPSC)‐based in vitro model of neuroinflammation is demonstrated. Moreover, nanoscaffold‐based approaches promote significant axonal growth and functional recovery in vivo in a spinal cord injury model through a unique mechanism of anti‐inflammation‐based fibrotic scar reduction. Given the critical role of neuroinflammation and ECM microenvironments in neuroinhibitory signaling, the developed nanobiomaterial‐based therapeutic intervention may pave a new road for treating CNS injuries.