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Delivery of nitric oxide-releasing silica nanoparticles for in vivo revascularization and functional recovery after acute peripheral nerve crush injury

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Neural Regeneration Research 2022年第9期17卷 2043-2049页

作者： Jung Il Lee Ji Hun Park Yeong-Rim Kim Kihak Gwon Hae Won Hwang Gayoung Jung Joo-Yup Lee Jeong-Yun Sun Jong Woong Park Jae Ho Shin Myoung-Ryul Ok Department of Orthopedic Surgery College of MedicineKorea UniversitySeoulRepublic of Korea Medical Sensor Biomaterial Research Institute Kwangwoon UniversitySeoulRepublic of Korea Center for Biomaterials Korea Institute of Science&TechnologySeoulRepublic of Korea Department of Materials Science and Engineering Seoul National UniversitySeoulRepublic of Korea Department of Orthopedic Surgery College of MedicineCatholic UniversitySeoulRepublic of Korea Department of Chemistry Kwangwoon UniversitySeoulRepublic of Korea

Nitric oxide(NO)has been shown to promote revascularization and nerve regeneration after peripheral nerve injury.However,in vivo application of NO remains challenging due to the lack of stable carrier materials capable of storing large amounts of NO molecules and releasing them on a clinically meaningful time scale.Recently,a silica nanoparticle system capable of reversible NO storage and release at a controlled and sustained rate was introduced.In this study,NO-releasing silica nanoparticles(NO-SNs)were delivered to the peripheral nerves in rats after acute crush injury,mixed with natural hydrogel,to ensure the effective application of NO to the lesion.Microangiography using a polymer dye and immunohistochemical staining for the detection of CD34(a marker for revascularization)results showed that NO-releasing silica nanoparticles increased revascularization at the crush site of the sciatic nerve.The sciatic functional index revealed that there was a significant improvement in sciatic nerve function in NO-treated animals.Histological and anatomical analyses showed that the number of myelinated axons in the crushed sciatic nerve and wet muscle weight excised from NO-treated rats were increased.Moreover,muscle function recovery was improved in rats treated with NO-SNs.Taken together,our results suggest that NO delivered to the injured sciatic nerve triggers enhanced revascularization at the lesion in the early phase after crushing injury,thereby promoting axonal regeneration and improving functional recovery.

关键词： crush injury nerve injury,nerve regeneration nitric oxide peripheral nerve revascularization silica nanoparticles

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Sustained delivery of vascular endothelial growth factor mediated by bioactive methacrylic anhydride hydrogel accelerates peripheral nerve regeneration after crush injury

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Neural Regeneration Research 2022年第9期17卷 2064-2071页

作者： Wanlin Xu Yifan Wu Hao Lu Yun Zhu Jinhai Ye Wenjun Yang Department of Oral and Maxillofacial-Head and Neck Oncology Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineCollege of StomatologyShanghai Jiao Tong UniversityNational Center for StomatologyNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of StomatologyShanghaiChina Jiangsu Key Laboratory of Oral Diseases Department of Oral and Maxillofacial SurgeryThe Affiliated Stomatological Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina

Neurotrophic factors,currently administered orally or by intravenous drip or intramuscular injection,are the main method for the treatment of peripheral nerve crush injury.However,the low effective drug concentration arriving at the injury site results in unsatisfactory outcomes.Therefore,there is an urgent need for a treatment method that can increase the effective drug concentration in the injured area.In this study,we first fabricated a gelatin modified by methacrylic anhydride hydrogel and loaded it with vascular endothelial growth factor that allowed the controlled release of the neurotrophic factor.This modified gelatin exhibited good physical and chemical properties,biocompatibility and supported the adhesion and proliferation of RSC96 cells and human umbilical vein endothelial cells.When injected into the epineurium of crushed nerves,the composite hydrogel in the rat sciatic nerve crush injury model promoted nerve regeneration,functional recovery and vascularization.The results showed that the modified gelatin gave sustained delivery of vascular endothelial growth factors and accelerated the repair of crushed peripheral nerves.

