Therapeutic Effectiveness of Leukocyte- and Platelet-rich Fibrin for Diabetic Foot Ulcers: A Retrospective Study

Abstract

Objective

Diabetic foot ulcer (DFU) is one of the most serious complications of diabetes. Leukocyte- and platelet-rich fibrin (L-PRF) is a second-generation autologous platelet-rich plasma. This study aims to investigate the clinical effects of L-PRF in patients with diabetes in real clinical practice.

Methods

Patients with DFU who received L-PRF treatment and standard of care (SOC) from 2018 to 2019 in Tongji Hospital were enrolled. The clinical information including patient characteristics, wound evaluation (area, severity, infection, blood supply), SOC of DFU, and images of ulcers was retrospectively extracted and analyzed. L-PRF treatment was performed every 7±2 days until the ulcer exhibited complete epithelialization or an overall percent volume reduction (PVR) greater than 80%. Therapeutic effectiveness, including overall PVR and the overall and weekly healing rates, was evaluated.

Results

Totally, 26 patients with DFU were enrolled, and they had an ulcer duration of 47.0 (35.0, 72.3) days. The severity and infection of ulcers varied, as indicated by the Site, Ischemia, Neuropathy, Bacterial Infection, and Depth (SINBAD) scores of 2–6, Wagner grades of 1–4, and the Perfusion, Extent, Depth, Infection and Sensation (PEDIS) scores of 2–4. The initial ulcer volume before L-PRF treatment was 4.94 (1.50, 13.83) cm³, and the final ulcer volume was 0.35 (0.03, 1.76) cm³. The median number of L-PRF doses was 3 (2, 5). A total of 11 patients achieved complete epithelialization after the fifth week of treatment, and 19 patients achieved at least an 80% volume reduction after the seventh week. The overall wound-healing rate was 1.47 (0.63, 3.29) cm³/week, and the healing rate was faster in the first 2 weeks than in the remaining weeks. Concurrent treatment did not change the percentage of complete epithelialization or healing rate.

Conclusion

Adding L-PRF to SOC significantly improved wound healing in patients with DFU independent of the ankle brachial index, SINBAD score, or Wagner grade, indicating that this method is appropriate for DFU treatment under different clinical conditions.

References

[1] LipskyBA, BerendtAR, CorniaPB, et al.. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis, 2012, 54(12): e132-e173

[2] LaveryLA, ArmstrongDG, WunderlichRP, et al.. Diabetic foot syndrome: evaluating the prevalence and incidence of foot pathology in Mexican Americans and non-Hispanic whites from a diabetes disease management cohort. Diabetes Care, 2003, 26(5): 1435-1438

[3] ZhangP, LuJ, JingY, et al.. Global epidemiology of diabetic foot ulceration: a systematic review and meta-analysis (dagger). Ann Med, 2017, 49(2): 106-116

[4] DingY, CuiL, ZhaoQ, et al.. Platelet-Rich Fibrin Accelerates Skin Wound Healing in Diabetic Mice. Ann Plast Surg, 2017, 79(3): e15-e19

[5] SchaperNC, Van NettenJJ, ApelqvistJ, et al.. International Working Group on the Diabetic F. Prevention and management of foot problems in diabetes: a Summary Guidance for Daily Practice 2015, based on the IWGDF Guidance Documents. Diabetes Metab Res Rev, 2016, 32(Suppl1): 7-15

[6] JiangY, WangX, XiaL, et al.. A cohort study of diabetic patients and diabetic foot ulceration patients in China. Wound Repair Regen, 2015, 23(2): 222-230

[7] ArmstrongDG, BoultonAJM, BusSA. Diabetic Foot Ulcers and Their Recurrence. N Engl J Med, 2017, 376(24): 2367-2375

[8] ShaoS, PanR, ChenY. Autologous Platelet-Rich Plasma for Diabetic Foot Ulcer. Trends Endocrinol Metab, 2020, 31(12): 885-890

