{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T03:21:23Z","timestamp":1773285683419,"version":"3.50.1"},"reference-count":70,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2017,11,28]],"date-time":"2017-11-28T00:00:00Z","timestamp":1511827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Health and Consumer Affairs of the Government of the Basque Country","award":["2011111127"],"award-info":[{"award-number":["2011111127"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Current biological treatments for non-healing wounds aim to address the common deviations in healing mechanisms, mainly inflammation, inadequate angiogenesis and reduced synthesis of extracellular matrix. In this context, regenerative medicine strategies, i.e., platelet rich plasmas and mesenchymal stromal cell products, may form part of adjuvant interventions in an integral patient management. We synthesized the clinical experience on ulcer management using these two categories of biological adjuvants. The results of ten controlled trials that are included in this systematic review favor the use of mesenchymal stromal cell based-adjuvants for impaired wound healing, but the number and quality of studies is moderate-low and are complicated by the diversity of biological products. Regarding platelet-derived products, 18 controlled studies investigated their efficacy in chronic wounds in the lower limb, but the heterogeneity of products and protocols hinders clinically meaningful quantitative synthesis. Most patients were diabetic, emphasizing an unmet medical need in this condition. Overall, there is not sufficient evidence to inform routine care, and further clinical research is necessary to realize the full potential of adjuvant regenerative medicine strategies in the management of chronic leg ulcers.<\/jats:p>","DOI":"10.3390\/ijms18122561","type":"journal-article","created":{"date-parts":[[2017,11,28]],"date-time":"2017-11-28T11:23:50Z","timestamp":1511868230000},"page":"2561","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Adjuvant Biological Therapies in Chronic Leg Ulcers"],"prefix":"10.3390","volume":"18","author":[{"given":"Natalia","family":"Burgos-Alonso","sequence":"first","affiliation":[{"name":"Primary Care Research Unit of Bizkaia, BioCruces Health Research Institute, 48014 Bilbao, Spain"},{"name":"Preventive Medicine and Public Health Department, Faculty of Medicine and Odontology, Universidad del Pa\u00eds Vasco\/Euskal Herriko Unibertsitatea UPV\/EHU, University of the Basque Country, 48940 Lejona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igone","family":"Lobato","sequence":"additional","affiliation":[{"name":"Enkarterrri-Ezkerraldea-Cruces Health Region, Basque Health Service (Osakidetza), 48903 Barakaldo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igone","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Enkarterrri-Ezkerraldea-Cruces Health Region, Basque Health Service (Osakidetza), 48903 Barakaldo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kepa","family":"Sebastian","sequence":"additional","affiliation":[{"name":"Primary Care Research Unit of Bizkaia, BioCruces Health Research Institute, 48014 Bilbao, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bego\u00f1a","family":"Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Bilbao-Basurto Health Region, Basque Health Service (Osakidetza), 48014 Bilbao, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gontzal","family":"Grandes","sequence":"additional","affiliation":[{"name":"Primary Care Research Unit of Bizkaia, BioCruces Health Research Institute, 48014 Bilbao, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0607-4767","authenticated-orcid":false,"given":"Isabel","family":"Andia","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Laboratory, BioCruces Health Research Institute, Cruces University Hospital, 48903 Barakaldo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17s","DOI":"10.1016\/j.jvs.2010.06.003","article-title":"The costs of diabetic foot: The economic case for the limb salvage team","volume":"52","author":"Driver","year":"2010","journal-title":"J. Vasc. Surg."},{"key":"ref_2","first-page":"10","article-title":"Wound care outcomes and associated cost among patients treated in us outpatient wound centers: Data from the US wound registry","volume":"24","author":"Fife","year":"2012","journal-title":"Wounds Compend. Clin. Res. Pract."