{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T21:40:21Z","timestamp":1791582021165,"version":"4.3.4"},"reference-count":77,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T00:00:00Z","timestamp":1646006400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Diabetes mellitus is one of the major concerns for health care systems, affecting 382 million people worldwide. Among the different complications of diabetes, lower limbs chronic ulceration is a common, severe and costly cause of morbidity. Diabetic foot ulcers are a leading cause of hospitalization in diabetic patients and its rate exceed the ones of congestive heart failure, depression or renal disease. Diabetic non-healing ulcers account for more than 60% of all non-traumatic lower limb amputations and the five-year mortality after amputation is higher than 50%, being equal to several types of advanced cancer. The primary management goals for an existing diabetic foot ulcer are to achieve primary healing as expeditiously as possible and to achieve a reduction of the amputation rate in the patients. Unfortunately, approximately a quarter of patients do not partially or fully respond to the standard of care. Advanced therapies for chronic wounds are existing, however, recent guidelines including the latest reviews and meta-analyses of the scientific and clinical evidence available from current treatment strategies and new therapeutic agents revealed that there is a lack of clinical data and persistent gap of evidence for many of the advanced therapeutic approaches. In addition, no pharmacological wound healing product has gained authority approval for more than 10 years in both US and EU, constituting a highly unmet medical need. In this publication we present data from a live biopharmaceutical product AUP1602-C designed as a single pharmaceutical entity based on the non-pathogenic, food-grade lactic acid bacterium<jats:italic>Lactococcus lactis<\/jats:italic>subsp.<jats:italic>c<\/jats:italic>r<jats:italic>emoris<\/jats:italic>that has been genetically engineered to produce human fibroblast growth factor 2,interleukin4 and colony stimulating factor 1. Designed to address different aspects of wound healing (i.e. fibroblast proliferation, angiogenesis and immune cell activation) and currently in phase I clinical study, we show how the combination of the individual components on the wound micro-environment initiates and improves the wound healing in chronic wounds.<\/jats:p>","DOI":"10.1371\/journal.pone.0264775","type":"journal-article","created":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T18:29:56Z","timestamp":1646072996000},"page":"e0264775","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":29,"title":["Four in one\u2014Combination therapy using live Lactococcus lactis expressing three therapeutic proteins for the treatment of chronic non-healing wounds"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5239-6532","authenticated-orcid":true,"given":"Jere","family":"Kurkipuro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Mierau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Wirth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haritha","family":"Samaranayake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wesley","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna-Riikka","family":"K\u00e4rkk\u00e4inen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirka","family":"Tikkanen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juha","family":"Yrj\u00e4nheikki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,2,28]]},"reference":[{"issue":"24","key":"pone.0264775.ref001","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1056\/NEJMra1615439","article-title":"Diabetic Foot Ulcers and Their Recurrence","volume":"376","author":"DG Armstrong","year":"2017","journal-title":"N Engl J Med"},{"key":"pone.0264775.ref002","article-title":"IDF Diabetes Atlas","author":"ID Federation"},{"issue":"12","key":"pone.0264775.ref003","doi-asserted-by":"crossref","DOI":"10.3390\/ijms17122085","article-title":"Inflammation in Chronic Wounds.","volume":"17","author":"R Zhao","year":"2016","journal-title":"Int J Mol Sci"},{"issue":"2","key":"pone.0264775.ref004","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1093\/qjmed\/hcl140","article-title":"Predicting foot ulcers in patients with diabetes: a systematic review and meta-analysis","volume":"100","author":"F