Wound healing, as a normal biological process in the human body, is achieved through four precisely and highly programmed phases: hemostasis, inflammation, proliferation, and remodeling. For a wound to heal successfully, all four phases must occur in the proper sequence and time frame. Many factors can interfere with one or more phases of this process, thus causing improper or impaired wound healing. This article reviews the recent literature on the most significant factors that affect cutaneous wound healing and the potential cellular and/or molecular mechanisms involved. The factors discussed include oxygenation, infection, age and sex hormones, stress, diabetes, obesity, medications, alcoholism, smoking, and nutrition. A better understanding of the influence of these factors on repair may lead to therapeutics that improve wound healing and resolve impaired wounds.
Get full access to this article
View all access options for this article.
References
1.
Ahn C, Mulligan P, Salcido RS (2008). Smoking—the bane of wound healing: biomedical interventions and social influences. Adv Skin Wound Care21:227–238.
2.
Anaya DA, Dellinger EP (2006). The obese surgical patient: a susceptible host for infection. Surg Infect (Larchmt)7:473–480.
3.
Arnold M, Barbul A (2006). Nutrition and wound healing. Plast Reconstr Surg117(7 Suppl):42S–58S.
4.
Balaji SM (2008). Tobacco smoking and surgical healing of oral tissues: a review. Indian J Dent Res19:344–348.
5.
Bishop A (2008). Role of oxygen in wound healing. J Wound Care17:399–402.
6.
Bjarnsholt T, Kirketerp-Moller K, Jensen P, Kit M, Krogfelt K, Phipps R, et al. (2008). Why chronic wounds won’t heal: a novel hypothesis. Wound Repair Regen1:2–10.
7.
Boyapati L, Wang HL (2007). The role of stress in periodontal disease and wound healing. Periodontol 200044:195–210.
8.
Brem H, Tomic-Canic M (2007). Cellular and molecular basis of wound healing in diabetes. J Clin Invest117:1219–1222.
9.
Broughton G 2nd, Janis JE, Attinger CE (2006). The basic science of wound healing (retraction of Witte M., Barbul A. In: Surg Clin North Am 1997; 77:509–528). Plast Reconstr Surg117(7 Suppl):12S–34S.
10.
Burgess C (2008). Topical vitamins. J Drugs Dermatol7(7 Suppl):s2–s6.
11.
Calabro P, Yeh ET (2007). Obesity, inflammation, and vascular disease: the role of the adipose tissue as an endocrine organ. Subcell Biochem42:63–91.
12.
Campos AC, Groth AK, Branco AB (2008). Assessment and nutritional aspects of wound healing. Curr Opin Clin Nutr Metab Care11:281–288.
13.
Cha J, Falanga V (2007). Stem cells in cutaneous wound healing. Clin Dermatol25:73–78.
14.
Chan LK, Withey S, Butler PE (2006). Smoking and wound healing problems in reduction mammaplasty: is the introduction of urine nicotine testing justified? Ann Plast Surg56:111–115.
15.
Choudhry MA, Chaudry IH (2006). Alcohol intoxication and post-burn complications. Front Biosci11:998–1005.
16.
da Costa MA, Campos AC, Coelho JC, de Barros AM, Matsumoto HM (2003). Oral glutamine and the healing of colonic anastomoses in rats. JPEN J Parenter Enteral Nutr27:182–185.
17.
Davis SC, Ricotti C, Cazzaniga A, Welsh E, Eaglstein WH, Mertz PM (2008). Microscopic and physiologic evidence for biofilm-associated wound colonization in vivo. Wound Repair Regen16:23–29.
18.
de Mello VD, Kolehmainen M, Schwab U, Mager U, Laaksonen DE, Pulkkinen L, et al. (2008). Effect of weight loss on cytokine messenger RNA expression in peripheral blood mononuclear cells of obese subjects with the metabolic syndrome. Metabolism57:192–199.
19.
Dong Y-L, Fleming RYD, Yan TZ, Herndon DN, Waymack JP (1993). Effect of ibuprofen on the inflammatory response to surgical wounds. J Trauma35:340–343.
20.
Dvivedi S, Tiwari SM, Sharma A (1997). Effect of ibuprofen and diclofenac sodium on experimental wound healing. Indian J Exp Biol35:1243–1245.
21.
Edwards R, Harding KG (2004). Bacteria and wound healing. Curr Opin Infect Dis17:91–96.
22.
Emery CF, Kiecolt-Glaser JK, Glaser R, Malarkey WB, Frid DJ (2005). Exercise accelerates wound healing among healthy older adults: a preliminary investigation. J Gerontol Med Sci60(A):1432–1436.
23.
Fitzgerald DJ, Radek KA, Chaar M, Faunce DE, DiPietro LA, Kovacs EJ (2007). Effects of acute ethanol exposure on the early inflammatory response after excisional injury. Alcohol Clin Exp Res31:317–323.
