REVIEW
A bioimpressão tridimensional permite a deposição controlada de células, biomateriais e moléculas bioativas e apresenta aplicações potenciais na modelagem e no reparo do sistema nervoso central (SNC). Este estudo mapeou as aplicações da bioimpressão 3D no SNC e sintetizou as evidências pré-clínicas sobre construtos celularizados produzidos por bioimpressão direta. Foi realizada uma revisão em duas etapas, compreendendo uma revisão de escopo conforme o PRISMA-ScR e uma revisão sistemática conforme o PRISMA 2020. As buscas no PubMed, Scopus e Web of Science identificaram 445 registros. Foram incluídos 60 estudos: 25 revisões ou sínteses técnicas, 17 estudos in vitro ou metodológicos e 18 estudos in vivo. Destes, 49 permaneceram exclusivamente na revisão de escopo e 11 preencheram os critérios da revisão sistemática. A lesão medular representou 14 dos 18 estudos in vivo. Entre os 11 estudos incluídos na revisão sistemática, GelMA foi utilizado em sete construtos, e células-tronco neurais foram a população mais frequente. Dos 110 julgamentos de risco de viés pelo SYRCLE, 98 foram classificados como risco incerto, 11 como baixo risco e um como alto risco. A bioimpressão 3D demonstrou potencial regenerativo, mas a heterogeneidade metodológica e o predomínio de julgamentos incertos ainda limitam a translação clínica.
Three-dimensional bioprinting enables the controlled deposition of cells, biomaterials, and bioactive molecules and has potential applications in central nervous system (CNS) modeling and repair. This study mapped CNS applications of 3D bioprinting and synthesized preclinical evidence on cell-laden constructs produced by direct bioprinting. A two-stage review was conducted, comprising a scoping review reported in accordance with PRISMA-ScR and a systematic review reported in accordance with PRISMA 2020. Searches of PubMed, Scopus, and Web of Science identified 445 records. Sixty studies were included: 25 reviews or technical syntheses, 17 in vitro or methodological studies, and 18 in vivo studies. Of these, 49 remained exclusive to the scoping review, and 11 met the systematic review criteria. Spinal cord injury accounted for 14 of the 18 in vivo studies. Among the 11 systematically reviewed studies, GelMA was used in seven constructs, and neural stem cells were the most frequent cell population. Of 110 SYRCLE risk-of-bias judgments, 98 were classified as unclear risk, 11 as low risk, and one as high risk. Three-dimensional bioprinting showed regenerative potential, but methodological heterogeneity and predominantly unclear judgments continue to limit clinical translation.
1. Cafferty WBJ, Duffy P, Huebner E, Strittmatter SM. MAG and OMgp synergize with Nogo-A to restrict axonal growth and neurological recovery after spinal cord trauma. J Neurosci. 2010;30(20):6825-37. https://doi.org/10.1523/JNEUROSCI.6239-09.2010. PMid:20484625.
2. Huang W, Chen S, Li K, et al. Nanoengineered extrusion-aligned tract bioprinting enables functional repair of spinal cord injuries. Cell Stem Cell. 2026;33(2):340-354.e7. https://doi.org/10.1016/j.stem.2025.12.021. PMid:41534522.
3. Wang J, Kong X, Li Q, et al. The spatial arrangement of cells in a 3D-printed biomimetic spinal cord promotes directional differentiation and repairs the motor function after spinal cord injury. Biofabrication. 2021;13(4):045016. https://doi.org/10.1088/1758-5090/ac0c5f. PMid:34139682.
4. Joung D, Truong V, Neitzke CC, et al. 3D printed stem-cell derived neural progenitors generate spinal cord scaffolds. Adv Funct Mater. 2018;28(39):1801850. https://doi.org/10.1002/adfm.201801850. PMid:32595422.
