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Zhang WJ, Chen D. Mesenchymal stem cell transplantation plays a role in relieving cancer pain. Front Pharmacol 2024; 15:1483716. [PMID: 39679363 PMCID: PMC11637888 DOI: 10.3389/fphar.2024.1483716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 11/18/2024] [Indexed: 12/17/2024] Open
Abstract
Tumors can invade, compress, and damage nerves, leading to persistent pain and seriously affecting the quality of life of patients. However, their treatment is challenging. Sensitization of peripheral receptors, abnormal activity of primary sensory neurons, activation of glial cells, enhanced inflammatory responses, and sensory information transmission contribute towards cancer pain. Therefore, considerable attention has been paid to exploring prospective methods to inhibit the occurrence of these factors and relieve cancer pain. Studies on different types of pains have revealed that the transplantation of functionally active cells into the host has the pharmacological effect of producing analgesia. Mesenchymal stem cells (MSCs) can act as small active pumps to reduce the expression of pain-related molecules and produce analgesic effects. Moreover, MSCs can establish complex communication networks with non-tumor and cancer cells in the microenvironment, interact with each other, and can be used as destinations for inflammation and tumor sites, affecting their potential for invasion and metastasis. This emphasizes the key role of MSCs in cancer and pain management. The pain relief mechanisms of MSCs include neuronutrition, neural protection, neural network reconstruction, immune regulation, and improvement of the inflammatory microenvironment around the nerve injury. All of these are beneficial for the recovery of injured or stimulated nerves and the reconstruction of neural function, and play a role in relieving pain. The pain treatment strategy of cell transplantation is to repair injured nerves and produce analgesic pharmacological properties that are different from those of painkillers and other physiotherapies. Although the therapeutic role of MSCs in cancer and pain is in its early stages, the therapeutic value of MSCs for cancer pain has great prospects. Therefore, in this study, we explored the possible mechanism between MSCs and cancer pain, the potential therapeutic role of therapeutic cells in cancer pain, and some problems and challenges.
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Affiliation(s)
- Wen-Jun Zhang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Nanchang University, Jiangxi Medical college, Nanchang, China
| | - Dingyi Chen
- Emergency department, The Second Affiliated Hospital, Nanchang University, Jiangxi Medical college, Nanchang, China
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2
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Nizam M, Purohit R, Taufik M. Materials for 3D printing in healthcare sector: A review. Proc Inst Mech Eng H 2024; 238:939-963. [PMID: 39397720 DOI: 10.1177/09544119241289731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Additive Manufacturing (AM) encompasses various techniques creating intricate components from digital models. The aim of incorporating 3D printing (3DP) in the healthcare sector is to transform patient care by providing personalized solutions, improving medical procedures, fostering research and development, and ultimately optimizing the efficiency and effectiveness of healthcare delivery. This review delves into the historical beginnings of AM's 9 integration into medical contexts exploring various categories of AM methodologies and their roles within the medical sector. This survey also dives into the issue of material requirements and challenges specific to AM's medical applications. Emphasis is placed on how AM processes directly enhance human well-being. The primary focus of this paper is to highlight the evolution and incentives for cross-disciplinary AM applications, particularly in the realm of healthcare by considering their principle, materials and applications. It is designed for a diverse audience, including manufacturing professionals and researchers, seeking insights into this transformative technology's medical dimensions.
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Affiliation(s)
- Maruf Nizam
- Centre of Excellence in Product Design and Smart Manufacturing, Maulana Azad National Institute of Technology, Bhopal, Madhya Pradesh, India
| | - Rajesh Purohit
- Centre of Excellence in Product Design and Smart Manufacturing, Maulana Azad National Institute of Technology, Bhopal, Madhya Pradesh, India
- Department of Mechanical Engineering, Maulana Azad National Institute of Technology, Bhopal, Madhya Pradesh, India
| | - Mohammad Taufik
- Centre of Excellence in Product Design and Smart Manufacturing, Maulana Azad National Institute of Technology, Bhopal, Madhya Pradesh, India
- Department of Mechanical Engineering, Maulana Azad National Institute of Technology, Bhopal, Madhya Pradesh, India
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Koh J, Liu J, Poon CH, Kang J, Basabrain MS, Lim LW, Zhang C. Transplantation of Neural Progenitor Cells Derived from Stem Cells from Apical Papilla Through Small-Molecule Induction in a Rat Model of Sciatic Nerve Injury. Tissue Eng Regen Med 2024; 21:867-879. [PMID: 38904732 PMCID: PMC11286922 DOI: 10.1007/s13770-024-00648-y] [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: 02/04/2024] [Revised: 04/22/2024] [Accepted: 04/28/2024] [Indexed: 06/22/2024] Open
Abstract
BACKGROUND Stem cell-based transplantation therapy holds promise for peripheral nerve injury treatment, but adult availability is limited. A cell culture protocol utilizing a small-molecule cocktail effectively reprogrammed stem cells from apical papilla (SCAPs) into neural progenitor cells, subsequently differentiating into neuron-like cells. This study aims to evaluate neural-induced SCAPs, with and without small-molecule cocktail, for sciatic nerve repair potential. METHODS A scaffold-free cell sheet technique was used to construct a three-dimensional cell sheet. Subsequently, this cell sheet was carefully rolled into a tube and seamlessly inserted into a collagen conduit, which was then transplanted into a 5 mm sciatic nerve injury rat model. Functional sciatic nerve regeneration was evaluated via toe spread test, walking track analysis and gastrocnemius muscle weight. Additionally, degree of sciatic nerve regeneration was determined based on total amount of myelinated fibers. RESULTS Small-molecule cocktail induced SCAPs enhanced motor function recovery, evident in improved sciatic function index and gastrocnemius muscle retention. We also observed better host myelinated fiber retention than undifferentiated SCAPs or neural-induced SCAPs without small-molecule cocktail. However, clusters of neuron-like cell bodies (surrounded by sparse myelinated fibers) were found in all cell sheet-implanted groups in the implantation region. This suggests that while the implanted cells likely survived transplantation, integration was poor and would likely hinder long-term recovery by occupying the space needed for host nerve fibers to project through. CONCLUSION Neural-induced SCAPs with small-molecule cocktail demonstrated promising benefits for nerve repair; further research is needed to improve its integration and optimize its potential for long-term recovery.
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Affiliation(s)
- Junhao Koh
- Restorative Dental Sciences, Endodontology, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China
| | - Junqing Liu
- Restorative Dental Sciences, Endodontology, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China
| | - Chi Him Poon
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Jun Kang
- Restorative Dental Sciences, Endodontology, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China
| | - Mohammed S Basabrain
- Restorative Dental Sciences, Endodontology, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China
- Restorative Dental Sciences, Faculty of Dentistry, Umm Al-Qura, University, Makkah, Saudi Arabia
| | - Lee Wei Lim
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
| | - Chengfei Zhang
- Restorative Dental Sciences, Endodontology, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China.
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Sharifi M, Kamalabadi-Farahani M, Salehi M, Ebrahimi-Brough S, Alizadeh M. Recent perspectives on the synergy of mesenchymal stem cells with micro/nano strategies in peripheral nerve regeneration-a review. Front Bioeng Biotechnol 2024; 12:1401512. [PMID: 39050683 PMCID: PMC11266111 DOI: 10.3389/fbioe.2024.1401512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 06/19/2024] [Indexed: 07/27/2024] Open
Abstract
Despite the intrinsic repair of peripheral nerve injury (PNI), it is important to carefully monitor the process of peripheral nerve repair, as peripheral nerve regeneration is slow and incomplete in large traumatic lesions. Hence, mesenchymal stem cells (MSCs) with protective and regenerative functions are utilized in synergy with innovative micro/nano technologies to enhance the regeneration process of peripheral nerves. Nonetheless, as MSCs are assessed using standard regenerative criteria including sensory-motor indices, structural features, and morphology, it is challenging to differentiate between the protective and regenerative impacts of MSCs on neural tissue. This study aims to analyze the process of nerve regeneration, particularly the performance of MSCs with and without synergistic approaches. It also focuses on the paracrine secretions of MSCs and their conversion into neurons with functional properties that influence nerve regeneration after PNI. Furthermore, the study explores new ideas for nerve regeneration after PNI by considering the synergistic effect of MSCs and therapeutic compounds, neuronal cell derivatives, biological or polymeric conduits, organic/inorganic nanoparticles, and electrical stimulation. Finally, the study highlights the main obstacles to developing synergy in nerve regeneration after PNI and aims to open new windows based on recent advances in neural tissue regeneration.
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Affiliation(s)
- Majid Sharifi
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
- Tissue Engineering and Stem Cells Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Mohammad Kamalabadi-Farahani
- Tissue Engineering and Stem Cells Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Majid Salehi
- Tissue Engineering and Stem Cells Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
- Health Technology Incubator Center, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Somayeh Ebrahimi-Brough
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Morteza Alizadeh
- Department of Tissue Engineering and Biomaterials, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
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Mobarakeh ZT, Hasanzadeh E, Farzin A, Goodarzi A, Farahani MS, Shirian S, Mahmoodi N, Zamani N, Karimi A, Ai J. Enhanced sciatic nerve regeneration with fibrin scaffold containing human endometrial stem cells and insulin encapsulated chitosan particles: An in vivo study. Injury 2023:S0020-1383(23)00082-7. [PMID: 36894467 DOI: 10.1016/j.injury.2023.01.041] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 08/05/2022] [Accepted: 01/23/2023] [Indexed: 03/11/2023]
Abstract
BACKGROUND Based on recent advances in tissue engineering and stem cell therapy in nervous system diseases treatments, this study aimed to investigate sciatic nerve regeneration using human endometrial stem cells (hEnSCs) encapsulated fibrin gel containing chitosan nanoparticle loaded by insulin (Ins-CPs). Stem cells and also Insulin (Ins), which is a strong signaling molecule in peripheral nerve regeneration, play an important role in neural tissue engineering. METHODS The fibrin hydrogel scaffold containing insulin loaded chitosan particles was synthesized and characterized. Release profiles of insulin from hydrogel was determined through UV-visible spectroscopy. Also, human endometrial stem cells encapsulated in hydrogel and its cell biocompatibility were assigned. Furthermore, the sciatic nerve crush injury was carried out and prepared fibrin gel was injected at the crush injury site by an 18-gage needle. Eight and twelve weeks later, the recovery of motor and sensory function and histopathological evaluation were assessed. RESULTS The in vitro experiments showed that the insulin can promote hEnSCs proliferation within a certain concentration range. Animals' treatment confirmed that developed fibrin gel containing Ins-CPs and hEnSCs significantly improves motor function and sensory recovery. Hematoxylin and Eosin (H&E) images provided from cross-sectional and, longitudinal-sections of the harvested regenerative nerve showed that regenerative nerve fibers had been formed and accompanied with new blood vessels in the fibrin/insulin/hEnSCs group. CONCLUSION Our results demonstrated that the prepared hydrogel scaffolds containing insulin nanoparticles and hEnSCs could be considered as a potential biomaterial aimed at regeneration of sciatic nerves.
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Affiliation(s)
- Zahra Taherian Mobarakeh
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Elham Hasanzadeh
- Immunogenetics Research Center, Department of Tissue Engineering & Regenerative Medicine, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Ali Farzin
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Arash Goodarzi
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Morteza Sagharjoghi Farahani
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sadegh Shirian
- Department of Pathology, School of Veterinary Medicine, Sharekord University, Shahrekord, Iran
| | - Narges Mahmoodi
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Narges Zamani
- Department of Obstetrics and Gynecology, Emam Complex Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Anita Karimi
- Chronic Respiratory Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Jafar Ai
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Wu SH, Liao YT, Huang CH, Chen YC, Chiang ER, Wang JP. Comparison of the Confluence-Initiated Neurogenic Differentiation Tendency of Adipose-Derived and Bone Marrow-Derived Mesenchymal Stem Cells. Biomedicines 2021; 9:biomedicines9111503. [PMID: 34829732 PMCID: PMC8615071 DOI: 10.3390/biomedicines9111503] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/18/2021] [Accepted: 10/18/2021] [Indexed: 12/27/2022] Open
Abstract
Adipose-derived mesenchymal stem cells (ADSCs), which tended to neurogenically differentiate spontaneously after achieving high confluence, were observed. Human ADSCs reaching 80% confluence were cultured in DMEM without an inducing factor for 24 h and then maintained in DMEM plus 1% FBS medium for 7 days. The neurogenic, adipogenic, and osteogenic genes of the factor-induced and confluence-initiated differentiation of the ADSCs and bone marrow-derived mesenchymal stem cells (BMSCs) at passages 3 to 5 were determined and compared using RT-qPCR, and the neurogenic differentiation was confirmed using immunofluorescent staining. In vitro tests revealed that the RNA and protein expression of neuronal markers, including class III β-tubulin (TUBB3), microtubule-associated protein 2 (MAP2), neurofilament medium polypeptide (NEFM), neurofilament heavy polypeptide (NEFH), and neurofilament light polypeptide (NEFL), had been enhanced in the confluence-initiated differentiation of the ADSCs. In addition, the expressions of neurotrophins, such as the nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF), were also elevated in the confluence-initiated differentiation of the ADSCs. However, the confluent ADSCs did not show a tendency toward spontaneous adipogenic and osteogenic differentiation. Moreover, compared with the confluent ADSCs, the tendency of spontaneous neurogenic, adipogenic, and osteogenic differentiation of the confluent human bone marrow mesenchymal stem cells (BMSCs) was not observed. The results indicated that ADSCs had the potential to spontaneously differentiate into neuron-like cells during the confluent culture period; however, this tendency was not observed in BMSCs.
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Affiliation(s)
- Szu-Hsien Wu
- Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan; (S.-H.W.); (C.-H.H.)
