Autogenously derived regenerative cell therapy for venous leg ulcers

Ali Aycan Kavala, Saygin Turkyilmaz, Ali Aycan Kavala, Saygin Turkyilmaz

Abstract

Introduction: Venous leg ulcers (VLUs), which arise from chronic venous insufficiency in the lower limbs, are a major cause of morbidity and significantly negatively impact patients' health-related quality of life. Treatment of venous ulcers can be either conservative or surgical. Despite appropriate treatment, VLUs can be resistant to healing. Clinical results of treatment of venous foot ulcers with adipose-derived autologous stem cells, which did not improve despite the surgical treatment of the underlying venous pathology in the following case series, are reported.

Material and methods: Between April 2015 and January 2016, a total of 31 patients who had undergone surgery for underlying venous pathology but the venous ulcer had not healed were included in the study. The mean venous ulcer size was 3.6-6.2 cm (range: 2 to 8 cm by 3 to 9 cm). All patients were treated with adipose-derived autologous stem cells prepared using the MyStem Regenerative Adipose-Derived Stem Cell Purification Kit (MyStem LLC, USA). The ulcer diameter was measured and recorded in the third, sixth and twelfth months. The follow-up time was 12 months after ulcer healing.

Results: Eighteen ulcers demonstrated complete healing at the 12th month. Thirteen ulcers exhibited serious contraction and epithelialization even though the ulcer was not completely closed. At the 12th month, the ulcer size was reduced by 96.00 ±1.74% in these patients. The reduction in the ulcer area based on the month analyzed was significant (p = 0.001; p < 0.01). After the ulcers healed, the patients were followed for recurrence for one year. Recurrent ulcers were observed at the treated sites in 3 of 31 patients (9%). No adverse events, such as infection, inflammation, or tissue reactions, were observed.

Conclusions: Application of cell therapy in venous leg ulcer is currently used exclusively in patients not responding to the standard treatment. Autogenously derived regenerative cell therapy for VLUs can be considered as an additional treatment to primary surgical therapy.

Keywords: autologous stem cells; leg ulcer; venous insufficiency.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Adipose tissue aspiration
Figure 2
Figure 2
Adipose-derived autologous stem cells injection and venous leg ulcer
Figure 3
Figure 3
Ulcer size reduction at 3rd, 6th and 12th month. The reduction in ulcer area according to the months was statistically significant (p = 0.001; p < 0.01)
Figure 4
Figure 4
Leg ulcer 36 × 40 mm
Figure 5
Figure 5
Complete recovery leg ulcer 36 × 40 mm