5. Liu X, Hao M, Chen Z, et al. 3D bioprinted neural tissue constructs for spinal cord injury repair. Biomaterials. 2021;272:120771. https:// doi.org/10.1016/j.biomaterials.2021.120771. PMid:33798962.
6. Haring AP, Thompson EG, Tong Y, et al. Process- and bio-inspired hydrogels for 3D bioprinting of soft free-standing neural and glial tissues. Biofabrication. 2019;11(2):025009. https://doi.org/10.1088/1758-5090/ ab02c9. PMid:30695770.
7. Kiyotake EA, Thomas EE, Homburg HB, et al. Conductive and injectable hyaluronic acid/gelatin/gold nanorod hydrogels for enhanced surgical translation and bioprinting. J Biomed Mater Res A. 2022;110(2):365-82. https://doi.org/10.1002/jbm.a.37294. PMid:34390325.
8. Yang J, Kim K, Liu Y, et al. 3D bioprinted dynamic bioactive living construct enhances mechanotransduction-assisted rapid neural network self-organization for spinal cord injury repair. Bioact Mater. 2025;46:531-54. https://doi.org/10.1016/j.bioactmat.2024.12.028. PMid:39886605.
9. Cao X, Li X, Shi W, et al. 3D-Bioprinted Scaffolds with Precise Factor Delivery for Spinal Cord Injury Repair. ACS Appl Mater Interfaces. 2025;17(30):42586-601. https://doi.org/10.1021/acsami.5c03076. PMid:40673827.
10. Zhang L, Chen G, Pang J, et al. 3D bioprinted NSC-EVs hydrogel scaffold promotes sustained functional repair via autophagy activation after TBI in mice. Chem Eng J. 2025;522:167836. https://doi. org/10.1016/j.cej.2025.167836.
11. Jiu J, Liu H, Li D, et al. 3D Mechanical Response Stem Cell Complex Repairs Spinal Cord Injury by Promoting Neurogenesis and Regulating Tissue Homeostasis. Adv Healthc Mater. 2025;14(7):e2404925. https://doi.org/10.1002/adhm.202404925. PMid:39853962.
12. Tricco AC, Lillie E, Zarin W, et al. PRISMA Extension for Scoping Reviews (PRISMA-ScR): checklist and explanation. Ann Intern Med. 2018;169(7):467-73. https://doi.org/10.7326/M18-0850. PMid:30178033.
13. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372(71):n71. https://doi.org/10.1136/bmj.n71. PMid:33782057.
14. Hooijmans CR, Rovers MM, de Vries RBM, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol. 2014;14(1):43. https://doi. org/10.1186/1471-2288-14-43. PMid:24667063.
15 McGuinness LA, Higgins JPT. Risk-of-bias VISualization (robvis): an R package and Shiny web app for visualizing risk-of-bias assessments. Res Synth Methods. 2021;12(1):55-61. https://doi.org/10.1002/jrsm.1411. PMid:32336025.
16. Knefel M, Kantor M, Kępka K, Owczarzy A, Kulig K, MaciążekJurczyk M. Applications of bio-printing to promote spinal cord regeneration. Polim Med. 2024;54(2):127-34. https://doi.org/10.17219/ pim/196553. PMid:39639728.
17. Benedek A, Cernica D, Mester A, et al. Modern concepts in regenerative therapy for ischemic stroke: from stem cells for promoting angiogenesis to 3D-bioprinted scaffolds customized via carotid shear stress analysis. Int J Mol Sci. 2019;20(10):2574. https://doi.org/10.3390/ ijms20102574. PMid:31130624.
18. He W, Xu C, Wu W, et al. The promising applications of 3D printing technology in neurotrauma. Int J Bioprint. 2024;10(3):2311. https:// doi.org/10.36922/ijb.2311.
19. Li S, Meng X, Zhong Z, Li C. Advances in 3D bioprinting of functional biomaterials for neural tissue engineering. Tissue Cell. 2025;96:103024. https://doi.org/10.1016/j.tice.2025.103024. PMid:40578149.