Crawford","year":"2007","journal-title":"QJM"},{"issue":"5","key":"pone.0264775.ref005","doi-asserted-by":"crossref","first-page":"822","DOI":"10.2337\/dc08-1223","article-title":"Long-term prognosis of diabetic patients with critical limb ischemia: a population-based cohort study","volume":"32","author":"E Faglia","year":"2009","journal-title":"Diabetes Care"},{"key":"pone.0264775.ref006","volume-title":"The Foot in Diabetis","author":"PRJ Vas","year":"2020","edition":"5"},{"issue":"2","key":"pone.0264775.ref007","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1001\/jama.293.2.217","article-title":"Preventing foot ulcers in patients with diabetes","volume":"293","author":"N Singh","year":"2005","journal-title":"JAMA"},{"issue":"7","key":"pone.0264775.ref008","doi-asserted-by":"crossref","first-page":"936","DOI":"10.2337\/dc16-2189","article-title":"Sr., Lavery LA, Armstrong DG. Health Care Service and Outcomes Among an Estimated 6.7 Million Ambulatory Care Diabetic Foot Cases in the U.S","volume":"40","author":"GH Skrepnek","year":"2017","journal-title":"Diabetes Care"},{"issue":"1","key":"pone.0264775.ref009","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s12262-010-0005-8","article-title":"Efficacy of topical recombinant human platelet derived growth factor on wound healing in patients with chronic diabetic lower limb ulcers","volume":"72","author":"SS Jaiswal","year":"2010","journal-title":"Indian J Surg"},{"issue":"1","key":"pone.0264775.ref010","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s13047-020-00383-2","article-title":"Five year mortality and direct costs of care for people with diabetic foot complications are comparable to cancer","volume":"13","author":"DG Armstrong","year":"2020","journal-title":"J Foot Ankle Res"},{"issue":"4","key":"pone.0264775.ref011","doi-asserted-by":"crossref","first-page":"926","DOI":"10.3390\/genes5040926","article-title":"The Role of MicroRNAs in Diabetic Complications-Special Emphasis on Wound Healing.","volume":"5","author":"J Moura","year":"2014","journal-title":"Genes (Basel)."},{"issue":"2","key":"pone.0264775.ref012","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1111\/bjd.13954","article-title":"Cellular and molecular mechanisms of repair in acute and chronic wound healing","volume":"173","author":"P Martin","year":"2015","journal-title":"Br J Dermatol"},{"issue":"5","key":"pone.0264775.ref013","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1046\/j.1523-1747.1998.00381.x","article-title":"Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds","volume":"111","author":"MA Loots","year":"1998","journal-title":"J Invest Dermatol"},{"key":"pone.0264775.ref014","doi-asserted-by":"crossref","first-page":"419","DOI":"10.3389\/fphys.2018.00419","article-title":"The Role of Macrophages in Acute and Chronic Wound Healing and Interventions to Promote Pro-wound Healing Phenotypes","volume":"9","author":"P Krzyszczyk","year":"2018","journal-title":"Front Physiol"},{"issue":"5","key":"pone.0264775.ref015","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1007\/s00125-008-0940-0","article-title":"Prediction of outcome in individuals with diabetic foot ulcers: focus on the differences between individuals with and without peripheral arterial disease. The EURODIALE Study","volume":"51","author":"L Prompers","year":"2008","journal-title":"Diabetologia"},{"issue":"9498","key":"pone.0264775.ref016","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1016\/S0140-6736(05)67695-7","article-title":"Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomised controlled trial","volume":"366","author":"DG Armstrong","year":"2005","journal-title":"Lancet"},{"issue":"4","key":"pone.0264775.ref017","doi-asserted-by":"crossref","first-page":"631","DOI":"10.2337\/dc07-2196","article-title":"Comparison of negative pressure wound therapy using vacuum-assisted closure with advanced moist wound therapy in the treatment of diabetic foot ulcers: a multicenter randomized controlled trial","volume":"31","author":"PA Blume","year":"2008","journal-title":"Diabetes Care"},{"issue":"5","key":"pone.0264775.ref018","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.pmrj.2009.03.012","article-title":"Hyperbaric oxygen therapy for wound healing and limb salvage: a systematic review","volume":"1","author":"RJ Goldman","year":"2009","journal-title":"PM R"},{"key":"pone.0264775.ref019","year":"2017","journal-title":"FDA. FDA permits marketing of device to treat diabetic