Research progress on silk fibroin-nerve guide conduits for peripheral nerve injury repair_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

DONG Fan ^1,2 , WANG Yining ² , WU Zixiang ² ,  TAN Quanchang ²

1. School of Medicine, Northwest University, Xi’an Shaanxi, 710069, P. R. China;
2. Department of Orthopedics, Xijing Hospital, Air Force Medical University, Xi’an Shaanxi, 710032, P. R. China;

Corresponding author：

TAN Quanchang, Email: sci_research@126.com

Keywords：

Peripheral nerve injury; neural regeneration; nerve guidance conduits; silk fibroin

DOI：

10.7507/1002-1892.202504070

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To review the research progress on silk fibroin (SF)-nerve guide conduits (NGCs) for peripheral nerve injury (PNI) repair. Methods To review the recent literature on PNI and SF-NGCs, expound the concepts and treatment strategies of PNI, and summarize the construction of SF-NGCs and its application in PNI repair.Results Autologous nerve transplantation remains the “gold standard” for treating severe PNI. However, it’s clinical applications are constrained by the limitations of limited donors and donor area damage. Natural SF exhibits good biocompatibility, low immunogenicity, and excellent physicochemical properties, making it an ideal candidate for the construction of NGCs. SF-NGCs constructed using different technologies have been found to have better biocompatibility and bioactivity. Their configurations can facilitate nerve regeneration by enhancing regenerative guidance and axonal extension. Besides, the adhesion, proliferation and differentiation of neurons and Schwann cells related to PNI repair can be effectively promote by NGCs. This accelerates the speed of nerve regeneration and improves the efficiency of repair. In addition, SF-NGCs can be used as regenerative scaffolds to provide biological templates for nerve repair. Conclusion The biodegradable natural SF has been extensively studied and demonstrated promising application prospects in the field of NGCs. It might be an effective and viable alternative to the “gold standard” for PNI treatment.

1.	Zhang PX, Yin XF, Kou YH, et al. Neural regeneration after peripheral nerve injury repair is a system remodelling process of interaction between nerves and terminal effector. Neural Regen Res, 2015, 10(1): 52. doi: 10.4103/1673-5374.150705.
2.	Vijayavenkataraman S. Nerve guide conduits for peripheral nerve injury repair: A review on design, materials and fabrication methods. Acta Biomater, 2020, 106: 54-69.
3.	Hu Y, Zhang H, Wei H, et al. Scaffolds with anisotropic structure for neural tissue engineering. Engineered Regeneration, 2022, 3(2): 154-162.
4.	Wang B, Lu CF, Liu ZY, et al. Chitin scaffold combined with autologous small nerve repairs sciatic nerve defects. Neural Regen Res, 2022, 17(5): 1106-1114.
5.	Zhang H, Guo J, Wang Y, et al. Natural polymer-derived bioscaffolds for peripheral nerve regeneration. Advanced Functional Materials, 2022, 32(41): 2203829. doi: 10.1002/adfm.202203829.
6.	Lee TH, Yen CT, Hsu SH. Preparation of polyurethane-graphene nanocomposite and evaluation of neurovascular regeneration. ACS Biomater Sci Eng, 2020, 6(1): 597-609.
7.	Costa Serrão de Araújo G, Couto Neto B, Harley Santos Botelho R, et al. Clinical evaluation after peripheral nerve repair with caprolactone neurotube. Hand (N Y), 2017, 12(2): 168-174.
8.	Vijayavenkataraman S, Zhang S, Thaharah S, et al. Electrohydrodynamic jet 3D printed nerve guide conduits (NGCs) for peripheral nerve injury repair. Polymers (Basel), 2018, 10(7): 753. doi: 10.3390/polym10070753.
9.	Dong R, Liu Y, Yang Y, et al. MSC-derived exosomes-based therapy for peripheral nerve injury: A novel therapeutic strategy. Biomed Res Int, 2019, 2019: 6458237. doi: 10.1155/2019/6458237.
