Research progress of hydrogel combined with mesenchymal stem cells in the treatment of spinal cord injury_Journal of Biomedical Engineering

Authors：

YUAN Xin , DING Lu ,  DENG David Y.B.

Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong 518107, P.R.China;

Corresponding author：

Keywords：

spinal cord injury; mesenchymal stem cells; adipose derived stem cells; hydrogel

DOI：

10.7507/1001-5515.202005055

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Spinal cord injury (SCI) is a complex pathological process. Based on the encouraging results of preclinical experiments, some stem cell therapies have been translated into clinical practice. Mesenchymal stem cells (MSCs) have become one of the most important seed cells in the treatment of SCI due to their abundant sources, strong proliferation ability and low immunogenicity. However, the survival rate of MSCs transplanted to spinal cord injury is rather low, which hinders its further clinical application. In recent years, hydrogel materials have been widely used in tissue engineering because of their good biocompatibility and biodegradability. The treatment strategy of hydrogel combined with MSCs has made some progress in SCI repair. This review discusses the significance and the existing problems of MSCs in the repair of SCI. It also describes the research progress of hydrogel combined with MSCs in repairing SCI, and prospects its application in clinical research, aiming at providing reference and new ideas for future SCI treatment.

Citation： YUAN Xin, DING Lu, DENG David Y.B.. Research progress of hydrogel combined with mesenchymal stem cells in the treatment of spinal cord injury. Journal of Biomedical Engineering, 2021, 38(4): 805-811. doi: 10.7507/1001-5515.202005055 Copy

