TSitologiya i Genetika 2023, vol. 57, no. 1, 26-43
Cytology and Genetics 2023, vol. 57, no. 1, 19–34, doi: https://www.doi.org/https://doi.org/10.3103/S0095452723010073

Influence of fibrin matrix implantation associated with mesenchymal wharton’s jelly stromal cells on the course of experimental spinal cord injury

Medvediev V.V., Oleksenko N.P., Pichkur L.D., Verbovska S.A., Savosko S.I., Draguntsova N.G., Lontkovskiy Yu.A., Vaslovych V.V., Tsymbalyuk V.I.

  1. Bogomolets National Medical University, 13, Tarasa Shevchenka Blv, Kyiv, 01601, Ukraine
  2. SI «Romodanov Neurosurgery Institute, National Academy of Medical Sciences of Ukraine», 32, Platona Mayborody Str., Kyiv, 04050, Ukraine
  3. Kamyanets-Podilsky city state hospital, 31, Pushkins’ka St., Kamianets-Podilskyi, Khmelnytskyi Oblast’, 32301, Ukrainе

SUMMARY. The effectiveness of immediate implantation of the fibrin matrix associated with mesenchymal stromal cells of Wharton’s jelly was investigated in a spinal cord injury (SCI) model. The study was conducted using white adult outbred male rats (~260 g, 4–5 months old). The trauma model is a left-sided section of a half of the spinal cord at the level of T13–L1 segments. The rehabilitation involved the immediate transplantation of the human fibrin matrix associated with mesenchymal stromal cells of human Wharton’s jelly (mesenchymal stromal cells, MSC, n = 9) into the injury area. The reference groups had the isolated SCI (trauma, Tr, n = 7) and the implantation of the human fibrin matrix (fibrin, Fb, n = 6) in the area of injury. The motor activity and spasticity of the paretic limb were evaluated on the BBB scale and the Ashworth scale in our own modifications, respectively. The morphological picture in the area of injury was studied in the remote period using the impregnation of longitudinal sections of the spinal cord with silver nitrate. Mesenchymal stromal cells of human Wharton’s jelly in the presence of fibrin matrix showed the signs of active vivality, growth, and migratory potential in the culture. The intense increase in the motor activity of the paretic limb in the Fb group was limited to the first 2 weeks of follow-up, in the MSC group – 3 weeks of follow-up. Throughout the experiment, the level of function in the MSC group was inferior to the level of the Fb group, but only in the first week of observation it was significant. Five months later, the index of motor function was 10.4 ± 1.0 points of BBB (MSC) and 11.6 ± 2.0 points of BBB (Fb), and in the group Tr – 5.9 ± 1.6 points of BBB. However, a significant difference in the values of the indicator was found for the MSC and Tr groups – 6 weeks, 3 and 5 months after the implantation. A significant advantage of the level of spasticity in the Tr group over the MSC group was found 6 and 7 weeks and 5 months after the injury, and an advantage over the Fb group – 7 weeks after injury. No significant differences in the level of spasticity between the MSC and Fb groups were found throughout the experiment. Immediate fibrin matrix implantation to the spinal cord injury area has a positive effect on the restoration of motor function of the paretic limb of the animal, especially in the presence of mesenchymal stromal cells of human Wharton’s jelly.

Keywords: spinal cord injury, Wharton’s jelly, mesenchymal stromal cells, fibrin matrix, locomotor function restoration, spasticity

TSitologiya i Genetika
2023, vol. 57, no. 1, 26-43

Current Issue
Cytology and Genetics
2023, vol. 57, no. 1, 19–34,
doi: https://doi.org/10.3103/S0095452723010073

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References

Abbaszadeh, H., Ghorbani, F., Derakhshani, M., et al., Regenerative potential of Wharton’s jelly-derived mesenchymal stem cells: A new horizon of stem cell therapy, J. Cell. Physiol., 2020, vol. 235, no. 12, pp. 9230–9240. https://doi.org/10.1002/jcp.29810

Abdallah, I., Ìedvediev, V., Draguntsova, N., et al., Dependence of the restorative effect of microporous poly(N-[2-Hydroxypropyl]-methacrylamide hydrogel on the severity of experimental lacerative spinal cord injury, USMYJ, 2021, vo. 127, no. 4, pp. 8–21. https://mmj.nmuofficial.com/index.php/journal/article/view/840.

