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Saadinam F, Azami M, Pedram MS, Sadeghinezhad J, Jabbari Fakhr M, Salimi A, Aminianfar H, Molazem M, Mokhber Dezfouli MR, Dehghan MM. Injectable alginate chitosan hydrogel as a promising bioengineered therapy for acute spinal cord injury. Sci Rep 2024; 14:26747. [PMID: 39500959 PMCID: PMC11538431 DOI: 10.1038/s41598-024-77995-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 10/28/2024] [Indexed: 11/08/2024] Open
Abstract
Dealing with spinal cord injuries presents problematic due to multiple secondary mechanisms. Beyond primary concerns like paralysis and disability, complications including urinary, gastrointestinal, cardiac, and respiratory disorders, along with substantial economic burdens may occur. Limited research focuses on modeling and treating contusion and compression injuries. Tissue engineering emerges as an innovative treatment, targeting lesion pathophysiology. This study was evaluated implanting injectable biomaterials into injury-induced cavity before glial scar formation, avoiding tissue incisions and minimizing further damage. The efficacy of injectable alginate/thiolated chitosan hydrogel was investigated for acute spinal cord injury induced by Vanický method in Wistar rats. Three days post-injury, hydrogel was administrated through microinjection after laminectomy. After 60 days, the hydrogel group demonstrated notable motor function enhancement compared to the control by the BBB locomotor test (P < 0.05). However, no statistically significant differences were observed in MRI assessment concerning lesion severity. Stereological and histopathological evaluations revealed a reduction in vacuole volume and the presence of axon profiles within the scaffold (P < 0.05), alongside reduced infiltration of inflammatory and Gitter cells in the hydrogel group, although the latter was not statistically significant compared to the control. Thiolated chitosan/ alginate hydrogel implantation may be regarded as a promising treatment to enhance motor function by restraining destructive processes post-acute spinal cord injury.
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Affiliation(s)
- Fatemeh Saadinam
- Department of Surgery and Diagnostic Imaging, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
- Institute of Biomedical Research, University of Tehran, Tehran, Iran
| | - Mahmoud Azami
- Department of Tissue Engineering and Applied Cell sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mir Sepehr Pedram
- Department of Surgery and Diagnostic Imaging, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
- Institute of Biomedical Research, University of Tehran, Tehran, Iran
| | - Javad Sadeghinezhad
- Department of Basic Sciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Massoumeh Jabbari Fakhr
- Institute of Biomedical Research, University of Tehran, Tehran, Iran
- Department of Tissue Engineering and Applied Cell sciences, School of Medicine, Qom University of Medical Science and Health Services, Qom, Iran
| | - Atena Salimi
- Department of Surgery and Diagnostic Imaging, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Hossein Aminianfar
- Institute of Biomedical Research, University of Tehran, Tehran, Iran
- Department of Pathology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Mohammad Molazem
- Department of Surgery and Diagnostic Imaging, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | | | - Mohammad Mehdi Dehghan
- Department of Surgery and Diagnostic Imaging, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
- Institute of Biomedical Research, University of Tehran, Tehran, Iran.
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Ghaffari N, Mokhtari T, Adabi M, Ebrahimi B, Kamali M, Gholaminejhad M, Hassanzadeh G. Neurological recovery and neurogenesis by curcumin sustained-release system cross-linked with an acellular spinal cord scaffold in rat spinal cord injury: Targeting NLRP3 inflammasome pathway. Phytother Res 2024; 38:2669-2686. [PMID: 38500263 DOI: 10.1002/ptr.8179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 01/03/2024] [Accepted: 02/11/2024] [Indexed: 03/20/2024]
Abstract
In the context of treating spinal cord injury (SCI), the modulation of inflammatory responses, and the creation of a suitable region for tissue regeneration may present a promising approach. This study aimed to evaluate the effects of curcumin (Cur)-loaded bovine serum albumin nanoparticles (Cur-BSA NPs) cross-linked with an acellular spinal cord scaffold (ASCS) on the functional recovery in a rat model of SCI. We developed an ASCS using chemical and physical methods. Cur-BSA, and blank (B-BSA) NPs were fabricated and cross-linked with ASCS via EDC-NHS, resulting in the production of Cur-ASCS and B-ASCS. We assessed the properties of scaffolds and NPs as well as their cross-links. Finally, using a male rat hemisection model of SCI, we investigated the consequences of the resulting scaffolds. The inflammatory markers, neuroregeneration, and functional recovery were evaluated. Our results showed that Cur was efficiently entrapped at the rate of 42% ± 1.3 in the NPs. Compared to B-ASCS, Cur-ASCS showed greater effectiveness in the promotion of motor recovery. The implantation of both scaffolds could increase the migration of neural stem cells (Nestin- and GFAP-positive cells) following SCI with the superiority of Cur-ASCS. Cur-ASCS was successful to regulate the gene expression and protein levels of NLRP3, ASC, and Casp1in the spinal cord lesion. Our results indicate that using ASCS can lead to the entrance of cells into the scaffold and promote neurogenesis. However, Cur-ASCS had greater effects in terms of inflammation relief and enhanced neurogenesis.
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Affiliation(s)
- Neda Ghaffari
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Tahmineh Mokhtari
- Hubei Key Laboratory of Embryonic Stem Cell Research, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
- Department of Histology and Embryology, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Mahdi Adabi
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Babak Ebrahimi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Morteza Kamali
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Morteza Gholaminejhad
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Gholamreza Hassanzadeh
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Department of Neurosciences and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Wang Z, Li J, Xu T, Guo B, Xie Z, Li M. The Efficacy of Different Material Scaffold-Guided Cell Transplantation in the Treatment of Spinal Cord Injury in Rats: A Systematic Review and Network Meta-analysis. Cell Mol Neurobiol 2024; 44:43. [PMID: 38703332 PMCID: PMC11069479 DOI: 10.1007/s10571-024-01465-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 02/23/2024] [Indexed: 05/06/2024]
Abstract
Cell transplantation is a promising treatment option for spinal cord injury (SCI). However, there is no consensus on the choice of carrier scaffolds to host the cells. This study aims to evaluate the efficacy of different material scaffold-mediated cell transplantation in treating SCI in rats. According to PRISMA's principle, Embase, PubMed, Web of Science, and Cochrane databases were searched, and relevant literature was referenced. Only original research on cell transplantation plus natural or synthetic scaffolds in SCI rats was included. Direct and indirect evidence for improving hind limb motor function was pooled through meta-analysis. A subgroup analysis of some factors that may affect the therapeutic effect was conducted to understand the results fully. In total, 25 studies met the inclusion criteria, in which 293 rats received sham surgery, 78 rats received synthetic material scaffolds, and 219 rats received natural materials scaffolds. The network meta-analysis demonstrated that although synthetic scaffolds were slightly inferior to natural scaffolds in terms of restoring motor function in cell transplantation of SCI rats, no statistical differences were observed between the two (MD: -0.35; 95% CI -2.6 to 1.9). Moreover, the subgroup analysis revealed that the type and number of cells may be important factors in therapeutic efficacy (P < 0.01). Natural scaffolds and synthetic scaffolds are equally effective in cell transplantation of SCI rats without significant differences. In the future, the findings need to be validated in multicenter, large-scale, randomized controlled trials in clinical practice. Trial registration: Registration ID CRD42024459674 (PROSPERO).
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Affiliation(s)
- Zhihua Wang
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, No.17, Yongwai Street, Nanchang, 330006, Jiangxi Province, China
- Postdoctoral Innovation Practice Base, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Jun Li
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, No.17, Yongwai Street, Nanchang, 330006, Jiangxi Province, China
- Department of the Second Clinical Medical College of Nanchang University, No.460, BaYi Street, Nanchang, 330006, Jiangxi Province, China
| | - Tianqi Xu
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, No.17, Yongwai Street, Nanchang, 330006, Jiangxi Province, China
- Department of the Second Clinical Medical College of Nanchang University, No.460, BaYi Street, Nanchang, 330006, Jiangxi Province, China
| | - Boyu Guo
- Department of the First Clinical Medical College of Nanchang University, No.460, BaYi Street, Nanchang, 330006, Jiangxi Province, China
| | - Zhiping Xie
- Department of Neurosurgery, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, No.152 Aiguo Road, Nanchang, 330006, Jiangxi Province, China.
- Department of Neurosurgery, Xiangya Hospital Jiangxi Hospital, Central South University, Nanchang, Jiangxi Province, China.
| | - Meihua Li
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, No.17, Yongwai Street, Nanchang, 330006, Jiangxi Province, China.
