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Polyethylene glycol has immunoprotective effects on sciatic allografts, but behavioral recovery and graft tolerance require neurorrhaphy and axonal fusion

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Neural regeneration research 2025年第4期20卷 1192-1206页

作者： Tyler A.Smith Liwen Zhou Cameron L.Ghergherehchi Michelle Mikesh Cathy Z.Yang Haley O.Tucker JuliAnne Allgood Jared S.Bushman George D.Bittner Department of Molecular Biosciences University of Texas at AustinAustinTXUSA Department of Neuroscience University of Texas at AustinAustinTXUSA Division of Pharmaceutical Sciences University of WyomingLaramieWYUSA

Behavioral recovery using(viable)peripheral nerve allografts to repair ablation-type(segmental-loss)peripheral nerve injuries is delayed or poor due to slow and inaccurate axonal ***,such peripheral nerve allografts undergo immunological rejection by the host immune *** contrast,peripheral nerve injuries repaired by polyethylene glycol fusion of peripheral nerve allografts exhibit excellent behavioral recovery within weeks,reduced immune responses,and many axons do not undergo Wallerian *** relative contribution of neurorrhaphy and polyethylene glycol-fusion of axons versus the effects of polyethylene glycol per se was unknown prior to this *** hypothesized that polyethylene glycol might have some immune-protective effects,but polyethylene glycol-fusion was necessary to prevent Wallerian degeneration and functional/behavioral *** examined how polyethylene glycol solutions per se affect functional and behavioral recovery and peripheral nerve allograft morphological and immunological responses in the absence of polyethylene glycol-induced axonal ***-type sciatic nerve injuries in outbred Sprague–Dawley rats were repaired according to a modified protocol using the same solutions as polyethylene glycol-fused peripheral nerve allografts,but peripheral nerve allografts were loose-sutured(loose-sutured polyethylene glycol)with an intentional gap of 1–2 mm to prevent fusion by polyethylene glycol of peripheral nerve allograft axons with host *** to negative control peripheral nerve allografts not treated by polyethylene glycol and in contrast to polyethylene glycol-fused peripheral nerve allografts,animals with loose-sutured polyethylene glycol peripheral nerve allografts exhibited Wallerian degeneration for all axons and myelin degeneration by 7 days postoperatively and did not recover sciatic-mediated behavioral functions by 42 days *** morphological signs of rejection,such as col

关键词： allograft rejection axotomy macrophage myelin nerve repair polyethylene glycol(PEG) sciatic nerve T cell transplantation Wallerian degeneration

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Survival of rat sciatic nerve segments preserved in storage solutions ex vivo assessed by novel electrophysiological and morphological criteria

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Neural regeneration research 2023年第9期18卷 2082-2088页

作者： Liwen Zhou Monzer Alatrach Ted Zhao Paul Oliphint George D.Bittner Department of Neuroscience University of Texas at AustinAustinTXUSA

Most organ or tissue allografts with viable cells are sto red in solutions ex vivo for hours to seve ral *** 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 *** 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 ***,ex vivo storage solutions have not been assessed for preserving normal axonal functions,i.e.,conducting action potentials or maintaining myelin *** hypothesized that most or all organ storage solutions would maintain axonal *** 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 *** 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 *** 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 a

关键词： axonal morphometrics axonal viability calcium osmolarity peripheral nerve grafts peripheral nerve injury temperature tissue storage solutions tonicity Wallerian degeneration

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Functional and immunological peculiarities of peripheral nerve allografts

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Neural regeneration research 2022年第4期17卷 721-727页

作者： Kelly C.S.roballo Jason P.Gigley Tyler A.Smith George D.Bittner Jared S.Bushman School of Pharmacy University of WyomingLaramieWYUSA Department of Molecular Biology University of WyomingLaramieWYUSA Department of Molecular Biosciences University of Texas at AustinAustinTXUSA Department of Neuroscience University of Texas at AustinAustinTXUSA

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 *** is relevant because live peripheral nerve allografts are very effective at promoting recovery after segmental peripheral nerve injury via axonal regeneration and axon *** the immunological peculiarities of peripheral nerve allografts may also be of interest to the field of transplantation in *** 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 *** 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 ***,potential mechanisms that may account for the immunological differences of peripheral nerve allografts are discussed.

关键词： allograft animal model immunology neuroimmunology peripheral nerve injury regeneration repair tissue regeneration tissue transplantation transplant

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repair of traumatic plasmalemmal damage to neurons and other eukaryotic cells

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Neural regeneration research 2016年第7期11卷 1033-1042页

作者： George D.Bittner Christopher S.Spaeth Andrew D.Poon Zachary S.Burgess Christopher H.Mc Gill Department of Neuroscience The University of Texas at Austin

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 *** first describe and evaluate different measures of cell *** measures,including morphological/ultra-structural observations,membrane potential,and input resistance,provide very ambiguous assessments of plasmalemmal *** contrast,measures of ionic current flow and dye barriers can,if appropriately used,provide more accurate *** 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 *** 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 ***,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 *** 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 ***,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 develo

关键词： sealing traumatic eukaryotic vesicles axonal membranous closer biochemical vesicular muscular

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Polyethylene glycol-fusion retards Wallerian degeneration and rapidly restores behaviors lost after nerve severance

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Neural regeneration research 2016年第2期11卷 217-219页

作者： George D.Bittner Michelle Mikesh Cameron L.Ghergherehchi Department of Neuroscience University of Texas at Austin

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 w... 详细信息

关键词： Figure PEG Polyethylene glycol-fusion retards Wallerian degeneration and rapidly restores behaviors lost after nerve severance

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Application and implications of polyethylene glycol-fusion as a novel technology to repair injured spinal cords

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Neural regeneration research 2015年第9期10卷 1406-1408页

作者： George D.Bittner Kiran K.rokkappanavar Jean D.Peduzzi Department of Neuroscience University of Texas at Austin Department of Biochemistry and Molecular Biology Wayne State University School of Medicine Department of Anatomy & Cell Biology Department of Physical Medicine and Rehabilitation at Oakwood Wayne State University School of Medicine

Conventional vs. polyethylene glycol （PEG）-fusion tech- nologies to repair severed spinal axons： Most spinal cord injuries （SCIs） involve cutor crush-severance of spinal tract axons in the central nervous system （Cns）. Clinical out- comes after Cns axonal severance is very poor because proximal segments of Cns axons lack a suitable environment for outgrowth （Kakulas, 1999; Fitch and Silver, 2008; rowland et al., 2008; Kwon et al., 2010） and therefore do not naturally regenerate （ramon y Caial, 1928）. Current strategies to try to increase behavioral recovery after SCI are focused on en- hancing the environment for axonal outgrowth.

关键词： PEG Application and implications of polyethylene glycol-fusion as a novel technology to repair injured spinal cords

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