{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:47:12Z","timestamp":1792010832708,"version":"4.4.0"},"reference-count":60,"publisher":"Bioscientifica","issue":"1","license":[{"start":{"date-parts":[[2024,1,1]],"date-time":"2024-01-01T00:00:00Z","timestamp":1704067200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["vb.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,10,7]]},"abstract":"<jats:p>Chronic limb-threatening ischemia (CLTI) is a critical end-stage disease that leads to high amputation rates. Over the past few decades, therapeutic angiogenesis has attracted a lot of attention as a means to reduce the necessity for amputations. Especially gene- and cell therapy are regarded to as possible treatment modalities to restore the hampered blood flow. So far, early-phase clinical trials often fail to prove a significant clinical improvement in mortality, amputation rate, and ulcer healing but still conclude that therapeutic angiogenesis might be promising as therapy. The subsequent phase III clinical trials based on these indecisive early trials fail consistently to demonstrate clinical benefits leaving the promising early results unvalidated. In this review we will illustrate that designing good trials for CLTI patients is challenging, not in the last place since patients are often not eligible due to strict inclusion criteria. Moreover, in this review, we advocate that clinical trials should be conducted with a low risk of bias and that it is of utmost importance to publish results, regardless of the outcome. It is definitely very concerning that many studies of a lower quality (due to small group size or high chance for bias) reporting positive outcomes are published while good quality trials (often with larger group sizes) are stopped prematurely due to lack of effects and remain unpublished. This keeps the \u2018promising but not yet proven\u2019 image of these therapeutic neovascularization studies alive, with still new groups starting similar trials.<\/jats:p>","DOI":"10.1530\/vb-24-0009","type":"journal-article","created":{"date-parts":[[2024,10,7]],"date-time":"2024-10-07T12:44:52Z","timestamp":1728305092000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-12","source":"Crossref","is-referenced-by-count":4,"title":["Therapeutic angiogenesis for patients with chronic limb-threatening ischemia: promising or hoax?"],"prefix":"10.1530","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0051-9836","authenticated-orcid":true,"given":"Judith A H M","family":"Peeters","sequence":"first","affiliation":[{"name":"Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abbey","family":"Schepers","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaap F","family":"Hamming","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6853-5760","authenticated-orcid":true,"given":"Paul H A","family":"Quax","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"bib1","series-title":"Circulation","first-page":"e153","article-title":"Heart disease and stroke statistics\u20142022 update: a report from the American Heart Association","volume":"145","author":"Tsao","year":"2022","unstructured":"Tsao CWAday AWAlmarzooq ZIAlonso ABeaton AZBittencourt MSBoehme AKBuxton AECarson APCommodore-Mensah Y, et al. Heart disease and stroke statistics\u20142022 update: a report from the American Heart Association. Circulation 2022 145 e153\u2013e639. (https:\/\/doi.org\/10.1161\/cir.0000000000001052)"},{"key":"bib2","series-title":"Journal of Vascular Surgery","first-page":"686-95.e2","article-title":"Epidemiology of peripheral arterial disease and critical limb ischemia in an insured national population","volume":"60","author":"Nehler","year":"2014","unstructured":"Nehler MRDuval SDiao LAnnex BHHiatt WRRogers KZakharyan A & Hirsch AT. Epidemiology of peripheral arterial disease and critical limb ischemia in an insured national population. Journal of Vascular Surgery 2014 60 686-95.e2. (https:\/\/doi.org\/10.1016\/j.jvs.2014.03.290)"},{"key":"bib3","series-title":"Journal of Clinical Medicine","first-page":"3303","article-title":"The incidence of chronic limb-threatening ischemia in the midland region of New Zealand over a 12-year period","volume":"11","author":"Hart","year":"2022","unstructured":"Hart OXue NDavis-Havill BPottier MPrakash MReimann S-AKing JXu W & Khashram M. The incidence of chronic limb-threatening ischemia in the midland region