16/11/2019 Basic principles of wound healing - UpToDate

Authors: David G Armstrong, DPM, MD, PhD, Andrew J Meyr, DPM

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2019. | This topic last updated: Sep 18, 2018.

INTRODUCTION

A wound is a disruption of the normal structure and function of the skin and underlying soft tissue
[1]. Wounds may be caused by a variety of mechanisms, including acute traumatic injury to the
skin (abrasion, puncture, crush, burns, gunshot, animal bite, surgery) and other etiologies that
cause initially intact skin to break down. Any mechanism that decreases blood flow in the skin for
a prolonged period of time has the potential to cause ischemic breakdown of the skin. Skin
perfusion may be impaired due to proximal arterial obstruction (eg, peripheral artery disease),
vascular compression (eg, hematoma, immobility causing focal pressure), or microvascular
occlusion or thrombosis (eg, vasculitis, cholesterol crystals).

Wound classification and the basic principles of wound healing are reviewed here. The factors
responsible for impaired wound healing and wound complications, as well as the clinical
assessment and management of wounds, are reviewed elsewhere. (See "Risk factors for
impaired wound healing and wound complications" and "Clinical assessment of chronic wounds"
and "Basic principles of wound management".)

WOUND ETIOLOGY AND CLASSIFICATION

Wounds may arise through traumatic injury (including surgery) or from the breakdown of
previously intact skin and are generally classified as acute or chronic.

Acute wounds — Acute wounds usually have an easily identifiable mechanism of injury with
skin integrity disrupted, typically due to some form of trauma. Acute traumatic skin disruption can
result from blunt or penetrating mechanisms with an array of wound sizes, depths, and locations.
Simple or complicated lacerations, burns, or significant tissue defects may result, each requiring
individualized management and care. (See "Basic principles of wound management", section on
'Acute wounds'.)

Surgical wounds are a controlled form of acute wound that is created in the operating room
environment. Surgical wounds are classified according to the degree of bacterial load or
https://www.uptodate.com/contents/basic-principles-of-wound-healing 1/8
16/11/2019 Basic principles of wound healing - UpToDate

contamination of the surgical wound and are used to predict the risk of surgical wound infection
that can impact wound healing. The four categories are clean, clean-contaminated,
contaminated, and dirty. The majority of clean and clean-contaminated wounds are closed
primarily at the completion of the surgery; contaminated and dirty wounds as well as surgical
wounds requiring removal of staples or sutures due to postoperative wound infection are left
open and require wound care. The classification of surgical wounds is presented in more detail
elsewhere.

Chronic wounds — Chronic wounds/ulcers affect a substantial proportion of the population and
contribute to a significant burden in the hospital setting. (See "Overview of treatment of chronic
wounds".)

Chronic wounds can develop from acute traumatic or surgical skin injury or result from
breakdown of previously intact skin (table 1). Patients with impaired 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.

Although there is no specific time frame that clearly differentiates an acute from a chronic
wound, chronic wounds are generally associated with physiological impairments that slow or
prevent wound healing (figure 1). For foot ulcers due to diabetes, some suggest that the lack of
an approximately 15 percent surface area reduction weekly or approximately 50 percent
reduction over a one-month period indicates a chronic state [2]. (See "Risk factors for impaired
wound healing and wound complications".)

WOUND HEALING

Wound healing occurs as a cellular response to tissue injury and involves activation of
keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets (figure 2). The process
involves organized cell migration and recruitment of endothelial cells for angiogenesis. The many
growth factors and cytokines released by these cell types coordinate and maintain wound
healing (figure 3). Once hemostasis is achieved, acute wounds normally heal in an orderly and
efficient manner characterized by overlapping phases that include inflammation, epithelialization,
fibroplasia, and maturation [3-5].

Acute wounds transition through the stages of wound healing as a linear pathway, with clear
start and endpoints (figure 4). Restoration of skin integrity following the development of an acute
surgical wound in normal individuals is usually complete within two to four weeks. However,
following initial successful surgical skin closure, open wounds or dehiscence may result from
disruption of the sutured skin, which can be due to technical error, infection, or the presence of
foreign material within the wound.

https://www.uptodate.com/contents/basic-principles-of-wound-healing 2/8
16/11/2019 Basic principles of wound healing - UpToDate

Chronic wounds are arrested in one of the wound healing stages, usually the inflammatory
stage, and fail to progress further (picture 1). In these situations, the normal physiology of the
linear pathway is transformed into the pathophysiology of a chronic cycle, without a clear wound
closure endpoint. Healing of a surgical wound can also be delayed or prolonged in patients with
disease states that impair the healing process. (See 'Impaired wound healing' below and "Risk
factors for impaired wound healing and wound complications".)

