Efficacy of hydrogels for repair of traumatic spinal cord injuries: A systematic review and meta-analysis
Zahra Ayar
Department of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
Search for more papers by this authorCorresponding Author
Zahra Hassannejad
Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
Correspondence
Zahra Hassannejad, Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
Email: [email protected]
Vafa Rahimi-Movaghar, Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Email: [email protected]
Search for more papers by this authorFarhad Shokraneh
London Institute of Healthcare Engineering, King's College London, London, UK
Cochrane Schizophrenia Group, Division of Psychiatry and Applied Psychology, School of Medicine, Institute of Mental Health, University of Nottingham, Nottingham, UK
Search for more papers by this authorNarges Saderi
Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran
Search for more papers by this authorCorresponding Author
Vafa Rahimi-Movaghar
Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran
Correspondence
Zahra Hassannejad, Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
Email: [email protected]
Vafa Rahimi-Movaghar, Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Email: [email protected]
Search for more papers by this authorZahra Ayar
Department of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
Search for more papers by this authorCorresponding Author
Zahra Hassannejad
Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
Correspondence
Zahra Hassannejad, Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
Email: [email protected]
Vafa Rahimi-Movaghar, Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Email: [email protected]
Search for more papers by this authorFarhad Shokraneh
London Institute of Healthcare Engineering, King's College London, London, UK
Cochrane Schizophrenia Group, Division of Psychiatry and Applied Psychology, School of Medicine, Institute of Mental Health, University of Nottingham, Nottingham, UK
Search for more papers by this authorNarges Saderi
Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran
Search for more papers by this authorCorresponding Author
Vafa Rahimi-Movaghar
Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran
Correspondence
Zahra Hassannejad, Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
Email: [email protected]
Vafa Rahimi-Movaghar, Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Email: [email protected]
Search for more papers by this authorFunding information: Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Grant/Award Number: 94-02-38-29104
Abstract
Hydrogels have been used as promising biomaterials for regeneration and control of pathophysiological events after traumatic spinal cord injuries (TSCI). However, no systematic comparison was conducted to show the effect of hydrogels on pathophysiological events. This study was designed to address this issue and evaluate the regenerative potential of hydrogels after TSCI. From 2857 records found in MEDLINE and EMBASE databases (April 23, 2021), 49 articles were included based on our inclusion/exclusion criteria. All studies discussing the effect of hydrogels on at least one of the main pathophysiological events after TSCI, including inflammation, axon growth, remyelination, glial scar formation, cavity size, and locomotor functional recovery were included. For statistical analysis, we used mean difference with 95% confidence intervals for locomotor functional recovery. The results showed that both natural and synthetic hydrogels could reduce the inflammatory response, hinder glial scar formation, and promote axon growth and vascularization. Also, the meta-analysis of the BBB score showed that using the hydrogels can lead to locomotor functional recovery. It was found that hydrogels are more efficient when used in transection and hemisection injuries (SMD: 1.89; 95% CI: 1.26, 2.52; P < .00001) compared to other injury models. The pre-formed implanted hydrogels (SMD: 1.79; 95% CI: 1.24, 2.34; P < .00001) found to be more effective compared to injection (SMD: 1.58; 95% CI: 0.64, 2.52; P = 0.0009). In conclusion, based on the available evidence, it was concluded that hydrogel composition as well as implantation method are dominant factors affecting tissue regeneration after TSCI and should be chosen according to the injury model in animal studies.
CONFLICT OF INTEREST
There are no competing financial interests.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
REFERENCES
- 1Rahimi-Movaghar V, Sayyah MK, Akbari H, et al. Epidemiology of traumatic spinal cord injury in developing countries: a systematic review. Neuroepidemiology. 2013; 41(2): 65-85.
- 2Rowland JW, Hawryluk GWJ, Kwon B, Fehlings MG. Current status of acute spinal cord injury pathophysiology and emerging therapies: promise on the horizon. Neurosurg Focus. 2008; 25(5):E2.
- 3Ahuja CS, Wilson JR, Nori S, et al. Traumatic spinal cord injury. Nat Rev Dis Primers. 2017; 3:17018.
- 4Siddiqui AM, Khazaei M, Fehlings MG. Translating mechanisms of neuroprotection, regeneration, and repair to treatment of spinal cord injury. Progress in Brain Research. Elsevier; 2015: 15-54.
- 5Aurand ER, Lampe KJ, Bjugstad KB. Defining and designing polymers and hydrogels for neural tissue engineering. Neurosci Res. 2012; 72(3): 199-213.
- 6Cooke M, Vulic K, Shoichet M. Design of biomaterials to enhance stem cell survival when transplanted into the damaged central nervous system. Soft Matter. 2010; 6(20): 4988-4998.
