Wound healing is an energetically demanding process that is easily disturbed by metabolic dysregulation. Metabolic dysregulation, induced by diabetes, obesity, insulin resistance, and various hormone imbalances, can disrupt each phase of wound repair, increasing the risk of post-operative complications, infection, wound dehiscence, and pathological scarring. We review the current evidence on the role of metabolic regulation in wound healing and highlight clinically relevant considerations for patient care.
Recent Advances:
Animal and human studies have advanced our understanding of how metabolic pathways influence inflammation, angiogenesis, fibroblast function, and extracellular matrix remodeling during wound healing. These insights have led to the development of novel therapies, including hormone-based topical agents and dressings that both sense and modulate metabolites during wound healing.
Critical Issues:
Despite growing recognition of the role of metabolic syndromes and hormonal regulation in wound healing, these factors are insufficiently integrated into clinical wound management. Bridging this gap requires a clear understanding of how metabolic syndromes and hormonal derangements influence healing.
Future Directions:
The continued development of treatments that modulate metabolic and hormonal pathways may enhance wound healing while minimizing systemic risk. Clinicians should also integrate local metabolic optimization with medical and lifestyle management to create the optimal wound healing environment for patients.
SenCK, GordilloGM, RoyS, et al.Human skin wounds: A major and snowballing threat to public health and the economy. Wound Repair Regen2009;17(6):763–771; doi: 10.1111/j.1524-475X.2009.00543.x
2.
HalesCM, CarrollMD, FryarCD, et al.Prevalence of obesity and severe obesity among adults: United States, 2017-2018. NCHS Data Brief2020(360):1–8.
3.
ThelwallS, HarringtonP, SheridanE, et al.Impact of obesity on the risk of wound infection following surgery: Results from a nationwide prospective multicentre cohort study in England. Clin Microbiol Infect2015;21(11):1008.e1–e8; doi: 10.1016/j.cmi.2015.07.003
4.
WaisbrenE, RosenH, BaderAM, et al.Percent body fat and prediction of surgical site infection. J Am Coll Surg2010;210(4):381–389; doi: 10.1016/j.jamcollsurg.2010.01.004
5.
HoudekMT, GriffinAM, FergusonPC, et al.Morbid obesity increases the risk of postoperative wound complications, infection, and repeat surgical procedures following upper extremity limb salvage surgery for soft tissue sarcoma. Hand (N Y)2019;14(1):114–120; doi: 10.1177/1558944718797336
6.
MolinaJE, LewRS-L, HylandKJ. Postoperative sternal dehiscence in obese patients: Incidence and prevention. Ann Thorac Surg2004;78(3):912–917; doi: 10.1016/j.athoracsur.2004.03.038
7.
MilicDJ, ZivicSS, BogdanovicDC, et al.Risk factors related to the failure of venous leg ulcers to heal with compression treatment. J Vasc Surg2009;49(5):1242–1247; doi: 10.1016/j.jvs.2008.11.069
8.
BarberGA, WellerCD, GibsonSJ. Effects and associations of nutrition in patients with venous leg ulcers: A systematic review. J Adv Nurs2018;74(4):774–787; doi: 10.1111/jan.13474
9.
AdotamaP, RutherfordA, GlassDA. Association of keloids with systemic medical conditions: A retrospective analysis. Int J Dermatol2016;55(1):e38–e40; doi: 10.1111/ijd.12969
10.
UngCY, WarwickA, OnoufriadisA, et al.Comorbidities of keloid and hypertrophic scars among participants in UK Biobank. JAMA Dermatol2023;159(2):172–181; doi: 10.1001/jamadermatol.2022.5607
11.
MarellaP, GlassDA. A retrospective study on the association of keloids with underlying health conditions in African-American Women. Int J Womens Dermatol2023;9(1):e074; doi: 10.1097/JW9.0000000000000074
12.
RutherfordA, GlassDA. A case–control study analyzing the association of keloids with hypertension and obesity. Int J Dermatol2017;56(9):e187–e189; doi: 10.1111/ijd.13618
13.
PinzurM, FreelandR, JuknelisD. The association between body mass index and foot disorders in diabetic patients. Foot Ankle Int2005;26(5):375–377; doi: 10.1177/107110070502600506
14.
CotterellA, GriffinM, DownerMA, et al.Understanding wound healing in obesity. World J Exp Med2024;14(1):86898; doi: 10.5493/wjem.v14.i1.86898
15.
FleischmannE, KurzA, NiedermayrM, et al.Tissue oxygenation in obese and non-obese patients during laparoscopy. Obes Surg2005;15(6):813–819; doi: 10.1381/0960892054222867
16.