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Zhang D, Sun Y, Liu W. Motor functional recovery efficacy of scaffolds with bone marrow stem cells in rat spinal cord injury: a Bayesian network meta-analysis. Spinal Cord 2023; 61:93-98. [PMID: 35842526 DOI: 10.1038/s41393-022-00836-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 07/03/2022] [Accepted: 07/04/2022] [Indexed: 11/09/2022]
Abstract
STUDY DESIGN A Bayesian network meta-analysis. OBJECTIVE Spinal cord injury (SCI) can profoundly influence human health and has been linked to lifelong disability. More high-level evidence-based medical research is expected to evaluate the value of stem cells and biomaterial scaffold material therapy for SCI. METHODS We performed a comprehensive search of Web of Science, Cochrane databases, Embase, and PubMed databases. 18 randomized controlled trials including both scaffolds and BMSCs were included. We performed a Bayesian network meta-analysis to compare the motor functional recovery efficacy of different scaffolds with BMSCs in rat SCI. RESULTS In our Bayesian network meta-analysis, the motor functional recovery was found to benefit from scaffolds, BMSCs, and BMSCs combined with scaffolds, but the scaffold and BMSC groups had similar motor functional recovery efficacy, and the BMSCs combined with scaffolds group appeared to show better efficacy than BMSCs and scaffolds alone. Subgroup analysis showed that BMSCs+fibrin, BMSCs+ASC, BMSCs+gelatine, and BMSCs+collagen were the best four treatments for SCI in rat models. CONCLUSIONS These Bayesian network meta-analysis findings strongly indicated that BMSCs combined with scaffolds is more effective to improve motor functional recovery than BMSCs and scaffolds alone. The fibrin, gelatine, ASC, and collagen may be favourable scaffolds for the injured spinal cord and that scaffolds with BMSCs could be a promising option in regeneration therapy for patients with SCI.
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Affiliation(s)
- Dong Zhang
- Changqing District People's Hospital, Jinan, China
| | - Yifeng Sun
- Department of Orthopedic Surgery, The First Affliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, China
| | - Wei Liu
- Department of Orthopedic Surgery, The First Affliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, China.
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Chaudhari LR, Kawale AA, Desai SS, Kashte SB, Joshi MG. Pathophysiology of Spinal Cord Injury and Tissue Engineering Approach for Its Neuronal Regeneration: Current Status and Future Prospects. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1409:51-81. [PMID: 36038807 DOI: 10.1007/5584_2022_731] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
A spinal cord injury (SCI) is a very debilitating condition causing loss of sensory and motor function as well as multiple organ failures. Current therapeutic options like surgery and pharmacotherapy show positive results but are incapable of providing a complete cure for chronic SCI symptoms. Tissue engineering, including neuroprotective or growth factors, stem cells, and biomaterial scaffolds, grabs attention because of their potential for regeneration and ability to bridge the gap in the injured spinal cord (SC). Preclinical studies with tissue engineering showed functional recovery and neurorestorative effects. Few clinical trials show the safety and efficacy of the tissue engineering approach. However, more studies should be carried out for potential treatment modalities. In this review, we summarize the pathophysiology of SCI and its current treatment modalities, including surgical, pharmacological, and tissue engineering approaches following SCI in preclinical and clinical phases.
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Affiliation(s)
- Leena R Chaudhari
- Department of Stem Cells and Regenerative Medicine, D. Y. Patil Education Society (Deemed to be University), Kolhapur, Maharashtra, India
| | - Akshay A Kawale
- Department of Stem Cells and Regenerative Medicine, D. Y. Patil Education Society (Deemed to be University), Kolhapur, Maharashtra, India
| | - Sangeeta S Desai
- Department of Obstetrics and Gynecology, Dr. D Y Patil Medical College, Hospital and Research Institute, Kolhapur, Maharashtra, India
| | - Shivaji B Kashte
- Department of Stem Cells and Regenerative Medicine, D. Y. Patil Education Society (Deemed to be University), Kolhapur, Maharashtra, India
| | - Meghnad G Joshi
- Department of Stem Cells and Regenerative Medicine, D. Y. Patil Education Society (Deemed to be University), Kolhapur, Maharashtra, India.
- Stem Plus Biotech, SMK Commercial Complex, Sangli, Maharashtra, India.
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Double crosslinked biomimetic composite hydrogels containing topographical cues and WAY-316606 induce neural tissue regeneration and functional recovery after spinal cord injury. Bioact Mater 2022; 24:331-345. [PMID: 36632504 PMCID: PMC9816912 DOI: 10.1016/j.bioactmat.2022.12.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 11/01/2022] [Accepted: 12/22/2022] [Indexed: 12/30/2022] Open
Abstract
Spinal cord injury (SCI) is an overwhelming and incurable disabling condition, for which increasing forms of multifunctional biomaterials are being tested, but with limited progression. The promising material should be able to fill SCI-induced cavities and direct the growth of new neurons, with effective drug loading to improve the local micro-organism environment and promote neural tissue regeneration. In this study, a double crosslinked biomimetic composite hydrogel comprised of acellularized spinal cord matrix (ASCM) and gelatin-acrylated-β-cyclodextrin-polyethene glycol diacrylate (designated G-CD-PEGDA) hydrogel, loaded with WAY-316606 to activate canonical Wnt/β-catenin signaling, and reinforced by a bundle of three-dimensionally printed aligned polycaprolactone (PCL) microfibers, was constructed. The G-CD-PEGDA component endowed the composite hydrogel with a dynamic structure with a self-healing capability which enabled cell migration, while the ASCM component promoted neural cell affinity and proliferation. The diffusion of WAY-316606 could recruit endogenous neural stem cells and improve neuronal differentiation. The aligned PCL microfibers guided neurite elongation in the longitudinal direction. Animal behavior studies further showed that the composite hydrogel could significantly recover the motor function of rats after SCI. This study provides a proficient approach to produce a multifunctional system with desirable physiological, chemical, and topographical cues for treating patients with SCI.
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Xia Y, Yang R, Wang H, Hou Y, Li Y, Zhu J, Xu F, Fu C. Biomaterials delivery strategies to repair spinal cord injury by modulating macrophage phenotypes. J Tissue Eng 2022; 13:20417314221143059. [PMID: 36600997 PMCID: PMC9806413 DOI: 10.1177/20417314221143059] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 11/17/2022] [Indexed: 12/28/2022] Open
Abstract
Spinal cord injury (SCI) causes tremendous harm to a patient's physical, mental, and financial health. Moreover, recovery of SCI is affected by many factors, inflammation is one of the most important as it engulfs necrotic tissue and cells during the early stages of injury. However, excessive inflammation is not conducive to damage repair. Macrophages are classified into either blood-derived macrophages or resident microglia based on their origin, their effects on SCI being two-sided. Microglia first activate and recruit blood-derived macrophages at the site of injury-blood-borne macrophages being divided into pro-inflammatory M1 phenotypes and anti-inflammatory M2 phenotypes. Among them, M1 macrophages secrete inflammatory factors such as interleukin-β (IL-β), tumor necrosis factor-α (TNF-α), IL-6, and interferon-γ (IFN-γ) at the injury site, which aggravates SCIs. M2 macrophages secrete IL-4, IL-10, IL-13, and neurotrophic factors to inhibit the inflammatory response and inhibit neuronal apoptosis. Consequently, modulating phenotypic differentiation of macrophages appears to be a meaningful therapeutic target for the treatment of SCI. Biomaterials are widely used in regenerative medicine and tissue engineering due to their targeting and bio-histocompatibility. In this review, we describe the effects of biomaterials applied to modulate macrophage phenotypes on SCI recovery and provide an outlook.
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Affiliation(s)
- Yuanliang Xia
- Department of Spine Surgery, The First
Hospital of Jilin University, Changchun, PR China
| | - Ruohan Yang
- Cancer Center, The First Hospital of
Jilin University, Changchun, PR China
| | - Hengyi Wang
- Department of Spine Surgery, The First
Hospital of Jilin University, Changchun, PR China
| | - Yulin Hou
- Depattment of Cardiology, Guangyuan
Central Hospital, Guangyuan, PR China
| | - Yuehong Li
- Department of Spine Surgery, The First
Hospital of Jilin University, Changchun, PR China
| | - Jianshu Zhu
- Department of Spine Surgery, The First
Hospital of Jilin University, Changchun, PR China
| | - Feng Xu
- Department of Spine Surgery, The First
Hospital of Jilin University, Changchun, PR China
| | - Changfeng Fu
- Department of Spine Surgery, The First
Hospital of Jilin University, Changchun, PR China,Changfeng Fu, Department of Spine Surgery,
The First Hospital of Jilin University, 1 Xinmin Street, Changchun 130021, PR
China.