},{"key":"ref_3","unstructured":"(2017, October 04). Global Industry Analysis, I. Advances Wound Care\u2014A Global Strategies Bussines Report. Available online: http:\/\/www.strategyr.com\/Advanced_Wound_Care_Market_Report.asp#sthash.FTA2Umdo.mqm1lRio.dpbs."},{"key":"ref_4","first-page":"255","article-title":"Limitations of daily living activities in patients with venous stasis ulcers undergoing compression bandaging: Problems with the concept of self-bandaging","volume":"19","author":"Fife","year":"2007","journal-title":"Wounds Compend. Clin. Res. Pract."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1524-475X.2008.00436.x","article-title":"Wound healing essentials: Let there be oxygen","volume":"17","author":"Sen","year":"2009","journal-title":"Wound Repair Regen."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1111\/j.1742-481X.2007.00349.x","article-title":"The use of marrow-derived stem cells to accelerate healing in chronic wounds","volume":"5","author":"Rogers","year":"2008","journal-title":"Int. Wound J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.jval.2014.08.001","article-title":"Cost-effectiveness of three adjunct cellular\/tissue-derived products used in the management of chronic venous leg ulcers","volume":"17","author":"Carter","year":"2014","journal-title":"Value Health"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1111\/j.1742-481X.2009.00641.x","article-title":"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","volume":"6","author":"Diaz","year":"2009","journal-title":"Int. Wound J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1038\/mt.2012.279","article-title":"DVC1\u20130101 to treat peripheral arterial disease: A phase I\/IIa open-label dose-escalation clinical trial","volume":"21","author":"Yonemitsu","year":"2013","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1001\/archdermatol.2011.84","article-title":"Topical treatment of hypertensive leg ulcers with platelet-derived growth factor-bb: A randomized controlled trial","volume":"147","author":"Senet","year":"2011","journal-title":"Arch. Dermatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"645","DOI":"10.2217\/rme.13.59","article-title":"Platelet-rich plasma: Underlying biology and clinical correlates","volume":"8","author":"Andia","year":"2013","journal-title":"Regen. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1007\/s40279-016-0620-z","article-title":"Biological therapies in regenerative sports medicine","volume":"47","author":"Andia","year":"2017","journal-title":"Sports Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1089\/rej.2009.0872","article-title":"Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells","volume":"12","author":"Dash","year":"2009","journal-title":"Rejuvenation Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1002\/dmrr.2399","article-title":"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","volume":"29","author":"Dubsky","year":"2013","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1111\/j.1524-475X.2010.00593.x","article-title":"The treatment of diabetic foot ulcers with uncultured, processed lipoaspirate cells: A pilot study","volume":"18","author":"Han","year":"2010","journal-title":"Wound Repair Regen."},{"key":"ref_16","first-page":"38","article-title":"The effect of autologous bone marrow-derived cells on healing chronic lower extremity wounds: Results of a randomized controlled study","volume":"57","author":"Jain","year":"2011","journal-title":"Ostomy Wound Manag."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1111\/j.1742-1241.2011.02886.x","article-title":"Autologous stem cell therapy in the treatment of limb ischaemia induced chronic tissue ulcers of diabetic foot patients","volume":"66","author":"Kirana","year":"2012","journal-title":"Int. J. Clin. Pract."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.diabres.2010.12.010","article-title":"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","volume":"92","author":"Lu","year":"2011","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_19","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":"Marino","year":"2013","journal-title":"J. Surg. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.3727\/096368910X514170","article-title":"Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer","volume":"19","author":"Prochazka","year":"2010","journal-title":"Cell Transplant."},{"key":"ref_21","first-page":"126","article-title":"Adipose-derived stem cells added to platelet-rich plasma for chronic skin ulcer therapy","volume":"28","author":"Raposio","year":"2016","journal-title":"Wounds Compend. Clin. Res. Pract."