Adegeest, C.Y., van Gent, J.A.N., Stolwijk-Swüste, J.M., Post, M.W.M., Vandertop, W.P., Öner, F.C., Peul, W.C., and Wengel, P.V.T., Influence of severity and level of injury on the occurrence of complications during the subacute and chronic stage of traumatic spinal cord injury: a systematic review, J. Neurosurg. Spine, 2021, vol. 36, no. 4, pp. 632–652. https://doi.org/10.3171/2021.7.SPINE21537

Alizadeh, A., Dyck, S.M., and Karimi-Abdolrezaee, S., Traumatic spinal cord injury: an overview of pathophysiology, models and acute injury mechanisms, Front. Neurol., 2019, vol. 10, p. 282. https://doi.org/10.3389/fneur.2019.00282

Allahbakhshi, M.E. and Taband, M.R., Isolation and characterization of human umbilical cord mesenchymal stem cells and their differentiation into Pdx-1+ cells, J. Biomed. Sci. Eng., 2015, vol. 8, no. 11, pp. 780–788. https://doi.org/10.4236/jbise.2015.811074

Amable, P.R., Carias, R.B.V., Teixeira, M.V.T., et al., Platelet-rich plasma preparation for regenerative medicine: optimization and quantification of cytokines and growth factors, Stem Cell Res. Ther., 2013, vol. 4, no. 3, p. 67. https://doi.org/10.1186/scrt218

Basso, D.M., Beattie, M.S., and Bresnahan, J.C., A sensitive and reliable locomotor rating scale for open field testing in rats, J. Neurotrauma, 1995, vol. 12, no. 1, pp. 1–21. https://doi.org/10.1089/neu.1995.12.1

Blesch, A. and Tuszynski, M.H., Spinal cord injury: plasticity, regeneration and the challenge of translational drug development, Trends Neurosci., 2009, vol. 32, no. 1, pp. 41–47. https://doi.org/10.1016/j.tins.2008.09.008

Bonaventura, G., Incontro, S., Iemmolo, R., et al., Dental mesenchymal stem cells and neuro-regeneration: a focus on spinal cord injury, Cell Tissue Res., 2020, vo. 379, no. 3, pp. 421–428. https://doi.org/10.1007/s00441-019-03109-4

Bresnahan, J.J., Scoblionko, B.R., Zorn, D., et al., The demographics of pain after spinal cord injury: a survey of our model system, Spinal Cord Ser. Cases, 2022, vol. 8, no. 1, p. 14. https://doi.org/10.1038/s41394-022-00482-1

Brown, A. and Martinez, M., From cortex to cord: motor circuit plasticity after spinal cord injury, Neural Regener. Res., 2019, vol. 14, no. 12, pp. 2054–2062. https://doi.org/10.4103/1673-5374.262572

Burns, A.S., Marino, R.J., Kalsi-Ryan, S., et al., Type and timing of rehabilitation following acute and subacute spinal cord injury: A systematic review, Global Spine J., 2017, vol. 7, no. 3, pp. 175S–194S. https://doi.org/10.1177/2192568217703084

Calguner, E., Erdogan, D., Elmas, C., et al., Innervation of the rat anterior abdominal wall as shown by modified Sihler’s stain, Med. Princ. Pract., 2006, vol. 15, no. 2, pp. 98–101. https://doi.org/10.1159/000090911

Cao, Y., Wu, T., Yuan, Z., et al., Three-dimensional imaging of microvasculature in the rat spinal cord following injury, Sci. Rep., 2015, vol. 5, p. 12643. https://doi.org/10.1038/srep12643

Cargnello, M. and Roux, P.P., Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases, Mol. Biol. Rev., 2011, vol. 75, no. 1, pp. 50–83. https://doi.org/10.1128/MMBR.00031-10

Carriel, V., Garrido-Gomez, J., Hernandez-Cortes, P., et al., Combination of fibrin-agarose hydrogels and adipose-derived mesenchymal stem cells for peripheral nerve regeneration, J. Neural Eng., 2013, vol. 10, no. 2, p. 026022. https://doi.org/10.1088/1741-2560/10/2/026022

Carriel, V., Scionti, G., Campos, F., et al., In vitro characterization of a nanostructered fibrin agarose bio-artificial nerve substitute, J. Tissue Eng. Regener. Med., 2015, vol. 11, no. 5, pp. 1412–1426. https://doi.org/10.1002/term.2039