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Zhang H, Gao L, Zhang W, Li K. Differentiation of rat bone marrow mesenchymal stem cells into neurons induced by bone morphogenetic protein 7 in vitro. Neurol Res 2022; 45:440-448. [PMID: 36542543 DOI: 10.1080/01616412.2022.2154487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Spinal cord injury (SCI) is caused by external direct or indirect factors with high disability rate, which may even endanger the life of patients. To explore the role of bone morphogenetic protein 7 (BMP-7) in the differentiation of rat bone marrow mesenchymal stem cells (BMSCs) into neurons in vitro. METHODS BMSCs were isolated and cultured by whole bone marrow adherence method. Adipogenic induction and osteogenic differentiation were used to test the multi⁃directional differentiation ability of BMSCs. RESULTS After 28 days of adipogenic induction, BMSCs showed lipid droplets in the cytoplasm. After osteogenic induction, there were opaque lumps of mineral nodules in BMSCs. There were also orange-red or red mineral nodules in the extracellular matrix. The BMSCs in the 75 ng/ml BMP-7 group were morphologically similar to the neurons. After induction with BMP-7 for 2 h, the NF200 mRNA expression was higher, mRNA expression levels of SYN1, MAP2 and GFAP were higher. Positive rate of immunofluorescence staining in the BMP-7 group was notably increased. The positive rate of NSE immunofluorescence staining in the BMP-7 group was higher. CONCLUSION BMP-7 can induce rat BMSCs to differentiate into neurons in vitro.
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Affiliation(s)
- Heng Zhang
- Department of Orthopaedics, First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
| | - Lei Gao
- Department of Orthopaedics, the Second Affiliated Hospital of Medical College, Shihezi University, Shihezi 832000, China
| | - Wen Zhang
- Department of Orthopaedics, the Second Affiliated Hospital of Medical College, Shihezi University, Shihezi 832000, China
| | - Kuanxin Li
- Department of Orthopaedics, First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Department of Orthopaedics, the Second Affiliated Hospital of Medical College, Shihezi University, Shihezi 832000, China
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He W, Wang H, Zhang X, Mao T, Lu Y, Gu Y, Ju D, Qi L, Wang Q, Dong C. Construction of a decellularized spinal cord matrix/GelMA composite scaffold and its effects on neuronal differentiation of neural stem cells. JOURNAL OF BIOMATERIALS SCIENCE. POLYMER EDITION 2022; 33:2124-2144. [PMID: 35835455 DOI: 10.1080/09205063.2022.2102275] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 07/11/2022] [Accepted: 07/13/2022] [Indexed: 06/15/2023]
Abstract
Spinal cord injury (SCI) leads to severe loss of motor and sensory functions, and the rehabilitation of SCI is a worldwide problem. Tissue-engineered scaffolds offer new hope for SCI patients, while the newly developed materials encountered a challenge in modeling the microenvironment around the lesion site. We constructed a new composite scaffold by mixing decellularized spinal cord extracellular matrix (dECM) with gelatin methacryloyl (GelMA). The dECM, as a natural biological material, retained a large number of proteins and growth factors related to neurogenesis. GelMA was a photopolymerizable material, harbored a polymer network structure, soft texture, certain shape and plenty of water. The viability, proliferation, and differentiation of neural stem cells (NSCs) on the composite scaffold were evaluated by cell count kit-8 (CCK8), Live/Dead assay, phalloidin staining, 5-Ethynyl-2'-deoxyurdine (EdU), immunofluorescence staining and western blot. The Live/Dead assay, phalloidin staining, EdU, and CCK8 assay showed that the composite scaffold had good biocompatibility and provided better support for proliferation of NSCs. Results of immunocytochemistry and western blot showed that the composite scaffolds promoted the specific differentiation of NSCs into neuron cells. Together, this dECM/GelMA composite scaffold can be used as a cell culture coating, the isolated NSCs seeded on the surface of composite scaffold expressed neuronal markers and assumed neuronal morphology. Our work provided a new method that would be widely used in tissue engineering of SCI.
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Affiliation(s)
- Wenhua He
- Department of Anatomy, Comparative Medicine Institution, Medical School of Nantong University, Nantong, China
| | - Hui Wang
- Department of Emergency, Affiliated Hospital of Nantong University, Nantong, China
| | - Xuanxuan Zhang
- Department of Anatomy, Comparative Medicine Institution, Medical School of Nantong University, Nantong, China
| | - Tiantian Mao
- Department of Anatomy, Comparative Medicine Institution, Medical School of Nantong University, Nantong, China
| | - Yan Lu
- Department of Anatomy, Comparative Medicine Institution, Medical School of Nantong University, Nantong, China
| | - Yu Gu
- Department of Anatomy, Comparative Medicine Institution, Medical School of Nantong University, Nantong, China
| | - Dingyue Ju
- Department of Anatomy, Comparative Medicine Institution, Medical School of Nantong University, Nantong, China
| | - Longju Qi
- Department of Hepatic Intervention, Affiliated Nantong Hospital 3 of Nantong University, Nantong, China
| | - Qinghua Wang
- Department of Anatomy, Comparative Medicine Institution, Medical School of Nantong University, Nantong, China
| | - Chuanming Dong
- Department of Anatomy, Comparative Medicine Institution, Medical School of Nantong University, Nantong, China
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Ma YH, Shi HJ, Wei QS, Deng QW, Sun JH, Liu Z, Lai BQ, Li G, Ding Y, Niu WT, Zeng YS, Zeng X. Developing a mechanically matched decellularized spinal cord scaffold for the in situ matrix-based neural repair of spinal cord injury. Biomaterials 2021; 279:121192. [PMID: 34700225 DOI: 10.1016/j.biomaterials.2021.121192] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 10/15/2021] [Accepted: 10/18/2021] [Indexed: 12/16/2022]
Abstract
Tissue engineering is a promising strategy to repair spinal cord injury (SCI). However, a bioscaffold with mechanical properties that match those of the pathological spinal cord tissue and a pro-regenerative matrix that allows robust neurogenesis for overcoming post-SCI scar formation has yet to be developed. Here, we report that a mechanically enhanced decellularized spinal cord (DSC) scaffold with a thin poly (lactic-co-glycolic acid) (PLGA) outer shell may fulfill the requirements for effective in situ neuroengineering after SCI. Using chemical extraction and electrospinning methods, we successfully constructed PLGA thin shell-ensheathed DSC scaffolds (PLGA-DSC scaffolds) in a way that removed major inhibitory components while preserving the permissive matrix. The DSCs exhibited good cytocompatibility with neural stem cells (NSCs) and significantly enhanced their differentiation toward neurons in vitro. Due to the mechanical reinforcement, the implanted PLGA-DSC scaffolds showed markedly increased resilience to infiltration by myofibroblasts and the deposition of dense collagen matrix, thereby creating a neurogenic niche favorable for the targeted migration, residence and neuronal differentiation of endogenous NSCs after SCI. Furthermore, PLGA-DSC presented a mild immunogenic property but prominent ability to polarize macrophages from the M1 phenotype to the M2 phenotype, leading to significant tissue regeneration and functional restoration after SCI. Taken together, the results demonstrate that the mechanically matched PLGA-DSC scaffolds show promise for effective tissue repair after SCI.
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Affiliation(s)
- Yuan-Huan Ma
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China; Key Laboratory for Stem Cells and Tissue Engineering, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong Province, 510080, China; Guangdong Key Laboratory of Age-Related Cardiocerebral Diseases, Institute of Neurology, Guangdong Medical University, Zhanjiang, Guangdong Province, 524023, China; Guangzhou Institute of Clinical Medicine, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, Guangdong Province, 510180, PR China
| | - Hui-Juan Shi
- Key Laboratory for Stem Cells and Tissue Engineering, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong Province, 510080, China
| | - Qing-Shuai Wei
- Key Laboratory for Stem Cells and Tissue Engineering, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong Province, 510080, China
| | - Qing-Wen Deng
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China
| | - Jia-Hui Sun
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China
| | - Zhou Liu
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China; Guangdong Key Laboratory of Age-Related Cardiocerebral Diseases, Institute of Neurology, Guangdong Medical University, Zhanjiang, Guangdong Province, 524023, China
| | - Bi-Qin Lai
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China; Key Laboratory for Stem Cells and Tissue Engineering, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong Province, 510080, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China
| | - Ge Li
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China; Key Laboratory for Stem Cells and Tissue Engineering, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong Province, 510080, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China
| | - Ying Ding
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China; Key Laboratory for Stem Cells and Tissue Engineering, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong Province, 510080, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China
| | - Wan-Ting Niu
- Department of Orthopedics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Yuan-Shan Zeng
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China; Key Laboratory for Stem Cells and Tissue Engineering, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong Province, 510080, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China; Institute of Spinal Cord Injury, Sun Yat-sen University, Guangzhou, Guangdong Province, 510120, China
| | - Xiang Zeng
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China; Key Laboratory for Stem Cells and Tissue Engineering, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong Province, 510080, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China; Institute of Spinal Cord Injury, Sun Yat-sen University, Guangzhou, Guangdong Province, 510120, China.