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
- Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, National Defense Medical Center, Taipei 112, Taiwan
| | - Yu-Ting Liao
- Department of Orthopaedics & Traumatology, Taipei Veterans General Hospital, Taipei 112, Taiwan;
| | - Chi-Han Huang
- Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan; (S.-H.W.); (C.-H.H.)
| | - Yi-Chou Chen
- Department of Orthopedics, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 330, Taiwan;
| | - En-Rung Chiang
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
- Department of Orthopaedics & Traumatology, Taipei Veterans General Hospital, Taipei 112, Taiwan;
| | - Jung-Pan Wang
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
- Department of Orthopaedics & Traumatology, Taipei Veterans General Hospital, Taipei 112, Taiwan;
- Correspondence: ; Tel.: +886-2-2875-7557; Fax: +886-2-2875-7657
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Yokoi T, Uemura T, Takamatsu K, Shintani K, Onode E, Hama S, Miyashima Y, Okada M, Nakamura H. Fate and contribution of induced pluripotent stem cell-derived neurospheres transplanted with nerve conduits to promote peripheral nerve regeneration in mice. Biomed Mater Eng 2021; 32:171-181. [PMID: 33780359 DOI: 10.3233/bme-201182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND We previously demonstrated that a bioabsorbable nerve conduit coated with mouse induced pluripotent stem cell (iPSC)-derived neurospheres accelerated peripheral nerve regeneration in mice. OBJECTIVE We examined the fate and utility of iPSC-derived neurospheres transplanted with nerve conduits for the treatment of sciatic nerve gaps in mice. METHODS Complete 5-mm defects were created in sciatic nerves and reconstructed using nerve conduits that were either uncoated or coated with mouse iPSC-derived neurospheres. The survival of the neurospheres on the nerve conduits was tracked using an in vivo imaging. The localization of the transplanted cells and regenerating axons was examined histologically. The gene expression levels in the nerve conduits were evaluated. RESULTS The neurospheres survived for at least 14 days, peaking at 4--7 days after implantation. The grafted neurospheres remained as Schwann-like cells within the nerve conduits and migrated into the regenerated axons. The expression levels of ATF3, BDNF, and GDNF in the nerve conduit coated with neurospheres were upregulated. CONCLUSIONS Mouse iPSC-derived neurospheres transplanted with nerve conduits for the treatment of sciatic nerve defects in mice migrated into regenerating axons, survived as Schwann-like cells, and promoted axonal growth with an elevation in the expression of nerve regeneration-associated trophic factors.
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Affiliation(s)
- Takuya Yokoi
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Takuya Uemura
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan.,Department of Orthopaedic Surgery, Osaka General Hospital of West Japan Railway Company, Osaka, Japan
| | - Kiyohito Takamatsu
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan.,Department of Orthopaedic Surgery, Yodogawa Christian Hospital, Osaka, Japan
| | - Kosuke Shintani
- Department of Pediatric Orthopaedic Surgery, Osaka City General Hospital, Osaka, Japan
| | - Ema Onode
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shunpei Hama
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yusuke Miyashima
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Mitsuhiro Okada
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hiroaki Nakamura
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
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Rodríguez-Sánchez DN, Pinto GBA, Cartarozzi LP, de Oliveira ALR, Bovolato ALC, de Carvalho M, da Silva JVL, Dernowsek JDA, Golim M, Barraviera B, Ferreira RS, Deffune E, Bertanha M, Amorim RM. 3D-printed nerve guidance conduits multi-functionalized with canine multipotent mesenchymal stromal cells promote neuroregeneration after sciatic nerve injury in rats. Stem Cell Res Ther 2021; 12:303. [PMID: 34051869 PMCID: PMC8164252 DOI: 10.1186/s13287-021-02315-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 03/29/2021] [Indexed: 01/09/2023] Open
Abstract
Background Nerve injuries are debilitating, leading to long-term motor deficits. Remyelination and axonal growth are supported and enhanced by growth factor and cytokines. Combination of nerve guidance conduits (NGCs) with adipose-tissue-derived multipotent mesenchymal stromal cells (AdMSCs) has been performing promising strategy for nerve regeneration. Methods 3D-printed polycaprolactone (PCL)-NGCs were fabricated. Wistar rats subjected to critical sciatic nerve damage (12-mm gap) were divided into sham, autograft, PCL (empty NGC), and PCL + MSCs (NGC multi-functionalized with 106 canine AdMSCs embedded in heterologous fibrin biopolymer) groups. In vitro, the cells were characterized and directly stimulated with interferon-gamma to evaluate their neuroregeneration potential. In vivo, the sciatic and tibial functional indices were evaluated for 12 weeks. Gait analysis and nerve conduction velocity were analyzed after 8 and 12 weeks. Morphometric analysis was performed after 8 and 12 weeks following lesion development. Real-time PCR was performed to evaluate the neurotrophic factors BDNF, GDNF, and HGF, and the cytokine and IL-10. Immunohistochemical analysis for the p75NTR neurotrophic receptor, S100, and neurofilament was performed with the sciatic nerve. Results The inflammatory environment in vitro have increased the expression of neurotrophins BDNF, GDNF, HGF, and IL-10 in canine AdMSCs. Nerve guidance conduits multi-functionalized with canine AdMSCs embedded in HFB improved functional motor and electrophysiological recovery compared with PCL group after 12 weeks. However, the results were not significantly different than those obtained using autografts. These findings were associated with a shift in the regeneration process towards the formation of myelinated fibers. Increased immunostaining of BDNF, GDNF, and growth factor receptor p75NTR was associated with the upregulation of BDNF, GDNF, and HGF in the spinal cord of the PCL + MSCs group. A trend demonstrating higher reactivity of Schwann cells and axonal branching in the sciatic nerve was observed, and canine AdMSCs were engrafted at 30 days following repair. Conclusions 3D-printed NGCs multi-functionalized with canine AdMSCs embedded in heterologous fibrin biopolymer as cell scaffold exerted neuroregenerative effects. Our multimodal approach supports the trophic microenvironment, resulting in a pro-regenerative state after critical sciatic nerve injury in rats.
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Affiliation(s)
- Diego Noé Rodríguez-Sánchez
- Department of Veterinary Clinics, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Giovana Boff Araujo Pinto
- Department of Veterinary Clinics, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Luciana Politti Cartarozzi
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
| | | | - Ana Livia Carvalho Bovolato
- Blood Transfusion Center, Cell Engineering Laboratory, Botucatu Medical School, São Paulo State University, Botucatu, SP, Brazil
| | - Marcio de Carvalho
- Department of Veterinary Clinics, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Jorge Vicente Lopes da Silva
- Renato Archer Information Technology Center (CTI), Three-dimensional Technologies Research Group, Campinas, SP, Brazil
| | - Janaina de Andréa Dernowsek
- Renato Archer Information Technology Center (CTI), Three-dimensional Technologies Research Group, Campinas, SP, Brazil
| | - Marjorie Golim
- Hemocenter division of Botucatu Medical School, São Paulo State University, Botucatu, SP, Brazil
| | - Benedito Barraviera
- Center for the Study of Venoms and Venomous Animals (CEVAP), São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Rui Seabra Ferreira
- Center for the Study of Venoms and Venomous Animals (CEVAP), São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Elenice Deffune
- Blood Transfusion Center, Cell Engineering Laboratory, Botucatu Medical School, São Paulo State University, Botucatu, SP, Brazil
| | - Mathues Bertanha
- Blood Transfusion Center, Cell Engineering Laboratory, Botucatu Medical School, São Paulo State University, Botucatu, SP, Brazil
| | - Rogério Martins Amorim
- Department of Veterinary Clinics, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu, SP, Brazil.
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Wu SH, Liao YT, Hsueh KK, Huang HK, Chen TM, Chiang ER, Hsu SH, Tseng TC, Wang JP. Adipose-Derived Mesenchymal Stem Cells From a Hypoxic Culture Improve Neuronal Differentiation and Nerve Repair. Front Cell Dev Biol 2021; 9:658099. [PMID: 33996818 PMCID: PMC8120285 DOI: 10.3389/fcell.2021.658099] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 04/09/2021] [Indexed: 01/09/2023] Open
Abstract
Hypoxic expansion has been demonstrated to enhance in vitro neuronal differentiation of bone-marrow derived mesenchymal stem cells (BMSCs). Whether adipose-derived mesenchymal stem cells (ADSCs) increase their neuronal differentiation potential following hypoxic expansion has been examined in the study. Real-time quantitative reverse transcription-polymerase chain reaction and immunofluorescence staining were employed to detect the expression of neuronal markers and compare the differentiation efficiency of hypoxic and normoxic ADSCs. A sciatic nerve injury animal model was used to analyze the gastrocnemius muscle weights as the outcomes of hypoxic and normoxic ADSC treatments, and sections of the regenerated nerve fibers taken from the conduits were analyzed by histological staining and immunohistochemical staining. Comparisons of the treatment effects of ADSCs and BMSCs following hypoxic expansion were also conducted in vitro and in vivo. Hypoxic expansion prior to the differentiation procedure promoted the expression of the neuronal markers in ADSC differentiated neuron-like cells. Moreover, the conduit connecting the sciatic nerve gap injected with hypoxic ADSCs showed the highest recovery rate of the gastrocnemius muscle weights in the animal model, suggesting a conceivable treatment for hypoxic ADSCs. The percentages of the regenerated myelinated fibers from the hypoxic ADSCs detected by toluidine blue staining and myelin basic protein (MBP) immunostaining were higher than those of the normoxic ones. On the other hand, hypoxic expansion increased the neuronal differentiation potential of ADSCs compared with that of the hypoxic BMSCs in vitro. The outcomes of animals treated with hypoxic ADSCs and hypoxic BMSCs showed similar results, confirming that hypoxic expansion enhances the neuronal differentiation potential of ADSCs in vitro and improves in vivo therapeutic potential.
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Affiliation(s)
- Szu-Hsien Wu
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yu-Ting Liao
- Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Kuang-Kai Hsueh
- Department of Orthopedics, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
| | - Hui-Kuang Huang
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Orthopaedics, Ditmanson Medical Foundation, Chiayi Christian Hospital, Chiayi, Taiwan.,Department of Food Nutrition, Chung Hwa University of Medical Technology, Tainan, Taiwan
| | - Tung-Ming Chen
- Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan.,Division of Orthopedics, Taipei City Hospital-Zhong Xiao Branch, Taipei, Taiwan
| | - En-Rung Chiang
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shan-Hui Hsu
- Institute of Polymer Science and Engineering, National Taiwan University, Taipei, Taiwan
| | - Ting-Chen Tseng
- Institute of Polymer Science and Engineering, National Taiwan University, Taipei, Taiwan
| | - Jung-Pan Wang
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan
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Selim OA, Lakhani S, Midha S, Mosahebi A, Kalaskar DM. Three-Dimensional Engineered Peripheral Nerve: Toward a New Era of Patient-Specific Nerve Repair Solutions. TISSUE ENGINEERING PART B-REVIEWS 2021; 28:295-335. [PMID: 33593147 DOI: 10.1089/ten.teb.2020.0355] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Reconstruction of peripheral nerve injuries (PNIs) with substance loss remains challenging because of limited treatment solutions and unsatisfactory patient outcomes. Currently, nerve autografting is the first-line management choice for bridging critical-sized nerve defects. The procedure, however, is often complicated by donor site morbidity and paucity of nerve tissue, raising a quest for better alternatives. The application of other treatment surrogates, such as nerve guides, remains questionable, and it is inefficient in irreducible nerve gaps. More importantly, these strategies lack customization for personalized patient therapy, which is a significant drawback of these nerve repair options. This negatively impacts the fascicle-to-fascicle regeneration process, critical to restoring the physiological axonal pathway of the disrupted nerve. Recently, the use of additive manufacturing (AM) technologies has offered major advancements to the bioengineering solutions for PNI therapy. These techniques aim at reinstating the native nerve fascicle pathway using biomimetic approaches, thereby augmenting end-organ innervation. AM-based approaches, such as three-dimensional (3D) bioprinting, are capable of biofabricating 3D-engineered nerve graft scaffolds in a patient-specific manner with high precision. Moreover, realistic in vitro models of peripheral nerve tissues that represent the physiologically and functionally relevant environment of human organs could also be developed. However, the technology is still nascent and faces major translational hurdles. In this review, we spotlighted the clinical burden of PNIs and most up-to-date treatment to address nerve gaps. Next, a summarized illustration of the nerve ultrastructure that guides research solutions is discussed. This is followed by a contrast of the existing bioengineering strategies used to repair peripheral nerve discontinuities. In addition, we elaborated on the most recent advances in 3D printing and biofabrication applications in peripheral nerve modeling and engineering. Finally, the major challenges that limit the evolution of the field along with their possible solutions are also critically analyzed.
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Affiliation(s)
- Omar A Selim
- Department of Surgical Biotechnology, Division of Surgery and Interventional Sciences, Royal Free Hospital, University College London (UCL), London, United Kingdom
| | - Saad Lakhani
- Department of Surgical Biotechnology, Division of Surgery and Interventional Sciences, Royal Free Hospital, University College London (UCL), London, United Kingdom
| | - Swati Midha
- Department of Surgical Biotechnology, Division of Surgery and Interventional Sciences, Royal Free Hospital, University College London (UCL), London, United Kingdom.,Department of Surgical Biotechnology, Special Centre for Nanoscience, Jawaharlal Nehru University, New Delhi, India
| | - Afshin Mosahebi
- Department of Plastic Surgery, Royal Free Hospital, University College London (UCL), London, United Kingdom
| | - Deepak M Kalaskar
- Department of Surgical Biotechnology, Division of Surgery and Interventional Sciences, Royal Free Hospital, University College London (UCL), London, United Kingdom.,Department of Surgical Biotechnology, Institute of Orthopaedics and Musculoskeletal Science, Royal National Orthopaedic Hospital, University College London (UCL), Stanmore, United Kingdom
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11
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Yokoi T, Uemura T, Takamatsu K, Onode E, Shintani K, Hama S, Miyashima Y, Okada M, Nakamura H. Long-term survival of transplanted induced pluripotent stem cell-derived neurospheres with nerve conduit into sciatic nerve defects in immunosuppressed mice. Biochem Biophys Rep 2021; 26:100979. [PMID: 33817351 PMCID: PMC8010205 DOI: 10.1016/j.bbrep.2021.100979] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 03/03/2021] [Indexed: 12/13/2022] Open
Abstract
Since the advent of induced pluripotent stem cells (iPSCs), clinical trials using iPSC-based cell transplantation therapy have been performed in various fields of regenerative medicine. We previously demonstrated that the transplantation of mouse iPSC-derived neurospheres containing neural stem/progenitor cells with bioabsorbable nerve conduits promoted nerve regeneration in the long term in murine sciatic nerve defect models. However, it remains unclear how long the grafted iPSC-derived neurospheres survived and worked after implantation. In this study, the long-term survival of the transplanted mouse iPSC-derived neurospheres with nerve conduits was evaluated in high-immunosuppressed or non-immunosuppressed mice using in vivo imaging for the development of iPSC-based cell therapy for peripheral nerve injury. Complete 5-mm long defects were created in the sciatic nerves of immunosuppressed and non-immunosuppressed mice and reconstructed using nerve conduits coated with iPSC-derived neurospheres labeled with ffLuc. The survival of mouse iPSC-derived neurospheres on nerve conduits was monitored using in vivo imaging. The transplanted iPSC-derived neurospheres with nerve conduits survived for 365 days after transplantation in the immunosuppressed allograft models, but only survived for at least 14 days in non-immunosuppressed allograft models. This is the first study to find the longest survival rate of stem cells with nerve conduits transplanted into the peripheral nerve defects using in vivo imaging and demonstrates the differences in graft survival rate between the immunosuppressed allograft model and immune responsive allograft model. In the future, if iPSC-derived neurospheres are successfully transplanted into peripheral nerve defects with nerve conduits using iPSC stock cells without eliciting an immune response, axonal regeneration will be induced due to the longstanding supportive effect of grafted cells on direct remyelination and/or secretion of trophic factors.
