{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T14:32:33Z","timestamp":1790087553935,"version":"4.0.1"},"reference-count":53,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2019,9,18]],"date-time":"2019-09-18T00:00:00Z","timestamp":1568764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Chronic ulcers are characterized by loss of substance without a normal tendency towards spontaneous healing. The Wound Bed Preparation Guideline advises that after diagnosis, the expert should correct the biological state of the ulcer micro-environment based on TIME principles (Tissue, Infection, Moisture balance, Epidermal). There are many ways to treat such ulcers, for example through use of advanced dressings, negative pressure, surgical toilets, dermal substitutes, autologous skin grafting, and free or local flaps. In vitro and in vivo pre-clinical models hold widely acknowledged potential yet complex limitations. Tissue bioengineering could be an ideal approach to foster innovative strategies in wound healing. Our observational study reports on an in vitro and in vivo evaluation of a bio-functionalized scaffold composed of platelet-rich plasma (PRP) and hyaluronic acid (HA) used in 182 patients affected by chronic ulcers (diabetic and vascular), comparing the results with a control group of 182 patients treated with traditional dressings (HA alone). After 30 days the patients who had undergone the combined treatment (PRP + HA), showed 96.8% \u00b1 1.5% re-epithelialization, as compared to 78.4% \u00b1 4.4% in the control group (HA only). Within 80 days, they had 98.4% \u00b1 1.3% re-epithelialization as compared to 87.8% \u00b1 4.1% in the control group (HA only; p &lt; 0.05). No local recurrence was observed during the follow-up period. PRP + HA treatment showed stronger regenerative potential in terms of epidermal proliferation and dermal renewal compared with HA alone.<\/jats:p>","DOI":"10.3390\/jcm8091486","type":"journal-article","created":{"date-parts":[[2019,9,18]],"date-time":"2019-09-18T11:01:15Z","timestamp":1568804475000},"page":"1486","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":88,"title":["Wound Healing: In Vitro and In Vivo Evaluation of a Bio-Functionalized Scaffold Based on Hyaluronic Acid and Platelet-Rich Plasma in Chronic Ulcers"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1712-6702","authenticated-orcid":false,"given":"Barbara","family":"De Angelis","sequence":"first","affiliation":[{"name":"Department of Surgical Science, University of Rome Tor Vergata, Rome 00133, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarida Fernandes Lopes Morais","family":"D\u2019Autilio","sequence":"additional","affiliation":[{"name":"Department of Surgical Science, University of Rome Tor Vergata, Rome 00133, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8241-1812","authenticated-orcid":false,"given":"Fabrizio","family":"Orlandi","sequence":"additional","affiliation":[{"name":"Department of Surgical Science, University of Rome Tor Vergata, Rome 00133, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giampiero","family":"Pepe","sequence":"additional","affiliation":[{"name":"Department of Surgical Science, University of Rome Tor Vergata, Rome 00133, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Garcovich","sequence":"additional","affiliation":[{"name":"Institute of Dermatology, F. Policlinico Gemelli IRCSS, Universit\u00e0 Cattolica del Sacro Cuore, Rome 00168, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Giovanna","family":"Scioli","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome 00133, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7202-5854","authenticated-orcid":false,"given":"Augusto","family":"Orlandi","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome 00133, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerio","family":"Cervelli","sequence":"additional","affiliation":[{"name":"Department of Surgical Science, University of Rome Tor Vergata, Rome 00133, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3123-3977","authenticated-orcid":false,"given":"Pietro","family":"Gentile","sequence":"additional","affiliation":[{"name":"Department of Surgical Science, University of Rome Tor Vergata, Rome 00133, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/j.biomaterials.2006.09.012","article-title":"Adult adipose-derived stem cell attachment to biomaterial","volume":"28","author":"Prichard","year":"2007","journal-title":"Biomaterials"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1590\/abd1806-4841.20143004","article-title":"Application of platelet-rich plasma in the treatment of chronic skin ulcer\u2014Case report","volume":"89","author":"Pinto","year":"2014","journal-title":"Anais Bras. Dermatol."