{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T04:22:06Z","timestamp":1744258926235,"version":"3.40.4"},"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T00:00:00Z","timestamp":1744156800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["443984\/2023-9"],"award-info":[{"award-number":["443984\/2023-9"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Peripheral artery disease (PAD) can develop into critical limb ischemia (CLI), which is characterized by resting pain at rest, ulcerations, or gangrene, with a high risk of amputation. The optimum course of treatment at this point is arterial revascularization, although this has a significant financial cost and is not always feasible or successful in reducing pain, healing ulcers, or preventing amputations. In situations where traditional alternatives for treating PAD have been exhausted, recent developments in cell therapy may offer a viable substitute.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Objective<\/jats:title>\n<jats:p>The purpose of this study is to assess the safety and effectiveness of using expanded autologous adipose-derived stem cells (ASCs) in cellular therapy for the treatment of PAD patients who developed chronic artery ulcers.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Methods<\/jats:title>\n<jats:p>An open randomized clinical trial will be carried out with two groups of twenty patients with CLI: In group 1, 2g of abdominal adipose tissue will be taken to produce ASCs. These cells will then be expanded in a lab (cell processing center) for 14\u201321 days before being applied to the lesion using bio-dressings and perilesional subcutaneous injections. Group 2 will receive conventional treatment with hydrogel-based dressing. There will be regular clinical assessments, supplementary tests, and photo documentation. The main efficacy outcome will be partial or complete healing of the wound. Safety outcomes will be monitored for infections, gangrene, amputations, and death. Participants will be monitored for 90 days. Cases of major amputation of the studied limb will not be included. The results will be evaluated by an independent external evaluator who is blind to the groups. Considering the high prevalence and socioeconomic consequences related to CLI and limb amputation, this study is expected to provide a positive social and financial impact on the Brazilian Unified Health System.<\/jats:p>\n<jats:p>ClinicalTrials.gov: NCT06326203.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0318922","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T17:30:43Z","timestamp":1744219843000},"page":"e0318922","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Study protocol for a randomized clinical trial evaluating the safety and efficacy of autologous adipose-derived stem cell therapy for ulcers in patients with critical limb ischemia"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-4814-7329","authenticated-orcid":true,"given":"Francisco Jos\u00e9 de","family":"Oliveira Filho","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7972-8472","authenticated-orcid":true,"given":"Lenize da Silva","family":"Rodrigues","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sidia Maria Baptista do","family":"Amaral","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro Luciano","family":"Mellucci Filho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nat\u00e1lia Bronzatto","family":"Medolago","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana L\u00edvia","family":"de Carvalho Bovolato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita de C\u00e1ssia","family":"Alvarado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6851-2841","authenticated-orcid":true,"given":"Matheus","family":"Bertanha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,4,9]]},"reference":[{"issue":"1","key":"pone.0318922.ref001","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1007\/s00428-006-0176-7","article-title":"Atherosclerosis research from past to present--on the track of two pathologists with opposing views, Carl von Rokitansky and Rudolf Virchow","volume":"449","author":"C Mayerl","year":"2006","journal-title":"Virchows Arch"},{"issue":"9289","key":"pone.0318922.ref002","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1016\/S0140-6736(01)06351-6","article-title":"Peripheral arterial disease","volume":"358","author":"K Ouriel","year":"2001","journal-title":"Lancet"},{"key":"pone.0318922.ref003","first-page":"379","volume-title":"Update on peripheral artery disease: Epidemiology and evidence-based facts. Atherosclerosis","author":"J