Programmable Controlled-Release Bionic Spinal Cord Graft Promotes Repair and Functional Recovery after Spinal Cord Injury

Chengcheng Luan; Qi Shan; Wei Shi; Yumin Yang; Hanyue Yang; Xiu Dai; Meiyuan Li; Jiahui Guo; Panjian Lu; Ye Zhu; Xiuyun Liu; Dong Ming; Songlin Zhou; Xiaosong Gu

doi:10.1016/j.eng.2026.06.012

Engineering ›› :202606012 DOI: 10.1016/j.eng.2026.06.012

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Programmable Controlled-Release Bionic Spinal Cord Graft Promotes Repair and Functional Recovery after Spinal Cord Injury

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Abstract

The existing strategies for spinal cord injury (SCI) repair are restricted by the limitations of experimental models and intervention measures. Although the potential of stem cells, biomaterials, and electromagnetic stimulation has been demonstrated in animal models, their clinical translation has been relatively ineffective. In the present study, using the concepts of biomimetic neural tissue engineering to address the complex spatiotemporal characteristics of injured spinal cord repair, we created a programmable controlled-release bionic spinal cord graft with a topological scaffold composed of silk fibroin and collagen. By employing microfluidic drug-loaded microsphere technology and dual regulation by exosomes and extracellular matrix derived from human stem cells, the graft exhibited sustained release of neurotrophic factors, providing a beneficial regenerative microenvironment for SCI repair. In a mouse T10 3-mm hemisection SCI model, the graft facilitated tissue repair of the injured spinal cord, vascular remodeling, sensory and motor functional reconstruction, bladder function recovery, and the reversal of muscle atrophy. This study presents a new strategy for effective injured spinal cord repair using a programmable controlled-release bionic spinal cord graft, and the results suggest potential for application in humans for spinal cord repair and functional reconstruction.

Keywords

Spinal cord injury / Programmable controlled release / Bionic topological scaffold / Tissue repair / Functional recovery / Regenerative microenvironment

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Chengcheng Luan, Qi Shan, Wei Shi, Yumin Yang, Hanyue Yang, Xiu Dai, Meiyuan Li, Jiahui Guo, Panjian Lu, Ye Zhu, Xiuyun Liu, Dong Ming, Songlin Zhou, Xiaosong Gu. Programmable Controlled-Release Bionic Spinal Cord Graft Promotes Repair and Functional Recovery after Spinal Cord Injury. Engineering 202606012 DOI:10.1016/j.eng.2026.06.012

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References

Publishing order | Descend order by publishing year | Descend order by cited within

[1]	Rubiano AM, Carney N, Chesnut R, Puyana JC . Global neurotrauma research challenges and opportunities. Nature 2015; 527(7578):S193—7.

[2]	Lu Y, Shang Z, Zhang W, Hu X, Shen R, Zhang K, et al. Global, regional, and national burden of spinal cord injury from 1990 to 2021 and projections for 2050: a systematic analysis for the Global Burden of Disease 2021 study. Ageing Res Rev 2025; 103:102598.

[3]

Huang H, Young W, Skaper S, Chen L, Moviglia G, Saberi H, et al. and the International Association of Neurorestoratology and The Chinese Association of Neurorestoratology. Clinical neurorestorative therapeutic guidelines for spinal cord injury (IANR/CANR version 2019). J Orthop Translat 2020; 20:14-24.

[4]	Karsy M, Hawryluk G . Modern medical management of spinal cord injury. Curr Neurol Neurosci Rep 2019; 19(9):65.

[5]	Griffin JM, Bradke F . Therapeutic repair for spinal cord injury: combinatory approaches to address a multifaceted problem. EMBO Mol Med 2020; 12(3):EMMM201911505.

[6]	Yao C, Tang X, Cao Y, Wang X, Yu B . A brief summary of current therapeutic strategies for spinal cord injury. Engineering 2022; 13:46-52.

[7]	Fan B, Wei Z, Feng S . Progression in translational research on spinal cord injury based on microenvironment imbalance. Bone Res 2022; 10(1):35.