GroszekDM. Promoting wound healing in the obese patient. Aorn J1982;35(6):1132–1138; doi: 10.1016/S0001-2092(07)62477-6
17.
SenCK, RoyS. Oxygenation state as a driver of myofibroblast differentiation and wound contraction: Hypoxia impairs wound closure. J Invest Dermatol2010;130(12):2701–2703; doi: 10.1038/jid.2010.316
18.
ModarressiA, PietramaggioriG, GodboutC, et al.Hypoxia impairs skin myofibroblast differentiation and function. J Invest Dermatol2010;130(12):2818–2827; doi: 10.1038/jid.2010.224
19.
FrascaD, StrboN. Effects of obesity on infections with emphasis on skin infections and wound healing. J Dermatol Skin Sci2022;4(3):5–10; doi: 10.29245/2767-5092/2022/3.1157
20.
MannV, SundaresanA, ShishodiaS. Overnutrition and lipotoxicity: Impaired efferocytosis and chronic inflammation as precursors to multifaceted disease pathogenesis. Biology (Basel)2024;13(4):241; doi: 10.3390/biology13040241
21.
MontgomeryMK, De NardoW, WattMJ. Impact of lipotoxicity on tissue “cross talk” and metabolic regulation. Physiology (Bethesda)2019;34(2):134–149; doi: 10.1152/physiol.00037.2018
22.
RömerA, LinnT, PetrySF. Lipotoxic impairment of mitochondrial function in β-cells: A review. Antioxidants (Basel)2021;10(2):293; doi: 10.3390/antiox10020293
23.
DingS, LiG, FuT, et al.Ceramides and mitochondrial homeostasis. Cell Signal2024;117:111099; doi: 10.1016/j.cellsig.2024.111099
24.
KruglovV, JangIH, CamellCD. Inflammaging and fatty acid oxidation in monocytes and macrophages. Immunometabolism (Cobham)2024;6(1):e00038; doi: 10.1097/IN9.0000000000000038
25.
VianelloE, BeltramiAP, AleksovaA, et al.The Advanced Glycation End-Products (AGE)-Receptor for AGE System (RAGE): An inflammatory pathway linking obesity and cardiovascular diseases. Int J Mol Sci2025;26(8):3707; doi: 10.3390/ijms26083707
26.
YuanC, LiaoJ, ZhengL, et al.Current knowledge of leptin in wound healing: A collaborative review. Front Pharmacol2022;13:968142; doi: 10.3389/fphar.2022.968142
27.
TadokoroS, IdeS, TokuyamaR, et al.Leptin promotes wound healing in the skin. PLoS One2015;10(3):e0121242; doi: 10.1371/journal.pone.0121242
28.
WangX, YanX, HuangF, et al.Adiponectin inhibits TGF-β1-induced skin fibroblast proliferation and phenotype transformation via the p38 MAPK signaling pathway. Open Life Sci2023;18(1):20220679; doi: 10.1515/biol-2022-0679
29.
BlüherM. The distinction of metabolically ‘healthy’ from ‘unhealthy’ obese individuals. Current Opinion in Lipidology2010;21(1):38–43; doi: 10.1097/MOL.0b013e3283346ccc
30.
VinerRM, SegalTY, Lichtarowicz-KrynskaE, et al.Prevalence of the insulin resistance syndrome in obesity. Arch Dis Child2005;90(1):10–14; doi: 10.1136/adc.2003.036467
SinghN, ArmstrongDG, LipskyBA. Preventing foot ulcers in patients with diabetes. JAMA2005;293(2):217–228; doi: 10.1001/jama.293.2.217
33.
LipiraAB, SoodRF, TatmanPD, et al.Complications within 30 days of hand surgery: An analysis of 10,646 patients. J Hand Surg Am2015;40(9):1852–1859.e3; doi: 10.1016/j.jhsa.2015.06.103
34.
GoltsmanD, MorrisonKA, AschermanJA. Defining the association between diabetes and plastic surgery outcomes: An analysis of nearly 40,000 patients. Plast Reconstr Surg Glob Open2017;5(8):e1461; doi: 10.1097/GOX.0000000000001461
35.
KantarRS, RifkinWJ, WilsonSC, et al.Abdominal panniculectomy: Determining the impact of diabetes on complications and risk factors for adverse events. Plast Reconstr Surg2018;142(4):462e–471e; doi: 10.1097/PRS.0000000000004732
36.
DortchJD, EckDL, LadlieB, et al.Perioperative glycemic control in plastic surgery: Review and discussion of an institutional protocol. Aesthet Surg J2016;36(7):821–830; doi: 10.1093/asj/sjw064
37.
