|
1
|
Chen SJ, Lin CM, Liu CH, Chen YH, Hsieh YL, Lin YC, Chu YH, Ku CY, Liao WL, Liao WC. Accelerated peripheral nerve repair using surface-modified biomaterials for targeted capture of glial-derived growth factors post-neurorrhaphy. PLoS One 2025; 20:e0319979. [PMID: 40215229 PMCID: PMC11990746 DOI: 10.1371/journal.pone.0319979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 02/11/2025] [Indexed: 04/14/2025] Open
Abstract
Peripheral nerve injury (PNI) commonly leads to motor or sensory dysfunction, with nerve grafts being the standard treatment for neurorrhaphy. Despite advancements in biomaterials for nerve-tissue engineering, the rate of nerve regeneration remains slow. Therefore, this study aims to improve further the understanding of the impact of syndecan-3 (SDC3)-modified small intestine submucosa (SIS) on nerve reconstruction by employing two advanced approaches: cation recruitment and local growth factor delivery. Immunofluorescence staining confirmed the presence of SDC3 conjugated on the SIS. The enzyme-linked immunosorbent assay measured sustained glial cell line-derived neurotrophic factor (GDNF) levels in the SDC3-coated SIS. In vitro studies showed that SDC3-coated SIS retained GDNF in a dose-dependent manner, significantly enhancing Schwann cell proliferation compared with basal conditions. RSC96 cells proliferated most effectively on SDC3-coated SIS loaded with GDNF, and neuro-2A neurites were significantly longer on this material at 48 hours. One-month post-neurorrhaphy, morphological analysis revealed a 1.6 ± 0.02-fold increase in the number of β3-tubulin-positive axons in the GDNF+SDC3-coated SIS group compared to the SIS group. CMAP amplitude increases in the GDNF+SDC3-coated SIS group as more functioning motor axons are connected to the target muscle of ESN rats. This study provides valuable insights into the development of customized SDC3-coated SIS for promoting nerve tissue regeneration and accelerating rehabilitation.
Collapse
Affiliation(s)
- Shiu-Jau Chen
- Department of Medicine, MacKay Medical College, New Taipei, Taiwan
- Department of Neurosurgery, MacKay Memorial Hospital, Taipei, Taiwan
| | - Chih-Ming Lin
- Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Chiung-Hui Liu
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
- Doctoral Program in Tissue Engineering and Regenerative Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Yin-Hsiu Chen
- Department of Anatomy, Faculty of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Yu-Lin Hsieh
- School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - You-Cheng Lin
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yin-Hung Chu
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Chung-Yao Ku
- Department of Anatomy, Faculty of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Wei-Li Liao
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Wen-Chieh Liao
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
- Doctoral Program in Tissue Engineering and Regenerative Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
| |
Collapse
|
|
2
|
Yergeshov A, Zoughaib M, Dayob K, Kamalov M, Luong D, Zakirova A, Mullin R, Salakhieva D, Abdullin TI. Newly Designed PCL-Wrapped Cryogel-Based Conduit Activated with IKVAV Peptide Derivative for Peripheral Nerve Repair. Pharmaceutics 2024; 16:1569. [PMID: 39771548 PMCID: PMC11677967 DOI: 10.3390/pharmaceutics16121569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 11/08/2024] [Accepted: 12/05/2024] [Indexed: 01/11/2025] Open
Abstract
Background: The combination of macroporous cryogels with synthetic peptide factors represents a promising but poorly explored strategy for the development of extracellular matrix (ECM)-mimicking scaffolds for peripheral nerve (PN) repair. Methods: In this study, IKVAV peptide was functionalized with terminal lysine residues to allow its in situ cross-linking with gelatin macromer, resulting in the formation of IKVAV-containing proteinaceous cryogels. The controllable inclusion and distribution of the peptide molecules within the scaffold was verified using a fluorescently labelled peptide counterpart. The optimized cryogel scaffold was combined with polycaprolactone (PCL)-based shell tube to form a suturable nerve conduit (NC) to be implanted into sciatic nerve diastasis in rats. Results: The NC constituents did not impair the viability of primary skin fibroblasts. Concentration-dependent effects of the peptide component on interrelated viscoelastic and swelling properties of the cryogels as well as on proliferation and morphological differentiation of neurogenic PC-12 cells were established, also indicating the existence of an optimal-density range of the introduced peptide. The in vivo implanted NC sustained the connection of the nerve stumps with partial degradation of the PCL tube over eight weeks, whereas the core-filling cryogel profoundly improved local electromyographic recovery and morphological repair of the nerve tissues, confirming the regenerative activity of the developed scaffold. Conclusions: These results provide proof-of-concept for the development of a newly designed PN conduit prototype based on IKVAV-activated cryogel, and they can be exploited to create other ECM-mimicking scaffolds.
Collapse
Affiliation(s)
- Abdulla Yergeshov
- Scientific and Educational Center of Pharmaceutics, Kazan (Volga Region) Federal University, 18 Kremlyovskaya St., 420008 Kazan, Russia (M.Z.); (K.D.)
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 18 Kremlyovskaya St., 420008 Kazan, Russia
| | - Mohamed Zoughaib
- Scientific and Educational Center of Pharmaceutics, Kazan (Volga Region) Federal University, 18 Kremlyovskaya St., 420008 Kazan, Russia (M.Z.); (K.D.)
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 18 Kremlyovskaya St., 420008 Kazan, Russia
| | - Kenana Dayob
- Scientific and Educational Center of Pharmaceutics, Kazan (Volga Region) Federal University, 18 Kremlyovskaya St., 420008 Kazan, Russia (M.Z.); (K.D.)
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 18 Kremlyovskaya St., 420008 Kazan, Russia
| | - Marat Kamalov
- Scientific and Educational Center of Pharmaceutics, Kazan (Volga Region) Federal University, 18 Kremlyovskaya St., 420008 Kazan, Russia (M.Z.); (K.D.)
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 18 Kremlyovskaya St., 420008 Kazan, Russia
| | - Duong Luong
- Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia
| | - Albina Zakirova
- Academy of Postgraduate Education under FSBU FSCC of FMBA of Russia, Department of Oncology and Plastic Surgery, 91 Volokolamsk Highway, 125371 Moscow, Russia
| | - Ruslan Mullin
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 18 Kremlyovskaya St., 420008 Kazan, Russia
- State Autonomous Healthcare Institution Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan, 138 Orenburg Highway, 420064 Kazan, Russia
| | - Diana Salakhieva
- Scientific and Educational Center of Pharmaceutics, Kazan (Volga Region) Federal University, 18 Kremlyovskaya St., 420008 Kazan, Russia (M.Z.); (K.D.)
| | - Timur I. Abdullin
- Scientific and Educational Center of Pharmaceutics, Kazan (Volga Region) Federal University, 18 Kremlyovskaya St., 420008 Kazan, Russia (M.Z.); (K.D.)
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 18 Kremlyovskaya St., 420008 Kazan, Russia
| |
Collapse
|
|
3
|
Ichinose Y, Nagira A, Sumitomo N, Kakegawa A, Fukushima N. Spontaneous regeneration after resection of various lengths of hypoglossal nerve in rats. J Oral Biosci 2024; 66:582-586. [PMID: 38821485 DOI: 10.1016/j.job.2024.05.010] [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] [Received: 03/13/2024] [Revised: 05/27/2024] [Accepted: 05/27/2024] [Indexed: 06/02/2024]
Abstract
OBJECTIVES The objective of this study was to investigate spontaneous neural regeneration and functional recovery after resection of various lengths of the hypoglossal (XII) nerve in adult rats. METHODS Twelve weeks after XII nerve resection at lengths ranging from 0.0 to 15.8 mm, the tongue deviation angle of rats was measured to evaluate the severity of paralysis; thereafter, the XII neurons in the XII nucleus were labeled with Fluoro-Gold (FG), which was injected into the tongue to visualize regenerated XII neurons re-innervating the tongue muscles. RESULTS In the XII nerve-resected rats, the regenerative rates, that is, the percentage of the total number of FG-positive neurons on the injured side relative to that on the uninjured side, were divided into two groups; the regenerative rates were more than 77% and less than 6%, respectively. Upon comparing the two groups, the boundary resection length was approximately 10.0 mm. Moreover, the former and latter groups demonstrated tongue deviation angles less than or greater than 15°, respectively. CONCLUSIONS The critical nerve gap length for spontaneous neural regeneration was approximately 10.0 mm in XII nerve-resected adult rats, and nerve regeneration occurred in both morphological and functional aspects after resection at less than the critical length.
Collapse
Affiliation(s)
- Yuko Ichinose
- Department of Anatomy, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Ayata Nagira
- Department of Anatomy, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Norimi Sumitomo
- Department of Anatomy, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Akira Kakegawa
- Department of Anatomy, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Nanae Fukushima
- Department of Anatomy, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.
| |
Collapse
|
|
4
|
Omar Khudhur Z, Ziyad Abdulqadir S, Faqiyazdin Ahmed Mzury A, Aziz Rasoul A, Wasman Smail S, Ghayour MB, Abdolmaleki A. Epothilone B loaded in acellular nerve allograft enhanced sciatic nerve regeneration in rats. Fundam Clin Pharmacol 2024; 38:307-319. [PMID: 37857403 DOI: 10.1111/fcp.12961] [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: 04/17/2023] [Revised: 08/19/2023] [Accepted: 10/06/2023] [Indexed: 10/21/2023]
Abstract
BACKGROUND Epothilone B (EpoB) is a microtubule-stabilizing agent with neuroprotective properties. OBJECTIVES This study examines the regenerative properties of ANA supplemented with EpoB on a sciatic nerve deficit in male Wistar rats. METHODS For this purpose, the 10 mm nerve gap was filled with acellular nerve allografts (ANAs) containing EpoB at 0.1, 1, and 10 nM concentrations. The sensorimotor recovery was evaluated up to 16 weeks after the operation. Real-time PCR, histomorphometry analysis, and electrophysiological evaluation were also used to evaluate the process of nerve regeneration. RESULTS ANA/EpoB (0.1 nM) significantly improved sensorimotor recovery in rats compared to ANA, ANA/EpoB (1 nM), and ANA/EpoB (10 nM) groups. This led to reduced muscle atrophy, improved sciatic functional index, and thermal paw withdrawal reflex latency, indicating nerve regeneration and target organ reinnervation. The electrophysiological and histomorphometry findings also confirmed the ANA/EpoB regenerative properties (0.1 nM). EpoB only enhanced ANA regenerative properties at 0.1 nM, with no therapeutic effects at higher concentrations. CONCLUSION Totally, we concluded that ANA loaded with 0.1 nM EpoB can effectively reconstruct the transected sciatic nerve in rats, likely by enhancing axonal sprouting and extension.
Collapse
Affiliation(s)
- Zhikal Omar Khudhur
- Department of Biology Education, Faculty of Education, Tishk International University, Erbil, Kurdistan Region, Iraq
| | | | | | | | - Shukur Wasman Smail
- Department of Biology, College of Science, Salahaddin University-Erbil, Iraq
- Department of Medical Microbiology, College of Science, Cihan University-Erbil, Kurdistan Region, Iraq
| | - Mohammad B Ghayour
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Arash Abdolmaleki
- Department of Biophysics, Faculty of Advanced Technologies, University of Mohaghegh Ardabili, Namin, Iran
| |
Collapse
|
|
5
|
Solomevich SO, Oranges CM, Kalbermatten DF, Schwendeman A, Madduri S. Natural polysaccharides and their derivatives as potential medical materials and drug delivery systems for the treatment of peripheral nerve injuries. Carbohydr Polym 2023; 315:120934. [PMID: 37230605 DOI: 10.1016/j.carbpol.2023.120934] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 04/07/2023] [Accepted: 04/17/2023] [Indexed: 05/27/2023]
Abstract
Peripheral nerve repair following injury is one of the most serious problems in neurosurgery. Clinical outcomes are often unsatisfactory and associated with a huge socioeconomic burden. Several studies have revealed the great potential of biodegradable polysaccharides for improving nerve regeneration. We review here the promising therapeutic strategies involving different types of polysaccharides and their bio-active composites for promoting nerve regeneration. Within this context, polysaccharide materials widely used for nerve repair in different forms are highlighted, including nerve guidance conduits, hydrogels, nanofibers and films. While nerve guidance conduits and hydrogels were used as main structural scaffolds, the other forms including nanofibers and films were generally used as additional supporting materials. We also discuss the issues of ease of therapeutic implementation, drug release properties and therapeutic outcomes, together with potential future directions of research.