关键词： bioactive material controlled release crush injury hydrogel muscle function nerve regeneration peripheral nerve sciatic function index vascular endothelial growth factor vascularization

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Recombinant human fibroblast growth factor-2 promotes nerve regeneration and functional recovery after mental nerve crush injury

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Neural Regeneration Research 2017年第4期12卷 629-636页

作者： Sung Ho Lee Wei-Peng Jin Na Ri Seo Kang-Mi Pang Bongju Kim Soung-Min Kim Jong-Ho Lee Dental Research Institute Department of Oral and Maxillofacial Surgery Seoul National University School of Dentistry Seoul Korea Dental Life Science Research Institute Clinical Translational Research Center for Dental Science Seoul National University Dental Hospital Seoul Korea Dental Research Institute Seoul National University Seoul Korea

Several studies have shown that fibroblast growth factor-2 （FGF2） can directly affect axon regeneration after peripheral nerve damage. In this study, we performed sensory tests and histological analyses to study the effect of recombinant human FGF-2 （rhFGF2） treatment on damaged mental nerves. The mental nerves of 6-week-old male Sprague-Dawley rats were crush-injured for 1 minute and then treated with 10 or 50 μg/mL rhFGF2 or PBS in crush injury area with a mini Osmotic pump. Sensory test using von Frey filaments at 1 week revealed the presence of sensory degeneration based on decreased gap score and increased difference score. However, at 2 weeks, the gap score and difference score were significantly rebounded in the mental nerve crush group treated with 10 μg/mL rhFGF2. Interestingly, treatment with 10 μg/mL rhFGF had a more obviously positive effect on the gap score than treatment with 50 μg/mL rhFGF2. In addition, retrograde neuronal tracing with Dil revealed a significant increase in nerve regeneration in the trigeminal ganglion at 2 and 4 weeks in the rhFGF2 groups （10 μg/mL and 50 μg/mL） than in the PBS group. The 10 μg/mL rhFGF2 group also showed an obviously robust regeneration in axon density in the mental nerve at 4 weeks. Our results demonstrate that 10 μg/mL rhFGF induces mental nerve regeneration and sensory recovery after mental nerve crush injury.

关键词： nerve regeneration mental nerve fibroblast growth factor crush injury sensory neuron functionalrecovery neural regeneration

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The Achyranthes bidentata polypeptide k fraction enhances neuronal growth in vitro and promotes peripheral nerve regeneration after crush injury in vivo

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Neural Regeneration Research 2014年第24期9卷 2142-2150页

作者： Qiong Cheng Chunyi Jiang Caiping Wang Shu Yu Qi Zhang Xiaosong Gu Fei Ding Jiangsu Key Laboratory of Neuroregeneration Co-innovation Center of Neuroregenration Nantong University

We have previously shown that Achyranthes bidentata polypeptides （ABPP）, isolated from Achyranthes bidentata Blume （a medicinal herb）, exhibit neurotrophic and neuroprotective effects on the nervous system. To identify the major active component of ABPP, and thus optimize the use of ABPP, we used reverse-phase high performance liquid chromatography to separate ABPP. We obtained 12 fractions, among which the fraction of ABPPk demonstrated the strongest neuroactivity. Immunocytochemistry and western blot analysis showed that ABPPk promoted neurite growth in cultured dorsal root ganglion explant and dorsal root ganglion neurons, which might be associated with activation of Erk1/2. A combination of behavioral tests, electrophysiological assessment, and histomorphometric analysis indicated that ABPPk enhanced nerve regeneration and function restoration in a mouse model of crushed sciatic nerve. All the results suggest that ABPPk, as the key component of ABPP, can be used for peripheral nerve repair to yield better outcomes than ABPP.