WetzlerC, KämpferH, StallmeyerB, et al.Large and sustained induction of chemokines during impaired wound healing in the genetically diabetic mouse: Prolonged persistence of neutrophils and macrophages during the late phase of repair. J Invest Dermatol2000;115(2):245–253; doi: 10.1046/j.1523-1747.2000.00029.x
38.
Shaikh‐KaderA, HoureldNN, RajendranNK, et al.The link between advanced glycation end products and apoptosis in delayed wound healing. Cell Biochemistry & Function2019;37(6):432–442; doi: 10.1002/cbf.3424
39.
ClaytonSM, ShafikhaniSH, SoulikaAM. Macrophage and neutrophil dysfunction in diabetic wounds. Adv Wound Care (New Rochelle)2024;13(9):463–484; doi: 10.1089/wound.2023.0149
40.
RosiqueRG, RosiqueMJ, Farina JuniorJA. Curbing inflammation in skin wound healing: A review. Int J Inflam2015;2015:316235–316239; doi: 10.1155/2015/316235
41.
WangZ-C, ZhaoW-Y, CaoY, et al.The roles of inflammation in keloid and hypertrophic scars. Front Immunol2020;11:603187; doi: 10.3389/fimmu.2020.603187
42.
VerzijlN, DeGrootJ, ZakenCB, et al.Crosslinking by advanced glycation end products increases the stiffness of the collagen network in human articular cartilage: A possible mechanism through which age is a risk factor for osteoarthritis. Arthritis & Rheumatism2002;46(1):114–123; doi: 10.1002/1529-0131(200201)46:1<114::AID-ART10025>3.0.CO;2-P
43.
StefanadiEC, DimitrakakisG, AntoniouC-K, et al.Metabolic syndrome and the skin: A more than superficial association. Reviewing the association between skin diseases and metabolic syndrome and a clinical decision algorithm for high risk patients. Diabetol Metab Syndr2018;10(1):9; doi: 10.1186/s13098-018-0311-z
44.
Van PutteL, De SchrijverS, MoortgatP. The effects of advanced glycation end products (AGEs) on dermal wound healing and scar formation: A systematic review. Scars Burn Heal2016;2:2059513116676828; doi: 10.1177/2059513116676828
45.
AlikhaniZ, AlikhaniM, BoydCM, et al.Advanced glycation end products enhance expression of pro-apoptotic genes and stimulate fibroblast apoptosis through cytoplasmic and mitochondrial pathways. J Biol Chem2005;280(13):12087–12095; doi: 10.1074/jbc.M406313200
46.
McCartySM, CochraneCA, CleggPD, et al.The role of endogenous and exogenous enzymes in chronic wounds: A focus on the implications of aberrant levels of both host and bacterial proteases in wound healing. Wound Repair Regen2012;20(2):125–136; doi: 10.1111/j.1524-475X.2012.00763.x
47.
DinhT, TecilazichF, KafanasA, et al.Mechanisms involved in the development and healing of diabetic foot ulceration. Diabetes2012;61(11):2937–2947; doi: 10.2337/db12-0227
48.
BeaversKM, NicklasBJ. Effects of lifestyle interventions on inflammatory markers in the metabolic syndrome. Front Biosci (Schol Ed)2011;3(1):168–177; doi: 10.2741/s142
49.
FizelovaM, JauhiainenR, KangasAJ, et al.Differential associations of inflammatory markers with insulin sensitivity and secretion: The prospective METSIM study. J Clin Endocrinol Metab2017;102(9):3600–3609; doi: 10.1210/jc.2017-01057
50.
XieY, YangJ, ZhuH, et al.The efferocytosis dilemma: How neutrophil extracellular traps and PI3K/Rac1 complicate diabetic wound healing. Cell Commun Signal2025;23(1):103; doi: 10.1186/s12964-025-02092-4
51.
SadikuP, WillsonJA, RyanEM, et al.Neutrophils fuel effective immune responses through gluconeogenesis and glycogenesis. Cell Metab2021;33(5):1062–1064; doi: 10.1016/j.cmet.2021.03.018
52.
JoshiMB, AhamedR, HegdeM, et al.Glucose induces metabolic reprogramming in neutrophils during type 2 diabetes to form constitutive extracellular traps and decreased responsiveness to lipopolysaccharides. Biochim Biophys Acta Mol Basis Dis2020;1866(12):165940; doi: 10.1016/j.bbadis.2020.165940
53.