foot ulcers"},{"issue":"6","key":"pone.0264775.ref020","first-page":"22","article-title":"A comparison of an opaque foam dressing versus a transparent film dressing in the management of skin tears in institutionalized subjects","volume":"45","author":"DR Thomas","year":"1999","journal-title":"Ostomy Wound Manage"},{"issue":"3","key":"pone.0264775.ref021","first-page":"223","article-title":"Efficacy and tolerance of calcium alginate versus vaseline gauze dressings in the treatment of diabetic foot lesions","volume":"28","author":"JD Lalau","year":"2002","journal-title":"Diabetes Metab"},{"issue":"50","key":"pone.0264775.ref022","first-page":"5755","article-title":"Iodine-induced hyperthyroidism after cadexomer iodine treatment of leg ulcers","volume":"95","author":"A Michanek","year":"1998","journal-title":"Lakartidningen"},{"key":"pone.0264775.ref023","first-page":"CD011255","article-title":"Skin grafting and tissue replacement for treating foot ulcers in people with diabetes","volume":"2","author":"TB Santema","year":"2016","journal-title":"Cochrane Database Syst Rev"},{"issue":"10","key":"pone.0264775.ref024","first-page":"CD008548","article-title":"Growth factors for treating diabetic foot ulcers","author":"AJ Marti-Carvajal","year":"2015","journal-title":"Cochrane Database Syst Rev"},{"issue":"2A","key":"pone.0264775.ref025","doi-asserted-by":"crossref","first-page":"74S","DOI":"10.1016\/S0002-9610(98)00185-8","article-title":"Clinical efficacy of becaplermin (rhPDGF-BB) gel. Becaplermin Gel Studies Group","volume":"176","author":"TJ Wieman","year":"1998","journal-title":"Am J Surg"},{"issue":"4","key":"pone.0264775.ref026","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1097\/01.sap.0000198731.12407.0c","article-title":"Recombinant human epidermal growth factor (EGF) to enhance healing for diabetic foot ulcers","volume":"56","author":"JP Hong","year":"2006","journal-title":"Ann Plast Surg"},{"issue":"1","key":"pone.0264775.ref027","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1111\/j.1742-481X.2008.00561.x","article-title":"Intralesional administration of epidermal growth factor-based formulation (Heberprot-P) in chronic diabetic foot ulcer: treatment up to complete wound closure","volume":"6","author":"JI Fernandez-Montequin","year":"2009","journal-title":"Int Wound J"},{"issue":"3","key":"pone.0264775.ref028","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.diabres.2007.06.004","article-title":"Recombinant human epidermal growth factor (REGEN-D 150): effect on healing of diabetic foot ulcers","volume":"78","author":"VK Mohan","year":"2007","journal-title":"Diabetes Res Clin Pract"},{"issue":"2","key":"pone.0264775.ref029","doi-asserted-by":"crossref","first-page":"290","DOI":"10.2337\/diacare.24.2.290","article-title":"Apligraf Diabetic Foot Ulcer S. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial","volume":"24","author":"A Veves","year":"2001","journal-title":"Diabetes Care"},{"issue":"6","key":"pone.0264775.ref030","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.2337\/diacare.26.6.1701","article-title":"Dermagraft Diabetic Foot Ulcer Study G. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial","volume":"26","author":"WA Marston","year":"2003","journal-title":"Diabetes Care"},{"issue":"6","key":"pone.0264775.ref031","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1111\/wrr.12357","article-title":"A clinical trial of Integra Template for diabetic foot ulcer treatment.","volume":"23","author":"VR Driver","year":"2015","journal-title":"Wound Repair Regen"},{"key":"pone.0264775.ref032","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/jb.154.1.1-9.1983","article-title":"Plasmid complements of Streptococcus lactis NCDO 712 and other lactic streptococci after protoplast-induced curing","volume":"154","author":"MJ Gasson","year":"1983","journal-title":"Journal of Bacteriology"},{"issue":"11","key":"pone.0264775.ref033","doi-asserted-by":"crossref","first-page":"5663","DOI":"10.1128\/AEM.68.11.5663-5670.2002","article-title":"Use of the alr gene as a food-grade selection marker in lactic acid bacteria","volume":"68","author":"PA Bron","year":"2002","journal-title":"Appl Environ Microbiol"},{"key":"pone.0264775.ref034","doi-asserted-by":"crossref","first-page":"4877","DOI":"10.1128\/aem.63.12.4877-4882.1997","article-title":"A chloride-inducible gene expression cassette and its use in induced lysis of Lactococcus lactis","volume":"63","author":"JW