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1161\/CIRCINTERVENTIONS.110.958348","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","journal-title":"Circ. Cardiovasc. Interv."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.avsg.2016.04.023","article-title":"Platelet-rich plasma for the treatment of clean diabetic foot ulcers","volume":"38","author":"Ahmed","year":"2017","journal-title":"Ann. Vasc. Surg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1002\/jbm.b.30886","article-title":"Effectiveness of autologous preparation rich in growth factors for the treatment of chronic cutaneous ulcers","volume":"84","author":"Anitua","year":"2008","journal-title":"J. Biomed. Mater. Res. Part B Appl. Biomater."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1097\/PRS.0b013e318188202c","article-title":"Effect of topical autologous platelet-rich fibrin versus no intervention on epithelialization of donor sites and meshed split-thickness skin autografts: A randomized clinical trial","volume":"122","author":"Danielsen","year":"2008","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_26","first-page":"68","article-title":"A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers","volume":"52","author":"Driver","year":"2006","journal-title":"Ostomy Wound Manag."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1097\/PRS.0b013e3181cb6589","article-title":"Treatment of diabetic foot ulcers using a blood bank platelet concentrate","volume":"125","author":"Jeong","year":"2010","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.jdiacomp.2007.03.006","article-title":"Synergistic action of protease-modulating matrix and autologous growth factors in healing of diabetic foot ulcers. A prospective randomized trial","volume":"21","author":"Kakagia","year":"2007","journal-title":"J. Diabetes Complicat."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Karimi, R., Afshar, M., Salimian, M., Sharif, A., and Hidariyan, M. (2016). The effect of platelet rich plasma dressing on healing diabetic foot ulcers. Nurs. Midwifery Stud., 5.","DOI":"10.17795\/nmsjournal30314"},{"key":"ref_30","first-page":"56","article-title":"Stimulation of repair in chronic, nonhealing, cutaneous ulcers using platelet-derived wound healing formula","volume":"170","author":"Knighton","year":"1990","journal-title":"Surg. Gynecol. Obstet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1016\/0741-5214(91)90247-R","article-title":"A prospective randomized trial of autologous platelet-derived wound healing factors for treatment of chronic nonhealing wounds: A preliminary report","volume":"14","author":"Krupski","year":"1991","journal-title":"J. Vasc. Surg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1111\/wrr.12294","article-title":"Autologous platelet-rich gel for treatment of diabetic chronic refractory cutaneous ulcers: A prospective, randomized clinical trial","volume":"23","author":"Li","year":"2015","journal-title":"Wound Repair Regen."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Moneib, H.A., Youssef, S.S., Aly, D.G., Rizk, M.A., and Abdelhakeem, Y.I. (2017). Autologous platelet-rich plasma versus conventional therapy for the treatment of chronic venous leg ulcers: A comparative study. J. Cosmet. Dermatol.","DOI":"10.1111\/jocd.12401"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.wndm.2017.09.001","article-title":"Clinical and economic effectiveness of the use of platelet-rich plasma in the treatment of chronic wounds","volume":"19","author":"Obolenskiy","year":"2017","journal-title":"Wound Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7460","DOI":"10.14260\/jemds\/2016\/1689","article-title":"Autologous platelet rich plasma (PRP) versus leucocyte-platelet rich fibrin (L-PRF) in chronic non-healing leg ulcers\u2014A randomised, open labelled, comparative study","volume":"5","author":"Pravin","year":"2016","journal-title":"J. Evol. Med. Dent. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1111\/j.1742-481X.2011.00797.x","article-title":"Platelet-rich plasma versus platelet-poor plasma in the management of chronic diabetic foot ulcers: A comparative study","volume":"8","author":"Elshahat","year":"2011","journal-title":"Int. Wound J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/S0939-4753(04)80029-2","article-title":"A controlled study of the use of autologous platelet gel for the treatment of diabetic foot ulcers","volume":"14","author":"Saldalamacchia","year":"2004","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1016\/S0741-5214(03)00908-X","article-title":"Randomized trial and local biological effect of autologous platelets used as adjuvant therapy for chronic venous leg ulcers","volume":"38","author":"Senet","year":"2003","journal-title":"J. Vasc. Surg."