[8]	Yang L, Conley BM, Cerqueira SR, Pongkulapa T, Wang S, Lee JK, et al. Effective modulation of CNS Inhibitory microenvironment using bioinspired hybrid—nanoscaffold—based therapeutic interventions. Adv Mater 2020; 32(43):2002578.

[9]	Chen K, Yu W, Zheng G, Xu Z, Yang C, Wang Y, et al. Biomaterial—based regenerative therapeutic strategies for spinal cord injury. NPG Asia Mater 2024; 16(1):5.

[10]	Patel PA, Nassar SI, Nguyen SA, Lee BJ, Kejner AE . The use of bone morphogenic protein and related therapies in the management of medication—related osteonecrosis of the jaw: a scoping review. Plast Aesthet Res 2025; 12:13.

[11]	Vignolo SM, Roth DM, Wu L, Cosgrove J, Bertassoni LE . Strategies for craniofacial tissue engineering: innovations for scalable bone regeneration. Plast Aesthet Res 2025; 12:20.

[12]	Viraji HA, Abeygunawardane A, Adikary SU, Edirisinghe S, Faleel A . Wireless bioelectric stimulation for bone regeneration using magnetoelectric PVDF/BaTiO₃—Fe₈₀Ga₂₀ laminates. Biomed Technol 2025; 12:100121.

[13]	Zhao C, Rao JS, Duan H, Hao P, Shang J, Fan Y, et al. Chronic spinal cord injury repair by NT3—chitosan only occurs after clearance of the lesion scar. Signal Transduct Target Ther 2022; 7(1):184.

[14]	Chen T, He X, Wang J, Du D, Xu Y . NT—3 combined with TGF—b signaling pathway enhance the repair of spinal cord injury by inhibiting glial scar formation and promoting axonal regeneration. Mol Biotechnol 2024; 66(6):1484-95.

[15]	Fang A, Wang Y, Guan N, Zuo Y, Lin L, Guo B, et al. Porous microneedle patch with sustained delivery of extracellular vesicles mitigates severe spinal cord injury. Nat Commun 2023; 14(1):4011.

[16]	Ceto S, Sekiguchi KJ, Takashima Y, Nimmerjahn A, Tuszynski MH . Neural stem cell grafts form extensive synaptic networks that integrate with host circuits after spinal cord injury. Cell Stem Cell 2020; 27(3):430—40.

[17]	Wu Q, Xiang Z, Ying Y, Huang Z, Tu Y, Chen M, et al. Nerve growth factor (NGF) with hypoxia response elements loaded by adeno—associated virus (AAV) combined with neural stem cells improve the spinal cord injury recovery. Cell Death Discov 2021; 7(1):301.

[18]	Cai P, Ding Y, Wang C, Wu J, Hart ML, Rolauffs B, et al. Advancing biomimetic bone scaffolds: from electrospun 2D membranes to functional 3D nanofiber constructs. Biomed Technol 2025; 11:100099.

[19]	Liu J, Yao Z, Hu Z, Zhang X, Gong B, Dai Y, et al. Spatiotemporal delivery of required facilitators for microenvironment remodeling propels neural regeneration after spinal cord injury. Adv Mater 2025:e03479.

[20]	Bai B, Zhang R, Zhang C, Liu Y, Liu S, Zou C, et al. Spinal cord—like scaffold with rapid tissue integration enhanced spinal cord nerve repair. Adv Mater 2025; 37(44):e05402.

[21]	Gu X. Biodegradable materials and the tissue engineering of nerves. Engineering 2021; 7(12):1700-3.

[22]	Xu L, Zhou S, Dai X, Gu X, Ouyang Z . Tissue engineering and spinal cord injury repair. Engineering 2025; 46:60-72.

[23]	Jiang JP, Liu XY, Zhao F, Zhu X, Li XY, Niu XG, et al. Three—dimensional bioprinting collagen/silk fibroin scaffold combined with neural stem cells promotes nerve regeneration after spinal cord injury. Neural Regen Res 2020; 15(5):959-68.

[24]	Yan Y, Li M, Guo L, Zhang W, Wu R, Guan T, et al. Silk fibroin hydrogel with recombinant silk fibroin/NT3 protein enhances wound healing by promoting type III collagen synthesis and hair follicle regeneration in skin injury. Mater Today Bio 2025; 33:101957.

