Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC1807110.15690/vramn18071РATHOPHYSIOLOGY: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ ПАТОФИЗИОЛОГИИReview ArticleA modern view of the problem of NETosis-associated diseasesСовременный взгляд на проблему нетоз-ассоциированных заболеванийhttps://orcid.org/0000-0003-2786-6181DobrokhotovaYuliya E.ДоброхотоваЮлия Эдуардовна
Russian Federation

MD, PhD, Professor

д.м.н., профессор

pr.dobrohotova@mail.ruhttps://orcid.org/0000-0001-7140-262X8897-8605BorovkovaEkaterina I.БоровковаЕкатерина Игоревна
Russian Federation

MD, PhD, Assistant Professor

д.м.н., доцент

Katyanikitina@mail.ruhttps://orcid.org/0009-0005-8515-64466479-8529KlaushukVladislava I.КлаушукВладислава Игоревна
Russian Federation

PhD Student

аспирант

doc.klaushuk@mail.ruhttps://orcid.org/0000-0001-5592-56909893-2630NizyaevaNatalia V.НизяеваНаталья Викторовна
Russian Federation

MD, PhD

д.м.н.

niziaeva@gmail.comhttps://orcid.org/0000-0002-1014-752X2057-7745ArtemevaKsenia A.АртемьеваКсения Александровна
Russian Federation

MD, PhD, Leading Researcher

к.м.н., ведущий научный сотрудник

artemjeva_ksenia@mail.ruhttps://orcid.org/0009-0009-9235-7384IakovlevaAlina N.ЯковлеваАлина Николаевна
Russian Federation

Resident

ординатор

A_L_I_N_A_0505@mail.ruPirogov Russian National Research Medical University (Pirogov Medical University)Российский национальный исследовательский медицинский университет им. Н.И. ПироговаThe Russian Scientific Center of Surgery Named after Academician B.V. PetrovskyРоссийский научный центр хирургии имени академика Б.В. Петровского051220258042752870404202504102025Copyright ©; 2025, "Paediatrician" Publishers LLCCopyright ©; 2025, Издательство "Педиатръ"2025"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/about/submissionshttps://vestnikramn.spr-journal.ru/jour/article/view/18071

Neutrophilic granulocytes play an important role in the realization of innate immunity. In 2004, the phenomenon of netosis was discovered, accompanied by the release of neutrophil extracellular traps (NETs). Since then, a large number of studies have accumulated on their structure and function in pathological conditions. The purpose of this review is to highlight scientific achievements in the field of netosis research. The contribution of NETs to the pathogenesis of tissue alteration, inflammation, and thromboembolic complications was assessed. The main netosis-associated diseases in which the concentration of circulating NETs components such as extracellular DNA, myeloperoxidase, neutrophil elastase, and histones is increased have been identified. The basic information about the success of therapeutic drugs that destroy NETs structures is summarized. The diagnostic and prognostic value of NETs detection in the development of a wide range of diseases is shown. The presented material emphasizes the need to study NETs-associated diseases as a promising area for a doctor's practice.

Нейтрофильные гранулоциты играют важную роль в реализации врожденного иммунитета. В 2004 г. было открыто явление нетоза, сопровождающееся выделением нейтрофильных внеклеточных ловушек (NETs). С тех пор накопилось большое количество исследований об их строении и функциях при патологических состояниях. Целью данного обзора является освещение научных достижений в области исследования нетоза. Оценен вклад NETs в патогенез альтерации тканей, воспаления и тромбоэмболических осложнений. Выделены основные нетоз-ассоциированные заболевания, при которых повышена концентрация циркулирующих компонентов NETs, таких как внеклеточная ДНК, миелопероксидаза, нейтрофильная эластаза и гистоны. Обобщены основные сведения об успешности применения терапевтических препаратов, разрушающих структуры NETs. Показана диагностическая и прогностическая ценность выявления NETs в развитии широкого круга заболеваний. Изложенный материал подчеркивает необходимость изучения нетоз-ассоциированных заболеваний как перспективное направление для практической деятельности врача.