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Affiliation(s)
- Takuya Yokoi
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Takuya Uemura
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan.,Department of Orthopaedic Surgery, Osaka General Hospital of West Japan Railway Company, Osaka, Japan
| | - Kiyohito Takamatsu
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan.,Department of Orthopaedic Surgery, Yodogawa Christian Hospital, Osaka, Japan
| | - Ema Onode
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kosuke Shintani
- Department of Pediatric Orthopaedic Surgery, Osaka City General Hospital, Osaka, Japan
| | - Shunpei Hama
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yusuke Miyashima
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Mitsuhiro Okada
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hiroaki Nakamura
- Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
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12
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Paiva GR, Viterbo F, Deffune E, Custódio MAD. Stem cells in end-to-side neurorrhaphy. Experimental study in rats. Acta Cir Bras 2021; 35:e351207. [PMID: 33503220 PMCID: PMC7819685 DOI: 10.1590/acb351207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 11/26/2020] [Indexed: 11/22/2022] Open
Abstract
Purpose: To evaluate the influence of mesenchymal stem cells from adipose tissue in
the end-to-side neurorrhaphy, focusing in the nerve regeneration and the
muscle reinnervation in acute trauma. Methods: 140 animals were randomly divided in seven groups: control, denervated,
end-to-side neurorrhaphy between distal stump of common peroneal nerve and
tibial nerve (ESN), ESN wrapped in fascia, ESN wrapped in fascia and
platelet gel, ESN wrapped in platelet gel, ESN wrapped in fascia and
platelet gel within stem cells (without culture) removed from the adipose
tissue. Mass measurements of the animal and of cranial tibial muscles,
electromyography, walking track analysis tests and histological examinations
of the nerves and muscles after 180 days was performed. Results: In the groups where the ESN was performed, the results were always better
when compared to the denervated group, showing reinnervation in all ESN
groups. The most sensitive methods were walking track and histological
analysis. Only the group with stem cells showed values similar to the
control group, as well as the functional indices of peroneal nerve and the
number of nerve fibers in the peroneal nerve. Conclusions: Stem cells were effective in ESN according with the functional index of the
peroneal nerve, evaluated by walking track analysis and the number of nerve
fibers in the peroneal nerve.
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Affiliation(s)
| | - Fausto Viterbo
- Universidade Estadual Paulista “Júliode Mesquita Filho”, Brazil
| | - Elenice Deffune
- Universidade Estadual Paulista “Júlio de Mesquita Filho”, Brazil
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13
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Meena P, Kakkar A, Kumar M, Khatri N, Nagar RK, Singh A, Malhotra P, Shukla M, Saraswat SK, Srivastava S, Datt R, Pandey S. Advances and clinical challenges for translating nerve conduit technology from bench to bed side for peripheral nerve repair. Cell Tissue Res 2020; 383:617-644. [PMID: 33201351 DOI: 10.1007/s00441-020-03301-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 09/14/2020] [Indexed: 12/19/2022]
Abstract
Injuries to the peripheral nervous system remain a large-scale clinical problem. These injuries often lead to loss of motor and/or sensory function that significantly affects patients' quality of life. The current neurosurgical approach for peripheral nerve repair involves autologous nerve transplantation, which often leads to clinical complications. The most pressing need is to increase the regenerative capacity of existing tubular constructs in the repair of large nerve gaps through development of tissue-engineered approaches that can surpass the performance of autografts. To fully realize the clinical potential of nerve conduit technology, there is a need to reconsider design strategies, biomaterial selection, fabrication techniques and the various potential modifications to optimize a conduit microenvironment that can best mimic the natural process of regeneration. In recent years, a significant progress has been made in the designing and functionality of bioengineered nerve conduits to bridge long peripheral nerve gaps in various animal models. However, translation of this work from lab to commercial scale has not been achieve. The current review summarizes recent advances in the development of tissue engineered nerve guidance conduits (NGCs) with regard to choice of material, novel fabrication methods, surface modifications and regenerative cues such as stem cells and growth factors to improve regeneration performance. Also, the current clinical potential and future perspectives to achieve therapeutic benefits of NGCs will be discussed in context of peripheral nerve regeneration.
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Affiliation(s)
- Poonam Meena
- Department of Life Sciences, Datt Mediproducts Pvt. Ltd., Roz Ka Meo Industrial Area, District Mewat, Nuh, 122103, District Haryana, India
| | - Anupama Kakkar
- Department of Life Sciences, Datt Mediproducts Pvt. Ltd., Roz Ka Meo Industrial Area, District Mewat, Nuh, 122103, District Haryana, India
| | - Mukesh Kumar
- Department of Life Sciences, Datt Mediproducts Pvt. Ltd., Roz Ka Meo Industrial Area, District Mewat, Nuh, 122103, District Haryana, India
| | - Nitin Khatri
- Department of Life Sciences, Datt Mediproducts Pvt. Ltd., Roz Ka Meo Industrial Area, District Mewat, Nuh, 122103, District Haryana, India
| | - Rakesh Kumar Nagar
- Department of Life Sciences, Datt Mediproducts Pvt. Ltd., Roz Ka Meo Industrial Area, District Mewat, Nuh, 122103, District Haryana, India
| | - Aarti Singh
- Department of Life Sciences, Datt Mediproducts Pvt. Ltd., Roz Ka Meo Industrial Area, District Mewat, Nuh, 122103, District Haryana, India
| | - Poonam Malhotra
- Department of Life Sciences, Datt Mediproducts Pvt. Ltd., Roz Ka Meo Industrial Area, District Mewat, Nuh, 122103, District Haryana, India
| | - Manish Shukla
- Department of Life Sciences, Datt Mediproducts Pvt. Ltd., Roz Ka Meo Industrial Area, District Mewat, Nuh, 122103, District Haryana, India
| | - Sumit Kumar Saraswat
- Department of Life Sciences, Datt Mediproducts Pvt. Ltd., Roz Ka Meo Industrial Area, District Mewat, Nuh, 122103, District Haryana, India
| | - Supriya Srivastava
- Department of Life Sciences, Datt Mediproducts Pvt. Ltd., Roz Ka Meo Industrial Area, District Mewat, Nuh, 122103, District Haryana, India
| | - Rajan Datt
- Department of Life Sciences, Datt Mediproducts Pvt. Ltd., Roz Ka Meo Industrial Area, District Mewat, Nuh, 122103, District Haryana, India
| | - Siddharth Pandey
- Department of Life Sciences, Datt Mediproducts Pvt. Ltd., Roz Ka Meo Industrial Area, District Mewat, Nuh, 122103, District Haryana, India.
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14
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Wang JP, Liao YT, Wu SH, Chiang ER, Hsu SH, Tseng TC, Hung SC. Mesenchymal stem cells from a hypoxic culture improve nerve regeneration. J Tissue Eng Regen Med 2020; 14:1804-1814. [PMID: 32976700 DOI: 10.1002/term.3136] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 08/27/2020] [Accepted: 09/10/2020] [Indexed: 12/31/2022]
Abstract
Repairing the peripheral nerves following a segmental defect injury remains surgically challenging. Because of some disadvantages of nerve grafts, nerve regeneration, such as conduits combined with bone marrow-derived mesenchymal stem cells (BMSCs), may serve as an alternative. BMSCs expand under hypoxic conditions, decrease in senescence, and increase in proliferation and differentiation potential into the bone, fat, and cartilage. The purpose of this study was to investigate whether BMSCs increased the neuronal differentiation potential following expansion under hypoxic conditions. Isolated human BMSCs (hBMSCs) expand under hypoxia or normoxia, and neuronal differentiation proceeds under normoxia. in vitro tests revealed hypoxia culture enhanced the RNA and protein expression of neuronal markers. The electrophysiology of hBMSC-differentiated neuron-like cells was also enhanced by the hypoxia culturing. Our animal model indicated that the potential treatment of hypoxic rat BMSCs (rBMSCs) was better than that of normoxic rBMSCs because the conduit with the hypoxic rBMSCs injection demonstrated the highest recovery rate of gastrocnemius muscle weights. There were more toluidine blue-stained myelinated nerve fibers in the hypoxic rBMSCs group than in the normoxic group. To sum up, BMSCs cultured under hypoxia increased the potential of neuronal differentiation both in vivo and in vitro.
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Affiliation(s)
- Jung-Pan Wang
- Department of Surgery, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yu-Ting Liao
- Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Szu-Hsien Wu
- Department of Surgery, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Plastic and Reconstructive Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - En-Rung Chiang
- Department of Surgery, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shan-Hui Hsu
- Institute of Polymer Science and Engineering, National Taiwan University, Taipei, Taiwan
| | - Ting-Chen Tseng
- Institute of Polymer Science and Engineering, National Taiwan University, Taipei, Taiwan
| | - Shih-Chieh Hung
- Graduate Institute of New Drug Development, Biomedical Sciences, China Medical University, Taichung, Taiwan
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15
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Tissue Plasminogen Activator Loaded PCL Nanofibrous Scaffold Promoted Nerve Regeneration After Sciatic Nerve Transection in Male Rats. Neurotox Res 2020; 39:413-428. [PMID: 32852719 DOI: 10.1007/s12640-020-00276-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 08/19/2020] [Accepted: 08/20/2020] [Indexed: 01/09/2023]
Abstract
According to the studies, damages to the peripheral nerve as a result of a trauma or acute compression, stretching, or burns accounts for a vast range of discomforts which strongly impressed the patient's life quality. Applying highly potent biomolecules and growth factors in the damaged nerve site would promote the probability of nerve regeneration and functional recovery. Tissue plasminogen activator (tPA) is one of the components that can contribute importantly to degenerating and regenerating the peripheral nerves following the injuries occurred and the absence of this biomolecule hinders the recoveries of the nerves. This technique would guarantee the direct accessibility of tPA for the regenerating axons. Structural, physical, and in vitro cytotoxicity evaluations were done before in vivo experiments. In this study, twenty-four mature male rats have been exploited. The rats have been classified into four groups: controls, axotomy, axotomy + scaffold, and axotomy + tPA-loaded scaffold. Four, 8, and 12 weeks post-surgical, the sciatic functional index (SFI) has been measured. After 12 weeks, the spinal cord, sciatic nerve, and dorsal root ganglion specimens have been removed and stereological procedures, immunohistochemistry, and gene expression have been used to analyze them. Stereological parameters, immunohistochemistry of GFAP, and gene expression of S100, NGF, and BDNF were significantly enhanced in tPA-loaded scaffold group compared with axotomy group. The most similarity was observed between the results of control group and tPA-loaded scaffold group. According to the results, a good regeneration of the functional nerve tissues in a short time was observed as a result of introducing tPA.
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16
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Yu X, Zhang T, Li Y. 3D Printing and Bioprinting Nerve Conduits for Neural Tissue Engineering. Polymers (Basel) 2020; 12:E1637. [PMID: 32717878 PMCID: PMC7465920 DOI: 10.3390/polym12081637] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/17/2020] [Accepted: 07/21/2020] [Indexed: 12/14/2022] Open
Abstract
Fabrication of nerve conduits for perfectly repairing or replacing damaged peripheral nerve is an urgent demand worldwide, but it is also a formidable clinical challenge. In the last decade, with the rapid development of manufacture technologies, 3D printing and bioprinting have been becoming remarkable stars in the field of neural engineering. In this review, we explore that the biomaterial inks (hydrogels, thermoplastic, and thermoset polyesters and composite) and bioinks have been selected for 3D printing and bioprinting of peripheral nerve conduits. This review covers 3D manufacturing technologies, including extrusion printing, inkjet printing, stereolithography, and bioprinting with inclusion of cells, bioactive molecules, and drugs. Finally, an outlook on the future directions of 3D printing and 4D printing in customizable nerve therapies is presented.