- 7Kwon SG, Kwon YW, Lee TW, Park GT, Kim JH. Recent advances in stem cell therapeutics and tissue engineering strategies. Biomater Res. 2018; 22(1): 1-8.
- 8Rafalowska J, Sulejczak D, Chrapusta SJ, et al. Non-woven nanofiber mats—a new perspective for experimental studies of the central nervous system? Folia Neuropathol. 2014; 52(4): 407-416.
- 9Gerardo-Nava J, Führmann T, Klinkhammer K, et al. Human neural cell interactions with orientated electrospun nanofibers in vitro. Nanomedicine (Lond). 2009; 4(1): 11-30.
- 10Lee KY, Mooney DJ. Hydrogels for tissue engineering. Chem Rev. 2001; 101(7): 1869-1880.
- 11Pina S, Ribeiro VP, Marques CF, et al. Scaffolding strategies for tissue engineering and regenerative medicine applications. Materials. 2019; 12(11): 1824.
- 12Estrada V, Tekinay A, Muller HW. Neural ECM mimetics. Prog Brain Res. 2014; 214: 391-413.
- 13Khaing ZZ, Thomas RC, Geissler SA, Schmidt CE. Advanced biomaterials for repairing the nervous system: what can hydrogels do for the brain? Mater Today. 2014; 17(7): 332-340.
- 14Hassannejad Z, Sharif-Alhoseini M, Shakouri-Motlagh A, et al. Potential variables affecting the quality of animal studies regarding pathophysiology of traumatic spinal cord injuries. Spinal Cord. 2015; 54: 579.
- 15Hassannejad Z, Zadegan SA, Shakouri-Motlagh A, et al. The fate of neurons after traumatic spinal cord injury in rats: a systematic review. Iran J Basic Med Sci. 2018; 21(6): 546-557.
- 16Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315(7109): 629-634.
- 17Marchand R, Woerly S. Transected spinal cords grafted with in situ self-assembled collagen matrices. Neuroscience. 1990; 36(1): 45-60.
- 18Marchand R, Woerly S, Bertrand L, Valdes N. Evaluation of two cross-linked collagen gels implanted in the transected spinal cord. Brain Res Bull. 1993; 30(3): 415-422.
- 19Woerly S, Pinet E, De Robertis L, et al. Heterogeneous PHPMA hydrogels for tissue repair and axonal regeneration in the injured spinal cord. J Biomater Sci Polym Ed. 1998; 9(7): 681-711.
- 20Woerly S, Petrov P, Syková E, Roitbak T, Simonová Z, Harvey AR. Neural tissue formation within porous hydrogels implanted in brain and spinal cord lesions: ultrastructural, immunohistochemical, and diffusion studies. Tissue Eng. 1999; 5(5): 467-488.
- 21Giannetti S, Lauretti L, Fernandez E, Salvinelli F, Tamburrini G, Pallini R. Acrylic hydrogel implants after spinal cord lesion in the adult rat. Neurol Res. 2001; 23(4): 405-409.
- 22Woerly S, Doan VD, Evans-Martin F, Paramore CG, Peduzzi JD. Spinal cord reconstruction using NeuroGel implants and functional recovery after chronic injury. J Neurosci Res. 2001; 66(6): 1187-1197.
- 23Woerly S, Doan D, Sosa N, Vellis J, Espinosa A. Reconstruction of the transected cat spinal cord following NeuroGel implantation: axonal tracing, immunohistochemical and ultrastructural studies. Int J Dev Neurosci. 2001; 19(1): 63-83.
- 24Tsai EC, Dalton PD, Shoichet MS, Tator CH. Synthetic hydrogel guidance channels facilitate regeneration of adult rat brainstem motor axons after complete spinal cord transection. J Neurotrauma. 2004; 21(6): 789-804.
- 25Woerly S et al. Prevention of gliotic scar formation by NeuroGel allows partial endogenous repair of transected cat spinal cord. J Neurosci Res. 2004; 75(2): 262-272.
- 26Prang P, Müller R, Eljaouhari A, et al. The promotion of oriented axonal regrowth in the injured spinal cord by alginate-based anisotropic capillary hydrogels. Biomaterials. 2006; 27(19): 3560-3569.
- 27Tsai EC, Dalton PD, Shoichet MS, Tator CH. Matrix inclusion within synthetic hydrogel guidance channels improves specific supraspinal and local axonal regeneration after complete spinal cord transection. Biomaterials. 2006; 27(3): 519-533.
- 28Hejcl A, Urdzikova L, Sedy J, et al. Acute and delayed implantation of positively charged 2-hydroxyethyl methacrylate scaffolds in spinal cord injury in the rat: laboratory investigation. J Neurosurg Spine. 2008; 8(1): 67-73.