PHASES OF WOUND HEALING

Hemostasis — Immediately after injury to the skin, small vessels within the wound constrict to
provide at least a measure of hemostasis for 5 to 10 minutes. Platelets aggregate in severed
vessels, trigger the clotting cascade, and release essential growth factors and cytokines that are
important for the initiation and progression of wound healing (eg, platelet-derived growth factor,
transforming growth factor beta). The fibrin matrix that results stabilizes the wound and provides
a provisional scaffold for the wound healing process. Hemostasis is discussed in detail
elsewhere. (See "Overview of hemostasis".)

Larger vessels may require pressure, ligation, hemostatic agents, electrocautery, or other
hemostatic energy devices to achieve hemostasis. (See "Overview of topical hemostatic agents
and tissue adhesives" and "Overview of electrosurgery".)

Inflammation — The inflammatory phase of healing is sometimes called the lag phase because
wound strength does not begin to return immediately. The inflammatory phase is completed
within three days except in the presence of infection or other factors associated with impaired
wound healing. (See "Risk factors for impaired wound healing and wound complications",
section on 'Infection'.)

Key components of this phase are increased vascular permeability and cellular recruitment.
Multiple events contribute to these processes, including:

● Mononuclear leukocytes accumulate and are transformed into macrophages [6]. The
maturation of blood-derived monocytes into macrophages is heralded by several events,
including secretion of vimentin, which is a structural filament protein involved in wound
healing [7].

● Mast cells degranulate, releasing histamine and other mediators of vasodilation and cellular
migration.

● Release of vasoactive substances from stromal mast cells makes small vessels permeable
to molecular and cellular mediators of the inflammatory response. The resulting
accumulation of plasma and cellular elements is noted clinically as edema or swelling.

https://www.uptodate.com/contents/basic-principles-of-wound-healing 3/8
16/11/2019 Basic principles of wound healing - UpToDate

● Chemotaxis results in migration and concentration of polymorphonuclear leukocytes that

In chronic wounds, the normal healing progression usually becomes arrested in this
inflammatory stage. The presence of necrotic tissue, foreign material, and bacteria result in the
abnormal production of matrix metalloproteases, which alter the balance of inflammation and
impair the function of the cytokines described above.

Epithelialization — Epithelialization (also called migration) refers to basal cell proliferation and
epithelial cell migration occurring in the fibrin bridgework inside a clot [8]. Proliferation continues
until individual cells are surrounded by cells of similar type. In a clean surgical wound, the
epithelial cells migrate downward to meet deep in the dermis (figure 5). Migration ceases when
the layer is rejuvenated. Following surgery, this process is normally complete within 48 hours.
The superficial layer of epithelium creates a barrier to bacteria and other foreign bodies.
However, it is very thin, is easily traumatized, and gives little tensile strength.

The process of epithelialization is difficult in wounds that are not primarily closed or need to heal
by secondary intention (picture 2). In these wounds, the physical distance of epithelial migration
is increased across the length, width, and depth of the wound.

This process may be further impaired by the presence of biofilm and senescent cells on the
wound edge or base. Biofilm is an extracellular matrix produced by bacteria that irreversibly
binds to the wound base, promoting inflammation and impairing epithelialization. Epithelial cells
at the wound edge may also become senescent or mitotically inactive and unable to perform the
DNA replication necessary for the process of proliferation [9].

Fibroplasia — Fibroplasia consists of fibroblast proliferation, accumulation of ground substance,

Fibroblasts are transformed from local mesenchymal cells (picture 3) and are usually present in
the wound within 24 hours and predominate by the tenth postoperative day [10]. They attach to
the fibrin matrix of the clot, multiply, and produce glycoprotein and mucopolysaccharides, which
make up ground substance. In addition, fibroblasts produce contractile proteins, designated
myofibroblasts (picture 4), which have characteristics of smooth muscle cells with the ability to
contract and are present in the wound by the fifth day. Pulling the edges of the wound together is
dependent upon tissue mobility. Myofibroblastic cells are lost via apoptosis as repair resolves to
form a scar.

Fibroblasts also synthesize collagen, the primary structural protein of the body. Collagen
production begins on the second postoperative day, when it is secreted as an amorphous gel
devoid of strength. Maximum collagen production does not begin until day 5 and continues for at
least six weeks [11]. The developing collagen matrix stimulates angiogenesis. Granulation tissue
is the result of the combined production of collagen and growth of capillaries (figure 6).
https://www.uptodate.com/contents/basic-principles-of-wound-healing 4/8
16/11/2019 Basic principles of wound healing - UpToDate

In pathological fibrosis, myofibroblasts persist and are responsible for fibrosis via increased
matrix synthesis and for wound contraction. The exuberant scarring may impede normal organ
function or, in the case of skin, result in keloid [12]. (See "Keloids and hypertrophic scars" and
"Hypertrophic scarring and keloids following burn injuries".)