},{"key":"ref_3","first-page":"58","article-title":"Wound care bed preparation: Time in practice","volume":"1","author":"Dowsett","year":"2005","journal-title":"Clin. Pract. Dev."},{"key":"ref_4","unstructured":"Chiaretti, M. (2014). Gel piastrinico nel piede diabetico: Case report. Med Estet."},{"key":"ref_5","first-page":"11","article-title":"Platelet rich plasma (PRP) matrix grafts","volume":"8","author":"Crane","year":"2008","journal-title":"Pract. Pain Manag."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Gentile, P., Cole, J.P., Cole, M.A., Garcovich, S., Bielli, A., Scioli, M.G., Orlandi, A., Insalaco, C., and Cervelli, V. (2017). Evaluation of not-activated and activated PRP in hair loss treatment: Role of growth factor and cytokine concentrations obtained by different collection systems. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18020408"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/0738-081X(94)90253-4","article-title":"Management of chronic venous leg ulcers: A literature-guided approach","volume":"12","author":"Margolis","year":"1994","journal-title":"Clin. Dermatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1097\/01.ASW.0000363551.82058.36","article-title":"Tissue regeneration in loss of substance on the lower limbs through use of platelet riche plasma, steem cells from adipose tissue and hyaluronic acid","volume":"23","author":"Cervelli","year":"2010","journal-title":"Adv. Skin Wound Care"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1185\/030079905X56510","article-title":"Second-degree burns: A comparative, multicenter, randomized trial of hyaluronic acid plus silver sulfadiazine vs silver sulfadiazine alone","volume":"21","author":"Costagliola","year":"2005","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5","DOI":"10.12968\/jowc.2010.19.5.48045","article-title":"Use of platelet rich plasma and hyaluronic acid on exposed tendons of the foot and ankle","volume":"19","author":"Cervelli","year":"2010","journal-title":"J. Wound Care"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"23","DOI":"10.2147\/CWCMR.S67054","article-title":"Objective evaluation for venous leg ulcer-related nociceptive pain using thermography","volume":"1","author":"Goto","year":"2014","journal-title":"Chronic Wound Care Manag. Res."},{"key":"ref_12","first-page":"124","article-title":"Use of platelet rich plasma and hyaluronic acid in the treatment of complications of achilles tendon reconstruction","volume":"5","author":"Gentile","year":"2016","journal-title":"World J. Plast. Surg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4321","DOI":"10.1016\/j.biomaterials.2007.05.029","article-title":"A naturally derived, cytocompatible, and architecturally optimized scaffold for tendon and ligament regeneration","volume":"28","author":"Whitlock","year":"2007","journal-title":"Biomaterials"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.ejps.2018.03.024","article-title":"A novel dressing for the combined delivery of platelet lysate and vancomycin hydrochloride to chronic skin ulcers: Hyaluronic acid particles in alginate matrices","volume":"118","author":"Rossi","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.scr.2010.11.003","article-title":"Application of enhanced stromal vascular fraction and fat grafting mixed with PRP in post-traumatic lower extremity ulcers","volume":"6","author":"Cervelli","year":"2011","journal-title":"Stem Cell Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Russo, F., D\u2019Este, M., Vadal\u00e0, G., Cattani, C., Papalia, R., Alini, M., and Denaro, V. (2016). Platelet rich plasma and hyaluronic acid blend for the treatment of osteoarthritis: Rheological and biological evaluation. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0157048"},{"key":"ref_17","first-page":"27","article-title":"Hyaluronic acid induces the release of growth factors from platelet-rich plasma","volume":"28","author":"Iio","year":"2016","journal-title":"Asia Pac. J. Sports Med. Arthrosc. Rehabil. Technol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1097\/01.ASW.0000396302.05959.d3","article-title":"Use of platelet-rich plasma and hyaluronic acid in the loss of substance with bone exposure","volume":"24","author":"Cervelli","year":"2011","journal-title":"Adv. Skin Wound Care"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1111\/1467-8519.00187","article-title":"International research