ZhuD, WeiW, ZhangJ, et al.Mechanism of damage of HIF-1 signaling in chronic diabetic foot ulcers and its related therapeutic perspectives. Heliyon2024;10(3):e24656; doi: 10.1016/j.heliyon.2024.e24656
54.
ForsytheJA, JiangB-H, IyerNV, et al.Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol1996;16(9):4604–4613; doi: 10.1128/MCB.16.9.4604
55.
ZhengX, NarayananS, XuC, et al.Repression of hypoxia-inducible factor-1 contributes to increased mitochondrial reactive oxygen species production in diabetes. Elife2022;11:e70714; doi: 10.7554/eLife.70714
56.
BauerleKT, HarrisC. Glucocorticoids and diabetes. Mo Med2016;113(5):378–383.
BaileyJM. New mechanisms for effects of anti-inflammatory glucocorticoids. Biofactors1991;3(2):97–102.
59.
WangAS, ArmstrongEJ, ArmstrongAW. Corticosteroids and wound healing: Clinical considerations in the perioperative period. Am J Surg2013;206(3):410–417; doi: 10.1016/j.amjsurg.2012.11.018
60.
IsmaelH, HorstM, FarooqM, et al.Adverse effects of preoperative steroid use on surgical outcomes. Am J Surg2011;201(3):305–309; doi: 10.1016/j.amjsurg.2010.09.018
61.
LindstedtE, SandblomP. Wound healing in man: Tensile strength of healing wounds in some patient groups. Ann Surg1975;181(6):842–846; doi: 10.1097/00000658-197506000-00014
GupteR, MuseGW, ChinenovY, et al.Glucocorticoid receptor represses proinflammatory genes at distinct steps of the transcription cycle. Proc Natl Acad Sci U S A2013;110(36):14616–14621; doi: 10.1073/pnas.1309898110
64.
BosanquetD, RangarajA, RichardsA, et al.Topical steroids for chronic wounds displaying abnormal inflammation. Ann R Coll Surg Engl2013;95(4):291–296; doi: 10.1308/003588413X13629960045634
65.
HübnerG, BrauchleM, SmolaH, et al.Differential regulation of pro-inflammatory cytokines during wound healing in normal and glucocorticoid-treated mice. Cytokine1996;8(7):548–556; doi: 10.1006/cyto.1996.0074
66.
BeerH-D, LongakerMT, WernerS. Reduced Expression of PDGF and PDGF receptors during impaired wound healing. J Invest Dermatol1997;109(2):132–138; doi: 10.1111/1523-1747.ep12319188
67.
DurantS, DuvalD, HomoDelarcheF. Factors involved in the control of fibroblast proliferation by glucocorticoids: A review. Endocr Rev1986;7(3):254–269; doi: 10.1210/edrv-7-3-254
68.
ShaoS, ChenJ, SwindellWR, et al.Phospholipase A2 enzymes represent a shared pathogenic pathway in psoriasis and pityriasis rubra pilaris. JCI Insight2021;6(20):e151911; doi: 10.1172/jci.insight.151911
69.
MurakamiM, YamamotoK, TaketomiY. Phospholipase A2 in skin biology: New insights from gene-manipulated mice and lipidomics. Inflamm Regen2018;38(1):31; doi: 10.1186/s41232-018-0089-2
GrasM‐P, VerrecchiaF, UittoJ, et al.Downregulation of human type VII collagen (COL7A1) promoter activity by dexamethasone: Identification of a glucocorticoid receptor binding region. Exp Dermatol2001;10(1):28–34; doi: 10.1034/j.1600-0625.2001.100104.x
73.
WickeC, HallidayB, AllenD, et al.Effects of steroids and retinoids on wound healing. Arch Surg2000;135(11):1265–1270; doi: 10.1001/archsurg.135.11.1265
74.
EhrlichHP, HuntTK. Effects of cortisone and vitamin a on wound healing. Ann Surg1968;167(3):324–328; doi: 10.1097/00000658-196803000-00004
75.
OishiY, FuZW, OhnukiY, et al.Molecular basis of the alteration in skin collagen metabolism in response to in vivo dexamethasone treatment: Effects on the synthesis of collagen type I and III, collagenase, and tissue inhibitors of metalloproteinases. Br J Dermatol2002;147(5):859–868; doi: 10.1046/j.1365-2133.2002.04949.x
76.
BrinkmanJE, TariqMA, LeavittL, et al.Physiology, Growth Hormone. In: StatPearls. StatPearls Publishing: Treasure Island, FL; 2025.
77.