Shu","year":"2018"},{"issue":"9","key":"pone.0318922.ref004","doi-asserted-by":"crossref","first-page":"e171","DOI":"10.1161\/CIR.0000000000001005","article-title":"Lower extremity peripheral artery disease: contemporary epidemiology, management gaps, and future directions: a scientific statement from the american heart association","volume":"144","author":"MH Criqui","year":"2021","journal-title":"Circulation"},{"issue":"22","key":"pone.0318922.ref005","doi-asserted-by":"crossref","first-page":"2746","DOI":"10.1161\/hc4601.099487","article-title":"Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization","volume":"104","author":"S Yusuf","year":"2001","journal-title":"Circulation"},{"issue":"23","key":"pone.0318922.ref006","doi-asserted-by":"crossref","first-page":"2855","DOI":"10.1161\/hc4701.099488","article-title":"Global burden of cardiovascular diseases: Part II: variations in cardiovascular disease by specific ethnic groups and geographic regions and prevention strategies","volume":"104","author":"S Yusuf","year":"2001","journal-title":"Circulation"},{"issue":"10","key":"pone.0318922.ref007","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1136\/hrt.2007.131060","article-title":"Global burden of cardiovascular disease","volume":"93","author":"JE Sanderson","year":"2007","journal-title":"Heart"},{"issue":"9","key":"pone.0318922.ref008","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1161\/CIRCRESAHA.116.303849","article-title":"Epidemiology of peripheral artery disease","volume":"116","author":"MH Criqui","year":"2015","journal-title":"Circ Res"},{"issue":"24","key":"pone.0318922.ref009","doi-asserted-by":"crossref","first-page":"e1313","DOI":"10.1161\/CIR.0000000000001251","article-title":"2024 ACC\/AHA\/AACVPR\/APMA\/ABC\/SCAI\/SVM\/SVN\/SVS\/SIR\/VESS guideline for the management of lower extremity peripheral artery disease: a report of the american college of cardiology\/American heart association joint committee on clinical practice guidelines","volume":"149","author":"HL Gornik","year":"2024","journal-title":"Circulation"},{"key":"pone.0318922.ref010","doi-asserted-by":"crossref","first-page":"1144806","DOI":"10.3389\/fendo.2023.1144806","article-title":"Clinical characteristics and risk factors of lower extremity amputation in the diabetic inpatients with foot ulcers","volume":"14","author":"H Gong","year":"2023","journal-title":"Front Endocrinol (Lausanne)"},{"key":"pone.0318922.ref011","first-page":"S5-67","article-title":"Inter-society consensus for the management of peripheral arterial disease (TASC II)","author":"L Norgren","year":"2007","journal-title":"J Vasc Surg"},{"issue":"5","key":"pone.0318922.ref012","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1177\/1526602815592206","article-title":"An update on methods for revascularization and expansion of the TASC lesion classification to include below-the-knee arteries: a supplement to the inter-society consensus for the management of peripheral arterial disease (TASC II)","volume":"22","author":"TASC Steering Committee","year":"2015","journal-title":"J Endovasc Ther"},{"issue":"16","key":"pone.0318922.ref013","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1056\/NEJMra1615243","article-title":"Evaluation and management of lower-extremity ulcers","volume":"377","author":"AJ Singer","year":"2017","journal-title":"N Engl J Med"},{"issue":"4\u20136","key":"pone.0318922.ref014","first-page":"311","article-title":"Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue","volume":"14","author":"RH Lee","year":"2004","journal-title":"Cell Physiol Biochem"},{"issue":"4","key":"pone.0318922.ref015","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1007\/s10047-006-0351-2","article-title":"Clinical study of therapeutic angiogenesis by autologous peripheral blood stem cell (PBSC) transplantation in 92 patients with critically ischemic limbs","volume":"9","author":"A Kawamura","year":"2006","journal-title":"J Artif Organs"},{"issue":"3","key":"pone.0318922.ref016","doi-asserted-by":"crossref","first-page":"132","DOI":"10.2302\/kjm.54.132","article-title":"Multipotential differentiation of adipose tissue-derived stem cells","volume":"54","author":"BM Strem","year":"2005","journal-title":"Keio J Med"},{"issue":"5","key":"pone.0318922.ref017","doi-asserted-by":"crossref","first-page":"69","DOI":"10.14797\/mdcvj.1291","article-title":"Stem cell therapy: a possible role in the treatment of patients with chronic limb-threatening ischemia?","volume":"19","author":"A Olson","year":"2023","journal-title":"Methodist Debakey Cardiovasc