Controlled local release of PPARγ agonists from biomaterials to treat peripheral nerve injury

M L D Rayner,T Zhang,E Tawfik,A Grillo,J B Phillips,J Healy,G R Williams,C Volitaki,D Q M Craig

doi:10.1088/1741-2552/aba7cc

Abstract

Objective. Poor clinical outcomes following peripheral nerve injury (PNI) are partly attributable to the limited rate of neuronal regeneration. Despite numerous potential drug candidates demonstrating positive effects on nerve regeneration rate in preclinical models, no drugs are routinely used to improve restoration of function in clinical practice. A key challenge associated with clinical adoption of drug treatments in nerve injured patients is the requirement for sustained administration of doses associated with undesirable systemic sideeffects. Local controlled-release drug delivery systems could potentially address this challenge, particularly through the use of biomaterials that can be implanted at the repair site during the microsurgical repair procedure. Approach. In order to test this concept, this study used various biomaterials to deliver ibuprofen sodium or sulindac sulfide locally in a controlled manner in a rat sciatic nerve injury model. Following characterisation of release parameters in vitro, ethylene vinyl acetate tubes or polylactic-co-glycolic acid wraps, loaded with ibuprofen sodium or sulindac sulfide, were placed around directly-repaired nerve transection or nerve crush injuries in rats. Main results. Ibuprofen sodium, but not sulindac sulfide caused an increase in neurites in distal nerve segments and improvements in functional recovery in comparison to controls with no drug treatment. Significance. This study showed for the first time that local delivery of ibuprofen sodium using biomaterials improves neurite growth and functional recovery following PNI and provides the basis for future development of drug-loaded biomaterials suitable for clinical translation.

Highlights

Peripheral nerve injury (PNI) is associated with substantial socioeconomic impact as the us cri resulting disability can be debilitating, significantly affecting the patient’s quality of life [1,2,3,4].Treatments mainly employ microsurgical interventions additional therapeutics that can be administered following PNI have emerged such as cell therapies, proteins, platelet-rich plasma and gene therapy [5,6,7,8]
With the ethylene vinyl acetate (EVA) membranes there was an initial burst release in the first 4 hours with 60% and 20% of drug released from the membranes and tubes respectively, within 24 hours this subsided and the release became more constant
This was consistent with a previous study that observed a burst release of ibuprofen from EVA in the first few hours with 50% of the initial loaded drug released within the 24 hours, the release an subsided after 48 hours with the remainder of the drug released in 10 days [33]

Summary

Introduction

Peripheral nerve injury (PNI) is associated with substantial socioeconomic impact as the us cri resulting disability can be debilitating, significantly affecting the patient’s quality of life [1,2,3,4].Treatments mainly employ microsurgical interventions additional therapeutics that can be administered following PNI have emerged such as cell therapies, proteins, platelet-rich plasma and gene therapy [5,6,7,8]. Peripheral nerve injury (PNI) is associated with substantial socioeconomic impact as the us cri resulting disability can be debilitating, significantly affecting the patient’s quality of life [1,2,3,4]. One drug which has been shown to improve regeneration when administered systemically to rats following PNI is ibuprofen, a non-steroidal antian inflammatory drug (NSAID) which is likely to accelerate neurite elongation as an agonist of peroxisome proliferator-activated receptor gamma (PPARγ) [11, 12]. PPARγ agonist activity is sulindac sulfide, which has not been tested for use in nerve repair

Methods

Results

Conclusion