Chan, B.C.F., Craven, B.C., and Furlan, J.C., A scoping review on health economics in neurosurgery for acute spine trauma, Neurosurg. Focus, 2018, vol. 44, no. 5, p. E15. https://doi.org/10.3171/2018.2

Chandrababu, K., Sreelatha, H.V., Sudhadevi, T., et al., In vivo neural tissue engineering using adipose-derived mesenchymal stem cells and fibrin matrix, J. Spinal Cord Med., 2021, vol. 1, pp. 1–15. https://doi.org/10.1080/10790268.2021.1930369

Cizkova, D., Murgoci, A.N., and Cubinkova, V., Spinal cord injury: animal models, imaging tools and the treatment strategies, Neurochem. Res., 2020, vol. 45, no. 1, pp. 134–143. https://doi.org/10.1007/s11064-019-02800-w

Dennie, D., Louboutin, J.P., and Strayer, D.S., Migration of bone marrow progenitor cells in the adult brain of rats and rabbits, World J. Stem Cells, 2016, vol. 8, no. 4, pp. 136–157. https://doi.org/10.4252/wjsc.v8.i4.136

DeVivo, M.J., Epidemiology of traumatic spinal cord injury: trends and future implications, Spinal Cord, 2012, vol. 50, no. 5, pp. 365–372. https://doi.org/10.1038/sc.2011.178

DeVivo, M.J., Savic, G., Frankel, H.L., et al., Comparison of statistical methods for calculating life expectancy after spinal cord injury, Spinal Cord, 2018, vol. 56, no. 7, pp. 666–673. https://doi.org/10.1038/s41393-018-0067-1

Dodd, W., Motwani, K., Small, C., et al., Spinal cord injury and neurogenic lower urinary tract dysfunction: what do we know and where are we going?, J. Men’s Health, 2022, vol. 18, no. 1, p. 24. https://doi.org/10.31083/j.jomh1801024

Dong, H.W., Wang, L.H., Zhang, M., et al., Decreased dynorphin A (1–17) in the spinal cord of spastic rats after the compressive injury, Brain Res. Bull., 2005, vol. 67, no. 3, pp. 189–195. https://doi.org/10.1016/j.brainresbull.2005.06.026

Fan, B., Wei, Z., and Feng, S., Progression in translational research on spinal cord injury based on microenvironment imbalance, Bone Res., 2022, vol. 10, no. 1, p. 35. https://doi.org/10.1038/s41413-022-00199-9

Farid, M.F.S., Abouelela, Y., and Rizk, H., Stem cell treatment trials of spinal cord injuries in animals, Auton. Neurosci., 2021, vol. 238, p. 102932. https://doi.org/10.1016/j.autneu.2021.102932

Flynn, J.R., Graham, B.A., Galea, M.P., et al., The role of propriospinal interneurons in recovery from spinal cord injury, Neuropharmacology, 2011, vol. 60, no. 5, pp. 809–822. https://doi.org/10.1016/j.neuropharm.2011.01.016

GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators, Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the Global Burden of Disease Study, Lancet Neurol., 2019, vol. 18, no. 1, pp. 56–87. https://doi.org/10.1016/S1474-4422(18)30415-0

Hotwani, K. and Sharma, K., Platelet rich fibrin – a novel acumen into regenerative endodontic therapy, Restor. Dent. Endod., 2014, vol. 39, no. 1, pp. 1–6. https://doi.org/10. 5395/rde.2014.39.1.1

Huang, B., Li, G., and Jiang, X.H., Fate determination in mesenchymal stem cells: a perspective from histone-modifying enzymes, Stem Cell Res. Ther., 2015, vol. 6, no. 1, p. 35. https://doi.org/10.1186/s13287-015-0018-0

Jeong, H.J., Yun, Y., Lee, S.J., et al., Biomaterials and strategies for repairing spinal cord lesions, Neurochem. Int., 2021, vol. 144, p. 104973. https://doi.org/10.1016/j.neuint.2021.104973

Joerger-Messerli, M.S., Marx, C., Oppliger, B., et al., Mesenchymal stem cells from Wharton's jelly and amniotic fluid, Best Pract. Res. Clin. Obstet. Gynaecol., 2016, vol. 31, pp. 30–44. https://doi.org/10.1016/j.bpobgyn.2015.07.006