1.	Spinal cord injury (SCI) 2016 facts and figures at a glance. Spinal cord injury (SCI) 2016 facts and figures at a glance. J Spinal Cord Med, Jul, 2016, 39(4): 493-494.
2.	Lu L L, Liu Y J, Yang S G, et al. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica, 2006, 91(8): 1017-1026.
3.	Zhou Y, Zhang X, Xue H, et al. Autologous mesenchymal stem cell transplantation in multiple sclerosis: A meta-analysis. Stem Cells Int, 2019, 2019: 8536785.
4.	Pan K, Deng L, Chen P, et al. Safety and feasibility of repeated intrathecal allogeneic bone marrow-derived mesenchymal stromal cells in patients with neurological diseases. Stem Cells Int, 2019, 2019: 8421281.
5.	Oliveira A G, Gonçalves M, Ferreira H, et al. Growing evidence supporting the use of mesenchymal stem cell therapies in multiple sclerosis: A systematic review. Mult Scler Relat Disord, 2019, 38: 101860.
6.	Hedayatzadeh M, Tehranipour M, Kobravi H R. Motor neuron recovery in rats after incomplete spinal cord injury using intra-spinal electrical stimulation and stem cell transfusion: A prelude to human applications. Medical Science, 2020, 24(102): 706-716.
7.	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, 115: 80-84.
8.	Muniswami D M, Kanthakumar P, Kanakasabapathy I, et al. Motor recovery after transplantation of bone marrow mesenchymal stem cells in rat models of spinal cord injury. Ann Neurosci, 2019, 25(3): 126-140.
9.	Chen S, Yi M, Zhou G, et al. Abdominal aortic transplantation of bone marrow mesenchymal stem cells regulates the expression of ciliary neurotrophic factor and inflammatory cytokines in a rat model of spinal cord ischemia-reperfusion injury. Med Sci Monit, 2019, 25: 1960-1969.
10.	苟杨, 刘丹彦, 刘金凤, 等. 骨髓间充质干细胞移植对急性脊髓损伤脱髓鞘病变的保护作用. 生物工程学报, 2018, 34(5): 761-776.
11.	Li H, Wang C, He T, et al. Mitochondrial transfer from bone marrow mesenchymal stem cells to motor neurons in spinal cord injury rats via gap junction. Theranostics, 2019, 9(7): 2017-2035.
12.	Sharma A, Sane H, Gokulchandran N, et al. Intrathecal transplantation of autologous bone marrow mononuclear cells in patients with sub-acute and chronic spinal cord injury: An open-label study. Int J Health Sci (Qassim), 2020, 14(2): 24-32.
13.	Yousefifard M, Nasirinezhad F, Shardi Manaheji H, et al. Human bone marrow-derived and umbilical cord-derived mesenchymal stem cells for alleviating neuropathic pain in a spinal cord injury model. Stem Cell Res Ther, 2016, 7: 36.
14.	Vymetalova L, Kucirkova T, Knopfova L, et al. Large-scale automated hollow-fiber bioreactor expansion of umbilical cord-derived human mesenchymal stromal cells for neurological disorders. Neurochem Res, 2020, 45(1): 204-214.
15.	Kim Y, Jo S H, Kim W H, et al. Antioxidant and anti-inflammatory effects of intravenously injected adipose derived mesenchymal stem cells in dogs with acute spinal cord injury. Stem Cell Res Ther, 2015, 6: 229.
16.	Khan I U, Yoon Y, Choi K U, et al. Therapeutic effects of intravenous injection of fresh and frozen thawed HO-1-overexpressed Ad-MSCs in dogs with acute spinal cord injury. Stem Cells Int, 2019, 2019: 8537541.
17.	Kokai L E, Marra K, Rubin J P. Adipose stem cells: biology and clinical applications for tissue repair and regeneration. Transl Res, 2014, 163(4): 399-408.
18.	Maqueda A, Rodriguez F J. Efficacy of human HC016 cell transplants on neuroprotection and functional recovery in a rat model of acute spinal cord injury. J Tissue Eng Regen Med, 2020, 14(2): 319-333.
19.	Barberini D J, Aleman M, Aristizabal F, et al. Safety and tracking of intrathecal allogeneic mesenchymal stem cell transplantation in healthy and diseased horses. Stem Cell Res Ther, 2018, 9(1): 96.
