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Principal Investigator: Sangamesh Gurappa Kumbar
Organization: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
Fiscal Year: 2024
Award: $430,763
Funding agency: National Institute of Neurological Disorders and Stroke
Peripheral nerve injuries (PNI) affect millions of people in the US, and PNI with large gaps require surgical repair.
Although biological and synthetic grafts are widely used to repair PNI with large gaps, they both can suffer from
suboptimal clinical outcomes. Autografts are the gold standard treatment but are limited by availability and defect
repair size, while synthetic grafts have poor biodegradability, strength, bioactivity, and functionality. Thus, the
long-term objective of this proposal is to engineer grafts with enhanced large-gap nerve regeneration capabilities.
Physical and chemical stimulation can enhance nerve regeneration responses, thus, incorporating these
modalities into engineered grafts may address some current treatment limitations. Electrical stimulation (ES) can
enhance nerve conduction, neurotrophin release, and functional recovery of nerve crush injuries, but these
benefits have not been established for large-gap PNI. Chemical stimulation using 4-aminopyridine (4-AP; a
potassium channel blocker) appears similar to ES in its effects on neurons and can enhance crush PNI repair,
yet may act synergistically with ES. Implementing these physical and chemical cues for effective large-gap PNI
repair will require surgical insertion of an electrically conductive scaffold with appropriate mechanical strength,
degradation, conductivity, and pore properties. This proposal aims to deliver 4-AP and ES via novel,
biodegradable, ionically conducting (IC) chitosan scaffolds and hybrid-engineered nerve allografts to repair large-
gap nerve defects. We found that IC scaffolds with ES+4-AP treatment in large-gap nerve defects increased
neurotrophin release, myelination, compound action potential, and gastrocnemius muscle weight beyond ES or
4-AP alone. Increased blood vessel growth and reduced fiber capsule thickness surrounding scaffolds with
ES+4-AP treatment indicate improved biocompatibility and regeneration. Significantly higher levels of genes for
TrkA, TrkB, and TrkC receptors and NGF, BDNF, NT3, and CD31 were found for ES+4AP treatment important
for nerve regeneration. Therefore, it was hypothesized that IC scaffolds combined with chemical and electrical
cues will modulate cell-material interactions to enhance axon regeneration rate and functional recovery
comparable to autografts. This will be tested with three Specific Aims: 1) Characterize ionically conducting (IC)
scaffolds with variations in drug release rate, conductivity, and biodegradation; 2) Assess human and rat
Schwann cell responses to IC scaffolds with 4-AP and/or ES in vitro to model in vivo responses and future
interventions; and 3) Test long-term safety and efficacy of engineered scaffolds and allografts with 4-AP +/- ES
in a critical-sized sciatic nerve defect. Engineered repair of large-gap PNI using bioactive electrical and chemical
cues will broadly impact the field. These studies will bridge the knowledge gap between the complex ES-
mediated cell-material interaction microenvironment and poorly studied underlying regeneration pathways.
These findings may improve the treatment of nerve defects, and inform exploratory work on regenerative
strategies for innervation in other musculoskeletal tissues.
