Cell transplantation: history of development, bioetic and legal aspects, prospects for treatment traumatic brain injury





traumatic brain injury, cell therapy, stem cells, transplantation, legal aspects of transplantation


In the modern world, a doctor of any specialty knows about a relatively new direction in the treatment of severe and previously untreatable diseases - stem cell (SC) transplantation. A scientific discussion around this is an actively developing direction. At present time laboratory studies of the cell therapy have gone beyond the limits of the experiment and began to actively find their application in practical medicine, which gives rise to scientific, ethical, legal and legislative problems. Thousands of laboratory experiments and clinical studies are carried out around the world, hundreds of stem cell culture laboratories and clinics are opened that use cell transplantation for the treatment of a wide range of diseases. The world governments start introduce SC transplantation into the medical system.

The classical dogma that CNS cells are unable to regenerate has been challenged in recent decades by studies demonstrating new mechanisms of stem cell migration in the brain in trauma models.

One of the most popular and promising areas for using cell therapy is treatment of nervous system diseases. Today, the actual problem for society is the cost of treating the consequences of moderate and severe traumatic brain injury, due to the wide prevalence (30-40% of all types of traumas), high disability rate in the working-age population and the global trend increase number of TBI cases by constant development of the technogenic environment.

The review provides information on the history of development, legal, bioethical aspects, the prospects for the use of SC in the treatment of TBI.

Author Biographies

Andrii I. Pavlov, Romodanov Neurosurgery Institute, Kyiv

Department of Neurotrauma

Mykola V. Kadzhaya, Romodanov Neurosurgery Institute, Kyiv

Department of Neurotrauma

Oleksandr S. Hotin, Romodanov Neurosurgery Institute, Kyiv

Department of Neurotrauma


1. Rumyantsev AG, Maschan AA. [Hematopoietic stem cell transplantation in children]. Moscow: MIA; 2003. Russian.

2. Maximow AA. Der Lymphozyt als gemeinsame Stammzelle der verschiedenen Blutelemente in der embryonalen Entwicklung und im postfetalen Leben der Säugetiere. Folia Haematologica. 1909;(8):125-134. [CrossRef]

3. Santos GW. History of bone marrow transplantation. Clin Haematol. 1983 Oct;12(3):611-39. [CrossRef] [PubMed]

4. Thomas ED, Lochte HL Jr, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N Engl J Med. 1957 Sep 12;257(11):491-6. [CrossRef] [PubMed]

5. Thomas ED, Lochte HL Jr, Caanon JH, Sahler OD, Ferrebee JW. Supralethal whole body irradiation and isologous marrow transplantation in man. J Clin Invest. 1959 Oct;38(10 Pt 1-2):1709-16. [CrossRef] [PubMed][PubMed Central]

6. Mathe G. Secondary syndrome: a stumbling block in the treatment of leukemia by whole-body irradiation and transfusion of allogenic hematopoietic cell. In: Diagnosis and treatment of acute radiation injury: proceedings of a scientific meeting, Geneva 17-21 October 1960. Geneva: WHO; 1961. https://apps.who.int/iris/handle/10665/40010

7. Friedenstein AJ. Precursor cells of mechanocytes. Int Rev Cytol. 1976;47:327-59. [CrossRef] [PubMed]

8. Friedenstein AJ. Stromal mechanisms of bone marrow: cloning in vitro and retransplantation in vivo. Haematol Blood Transfus. 1980;25:19-29. [CrossRef] [PubMed]

9. Ying QL, Nichols J, Evans EP, Smith AG. Changing potency by spontaneous fusion. Nature. 2002 Apr 4;416(6880):545-8. [CrossRef] [PubMed]

10. Ying QL, Nichols J, Evans EP, Smith AG. Changing potency by spontaneous fusion. Nature. 2002 Apr 4;416(6880):545-8. [CrossRef] [PubMed]

11. Cyranoski D. The potent effects of Japan’s stem-cell policies. Nature. 2019 Sep;573(7775):482-485. [CrossRef] [PubMed]

12. Grebenshchikova EG, Yudin BG, editors. [Bioethics and Biotechnology: The Limits of Human Improvement]. Moscow: Publishing house of the Moscow University for the Humanities. 2017. Russian. https://www.researchgate.net/publication/322603924

13. Yudin BG, editor. [Actual problems of bioethics]. Moscow: INION RAS; 2016. Russian.

14. Kukharchuk AL, Radchenko VV, Sirman VM. [Stem cells: experiment, theory, clinic. Embryonic, mesenchymal, neural and hematopoietic stem cells]. Chernivtsi: Zoloti lytavry. 2004. Russian.