neutrophilneutrophil extracellular trapNETsNETosisнейтрофилынейтрофильные внеклеточные ловушкиNETsнетозBrinkmann V. Neutrophil Extracellular Traps in the Second Decade. J Innate Immun. 2018;10(5-6):414–421. doi: https://doi.org/10.1159/000489829Ravindran M, Khan MA, Palaniyar N. Neutrophil Extracellular Trap Formation: Physiology, Pathology, and Pharmacology. Biomolecules. 2019;9(8):365. doi: https://doi.org/10.3390/biom9080365Воробьева Н.В. Нейтрофильные внеклеточные ловушки: новые аспекты // Вестник Московского университета. Серия 16. Биология. — 2020. — Т. 75. — № 4. — С. 210–225. [Vorobjeva NV. Neutrophil extracellular traps: new aspects. Vestnik Moskovskogo universiteta. Seriya 16. Biologiya. 2020;75(4):210–225. (In Russ.)].Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol. 2018;18(2):134–147. doi: https://doi.org/10.1038/nri.2017.105Zhu CL, Wang Y, Liu Q, et al. Dysregulation of neutrophil death in sepsis. Front Immunol. 2022;13:963955. doi: https://doi.org/10.3389/fimmu.2022.963955Noreng S, Ota N, Sun Y, et al. Structure of the core human NADPH oxidase NOX2. Nat Commun. 2022;13(1):6079. doi: https://doi.org/10.1038/s41467-022-33711-0Poli V, Zanoni I. Neutrophil intrinsic and extrinsic regulation of NETosis in health and disease. Trends Microbiol. 2023;31(3):280–293. doi: https://doi.org/10.1016/j.tim.2022.10.002Guillotin F, Fortier M, Portes M, et al. Vital NETosis vs. suicidal NETosis during normal pregnancy and preeclampsia. Front Cell Dev Biol. 2023;10:1099038. doi: https://doi.org/10.3389/fcell.2022.1099038Thiam HR, Wong SL, Wagner DD, et al. Cellular Mechanisms of NETosis. Annu Rev Cell Dev Biol. 2020;36:191–218. doi: https://doi.org/10.1146/annurev-cellbio-020520-111016Tatsiy O, McDonald PP. Physiological Stimuli Induce PAD4-Dependent, ROS-Independent NETosis, With Early and Late Events Controlled by Discrete Signaling Pathways. Front Immunol. 2018;9:2036. doi: https://doi.org/10.3389/fimmu.2018.02036Majewski P, Majchrzak-Gorecka M, Grygier B, et al. Inhibitors of Serine Proteases in Regulating the Production and Function of Neutrophil Extracellular Traps. Front Immunol. 2016;7:261. doi: https://doi.org/10.3389/fimmu.2016.00261Gupta AK, Hasler P, Holzgreve W, et al. Neutrophil NETs: a novel contributor to preeclampsia-associated placental hypoxia? Semin Immunopathol. 2007;29(2):163–167. doi: https://doi.org/10.1007/s00281-007-0073-4Döring Y, Soehnlein O, Weber C. Neutrophil Extracellular Traps in Atherosclerosis and Atherothrombosis. Circ Res. 2017;120(4):736–743. doi: https://doi.org/10.1161/CIRCRESAHA.116.309692Moser G, Guettler J, Forstner D, et al. Maternal Platelets — Friend or Foe of the Human Placenta? Int J Mol Sci. 2019;20(22):5639. doi: https://doi.org/10.3390/ijms20225639Pfeiler S, Stark K, Massberg S, et al. Propagation of thrombosis by neutrophils and extracellular nucleosome networks. Haematologica. 2017;102(2):206–213. doi: https://doi.org/10.3324/haematol.2016.142471Xu X, Wu Y, Xu S, et al. Clinical significance of neutrophil extracellular traps biomarkers in thrombosis. Thromb J. 2022;20(1):63. doi: https://doi.org/10.1186/s12959-022-00421-yZhu S, Yu Y, Qu M, et al. Neutrophil extracellular traps contribute to immunothrombosis formation via the STING pathway in sepsis-associated lung injury. Cell Death Discov. 2023;9(1):315. doi: https://doi.org/10.1038/s41420-023-01614-8Warnatsch A, Ioannou M, Wang Q, et al. Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science. 