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11
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Zilberman A, Cornelison RC. Microphysiological models of the central nervous system with fluid flow. Brain Res Bull 2021; 174:72-83. [PMID: 34029679 DOI: 10.1016/j.brainresbull.2021.05.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 05/08/2021] [Accepted: 05/17/2021] [Indexed: 12/11/2022]
Abstract
There are over 1,000 described neurological and neurodegenerative disorders affecting nearly 100 million Americans - roughly one third of the U.S. population. Collectively, treatment of neurological conditions is estimated to cost $800 billion every year. Lowering this societal burden will require developing better model systems in which to study these diverse disorders. Microphysiological systems are promising tools for modeling healthy and diseased neural tissues to study mechanisms and treatment of neuropathology. One major benefit of microphysiological systems is the ability to incorporate biophysical forces, namely the forces derived from biological fluid flow. Fluid flow in the central nervous system (CNS) is a complex but important element of physiology, and pathologies as diverse as traumatic or ischemic injury, cancer, neurodegenerative disease, and natural aging have all been found to alter flow pathways. In this review, we summarize recent advances in three-dimensional microphysiological systems for studying the biology and therapy of CNS disorders and highlight the ability and growing need to incorporate biological fluid flow in these miniaturized model systems.
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Affiliation(s)
- Aleeza Zilberman
- Department of Biomedical Engineering, University of Massachusetts Amherst, Amherst, MA, 01003, United States
| | - R Chase Cornelison
- Department of Biomedical Engineering, University of Massachusetts Amherst, Amherst, MA, 01003, United States.
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12
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Muheremu A, Shu L, Liang J, Aili A, Jiang K. Sustained delivery of neurotrophic factors to treat spinal cord injury. Transl Neurosci 2021; 12:494-511. [PMID: 34900347 PMCID: PMC8633588 DOI: 10.1515/tnsci-2020-0200] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 11/04/2021] [Accepted: 11/05/2021] [Indexed: 12/16/2022] Open
Abstract
Acute spinal cord injury (SCI) is a devastating condition that results in tremendous physical and psychological harm and a series of socioeconomic problems. Although neurons in the spinal cord need neurotrophic factors for their survival and development to reestablish their connections with their original targets, endogenous neurotrophic factors are scarce and the sustainable delivery of exogeneous neurotrophic factors is challenging. The widely studied neurotrophic factors such as brain-derived neurotrophic factor, neurotrophin-3, nerve growth factor, ciliary neurotrophic factor, basic fibroblast growth factor, and glial cell-derived neurotrophic factor have a relatively short cycle that is not sufficient enough for functionally significant neural regeneration after SCI. In the past decades, scholars have tried a variety of cellular and viral vehicles as well as tissue engineering scaffolds to safely and sustainably deliver those necessary neurotrophic factors to the injury site, and achieved satisfactory neural repair and functional recovery on many occasions. Here, we review the neurotrophic factors that have been used in trials to treat SCI, and vehicles that were commonly used for their sustained delivery.
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Affiliation(s)
- Aikeremujiang Muheremu
- Department of Spine Surgery, Sixth Affiliated Hospital of Xinjiang Medical University, 39 Wuxing Nan Rd, Tianshan District, Urumqi, Xinjiang, 86830001, People’s Republic of China
| | - Li Shu
- Department of Orthopedics, Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 86830001, People’s Republic of China
| | - Jing Liang
- Department of Laboratory Medicine, Sixth Affiliated Hospital of Xinjiang Medical University, 39, Wuxing Nan Rd, Tianshan District, Urumqi, Xinjiang, 86830001, People’s Republic of China
| | - Abudunaibi Aili
- Department of Spine Surgery, Sixth Affiliated Hospital of Xinjiang Medical University, 39 Wuxing Nan Rd, Tianshan District, Urumqi, Xinjiang, 86830001, People’s Republic of China
| | - Kan Jiang
- Department of Orthopedics, Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 86830001, People’s Republic of China
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13
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Xu ZX, Zhang LQ, Zhou YN, Chen XM, Xu WH. Histological and functional outcomes in a rat model of hemisected spinal cord with sustained VEGF/NT-3 release from tissue-engineered grafts. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2020; 48:362-376. [PMID: 31899965 DOI: 10.1080/21691401.2019.1709860] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Microvascular disturbance, excessive inflammation and gliosis are key pathophysiologic changes in relation to functional status following the traumatic spinal cord injury (SCI). Continuous release of vascular endothelial growth factor (VEGF) to the lesion site was proved be able to promote the vascular remodelling, whereas the effects on reduction of inflammation and gliosis remain unclear. Currently, aiming at exploring the synergistic roles of VEGF and neurotrophin-3 (NT-3) on angiogenesis, anti-inflammation and neural repair, we developed a technique to co-deliver VEGF165 and NT-3 locally with a homotopic graft of tissue-engineered acellular spinal cord scaffold (ASCS) in a hemisected (3 mm in length) SCI model. As the potential in secretion of growth factors (GFs), bone mesenchymal stem cells (BMSCs) were introduced with the aim to enhance the VEGF/NT-3 release. Our data demonstrate that sustained VEGF/NT-3 release from ASCS significantly increases the local levels of VEGF/NT-3 and angiogenesis, regardless of whether it is in combination with BMSCs transplantation that exhibits positive effects on anti-inflammation, axonal outgrowth and locomotor recovery. This study verifies that co-delivery of VEGF/NT-3 reduces inflammation and gliosis in the hemisected spinal cord, promotes axonal outgrowth and results in better locomotor recovery, while the BMSCs transplantation facilitates these functions limitedly.
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Affiliation(s)
- Zi-Xing Xu
- Department of Spinal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, P.R. China
| | - Li-Qun Zhang
- Department of Spinal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, P.R. China
| | - Yi-Nan Zhou
- Department of Spinal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, P.R. China
| | - Xue-Min Chen
- Department of Spinal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, P.R. China
| | - Wei-Hong Xu
- Department of Spinal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, P.R. China
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14
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Li X, Zhang C, Haggerty AE, Yan J, Lan M, Seu M, Yang M, Marlow MM, Maldonado-Lasunción I, Cho B, Zhou Z, Chen L, Martin R, Nitobe Y, Yamane K, You H, Reddy S, Quan DP, Oudega M, Mao HQ. The effect of a nanofiber-hydrogel composite on neural tissue repair and regeneration in the contused spinal cord. Biomaterials 2020; 245:119978. [PMID: 32217415 PMCID: PMC8787820 DOI: 10.1016/j.biomaterials.2020.119978] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 03/15/2020] [Indexed: 01/16/2023]
Abstract
An injury to the spinal cord causes long-lasting loss of nervous tissue because endogenous nervous tissue repair and regeneration at the site of injury is limited. We engineered an injectable nanofiber-hydrogel composite (NHC) with interfacial bonding to provide mechanical strength and porosity and examined its effect on repair and neural tissue regeneration in an adult rat model of spinal cord contusion. At 28 days after treatment with NHC, the width of the contused spinal cord segment was 2-fold larger than in controls. With NHC treatment, tissue in the injury had a 2-fold higher M2/M1 macrophage ratio, 5-fold higher blood vessel density, 2.6-fold higher immature neuron presence, 2.4-fold higher axon density, and a similar glial scar presence compared with controls. Spared nervous tissue volume in the contused segment and hind limb function was similar between groups. Our findings indicated that NHC provided mechanical support to the contused spinal cord and supported pro-regenerative macrophage polarization, angiogenesis, axon growth, and neurogenesis in the injured tissue without any exogenous factors or cells. These results motivate further optimization of the NHC and delivery protocol to fully translate the potential of the unique properties of the NHC for treating spinal cord injury.