15. Chiba S, Ikeda R, Kurokawa MS, Yoshikawa H, Takeno M, Nagafuchi H, Tadokoro M, Sekino H, Hashimoto T, Suzuki N. Anatomical and functional recovery by embryonic stem cell-derived neural tissue of a mouse model of brain damage. J Neurol Sci. 2004 Apr 15;219(1-2):107-17. [CrossRef] [PubMed]

16. Maas AIR, Menon DK, Adelson PD, Andelic N, Bell MJ, Belli A, Bragge P, Brazinova A, Büki A, Chesnut RM, Citerio G, Coburn M, Cooper DJ, Crowder AT, Czeiter E, Czosnyka M, Diaz-Arrastia R, Dreier JP, Duhaime AC, Ercole A. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 2017 Dec;16(12):987-1048. [CrossRef] [PubMed]

17. Zhou Y, Shao A, Xu W, Wu H, Deng Y. Advance of Stem Cell Treatment for Traumatic Brain Injury. Front Cell Neurosci. 2019 Aug; 13:301. [CrossRef] [PubMed][PubMed Central]

18. Pedachenko EG. [Neurosurgery in Ukraine: nowadays and perspectives]. Ukrainian Neurosurgical Journal. 2018;(1):5-18. Ukrainian. [CrossRef]

19. Pedachenko EG, Shlapak IP, Huk AP, Pilipenko MN. [Traumatic brain injury: modern principles of emergency care]. Kyiv: VIPOL; 2009. Russian.

20. Konovalov AN, Likhterman LB, Potapov AA. [Clinical guidelines for traumatic brain injury]. Moscow: Antidor; 1998. Russian.

21. Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet. 1975 Mar 1;1(7905):480-4. [CrossRef] [PubMed]

22. Likhterman LB. [Doctrine of head injury sequelae]. Russian Journal of Neurosurgery. 2015;(1):9-22. Russian. [CrossRef]

23. Maroon JC, Winkelman R, Bost J, Amos A, Mathyssek C, Miele V. Chronic traumatic encephalopathy in contact sports: a systematic review of all reported pathological cases. PLoS One. 2015 Feb 11;10(2):e0117338. [CrossRef] [PubMed][PubMed Central]

24. Shah EJ, Gurdziel K, Ruden DM. Mammalian Models of Traumatic Brain Injury and a Place for Drosophila in TBI Research. Front Neurosci. 2019 Apr 26;13:409. [CrossRef] [PubMed][PubMed Central]

25. Umile EM, Sandel ME, Alavi A, Terry CM, Plotkin RC. Dynamic imaging in mild traumatic brain injury: support for the theory of medial temporal vulnerability. Arch Phys Med Rehabil. 2002 Nov;83(11):1506-13. [CrossRef] [PubMed]

26. Algattas H, Huang JH. Traumatic Brain Injury pathophysiology and treatments: early, intermediate, and late phases postinjury. Int J Mol Sci. 2013 Dec;15(1):309-41. [CrossRef] [PubMed][PubMed Central]

27. Jain KK. Neuroprotection in traumatic brain injury. Drug Discov Today. 2008 Dec;13(23-24):1082-9. [CrossRef] [PubMed]

28. Bedi SS, Walker PA, Shah SK, Jimenez F, Thomas CP, Smith P, Hetz RA, Xue H, Pati S, Dash PK, Cox CS Jr. Autologous bone marrow mononuclear cells therapy attenuates activated microglial/macrophage response and improves spatial learning after traumatic brain injury. J Trauma Acute Care Surg. 2013 Sep;75(3):410-6. [CrossRef] [PubMed][PubMed Central]

29. Richardson RM, Singh A, Sun D, Fillmore HL, Dietrich DW 3rd, Bullock MR. Stem cell biology in traumatic brain injury: effects of injury and strategies for repair. J Neurosurg. 2010 May;112(5):1125-38. [CrossRef] [PubMed]

30. Molcanyi M, Riess P, Bentz K, Maegele M, Hescheler J, Schäfke B, Trapp T, Neugebauer E, Klug N, Schäfer U. Traumaassociated inflammatory response impairs embryonic stem cell survival and integration after implantation into injured rat brain. J Neurotrauma. 2007 Apr;24(4):625-37. [CrossRef] [PubMed]

31. Cox CS Jr. Cellular therapy for traumatic neurological injury. Pediatr Res. 2018 Jan;83(1-2):325-332. [CrossRef] [PubMed]

32. Sanchez-Ramos J, Song S, Cardozo-Pelaez F, Hazzi C, Stedeford T, Willing A, Freeman TB, Saporta S, Janssen W, Patel N, Cooper DR, Sanberg PR. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol. 2000 Aug;164(2):247-56. [CrossRef] [PubMed]

33. Riess P, Zhang C, Saatman KE, Laurer HL, Longhi LG, Raghupathi R, Lenzlinger PM, Lifshitz J, Boockvar J, Neugebauer E, Snyder EY, McIntosh TK. Transplanted neural stem cells survive, differentiate, and improve neurological motor function after experimental traumatic brain injury. Neurosurgery. 2002 Oct;51(4):1043-52; discussion 1052-4. [CrossRef] [PubMed]

34. Philips MF, Mattiasson G, Wieloch T, Björklund A, Johansson BB, Tomasevic G, Martínez-Serrano A, Lenzlinger PM, Sinson G, Grady MS, McIntosh TK. Neuroprotective and behavioral efficacy of nerve growth factor-transfected hippocampal progenitor cell transplants after experimental traumatic brain injury. J Neurosurg. 2001 May;94(5):765-74. [CrossRef] [PubMed]