2015;349(6245):316–320. doi: https://doi.org/10.1126/science.aaa8064Molinaro R, Yu M, Sausen G, et al. Targeted delivery of protein arginine deiminase-4 inhibitors to limit arterial intimal NETosis and preserve endothelial integrity. Cardiovasc Res. 2021;117(13):2652–2663. doi: https://doi.org/10.1093/cvr/cvab074Zhu S, Yu Y, Qu M, et al. Neutrophil extracellular traps contribute to immunothrombosis formation via the STING pathway in sepsis-associated lung injury. Cell Death Discov. 2023;9(1):315. doi: https://doi.org/10.1038/s41420-023-01614-8Tóth E, Beinrohr L, Gubucz I, et al. Fibrin to von Willebrand factor ratio in arterial thrombi is associated with plasma levels of inflammatory biomarkers and local abundance of extracellular DNA. Thromb Res. 2022;209:8–15. doi: https://doi.org/10.1016/j.thromres.2021.11.011Borissoff JI, Joosen IA, Versteylen MO, et al. Elevated levels of circulating DNA and chromatin are independently associated with severe coronary atherosclerosis and a prothrombotic state. Arterioscler Thromb Vasc Biol. 2013;33(8):2032–2040. doi: https://doi.org/10.1161/ATVBAHA.113.301627Maugeri N, Campana L, Gavina M, et al. Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps. J Thromb Haemost. 2014;12(12):2074–2088. doi: https://doi.org/10.1111/jth.12710Ge L, Zhou X, Ji WJ, et al. Neutrophil extracellular traps in ischemia-reperfusion injury-induced myocardial no-reflow: therapeutic potential of DNase-based reperfusion strategy. Am J Physiol Heart Circ Physiol. 2015;308(5):H500-9. doi: https://doi.org/10.1152/ajpheart.00381.2014Laridan E, Denorme F, Desender L, et al. Neutrophil extracellular traps in ischemic stroke thrombi. Ann Neurol. 2017;82(2):223–232. doi: https://doi.org/10.1002/ana.24993Essig F, Kollikowski AM, Pham M, et al. Immunohistological analysis of neutrophils and neutrophil extracellular traps in human thrombemboli causing acute ischemic stroke. Int J Mol Sci. 2020;21(19):7387. doi: https://doi.org/10.3390/ijms21197387Zhou P, Li T, Jin J, et al. Interactions between neutrophil extracellular traps and activated platelets enhance procoagulant activity in acute stroke patients with ICA occlusion. EBioMedicine. 2020;53:102671. doi: https://doi.org/10.1016/j.ebiom.2020.102671de Vries JJ, Autar ASA, van Dam-Nolen DHK, et al. Association between plaque vulnerability and neutrophil extracellular traps (NETs) levels: The Plaque at RISK study. PLoS One. 2022;17(6):e0269805. doi: https://doi.org/10.1371/journal.pone.0269805Donkel SJ, Wolters FJ, Ikram MA, et al. Circulating Myeloperoxidase (MPO)-DNA complexes as marker for Neutrophil Extracellular Traps (NETs) levels and the association with cardiovascular risk factors in the general population. PLoS One. 2021;16(8):e0253698. doi: https://doi.org/10.1371/journal.pone.0253698Sabbatini M, Bona E, Novello G, et al. Aging hampers neutrophil extracellular traps (NETs) efficacy. Aging Clin Exp Res. 2022;34(10):2345–2353. doi: https://doi.org/10.1007/s40520-022-02201-0Martos L, Oto J, Fernández-Pardo Á, et al. Increase of Neutrophil Activation Markers in Venous Thrombosis-Contribution of Circulating Activated Protein C. Int J Mol Sci. 2020;21(16):5651. doi: https://doi.org/10.3390/ijms21165651Zhou Y, Tao W, Shen F, et al. The Emerging Role of Neutrophil Extracellular Traps in Arterial, Venous and Cancer-Associated Thrombosis. Front Cardiovasc Med. 2021;8:786387. doi: https://doi.org/10.3389/fcvm.2021.786387Cugno M, Meroni PL, Gualtierotti R, et al. Complement activation in patients with COVID-19: A novel therapeutic target. J Allergy Clin Immunol. 