title: Single injection of a novel nerve growth factor coacervate improves structural and functional regeneration after sciatic nerve injury in adult rats.
abstract: The prototypical neurotrophin, nerve growth factor (NGF), plays an important role in the development and maintenance of many neurons in both the central and peripheral nervous systems, and can promote functional recovery after peripheral nerve injury in adulthood. However, repair of peripheral nerve defects is hampered by the short half-life of NGF in vivo, and treatment with either NGF alone or NGF contained in synthetic nerve conduits is inferior to the use of nerve autografts, the current gold standard. We tested the reparative ability of a single local injection of a polyvalent coacervate containing polycation-poly(ethylene argininylaspartate diglyceride; PEAD), heparin, and NGF, in adult rats following sciatic nerve crush injury, using molecular, histological and behavioral approaches. In vitro assays demonstrated that NGF was loaded into the coacervate at nearly 100% efficiency, and was protected from proteolytic degradation. In vivo, the coacervate enhanced NGF bioavailability, leading to a notable improvement in motor function (track walking analysis) after 30days. The NGF coacervate treatment was also associated with better weight gain and reduction in atrophy of the gastrocnemius muscle. Furthermore, light and electron microscopy showed that the number of myelinated axons and axon-to-fiber ratio (G-ratio) were significantly higher in NGF coacervate-treated rats compared with control groups. Expression of markers of neural tissue regeneration (MAP-2, S-100β, MBP and GAP-43), as well as proliferating Schwann cells and myelin-axon relationships (GFAP and NF200), were also increased. These observations suggest that even a single administration of NGF coacervate could have therapeutic value for peripheral nerve regeneration and functional recovery.
authors.affiliation: WZMU-JCU Joint Research Group for Stem Cell and Tissue Engineering, Institute of Stem Cell and Tissue Engineering, Wenzhou Medical University, Wenzhou 325035, China; Growth Factors and Clinical Application Group, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: 791853868@qq.com.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: WZMU-JCU Joint Research Group for Stem Cell and Tissue Engineering, Institute of Stem Cell and Tissue Engineering, Wenzhou Medical University, Wenzhou 325035, China; Growth Factors and Clinical Application Group, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: woody870402@zju.edu.cn.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wu
authors.affiliation: WZMU-JCU Joint Research Group for Stem Cell and Tissue Engineering, Institute of Stem Cell and Tissue Engineering, Wenzhou Medical University, Wenzhou 325035, China. Electronic address: zklin@wmu.edu.cn.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lin
authors.affiliation: WZMU-JCU Joint Research Group for Stem Cell and Tissue Engineering, Institute of Stem Cell and Tissue Engineering, Wenzhou Medical University, Wenzhou 325035, China; Regenerative Dentistry & Oral Biology Lab, Oral Health Centre, University of Queensland, Brisbane 4006, Australia. Electronic address: m.nangle@uq.edu.au.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Nangle
authors.affiliation: Growth Factors and Clinical Application Group, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: liyi20060507@163.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Growth Factors and Clinical Application Group, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: 1261206149@qq.com.
authors.forename: Pingtao
authors.initials: P
authors.lastname: Cai
authors.affiliation: Growth Factors and Clinical Application Group, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: 1328251262@qq.com.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Growth Factors and Clinical Application Group, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: 190435904@qq.com.
authors.forename: Libin
authors.initials: L
authors.lastname: Ye
authors.affiliation: Growth Factors and Clinical Application Group, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: xiaozecong.1314@qq.com.
authors.forename: Zecong
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Growth Factors and Clinical Application Group, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: 928282661@qq.com.
authors.forename: Chaochao
authors.initials: C
authors.lastname: He
authors.affiliation: Growth Factors and Clinical Application Group, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: jbb_2006@126.com.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Ye
authors.affiliation: Growth Factors and Clinical Application Group, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: st_hyz@126.com.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Growth Factors and Clinical Application Group, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: lwhwz1@126.com.
authors.forename: Yingzheng
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Peripheral Neurosurgery, the First Affiliated Hospital Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: lswangjw@sina.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Growth Factors and Clinical Application Group, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: xiaokunli@163.net.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.affiliation: WZMU-JCU Joint Research Group for Stem Cell and Tissue Engineering, Institute of Stem Cell and Tissue Engineering, Wenzhou Medical University, Wenzhou 325035, China; Regenerative Dentistry & Oral Biology Lab, Oral Health Centre, University of Queensland, Brisbane 4006, Australia. Electronic address: h.he@uq.edu.au.
authors.forename: Yan
authors.initials: Y
authors.lastname: He
authors.affiliation: WZMU-JCU Joint Research Group for Stem Cell and Tissue Engineering, Institute of Stem Cell and Tissue Engineering, Wenzhou Medical University, Wenzhou 325035, China; Regenerative Dentistry & Oral Biology Lab, Oral Health Centre, University of Queensland, Brisbane 4006, Australia. Electronic address: qingsongye@hotmail.com.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Ye
authors.affiliation: WZMU-JCU Joint Research Group for Stem Cell and Tissue Engineering, Institute of Stem Cell and Tissue Engineering, Wenzhou Medical University, Wenzhou 325035, China; Growth Factors and Clinical Application Group, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: xfxj2000@126.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Xiao
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D019922:GAP-43 Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006493:Heparin / Q000627:therapeutic use*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000097:blood / Q000378:metabolism; D004676:Myelin Basic Protein / Q000378:metabolism; D020932:Nerve Growth Factor / Q000627:therapeutic use*; D009416:Nerve Regeneration / Q000187:drug effects*; D010455:Peptides / Q000627:therapeutic use*; D011091:Polyesters / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects*; D064568:S100 Calcium Binding Protein beta Subunit / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000473:pathology / Q000648:ultrastructure; D020426:Sciatic Neuropathy / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
chemical_list: D019922:GAP-43 Protein; D005904:Glial Fibrillary Acidic Protein; D004676:Myelin Basic Protein; D010455:Peptides; D011091:Polyesters; D064568:S100 Calcium Binding Protein beta Subunit; C572412:poly(ethylene argininylaspartate diglyceride); D006493:Heparin; D020932:Nerve Growth Factor; D020928:Mitogen-Activated Protein Kinases
keywords: Coacervate; Controlled release; Heparin; Nerve growth factor; Peripheral nerve regeneration; Sciatic nerve injury