35. Zhang C, Saatman KE, Royo NC, Soltesz KM, Millard M, Schouten JW, Motta M, Hoover RC, McMillan A, Watson DJ, Lee VM, Trojanowski JQ, McIntosh TK. Delayed transplantation of human neurons following brain injury in rats: a long-term graft survival and behavior study. J Neurotrauma. 2005 Dec;22(12):1456-74. [CrossRef] [PubMed]

36. Chiba S, Iwasaki Y, Sekino H, Suzuki N. Transplantation o f motoneuron-enriched neural cell s derived f rom mouse embryonic stem cells improves motor function of hemiplegic mice. Cell Transplant. 2003;12(5):457-68. [CrossRef] [PubMed]

37. Chiba S, Ikeda R, Kurokawa MS, Yoshikawa H, Takeno M, Nagafuchi H, Tadokoro M, Sekino H, Hashimoto T, Suzuki N. Anatomical and functional recovery by embryonic stem cell-derived neural tissue of a mouse model of brain damage. J Neurol Sci. 2004 Apr 15;219(1-2):107-17. [CrossRef] [PubMed]

38. Qu K, Ortoleva P. Understanding stem cell differentiation through self-organization theory. J Theor Biol. 2008 Feb 21;250(4):606-20. [CrossRef] [PubMed]

39. Zhang R, Liu Y, Yan K, Chen L, Chen XR, Li P, Chen FF, Jiang XD. Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury. J Neuroinflammation. 2013 Aug 23;10:106. [CrossRef] [PubMed][PubMed Central]

40. Zhang ZX, Guan LX, Zhang K, Zhang Q, Dai LJ. A combined procedure to deliver autologous mesenchymal stromal cells to patients with traumatic brain injury. Cytotherapy. 2008;10(2):134-9. [CrossRef] [PubMed]

41. Cox CS Jr, Baumgartner JE, Harting MT, Worth LL, Walker PA, Shah SK, Ewing-Cobbs L, Hasan KM, Day MC, Lee D, Jimenez F, Gee A. Autologous bone marrow mononuclear cell therapy for severe traumatic brain injury in children. Neurosurgery. 2011 Mar;68(3):588-600. [CrossRef] [PubMed]

42. Cox CS Jr, Hetz RA, Liao GP, Aertker BM, Ewing-Cobbs L, Juranek J, Savitz SI, Jackson ML, Romanowska-Pawliczek AM, Triolo F, Dash PK, Pedroza C, Lee DA, Worth L, Aisiku IP, Choi HA, Holcomb JB, Kitagawa RS. Treatment of Severe Adult Traumatic Brain Injury Using Bone Marrow Mononuclear Cells. Stem Cells. 2017 Apr;35(4):1065-1079. [CrossRef] [PubMed][PubMed Central]

43. Steinberg GK, Kondziolka D, Bates D; SB623 Stroke Phase 1/2A Study Group. Response by Steinberg et al to Letter Regarding Article, "Clinical Outcomes of Transplanted Modified Bone Marrow-Derived Mesenchymal Stem Cells in Stroke: A Phase 1/2A Study". Stroke. 2016 Dec;47(12):e269. [CrossRef] [PubMed]

44. Wang S, Cheng H, Dai G, Wang X, Hua R, Liu X, Wang P, Chen G, Yue W, An Y. Umbilical cord mesenchymal stem cell transplantation significantly improves neurological function in patients with sequelae of traumatic brain injury. Brain Res. 2013 Sep 26;1532:76-84. [CrossRef] [PubMed]

45. Ting AE, Mays RW, Frey MR, Hof WV, Medicetty S, Deans R. Therapeutic pathways of adult stem cell repair. Crit Rev Oncol Hematol. 2008 Jan;65(1):81-93. [CrossRef] [PubMed]

46. Mays RW, van’t Hof W, Ting AE, Perry R, Deans R. Development of adult pluripotent stem cell therapies for ischemic injury and disease. Expert Opin Biol Ther. 2007 Feb;7(2):173-84. [CrossRef] [PubMed]

47. Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, Gerstenblith G, DeMaria AN, Denktas AE, Gammon RS, Hermiller JB Jr, Reisman MA, Schaer GL, Sherman W. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol. 2009 Dec 8;54(24):2277-86. [CrossRef] [PubMed][PubMed Central]

48. Newman RE, Yoo D, LeRoux MA, Danilkovitch-Miagkova A. Treatment of inflammatory diseases with mesenchymal stem cells. Inflamm Allergy Drug Targets. 2009 Jun;8(2):110-23. [CrossRef] [PubMed]



How to Cite

Pavlov, A. I., Kadzhaya, M. V., & Hotin, O. S. (2021). Cell transplantation: history of development, bioetic and legal aspects, prospects for treatment traumatic brain injury. Ukrainian Neurosurgical Journal, 27(3), 17–24. https://doi.org/10.25305/unj.232454



Review articles