New frontiers in nerve regeneration: combining surgical, pharmacological and 3D bioprinting approaches

• Grant number: 23/02615-4
• Support Opportunities: Research Projects - Thematic Grants
• Start date: February 01, 2025
• End date: January 31, 2030
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Alexandre Leite Rodrigues de Oliveira
• Grantee: Alexandre Leite Rodrigues de Oliveira
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated researchers: Alessandra Sussulini ; Angela Maria Moraes ; Benedito Barraviera ; Kelly Cristine Santos Roballo ; Luciana Politti Cartarozzi ; Marcos Akira d'Ávila ; Rogério Martins Amorim ; Rui Seabra Ferreira Junior

Abstract

Regeneration of the Nervous System is a challenge that endures to the present day, given the complexity of events that follow trauma or during neurodegenerative diseases. It is well established that the Central Nervous System (CNS) contrasts with the Peripheral Nervous System (PNS) in terms of regenerative potential, the latter being more likely to restore its structure and function. However, in both cases, important functional losses, often associated with neuropathic pain, are permanently installed, leading to reduced quality of life. From both clinical and basic science perspectives, understanding the neural/glial degenerative and regenerative processes is fundamental for the development of more effective treatment strategies. The present proposal approaches the issue of nerve regeneration under three fundamental aspects: the anatomical/surgical reestablishment of the lesion, be it in the CNS or PNS; the use of immunomodulatory and pro-regenerative molecules/drugs, as well as the use of new techniques, such as 3D printing, as a framework to obtain biofunctional constructs capable of sustaining the regenerative process. Thus, in terms of anatomical restoration of injuries, we will use axonal fusion with polyethylene glycol, associated with the use of the antioxidant 4-hydroxy-tempo and a fibrin biopolymer to repair the sciatic nerve transection. After sciatic nerve repair, we will also use a 3D printed polycaprolactone bandage associated with methacrylated gelatin (GelMA) containing FGF-2 to stimulate the regenerative process. An electroneuromyographic record will be made to identify the success of the use of fusogen and the biofunctional bandage. The functional recovery will be monitored by gait analysis (CatWalk system), and the morphology and molecular mechanisms will be investigated by immunohistochemistry and qRT-PCR. At the CNS/PNS interface, root avulsion repair will be performed with fibrin biopolymer, associated with treatment with N, N-dimethyltryptamine (DMT), FGF-2, demeclocycline (DMC), and doubly reduced DMC (DDMC). These molecules have different impacts on neuroprotection and modulation of inflammation and glial reaction, and behavioral, molecular, and in situ analyses are employed to evaluate the success of such treatments. The positive effects of FGF-2, as well as of stem cell-derived exosomes modified to overexpress this molecule, will be investigated in the animal model of multiple sclerosis, the experimental autoimmune encephalomyelitis (EAE). (AU)