Genetic and cellular techniques emerge as promising modalities for the treatment of diabetic foot syndrome
https://doi.org/10.14341/DM2014163-69
Abstract
Two patient groups potentially to benefit most from these novel methods are patients with critical lower limb ischemia (CLLI) in whom angiosurgery is not indicated, and patients with trophic ulcers resistant to conventional therapy. A series of clinical trials has shown positive effects of transferring VEGF, HIF-1, FGF, PDGF, HGF and certain other growth factor genes to stimulate blood vessel formation and healing of diabetic ulcers. Autologous transplantation of mononuclear bone marrow and peripheral blood cells, endothelial progenitor cells, mesenchymal stem cells and stromal cell of the adipose tissue has also demonstrated its clinical potential in patients with diabetes mellitus and CLLI. Randomized clinical trials report beneficial effects of gene and cell therapy on such surrogate endpoints as ischemic index, rest pain and ulcer healing, though data on amputation rates is controversial. Further studies are necessary to determine optimal dosage and route of administration of biological agents and predictors of their efficacy, as well as long-term safety of these novel treatment modalities.
About the Authors
Vladimir Iosifovich Konenkov
Research Institute of Clinical and Experimental Lymphology, Novosibirsk
Russian Federation
Fellow of Russian Academy of Sciences, Director of the institute
Russian Federation
Fellow of Russian Academy of Sciences, Director of the institute
Vadim Valerievich Klimontov
Research Institute of Clinical and Experimental Lymphology, Novosibirsk
Russian Federation
MD, PhD, Head of the Endoccrinology laboratory
Russian Federation
MD, PhD, Head of the Endoccrinology laboratory
References
1. Галстян ГР, Дедов ИИ. Организация помощи больным с синдромом диабетической стопы в Российской Федерации. Сахарный диабет. 2009;(1):4-7. [Galstjan GR, Dedov II. Principles of care in diabetic foot patients in Russia. Diabetes mellitus 2009;1:4-7]. doi: 10.14341/2072-0351-5411.
2. Дедов ИИ, Шестакова МВ, Сунцов ЮИ, Петеркова ВА, Галстян ГР, Майоров АЮ, Кураева ТЛ, Сухарева ОЮ. Результаты реализации подпрограммы "Сахарный диабет" Федеральной целевой программы "Предупреждение и борьба с социально значимыми заболеваниями 2007–2012 годы". Сахарный диабет. 2013;(Прил.2):1-48. [Dedov II, Shestakova MV, Suntsov YI, Peterkova VA, Galstyan GR, Mayorov AY, et al. Federal targeted programme “Prevention and Management of Socially Significant Diseases (2007-2012)”: results of the “Diabetes mellitus” sub-programme. Diabetes mellitus 2013;2S:1-48]. doi: 10.14341/2072-0351-2013-2S.
3. Fernández-Montequín JI, Valenzuela-Silva CM, Díaz OG, Savigne W, Sancho-Soutelo N, Rivero-Fernández F, et al. Intra-lesional injections of recombinant human epidermal growth factor promote granulation and healing in advanced diabetic foot ulcers: multicenter, randomised, placebo-controlled, double-blind study. Int Wound J 2009;6(6):432-443. Available from: http://www.nlm.nih.gov/medlineplus/diabeticfoot.html PubMed PMID: 20051095. doi: 10.1111/j.1742-481X.2009.00641.x.
4. Wieman TJ, Smiell JM, Su Y. Efficacy and safety of a topical gel formulation of recombinant human platelet-derived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers. A phase III randomized placebo-controlled double-blind study. Diabetes Care 1998;21(5):822-827. Available from: http://care.diabetesjournals.org/cgi/doi/10.2337/diacare.21.5.822 PubMed PMID: 9589248. doi: 10.2337/diacare.21.5.822.
5. Uchi H, Igarashi A, Urabe K, Koga T, Nakayama J, Kawamori R, et al. Clinical efficacy of basic fibroblast growth factor (bFGF) for diabetic ulcer. Eur J Dermatol 2009;19(5):461-468. Available from: http://www.jle.com/medline.md?issn=1167-1122&vol=19&iss=5&page=461 PubMed PMID: 19638336. doi: 10.1684/ejd.2009.0750.