Johnson, P.J., Parker, S.R., and Sakiyama-Elbert, S.E., Fibrin-based tissue engineering scaffolds enhance neural fiber sprouting and delay the accumulation of reactive astrocytes at the lesion in a subacute model of spinal cord injury, J. Biomed. Mater. Res., Part A, 2010, vol. 92A, no. 1, pp. 152–163. https://doi.org/10.1002/jbm.a.32343

Karantalis, V. and Hare, J.M., Use of mesenchymal stem cells for therapy of cardiac disease, Circ. Res., 2015, vol. 116, no. 8, pp. 1413–1430. https://doi.org/10.1161/CIRCRESAHA.116.303614

Khorasanizadeh, M., Yousefifard, M., Eskian, M., et al., Neurological recovery following traumatic spinal cord injury: a systematic review and meta-analysis, J. Neurosurg., 2019, vol. 30, pp. 683–699. https://doi.org/10.3171/2018.10.SPINE18802

Kolomiĭtsev, A.K., Chaikovskiĭ, Yu.B., and Tereshchen-ko, T.L., Rapid method of silver nitrate impregnation of elements of the peripheral nervous system suitable for celloidin and paraffin sections, Arkh. Anat. Gistol. Embriol., 1981, vol. 81, no. 8, pp. 93–96.

Kopach, O., Medvediev, V., Krotov, V., et al., Opposite, bidirectional shifts in excitation and inhibition in specific types of dorsal horn interneurons are associated with spasticity and pain post-SCI, Sci. Rep., 2017, vol. 7, no. 1, p. 5884. https://doi.org/10.1038/s41598-017-06049-7

Li, J.A., Zhao, C.F., Li, S.J., et al., Modified insulin-like growth factor 1 containing collagen-binding domain for nerve regeneration, Neural Reg. Res., 2018, vol. 13, no. 2, pp. 298–303. https://doi.org/10.4103/1673-5374.226400

Li, P., Xu, Y., Cao, Y., et al., 3D Digital Anatomic Angioarchitecture of the rat spinal cord: A synchrotron radiation micro-CT study, Front. Neuroanat., 2020, vol. 14, p. 41. https://doi.org/10.3389/fnana.2020.00041

Lin, L., Lin, H., Bai, S., et al., Bone marrow mesenchymal stem cells (BMSCs) improved functional recovery of spinal cord injury partly by promoting axonal regeneration, Neurochem. Int., 2018, vol. 115, pp. 80–84. https://doi.org/10.1016/j.neuint.2018.02.007

Litvinov, R.I., Gorkun, O.V., Owen, S.F., et al., Polymerization of fibrin: specificity, strength, and stability of knob-hole interactions studied at the single-molecule level, Blood, 2005, vol. 106, no. 9, pp. 2944–2951. https://doi.org/10.1182/blood-2005-05-2039

Liu, J., Chen, Q., Zhang, Z., et al., Fibrin scaffolds containing ectomesenchymal stem cells enhance behavioral and histological improvement in a rat model of spinal cord injury, Cells Tissues Organs, 2013, vol. 198, no. 1, pp. 35–46. https://doi.org/10.1159/000351665

Liu, S., Schackel, T., Weidner, N., and Puttagunta, R., Biomaterial-supported cell transplantation treatments for spinal cord injury: challenges and perspectives, Front. Cell Neurosci., 2018, vol. 11, p. 430. https://doi.org/10.3389/fncel.2017.00430

Liu, S., Xie, Y.Y., and Wang, B., Role and prospects of regenerative biomaterials in the repair of spinal cord injury, Neural Reg. Res., 2019, vol. 14, no. 8, pp. 1352–1363. https://doi.org/10.4103/1673-5374.253512

Lu, P., Grahman, L., Wang, Y., et al., Promotion of survival and differentiation of neural stem cells with fibrin and growth factor coctails after severe spinal cord injury, J. Visualized Exp., 2014, vol. 89, p. e50641. https://doi.org/10.3791/50641

Lv, B., Zhang, X., Yuan, J., et al., Biomaterial-supported MSC transplantation enhances cell-cell communication for spinal cord injury, Stem Cell Res. Ther., 2021, vol. 12, no. 1, p. 36. https://doi.org/10.1186/s13287-020-02090-y

Main, B.J., Maffulli, N., Valk, J.A., et al., Umbilical cord-derived Wharton’s jelly for regenerative medicine applications: A systematic review, Pharmaceuticals (Basel), 2021, vol. 14, no. 11, p. 1090. https://doi.org/10.3390/ph14111090

Majczynski, H. and Sławińska, U., Locomotor recovery after thoracic spinal cord lesions in cats, rats and humans, Àcta Neurobiol. Exp. (Wars), 2007, vol. 67, no. 3, pp. 235–257.