关键词： nerve regeneration Achyranthes bidentata polypeptides neuroactive component dorsal root ganglion neurite outgrowth crush injury sciatic nerve peripheral nerve regeneration neural regeneration

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Exogenous nerve growth factor protects the hypoglossal nerve against crush injury

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Neural Regeneration Research 2015年第12期10卷 1982-1988页

作者： Li-yuan Fan Zhong-chao Wang Pin Wang Yu-yan Lan Ling Tu Department of Prosthodontics Stomatological Hospital of Sichuan Medical University Orofacial Reconstruction and Regeneration Laboratory Sichuan Medical University Department of Endodontics Stomatological Hospital of Sichuan Medical University Department of Anatomy and Physiology College of StomatologyCentral South University

Studies have shown that sensory nerve damage can activate the p38 mitogen-activated protein kinase（MAPK）pathway,but whether the same type of nerve injury after exercise activates the p38MAPK pathway remains unclear.Several studies have demonstrated that nerve growth factor may play a role in the repair process after peripheral nerve injury,but there has been little research focusing on the hypoglossal nerve injury and repair.In this study,we designed and established rat models of hypoglossal nerve crush injury and gave intraperitoneal injections of exogenous nerve growth factor to rats for 14 days.p38MAPK activity in the damaged neurons was increased following hypoglossal nerve crush injury;exogenous nerve growth factor inhibited this increase in acitivity and increased the survival rate of motor neurons within the hypoglossal nucleus.Under transmission electron microscopy,we found that the injection of nerve growth factor contributed to the restoration of the morphology of hypoglossal nerve after crush injury.Our experimental findings indicate that exogenous nerve growth factor can protect damaged neurons and promote hypoglossal nerve regeneration following hypoglossal nerve crush injury.

关键词： nerve regeneration p38MAPK mitogen-activated protein kinase nerve growth factor hypoglossal nerve crush injury nerve injury neural regeneration

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L-carnitine alleviates sciatic nerve crush injury in rats:functional and electron microscopy assessments

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Neural Regeneration Research 2014年第10期9卷 1020-1024页

作者： ümmü Zeynep Avsar Umit Avsar Ali Aydin Muhammed Yayla Berna Ozturkkaragoz Harun Un Murat Saritemur Tolga Mercantepe Department of Medical Education Faculty of MedicineAtaturk University Department of Family Medicine Faculty of MedicineAtaturk University Department of Orthopedics and Traumatology Faculty of MedicineAtaturk University Department of Pharmacology Faculty of MedicineAtaturk University Department of Pharmacology Faculty of PharmacyAgr? University Department of Biochemistry Faculty of PharmacyAgr? University Department of Emergency Medicine Faculty of MedicineAtaturk University Department of Histology and Embryology Faculty of MedicineAtaturk University

Several studies have demonstrated that L-carnitine exhibits neuroprotective effects on injured sciatic nerve of rats with diabetes mellitus. It is hypothesized that L-carnitine exhibits neuro-protective effects on injured sciatic nerve of rats. Rat sciatic nerve was crush injured by a forceps and exhibited degenerative changes. After intragastric administration of 50 and 100 mg/kg L-carnitine for 30 days, axon area, myelin sheath area, axon diameter, myelin sheath diameter, and numerical density of the myelinated axons of injured sciatic nerve were similar to normal, and the function of injured sciatic nerve also improved signiifcantly. These ifndings suggest that L-carnitine exhibits neuroprotective effects on sciatic nerve crush injury in rats.

关键词： nerve regeneration peripheral nerve injury sciatic nerve L-carnitine neuroprotection crush injury electron microscopy axon myelin sheath neural regeneration

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Ultrasonic appearance of rhabdomyolysis in patients with crush injury in the Wenchuan earthquake

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Chinese Medical Journal 2009年第16期122卷 1872-1876页

作者： SU Bai-hai QIU Li FU Ping LUO Yan TAO Ye PENG Yu-lan Department of Nephrology West China Hospital Sichuan University Chengdu Sichuan 610041 China Department of Ultrasound West China Hospital Sichuan University Chengdu Sichuan 610041 China