2020;146(1):215–217. doi: https://doi.org/10.1016/j.jaci.2020.05.006Veras FP, Pontelli MC, Silva CM, et al. SARS-CoV- 2-triggered neutrophil extracellular traps mediate COVID-19 pathology. J Exp Med. 2020;217(12):e20201129. doi: https://doi.org/10.1084/jem.20201129Leppkes M, Knopf J, Naschberger E, et al. Vascular occlusion by neutrophil extracellular traps in COVID-19. EBioMedicine. 2020;58:102925. doi: https://doi.org/10.1016/j.ebiom.2020.102925Ackermann M, Anders HJ, Bilyy R, et al. Patients with COVID-19: in the dark-NETs of neutrophils. Cell Death Differ. 2021;28(11):3125–3139. doi: https://doi.org/10.1038/s41418-021-00805-zMai SHC, Khan M, Dwivedi DJ, et al. Delayed but not early treatment with DNase reduces organ damage and improves outcome in a murine model of sepsis. Shock. 2015;44(2):166–172. doi: https://doi.org/10.1097/SHK.0000000000000396Boufenzer A, Carrasco K, Jolly L, et al. Potentiation of NETs release is novel characteristic of TREM-1 activation and the pharmacological inhibition of TREM-1 could prevent from the deleterious consequences of NETs release in sepsis. Cell Mol Immunol. 2021;18(2):452–460. doi: https://doi.org/10.1038/s41423-020-00591-7Yu AP, Tam BT, Yau WY, et al. Association of endothelin-1 and matrix metallopeptidase-9 with metabolic syndrome in middle-aged and older adults. Diabetol Metab Syndr. 2015;7:111. doi: https://doi.org/10.1186/s13098-015-0108-2van der Velden S, van Osch TLJ, Seghier A, et al. Complement activation drives antibody-mediated transfusion-related acute lung injury via macrophage trafficking and formation of NETs. Blood. 2024;143(1):79–91. doi: https://doi.org/10.1182/blood.2023020484Scozzi D, Liao F, Krupnick AS, et al. The role of neutrophil extracellular traps in acute lung injury. Front Immunol. 2022;13:953195. doi: https://doi.org/10.3389/fimmu.2022.953195Poto R, Loffredo S, Palestra F, et al. Angiogenesis, Lymphangiogenesis, and Inflammation in Chronic Obstructive Pulmonary Disease (COPD): Few Certainties and Many Outstanding Questions. Cells. 2022;11(10):1720. doi: https://doi.org/10.3390/cells11101720Papayannopoulos V, Staab D, Zychlinsky A. Neutrophil elastase enhances sputum solubilization in cystic fibrosis patients receiving DNase therapy. PLoS One. 2011;6(12):e28526. doi: https://doi.org/10.1371/journal.pone.0028526Dinallo V, Marafini I, Di Fusco D, et al. Neutrophil Extracellular Traps Sustain Inflammatory Signals in Ulcerative Colitis. J Crohns Colitis. 2019;13(6):772–784. doi: https://doi.org/10.1093/ecco-jcc/jjy215Zhou GX, Liu ZJ. Potential roles of neutrophils in regulating intestinal mucosal inflammation of inflammatory bowel disease. J Dig Dis. 2017;18(9):495–503. doi: https://doi.org/10.1111/1751-2980.12540Lu H, Lin J, Xu C, et al. Cyclosporine modulates neutrophil functions via the SIRT6-HIF-1α-glycolysis axis to alleviate severe ulcerative colitis. Clin Transl Med. 2021;11(2):e334. doi: https://doi.org/10.1002/ctm2.334Kapel N, Ouni H, Benahmed NA, et al. Fecal Calprotectin for the Diagnosis and Management of Inflammatory Bowel Diseases. Clin Transl Gastroenterol. 2023;14(9):e00617. doi: https://doi.org/10.14309/ctg.0000000000000617Fa P, Ke BG, Dupre A, et al. The implication of neutrophil extracellular traps in nonalcoholic fatty liver disease. Front Immunol. 