Drug-Induced Regeneration and Re-Innervation in a Mouse Digit Amputation Model

In the proposed studies, we have used our experience in soft and hard tissue regeneration induced by the HIF1-stabilizing drug, 1,4-DPCA,in a drug delivery system (PEG-DPCA nanogel) towards therapies for hand, nerve, and digit regeneration. In the current studies, we are exploring the effect of this drug on 1) digit regrowth post-amputation and nerve regeneration, 2) drug effects on peripheral re-innervation in rat forelimbs after injury and 3) optimization of drug potency and delivery in these systems. Our progress during this third year includes studies on surgically-amputated digits in mice using Micro-CT analysis showing changes with 1,4-DPCA drug therapy with and without BMP2.Significant changes at 3 months showed changes in bone density and volume. In the Tuffaha/Brandacher model of rat forelimb nerve resection, using larger rat cohorts than previously reported, we again showed drug-enhanced grip strength, reduced muscle atrophy, and nerve fiber regeneration. During this no-cost extension year, we explored multiple drug injections for longer periods of time, new dosing, effects of BMP2 addition post digit amputation, continue studies in forelimb nerve regrowth, effects on digit function, further development of the 1,4-DPCA drug delivery system and modification of 1,4-DPCA compounds. We found that a second administration of drug, at 30 days post nerve transection in the rat, showed surprising nerve growth with a grip strength recovery BETTER than the normal rat itself.