- 29Tysseling VM, Sahni V, Niece KL, Birch D, et al. Self-assembling nanofibers inhibit glial scar formation and promote axon elongation after spinal cord injury. J Neurosci. 2008; 28(14): 3814-3823.
- 30Hejcl A, Lesný P, Prádný M, et al. Macroporous hydrogels based on 2-hydroxyethyl methacrylate. Part 6: 3D hydrogels with positive and negative surface charges and polyelectrolyte complexes in spinal cord injury repair. J Mater Sci Mater Med. 2009; 20(7): 1571-1577.
- 31King VR, Alovskaya A, Wei DYT, Brown RA, Priestley JV. The use of injectable forms of fibrin and fibronectin to support axonal ingrowth after spinal cord injury. Biomaterials. 2010; 31(15): 4447-4456.
- 32Tysseling VM, Sahni V, Pashuck ET, et al. Self-assembling peptide amphiphile promotes plasticity of serotonergic fibers following spinal cord injury. J Neurosci Res. 2010; 88(14): 3161-3170.
- 33Cigognini D, Satta A, Colleoni B, et al. Evaluation of early and late effects into the acute spinal cord injury of an injectable functionalized self-assembling scaffold. PLoS One. 2011; 6(5):e19782.
- 34Gelain F, Panseri S, Antonini S, et al. Transplantation of nanostructured composite scaffolds results in the regeneration of chronically injured spinal cords. ACS Nano. 2011; 5(1): 227-236.
- 35Kubinova S, Horák D, Hejčl A, Plichta Z, Kotek J, Syková E. Highly superporous cholesterol-modified poly(2-hydroxyethyl methacrylate) scaffolds for spinal cord injury repair. J Biomed Mater Res A. 2011; 99(4): 618-629.
- 36Austin JW, Kang CE, Baumann MD, et al. The effects of intrathecal injection of a hyaluronan-based hydrogel on inflammation, scarring and neurobehavioural outcomes in a rat model of severe spinal cord injury associated with arachnoiditis. Biomaterials. 2012; 33(18): 4555-4564.
- 37Gelain F, Cigognini D, Caprini A, et al. New bioactive motifs and their use in functionalized self-assembling peptides for NSC differentiation and neural tissue engineering. Nanoscale. 2012; 4(9): 2946-2957.
- 38Sharp KG, Dickson AR, Marchenko SA, et al. Salmon fibrin treatment of spinal cord injury promotes functional recovery and density of serotonergic innervation. Exp Neurol. 2012; 235(1): 345-356.
- 39Pertici V, Amendola J, Laurin J, et al. The use of poly (N-[2-hydroxypropyl]-methacrylamide) hydrogel to repair a T10 spinal cord hemisection in rat: a behavioural, electrophysiological and anatomical examination; 2013.
- 40Estrada V, Brazda N, Schmitz C, et al. Long-lasting significant functional improvement in chronic severe spinal cord injury following scar resection and polyethylene glycol implantation. Neurobiol Dis. 2014; 67: 165-179.
- 41Pertici V, Trimaille T, Laurin J, et al. Repair of the injured spinal cord by implantation of a synthetic degradable block copolymer in rat. Biomaterials. 2014; 35(24): 6248-6258.
- 42Kaneko A, Matsushita A, Sankai Y. A 3D nanofibrous hydrogel and collagen sponge scaffold promotes locomotor functional recovery, spinal repair, and neuronal regeneration after complete transection of the spinal cord in adult rats. Biomed Mater. 2015; 10(1):015008.
- 43Shahriari D, Koffler J, Lynam DA, Tuszynski MH, Sakamoto JS. Characterizing the degradation of alginate hydrogel for use in multilumen scaffolds for spinal cord repair. J Biomed Mater Res A. 2016; 104(3): 611-619.
- 44Hong LTA, Kim YM, Park HH, et al. An injectable hydrogel enhances tissue repair after spinal cord injury by promoting extracellular matrix remodeling. Nat Commun. 2017; 8(1): 533.
- 45Nawrotek K, Marqueste T, Modrzejewska Z, Zarzycki R, Rusak A, Decherchi P. Thermogelling chitosan lactate hydrogel improves functional recovery after a C2 spinal cord hemisection in rat. J Biomed Mater Res A. 2017; 105(7): 2004-2019.
- 46Zhang Z, Yao S, Xie S, et al. Effect of hierarchically aligned fibrin hydrogel in regeneration of spinal cord injury demonstrated by tractography: a pilot study. Sci Rep. 2017; 7: 40017-40017.
- 47Hejcl A, Růžička J, Kekulová K, et al. Modified methacrylate hydrogels improve tissue repair after spinal cord injury. Int J Mol Sci. 2018; 19(9): 2481–2497.