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Affiliation(s)
- Xiaoling Yu
- School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan 430070, China;
| | - Tian Zhang
- School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan 430070, China;
- State Key Laboratory of Silicate Materials for Architectures, Wuhan University of Technology, Wuhan 430070, China
| | - Yuan Li
- School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan 430070, China;
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17
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Jahromi HK, Farzin A, Hasanzadeh E, Barough SE, Mahmoodi N, Najafabadi MRH, Farahani MS, Mansoori K, Shirian S, Ai J. Enhanced sciatic nerve regeneration by poly-L-lactic acid/multi-wall carbon nanotube neural guidance conduit containing Schwann cells and curcumin encapsulated chitosan nanoparticles in rat. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2019; 109:110564. [PMID: 32228906 DOI: 10.1016/j.msec.2019.110564] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 11/30/2019] [Accepted: 12/14/2019] [Indexed: 01/10/2023]
Abstract
The main aim of this study was to improve the efficacy of peripheral nerve regeneration by an artificial neural guidance conduit (NGC) as a carrier to transplant allogeneic Schwann cells (SCs) and curcumin encapsulated chitosan nanoparticles (nanocurcumin). The conduit was prepared by poly-L-lactic acid (PLLA) and surface-modified multi-wall carbon nanotubes (mMWCNT) and filled with SCs and nanocurcumin. SCs play an important role in the regeneration of injured peripheral nerve and controlled curcumin release can decrease SCs apoptosis, and enhance the regeneration and functional recovery of injured peripheral nerves. The mechanical properties, contact angle, and cell biocompatibility experiments showed that the optimized concentration of mMWCNT inside PLLA wall of conduits was 0.15 wt%. The drug release experiments showed slower release of curcumin from nanocurcumin samples compared to nanocurcumin encapsulated inside NGC wrapped fibrin gel sample. It was found that simultaneous using of both SCs and curcumin inside NGC had a significant role in sciatic nerve regeneration in vivo. Histological examination revealed a significant increase in the number of axons in injured sciatic nerve following treatment by SCs and nanocurcumin compared to negative control group. Histological evaluation also revealed a significant decrease in the number of vessels in fibrin groups compared to positive control group. The results showed that there was no significant difference between the reaction time and sciatic functional index (SFI) values of rats with injured sciatic nerve treated by NGC/SCs/nanocurcumin sample and autograft sample. In conclusion, our results strongly showed that PLLA/mMWCNT nanofibrous conduit filled with fibrin gel containing SCs and nanocurcumin is a proper strategy for improving nerve regeneration after a nerve transaction in the rat.
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Affiliation(s)
- Hossein Kargar Jahromi
- Zoonoses Research Center, Jahrom University of Medical Sciences, Jahrom, Iran; Research Center for Noncommunicable Diseases, Jahrom University of Medical Sciences, Jahrom, Iran
| | - Ali Farzin
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Research Center for Science and Technology in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Elham Hasanzadeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Tehran, Iran
| | - Somayeh Ebrahimi Barough
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Tehran, Iran
| | - Narges Mahmoodi
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza H Najafabadi
- Department of Medical Nanotechnology, School of Advanced Technology in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Morteza Sagharjoghi Farahani
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Korosh Mansoori
- Neuromusculoskeletal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Sadegh Shirian
- Department of Pathology, School of Veterinary Medicine, Sharekord University, Shahrekord, Iran
| | - Jafar Ai
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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18
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Jahromi M, Razavi S, Bakhtiari A. The advances in nerve tissue engineering: From fabrication of nerve conduit to in vivo nerve regeneration assays. J Tissue Eng Regen Med 2019; 13:2077-2100. [PMID: 31350868 DOI: 10.1002/term.2945] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 07/09/2019] [Accepted: 07/12/2019] [Indexed: 12/14/2022]
Abstract
Peripheral nerve damage is a common clinical complication of traumatic injury occurring after accident, tumorous outgrowth, or surgical side effects. Although the new methods and biomaterials have been improved recently, regeneration of peripheral nerve gaps is still a challenge. These injuries affect the quality of life of the patients negatively. In the recent years, many efforts have been made to develop innovative nerve tissue engineering approaches aiming to improve peripheral nerve treatment following nerve injuries. Herein, we will not only outline what we know about the peripheral nerve regeneration but also offer our insight regarding the types of nerve conduits, their fabrication process, and factors associated with conduits as well as types of animal and nerve models for evaluating conduit function. Finally, nerve regeneration in a rat sciatic nerve injury model by nerve conduits has been considered, and the main aspects that may affect the preclinical outcome have been discussed.
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Affiliation(s)
- Maliheh Jahromi
- Department of Anatomical Science, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shahnaz Razavi
- Department of Anatomical Science, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Abbas Bakhtiari
- Department of Anatomical Science, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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19
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Altun E, Aydogdu MO, Togay SO, Sengil AZ, Ekren N, Haskoylu ME, Oner ET, Altuncu NA, Ozturk G, Crabbe-Mann M, Ahmed J, Gunduz O, Edirisinghe M. Bioinspired scaffold induced regeneration of neural tissue. Eur Polym J 2019. [DOI: 10.1016/j.eurpolymj.2019.02.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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20
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Leitão L, Alves CJ, Sousa DM, Neto E, Conceição F, Lamghari M. The alliance between nerve fibers and stem cell populations in bone marrow: life partners in sickness and health. FASEB J 2019; 33:8697-8710. [PMID: 31017803 DOI: 10.1096/fj.201900454r] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The bone marrow (BM) is the central hematopoietic organ in adult mammals, with great potential to be used as a tool to improve the efficacy of the body's response to a number of malignancies and stressful conditions. The nervous system emerges as a critical regulatory player of the BM both under homeostatic and pathologic settings, with essential roles in cellular anchorage and egress, stem cell differentiation, and endothelial cell permeability. This review collects the current knowledge on the interplay between the nervous system and the BM cell populations, with a focus on how the nervous system modulates hematopoietic stem and progenitor cell, mesenchymal stromal cell, and endothelial progenitor cell activity in BM. We have also highlighted the pathologies that have been associated with disturbances in the neuronal signaling in BM and discussed if targeting the nervous system, either by modulating the activity of specific neuronal circuits or by pharmacologically leveling the activity of sympathetic and sensorial signaling-responsive cells in BM, is a promising therapeutic approach to tackling pathologies from BM origin.-Leitão, L., Alves, C. J., Sousa, D. M., Neto, E., Conceição, F., Lamghari, M. The alliance between nerve fibers and stem cell populations in bone marrow: life partners in sickness and health.
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Affiliation(s)
- Luís Leitão
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
| | - Cecília J Alves
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal
| | - Daniela M Sousa
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal
| | - Estrela Neto
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal
| | - Francisco Conceição
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
| | - Meriem Lamghari
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
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Zhang ZY, Yang J, Fan ZH, Wang DL, Wang YY, Zhang T, Yu LM, Yu CY. Fresh human amniotic membrane effectively promotes the repair of injured common peroneal nerve. Neural Regen Res 2019; 14:2199-2208. [PMID: 31397360 PMCID: PMC6788240 DOI: 10.4103/1673-5374.262596] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Suture and autologous nerve transplantation are the primary therapeutic measures for completely severed nerves. However, imbalances in the microenvironment and adhesion of surrounding tissues can affect the quality of nerve regeneration and repair. Previous studies have shown that human amniotic membrane can promote the healing of a variety of tissues. In this study, the right common peroneal nerve underwent a 5-mm transection in rats. Epineural nerve repair was performed using 10/0 non-absorbable surgical suture. The repair site was wrapped with a two-layer amniotic membrane with α-cyanoacrylate rapid medical adhesive after suture. Hindlimb motor function was assessed using footprint analysis. Conduction velocity of the common peroneal nerve was calculated by neural electrical stimulation. The retrograde axoplasmic transport of the common peroneal nerve was observed using fast blue BB salt retrograde fluorescent staining. Hematoxylin-eosin staining was used to detect the pathological changes of the common peroneal nerve sputum. The mRNA expression of axon regeneration-related neurotrophic factors and inhibitors was measured using real-time polymerase chain reaction. The results showed that the amniotic membrane significantly improved the function of the injured nerve; the toe spread function rapidly recovered, the nerve conduction velocity was restored, and the number of fast blue BB salt particles were increased in the spinal cord. The amniotic membrane also increased the recovery rate of the tibialis anterior muscle and improved the tissue structure of the muscle. Meanwhile, mRNA expression of nerve growth factor, growth associated protein-43, collapsin response mediator protein-2, and brain-derived neurotrophic factor recovered to near-normal levels, while Lingo-1 mRNA expression decreased significantly in spinal cord tissues. mRNA expression of glial-derived neurotrophic factor did not change significantly. Changes in mRNA levels were more significant in amniotic-membrane-wrapping-treated rats compared with model and nerve sutured rats. These results demonstrate that fresh amniotic membrane wrapping can promote the functional recovery of sutured common peroneal nerve via regulation of expression levels of neurotrophic factors and inhibitors associated with axonal regeneration. The study was approved by the Committee on Animal Research and Ethics at the Affiliate Hospital of Zunyi Medical University, China (approval No. 112) on December 1, 2017.
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Affiliation(s)
- Zhong-Yuan Zhang
- Key Laboratory of Cell Engineering in Guizhou Province, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Jin Yang
- Key Laboratory of Cell Engineering in Guizhou Province, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province; Department of Thyroid and Breast Surgery, Fifth People's Hospital of Chengdu, Chengdu, Sichuan Province, China
| | - Zhen-Hai Fan
- Key Laboratory of Cell Engineering in Guizhou Province, The Affiliated Hospital of Zunyi Medical University; The Team of Scientific and Technological Innovation Talents on The Basic and Clinical Research of Amniotic Membrane and Bone Marrow Stem Cells in Guizhou Province, Zunyi, Guizhou Province, China
| | - Da-Li Wang
- Department of Burn and Plastic Surgery, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Yu-Ying Wang
- Key Laboratory of Cell Engineering in Guizhou Province, The Affiliated Hospital of Zunyi Medical University; The Team of Scientific and Technological Innovation Talents on The Basic and Clinical Research of Amniotic Membrane and Bone Marrow Stem Cells in Guizhou Province, Zunyi, Guizhou Province, China
| | - Tao Zhang
- Key Laboratory of Cell Engineering in Guizhou Province, The Affiliated Hospital of Zunyi Medical University; The Team of Scientific and Technological Innovation Talents on The Basic and Clinical Research of Amniotic Membrane and Bone Marrow Stem Cells in Guizhou Province, Zunyi, Guizhou Province, China
| | - Li-Mei Yu
- Key Laboratory of Cell Engineering in Guizhou Province, The Affiliated Hospital of Zunyi Medical University; The Team of Scientific and Technological Innovation Talents on The Basic and Clinical Research of Amniotic Membrane and Bone Marrow Stem Cells in Guizhou Province, Zunyi, Guizhou Province, China
| | - Chang-Yin Yu
- Department of Neurology, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
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Rodríguez Sánchez DN, de Lima Resende LA, Boff Araujo Pinto G, de Carvalho Bovolato AL, Possebon FS, Deffune E, Amorim RM. Canine Adipose-Derived Mesenchymal Stromal Cells Enhance Neuroregeneration in a Rat Model of Sciatic Nerve Crush Injury. Cell Transplant 2019; 28:47-54. [PMID: 30369261 PMCID: PMC6322136 DOI: 10.1177/0963689718809045] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/27/2018] [Accepted: 10/01/2018] [Indexed: 12/24/2022] Open
Abstract
Crush injuries in peripheral nerves are frequent and induce long-term disability with motor and sensory deficits. Due to axonal and myelin sheath disruptions, strategies for optimized axonal regeneration are needed. Multipotent mesenchymal stromal cells (MSC) are promising because of their anti-inflammatory properties and secretion of neurotrophins. The present study investigated the effect of canine adipose tissue MSC (Ad-MSC) transplantation in an experimental sciatic nerve crush injury. Wistar rats were divided into three groups: sham ( n = 8); Crush+PBS ( n = 8); Crush+MSC ( n = 8). Measurements of sciatic nerve functional index (SFI), muscle mass, and electromyography (EMG) were performed. Canine Ad-MSC showed mesodermal characteristics (CD34-, CD45-, CD44+, CD90+ and CD105+) and multipotentiality due to chondrogenic, adipogenic, and osteogenic differentiation. SFI during weeks 3 and 4 was significantly higher in the Crush+MSC group ( p < 0.001). During week 4, the EMG latency in the Crush+MSC groups had better near normality ( p < 0.05). The EMG amplitude showed results close to normality during week 4 in the Crush+MSC group ( p < 0.04). There were no statistical differences in muscle weight between the groups ( p > 0.05), but there was a tendency toward weight gain in the Crush+MSC groups. Better motor functional recovery after crush and perineural canine Ad-MSC transplantation was observed during week 2. This was maintained till week 4. In conclusion, the canine Ad-MSC transplantation showed early pro-regenerative effects between 2-4 weeks in the rat model of sciatic nerve crush injury.
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Affiliation(s)
- Diego Noé Rodríguez Sánchez
- Department of Veterinary Clinics, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), São Paulo, Brazil
- Blood Transfusion Center, Cell Engineering Laboratory, Botucatu Medical School, São Paulo State University (UNESP), São Paulo, Brazil
| | - Luiz Antonio de Lima Resende
- Department of Neurology and Psychiatry, Botucatu Medical School, São Paulo State University (UNESP), São Paulo, Brazil
| | - Giovana Boff Araujo Pinto
- Department of Veterinary Clinics, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), São Paulo, Brazil
- Blood Transfusion Center, Cell Engineering Laboratory, Botucatu Medical School, São Paulo State University (UNESP), São Paulo, Brazil
| | - Ana Lívia de Carvalho Bovolato
- Blood Transfusion Center, Cell Engineering Laboratory, Botucatu Medical School, São Paulo State University (UNESP), São Paulo, Brazil
| | - Fábio Sossai Possebon
- Department of Veterinary Hygiene and Public Health, College of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), São Paulo, Brazil
| | - Elenice Deffune
- Blood Transfusion Center, Cell Engineering Laboratory, Botucatu Medical School, São Paulo State University (UNESP), São Paulo, Brazil
| | - Rogério Martins Amorim
- Department of Veterinary Clinics, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), São Paulo, Brazil
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23
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Duffy P, McMahon S, Wang X, Keaveney S, O'Cearbhaill ED, Quintana I, Rodríguez FJ, Wang W. Synthetic bioresorbable poly-α-hydroxyesters as peripheral nerve guidance conduits; a review of material properties, design strategies and their efficacy to date. Biomater Sci 2019; 7:4912-4943. [DOI: 10.1039/c9bm00246d] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Implantable tubular devices known as nerve guidance conduits (NGCs) have drawn considerable interest as an alternative to autografting in the repair of peripheral nerve injuries.
