Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Wound healing and risk factors for non-healing

David G Armstrong, DPM, MD, PhD
Andrew J Meyr, DPM
Section Editors
Hilary Sanfey, MD
John F Eidt, MD
Joseph L Mills, Sr, MD
Russell S Berman, MD
Deputy Editor
Kathryn A Collins, MD, PhD, FACS


A wound is a disruption of the normal structure and function of the skin and underlying soft tissue [1]. Acute wounds in normal, healthy individuals heal through an orderly sequence of physiological events that include hemostasis, inflammation, epithelialization, fibroplasia, and maturation [2]. When this process is altered or stalled, a chronic wound may develop and this is more likely to occur in patients with underlying disorders such as peripheral artery disease, diabetes, venous insufficiency, nutritional deficiencies, and other disease states. Chronic ulceration commonly affects the lower extremities with a prevalence that ranges between 0.18 and 1.3 percent in the adult population [2-5].

Wounding mechanisms, the normal phases of wound healing and alterations in wound healing due to disease are reviewed here. The clinical evaluation and topical management of open wounds is discussed separately. (See "Clinical assessment of wounds".)


Wounds are generally classified as acute or chronic. Although there is no specific time frame determining the difference between an acute or chronic wound, chronic wounds are generally associated with physiological impairments that slow or prevent wound healing. Wounds may be caused by a variety of mechanisms including acute injury to the skin (abrasion, puncture, crush), surgery and other etiologies that cause initially intact skin to break down (eg, ischemia, pressure).

Acute wounds have an easily identifiable mechanism of injury with skin integrity disrupted typically due to some form of trauma. Traumatic skin disruption can result from blunt or penetrating mechanisms (gunshot, animal bite) and an array of wound sizes, depths, and locations can result. Simple or complicated lacerations, abrasions, burns and significant tissue defects can occur, each requiring individualized management and care.

