A New Paradigm for Local and Sustained Release of Therapeutic Molecules to the Injured Spinal Cord for Neuroprotection and Tissue Repair

Abstract

After spinal cord injury (SCI), a complex cascade of events leads to tissue degeneration and a penumbra of cell death. Neuroprotective molecules to limit tissue loss are promising; however, intravenous delivery is limited by the blood-spinal cord barrier and short systemic half-life. Current local delivery strategies are flawed: bolus injection results in drug dispersion throughout the intrathecal (IT) space, and catheters/pumps are invasive and open to infection. Our laboratory previously developed a hydrogel of hyaluronan (HA) and methylcellulose (MC) (HAMC) that, when injected into the IT space, was safe and, remarkably, had some therapeutic benefit on its own. In order to test this new paradigm of local and sustained delivery, relative to conventional delivery strategies, we tested, for the first time, the in vivo efficacy of HAMC as an IT drug delivery system by delivering a known neuroprotective molecule, erythropoietin (EPO). In vitro studies showed that EPO was released from HAMC within 16 h, with 80% bioactivity maintained. When the material alone was injected in vivo, individual fluorescent labels on HA and MC showed that HA dissolved from the gel within 24 h, whereas the hydrophobically associated MC persisted in the IT space for 4-7 days. Using a clip compression injury model of moderate severity, HAMC with EPO was injected in the IT space and, in order to better understand the potential of this delivery system, compared to the therapeutic effect of both common delivery strategies-IT EPO and intraperitoneal EPO-and a control of IT HAMC alone. IT HAMC delivery of EPO resulted in both reduced cavitation after SCI and a greater number of neurons relative to the other delivery strategies. These data suggest that the localized and sustained release of EPO at the tissue site by HAMC delivery enhances neuroprotection. This new system of IT delivery holds great promise for the safe, efficacious, and local delivery of therapeutic molecules directly to the spinal cord.

The Use of Chitosan-Based Scaffolds to Enhance Regeneration in the Nervous System

“…NSCs seeded in fibrin scaffolds within a chitosan channel, containing PLGA microspheres releasing dibutyryl cyclic-AMP, differentiate in vitro tob-III-tubulin positive neurons providing further confirmation of chitosan scaffold biocompatibility (Kim, Zahir, Tator, & Shoichet, 2011). Yet, scaffolds made of chitin, chitosan, and gelatinwith pore geometry of inverted colloidal crystals have been successfully used to guide the differentiation of iPS cells into neurons (Kuo & Lin, 2013).…”

“…Lamininisan180-KDaglycoproteinthatplaysanimportantroleinneuronal cell adhesion, differentiation, and neurite outgrowth (Madison, da Silva, Dikkes, Sidman, & Chiu, 1987;Manthorpe et al, 1983). Two peptides of the lamin-1 molecule, namely, YIGSR (Tyr-Ile-Gly-Ser-Arg) and IKVAV (Ile-Lys-Val-AlaVal) sequences, mediate receptor-specific neural cell adhesion and are known to promote cell adhesion and neurite outgrowth, respectively (Graf et al, 1987;Kleinman et al, 1988;Pierschbacher & Ruoslahti, 1984;Sephel, Burrous, & Kleinman, 1989;Tashiro et al, 1989). Moreover, these domains enhance SC migration.…”

Dual Delivery of EPO and BMP2 from a Novel Modular Poly-ɛ-Caprolactone Construct to Increase the Bone Formation in Prefabricated Bone Flaps

“…EPO has been delivered through injectable hydrogels, 37,38 gelatin, 26 and fibrin gel 27 for angiogenesis studies; however, only one study of which we are aware has locally delivered EPO and BMP2 from a porogenleached protein microbubble polyglycolic acid (PLGA) scaffold to assess bone regeneration in a calvarial defect model. 29 In another study, BMP2 was delivered from a collagen scaffold implanted in a rat calvarial defect, and EPO was injected subcutaneously at the defect site every other day for 2 weeks.…”

Processing and Templating of Bioactive-Loaded Polymeric Neural Architectures: Challenges and Innovative Strategies

“…Specifically, nimodipine-loaded gels yielded particle size-dependent biphasic release profiles suggesting the accelerated delivery of poorly soluble drugs with tuneable release rates. In an another report, in vitro erythropoietin release studies revealed a 16 h release profile with the implant showing reduced cavitation after spinal cord injury along with enhanced neuronal number proving the potential of HAMC in neuroprotection after neural injury [2][3][4].…”