10.	Hatzenbuehler J. Peripheral Nerve Injury. Curr Sports Med Rep, 2015, 14(5): 356-357.
11.	Wijntjes J, Borchert A, van Alfen N. Nerve ultrasound in traumatic and iatrogenic peripheral nerve injury. Diagnostics (Basel), 2020, 11(1): 30. doi: 10.3390/diagnostics11010030.
12.	Robinson LR. Traumatic injury to peripheral nerves. Muscle Nerve, 2000, 23(6): 863-873.
13.	中国康复医学会居家康复专业委员会居家康复指南编写委员会, 世界卫生组织康复合作中心. 周围神经损伤居家康复指南. 中国康复医学杂志, 2022, 37(4): 433-442.
14.	Modrak M, Talukder MAH, Gurgenashvili K, et al. Peripheral nerve injury and myelination: Potential therapeutic strategies. J Neurosci Res, 2020, 98(5): 780-795.
15.	Campbell WW. Evaluation and management of peripheral nerve injury. Clin Neurophysiol, 2008, 119(9): 1951-1965.
16.	Miller RG. AAEE minimonograph #28: injury to peripheral motor nerves. Muscle Nerve, 1987, 10(8): 698-710.
17.	Sulaiman W, Gordon T. Neurobiology of peripheral nerve injury, regeneration, and functional recovery: from bench top research to bedside application. Ochsner J, 2013, 13(1): 100-108.
18.	Han GH, Peng J, Liu P, et al. Therapeutic strategies for peripheral nerve injury: decellularized nerve conduits and Schwann cell transplantation. Neural Regen Res, 2019, 14(8): 1343-1351.
19.	Saffari TM, Mathot F, Friedrich PF, et al. Revascularization patterns of nerve allografts in a rat sciatic nerve defect model. J Plast Reconstr Aesthet Surg, 2020, 73(3): 460-468.
20.	Mohammad J, Shenaq J, Rabinovsky E, et al. Modulation of peripheral nerve regeneration: a tissue-engineering approach. The role of amnion tube nerve conduit across a 1-centimeter nerve gap. Plast Reconstr Surg, 2000, 105(2): 660-666.
21.	Lans J, Eberlin KR, Evans PJ, et al. A systematic review and meta-analysis of nerve gap repair: Comparative effectiveness of allografts, autografts, and conduits. Plast Reconstr Surg, 2023, 151(5): 814e-827e.
22.	李平生, 林国叶, 何向阳, 等. 周围神经损伤的修复治疗. 中国骨伤杂志, 2005, 18(11): 667-669.
23.	Zhang H, Zhang H, Wang H, et al. Natural proteins-derived asymmetric porous conduit for peripheral nerve regeneration. Applied Materials Today, 2022, 27: 101431. doi: 10.1016/j.apmt.2022.101431.
24.	Lin YC, Marra KG. Injectable systems and implantable conduits for peripheral nerve repair. Biomed Mater, 2012, 7(2): 024102. doi: 10.1088/1748-6041/7/2/024102.
25.	Safa B, Jain S, Desai MJ, et al. Peripheral nerve repair throughout the body with processed nerve allografts: Results from a large multicenter study. Microsurgery, 2020, 40(5): 527-537.
26.	龚超, 张玉强, 王伟. 细胞治疗周围神经损伤的作用及机制. 中国组织工程研究, 2022, 26(13): 2216-2221.
27.	Li R, Liu Z, Pan Y, et al. Peripheral nerve injuries treatment: a systematic review. Cell Biochem Biophys, 2014, 68(3): 449-454.
28.	Zennifer A, Thangadurai M, Sundaramurthi D, et al. Additive manufacturing of peripheral nerve conduits - Fabrication methods, design considerations and clinical challenges. SLAS Technol, 2023, 28(3): 102-126.
29.	Navissano M, Malan F, Carnino R, et al. Neurotube for facial nerve repair. Microsurgery, 2005, 25(4): 268-271.
30.	Rbia N, Bulstra LF, Saffari TM, et al. Collagen nerve conduits and processed nerve allografts for the reconstruction of digital nerve gaps: A single-institution case series and review of the literature. World Neurosurg, 2019, 127: e1176-e1184.
31.	Magaz A, Faroni A, Gough JE, et al. Bioactive silk-based nerve guidance conduits for augmenting peripheral nerve repair. Adv Healthc Mater, 2018, 7(23): e1800308. doi: 10.1002/adhm.201800308.
