间充质干细胞治疗糖尿病足溃疡的Meta分析
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摘要
目的以Meta分析系统评价间充质干细胞(MSC)治疗糖尿病足溃疡(DFU)的疗效。方法通过计算机检索Pubmed、Web of Science、OVID数据库、Embase、Medline、Cochrane Central、中国知网、中国生物医学数据库等数据库,自建库至2018年11月份的随机对照试验进行系统评价。结果共纳入8个随机对照临床试验。Meta分析结果显示,与对照组相比,MSC疗法可增加溃疡愈合率[OR(95%CI)2. 50(1. 26～4. 97),P<0. 01],减少溃疡面积[加权均数差值(WMD)=―3. 510,95%CI(―4. 654～―2. 366),P<0. 01],针对难治性溃疡有显著的疗效,改善踝肱指数[WMD=0. 11,95%CI(0. 07～0. 15),P<0. 01],提高经皮氧分压[标化均数差值=1. 82,95%CI(1. 28～2. 37),P<0. 01],改善患肢血流情况,提高无截肢生存率[OR(95%CI)0. 11(0. 02～0. 61),P<0. 05];无明显不良反应。结论 MSC疗法可促进DFU伤口愈合,改善局部循环,提高无截肢生存率,是DFU有效的综合治疗对策。
Objective To perform a meta-analysis to evaluate the efficacy of mesenchymal stem cell therapy in the management of diabetic foot ulcer(DFU).MethodsWe systematically searched randomized controlled trials assessing the efficacy of mesenchymal stem cell therapy in the treatment of DFU from databases including PubMed,Web of Science,Embase,Medline,Cochrane Library,OVID Database,CNKI and CBM published before November 2018.ResultsEight randomized controlled clinical trials were included. Meta-analysis showed that the mesenchymal stem cell therapy could increase ulcer healing rate[OR(95%CI)2. 50(1. 26～4. 97),P<0. 01],reduce the ulcer size[WMD=―3. 510,95%CI(―4. 654～―2. 366),P<0. 01],improve ankle-brachial index[WMD=0. 11,95%CI(0. 07～0. 15),P<0. 01]and transcutaneous arterial oxygen tension[SMD=1. 82,95%CI(1. 28～2. 37),P<0. 01],increase the amputation-free survival rate[OR(95%CI)0. 11(0. 02～0. 61),P<0. 05]. No patient in these trials had significant adverse effect.ConclusionMesenchymal stem cell therapy can accelerate the healing of DFU,improve local circulation and amputation-free survival rate. This may be a promising comprehensive therapy strategy for DFU.
Objective To perform a meta-analysis to evaluate the efficacy of mesenchymal stem cell therapy in the management of diabetic foot ulcer(DFU).MethodsWe systematically searched randomized controlled trials assessing the efficacy of mesenchymal stem cell therapy in the treatment of DFU from databases including PubMed,Web of Science,Embase,Medline,Cochrane Library,OVID Database,CNKI and CBM published before November 2018.ResultsEight randomized controlled clinical trials were included. Meta-analysis showed that the mesenchymal stem cell therapy could increase ulcer healing rate[OR(95%CI)2. 50(1. 26～4. 97),P<0. 01],reduce the ulcer size[WMD=―3. 510,95%CI(―4. 654～―2. 366),P<0. 01],improve ankle-brachial index[WMD=0. 11,95%CI(0. 07～0. 15),P<0. 01]and transcutaneous arterial oxygen tension[SMD=1. 82,95%CI(1. 28～2. 37),P<0. 01],increase the amputation-free survival rate[OR(95%CI)0. 11(0. 02～0. 61),P<0. 05]. No patient in these trials had significant adverse effect.ConclusionMesenchymal stem cell therapy can accelerate the healing of DFU,improve local circulation and amputation-free survival rate. This may be a promising comprehensive therapy strategy for DFU.
引文
[1]International Diabetes Federation.IDF Diabetes Atlas.8th ed.http://www.diabetesatlas.org.
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[8]Shi YF,Wang Y,Li Q,et al.Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases.Nat Rev Nephrol,2018,14:493-507.
[9]Albehairy A,Abdelghaffar H,Abdelhafez H,et al.Autologous mesenchymal stem cells in treatment of recalcitrant neuropathic diabetic foot ulcer:randomised controlled trial.Diabetologia,2016,59:S19.
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[13]Debin L,Youzhao J,Ziwen L,et al.Autologous transplantation of bone marrow mesenchymal stem cells on diabetic patients with lower limb ischemia.Journal of Medical of PLA,2008,23:106-115.
[14]Mohammadzadeh L,Samedanifard SH,Keshavarzi A,et al.Therapeutic outcomes of transplanting autologous granulocyte colony-stimulating factor-mobilised peripheral mononuclear cells in diabetic patients with critical limb ischaemia.Exp Clin Endocrinol Diabetes,2013,121:48-53.
[15]Qin HL,Zhu XH,Zhang B,et al.Clinical evaluation of human umbilical cord mesenchymal stem cell transplantation after angioplasty for diabetic foot.Exp Clin Endocrinol Diabetes,2016,124:497-503.
[16]陈兵,陆德宾,梁自文,等.自体骨髓间充质干细胞体外扩增后移植治疗糖尿病足.中国组织工程研究与临床康复,2009,13:6227-6230.
[17]Armstrong DG,Boulton AJM,Bus SA.Diabetic foot ulcers and their recurrence.New Engl J Med,2017,376:2367-2375.
[18]Chung J,Timaran DA,Modrall JG,et al.Optimal medical therapy predicts amputation-free survival in chronic critical limb ischemia.J Vasc Surg,2013,58:972-980.