Background On May 12, 2008, a major earthquake hit Wenchuan County in Sichuan Province of China. The number of cases of crush injury following this event was high. Ultrasonic appearance of rhabdomyolysis （RM） caused by crush injury in the Wenchuan earthquake was observed to evaluate the diagnostic value of ultrasound for detection of rhabdomyolysis. Methods We analyzed clinical and ultrasonic manifestations of 50 cases of RM and 18 cases of RM with osteofascial compartment syndrome （OCS）. All cases were caused by crush injury in the Wenchuan earthquake. For these RM patients, we also evaluated the correlations between creatine kinase （CK） and the scope of the muscle lesions as observed by ultrasound. Results There were differences in clinical symptoms, physical signs and ultrasonic appearance between the two groups of patients. The ultrasonic characteristics of the RM were as follows： the striated muscle in the lesions thickened with good overall continuity, and the muscle texture was vague; the strength of the echo was uneven and the echo was cloudy or ground glass-like. Liquid dark zones appeared between muscles and were spindle-like or irregular in shape. There were no blood flow signals in the liquid dark areas. The volume of the striated muscle increased in patients with OCS; the fascia wrapping the muscle showed arched protrusions and significant displacement. The flow velocity of the distal arteries decreased and the spectrum was abnormal. The muscle lesion scope of RM group and RM and OCS group was （7.8±2.0） cm and （13.6±3.1） cm, respectively. The correlation coefficient （r） between the muscle lesion scope and the CK was 0.681 for the RM group （P 〈0.05） and 0.516 for the RM and OCS group （P 〈0.05）. Conclusions The ultrasonogram of RM has characteristic manifestations and can provide important information for clinical diagnosis and treatment of rhabdomyolysis.

关键词： Wenchuan earthquake ultrasonography crush injury rhabdomyolysis osteofascial compartment syndrome

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ISP and PAP4 peptides promote motor functional recovery after peripheral nerve injury

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Neural Regeneration Research 2021年第8期16卷 1598-1605页

作者： Shi-Qin Lv Wutian Wu Guangdong-Hong Kong-Macao Institute of CNS Regeneration Ministry of Education CNS Regeneration Collaborative Joint LaboratoryJinan UniversityGuangzhouGuangdong ProvinceChina Re-Stem Biotechnology Co. Ltd.SuzhouJiangsu ProvinceChina

Both intracellular sigma peptide(ISP) and phosphatase and tensin homolog agonist protein(PAP4) promote nerve regeneration and motor functional recovery after spinal cord injury. However, the role of these two small peptides in peripheral nerve injury remains unclear. A rat model of brachial plexus injury was established by crush of the C6 ventral root. The rats were then treated with subcutaneous injection of PAP4(497 μg/d, twice per day) or ISP(11 μg/d, once per day) near the injury site for 21 successive days. After ISP and PAP treatment, the survival of motoneurons was increased, the number of regenerated axons and neuromuscular junctions was increased, muscle atrophy was reduced, the electrical response of the motor units was enhanced and the motor function of the injured upper limbs was greatly improved in rats with brachial plexus injury. These findings suggest that ISP and PAP4 promote the recovery of motor function after peripheral nerve injury in rats. The animal care and experimental procedures were approved by the Laboratory Animal Ethics Committee of Jinan University of China(approval No. 20111008001) in 2011.

关键词： axon brachial plexus injury crush injury intracellular sigma peptide motor function PAP4 peripheral nerve protection regeneration repair

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Decellularized peripheral nerve grafts by a modified protocol for repair of rat sciatic nerve injury

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Neural Regeneration Research 2021年第6期16卷 1086-1092页

作者： Arash Zaminy Sara Sayad-Fathi Farshad Moharrami Kasmaie Zohreh Jahromi Adib Zendedel Neuroscience Research Center School of MedicineGuilan University of Medical SciencesRashtIran Student Research Committee School of MedicineGuilan University of Medical SciencesRashtIran Institute of Neuroanatomy Faculty of MedicineRheinisch-Westfälische Technische Hochschule(RWTH)Aachen UniversityAachenGermany