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Affiliation(s)
- Xiaowei Li
- Translational Tissue Engineering Center, Baltimore, MD 21205, USA; Department of Materials Science & Engineering, Baltimore, MD 21205, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Chi Zhang
- Translational Tissue Engineering Center, Baltimore, MD 21205, USA; Department of Materials Science & Engineering, Baltimore, MD 21205, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21205, USA; School of Chemistry, Sun Yat-Sen University, Guangzhou, Guangdong 510275, PR China
| | - Agnes E Haggerty
- The Miami Project to Cure Paralysis, University of Miami, Miami, FL 33136, USA
| | - Jerry Yan
- Translational Tissue Engineering Center, Baltimore, MD 21205, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Michael Lan
- Translational Tissue Engineering Center, Baltimore, MD 21205, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Michelle Seu
- Translational Tissue Engineering Center, Baltimore, MD 21205, USA; Department of Plastic and Reconstructive Surgery, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
| | - Mingyu Yang
- Translational Tissue Engineering Center, Baltimore, MD 21205, USA; Department of Materials Science & Engineering, Baltimore, MD 21205, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Megan M Marlow
- The Miami Project to Cure Paralysis, University of Miami, Miami, FL 33136, USA
| | - Inés Maldonado-Lasunción
- The Miami Project to Cure Paralysis, University of Miami, Miami, FL 33136, USA; Department of Regeneration of Sensorimotor Systems, Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, Netherlands; Shirley Ryan AbilityLab, Chicago, IL 60611, USA; Department of Physical Therapy and Human Movements Sciences, Chicago, IL 60611, USA; Department of Physiology Northwestern University, Chicago, IL 60611, USA
| | - Brian Cho
- Translational Tissue Engineering Center, Baltimore, MD 21205, USA; Department of Plastic and Reconstructive Surgery, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
| | - Zhengbing Zhou
- Translational Tissue Engineering Center, Baltimore, MD 21205, USA; Department of Materials Science & Engineering, Baltimore, MD 21205, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Long Chen
- Translational Tissue Engineering Center, Baltimore, MD 21205, USA; Department of Materials Science & Engineering, Baltimore, MD 21205, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Russell Martin
- Translational Tissue Engineering Center, Baltimore, MD 21205, USA; Department of Materials Science & Engineering, Baltimore, MD 21205, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Yohshiro Nitobe
- The Miami Project to Cure Paralysis, University of Miami, Miami, FL 33136, USA; Department of Orthopedic Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori, 036-8562, Japan
| | - Kentaro Yamane
- The Miami Project to Cure Paralysis, University of Miami, Miami, FL 33136, USA; Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Kitaku, Okayama, 700-8558, Japan
| | - Hua You
- Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510095, PR China
| | - Sashank Reddy
- Department of Plastic and Reconstructive Surgery, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
| | - Da-Ping Quan
- School of Chemistry, Sun Yat-Sen University, Guangzhou, Guangdong 510275, PR China.
| | - Martin Oudega
- Shirley Ryan AbilityLab, Chicago, IL 60611, USA; Department of Physical Therapy and Human Movements Sciences, Chicago, IL 60611, USA; Department of Physiology Northwestern University, Chicago, IL 60611, USA; Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510095, PR China; Edward Hines Jr. VA Hospital, Hines IL, 60141, USA.
| | - Hai-Quan Mao
- Translational Tissue Engineering Center, Baltimore, MD 21205, USA; Department of Materials Science & Engineering, Baltimore, MD 21205, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205, USA.
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15
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Yousefifard M, Nasseri Maleki S, Askarian-Amiri S, Vaccaro AR, Chapman JR, Fehlings MG, Hosseini M, Rahimi-Movaghar V. A combination of mesenchymal stem cells and scaffolds promotes motor functional recovery in spinal cord injury: a systematic review and meta-analysis. J Neurosurg Spine 2020; 32:269-284. [PMID: 31675724 DOI: 10.3171/2019.8.spine19201] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Accepted: 08/01/2019] [Indexed: 11/06/2022]
Abstract
OBJECTIVE There is controversy about the role of scaffolds as an adjunctive therapy to mesenchymal stem cell (MSC) transplantation in spinal cord injury (SCI). Thus, the authors aimed to design a meta-analysis on preclinical evidence to evaluate the effectiveness of combination therapy of scaffold + MSC transplantation in comparison with scaffolds alone and MSCs alone in improving motor dysfunction in SCI. METHODS Electronic databases including Medline, Embase, Scopus, and Web of Science were searched from inception until the end of August 2018. Two independent reviewers screened related experimental studies. Animal studies that evaluated the effectiveness of scaffolds and/or MSCs on motor function recovery following experimental SCI were included. The findings were reported as standardized mean difference (SMD) and 95% confidence interval (CI). RESULTS A total of 34 articles were included in the meta-analysis. Analyses show that combination therapy in comparison with the scaffold group alone (SMD 2.00, 95% CI 1.53-2.46, p < 0.0001), the MSCs alone (SMD 1.58, 95% CI 0.84-2.31, p < 0.0001), and the nontreated group (SMD 3.52, 95% CI 2.84-4.20, p < 0.0001) significantly improved motor function recovery. Co-administration of MSCs + scaffolds only in the acute phase of injury (during the first 3 days after injury) leads to a significant recovery compared to scaffold alone (SMD 2.18, p < 0.0001). In addition, the cotransplantation of scaffolds with bone marrow-derived MSCs (SMD 1.99, p < 0.0001) and umbilical cord-derived MSCs (SMD 1.50, p = 0.001) also improved motor function following SCI. CONCLUSIONS The findings showed that scaffolds + MSCs is more effective than scaffolds and MSCs alone in improving motor function following SCI in animal models, when used in the acute phase of injury.
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Affiliation(s)
- Mahmoud Yousefifard
- 1Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Solmaz Nasseri Maleki
- 1Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Alexander R Vaccaro
- 2Department of Orthopedics and Neurosurgery, Rothman Institute, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Jens R Chapman
- 3Swedish Neuroscience Institute, Swedish Medical Center, Seattle, Washington
| | - Michael G Fehlings
- 4Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
- 5Division of Neurosurgery, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
- 6Department of Surgery and Spine Program, University of Toronto, Ontario, Canada
| | - Mostafa Hosseini
- 7Department of Epidemiology and Biostatistics, School of Public Health, and
| | - Vafa Rahimi-Movaghar
- 8Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran; and
- 9Brain and Spinal Injuries Research Center (BASIR), Neuroscience Institute, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
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16
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Xing H, Ren X, Yin H, Sun C, Jiang T. Construction of a NT-3 sustained-release system cross-linked with an acellular spinal cord scaffold and its effects on differentiation of cultured bone marrow mesenchymal stem cells. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2019; 104:109902. [PMID: 31500033 DOI: 10.1016/j.msec.2019.109902] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 05/28/2019] [Accepted: 06/16/2019] [Indexed: 12/24/2022]
Abstract
OBJECTIVE This study sought to promote the adhesion, proliferation and differentiation of rat bone marrow mesenchymal stem cells by constructing a neurotrophin-3 (NT-3) sustained-release system cross-linked with an acellular spinal cord scaffold. METHODS 1-Ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride (EDC) chemistry combined with chemical extraction was used to construct an acellular spinal cord scaffold. The decellularization completion was validated. An EDC cross-linking method was used to construct the NT-3 cross-linked acellular spinal scaffold. ELISA was used to verify sustained release of NT-3; the dorsal root ganglion method was used to verify the biological activity of the sustained-release NT-3. DAPI staining was used to confirm the adhesion of the cultured rat bone marrow mesenchymal stem cells (P3) to the NT-3 scaffold, and cell counting kit-8 (CCK-8) analysis was used to verify the cellular proliferation after 24 h and 48 h of culture. Immunohistochemistry was used to confirm the differentiation of the bone marrow cells into neuron-like cells. RESULTS An NT-3 sustained-release system cross-linked to an acellular spinal cord scaffold was successfully constructed. Sustained-release NT-3 could persist for 35 days and had biological activity for at least 21 days. It could promote the adhesion, proliferation and differentiation of rat bone marrow mesenchymal stem cells. CONCLUSION As a composite scaffold, an NT-3 sustained-release system cross-linked with an acellular spinal cord scaffold has potential applications for tissue engineering.
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Affiliation(s)
- Hui Xing
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, The Third Military Medical University, Chongqing 400037, PR China
| | - Xianjun Ren
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, The Third Military Medical University, Chongqing 400037, PR China
| | - Hong Yin
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, The Third Military Medical University, Chongqing 400037, PR China
| | - Chao Sun
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, The Third Military Medical University, Chongqing 400037, PR China
| | - Tao Jiang
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, The Third Military Medical University, Chongqing 400037, PR China.
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Xing H, Yin H, Sun C, Ren X, Tian Y, Yu M, Jiang T. Preparation of an acellular spinal cord scaffold to improve its biological properties. Mol Med Rep 2019; 20:1075-1084. [PMID: 31173271 PMCID: PMC6625434 DOI: 10.3892/mmr.2019.10364] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Accepted: 04/30/2019] [Indexed: 11/14/2022] Open
Abstract
In recent years, acellular spinal cord scaffolds have been extensively studied in tissue engineering. Notably, acellular spinal cord scaffolds may be used to treat spinal cord injury; however, the method of preparation can result in low efficiency and may affect the biological properties of cells. This study aimed to use EDC crosslinking, combined with chemical extraction for tissue decellularization, in order to improve the efficiency of acellular scaffolds. To make the improved stent available for the clinical treatment of spinal cord injury, it is necessary to study its immunogenicity. Therefore, this study also focused on the adherence of rat bone marrow mesenchymal stem cells to scaffolds, and their differentiation into neuron-like cells in the presence of suitable trophic factors. The results revealed that EDC crosslinking combined with chemical extraction methods may significantly improve the efficiency of acellular scaffolds, and may also confer better biological characteristics, including improved immunogenicity. Notably, it was able to promote adhesion of rat bone marrow mesenchymal stem cells and their differentiation into neuron-like cells. These results suggested that the improved preparation method may be promising for the construction of multifunctional acellular scaffolds for the treatment of spinal cord injury.