Collapse
Affiliation(s)
- Sergey O Solomevich
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA; Research Institute for Physical Chemical Problems of the Belarusian State University, Minsk, Belarus
| | - Carlo M Oranges
- Plastic, Reconstructive and Aesthetic Surgery Division, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Daniel F Kalbermatten
- Plastic, Reconstructive and Aesthetic Surgery Division, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland; Bioengineering and Neuroregeneration Laboratory, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Anna Schwendeman
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA
| | - Srinivas Madduri
- Plastic, Reconstructive and Aesthetic Surgery Division, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland; Bioengineering and Neuroregeneration Laboratory, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
| |
Collapse
|
|
6
|
Lazăr AI, Aghasoleimani K, Semertsidou A, Vyas J, Roșca AL, Ficai D, Ficai A. Graphene-Related Nanomaterials for Biomedical Applications. NANOMATERIALS (BASEL, SWITZERLAND) 2023; 13:1092. [PMID: 36985986 PMCID: PMC10051126 DOI: 10.3390/nano13061092] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/03/2023] [Accepted: 03/12/2023] [Indexed: 06/18/2023]
Abstract
This paper builds on the context and recent progress on the control, reproducibility, and limitations of using graphene and graphene-related materials (GRMs) in biomedical applications. The review describes the human hazard assessment of GRMs in in vitro and in vivo studies, highlights the composition-structure-activity relationships that cause toxicity for these substances, and identifies the key parameters that determine the activation of their biological effects. GRMs are designed to offer the advantage of facilitating unique biomedical applications that impact different techniques in medicine, especially in neuroscience. Due to the increasing utilization of GRMs, there is a need to comprehensively assess the potential impact of these materials on human health. Various outcomes associated with GRMs, including biocompatibility, biodegradability, beneficial effects on cell proliferation, differentiation rates, apoptosis, necrosis, autophagy, oxidative stress, physical destruction, DNA damage, and inflammatory responses, have led to an increasing interest in these regenerative nanostructured materials. Considering the existence of graphene-related nanomaterials with different physicochemical properties, the materials are expected to exhibit unique modes of interactions with biomolecules, cells, and tissues depending on their size, chemical composition, and hydrophil-to-hydrophobe ratio. Understanding such interactions is crucial from two perspectives, namely, from the perspectives of their toxicity and biological uses. The main aim of this study is to assess and tune the diverse properties that must be considered when planning biomedical applications. These properties include flexibility, transparency, surface chemistry (hydrophil-hydrophobe ratio), thermoelectrical conductibility, loading and release capacity, and biocompatibility.
Collapse
Affiliation(s)
- Andreea-Isabela Lazăr
- Department of Science and Engineering of Oxide Materials and Nanomaterials, Faculty of Chemical Engineering and Biotechnologies, University Politehnica of Bucharest, Gh. Polizu St. 1–7, 011061 Bucharest, Romania
- National Centre for Micro- and Nanomaterials, University POLITEHNICA of Bucharest, Spl. Independentei 313, 060042 Bucharest, Romania;
- National Centre for Food Safety, University Politehnica of Bucharest, Spl. Independentei 313, 060042 Bucharest, Romania
| | | | - Anna Semertsidou
- Charles River Laboratories, Margate, Manston Road, Kent CT9 4LT, UK
| | - Jahnavi Vyas
- Drug Development Solution, Newmarket road, Ely, CB7 5WW, UK
| | - Alin-Lucian Roșca
- National Centre for Food Safety, University Politehnica of Bucharest, Spl. Independentei 313, 060042 Bucharest, Romania
| | - Denisa Ficai
- National Centre for Micro- and Nanomaterials, University POLITEHNICA of Bucharest, Spl. Independentei 313, 060042 Bucharest, Romania;
- National Centre for Food Safety, University Politehnica of Bucharest, Spl. Independentei 313, 060042 Bucharest, Romania
- Department of Inorganic Chemistry, Physical Chemistry and Electrochemistry, Faculty of Chemical Engineering and Biotechnologies, University Politehnica of Bucharest, Gh. Polizu St. 1–7, 011061 Bucharest, Romania
| | - Anton Ficai
- Department of Science and Engineering of Oxide Materials and Nanomaterials, Faculty of Chemical Engineering and Biotechnologies, University Politehnica of Bucharest, Gh. Polizu St. 1–7, 011061 Bucharest, Romania
- National Centre for Micro- and Nanomaterials, University POLITEHNICA of Bucharest, Spl. Independentei 313, 060042 Bucharest, Romania;
- National Centre for Food Safety, University Politehnica of Bucharest, Spl. Independentei 313, 060042 Bucharest, Romania
- Academy of Romanian Scientists, Ilfov St. 3, 050045 Bucharest, Romania
| |
Collapse
|
|
7
|
Huang WJ, Wang J. Development of 3D-Printed, Biodegradable, Conductive PGSA Composites for Nerve Tissue Regeneration. Macromol Biosci 2023; 23:e2200470. [PMID: 36525352 DOI: 10.1002/mabi.202200470] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/07/2022] [Indexed: 12/23/2022]
Abstract
Nerve conduits are used to reconnect broken nerve bundles and provide protection to facilitate nerve regeneration. However, the low degradation rate and regeneration rate, as well as the requirement for secondary surgery are some of the most criticized drawbacks of existing nerve conduits. With high processing flexibility from the photo-curability, poly (glycerol sebacate) acrylate (PGSA) is a promising material with tunable mechanical properties and biocompatibility for the development of medical devices. Here, polyvinylpyrrolidone (PVP), silver nanoparticles (AgNPs), and graphene are embedded in biodegradable PGSA matrix. The polymer composites are then assessed for their electrical conductivity, biodegradability, three-dimensional-printability (3D-printability), and promotion of cell proliferation. Through the four-probe technique, it is shown that the PGSA composites are identified as highly conductive in swollen state. Furthermore, biodegradability is evaluated through enzymatic degradation and facilitated hydrolysis. Cell proliferation and guidance are significantly promoted by three-dimensional-printed microstructures and electrical stimulation on PGSA composites, especially on PGSA-PVP. Hence, microstructured nerve conduits are 3D-printed with PGSA-PVP. Guided cell growth and promoted proliferation are subsequently demonstrated by Schwann cell culture combined with electrical stimulation. Consequently, 3D-printed nerve conduits fabricated with PGSA composites hold great potential in nerve tissue regeneration through electrical stimulation.
Collapse
Affiliation(s)
- Wei-Jia Huang
- Department of Chemical Engineering, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu, ROC 30013, Taiwan
| | - Jane Wang
- Department of Chemical Engineering, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu, ROC 30013, Taiwan
| |
Collapse
|
|
8
|
Ceran F, Pilanci O, Ozel A, Ilbay G, Karabacak R, Kanter M, Ilbay K, Kuvat SV. Use of acellular dermal matrix in peripheral nerve reconstruction: an experimental study on rat sciatic nerve defect. J Plast Surg Hand Surg 2023; 57:445-452. [PMID: 36476277 DOI: 10.1080/2000656x.2022.2152824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND In patients with nerve tissue defects, the use of autologous nerve grafts is the standard method of treatment. Alternatives to autologous, nerve grafts have attracted the attention of reconstructive surgeons. In this study, the results of nerve repairs using acellular dermal matrix (ADM) in an experimental rat sciatic nerve defect model are presented. METHODS Thirty-six Sprague-Dawley rats were randomized into 5 groups: Group 1: control group, Group 2: negative control group (n = 6), Group 3: autologous nerve graft group (n = 10), Group 4: donor site entubulated with ADM group (n = 10); and Group 5: nerve graft entubulated with ADM group (n = 10). The animals in each group were evaluated for electrophysiologic functions, gastrocnemius muscle weight and histomorphology on the 3rd and 6th month. RESULTS The compound muscle action potential was observed to be distinctly lower in Groups 3, 4 and 5 in comparison to the control group. In Group 4, the gastrocnemius ratio (GCR) values on the 6th month were statistically significantly lower than the GCR values in Group 3 and Group 5, The histological scores and myelinated axonal counts in Group 5 were statistically significantly higher than the values in Group 3 and Group 4. CONCLUSION The results of this study showed that wrapping ADM around nerve grafts resulted in better outcomes with respect to nerve healing.
Collapse
Affiliation(s)
- Fatih Ceran
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medicalpark Hospital, Batman, Turkey
| | - Ozgur Pilanci
- Department of Plastic, Reconstructive and Aesthetic Surgery, Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Asuman Ozel
- Department of Plastic, Reconstructive and Aesthetic Surgery, Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Gul Ilbay
- Faculty of Medicine, Department of Physiology, Kocaeli University, Kocaeli, Turkey
| | - Rukiye Karabacak
- Faculty of Medicine, Department of Histology, Medeniyet University, Istanbul, Turkey
| | - Mehmet Kanter
- Faculty of Medicine, Department of Histology, Medeniyet University, Istanbul, Turkey
| | - Konuralp Ilbay
- Faculty of Medicine, Department of Neurosurgery, Kocaeli University, Kocaeli, Turkey
| | - Samet Vasfi Kuvat
- Department of Plastic, Reconstructive and Aesthetic Surgery, Bagcilar Training and Research Hospital, Istanbul, Turkey
| |
Collapse
|
|
9
|
Zhao YN, Wu P, Zhao ZY, Chen FX, Xiao A, Yue ZY, Han XW, Zheng Y, Chen Y. Electrodeposition of chitosan/graphene oxide conduit to enhance peripheral nerve regeneration. Neural Regen Res 2023; 18:207-212. [PMID: 35799544 PMCID: PMC9241416 DOI: 10.4103/1673-5374.344836] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Currently available commercial nerve guidance conduits have been applied in the repair of peripheral nerve defects. However, a conduit exhibiting good biocompatibility remains to be developed. In this work, a series of chitosan/graphene oxide (GO) films with concentrations of GO varying from 0–1 wt% (collectively referred to as CHGF-n) were prepared by an electrodeposition technique. The effects of CHGF-n on proliferation and adhesion abilities of Schwann cells were evaluated. The results showed that Schwann cells exhibited elongated spindle shapes and upregulated expression of nerve regeneration-related factors such as Krox20 (a key myelination factor), Zeb2 (essential for Schwann cell differentiation, myelination, and nerve repair), and transforming growth factor β (a cytokine with regenerative functions). In addition, a nerve guidance conduit with a GO content of 0.25% (CHGFC-0.25) was implanted to repair a 10-mm sciatic nerve defect in rats. The results indicated improvements in sciatic functional index, electrophysiology, and sciatic nerve and gastrocnemius muscle histology compared with the CHGFC-0 group, and similar outcomes to the autograft group. In conclusion, we provide a candidate method for the repair of peripheral nerve defects using free-standing chitosan/GO nerve conduits produced by electrodeposition.
Collapse
|
|
10
|
Tiwari AP, Lokai T, Albin B, Yang IH. A Review on the Technological Advances and Future Perspectives of Axon Guidance and Regeneration in Peripheral Nerve Repair. Bioengineering (Basel) 2022; 9:bioengineering9100562. [PMID: 36290530 PMCID: PMC9598559 DOI: 10.3390/bioengineering9100562] [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: 08/02/2022] [Revised: 10/03/2022] [Accepted: 10/11/2022] [Indexed: 11/16/2022] Open
Abstract
Despite a significant advance in the pathophysiological understanding of peripheral nerve damage, the successful treatment of large nerve defects remains an unmet medical need. In this article, axon growth guidance for peripheral nerve regeneration was systematically reviewed and discussed mainly from the engineering perspective. In addition, the common approaches to surgery, bioengineering approaches to emerging technologies such as optogenetic stimulation and magnetic stimulation for functional recovery were discussed, along with their pros and cons. Additionally, clear future perspectives of axon guidance and nerve regeneration were addressed.
Collapse
|
|
11
|
Rao Z, Lin Z, Song P, Quan D, Bai Y. Biomaterial-Based Schwann Cell Transplantation and Schwann Cell-Derived Biomaterials for Nerve Regeneration. Front Cell Neurosci 2022; 16:926222. [PMID: 35836742 PMCID: PMC9273721 DOI: 10.3389/fncel.2022.926222] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 05/31/2022] [Indexed: 12/13/2022] Open
Abstract
Schwann cells (SCs) dominate the regenerative behaviors after peripheral nerve injury by supporting axonal regrowth and remyelination. Previous reports also demonstrated that the existence of SCs is beneficial for nerve regeneration after traumatic injuries in central nervous system. Therefore, the transplantation of SCs/SC-like cells serves as a feasible cell therapy to reconstruct the microenvironment and promote nerve functional recovery for both peripheral and central nerve injury repair. However, direct cell transplantation often leads to low efficacy, due to injection induced cell damage and rapid loss in the circulatory system. In recent years, biomaterials have received great attention as functional carriers for effective cell transplantation. To better mimic the extracellular matrix (ECM), many biodegradable materials have been engineered with compositional and/or topological cues to maintain the biological properties of the SCs/SCs-like cells. In addition, ECM components or factors secreted by SCs also actively contribute to nerve regeneration. Such cell-free transplantation approaches may provide great promise in clinical translation. In this review, we first present the current bio-scaffolds engineered for SC transplantation and their achievement in animal models and clinical applications. To this end, we focus on the physical and biological properties of different biomaterials and highlight how these properties affect the biological behaviors of the SCs/SC-like cells. Second, the SC-derived biomaterials are also reviewed and discussed. Finally, the relationship between SCs and functional biomaterials is summarized, and the trends of their future development are predicted toward clinical applications.