Mazensky, D., Flesarova S., and Sulla, I., Arterial blood supply to the spinal cord in animal models of spinal cord injury. A review, Anat. Rec. (Hoboken), 2017, vol. 300, no. 12, pp. 2091–2106. https://doi.org/10.1002/ar.23694/

Medvediev, V.V., Abdallah, I.M., Draguntsova, N.G., et al., Model of spinal cord lateral hemi-excision at the lower thoracic level for the tasks of reconstructive and experimental neurosurgery, Ukr. Neurosurg. J., 2021, vol. 27, no. 3, pp. 33–35. http://theunj.org/article/view/234154.

Medvediev, V.V., Savosko, S.I., Abdallah, I.M., et al., The efficacy of immediate implantation of microporous poly(N-[2-hydroxypropyl]-methacrylamide) hydrogel after laceration spinal cord injury in young rats, Int. J. Morphol., 2021, vol. 39, no. 6, pp. 1749–1757. http://www.intjmorphol.com/abstract/?art_id=8375

Medvediev, V.V., Oleksenko, N.P., Pichkur, L.D., et al., Effect of implantation of a fibrin matrix associated with neonatal brain cells on the course of an experimental spinal cord injury, Cytol. Genet., 2022, vol. 56, pp. 125–138. https://doi.org/10.3103/S0095452722020086

Merritt, C.H., Taylor, M.A., Yelton, C.J., et al., Economic impact of traumatic spinal cord injuries in the United States, Neuroimmunol. Neuroinflammation, 2019, vol. 6, p. 9. https://doi.org/10.20517/2347-8659.2019.15

Muheremu, A., Peng, J., and Ao, Q., Stem cell based therapies for spinal cord injury, Tissue Cell, 2016, vol. 48, no. 4, pp. 328–333. https://doi.org/10.1016/j.tice.2016.05.008

Mukhamedshina, Y.O., Akhmetzyanova, E.R., Kostennikov, A.A., et al., Adipose-derived mesenchymal stem cell application combined with fibrin matrix promotes structural and functional recovery following spinal cord injury in rats, Front. Pharmacol., 2018, vol. 9, p. 343. https://doi.org/10.3389/fphar.2018.00343

Muller, Ì.F., Ris, I., Ferry, J.D., Electron microscopy of fine fibrin clots and fine and coarse fibrin films. Observations of fibers in cross-section and in deformed states, J. Mol. Biol., 1984, vol. 174, no. 2, pp. 369–384. https://doi.org/10.1016/0022-2836(84)90343-7

Noiseux, N., Gnecchi, M., Lopez-Ilasaca, M., et al., Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation, Mol. Ther., 2006, vol. 14, no. 6, pp. 840–850. https://doi.org/10.1016/j.ymthe.2006.05.016

Okudo, Å., Hayashi, D., Yaguchi, T., et al., Differentiation of rat adipose tissue-derived stem cells into neuron-like cells by valproic acid, a histone deacetylase inhibitor, Exp. Anim., 2016, vol. 65, no. 1, pp. 45–51. https://doi.org/10.1538/expanim.15-0038

Oliveri, R.S., Bello, S., and Biering-Sørensen, F., Mesenchymal stem cells improve locomotor recovery in traumatic spinal cord injury: Systematic review with meta-analyses of rat models, Neurobiol. Dis., 2014, vol. 62, pp. 338–353. https://doi.org/10.1016/j.nbd.2013.10.014

Pang, Q.M., Chen, S.Y., Xu, Q.J., et al., Neuroinflammation and scarring after spinal cord injury: Therapeutic roles of MSCs on inflammation and glial scar, Front. Immunol., 2021, vol. 12, p. 751021. https://doi.org/10.3389/fimmu.2021.751021

Pang, Q.M., Chen, S.Y., Fu, S.P., et al., Regulatory Role of mesenchymal stem cells on secondary inflammation in spinal cord injury, J. Inflamm. Res., 2022, vol. 15, pp. 573–593. https://doi.org/10.2147/JIR.S349572