- 48Mohrman AE, Farrag M, Grimm RK, Leipzig ND. Evaluation of in situ gelling chitosan-PEG copolymer for use in the spinal cord. J Biomater Appl. 2018; 33(3): 435-446.
- 49Zhou L, Fan L, Yi X, et al. Soft conducting polymer hydrogels cross-linked and doped by tannic acid for spinal cord injury repair. ACS Nano. 2018; 12(11): 10957-10967.
- 50Park J, Lim E, Back S, Na H, Park Y, Sun K. Nerve regeneration following spinal cord injury using matrix metalloproteinase-sensitive, hyaluronic acid-based biomimetic hydrogel scaffold containing brain-derived neurotrophic factor. J Biomed Mater Res A. 2010; 93(3): 1091-1099.
- 51Jooe NY, Knowles JC, Lee G-S, et al. Effects of phosphate glass fiber-collagen scaffolds on functional recovery of completely transected rat spinal cords. Acta Biomater. 2012; 8(5): 1802-1812.
- 52Liu Y, Ye H, Satkunendrarajah K, Yao GS, Bayon Y, Fehlings MG. A self-assembling peptide reduces glial scarring, attenuates post-traumatic inflammation and promotes neurological recovery following spinal cord injury. Acta Biomater. 2013; 9(9): 8075-8088.
- 53Khaing ZZ, Milman BD, Vanscoy JE, Seidlits SK, Grill RJ, Schmidt CE. High molecular weight hyaluronic acid limits astrocyte activation and scar formation after spinal cord injury. J Neural Eng. 2011; 8(4):046033.
- 54Li HY, Führmann T, Zhou Y, Dalton PD. Host reaction to poly(2-hydroxyethyl methacrylate) scaffolds in a small spinal cord injury model. J Mater Sci Mater Med. 2013; 24(8): 2001-2011.
- 55Silva NA, Salgado AJ, Sousa RA, et al. Development and characterization of a novel hybrid tissue engineering-based scaffold for spinal cord injury repair. Tissue Eng Part A. 2010; 16(1): 45-54.
- 56Marchini A, Raspa A, Pugliese R, et al. Multifunctionalized hydrogels foster hNSC maturation in 3D cultures and neural regeneration in spinal cord injuries. Proc Natl Acad Sci. 2019; 116(15): 7483-7492.
- 57Bonnet M, Trimaille T, Brezun JM, et al. Motor and sensitive recovery after injection of a physically cross-linked PNIPAAm-g-PEG hydrogel in rat hemisectioned spinal cord. Mater Sci Eng C. 2020; 107:110354.
- 58Liu H, Xu X, Tu Y, et al. Engineering microenvironment for endogenous neural regeneration after spinal cord injury by reassembling extracellular matrix. ACS Appl Mater Interfaces. 2020; 12(15): 17207-17219.
- 59Huang L, Wang Y, Zhu M, et al. Anisotropic alginate hydrogels promote axonal growth across chronic spinal cord transections after scar removal. ACS Biomater Sci Eng. 2020; 6(4): 2274-2286.
- 60Zhang Y, Li L, Mu J, Chen J, Feng S, Gao J. Implantation of a functional TEMPO-hydrogel induces recovery from rat spinal cord transection through promoting nerve regeneration and protecting bladder tissue. Biomater Sci. 2020; 8(6): 1695-1701.
- 61Cao Z, Yao S, Xiong Y, et al. Directional axonal regrowth induced by an aligned fibrin nanofiber hydrogel contributes to improved motor function recovery in canine L2 spinal cord injury. J Mater Sci Mater Med. 2020; 31(5): 1-13.
- 62Horn EM, Beaumont M, Shu XZ, et al. Influence of cross-linked hyaluronic acid hydrogels on neurite outgrowth and recovery from spinal cord injury. J Neurosurg Spine. 2007; 6(2): 133-140.
- 63Sun Y, Li W, Wu X, et al. Functional self-assembling peptide nanofiber hydrogels designed for nerve degeneration. ACS Appl Mater Interfaces. 2016; 8(3): 2348-2359.
- 64Woerly S, Pinet E, De Robertis L, Van Diep D, Bousmina M. Spinal cord repair with PHPMA hydrogel containing RGD peptides (NeuroGel). Biomaterials. 2001; 22(10): 1095-1111.
- 65Assunção-Silva RC, Gomes ED, Sousa N, et al. Hydrogels and cell based therapies in spinal cord injury regeneration. Stem Cells Int. 2015; 2015:948040.
- 66Perale G, Rossi F, Sundstrom E, et al. Hydrogels in spinal cord injury repair strategies. ACS Chem Nerosci. 2011; 2(7): 336-345.