Wound healing is a complex restorative process of the altered cutaneous tissue, which is impaired by numerous local and systemic factors, leading to chronic non-healing lesions with few efficient therapeutic options. Stem cells possess the capacity to differentiate into various types of cell lines. Furthermore, stem cells are able to secrete cytokines and growth factors, modulating inflammation and ultimately leading to angiogenesis, fibrogenesis, and epithelization. Because of their paracrine activity, these cells are able to attract other cell types to the base of the wound, improving the formation of new skin layers. Mesenchymal stem cells derived from the adipose tissue, bone marrow, and placenta, offer numerous ways of implementation. The process of harvesting, growing, and administrating stem cells depends on the site and type of the cells, but recent trial results showed improvement of wound healing independent of the administration site. Bioengineered skin substitutes are validated for treatment of chronic wounds with direct application on the skin surface. These offer physical scaffolding for the migrating cells and promote secretion of growth factors, thus facilitating rapid wound healing. Obtaining further clinical data is essential, but stem cell therapy may become a first-line therapeutic choice for the treatment of non-healing chronic wounds.
If the inline PDF is not rendering correctly, you can download the PDF file here.
1. Boulton AJ Vileikyte L Ragnarson-Tennvall G Apelqvist J. The global burden of diabetic foot disease. Lancet. 2005;366:1719-1724.
2. Rando TA. Stem cells ageing and the quest for immortality. Nature. 2006;441:1080-1086.
3. Sen CK Gordillo GM Roy S et al. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen. 2009;17:763-771.
4. Crovetti G Martinelli G Issi M et al. Platelet gel for healing cutaneous chronic wounds. Transfus Apher Sci. 2004;30:145-151.
5. Simka M Majewski E. The social and economic burden of venous leg ulcers—focus on the role of micronized purified flavonoid fraction adjuvant therapy. Am J Clin Dermatol. 2003;4:573-581.
6. Li MD Atkins H Bubela T. The global landscape of stem cell clinical trials. Regen Med. 2014;9:27-39.
7. Kanji S Das H. Advances of Stem Cell Therapeutics in Cutaneous Wound Healing and Regeneration. Mediators of Inflammation. 2017;2017:5217967.
8. Zomer HD Trentin AG Skin wound healing in humans and mice: Challenges in translational research. J Dermatol Sci. 2017;pii:S0923-1811(17)31013-7.
9. Körbling M Estrov Z. Adult stem cells for tissue repair—a new therapeutic concept? N Engl J Med. 2003;349:570-582.
10. Mimeault M Hauke R Batra S. Stem cells: a revolution in therapeutics — recent advances in stem cell biology and their therapeutic applications in regenerative medicine and cancer therapies. Clin Pharmacol Therap. 2007;82:252-264.
11. Benedek I Bucur O Benedek T. Intracoronary infusion of mononuclear bone marrow-derived stem cells is associated with a lower plaque burden after four years. J Atheroscler Thromb. 2014;21:217-229.
12. Gremmels H Teraa M Quax PH den Ouden K Fledderus JO Verhaar MC. Neovascularization capacity of mesenchymal stromal cells from critical limb ischemia patients is equivalent to healthy controls. Mol Ther. 2014;22:1960-1970.
13. Madaric J Klepanec A Valachovicova M et al. Characteristics of responders to autologous bone marrow cell therapy for no-option critical limb ischemia. Stem Cell Res Ther. 2016;7:116.
14. Duscher D Barrera Wong VW et al. Stem Cells in Wound Healing: The Future of Regenerative Medicine? A Mini-Review. Gerontology. 2016;62:216-225.
15. Gosain A DiPietro LA. Aging and wound healing. World J Surg. 2004;28:321-326.
17. Mansbridge J. Commercial considerations in tissue engineering. J Anat. 2006;209:527-532.
18. Hassan WU Greiser U Wang W. Role of adipose-derived stem cells in wound healing. Wound Repair Regen. 2014;22:313-325.
19. Behr B Ko SH Wong VW Gurtner GC Longaker MT. Stem cells. Plast Reconstr Surg. 2010;126:1163-1171.
20. Garg RK Rennert RC Duscher D et al. Capillary force seeding of hydrogels for adipose-derived stem cell delivery in wounds. Stem Cells Transl Med. 2014;3:1079-1089.
21. Rustad KC Wong VW Sorkin M et al. Enhancement of mesenchymal stem cell angiogenic capacity and stemness by a biomimetic hydrogel scaffold. Biomaterials. 2012;33:80-90.
22. Yoshikawa T Mitsuno H Nonaka I et al. Wound therapy by marrow mesenchymal cell transplantation. Plast Reconstr Surg. 2008;121:860-877.
23. Ren G Zhang L Zhao X et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. 2008;2:141-150.
24. Hu MS Rennert RC McArdle A et al. The role of stem cells during scarless skin wound healing. Adv Wound Care. 2014;3:304-314.
25. Procházka V Gumulec J Jalůvka F et al. Cell therapy a new standard in management of chronic critical limb ischemia and foot ulcer. Cell Transplant. 2010;19:1413-1424.
26. Kern S Eichler H Stoeve J Kluter H Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow umbilical cord blood or adipose tissue. Stem Cells. 2006; 24:1294-1301.
27. Kolle SF Fischer-Nielsen A Mathiasen AB et al. Enrichment of autologous fat grafts with ex-vivo expanded adipose tissue derived stem cells for graft survival: a randomized placebo-controlled trial. Lancet. 2013;382:1113-1120.