Collapse
Affiliation(s)
- Zilong Rao
- Guangdong Engineering Technology Research Centre for Functional Biomaterials, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, China
| | - Zudong Lin
- PCFM Lab, GD HPPC Lab, School of Chemistry, Sun Yat-sen University, Guangzhou, China
| | - Panpan Song
- Guangdong Engineering Technology Research Centre for Functional Biomaterials, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, China
| | - Daping Quan
- Guangdong Engineering Technology Research Centre for Functional Biomaterials, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, China
| | - Ying Bai
- Guangdong Engineering Technology Research Centre for Functional Biomaterials, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
|
12
|
Suh T, Twiddy J, Mahmood N, Ali KM, Lubna MM, Bradford PD, Daniele MA, Gluck JM. Electrospun Carbon Nanotube-Based Scaffolds Exhibit High Conductivity and Cytocompatibility for Tissue Engineering Applications. ACS OMEGA 2022; 7:20006-20019. [PMID: 35721944 PMCID: PMC9202252 DOI: 10.1021/acsomega.2c01807] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 05/17/2022] [Indexed: 06/01/2023]
Abstract
Carbon nanotubes (CNTs) are known for their excellent conductive properties. Here, we present two novel methods, "sandwich" (sCNT) and dual deposition (DD CNT), for incorporating CNTs into electrospun polycaprolactone (PCL) and gelatin scaffolds to increase their conductance. Based on CNT percentage, the DD CNT scaffolds contain significantly higher quantities of CNTs than the sCNT scaffolds. The inclusion of CNTs increased the electrical conductance of scaffolds from 0.0 ± 0.00 kS (non-CNT) to 0.54 ± 0.10 kS (sCNT) and 5.22 ± 0.49 kS (DD CNT) when measured parallel to CNT arrays and to 0.25 ± 0.003 kS (sCNT) and 2.85 ± 1.12 (DD CNT) when measured orthogonally to CNT arrays. The inclusion of CNTs increased fiber diameter and pore size, promoting cellular migration into the scaffolds. CNT inclusion also decreased the degradation rate and increased hydrophobicity of scaffolds. Additionally, CNT inclusion increased Young's modulus and failure load of scaffolds, increasing their mechanical robustness. Murine fibroblasts were maintained on the scaffolds for 30 days, demonstrating high cytocompatibility. The increased conductivity and high cytocompatibility of the CNT-incorporated scaffolds make them appropriate candidates for future use in cardiac and neural tissue engineering.
Collapse
Affiliation(s)
- Taylor
C. Suh
- Department
of Textile Engineering, Chemistry, and Science, North Carolina State University, Raleigh, North Carolina 27606, United States
| | - Jack Twiddy
- Joint
Department of Biomedical Engineering, North
Carolina State University and The University of North Carolina at
Chapel Hill, Raleigh, North Carolina 27606, United States
| | - Nasif Mahmood
- Department
of Textile Engineering, Chemistry, and Science, North Carolina State University, Raleigh, North Carolina 27606, United States
| | - Kiran M. Ali
- Department
of Textile Engineering, Chemistry, and Science, North Carolina State University, Raleigh, North Carolina 27606, United States
| | - Mostakima M. Lubna
- Department
of Textile Engineering, Chemistry, and Science, North Carolina State University, Raleigh, North Carolina 27606, United States
| | - Philip D. Bradford
- Department
of Textile Engineering, Chemistry, and Science, North Carolina State University, Raleigh, North Carolina 27606, United States
| | - Michael A. Daniele
- Joint
Department of Biomedical Engineering, North
Carolina State University and The University of North Carolina at
Chapel Hill, Raleigh, North Carolina 27606, United States
- Department
of Electrical and Computer Engineering, North Carolina State University, Raleigh, North Carolina 27606, United States
| | - Jessica M. Gluck
- Department
of Textile Engineering, Chemistry, and Science, North Carolina State University, Raleigh, North Carolina 27606, United States
| |
Collapse
|
|
13
|
Mini review: Biomaterials in repair and regeneration of nerve in a volumetric muscle loss. Neurosci Lett 2021; 762:136145. [PMID: 34332029 DOI: 10.1016/j.neulet.2021.136145] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 06/28/2021] [Accepted: 07/26/2021] [Indexed: 01/23/2023]
Abstract
Volumetric muscle loss (VML) following a severe trauma or injury is beyond the intrinsic regenerative capacity of muscle tissues, and hence interventional therapy is required. Extensive muscle loss concomitant with damage to neuromuscular components overwhelms the muscles' remarkable regenerative capacity. The loss of nervous and vascular tissue leads to further damage and atrophy, so a combined treatment for neuromuscular junction (NMJ) along with the volumetric muscle regeneration is important. There have been immense advances in the field of tissue engineering for skeletal muscle tissue and peripheral nerve regeneration, but very few address the interdependence of the tissues and the need for combined therapies to repair and regenerate fully functional muscle tissue. This review addresses the problem and presents an overview of the biomaterials that have been studied for tissue engineering of neuromuscular tissues associated with skeletal muscles.
Collapse
|
|
14
|
Yan Z, Qian Y, Fan C. Biomimicry in 3D printing design: implications for peripheral nerve regeneration. Regen Med 2021; 16:683-701. [PMID: 34189955 DOI: 10.2217/rme-2020-0182] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Nerve guide conduits (NGCs) connect dissected nerve stumps and effectively repair short-range peripheral nerve defects. However, for long-range defects, autografts show better therapeutic effects, despite intrinsic limitations. Recent evidence shows that biomimetic design is essential for high-performance NGCs, and 3D printing is a promising fabricating technique. The current work includes a brief review of the challenges for peripheral nerve regeneration. The authors propose a potential solution using biomimetic 3D-printed NGCs as alternative therapies. The assessment of biomimetic designs includes microarchitecture, mechanical property, electrical conductivity and biologics inclusion. The applications of 3D printing in preparing NGCs and present strategies to improve therapeutic effects are also discussed.
Collapse
Affiliation(s)
- Zhiwen Yan
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.,Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai, 200233, China.,Youth Science and Technology Innovation Studio, Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yun Qian
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.,Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai, 200233, China.,Youth Science and Technology Innovation Studio, Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Cunyi Fan
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.,Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai, 200233, China.,Youth Science and Technology Innovation Studio, Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| |
Collapse
|
|
15
|
Sencar L, Coşkun G, Şaker D, Sapmaz T, Kara S, Çelenk A, Polat S, Yılmaz DM, Dağlıoğlu YK, Polat S. Effects of Theranekron and alpha-lipoic acid combined treatment on GAP-43 and Krox-20 gene expressions and inflammation markers in peripheral nerve injury. Ultrastruct Pathol 2021; 45:167-181. [PMID: 34184615 DOI: 10.1080/01913123.2021.1923600] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Peripheral nerve injury (PNI) is a major health problem that results in loss of motor and sensory functions. In treatment of PNI, various methods such as anastomosis, nerve grafts, nonneural tissue grafts, and nerve conduits are applied. In the present study, it was aimed to investigate the effects of Theranekron and Alpha-lipoic acid (ALA) combined treatment on nerve healing in experimental PNI by using histomorphometric, electron microscopic, immunohistochemical and molecular biological methods. Sixty-two Wistar rats were divided into six groups; the normal control group, sham operation group, experimental control group having a crush type injury with no treatment, Theranekron treatment group, ALA treatment group and Theranekron+ALA combined treatment group. Sciatic nerve tissue samples were obtained on days 1, 7 and 14 following injury in all groups. GAP-43 expression was upregulated in all PNI received groups compared to the control group. Krox-20 expression was downregulated in all groups that received PNI compared to the control group. While intensely positive TNF-α and IL-6 expressions were observed up to the 1st to the 14th day for the experimental control group, these expressions were seen as "weakly positive" in the treatment groups from the 1st day to the 14th day. The number of myelinated fibers was higher in the control and sham operation groups. Additionally, the number of myelinated nerve fibers increased in the combined treatment group. In conclusion, these findings suggest that combined therapy of Theranekron and ALA promotes structural recovery and it should be considered as an effective treatment protocol following PNI.
Collapse
Affiliation(s)
- Leman Sencar
- Department of Histology and Embryology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - Gülfidan Coşkun
- Department of Histology and Embryology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - Dilek Şaker
- Department of Histology and Embryology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - Tuğçe Sapmaz
- Department of Histology and Embryology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - Samet Kara
- Department of Histology and Embryology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - Alper Çelenk
- Department of Histology and Embryology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - Sema Polat
- Department of Anatomy, Faculty of Medicine, Çukurova University, Adana, Turkey
| | | | - Y Kenan Dağlıoğlu
- Medical Sciences and Experimental Research and Application Center of Çukurova University, Adana, Turkey
| | - Sait Polat
- Department of Histology and Embryology, Faculty of Medicine, Çukurova University, Adana, Turkey
| |
Collapse
|
|
16
|
Kim YJ, Kim KJ, Lee JH, Park SU, Cho SY. Effect of herbal extracts on peripheral nerve regeneration after microsurgery of the sciatic nerve in rats. BMC Complement Med Ther 2021; 21:162. [PMID: 34088292 PMCID: PMC8178854 DOI: 10.1186/s12906-021-03335-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 05/24/2021] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Recent experimental studies using herbal extracts have shown the possibility of peripheral nerve regeneration. This study aimed to investigate the effects of herbal extracts on peripheral nerve regeneration in a rat sciatic nerve injury model. METHODS A total of 53 rats were randomly assigned to a control group or one of four experimental groups. In all rats, the sciatic nerve was completely severed and microscopic epineural end-to-end neurorrhaphy was performed. Normal saline (2 mL) was topically applied to the site of nerve repair in the control group, whereas four different herbal extracts - 2 mL each of Astragalus mongholicus Bunge, Coptis japonica (Thunb.) Makino, Aconitum carmichaelii Debeaux, or Paeonia lactiflora Pall. - were topically applied to the site of nerve repair in each experimental group. Nerve conduction studies were performed at an average of 11.9 weeks after the operation, and conduction velocity and proximal and distal amplitudes were measured. Biopsies were performed at an average of 13.2 weeks after the initial neurorrhaphy. The quality of nerve anastomosis and perineural adhesion to the surrounding soft tissues was macroscopically evaluated. The neuroma size at the site of the neurorrhaphy was microscopically measured, whereas the size of the scar tissue was evaluated relative to the diameter of the repaired nerve. RESULTS The nerve conduction study results showed the highest nerve conduction velocity in the experimental group that used the Coptis japonica (Thunb.) Makino extract and the highest proximal and distal amplitudes in the experimental group that used the Aconitum carmichaelii Debeaux extract. Macroscopic evaluations after the second operation showed that grade 2 perineural adhesion was found in 70.8% of rats. The mean neuroma size in the Coptis japonica (Thunb.) Makino, Aconitum carmichaelii Debeaux, and Paeonia lactiflora Pall. groups showed statistically significant decreases relative to the control group. The mean scar tissue formation index in the Paeonia lactiflora Pall. group showed a statistically significant decrease relative to the control group. CONCLUSIONS The peripheral nerve regeneration effect of the herbal extracts was confirmed through decreased neuroma and scar tissue formation.
Collapse
Affiliation(s)
- Young Jun Kim
- Department of Orthopedic Surgery, Kyung Hee University Hospital at Gangdong, School of Medicine, Kyung Hee University, 892 Dongnam-ro, Gangdong-gu, Seoul, Republic of Korea
| | - Kyu Jin Kim
- Department of Orthopedic Surgery, Kyung Hee University Hospital at Gangdong, School of Medicine, Kyung Hee University, 892 Dongnam-ro, Gangdong-gu, Seoul, Republic of Korea
| | - Jae Hoon Lee
- Department of Orthopedic Surgery, Kyung Hee University Hospital at Gangdong, School of Medicine, Kyung Hee University, 892 Dongnam-ro, Gangdong-gu, Seoul, Republic of Korea
| | - Seong-Uk Park
- Department of Cardiology and Neurology, Kyung Hee University Hospital at Gangdong, College of Korean Medicine, Kyung Hee University, 892 Dongnam-ro, Gangdong-gu, Seoul, Republic of Korea
- Department of Cardiology and Neurology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, Republic of Korea
| | - Seung-Yeon Cho
- Department of Cardiology and Neurology, Kyung Hee University Hospital at Gangdong, College of Korean Medicine, Kyung Hee University, 892 Dongnam-ro, Gangdong-gu, Seoul, Republic of Korea.
- Department of Cardiology and Neurology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, Republic of Korea.
| |
Collapse
|
|
17
|
Minini A, Megaro A. Muscle in vein conduits: our experience. ACTA BIO-MEDICA : ATENEI PARMENSIS 2021; 92:e2021163. [PMID: 33944845 PMCID: PMC8142788 DOI: 10.23750/abm.v92is1.9202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 02/10/2020] [Indexed: 01/09/2023]
Abstract
Muscle in vein (MIV ) conduits have gradually been employed in the last 20 years as a valuable technique in bridging peripheral nerve gaps after nerve lesions who cannot undergo a direct tension-free coaptation. The advantages of this procedure comparing to the actual benchmark (autograft) is the sparing of the donor site, and the huge availability of both components (i.e. muscle and veins). Here we present a case serie of four MIV performed at our hospital from 2018 to 2019. The results we obtained in our experi-ence confirmed its effectiveness both in nerve regeneration (as sensibility recovery) and in neuropathic pain eradication. Our positive outcomes encourage its use in selected cases of residual nerve gaps up to 30 mm.
Collapse
Affiliation(s)
- Andrea Minini
- Clinica Ortopedica dell'Università degli Studi di Brescia.
| | | |
Collapse
|
|
18
|
DeLeonibus A, Rezaei M, Fahradyan V, Silver J, Rampazzo A, Bassiri Gharb B. A meta-analysis of functional outcomes in rat sciatic nerve injury models. Microsurgery 2021; 41:286-295. [PMID: 33511636 DOI: 10.1002/micr.30713] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 10/30/2020] [Accepted: 12/31/2020] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Rat sciatic nerve injury (PNR) is the most utilized model in studies on peripheral nerve regeneration. However, large animal models are increasingly favored based on the assumption that nerve regeneration in rodents achieves more favorable outcomes than in humans. The purpose of this meta-analysis was to investigate which rat PNR models are more stringent and should be used before utilizing large animal experimentation. METHODS A PRISMA-guided meta-analysis of the English literature regarding functional outcomes in rat peripheral nerve injury models was conducted. Outcomes of five basic scenarios: (1) transected nerve/negative control, (2) transection with primary microsurgical repair, (3) isogenic/autologous grafts, (4) acellular-allogenic grafts, and (5) limb transplantation were compared to sciatic nerves without any intervention/positive control. Outcomes were compared using Sciatic Functional Index (SFI). Log-based projections were generated and evaluated using mean squared error (MSE), one-way-ANOVA, and Tukey-HSD post-hoc analysis. RESULTS In total, 167 articles met the inclusion criteria. The earliest manifestations of motor recovery were encountered in the transection and primary repair group (p <.0005). There was a significant difference in recovery time and degree of recovery between all surgical models (p <.0005). At 24 weeks, the SFI in hindlimb transplantation group was significantly worse than all other groups (-74.07 ± 2.74, p <.0005). Autografts smaller than 10 mm recovered sooner than autografts longer than 10 mm (p = .021) and autografts recovered faster than allografts. CONCLUSION This meta-analysis does not support the belief that neuro-regeneration is exceptional in transection models. These models remain adequate to provide translatable information and should initially be used in investigational studies.
