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| 1 | Conundrums and confusions regarding how polyethylene glycol-fusion produces excellent behavioral recovery after peripheral nerve injuries显示文摘Current Neuroscience dogma holds that transections or ablations of a segment of peripheral nerves produce:(1) Immediate loss of axonal continuity, sensory signaling, and motor control;(2) Wallerian rapid(1-3 days) degeneration of severed distal axons, muscle atrophy, and poor behavioral recovery after many months(if ever, after ablations) by slowly-regenerating(1 mm/d), proximal-stump outgrowths that must specifically reinnervate denervated targets;(3) Poor acceptance of microsutured nerve allografts, even if tissue-matched and immune-suppressed. Repair of transections/ablations by neurorrhaphy and well-specified-sequences of PEG-fusion solutions(one containing polyethylene glycol, PEG) successfully address these problems. However, conundrums and confusions regarding unorthodox and dramatic results of PEG-fusion repair in animal model systems often lead to misunderstandings. For example,(1) Axonal continuity and signaling is re-established within minutes by non-specifically PEG-fusing(connecting) severed motor and sensory axons across each lesion site, but remarkable behavioral recovery to near-unoperated levels takes several weeks;(2) Many distal stumps of inappropriately-reconnected, PEG-fused axons do not ever(Wallerian) degenerate and continuously innervate muscle fibers that undergo much less atrophy than otherwise-denervated muscle fibers;(3) Host rats do not reject PEG-fused donor nerve allografts in a non-immuno-privileged environment with no tissue matching or immunosuppression;(4) PEG fuses apposed open axonal ends or seals each shut(thereby preventing PEG-fusion), depending on the experimental protocol;(5) PEG-fusion protocols produce similar results in animal model systems and early human case studies. Hence, iconoclastic PEG-fusion data appropriately understood might provoke a re-thinking of some Neuroscience dogma and a paradigm shift in clinical treatment of peripheral nerve injuries. | George D.Bittner Dale R.Sengelaub Cameron L.Ghergherehchi | 2018 | Neural Regeneration Research2018，13，1： | 3 |
| 2 | Repair of traumatic plasmalemmal damage to neurons and other eukaryotic cells显示文摘The repair(sealing) of plasmalemmal damage,consisting of small holes to complete transections,is critical for cell survival,especially for neurons that rarely regenerate cell bodies.We first describe and evaluate different measures of cell sealing.Some measures,including morphological/ultra-structural observations,membrane potential,and input resistance,provide very ambiguous assessments of plasmalemmal sealing.In contrast,measures of ionic current flow and dye barriers can,if appropriately used,provide more accurate assessments.We describe the effects of various substances(calcium,calpains,cytoskeletal proteins,ESCRT proteins,m UNC-13,NSF,PEG) and biochemical pathways(PKA,PKC,PLC,Epac,cytosolic oxidation) on plasmalemmal sealing probability,and suggest that substances,pathways,and cellular events associated with plasmalemmal sealing have undergone a very conservative evolution.During sealing,calcium ion influx mobilizes vesicles and other membranous structures(lysosomes,mitochondria,etc.) in a continuous fashion to form a vesicular plug that gradually restricts diffusion of increasingly smaller molecules and ions over a period of seconds to minutes.Furthermore,we find no direct evidence that sealing occurs through the collapse and fusion of severed plasmalemmal leaflets,or in a single step involving the fusion of one large wound vesicle with the nearby,undamaged plasmalemma.We describe how increases in perikaryal calcium levels following axonal transection account for observations that cell body survival decreases the closer an axon is transected to the perikaryon.Finally,we speculate on relationships between plasmalemmal sealing,Wallerian degeneration,and the ability of polyethylene glycol(PEG) to seal cell membranes and rejoin severed axonal ends – an important consideration for the future treatment of trauma to peripheral nerves.A better knowledge of biochemical pathways and cytoplasmic structures involved in plasmalemmal sealing might provide insights to develop treatments for traumatic nerve injuries,stroke,muscular dystrophy,and other pathologies. | George D.Bittner Christopher S.Spaeth Andrew D.Poon Zachary S.Burgess Christopher H.Mc Gill | 2016 | Neural Regeneration Research2016，11，7： | 2 |
