Combination therapy of stem cell derived neural progenitors and drug delivery of anti-inhibitory molecules for spinal cord injury.

Regeneration of lost synaptic connections following spinal cord injury (SCI) is limited by local ischemia, cell death, and an excitotoxic environment, which leads to the development of an inhibitory glial scar surrounding a cystic cavity. While a variety of single therapy interventions provide incremental improvements to functional recovery after SCI, they are limited; a multifactorial approach that combines several single therapies may provide a better chance of overcoming the multitude of obstacles to recovery. To this end, fibrin scaffolds were modified to provide sustained delivery of neurotrophic factors and anti-inhibitory molecules, as well as encapsulation of embryonic stem cell-derived progenitor motor neurons (pMNs). In vitro characterization of this combination scaffold confirmed that pMN viability was unaffected by culture alongside sustained delivery systems. When transplanted into a rat sub-acute SCI model, fibrin scaffolds containing growth factors (GFs), anti-inhibitory molecules without pMNs, or pMNs with GFs had lower chondroitin sulfate proteoglycan levels compared to scaffolds containing anti-inhibitory molecules with pMNs. Scaffolds containing pMNs, but not anti-inhibitory molecules, showed survival, differentiation into neuronal cell types, axonal extension in the transplant area, and the ability to integrate into host tissue. However, the combination of pMNs with sustained-delivery of anti-inhibitory molecules led to reduced cell survival and increased macrophage infiltration. While combination therapies retain potential for effective treatment of SCI, further work is needed to improve cell survival and to limit inflammation. STATEMENT OF SIGNIFICANCE: Spinal cord injury (SCI) creates a highly complex inhibitory environment with a multitude of obstacles that limit recovery. Many therapeutic options have been developed to overcome single obstacles, but single therapies typically only lead to limited functional improvement. Therefore combination therapies may improve recovery by targeting several inhibitory obstacles simultaneously. The present study used biomaterial scaffolds to combine the sustained release of anti-inhibitory molecules and growth factors with cell transplantation of highly purified progenitor motor neurons. This expands upon previously established biomaterial scaffolds by supporting surviving cells, limiting inhibition from the extracellular environment, and replenishing lost cell populations. We show that while promising, certain combinations may exacerbate negative side-effects instead of augmenting positive features.