20. Joung D, Lavoie NS, Guo SZ, Park SH, Parr AM, McAlpine MC. 3D printed neural regeneration devices. Adv Funct Mater. 2020;30(1):1906237. https://doi.org/10.1002/adfm.201906237. PMid:32038121.
21. Pokharel R, Leipzig ND. 3D bioprinting for spinal cord injury: engineering scaffolds for functional recovery. ACS Biomater Sci Eng. 2026;12(2):757-72. https://doi.org/10.1021/acsbiomaterials.5c01474. PMid:41505565.
22. Bedir T, Ulag S, Ustundag CB, Gunduz O. 3D bioprinting applications in neural tissue engineering for spinal cord injury repair. Mater Sci Eng C. 2020;110:110741. https://doi.org/10.1016/j.msec.2020.110741. PMid:32204049.
23. Lu D, Yang Y, Zhang P, et al. Development and application of threedimensional bioprinting scaffold in the repair of spinal cord injury. Tissue Eng Regen Med. 2022;19(6):1113-27. https://doi.org/10.1007/ s13770-022-00465-1. PMid:35767151.
24. Kim DY, Liu Y, Kim G, An SB, Han I. Innovative strategies in 3D bioprinting for spinal cord injury repair. Int J Mol Sci. 2024;25(17):9592. https://doi.org/10.3390/ijms25179592. PMid:39273538.
25. Wang L, Zhou X, Wang S, et al. Bioinks used in the repair of nerve injury in vivo. Prog Mater Sci. 2026;158:101643. https://doi.org/10.1016/j. pmatsci.2025.101643.
26. Zarepour A, Hooshmand S, Gökmen A, Zarrabi A, Mostafavi E. Spinal cord injury management through the combination of stem cells and implantable 3D bioprinted platforms. Cells. 2021;10(11):3189. https://doi.org/10.3390/cells10113189. PMid:34831412.
27. St Clair-Glover M, Yue Z, Dottori M. 3D Printing for Neural Repair: Bridging the Gap in Regenerative Medicine. Adv Mater. 2025;37(36):e07590. https://doi.org/10.1002/adma.202507590.
PMid:40736088.
28. Thomas M, Willerth SM. 3-D bioprinting of neural tissue for applications in cell therapy and drug screening. Front Bioeng Biotechnol. 2017;5:69. https://doi.org/10.3389/fbioe.2017.00069. PMid:29204424.
29. Dhar S, Ahmad F, Deshpande A, Rana SS, Ahmed TA, Priyadarsini S. 3-Dimensional printing and bioprinting in neurological sciences: applications in surgery, imaging, tissue engineering, and pharmacology and therapeutics. J Mater Sci Mater Med. 2025;36(1):32. https://doi. org/10.1007/s10856-025-06877-4. PMid:40205004.
30. Oliveira EP, Malysz-Cymborska I, Golubczyk D, et al. Advances in bioinks and in vivo imaging of biomaterials for CNS applications. Acta Biomater. 2019;95:60-72. https://doi.org/10.1016/j.actbio.2019.05.006. PMid:31075514.
31. Rotaru-Zavaleanu AD, Bica M, Dinescu SN, et al. Bioactive hydrogels for spinal cord injury repair: emphasis on gelatin and its derivatives. Gels. 2025;11(7):497. https://doi.org/10.3390/gels11070497. PMid:40710658.
32. dos Santos MG, França FS, Prestes JP, et al. Production of a bioink containing decellularized spinal cord tissue for 3D bioprinting. Tissue Eng Part A. 2024;30(1-2):61-74. https://doi.org/10.1089/ten.tea.2023.0078. PMid:37772706.
33. Song S, Liu X, Huang J, Zhang Z. Neural stem cell-laden 3D bioprinting of polyphenol-doped electroconductive hydrogel scaffolds for enhanced neuronal differentiation. Biomater Adv. 2022;133:112639. https://doi.org/10.1016/j.msec.2021.112639. PMid:35527143.