LeeSW, KimSH, KimJY, et al.The effect of growth hormone on fibroblast proliferation and keratinocyte migration. J Plast Reconstr Aesthet Surg2010;63(4):e364–e369; doi: 10.1016/j.bjps.2009.10.027
78.
DunaiskiV, BelfordDA. Contribution of circulating IGF-I to wound repair in GH-treated rats. Growth Horm IGF Res2002;12(6):381–387; doi: 10.1016/S1096-6374(02)00080-1
79.
LosadaF, García‐LunaPP, Gómez‐CíaT, et al.Effects of human recombinant growth hormone on donor‐site healing in burned adults. World J Surg2002;26(1):2–8; doi: 10.1007/s00268-001-0170-9
80.
ZaizenY, FordE, ShimadaH, et al.Growth hormone effects on wound healing in malnourished animals: A histological study. Eur J Pediatr Surg1995;5(4):226–230; doi: 10.1055/s-2008-1066211
81.
ShaoY, HanM, ChenG, et al.Recombinant human growth hormone promotes wound angiogenesis in burnedmice through the ERK signaling pathway. Cell Mol Biol (Noisy-le-Grand)2024;70(5):243–247; doi: 10.14715/cmb/2024.70.5.36
82.
CristóbalL, De Los ReyesN, OrtegaMA, et al.Local growth hormone therapy for pressure ulcer healing on a human skin mouse model. Int J Mol Sci2019;20(17):4157; doi: 10.3390/ijms20174157
83.
CuiT, JimenezJJ, BlockNL, et al.Agonistic analogs of growth hormone releasing hormone (GHRH) promote wound healing by stimulating the proliferation and survival of human dermal fibroblasts through ERK and AKT pathways. Oncotarget2016;7(33):52661–52672; doi: 10.18632/oncotarget.11024
84.
DioufaN, SchallyAV, ChatzistamouI, et al.Acceleration of wound healing by growth hormone-releasing hormone and its agonists. Proc Natl Acad Sci U S A2010;107(43):18611–18615; doi: 10.1073/pnas.1013942107
85.
GilpinDA, BarrowRE, RutanRL, et al.Recombinant human growth hormone accelerates wound healing in children with large cutaneous burns. Ann Surg1994;220(1):19–24; doi: 10.1097/00000658-199407000-00004
86.
HerndonDN, HawkinsHK, NguyenTT, et al.Characterization of growth hormone enhanced donor site healing in patients with large cutaneous burns. Ann Surg1995;221(6):649–659; doi: 10.1097/00000658-199506000-00004
87.
ZouboulisCC, BoschnakowA. Chronological ageing and photoageing of the human sebaceous gland. Clin Exp Dermatol2001;26(7):600–607; doi: 10.1046/j.1365-2230.2001.00894.x
88.
AshcroftGS, DodsworthJ, BoxtelEV, et al.Estrogen accelerates cutaneous wound healing associated with an increase in TGF-β1 levels. Nat Med1997;3(11):1209–1215; doi: 10.1038/nm1197-1209
89.
HenryF, Piérard‐FranchimontC, CauwenberghG, et al.Age‐related changes in facial skin contours and rheology. J Am Geriatr Soc1997;45(2):220–222; doi: 10.1111/j.1532-5415.1997.tb04512.x
90.
El MohtadiM, WhiteheadK, Dempsey-HibbertN, et al.Estrogen deficiency - a central paradigm in age-related impaired healing? Excli J2021;20:99–116; doi: 10.17179/EXCLI2020-3210
91.
MargolisDJ, KnaussJ, BilkerW. Hormone replacement therapy and prevention of pressure ulcers and venous leg ulcers. Lancet2002;359(9307):675–677; doi: 10.1016/S0140-6736(02)07806-6
92.
ThorntonMJ. Estrogens and aging skin. Dermatoendocrinol2013;5(2):264–270; doi: 10.4161/derm.23872
93.
LopezMM, CastilloAC, KaltwasserK, et al.Surgical timing and the menstrual cycle affect wound healing in young breast reduction patients. Plast Reconstr Surg2016;137(2):406–410; doi: 10.1097/01.prs.0000475748.02721.3d
94.
AshcroftGS, Greenwell-WildT, HoranMA, et al.Topical estrogen accelerates cutaneous wound healing in aged humans associated with an altered inflammatory response. Am J Pathol1999;155(4):1137–1146; doi: 10.1016/S0002-9440(10)65217-0
95.
OmotoY, IwaseH. Clinical significance of estrogen receptor β in breast and prostate cancer from biological aspects. Cancer Sci2015;106(4):337–343; doi: 10.1111/cas.12613
96.
