Drug-eluting microfibrous patches for the local delivery of rolipram in spinal cord repair

Abstract

Spinal cord injury (SCI) remains a major challenge for regenerative medicine. Following SCI, axon growth inhibitors and other inflammatory responses prevent functional recovery. Previous studies have demonstrated that rolipram, an anti-inflammatory and cyclic adenosine monophosphate preserving small molecule, improves spinal cord regeneration when delivered systemically. However, more recent studies showed that rolipram has some adverse effects in spinal cord repair. Here, we developed a drug-delivery platform for the local delivery of rolipram into the spinal cord. The potential of drug-eluting microfibrous patches for continuous delivery of high and low-dose rolipram concentrations was characterized in vitro. Following C5 hemisections, athymic rats were treated with patches loaded with low and high doses of rolipram. In general, animals treated with low-dose rolipram experienced greater functional and anatomical recovery relative to all other groups. Outcomes from the high-dose rolipram treatment were similar to those with no treatment. In addition, high-dose treated animals experienced reduced survival rates suggesting that systemic toxicity was reached. With the ability to control the release of drug dosage locally within the spinal cord, drug-eluting microfibrous patches demonstrate the importance of appropriate local release-kinetics of rolipram, proving their usefulness as a therapeutic platform for the study and repair of SCI.

Integration of drug, protein, and gene delivery systems with regenerative medicine

“…Fibrous scaffolds have been hallmarked as biomaterial implants due to their high surface to volume ratio and tunable biomimicry [68]. Electrospun fibrous scaffolds have been applied towards a broad range of regenerative medicine applications including dermal wound healing, skeletal muscle regeneration, nerve regeneration, and spinal cord regeneration [86, 26, 72, 87]. Soluble factors can be immobilized on the surface of fibers to for local delivery to the site of interest (Fig.…”

“…For example, rolipram, an anti-inflammatory and phosphodiesterase 4 inhibiting SMD, had been previously shown to improve spinal cord regeneration in small doses but had adverse effects when delivered in larger doses [25]. The incoporation of this SMD into a microfibrous patch for continuous local delivery generated greater functional and anatomical recovery in rats following spinal cord injury in low dose groups, and resulted in reduced survival rates in high dose groups [26]. Another previously developed SMD, valproaric acid (VPA), had been shown to promote cortical neuronal growth in vitro [27], and was recently shown to enhance sciatic nerve regeneration in rats when delivered locally within silicone tubes [28].…”

Alginate Hydrogels as Scaffolds and Delivery Systems to Repair the Damaged Spinal Cord

“…For example, interesting strategies have been proposed to achieve controlled release of rolipram—a blood‐brain barrier permeable neuroprotectant with significant effects on functional recovery after SCI—and increase its therapeutic effects at the action site. In this direction, Downing and coworkers prepared series of ALG microfibrous patches for the continuous delivery of rolipram in vivo, achieving good therapeutic results ( Figure ) . Improvements in the functional recovery of motor function after injury were observed (open‐field locomotion, forelimb articular movement, and animal coordination) when small doses of rolipram were released (≈60 µg cm −2 ) over 12 days through the material.…”

Immune-Based Therapies for Spinal Cord Injury

“…For example, rolipram has been shown to prevent the reduction in cAMP levels after acute CNS injury as well as promote tissue protection, repair and functional recovery (Pearse et al, 2004;Atkins et al, 2006;Schaal et al, 2012). Additionally, a recent study described the benefits of utilizing a drugeluting microfibrous patch as means to deliver rolipram into the injured spinal cord and data indicated significant improvements in both functional and anatomical recovery (Downing et al, 2012). Clodronate has been shown to induce macrophage apoptosis (Monkkonen et al, 1994) and microglia elimination (Kumamaru et al, 2012) in vitro but the overall necessity of completely eradicating each is controversial at best.…”