of New Zealand over a 12-year period. Journal of Clinical Medicine 2022 11 3303. (https:\/\/doi.org\/10.3390\/jcm11123303)"},{"issue":"Supplement S","key":"bib4","series-title":"Journal of Vascular Surgery","first-page":"S5","article-title":"Inter-society consensus for the management of peripheral arterial disease (TASC II)","volume":"45","author":"Norgren","year":"2007","unstructured":"Norgren LHiatt WRDormandy JANehler MRHarris KAFowkes FGR & TASC II Working Group. Inter-society consensus for the management of peripheral arterial disease (TASC II). Journal of Vascular Surgery 2007 45(Supplement S) S5\u2013S67. (https:\/\/doi.org\/10.1016\/j.jvs.2006.12.037)"},{"key":"bib5","series-title":"Diabetes Research and Clinical Practice","first-page":"110194","article-title":"Global estimates of diabetes-related amputations incidence in 2010\u20132020: a systematic review and meta-analysis","volume":"195","author":"Ezzatvar","year":"2023","unstructured":"Ezzatvar Y & Garc\u00eda-Hermoso A. Global estimates of diabetes-related amputations incidence in 2010\u20132020: a systematic review and meta-analysis. Diabetes Research and Clinical Practice 2023 195 110194. (https:\/\/doi.org\/10.1016\/j.diabres.2022.110194)"},{"key":"bib6","series-title":"Disability and Rehabilitation","first-page":"1201","article-title":"Psychological adjustment to lower limb amputation amongst prosthesis users","volume":"28","author":"Atherton","year":"2006","unstructured":"Atherton R & Robertson N. Psychological adjustment to lower limb amputation amongst prosthesis users. Disability and Rehabilitation 2006 28 1201\u20131209. (https:\/\/doi.org\/10.1080\/09638280600551674)"},{"key":"bib7","series-title":"Journal of the American Academy of Orthopaedic Surgeons","first-page":"e59","article-title":"The burden of patients with lower limb amputations in a community safety-net hospital","volume":"30","author":"Stewart","year":"2022","unstructured":"Stewart CCBerhaneselase E & Morshed S. The burden of patients with lower limb amputations in a community safety-net hospital. Journal of the American Academy of Orthopaedic Surgeons 2022 30 e59\u2013e66. (https:\/\/doi.org\/10.5435\/JAAOS-D-21-00293)"},{"key":"bib8","series-title":"International Journal of Molecular Sciences","article-title":"Exploring the effects of human bone marrow-derived mononuclear cells on angiogenesis in vitro","volume":"24","author":"Peeters","year":"2023","unstructured":"Peeters JAHMPeters HABVideler AJHamming JFSchepers A & Quax PHA. Exploring the effects of human bone marrow-derived mononuclear cells on angiogenesis in vitro. International Journal of Molecular Sciences 2023 24. (https:\/\/doi.org\/10.3390\/ijms241813822)"},{"key":"bib9","series-title":"PLoS One","first-page":"e55592","article-title":"Bone marrow alterations and lower endothelial progenitor cell numbers in critical limb ischemia patients","volume":"8","author":"Teraa","year":"2013","unstructured":"Teraa MSprengers RWWesterweel PEGremmels HGoumans MJTHTeerlink TMoll FLVerhaar MC & JUVENTAS study group. Bone marrow alterations and lower endothelial progenitor cell numbers in critical limb ischemia patients. PLoS One 2013 8 e55592. (https:\/\/doi.org\/10.1371\/journal.pone.0055592)"},{"key":"bib10","series-title":"Physiological Reviews","first-page":"1743","article-title":"Postischemic revascularization: from cellular and molecular mechanisms to clinical applications","volume":"93","author":"Silvestre","year":"2013","unstructured":"Silvestre JSSmadja DM & L\u00e9vy BI. Postischemic revascularization: from cellular and molecular mechanisms to clinical applications. Physiological Reviews 2013 93 1743\u20131802. (https:\/\/doi.org\/10.1152\/physrev.00006.2013)"},{"key":"bib11","series-title":"Journal of Clinical Oncology","first-page":"2780","article-title":"Talimogene laherparepvec improves durable response rate in patients with advanced melanoma","volume":"33","author":"Andtbacka","year":"2015","unstructured":"Andtbacka RHIKaufman HLCollichio FAmatruda TSenzer NChesney JDelman KASpitler LEPuzanov IAgarwala SS, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. Journal of Clinical Oncology 2015 33 2780\u20132788. (https:\/\/doi.org\/10.1200\/JCO.2014.58.3377)"},{"key":"bib12","series-title":"New England Journal of Medicine","first-page":"439","article-title":"Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia","volume":"378","author":"Maude","year":"2018","unstructured":"Maude