[25]	Zhao YZ, Jiang X, Xiao J, Lin Q, Yu WZ, Tian FR, et al. Using NGF heparin—poloxamer thermosensitive hydrogels to enhance the nerve regeneration for spinal cord injury. Acta Biomater 2016; 29:71-80.

[26]	Liu J, Yan R, Wang B, Chen S, Hong H, Liu C, et al. Decellularized extracellular matrix enriched with GDNF enhances neurogenesis and remyelination for improved motor recovery after spinal cord injury. Acta Biomater 2024; 180:308—22.

[27]	Zhu B, Gu G, Ren J, Song X, Li J, Wang C, et al. Schwann cell—derived exosomes and methylprednisolone composite patch for spinal cord injury repair. ACS Nano 2023; 17(22):22928-43.

[28]	Li L, Zhang Y, Mu J, Chen J, Zhang C, Cao H, et al. Transplantation of human mesenchymal stem—cell—derived exosomes immobilized in an adhesive hydrogel for effective treatment of spinal cord injury. Nano Lett 2020; 20(6):4298-305.

[29]	Han M, Yang H, Lu X, Li Y, Liu Z, Li F, et al. Three—dimensional—cultured MSC—derived exosome—hydrogel hybrid microneedle array patch for spinal cord repair. Nano Lett 2022; 22(15):6391-401.

[30]	Luan Z, Liu J, Li M, Wang Y, Wang Y . Exosomes derived from umbilical cord—mesenchymal stem cells inhibit the NF—jB/MAPK signaling pathway and reduce the inflammatory response to promote recovery from spinal cord injury. J Orthop Surg Res 2024; 19(1):184.

[31]	Chew DJ, Zhu L, Delivopoulos E, Minev IR, Musick KM, Mosse CA, et al. A microchannel neuroprosthesis for bladder control after spinal cord injury in rat. Sci Transl Med 2013; 5(210):210ra155.

[32]	Wyndaele JJ . The management of neurogenic lower urinary tract dysfunction after spinal cord injury. Nat Rev Urol 2016; 13(12):705—14.

[33]	Hao F, Jia F, Hao P, Duan H, Wang Z, Fan Y, et al. Proper wiring of newborn neurons to control bladder function after complete spinal cord injury. Biomaterials 2023; 292:121919.

[34]	Fan B, Wei Z, Yao X, Shi G, Cheng X, Zhou X, et al. Microenvironment imbalance of spinal cord injury. Cell Transplant 2018; 27(6):853-66.

[35]	Li X, Liu D, Xiao Z, Zhao Y, Han S, Chen B, et al. Scaffold—facilitated locomotor improvement post complete spinal cord injury: motor axon regeneration versus endogenous neuronal relay formation. Biomaterials 2019; 197:20-31.

[36]	Sha Q, Wang Y, Zhu Z, Wang H, Qiu H, Niu W, et al. A hyaluronic acid/silk fibroin/poly—dopamine—coated biomimetic hydrogel scaffold with incorporated neurotrophin—3 for spinal cord injury repair. Acta Biomater 2023; 167:219-33.

[37]	Hu X, Xu W, Ren Y, Wang Z, He X, Huang R, et al. Spinal cord injury: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther 2023; 8(1):245.

[38]	Ibarra A, Diaz—Ruiz A . Protective effect of cyclosporin—A in spinal cord injury: an overview. Curr Med Chem 2006; 13(22):2703—10.

[39]	Wang G, Li Q, Liu S, Li M, Liu B, Zhao T, et al. An injectable decellularized extracellular matrix hydrogel with cortical neuron—derived exosomes enhances tissue repair following traumatic spinal cord injury. Mater Today Bio 2024; 28:101250.

[40]	Kobashi S, Terashima T, Katagi M, Nakae Y, Okano J, Suzuki Y, et al. Transplantation of M2—deviated microglia promotes recovery of motor function after spinal cord injury in mice. Mol Ther 2020; 28(1):254-65.