Studies have shown that acellular nerve xenografts do not require immunosuppression and use of acellular nerve xenografts for repair of peripheral nerve injury is safe and effective.However,there is currently no widely accepted standard chemical decellularization method.The purpose of this study is to investigate the efficiency of bovine-derived nerves decellularized by the modified Hudson’s protocol in the repair of rat sciatic nerve injury.In the modified Hudson’s protocol,Triton X-200 was replaced by Triton X-100,and DNase and RNase were used to prepare accelular nerve xenografts.The efficiency of bovine-derived nerves decellularized by the modified Hudson’s protocol was tested in vitro by hematoxylin&eosin,Alcian blue,Masson’s trichrome,and Luxol fast blue staining,immunohistochemistry,and biochemical assays.The decellularization approach excluded cells,myelin,and axons of nerve xenografts,without affecting the organization of nerve xenografts.The decellularized nerve xenograft was used to bridge a 7 mm-long sciatic nerve defect to evaluate its efficiency in the repair of peripheral nerve injury.At 8 weeks after transplantation,sciatic function index in rats subjected to transplantation of acellular nerve xenograft was similar to that in rats undergoing transplantation of nerve allograft.Morphological analysis revealed that there were a large amount of regenerated myelinated axons in acellular nerve xenograft;the number of Schwann cells in the acellular nerve xenograft was similar to that in the nerve allograft.These findings suggest that acellular nerve xenografts prepared by the modified Hudson’s protocol can be used for repair of peripheral nerve injury.This study was approved by the Research Ethics Committee,Research and Technology Chancellor of Guilan University of Medical Sciences,Iran(approval No.IR.GUMS.REC.1395.332)on February 11,2017.

关键词： acellular scaffold axonotmesis bovine crush injury detergent rat sciatic nerve xenograft

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Human umbilical cord blood-derived mesenchymal stem cells promote regeneration of crush-injured rat sciatic nerves

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Neural Regeneration Research 2012年第26期7卷 2018-2027页

作者： Mi-Ae Sung Hun Jong Jung Jung-Woo Lee Jin-Yong Lee Kang-Mi Pang Sang Bae Yoo Mohammad S. Alrashdan Soung-Min Kim Jeong Won Jahng Jong-Ho Lee Department of Craniofacial Structure & Functional Biology School of Dentistry Seoul National University Seoul Republic of Korea Department of Occupation and Environment Postgraduate College of Medicine Konkuk University Choong-ju Republic of Korea Department of Oral & Maxillofacial Surgery School of Dentistry Seoul National University Seoul Republic of Korea Department of Dentistry Oral and Maxillofacial Surgery Ajou University School of Medicine Suwon Republic of Korea Dental Research Institute Seoul National University Seoul Republic of Korea

Several studies have demonstrated that human umbilical cord blood-derived mesenchymal stem cells can promote neural regeneration following brain injury. However, the therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells in guiding peripheral nerve regeneration remain poorly understood. This study was designed to investigate the effects of human umbilical cord blood-derived mesenchymal stem cells on neural regeneration using a rat sciatic nerve crush injury model. Human umbilical cord blood-derived mesenchymal stem cells （1 ~ 106） or a PBS control were injected into the crush-injured segment of the sciatic nerve. Four weeks after cell injection, brain-derived neurotrophic factor and tyrosine kinase receptor B mRNA expression at the lesion site was increased in comparison to control. Furthermore, sciatic function index, Fluoro Gold-labeled neuron counts and axon density were also significantly increased when compared with control. Our results indicate that human umbilical cord blood-derived mesenchvmal stem cells promote the functinnal r~.RcJv^rv nf P.n I^h-inillr^4 ~r^i~tit, n^r~e

关键词： human umbilical cord blood-derived mesenchymal stem cells sciatic nerve crush injury FluoroGold stem cells peripheral nerve regeneration regeneration neural regeneration

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