6. Davidson JM. New and alternative treatment for the diabetic foot: stem cells and gene transfer. In: The Foot in Diabetes. Fourth ed. Eds. Boulton AJM, Cavanagh PR, Rayman G. John Wiley and Sons Ltd, 2006:198-206.
7. Ko J, Jun H, Chung H, Yoon C, Kim T, Kwon M, et al. Comparison of EGF with VEGF Non-Viral Gene Therapy for Cutaneous Wound Healing of Streptozotocin Diabetic Mice. Diabetes Metab J 2011;35(3):226-235. Available from: http://synapse.koreamed.org/DOIx.php?id=10.4093/dmj.2011.35.3.226 PubMed PMID: 21785742. doi: 10.4093/dmj.2011.35.3.226.
8. Kim HS, Yoo HS. In vitro and in vivo epidermal growth factor gene therapy for diabetic ulcers with electrospun fibrous meshes. Acta Biomaterialia 2013;9(7):7371-7380. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1742706113001360 PubMed PMID: 23528498. doi: 10.1016/j.actbio.2013.03.018.
9. Man L, Park JC, Terry MJ, Mason JM, Burrell WA, Liu F, et al. Lentiviral Gene Therapy With Platelet-Derived Growth Factor B Sustains Accelerated Healing of Diabetic Wounds Over Time. Annals of Plastic Surgery 2005;55(1):81-86. Available from: http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00000637-200507000-00015 PubMed PMID: 15985796. doi: 10.1097/01.sap.0000168211.76318.fa.
10. Lee P, Chesnoy S, Huang L. Electroporatic Delivery of TGF-beta1 Gene Works Synergistically with Electric Therapy to Enhance Diabetic Wound Healing in db/db Mice. J Invest Dermatol 2004;123(4):791-798. Available from: http://www.nature.com/doifinder/10.1111/j.0022-202X.2004.23309.x doi: 10.1111/j.0022-202X.2004.23309.x.
11. Jazwa A, Kucharzewska P, Leja J, Zagorska A, Sierpniowska A, Stepniewski J, et al. Combined vascular endothelial growth factor-A and fibroblast growth factor 4 gene transfer improves wound healing in diabetic mice.. Genet Vaccines Ther 2010;8:6-10. Available from: http://www.gvt-journal.com/content/8//6 PubMed PMID: 20804557. doi: 10.1186/1479-0556-8-6.
12. Mulder G, Tallis AJ, Marshall VT, Mozingo D, Phillips L, Pierce GF, et al. Treatment of nonhealing diabetic foot ulcers with a platelet-derived growth factor gene-activated matrix (GAM501): Results of a Phase 1/2 trial. Wound Repair and Regeneration 2009;17(6):772-779. Available from: http://dx.doi.org/10.1111/j.1524 PubMed PMID: 19821960. doi: -475X.2009.00541.x.
13. Bhansali A, Venkatesh S, Dutta P, Dhillon MS, Das S, Agrawal A. Which is the better option: recombinant human PDGF-BB 0.01% gel or standard wound care, in diabetic neuropathic large plantar ulcers off-loaded by a customized contact cast?. Diabetes Res Clin Pract 2008;83(1). Available from: http://www.nlm.nih.gov/medlineplus/diabeticfoot.html PubMed PMID: 19081156. doi: 10.1016/j.diabres.2008.10.005.
14. Ropper AH, Gorson KC, Gooch CL, Weinberg DH, Pieczek A, Ware JH, et al. Vascular endothelial growth factor gene transfer for diabetic polyneuropathy: A randomized, double-blinded trial. Ann Neurol 2009;65(4):386-393. Available from: http://doi.wiley.com/10.1002/ana.21675 PubMed PMID: 19399887. doi: 10.1002/ana.21675.
15. Коненков ВИ, Климонтов ВВ. Ангиогенез и васкулогенез при сахарном диабете: новые концепции патогенеза и лечения сосудистых осложнений. Сахарный диабет. 2012;(4):17-27. [Konenkov VI, Klimontov VV. Vasculogenesis and angiogenesis in diabetes mellitus: novel pathogenetic concepts for treatment of vascularcomplications. Diabetes mellitus 2012;4:17-27]. doi: 10.14341/2072-0351-5533.