[9] Dohan EhrenfestDM, de PeppoGM, DoglioliP, et al.. Slow release of growth factors and thrombospondin-1 in Choukroun’s platelet-rich fibrin (PRF): a gold standard to achieve for all surgical platelet concentrates technologies. Growth Factors, 2009, 27(1): 63-69

[10] ChoukrounJ, AddaF, SchoefflerC, et al.Une opportunité en paro-implantologie: le PRF. Implantodontie, 2001, 42(55): e62

[11] DasN, Janardhana AmaranathBJ. Quantitative evaluation of modified advanced platelet-rich fibrin buffy coat among diabetic patients and tobacco smokers with chronic periodontitis. J Indian Soc Periodontol, 2022, 26(1): 24-31

[12] ChandraV, BainsVK, JhingranR, et al.. Comparative Evaluation of Platelet-Rich Fibrin versus Connective Tissue Grafting in Treatment of Gingival Recession Using Pouch and Tunnel Technique: A Randomized Clinical Study. Contemp Clin Dent, 2022, 13(3): 217-226

[13] CevolaniL, BianchiG, CostantinoE, et al.. Minimally invasive treatment of long bone non-unions with bone marrow concentrate, demineralized bone matrix and platelet-rich fibrin in 38 patients. J Tissue Eng Regen Med, 2021, 15(10): 831-840

[14] PintoNR, UbillaM, ZamoraY, et al.. Leucocyte- and plateletrich fibrin (L-PRF) as a regenerative medicine strategy for the treatment of refractory leg ulcers: a prospective cohort study. Platelets, 2018, 29(5): 468-475

[15] NapitIB, ShresthaD, BishopJ, et al.. An individual randomised efficacy trial of autologous blood products, leukocyte and platelet-rich fibrin (L-PRF), to promote ulcer healing in leprosy in Nepal: the TABLE trial protocol. Trials, 2021, 22(1): 453

[16] LondahlM, TarnowL, KarlsmarkT, et al.. Use of an autologous leucocyte and platelet-rich fibrin patch on hard-to-heal DFUs: a pilot study. J Wound Care, 2015, 24(4): 172-174

[17] KartikaRW, AlwiI, SuyatnaFD, et al.. Wound Healing in Diabetic Foot Ulcer Patients Using Combined Use of Platelet Rich Fibrin and Hyaluronic Acid, Platelet Rich Fibrin and Placebo: An Open Label, Randomized Controlled Trial. Acta Med Indones, 2021, 53(3): 268-275

[18] YarahmadiA, Saeed ModagheghMH, Mostafavi-PourZ, et al.. The effect of platelet-rich plasma-fibrin glue dressing in combination with oral vitamin E and C for treatment of non-healing diabetic foot ulcers: a randomized, doubleblind, parallel-group, clinical trial. Expert Opin Biol Ther, 2021, 21(5): 687-696

[19] WangYQ, WangXT, ChenR, et al.. The Role of Leukocyte- Platelet-Rich Fibrin in Promoting Wound Healing in Diabetic Foot Ulcers. Int J Low Extrem Wounds, 2024, 23(2): 306-314

[20] AlbertiKG, ZimmetPZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med, 1998, 15(7): 539-553

[21] St-SuperyV, TahiriY, SampalisJ, et al.. Wound healing assessment: does the ideal methodology for a research setting exist?. Ann Plast Surg, 2011, 67(2): 193-200

[22] WangA, LvG, ChengX, et al.. Guidelines on multidisciplinary approaches for the prevention and management of diabetic foot disease (2020 edition). Burns Trauma, 2020, 8: tkaa017

[23] Monteiro-SoaresM, RussellD, BoykoEJ, et al.. Guidelines on the classification of diabetic foot ulcers ^(IWGDF 2019). Diabetes Metab Res Rev, 2020, 36(Suppl1): e3273

[24] ChuanF, TangK, JiangP, et al.. Reliability and validity of the perfusion, extent, depth, infection and sensation (PEDIS) classification system and score in patients with diabetic foot ulcer. PLoS One, 2015, 1(4): e0124739

[25] LiC, ZhangJ, WangF, et al.. Leukocyte- and platelet-rich fibrin treatment of chronic lower extremity ulcer in a patient with systemic lupus erythematosus: a case report. Wounds, 2023, 35(1): E1-E6