32.	Fountain JN, Hawker MJ, Hartle L, et al. Towards non-stick silk: Tuning the hydrophobicity of silk fibroin protein. Chembiochem, 2022, 23(22): e202200429. doi: 10.1002/cbic.202200429.
33.	Kundu SC, Kundu B, Talukdar S, et al. Invited review nonmulberry silk biopolymers. Biopolymers, 2012, 97(6): 455-467.
34.	Sun W, Gregory DA, Tomeh MA, et al. Silk fibroin as a functional biomaterial for tissue engineering. Int J Mol Sci, 2021, 22(3): 1499. doi: 10.3390/ijms22031499.
35.	Lin DM, Li MQ, Wang LL, et al. Multifunctional hydrogel based on silk fibroin promotes tissue repair and regeneration. Advanced Functional Materials, 2024, 34(39). doi: 10.1002/adfm.202405255.
36.	He YX, Zhang NN, Li WF, et al. N-Terminal domain of Bombyx mori fibroin mediates the assembly of silk in response to pH decrease. J Mol Biol, 2012, 418(3-4): 197-207.
37.	Houshyar S, Bhattacharyya A, Shanks R. Peripheral nerve conduit: Materials and structures. ACS Chem Neurosci, 2019, 10(8): 3349-3365.
38.	Carvalho CR, Oliveira JM, Reis RL. Modern trends for peripheral nerve repair and regeneration: Beyond the hollow nerve guidance conduit. Front Bioeng Biotechnol, 2019, 7: 337. doi: 10.3389/fbioe.2019.00337.
39.	Sun B, Zhou Z, Wu T, et al. Development of nanofiber sponges-containing nerve guidance conduit for peripheral nerve regeneration in vivo. ACS Appl Mater Interfaces, 2017, 9(32): 26684-26696.
40.	Chen YS, Hsieh CL, Tsai CC, et al. Peripheral nerve regeneration using silicone rubber chambers filled with collagen, laminin and fibronectin. Biomaterials, 2000, 21(15): 1541-1547.
41.	Dinis TM, Elia R, Vidal G, et al. 3D multi-channel bi-functionalized silk electrospun conduits for peripheral nerve regeneration. J Mech Behav Biomed Mater, 2015, 41: 43-55.
42.	Wieringa P, Tonazzini I, Micera S, et al. Nanotopography induced contact guidance of the F11 cell line during neuronal differentiation: a neuronal model cell line for tissue scaffold development. Nanotechnology, 2012, 23(27): 275102. doi: 10.1088/0957-4484/23/27/275102.
43.	Zhang Q, Zhao Y, Yan S, et al. Preparation of uniaxial multichannel silk fibroin scaffolds for guiding primary neurons. Acta Biomater, 2012, 8(7): 2628-2638.
44.	Wang Y, Kong Y, Zhao Y, et al. Electrospun, reinforcing network-containing, silk fibroin-based nerve guidance conduits for peripheral nerve repair. Journal of Biomaterials and Tissue Engineering, 2016, 6(1): 53-60.
45.	Wei GJ, Yao M, Wang YS, et al. Promotion of peripheral nerve regeneration of a peptide compound hydrogel scaffold. Int J Nanomedicine, 2013, 8: 3217-3225.
46.	Xue C, Zhu H, Tan D, et al. Electrospun silk fibroin-based neural scaffold for bridging a long sciatic nerve gap in dogs. J Tissue Eng Regen Med, 2018, 12(2): e1143-e1153.
47.	Yonesi M, Garcia-Nieto M, Guinea GV, et al. Silk fibroin: An ancient material for repairing the injured nervous system. Pharmaceutics, 2021, 13(3): 429. doi: 10.3390/pharmaceutics13030429.
48.	Tian L, Prabhakaran MP, Hu J, et al. Coaxial electrospun poly (lactic acid)/silk fibroin nanofibers incorporated with nerve growth factor support the differentiation of neuronal stem cells. RSC Advances, 2015, 5(62): 49838-49848.