ethics","volume":"14","author":"Schuklenk","year":"2000","journal-title":"Bioethics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.jclinepi.2007.11.008","article-title":"The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies","volume":"61","author":"Altman","year":"2008","journal-title":"J. Clin. Epidemiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1089\/ten.tec.2014.0245","article-title":"Limb rescue: A new autologous-peripheral blood mononuclear cells technology in critical limb ischemia and chronic ulcers","volume":"21","author":"Gentile","year":"2015","journal-title":"Tissue Eng. Part C Methods"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2733","DOI":"10.1089\/ten.2007.0109","article-title":"Hyalomatrix: A temporary epidermal barrier, hyaluronan delivery, and neodermis induction system for keratinocyte stem cell therapy","volume":"13","author":"Myers","year":"2007","journal-title":"Tissue Eng."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1177\/1553350611421022","article-title":"Complex abdominal wall repair using a porcine dermal matrix","volume":"20","author":"Gentile","year":"2013","journal-title":"Surg. Innov."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1007\/s00464-007-9293-x","article-title":"The use of autologous platelet-leukocyte gels to enhance the healing process in surgery, a review","volume":"21","author":"Everts","year":"2007","journal-title":"Surg. Endosc."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1046\/j.1365-2702.2003.00859.x","article-title":"Leg ulcers: A review of their impact on daily life","volume":"13","author":"Persoon","year":"2004","journal-title":"J. Clin. Nurs."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Schaible, H.G. (2006). Peripheral and central mechanisms of pain generation. Analgesia, Springer.","DOI":"10.1007\/978-3-540-33823-9_1"},{"key":"ref_27","first-page":"26","article-title":"Assessing quality of life in patients with chronic leg ulceration using the Medical Outcomes Short Form-36 questionnaire","volume":"49","author":"Franks","year":"2003","journal-title":"Ostomy Wound Manag."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1055\/s-2004-833479","article-title":"Platelet secretory mechanisms","volume":"30","author":"Reed","year":"2004","journal-title":"Seminars in Thrombosis and Hemostasis"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1111\/j.1423-0410.2009.01188.x","article-title":"Not every PRP gel is born equal. Evaluation of growth factor availability for tissues through four PRP-gel preparations: Fibrinet, RegenPRP-Kit, Plateltex and one manual procedure","volume":"97","author":"Mazzucco","year":"2009","journal-title":"Vox Sang."},{"key":"ref_30","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_31","doi-asserted-by":"crossref","first-page":"512","DOI":"10.3389\/fphys.2019.00512","article-title":"Engineered extracellular vesicles from human periodontal-ligament stem cells increase VEGF\/VEGFR2 expression during bone regeneration","volume":"30","author":"Pizzicannella","year":"2019","journal-title":"Front. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1111\/j.1365-4362.1996.tb03650.x","article-title":"Hyaluronic acid and skin: Wound healing and aging","volume":"35","author":"Manusukiatti","year":"1996","journal-title":"Int. J. Dermatol."},{"key":"ref_33","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":"Barrientos","year":"2008","journal-title":"Wound Repair Regen."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1078\/0171-9335-00435","article-title":"Authentic fibroblast matrix in dermal equivalents normalises epidermal histogenesis and dermoepidermal junction in organotypic coculture","volume":"83","author":"Stark","year":"2004","journal-title":"Eur. J. Cell. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2398","DOI":"10.1002\/term.2139","article-title":"Combined treatment with platelet-rich plasma and insulin favours chondrogenic and osteogenic differentiation of human adipose-derived stem cells in three-dimensional collagen scaffolds","volume":"11","author":"Scioli","year":"2017","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"424","DOI":"10.5021\/ad.2011.23.4.424","article-title":"Can platelet-rich plasma be used for skin rejuvenation? Evaluation of effects of platelet-rich plasma on human dermal fibroblast","volume":"23","author":"Kim","year":"2011","journal-title":"Ann. Dermatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1111\/j.1524-475X.2000.00347.x","article-title":"Classifications for wound bed preparation and stimulation of chronic wounds","volume":"8","author":"Falanga","year":"2000","journal-title":"Wound Repair Regen."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"193","DOI":"10.4103\/0970-0358.101277","article-title":"Wound bed preparation from a clinical perspective","volume":"45","author":"Halim","year":"2012","journal-title":"Indian J. Plast. Surg."