Collapse
Affiliation(s)
- Anthony DeLeonibus
- Department of Plastic and Reconstructive Surgery, Cleveland Clinic, Cleveland, Ohio, USA
| | - Majid Rezaei
- Department of Plastic and Reconstructive Surgery, Cleveland Clinic, Cleveland, Ohio, USA
| | - Vahe Fahradyan
- Department of Plastic and Reconstructive Surgery, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jerry Silver
- Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio, USA
| | - Antonio Rampazzo
- Department of Plastic and Reconstructive Surgery, Cleveland Clinic, Cleveland, Ohio, USA
| | - Bahar Bassiri Gharb
- Department of Plastic and Reconstructive Surgery, Cleveland Clinic, Cleveland, Ohio, USA
| |
Collapse
|
|
19
|
Lavorato A, Raimondo S, Boido M, Muratori L, Durante G, Cofano F, Vincitorio F, Petrone S, Titolo P, Tartara F, Vercelli A, Garbossa D. Mesenchymal Stem Cell Treatment Perspectives in Peripheral Nerve Regeneration: Systematic Review. Int J Mol Sci 2021; 22:E572. [PMID: 33430035 PMCID: PMC7827385 DOI: 10.3390/ijms22020572] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/05/2021] [Accepted: 01/06/2021] [Indexed: 12/14/2022] Open
Abstract
Traumatic peripheral nerve lesions affect hundreds of thousands of patients every year; their consequences are life-altering and often devastating and cause alterations in movement and sensitivity. Spontaneous peripheral nerve recovery is often inadequate. In this context, nowadays, cell therapy represents one of the most innovative approaches in the field of nerve repair therapies. The purpose of this systematic review is to discuss the features of different types of mesenchymal stem cells (MSCs) relevant for peripheral nerve regeneration after nerve injury. The published literature was reviewed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A combination of the keywords "nerve regeneration", "stem cells", "peripheral nerve injury", "rat", and "human" were used. Additionally, a "MeSH" research was performed in PubMed using the terms "stem cells" and "nerve regeneration". The characteristics of the most widely used MSCs, their paracrine potential, targeted stimulation, and differentiation potentials into Schwann-like and neuronal-like cells are described in this paper. Considering their ability to support and stimulate axonal growth, their remarkable paracrine activity, their presumed differentiation potential, their extremely low immunogenicity, and their high survival rate after transplantation, ADSCs appear to be the most suitable and promising MSCs for the recovery of peripheral nerve lesion. Clinical considerations are finally reported.
Collapse
Affiliation(s)
- Andrea Lavorato
- Neurosurgery Unit, Department of Neuroscience “Rita Levi Montalcini”, University of Turin, 10126 Turin, TO, Italy; (F.C.); (F.V.); (S.P.); (D.G.)
| | - Stefania Raimondo
- Department of Clinical and Biological Sciences, Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Orbassano, TO, Italy; (S.R.); (L.M.)
| | - Marina Boido
- Department of Neuroscience “Rita Levi Montalcini”, Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Orbassano, TO, Italy; (M.B.); (A.V.)
| | - Luisa Muratori
- Department of Clinical and Biological Sciences, Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Orbassano, TO, Italy; (S.R.); (L.M.)
| | - Giorgia Durante
- Faculty of Medicine and Surgery, University of Turin, 10126 Turin, TO, Italy;
| | - Fabio Cofano
- Neurosurgery Unit, Department of Neuroscience “Rita Levi Montalcini”, University of Turin, 10126 Turin, TO, Italy; (F.C.); (F.V.); (S.P.); (D.G.)
| | - Francesca Vincitorio
- Neurosurgery Unit, Department of Neuroscience “Rita Levi Montalcini”, University of Turin, 10126 Turin, TO, Italy; (F.C.); (F.V.); (S.P.); (D.G.)
| | - Salvatore Petrone
- Neurosurgery Unit, Department of Neuroscience “Rita Levi Montalcini”, University of Turin, 10126 Turin, TO, Italy; (F.C.); (F.V.); (S.P.); (D.G.)
| | - Paolo Titolo
- Traumatology–Reconstructive Microsurgery, Department of Orthopaedics and Traumatology, CTO Hospital, 10126 Turin, TO, Italy;
| | - Fulvio Tartara
- Neurosurgery Unit, Istituto Clinico Città Studi (ICCS), 20131 Milan, MI, Italy;
| | - Alessandro Vercelli
- Department of Neuroscience “Rita Levi Montalcini”, Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Orbassano, TO, Italy; (M.B.); (A.V.)
| | - Diego Garbossa
- Neurosurgery Unit, Department of Neuroscience “Rita Levi Montalcini”, University of Turin, 10126 Turin, TO, Italy; (F.C.); (F.V.); (S.P.); (D.G.)
| |
Collapse
|
|
20
|
Fundamentals and Current Strategies for Peripheral Nerve Repair and Regeneration. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1249:173-201. [PMID: 32602098 DOI: 10.1007/978-981-15-3258-0_12] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
A body of evidence indicates that peripheral nerves have an extraordinary yet limited capacity to regenerate after an injury. Peripheral nerve injuries have confounded professionals in this field, from neuroscientists to neurologists, plastic surgeons, and the scientific community. Despite all the efforts, full functional recovery is still seldom. The inadequate results attained with the "gold standard" autograft procedure still encourage a dynamic and energetic research around the world for establishing good performing tissue-engineered alternative grafts. Resourcing to nerve guidance conduits, a variety of methods have been experimentally used to bridge peripheral nerve gaps of limited size, up to 30-40 mm in length, in humans. Herein, we aim to summarize the fundamentals related to peripheral nerve anatomy and overview the challenges and scientific evidences related to peripheral nerve injury and repair mechanisms. The most relevant reports dealing with the use of both synthetic and natural-based biomaterials used in tissue engineering strategies when treatment of nerve injuries is envisioned are also discussed in depth, along with the state-of-the-art approaches in this field.
Collapse
|
|
21
|
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.
Collapse
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.
| |
Collapse
|
|
22
|
Dietzmeyer N, Förthmann M, Grothe C, Haastert-Talini K. Modification of tubular chitosan-based peripheral nerve implants: applications for simple or more complex approaches. Neural Regen Res 2020; 15:1421-1431. [PMID: 31997801 PMCID: PMC7059590 DOI: 10.4103/1673-5374.271668] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 08/02/2019] [Accepted: 09/03/2019] [Indexed: 12/21/2022] Open
Abstract
Surgical treatment of peripheral nerve injuries is still a major challenge in human clinic. Up to now, none of the well-developed microsurgical treatment options is able to guarantee a complete restoration of nerve function. This restriction is also effective for novel clinically approved artificial nerve guides. In this review, we compare surgical repair techniques primarily for digital nerve injuries reported with relatively high prevalence to be valuable attempts in clinical digital nerve repair and point out their advantages and shortcomings. We furthermore discuss the use of artificial nerve grafts with a focus on chitosan-based nerve guides, for which our own studies contributed to their approval for clinical use. In the second part of this review, very recent future perspectives for the enhancement of tubular (commonly hollow) nerve guides are discussed in terms of their clinical translatability and ability to form three-dimensional constructs that biomimick the natural nerve structure. This includes materials that have already shown their beneficial potential in in vivo studies like fibrous intraluminal guidance structures, hydrogels, growth factors, and approaches of cell transplantation. Additionally, we highlight upcoming future perspectives comprising co-application of stem cell secretome. From our overview, we conclude that already simple attempts are highly effective to increase the regeneration supporting properties of nerve guides in experimental studies. But for bringing nerve repair with bioartificial nerve grafts to the next level, e.g. repair of defects > 3 cm in human patients, more complex intraluminal guidance structures such as innovatively manufactured hydrogels and likely supplementation of stem cells or their secretome for therapeutic purposes may represent promising future perspectives.
Collapse
Affiliation(s)
- Nina Dietzmeyer
- Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Center for Systems Neuroscience (ZSN) Hannover, Hannover, Germany
| | - Maria Förthmann
- Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Center for Systems Neuroscience (ZSN) Hannover, Hannover, Germany
| | - Claudia Grothe
- Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Center for Systems Neuroscience (ZSN) Hannover, Hannover, Germany
| | - Kirsten Haastert-Talini
- Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Center for Systems Neuroscience (ZSN) Hannover, Hannover, Germany
| |
Collapse
|
|
23
|
Samadian H, Maleki H, Fathollahi A, Salehi M, Gholizadeh S, Derakhshankhah H, Allahyari Z, Jaymand M. Naturally occurring biological macromolecules-based hydrogels: Potential biomaterials for peripheral nerve regeneration. Int J Biol Macromol 2020; 154:795-817. [DOI: 10.1016/j.ijbiomac.2020.03.155] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 03/15/2020] [Accepted: 03/16/2020] [Indexed: 12/18/2022]
|
|
24
|
Haidar MK, Timur SS, Kazanci A, Turkoglu OF, Gürsoy RN, Nemutlu E, Sargon MF, Bodur E, Gök M, Ulubayram K, Öner L, Eroğlu H. Composite nanofibers incorporating alpha lipoic acid and atorvastatin provide neuroprotection after peripheral nerve injury in rats. Eur J Pharm Biopharm 2020; 153:1-13. [PMID: 32504798 DOI: 10.1016/j.ejpb.2020.05.032] [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: 04/05/2020] [Revised: 05/25/2020] [Accepted: 05/31/2020] [Indexed: 12/27/2022]
Abstract
Despite the new treatment strategies within the last 30 years, peripheral nerve injury (PNI) is still a worldwide clinical problem. The incidence rate of PNIs is 1 in 1000 individuals per year. In this study, we designed a composite nanoplatform for dual therapy in peripheral nerve injury and investigated the in-vivo efficacy in rat sciatic nerve crush injury model. Alpha-lipoic acid (ALA) was loaded into poly lactic-co-glycolic acid (PLGA) electrospun nanofibers which would release the drug in a faster manner and atorvastatin (ATR) loaded chitosan (CH) nanoparticles were embedded into PLGA nanofibers to provide sustained release. Sciatic nerve crush was generated via Yasargil aneurism clip with a holding force of 50 g/cm2. Nanofiber formulations were administered to the injured nerve immediately after trauma. Functional recovery of operated rat hind limb was evaluated using the sciatic functional index (SFI), extensor postural thrust (EPT), withdrawal reflex latency (WRL) and Basso, Beattie, and Bresnahan (BBB) test up to one month in the post-operative period at different time intervals. In addition to functional recovery assessments, ultrastructural and biochemical analyses were carried out on regenerated nerve fibers. L-929 mouse fibroblast cell line and B35 neuroblastoma cell line were used to investigate the cytotoxicity of nanofibers before in-vivo experiments. The neuroprotection potential of these novel nanocomposite fiber formulations has been demonstrated after local implantation of composite nanofiber sheets incorporating ALA and ATR, which contributed to the recovery of the motor and sensory function and nerve regeneration in a rat sciatic nerve crush injury model.
Collapse
Affiliation(s)
- Mohammad Karim Haidar
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Turkey; Department of Pharmaceutical Technology, Faculty of Pharmacy, Erzincan Binali Yıldırım University, 24100 Erzincan, Turkey
| | - Selin Seda Timur
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Turkey
| | - Atilla Kazanci
- Department of Neurosurgery Faculty of Medicine, Ankara Yıldırım Beyazıt University, 06810 Ankara, Turkey
| | - Omer Faruk Turkoglu
- Department of Neurosurgery, City Hospital, Turkish Republic Ministry of Health, 06810 Ankara, Turkey
| | - R Neslihan Gürsoy
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Turkey
| | - Emirhan Nemutlu
- Department of Analytical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Turkey
| | - Mustafa Fevzi Sargon
- Department of Anatomy, School of Medicine, Atilim University, 06830 Ankara, Turkey
| | - Ebru Bodur
- Department of Biochemistry, Faculty of Medicine, Hacettepe University, 06100 Ankara, Turkey
| | - Müslüm Gök
- Department of Biochemistry, Faculty of Medicine, Hacettepe University, 06100 Ankara, Turkey
| | - Kezban Ulubayram
- Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Hacettepe University 06100 Ankara, Turkey
| | - Levent Öner
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Turkey
| | - Hakan Eroğlu
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Turkey.
| |
Collapse
|
|
25
|
Wang Y, Zhang Y, Li X, Zhang Q. The progress of biomaterials in peripheral nerve repair and regeneration. JOURNAL OF NEURORESTORATOLOGY 2020. [DOI: 10.26599/jnr.2020.9040022] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Repair and regeneration of the injured peripheral nerve (PN) is a challenging issue in clinics. Although the regeneration outcome of large PN defects is currently unsatisfactory, recently, the study of PN repair has considerably progressed. In particular, biomaterials for repairing PNs, such as nerve guidance conduits and nerve repair membranes, have been well developed. Herein, we summarize the anatomy of the PN, the pathophysiological features of the nerve injury, and the repair process post injury. Then, we highlight the progress in the development of natural and synthetic biomaterials and summarize the applications, advantages, and disadvantages of these materials. These materials can be used as nerve repair membranes and nerve conduits in the field of PN repair. Finally, we discuss the challenges encountered and development strategies for PN repair in the future.