SLLaetsch TWBuechner JRives SBoyer MBittencourt HBader PVerneris MRStefanski HEMyers GD, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. New England Journal of Medicine 2018 378 439\u2013448. (https:\/\/doi.org\/10.1056\/NEJMoa1709866)"},{"key":"bib13","series-title":"Oncologist","first-page":"894","article-title":"EMA review of axicabtagene ciloleucel (Yescarta) for the treatment of diffuse large B-cell lymphoma","volume":"25","author":"Papadouli","year":"2020","unstructured":"Papadouli IMueller-Berghaus JBeuneu CAli SHofner BPetavy FTzogani KMiermont ANorga KKholmanskikh O, et al. EMA review of axicabtagene ciloleucel (Yescarta) for the treatment of diffuse large B-cell lymphoma. Oncologist 2020 25 894\u2013902. (https:\/\/doi.org\/10.1634\/theoncologist.2019-0646)"},{"key":"bib14","series-title":"Lancet. Neurology","first-page":"284","article-title":"Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial","volume":"20","author":"Day","year":"2021","unstructured":"Day JWFinkel RSChiriboga CAConnolly AMCrawford TODarras BTIannaccone STKuntz NLPe\u00f1a LDMShieh PB, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet. Neurology 2021 20 284\u2013293. (https:\/\/doi.org\/10.1016\/S1474-4422(2100001-6)"},{"key":"bib15","series-title":"New England Journal of Medicine","first-page":"415","article-title":"Betibeglogene autotemcel gene therapy for non-\u03b2(0)","volume":"386","author":"Locatelli","year":"2022","unstructured":"Locatelli FThompson AAKwiatkowski JLPorter JBThrasher AJHongeng SSauer MGThuret ILal AAlgeri M, et al. Betibeglogene autotemcel gene therapy for non-\u03b2(0). New England Journal of Medicine 2022 386 415\u2013427. (https:\/\/doi.org\/10.1056\/NEJMoa2113206)"},{"key":"bib16","series-title":"Lancet","first-page":"370","article-title":"Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb","volume":"348","author":"Isner","year":"1996","unstructured":"Isner JMPieczek ASchainfeld RBlair RHaley LAsahara TRosenfield KRazvi SWalsh K & Symes JF. Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb. Lancet 1996 348 370\u2013374. (https:\/\/doi.org\/10.1016\/s0140-6736(9603361-2)"},{"key":"bib17","series-title":"Molecular Therapy","first-page":"127","article-title":"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","volume":"6","author":"M\u00e4kinen","year":"2002","unstructured":"M\u00e4kinen KManninen HHedman MMatsi PMussalo HAlhava E & Yl\u00e4-Herttuala S. 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 6 127\u2013133. (https:\/\/doi.org\/10.1006\/mthe.2002.0638)"},{"key":"bib18","series-title":"Human Gene Therapy","first-page":"683","article-title":"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","volume":"17","author":"Kusumanto","year":"2006","unstructured":"Kusumanto YHvan Weel VMulder NHSmit AJvan den Dungen JJHooymans JMSluiter WJTio RAQuax PHGans RO, 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 17 683\u2013691. (https:\/\/doi.org\/10.1089\/hum.2006.17.683)"},{"key":"bib19","series-title":"Circulation","first-page":"1933","article-title":"Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication","volume":"108","author":"Rajagopalan","year":"2003","unstructured":"Rajagopalan SMohler ER3rdLederman RJMendelsohn FOSaucedo JFGoldman CKBlebea JMacko JKessler PDRasmussen HS, et al. Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication. Circulation 2003 108 1933\u20131938. (https:\/\/doi.org\/10.1161\/01.CIR.0000093398.16124.29)"},{"key":"bib20","series-title":"Vascular Pharmacology","first-page":"3","article-title":"Hepatocyte growth factor stimulated angiogenesis without inflammation: differential actions between hepatocyte growth factor, vascular endothelial growth factor and basic fibroblast growth factor","volume":"57","author":"Kaga","year":"2012","unstructured":"Kaga TKawano HSakaguchi MNakazawa TTaniyama 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 3\u20139. (https:\/\/doi.org\/10.1016\/j.vph.2012.02.002)"},{"key":"bib21","series-title":"Gene Therapy","first-page":"1152","article-title":"Randomized, double-blind, placebo-controlled clinical trial of hepatocyte growth factor plasmid for critical limb ischemia","volume":"17","author":"Shigematsu","year":"2010","unstructured":"Shigematsu HYasuda KIwai TSasajima TIshimaru SOhashi YYamaguchi TOgihara T & Morishita R. Randomized, double-blind, placebo-controlled clinical trial of