24.
Fontana L, Eagon JC, Colonna M, Klein S (2007). Impaired mononuclear cell immune function in extreme obesity is corrected by weight loss. Rejuvenation Res10:41–46.
25.
Franz MG, Steed DL, Robson MC (2007). Optimizing healing of the acute wound by minimizing complications. Curr Probl Surg44:691–763.
26.
Galiano RD, Tepper OM, Pelo CR, Bhatt KA, Callaghan M, Bastidas N, et al. (2004). Topical vascular endothelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow-derived cells. Am J Pathol164:1935–1947.
27.
Galkowska H, Olszewski WL, Wojewodzka U, Rosinski G, Karnafel W (2006). Neurogenic factors in the impaired healing of diabetic foot ulcers. J Surg Res134:252–258.
28.
Gallagher KA, Liu ZJ, Xiao M, Chen H, Goldstein LJ, Buerk DG, et al. (2007). Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1 alpha. J Clin Invest117:1249–1259.
29.
Gawronska-Kozak B, Bogacki M, Rim JS, Monroe WT, Manuel JA (2006). Scarless skin repair in immunodeficient mice. Wound Repair Regen14:265–276.
30.
Gentilello LM, Cobean RA, Walker AP, Moore EE, Wertz MJ, Dellinger EP (1993). Acute ethanol intoxication increases the risk of infection following penetrating abdominal trauma. J Trauma34:669–674.
31.
Gilliver SC, Ashworth JJ, Ashcroft GS (2007). The hormonal regulation of cutaneous wound healing. Clin Dermatol25:56–62.
32.
Glaser R, Kiecolt-Glaser JK (2005). Stress-induced immune dysfunction: implications for health. Nat Rev Immunol5:243–251.
33.
Godbout JP, Glaser R (2006). Stress-induced immune dysregulation: implications for wound healing, infectious disease and cancer. J Neuroimmune Pharmacol1:421–427.
Goldminz D, Bennett RG (1991). Cigarette smoking and flap and fullthickness graft necrosis. Arch Dermatol127:1012–1015.
36.
Gosain A, DiPietro LA (2004). Aging and wound healing. World J Surg28:321–326.
37.
Greco JA 3rd, Castaldo ET, Nanney LB, Wendel JJ, Summitt JB, Kelly KJ, et al. (2008). The effect of weight loss surgery and body mass index on wound complications after abdominal contouring operations. Ann Plast Surg61:235–242.
38.
Greiffenstein P, Molina PE (2008). Alcohol-induced alterations on host defense after traumatic injury. J Trauma64:230–240.
39.
Hardman MJ, Ashcroft GS (2008). Estrogen, not intrinsic aging, is the major regulator of delayed human wound healing in the elderly. Genome Biol9:R80.
40.
Heyman H, Van De Looverbosch DE, Meijer EP, Schols JM (2008). Benefits of an oral nutritional supplement on pressure ulcer healing in long-term care residents. J Wound Care17:476–478, 480.
41.
Hofman D, Moore K, Cooper R, Eagle M, Cooper S (2007). Use of topical corticosteroids on chronic leg ulcers. J Wound Care16:227–230.
42.
Huijberts MS, Schaper NC, Schalkwijk CG (2008). Advanced glycation end products and diabetic foot disease. Diabetes Metab Res Rev24(Suppl 1):S19–S24.
43.
Jacobi J, Jang JJ, Sundram U, Dayoub H, Fajardo LF, Cooke JP (2002). Nicotine accelerates angiogenesis and wound healing in genetically diabetic mice. Am J Pathol161:97–104.
44.
Jameson J, Havran WL (2007). Skin gammadelta T-cell functions in homeostasis and wound healing. Immunol Rev215:114–122.
Jones MK, Wang H, Peskar BM, Levin E, Itani RM, Sarfeh IJ, et al. (1999). Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nat Med5:1418–1423.
47.
Juge-Aubry CE, Henrichot E, Meier CA (2005). Adipose tissue: a regulator of inflammation. Best Pract Res Clin Endocrinol Metab19:547–566.
48.
Keylock KT, Vieira VJ, Wallig MA, DiPietro LA, Schrementi M, Woods JA (2008). Exercise accelerates cutaneous wound healing and decreases wound inflammation in aged mice. Am J Physiol Regul Integr Comp Physiol294:R179–R184.
49.
Khoosal D, Goldman RD (2006). Vitamin E for treating children’s scars. Does it help reduce scarring? Can Fam Physician52:855–856.
50.
Kiecolt-Glaser JK, Marucha PT, Malarkey WB, Mercado AM, Glaser R (1995). Slowing of wound healing by psychological stress. Lancet346:1194–1196.
51.