Collapse
|
|
26
|
Pawitan JA, Margiana R, Aman RA, Jusuf AA, Ibrahim N, Wibowo H. The effect of human umbilical cord-derived mesenchymal stem cell conditioned medium on the peripheral nerve regeneration of injured rats. ELECTRONIC JOURNAL OF GENERAL MEDICINE 2019. [DOI: 10.29333/ejgm/115468] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
|
|
27
|
Idini M, Wieringa P, Rocchiccioli S, Nieddu G, Ucciferri N, Formato M, Lepedda A, Moroni L. Glycosaminoglycan functionalization of electrospun scaffolds enhances Schwann cell activity. Acta Biomater 2019; 96:188-202. [PMID: 31265920 DOI: 10.1016/j.actbio.2019.06.054] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 06/06/2019] [Accepted: 06/27/2019] [Indexed: 12/13/2022]
Abstract
Nerve fibers of the peripheral nervous system (PNS) have a remarkable ability to regenerate up to an almost complete recovery of normal function following a crush or a Sunderland Type II injury. This process is governed by glial cells, known as Schwann cells, through their unique capacity to dedifferentiate into cells that drive the healing process. Despite that many progresses have occurred in restorative medicine and microsurgery, the regenerative process after a severe lesion of a major nerve trunk (e.g., Sunderland Types III-V) is often incomplete and functional recovery is unsatisfactory. In this aspect, it is known that glycosaminoglycans (GAGs) of the extracellular matrix are involved in proliferation, synaptogenesis, neural plasticity, and regeneration of the PNS. Here, we developed poly(caprolactone) (PCL) fibrous scaffolds functionalized with GAGs, which allowed us to assess their influence on the adhesion, proliferation, and differentiation of Schwann cells. We found that both aligned and random fiber scaffolds functionalized with GAGs resulted in increased cell proliferation on day 1. In addition, aligned functionalized scaffolds also resulted in increased GAG presence on day 1, probably because of cell extracellular matrix (ECM) formation and an increased syndecan-4 expression on day 7. A different modification and activation of Schwann cells in the presence of GAG versus no-GAG scaffolds was underlined by proteomic comparative analysis, where a general downregulation of the expression of intracellular/structural and synthetic proteins was shown on day 7 for GAG-functionalized scaffolds with regard to the nonfunctionalized ones. In conclusion, we have shown that GAG-functionalized scaffolds are effective in modulating Schwann cell behavior in terms of adhesion, proliferation, and differentiation and should be considered in strategies to improve PNS repair. STATEMENT OF SIGNIFICANCE: Nerve fibers functional recovery following a severe trauma of the Peripheral Nervous System (PNS) still represents a huge challenge for neurosurgery nowadays. In this respect, tissue engineering is committed to develop new constructs able to guide Schwann cells by mimicking the natural extracellular matrix environment. To this purpose, we successfully fabricated polycaprolactone (PCL) scaffolds with two well-defined fiber deposition patterns, functionalized with glycosaminoglycans (GAGs) and assessed for their potential as support for Schwann cells adhesion, growth and differentiation, by both classical biochemistry and LC-MS-based proteomic profiling. By this way, we showed that PCL-GAGs scaffolds could represent a promising artificial substrate that closely mimics the recently established pattern of Schwann cells migration into the regenerating nerve and, therefore, it should be considered in strategies to improve PNS repair.
Collapse
Affiliation(s)
- Michela Idini
- Dipartimento di Scienze Biomediche University of Sassari, Viale S. Pietro 43/B, 07100 Sassari, Italy
| | - Paul Wieringa
- Department of Complex Tissue Regeneration, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Universiteitsingel 40, 6229ER Maastricht, The Netherlands
| | - Silvia Rocchiccioli
- Institute of Clinical Physiology, National Research Council, Via Moruzzi 1, 56124 Pisa, Italy
| | - Gabriele Nieddu
- Dipartimento di Scienze Biomediche University of Sassari, Viale S. Pietro 43/B, 07100 Sassari, Italy
| | - Nadia Ucciferri
- Institute of Clinical Physiology, National Research Council, Via Moruzzi 1, 56124 Pisa, Italy
| | - Marilena Formato
- Dipartimento di Scienze Biomediche University of Sassari, Viale S. Pietro 43/B, 07100 Sassari, Italy
| | - Antonio Lepedda
- Dipartimento di Scienze Biomediche University of Sassari, Viale S. Pietro 43/B, 07100 Sassari, Italy
| | - Lorenzo Moroni
- Dipartimento di Scienze Biomediche University of Sassari, Viale S. Pietro 43/B, 07100 Sassari, Italy; Department of Complex Tissue Regeneration, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Universiteitsingel 40, 6229ER Maastricht, The Netherlands.
| |
Collapse
|
|
28
|
Dietzmeyer N, Förthmann M, Leonhard J, Helmecke O, Brandenberger C, Freier T, Haastert-Talini K. Two-Chambered Chitosan Nerve Guides With Increased Bendability Support Recovery of Skilled Forelimb Reaching Similar to Autologous Nerve Grafts in the Rat 10 mm Median Nerve Injury and Repair Model. Front Cell Neurosci 2019; 13:149. [PMID: 31133803 PMCID: PMC6523043 DOI: 10.3389/fncel.2019.00149] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 04/08/2019] [Indexed: 12/18/2022] Open
Abstract
Tension-free surgical reconstruction of transected digital nerves in humans is regularly performed using autologous nerve grafts (ANGs) or bioartificial nerve grafts. Nerve grafts with increased bendability are needed to protect regenerating nerves in highly mobile extremity parts. We have recently demonstrated increased bendability and regeneration supporting properties of chitosan nerve guides with a corrugated outer wall (corrCNGs) in the common rat sciatic nerve model (model of low mobility). Here, we further modified the hollow corrCNGs into two-chambered nerve guides by inserting a perforated longitudinal chitosan-film (corrCNG[F]s) and comprehensively monitored functional recovery in the advanced rat median nerve model. In 16 adult female Lewis rats, we bilaterally reconstructed 10 mm median nerve gaps with either ANGs, standard chitosan nerve guides (CNGs), CNGs (CNG[F]s), or corrCNG[F]s (n = 8, per group). Over 16 weeks, functional recovery of each forelimb was separately surveyed using the grasping test (reflex-based motor task), the staircase test (skilled forelimb reaching task), and non-invasive electrophysiological recordings from the thenar muscles. Finally, regenerated tissue harvested from the distal part of the nerve grafts was paraffin-embedded and cross-sections were analyzed regarding the number of Neurofilament 200-immunopositive axons and the area of newly formed blood vessels. Nerve tissue harvested distal to the grafts was epon-embedded and semi-thin cross-sections underwent morphometrical analyses (e.g., number of myelinated axons, axon and fiber diameters, and myelin thicknesses). Functional recovery was fastest and most complete in the ANG group (100% recovery rate regarding all parameters), but corrCNG[F]s accelerated the recovery of all functions evaluated in comparison to the other nerve guides investigated. Furthermore, corrCNG[F]s supported recovery of reflex-based grasping (87.5%) and skilled forelimb reaching (100%) to eventually significantly higher rates than the other nerve guides (grasping test: CNGs: 75%, CNG[F]s: 62.5%; staircase test: CNGs: 66.7%, CNG[F]s: 83.3%). Histological and nerve morphometrical evaluations, in accordance to the functional results, demonstrated best outcome in the ANG group and highest myelin thicknesses in the corrCNG[F] group compared to the CNG and CNG[F] groups. We thus clearly demonstrate that corrCNG[F]s represent promising innovative nerve grafts for nerve repair in mobile body parts such as digits.
Collapse
Affiliation(s)
- Nina Dietzmeyer
- Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hanover, Germany.,Center for Systems Neuroscience (ZSN) Hannover, Hanover, Germany
| | - Maria Förthmann
- Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hanover, Germany.,Center for Systems Neuroscience (ZSN) Hannover, Hanover, Germany
| | - Julia Leonhard
- Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hanover, Germany
| | | | | | | | - Kirsten Haastert-Talini
- Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hanover, Germany.,Center for Systems Neuroscience (ZSN) Hannover, Hanover, Germany
| |
Collapse
|
|
29
|
Mohammad-Bagher G, Arash A, Morteza BR, Naser MS, Ali M. Synergistic Effects of Acetyl-l-Carnitine and Adipose-Derived Stromal Cells on Improving Regenerative Capacity of Acellular Nerve Allograft in Sciatic Nerve Defect. J Pharmacol Exp Ther 2019; 368:490-502. [PMID: 30591528 DOI: 10.1124/jpet.118.254540] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Accepted: 12/19/2018] [Indexed: 12/15/2022] Open
Abstract
The combination of decellularized nerve allograft and adipose-derived stromal cells (ASCs) represents a good alternative to nerve autograft for bridging peripheral nerve defects by providing physical guidance and biologic cues. However, the regeneration outcome of acellular nerve allograft (ANA) is often inferior to autograft. Therefore, we hypothesized that acetyl-l-carnitine (ALCAR) treatment and implantation of ASC-embedded ANA would work synergistically to promote nerve regeneration. Seventy rats were randomly allocated into seven experimental groups (n = 10), including the healthy control group, sham surgery group, autograft group, ANA group, ANA + ASCs group, ANA + ALCAR group (50 mg/kg for 2 weeks), and ANA + ASCs + ALCAR (50 mg/kg for 2 weeks) group. All grafts were implanted to bridge long-gap (10-mm) sciatic nerve defects. Functional, electrophysiological, and morphologic analysis was conducted during the experimental period. We found that ALCAR potentiated the survival and retention of transplanted ASCs and upregulated the expression of neurotrophic factor mRNAs in transplanted grafts. Sixteen weeks following implantation in the rat, the ANA supplemented by ASCs was capable of supporting reinnervation across a 10-mm sciatic nerve gap, with results close to that of the autografts in terms of functional, electrophysiological, and histologic assessments. Results demonstrated that ALCAR treatment improved regenerative effects of ANA combined with ASCs on reconstruction of a 10-mm sciatic nerve defect in rat comparable to those of autograft.
Collapse
Affiliation(s)
- Ghayour Mohammad-Bagher
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran (G.M.-B., B.-R.M., M.-S.N., M.A.); Department of Engineering Sciences, Faculty of Advanced Technologies, University of Mohaghegh Ardabili, Namin, Iran (A.A.); and Bio Science and Biotechnology Research center (BBRC), Sabalan University of Advanced Technologies (SUAT), Namin, Iran (A.A.)
| | - Abdolmaleki Arash
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran (G.M.-B., B.-R.M., M.-S.N., M.A.); Department of Engineering Sciences, Faculty of Advanced Technologies, University of Mohaghegh Ardabili, Namin, Iran (A.A.); and Bio Science and Biotechnology Research center (BBRC), Sabalan University of Advanced Technologies (SUAT), Namin, Iran (A.A.)
| | - Behnam-Rassouli Morteza
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran (G.M.-B., B.-R.M., M.-S.N., M.A.); Department of Engineering Sciences, Faculty of Advanced Technologies, University of Mohaghegh Ardabili, Namin, Iran (A.A.); and Bio Science and Biotechnology Research center (BBRC), Sabalan University of Advanced Technologies (SUAT), Namin, Iran (A.A.)
| | - Mahdavi-Shahri Naser
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran (G.M.-B., B.-R.M., M.-S.N., M.A.); Department of Engineering Sciences, Faculty of Advanced Technologies, University of Mohaghegh Ardabili, Namin, Iran (A.A.); and Bio Science and Biotechnology Research center (BBRC), Sabalan University of Advanced Technologies (SUAT), Namin, Iran (A.A.)
| | - Moghimi Ali
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran (G.M.-B., B.-R.M., M.-S.N., M.A.); Department of Engineering Sciences, Faculty of Advanced Technologies, University of Mohaghegh Ardabili, Namin, Iran (A.A.); and Bio Science and Biotechnology Research center (BBRC), Sabalan University of Advanced Technologies (SUAT), Namin, Iran (A.A.)