28. Casteilla L Planat-Benard V Laharrague P Cousin B. Adipose-derived stromal cells: Their identity and uses in clinical trials an update. World J Stem Cells. 2011;3:25-33.
29. Zuk P. The ASC: Critical Participants in Paracrine-Mediated Tissue Health and Function. Available at: https://www.intechopen.com/books/regenerative-medicine-and-tissue-engineering/the-asc-criticalparticipants-in-paracrine-mediated-tissue-health-and-function.
30. Park BS Jang KA Sung JH et al. Adipose-derived stem cells and their secretory factors as a promising therapy for skin aging. Dermatol Surg. 2008;34:1323-1326.
31. Amos PJ Kapur SK Stapor PC et al. Human adipose-derived stromal cells accelerate diabetic wound healing: impact of cell formulation and delivery. Tissue Eng Part A. 2010;16:1595-1606.
32. Rigotti G Marchi A Galiè M et al. Clinical treatment of radiotherapy tissue damage by lipoaspirate transplant: a healing process mediated by adipose-derived adult stem cells. Plast Reconstr Surg. 2007;119:1409-1422.
33. Haubner F Ohmann E Pohl F et al. Wound healing after radiation therapy: review of the literature. Radiat Oncol. 2012;7:162.
34. Kato Y Iwata T Washio K et al. Creation and Transplantation of an Adiposederived Stem Cell (ASC) Sheet in a Diabetic Wound-healing Model. J Vis Exp. 2017. doi: 10.3791/54539.
35. Maharlooei MK Bagheri M Solhjou Z et al. Adipose tissue derived mesenchymal stem cell (AD-MSC) promotes skin wound healing in diabetic rats. Diabetes Res Clin Pract. 2011;93:228-234.
36. Cianfarani F Toietta G Di Rocco G et al. Diabetes impairs adipose tissuederived stem cell function and efficiency in promoting wound healing. Wound Repair Regen. 2013;21:543-553.
37. Mesimäki K Lindroos B To˝rnwall J et al. Novel maxillary reconstruction with ectopic bone formation by GMP adipose stem cells. Int J Oral Maxillofac Surg. 2009;38:201-209.
38. Garcia-Olmo D Herreros D Pascual M et al. Treatment of enterocutaneous fistula in Crohn’s disease with adipose-derived stem cells: a comparison of protocols with and without cell expansion. Int J Colorectal Dis. 2009;24:27-30.
39. Rodriguez-Menocal L Shareef S Salgado M Shabbir A Van Badiavas E. Role of whole bone marrow whole bone marrow cultured cells and mesenchymal stem cells in chronic wound healing. Stem Cell Res Ther. 2015;6:24.
40. Maxson S Lopez EA Yoo D Danilkovitch-Miagkova A Leroux MA. Concise review: role of mesenchymal stem cells in wound repair. Stem Cells Transl Med. 2012;1:142-149.
41. Dash NR Dash SN Routray P Mohapatra S Mohapatra PC. Targeting non-healing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells. Rejuvenation Res. 2009;12:359-366.
42. Falanga V Iwamoto S Chartier M et al. Autologous bone marrowderived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds. Tissue Eng. 2007;13:1299-1312.
43. Vojtassák J Danisovic L Kubes M et al. Autologous biograft and mesenchymal stem cells in treatment of the diabetic foot. Neuro Endocrinol Lett. 2006;27:134-137.
44. Badiavas EV Falanga V. Treatment of chronic wounds with bone marrowderived cells. Arch Dermatol. 2003;139: 510-516.
45. Lu D Chen B Liang Z et al. Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind randomized controlled trial. Diabetes Res Clin Pract. 2011;92:26-36.
46. Banas RA Trumpower C Bentlejewski C Marshall V Sing G Zeevi A. Immunogenicity and immunomodulatory effects of amnion-derived multipotent progenitor cells. Hum Immunol. 2008;69:321-328.
47. Yoo D Jansen T Kuang J et al. Characterization of novel human mesenchymal stem cell-containing skin substitutes for the treatment of wounds. Ostomy Wound Manage. 2011;57:71.
48. Bieback K Brinkmann I. Mesenchymal stromal cells from human perinatal tissues: From biology to cell therapy. World J Stem Cells. 2010;2:81-92.
49. Marston WA Hanft J Norwood P Pollak R. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care. 2003;26:1701-1705.
50. Navsaria HA Myers SR Leigh IM McKay IA. Culturing skin in vitro for wound therapy. Trends Biotechnol. 1995;13:91-100.
51. Snyder RJ Shimozaki K Tallis A et al. A Prospective Randomized Multicenter Controlled Evaluation of the Use of Dehydrated Amniotic Membrane Allograft Compared to Standard of Care for the Closure of Chronic Diabetic Foot Ulcer. Wounds. 2016;28:70-77.
52. Stone RC Stojadinovic O Rosa AM et al. A bioengineered living cell construct activates an acute wound healing response in venous leg ulcers. Sci Transl Med. 2017;pii:eaaf8611.
53. Falanga V Margolis D Alvarez O et al. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Human Skin Equivalent Investigators Group. Arch Dermatol. 1998;134:293-300.
54. Simonacci F Bertozzi N Raposio E. Off-label use of adipose-derived stem cells. Ann Med Surg (Lond). 2017;24:44-51.