},{"key":"ref_39","first-page":"2","article-title":"Role of cultured skin fibroblasts in aesthetic and plastic surgery","volume":"2","author":"Mehrabani","year":"2013","journal-title":"World J. Plast. Surg."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1097\/PRS.0b013e3181882046","article-title":"Proliferation promoting effect of platelet-rich plasma on human adipose derived stem cells and human dermal fibroblasts","volume":"122","author":"Kakudo","year":"2008","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"434191","DOI":"10.1155\/2013\/434191","article-title":"P.R.L. platelet rich lipotransfert: Our experience and current state of art in the combined use of fat and PRP","volume":"2013","author":"Cervelli","year":"2013","journal-title":"Biomed. Res. Int."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1177\/1099800414535840","article-title":"Effectiveness of platelet-rich plasma and hyaluronic acid for the treatment and care of pressure ulcers","volume":"17","author":"Ruiz","year":"2015","journal-title":"Biol. Res. Nurs."},{"key":"ref_43","unstructured":"Martin, V., and Maibach, H.I. (2019, September 17). The Principles of Wound Care Bed Preparation. Available online: https:\/\/www.woundsource.com\/."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Mammana, S., Gugliandolo, A., Cavalli, E., Diomede, F., Iori, R., Zappacosta, R., Bramanti, P., Conti, P., Fontana, A., and Pizzicannella, J. (2019). Human gingival mesenchymal stem cells pretreated with vesicular moringin nanostructures as a new therapeutic approach in a mouse model of spinal cord injury. J. Tissue Eng. Regen. Med.","DOI":"10.1002\/term.2857"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.anplas.2007.06.010","article-title":"Bone-anchored implant in cosmetic finger reconstruction","volume":"53","author":"Cervelli","year":"2008","journal-title":"Ann. Chir. Plast. Esthet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1097\/SCS.0b013e31816ae30f","article-title":"The use of bone-anchored implants for absent ear","volume":"19","author":"Gentile","year":"2008","journal-title":"J. Craniofac. Surg."},{"key":"ref_47","first-page":"156","article-title":"Use of platelet growth factors in treating wounds and soft-tissue injuries","volume":"16","author":"Rozman","year":"2007","journal-title":"Acta Dermatovenerol. Alp. Panonica Adriat."},{"key":"ref_48","first-page":"468","article-title":"The topicality and use of the radiological exam in gunshot wounds of the limbs an assessment of 132 cases","volume":"98","author":"Salzano","year":"1999","journal-title":"Radiol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.tibtech.2004.12.003","article-title":"The growing importance of fat in regenerative medicine","volume":"23","author":"Strem","year":"2005","journal-title":"Trends Biotechnol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"American Society of Anesthesiologists Task Force on Acute Pain Management (2012). Practice guidelines for acute pain management in the perioperative setting an updated report by the American society of anesthesiologists task force on acute pain management. Anesthesiology, 116, 248\u2013273.","DOI":"10.1097\/ALN.0b013e31823c1030"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"97","DOI":"10.4103\/0974-2077.112671","article-title":"Autologous platelet rich plasma in chronic venous ulcers: Study of 17 cases","volume":"6","author":"Sarvajnamurthy","year":"2013","journal-title":"J. Cutan. Aesth. Surg."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1111\/iwj.12117","article-title":"Severe hidradenitis suppurativa treatment using platelet-rich plasma gel and Hyalomatrix","volume":"12","author":"Nicoli","year":"2015","journal-title":"Int. Wound J."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e406","DOI":"10.1097\/GOX.0000000000000285","article-title":"Breast reconstruction with enhanced stromal vascular fraction fat grafting: What is the best method?","volume":"8","author":"Gentile","year":"2015","journal-title":"Plast. Reconstr. Surg. Glob. Open"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/9\/1486\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:21:23Z","timestamp":1760188883000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/9\/1486"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,18]]},"references-count":53,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2019,9]]}},"alternative-id":["jcm8091486"],"URL":"https:\/\/doi.org\/10.3390\/jcm8091486","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,18]]}}}