[19]Peng C,Chen B,Kao HK,et al.Lack of FGF-7 further delays cutaneous wound healing in diabetic mice.Plast Reconstr Surg,2011,128:673e-684e.
[20]Usui ML,Mansbridge JN,Carter WG,et al.Keratinocyte migration,proliferation,and differentiation in chronic ulcers from patients with diabetes and normal wounds.J Histochem Cytochem,2008,56:687-696.
[21]Desta T,Li J,Chino T,et al.Altered fibroblast proliferation and apoptosis in diabetic gingival wounds.J Dent Res,2010,89:609-614.
[22]Mcdonald AM,Bonbright DI,Oers WTHV,et al.Fibroblasts derived from chronic diabetic ulcers differ in their response to stimulation with EGF,IGF-I,bFGF and PDGF-AB compared to controls.Eur J Cell Biol,2002,81:153-160.
[23]Chen L,Tredget EE,Wu PY,et al.Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound ealing.PLoS One,2008,3:e1886.
[24]Kim SW,Zhang HZ,Guo L,et al.Amniotic mesenchymal stem cells enhance wound healing in diabetic NOD/SCID mice through high angiogenic and engraftment capabilities.PLoS One,2012,7:e41105.
[25]Wu Y,Chen L,Scott PG,et al.Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis.Stem Cells,2010,25:2648-2659.
[2]Zhang P,Lu J,Jing Y,et al.Global epidemiology of diabetic foot ulceration:a systematic review and meta-analysis.Ann Med,2017,49:106-116.
[3]Singh N,Armstrong DG,Lipsky BA.Preventing foot ulcers in patients with diabetes.JAMA,2005,293:217-228.
[4]Jeffcoate W,Bakker K.World Diabetes Day:footing the bill.The Lancet,2005,365:1527.
[5]Monteiro-Soares M,Boyko EJ,Ribeiro J,et al.Predictive factors for diabetic foot ulceration:a systematic review.Diabetes Metab Res Rev,2012,28:574-600.
[6]Hartmann B,Fottner C,Herrmann K,et al.Interdisciplinary treatment of diabetic foot wounds in the elderly:low risk of amputations and mortality and good chance of being mobile with good quality of life.Diab Vasc Dis Res,2017,14:55-58.
[7]Yang M,Sheng L,Zhang TR,et al.Stem cell therapy for lower extremity diabetic ulcers:where do we stand?.Biomed Res Int,2013,2013:462179.
[8]Shi YF,Wang Y,Li Q,et al.Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases.Nat Rev Nephrol,2018,14:493-507.
[9]Albehairy A,Abdelghaffar H,Abdelhafez H,et al.Autologous mesenchymal stem cells in treatment of recalcitrant neuropathic diabetic foot ulcer:randomised controlled trial.Diabetologia,2016,59:S19.
[10]Dash NR,Dash SN,Routray P,et al.Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells.Rejuvenation Res,2009,12:359-366.
[11]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.
[12]Kirana S,Stratmann B,Prante C,et al.Autologous stem cell therapy in the treatment of limb ischaemia induced chronic tissue ulcers of diabetic foot patients.Int J Clin Pract,2012,66:384-393.
[13]Debin L,Youzhao J,Ziwen L,et al.Autologous transplantation of bone marrow mesenchymal stem cells on diabetic patients with lower limb ischemia.Journal of Medical of PLA,2008,23:106-115.
[14]Mohammadzadeh L,Samedanifard SH,Keshavarzi A,et al.Therapeutic outcomes of transplanting autologous granulocyte colony-stimulating factor-mobilised peripheral mononuclear cells in diabetic patients with critical limb ischaemia.Exp Clin Endocrinol Diabetes,2013,121:48-53.
[15]Qin HL,Zhu XH,Zhang B,et al.Clinical evaluation of human umbilical cord mesenchymal stem cell transplantation after angioplasty for diabetic foot.Exp Clin Endocrinol Diabetes,2016,124:497-503.
[16]陈兵,陆德宾,梁自文,等.自体骨髓间充质干细胞体外扩增后移植治疗糖尿病足.中国组织工程研究与临床康复,2009,13:6227-6230.
[17]Armstrong DG,Boulton AJM,Bus SA.Diabetic foot ulcers and their recurrence.New Engl J Med,2017,376:2367-2375.
[18]Chung J,Timaran DA,Modrall JG,et al.Optimal medical therapy predicts amputation-free survival in chronic critical limb ischemia.J Vasc Surg,2013,58:972-980.
[19]Peng C,Chen B,Kao HK,et al.Lack of FGF-7 further delays cutaneous wound healing in diabetic mice.Plast Reconstr Surg,2011,128:673e-684e.
[20]Usui ML,Mansbridge JN,Carter WG,et al.Keratinocyte migration,proliferation,and differentiation in chronic ulcers from patients with diabetes and normal wounds.J Histochem Cytochem,2008,56:687-696.
[21]Desta T,Li J,Chino T,et al.Altered fibroblast proliferation and apoptosis in diabetic gingival wounds.J Dent Res,2010,89:609-614.
[22]Mcdonald AM,Bonbright DI,Oers WTHV,et al.Fibroblasts derived from chronic diabetic ulcers differ in their response to stimulation with EGF,IGF-I,bFGF and PDGF-AB compared to controls.Eur J Cell Biol,2002,81:153-160.
[23]Chen L,Tredget EE,Wu PY,et al.Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound ealing.PLoS One,2008,3:e1886.
[24]Kim SW,Zhang HZ,Guo L,et al.Amniotic mesenchymal stem cells enhance wound healing in diabetic NOD/SCID mice through high angiogenic and engraftment capabilities.PLoS One,2012,7:e41105.
[25]Wu Y,Chen L,Scott PG,et al.Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis.Stem Cells,2010,25:2648-2659.