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Affiliation(s)
- Hui Xing
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing 400037, P.R. China
| | - Hong Yin
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing 400037, P.R. China
| | - Chao Sun
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing 400037, P.R. China
| | - Xianjun Ren
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing 400037, P.R. China
| | - Yongyang Tian
- Emergency Department of University‑Town Hospital of Chongqing Medical University, Chongqing 401331, P.R. China
| | - Miao Yu
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing 400037, P.R. China
| | - Tao Jiang
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing 400037, P.R. China
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Hou B, Cai M, Chen C, Ji W, Ye Z, Ling C, Chen Z, Guo Y. Xenogeneic acellular nerve scaffolds supplemented with autologous bone marrow-derived stem cells promote axonal outgrowth and remyelination but not nerve function. J Biomed Mater Res A 2018; 106:3065-3078. [PMID: 30260554 DOI: 10.1002/jbm.a.36497] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 06/07/2018] [Accepted: 06/27/2018] [Indexed: 12/29/2022]
Abstract
Autologous nerves, artificial scaffolds or acellular nerve scaffolds are commonly used in bridging treatment for peripheral nerve defects. Xenogeneic acellular nerve scaffolds and allogeneic cellular nerve scaffolds have the same structural characteristics. Due to the wider source of raw materials, these latter scaffolds have high-potential value for applications. However, whether their heterogeneity will affect nerve regeneration is unknown. The current study evaluated the efficiency of xenogeneic acellular nerve scaffolds (XANs) combined with 5-ethynyl-2'-deoxyuridine (EdU)-labeling of autologous bone marrow-derived stem cells (BMSCs) for repair of a 1.5 cm gap in rat sciatic nerves. XANs from rabbit tibial nerves were prepared, the structure and components of the scaffolds were evaluated after completely removing the cellular components. Animals were divided into four groups based on graft: the simple XAN group, the XAN + BMSC group, the XAN + Media (from BMSC culture) group, and the autograft group. Serological immune tests showed that XANs induce an immune response in the first 2 weeks after transplantation. Moreover, cell tracking revealed that the proportion of EdU+ cells decreased over time, as shown by the measures at 2 days (70%), 4 days (20%), and 8 days (even <3%) postoperatively. Nerve functional analyses revealed that in contrast to the autograft group results, the XAN-BMSC, XAN + Media, and XAN groups did not exhibit good restoration of the sciatic functional index (SFI) or electrophysiological results (the peak action potential amplitudes) 12 weeks, postoperatively. However, the XAN-BMSC and autograft groups demonstrated greater remyelination and increased axon numbers and myelin thickness than the XAN + Media and XAN groups 12 weeks, postoperatively (p < .05). In conclusion, in the early stage of transplantation, XANs induce a certain degree of inflammation. Although the combination of XANs with autologous BMSCs enhanced the number of regenerated axons and the remyelination, the combination did not effectively improve the recovery of nervous motor function. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3065-3078, 2018.
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Affiliation(s)
- Bo Hou
- Departments of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangdong Province, 510630, Guangzhou, China
| | - Meiqin Cai
- Departments of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangdong Province, 510630, Guangzhou, China
| | - Chuan Chen
- Departments of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangdong Province, 510630, Guangzhou, China
| | - Wanqing Ji
- Department of Obstetrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Province, 510623, Guangzhou, China
| | - Zhuopeng Ye
- Departments of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangdong Province, 510630, Guangzhou, China
| | - Cong Ling
- Departments of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangdong Province, 510630, Guangzhou, China
| | - Zhuopeng Chen
- Departments of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangdong Province, 510630, Guangzhou, China
| | - Ying Guo
- Departments of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangdong Province, 510630, Guangzhou, China
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19
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Chen C, Bai GC, Jin HL, Lei K, Li KX. Local injection of bone morphogenetic protein 7 promotes neuronal regeneration and motor function recovery after acute spinal cord injury. Neural Regen Res 2018; 13:1054-1060. [PMID: 29926833 PMCID: PMC6022460 DOI: 10.4103/1673-5374.233449] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
After spinal cord injury, the number of glial cells and motor neurons expressing bone morphogenetic protein 7 (BMP7) increases, indicating that upregulation of BMP7 can promote nerve repair. We, therefore, tested whether direct injection of BMP7 into acutely injured rat spinal cord can affect neurological recovery. Allen's impactor was used to create spinal cord injury at T10. The injury site was then injected with 50 ng BMP7 (BMP7 group) or physiological saline (control group) for 7 consecutive days. Electrophysiological examination showed that the amplitude of N1 in motor evoked potentials (MEP) decreased after spinal cord injury. At 8 weeks post-operation, the amplitude of N1 in the BMP7 group was remarkably higher than that at 1 week post-operation and was higher than that of the control group. Basso, Beattie, Bresnahan scale (BBB) scores, hematoxylin-eosin staining, and western blot assay showed that at 1, 2, 4 and 8 weeks post-operation, BBB scores were increased; Nissl body staining was stronger; the number of Nissl-stained bodies was increased; the number of vacuoles gradually decreased; the number of synapses was increased; and the expression of neuronal marker, neurofilament protein 200, was increased in the hind limbs of the BMP7 group compared with the control group. Western blot assay showed that the expression of GFAP protein in BMP7 group and control group did not change significantly and there was no significant difference between the BMP7 and control groups. These data confirmed that local injection of BMP7 can promote neuronal regeneration after spinal cord injury and promote recovery of motor function in rats.
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Affiliation(s)
- Chen Chen
- Department of Joint and Spine, Xinjiang Production and Construction Corps Hospital, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Guang-Chao Bai
- Department of Joint and Spine, Xinjiang Production and Construction Corps Hospital, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Hong-Liang Jin
- Department of Joint and Spine, Xinjiang Production and Construction Corps Hospital, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Kun Lei
- Department of Joint and Spine, Xinjiang Production and Construction Corps Hospital, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Kuan-Xin Li
- Department of Joint and Spine, Xinjiang Production and Construction Corps Hospital, Urumqi, Xinjiang Uygur Autonomous Region, China
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20
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Zhu J, Lu Y, Yu F, Zhou L, Shi J, Chen Q, Ding W, Wen X, Ding YQ, Mei J, Wang J. Effect of decellularized spinal scaffolds on spinal axon regeneration in rats. J Biomed Mater Res A 2017; 106:698-705. [PMID: 28986946 DOI: 10.1002/jbm.a.36266] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 09/17/2017] [Accepted: 09/21/2017] [Indexed: 01/11/2023]
Affiliation(s)
- Junyi Zhu
- Department of Hand Surgery and Peripheral Neurosurgery; The First Affiliated Hospital of Wenzhou Medical University; Wenzhou 325035 China
| | - Yingfeng Lu
- Department of Hand Surgery and Peripheral Neurosurgery; The First Affiliated Hospital of Wenzhou Medical University; Wenzhou 325035 China
| | - Fangzheng Yu
- Department of Hand Surgery and Peripheral Neurosurgery; The First Affiliated Hospital of Wenzhou Medical University; Wenzhou 325035 China
| | - Lebin Zhou
- Wenzhou Medical University; Wenzhou 325035 China
| | - Jiawei Shi
- Wenzhou Medical University; Wenzhou 325035 China
| | - Qihui Chen
- Wenzhou Medical University; Wenzhou 325035 China
| | - Weili Ding
- The People's Hospital of Yuhuan; Taizhou 317600 China
| | - Xin Wen
- Department of Hand Surgery and Peripheral Neurosurgery; The First Affiliated Hospital of Wenzhou Medical University; Wenzhou 325035 China
| | - Yu-Qiang Ding
- Institute of Neuroscience, Wenzhou Medical University; Wenzhou 325035 China
| | - Jin Mei
- Institute of Neuroscience, Wenzhou Medical University; Wenzhou 325035 China
- Anatomy Department; Wenzhou Medical University; Wenzhou 325035 China
| | - Jian Wang
- Department of Hand Surgery and Peripheral Neurosurgery; The First Affiliated Hospital of Wenzhou Medical University; Wenzhou 325035 China
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21
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Libro R, Bramanti P, Mazzon E. The combined strategy of mesenchymal stem cells and tissue-engineered scaffolds for spinal cord injury regeneration. Exp Ther Med 2017; 14:3355-3368. [PMID: 29042919 PMCID: PMC5639409 DOI: 10.3892/etm.2017.4939] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 08/03/2017] [Indexed: 01/02/2023] Open
Abstract
Spinal cord injury (SCI) is a traumatic lesion that can result in the loss of motor or sensory neurons. Stem cell (SC)-based therapies have been demonstrated to promote neuronal regeneration following SCI, by releasing a range of trophic factors that support endogenous repair or by differentiating into neurons, or glial cells in order to replace the damaged cells. However, numerous limitations remain for therapies based on SC transplantion alone, including a low rate of survival/engraftment. Nevertheless, scaffolds are 3-dimentional substrates that have revealed to support cell survival, proliferation and differentiation in vivo, by mimicking a more favorable endogenous microenvironment. A multidisciplinary approach, which combines engineered scaffolds with SCs has been proposed as a promising strategy for encouraging spinal cord regeneration. The present review has focused on the regenerative potential of mesenchymal SCs isolated from different sources and combined with various scaffold types, in preclinical and clinical SCI studies.