Sanders","year":"1997","journal-title":"Applied and Environmental Microbiology"},{"key":"pone.0264775.ref035","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1046\/j.1365-2958.1998.00676.x","article-title":"A chloride-inducible acid resistance mechanism in Lactococcus lactis and its regulation","volume":"27","author":"JW Sanders","year":"1998","journal-title":"Molecular Microbiology"},{"issue":"10","key":"pone.0264775.ref036","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/nmeth.1701","article-title":"SignalP 4.0: discriminating signal peptides from transmembrane regions","volume":"8","author":"TN Petersen","year":"2011","journal-title":"Nat Methods"},{"issue":"7","key":"pone.0264775.ref037","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1073\/pnas.84.7.1839","article-title":"Multiple forms of basic fibroblast growth factor: amino-terminal cleavages by tumor cell- and brain cell-derived acid proteinases","volume":"84","author":"M Klagsbrun","year":"1987","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"8","key":"pone.0264775.ref038","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/0161-5890(88)90112-5","article-title":"Human macrophage-colony stimulating factor: alternative RNA and protein processing from a single gene","volume":"25","author":"DP Cerretti","year":"1988","journal-title":"Mol Immunol"},{"key":"pone.0264775.ref039","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1007\/BF00280397","article-title":"Functional analysis of the Lactococcus lactis usp45 secretion signal in the secretion of a homologous proteinase and a heterologous alpha-amylase","volume":"240","author":"M van Asseldonk","year":"1993","journal-title":"Molecular and General Genetics"},{"key":"pone.0264775.ref040","doi-asserted-by":"crossref","first-page":"4738","DOI":"10.1128\/JB.182.17.4738-4743.2000","article-title":"The membrane-bound H(+)-ATPase complex is essential for growth of Lactococcus lactis","volume":"182","author":"BJ Koebmann","year":"2000","journal-title":"Journal of Bacteriology"},{"key":"pone.0264775.ref041","doi-asserted-by":"crossref","first-page":"2273","DOI":"10.1128\/jb.174.7.2273-2280.1992","article-title":"Characterization of the Lactococcus lactis lactose operon promoter: contribution of flanking sequences and LacR repressor to promoter activity","volume":"174","author":"RJ van Rooijen","year":"1992","journal-title":"Journal of bacteriology"},{"key":"pone.0264775.ref042","author":"MR Green","year":"2012","journal-title":"Molecular Cloning: a Laboratory Manual"},{"key":"pone.0264775.ref043","first-page":"195","article-title":"Transformation of Lactococcus by electroporation","volume":"47","author":"H Holo","year":"1995","journal-title":"Methods in Molecular Biology"},{"key":"pone.0264775.ref044","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1002\/btpr.277","article-title":"Using highly efficient nonlinear experimental design methods for optimization of Lactococcus lactis fermentation in chemically defined media","volume":"25","author":"G Zhang","year":"2009","journal-title":"Biotechnology progress"},{"issue":"1","key":"pone.0264775.ref045","first-page":"26","article-title":"Biological roles of fibroblast growth factor-2","volume":"18","author":"A Bikfalvi","year":"1997","journal-title":"Endocr Rev"},{"issue":"5","key":"pone.0264775.ref046","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1111\/j.1524-475X.2008.00410.x","article-title":"Growth factors and cytokines in wound healing","volume":"16","author":"S Barrientos","year":"2008","journal-title":"Wound Repair Regen"},{"key":"pone.0264775.ref047","doi-asserted-by":"crossref","first-page":"3803","DOI":"10.1073\/pnas.86.10.3803","article-title":"Potential antiinflammatory effects of interleukin 4: Suppression of human monocyte tumor necrosis factor alpha, interleukin 1, and prostaglandin E2","volume":"86","author":"PH Hart","year":"1989","journal-title":"PNAS"},{"issue":"3","key":"pone.0264775.ref048","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1172\/JCI59643","article-title":"Macrophage plasticity and polarization: in vivo veritas","volume":"122","author":"A Sica","year":"2012","journal-title":"J Clin Invest"},{"issue":"4","key":"pone.0264775.ref049","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1172\/JCI116015","article-title":"Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin 4","volume":"90","author":"AE Postlethwaite","year":"1992","journal-title":"J Clin