Maturation — Key elements of the maturation stage include collagen cross-linking, collagen
remodeling, wound contraction, and repigmentation (picture 5).

The tensile strength of the wound is directly proportional to the amount of collagen present [13].
Numerous types of collagen have been identified; types I and III predominate in the skin and
aponeurotic layers. Initially, a triple helix (tropocollagen) is formed by three protein chains; two
are identical alpha-1 protein chains, and the third is an alpha-2 protein. Bundles of tropocollagen
combine to form collagen. As disorganized collagen is degraded and reformed, covalent cross-
links are formed that enhance tensile strength (figure 7).

The maximum strength of the healed wound depends upon the interconnection of collagen
subunits. Approximately 80 percent of the original strength of the tissue is obtained by six weeks
after surgery (figure 8), but the diameter and morphology of collagen fibers do not have the
appearance of normal skin until approximately 180 days [14]. Wounds slowly continue to get
stronger but may never achieve 100 percent of their previous strength [3,4].

The quality of healing that is achieved also depends upon the severity of tissue trauma and the
presence of factors that may delay healing or reduce the tensile strength of the final scar; for
surgical wounds, the suture material used in repair may contribute as well. Rest and immobility
are important during the immediate postoperative period for successful healing to occur.
However, some physical activity is essential during the maturation phase because light tension
increases tensile strength by remodeling, which may continue for many years.

IMPAIRED WOUND HEALING

There is usually not a single primary factor that contributes to impaired wound healing; in fact,
the overlapping intricacy of the pathway serves to prevent this from happening. Instead, there
are most often multiple, smaller contributing issues that can disrupt the process. As examples,
local tissue ischemia and neuropathy can impair chemotaxis during the hemostasis and
inflammatory stages. Tissue necrosis and infection alter the balance of inflammation and
compete for oxygen. Uncontrolled periwound edema and wound instability disrupt myofibroblast
activity and collagen deposition and cross-linking. The risk factors associated with impaired
wound healing and wound complications are reviewed separately. (See "Risk factors for
impaired wound healing and wound complications".)

https://www.uptodate.com/contents/basic-principles-of-wound-healing 5/8
16/11/2019 Basic principles of wound healing - UpToDate

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Minor wound
management" and "Society guideline links: Chronic wound management".)

SUMMARY AND RECOMMENDATIONS

● A wound is a disruption of the normal structure and function of the epidermis. Wounds may
be caused by a variety of mechanisms, including acute traumatic injury to the skin
(abrasion, puncture, crush, burns, gunshot, animal bite, surgery) or other etiologies that
cause initially intact skin to break down. (See 'Introduction' above.)

● There is no specific time frame that clearly differentiates an acute from a chronic wound.
Chronic wounds are generally associated with physiologic derangements that impair the
wound healing process. (See 'Chronic wounds' above.)

● After hemostasis has been achieved, acute wounds normally heal in an orderly and efficient
manner characterized by four distinct but overlapping phases: inflammation,
epithelialization, fibroplasia, and maturation. Chronic wounds are arrested in one of the
wound healing stages, usually the inflammatory stage, and fail to progress further unless the
underlying causes are addressed. (See 'Wound healing' above.)

● Many disease states alter the process of wound healing, the most common of which are
peripheral artery disease, diabetes, and chronic venous disease. Small vessel arterial
diseases (the vasculitides) are also associated with the development of skin ulcers and poor
wound healing due to vascular obstruction or vascular thrombosis. Other factors that
contribute to skin or surgical wound breakdown or nonhealing ulcers include infection,
smoking, aging, malnutrition, immobilization, immunosuppressive therapy, chemotherapy,
and radiation therapy. (See 'Impaired wound healing' above and "Risk factors for impaired
wound healing and wound complications".)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Orr JW, Taylor PT. Wound healing. In: Complications in gynecological surgery: Prevention,
recognition, and management, JB Lippincott, Philadelphia p.167.

https://www.uptodate.com/contents/basic-principles-of-wound-healing 6/8
16/11/2019 Basic principles of wound healing - UpToDate

2. Sheehan P, Jones P, Giurini JM, et al. Percent change in wound area of diabetic foot ulcers
over a 4-week period is a robust predictor of complete healing in a 12-week prospective
trial. Plast Reconstr Surg 2006; 117:239S.

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

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 Diab
etes 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. 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.

12. Haukipuro K. Synthesis of collagen types I and III in reincised wounds in humans. Br J
Surg 1991; 78:708.

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.

Topic 15080 Version 21.0

https://www.uptodate.com/contents/basic-principles-of-wound-healing 7/8
16/11/2019 Basic principles of wound healing - UpToDate

https://www.uptodate.com/contents/basic-principles-of-wound-healing 8/8