[41]	Kuboyama T, Kominato S, Nagumo M, Tohda C . Recovery from spinal cord injury via M2 microglial polarization induced by Polygalae Radix. Phytomedicine 2021; 82:153452.

[42]	Li G, Che MT, Zeng X, Qiu XC, Feng B, Lai BQ, et al. Neurotrophin—3 released from implant of tissue—engineered fibroin scaffolds inhibits inflammation, enhances nerve fiber regeneration, and improves motor function in canine spinal cord injury. J Biomed Mater Res A 2018; 106(8):2158-70.

[43]	Qian D, Xu J, Zhang X, Hu F, Cao S, Dong Y, et al. Microenvironment self—adaptive nanomedicine promotes spinal cord repair by suppressing inflammation cascade and neural apoptosis. Adv Mater 2024; 36(50):2307624.

[44]	Gong L, Gu Y, Han X, Luan C, Liu C, Wang X, et al. Spatiotemporal dynamics of the molecular expression pattern and intercellular interactions in the glial scar response to spinal cord injury. Neurosci Bull 2023; 39(2):213—44.

[45]	Xu X, Gao F, Chen Q, Chen B, Liang W, Huang R, et al. F—box/LRR—repeat protein 12 reorchestrated microglia to inhibit scarring and achieve adult spinal cord injury repair. Signal Transduct Target Ther 2025; 10(1):259.

[46]	Dimakakos P, Arkadopoulos N . Spinal cord ischaemia. Eur J Vasc Endovasc Surg 1999; 17(6):544—5.

[47]	Himmels P, Paredes I, Adler H, Karakatsani A, Luck R, Marti HH, et al. Motor neurons control blood vessel patterning in the developing spinal cord. Nat Commun 2017; 8(1):14583.

[48]	Ju C, Dong H, Liu R, Wang X, Xu R, Hu H, et al. Exosomes—based nanotherapeutic strategies: an important approach for spinal cord injury repair. Int J Nanomedicine 2025; 20:10407-31.

[49]

Rauch MF, Hynes SR, Bertram J, Redmond A, Robinson R, Williams C, et al. Engineering angiogenesis following spinal cord injury: a coculture of neural progenitor and endothelial cells in a degradable polymer implant leads to an increase in vessel density and formation of the blood—spinal cord barrier. Eur J Neurosci 2009; 29(1):132-45.

[50]	Sakiyama—Elbert S, Johnson PJ, Hodgetts SI, Plant GW, Harvey AR . Chapter 36—scaffolds to promote spinal cord regeneration. In: Verhaagen J, McDonald JW, editors. Handbook of clinical neurology. Amsterdam: Elsevier; 2012. p. 575-94.

[51]	He J, Sun C, Gu Z, Yang Y, Gu M, Xue C, et al. Morphology, migration, and transcriptome analysis of Schwann cell culture on butterfly wings with different surface architectures. ACS Nano 2018; 12(10):9660—8.

[52]	Xue W, Shi W, Kong Y, Kuss M, Duan B . Anisotropic scaffolds for peripheral nerve and spinal cord regeneration. Bioact Mater 2021; 6(11):4141—60.

[53]	Zhang X, Qi T, Sun Y, Chen X, Yang P, Wei S, et al. Chitosan nerve conduit filled with ZIF—8—functionalized guide microfibres enhances nerve regeneration and sensory function recovery in sciatic nerve defects. Chem Eng J 2024; 480:147933.

[54]	Li Y, Gu Y, Wang Z, Wang Y, Jiang S, Wang K, et al. GelMA hydrogel encapsulating iPSC—derived human spinal cord organoids enhances neural regeneration and restores motor function in rat spinal cord injury. J Biomed Mater Res A 2025; 113(10):e38001.

[55]	Zhu Y, Huang R, Yu L, Liu Z, Liu Y, Fan W, et al. Engineered thoracic spinal cord organoids for transplantation after spinal cord injury. Nat Biomed Eng. In press.

[56]	Anderson MA, Squair JW, Gautier M, Hutson TH, Kathe C, Barraud Q, et al. Natural and targeted circuit reorganization after spinal cord injury. Nat Neurosci 2022; 25(12):1584-96.