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Affiliation(s)
- Patrick Duffy
- The Charles Institute of Dermatology
- School of Medicine
- University College Dublin
- Dublin
- Ireland
| | - Seán McMahon
- Ashland Specialties Ireland Ltd
- Synergy Centre
- Dublin
- Ireland
| | - Xi Wang
- The Charles Institute of Dermatology
- School of Medicine
- University College Dublin
- Dublin
- Ireland
| | - Shane Keaveney
- School of Mechanical & Materials Engineering
- UCD Centre for Biomedical Engineering
- UCD Conway Institute of Biomolecular and Biomedical Research
- University College Dublin
- Dublin
| | - Eoin D. O'Cearbhaill
- School of Mechanical & Materials Engineering
- UCD Centre for Biomedical Engineering
- UCD Conway Institute of Biomolecular and Biomedical Research
- University College Dublin
- Dublin
| | - Iban Quintana
- IK4-Tekniker
- Surface Engineering and Materials Science Unit
- Eibar
- Spain
| | | | - Wenxin Wang
- The Charles Institute of Dermatology
- School of Medicine
- University College Dublin
- Dublin
- Ireland
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24
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Petrova ES. Differentiation Potential of Mesenchymal Stem Cells and Stimulation of Nerve Regeneration. Russ J Dev Biol 2018. [DOI: 10.1134/s1062360418040033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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25
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Chan KM, Beveridge J, Webber CA. Adipose-derived stem cells: From mice to man. Muscle Nerve 2018; 58:186-188. [PMID: 29742793 DOI: 10.1002/mus.26154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 04/27/2018] [Accepted: 05/05/2018] [Indexed: 11/06/2022]
Affiliation(s)
- K Ming Chan
- Division of Physical Medicine and Rehabilitation, 5005, Katz Group Centre, University of Alberta, Edmonton, Alberta, Canada, T6G 2E1.,Division of Plastic Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Julie Beveridge
- Division of Plastic Surgery, University of Alberta, Edmonton, Alberta, Canada
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Salehi M, Naseri-Nosar M, Ebrahimi-Barough S, Nourani M, Khojasteh A, Farzamfar S, Mansouri K, Ai J. Polyurethane/Gelatin Nanofibrils Neural Guidance Conduit Containing Platelet-Rich Plasma and Melatonin for Transplantation of Schwann Cells. Cell Mol Neurobiol 2018; 38:703-713. [PMID: 28823058 PMCID: PMC11481952 DOI: 10.1007/s10571-017-0535-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 08/08/2017] [Indexed: 10/19/2022]
Abstract
The current study aimed to enhance the efficacy of peripheral nerve regeneration using a biodegradable porous neural guidance conduit as a carrier to transplant allogeneic Schwann cells (SCs). The conduit was prepared from polyurethane (PU) and gelatin nanofibrils (GNFs) using thermally induced phase separation technique and filled with melatonin (MLT) and platelet-rich plasma (PRP). The prepared conduit had the porosity of 87.17 ± 1.89%, the contact angle of 78.17 ± 5.30° and the ultimate tensile strength and Young's modulus of 5.40 ± 0.98 MPa and 3.13 ± 0.65 GPa, respectively. The conduit lost about 14% of its weight after 60 days in distilled water. The produced conduit enhanced the proliferation of SCs demonstrated by a tetrazolium salt-based assay. For functional analysis, the conduit was seeded with 1.50 × 104 SCs (PU/GNFs/PRP/MLT/SCs) and implanted into a 10-mm sciatic nerve defect of Wistar rat. Three control groups were used: (1) PU/GNFs/SCs, (2) PU/GNFs/PRP/SCs, and (3) Autograft. The results of sciatic functional index, hot plate latency, compound muscle action potential amplitude and latency, weight-loss percentage of wet gastrocnemius muscle and histopathological examination using hematoxylin-eosin and Luxol fast blue staining, demonstrated that using the PU/GNFs/PRP/MLT conduit to transplant SCs to the sciatic nerve defect resulted in a higher regenerative outcome than the PU/GNFs and PU/GNFs/PRP conduits.
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Affiliation(s)
- Majid Salehi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, P.O. Box 1417755469, Tehran, Iran
| | - Mahdi Naseri-Nosar
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, P.O. Box 1417755469, Tehran, Iran
| | - Somayeh Ebrahimi-Barough
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, P.O. Box 1417755469, Tehran, Iran
| | - Mohammdreza Nourani
- Nano Biotechnology Research Center, Baqiyatallah University of Medical Sciences, P.O. Box 1435944711, Tehran, Iran
| | - Arash Khojasteh
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, P.O. Box 1983969411, Tehran, Iran
| | - Saeed Farzamfar
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, P.O. Box 1417755469, Tehran, Iran
| | - Korosh Mansouri
- Department of Physical Medicine and Rehabilitation, Iran University of Medical Sciences, P.O. Box 14665354, Tehran, Iran
| | - Jafar Ai
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, P.O. Box 1417755469, Tehran, Iran.
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27
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Ozer H, Bozkurt H, Bozkurt G, Demirbilek M. Regenerative potential of chitosan-coated poly-3-hydroxybutyrate conduits seeded with mesenchymal stem cells in a rat sciatic nerve injury model. Int J Neurosci 2018; 128:828-834. [PMID: 29384433 DOI: 10.1080/00207454.2018.1435536] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVES A number of chemical and biological factors, including mesenchymal stem cells (MSCs), have been developed to enhance nerve regeneration by introduction through a variety of nerve conduits. This study was designed to assess the efficacy of using chitosan-coated poly-3-hydroxybutyrate (PHB) nerve conduits seeded with human bone marrow-derived MSCs (hMSC-bm) to augment repair in an experimental rat model of sciatic nerve injury. METHODS A total of 30 rats were randomly assigned to one of three groups (n = 10). In each rat, a 10 mm segment of the sciatic nerve was removed and was replaced by a chitosan-coated PHB conduit seeded with hMSC-bm (PHB/chitosan-hMSC-bm group), a chitosan-coated PHB conduit (PHB/chitosan group), or an autograft (autograft group) as the control. The results were evaluated 8 weeks postoperatively by observation, electromyography and histologic examination with light microscopy and immunostaining. RESULTS Histologic examination showed that both PHB/chitosan-hMSC-bm conduits and PHB/chitosan conduits led the damaged axons through the injured area. When the effects were compared, the results with the PHB/chitosan-hMSC-bm conduits were superior to those with the PHB/chitosan conduits (p < 0.05) but not as successful as with the autologous nerve grafts (p < 0.05). CONCLUSION PHB/chitosan-hMSC-bm nerve conduits may be a useful artificial guide for nerve regeneration.
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Affiliation(s)
- Hidir Ozer
- a Department of Neurosurgery , Hacettepe University Faculty of Medicine , Ankara , Turkey
| | - Huseyin Bozkurt
- b Department of Neurosurgery , Cumhuriyet University Faculty of Medicine , Sivas , Turkey
| | - Gokhan Bozkurt
- c Department of Neurosurgery , Memorial Private Hospital , Ankara , Turkey
| | - Murat Demirbilek
- d Advanced Technologies Application and Research Center , Hacettepe University , Ankara , Turkey
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28
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Gonzalez-Perez F, Hernández J, Heimann C, Phillips JB, Udina E, Navarro X. Schwann cells and mesenchymal stem cells in laminin- or fibronectin-aligned matrices and regeneration across a critical size defect of 15 mm in the rat sciatic nerve. J Neurosurg Spine 2018; 28:109-118. [DOI: 10.3171/2017.5.spine161100] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
OBJECTIVEArtificial nerve guides are being developed to substitute for autograft repair after peripheral nerve injuries. However, the use of conduits is limited by the length of the gap that needs to be bridged, with the success of regeneration highly compromised in long gaps. Addition of aligned proregenerative cells and extracellular matrix (ECM) components inside the conduit can be a good strategy to achieve artificial grafts that recreate the natural environment offered by a nerve graft. The purpose of this study was to functionalize chitosan devices with different cell types to support regeneration in limiting gaps in the rat peripheral nerve.METHODSThe authors used chitosan devices combined with proteins of the ECM and cells in a rat model of sciatic nerve injury. Combinations of fibronectin and laminin with mesenchymal stem cells (MSCs) or Schwann cells (SCs) were aligned within tethered collagen-based gels, which were placed inside chitosan tubes that were then used to repair a critical-size gap of 15 mm in the rat sciatic nerve. Electrophysiology and algesimetry tests were performed to analyze functional recovery during the 4 months after injury and repair. Histological analysis was performed at the midlevel and distal level of the tubes to assess the number of regenerated myelinated fibers.RESULTSFunctional analysis demonstrated that SC-aligned scaffolds resulted in 100% regeneration success in a 15-mm nerve defect in this rat model. In contrast, animals that underwent repair with MSC-aligned constructs had only 90% regeneration success, and those implanted with acellular bridges had only 75% regeneration success.CONCLUSIONSThese results indicate that the combination of chitosan conduits with ECM-enriched cellular gels represents a good alternative to the use of autografts for repairing long nerve gaps.
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Affiliation(s)
- Francisco Gonzalez-Perez
- 1Institute of Neurosciences and Department of Cell Biology, Physiology, and Immunology, Universitat Autònoma de Barcelona, and CIBERNED, Bellaterra, Spain
| | - Joaquim Hernández
- 1Institute of Neurosciences and Department of Cell Biology, Physiology, and Immunology, Universitat Autònoma de Barcelona, and CIBERNED, Bellaterra, Spain
| | | | - James B. Phillips
- 3Biomaterials & Tissue Engineering, UCL Eastman Dental Institute, University College London, United Kingdom
| | - Esther Udina
- 1Institute of Neurosciences and Department of Cell Biology, Physiology, and Immunology, Universitat Autònoma de Barcelona, and CIBERNED, Bellaterra, Spain
| | - Xavier Navarro
- 1Institute of Neurosciences and Department of Cell Biology, Physiology, and Immunology, Universitat Autònoma de Barcelona, and CIBERNED, Bellaterra, Spain
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29
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Fernandes M, Valente SG, Sabongi RG, Gomes dos Santos JB, Leite VM, Ulrich H, Nery AA, da Silva Fernandes MJ. Bone marrow-derived mesenchymal stem cells versus adipose-derived mesenchymal stem cells for peripheral nerve regeneration. Neural Regen Res 2018; 13:100-104. [PMID: 29451213 PMCID: PMC5840974 DOI: 10.4103/1673-5374.224378] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/16/2017] [Indexed: 12/15/2022] Open
Abstract
Studies have confirmed that bone marrow-derived mesenchymal stem cells (MSCs) can be used for treatment of several nervous system diseases. However, isolation of bone marrow-derived MSCs (BMSCs) is an invasive and painful process and the yield is very low. Therefore, there is a need to search for other alterative stem cell sources. Adipose-derived MSCs (ADSCs) have phenotypic and gene expression profiles similar to those of BMSCs. The production of ADSCs is greater than that of BMSCs, and ADSCs proliferate faster than BMSCs. To compare the effects of venous grafts containing BMSCs or ADSCs on sciatic nerve injury, in this study, rats were randomly divided into four groups: sham (only sciatic nerve exposed), Matrigel (MG; sciatic nerve injury + intravenous transplantation of MG vehicle), ADSCs (sciatic nerve injury + intravenous MG containing ADSCs), and BMSCs (sciatic nerve injury + intravenous MG containing BMSCs) groups. Sciatic functional index was calculated to evaluate the function of injured sciatic nerve. Morphologic characteristics of nerves distal to the lesion were observed by toluidine blue staining. Spinal motor neurons labeled with Fluoro-Gold were quantitatively assessed. Compared with sham-operated rats, sciatic functional index was lower, the density of small-diameter fibers was significantly increased, and the number of motor neurons significantly decreased in rats with sciatic nerve injury. Neither ADSCs nor BMSCs significantly improved the sciatic nerve function of rats with sciatic nerve injury, increased fiber density, fiber diameters, axonal diameters, myelin sheath thickness, and G ratios (axonal diameter/fiber diameter ratios) in the sciatic nerve distal to the lesion site. There was no significant difference in the number of spinal motor neurons among ADSCs, BMSCs and MG groups. These results suggest that neither BMSCs nor ADSCs provide satisfactory results for peripheral nerve repair when using MG as the conductor for engraftment.
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Affiliation(s)
- Marcela Fernandes
- Division of Hand and Upper Limb Surgery, Department of Orthopedics and Traumatology, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Sandra Gomes Valente
- Division of Hand and Upper Limb Surgery, Department of Orthopedics and Traumatology, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Rodrigo Guerra Sabongi
- Division of Hand and Upper Limb Surgery, Department of Orthopedics and Traumatology, Universidade Federal de São Paulo, São Paulo, Brazil
| | - João Baptista Gomes dos Santos
- Division of Hand and Upper Limb Surgery, Department of Orthopedics and Traumatology, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Vilnei Mattioli Leite
- Division of Hand and Upper Limb Surgery, Department of Orthopedics and Traumatology, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Henning Ulrich
- Department of Biochemistry, Institute of Chemistry, Universidade de São Paulo, São Paulo, Brazil
| | - Arthur Andrade Nery
- Department of Biochemistry, Institute of Chemistry, Universidade de São Paulo, São Paulo, Brazil
| | - Maria José da Silva Fernandes
- Division of Neurosciences, Department of Neurology and Neurosurgery, Universidade Federal de São Paulo, São Paulo, Brazil
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30
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Mohamadi F, Ebrahimi-Barough S, Nourani MR, Mansoori K, Salehi M, Alizadeh AA, Tavangar SM, Sefat F, Sharifi S, Ai J. Enhanced sciatic nerve regeneration by human endometrial stem cells in an electrospun poly (ε-caprolactone)/collagen/NBG nerve conduit in rat. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2017; 46:1731-1743. [DOI: 10.1080/21691401.2017.1391823] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- Forouzan Mohamadi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Somayeh Ebrahimi-Barough
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Nourani
- Nano Biotechnology Research Centre, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Korosh Mansoori
- Neuromusculoskletal Research Centre Firozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Majid Salehi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Akbar Alizadeh
- Department of Tissue Engineering and Applied Cell Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Mohammad Tavangar
- Department of Pathology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Farshid Sefat
- Department of Medical Engineering, School of Engineering, University of Bradford, Bradford, UK
| | - Siavash Sharifi
- Department of Veterinary Surgery and Radiology, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran
| | - Jafar Ai
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
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31
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Pinho AC, Fonseca AC, Serra AC, Santos JD, Coelho JFJ. Peripheral Nerve Regeneration: Current Status and New Strategies Using Polymeric Materials. Adv Healthc Mater 2016; 5:2732-2744. [PMID: 27600578 DOI: 10.1002/adhm.201600236] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Indexed: 12/16/2022]
Abstract
Experiments concerning peripheral nerve regeneration have been reported since the end of the 19th century. The need to implement an effective surgical procedure in terms of functional recovery has resulted in the appearance of several approaches to solve this problem. Nerve autograft was the first approach studied and is still considered the gold standard. Since autografts require donor harvesting, other strategies involving the use of natural materials have also been studied. Nevertheless, the results were not very encouraging and attention has moved towards the use of nerve conduits made from polymers, whose properties can be easily tailored and which allow the nerve conduit to be easily processed into a variety of shapes and forms. Some of these materials are already approved by the US Food and Drug Administration (FDA), as is presented here. Furthermore, polymers with conductive properties have very recently been subject to intensive study in this field, since it is believed that such properties have a positive influence in the regeneration of the new axons. This manuscript intends to give a global view of the mechanisms involved in peripheral nerve regeneration and the main strategies used to recover motor and sensorial function of injured nerves.
