Uric acid released from poly(ε‐caprolactone) fibers as a treatment platform for spinal cord injury

Abstract

Spinal cord injury (SCI) is characterized by a primary mechanical phase of injury, resulting in physical tissue damage, and a secondary pathological phase, characterized by biochemical processes contributing to inflammation, neuronal death, and axonal demyelination. Glutamate‐induced excitotoxicity (GIE), in which excess glutamate is released into synapses and overstimulates glutamate receptors, is a major event in secondary SCI. GIE leads to mitochondrial damage and dysfunction, release of reactive oxygen species (ROS), DNA damage, and cell death. There is no clinical treatment that targets GIE after SCI, and there is a need for therapeutic targets for secondary damage in patients. Uric acid (UA) acts as an antioxidant and scavenges free radicals, upregulates glutamate transporters on astrocytes, and preserves neuronal viability in in vitro and in vivo SCI models, making it a promising therapeutic candidate. However, development of a drug release platform that delivers UA locally to the injured region in a controlled manner is crucial, as high systemic UA concentrations can be detrimental. Here, we used the electrospinning technique to synthesize UA‐containing poly(ɛ‐caprolactone) fiber mats that are biodegradable, biocompatible, and have a tunable degradation rate. We optimized delivery of UA as a burst within 20 min from uncoated fibers and sustained release over 2 h with poly(ethylene glycol) diacrylate coating. We found that both of these fibers protected neurons and decreased ROS generation from GIE in organotypic spinal cord slice culture. Thus, fiber mats represent a promising therapeutic for UA release to treat patients who have suffered a SCI.

Biomaterial-based regenerative therapeutic strategies for spinal cord injury

“…Using PCL as a drug delivery system to deliver uric acid, Singh and coworkers successfully protected spinal cord tissue from excitotoxic injury in an in vitro injury model 250 .…”

Electrospun drug‐loaded scaffolds for nervous system repair

“…However, when administered in high doses it can lead to kidney toxicity and gout (Fathallah-Shaykh & Cramer, 2014). Therefore, a localized delivery of uric acid to the spinal cord via electrospun fibers was proposed by Singh et al (2021).The release of uric acid from PCL fibers was calculated by measuring the drop in pH over 2 h of incubation in PBS. In an organotypic SCI model, treatment of spinal cord slices with uric acid-loaded fibers reduced glutamate-induced cell death and ROS in both dorsal and ventral regions, suggesting that local treatment with uric acid protects spinal cord tissue from glutamate-induced excitotoxicity.…”

“…However, when administered in high doses it can lead to kidney toxicity and gout (Fathallah‐Shaykh & Cramer, 2014). Therefore, a localized delivery of uric acid to the spinal cord via electrospun fibers was proposed by Singh et al (2021). The release of uric acid from PCL fibers was calculated by measuring the drop in pH over 2 h of incubation in PBS.…”

Hormetic Effects of Bioactive Compounds from Foods, Beverages, and Food Dressing: The Potential Role in Spinal Cord Injury

“…•− and HO • and is the major antioxidant in body fluids and preserves neuronal viability in preclinical models of SCI [36]. GPX is a selenium-(Se-) dependent enzyme and it was shown that Se nanoparticles could reverse oxidative stress-induced SCI in rats [37].…”