title: Using NGF heparin-poloxamer thermosensitive hydrogels to enhance the nerve regeneration for spinal cord injury.
abstract: OBJECTIVE
  Nerve growth factor (NGF) has potential in spinal cord injury (SCI) therapy, but limited by the poor physicochemical stability and low ability to cross the blood spinal cord barrier. Novel heparin-poloxamer (HP) thermo-sensitive hydrogel was constructed to enhance the NGF regeneration on SCI.
  
  
  METHODS
  NGF-HP thermo-sensitive hydrogel was prepared and related characteristics including gelation temperature, rheological behavior and micromorphology were measured. Local NGF delivery to the injured spinal cord was achieved by in situ injection in the injured space. The cellular uptake of NGF-HP hydrogel was evaluated with PC12 cells in vitro. Pathologic characteristics and neuron regeneration effects on the SCI rats were studied to evaluate the enhanced therapy of NGF-HP hydrogel. Endoplasmic reticulum (ER) stress-induced apoptosis was analyzed to explore the related mechanism in SCI regeneration.
  
  
  RESULTS
  NGF-HP hydrogel showed good morphology and stable bioactivity of NGF in vitro. NGF-HP hydrogel combined treatment significantly enhanced the efficiency of NGF cellular uptake (P<0.05) without obvious cytotoxicity. Significant improvements in both neuron functions and tissue morphology on the SCI rats were observed in NGF-HP hydrogel group. Compared with free HP hydrogel and NGF treatment groups, NGF-HP hydrogel group showed significant inhibition on the formation of glial scars in the extreme crushed rat SCI model. The neuroprotective effects of NGF-HP were related to the inhibition of chronic ER stress-induced apoptosis.
  
  
  CONCLUSIONS
  HP hydrogel combined with orthotopic injection technique might be an effective method to deliver NGF into the injured site, which will provide an effective strategy for SCI regeneration.
  
  
  CONCLUSIONS
  Spinal cord injury (SCI) is a devastating condition that can lead to sudden loss of sensory and autonomic function. Current treatment includes decompression surgery, injury stabilization, secondary complications prevention and rehabilitation. However, neurological recovery is limited. Nerve growth factor (NGF) has potential in SCI therapy, but limited by the poor physicochemical stability and low ability to cross the blood spinal cord barrier. Hydrogels have good affinity and compatibility to biological tissue. In this study, we developed a novel heparin-poloxamer (HP) thermo-sensitive hydrogel to enhance the spinal cord regeneration of NGF. From SCI rat experiment, HP hydrogel combined with orthotopic injection technique showed best neuroprotective effects among experimental groups. This novel combined technique will provide an effective strategy for SCI regeneration.
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China; The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China; Hainan Medical College, Haikou City, Hainan Province 571000, China.
authors.forename: Ying-Zheng
authors.initials: YZ
authors.lastname: Zhao
authors.affiliation: Zhejiang University Mingzhou Hospital, Zhejiang Province 315104, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xiao
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Lin
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China.
authors.forename: Wen-Ze
authors.initials: WZ
authors.lastname: Yu
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China.
authors.forename: Fu-Rong
authors.initials: FR
authors.lastname: Tian
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China.
authors.forename: Kai-Li
authors.initials: KL
authors.lastname: Mao
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: School of Pharmacy, Temple University, Philadelphia, PA 19140, USA. Electronic address: ho-lun.wong@temple.edu.
authors.forename: Ho Lun
authors.initials: HL
authors.lastname: Wong
authors.affiliation: The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China. Electronic address: lctuua@sina.com.
authors.forename: Cui-Tao
authors.initials: CT
authors.lastname: Lu
mesh_terms: D000818:Animals; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006493:Heparin / Q000493:pharmacokinetics / Q000494:pharmacology; D006358:Hot Temperature; D020100:Hydrogels / Q000493:pharmacokinetics / Q000494:pharmacology; D020932:Nerve Growth Factor / Q000493:pharmacokinetics / Q000494:pharmacology; D009416:Nerve Regeneration / Q000187:drug effects*; D016716:PC12 Cells; D020442:Poloxamer / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology
chemical_list: D003692:Delayed-Action Preparations; D020100:Hydrogels; D020442:Poloxamer; D006493:Heparin; D020932:Nerve Growth Factor
keywords: Controlled release; Nerve growth factor (NGF); Nerve regeneration; Spinal cord injury; Thermosensitive hydrogel