2023;14:1292679. doi: https://doi.org/10.3389/fimmu.2023.1292679Казимирский А.Н., Салмаси Ж.М., Порядин Г.В., и др. Новые возможности диагностики и исследования патогенеза различных видов воспаления // Патологическая физиология и экспериментальная терапия. — 2022. — Т. 66. — № 2. — С. 34–42. [Kazimirskii AN, Salmasi JM, Poryadin GV, et al. New opportunities for diagnosis and investigation of the pathogenesis of various types of inflammation. Patologicheskaya Fiziologiya i Eksperimental`naya terapiya. (Pathological Physiology and Experimental Therapy, Russian Journal). 2022;66(2):34–42. (In Russ.)] doi: https://doi.org/10.25557/0031-2991.2022.02.34-42Lee KH, Kronbichler A, Park DD, et al. Neutrophil extracellular traps (NETs) in autoimmune diseases: A comprehensive review. Autoimmun Rev. 2017;16(11):1160–1173. doi: https://doi.org/10.1016/j.autrev.2017.09.012Bruschi M, Bonanni A, Petretto A, et al. Neutrophil Extracellular Traps Profiles in Patients with Incident Systemic Lupus Erythematosus and Lupus Nephritis. J Rheumatol. 2020;47(3):377–386. doi: https://doi.org/10.3899/jrheum.181232Moore S, Juo HH, Nielsen CT, et al. Role of Neutrophil Extracellular Traps Regarding Patients at Risk of Increased Disease Activity and Cardiovascular Comorbidity in Systemic Lupus Erythematosus. J Rheumatol. 2020;47(11):1652–1660. doi: https://doi.org/10.3899/jrheum.190875Mutua V, Gershwin LJ. A Review of Neutrophil Extracellular Traps (NETs) in Disease: Potential Anti-NETs Therapeutics. Clin Rev Allergy Immunol. 2021;61(2):194–211. doi: https://doi.org/10.1007/s12016-020-08804-7Salemme R, Peralta LN, Meka SH, et al. The Role of NETosis in Systemic Lupus Erythematosus. J Cell Immunol. 2019;1(2):33–42. doi: https://doi.org/10.33696/immunology.1.008Kumar SV, Kulkarni OP, Mulay SR, et al. Neutrophil Extracellular Trap-Related Extracellular Histones Cause Vascular Necrosis in Severe GN. J Am Soc Nephrol. 2015;26(10):2399–2413. doi: https://doi.org/10.1681/ASN.2014070673Wu X, You D, Pan M, et al. Knockout of the C3a receptor protects against renal ischemia reperfusion injury by reduction of NETs formation. Cell Mol Life Sci. 2023;80(11):322. doi: https://doi.org/10.1007/s00018-023-04967-6Vecchio F, Lo Buono N, Stabilini A, et al. Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes. JCI Insight. 2018;3(18):e122146. doi: https://doi.org/10.1172/jci.insight.122146Skoglund C, Appelgren D, Johansson I, et al. Increase of Neutrophil Extracellular Traps, Mitochondrial DNA and Nuclear DNA in Newly Diagnosed Type 1 Diabetes Children but Not in High-Risk Children. Front Immunol. 2021;12:628564. doi: https://doi.org/10.3389/fimmu.2021.628564Aukrust SG, Holte KB, Opstad TB, et al. NETosis in Long-Term Type 1 Diabetes Mellitus and Its Link to Coronary Artery Disease. Front Immunol. 2022;12:799539. doi: https://doi.org/10.3389/fimmu.2021.799539Njeim R, Azar WS, Fares AH, et al. NETosis contributes to the pathogenesis of diabetes and its complications. J Mol Endocrinol. 2020;65(4):R65–R76. doi: https://doi.org/10.1530/JME-20-0128Masucci MT, Minopoli M, Del Vecchio S, et al. The Emerging Role of Neutrophil Extracellular Traps (NETs) in Tumor Progression and Metastasis. Front Immunol. 2020;11:1749. doi: https://doi.org/10.3389/fimmu.2020.01749Слуханчук Е.В. NETs и онкологический процесс // Акушерство, Гинекология и Репродукция. — 2021. — Т. 15. — № 1. — С. 107–116. [Slukhanchuk EV. NETs and oncologic process. Obstetrics, Gynecology and Reproduction. 