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1053\/ejvs.2000.1134","article-title":"Randomised double-blind placebo controlled trial of topical autologous platelet lysate in venous ulcer healing","volume":"20","author":"Stacey","year":"2000","journal-title":"Eur. J. Vasc. Endovasc. Surg. Off. J. Eur. Soc. Vasc. Surg."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.2337\/diacare.15.11.1598","article-title":"Randomized prospective double-blind trial in healing chronic diabetic foot ulcers. Ct-102 activated platelet supernatant, topical versus placebo","volume":"15","author":"Steed","year":"1992","journal-title":"Diabetes Care"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1016\/j.bjps.2017.07.015","article-title":"Risk of major limb amputation in diabetic foot ulcer and accompanying disease: A meta-analysis","volume":"70","author":"Shin","year":"2017","journal-title":"J. Plast. Reconstruct. Aesthet. Surg."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.atherosclerosis.2009.08.033","article-title":"Autologous stem cell therapy for peripheral arterial disease meta-analysis and systematic review of the literature","volume":"209","author":"Fadini","year":"2010","journal-title":"Atherosclerosis"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1097\/SLA.0b013e3182854cf1","article-title":"Autologous bone marrow-derived cell therapy in patients with critical limb ischemia: A meta-analysis of randomized controlled clinical trials","volume":"258","author":"Teraa","year":"2013","journal-title":"Ann. Surg."},{"key":"ref_44","unstructured":"Catherine Foss, S.R., Ambrose, J., Carney, J., and Nilsson, M. (2017, October 04). International Federation for Adipose Therapeutics and Science. Available online: http:\/\/www.ifats.org\/."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1080\/14653240600855905","article-title":"Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement","volume":"8","author":"Dominici","year":"2006","journal-title":"Cytotherapy"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1089\/107632701300062859","article-title":"Multilineage cells from human adipose tissue: Implications for cell-based therapies","volume":"7","author":"Zuk","year":"2001","journal-title":"Tissue Eng."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"201","DOI":"10.3389\/fimmu.2013.00201","article-title":"Mesenchymal stem cells in tissue repair","volume":"4","author":"Dimarino","year":"2013","journal-title":"Front. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1007\/s00264-016-3162-y","article-title":"A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions","volume":"40","author":"Centeno","year":"2016","journal-title":"Int. Orthop."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Pak, J., Chang, J.J., Lee, J.H., and Lee, S.H. (2013). Safety reporting on implantation of autologous adipose tissue-derived stem cells with platelet-rich plasma into human articular joints. BMC Musculoskelet. Disord., 14.","DOI":"10.1186\/1471-2474-14-337"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1016\/j.joca.2013.06.025","article-title":"Safety of intra-articular cell-therapy with culture-expanded stem cells in humans: A systematic literature review","volume":"21","author":"Peeters","year":"2013","journal-title":"Osteoarthr. Cartil."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1097\/00000658-198609000-00011","article-title":"Classification and treatment of chronic nonhealing wounds. Successful treatment with autologous platelet-derived wound healing factors (PDWHF)","volume":"204","author":"Knighton","year":"1986","journal-title":"Ann. Surg."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Andia, I., and Abate, M. (2017). Platelet-rich plasma: Combinational treatment modalities for musculoskeletal conditions. Front. Med.","DOI":"10.1007\/s11684-017-0551-6"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/j.arthro.2014.11.024","article-title":"Muscle and tendon injuries: The role of biological interventions to promote and assist healing and recovery","volume":"31","author":"Andia","year":"2015","journal-title":"Arthrosc. J. Arthrosc. Relat. Surg. Off. Publ. Arthrosc. Assoc. N. Am. Int. Arthrosc. Assoc."