Peyronnard, J.M., Charron, L.F., Lavoie, J., et al., Motor, sympathetic and sensory innervation of rat skeletal muscles, Brain Res., 1986, vol. 373, nos. 1–2, pp. 288–302. https://doi.org/10.1016/0006-8993(86)90343-4

Pretz, C.R., Kozlowski, A.J., Chen, Y., et al., Trajectories of life satisfaction after spinal cord injury, Arch. Phys. Med. Rehabil., 2016, vol. 97, no. 10, pp. 1706–1713. https://doi.org/10.1016/j.apmr.2016.04.022

Rao, S.N. and Pearse, D.D., Regulating axonal responses to injury: The intersection between signaling pathways involved in axon myelination and the inhibition of axon regeneration, Front. Mol. Neurosci., 2016, vol. 9, p. 33. https://doi.org/10.3389/fnmol.2016.00033

Robinson, J. and Lu, P., Optimization of trophic support for stem cell graft in sites of spinal cord injury, Exp. Neurol., 2017, vol. 291, pp. 87–97. https://doi.org/10.1016/j.expneurol.2017.02.007

Rodríguez-Barrera, R., Flores-Romero, A., Buzoianu-Anguiano, V., et al., Use of a combination strategy to improve morphological and functional recovery in rats with chronic spinal cord injury, Front. Neurol., 2020, vol. 11, p. 189. https://doi.org/10.3389/fneur.2020.00189

Rohde, E., Pachler, K., and Gimona, M., Manufacturing and characterization of extracellular vesicles from umbilical cord-derived mesenchymal stromal cells for clinical testing, Cytotherapy, 2019, vol. 21, no. 6, pp. 581–592. https://doi.org/10.1016/j.jcyt.2018.12.006

Savic, G., DeVivo, M.J., Frankel, H.L., et al., Long-term survival after traumatic spinal cord injury: a 70-year British study, Spinal Cord, 2017, vol. 55, no. 7, pp. 651–658. https://doi.org/10.1038/sc.2017.23

Schuh, C.M., Morton, T.J., Banerjee, A., et al., Activation of schwann cell-like cells on aligned fibrinpoly (lactic-co-glycolic acid) structures: a novel construct for application in peripheral nerve regeneration, Cells Tissues Organs, 2015, vol. 200, no. 5, pp. 287–299. https://doi.org/10.1159/000437091

Shah, M., Peterson, C., and Yilmaz, E., Current advancements in the management of spinal cord injury: A comprehensive review of literature, Surg. Neurol. Int., 2020, vol. 11, p. 2. https://doi.org/10.25259/SNI_568_2019

Shakhbasau, N.V., Petyovka, S.M., Kosmacheva, A.V., et al., Neurogenic induction of human mesenchymal stem cells in fibrin 3D matrix, Bull. Exp. Biol. Med., 2011, vol. 150, no. 4, pp. 547–550. https://doi.org/10.1007/s10517-011-1186-2

Skoog, B. and Jakobsson, K.E., Prevalence of spasticity and below-level neuropathic pain related to spinal cord injury level and damage to the lower spinal segments, J. Rehabil. Med., Clin. Commun., 2020, vol. 3, p. 1000039. https://doi.org/10.2340/20030711-1000039

Steeves, J.D., Bench to bedside: challenges of clinical translation, Prog. Brain Res., 2015, vol. 218, pp. 227–239. https://doi.org/10.1016/bs.pbr.2014.12.008

Stefańska, K., Ożegowska, K., Hutchings, G., et al., Human Wharton’s jelly—cellular specificity, stemness potency, animal models, and current application in human clinical trials, J. Clin. Med., 2020, vol. 9, no. 4, p. 1102. https://doi.org/10.3390/jcm9041102

Swieck, K., Conta-Steencken, A., Middleton, F.A., et al., Effect of lesion proximity on the regenerative response of long descending propriospinal neurons after spinal transection injury, BMC Neurosci., 2019, vol. 20, no. 1, p. 10. https://doi.org/10.1186/s12868-019-0491-y

Tara, S. and Krishnan, L.K., Bioengineered fibrin-based niche to direct outgrowth of circulating progenitors into neuron-like cells for potential use in cellular therapy, J. Neural Eng., 2015, vol. 12, no. 3, p. 036011. https://doi.org/10.1088/1741-2560/12/3/036011