49.	Bai S, Zhang W, Lu Q, et al. Silk nanofiber hydrogels with tunable modulus to regulate nerve stem cell fate. J Mater Chem B, 2014, 2(38): 6590-6600.
50.	Martín-Martín Y, Fernández-García L, Sanchez-Rebato MH, et al. Evaluation of neurosecretome from mesenchymal stem cells encapsulated in silk fibroin hydrogels. Sci Rep, 2019, 9(1): 8801. doi: 10.1038/s41598-019-45238-4.
51.	Sultan MT, Choi BY, Ajiteru O, et al. Reinforced-hydrogel encapsulated hMSCs towards brain injury treatment by trans-septal approach. Biomaterials, 2021, 266: 120413. doi: 10.1016/j.biomaterials.2020.120413.
52.	Yang C, Li S, Huang X, et al. Silk fibroin hydrogels could be therapeutic biomaterials for neurological diseases. Oxid Med Cell Longev, 2022, 2022: 2076680. doi: 10.1155/2022/2076680.
53.	Chen S, Liu S, Zhang L, et al. Construction of injectable silk fibroin/polydopamine hydrogel for treatment of spinal cord injury. Chemical Engineering Journal, 2020, 399: 125795. doi: 10.1016/j.cej.2020.125795.
54.	Xuan H, Tang X, Zhu Y, et al. Freestanding hyaluronic acid/silk-based self-healing coating toward tissue repair with antibacterial surface. ACS Appl Bio Mater, 2020, 3(3): 1628-1635.
55.	Zhang L, Xu L, Li G, et al. Fabrication of high-strength mecobalamin loaded aligned silk fibroin scaffolds for guiding neuronal orientation. Colloids Surf B Biointerfaces, 2019, 173: 689-697.
56.	Nguyen TP, Nguyen QV, Nguyen VH, et al. Silk fibroin-based biomaterials for biomedical applications: A review. Polymers (Basel), 2019, 11(12): 1933. doi: 10.3390/polym11121933.
57.	Yang Y, Chen X, Ding F, et al. Biocompatibility evaluation of silk fibroin with peripheral nerve tissues and cells in vitro. Biomaterials, 2007, 28(9): 1643-1652.
58.	Ziemba AM, Fink TD, Crochiere MC, et al. Coating topologically complex electrospun fibers with nanothin silk fibroin enhances neurite outgrowth in vitro. ACS Biomater Sci Eng, 2020, 6(3): 1321-1332.
59.	林强蔡李. 负载浓度梯度NGF的周围神经导管修复大鼠周围神经缺损的实验研究. 中国修复重建外科杂志, 28(2): 167-172.
60.	Benfenati V, Stahl K, Gomis-Perez C, et al. Biofunctional silk/neuron interfaces. Advanced Functional Materials, 2012, 22(9): 1871-1884.
61.	Hu J, Jiang Z, Zhang J, et al. Application of silk fibroin coatings for biomaterial surface modification: a silk road for biomedicine. J Zhejiang Univ Sci B, 2023, 24(11): 943-956.
62.	White JD, Wang S, Weiss AS, et al. Silk-tropoelastin protein films for nerve guidance. Acta Biomater, 2015, 14: 1-10.

1. Zhang PX, Yin XF, Kou YH, et al. Neural regeneration after peripheral nerve injury repair is a system remodelling process of interaction between nerves and terminal effector. Neural Regen Res, 2015, 10(1): 52. doi: 10.4103/1673-5374.150705.
2. Vijayavenkataraman S. Nerve guide conduits for peripheral nerve injury repair: A review on design, materials and fabrication methods. Acta Biomater, 2020, 106: 54-69.
3. Hu Y, Zhang H, Wei H, et al. Scaffolds with anisotropic structure for neural tissue engineering. Engineered Regeneration, 2022, 3(2): 154-162.
4. Wang B, Lu CF, Liu ZY, et al. Chitin scaffold combined with autologous small nerve repairs sciatic nerve defects. Neural Regen Res, 2022, 17(5): 1106-1114.
5. Zhang H, Guo J, Wang Y, et al. Natural polymer-derived bioscaffolds for peripheral nerve regeneration. Advanced Functional Materials, 2022, 32(41): 2203829. doi: 10.1002/adfm.202203829.