| |
Collapse
|
|
30
|
Chen S, Zhao Y, Yan X, Zhang L, Li G, Yang Y. PAM/GO/gel/SA composite hydrogel conduit with bioactivity for repairing peripheral nerve injury. J Biomed Mater Res A 2019; 107:1273-1283. [DOI: 10.1002/jbm.a.36637] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 01/02/2019] [Accepted: 01/28/2019] [Indexed: 11/06/2022]
Affiliation(s)
- Shiyu Chen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of EducationNantong University 226001, Nantong People's Republic of China
- Co‐innovation Center of NeuroregenerationNantong University 226001, Nantong People's Republic of China
| | - Yinxin Zhao
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of EducationNantong University 226001, Nantong People's Republic of China
- Co‐innovation Center of NeuroregenerationNantong University 226001, Nantong People's Republic of China
| | - Xiaoli Yan
- Jiangsu Testing and Inspection Institute for Medical Devices 17 Kangwen Road, Nanjing JS 210019 People's Republic of China
| | - Luzhong Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of EducationNantong University 226001, Nantong People's Republic of China
- Co‐innovation Center of NeuroregenerationNantong University 226001, Nantong People's Republic of China
| | - Guicai Li
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of EducationNantong University 226001, Nantong People's Republic of China
- Co‐innovation Center of NeuroregenerationNantong University 226001, Nantong People's Republic of China
| | - Yumin Yang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of EducationNantong University 226001, Nantong People's Republic of China
- Co‐innovation Center of NeuroregenerationNantong University 226001, Nantong People's Republic of China
| |
Collapse
|
|
31
|
Gu J, Xu H, Xu YP, Liu HH, Lang JT, Chen XP, Xu WH, Deng Y, Fan JP. Olfactory ensheathing cells promote nerve regeneration and functional recovery after facial nerve defects. Neural Regen Res 2019; 14:124-131. [PMID: 30531086 PMCID: PMC6263002 DOI: 10.4103/1673-5374.243717] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Olfactory ensheathing cells from the olfactory bulb and olfactory mucosa have been found to increase axonal sprouting and pathfinding and promote the recovery of vibrissae motor performance in facial nerve transection injured rats. However, it is not yet clear whether olfactory ensheathing cells promote the reparation of facial nerve defects in rats. In this study, a collagen sponge and silicone tube neural conduit was implanted into the 6-mm defect of the buccal branch of the facial nerve in adult rats. Olfactory ensheathing cells isolated from the olfactory bulb of newborn Sprague-Dawley rats were injected into the neural conduits connecting the ends of the broken nerves, the morphology and function of the regenerated nerves were compared between the rats implanted with olfactory ensheathing cells with the rats injected with saline. Facial paralysis was assessed. Nerve electrography was used to measure facial nerve-induced action potentials. Visual inspection, anatomical microscopy and hematoxylin-eosin staining were used to assess the histomorphology around the transplanted neural conduit and the morphology of the regenerated nerve. Using fluorogold retrograde tracing, toluidine blue staining and lead uranyl acetate staining, we also measured the number of neurons in the anterior exterior lateral facial nerve motor nucleus, the number of myelinated nerve fibers, and nerve fiber diameter and myelin sheath thickness, respectively. After surgery, olfactory ensheathing cells decreased facial paralysis and the latency of the facial nerve-induced action potentials. There were no differences in the general morphology of the regenerating nerves between the rats implanted with olfactory ensheathing cells and the rats injected with saline. Between-group results showed that olfactory ensheathing cell treatment increased the number of regenerated neurons, improved nerve fiber morphology, and increased the number of myelinated nerve fibers, nerve fiber diameter, and myelin sheath thickness. In conclusion, implantation of olfactory ensheathing cells can promote regeneration and functional recovery after facial nerve damage in rats.
Collapse
Affiliation(s)
- Jian Gu
- Department of Otolaryngology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - He Xu
- Department of Otolaryngology Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Ya-Ping Xu
- Department of Otolaryngology Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Huan-Hai Liu
- Department of Otolaryngology Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jun-Tian Lang
- Department of Otolaryngology Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Xiao-Ping Chen
- Department of Otolaryngology Head and Neck Surgery, Gongli Hospital, Second Military Medical University, Shanghai, China
| | - Wei-Hua Xu
- Department of Otolaryngology Head and Neck Surgery, Gongli Hospital, Second Military Medical University, Shanghai, China
| | - Yue Deng
- Department of Otolaryngology Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jing-Ping Fan
- Department of Otolaryngology Head and Neck Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| |
Collapse
|
|
32
|
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.
Collapse
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
| |
Collapse
|
|
33
|
Siemionow M, Cwykiel J, Uygur S, Kwiecien G, Oztürk C, Szopinski J, Madajka M. Application of epineural sheath conduit for restoration of 6-cm long nerve defects in a sheep median nerve model. Microsurgery 2018; 39:332-339. [PMID: 30512213 DOI: 10.1002/micr.30393] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 09/12/2018] [Accepted: 10/05/2018] [Indexed: 11/08/2022]
Abstract
BACKGROUND Due to limited number of studies, we tested feasibility of autologous epineural sheath conduit (ESC) in repair of 6-cm median nerve gaps in a sheep-the large animal model. MATERIALS AND METHODS Eight ewes, 6-8 months old, 30-35 kg, were divided into three experimental groups: group 1-no defect repair (n = 4 nerves/group), group 2-autograft controls (n = 6 nerves/group), group 3-autologous ESC filled with saline (n = 6 nerves/group). ESC was constructed from a 6-cm long segment of sheep median nerve and tested for expression of laminin B, Glial fibrillary acidic protein (GFAP), S-100 and CD31 using immunofluorescent staining. At 6 months after nerve repair, nerve conduction velocity and somatosensory evoked potentials (SSEP) assessed neurosensory recovery, while histomorphometry tested nerve regeneration. RESULTS Ex vivo characterization of ESC, before in vivo nerve gap repair, showed high laminin B expression, which supports axonal growth. At 6 months post-repair, structural integrity of ESC was preserved. ESC was well-vascularized and tissue adhesions were comparable to autograft controls. The maximal conduction velocities (29.80 ± 5.85 ms vs. 32.28 ± 6.75 ms; p = .44), action potential amplitudes (32.68 ± 17.44 mV vs. 44.14 ± 23.10 mV; p = .38) and SSEP amplitude values (6.18 ± 5.84 mV vs. 4.68 ± 2.53 mV; p = .28) were comparable between autograft and ESC groups. Presence of regenerating axons was confirmed in the distal segment of ESC at 6 months after repair. CONCLUSION The feasibility of ESC in restoration of 6-cm long nerve defects in a sheep median nerve model was confirmed by nerve conduction assessments and correlated with axonal regeneration tested by histomorphometry. We confirmed ESC potential in support of regeneration of long nerve defects.
Collapse
Affiliation(s)
- Maria Siemionow
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, Illinois.,Department of Plastic Surgery, Cleveland Clinic, Cleveland, Ohio
| | - Joanna Cwykiel
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, Illinois.,Department of Plastic Surgery, Cleveland Clinic, Cleveland, Ohio
| | - Safak Uygur
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, Illinois
| | | | - Can Oztürk
- Department of Plastic Surgery, Cleveland Clinic, Cleveland, Ohio
| | - Jacek Szopinski
- Department of Plastic Surgery, Cleveland Clinic, Cleveland, Ohio.,Department of General Surgery, Hepatobiliary Surgery and Transplant Surgery, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Torun, Poland
| | - Maria Madajka
- Department of Plastic Surgery, Cleveland Clinic, Cleveland, Ohio
| |
Collapse
|
|
34
|
Magaz A, Faroni A, Gough JE, Reid AJ, Li X, Blaker JJ. Bioactive Silk-Based Nerve Guidance Conduits for Augmenting Peripheral Nerve Repair. Adv Healthc Mater 2018; 7:e1800308. [PMID: 30260575 DOI: 10.1002/adhm.201800308] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 05/22/2018] [Indexed: 02/03/2023]
Abstract
Repair of peripheral nerve injuries depends upon complex biology stemming from the manifold and challenging injury-healing processes of the peripheral nervous system. While surgical treatment options are available, they tend to be characterized by poor clinical outcomes for the injured patients. This is particularly apparent in the clinical management of a nerve gap whereby nerve autograft remains the best clinical option despite numerous limitations; in addition, effective repair becomes progressively more difficult with larger gaps. Nerve conduit strategies based on tissue engineering approaches and the use of silk as scaffolding material have attracted much attention in recent years to overcome these limitations and meet the clinical demand of large gap nerve repair. This review examines the scientific advances made with silk-based conduits for peripheral nerve repair. The focus is on enhancing bioactivity of the conduits in terms of physical guidance cues, inner wall and lumen modification, and imbuing novel conductive functionalities.
Collapse
Affiliation(s)
- Adrián Magaz
- Bio‐Active Materials GroupSchool of MaterialsMSS TowerThe University of Manchester Manchester M13 9PL UK
- Institute of Materials Research and Engineering (IMRE)Agency for Science Technology and Research (A*STAR) 2 Fusionopolis, Way, Innovis #08‐03 Singapore 138634 Singapore
| | - Alessandro Faroni
- Blond McIndoe LaboratoriesDivision of Cell Matrix Biology and Regenerative MedicineSchool of Biological SciencesFaculty of Biology, Medicine and HealthThe University of ManchesterManchester Academic Health Science Centre Manchester M13 9PL UK
| | - Julie E. Gough
- School of MaterialsThe University of Manchester Manchester M13 9PL UK
| | - Adam J. Reid
- Blond McIndoe LaboratoriesDivision of Cell Matrix Biology and Regenerative MedicineSchool of Biological SciencesFaculty of Biology, Medicine and HealthThe University of ManchesterManchester Academic Health Science Centre Manchester M13 9PL UK
- Department of Plastic Surgery and BurnsWythenshawe HospitalManchester University NHS Foundation TrustManchester Academic Health Science Centre Manchester M23 9LT UK
| | - Xu Li
- Institute of Materials Research and Engineering (IMRE)Agency for Science Technology and Research (A*STAR) 2 Fusionopolis, Way, Innovis #08‐03 Singapore 138634 Singapore
| | - Jonny J. Blaker
- Bio‐Active Materials GroupSchool of MaterialsMSS TowerThe University of Manchester Manchester M13 9PL UK
- School of MaterialsThe University of Manchester Manchester M13 9PL UK
| |
Collapse
|
|
35
|
Neumann B, Linton C, Giordano-Santini R, Hilliard MA. Axonal fusion: An alternative and efficient mechanism of nerve repair. Prog Neurobiol 2018; 173:88-101. [PMID: 30500382 DOI: 10.1016/j.pneurobio.2018.11.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 11/22/2018] [Accepted: 11/26/2018] [Indexed: 02/07/2023]
Abstract
Injuries to the nervous system can cause lifelong morbidity due to the disconnect that occurs between nerve cells and their cellular targets. Re-establishing these lost connections is the ultimate goal of endogenous regenerative mechanisms, as well as those induced by exogenous manipulations in a laboratory or clinical setting. Reconnection between severed neuronal fibers occurs spontaneously in some invertebrate species and can be induced in mammalian systems. This process, known as axonal fusion, represents a highly efficient means of repair after injury. Recent progress has greatly enhanced our understanding of the molecular control of axonal fusion, demonstrating that the machinery required for the engulfment of apoptotic cells is repurposed to mediate the reconnection between severed axon fragments, which are subsequently merged by fusogen proteins. Here, we review our current understanding of naturally occurring axonal fusion events, as well as those being ectopically produced with the aim of achieving better clinical outcomes.
Collapse
Affiliation(s)
- Brent Neumann
- Neuroscience Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne VIC 3800, Australia.
| | - Casey Linton
- Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Rosina Giordano-Santini
- Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Massimo A Hilliard
- Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
| |
Collapse
|
|
36
|
Liu Y, Yu F, Zhang B, Zhou M, Bei Y, Zhang Y, Tang J, Yang Y, Huang Y, Xiang Q, Zhao Y, Liang Q, Liu Y. Improving the protective effects of aFGF for peripheral nerve injury repair using sulfated chitooligosaccharides. Asian J Pharm Sci 2018; 14:511-520. [PMID: 32104478 PMCID: PMC7032102 DOI: 10.1016/j.ajps.2018.09.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Revised: 08/17/2018] [Accepted: 09/27/2018] [Indexed: 01/07/2023] Open
Abstract
Injury to the peripheral nerves can result in temporary or life-long neuronal dysfunction and subsequent economic or social disability. Acidic fibroblast growth factor (aFGF) promotes the growth and survival of neurons and is a possible treatment for peripheral nerve injury. Yet, the actual therapeutic utility of aFGF is limited by its short half-life and instability in vivo. In the present study, we prepared sulfated chitooligosaccharides (SCOS), which have heparin-like properties, to improve the bioactivity of aFGF. We investigated the protective effects of SCOS with or without aFGF on RSC96 cells exposed to Na2S2O4 hypoxia/reoxygenation injury. Cell viability was measured by MTT assay and cytotoxicity induced by Na2S2O4 was assessed by lactate dehydrogenase (LDH) release into the culture medium. Pretreatment with aFGF and SCOS dramatically decreased LDH release after injury compared to pretreatment with aFGF or SCOS alone. We subsequently prepared an aFGF/SCOS thermo-sensitive hydrogel with poloxamer and examined its effects in vivo. Paw withdrawal thresholds and thermal withdrawal latencies were measured in rats with sciatic nerve injury. Local injection of the aFGF/SCOS hydrogels (aFGF: 40, 80 µg/kg) increased the efficiency of sciatic nerve repair compared to aFGF (80 µg/kg) hydrogel alone. Especially aFGF/SCOS thermo-sensitive hydrogel decreased paw withdrawal thresholds from 117.75 ± 8.38 (g, 4 d) to 65.74 ± 3.39 (g, 10 d), but aFGF alone group were 140.58 ± 27.54 (g, 4 d) to 89.12 ± 5.60 (g, 10 d) (aFGF dose was 80 µg/kg, P < 0.05, n = 8). The thermal withdrawal latencies decreased from 11.61 ± 2.26 (s, 4 d) to 2.37 ±0.67 (s, 10 d). However, aFGF alone group were from 17.69 ± 1.47 (s, 4 d) to 4.65 ± 1.73 (s, 10 d) (P < 0.05, n = 8). Furthermore, the aFGF/SCOS hydrogels also exhibited good biocompatibility in mice. In summary, SCOS improved the protective effects of aFGF in RSC96 cells injured with Na2S2O4 and increased the efficiency of nerve repair and recovery of function in rats with sciatic nerve injury. These findings pave an avenue for the development of novel prophylactic and therapeutic strategies for peripheral nerve injury.