hepatocyte growth factor plasmid for critical limb ischemia. Gene Therapy 2010 17 1152\u20131161. (https:\/\/doi.org\/10.1038\/gt.2010.51)"},{"key":"bib22","series-title":"Journal of Vascular Surgery","first-page":"1525","article-title":"Safety and efficacy of patient specific intramuscular injection of HGF plasmid gene therapy on limb perfusion and wound healing in patients with ischemic lower extremity ulceration: results of the HGF-0205 trial","volume":"52","author":"Powell","year":"2010","unstructured":"Powell RJGoodney PMendelsohn FOMoen EKAnnex BH & HGF-0205 Trial Investigators. Safety and efficacy of patient specific intramuscular injection of HGF plasmid gene therapy on limb perfusion and wound healing in patients with ischemic lower extremity ulceration: results of the HGF-0205 trial. Journal of Vascular Surgery 2010 52 1525\u20131530. (https:\/\/doi.org\/10.1016\/j.jvs.2010.07.044)"},{"key":"bib23","series-title":"Molecular Therapy","first-page":"2158","article-title":"A randomized, double-blind, placebo-controlled phase II study of hepatocyte growth factor in the treatment of critical limb ischemia","volume":"27","author":"Gu","year":"2019","unstructured":"Gu YCui SWang QLiu CJin BGuo WLiu CChu TShu CZhang F, et al. A randomized, double-blind, placebo-controlled phase II study of hepatocyte growth factor in the treatment of critical limb ischemia. Molecular Therapy 2019 27 2158\u20132165. (https:\/\/doi.org\/10.1016\/j.ymthe.2019.10.017)"},{"key":"bib24","series-title":"Molecular Therapy","first-page":"972","article-title":"Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia","volume":"16","author":"Nikol","year":"2008","unstructured":"Nikol SBaumgartner IVan Belle EDiehm CVison\u00e1 ACapogrossi MCFerreira-Maldent NGallino AWyatt MGWijesinghe LD, et al. Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia. Molecular Therapy 2008 16 972\u2013978. (https:\/\/doi.org\/10.1038\/mt.2008.33)"},{"key":"bib25","series-title":"Lancet","first-page":"1929","article-title":"Effect of fibroblast growth factor NV1FGF on amputation and death: a randomised placebo-controlled trial of gene therapy in critical limb ischaemia","volume":"377","author":"Belch","year":"2011","unstructured":"Belch JHiatt WRBaumgartner IDriver IVNikol SNorgren LVan Belle E & TAMARIS Committees and Investigators. 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 1929\u20131937. (https:\/\/doi.org\/10.1016\/S0140-6736(1160394-2)"},{"key":"bib26","series-title":"European Journal of Vascular and Endovascular Surgery","first-page":"365","article-title":"Insights on the role of diabetes and geographic variation in patients with critical limb ischaemia","volume":"42","author":"Van Belle","year":"2011","unstructured":"Van Belle ENikol SNorgren LBaumgartner IDriver VHiatt WR & Belch J. Insights on the role of diabetes and geographic variation in patients with critical limb ischaemia. European Journal of Vascular and Endovascular Surgery 2011 42 365\u2013373. (https:\/\/doi.org\/10.1016\/j.ejvs.2011.04.030)"},{"key":"bib27","series-title":"Annals of Vascular Diseases","first-page":"109","article-title":"Therapeutic angiogenesis using HGF plasmid","volume":"13","author":"Sanada","year":"2020","unstructured":"Sanada FFujikawa TShibata KTaniyama YRakugi H & Morishita R. Therapeutic angiogenesis using HGF plasmid. Annals of Vascular Diseases 2020 13 109\u2013115. (https:\/\/doi.org\/10.3400\/avd.ra.20-00035)"},{"key":"bib28","series-title":"Annals of Vascular Surgery","first-page":"346","article-title":"Treatment of critical limb ischemia by pIRES\/VEGF165\/HGF administration","volume":"60","author":"Bar\u0107","year":"2019","unstructured":"Bar\u0107 PAntkiewicz M\u015aliwa BBaczy\u0144ska DWitkiewicz W & Sk\u00f3ra JP. Treatment of critical limb ischemia by pIRES\/VEGF165\/HGF administration. Annals of Vascular Surgery 2019 60 346\u2013354. (https:\/\/doi.org\/10.1016\/j.avsg.2019.03.013)"},{"key":"bib29","series-title":"Journal of Cardiovascular Translational Research","first-page":"409","article-title":"Double VEGF\/HGF gene therapy in critical limb ischemia complicated by diabetes mellitus","volume":"14","author":"Bar\u0107","year":"2021","unstructured":"Bar\u0107 PAntkiewicz M\u015aliwa BFr\u0105czkowska KGuzi\u0144ski MDawiskiba TMa\u0142odobra-Mazur MWitkiewicz WKupczy\u0144ska DStrzelec B, et al. Double VEGF\/HGF gene therapy in critical limb ischemia complicated