6. Lee TH, Yen CT, Hsu SH. Preparation of polyurethane-graphene nanocomposite and evaluation of neurovascular regeneration. ACS Biomater Sci Eng, 2020, 6(1): 597-609.
7. Costa Serrão de Araújo G, Couto Neto B, Harley Santos Botelho R, et al. Clinical evaluation after peripheral nerve repair with caprolactone neurotube. Hand (N Y), 2017, 12(2): 168-174.
8. Vijayavenkataraman S, Zhang S, Thaharah S, et al. Electrohydrodynamic jet 3D printed nerve guide conduits (NGCs) for peripheral nerve injury repair. Polymers (Basel), 2018, 10(7): 753. doi: 10.3390/polym10070753.
9. Dong R, Liu Y, Yang Y, et al. MSC-derived exosomes-based therapy for peripheral nerve injury: A novel therapeutic strategy. Biomed Res Int, 2019, 2019: 6458237. doi: 10.1155/2019/6458237.
10. Hatzenbuehler J. Peripheral Nerve Injury. Curr Sports Med Rep, 2015, 14(5): 356-357.
11. Wijntjes J, Borchert A, van Alfen N. Nerve ultrasound in traumatic and iatrogenic peripheral nerve injury. Diagnostics (Basel), 2020, 11(1): 30. doi: 10.3390/diagnostics11010030.
12. Robinson LR. Traumatic injury to peripheral nerves. Muscle Nerve, 2000, 23(6): 863-873.
13. 中国康复医学会居家康复专业委员会居家康复指南编写委员会, 世界卫生组织康复合作中心. 周围神经损伤居家康复指南. 中国康复医学杂志, 2022, 37(4): 433-442.
14. Modrak M, Talukder MAH, Gurgenashvili K, et al. Peripheral nerve injury and myelination: Potential therapeutic strategies. J Neurosci Res, 2020, 98(5): 780-795.
15. Campbell WW. Evaluation and management of peripheral nerve injury. Clin Neurophysiol, 2008, 119(9): 1951-1965.
16. Miller RG. AAEE minimonograph #28: injury to peripheral motor nerves. Muscle Nerve, 1987, 10(8): 698-710.
17. Sulaiman W, Gordon T. Neurobiology of peripheral nerve injury, regeneration, and functional recovery: from bench top research to bedside application. Ochsner J, 2013, 13(1): 100-108.
18. Han GH, Peng J, Liu P, et al. Therapeutic strategies for peripheral nerve injury: decellularized nerve conduits and Schwann cell transplantation. Neural Regen Res, 2019, 14(8): 1343-1351.
19. Saffari TM, Mathot F, Friedrich PF, et al. Revascularization patterns of nerve allografts in a rat sciatic nerve defect model. J Plast Reconstr Aesthet Surg, 2020, 73(3): 460-468.
20. Mohammad J, Shenaq J, Rabinovsky E, et al. Modulation of peripheral nerve regeneration: a tissue-engineering approach. The role of amnion tube nerve conduit across a 1-centimeter nerve gap. Plast Reconstr Surg, 2000, 105(2): 660-666.
21. Lans J, Eberlin KR, Evans PJ, et al. A systematic review and meta-analysis of nerve gap repair: Comparative effectiveness of allografts, autografts, and conduits. Plast Reconstr Surg, 2023, 151(5): 814e-827e.
22. 李平生, 林国叶, 何向阳, 等. 周围神经损伤的修复治疗. 中国骨伤杂志, 2005, 18(11): 667-669.
23. Zhang H, Zhang H, Wang H, et al. Natural proteins-derived asymmetric porous conduit for peripheral nerve regeneration. Applied Materials Today, 2022, 27: 101431. doi: 10.1016/j.apmt.2022.101431.
24. Lin YC, Marra KG. Injectable systems and implantable conduits for peripheral nerve repair. Biomed Mater, 2012, 7(2): 024102. doi: 10.1088/1748-6041/7/2/024102.
25. Safa B, Jain S, Desai MJ, et al. Peripheral nerve repair throughout the body with processed nerve allografts: Results from a large multicenter study. Microsurgery, 2020, 40(5): 527-537.