Invest"},{"issue":"6","key":"pone.0264775.ref050","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1172\/JCI115247","article-title":"Fibroblast chemotaxis induction by human recombinant interleukin-4. Identification by synthetic peptide analysis of two chemotactic domains residing in amino acid sequences 70\u201388 and 89\u2013122","volume":"87","author":"AE Postlethwaite","year":"1991","journal-title":"J Clin Invest"},{"issue":"3","key":"pone.0264775.ref051","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1111\/1523-1747.ep12363346","article-title":"Interleukin 4-induced proliferation in normal human keratinocytes is associated with c-myc gene expression and inhibited by genistein","volume":"107","author":"Y Yang","year":"1996","journal-title":"J Invest Dermatol"},{"issue":"7","key":"pone.0264775.ref052","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1136\/ard.56.7.426","article-title":"Transforming growth factor beta 1 and interleukin 4 induced alpha smooth muscle actin expression and myofibroblast-like differentiation in human synovial fibroblasts in vitro: modulation by basic fibroblast growth factor","volume":"56","author":"DL Mattey","year":"1997","journal-title":"Ann Rheum Dis"},{"issue":"2","key":"pone.0264775.ref053","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1172\/JCI115872","article-title":"Suppression of metalloproteinase biosynthesis in human alveolar macrophages by interleukin-4","volume":"90","author":"S Lacraz","year":"1992","journal-title":"J Clin Invest"},{"issue":"5","key":"pone.0264775.ref054","doi-asserted-by":"crossref","first-page":"2818","DOI":"10.4049\/jimmunol.165.5.2818","article-title":"The Activity of Soluble VCAM-1 in Angiogenesis Stimulated by IL-4 and IL-13","volume":"165","author":"Fukushi Ji","year":"2000","journal-title":"The Journal of Immunology"},{"key":"pone.0264775.ref055","first-page":"370","article-title":"The Many Alternative Faces of Macrophage Activation","volume":"6","author":"DA Hume","year":"2015","journal-title":"Front Immunol"},{"issue":"8","key":"pone.0264775.ref056","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1182\/blood-2011-09-379214","article-title":"Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling","volume":"119","author":"DA Hume","year":"2012","journal-title":"Blood"},{"issue":"2","key":"pone.0264775.ref057","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.cellsig.2013.11.004","article-title":"Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways","volume":"26","author":"D Zhou","year":"2014","journal-title":"Cell Signal"},{"issue":"10","key":"pone.0264775.ref058","doi-asserted-by":"crossref","first-page":"7303","DOI":"10.4049\/jimmunol.177.10.7303","article-title":"Transcriptional Profiling of the Human Monocyte-to-Macrophage Differentiation and Polarization: New Molecules and Patterns of Gene Expression","volume":"177","author":"FO Martinez","year":"2006","journal-title":"The Journal of Immunology"},{"issue":"11","key":"pone.0264775.ref059","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1089\/jir.2005.25.674","article-title":"Paracrine regulation of vascular endothelial growth factor\u2014a expression during macrophage-melanoma cell interaction: role of monocyte chemotactic protein-1 and macrophage colony-stimulating factor","volume":"25","author":"ML Varney","year":"2005","journal-title":"J Interferon Cytokine Res"},{"issue":"22","key":"pone.0264775.ref060","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.1016\/j.vaccine.2008.03.024","article-title":"Innate inflammatory responses to the Gram-positive bacterium Lactococcus lactis","volume":"26","author":"KK Yam","year":"2008","journal-title":"Vaccine"},{"key":"pone.0264775.ref061","doi-asserted-by":"crossref","first-page":"313","DOI":"10.4161\/bbug.1.5.12086","article-title":"Lactococcus lactis as an adjuvant and delivery vehicle of antigens against pneumococcal respiratory infections","volume":"1","author":"M Medina","year":"2010","journal-title":"Bioengineered Bugs"},{"issue":"6","key":"pone.0264775.ref062","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1111\/wrr.12338","article-title":"The murine excisional wound model: Contraction revisited","volume":"23","author":"L Chen","year":"2015","journal-title":"Wound Repair Regen"},{"key":"pone.0264775.ref063","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/1475-2840-11-18","article-title":"A retrospective analysis of amputation rates in diabetic