Patients with impairment in pain sensation are vulnerable to acute and chronic repetitive injuries. In some patients with sensory neuropathy, the injury may go unnoticed if the injured area is not routinely inspected. Patients with diabetes, particularly those with arterial obstruction, are at high risk. (See 'Diabetes' below.)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: May 2017. | This topic last updated: May 16, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Orr JW, Taylor PT. Wound healing. In: Complications in gynecological surgery: Prevention, recognition, and management, JB Lippincott, Philadelphia p.167.
  2. Lipscomb, GH, Ling, FG. Wound Healing, Suture Material, and Surgical Instrumentation. In: TeLinde's Operative Gynecology, 9th edition, Rock, JA, Jones, HA, III (Eds), 2003. p.233.
  3. Diegelmann RF, Evans MC. Wound healing: an overview of acute, fibrotic and delayed healing. Front Biosci 2004; 9:283.
  4. Leibovich SJ, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol 1975; 78:71.
  5. Mor-Vaknin N, Punturieri A, Sitwala K, Markovitz DM. Vimentin is secreted by activated macrophages. Nat Cell Biol 2003; 5:59.
  6. Odland G, Ross R. Human wound repair. I. Epidermal regeneration. J Cell Biol 1968; 39:135.
  7. Ross R, Everett NB, Tyler R. Wound healing and collagen formation. VI. The origin of the wound fibroblast studied in parabiosis. J Cell Biol 1970; 44:645.
  8. Darby IA, Hewitson TD. Fibroblast differentiation in wound healing and fibrosis. Int Rev Cytol 2007; 257:143.
  9. Attinger CE, Steinberg JS, Meyr AJ. Debridement of the Diabetic Foot Wound. In: Clinical Care of the Diabetic Foot, Second Edition, Armstrong DG, Lavery LA. (Eds), American Diabetes Association, Alexandria 2010. p.49.
  10. Doillon CJ, Dunn MG, Bender E, Silver FH. Collagen fiber formation in repair tissue: development of strength and toughness. Coll Relat Res 1985; 5:481.
  11. Haukipuro K. Synthesis of collagen types I and III in reincised wounds in humans. Br J Surg 1991; 78:708.
  12. Howes EL, Harvey SC. The strength of the healing wound in relation to the holding strength of the catgut suture. N Engl J Med 1929 1929; 200:1285.
  13. Dodson MK, Magann EF, Meeks GR. A randomized comparison of secondary closure and secondary intention in patients with superficial wound dehiscence. Obstet Gynecol 1992; 80:321.
  14. Walters MD, Dombroski RA, Davidson SA, et al. Reclosure of disrupted abdominal incisions. Obstet Gynecol 1990; 76:597.
  15. Armstrong DG, Lavery LA, Harkless LB. Validation of a diabetic wound classification system. The contribution of depth, infection, and ischemia to risk of amputation. Diabetes Care 1998; 21:855.
  16. Morbach S, Furchert H, Gröblinghoff U, et al. Long-term prognosis of diabetic foot patients and their limbs: amputation and death over the course of a decade. Diabetes Care 2012; 35:2021.
  17. Mills JL Sr, Conte MS, Armstrong DG, et al. The Society for Vascular Surgery Lower Extremity Threatened Limb Classification System: risk stratification based on wound, ischemia, and foot infection (WIfI). J Vasc Surg 2014; 59:220.
  18. Santilli JD, Santilli SM. Chronic critical limb ischemia: diagnosis, treatment and prognosis. Am Fam Physician 1999; 59:1899.
  19. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA 2005; 293:217.
  20. Deatrick KB, Wakefield TW, Henke PK. Chronic venous insufficiency: current management of varicose vein disease. Am Surg 2010; 76:125.
  21. Kurd SK, Hoffstad OJ, Bilker WB, Margolis DJ. Evaluation of the use of prognostic information for the care of individuals with venous leg ulcers or diabetic neuropathic foot ulcers. Wound Repair Regen 2009; 17:318.
  22. Mendelsohn FA, Divino CM, Reis ED, Kerstein MD. Wound care after radiation therapy. Adv Skin Wound Care 2002; 15:216.
  23. Bowering CK. Diabetic foot ulcers. Pathophysiology, assessment, and therapy. Can Fam Physician 2001; 47:1007.
  24. Boulton AJ, Armstrong DG, Albert SF, et al. Comprehensive foot examination and risk assessment: a report of the task force of the foot care interest group of the American Diabetes Association, with endorsement by the American Association of Clinical Endocrinologists. Diabetes Care 2008; 31:1679.
  25. Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes. J Clin Invest 2007; 117:1219.
  26. Reddy M. Skin and wound care: important considerations in the older adult. Adv Skin Wound Care 2008; 21:424.
  27. Fore J. A review of skin and the effects of aging on skin structure and function. Ostomy Wound Manage 2006; 52:24.
  28. Wang AS, Armstrong EJ, Armstrong AW. Corticosteroids and wound healing: clinical considerations in the perioperative period. Am J Surg 2013; 206:410.
  29. Bosanquet DC, Rangaraj A, Richards AJ, et al. Topical steroids for chronic wounds displaying abnormal inflammation. Ann R Coll Surg Engl 2013; 95:291.
  30. Hofman D, Moore K, Cooper R, et al. Use of topical corticosteroids on chronic leg ulcers. J Wound Care 2007; 16:227.
  31. Trent JT, Kirsner RS. Leg ulcers in sickle cell disease. Adv Skin Wound Care 2004; 17:410.