20.	Bydon M, Dietz A B, Goncalves S, et al. CELLTOP clinical trial: First report from a phase 1 trial of autologous adipose tissue-derived mesenchymal stem cells in the treatment of paralysis due to traumatic spinal cord injury. Mayo Clin Proc, 2020, 95(2): 406-414.
21.	Malafaya P B, Silva G A, Reis R L. Natural-origin polymers as carriers and scaffolds for biomolecules and cell delivery in tissue engineering applications. Adv Drug Deliv Rev, 2007, 59(4-5): 207-233.
22.	Hejcl A, Lesný P, Prádný M, et al. Biocompatible hydrogels in spinal cord injury repair. Physiol Res, 2008, 57(Suppl 3): S121-S132.
23.	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, 9: 343.
24.	Cowman M K, Lee H G, Schwertfeger K L, et al. The content and size of hyaluronan in biological fluids and tissues. Front Immunol, 2015, 6: 261.
25.	Li L M, Huang L L, Jiang X C, et al. Transplantation of BDNF gene recombinant mesenchymal stem cells and adhesive peptide-modified hydrogel scaffold for spinal cord repair. Curr Gene Ther, 2018, 18(1): 29-39.
26.	Zaviskova K, Tukmachev D, Dubisova J, et al. Injectable hydroxyphenyl derivative of hyaluronic acid hydrogel modified with RGD as scaffold for spinal cord injury repair. J Biomed Mater Res A, 2018, 106(4): 1129-1140.
27.	Li L, Xiao B, Mu J, et al. A MnO₂ nanoparticle-dotted hydrogel promotes spinal cord repair via regulating reactive oxygen species microenvironment and synergizing with mesenchymal stem cells. ACS Nano, 2019, 13(12): 14283-14293.
28.	Wang L S, Chung J E, Chan P P, et al. Injectable biodegradable hydrogels with tunable mechanical properties for the stimulation of neurogenesic differentiation of human mesenchymal stem cells in 3D culture. Biomaterials, 2010, 31(6): 1148-1157.
29.	Horne M K, Nisbet D R, Forsythe J S, et al. Three-dimensional nanofibrous scaffolds incorporating immobilized BDNF promote proliferation and differentiation of cortical neural stem cells. Stem Cells Dev, 2010, 19(6): 843-852.
30.	Hejčl A, Lesný P, Přádný 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.
31.	Kubinová S, Horák D, Kozubenko N, et al. The use of superporous Ac-CGGASIKVAVS-OH-modified PHEMA scaffolds to promote cell adhesion and the differentiation of human fetal neural precursors. Biomaterials, 2010, 31(23): 5966-5975.
32.	Kubinová S, Horák D, Hejčl A, et al. Highly superporous cholesterol-modified poly(2-hydroxyethyl methacrylate) scaffolds for spinal cord injury repair. J Biomed Mater Res A, 2011, 99(4): 618-629.
33.	Hejčl A, Růžička J, ProkS V, et al. Dynamics of tissue ingrowth in SIKVAV-modified highly superporous PHEMA scaffolds with oriented pores after bridging a spinal cord transection. J Mater Sci Mater Med, 2018, 29(7): 89.
34.	Yang E Z, Zhang G W, Xu J G, et al. Multichannel polymer scaffold seeded with activated Schwann cells and bone mesenchymal stem cells improves axonal regeneration and functional recovery after rat spinal cord injury. Acta Pharmacol Sin, 2017, 38(5): 623-637.
35.	Han I B, Thakor D K, Ropper A E, et al. Physical impacts of PLGA scaffolding on hMSCs: Recovery neurobiology insight for implant design to treat spinal cord injury. Exp Neurol, 2019, 320: 112980.
36.	Perale G, Giordano C, Bianco F, et al. Hydrogel for cell housing in the brain and in the spinal cord. Int J Artif Organs, 2011, 34(3): 295-303.
37.	Fan L, Liu C, Chen X, et al. Directing induced pluripotent stem cell derived neural stem cell fate with a three-dimensional biomimetic hydrogel for spinal cord injury repair. ACS Appl Mater Interfaces, 2018, 10(21): 17742-17755.
38.	Chen C M, Tang J C, Gu Y, et al. Bioinspired hydrogel electrospun fibers for spinal cord regeneration. Adv Funct Mater, 2019, 29(4): 1806899.
39.	Li L, Zhang Y, Mu J, 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): 4298-4305.
40.	Koffler J, Zhu W, Qu X, et al. Biomimetic 3D-printed scaffolds for spinal cord injury repair. Nat Med, 2019, 25(2): 263-269.