patients: can lower extremity amputations be further prevented?","volume":"11","author":"A Alvarsson","year":"2012","journal-title":"Cardiovasc Diabetol"},{"issue":"3","key":"pone.0264775.ref064","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1007\/s00125-008-1226-2","article-title":"Complexity of factors related to outcome of neuropathic and neuroischaemic\/ischaemic diabetic foot ulcers: a cohort study","volume":"52","author":"MA Gershater","year":"2009","journal-title":"Diabetologia"},{"key":"pone.0264775.ref065","doi-asserted-by":"crossref","first-page":"747618","DOI":"10.3389\/fmicb.2021.747618","article-title":"Alternative Approaches for the Management of Diabetic Foot Ulcers.","volume":"12","author":"C Pouget","year":"2021","journal-title":"Front Microbiol"},{"key":"pone.0264775.ref066","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.humic.2017.09.002","article-title":"The diabetic foot microbiota: A review.","volume":"5\u20136","author":"J Jneid","year":"2017","journal-title":"Human Microbiome Journal"},{"key":"pone.0264775.ref067","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.3389\/fmicb.2017.01791","article-title":"Microbiota of Chronic Diabetic Wounds: Ecology, Impact, and Potential for Innovative Treatment Strategies","volume":"8","author":"SG Pereira","year":"2017","journal-title":"Front Microbiol."},{"key":"pone.0264775.ref068","first-page":"1","article-title":"Introduction of a Qualified Presumption of Safety (QPS) approach for assessment of selected microorganisms referred to EFSA1","volume":"587","author":"EFSA","year":"2007","journal-title":"The EFSA Journal"},{"key":"pone.0264775.ref069","volume-title":"Lactic Acid Bacteria: Microbiological and Functional Aspects.","author":"CRC Press","year":"2019","edition":"5"},{"key":"pone.0264775.ref070","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/978-1-4615-5817-0_6","volume-title":"The Genera of Lactic Acid Bacteria","author":"M Teuber","year":"1995"},{"issue":"3","key":"pone.0264775.ref071","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1080\/00365540110080377","article-title":"Endocarditis caused by Lactococcus cremoris","volume":"34","author":"HD Halldorsdottir","year":"2002","journal-title":"Scand J Infect Dis"},{"issue":"2","key":"pone.0264775.ref072","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s15010-010-9219-3","article-title":"Infective endocarditis complicated by intracerebral hemorrhage due to Lactococcus lactis subsp. cremoris.","volume":"38","author":"KH Lin","year":"2010","journal-title":"Infection"},{"issue":"3","key":"pone.0264775.ref073","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/S1198-743X(14)65148-X","article-title":"Bacterial endocarditis due to Lactococcus lactis subsp. cremoris: case report","volume":"2","author":"G Pellizzer","year":"1996","journal-title":"Clin Microbiol Infect"},{"issue":"1","key":"pone.0264775.ref074","doi-asserted-by":"crossref","first-page":"e8","DOI":"10.1016\/j.ijcard.2006.12.068","article-title":"General aneurysmatosis due to cheese consumption: complications of an endocarditis caused by Lactococcus cremoris","volume":"126","author":"M Resch","year":"2008","journal-title":"Int J Cardiol"},{"key":"pone.0264775.ref075","article-title":"Scientific opinion on the update of the list of QPS-recommended biological agents intentionally added to food or feed as notified to EFSA","author":"EFSA","year":"2017"},{"issue":"6","key":"pone.0264775.ref076","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1007\/s00253-005-0107-6","article-title":"10 years of the nisin-controlled gene expression system (NICE) in Lactococcus lactis","volume":"68","author":"I Mierau","year":"2005","journal-title":"Appl Microbiol Biotechnol"},{"key":"pone.0264775.ref077","unstructured":"Starter Cultures in Food Production. Speranza B, Bevilacqua A, Corbo MR, Sinigaglia M, editors: John Wiley and Sons, Ltd.; 2017."}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0264775","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,18]],"date-time":"2023-11-18T06:13:34Z","timestamp":1700288014000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0264775"}},"subtitle":[],"editor":[{"given":"Jaemin","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,2,28]]},"references-count":77,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2,28]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0264775","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,28]]}}}