Kirchner LM, Meerbaum SO, Gruber BS, Knoll AK, Bulgrin J, Taylor RA, et al. (2003). Effects of vascular endothelial growth factor on wound closure rates in the genetically diabetic mouse model. Wound Repair Regen11:127–131.
52.
Kolb BA, Buller RE, Connor JP, DiSaia PJ, Berman ML (1992). Effects of early postoperative chemotherapy on wound healing. Obstet Gynecol79:988–992.
53.
Krischak GD, Augat P, Claes L, Kinzl L, Beck A (2007). The effects of non-steroidal anti-inflammatory drug application on incisional wound healing in rats. J Wound Care16:76–78.
54.
Lauerman CJ (2008). Surgical patient education related to smoking. AORN J87:599–609.
55.
Lawrence WT, Talbot TL, Norton JA (1986). Preoperative or postoperative doxorubicin hydrochloride (adriamycin): which is better for wound healing? Surgery100:9–13.
56.
Lemmens L, Claes V, Uzzell M (2008). Managing patients with metastatic colorectal cancer on bevacizumab. Br J Nurs17:944–949.
57.
Levin L, Schwartz-Arad D (2005). The effect of cigarette smoking on dental implants and related surgery. Implant Dent14:357–361.
58.
Liu ZJ, Velazquez OC (2008). Hyperoxia, endothelial progenitor cell mobilization, and diabetic wound healing. Antioxid Redox Signal10:1869–1882.
59.
Loots MA, Lamme EN, Zeegelaar J, Mekkes JR, Bos JD, Middelkoop E (1998). Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. J Invest Dermatol111:850–857.
60.
Madan AK, Yu K, Beech DJ (1999). Alcohol and drug use in victims of life-threatening trauma. J Trauma47:568–571.
61.
Marucha PT, Kiecolt-Glaser JK, Favagehi M (1998). Mucosal wound healing is impaired by examination stress. Psychosom Med60:362–365.
62.
Mathieu D, Linke J-C, Wattel F (2006). Non-healing wounds. In: Handbook on hyperbaric medicine, Mathieu DE, editor. Netherlands: Springer, pp. 401–427.
63.
McDaniel JC, Belury M, Ahijevych K, Blakely W (2008). Omega-3 fatty acids effect on wound healing. Wound Repair Regen16:337–345.
64.
McMaster SK, Paul-Clark MJ, Walters M, Fleet M, Anandarajah J, Sriskandan S, et al. (2008). Cigarette smoke inhibits macrophage sensing of Gram-negative bacteria and lipopolysaccharide: relative roles of nicotine and oxidant stress. Br J Pharmacol153:536–543.
Mills RE, Taylor KR, Podshivalova K, McKay DB, Jameson JM (2008). Defects in skin gamma delta T cell function contribute to delayed wound repair in rapamycin-treated mice. J Immunol181:3974–3983.
68.
Momeni A, Heier M, Bannasch H, Stark GB (2009). Complications in abdominoplasty: a risk factor analysis. J Plast Reconstr Aesthet Surg62:1250–1254.
69.
Morimoto N, Takemoto S, Kawazoe T, Suzuki S (2008). Nicotine at a low concentration promotes wound healing. J Surg Res145:199–204.
70.
Mosser DM, Edwards JP (2008). Exploring the full spectrum of macrophage activation. Nat Rev Immunol8:958–969.
71.
Nieman DC, Henson DA, Nehlsen-Cannarella SL, Ekkens M, Utter AC, Butterworth DE, et al. (1999). Influence of obesity on immune function. J Am Diet Assoc99:294–299.
72.
Park JE, Barbul A (2004). Understanding the role of immune regulation in wound healing. Am J Surg187:11–16.
73.
Pieringer H, Stuby U, Biesenbach G (2007). Patients with rheumatoid arthritis undergoing surgery: how should we deal with antirheumatic treatment? Semin Arthritis Rheum36:278–286.
74.
Price P, Fogh K, Glynn C, Krasner DL, Osterbrink J, Sibbald RG (2007). Why combine a foam dressing with ibuprofen for wound pain and moist wound healing? Int Wound J4(Suppl 1):1–3.
75.
Quattrini C, Jeziorska M, Boulton AJ, Malik RA (2008). Reduced vascular endothelial growth factor expression and intra-epidermal nerve fiber loss in human diabetic neuropathy. Diabetes Care31:140–145.
76.
Radek KA, Matthies AM, Burns AL, Heinrich SA, Kovacs EJ, Dipietro LA (2005). Acute ethanol exposure impairs angiogenesis and the proliferative phase of wound healing. Am J Physiol Heart Circ Physiol289:H1084–H1090.
77.
Radek KA, Kovacs EJ, DiPietro LA (2007). Matrix proteolytic activity during wound healing: modulation by acute ethanol exposure. Alcohol Clin Exp Res31:1045–1052.