26. 龚超, 张玉强, 王伟. 细胞治疗周围神经损伤的作用及机制. 中国组织工程研究, 2022, 26(13): 2216-2221.
27. Li R, Liu Z, Pan Y, et al. Peripheral nerve injuries treatment: a systematic review. Cell Biochem Biophys, 2014, 68(3): 449-454.
28. Zennifer A, Thangadurai M, Sundaramurthi D, et al. Additive manufacturing of peripheral nerve conduits - Fabrication methods, design considerations and clinical challenges. SLAS Technol, 2023, 28(3): 102-126.
29. Navissano M, Malan F, Carnino R, et al. Neurotube for facial nerve repair. Microsurgery, 2005, 25(4): 268-271.
30. Rbia N, Bulstra LF, Saffari TM, et al. Collagen nerve conduits and processed nerve allografts for the reconstruction of digital nerve gaps: A single-institution case series and review of the literature. World Neurosurg, 2019, 127: e1176-e1184.
31. Magaz A, Faroni A, Gough JE, et al. Bioactive silk-based nerve guidance conduits for augmenting peripheral nerve repair. Adv Healthc Mater, 2018, 7(23): e1800308. doi: 10.1002/adhm.201800308.
32. Fountain JN, Hawker MJ, Hartle L, et al. Towards non-stick silk: Tuning the hydrophobicity of silk fibroin protein. Chembiochem, 2022, 23(22): e202200429. doi: 10.1002/cbic.202200429.
33. Kundu SC, Kundu B, Talukdar S, et al. Invited review nonmulberry silk biopolymers. Biopolymers, 2012, 97(6): 455-467.
34. Sun W, Gregory DA, Tomeh MA, et al. Silk fibroin as a functional biomaterial for tissue engineering. Int J Mol Sci, 2021, 22(3): 1499. doi: 10.3390/ijms22031499.
35. Lin DM, Li MQ, Wang LL, et al. Multifunctional hydrogel based on silk fibroin promotes tissue repair and regeneration. Advanced Functional Materials, 2024, 34(39). doi: 10.1002/adfm.202405255.
36. He YX, Zhang NN, Li WF, et al. N-Terminal domain of Bombyx mori fibroin mediates the assembly of silk in response to pH decrease. J Mol Biol, 2012, 418(3-4): 197-207.
37. Houshyar S, Bhattacharyya A, Shanks R. Peripheral nerve conduit: Materials and structures. ACS Chem Neurosci, 2019, 10(8): 3349-3365.
38. Carvalho CR, Oliveira JM, Reis RL. Modern trends for peripheral nerve repair and regeneration: Beyond the hollow nerve guidance conduit. Front Bioeng Biotechnol, 2019, 7: 337. doi: 10.3389/fbioe.2019.00337.
39. Sun B, Zhou Z, Wu T, et al. Development of nanofiber sponges-containing nerve guidance conduit for peripheral nerve regeneration in vivo. ACS Appl Mater Interfaces, 2017, 9(32): 26684-26696.
40. Chen YS, Hsieh CL, Tsai CC, et al. Peripheral nerve regeneration using silicone rubber chambers filled with collagen, laminin and fibronectin. Biomaterials, 2000, 21(15): 1541-1547.
41. Dinis TM, Elia R, Vidal G, et al. 3D multi-channel bi-functionalized silk electrospun conduits for peripheral nerve regeneration. J Mech Behav Biomed Mater, 2015, 41: 43-55.
42. Wieringa P, Tonazzini I, Micera S, et al. Nanotopography induced contact guidance of the F11 cell line during neuronal differentiation: a neuronal model cell line for tissue scaffold development. Nanotechnology, 2012, 23(27): 275102. doi: 10.1088/0957-4484/23/27/275102.
43. Zhang Q, Zhao Y, Yan S, et al. Preparation of uniaxial multichannel silk fibroin scaffolds for guiding primary neurons. Acta Biomater, 2012, 8(7): 2628-2638.
44. Wang Y, Kong Y, Zhao Y, et al. Electrospun, reinforcing network-containing, silk fibroin-based nerve guidance conduits for peripheral nerve repair. Journal of Biomaterials and Tissue Engineering, 2016, 6(1): 53-60.