J"},{"issue":"5","key":"pone.0318922.ref018","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.3390\/ijms22052335","article-title":"Current status of angiogenic cell therapy and related strategies applied in critical limb ischemia","volume":"22","author":"L Beltr\u00e1n-Camacho","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"12","key":"pone.0318922.ref019","doi-asserted-by":"crossref","first-page":"3307","DOI":"10.3390\/cells10123307","article-title":"Autologous stem cell therapy for chronic lower extremity wounds: a meta-analysis of randomized controlled trials","volume":"10","author":"K-J Chiang","year":"2021","journal-title":"Cells"},{"key":"pone.0318922.ref020","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.scr.2016.12.001","article-title":"Non-reconstructable peripheral vascular disease of the lower extremity in ten patients treated with adipose-derived stromal vascular fraction cells","volume":"18","author":"MH Carstens","year":"2017","journal-title":"Stem Cell Res"},{"key":"pone.0318922.ref021","article-title":"Mesenchymal stem cells and immunomodulation: Current status and future prospects","volume-title":"Cell death and disease","author":"F Gao","year":"2016"},{"key":"pone.0318922.ref022","doi-asserted-by":"crossref","first-page":"1113982","DOI":"10.3389\/fcvm.2023.1113982","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":"CT Huerta","year":"2023","journal-title":"Front Cardiovasc Med"},{"issue":"4","key":"pone.0318922.ref023","first-page":"1440-1449.e5","article-title":"A meta-analysis of randomized controlled trials on therapeutic efficacy and safety of autologous cell therapy for atherosclerosis obliterans","volume":"75","author":"H Pu","year":"2022","journal-title":"J Vasc Surg"},{"key":"pone.0318922.ref024","first-page":"7528464","article-title":"Autologous stem cell therapy in critical limb ischemia: a meta-analysis of randomized controlled trials","author":"B Xie","year":"2018","journal-title":"Stem Cells Int"},{"issue":"11","key":"pone.0318922.ref025","doi-asserted-by":"crossref","first-page":"e2716","DOI":"10.1097\/MD.0000000000002716","article-title":"Effectiveness of autologous stem cell therapy for the treatment of lower extremity ulcers: a systematic review and meta-analysis","volume":"95","author":"X Jiang","year":"2016","journal-title":"Medicine (Baltimore)"},{"issue":"7","key":"pone.0318922.ref026","doi-asserted-by":"crossref","first-page":"2003119","DOI":"10.1002\/advs.202003119","article-title":"Therapeutic biomaterial approaches to alleviate chronic limb threatening ischemia","volume":"8","author":"G Marsico","year":"2021","journal-title":"Adv Sci (Weinh)"},{"issue":"5\u20136","key":"pone.0318922.ref027","first-page":"499","article-title":"Surgical treatment of peripheral circulation disorders","volume":"21","author":"R Fontaine","year":"1954","journal-title":"Helv Chir Acta"},{"issue":"3","key":"pone.0318922.ref028","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/S0741-5214(97)70045-4","article-title":"Recommended standards for reports dealing with lower extremity ischemia: revised version","volume":"26","author":"RB Rutherford","year":"1997","journal-title":"J Vasc Surg"},{"issue":"24","key":"pone.0318922.ref029","doi-asserted-by":"crossref","first-page":"2890","DOI":"10.1161\/CIR.0b013e318276fbcb","article-title":"Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association","volume":"126","author":"V Aboyans","year":"2012","journal-title":"Circulation"},{"issue":"6","key":"pone.0318922.ref030","doi-asserted-by":"crossref","first-page":"V303-11","DOI":"10.1016\/S0049-3848(01)00366-8","article-title":"Evaluation of patients with peripheral vascular disease","volume":"106","author":"JL Halperin","year":"2002","journal-title":"Thromb Res"},{"issue":"1","key":"pone.0318922.ref031","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.jss.2013.05.024","article-title":"Therapy with autologous adipose-derived regenerative cells for the care of chronic ulcer of lower limbs in patients with peripheral arterial disease","volume":"185","author":"G Marino","year":"2013","journal-title":"J Surg Res"},{"issue":"3","key":"pone.0318922.ref032","doi-asserted-by":"crossref","first-page":"312","DOI":"10.4252\/wjsc.v6.i3.312","article-title":"Adipose-derived stem cells: Implications in tissue regeneration","volume":"6","author":"W Tsuji","year":"2014","journal-title":"World J Stem Cells"},{"issue":"1","key":"pone.0318922.ref033","article-title":"Adipose\u2010Derived Stem Cells for Tissue Engineering and Regenerative Medicine Applications","author":"R