Abstract
Tissue engineering, including cell transplantation and the application of biomaterials and bioactive molecules, represents a promising approach for regeneration following spinal cord injury (SCI). We designed a combinatorial tissue-engineered approach for the minimally invasive treatment of SCI—a hyaluronic acid (HA)-based scaffold containing polypyrrole-coated fibers (PPY) combined with the RAD16-I self-assembling peptide hydrogel (Corning® PuraMatrix™ peptide hydrogel (PM)), human induced neural progenitor cells (iNPCs), and a nanoconjugated form of curcumin (CURC). In vitro cultures demonstrated that PM preserves iNPC viability and the addition of CURC reduces apoptosis and enhances the outgrowth of Nestin-positive neurites from iNPCs, compared to non-embedded iNPCs. The treatment of spinal cord organotypic cultures also demonstrated that CURC enhances cell migration and prompts a neuron-like morphology of embedded iNPCs implanted over the tissue slices. Following sub-acute SCI by traumatic contusion in rats, the implantation of PM-embedded iNPCs and CURC with PPY fibers supported a significant increase in neuro-preservation (as measured by greater βIII-tubulin staining of neuronal fibers) and decrease in the injured area (as measured by the lack of GFAP staining). This combination therapy also restricted platelet-derived growth factor expression, indicating a reduction in fibrotic pericyte invasion. Overall, these findings support PM-embedded iNPCs with CURC placed within an HA demilune scaffold containing PPY fibers as a minimally invasive combination-based alternative to cell transplantation alone.
Highlights
We previously discovered that a highly porous hyaluronic acid (HA) demilune scaffold containing polylactic acid (PLA) fibers in the internal lumen seeded with NPCs derived from neonatal rat spinal cord tissue successfully preserved neural tissue with minimal cyst and scar formation [17]
To evaluate the viability of induced pluripotent stem cells (iNPCs) embedded in the PM hydrogel and 3D in vitro culture in the presence or absence of CURC, we first performed an MTS assay to evaluate cell metabolic activity after one and five days of culture (Figure 1A)
Embedding cells in PM in the presence or absence of CURC (PM_CURC_iNPC and PM_iNPC, respectively) significantly reduced the metabolic activity of iNPCs during the first day of culture compared with iNPCs cultured under traditional conditions
Summary
Spinal cord injury (SCI) treatment remains a significant challenge due to the complexity and dynamic nature of the intrinsic pathological cascades that occur immediately after the primary lesion and progress to the permanent loss of neuronal activity and the creation. Secondary injury damage beginning soon after the initial trauma results in massive neuronal and glial cell death (including oligodendrocytes), prompting demyelination and expanding the loss of efficient neuronal connectivity to additional neuronal tracts. The formation of a permissive platform bridging the extrinsic inhibitory microenvironment characteristic of the injured spinal area via cell transplantation could afford collateral neuroplasticity and neuronal regeneration [1]. The transplantation of neural progenitor cells derived from human induced pluripotent stem cells (iNPCs) [2] has provided promising results in terms of repair and neuronal regeneration in rodent [3,4] and primate [5,6]
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