ThorntonMJ, TaylorAH, MulliganK, et al.The distribution of estrogen receptor β is distinct to that of estrogen receptor α and the androgen receptor in human skin and the pilosebaceous unit. J Investig Dermatol Symp Proc2003;8(1):100–103; doi: 10.1046/j.1523-1747.2003.12181.x
97.
HaczynskiJ, TarkowskiR, JarzabekK, et al.Differential effects of estradiol, raloxifene and tamoxifen on estrogen receptor expression in cultured human skin fibroblasts. Int J Mol Med2004;13(6):903–908; doi: 10.3892/ijmm.13.6.903
98.
CampbellL, EmmersonE, DaviesF, et al.Estrogen promotes cutaneous wound healing via estrogen receptor β independent of its antiinflammatory activities. J Exp Med2010;207(9):1825–1833; doi: 10.1084/jem.20100500
99.
AshcroftGS, MillsSJ, LeiK, et al.Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor. J Clin Invest2003;111(9):1309–1318; doi: 10.1172/JCI16288
100.
LiZ, MaR, TanJ, et al.Hormonal interventions in skin wounds – a mini review. Mol Med2024;30(1):217; doi: 10.1186/s10020-024-00978-6
101.
AmbrozovaN, UlrichovaJ, GalandakovaA. Models for the study of skin wound healing. The role of Nrf2 and NF-κB. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub2017;161(1):1–13; doi: 10.5507/bp.2016.063
102.
KandaN, WatanabeS. 17β-estradiol inhibits oxidative stress-induced apoptosis in keratinocytes by promoting Bcl-2 expression. J Invest Dermatol2003;121(6):1500–1509; doi: 10.1111/j.1523-1747.2003.12617.x
103.
SavoiaP, RainaG, CamilloL, et al.Anti-oxidative effects of 17 β-estradiol and genistein in human skin fibroblasts and keratinocytes. J Dermatol Sci2018;92(1):62–77; doi: 10.1016/j.jdermsci.2018.07.007
104.
HorngH-C, ChangW-H, YehC-C, et al.Estrogen effects on wound healing. Int J Mol Sci2017;18(11):2325; doi: 10.3390/ijms18112325
105.
ZomerHD, CookePS. Targeting estrogen signaling and biosynthesis for aged skin repair. Front Physiol2023;14:1281071; doi: 10.3389/fphys.2023.1281071
106.
Gawronska-KozakB, KopcewiczM, Machcinska-ZielinskaS, et al.Gender differences in post-operative human skin. Biomedicines2023;11(10):2653; doi: 10.3390/biomedicines11102653
107.
LiangT, HoyerS, YuR, et al.Immunocytochemical localization of androgen receptors in human skin using monoclonal antibodies against the androgen receptors. J Invest Dermatol1993;100(5):663–666; doi: 10.1111/1523-1747.ep12472330
108.
ZouboulisCC, DegitzK. Androgen action on human skin – from basic research to clinical significance. Exp Dermatol2004;13(Suppl 4):5–10; doi: 10.1111/j.1600-0625.2004.00255.x
109.
GilliverSC, AshworthJJ, MillsSJ, et al.Androgens modulate the inflammatory response during acute wound healing. J Cell Sci2006;119(Pt 4):722–732; doi: 10.1242/jcs.02786
110.
FimmelS, ZouboulisCC. Influence of physiological androgen levels on wound healing and immune status in men. Aging Male2005;8(3–4):166–174; doi: 10.1080/13685530500233847
111.
AshcroftGS. Sex differences in wound healing. In: Advances in Molecular and Cell Biology. Elsevier; 2004; pp. 321–328; doi: 10.1016/S1569-2558(03)34022-6
112.
ToraldoG, BhasinS, BakhitM, et al.Topical androgen antagonism promotes cutaneous wound healing without systemic androgen deprivation by blocking β‐catenin nuclear translocation and cross‐talk with TGF‐β signaling in keratinocytes. Wound Repair Regen2012;20(1):61–73; doi: 10.1111/j.1524-475X.2011.00757.x
113.
FordLC, KingDF, LagasseLD, et al.Increased androgen binding in keloids: A preliminary communication. J Dermatol Surg Oncol1983;9(7):545–547; doi: 10.1111/j.1524-4725.1983.tb00851.x
114.
EngelandCG, SabzeheiB, MaruchaPT. Sex hormones and mucosal wound healing. Brain Behav Immun2009;23(5):629–635; doi: 10.1016/j.bbi.2008.12.001
115.
ShiH, CheerK, SimanainenU, et al.The contradictory role of androgens in cutaneous and major burn wound healing. Burns Trauma2021;9:tkaa046; doi: 10.1093/burnst/tkaa046
116.