16. Коненков ВИ, Шевченко АВ, Прокофьев ВФ, Климонтов ВВ, Королев МА, Фазуллина ОН, и соав. Ассоциации вариантов гена фактора роста сосудистого эндотелия (VEGF) и генов цитокинов (IL-1В, IL-4, IL-6, IL-10, TNFA) c сахарным диабетом 2 типа у женщин. Сахарный диабет. 2012;(3):4-10. [Konenkov VI, Shevchenko AV, Prokof'ev VF, Klimontov VV, Korolev MA, Fazullina ON, et al. Associations of vascular endothelial growth factor (VEGF) gene and cytokine (IL1B, IL4, IL6, IL10, TNFA) genescombinations with type 2 diabetes mellitus in women. Diabetes mellitus 2012;3:4-10]. doi: 10.14341/2072-0351-6079.
17. Ylä-Herttuala S, Rissanen TT, Vajanto I, Hartikainen J. Vascular Endothelial Growth Factors. Journal of the American College of Cardiology 2007;49(10):1015-1026. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0735109706031147 PubMed PMID: 17349880. doi: 10.1016/j.jacc.2006.09.053.
18. Baumgartner I, Pieczek A, Manor O, Blair R, Kearney M, Walsh K, et al. Constitutive Expression of phVEGF165 After Intramuscular Gene Transfer Promotes Collateral Vessel Development in Patients With Critical Limb Ischemia. Circulation 1998;97(12):1114-1123. Available from: http://circ.ahajournals.org/cgi/doi/10.1161/01.CIR.97.12.1114 PubMed PMID: 9537336. doi: 10.1161/01.CIR.97.12.1114.
19. Makinen K. Increased Vascularity Detected by Digital Subtraction Angiography after VEGF Gene Transfer to Human Lower Limb Artery: A Randomized, Placebo-Controlled, Double-Blinded Phase II Study. Molecular Therapy 2002;6(1):127-133. Available from: http://www.nature.com/doifinder/10.1006/mthe.2002.0638 PubMed PMID: 12095313. doi: 10.1006/mthe.2002.0638.
20. Kusumanto YH, Weel, V. van , Mulder NH, Smit AJ, Dungen, J.J.A.M. van den , Hooymans JMM, et al. Treatment with Intramuscular Vascular Endothelial Growth Factor Gene Compared with Placebo for Patients with Diabetes Mellitus and Critical Limb Ischemia: A Double-Blind Randomized Trial. Human Gene Therapy 2006;17(6):683-691. Available from: http://www.liebertonline.com/doi/abs/10.1089/hum.2006.17.683 doi: 10.1089/hum.2006.17.683.
21. Xiao H. The Possible Mechanisms Underlying the Impairment of HIF-1α Pathway Signaling in Hyperglycemia and the Beneficial Effects of Certain Therapies. Int. J. Med. Sci 2013;10(10):1412-1421. Available from: http://www.medsci.org/v10p1412.htm PubMed PMID: 23983604. doi: 10.7150/ijms.5630.
22. Liu L, Marti GP, Wei X, Zhang X, Zhang H, Liu YV, et al. Age-dependent impairment of HIF-1α expression in diabetic mice: Correction with electroporation-facilitated gene therapy increases wound healing, angiogenesis, and circulating angiogenic cells. J. Cell. Physiol 2008;217(2):319-327. Available from: http://doi.wiley.com/10.1002/jcp.21503 PubMed PMID: 18506785. doi: 10.1002/jcp.21503.
23. Rajagopalan S, Olin J, Deitcher S, Pieczek A, Laird J, Grossman PM, et al. Use of a constitutively active hypoxia-inducible factor-1alpha transgene as a therapeutic strategy in no-option critical limb ischemia patients: phase I dose-escalation experience. Circulation 2007;115(10):1234-1243. Available from: http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=17309918 PubMed PMID: 17309918. doi: 10.1161/CIRCULATIONAHA.106.607994.