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Affiliation(s)
- Ana C. Pinho
- CEMUC Department of Chemical Engineering; University of Coimbra; Rua Sílvio Lima-Pólo II 3030-790 Coimbra Portugal
| | - Ana C. Fonseca
- CEMUC Department of Chemical Engineering; University of Coimbra; Rua Sílvio Lima-Pólo II 3030-790 Coimbra Portugal
| | - Arménio C. Serra
- CEMUC Department of Chemical Engineering; University of Coimbra; Rua Sílvio Lima-Pólo II 3030-790 Coimbra Portugal
| | - José D. Santos
- CEMUC Department of Metallurgical and Materials Engineering; University of Porto; Rua Dr Roberto Frias 4200-465 Porto Portugal
| | - Jorge F. J. Coelho
- CEMUC Department of Chemical Engineering; University of Coimbra; Rua Sílvio Lima-Pólo II 3030-790 Coimbra Portugal
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32
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Hofer HR, Tuan RS. Secreted trophic factors of mesenchymal stem cells support neurovascular and musculoskeletal therapies. Stem Cell Res Ther 2016; 7:131. [PMID: 27612948 PMCID: PMC5016979 DOI: 10.1186/s13287-016-0394-0] [Citation(s) in RCA: 255] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Adult mesenchymal stem cells (MSCs) represent a subject of intense experimental and biomedical interest. Recently, trophic activities of MSCs have become the topic of a number of revealing studies that span both basic and clinical fields. In this review, we focus on recent investigations that have elucidated trophic mechanisms and shed light on MSC clinical efficacy relevant to musculoskeletal applications. Innate differences due to MSC sourcing may play a role in the clinical utility of isolated MSCs. Pain management, osteochondral, nerve, or blood vessel support by MSCs derived from both autologous and allogeneic sources have been examined. Recent mechanistic insights into the trophic activities of these cells point to ultimate regulation by nitric oxide, nuclear factor-kB, and indoleamine, among other signaling pathways. Classic growth factors and cytokines-such as VEGF, CNTF, GDNF, TGF-β, interleukins (IL-1β, IL-6, and IL-8), and C-C ligands (CCL-2, CCL-5, and CCL-23)-serve as paracrine control molecules secreted or packaged into extracellular vesicles, or exosomes, by MSCs. Recent studies have also implicated signaling by microRNAs contained in MSC-derived exosomes. The response of target cells is further regulated by their microenvironment, involving the extracellular matrix, which may be modified by MSC-produced matrix metalloproteinases (MMPs) and tissue inhibitor of MMPs. Trophic activities of MSCs, either resident or introduced exogenously, are thus intricately controlled, and may be further fine-tuned via implant material modifications. MSCs are actively being investigated for the repair and regeneration of both osteochondral and other musculoskeletal tissues, such as tendon/ligament and meniscus. Future rational and effective MSC-based musculoskeletal therapies will benefit from better mechanistic understanding of MSC trophic activities, for example using analytical "-omics" profiling approaches.
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Affiliation(s)
- Heidi R Hofer
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Room 221, Pittsburgh, PA, 15219, USA
| | - Rocky S Tuan
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Room 221, Pittsburgh, PA, 15219, USA.
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Song YS, Joe JH, Joo HW, Park IH, Shen GY, Kim KJ, Lee Y, Shin JH, Kim H, Kim KS. The Effects of Granulocyte-Colony Stimulating Factor on Regeneration in Nerve Crush Injuries in Rats. Neurochem Res 2016; 41:1645-50. [PMID: 26980007 DOI: 10.1007/s11064-016-1879-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Revised: 02/03/2016] [Accepted: 02/26/2016] [Indexed: 11/25/2022]
Abstract
Granulocyte-colony stimulating factor (G-CSF) is widely known to have a neuroprotective effect, but its effects on function and morphology in mechanical nerve injury are not well understood. The aim of this study was to confirm the time course of the functional changes and morphological effects of G-CSF in a rat model of nerve crush injury. Twelve-eight rats were divided into three group: sham-operated control group, G-CSF-treated group, and saline treated group. 2 weeks after the nerve crush injury, G-CSF was injected for 5 days. After 4 weeks, functional tests such as motor nerve conduction velocity (MNCV), mechanical and cold allodynia tests, and morphological studies were performed. G-CSF-treated rats had significantly improved nerve function including MNCV and mechanical and cold allodynia. In addition, G-CSF-treated rats had significantly higher the density of myelinated fibers than saline-treated rats. In conclusion, we found that 100 μg/kg administration of G-CSF promoted long-term functional recovery in a rat model of nerve crush injury.
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Affiliation(s)
- Yi-Sun Song
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea
| | - Jun-Ho Joe
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea
| | - Hyun-Woo Joo
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea
| | - In-Hwa Park
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea
| | - Guang-Yin Shen
- Cardiology Division, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, South Korea
| | - Ki-Jun Kim
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea
| | - Yonggu Lee
- Department of Cardiology, Sungae Hospital, Seoul, South Korea
| | - Jeong Hun Shin
- Cardiology Division, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, South Korea
| | - Hyuck Kim
- Department of Thoracic and Cardiovascular Surgery, Hanyang University College of Medicine, Seoul, South Korea
| | - Kyung-Soo Kim
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea.
- Cardiology Division, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, South Korea.
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Man AJ, Kujawski G, Burns TS, Miller EN, Fierro FA, Leach JK, Bannerman P. Neurogenic potential of engineered mesenchymal stem cells overexpressing VEGF. Cell Mol Bioeng 2016; 9:96-106. [PMID: 27087859 PMCID: PMC4830493 DOI: 10.1007/s12195-015-0425-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Accepted: 12/08/2015] [Indexed: 02/04/2023] Open
Abstract
Numerous signaling molecules are altered following nerve injury, serving as a blueprint for drug delivery approaches that promote nerve repair. However, challenges with achieving the appropriate temporal duration of recombinant protein delivery have limited the therapeutic success of this approach. Genetic engineering of mesenchymal stem cells (MSCs) to enhance the secretion of proangiogenic molecules such as vascular endothelial growth factor (VEGF) may provide an alternative. We hypothesized that the administration of VEGF-expressing human MSCs would stimulate neurite outgrowth and proliferation of cell-types involved in neural repair. When cultured with dorsal root ganglion (DRG) explants in vitro, control and VEGF-expressing MSCs (VEGF-MSCs) increased neurite extension and proliferation of Schwann cells (SCs) and endothelial cells, while VEGF-MSCs stimulated significantly greater proliferation of endothelial cells. When embedded within a 3D fibrin matrix, VEGF-MSCs maintained overexpression and expressed detectable levels over 21 days. After transplantation into a murine sciatic nerve injury model, VEGF-MSCs maintained high VEGF levels for 2 weeks. This study provides new insight into the role of VEGF on peripheral nerve injury and the viability of transplanted genetically engineered MSCs. The study aims to provide a framework for future studies with the ultimate goal of developing an improved therapy for nerve repair.
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Affiliation(s)
- Alan J. Man
- Institute for Pediatric Regenerative Medicine, Shriners Hospital for Children Northern California, Sacramento, CA 95817
- Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616
| | - Gregory Kujawski
- Institute for Pediatric Regenerative Medicine, Shriners Hospital for Children Northern California, Sacramento, CA 95817
| | - Travis S. Burns
- Institute for Pediatric Regenerative Medicine, Shriners Hospital for Children Northern California, Sacramento, CA 95817
| | - Elaine N. Miller
- Institute for Pediatric Regenerative Medicine, Shriners Hospital for Children Northern California, Sacramento, CA 95817
| | - Fernando A. Fierro
- Institute of Regenerative Cures, University of California, Davis, Sacramento, CA 95817
| | - J. Kent Leach
- Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616
| | - Peter Bannerman
- Institute for Pediatric Regenerative Medicine, Shriners Hospital for Children Northern California, Sacramento, CA 95817
- Department of Cell Biology, UC Davis School of Medicine, UC Davis Medical Center, Sacramento, CA 95817
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Xu Y, Zhang Z, Chen X, Li R, Li D, Feng S. A Silk Fibroin/Collagen Nerve Scaffold Seeded with a Co-Culture of Schwann Cells and Adipose-Derived Stem Cells for Sciatic Nerve Regeneration. PLoS One 2016; 11:e0147184. [PMID: 26799619 PMCID: PMC4723261 DOI: 10.1371/journal.pone.0147184] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 12/30/2015] [Indexed: 11/19/2022] Open
Abstract
As a promising alternative to autologous nerve grafts, tissue-engineered nerve grafts have been extensively studied as a way to bridge peripheral nerve defects and guide nerve regeneration. The main difference between autogenous nerve grafts and tissue-engineered nerve grafts is the regenerative microenvironment formed by the grafts. If an appropriate regenerative microenvironment is provided, the repair of a peripheral nerve is feasible. In this study, to mimic the body's natural regenerative microenvironment closely, we co-cultured Schwann cells (SCs) and adipose-derived stem cells (ADSCs) as seed cells and introduced them into a silk fibroin (SF)/collagen scaffold to construct a tissue-engineered nerve conduit (TENC). Twelve weeks after the three different grafts (plain SF/collagen scaffold, TENC, and autograft) were transplanted to bridge 1-cm long sciatic nerve defects in rats, a series of electrophysiological examinations and morphological analyses were performed to evaluate the effect of the tissue-engineered nerve grafts on peripheral nerve regeneration. The regenerative outcomes showed that the effect of treatment with TENCs was similar to that with autologous nerve grafts but superior to that with plain SF/collagen scaffolds. Meanwhile, no experimental animals had inflammation around the grafts. Based on this evidence, our findings suggest that the TENC we developed could improve the regenerative microenvironment and accelerate nerve regeneration compared to plain SF/collagen and may serve as a promising strategy for peripheral nerve repair.
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Affiliation(s)
- Yunqiang Xu
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
- * E-mail:
| | - Zhenhui Zhang
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Xuyi Chen
- Department of Neurosurgery, Affiliated Brain Hospital of Armed Logistics, Tianjin, China
| | - Ruixin Li
- Institute of Medical Equipment, Academy of Military and Medical Sciences, Tianjin, China
| | - Dong Li
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Shiqing Feng
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
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Knowlton S, Cho Y, Li XJ, Khademhosseini A, Tasoglu S. Utilizing stem cells for three-dimensional neural tissue engineering. Biomater Sci 2016; 4:768-84. [DOI: 10.1039/c5bm00324e] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Three-dimensional neural tissue engineering has significantly advanced the development of neural disease models and replacement tissues for patients by leveraging the unique capabilities of stem cells.
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Affiliation(s)
| | - Yongku Cho
- Department of Chemical & Biomolecular Engineering
- University of Connecticut
- Storrs
- USA
| | - Xue-Jun Li
- Department of Neuroscience
- University of Connecticut Health Center
- Farmington
- USA
| | - Ali Khademhosseini
- Center for Biomedical Engineering
- Department of Medicine
- Brigham and Women's Hospital Harvard Medical School
- Harvard-MIT Division of Health Sciences and Technology Massachusetts Institute of Technology
- Cambridge
| | - Savas Tasoglu
- Department of Biomedical Engineering
- University of Connecticut
- Storrs
- USA
- Department of Mechanical Engineering
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Madhu V, Dighe AS, Cui Q, Deal DN. Dual Inhibition of Activin/Nodal/TGF-β and BMP Signaling Pathways by SB431542 and Dorsomorphin Induces Neuronal Differentiation of Human Adipose Derived Stem Cells. Stem Cells Int 2015; 2016:1035374. [PMID: 26798350 PMCID: PMC4699250 DOI: 10.1155/2016/1035374] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 09/03/2015] [Indexed: 12/16/2022] Open
Abstract
Damage to the nervous system can cause devastating diseases or musculoskeletal dysfunctions and transplantation of progenitor stem cells can be an excellent treatment option in this regard. Preclinical studies demonstrate that untreated stem cells, unlike stem cells activated to differentiate into neuronal lineage, do not survive in the neuronal tissues. Conventional methods of inducing neuronal differentiation of stem cells are complex and expensive. We therefore sought to determine if a simple, one-step, and cost effective method, previously reported to induce neuronal differentiation of embryonic stem cells and induced-pluripotent stem cells, can be applied to adult stem cells. Indeed, dual inhibition of activin/nodal/TGF-β and BMP pathways using SB431542 and dorsomorphin, respectively, induced neuronal differentiation of human adipose derived stem cells (hADSCs) as evidenced by formation of neurite extensions, protein expression of neuron-specific gamma enolase, and mRNA expression of neuron-specific transcription factors Sox1 and Pax6 and matured neuronal marker NF200. This process correlated with enhanced phosphorylation of p38, Erk1/2, PI3K, and Akt1/3. Additionally, in vitro subcutaneous implants of SB431542 and dorsomorphin treated hADSCs displayed significantly higher expression of active-axonal-growth-specific marker GAP43. Our data offers novel insights into cell-based therapies for the nervous system repair.