[26] TurhalG, OzturkA, KirazliT, et al.. A Comparative Study: Platelet-Rich Fibrin Packing as an Alternative to the Absorbable Gelatine in Tympanoplasty. J Int Adv Otol, 2022, 18(5): 405-410

[27] PicardF, HersantB, BoscR, et al.. The growing evidence for the use of platelet-rich plasma on diabetic chronic wounds: A review and a proposal for a new standard care. Wound Repair Regen, 2015, 23(5): 638-643

[28] Moreno-SerranoA, Garcia-DiazJJ, Ferrer-MarquezM, et al.. Using autologous platelet-rich plasma for the treatment of complex fistulas. Rev Esp Enferm Dig, 2016, 108(3): 123-128

[29] PonteAL, MaraisE, GallayN, et al.. The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells, 2007, 25(7): 1737-1745

[30] ElsaidA, El-SaidM, EmileS, et al.. Randomized Controlled Trial on Autologous Platelet-Rich Plasma Versus Saline Dressing in Treatment of Non-healing Diabetic Foot Ulcers. World J Surg, 2020, 44(4): 1294-1301

[31] DriverVR, HanftJ, FyllingCP, et al.. A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers. Ostomy Wound Manage, 2006, 52(6): 68-70

[32] SakataJ, SasakiS, HandaK, et al.. A retrospective, longitudinal study to evaluate healing lower extremity wounds in patients with diabetes mellitus and ischemia using standard protocols of care and platelet-rich plasma gel in a Japanese wound care program. Ostomy Wound Manage, 2012, 58(4): 36-49

[33] ShanGQ, ZhangYN, MaJ, et al.. Evaluation of the effects of homologous platelet gel on healing lower extremity wounds in patients with diabetes. Int J Low Extrem Wounds, 2013, 12(1): 22-29

[34] AhmedM, ReffatSA, HassanA, et al.. Platelet-Rich Plasma for the Treatment of Clean Diabetic Foot Ulcers. Ann Vasc Surg, 2017, 38: 206-211

[35] SaldalamacchiaG, LapiceE, CuomoV, et al.. A controlled study of the use of autologous platelet gel for the treatment of diabetic foot ulcers. Nutr Metab Cardiovasc Dis, 2004, 14(6): 395-396

[36] HossamEM, AlserrAHK, AntonopoulosCN, et al.. Autologous Platelet Rich Plasma Promotes the Healing of Non-Ischemic Diabetic Foot Ulcers. A Randomized Controlled Trial. Ann Vasc Surg, 2022, 82: 165-171

[37] SteedDL, GoslenJB, HollowayGA, et al.. Randomized prospective double-blind trial in healing chronic diabetic foot ulcers. CT-102 activated platelet supernatant, topical versus placebo. Diabetes Care, 1992, 15(11): 1598-1604

[38] XiongG, LingampalliN, KoltsovJCB, et al.. Men and Women Differ in the Biochemical Composition of Platelet-Rich Plasma. Am J Sports Med, 2018, 46(2): 409-419

[39] VorstandlechnerV, LaggnerM, CopicD, et al.. The serine proteases dipeptidyl-peptidase 4 and urokinase are key molecules in human and mouse scar formation. Nat Commun, 2021, 12(1): 6242

[40] LongM, CaiL, LiW, et al.. DPP-4 Inhibitors Improve Diabetic Wound Healing via Direct and Indirect Promotion of Epithelial- Mesenchymal Transition and Reduction of Scarring. Diabetes, 2018, 67(3): 518-531

[41] ShihCM, HuangCY, HuangCY, et al.. A dipeptidyl peptidase-4 inhibitor promotes wound healing in normoglycemic mice by modulating keratinocyte activity. Exp Dermatol, 2018, 27(10): 1134-1141

[42] EtulainJ, MenaHA, MeissRP, et al.. An optimised protocol for platelet-rich plasma preparation to improve its angiogenic and regenerative properties. Sci Rep, 2018, 8(1): 1513