  32. Erinjeri JP, Fong AJ, Kemeny NE, et al. Timing of administration of bevacizumab chemotherapy affects wound healing after chest wall port placement. Cancer 2011; 117:1296.
  33. Wang J, Boerma M, Fu Q, Hauer-Jensen M. Radiation responses in skin and connective tissues: effect on wound healing and surgical outcome. Hernia 2006; 10:502.
  34. Boffeli TJ, Thompson JC, Waverly BJ, et al. Incidence and Clinical Significance of Heterotopic Ossification After Partial Ray Resection. J Foot Ankle Surg 2016; 55:714.
  35. Regan MA, Teasell RW, Wolfe DL, et al. A systematic review of therapeutic interventions for pressure ulcers after spinal cord injury. Arch Phys Med Rehabil 2009; 90:213.
  36. Wu SC, Crews RT, Armstrong DG. The pivotal role of offloading in the management of neuropathic foot ulceration. Curr Diab Rep 2005; 5:423.
  37. Heinen MM, van Achterberg T, op Reimer WS, et al. Venous leg ulcer patients: a review of the literature on lifestyle and pain-related interventions. J Clin Nurs 2004; 13:355.
  38. Wilkinson EA. Oral zinc for arterial and venous leg ulcers. Cochrane Database Syst Rev 2012; :CD001273.
  39. Raffoul W, Far MS, Cayeux MC, Berger MM. Nutritional status and food intake in nine patients with chronic low-limb ulcers and pressure ulcers: importance of oral supplements. Nutrition 2006; 22:82.
  40. Arnold M, Barbul A. Nutrition and wound healing. Plast Reconstr Surg 2006; 117:42S.
  41. Abu-Rumman PL, Armstrong DG, Nixon BP. Use of clinical laboratory parameters to evaluate wound healing potential in diabetes mellitus. J Am Podiatr Med Assoc 2002; 92:38.
  42. Freedman G, Cean C, Duron V, et al. Pathogenesis and treatment of pain in patients with chronic wounds. Surg Technol Int 2003; 11:168.
  43. Bowler PG, Duerden BI, Armstrong DG. Wound microbiology and associated approaches to wound management. Clin Microbiol Rev 2001; 14:244.
  44. Lipsky BA, Berendt AR, Cornia PB, 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:e132.
  45. Turan A, Mascha EJ, Roberman D, et al. Smoking and perioperative outcomes. Anesthesiology 2011; 114:837.
  46. Sørensen LT. Wound healing and infection in surgery: the pathophysiological impact of smoking, smoking cessation, and nicotine replacement therapy: a systematic review. Ann Surg 2012; 255:1069.
  47. Harris JE. Smoke yields of tobacco-specific nitrosamines in relation to FTC tar level and cigarette manufacturer: analysis of the Massachusetts Benchmark Study. Public Health Rep 2001; 116:336.
  48. Bodnar JA, Morgan WT, Murphy PA, Ogden MW. Mainstream smoke chemistry analysis of samples from the 2009 US cigarette market. Regul Toxicol Pharmacol 2012; 64:35.
  49. Sørensen LT. Wound healing and infection in surgery. The clinical impact of smoking and smoking cessation: a systematic review and meta-analysis. Arch Surg 2012; 147:373.
  50. Wukich DK, McMillen RL, Lowery NJ, Frykberg RG. Surgical site infections after foot and ankle surgery: a comparison of patients with and without diabetes. Diabetes Care 2011; 34:2211.
  51. Monfrecola G, Riccio G, Savarese C, et al. The acute effect of smoking on cutaneous microcirculation blood flow in habitual smokers and nonsmokers. Dermatology 1998; 197:115.
  52. Sørensen LT, Jørgensen S, Petersen LJ, et al. Acute effects of nicotine and smoking on blood flow, tissue oxygen, and aerobe metabolism of the skin and subcutis. J Surg Res 2009; 152:224.
  53. Black CE, Huang N, Neligan PC, et al. Effect of nicotine on vasoconstrictor and vasodilator responses in human skin vasculature. Am J Physiol Regul Integr Comp Physiol 2001; 281:R1097.
  54. Jensen JA, Goodson WH, Hopf HW, Hunt TK. Cigarette smoking decreases tissue oxygen. Arch Surg 1991; 126:1131.
  55. Møller AM, Villebro N, Pedersen T, Tønnesen H. Effect of preoperative smoking intervention on postoperative complications: a randomised clinical trial. Lancet 2002; 359:114.
  56. Sorensen LT, Karlsmark T, Gottrup F. Abstinence from smoking reduces incisional wound infection: a randomized controlled trial. Ann Surg 2003; 238:1.
  57. Møller AM, Kjellberg J, Pedersen T. [Health economic analysis of smoking cessation prior to surgery--based on a randomised trial]. Ugeskr Laeger 2006; 168:1026.
  58. Sørensen LT, Jørgensen T. Short-term pre-operative smoking cessation intervention does not affect postoperative complications in colorectal surgery: a randomized clinical trial. Colorectal Dis 2003; 5:347.
  59. Sørensen LT, Zillmer R, Agren M, et al. Effect of smoking, abstention, and nicotine patch on epidermal healing and collagenase in skin transudate. Wound Repair Regen 2009; 17:347.
  60. Sørensen LT, Toft B, Rygaard J, et al. Smoking attenuates wound inflammation and proliferation while smoking cessation restores inflammation but not proliferation. Wound Repair Regen 2010; 18:186.
  61. Sørensen LT, Toft BG, Rygaard J, et al. Effect of smoking, smoking cessation, and nicotine patch on wound dimension, vitamin C, and systemic markers of collagen metabolism. Surgery 2010; 148:982.
  62. Sørensen LT, Jorgensen LN, Zillmer R, et al. Transdermal nicotine patch enhances type I collagen synthesis in abstinent smokers. Wound Repair Regen 2006; 14:247.