| 3 | Application and implications of polyethylene glycol-fusion as a novel technology to repair injured spinal cords显示文摘Conventional vs.polyethylene glycol(PEG)-fusion technologies to repair severed spinal axons:Most spinal cord injuries(SCIs)involve cut-or crush-severance of spinal tract axons in the central nervous system(CNS).Clinical outcomes after CNS axonal severance is very poor because proximal segments of CNS axons lack a suitable environment | George D.Bittner Kiran K.Rokkappanavar Jean D.Peduzzi | 2015 | Neural Regeneration Research2015，10，9： | 2 |
| 4 | Methylene blue enhances polyethylene glycol-fusion repair of completely severed rat sciatic nerves显示文摘Complete transection of peripheral mixed nerves immediately produces loss of sensory perception,muscle contractions and voluntary behavior mediated by the severed distal axons.In contrast to natural regeneration(~1 mm/d)of proximal axons that may eventually reinnervate denervated targets,re-innervation is restored within minutes by PEG-fusion that consists of neurorrhaphy and a sequence of well specified hypo-and isotonic calcium-free or calcium-containing solutions,the anti-oxidant methylene blue(MB)and the membrane fusogen polyethylene glycol(PEG).In this study,we examined the relative efficacy of PEG-fusion with no MB(0%),0.5%MB,or 1%MB on the recovery of voluntary behaviors by female Sprague-Dawley rats with a complete mid-thigh severance of their sciatic nerve bathed in extracellular fluid or calcium-containing isotonic saline.The recovery of voluntary behaviors is the most relevant measure of success of any technique to repair peripheral nerve injuries.We assessed recovery by the sciatic functional index,a commonly used measure of voluntary hindlimb behaviors following complete sciatic transections.We reported that both 1%MB and 0.5%MB in sterile distilled water in our PEG-fusion protocol with neurorrhaphy significantly increased the rate and extent of behavioral recovery compared to PEG plus neurorrhaphy alone.Furthermore,0.5%MB was as effective as 1%MB in voluntary behavioral recovery as assessed by the sciatic functional index.Since sterile 1%MB is no longer clinically available,we therefore recommend that 0.5%MB be included in upcoming human clinical trials to evaluate the safety and efficacy of PEG-fusion.All animal procedures were approved by the University of Texas Institutional Animal Care and Use Committee(AUP-2019-00225)on September 9,2020. | Cameron L.Ghergherehchi Jaimie T.Shores Joseph Alderete Erik K.Weitzel George D.Bittner | 2021 | Neural Regeneration Research2021，16，10： | 1 |
| 5 | Functional and immunological peculiarities of peripheral nerve allografts显示文摘This review addresses the accumulating evidence that live(not decellularized)allogeneic peripheral nerves are functionally and immunologically peculiar in comparison with many other transplanted allogeneic tissues.This is relevant because live peripheral nerve allografts are very effective at promoting recovery after segmental peripheral nerve injury via axonal regeneration and axon fusion.Understanding the immunological peculiarities of peripheral nerve allografts may also be of interest to the field of transplantation in general.Three topics are addressed:The first discusses peripheral nerve injury and the potential utility of peripheral nerve allografts for bridging segmental peripheral nerve defects via axon fusion and axon regeneration.The second reviews evidence that peripheral nerve allografts elicit a more gradual and less severe host immune response allowing for prolonged survival and function of allogeneic peripheral nerve cells and structures.Lastly,potential mechanisms that may account for the immunological differences of peripheral nerve allografts are discussed. | Kelly C.S.Roballo Jason P.Gigley Tyler A.Smith George D.Bittner Jared S.Bushman | 2022 | Neural Regeneration Research2022，17，4： | 1 |
| 6 | Polyethylene glycol-fusion retards Wallerian degeneration and rapidly restores behaviors lost after nerve severance显示文摘Some biological uses of polyethylene glycol(PEG):The use of PEG as a membrane fusogen was first reported in 1976with the creation of cell hybrids,formed by suspending two cell lines in a 50%w/w solution of PEG in water.More recently,direct application of PEG has been found to seal off small holes in axons after complete transections of | George D.Bittner Michelle Mikesh Cameron L.Ghergherehchi | 2016 | Neural Regeneration Research2016，11，2： | 0 |