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1111\/j.1365-2184.2009.00583.x","article-title":"Fibroblastic response to treatment with different preparations rich in growth factors","volume":"42","author":"Anitua","year":"2009","journal-title":"Cell Prolif."},{"key":"ref_55","first-page":"3532","article-title":"Platelets and wound healing","volume":"13","author":"Nurden","year":"2008","journal-title":"Front. Biosci."},{"key":"ref_56","first-page":"e38","article-title":"Use of platelet rich plasma gel on wound healing: A systematic review and meta-analysis","volume":"11","author":"Carter","year":"2011","journal-title":"Eplasty"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Martinez-Zapata, M.J., Marti-Carvajal, A.J., Sola, I., Exposito, J.A., Bolibar, I., Rodriguez, L., Garcia, J., and Zaror, C. (2016). Autologous platelet-rich plasma for treating chronic wounds. Cochrane Database Syst. Rev.","DOI":"10.1002\/14651858.CD006899.pub3"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"809","DOI":"10.2106\/JBJS.16.00793","article-title":"Minimum information for studies evaluating biologics in orthopaedics (MIBO): Platelet-rich plasma and mesenchymal stem cells","volume":"99","author":"Murray","year":"2017","journal-title":"J. Bone Jt. Surg. Am. Vol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1111\/j.1742-481X.2011.00868.x","article-title":"Analysis of run-in and treatment data in a wound outcomes registry: Clinical impact of topical platelet-rich plasma gel on healing trajectory","volume":"8","author":"Carter","year":"2011","journal-title":"Int. Wound J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1097\/01.ASW.0000403249.85131.6f","article-title":"The clinical relevance of treating chronic wounds with an enhanced near-physiological concentration of platelet-rich plasma gel","volume":"24","author":"Driver","year":"2011","journal-title":"Adv. Skin Wound Care"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"483","DOI":"10.2337\/diacare.24.3.483","article-title":"Effectiveness of platelet releasate for the treatment of diabetic neuropathic foot ulcers","volume":"24","author":"Margolis","year":"2001","journal-title":"Diabetes Care"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.molmed.2013.12.004","article-title":"Treating the whole not the hole: Necessary coupling of technologies for diabetic foot ulcer treatment","volume":"20","author":"Futrega","year":"2014","journal-title":"Trends Mol. Med."},{"key":"ref_63","first-page":"4488","article-title":"Infected bone inactivation combined with transplantation of autologous platelet-rich plasma and bone marrow for treatment of chronic osteomyelitis","volume":"19","author":"Wang","year":"2015","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Morimoto, N., Kakudo, N., Matsui, M., Ogura, T., Hara, T., Suzuki, K., Yamamoto, M., Tabata, Y., and Kusumoto, K. (2015). Exploratory clinical trial of combination wound therapy with a gelatin sheet and platelet-rich plasma in patients with chronic skin ulcers: Study protocol. BMJ Open, 5.","DOI":"10.1136\/bmjopen-2015-007733"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.jtv.2016.03.003","article-title":"Biological approach for the management of non-healing diabetic foot ulcers","volume":"25","author":"Basterretxea","year":"2016","journal-title":"J. Tissue Viability"},{"key":"ref_66","unstructured":"Higgins, J.P.T. (2017, October 09). Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0. Available online: www.cochrane-handbook.org."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"PRISMA (2015). Preferred reporting items for systematic reviews and meta-analysis. Syst. Rev., 4, 1.","DOI":"10.1186\/2046-4053-4-1"},{"key":"ref_68","unstructured":"(2017, July 30). MEDLINE, Available online: https:\/\/www.ncbi.nlm.nih.gov\/pubmed."},{"key":"ref_69","unstructured":"(2017, July 30). EMBASE. Available online: http:\/\/ovidsp.uk.ovid.com\/sp-3.27.1a\/ovidweb.cgi."},{"key":"ref_70","unstructured":"(2017, July 30). The Cochrane Library Clinical Trials Database. Available online: http:\/\/www.cochranelibrary.com\/."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/12\/2561\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:51:42Z","timestamp":1760208702000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/12\/2561"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11,28]]},"references-count":70,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["ijms18122561"],"URL":"https:\/\/doi.org\/10.3390\/ijms18122561","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,11,28]]}}}