References

    1. Lazarus G, Valle MF, Malas M, et al. Chronic venous leg ulcer treatment: future research needs. Wound Repair Regen. 2014;22:34–42. Erratum In: Wound Repair Regen 2014; 22: 291.
    1. Van Gent WB, Wilschut ED, Wittens C. Management of venous ulcer disease. BMJ. 2010;341:c6045.
    1. Kelly T, Yang W, Chen CS, Reynolds K, He J. Global burden of obesity in 2005 and projections to 2030. Int J Obes (Lond) 2008;32:1431–7.
    1. Lo YF, Yang CH. Stripping and ligation of the saphenous vein. Semin Cutan Med Surg. 2005;24:200–8.
    1. Szendro G, Nicolaides AN, Zukowski AJ, et al. Duplex scanning in the assessment of deep venous incompetence. J Vasc Surg. 1986;4:237–42.
    1. Hanrahan LM, Kechejian GJ, Cordts PR, et al. Patterns of venous insufficiency in patients with varicose veins. Arch Surg. 1991;126:687–90.
    1. Zollino I, Zuolo M, Gianesini S, et al. Autologous adipose-derived stem cells: basic science, technique, and rationale for application in ulcer and wound healing. Phlebology. 2017;32:160–71.
    1. Coleridge-Smith P, Labropoulos N, Partsch H, Myers K, Nicolaides A, Cavezzi A. Duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs-UIP concensus document. Part I. Basic principles. Eur J Vasc Endovasc Surg. 2006;31:83–92.
    1. Agrifoglio G, Edwards EA. Results of surgical treatment of varicose veins: one- to fourteen-year follow-up study of 416 patients. JAMA. 1961;178:906–11.
    1. Fraser JK, Wulur I. Fat tissue: an underappreciated source of stem cells for biotechnology. Trends Biotechnol. 2006;24:150–4.
    1. Min RJ, Khilnani NM, Golia P. Duplex ultrasound evaluation of lower extremity venous insufficiency. J Vasc Interv Radiol. 2000;14:1233–41.
    1. De Ugarte DA, Morizono K, Elbarbary A, et al. Comparison of multi-lineage cells from human adipose tissue and bone marrow. Cells Tissues Organs. 2003;174:101–9.
    1. Sensebe L, Bourin P. Mesenchymal stem cells for therapeutic purposes. Transplantation. 2009;87:S49–53.
    1. Baglioni S, Francalanci M, Squecco R, et al. Characterization of human adult stem-cell populations isolated from visceral and subcutaneous adipose tissue. FASEB J. 2009;23:3494–505.
    1. Hassan WU, Greiser U, Wang W. Role of adipose-derived stem cells in wound healing. Wound Repair Regen. 2014;22:313–25.
    1. Kim WS, Park BS, Sung JH. The wound-healing and antioxidant effects of adipose-derived stem cells. Expert Opin Biol Ther. 2009;9:879–87.
    1. van Neer PA, Veraart JC, Neumann HA. Venae perforantes: a clinical review. Dermatol Surg. 2013;29:931–42.
    1. Barwell JR, Davies CE, Deacon J, et al. Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomised controlled trial. Lancet. 2004;363:1854–9.
    1. Iafrati MD, Pare GJ, O’Donnell TF, Estes J. Is the nihilistic approach to surgical reduction of superficial and perforator vein incompetence for venous ulcer justified? J Vasc Surg. 2002;36:1167–74.
    1. Royle JP. Recurrent varicose veins. World J Surg. 1986;10:944–53.
    1. Folse R, Alexander RH. Directional flow detection for localizing venous valvular incompetency. Surgery. 1970;67:114–21.
    1. Mauck KF, Asi N, Undavalli C, et al. Systematic review and meta-analysis of surgical interventions versus conservative therapy for venous ulcers. J Vasc Surg. 2014;60:60S–70S.e1-2.
    1. Pappas PJ, Lal BK, Ohara N, Saito S, Zapiach L, Durán WN. Regulation of matrix contraction in CVI patients. Eur J Endovasc Surg. 2009;38:518–29.
    1. Woźniak W, Tarnas M, Miłek T, Mlosek KR, Ciostek P. The effect of local platelet rich plasma therapy on the composition of bacterial flora in chronic venous leg ulcer. Pol J Microbiol. 2016;65:353–7.
    1. Toyserkani NM, Christensen ML, Sheikh SP, Sorensen JA. Adipose-derived stem cells: new treatment for wound healing? Ann Plast Surg. 2015;75:117–23.
    1. Kirana S, Stratmann B, Lammers D, et al. Wound therapy with autologous bone marrow stem cells in diabetic patients with ischaemia-induced tissue ulcers affecting the lower limbs. Int J Clin Pract. 2007;61:690–4.
    1. Strem BM, Hicok KC, Zhu M, et al. Multipotential differentiation of adipose tissue-derived stem cells. Keio J Med. 2005;54:132–41.
    1. Zuk PA, Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13:4279–95.
    1. Ebrahimian TG, Pouzoulet F, Squiban C, et al. Cell therapy based on adipose tissue-derived stromal cells promotes physiological and pathological wound healing. Arterioscler Thromb Vasc Biol. 2009;29:503–10.
    1. Nie C, Yang D, Xu J, Si Z, Jin X, Zhang J. Locally administered adipose-derived stem cells accelerate wound healing through differentiation and vasculogenesis. Cell Transplant. 2011;20:205–16.
    1. Kim WS, Park BS, Sung JH. The wound-healing and antioxidant effects of adipose-derived stem cells. Expert Opin Biol Ther. 2009;9:879–87.
    1. Fraser JK, Wulur I, Alfonso Z, Hedrick MH. Fat tissue: an underappreciated source of stem cells for biotechnology. Trends Biotechnol. 2006;24:150–4.
    1. Aronowitz JA, Lockhart RA, Hakakian CS. Mechanical versus enzymatic isolation of stromal vascular fraction cells from adipose tissue. Springerplus. 2015;4:713.
    1. Oberbauer E, Steffenhagen C, Wurzer C, Gabriel C, Redl H, Wolbank S. Enzymatic and non-enzymatic isolation systems for adipose tissue-derived cells: current state of the art. Cell Regen (Lond) 2015;4:7.
    1. Moffatt CJ, Dorman MC. Recurrence of leg ulcers within a community leg ulcer service. J Wound Care. 1995;4:57–61.
    1. Nelson EA, Cullum N, Jones J. Venous leg ulcers. Br Med J (Clin Res Ed) 2006;172:1447–52.
    1. Kässmeyer S, Plendl J, Custodis P, Bahram-soltani M. New insights in vascular development: vasculogenesis and endothelial progenitor cells. Anat Histol Embryol. 2009;38:1–11.
    1. Badillo AT, Redden RA, Zhang L, Doolin EJ, Liechty KW. Treatment of diabetic wounds with fetal murine mesenchymal stromal cells enhances wound closure. Cell Tissue Res. 2007;329:301–11.
    1. Grayson WL, Zhao F, Bunnell B, Ma T. Hypoxia enhances proliferation and tissue formation of human mesenchymal stem cells. Biochem Biophys Res Commun. 2007;358:948–53.
    1. Capla JM, Grogan RH, Callaghan MJ, et al. Diabetes impairs endothelial progenitor cell-mediated blood vessel formation in response to hypoxia. Plast Reconstr Surg. 2007;119:59–70.
    1. Moreno-Eutimio MA, Espinosa-Monroy L, Orozco-Amaro T, et al. Enhanced healing and anti-inflammatory effects of a carbohydrate polymer with zinc oxide in patients with chronic venous leg ulcers: preliminary results. Arch Med Sci. 2018;14:336–44.

Source: PubMed

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