ShiH, LoT-H, MaD, et al.Dihydrotestosterone (DHT) enhances wound healing of major burn injury by accelerating resolution of inflammation in mice. Int J Mol Sci2020;21(17):6231; doi: 10.3390/ijms21176231
117.
JeschkeMG, FinnertyCC, SumanOE, et al.The effect of oxandrolone on the endocrinologic, inflammatory, and hypermetabolic responses during the acute phase postburn. Ann Surg2007;246(3):351–360; discussion 360–362; doi: 10.1097/SLA.0b013e318146980e
118.
AshcroftGS, MillsSJ, FlandersKC, et al.Role of Smad3 in the hormonal modulation of in vivo wound healing responses. Wound Repair Regen2003;11(6):468–473; doi: 10.1046/j.1524-475X.2003.11614.x
119.
EngelME, McDonnellMA, LawBK, et al.Interdependent SMAD and JNK Signaling in Transforming Growth Factor-β-mediated Transcription. J Biol Chem1999;274(52):37413–37420; doi: 10.1074/jbc.274.52.37413
120.
BensonRC, UtzDC, HolickyE, et al.Androgen receptor binding activity in human prostate cancer. Cancer1985;55(2):382–388; doi: 10.1002/1097-0142(19850115)55:2<382::AID-CNCR2820550215>3.0.CO;2-2
121.
BaylisC. Age-dependent glomerular damage in the rat. Dissociation between glomerular injury and both glomerular hypertension and hypertrophy. Male gender as a primary risk factor. J Clin Invest1994;94(5):1823–1829; doi: 10.1172/JCI117531
122.
KangH-Y, LinH-K, HuY-C, et al.From transforming growth factor-β signaling to androgen action: Identification of Smad3 as an androgen receptor coregulator in prostate cancer cells. Proc Natl Acad Sci U S A2001;98(6):3018–3023; doi: 10.1073/pnas.061305498
123.
MukaiK, HorikeS, Meguro-HorikeM, et al.Topical estrogen application promotes cutaneous wound healing in db/db female mice with type 2 diabetes. PLoS One2022;17(3):e0264572; doi: 10.1371/journal.pone.0264572
124.
LiZ, ChongC, WangY, et al.An electrospun scaffold loaded with anti-androgen receptor compound for accelerating wound healing. Burns Trauma2013;1(2):95–101; doi: 10.4103/2321-3868.118935
125.
BreederveldRS, TuinebreijerWE. Recombinant human growth hormone for treating burns and donor sites. Cochrane Database Syst Rev2014;2014(9):CD008990; doi: 10.1002/14651858.CD008990.pub3
126.
BarretJP, DziewulskiP, JeschkeMG, et al.Effects of recombinant human growth hormone on the development of burn scarring. Plast Reconstr Surg1999;104(3):726–729; doi: 10.1097/00006534-199909010-00017
127.
EmeryCF, Kiecolt-GlaserJK, GlaserR, et al.Exercise accelerates wound healing among healthy older adults: A preliminary investigation. J Gerontol A Biol Sci Med Sci2005;60(11):1432–1436; doi: 10.1093/gerona/60.11.1432
128.
MolnarJA, UnderdownMJ, ClarkWA. Nutrition and chronic wounds. Adv Wound Care (New Rochelle)2014;3(11):663–681; doi: 10.1089/wound.2014.0530
129.
KeylockKT, VieiraVJ, WalligMA, et al.Exercise accelerates cutaneous wound healing and decreases wound inflammation in aged mice. Am J Physiol Regul Integr Comp Physiol2008;294(1):R179–R184; doi: 10.1152/ajpregu.00177.2007
130.
BarnesLA, MarshallCD, LeavittT, et al.Mechanical forces in cutaneous wound healing: Emerging therapies to minimize scar formation. Adv Wound Care (New Rochelle)2018;7(2):47–56; doi: 10.1089/wound.2016.0709
131.
HanX, JuLS, IrudayarajJ. Oxygenated wound dressings for hypoxia mitigation and enhanced wound healing. Mol Pharm2023;20(7):3338–3355; doi: 10.1021/acs.molpharmaceut.3c00352
132.
DimmelerS, AicherA, VasaM, et al.HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest2001;108(3):391–397; doi: 10.1172/JCI200113152
133.
SpampinatoSF, CarusoGI, De PasqualeR, et al.The treatment of impaired wound healing in diabetes: Looking among old drugs. Pharmaceuticals (Basel)2020;13(4):60; doi: 10.3390/ph13040060
134.
