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Spinal cord injury (SCI) results in progressive destruction of spinal cord tissue. Controlling inflammation, which is amplified within the first several post-injury days, has become a critical objective in controlling SCI damage. Recent studies have attributed the degenerative inflammatory cascade to the activation of the proinflammatory M1 macrophage subpopulation, and the absence of the M2 alternative anti-inflammatory subpopulation. An expanding body of evidence suggests that transplanted mesenchymal stem cells (MSC) can improve functional SCI outcomes by modulating inflammatory reactions and decreasing scar tissue formation via secretion of cytokines and neurotrophic factors. While others have directly infused millions of cells, we have utilized alginate microencapsulation to develop an implantable MSC vehicle that stably houses thousands of cells and permits MSC secretion through its porous structure. The potential of MSC therapeutics has only begun to be harnessed and while functional improvements have been documented in many animal model studies, therapeutic protocols have not been sufficiently or precisely developed for successful translation to the clinic. The objectives of our proposed studies are to incorporate and improve upon current anti-inflammatory approaches by carefully designing combinatorial molecular and MSC therapeutic strategies. We will improve upon our initial successful results by identifying, using multifactorial design, combinations of known anti-inflammatory molecular therapies, which in conjunction with ligand conjugated-nanoparticle primed encapsulated MSC (eMSC), will augment anti-inflammatory responses. We will evaluate the therapeutic effect over time via quantitative biochemical and histological analyses, with an emphasis on M1 and M2 macrophage population changes, and ultimately assess functional recovery over time. In addition, by developing a miniaturized device, we will be able to temporally analyze the inflammatory cytokine secretion within the cerebrospinal fluid (CSF) and thereby more effectively, monitor post-injury inflammation from individual animals.
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