Cameron L Ghergherehchi1, Michelle Mikesh2, Dale R Sengelaub3, David M Jackson4, Tyler Smith5, Jacklyn Nguyen6, Jaimie T Shores7, George D Bittner8. 1. Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, 78712, USA. Electronic address: cameronlgh@utexas.edu. 2. Department of Neuroscience, University of Texas at Austin, Austin, TX, 78712, USA. Electronic address: mfmikesh@utexas.edu. 3. Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, 47405, USA. Electronic address: sengelau@indiana.edu. 4. Neuraptive Therapeutics, Lafayette, CO, USA. Electronic address: david.jackson@neuraptive.com. 5. Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, 78712, USA. Electronic address: tylersmith128@utexas.edu. 6. Department of Neuroscience, University of Texas at Austin, Austin, TX, 78712, USA. Electronic address: jacklyn.nguyen@utexas.edu. 7. Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Ross Research Building 749D, 720 Rutland Avenue, Baltimore, MD, 21205, USA. Electronic address: jshores3@jhmi.edu. 8. Department of Neuroscience, University of Texas at Austin, Austin, TX, 78712, USA. Electronic address: bittner@austin.utexas.edu.
Abstract
BACKGROUND: Nervous system injuries in mammals often involve transection or segmental loss of peripheral nerves. Such injuries result in functional (behavioral) deficits poorly restored by naturally occurring 1-2 mm/d axonal outgrowths aided by primary repair or reconstruction. "Neurorrhaphy" or nerve repair joins severed connective tissues, but not severed cytoplasmic/plasmalemmal extensions (axons) within the tissue. NEW METHOD: PEG-fusion consists of neurorrhaphy combined with a well-defined sequence of four pharmaceutical agents in solution, one containing polyethylene glycol (PEG), applied directly to closely apposed viable ends of severed axons. RESULTS: PEG-fusion of rat sciatic nerves: (1) restores axonal continuity across coaptation site(s) within minutes, (2) prevents Wallerian degeneration of many distal severed axons, (3) preserves neuromuscular junctions, (4) prevents target muscle atrophy, (5) produces rapid and improved recovery of voluntary behaviors compared with neurorrhaphy alone, and (6) PEG-fused allografts are not rejected, despite no tissue-matching nor immunosuppression. COMPARISON WITH EXISTING METHODS: If PEG-fusion protocols are not correctly executed, the results are similar to that of neurorrhaphy alone: (1) axonal continuity across coaptation site(s) is not re-established, (2) Wallerian degeneration of all distal severed axons rapidly occurs, (3) neuromuscular junctions are non-functional, (4) target muscle atrophy begins within weeks, (5) recovery of voluntary behavior occurs, if ever, after months to levels well-below that observed in unoperated animals, and (6) allografts are either rejected or not well-accepted. CONCLUSION: PEG-fusion produces rapid and dramatic recovery of function following rat peripheral nerve injuries.
BACKGROUND:Nervous system injuries in mammals often involve transection or segmental loss of peripheral nerves. Such injuries result in functional (behavioral) deficits poorly restored by naturally occurring 1-2 mm/d axonal outgrowths aided by primary repair or reconstruction. "Neurorrhaphy" or nerve repair joins severed connective tissues, but not severed cytoplasmic/plasmalemmal extensions (axons) within the tissue. NEW METHOD:PEG-fusion consists of neurorrhaphy combined with a well-defined sequence of four pharmaceutical agents in solution, one containing polyethylene glycol (PEG), applied directly to closely apposed viable ends of severed axons. RESULTS:PEG-fusion of rat sciatic nerves: (1) restores axonal continuity across coaptation site(s) within minutes, (2) prevents Wallerian degeneration of many distal severed axons, (3) preserves neuromuscular junctions, (4) prevents target muscle atrophy, (5) produces rapid and improved recovery of voluntary behaviors compared with neurorrhaphy alone, and (6) PEG-fused allografts are not rejected, despite no tissue-matching nor immunosuppression. COMPARISON WITH EXISTING METHODS: If PEG-fusion protocols are not correctly executed, the results are similar to that of neurorrhaphy alone: (1) axonal continuity across coaptation site(s) is not re-established, (2) Wallerian degeneration of all distal severed axons rapidly occurs, (3) neuromuscular junctions are non-functional, (4) target muscle atrophy begins within weeks, (5) recovery of voluntary behavior occurs, if ever, after months to levels well-below that observed in unoperated animals, and (6) allografts are either rejected or not well-accepted. CONCLUSION:PEG-fusion produces rapid and dramatic recovery of function following ratperipheral nerve injuries.
Authors: A B Lore; J A Hubbell; D S Bobb; M L Ballinger; K L Loftin; J W Smith; M E Smyers; H D Garcia; G D Bittner Journal: J Neurosci Date: 1999-04-01 Impact factor: 6.167
Authors: Scott N Loewenstein; Reed Wulbrecht; Vanessa Leonhard; Sarah Sasor; Julia Cook; Lava Timsina; Joshua Adkinson Journal: Hand (N Y) Date: 2019-08-13
Authors: George D Bittner; Jared S Bushman; Cameron L Ghergherehchi; Kelly C S Roballo; Jaimie T Shores; Tyler A Smith Journal: J Neuroinflammation Date: 2022-02-28 Impact factor: 8.322
Authors: Justin C Burrell; Suradip Das; Franco A Laimo; Kritika S Katiyar; Kevin D Browne; Robert B Shultz; Vishal J Tien; Phuong T Vu; Dmitriy Petrov; Zarina S Ali; Joseph M Rosen; D Kacy Cullen Journal: Bioact Mater Date: 2022-03-24
Authors: Dmitriy Petrov; Justin C Burrell; Kevin D Browne; Franco A Laimo; Sanford E Roberts; Zarina S Ali; D Kacy Cullen Journal: Front Surg Date: 2022-03-07
Authors: Mohammed Nazmy Hamad; Nickolas Boroda; Diego Barragan Echenique; Raymond A Dieter; Farid M L Amirouche; Mark H Gonzalez; James M Kerns Journal: Front Cell Neurosci Date: 2022-03-30 Impact factor: 5.505
Authors: Cameron L Ghergherehchi; Emily A Hibbard; Michelle Mikesh; George D Bittner; Dale R Sengelaub Journal: PLoS One Date: 2019-10-04 Impact factor: 3.240