Dai","year":"2016","journal-title":"Stem Cells International"},{"issue":"1","key":"pone.0318922.ref034","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1053\/j.semvascsurg.2014.12.001","article-title":"Contemporary assessment of foot perfusion in patients with critical limb ischemia","volume":"27","author":"E Benitez","year":"2014","journal-title":"Semin Vasc Surg"},{"issue":"9","key":"pone.0318922.ref035","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1097\/01.ASW.0000694156.62834.8b","article-title":"Infrared Thermography as a Diagnostic Tool for Peripheral Artery Disease","volume":"33","author":"A Ilo","year":"2020","journal-title":"Adv Skin Wound Care"},{"key":"pone.0318922.ref036","doi-asserted-by":"crossref","first-page":"103467","DOI":"10.1016\/j.jtherbio.2023.103467","article-title":"Assessment of chronic limb threatening ischemia using thermal imaging","volume":"112","author":"T Pakarinen","year":"2023","journal-title":"J Therm Biol"},{"key":"pone.0318922.ref037","doi-asserted-by":"crossref","first-page":"e940829","DOI":"10.12659\/MSM.940829","article-title":"Assessing automatic plethysmographic ankle-brachial index devices in peripheral artery disease detection: a comparative study with doppler ankle-brachial index measurements","volume":"29","author":"A Danieluk","year":"2023","journal-title":"Med Sci Monit"},{"issue":"1","key":"pone.0318922.ref038","first-page":"220-34.e1-2","article-title":"The society for vascular surgery lower extremity threatened limb classification system: risk stratification based on wound, ischemia, and foot infection (WIfI)","volume":"59","author":"Sr Mills JL","year":"2014","journal-title":"J Vasc Surg"},{"issue":"3","key":"pone.0318922.ref039","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.jvs.2016.03.417","article-title":"Predictive ability of the society for vascular surgery wound, ischemia, and foot Infection (WIfI) classification system following infrapopliteal endovascular interventions for critical limb ischemia","volume":"64","author":"JD Darling","year":"2016","journal-title":"J Vasc Surg"},{"issue":"6846","key":"pone.0318922.ref040","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1136\/bmj.305.6846.160","article-title":"Validating the SF-36 health survey questionnaire: new outcome measure for primary care","volume":"305","author":"JE Brazier","year":"1992","journal-title":"BMJ"},{"issue":"1","key":"pone.0318922.ref041","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/0304-3959(83)90126-4","article-title":"The validation of visual analogue scales as ratio scale measures for chronic and experimental pain","volume":"17","author":"DD Price","year":"1983","journal-title":"Pain"},{"issue":"7","key":"pone.0318922.ref042","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"CA Schneider","year":"2012","journal-title":"Nat Methods"},{"issue":"4","key":"pone.0318922.ref043","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1177\/1534734617744951","article-title":"ImageJ: a free, easy, and reliable method to measure leg ulcers using digital pictures","volume":"16","author":"J Arag\u00f3n-S\u00e1nchez","year":"2017","journal-title":"Int J Low Extrem Wounds"},{"issue":"3","key":"pone.0318922.ref044","doi-asserted-by":"crossref","first-page":"155","DOI":"10.4081\/monaldi.2012.121","article-title":"EuroQol-5D (EQ-5D): an instrument for measuring quality of life","volume":"78","author":"G Balestroni","year":"2015","journal-title":"Monaldi Arch Chest Dis"},{"issue":"4","key":"pone.0318922.ref045","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1182\/blood-2004-04-1559","article-title":"Human mesenchymal stem cells modulate allogeneic immune cell responses","volume":"105","author":"S Aggarwal","year":"2005","journal-title":"Blood"},{"issue":"1","key":"pone.0318922.ref046","doi-asserted-by":"crossref","first-page":"41","DOI":"10.3727\/096368912X636984","article-title":"Interaction between adipose tissue-derived mesenchymal stem cells and regulatory T-cells","volume":"22","author":"AU Engela","year":"2013","journal-title":"Cell Transplant"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0318922","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T17:30:54Z","timestamp":1744219854000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0318922"}},"subtitle":[],"editor":[{"given":"Emma","family":"Campbell","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,4,9]]},"references-count":46,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4,9]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0318922","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,9]]}}}