24. Comerota AJ, Throm RC, Miller KA, Henry T, Chronos N, Laird J, et al. Naked plasmid DNA encoding fibroblast growth factor type 1 for the treatment of end-stage unreconstructible lower extremity ischemia: Preliminary results of a phase I trial. Journal of Vascular Surgery 2002;35(5):930-936. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0741521402972939 PubMed PMID: 12021709. doi: 10.1067/mva.2002.123677.
25. Nikol S, Baumgartner I, Van Belle E, Diehm C, Visoná A, Capogrossi MC, et al. Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia. Mol Ther 2008;16(5):972-978. Available from: http://www.scholaruniverse.com/ncbi-linkout?id=18388929 PubMed PMID: 18388929. doi: 10.1038/mt.2008.33.
26. Belch J, Hiatt WR, Baumgartner I, Driver IV, Nikol S, Norgren L, et al. Effect of fibroblast growth factor NV1FGF on amputation and death: a randomised placebo-controlled trial of gene therapy in critical limb ischaemia.. Lancet 2011;377(9781):1929-1937. Available from: http://ClinicalTrials.gov/search/term=21621834%20%5BPUBMED-IDS%5D PubMed PMID: 21621834. doi: 10.1016/S0140-6736(11)60394-2.
27. Kaga T, Kawano H, Sakaguchi M, Nakazawa T, Taniyama Y, Morishita R. Hepatocyte growth factor stimulated angiogenesis without inflammation: Differential actions between hepatocyte growth factor, vascular endothelial growth factor and basic fibroblast growth factor. Vascular Pharmacology 2012;57(1):3-9. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1537189112000353 PubMed PMID: 22361334. doi: 10.1016/j.vph.2012.02.002.
28. Morishita R, Makino H, Aoki M, Hashiya N, Yamasaki K, Azuma J, et al. Phase I/IIa Clinical Trial of Therapeutic Angiogenesis Using Hepatocyte Growth Factor Gene Transfer to Treat Critical Limb Ischemia. Arteriosclerosis, Thrombosis, and Vascular Biology 2011;31(3):713. Available from: http://atvb.ahajournals.org/cgi/doi/10.1161/ATVBAHA.110.219550 PubMed PMID: 21183732. doi: 10.1161/ATVBAHA.110.219550.
29. Makino H, Aoki M, Hashiya N, Yamasaki K, Azuma J, Sawa Y, et al. Long-Term Follow-Up Evaluation of Results From Clinical Trial Using Hepatocyte Growth Factor Gene to Treat Severe Peripheral Arterial Disease. Arteriosclerosis, Thrombosis, and Vascular Biology 2012;32(10):2503-2509. Available from: http://atvb.ahajournals.org/cgi/doi/10.1161/ATVBAHA.111.244632 PubMed PMID: 22904270. doi: 10.1161/ATVBAHA.111.244632.
30. Shigematsu H, Yasuda K, Iwai T, Sasajima T, Ishimaru S, Ohashi Y, et al. Randomized, double-blind, placebo-controlled clinical trial of hepatocyte growth factor plasmid for critical limb ischemia. Gene Ther 2010;17(9):1152-1161. Available from: http://www.nature.com/doifinder/10.1038/gt.2010.51 PubMed PMID: 20393508. doi: 10.1038/gt.2010.51.
31. Powell RJ, Simons M, Mendelsohn FO, Daniel G, Henry TD, Koga M, et al. Results of a Double-Blind, Placebo-Controlled Study to Assess the Safety of Intramuscular Injection of Hepatocyte Growth Factor Plasmid to Improve Limb Perfusion in Patients With Critical Limb Ischemia. Circulation 2008;118(1):58-65. Available from: http://circ.ahajournals.org/cgi/doi/10.1161/CIRCULATIONAHA.107.727347 PubMed PMID: 18559703. doi: 10.1161/CIRCULATIONAHA.107.727347.
32. Hammer A, Steiner S. Gene therapy for therapeutic angiogenesis in peripheral arterial disease - a systematic review and meta-analysis of randomized, controlled trials. Vasa 2013;42(5):331-339. Available from: http://www.nlm.nih.gov/medlineplus/peripheralarterialdisease.html PubMed PMID: 23989068. doi: 10.1024/0301-1526/a000298.