by diabetes mellitus. Journal of Cardiovascular Translational Research 2021 14 409\u2013415. (https:\/\/doi.org\/10.1007\/s12265-020-10066-9)"},{"key":"bib30","series-title":"Vasa","first-page":"331","article-title":"Gene therapy for therapeutic angiogenesis in peripheral arterial disease - a systematic review and meta-analysis of randomized, controlled trials","volume":"42","author":"Hammer","year":"2013","unstructured":"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 42 331\u2013339. (https:\/\/doi.org\/10.1024\/0301-1526\/a000298)"},{"key":"bib31","series-title":"Nature Reviews. Cardiology","first-page":"387","article-title":"Therapeutic angiogenesis for critical limb ischaemia","volume":"10","author":"Annex","year":"2013","unstructured":"Annex BH. Therapeutic angiogenesis for critical limb ischaemia. Nature Reviews. Cardiology 2013 10 387\u2013396. (https:\/\/doi.org\/10.1038\/nrcardio.2013.70)"},{"key":"bib32","series-title":"Cochrane Database of Systematic Reviews","first-page":"CD012058","article-title":"Gene therapy for peripheral arterial disease","volume":"10","author":"Forster","year":"2018","unstructured":"Forster RLiew ABhattacharya VShaw J & Stansby G. Gene therapy for peripheral arterial disease. Cochrane Database of Systematic Reviews 2018 10 CD012058. (https:\/\/doi.org\/10.1002\/14651858.CD012058.pub2)"},{"key":"bib33","series-title":"Science","first-page":"964","article-title":"Isolation of putative progenitor endothelial cells for angiogenesis","volume":"275","author":"Asahara","year":"1997","unstructured":"Asahara TMurohara TSullivan ASilver Mvan der Zee RLi TWitzenbichler BSchatteman G & Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997 275 964\u2013967. (https:\/\/doi.org\/10.1126\/science.275.5302.964)"},{"key":"bib34","series-title":"Circulation Journal","first-page":"1093","article-title":"Granulocyte colony-stimulating factor: a noninvasive regeneration therapy for treating atherosclerotic peripheral artery disease","volume":"70","author":"Arai","year":"2006","unstructured":"Arai MMisao YNagai HKawasaki MNagashima KSuzuki KTsuchiya KOtsuka SUno YTakemura G, et al. Granulocyte colony-stimulating factor: a noninvasive regeneration therapy for treating atherosclerotic peripheral artery disease. Circulation Journal 2006 70 1093\u20131098. (https:\/\/doi.org\/10.1253\/circj.70.1093)"},{"key":"bib35","series-title":"Lancet","first-page":"427","article-title":"Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial","volume":"360","author":"Tateishi-Yuyama","year":"2002","unstructured":"Tateishi-Yuyama EMatsubara HMurohara TIkeda UShintani SMasaki HAmano KKishimoto YYoshimoto KAkashi 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 360 427\u2013435. (https:\/\/doi.org\/10.1016\/S0140-6736(0209670-8)"},{"key":"bib36","series-title":"Circulation. Cardiovascular Interventions","first-page":"821","article-title":"A randomized, controlled pilot study of autologous CD34+ cell therapy for critical limb ischemia","volume":"5","author":"Losordo","year":"2012","unstructured":"Losordo DWKibbe MRMendelsohn FMarston WDriver VRSharafuddin MTeodorescu VWiechmann BNThompson CKraiss L, et al. A randomized, controlled pilot study of autologous CD34+ cell therapy for critical limb ischemia. Circulation. Cardiovascular Interventions 2012 5 821\u2013830. (https:\/\/doi.org\/10.1161\/CIRCINTERVENTIONS.112.968321)"},{"key":"bib37","series-title":"Stem Cell Research and Therapy","first-page":"174","article-title":"Report of a phase 1 clinical trial for safety assessment of human placental mesenchymal stem cells therapy in patients with critical limb ischemia (CLI)","volume":"14","author":"Shirbaghaee","year":"2023","unstructured":"Shirbaghaee ZHeidari Keshel SRasouli MValizadeh MHashemi Nazari SSHassani M & Soleimani M. Report of a phase 1 clinical trial for safety assessment of human placental mesenchymal stem cells therapy in patients with critical limb ischemia (CLI). Stem Cell Research and Therapy 2023 14 174. (https:\/\/doi.org\/10.1186\/s13287-023-03390-9)"},{"key":"bib38","series-title":"Frontiers in Cardiovascular Medicine","first-page":"1113982","article-title":"Mesenchymal stem cell-based therapy for non-healing wounds due to chronic limb-threatening ischemia: a review of preclinical and clinical studies","volume":"10","author":"Huerta","year":"2023","unstructured":"Huerta CTVoza FAOrtiz YYLiu ZJ & Velazquez