WangJ, XuJ. Effects of topical insulin on wound healing: A review of animal and human evidences. Diabetes Metab Syndr Obes2020;13:719–727; doi: 10.2147/DMSO.S237294
135.
ChenX, LiuY, ZhangX. Topical insulin application improves healing by regulating the wound inflammatory response. Wound Repair Regen2012;20(3):425–434; doi: 10.1111/j.1524-475X.2012.00792.x
136.
LimaMHM, CaricilliAM, De AbreuLL, et al.Topical insulin accelerates wound healing in diabetes by enhancing the AKT and ERK pathways: A double-blind placebo-controlled clinical trial. PLoS One2012;7(5):e36974; doi: 10.1371/journal.pone.0036974
137.
Martínez-JiménezMA, Aguilar-GarcíaJ, Valdés-RodríguezR, et al.Local use of insulin in wounds of diabetic patients: Higher temperature, fibrosis, and angiogenesis. Plast Reconstr Surg2013;132(6):1015e–1019e; doi: 10.1097/PRS.0b013e3182a806f0
138.
HuS, GongY, ZhangH, et al.The effect of topical insulin therapy on diabetic foot ulcers: A systematic review and meta-analysis. J Tissue Viability2025;34(3):100932; doi: 10.1016/j.jtv.2025.100932
139.
Ramirez-GarciaLunaJL, Rangel-BerridiK, BergeronA, et al.Local insulin improves wound healing: A systematic review and bayesian network meta-analysis. Plast Reconstr Surg2023;152(6):1114e–1130e; doi: 10.1097/PRS.0000000000010432
140.
ChenJ, QinS, XingZ, et al.Targeting angiogenesis in diabetic wound healing: New insight from chemical architecture to functional outcomes. J Pharm Anal2025:101475; doi: 10.1016/j.jpha.2025.101475
141.
LuoB, DingX, HuY, et al.Shikonin hastens diabetic wound healing by inhibiting M1 macrophage polarisation through the MAPK signaling pathway. Mol Immunol2025;177:73–84; doi: 10.1016/j.molimm.2024.12.002
142.
XueC, DouJ, ZhangS, et al.Shikonin potentiates skin wound healing in Sprague–Dawley rats by stimulating fibroblast and endothelial cell proliferation and angiogenesis. J Gene Med2024;26(1):e3633; doi: 10.1002/jgm.3633
143.
LiangY, LiM, YangY, et al.pH/glucose dual responsive metformin release hydrogel dressings with adhesion and self-healing via dual-dynamic bonding for athletic diabetic foot wound healing. ACS Nano2022;16(2):3194–3207; doi: 10.1021/acsnano.1c11040
144.
YangJ, ZengW, XuP, et al.Glucose-responsive multifunctional metal–organic drug-loaded hydrogel for diabetic wound healing. Acta Biomater2022;140:206–218; doi: 10.1016/j.actbio.2021.11.043
145.
DuscherD, NeofytouE, WongVW, et al.Transdermal deferoxamine prevents pressure-induced diabetic ulcers. Proc Natl Acad Sci U S A2015;112(1):94–99; doi: 10.1073/pnas.1413445112
146.
HuangY-Y, LinC-W, ChengN-C, et al.Effect of a novel macrophage-regulating drug on wound healing in patients with diabetic foot ulcers: A randomized clinical trial. JAMA Netw Open2021;4(9):e2122607; doi: 10.1001/jamanetworkopen.2021.22607
147.
LeuW-J, ChenJ-C, GuhJ-H. Extract from plectranthus amboinicus inhibit maturation and release of interleukin 1β through inhibition of NF-κB nuclear translocation and NLRP3 inflammasome activation. Front Pharmacol2019;10:573; doi: 10.3389/fphar.2019.00573
148.
SawatdeeS, ChoochuayK, ChanthornW, et al.Evaluation of the topical spray containing Centella asiatica extract and its efficacy on excision wounds in rats. Acta Pharm2016;66(2):233–244; doi: 10.1515/acph-2016-0018
149.
PolczME, BarbulA. The role of vitamin a in wound healing. Nutr Clin Pract2019;34(5):695–700; doi: 10.1002/ncp.10376
150.
HuntTK. Vitamin A and wound healing. J Am Acad Dermatol1986;15(4 Pt 2):817–821; doi: 10.1016/S0190-9622(86)70238-7
151.
PaquetteD, BadiavasE, FalangaV. Short-contact topical tretinoin therapy to stimulate granulation tissue in chronic wounds. J Am Acad Dermatol2001;45(3):382–386; doi: 10.1067/mjd.2001.116238