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Affiliation(s)
- Rosaliana Libro
- Department of Experimental Neurology, IRCCS Centro Neurolesi ‘Bonino-Pulejo’, I-98124 Messina, Italy
| | - Placido Bramanti
- Department of Experimental Neurology, IRCCS Centro Neurolesi ‘Bonino-Pulejo’, I-98124 Messina, Italy
| | - Emanuela Mazzon
- Department of Experimental Neurology, IRCCS Centro Neurolesi ‘Bonino-Pulejo’, I-98124 Messina, Italy
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22
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Liu Y, Li Q, Zhang B, Ban DX, Feng SQ. Multifunctional biomimetic spinal cord: New approach to repair spinal cord injuries. World J Exp Med 2017; 7:78-83. [PMID: 28890869 PMCID: PMC5571451 DOI: 10.5493/wjem.v7.i3.78] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 05/17/2017] [Accepted: 06/13/2017] [Indexed: 02/06/2023] Open
Abstract
The incidence of spinal cord injury (SCI) has been gradually increasing, and the treatment has troubled the medical field all the time. Primary and secondary injuries ultimately lead to nerve impulse conduction block. Microglia and astrocytes excessively accumulate and proliferate to form the glial scar. At present, to reduce the effect of glial scar on nerve regeneration is a hot spot in the research on the treatment of SCI. According to the preliminary experiments, we would like to provide a new bionic spinal cord to reduce the negative effect of glial scar on nerve regeneration. In this hypothesis we designed a new scaffold that combine the common advantage of acellular scaffold of spinal cord and thermosensitive gel, which could continue to release exogenous basic fibroblast growth factor (BFGF) in the spinal lesion area on the basis of BFGF modified thermosensitive gel. Meanwhile, the porosity, pore size and material of the gray matter and white matter regions were distinguished by an isolation layer, so as to induce the directed differentiation of cells into the defect site and promote regeneration of spinal cord tissue.
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23
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Bi JJ, Li J, Cheng BF, Yang HJ, Ding QQ, Wang RF, Chen SJ, Feng ZW. NCAM affects directional lamellipodia formation of BMSCs via β1 integrin signal-mediated cofilin activity. Mol Cell Biochem 2017; 435:175-183. [PMID: 28536952 DOI: 10.1007/s11010-017-3066-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2017] [Accepted: 05/05/2017] [Indexed: 12/20/2022]
Abstract
The neural cell adhesion molecule (NCAM), a key member of the immunoglobulin-like CAM family, was reported to regulate the migration of bone marrow-derived mesenchymal stem cells (BMSCs). However, the detailed cellular behaviors including lamellipodia formation in the initial step of directional migration remain largely unknown. In the present study, we reported that NCAM affects the lamellipodia formation of BMSCs. Using BMSCs from Ncam knockout mice we found that Ncam deficiency significantly impaired the migration and the directional lamellipodia formation of BMSCs. Further studies revealed that Ncam knockout decreased the activity of cofilin, an actin-cleaving protein, which was involved in directional protrusions. To explore the molecular mechanisms involved, we examined protein tyrosine phosphorylation levels in Ncam knockout BMSCs by phosphotyrosine peptide array analyses, and found that the tyrosine phosphorylation level of β1 integrin, a protein upstream of cofilin, was greatly upregulated in Ncam-deficient BMSCs. Notably, by blocking the function of β1 integrin with RGD peptide or ROCK inhibitor, the cofilin activity and directional lamellipodia formation of Ncam knockout BMSCs could be rescued. Finally, we found that the effect of NCAM on tyrosine phosphorylation of β1 integrin was independent of the fibroblast growth factor receptor. These results indicated that NCAM regulates directional lamellipodia formation of BMSCs through β1 integrin signal-mediated cofilin activity.
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Affiliation(s)
- Jia-Jia Bi
- School of Life Sciences and Technology, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453003, Henan, China
| | - Jing Li
- School of Life Sciences and Technology, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453003, Henan, China
| | - Bin-Feng Cheng
- School of Life Sciences and Technology, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453003, Henan, China
| | - Hai-Jie Yang
- School of Life Sciences and Technology, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453003, Henan, China
| | - Qiong-Qiong Ding
- School of Life Sciences and Technology, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453003, Henan, China
| | - Rui-Fei Wang
- College of Life Sciences, Henan Normal University, Xinxiang, 453007, China
| | - Su-Juan Chen
- School of Life Sciences and Technology, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453003, Henan, China.
| | - Zhi-Wei Feng
- School of Basic Medical Sciences, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453003, Henan, China.
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24
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Wang YH, Chen J, Zhou J, Nong F, Lv JH, Liu J. Reduced inflammatory cell recruitment and tissue damage in spinal cord injury by acellular spinal cord scaffold seeded with mesenchymal stem cells. Exp Ther Med 2016; 13:203-207. [PMID: 28123490 PMCID: PMC5244979 DOI: 10.3892/etm.2016.3941] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 09/26/2016] [Indexed: 12/23/2022] Open
Abstract
Therapy using acellular spinal cord (ASC) scaffolds seeded with bone marrow stromal cells (BMSCs) has previously been shown to restore function of the damaged spinal cord and improve functional recovery in a rat model of acute hemisected spinal cord injury (SCI). The aim of the present study was to determine whether BMSCs and ASC scaffolds promote the functional recovery of the damaged spinal cord in a rat SCI model through regulation of apoptosis and immune responses. Whether this strategy regulates secondary inflammation, which is characterized by the infiltration of immune cells and inflammatory mediators to the lesion site, in SCI repair was investigated. Basso, Beattie, and Bresnahan scores revealed that treatment with BMSCs seeded into an ASC scaffold led to a significant improvement in motor function recovery compared with treatment with an ASC scaffold alone or untreated controls at 2 and 8 weeks after surgery (P<0.05). Two weeks after transplantation, the BMSCs seeded into an ASC scaffold significantly decreased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells, as compared with the ASC scaffold only and control groups. These results suggested that the use of BMSCs decreased the apoptosis of neural cells and thereby limited tissue damage at the lesion site. Notably, the use of BMSCs with an ASC scaffold also decreased the recruitment of macrophages (microglia; P<0.05) and T lymphocytes (P<0.05) around the SCI site, as indicated by immunofluorescent markers. By contrast, there was no inhibition of the inflammatory response in the control and ASC scaffold only groups. BMSCs regulated inflammatory cell recruitment to promote functional recovery. However, there was no significant difference in IgM-positive expression among the three groups (P>0.05). The results of this study demonstrated that BMSCs seeded into ASC scaffolds for repair of spinal cord hemisection defects promoted functional recovery through the early regulation of inflammatory cell recruitment with inhibition of apoptosis and secondary inflammation.