33. Tateishi-Yuyama E, Matsubara H, Murohara T, Ikeda U, Shintani S, Masaki H, et al. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 2002;360(9331):427-435. Available from: http://ClinicalTrials.gov/search/term=12241713%20%5BPUBMED-IDS%5D PubMed PMID: 12241713. doi: 10.1016/S0140-6736(02)09670-8.
34. Matoba S, Tatsumi T, Murohara T, Imaizumi T, Katsuda Y, Ito M, et al. Long-term clinical outcome after intramuscular implantation of bone marrow mononuclear cells (Therapeutic Angiogenesis by Cell Transplantation [TACT] trial) in patients with chronic limb ischemia. American Heart Journal 2008;156(5):1010-1018. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0002870308005474 doi: 10.1016/j.ahj.2008.06.025.
35. Durdu S, Akar AR, Arat M, Sancak T, Eren NT, Ozyurda U. Autologous bone-marrow mononuclear cell implantation for patients with Rutherford grade II-III thromboangiitis obliterans. Journal of Vascular Surgery 2006;44(4):732-739. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0741521406011426 PubMed PMID: 16926085. doi: 10.1016/j.jvs.2006.06.023.
36. Murphy MP, Lawson JH, Rapp BM, Dalsing MC, Klein J, Wilson MG, et al. Autologous bone marrow mononuclear cell therapy is safe and promotes amputation-free survival in patients with critical limb ischemia. Journal of Vascular Surgery 2011;53(6):1565-1574. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0741521411002916 PubMed PMID: 21514773. doi: 10.1016/j.jvs.2011.01.074.
37. Huang PP, Yang XF, Li SZ, Wen JC, Zhang Y, Han ZC. Randomised comparison of G-CSF-mobilized peripheral blood mononuclear cells versus bone marrow-mononuclear cells for the treatment of patients with lower limb arteriosclerosis obliterans. Thromb Haemost 2007;98(6):1335-1342. Available from: http://www.nlm.nih.gov/medlineplus/bonemarrowtransplantation.html PubMed PMID: 18064333. doi: 10.1160/TH07-02-0137.
38. Kawamoto A, Katayama M, Handa N, Kinoshita M, Takano H, Horii M, et al. Intramuscular Transplantation of G-CSF-Mobilized CD34 + Cells in Patients With Critical Limb Ischemia: A Phase I/IIa, Multicenter, Single-Blinded, Dose-Escalation Clinical Trial. Stem Cells 2009;27(11):2857-2864. Available from: http://doi.wiley.com/10.1002/stem.207 PubMed PMID: 19711453. doi: 10.1002/stem.207.
39. Losordo DW, Kibbe MR, Mendelsohn F, Marston W, Driver VR, Sharafuddin M, et al. A Randomized, Controlled Pilot Study of Autologous CD34+ Cell Therapy for Critical Limb Ischemia. Circulation: Cardiovascular Interventions 2012;5(6):821-830. Available from: http://circinterventions.ahajournals.org/cgi/doi/10.1161/CIRCINTERVENTIONS.112.968321 PubMed PMID: 23192920. doi: 10.1161/CIRCINTERVENTIONS.112.968321.
40. Walter DH, Krankenberg H, Balzer JO, Kalka C, Baumgartner I, Schluter M, et al. Intraarterial Administration of Bone Marrow Mononuclear Cells in Patients With Critical Limb Ischemia: A Randomized-Start, Placebo-Controlled Pilot Trial (PROVASA. Circulation: Cardiovascular Interventions 2011;4(1):26-37. Available from: http://circinterventions.ahajournals.org/cgi/doi/10.1161/CIRCINTERVENTIONS.110.958348 PubMed PMID: 21205939. doi: 10.1161/CIRCINTERVENTIONS.110.958348.
41. Teraa M, Sprengers RW, van der Graaf Y, Peters CEJ, Moll FL, Verhaar MC. Autologous Bone Marrow–Derived Cell Therapy in Patients With Critical Limb Ischemia. Annals of Surgery 2013;258(6):922-929. Available from: http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00000658-201312000-00012 PubMed PMID: 23426345. doi: 10.1097/SLA.0b013e3182854cf1
42. Kawamura A, Horie T, Tsuda I, Abe Y, Yamada M, Egawa H, et al. Clinical study of therapeutic angiogenesis by autologous peripheral blood stem cell (PBSC) transplantation in 92 patients with critically ischemic limbs.. J Artif Organs 2006;9(4):226-233. Available from: http://dx.doi.org/10.1007/s10047 PubMed PMID: 17171401. doi: 10.1007/s10047-006-0351-2.