1. Spinal cord injury (SCI) 2016 facts and figures at a glance. Spinal cord injury (SCI) 2016 facts and figures at a glance. J Spinal Cord Med, Jul, 2016, 39(4): 493-494.
2. Lu L L, Liu Y J, Yang S G, et al. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica, 2006, 91(8): 1017-1026.
3. Zhou Y, Zhang X, Xue H, et al. Autologous mesenchymal stem cell transplantation in multiple sclerosis: A meta-analysis. Stem Cells Int, 2019, 2019: 8536785.
4. Pan K, Deng L, Chen P, et al. Safety and feasibility of repeated intrathecal allogeneic bone marrow-derived mesenchymal stromal cells in patients with neurological diseases. Stem Cells Int, 2019, 2019: 8421281.
5. Oliveira A G, Gonçalves M, Ferreira H, et al. Growing evidence supporting the use of mesenchymal stem cell therapies in multiple sclerosis: A systematic review. Mult Scler Relat Disord, 2019, 38: 101860.
6. Hedayatzadeh M, Tehranipour M, Kobravi H R. Motor neuron recovery in rats after incomplete spinal cord injury using intra-spinal electrical stimulation and stem cell transfusion: A prelude to human applications. Medical Science, 2020, 24(102): 706-716.
7. 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, 115: 80-84.
8. Muniswami D M, Kanthakumar P, Kanakasabapathy I, et al. Motor recovery after transplantation of bone marrow mesenchymal stem cells in rat models of spinal cord injury. Ann Neurosci, 2019, 25(3): 126-140.
9. Chen S, Yi M, Zhou G, et al. Abdominal aortic transplantation of bone marrow mesenchymal stem cells regulates the expression of ciliary neurotrophic factor and inflammatory cytokines in a rat model of spinal cord ischemia-reperfusion injury. Med Sci Monit, 2019, 25: 1960-1969.
10. 苟杨, 刘丹彦, 刘金凤, 等. 骨髓间充质干细胞移植对急性脊髓损伤脱髓鞘病变的保护作用. 生物工程学报, 2018, 34(5): 761-776.
11. Li H, Wang C, He T, et al. Mitochondrial transfer from bone marrow mesenchymal stem cells to motor neurons in spinal cord injury rats via gap junction. Theranostics, 2019, 9(7): 2017-2035.
12. Sharma A, Sane H, Gokulchandran N, et al. Intrathecal transplantation of autologous bone marrow mononuclear cells in patients with sub-acute and chronic spinal cord injury: An open-label study. Int J Health Sci (Qassim), 2020, 14(2): 24-32.
13. Yousefifard M, Nasirinezhad F, Shardi Manaheji H, et al. Human bone marrow-derived and umbilical cord-derived mesenchymal stem cells for alleviating neuropathic pain in a spinal cord injury model. Stem Cell Res Ther, 2016, 7: 36.
14. Vymetalova L, Kucirkova T, Knopfova L, et al. Large-scale automated hollow-fiber bioreactor expansion of umbilical cord-derived human mesenchymal stromal cells for neurological disorders. Neurochem Res, 2020, 45(1): 204-214.
15. Kim Y, Jo S H, Kim W H, et al. Antioxidant and anti-inflammatory effects of intravenously injected adipose derived mesenchymal stem cells in dogs with acute spinal cord injury. Stem Cell Res Ther, 2015, 6: 229.
16. Khan I U, Yoon Y, Choi K U, et al. Therapeutic effects of intravenous injection of fresh and frozen thawed HO-1-overexpressed Ad-MSCs in dogs with acute spinal cord injury. Stem Cells Int, 2019, 2019: 8537541.
17. Kokai L E, Marra K, Rubin J P. Adipose stem cells: biology and clinical applications for tissue repair and regeneration. Transl Res, 2014, 163(4): 399-408.
18. Maqueda A, Rodriguez F J. Efficacy of human HC016 cell transplants on neuroprotection and functional recovery in a rat model of acute spinal cord injury. J Tissue Eng Regen Med, 2020, 14(2): 319-333.
19. Barberini D J, Aleman M, Aristizabal F, et al. Safety and tracking of intrathecal allogeneic mesenchymal stem cell transplantation in healthy and diseased horses. Stem Cell Res Ther, 2018, 9(1): 96.
20. Bydon M, Dietz A B, Goncalves S, et al. CELLTOP clinical trial: First report from a phase 1 trial of autologous adipose tissue-derived mesenchymal stem cells in the treatment of paralysis due to traumatic spinal cord injury. Mayo Clin Proc, 2020, 95(2): 406-414.