34. Lee YB, Polio S, Lee W, et al. Bio-printing of collagen and VEGFreleasing fibrin gel scaffolds for neural stem cell culture. Exp Neurol. 2010;223(2):645-52. https://doi.org/10.1016/j.expneurol.2010.02.014. PMid:20211178.
35. Li YE, Jodat YA, Samanipour R, et al. Toward a neurospheroid niche model: optimizing embedded 3D bioprinting for fabrication of neurospheroid brain-like co-culture constructs. Biofabrication. 2021;13(1):015014. https://doi.org/10.1088/1758-5090/abc1be. PMid:33059333.
36. De la Vega L, Rosas Gómez DA, Abelseth E, Abelseth L, Allisson da Silva V, Willerth SM. 3D bioprinting human induced pluripotent stem cell-derived neural tissues using a novel lab-on-a-printer technology. Appl Sci (Basel). 2018;8(12):2414. https://doi.org/10.3390/app8122414.
37. Kwokdinata C, Chai KL, Lau K, Tan J, Chew SY. Bioprinted microchannel scaffolds modulate neuronal differentiation of encapsulated human spinal cord progenitor cells. ACS Appl Bio Mater. 2025;8(5):4337-50. https://doi.org/10.1021/acsabm.5c00441. PMid:40312827.
38. Cruz EM, Machado LS, Zamproni LN, et al. A gelatin methacrylatebased hydrogel as a potential bioink for 3D bioprinting and neuronal differentiation. Pharmaceutics. 2023;15(2):627. https://doi.org/10.3390/ pharmaceutics15020627. PMid:36839949.
39. Hamid OA, Eltaher HM, Sottile V, Yang J. 3D bioprinting of a stem cell-laden, multi-material tubular composite: an approach for spinal cord repair. Mater Sci Eng C. 2021;120:111707. https://doi.org/10.1016/j. msec.2020.111707. PMid:33545866.
40 Lozano R, Stevens L, Thompson BC, et al. 3D printing of layered brain-like structures using peptide modified gellan gum substrates. Biomaterials. 2015;67:264-73. https://doi.org/10.1016/j. biomaterials.2015.07.022. PMid:26231917.
41. Bordoni M, Rey F, Fantini V, et al. From neuronal differentiation of iPSCs to 3D neuro-organoids: modelling and therapy of neurodegenerative diseases. Int J Mol Sci. 2018;19(12):3972. https://doi.org/10.3390/ijms19123972. PMid:30544711.
42. Zhuang P, Sun AX, An J, Chua CK, Chew SY. 3D neural tissue models: from spheroids to bioprinting. Biomaterials. 2018;154:113-33. https://doi.org/10.1016/j.biomaterials.2017.10.002. PMid:29120815.
43. Choi T, Park J, Lee S, et al. 3D Bioprinted Neural Tissues: Emerging Strategies for Regeneration and Disease Modeling. Pharmaceutics. 2025;17(9):1176. https://doi.org/10.3390/pharmaceutics17091176. PMid:41012512.
44. Rey F, Barzaghini B, Nardini A, et al. Advances in tissue engineering and innovative fabrication techniques for 3-D-structures: translational applications in neurodegenerative diseases. Cells. 2020;9(7):1636. https://doi.org/10.3390/cells9071636. PMid:32646008.
45. Samanipour R, Tahmooressi H, Rezaei Nejad H, Hirano M, Shin SR, Hoorfar M. A review on 3D printing functional brain model. Biomicrofluidics. 2022;16(1):011501. https://doi.org/10.1063/5.0074631. PMid:35145569.