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Affiliation(s)
- Vedavathi Madhu
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA 22908, USA
| | - Abhijit S. Dighe
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA 22908, USA
| | - Quanjun Cui
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA 22908, USA
| | - D. Nicole Deal
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA 22908, USA
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Repair and regeneration of lumbosacral nerve defects in rats with chitosan conduits containing bone marrow mesenchymal stem cells. Injury 2015; 46:2156-63. [PMID: 26429103 DOI: 10.1016/j.injury.2015.08.035] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 08/07/2015] [Accepted: 08/25/2015] [Indexed: 02/02/2023]
Abstract
OBJECTIVES Despite the great progress in surgical treatment of lumbosacral nerve injuries caused by high-energy trauma, functional recovery remains poor and insufficient. Bone marrow mesenchymal stem cells (BMSCs), which express neurotrophic factors and can also differentiate into nerve cells, have potential as an effective alternative therapy for lumbosacral nerve defects. The aim of the present study was to evaluate the functional recovery, nerve regeneration, motor neuron survival and apoptosis after lumbosacral nerve transection in rats receiving BMSC transplantation into the chitosan conduit. METHODS The right L4-L6 nerve roots of rats were transected and bridged with three 1-cm-long chitosan conduits, which were further injected with the BMSCs (MSC-treated group) or culture medium (DMEM group). The nerve regeneration and motor function recovery were assessed by the sciatic functional index (SFI) and analysed electrophysiologically and morphologically. RESULTS At 6 and 12 weeks after surgery, the SFI values in MSC-treated group were significantly higher than those in DMEM group (P≤0.05). The peak amplitude of CMAP (compound muscle action potential) and nerve conduction velocity in MSC-treated group were significantly higher than that in DMEM group (P≤0.01), while the latency of CMAP onset in MSC-treated group was significantly shorter than that in DMEM group (P≤0.01). The diameter of the myelinated fibres and thickness of the myelin sheath in MSC-treated group were significantly higher than those in DMEM group (P≤0.05). There was no difference in the number of motor neurons in the anterior horn of the spinal cord at 6 weeks post-operation (P>0.05), while the number of motor neurons was significantly greater in MSC-treated group than that in DMEM group at 12 weeks post-operation (P≤0.001). The number of apoptotic cells was also significantly lower (P≤0.01). CONCLUSIONS The results of the present study showed that BMSCs treatment improved lumbosacral nerve regeneration and motor function. In addition, our data suggested that BMSCs inhibited motor neuron apoptosis, and improved motor neuron function and survival in the anterior horn of the spinal cord.
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Goulart CO, Lopes FRP, Monte ZO, Dantas SV, Souto A, Oliveira JT, Almeida FM, Tonda-Turo C, Pereira CC, Borges CP, Martinez AMB. Evaluation of biodegradable polymer conduits--poly(L-lactic acid)--for guiding sciatic nerve regeneration in mice. Methods 2015; 99:28-36. [PMID: 26361830 DOI: 10.1016/j.ymeth.2015.09.008] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Revised: 07/26/2015] [Accepted: 09/08/2015] [Indexed: 01/08/2023] Open
Abstract
Polymeric biomaterials are often used for stimulating nerve regeneration. Among different conduits, poly(lactide acid) - PLA polymer is considered to be a good substrate due to its biocompatibility and resorbable characteristics. This polymer is an aliphatic polyester which has been mostly used in biomedical application. It is an organic compound with low allergenic potential, low toxicity, high biocompatibility and predictable kinetics of degradation. In this study we fabricated and evaluated a PLA microporous hollow fiber as a conduit for its ability to bridge a nerve gap in a mouse sciatic nerve injury model. The PLA conduit was prepared from a polymer solution, throughout extrusion technique. The left sciatic nerve of C57BL/6 mouse was transected and the nerve stumps were placed into a resorbable PLA (PLA group) or a PCL conduit (PCL group), n=5 each group. We have also used another group in which the nerves were repaired by autograft (autograft group, n=5). Motor function was analyzed according to sciatic functional index (SFI). After 56days, the regenerated nerves were processed for light and electron microscopy and morphometric analyses were performed. A quantitative analysis of regenerated nerves showed significant increase in the number of myelinated fibers and blood vessels in animals that received PLA conduit. The PLA group exhibited better overall tissue organization compared to other groups. Presenting well-organized bundles, many regenerating clusters composed of preserved nerve fibers surrounded by layers of compacted perineurium-like cells. Also the SFI revealed a significant improvement in functional recovery. This work suggests that PLA conduits are suitable substrate for cell survival and it provides an effective strategy to be used to support axonal growth becoming a potential alternative to autograft.
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Affiliation(s)
- Camila Oliveira Goulart
- Pós Graduação em Anatomia Patológica, Faculdade de Medicina, HUCFF, UFRJ, Rio de Janeiro, RJ, Brazil; Laboratório de Neurodegeneração e Reparo, Faculdade de Medicina, HUCFF, UFRJ, Rio de Janeiro, RJ, Brazil
| | | | - Zulmira Oliveira Monte
- Laboratório de Neurodegeneração e Reparo, Faculdade de Medicina, HUCFF, UFRJ, Rio de Janeiro, RJ, Brazil; Departamento de Morfologia, UFPI, Piauí, PI, Brazil
| | - Severino Valentim Dantas
- Pós Graduação em Anatomia Patológica, Faculdade de Medicina, HUCFF, UFRJ, Rio de Janeiro, RJ, Brazil
| | - Allana Souto
- Laboratório de Neurodegeneração e Reparo, Faculdade de Medicina, HUCFF, UFRJ, Rio de Janeiro, RJ, Brazil
| | - Júlia Teixeira Oliveira
- Laboratório de Neurodegeneração e Reparo, Faculdade de Medicina, HUCFF, UFRJ, Rio de Janeiro, RJ, Brazil
| | - Fernanda Martins Almeida
- Laboratório de Neurodegeneração e Reparo, Faculdade de Medicina, HUCFF, UFRJ, Rio de Janeiro, RJ, Brazil; Pólo Universitário Macaé, UFRJ, Macaé, RJ, Brazil
| | | | | | | | - Ana Maria Blanco Martinez
- Pós Graduação em Anatomia Patológica, Faculdade de Medicina, HUCFF, UFRJ, Rio de Janeiro, RJ, Brazil; Laboratório de Neurodegeneração e Reparo, Faculdade de Medicina, HUCFF, UFRJ, Rio de Janeiro, RJ, Brazil.
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Carrier-Ruiz A, Evaristo-Mendonça F, Mendez-Otero R, Ribeiro-Resende VT. Biological behavior of mesenchymal stem cells on poly-ε-caprolactone filaments and a strategy for tissue engineering of segments of the peripheral nerves. Stem Cell Res Ther 2015; 6:128. [PMID: 26149068 PMCID: PMC4522087 DOI: 10.1186/s13287-015-0121-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2015] [Revised: 06/10/2015] [Accepted: 06/26/2015] [Indexed: 12/14/2022] Open
Abstract
Introduction Peripheral nerves may fail to regenerate across tube implants because these lack the microarchitecture of native nerves. Bone marrow mesenchymal stem cells (MSC) secrete soluble factors that improve the regeneration of the peripheral nerves. Also, microstructured poly-caprolactone (PCL) filaments are capable of inducing bands of Büngner and promote regeneration in the peripheral nervous system (PNS). We describe here the interaction between PCL filaments and MSC, aiming to optimize PNS tubular implants. Methods MSC were plated on PCL filaments for 48 h and the adhesion profile, viability, proliferation and paracrine capacity were evaluated. Also, Schwann cells were plated on PCL filaments covered with MSC for 24 h to analyze the feasibility of the co-culture system. Moreover, E16 dorsal root ganglia were plated in contact with PCL filaments for 4 days to analyze neurite extension. Right sciatic nerves were exposed and a 10 mm nerve segment was removed. Distal and proximal stumps were reconnected inside a 14-mm polyethylene tube, leaving a gap of approximately 13 mm between the two stumps. Animals then received phosphate-buffered saline 1×, PCL filaments or PCL filaments previously incubated with MSC and, after 12 weeks, functional gait performance and histological analyses were made. Statistical analyses were made using Student’s unpaired t-test, one-way analysis of variance (ANOVA) or two-way ANOVA followed by Bonferroni post-test. Results MSC were confined to lateral areas and ridges of PCL filaments, aligning along the longitudinal. MSC showed high viability (90 %), and their proliferation and secretion capabilities were not completely inhibited by the filaments. Schwann cells adhered to filaments plated with MSC, maintaining high viability (90 %). Neurites grew and extended over the surface of PCL filaments, reaching greater distances when over MSC-plated filaments. Axons showed more organized and myelinized fibers and reinnervated significantly more muscle fibers when they were previously implanted with MSC-covered PLC filaments. Moreover, animals with MSC-covered filaments showed increased functional recovery after 12 weeks. Conclusions We provide evidence for the interaction among MSC, Schwann cells and PCL filaments, and we also demonstrate that this system can constitute a stable and permissive support for regeneration of segments of the peripheral nerves. Electronic supplementary material The online version of this article (doi:10.1186/s13287-015-0121-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- A Carrier-Ruiz
- Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Laboratório de Neuroquímica, Centro de Ciências da Saúde Bl. C, Cidade Universitária, 21949-900, Rio de Janeiro, RJ, Brazil. .,Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Laboratório de Neurobiologia Celular e Molecular, Centro de Ciências da Saúde Bl. G Cidade Universitária, 21949-900, Rio de Janeiro, RJ, Brazil.
| | - F Evaristo-Mendonça
- Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Laboratório de Neuroquímica, Centro de Ciências da Saúde Bl. C, Cidade Universitária, 21949-900, Rio de Janeiro, RJ, Brazil. .,Universidade Federal do Rio de Janeiro, Núcleo Multidisciplinar de Pesquisa em Biologia - Numpex-Bio, Pólo de Xerém, Estrada de Xerém, N° 27, CEP: 25245-390, Duque de Caxias, RJ, Brazil.
| | - R Mendez-Otero
- Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Laboratório de Neurobiologia Celular e Molecular, Centro de Ciências da Saúde Bl. G Cidade Universitária, 21949-900, Rio de Janeiro, RJ, Brazil.
| | - V T Ribeiro-Resende
- Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Laboratório de Neuroquímica, Centro de Ciências da Saúde Bl. C, Cidade Universitária, 21949-900, Rio de Janeiro, RJ, Brazil. .,Universidade Federal do Rio de Janeiro, Núcleo Multidisciplinar de Pesquisa em Biologia - Numpex-Bio, Pólo de Xerém, Estrada de Xerém, N° 27, CEP: 25245-390, Duque de Caxias, RJ, Brazil. .,Programa de Neurobiologia, Instituto de Biofísica Carlos Chagas Filho, UFRJ, Centro de Ciências da Saúde, Bloco C, Cidade Universitária, 21941-902, Rio de Janeiro, Brazil.
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Zhu W, Masood F, O'Brien J, Zhang LG. Highly aligned nanocomposite scaffolds by electrospinning and electrospraying for neural tissue regeneration. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2015; 11:693-704. [DOI: 10.1016/j.nano.2014.12.001] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Revised: 10/19/2014] [Accepted: 12/04/2014] [Indexed: 10/24/2022]
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Anderson M, Shelke NB, Manoukian OS, Yu X, McCullough LD, Kumbar SG. Peripheral Nerve Regeneration Strategies: Electrically Stimulating Polymer Based Nerve Growth Conduits. Crit Rev Biomed Eng 2015; 43:131-59. [PMID: 27278739 PMCID: PMC5266796 DOI: 10.1615/critrevbiomedeng.2015014015] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Treatment of large peripheral nerve damages ranges from the use of an autologous nerve graft to a synthetic nerve growth conduit. Biological grafts, in spite of many merits, show several limitations in terms of availability and donor site morbidity, and outcomes are suboptimal due to fascicle mismatch, scarring, and fibrosis. Tissue engineered nerve graft substitutes utilize polymeric conduits in conjunction with cues both chemical and physical, cells alone and or in combination. The chemical and physical cues delivered through polymeric conduits play an important role and drive tissue regeneration. Electrical stimulation (ES) has been applied toward the repair and regeneration of various tissues such as muscle, tendon, nerve, and articular tissue both in laboratory and clinical settings. The underlying mechanisms that regulate cellular activities such as cell adhesion, proliferation, cell migration, protein production, and tissue regeneration following ES is not fully understood. Polymeric constructs that can carry the electrical stimulation along the length of the scaffold have been developed and characterized for possible nerve regeneration applications. We discuss the use of electrically conductive polymers and associated cell interaction, biocompatibility, tissue regeneration, and recent basic research for nerve regeneration. In conclusion, a multifunctional combinatorial device comprised of biomaterial, structural, functional, cellular, and molecular aspects may be the best way forward for effective peripheral nerve regeneration.
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Affiliation(s)
- Matthew Anderson
- Department of Orthopaedic Surgery, UConn Health, Farmington, CT
- Institute for Regenerative Engineering, UConn Health, Farmington, CT
- Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, UConn Health, Farmington, CT
| | - Namdev B. Shelke
- Department of Orthopaedic Surgery, UConn Health, Farmington, CT
- Institute for Regenerative Engineering, UConn Health, Farmington, CT
- Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, UConn Health, Farmington, CT
| | - Ohan S. Manoukian
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT
| | - Xiaojun Yu
- Department of Chemistry, Chemical Biology and Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ
| | | | - Sangamesh G. Kumbar
- Department of Orthopaedic Surgery, UConn Health, Farmington, CT
- Institute for Regenerative Engineering, UConn Health, Farmington, CT
- Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, UConn Health, Farmington, CT
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT
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Arslantunali D, Dursun T, Yucel D, Hasirci N, Hasirci V. Peripheral nerve conduits: technology update. MEDICAL DEVICES-EVIDENCE AND RESEARCH 2014; 7:405-24. [PMID: 25489251 PMCID: PMC4257109 DOI: 10.2147/mder.s59124] [Citation(s) in RCA: 102] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Peripheral nerve injury is a worldwide clinical problem which could lead to loss of neuronal communication along sensory and motor nerves between the central nervous system (CNS) and the peripheral organs and impairs the quality of life of a patient. The primary requirement for the treatment of complete lesions is a tension-free, end-to-end repair. When end-to-end repair is not possible, peripheral nerve grafts or nerve conduits are used. The limited availability of autografts, and drawbacks of the allografts and xenografts like immunological reactions, forced the researchers to investigate and develop alternative approaches, mainly nerve conduits. In this review, recent information on the various types of conduit materials (made of biological and synthetic polymers) and designs (tubular, fibrous, and matrix type) are being presented.