OC. Mesenchymal stem cell-based therapy for non-healing wounds due to chronic limb-threatening ischemia: a review of preclinical and clinical studies. Frontiers in Cardiovascular Medicine 2023 10 1113982. (https:\/\/doi.org\/10.3389\/fcvm.2023.1113982)"},{"key":"bib39","series-title":"International Journal of Molecular Sciences","article-title":"Current status of angiogenic cell therapy and related strategies applied in critical limb ischemia","volume":"22","author":"Beltr\u00e1n-Camacho","year":"2021","unstructured":"Beltr\u00e1n-Camacho LRojas-Torres M & Dur\u00e1n-Ruiz MC. Current status of angiogenic cell therapy and related strategies applied in critical limb ischemia. International Journal of Molecular Sciences 2021 22. (https:\/\/doi.org\/10.3390\/ijms22052335)"},{"key":"bib40","series-title":"Circulation. Cardiovascular Interventions","first-page":"15","article-title":"Autologous bone-marrow mononuclear cell implantation reduces long-term major amputation risk in patients with critical limb ischemia: a comparison of atherosclerotic peripheral arterial disease and Buerger disease","volume":"4","author":"Idei","year":"2011","unstructured":"Idei NSoga JHata TFujii YFujimura NMikami SMaruhashi TNishioka KHidaka TKihara Y, et al. Autologous bone-marrow mononuclear cell implantation reduces long-term major amputation risk in patients with critical limb ischemia: a comparison of atherosclerotic peripheral arterial disease and Buerger disease. Circulation. Cardiovascular Interventions 2011 4 15\u201325. (https:\/\/doi.org\/10.1161\/CIRCINTERVENTIONS.110.955724)"},{"key":"bib41","series-title":"Circulation","first-page":"851","article-title":"Effect of repetitive intra-arterial infusion of bone marrow mononuclear cells in patients with no-option limb ischemia: the randomized, double-blind, placebo-controlled rejuvenating endothelial progenitor cells via transcutaneous intra-arterial supplementation (JUVENTAS) trial","volume":"131","author":"Teraa","year":"2015","unstructured":"Teraa MSprengers RWSchutgens REGSlaper-Cortenbach ICMvan der Graaf YAlgra Avan der Tweel IDoevendans PAMali WPTMMoll FL, et al. Effect of repetitive intra-arterial infusion of bone marrow mononuclear cells in patients with no-option limb ischemia: the randomized, double-blind, placebo-controlled rejuvenating endothelial progenitor cells via transcutaneous intra-arterial supplementation (JUVENTAS) trial. Circulation 2015 131 851\u2013860. (https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.114.012913)"},{"key":"bib42","series-title":"Annals of Surgery","first-page":"756","article-title":"No clinical benefit of intramuscular delivery of bone marrow-derived mononuclear cells in nonreconstructable peripheral arterial disease: results of a phase-III randomized-controlled trial","volume":"268","author":"Lindeman","year":"2018","unstructured":"Lindeman JHNZwaginga JJKallenberg-Lantrua Gvan Wissen RCSchepers Avan Bockel HJFibbe WE & Hamming JF. No clinical benefit of intramuscular delivery of bone marrow-derived mononuclear cells in nonreconstructable peripheral arterial disease: results of a phase-III randomized-controlled trial. Annals of Surgery 2018 268 756\u2013761. (https:\/\/doi.org\/10.1097\/SLA.0000000000002896)"},{"key":"bib43","series-title":"Circulation. Cardiovascular Interventions","first-page":"26","article-title":"Intraarterial administration of bone marrow mononuclear cells in patients with critical limb ischemia: a randomized-start, placebo-controlled pilot trial (PROVASA)","volume":"4","author":"Walter","year":"2011","unstructured":"Walter DHKrankenberg HBalzer JOKalka CBaumgartner ISchl\u00fcter MTonn TSeeger FDimmeler SLindhoff-Last E, 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 26\u201337. (https:\/\/doi.org\/10.1161\/CIRCINTERVENTIONS.110.958348)"},{"key":"bib44","series-title":"Circulation Journal","first-page":"1713","article-title":"Autologous bone marrow mononuclear cell implantation and its impact on the outcome of patients with critical limb ischemia - results of a randomized, double-blind, placebo-controlled trial","volume":"81","author":"Pignon","year":"2017","unstructured":"Pignon BSevestre MAKanagaratnam LPernod GStephan DEmmerich JClement CSarlon GBoulon CTournois C, et al. Autologous bone marrow mononuclear cell implantation and its impact on the outcome of patients with critical limb ischemia - results of a