78.
Radek KA, Kovacs EJ, Gallo RL, DiPietro LA (2008). Acute ethanol exposure disrupts VEGF receptor cell signaling in endothelial cells. Am J Physiol Heart Circ Physiol295:H174–H184.
79.
Rea S, Giles NL, Webb S, Adcroft KF, Evill LM, Strickland DH, et al. (2009). Bone marrow-derived cells in the healing burn wound—more than just inflammation. Burns35:356–364.
80.
Rivara FP, Jurkovich GJ, Gurney JG, Seguin D, Fligner CL, Ries R, et al. (1993). The magnitude of acute and chronic alcohol abuse in trauma patients. Arch Surg128:907–912.
81.
Rodriguez PG, Felix FN, Woodley DT, Shim EK (2008). The role of oxygen in wound healing: a review of the literature. Dermatol Surg34:1159–1169.
82.
Scappaticci FA, Fehrenbacher L, Cartwright T, Hainsworth JD, Heim W, Berlin J, et al. (2005). Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol91:173–180.
83.
Scott LJ (2007). Bevacizumab: in first-line treatment of metastatic breast cancer. Drugs67:1793–1799.
84.
Shepherd AA (2003). Nutrition for optimum wound healing. Nurs Stand18:55–58.
85.
Shingel KI, Faure MP, Azoulay L, Roberge C, Deckelbaum RJ (2008). Solid emulsion gel as a vehicle for delivery of polyunsaturated fatty acids: implications for tissue repair, dermal angiogenesis and wound healing. J Tissue Eng Regen Med2:383–393.
86.
Siana JE, Rex S, Gottrup F (1989). The effect of cigarette smoking on wound healing. Scand J Plast Reconstr Surg Hand Surg23:207–209.
87.
Sibbald RG, Woo KY (2008). The biology of chronic foot ulcers in persons with diabetes. Diabetes Metab Res Rev24(Suppl 1):25–30.
88.
Sorensen LT, Karlsmark T, Gottrup F (2003). Abstinence from smoking reduces incisional wound infection: a randomized controlled trial. Ann Surg238:1–5.
89.
Sørensen LT, Jorgensen LN, Zillmer R, Vange J, Hemmingsen U, Gottrup F (2006). Transdermal nicotine patch enhances type I collagen synthesis in abstinent smokers. Wound Repair Regen14:247–251.
90.
Sørensen LT, Jørgensen S, Petersen LJ, Hemmingsen U, Bülow J, Loft S, et al. (2009). Acute effects of nicotine and smoking on blood flow, tissue oxygen, and aerobe metabolism of the skin and subcutis. J Surg Res152:224–230.
91.
Sternberg EM (2006). Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol6:318–328.
92.
Swift ME, Kleinman HK, DiPietro LA (1999). Impaired wound repair and delayed angiogenesis in aged mice. Lab Invest79:1479–1487.
93.
Swift ME, Burns AL, Gray KL, DiPietro LA (2001). Age-related alterations in the inflammatory response to dermal injury. J Invest Dermatol117:1027–1035.
94.
Szabo G, Mandrekar P (2009). A recent perspective on alcohol, immunity, and host defense. Alcohol Clin Exp Res33:220–232.
95.
Tandara AA, Mustoe TA (2004). Oxygen in wound healing—more than a nutrient. World J Surg28:294–300.
96.
Tong BC, Barbul A (2004). Cellular and physiological effects of arginine. Mini Rev Med Chem4:823–832.
97.
Vileikyte L (2007). Stress and wound healing. Clin Dermatol25:49–55.
98.
Vincent AM, Russell JW, Low P, Feldman EL (2004). Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev25:612–628.
99.
Wagner AE, Huck G, Stiehl DP, Jelkmann W, Hellwig-Bürgel T (2008). Dexamethasone impairs hypoxia-inducible factor-1 function. Biochem Biophys Res Commun372:336–340.
100.
Waldron DR, Zimmerman-Pope N (2003). Superficial skin wounds. In: Textbook of small animal surgery. Slatter DH, editor. NY: Saunders, pp 260–271.
101.
Wilson JA, Clark JJ (2004). Obesity: impediment to postsurgical wound healing. Adv Skin Wound Care17:426–435.
102.
Woo K, Ayello EA, Sibbald RG (2007). The edge effect: current therapeutic options to advance the wound edge. Adv Skin Wound Care20:99–117.
103.
Wozniak SE, Gee LL, Wachtel MS, Frezza EE (2009). Adipose tissue: the new endocrine organ? A review article. Dig Dis Sci54:1847–1856.
104.
Wu Y, Wang J, Scott PG, Tredget EE (2007). Bone marrow-derived stem cells in wound healing: a review. Wound Repair Regen15(Suppl 1):S18–S26.