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Affiliation(s)
- D Arslantunali
- BIOMATEN, Center of Excellence in Biomaterials and Tissue Engineering, Middle East Technical University (METU), Ankara, Turkey ; Department of Biotechnology, METU, Ankara, Turkey ; Department of Bioengineering, Gumushane University, Gumushane, Turkey
| | - T Dursun
- BIOMATEN, Center of Excellence in Biomaterials and Tissue Engineering, Middle East Technical University (METU), Ankara, Turkey ; Department of Biotechnology, METU, Ankara, Turkey
| | - D Yucel
- BIOMATEN, Center of Excellence in Biomaterials and Tissue Engineering, Middle East Technical University (METU), Ankara, Turkey ; Faculty of Engineering, Department of Medical Engineering, Acibadem University, Istanbul, Turkey ; School of Medicine, Department of Histology and Embryology, Acibadem University, Istanbul, Turkey
| | - N Hasirci
- BIOMATEN, Center of Excellence in Biomaterials and Tissue Engineering, Middle East Technical University (METU), Ankara, Turkey ; Department of Biotechnology, METU, Ankara, Turkey ; Department of Chemistry, Faculty of Arts and Sciences, METU, Ankara, Turkey
| | - V Hasirci
- BIOMATEN, Center of Excellence in Biomaterials and Tissue Engineering, Middle East Technical University (METU), Ankara, Turkey ; Department of Biotechnology, METU, Ankara, Turkey ; Department of Biological Sciences, Faculty of Arts and Sciences, METU, Ankara, Turkey
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Oliveira JT, Bittencourt-Navarrete RE, de Almeida FM, Tonda-Turo C, Martinez AMB, Franca JG. Enhancement of median nerve regeneration by mesenchymal stem cells engraftment in an absorbable conduit: improvement of peripheral nerve morphology with enlargement of somatosensory cortical representation. Front Neuroanat 2014; 8:111. [PMID: 25360086 PMCID: PMC4199278 DOI: 10.3389/fnana.2014.00111] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 09/18/2014] [Indexed: 12/12/2022] Open
Abstract
We studied the morphology and the cortical representation of the median nerve (MN), 10 weeks after a transection immediately followed by treatment with tubulization using a polycaprolactone (PCL) conduit with or without bone marrow-derived mesenchymal stem cell (MSC) transplant. In order to characterize the cutaneous representation of MN inputs in primary somatosensory cortex (S1), electrophysiological cortical mapping of the somatosensory representation of the forepaw and adjacent body parts was performed after acute lesion of all brachial plexus nerves, except for the MN. This was performed in ten adult male Wistar rats randomly assigned in three groups: MN Intact (n = 4), PCL-Only (n = 3), and PCL+MSC (n = 3). Ten weeks before mapping procedures in animals from PCL-Only and PCL+MSC groups, animal were subjected to MN transection with removal of a 4-mm-long segment, immediately followed by suturing a PCL conduit to the nerve stumps with (PCL+MSC group) or without (PCL-Only group) injection of MSC into the conduit. After mapping the representation of the MN in S1, animals had a segment of the regenerated nerve processed for light and transmission electron microscopy. For histomorphometric analysis of the nerve segment, sample size was increased to five animals per experimental group. The PCL+MSC group presented a higher number of myelinated fibers and a larger cortical representation of MN inputs in S1 (3,383 ± 390 fibers; 2.3 mm2, respectively) than the PCL-Only group (2,226 ± 575 fibers; 1.6 mm2). In conclusion, MSC-based therapy associated with PCL conduits can improve MN regeneration. This treatment seems to rescue the nerve representation in S1, thus minimizing the stabilization of new representations of adjacent body parts in regions previously responsive to the MN.
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Affiliation(s)
- Julia T Oliveira
- Laboratório de Neurodegeneração e Reparo, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil
| | | | - Fernanda M de Almeida
- Laboratório de Neurodegeneração e Reparo, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil ; Universidade Federal do Rio de Janeiro Macaé, Brazil
| | - Chiara Tonda-Turo
- Department of Mechanical and Aerospace Engineering, Politecnico di Torino Torino, Italy
| | - Ana Maria B Martinez
- Laboratório de Neurodegeneração e Reparo, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil ; Departamento de Anatomia Patológica, Faculdade de Medicina, e Pós Graduação em Anatomia Patológica, Centro de Ciências da Saúde, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil
| | - João G Franca
- Programa de Neurobiologia, Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil
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A combination of Schwann-cell grafts and aerobic exercise enhances sciatic nerve regeneration. PLoS One 2014; 9:e110090. [PMID: 25333892 PMCID: PMC4198198 DOI: 10.1371/journal.pone.0110090] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Accepted: 09/15/2014] [Indexed: 01/28/2023] Open
Abstract
Background Despite the regenerative potential of the peripheral nervous system, severe nerve lesions lead to loss of target-organ innervation, making complete functional recovery a challenge. Few studies have given attention to combining different approaches in order to accelerate the regenerative process. Objective Test the effectiveness of combining Schwann-cells transplantation into a biodegradable conduit, with treadmill training as a therapeutic strategy to improve the outcome of repair after mouse nerve injury. Methods Sciatic nerve transection was performed in adult C57BL/6 mice; the proximal and distal stumps of the nerve were sutured into the conduit. Four groups were analyzed: acellular grafts (DMEM group), Schwann cell grafts (3×105/2 µL; SC group), treadmill training (TMT group), and treadmill training and Schwann cell grafts (TMT + SC group). Locomotor function was assessed weekly by Sciatic Function Index and Global Mobility Test. Animals were anesthetized after eight weeks and dissected for morphological analysis. Results Combined therapies improved nerve regeneration, and increased the number of myelinated fibers and myelin area compared to the DMEM group. Motor recovery was accelerated in the TMT + SC group, which showed significantly better values in sciatic function index and in global mobility test than in the other groups. The TMT + SC group showed increased levels of trophic-factor expression compared to DMEM, contributing to the better functional outcome observed in the former group. The number of neurons in L4 segments was significantly higher in the SC and TMT + SC groups when compared to DMEM group. Counts of dorsal root ganglion sensory neurons revealed that TMT group had a significant increased number of neurons compared to DMEM group, while the SC and TMT + SC groups had a slight but not significant increase in the total number of motor neurons. Conclusion These data provide evidence that this combination of therapeutic strategies can significantly improve functional and morphological recovery after sciatic injury.
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Tseng TC, Yen CT, Hsu SH. Visualization of peripheral nerve regeneration. Neural Regen Res 2014; 9:997-9. [PMID: 25206750 PMCID: PMC4146305 DOI: 10.4103/1673-5374.133157] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/30/2014] [Indexed: 11/20/2022] Open
Affiliation(s)
- Ting-Chen Tseng
- Institute of Polymer Science and Engineering, National Taiwan University, Taipei, Taiwan, China
| | - Chen-Tung Yen
- Department of Life Science, National Taiwan University, Taipei, Taiwan, China
| | - Shan-Hui Hsu
- Institute of Polymer Science and Engineering, National Taiwan University, Taipei, Taiwan, China ; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan, China
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Oliveira JT, Mostacada K, de Lima S, Martinez AMB. Bone marrow mesenchymal stem cell transplantation for improving nerve regeneration. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2014; 108:59-77. [PMID: 24083431 DOI: 10.1016/b978-0-12-410499-0.00003-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Although the peripheral nervous system has an inherent capacity for regeneration, injuries to nerves still result in considerable disabilities. The persistence of these disabilities along with the underlying problem of nerve reconstruction has motivated neuroscientists worldwide to seek additional therapeutic strategies. In recent years, cell-based therapy has emerged as a promising therapeutic tool. Schwann cells (SCs) are the main supportive cells for peripheral nerve regeneration; however, there are several technical limitations regarding its application for cell-based therapy. In this context, bone marrow mesenchymal stem cells (BM-MSCs) have been used as alternatives to SCs for treating peripheral neuropathies, showing great promise. Several studies have been trying to shed light on the mechanisms behind the nerve regeneration-promotion potential of BM-MSCs. Although not completely clarified, understanding how BM-MSCs exert tissue repair effects will facilitate their development as therapeutic agents before they become a clinically viable tool for encouraging peripheral nerve regeneration.
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Affiliation(s)
- Júlia Teixeira Oliveira
- Programa de Neurociência Básica e Clínica, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
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Martinez AMB, Goulart CDO, Ramalho BDS, Oliveira JT, Almeida FM. Neurotrauma and mesenchymal stem cells treatment: From experimental studies to clinical trials. World J Stem Cells 2014; 6:179-94. [PMID: 24772245 PMCID: PMC3999776 DOI: 10.4252/wjsc.v6.i2.179] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 02/26/2014] [Accepted: 03/11/2014] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cell (MSC) therapy has attracted the attention of scientists and clinicians around the world. Basic and pre-clinical experimental studies have highlighted the positive effects of MSC treatment after spinal cord and peripheral nerve injury. These effects are believed to be due to their ability to differentiate into other cell lineages, modulate inflammatory and immunomodulatory responses, reduce cell apoptosis, secrete several neurotrophic factors and respond to tissue injury, among others. There are many pre-clinical studies on MSC treatment for spinal cord injury (SCI) and peripheral nerve injuries. However, the same is not true for clinical trials, particularly those concerned with nerve trauma, indicating the necessity of more well-constructed studies showing the benefits that cell therapy can provide for individuals suffering the consequences of nerve lesions. As for clinical trials for SCI treatment the results obtained so far are not as beneficial as those described in experimental studies. For these reasons basic and pre-clinical studies dealing with MSC therapy should emphasize the standardization of protocols that could be translated to the clinical set with consistent and positive outcomes. This review is based on pre-clinical studies and clinical trials available in the literature from 2010 until now. At the time of writing this article there were 43 and 36 pre-clinical and 19 and 1 clinical trials on injured spinal cord and peripheral nerves, respectively.
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Affiliation(s)
- Ana Maria Blanco Martinez
- Ana Maria Blanco Martinez, Camila de Oliveira Goulart, Bruna dos Santos Ramalho, Júlia Teixeira Oliveira, Fernanda Martins Almeida, Laboratory of Neurodegeneration and Repair, Institute of Biomedical Sciences, Health Science Center, 21941-902, Rio de Janeiro, Brazil
| | - Camila de Oliveira Goulart
- Ana Maria Blanco Martinez, Camila de Oliveira Goulart, Bruna dos Santos Ramalho, Júlia Teixeira Oliveira, Fernanda Martins Almeida, Laboratory of Neurodegeneration and Repair, Institute of Biomedical Sciences, Health Science Center, 21941-902, Rio de Janeiro, Brazil
| | - Bruna Dos Santos Ramalho
- Ana Maria Blanco Martinez, Camila de Oliveira Goulart, Bruna dos Santos Ramalho, Júlia Teixeira Oliveira, Fernanda Martins Almeida, Laboratory of Neurodegeneration and Repair, Institute of Biomedical Sciences, Health Science Center, 21941-902, Rio de Janeiro, Brazil
| | - Júlia Teixeira Oliveira
- Ana Maria Blanco Martinez, Camila de Oliveira Goulart, Bruna dos Santos Ramalho, Júlia Teixeira Oliveira, Fernanda Martins Almeida, Laboratory of Neurodegeneration and Repair, Institute of Biomedical Sciences, Health Science Center, 21941-902, Rio de Janeiro, Brazil
| | - Fernanda Martins Almeida
- Ana Maria Blanco Martinez, Camila de Oliveira Goulart, Bruna dos Santos Ramalho, Júlia Teixeira Oliveira, Fernanda Martins Almeida, Laboratory of Neurodegeneration and Repair, Institute of Biomedical Sciences, Health Science Center, 21941-902, Rio de Janeiro, Brazil
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Xu FT, Li HM, Yin QS, Cui SE, Liu DL, Nan H, Han ZA, Xu KM. Effect of ginsenoside Rg1 on proliferation and neural phenotype differentiation of human adipose-derived stem cells in vitro. Can J Physiol Pharmacol 2014; 92:467-75. [PMID: 24873669 DOI: 10.1139/cjpp-2013-0377] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
AIMS To investigate whether ginsenoside Rg1 can promote neural phenotype differentiation of human adipose-derived stem cells (hASCs) in vitro. METHODS hASCs were isolated from lipo-aspirates, and characterized by specific cell markers and multilineage differentiation capacity after culturing to the 3rd passage. Cultured hASCs were treated with neural inductive media alone (group A, control) or inductive media plus 10, 50, or 100 μg/mL ginsenoside Rg1 (groups B, C, and D, respectively). Cell proliferation was assessed by CCK-8 assay. Neuron specific enolase (NSE) and microtubule-associated protein-2 (MAP-2) levels were measured by Western blot. mRNA levels of growth associated protein-43 (GAP-43), neural cell adhesion molecule (NCAM), and synapsin-1 (SYN-1) were determined by real-time PCR. RESULTS Ginsenoside Rg1 promoted the proliferation of hASCs (groups B, C, and D) and resulted in higher expression of NSE and MAP-2 compared with the control group. Gene expression levels of GAP-43, NCAM, and SYN-1 in the test groups were higher than that in thw control. The results displayed a dose-dependent effect of ginsenoside Rg1 on cell proliferation and neural phenotype differentiation. CONCLUSION This study indicated that ginsenoside Rg1 promotes cell proliferation and neural phenotype differentiation of hASCs in vitro, suggesting a potential use for hASCs in neural regeneration medicine.
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Affiliation(s)
- Fang-Tian Xu
- a Southern Medical University, Guangzhou 510515, China
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Substrate-mediated nanoparticle/gene delivery to MSC spheroids and their applications in peripheral nerve regeneration. Biomaterials 2014; 35:2630-41. [DOI: 10.1016/j.biomaterials.2013.12.021] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Accepted: 12/12/2013] [Indexed: 12/27/2022]
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