randomized, double-blind, placebo-controlled trial. Circulation Journal 2017 81 1713\u20131720. (https:\/\/doi.org\/10.1253\/circj.CJ-17-0045)"},{"key":"bib45","series-title":"Journal of Vascular and Interventional Radiology","first-page":"157","article-title":"Randomized, double-blind, placebo-controlled trial to evaluate safety and therapeutic efficacy of angiogenesis induced by intraarterial autologous bone marrow-derived stem cells in patients with severe peripheral arterial disease","volume":"32","author":"Sharma","year":"2021","unstructured":"Sharma SPandey NNSinha MKumar SJagia PGulati GSGond KMohanty S & Bhargava B. Randomized, double-blind, placebo-controlled trial to evaluate safety and therapeutic efficacy of angiogenesis induced by intraarterial autologous bone marrow-derived stem cells in patients with severe peripheral arterial disease. Journal of Vascular and Interventional Radiology 2021 32 157\u2013163. (https:\/\/doi.org\/10.1016\/j.jvir.2020.09.003)"},{"key":"bib46","series-title":"Cytotherapy","first-page":"1270","article-title":"Autologous bone marrow mononuclear cell therapy improves symptoms in patients with end-stage peripheral arterial disease and reduces inflammation-associated parameters","volume":"16","author":"Malyar","year":"2014","unstructured":"Malyar NMRadtke SMalyar KArjumand JHorn PAKr\u00f6ger KFreisinger EReinecke HGiebel B & Brock FE. Autologous bone marrow mononuclear cell therapy improves symptoms in patients with end-stage peripheral arterial disease and reduces inflammation-associated parameters. Cytotherapy 2014 16 1270\u20131279. (https:\/\/doi.org\/10.1016\/j.jcyt.2014.05.001)"},{"key":"bib47","series-title":"Circulation Research","first-page":"1326","article-title":"Autologous cell therapy for peripheral arterial disease: systematic review and meta-analysis of randomized, nonrandomized, and noncontrolled studies","volume":"120","author":"Rigato","year":"2017","unstructured":"Rigato MMonami M & Fadini GP. Autologous cell therapy for peripheral arterial disease: systematic review and meta-analysis of randomized, nonrandomized, and noncontrolled studies. Circulation Research 2017 120 1326\u20131340. (https:\/\/doi.org\/10.1161\/CIRCRESAHA.116.309045)"},{"key":"bib48","series-title":"Current Cardiology Reports","first-page":"447","article-title":"The current state of stem cell therapy for peripheral artery disease","volume":"16","author":"Gupta","year":"2014","unstructured":"Gupta NKArmstrong EJ & Parikh SA. The current state of stem cell therapy for peripheral artery disease. Current Cardiology Reports 2014 16 447. (https:\/\/doi.org\/10.1007\/s11886-013-0447-2)"},{"key":"bib49","series-title":"Cardiovascular Research","first-page":"205","article-title":"Towards the therapeutic use of vascular smooth muscle progenitor cells","volume":"95","author":"Merkulova-Rainon","year":"2012","unstructured":"Merkulova-Rainon TBroqu\u00e8res-You DKubis NSilvestre JS & L\u00e9vy BI. Towards the therapeutic use of vascular smooth muscle progenitor cells. Cardiovascular Research 2012 95 205\u2013214. (https:\/\/doi.org\/10.1093\/cvr\/cvs097)"},{"key":"bib50","series-title":"Stem Cell Research and Therapy","first-page":"47","article-title":"Development of a surrogate potency assay to determine the angiogenic activity of Stempeucel\u00ae, a pooled, ex-vivo expanded, allogeneic human bone marrow mesenchymal stromal cell product","volume":"8","author":"Thej","year":"2017","unstructured":"Thej CRamadasse BWalvekar AMajumdar AS & Balasubramanian S. Development of a surrogate potency assay to determine the angiogenic activity of Stempeucel\u00ae, a pooled, ex-vivo expanded, allogeneic human bone marrow mesenchymal stromal cell product. Stem Cell Research and Therapy 2017 8 47. (https:\/\/doi.org\/10.1186\/s13287-017-0488-3)"},{"key":"bib51","series-title":"iScience","first-page":"421","article-title":"Mesenchymal stromal cell homing: mechanisms and strategies for improvement","volume":"15","author":"Ullah","year":"2019","unstructured":"Ullah MLiu DD & Thakor AS. Mesenchymal stromal cell homing: mechanisms and strategies for improvement. iScience 2019 15 421\u2013438. (https:\/\/doi.org\/10.1016\/j.isci.2019.05.004)"},{"key":"bib52","series-title":"World Journal of Stem Cells","first-page":"73","article-title":"Homing and migration of mesenchymal stromal cells: how to improve the efficacy of cell therapy?","volume":"8","author":"De