Collapse
Affiliation(s)
- Yanmei Liu
- Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China
| | - Fenglin Yu
- Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China
| | - Beibei Zhang
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Meng Zhou
- College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Yu Bei
- College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Yifan Zhang
- Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China
| | - Jianzhong Tang
- Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China
| | - Yan Yang
- Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China
| | - Yadong Huang
- Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China.,College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Qi Xiang
- Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou 510632, China.,College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Yueping Zhao
- Department of Stomatology, Jinan University Medical College, Guangzhou 510632, China
| | - Qian Liang
- Department of Stomatology, Jinan University Medical College, Guangzhou 510632, China
| | - Yang Liu
- Department of Stomatology, Jinan University Medical College, Guangzhou 510632, China
| |
Collapse
|
|
37
|
Maiti B, Díaz Díaz D. 3D Printed Polymeric Hydrogels for Nerve Regeneration. Polymers (Basel) 2018; 10:E1041. [PMID: 30960966 PMCID: PMC6403752 DOI: 10.3390/polym10091041] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 09/12/2018] [Accepted: 09/14/2018] [Indexed: 12/23/2022] Open
Abstract
The human nervous system lacks an inherent ability to regenerate its components upon damage or diseased conditions. During the last decade, this has motivated the development of a number of strategies for nerve regeneration. However, most of those approaches have not been used in clinical applications till today. For instance, although biomaterial-based scaffolds have been extensively used for nerve reparation, the lack of more customized structures have hampered their use in vivo. This highlight focuses mainly on how 3D bioprinting technology, using polymeric hydrogels as bio-inks, can be used for the development of new nerve guidance channels or devices for peripheral nerve cell regeneration. In this concise contribution, some of the most recent and representative examples are highlighted to discuss the challenges involved in various aspects of 3D bioprinting for nerve cell regeneration, specifically when using polymeric hydrogels.
Collapse
Affiliation(s)
- Binoy Maiti
- Institute of Organic Chemistry, University of Regensburg, Universitätstr. 31, 93053 Regensburg, Germany.
| | - David Díaz Díaz
- Institute of Organic Chemistry, University of Regensburg, Universitätstr. 31, 93053 Regensburg, Germany.
- Instituto de Química Avanzada de Cataluña-Consejo Superior de Investigaciones Científicas (IQAC-CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain.
| |
Collapse
|
|
38
|
Carvalho CR, Wrobel S, Meyer C, Brandenberger C, Cengiz IF, López-Cebral R, Silva-Correia J, Ronchi G, Reis RL, Grothe C, Oliveira JM, Haastert-Talini K. Gellan Gum-based luminal fillers for peripheral nerve regeneration: an in vivo study in the rat sciatic nerve repair model. Biomater Sci 2018; 6:1059-1075. [PMID: 29464240 DOI: 10.1039/c7bm01101f] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Peripheral nerve injuries (PNI) resulting in a gap to be bridged between the transected nerve ends are commonly reconstructed with autologous nerve tissue, but there is a need for valuable alternatives. This experimental work considers the innovative use of the biomaterial Gellan Gum (GG) as a luminal filler for nerve guidance channels made from chitosan with a 5% degree of acetylation. The engineered constructs should remodel the structural support given to regenerating axons by the so-called bands of Büngner. Four different GG formulations were produced by combining varying amounts of High-Acyl GG (HA-GG) and Methacrylated GG (MA-GG). The effective porosity of the freeze-dried networks was analysed by SEM and micro-CT 3D reconstructions, while the degradation and swelling abilities were characterized in vitro for up to 30 days. The metabolic activity and viability of immortalized Schwann cells seeded onto the freeze-dried networks were also evaluated. Finally, the developed hydrogel formulations were freeze-dried within the chitosan nerve guides and implanted in a 10 mm rat sciatic nerve defect. Functional and histomorphological analyses after 3, 6, and 12 weeks in vivo revealed that although it did not result in improved nerve regeneration, the NGC25:75 formulations could provide a basis for further development of GG scaffolds as luminal fillers for hollow nerve guidance channels.
Collapse
Affiliation(s)
- C R Carvalho
- 3B's Research Group - Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark - Parque de Ciência e Tecnologia, Zona Industrial de Gandra, 4805-017 Barco, Guimarães, Portugal.
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Riccio M, Marchesini A, Pugliese P, Francesco F. Nerve repair and regeneration: Biological tubulization limits and future perspectives. J Cell Physiol 2018; 234:3362-3375. [DOI: 10.1002/jcp.27299] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Accepted: 08/01/2018] [Indexed: 12/20/2022]
Affiliation(s)
- Michele Riccio
- Department of Reconstructive Surgery and Hand Surgery AOU “Ospedali Riuniti,” Ancona Italy
| | - Andrea Marchesini
- Department of Reconstructive Surgery and Hand Surgery AOU “Ospedali Riuniti,” Ancona Italy
| | - Pierfrancesco Pugliese
- Department of Reconstructive Surgery and Hand Surgery AOU “Ospedali Riuniti,” Ancona Italy
| | - Francesco Francesco
- Department of Reconstructive Surgery and Hand Surgery AOU “Ospedali Riuniti,” Ancona Italy
| |
Collapse
|
|
40
|
Geuna S, Muratori L, Fregnan F, Manfredi M, Bertolo R, Porpiglia F. Strategies to improve nerve regeneration after radical prostatectomy: a narrative review. MINERVA UROL NEFROL 2018; 70:546-558. [PMID: 30037210 DOI: 10.23736/s0393-2249.18.03157-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Peripheral nerves are complex organs that spread throughout the entire human body. They are frequently affected by lesions not only as a result of trauma but also following radical tumor resection. In fact, despite the advancement in surgical techniques, such as nerve-sparing robot assisted radical prostatectomy, some degree of nerve injury may occur resulting in erectile dysfunction with significant impairment of the quality of life. The aim of this review was to provide an overview on the mechanisms of the regeneration of injured peripheral nerves and to describe the potential strategies to improve the regeneration process and the functional recovery. Yet, the recent advances in bio-engineering strategies to promote nerve regeneration in the urological field are outlined with a view on the possible future regenerative therapies which might ameliorate the functional outcome after radical prostatectomy.
Collapse
Affiliation(s)
- Stefano Geuna
- Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy - .,Neuroscience Institute Cavalieri Ottolenghi (NICO), Orbassano, Turin, Italy -
| | - Luisa Muratori
- Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy.,Neuroscience Institute Cavalieri Ottolenghi (NICO), Orbassano, Turin, Italy
| | - Federica Fregnan
- Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy.,Neuroscience Institute Cavalieri Ottolenghi (NICO), Orbassano, Turin, Italy
| | - Matteo Manfredi
- Department of Oncology, University of Turin, Orbassano, Turin, Italy
| | - Riccardo Bertolo
- Department of Oncology, University of Turin, Orbassano, Turin, Italy.,Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA
| | | |
Collapse
|
|
41
|
McGrath AM, Brohlin M, Wiberg R, Kingham PJ, Novikov LN, Wiberg M, Novikova LN. Long-Term Effects of Fibrin Conduit with Human Mesenchymal Stem Cells and Immunosuppression after Peripheral Nerve Repair in a Xenogenic Model. CELL MEDICINE 2018; 10:2155179018760327. [PMID: 32634185 PMCID: PMC6172997 DOI: 10.1177/2155179018760327] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 01/07/2018] [Accepted: 01/12/2018] [Indexed: 12/22/2022]
Abstract
Introduction: Previously we showed that a fibrin glue conduit with human mesenchymal stem cells
(hMSCs) and cyclosporine A (CsA) enhanced early nerve regeneration. In this study long
term effects of this conduit are investigated. Methods: In a rat model, the sciatic nerve was repaired with fibrin conduit containing fibrin
matrix, fibrin conduit containing fibrin matrix with CsA treatment and fibrin conduit
containing fibrin matrix with hMSCs and CsA treatment, and also with nerve graft as
control. Results: At 12 weeks 34% of motoneurons of the control group regenerated axons through the
fibrin conduit. CsA treatment alone or with hMSCs resulted in axon regeneration of 67%
and 64% motoneurons respectively. The gastrocnemius muscle weight was reduced in the
conduit with fibrin matrix. The treatment with CsA or CsA with hMSCs induced recovery of
the muscle weight and size of fast type fibers towards the levels of the nerve graft
group. Discussion: The transplantation of hMSCs for peripheral nerve injury should be optimized to
demonstrate their beneficial effects. The CsA may have its own effect on nerve
regeneration.
Collapse
Affiliation(s)
- Aleksandra M McGrath
- Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden.,Department of Surgical and Perioperative Science, Section for Hand and Plastic Surgery, Norrland's University Hospital, Umeå, Sweden
| | - Maria Brohlin
- Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden.,Department of Clinical Microbiology, Infection and Immunology, Umeå University, Umeå, Sweden
| | - Rebecca Wiberg
- Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden.,Department of Surgical and Perioperative Science, Section for Hand and Plastic Surgery, Norrland's University Hospital, Umeå, Sweden
| | - Paul J Kingham
- Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden
| | - Lev N Novikov
- Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden
| | - Mikael Wiberg
- Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden.,Department of Surgical and Perioperative Science, Section for Hand and Plastic Surgery, Norrland's University Hospital, Umeå, Sweden
| | - Liudmila N Novikova
- Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden
| |
Collapse
|
|
42
|
Du J, Chen H, Qing L, Yang X, Jia X. Biomimetic neural scaffolds: a crucial step towards optimal peripheral nerve regeneration. Biomater Sci 2018; 6:1299-1311. [PMID: 29725688 PMCID: PMC5978680 DOI: 10.1039/c8bm00260f] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Peripheral nerve injury is a common disease that affects more than 20 million people in the United States alone and remains a major burden to society. The current gold standard treatment for critical-sized nerve defects is autologous nerve graft transplantation; however, this method is limited in many ways and does not always lead to satisfactory outcomes. The limitations of autografts have prompted investigations into artificial neural scaffolds as replacements, and some neural scaffold devices have progressed to widespread clinical use; scaffold technology overall has yet to be shown to be consistently on a par with or superior to autografts. Recent advances in biomimetic scaffold technologies have opened up many new and exciting opportunities, and novel improvements in material, fabrication technique, scaffold architecture, and lumen surface modifications that better reflect biological anatomy and physiology have independently been shown to benefit overall nerve regeneration. Furthermore, biomimetic features of neural scaffolds have also been shown to work synergistically with other nerve regeneration therapy strategies such as growth factor supplementation, stem cell transplantation, and cell surface glycoengineering. This review summarizes the current state of neural scaffolds, highlights major advances in biomimetic technologies, and discusses future opportunities in the field of peripheral nerve regeneration.
Collapse
Affiliation(s)
- Jian Du
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. ; Tel: +1 410-706-5025
| | - Huanwen Chen
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. ; Tel: +1 410-706-5025
| | - Liming Qing
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. ; Tel: +1 410-706-5025
| | - Xiuli Yang
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. ; Tel: +1 410-706-5025
| | - Xiaofeng Jia
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. ; Tel: +1 410-706-5025
- Department of Orthopedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| |
Collapse
|
|
43
|
Stößel M, Wildhagen VM, Helmecke O, Metzen J, Pfund CB, Freier T, Haastert-Talini K. Comparative Evaluation of Chitosan Nerve Guides with Regular or Increased Bendability for Acute and Delayed Peripheral Nerve Repair: A Comprehensive Comparison with Autologous Nerve Grafts and Muscle-in-Vein Grafts. Anat Rec (Hoboken) 2018; 301:1697-1713. [PMID: 29740965 DOI: 10.1002/ar.23847] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Revised: 11/01/2017] [Accepted: 11/15/2017] [Indexed: 12/13/2022]
Abstract
Reconstruction of joint-crossing digital nerves requires the application of nerve guides with a much higher flexibility than used for peripheral nerve repair along larger bones. Nevertheless, collapse-resistance should be preserved to avoid secondary damage to the regrowing nerve tissue. In recent years, we presented chitosan nerve guides (CNGs) to be highly supportive for the regeneration of critical gap length peripheral nerve defects in the rat. Now, we evidently increased the bendability of regular CNGs (regCNGs) by developing a wavy wall structure, that is, corrugated CNGs (corrCNGs). In a comprehensive in vivo study, we compared both types of CNGs with clinical gold standard autologous nerve grafts (ANGs) and muscle-in-vein grafts (MVGs) that have recently been highlighted in the literature as a suitable alternative to ANGs. We reconstructed rat sciatic nerves over a critical gap length of 15 mm either immediately upon transection or after a delay period of 45 days. Electrodiagnostic measurements were applied to monitor functional motor recovery at 60, 90, 120, and 150 (only delayed repair) days postreconstruction. Upon explanation, tube properties were analyzed. Furthermore, distal nerve ends were evaluated using histomorphometry, while connective tissue specimens were subjected to immunohistological stainings. After 120 days (acute repair) or 150 days (delayed repair), respectively, compression-stability of regCNGs was slightly increased while it remained stable in corrCNGs. In both substudies, regCNGs and corrCNGs supported functional recovery of distal plantar muscles in a similar way and to a greater extent when compared with MVGs, while ANGs demonstrated the best support of regeneration. Anat Rec, 301:1697-1713, 2018. © 2018 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Maria Stößel
- Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.,Center for Systems Neuroscience (ZSN), Hannover, 30559, Germany
| | - Vivien M Wildhagen
- Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Germany
| | - Olaf Helmecke
- Medovent GmbH, Friedrich-Koenig-Str. 3, Mainz, 55129, Germany
| | - Jennifer Metzen
- Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Germany
| | - Charlotte B Pfund
- Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Germany
| | - Thomas Freier
- Medovent GmbH, Friedrich-Koenig-Str. 3, Mainz, 55129, Germany
| | - Kirsten Haastert-Talini
- Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.,Center for Systems Neuroscience (ZSN), Hannover, 30559, Germany
| |
Collapse
|
|
44
|
Patel NP, Lyon KA, Huang JH. An update-tissue engineered nerve grafts for the repair of peripheral nerve injuries. Neural Regen Res 2018; 13:764-774. [PMID: 29862995 PMCID: PMC5998615 DOI: 10.4103/1673-5374.232458] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/28/2018] [Indexed: 01/04/2023] Open
Abstract
Peripheral nerve injuries (PNI) are caused by a range of etiologies and result in a broad spectrum of disability. While nerve autografts are the current gold standard for the reconstruction of extensive nerve damage, the limited supply of autologous nerve and complications associated with harvesting nerve from a second surgical site has driven groups from multiple disciplines, including biomedical engineering, neurosurgery, plastic surgery, and orthopedic surgery, to develop a suitable or superior alternative to autografting. Over the last couple of decades, various types of scaffolds, such as acellular nerve grafts (ANGs), nerve guidance conduits, and non-nervous tissues, have been filled with Schwann cells, stem cells, and/or neurotrophic factors to develop tissue engineered nerve grafts (TENGs). Although these have shown promising effects on peripheral nerve regeneration in experimental models, the autograft has remained the gold standard for large nerve gaps. This review provides a discussion of recent advances in the development of TENGs and their efficacy in experimental models. Specifically, TENGs have been enhanced via incorporation of genetically engineered cells, methods to improve stem cell survival and differentiation, optimized delivery of neurotrophic factors via drug delivery systems (DDS), co-administration of platelet-rich plasma (PRP), and pretreatment with chondroitinase ABC (Ch-ABC). Other notable advancements include conduits that have been bioengineered to mimic native nerve structure via cell-derived extracellular matrix (ECM) deposition, and the development of transplantable living nervous tissue constructs from rat and human dorsal root ganglia (DRG) neurons. Grafts composed of non-nervous tissues, such as vein, artery, and muscle, will be briefly discussed.