21. Malafaya P B, Silva G A, Reis R L. Natural-origin polymers as carriers and scaffolds for biomolecules and cell delivery in tissue engineering applications. Adv Drug Deliv Rev, 2007, 59(4-5): 207-233.
22. Hejcl A, Lesný P, Prádný M, et al. Biocompatible hydrogels in spinal cord injury repair. Physiol Res, 2008, 57(Suppl 3): S121-S132.
23. 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, 9: 343.
24. Cowman M K, Lee H G, Schwertfeger K L, et al. The content and size of hyaluronan in biological fluids and tissues. Front Immunol, 2015, 6: 261.
25. Li L M, Huang L L, Jiang X C, et al. Transplantation of BDNF gene recombinant mesenchymal stem cells and adhesive peptide-modified hydrogel scaffold for spinal cord repair. Curr Gene Ther, 2018, 18(1): 29-39.
26. Zaviskova K, Tukmachev D, Dubisova J, et al. Injectable hydroxyphenyl derivative of hyaluronic acid hydrogel modified with RGD as scaffold for spinal cord injury repair. J Biomed Mater Res A, 2018, 106(4): 1129-1140.
27. Li L, Xiao B, Mu J, et al. A MnO₂ nanoparticle-dotted hydrogel promotes spinal cord repair via regulating reactive oxygen species microenvironment and synergizing with mesenchymal stem cells. ACS Nano, 2019, 13(12): 14283-14293.
28. Wang L S, Chung J E, Chan P P, et al. Injectable biodegradable hydrogels with tunable mechanical properties for the stimulation of neurogenesic differentiation of human mesenchymal stem cells in 3D culture. Biomaterials, 2010, 31(6): 1148-1157.
29. Horne M K, Nisbet D R, Forsythe J S, et al. Three-dimensional nanofibrous scaffolds incorporating immobilized BDNF promote proliferation and differentiation of cortical neural stem cells. Stem Cells Dev, 2010, 19(6): 843-852.
30. Hejčl A, Lesný P, Přádný 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.
31. Kubinová S, Horák D, Kozubenko N, et al. The use of superporous Ac-CGGASIKVAVS-OH-modified PHEMA scaffolds to promote cell adhesion and the differentiation of human fetal neural precursors. Biomaterials, 2010, 31(23): 5966-5975.
32. Kubinová S, Horák D, Hejčl A, et al. Highly superporous cholesterol-modified poly(2-hydroxyethyl methacrylate) scaffolds for spinal cord injury repair. J Biomed Mater Res A, 2011, 99(4): 618-629.
33. Hejčl A, Růžička J, ProkS V, et al. Dynamics of tissue ingrowth in SIKVAV-modified highly superporous PHEMA scaffolds with oriented pores after bridging a spinal cord transection. J Mater Sci Mater Med, 2018, 29(7): 89.
34. Yang E Z, Zhang G W, Xu J G, et al. Multichannel polymer scaffold seeded with activated Schwann cells and bone mesenchymal stem cells improves axonal regeneration and functional recovery after rat spinal cord injury. Acta Pharmacol Sin, 2017, 38(5): 623-637.
35. Han I B, Thakor D K, Ropper A E, et al. Physical impacts of PLGA scaffolding on hMSCs: Recovery neurobiology insight for implant design to treat spinal cord injury. Exp Neurol, 2019, 320: 112980.
36. Perale G, Giordano C, Bianco F, et al. Hydrogel for cell housing in the brain and in the spinal cord. Int J Artif Organs, 2011, 34(3): 295-303.
37. Fan L, Liu C, Chen X, et al. Directing induced pluripotent stem cell derived neural stem cell fate with a three-dimensional biomimetic hydrogel for spinal cord injury repair. ACS Appl Mater Interfaces, 2018, 10(21): 17742-17755.
38. Chen C M, Tang J C, Gu Y, et al. Bioinspired hydrogel electrospun fibers for spinal cord regeneration. Adv Funct Mater, 2019, 29(4): 1806899.
39. Li L, Zhang Y, Mu J, 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): 4298-4305.
40. Koffler J, Zhu W, Qu X, et al. Biomimetic 3D-printed scaffolds for spinal cord injury repair. Nat Med, 2019, 25(2): 263-269.

Previous Article
Recent advances in emerging three-dimensional in vitro models for sport-related traumatic brain injury
Next Article
The research progress of bionic scaffolds in ligament tissue engineering

Journal of Biomedical Engineering

Research progress of hydrogel combined with mesenchymal stem cells in the treatment of spinal cord injury

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content