Becker","year":"2016","unstructured":"De Becker A & Riet IV. Homing and migration of mesenchymal stromal cells: how to improve the efficacy of cell therapy? World Journal of Stem Cells 2016 8 73\u201387. (https:\/\/doi.org\/10.4252\/wjsc.v8.i3.73)"},{"key":"bib53","series-title":"European Journal of Vascular and Endovascular Surgery","first-page":"72","article-title":"Geographical variation in the management of peripheral arterial occlusive disease: a nationwide danish cohort study","volume":"63","author":"S\u00f8gaard","year":"2022","unstructured":"S\u00f8gaard RLondero LS & Lindholt J. Geographical variation in the management of peripheral arterial occlusive disease: a nationwide danish cohort study. European Journal of Vascular and Endovascular Surgery 2022 63 72\u201379. (https:\/\/doi.org\/10.1016\/j.ejvs.2021.10.037)"},{"key":"bib54","series-title":"Mayo Clinic Proceedings","first-page":"1770","article-title":"Geographic variation in cardiovascular health among american adults","volume":"96","author":"Parcha","year":"2021","unstructured":"Parcha VKalra RSuri SSMalla GWang TJArora G & Arora P. Geographic variation in cardiovascular health among american adults. Mayo Clinic Proceedings 2021 96 1770\u20131781. (https:\/\/doi.org\/10.1016\/j.mayocp.2020.12.034)"},{"key":"bib55","series-title":"Thrombosis and Haemostasis","first-page":"1335","article-title":"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","volume":"98","author":"Huang","year":"2007","unstructured":"Huang PPYang XFLi SZWen JCZhang 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. Thrombosis and Haemostasis 2007 98 1335\u20131342. (https:\/\/doi.org\/10.1160\/th07-02-0137)"},{"key":"bib56","series-title":"Journal of Vascular Surgery","first-page":"673","article-title":"Autologous bone marrow mononuclear cell implantation therapy is an effective limb salvage strategy for patients with severe peripheral arterial disease","volume":"62","author":"Franz","year":"2015","unstructured":"Franz RWShah KJPin RHHankins THartman JF & Wright ML. Autologous bone marrow mononuclear cell implantation therapy is an effective limb salvage strategy for patients with severe peripheral arterial disease. Journal of Vascular Surgery 2015 62 673\u2013680. (https:\/\/doi.org\/10.1016\/j.jvs.2015.02.059)"},{"key":"bib57","series-title":"PLoS One","first-page":"e110418","article-title":"Why are medical and health-related studies not being published? A systematic review of reasons given by investigators","volume":"9","author":"Song","year":"2014","unstructured":"Song FLoke Y & Hooper L. Why are medical and health-related studies not being published? A systematic review of reasons given by investigators. PLoS One 2014 9 e110418. (https:\/\/doi.org\/10.1371\/journal.pone.0110418)"},{"key":"bib58","series-title":"BMJ","first-page":"f6104","article-title":"Non-publication of large randomized clinical trials: cross sectional analysis","volume":"347","author":"Jones","year":"2013","unstructured":"Jones CWHandler LCrowell KEKeil LGWeaver MA & Platts-Mills TF. Non-publication of large randomized clinical trials: cross sectional analysis. BMJ 2013 347 f6104. (https:\/\/doi.org\/10.1136\/bmj.f6104)"},{"issue":"180","key":"bib59","series-title":"Handbook of Experimental Pharmacology","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/978-3-540-68976-8_8","article-title":"Cell therapy and gene therapy using endothelial progenitor cells for vascular regeneration","author":"Asahara","year":"2007","unstructured":"Asahara T. Cell therapy and gene therapy using endothelial progenitor cells for vascular regeneration. Handbook of Experimental Pharmacology 2007 (180) 181\u2013194. (https:\/\/doi.org\/10.1007\/978-3-540-68976-8_8)"},{"key":"bib60","series-title":"European Journal of Cardio-Thoracic Surgery","first-page":"153","article-title":"Efficacy of adenoviral gene transfer with manganese superoxide dismutase and endothelial nitric oxide synthase in reducing ischemia and reperfusion injury","volume":"20","author":"Abunasra","year":"2001","unstructured":"Abunasra HJSmolenski RTMorrison KYap JSheppard MNO'Brien TSuzuki KJayakumar J & Yacoub MH. Efficacy of adenoviral gene transfer with manganese superoxide dismutase and endothelial nitric oxide synthase in reducing ischemia and reperfusion injury. European Journal of Cardio-Thoracic Surgery 2001 20 153\u2013158. 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