Collapse
Affiliation(s)
| | - Kristopher A. Lyon
- Texas A&M College of Medicine, Temple, TX, USA
- Department of Neurosurgery, Baylor Scott & White Healthcare, Temple, TX, USA
| | - Jason H. Huang
- Texas A&M College of Medicine, Temple, TX, USA
- Department of Neurosurgery, Baylor Scott & White Healthcare, Temple, TX, USA
| |
Collapse
|
|
45
|
Zhao Y, Wang Y, Niu C, Zhang L, Li G, Yang Y. Construction of polyacrylamide/graphene oxide/gelatin/sodium alginate composite hydrogel with bioactivity for promoting Schwann cells growth. J Biomed Mater Res A 2018; 106:1951-1964. [DOI: 10.1002/jbm.a.36393] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Revised: 02/06/2018] [Accepted: 02/28/2018] [Indexed: 11/08/2022]
Affiliation(s)
- Yinxin Zhao
- Key Laboratory of Neuroregeneration, Ministry of Education; Nantong University; Nantong 226001 People's Republic of China
- Co-innovation Center of Neuroregeneration, Nantong University; Nantong 226001 People's Republic of China
| | - Yingjie Wang
- Key Laboratory of Neuroregeneration, Ministry of Education; Nantong University; Nantong 226001 People's Republic of China
- Co-innovation Center of Neuroregeneration, Nantong University; Nantong 226001 People's Republic of China
| | - Changmei Niu
- Key Laboratory of Neuroregeneration, Ministry of Education; Nantong University; Nantong 226001 People's Republic of China
- Co-innovation Center of Neuroregeneration, Nantong University; Nantong 226001 People's Republic of China
| | - Luzhong Zhang
- Key Laboratory of Neuroregeneration, Ministry of Education; Nantong University; Nantong 226001 People's Republic of China
- Co-innovation Center of Neuroregeneration, Nantong University; Nantong 226001 People's Republic of China
| | - Guicai Li
- Key Laboratory of Neuroregeneration, Ministry of Education; Nantong University; Nantong 226001 People's Republic of China
- Co-innovation Center of Neuroregeneration, Nantong University; Nantong 226001 People's Republic of China
| | - Yumin Yang
- Key Laboratory of Neuroregeneration, Ministry of Education; Nantong University; Nantong 226001 People's Republic of China
- Co-innovation Center of Neuroregeneration, Nantong University; Nantong 226001 People's Republic of China
| |
Collapse
|
|
46
|
Wieringa PA, Gonçalves de Pinho AR, Micera S, Wezel RJA, Moroni L. Biomimetic Architectures for Peripheral Nerve Repair: A Review of Biofabrication Strategies. Adv Healthc Mater 2018; 7:e1701164. [PMID: 29349931 DOI: 10.1002/adhm.201701164] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Revised: 11/13/2017] [Indexed: 12/19/2022]
Abstract
Biofabrication techniques have endeavored to improve the regeneration of the peripheral nervous system (PNS), but nothing has surpassed the performance of current clinical practices. However, these current approaches have intrinsic limitations that compromise patient care. The "gold standard" autograft provides the best outcomes but requires suitable donor material, while implantable hollow nerve guide conduits (NGCs) can only repair small nerve defects. This review places emphasis on approaches that create structural cues within a hollow NGC lumen in order to match or exceed the regenerative performance of the autograft. An overview of the PNS and nerve regeneration is provided. This is followed by an assessment of reported devices, divided into three major categories: isotropic hydrogel fillers, acting as unstructured interluminal support for regenerating nerves; fibrous interluminal fillers, presenting neurites with topographical guidance within the lumen; and patterned interluminal scaffolds, providing 3D support for nerve growth via structures that mimic native PNS tissue. Also presented is a critical framework to evaluate the impact of reported outcomes. While a universal and versatile nerve repair strategy remains elusive, outlined here is a roadmap of past, present, and emerging fabrication techniques to inform and motivate new developments in the field of peripheral nerve regeneration.
Collapse
Affiliation(s)
- Paul A. Wieringa
- Department of Complex Tissue RegenerationMERLN Institute for Technology‐Inspired Regenerative MedicineMaastricht University Universiteitssingel 40 Maastricht 6229 ER The Netherlands
| | - Ana Rita Gonçalves de Pinho
- Tissue Regeneration DepartmentMIRA InstituteUniversity of Twente Drienerlolaan 5 Enschede 7522 NB The Netherlands
| | - Silvestro Micera
- BioRobotics InstituteScuola Superiore Sant'Anna Viale Rinaldo Piaggio 34 Pontedera 56025 Italy
- Translational Neural Engineering LaboratoryEcole Polytechnique Federale de Lausanne Ch. des Mines 9 Geneva CH‐1202 Switzerland
| | - Richard J. A. Wezel
- BiophysicsDonders Institute for BrainCognition and BehaviourRadboud University Kapittelweg 29 Nijmegen 6525 EN The Netherlands
- Biomedical Signals and SystemsMIRA InstituteUniversity of Twente Drienerlolaan 5 Enschede 7522 NB The Netherlands
| | - Lorenzo Moroni
- Department of Complex Tissue RegenerationMERLN Institute for Technology‐Inspired Regenerative MedicineMaastricht University Universiteitssingel 40 Maastricht 6229 ER The Netherlands
| |
Collapse
|
|
47
|
Huang J, Patel N, Lyon K. An update–tissue engineered nerve grafts for the repair of peripheral nerve injuries. Neural Regen Res 2018. [DOI: 10.4103/1673-5374.232458
expr 973353844 + 912195704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
|
|
48
|
Wang Y, Li D, Wang G, Chen L, Chen J, Liu Z, Zhang Z, Shen H, Jin Y, Shen Z. The effect of co-transplantation of nerve fibroblasts and Schwann cells on peripheral nerve repair. Int J Biol Sci 2017; 13:1507-1519. [PMID: 29230099 PMCID: PMC5723917 DOI: 10.7150/ijbs.21976] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 09/10/2017] [Indexed: 01/27/2023] Open
Abstract
Combinations of fibroblasts (Fbs) and corresponding epithelial cells have been widely used in many tissues, such as the skin and breast tissues, to augment tissue repair and remodeling. Recently, a large amount of new data has indicated that nerve Fbs play critical roles in Schwann cells (SCs) and axons in vitro. However, little is known regarding the effects of co-transplanting nerve Fbs and SCs on peripheral nerve repair in vivo. The aim of this study was to investigate the effect of co-transplanting sciatic nerve Fbs (SN-Fbs) and sciatic nerve SCs (SN-SCs) on nerve regeneration. We developed a 5 mm nerve-defect model in mice using a polyurethane (PUR) catheter and then injected one of four different mixtures of cells into the catheters to form the following four groups: pure Matrigel (Control group), SN-Fbs alone (SN-Fb group), SN-Fbs combined with SN-SCs at a ratio of 1:2 (Fb&SC group) and SN-SCs alone (SN-SC group). Histological and functional analyses were performed 3 months later. The results indicated that in vitro, the expression levels of NGF, BDNF and GDNF were significantly higher, and in vivo, a more moderate amount of extracellular matrix was produced in the Fb&SC group than in the SN-SC group. Compared to the other groups, co-transplanting SN-Fbs with SCs at a 1:2 ratio had significantly positive effects on nerve regeneration and functional recovery.
Collapse
Affiliation(s)
- Yang Wang
- Department of Plastic and Reconstructive Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Dong Li
- Department of Plastic and Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Gangyang Wang
- Department of Plastic and Reconstructive Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Lulu Chen
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
| | - Jun Chen
- Department of Plastic and Reconstructive Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Zhangyin Liu
- Jiangpu Primary Health Service Center, Shanghai, People's Republic of China
| | - Zhaofeng Zhang
- Department of Plastic and Reconstructive Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Hua Shen
- Department of Plastic and Reconstructive Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Yuqing Jin
- Department of Plastic and Reconstructive Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Zunli Shen
- Department of Plastic and Reconstructive Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| |
Collapse
|
|
49
|
Wu H, Liu J, Fang Q, Xiao B, Wan Y. Establishment of nerve growth factor gradients on aligned chitosan-polylactide /alginate fibers for neural tissue engineering applications. Colloids Surf B Biointerfaces 2017; 160:598-609. [PMID: 29028608 DOI: 10.1016/j.colsurfb.2017.10.017] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Revised: 10/01/2017] [Accepted: 10/04/2017] [Indexed: 12/18/2022]
Abstract
Nerve conduits containing aligned fibrous fillers with gradiently distributed signal molecules are essential for long-gap nerve repair. This study was to develop an approach for establishing nerve growth factor (NGF) gradients onto the aligned chitosan-polylactide (CH-PLA) fibers. CH-PLA containing 37wt% of PLA was spun into fibers using a wet-spinning technique. CH-PLA fibers showed much higher wet-state tensile strength, enhanced degradation tolerance and significantly lower swelling degree in comparison to chitosan fibers. The CH-PLA fibers with diameters from 40 to 60μm were selected and segmentally coated in bundles using NGF-contained alginate solutions to establish NGF gradients lengthwise along fibers. The diameter of resulting NGF-loaded CH-PLA/alginate fibers was well controlled within a range between 60 and 120μm. Calcium ion crosslinked alginate coating layers on fibers showed abilities to administer the sustainable NGF release in a gradient distribution manner for at least 5 weeks. NGF-induced neurite outgrowth of PC12 cells confirmed that bioactivity of NGF released from fibers was well retained.
Collapse
Affiliation(s)
- Hua Wu
- Department of Nuclear Medicine and Minnan PET Center, The First Affiliated Hospital of Xiamen University, Xiamen 316003, PR China
| | - Jiaoyan Liu
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China
| | - Qing Fang
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China
| | - Bo Xiao
- Institute for Clean Energy and Advanced Materials, Faculty for Materials and Energy, Southwest University, Chongqing 400715, PR China.
| | - Ying Wan
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China.
| |
Collapse
|
|
50
|
Sayad Fathi S, Zaminy A. Stem cell therapy for nerve injury. World J Stem Cells 2017; 9:144-151. [PMID: 29026460 PMCID: PMC5620423 DOI: 10.4252/wjsc.v9.i9.144] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Revised: 06/29/2017] [Accepted: 07/14/2017] [Indexed: 02/06/2023] Open
Abstract
Peripheral nerve injury has remained a substantial clinical complication with no satisfactory treatment options. Despite the great development in the field of microsurgery, some severe types of neural injuries cannot be treated without causing tension to the injured nerve. Thus, current studies have focused on the new approaches for the treatment of peripheral nerve injuries. Stem cells with the ability to differentiate into a variety of cell types have brought a new perspective to this matter. In this review, we will discuss the use of three main sources of mesenchymal stem cells in the treatment of peripheral nerve injuries.
Collapse
Affiliation(s)
- Sara Sayad Fathi
- Department of Anatomical Sciences, School of Medicine, Guilan University of Medical Sciences, Rasht 41996-13769, Iran
| | - Arash Zaminy
- Department of Anatomical Sciences, School of Medicine, Guilan University of Medical Sciences, Rasht 41996-13769, Iran
- Neuroscience Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht 41996-13769, Iran.
| |
Collapse
|