45. Wei GJ, Yao M, Wang YS, et al. Promotion of peripheral nerve regeneration of a peptide compound hydrogel scaffold. Int J Nanomedicine, 2013, 8: 3217-3225.
46. Xue C, Zhu H, Tan D, et al. Electrospun silk fibroin-based neural scaffold for bridging a long sciatic nerve gap in dogs. J Tissue Eng Regen Med, 2018, 12(2): e1143-e1153.
47. Yonesi M, Garcia-Nieto M, Guinea GV, et al. Silk fibroin: An ancient material for repairing the injured nervous system. Pharmaceutics, 2021, 13(3): 429. doi: 10.3390/pharmaceutics13030429.
48. Tian L, Prabhakaran MP, Hu J, et al. Coaxial electrospun poly (lactic acid)/silk fibroin nanofibers incorporated with nerve growth factor support the differentiation of neuronal stem cells. RSC Advances, 2015, 5(62): 49838-49848.
49. Bai S, Zhang W, Lu Q, et al. Silk nanofiber hydrogels with tunable modulus to regulate nerve stem cell fate. J Mater Chem B, 2014, 2(38): 6590-6600.
50. Martín-Martín Y, Fernández-García L, Sanchez-Rebato MH, et al. Evaluation of neurosecretome from mesenchymal stem cells encapsulated in silk fibroin hydrogels. Sci Rep, 2019, 9(1): 8801. doi: 10.1038/s41598-019-45238-4.
51. Sultan MT, Choi BY, Ajiteru O, et al. Reinforced-hydrogel encapsulated hMSCs towards brain injury treatment by trans-septal approach. Biomaterials, 2021, 266: 120413. doi: 10.1016/j.biomaterials.2020.120413.
52. Yang C, Li S, Huang X, et al. Silk fibroin hydrogels could be therapeutic biomaterials for neurological diseases. Oxid Med Cell Longev, 2022, 2022: 2076680. doi: 10.1155/2022/2076680.
53. Chen S, Liu S, Zhang L, et al. Construction of injectable silk fibroin/polydopamine hydrogel for treatment of spinal cord injury. Chemical Engineering Journal, 2020, 399: 125795. doi: 10.1016/j.cej.2020.125795.
54. Xuan H, Tang X, Zhu Y, et al. Freestanding hyaluronic acid/silk-based self-healing coating toward tissue repair with antibacterial surface. ACS Appl Bio Mater, 2020, 3(3): 1628-1635.
55. Zhang L, Xu L, Li G, et al. Fabrication of high-strength mecobalamin loaded aligned silk fibroin scaffolds for guiding neuronal orientation. Colloids Surf B Biointerfaces, 2019, 173: 689-697.
56. Nguyen TP, Nguyen QV, Nguyen VH, et al. Silk fibroin-based biomaterials for biomedical applications: A review. Polymers (Basel), 2019, 11(12): 1933. doi: 10.3390/polym11121933.
57. Yang Y, Chen X, Ding F, et al. Biocompatibility evaluation of silk fibroin with peripheral nerve tissues and cells in vitro. Biomaterials, 2007, 28(9): 1643-1652.
58. Ziemba AM, Fink TD, Crochiere MC, et al. Coating topologically complex electrospun fibers with nanothin silk fibroin enhances neurite outgrowth in vitro. ACS Biomater Sci Eng, 2020, 6(3): 1321-1332.
59. 林强蔡李. 负载浓度梯度NGF的周围神经导管修复大鼠周围神经缺损的实验研究. 中国修复重建外科杂志, 28(2): 167-172.
60. Benfenati V, Stahl K, Gomis-Perez C, et al. Biofunctional silk/neuron interfaces. Advanced Functional Materials, 2012, 22(9): 1871-1884.
61. Hu J, Jiang Z, Zhang J, et al. Application of silk fibroin coatings for biomaterial surface modification: a silk road for biomedicine. J Zhejiang Univ Sci B, 2023, 24(11): 943-956.
62. White JD, Wang S, Weiss AS, et al. Silk-tropoelastin protein films for nerve guidance. Acta Biomater, 2015, 14: 1-10.

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