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

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.

Perspectives on optimizing local delivery of drugs to peripheral nerves using mathematical models

“…In addition, the increasing body of research into the development of allogeneic nerve grafts, including allografts and cellular tissue engineered constructs, may necessitate the need for immunosuppressive treatment. However, Treatments under investigation have not yet been successfully translated to the clinic, in part due to the requirement for improved delivery methods to reduce issues with bioavailability and off target effects, for example through the use of local delivery systems (Rayner, Grillo, et al, 2020).…”

Repurposing Small Molecules to Target PPAR-γ as New Therapies for Peripheral Nerve Injuries

“…Drugs with potential to promote nerve regeneration have been identified as a result of this repurposing approach and in particular, agents targeting PPAR-γ currently used for the treatment of other clinical conditions have already shown benefit in preclinical nerve regeneration studies (Table 1). [ [61][62][63] Diclofenac generation have been identified as a result of this repurposing approach and in particular, agents targeting PPAR-γ currently used for the treatment of other clinical conditions have already shown benefit in preclinical nerve regeneration studies (Table 1). Improved functional recovery and faster recovery of regenerated axons.…”

“…Both ibuprofen and indomethacin demonstrated positive effects on neurite elongation in cell culture models [ 61 , 70 ]. This has been extrapolated into animal models with positive effects demonstrated on neurite elongation [ 62 , 63 ], and improvements seen in myelination and functional recovery [ 69 , 71 , 72 ] with ibuprofen.…”

Exploring the Nerve Regenerative Capacity of Compounds with Differing Affinity for PPARγ In Vitro and In Vivo

“…Ibuprofen and diclofenac are the most commonly studied NSAIDs for PNI treatment [9,[14][15][16]. The pharmacological effects of NSAIDs are thought to be independent of their well-known anti-inflammatory activity on cyclooxygenase (COX) 1 and 2 [17,18].…”