43. Procházka V, Gumulec J, Jalůvka F, Šalounová D, Jonszta T, Czerný D, et al. Cell Therapy, a New Standard in Management of Chronic Critical Limb Ischemia and Foot Ulcer. cell transplant 2010;19(11):1413-1424. PubMed PMID: 20529449. doi: 10.3727/096368910X514170.
44. Dubsky M, Jirkovska A, Bem R, Fejfarova V, Pagacova L, Sixta B, et al. Both autologous bone marrow mononuclear cell and peripheral blood progenitor cell therapies similarly improve ischaemia in patients with diabetic foot in comparison with control treatment. Diabetes Metab Res Rev 2013;29(5):369-376. Available from: http://doi.wiley.com/10.1002/dmrr.2399 PubMed PMID: 23390092. doi: 10.1002/dmrr.2399.
45. Ruiz-Salmeron R, de la Cuesta-Diaz A, Constantino-Bermejo M, Pérez-Camacho I, Marcos-Sánchez F, Hmadcha A, et al. Angiographic Demonstration of Neoangiogenesis After Intra-arterial Infusion of Autologous Bone Marrow Mononuclear Cells in Diabetic Patients With Critical Limb Ischemia. Cell Transplant 2011;20(10):1629-1639. Available from: http://openurl.ingenta.com/content/xref?genre=article&issn=0963-6897&volume=20&issue=10&spage=1629 PubMed PMID: 22289660. doi: 10.3727/096368910X0177.
46. Lu D, Chen B, Liang Z, Deng W, Jiang Y, Li S, 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 Research and Clinical Practice 2011;92(1):26-36. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0168822710006005 PubMed PMID: 21216483. doi: 10.1016/j.diabres.2010.12.010.
47. Kirana S, Stratmann B, Prante C, Prohaska W, Koerperich H, Lammers D, et al. Autologous stem cell therapy in the treatment of limb ischaemia induced chronic tissue ulcers of diabetic foot patients. Int J Clin Pract 2012;66(4):384-393. Available from: http://ClinicalTrials.gov/search/term=22284892%20%5BPUBMED-IDS%5D PubMed PMID: 22284892. doi: 10.1111/j.1742-1241.2011.02886.x.
48. Bura A, Planat-Benard V, Bourin P, Silvestre J, Gross F, Grolleau J, et al. Phase I trial: the use of autologous cultured adipose-derived stroma/stem cells to treat patients with non-revascularizable critical limb ischemia. Cytotherapy 2014;16(2):245-257. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1465324913007846 PubMed PMID: 24438903. doi: 10.1016/j.jcyt.2013.11.011
49. Jonsson TB, Larzon T, Arfvidsson B, Tidefelt U, Axelsson CG, Jurstrand M, et al. Adverse events during treatment of critical limb ischemia with autologous peripheral blood mononuclear cell implant.. Int Angiol 2012;31(1):77-84. PubMed PMID: 22330628.
50. Dubsky M, Jirkovska A, Bem R, Fejfarova V, Varga M, Kolesar L, et al. Role of serum levels of angiogenic cytokines in assessment of angiogenesis after stem cell therapy of diabetic patients with critical limb ischemia. Cell Transplantation 2013. doi: 10.3727/096368913X674071.
51. Muona K, Mäkinen K, Hedman M, Manninen H, Ylä-Herttuala S. 10-year safety follow-up in patients with local VEGF gene transfer to ischemic lower limb. Gene Ther 2012;19(4):392-395. Available from: http://www.nature.com/doifinder/10.1038/gt.2011.109 PubMed PMID: 21776026. doi: 10.1038/gt.2011.109.
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Konenkov V.I., Klimontov V.V. Genetic and cellular techniques emerge as promising modalities for the treatment of diabetic foot syndrome. Diabetes mellitus. 2014;17(1):63-69. (In Russ.) https://doi.org/10.14341/DM2014163-69
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