46. Amiri E, Sanjarnia P, Sadri B, Jafarkhani S, Khakbiz M. Recent advances and future directions of 3D to 6D printing in brain cancer treatment and neural tissue engineering. Biomed Mater. 2023;18(5):052005. https://doi.org/10.1088/1748-605X/ace9a4. PMid:37478841.
47. Qian Y, Gong J, Lu K, et al. DLP printed hDPSC-loaded GelMA microsphere regenerates dental pulp and repairs spinal cord. Biomaterials. 2023;299:122137. https://doi.org/10.1016/j.biomaterials.2023.122137. PMid:37172537.
48. Lee SJ, Nowicki M, Harris B, Zhang LG. Fabrication of a highly aligned neural scaffold via a table top stereolithography 3D printing and electrospinning. Tissue Eng Part A. 2017;23(11-12):491-502. https://doi.org/10.1089/ten.tea.2016.0353. PMid:27998214.
49. Zhou X, Cui H, Nowicki M, et al. Three-dimensional-bioprinted dopamine-based matrix for promoting neural regeneration. ACS Appl Mater Interfaces. 2018;10(10):8993-9001. https://doi.org/10.1021/ acsami.7b18197. PMid:29461046.
50. Song S, Zhou J, Wan J, et al. Three-dimensional printing of microfiberreinforced hydrogel loaded with oxymatrine for treating spinal cord injury. Int J Bioprint. 2023;9(3):692. https://doi.org/10.18063/ijb.692. PMid:37273987.
51. Wang Q, Liu K, Cao X, et al. Plant-derived exosomes extracted from Lycium barbarum L. loaded with isoliquiritigenin to promote spinal cord injury repair based on 3D printed bionic scaffold. Bioeng Transl Med. 2024;9(4):e10646. https://doi.org/10.1002/btm2.10646.
PMid:39036078.
52. Li Y, Cheng S, Wen H, et al. Coaxial 3D printing of hierarchical structured hydrogel scaffolds for on-demand repair of spinal cord injury. Acta Biomater. 2023;168:400-15. https://doi.org/10.1016/j. actbio.2023.07.020. PMid:37479156.
53. Chen M, Ye Y, Wang T, Zhang X, Chen J, Zhang J. Neural network reconstruction and motor function recovery in traumatic brain injury rat models via a 3D collagen/heparan/bFGF/NGF scaffold combined with mesenchymal stem cells. J Neural Eng. 2025;22(5):056022. https://doi.org/10.1088/1741-2552/ae09fd. PMid:40983084.
54. Gai K, Song Y, Gao D, et al. Advanced stem cell therapy: 3d-bioprinted brain-like transplants for Alzheimer’s disease-like dementia. Adv Sci (Weinh). 2026;13(4):e10062. https://doi.org/10.1002/advs.202510062. PMid:41201135.
55. Hsieh FY, Lin HH, Hsu SH. 3D bioprinting of neural stem cell-laden thermoresponsive biodegradable polyurethane hydrogel and potential in central nervous system repair. Biomaterials. 2015;71:48-57. https://doi.org/10.1016/j.biomaterials.2015.08.028. PMid:26318816.
56. Li X, Zhang J, Zhang Y, et al. Conjugated therapy with coaxially printed neural stem cell-laden microfibers and umbilical cord mesenchymal stem cell derived exosomes on complete transactional spinal cord defects. Mater Today Bio. 2025;32:101639. https://doi.org/10.1016/j. mtbio.2025.101639. PMid:40160243.
57. Liu X, Song S, Chen Z, et al. Release of O-GlcNAc transferase inhibitor promotes neuronal differentiation of neural stem cells in 3D bioprinted supramolecular hydrogel scaffold for spinal cord injury repair. Acta Biomater. 2022;151:148-62. https://doi.org/10.1016/j. actbio.2022.08.031. PMid:36002129.
58. Song S, Li Y, Huang J, Cheng S, Zhang Z. Inhibited astrocytic differentiation in neural stem cell-laden 3D bioprinted conductive composite hydrogel scaffolds for repair of spinal cord injury. Biomater Adv. 2023;148:213385. https://doi.org/10.1016/j.bioadv.2023.213385. PMid:36934714.