2021;15(1):107–116. (In Russ.)] doi: https://doi.org/10.17749/2313-7347/ob.gyn.rep.2021.204Furumaya C, Martinez-Sanz P, Bouti P, et al. Plasticity in Pro- and Anti-tumor Activity of Neutrophils: Shifting the Balance. Front Immunol. 2020;11:2100. doi: https://doi.org/10.3389/fimmu.2020.02100Munir H, Jones JO, Janowitz T, et al. Stromal-driven and Amyloid β-dependent induction of neutrophil extracellular traps modulates tumor growth. Nat Commun. 2021;12(1):683. doi: https://doi.org/10.1038/s41467-021-20982-2Shinde-Jadhav S, Mansure JJ, Rayes RF, et al. Role of neutrophil extracellular traps in radiation resistance of invasive bladder cancer. Nat Commun. 2021;12(1):2776. doi: https://doi.org/10.1038/s41467-021-23086-zOrtiz-Espinosa S, Morales X, Senent Y, et al. Complement C5a induces the formation of neutrophil extracellular traps by myeloid-derived suppressor cells to promote metastasis. Cancer Lett. 2022;529:70–84. doi: https://doi.org/10.1016/j.canlet.2021.12.027Castell SD, Harman MF, Morón G, et al. Neutrophils which Migrate to Lymph Nodes Modulate CD4+ T Cell Response by a PD-L1 Dependent Mechanism. Front Immunol. 2019;10:105. doi: https://doi.org/10.3389/fimmu.2019.00105Воробьева Н.В. Нейтрофилы — атипичные антигенпрезентирующие клетки // Вестник Московского университета. Серия 16. Биология. — 2023. — Т. 78. — № 2. — С. 55–63. [Vorobjeva NV. Neutrophils are atypical antigen-presenting cells. Vestnik Moskovskogo universiteta. Seriya 16. Biologiya. 2023;78(2):55–63. (In Russ.)] doi: https://doi.org/10.55959/MSU0137-0952-16-78-2-8Jung YJ, Lee Y, Kwon H, et al. Decidual lymphatic endothelial cell-derived granulocyte-macrophage colony-stimulating factor induces M1 macrophage polarization via the NF-κB pathway in severe pre-eclampsia. Am J Reprod Immunol. 2023;90(2):e13744. doi: https://doi.org/10.1111/aji.13744Omeljaniuk WJ, Jabłońska E, Garley M, et al. Biomarkers of neutrophil extracellular traps (NETs) and nitric oxide-(NO)-dependent oxidative stress in women who miscarried. Sci Rep. 2020;10(1):13088. doi: https://doi.org/10.1038/s41598-020-70106-хMangold A, Alias S, Scherz T, et al. Coronary neutrophil extracellular trap burden and deoxyribonuclease activity in ST-elevation acute coronary syndrome are predictors of ST-segment resolution and infarct size. Circ Res. 2015;116(7):1182–1192. doi: https://doi.org/10.1161/CIRCRESAHA.116.304944Слуханчук Е.В., Бицадзе В.О., Солопова А.Г., и др. Внеклеточные ловушки нейтрофилов как маркеры тромбовоспаления в патогенезе злокачественных новообразований женских половых органов и молочной железы // Акушерство, Гинекология и Репродукция. — 2022. — Т. 16. — № 4. — С. 426–437. [Slukhanchuk EV, Bitsadze VO, Solopova AG, et al. Neutrophil extracellular traps as markers of thromboinflammation in the pathogenesis of female genital tract and breast malignant neoplasms. Obstetrics, Gynecology and Reproduction. 2022;16(4):426–437. (In Russ.)] doi: https://doi.org/10.17749/2313-7347/ob.gyn.rep.2022.33Boettcher M, Schacker AL, Esser M, et al. Markers of neutrophil activation and extracellular trap formation predict appendicitis. Surgery. 2022;171(2):312–319. doi: https://doi.org/10.1016/j.surg.2021.07.010Yang S, Gu Z, Lu C, et al. Neutrophil Extracellular Traps Are Markers of Wound Healing Impairment in Patients with Diabetic Foot Ulcers Treated in a Multidisciplinary Setting. Adv Wound Care (New Rochelle). 2020;9(1):16–27. doi: https://doi.org/10.1089/wound.2019.0943