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Affiliation(s)
- Yu-Hai Wang
- Department of Orthopedics, Ningxia People's Hospital, First Affiliated Hospital of Northwest University for Nationalities, Yinchuan, Ningxia 750000, P.R. China
| | - Jian Chen
- Department of Orthopedic Surgery, Chongqing Three Gorges Central Hospital, Chongqing 404000, P.R. China
| | - Jing Zhou
- Department of Anatomy, Youjiang Medical College for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Feng Nong
- Department of Orthopedics, Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Jin-Han Lv
- Department of Orthopedics, Ningxia People's Hospital, First Affiliated Hospital of Northwest University for Nationalities, Yinchuan, Ningxia 750000, P.R. China
| | - Jia Liu
- Department of Orthopedics, Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, Guangxi 533000, P.R. China
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25
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Palejwala AH, Fridley JS, Mata JA, Samuel ELG, Luerssen TG, Perlaky L, Kent TA, Tour JM, Jea A. Biocompatibility of reduced graphene oxide nanoscaffolds following acute spinal cord injury in rats. Surg Neurol Int 2016; 7:75. [PMID: 27625885 PMCID: PMC5009578 DOI: 10.4103/2152-7806.188905] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 06/20/2016] [Indexed: 11/05/2022] Open
Abstract
Background: Graphene has unique electrical, physical, and chemical properties that may have great potential as a bioscaffold for neuronal regeneration after spinal cord injury. These nanoscaffolds have previously been shown to be biocompatible in vitro; in the present study, we wished to evaluate its biocompatibility in an in vivo spinal cord injury model. Methods: Graphene nanoscaffolds were prepared by the mild chemical reduction of graphene oxide. Twenty Wistar rats (19 male and 1 female) underwent hemispinal cord transection at approximately the T2 level. To bridge the lesion, graphene nanoscaffolds with a hydrogel were implanted immediately after spinal cord transection. Control animals were treated with hydrogel matrix alone. Histologic evaluation was performed 3 months after the spinal cord transection to assess in vivo biocompatibility of graphene and to measure the ingrowth of tissue elements adjacent to the graphene nanoscaffold. Results: The graphene nanoscaffolds adhered well to the spinal cord tissue. There was no area of pseudocyst around the scaffolds suggestive of cytotoxicity. Instead, histological evaluation showed an ingrowth of connective tissue elements, blood vessels, neurofilaments, and Schwann cells around the graphene nanoscaffolds. Conclusions: Graphene is a nanomaterial that is biocompatible with neurons and may have significant biomedical application. It may provide a scaffold for the ingrowth of regenerating axons after spinal cord injury.
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Affiliation(s)
- Ali H Palejwala
- Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA; Division of Pediatric Neurosurgery, Texas Children's Hospital, Houston, Texas, USA
| | - Jared S Fridley
- Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA; Division of Pediatric Neurosurgery, Texas Children's Hospital, Houston, Texas, USA
| | - Javier A Mata
- Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA; Division of Pediatric Neurosurgery, Texas Children's Hospital, Houston, Texas, USA
| | | | - Thomas G Luerssen
- Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA; Division of Pediatric Neurosurgery, Texas Children's Hospital, Houston, Texas, USA
| | - Laszlo Perlaky
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA; Research and Tissue Support Services Core Laboratory, Texas Children's Cancer and Hematology Services, Houston, Texas, USA
| | - Thomas A Kent
- Department of Neurology, Baylor College of Medicine, Houston, Texas, USA; Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, USA; Center for Translational Research in Inflammatory Diseases, Michael E. DeBakey VA Medical Center, Houston, Texas, USA
| | - James M Tour
- Department of Chemistry, Rice University, Houston, Texas, USA; Department of Chemistry and Materials Science and NanoEngineering, Rice University, Houston, Texas, USA
| | - Andrew Jea
- Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA; Division of Pediatric Neurosurgery, Texas Children's Hospital, Houston, Texas, USA
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26
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The hetero-transplantation of human bone marrow stromal cells carried by hydrogel unexpectedly demonstrates a significant role in the functional recovery in the injured spinal cord of rats. Brain Res 2015; 1634:21-33. [PMID: 26523673 DOI: 10.1016/j.brainres.2015.10.038] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2015] [Revised: 09/19/2015] [Accepted: 10/22/2015] [Indexed: 12/21/2022]
Abstract
Spinal cord injury (SCI) often causes a disturbance in the microenvironment in the lesion site resulting in sudden loss of sensory and motor function. Transplantation of stem cells provides a promising strategy in the treatment of SCI. But limited growth and immunological incompatibility of the stem cells with the host limits the application of this strategy. In order to get better survival and integration with the host, we employed a hyaluronic acid (HA) based scaffold covalently modified by poly-l-Lysine (PLL) as a vehicle to deliver the human bone marrow stromal cells (BMSCs) to the injured spinal cord of rats. The BMSCs were chosen as an ideal candidate for its advantage of low expression of major histocompatibility complex II. The data unexpectedly showed that the hetero-transplanted cells survived well in the lesion site even at 8 weeks post injury. Both the immunofluorescent and the electrophysiological assay indicated better survival of the transplanted cells and improved axonal growth in SCI rats transplanted with BMSCs in HA-PLL in contrast to the groups without either BMSCs or the HA scaffold transplantation. These promotions may account for the functional recovery assessed by Basso-Beattie-Bresnahan (BBB) locomotor rating scale in the HA-PLL seeded with BMSCs group. These data suggests that hetero-transplantation of human BMSCs delivered by HA scaffold demonstrates a significant role in the functional recovery in the injured spinal cord of rats.
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27
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Alvarez-Mejia L, Morales J, Cruz GJ, Olayo MG, Olayo R, Díaz-Ruíz A, Ríos C, Mondragón-Lozano R, Sánchez-Torres S, Morales-Guadarrama A, Fabela-Sánchez O, Salgado-Ceballos H. Functional recovery in spinal cord injured rats using polypyrrole/iodine implants and treadmill training. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2015; 26:209. [PMID: 26169188 DOI: 10.1007/s10856-015-5541-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 07/03/2015] [Indexed: 06/04/2023]
Abstract
Currently, there is no universally accepted treatment for traumatic spinal cord injury (TSCI), a pathology that can cause paraplegia or quadriplegia. Due to the complexity of TSCI, more than one therapeutic strategy may be necessary to regain lost functions. Therefore, the present study proposes the use of implants of mesoparticles (MPs) of polypyrrole/iodine (PPy/I) synthesized by plasma for neuroprotection promotion and functional recovery in combination with treadmill training (TT) for neuroplasticity promotion and maintenance of muscle tone. PPy/I films were synthesized by plasma and pulverized to obtain MPs. Rats with a TSCI produced by the NYU impactor were divided into four groups: Vehicle (saline solution); MPs (PPy/I implant); Vehicle-TT (saline solution + TT); and MPs-TT (PPy/I implant + TT). The vehicle or MPs (30 μL) were injected into the lesion site 48 h after a TSCI. Four days later, TT was carried out 5 days a week for 2 months. Functional recovery was evaluated weekly using the BBB motor scale for 9 weeks and tissue protection using histological and morphometric analysis thereafter. Although the MPs of PPy/I increased nerve tissue preservation (P = 0.03) and promoted functional recovery (P = 0.015), combination with TT did not produce better neuroprotection, but significantly improved functional results (P = 0.000) when comparing with the vehicle group. So, use these therapeutic strategies by separately could stimulate specific mechanisms of neuroprotection and neuroregeneration, but when using together they could mainly potentiate different mechanisms of neuronal plasticity in the preserved spinal cord tissue after a TSCI and produce a significant functional recovery. The implant of mesoparticles of polypyrrole/iodine into the injured spinal cord displayed good integration into the nervous tissue without a response of rejection, as well as an increased in the amount of preserved tissue and a better functional recovery than the group without transplant after a traumatic spinal cord injury by contusion in rats. The relevance of the present results is that polypyrrole/iodine implants were synthesized by plasma instead by conventional chemical or electrochemical methods. Synthesis by plasma modifies physicochemical properties of polypyrrole/iodine implants, which can be responsible of the histological response and functional results. Furthermore, no additional molecules or trophic factors or cells were added to the implant for obtain such results. Even more, when the implant was used together with physical rehabilitation, better functional recovery was obtained than that observed when these strategies were used by separately.
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Affiliation(s)
- Laura Alvarez-Mejia
- Department of Electric Engineering, Universidad Autónoma Metropolitana Iztapalapa, Apdo. Postal 55-534, CP 09340, Mexico, DF, Mexico
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28
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Complete rat spinal cord transection as a faithful model of spinal cord injury for translational cell transplantation. Sci Rep 2015; 5:9640. [PMID: 25860664 PMCID: PMC5381701 DOI: 10.1038/srep09640] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Accepted: 03/09/2015] [Indexed: 01/09/2023] Open
Abstract
Spinal cord injury (SCI) results in neural loss and consequently motor and sensory impairment below the injury. There are currently no effective therapies for the treatment of traumatic SCI in humans. Various animal models have been developed to mimic human SCI. Widely used animal models of SCI are complete or partial transection or experimental contusion and compression, with both bearing controversy as to which one more appropriately reproduces the human SCI functional consequences. Here we present in details the widely used procedure of complete spinal cord transection as a faithful animal model to investigate neural and functional repair of the damaged tissue by exogenous human transplanted cells. This injury model offers the advantage of complete damage to a spinal cord at a defined place and time, is relatively simple to standardize and is highly reproducible.
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