Tashiro, S., Nakamura, M., and Okano, H., Regenerative rehabilitation and stem cell therapy targeting chronic spinal cord injury: A review of preclinical studies, Cells, 2022, vol. 11, no. 4, p. 685. https://doi.org/10.3390/cells11040685

Tatullo, M., Marrelli, M., Cassetta, M., et al., Platelet rich fibrin (P.R.F.) in reconstructive surgery of atrophied maxillary bones: Clinical and histological evaluations, Int. J. Med. Sci., 2012, vol. 9, pp. 872–880. https://doi.org/10.7150/ijms.5119

The Rat Nervous System, Paxinos, G., Ed., London: Elsevier, 2015, pp. 985–1011.

Tran, A.P., Warren, P.M., Silver, J., et al., The biology of regeneration failure and success after spinal cord injury, Physiol. Rev., 2018, vol. 98, no. 2, pp. 881–917. https://doi.org/10.1152/physrev.00017.2017

Tveten, L., Spinal cord vascularity. IV. The spinal cord arteries in the rat, Acta Radiol.: Diagn., (Stockholm), 1976, vol. 17, no. 4, pp. 385–398. https://doi.org/10.1177/028418517601700401

Tveten, L., Spinal cord vascularity. IV. The spinal cord arteries in the rat, Acta Radiol.: Diagn. (Stockholm), 1976, vol. 17, no. 4, pp. 385–398. https://doi.org/10.1177/028418517601700401

Wang, A.Y.L., Loh, C.Y.Y., Shen, H.H., et al., Human Wharton’s jelly mesenchymal stem cell-mediated sciatic nerve recovery is associated with the upregulation of regulatory T cells, Int. J. Mol. Sci., 2020, vol. 21, no. 17, p. 6310. https://doi.org/10.3390/ijms21176310

Wang, Y., Tan, H., and Hui, X., Biomaterial scaffolds in regenerative therapy of the central nervous system, Biomed. Res. Int., 2018, p. 784890. https://doi.org/10.1155/2018/7848901

Wang, Y., Lv, H.Q., Chao, X., et al., Multimodal therapy strategies based on hydrogels for the repair of spinal cord injury, Mil. Med. Res., 2022, vol. 9, no. 1, p. 16. https://doi.org/10.1186/s40779-022-00376-1

Weisel, J.W. and Litviniv, R.I., Fibrin Formation, Structure and Properties, vol. 82: Subcellular biochemistry, 2017, pp. 405–456. https://doi.org/10.1007/978-3-319-49674-0_13

Xin, H., Li, Y., and Chopp, M., Exosomes/miRNAs as mediating cell-based therapy of stroke, Front. Cell. Neurosci., 2014, vol. 8, p. 377. https://doi.org/10.3389/fncel.2014.00377

Yao, S., Liu, X., Yu, S., et al., Co-effects of matrix low elasticity and aligned topography on stem cell neurogenic differentiation and rapid neurite outgrowth, Nanoscale, 2016, vol. 8, no. 19, pp. 10252–10265. https://doi.org/10.1039/c6nr01169a

Yasuda, H., Kuroda, S., and Shichinohe, H., Effect of biodegradable fibrin scaffold on survival, migration and differentiation of transplanted bone marrow stromal cells after cortical injury in rats, J. Neurosurg., 2010, vol. 112, no. 2, pp. 336–344. https://doi.org/10.3171/2009.2.JNS08495

Yin, K., Wang, S., and Zhao, R.C., Exosomes from mesenchymal stem/stromal cells: a new therapeutic paradigm, Biomarker Res., 2019, vol. 7, p. 8. https://doi.org/10.1186/s40364-019-0159-x

Yousefifard, M., Nasseri Maleki, S., Askarian-Amiri, S., et al., A combination of mesenchymal stem cells and scaffolds promotes motor functional recovery in spinal cord injury: a systematic review and metaanalysis, J. Neurosurg. Spine, 2019, vol. 32, no. 2, pp. 269–284. https://doi.org/10.3171/2019.8.SPINE19201

Zhang, Q., Shi, B., and Ding, J., Polymer scaffolds facilitate spinal cord injury repair, Acta Biomater., 2019, vol. 88, pp. 57–77. https://doi.org/10.1016/j.actbio.2019.01.056