| 7 | Repair and regeneration of peripheral nerve injuries that ablate branch points显示文摘The peripheral nervous system has an extensive branching organization, and peripheral nerve injuries that ablate branch points present a complex challenge for clinical repair. Ablations of linear segments of the PNS have been extensively studied and routinely treated with autografts, acellular nerve allografts, conduits, wraps, and nerve transfers. In contrast, segmental-loss peripheral nerve injuries, in which one or more branch points are ablated so that there are three or more nerve endings, present additional complications that have not been rigorously studied or documented. This review discusses:(1) the branched anatomy of the peripheral nervous system,(2) case reports describing how peripheral nerve injuries with branched ablations have been surgically managed,(3) factors known to influence regeneration through branched nerve structures,(4) techniques and models of branched peripheral nerve injuries in animal models, and(5) conclusions regarding outcome measures and studies needed to improve understanding of regeneration through ablated branched structures of the peripheral nervous system. | JuliAnne E.Allgood George D.Bittner Jared S.Bushman | 2023 | Neural Regeneration Research2023，18，12： | 0 |
| 8 | Survival of rat sciatic nerve segments preserved in storage solutions ex vivo assessed by novel electrophysiological and morphological criteria显示文摘Most organ or tissue allografts with viable cells are sto red in solutions ex vivo for hours to seve ral days.Most allografts then require rapid host revascula rization upon transplantation to maintain donor-cell functions(e.g.,cardiac muscle contra ctions,hepatic secretions).In contrast,peripheral nerve allografts stored ex vivo do not require revascularization to act as scaffolds to guide outgrowth by host axons at 1-2 mm/d,likely aided by viable donor Schwann cells.Using current storage solutions and protocols,axons in all these donor orga n/tissue/nerve transplants are expected to rapidly become non-viable due to Wallerian degeneration within days.Therefore,ex vivo storage solutions have not been assessed for preserving normal axonal functions,i.e.,conducting action potentials or maintaining myelin sheaths.We hypothesized that most or all organ storage solutions would maintain axonal viability.We examined several common organ/tissue storage solutions(University of Wisconsin Cold Storage Solution,Normosol-R,Normal Saline,and La ctated Ringe rs) for axonal viability in rat sciatic nerves ex vivo as assessed by maintaining:(1) conduction of artificially-induced compound action potentials;and(2) axonal and myelin morphology in a novel assay method.The ten diffe rent storage solution conditions for peripheral nerves with viable axons(PNVAs) diffe red in their solution composition,osmolarity(250-318 mOsm),temperature(4℃ vs.25℃),and presence of calcium.Compound action potentials and axonal morphology in PNVAs were best maintained for up to 9 days ex vivo in calcium-free hypotonic diluted(250 mOsm) Normosol-R(dNR) at 4℃.Surprisingly,compound action potentials were maintained for only 1-2 days in UW and NS at 4℃,a much shorter duration than PNVAs maintained in 4℃ dNR(9 days) or even in 25℃ dNR(5 days).Viable axons in peripheral nerve allografts are critical for successful polyethylene glycol(PEG)-fusion of viable proximal and distal ends of host axons with viable donor axons to repair segmental-loss peripheral nerve injuries.PEG-fusion repair using PNVAs prevents Wallerian degeneration of many axons within and distal to the graft and results in excellent recovery of sensory/motor functions and voluntary behaviors within weeks.Such PEG-fused PNVAs,unlike all other types of conventional donor transplants,are immune-tolerated without tissue matching or immune suppression.Preserving axonal viability in sto red PNVAs would enable the establishment of PNVA tissue banks to address the current shortage of transplantable nerve grafts and the use of stored PEG-fused PNVAs to repair segmentalloss peripheral nerve injuries.Furthermore,PNVA storage solutions may enable the optimization of ex vivo storage solutions to maintain axons in other types of organ/tissue transplants. | Liwen Zhou Monzer Alatrach Ted Zhao Paul Oliphint George D.Bittner | 2023 | Neural Regeneration Research2023，18，9： | 0 |
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