59. Yang J, Yang K, Man W, et al. 3D bio-printed living nerve-like fibers refine the ecological niche for long-distance spinal cord injury regeneration. Bioact Mater. 2023;25:160-75. https://doi.org/10.1016/j.
bioactmat.2023.01.023. PMid:36817821.
60. Cadena M, Ning L, King A, et al. 3D bioprinting of neural tissues. Adv Healthc Mater. 2021;10(15):e2001600. https://doi.org/10.1002/ adhm.202001600. PMid:33200587.
61. Yuan TY, Zhang J, Yu T, Wu JP, Liu QY. 3D bioprinting for spinal cord injury repair. Front Bioeng Biotechnol. 2022;10:847344. https://doi.org/10.3389/fbioe.2022.847344. PMid:35519617.
62. Lee SJ, Esworthy T, Stake S, et al. Advances in 3D bioprinting for neural tissue engineering. Adv Biosyst. 2018;2(4):1700213. https://doi. org/10.1002/adbi.201700213.
63. Bupphathong S, Quiroz C, Huang W, Chung PF, Tao HY, Lin CH. Gelatin methacrylate hydrogel for tissue engineering applications – a review on material modifications. Pharmaceuticals (Basel). 2022;15(2):171. https://doi.org/10.3390/ph15020171.
PMid:35215284.
64 Kwokdinata C, Chew SY. Additive manufacturing in spatial patterning for spinal cord injury treatment. Adv Drug Deliv Rev. 2025;218:115523. https://doi.org/10.1016/j.addr.2025.115523. PMid:39880332.
65. Ju D, Dong C. The combined application of stem cells and threedimensional bioprinting scaffolds for the repair of spinal cord injury. Neural Regen Res. 2024;19(8):1751-8. https://doi.org/10.4103/16735374.385842. PMid:38103241.
66. Steele EM, Carr ZL, Dosmar E. Bioprinting of hydrogel-based drug delivery systems for nerve tissue regeneration. Biophysica. 2024;4(1): 58-73. https://doi.org/10.3390/biophysica4010004.
67. Bradbury EJ, Moon LD, Popat RJ, et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature. 2002;416(6881): 636-40. https://doi.org/10.1038/416636a. PMid:11948352.
68. Anderson MA, Burda JE, Ren Y, et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature. 2016;532(7598): 195-200. https://doi.org/10.1038/nature17623. PMid:27027288.
69. Jiu J, Liu H, Li D, et al. 3D bioprinting approaches for spinal cord injury repair. Biofabrication. 2024;16(3):032003. https://doi. org/10.1088/1758-5090/ad3a13. PMid:38569491.
70. Mladenovska T, Choong PF, Wallace GG, O’Connell CD. The regulatory challenge of 3D bioprinting. Regen Med. 2023;18(8):659-74. https://doi.org/10.2217/rme-2022-0194. PMid:37403962.
71. Ng WL, An J, Chua CK. Process, Material, and Regulatory Considerations for 3D Printed Medical Devices and Tissue Constructs. Engineering (Beijing). 2024;36:146-66. https://doi.org/10.1016/j.eng.2024.01.028.
72. Ozbolat IT. Bioprinting scale-up tissue and organ constructs for transplantation. Trends Biotechnol. 2015;33(7):395-400. https://doi. org/10.1016/j.tibtech.2015.04.005. PMid:25978871.
1Universidade Positivo, Curitiba, PR, Brazil.
2INC 3D, Instituto de Neurologia de Curitiba – INC, Curitiba, PR, Brazil.
3Department of Neurosurgery, Instituto de Neurologia de Curitiba – INC, Curitiba, PR, Brazil.
Received Aug 3, 2026
Accepted Aug 16, 2026