Terms: <4 Aminopyridine Sustained Release><4-Aminopyridine><4-Pyridinamine><Action Potentials><Address><Adverse effects><Affect><Alkanesulfonates><Alkyl Sulfonates><Alkylsulfonate Compound><Allografting><American><Animals><Autograft><Autologous Transplantation><Autotransplant><BDNF><BDNF Receptor><BDNF/NT-3 Growth Factors Receptor><Biocompatible Materials><Biodegradation><Biological><Biomaterials><Biomedical Engineering><Blood Vessels><Body Tissues><Brain-Derived Neurotrophic Factor><Brain-Derived Neurotrophic Factor Receptor><CD31><Capsules><Cell Body><Cell Locomotion><Cell Migration><Cell Movement><Cells><Cellular Migration><Cellular Motility><Chemical Stimulation><Chemicals><Chitosan><Clinical><Common Rat Strains><Complex><Convulsants><Crush Injury><Cues><Defect><Disease><Disorder><Disseminated Sclerosis><Drug Modelings><Drugs><E-stim><Electric Conductivity><Electric Stimulation><Electrical Conductivity><Engineering><Ensure><Fampridine-SR><Fiber><Future><GP145-TRKB><GP145-TRKC><Gastrocnemius Muscle><Generalized Growth><Genes><Growth><Human><Hybrids><Hydrophobicity><Immune response><Immunological response><Implant><In Vitro><Injury><Intervention><Intervention Strategies><Knowledge><Mechanics><Mediating><Medication><Minor><Modality><Modern Man><Multiple Sclerosis><Musculoskeletal><Myelin><NGF-2><NT3><NT3 Growth Factor Receptor><NTF3><NTF3 gene><NTRK1 Receptor><NTRK2 Receptor><NTRK3 Protein><NTRK3 Receptor><Natural regeneration><Nerve><Nerve Cells><Nerve Conduction><Nerve Crush><Nerve Growth Factor Receptor Type 1><Nerve Regeneration><Nerve Unit><Neural Cell><Neural Conduction><Neurilemma Cell><Neurilemmal Cell><Neuro-regeneration><Neurocyte><Neurons><Neuroregeneration><Neurotrophic Tyrosine Kinase Receptor Type 1><Neurotrophic Tyrosine Kinase Receptor Type 2><Neurotrophic Tyrosine Kinase Receptor Type 3><Neurotrophin 3 Receptor><Operative Procedures><Operative Surgical Procedures><Outcome><Oxidation-Reduction><PECAM1><PECAM1 gene><Pathway interactions><Patients><Pattern><Peripheral nerve injury><Persons><Pharmaceutical Preparations><Physical Stimulation><Physiologic><Physiological><Poliglusam><Polymers><Potassium Channel Blockers><Property><Protein-Tyrosine Kinase TRKC><Pymadine><Rat><Rats Mammals><Rattus><Recovery of Function><Redox><Regeneration><Regenerative pathway><Regenerative response><Safety><Schwann Cells><Site><Supporting Cell><Surgical><Surgical Interventions><Surgical Procedure><TRKB Tyrosine Kinase><TRKC Tyrosine Kinase><Testing><Thick><Thickness><Tissue Growth><Tissues><Variant><Variation><Weight><Work><autologous graft><autotransplantation><axon regeneration><axonal regeneration><bio-engineered><bio-engineers><biocompatibility><biodegradable scaffold><bioengineering><biologic><biological engineering><biological material><biomaterial compatibility><capsule><cell motility><communicable disease transmission><controlled release><disease transmission><dosage><drug release kinetics><drug release rate><drug/agent><electrical conductance><electrostimulation><functional recovery><functional restoration><gastrocnemius><healing><host response><immune system response><immunoresponse><improved><in vitro Model><in vivo><in vivo Model><infectious disease transmission><injuries><injury and repair><innervation><insular sclerosis><interventional strategy><mechanic><mechanical><myelination><nerve autograft><nerve gap><nerve injury><nerve reconstruction><nerve repair><nerve supply><nervous system regeneration><neural><neural graft><neural injury><neural regeneration><neuronal><neuroregenerative><neurotransmitter release><neurotrophic factor><neurotrophin><neutrophin><novel><ontogeny><oxidation reduction reaction><p140-trkA><pathway><peripheral nerve crush injuries><peripheral nerve repair><polymer><polymeric><re-myelinate><re-myelination><regenerate><regenerated nerve><regeneration pathway><regeneration response><regenerative approach><regenerative strategy><regenerative technique><remyelinate><remyelination><repair><repaired><response><restore function><restore functionality><restore lost function><scaffold><scaffolding><sciatic nerve><small molecule><standard care><standard treatment><sulfonate><surgery><translational opportunities><translational potential><trk1 Transforming Tryrosine Kinase><trkA Receptor><trkB Receptor><trkB(gp145) Protein><trkC Protein><trkC Receptor><vascular><weights>