Wound healing — Medicine Library

Summary

Wounds are a break in the skin and/or a disruption of the skin's normal barrier function. Wound healing is a step-wise cellular response involving fibroblasts, macrophages, endothelial cells, and keratinocytes that restore the structural and functional integrity of the skin. The four general stages of wound healing are exudative, resorptive, proliferative, and maturation. While the three initial stages take place within the first two weeks, the last stage proceeds over months. Many factors affect wound healing, including the size of the wound, tension on wound edges, the presence of foreign bodies or infection, and the baseline health and nutrition of the patient. In addition, chronic health conditions such as diabetes and peripheral vascular disease can slow the wound healing process. Delayed wound healing may lead to the formation of a chronic wound.

Phases of wound healing

Phases of wound healing [1]
Phase	Timing	Cells involved	Characteristics	Involved tissue mediators
Exudative	Day 1	Platelets Neutrophils Macrophages	Hemostasis: platelet aggregation → clot formation Scab formation Immediate local vasoconstriction (lasts 5–10 minutes) due to the release of prostaglandins, kinins, leukotrienes, and thromboxane A2 (TXA₂) from ruptured cell membranes and platelets Followed by vasodilation and increased vessel permeability Wound pain may occur.	PDGF FGF EGF Prostaglandins TXA₂
Resorptive	Days 1–3	Platelets Neutrophils Macrophages	Chemotaxis (via PAF, PDGF, and TGF-β) of inflammatory cells (i.e., neutrophils, macrophages, lymphocytes) to the site of injury Macrophages release growth factors and cytokines that recruit other immune cells, stimulate fibroblast proliferation (fibrosis) and resorb debris. Lymphocytes migrate to injury approx. 72 hours after the injury to promote cellular immunity. Continued vasodilation EGF induces tyrosine kinases such as EGFR → epithelium at wound margins begins to proliferate	PAF PDGF TGF-β
Proliferative	Days 3–7	Macrophages Fibroblasts Myofibroblasts, Endothelial cells Keratinocytes	Formation of granulation tissue Fibroplasia → synthesis and deposition of type III collagen. Growth factors (FGF, EGF, VEGF, PDGF, and TGF-β) from fibroblasts and epithelial cells promote angiogenesis. PDGF stimulates smooth muscle cell migration and fibroblast growth → collagen synthesis Wound contraction occurs as collagen synthesis increases and pulls the wound edges together. This process is facilitated by myofibroblasts. Epidermal cells Migrate across the collagen matrix to form a full layer Secrete collagenase to dissolve the clot Replicate along a provisional matrix formed by inflammatory cells to completely cover the wound	FGF EGF PDGF VEGF TGF-β
Maturation	Weeks to 1 year	Fibroblasts	Scar forms with the proliferation of fibroblasts and remodeling of connective tissue. Removal of excess collagen Macrophages release matrix metalloproteinases and collagenases (require zinc), which facilitate the final remodeling of type III collagen into type I collagen. Collagen becomes more organized, returning strength to the region of injury. Peak tensile strength (∼ 80% of original strength) is reached ∼ 60 days after injury. Sweat and sebaceous glands do not regenerate.	Matrix metalloproteinase

Exudative phase of wound healing Resorptive phase of wound healing Proliferative phase of wound healing Maturation phase of wound healing

**Proliferative phase of wound healing**
Granulation tissue develops during the proliferative stage. It consists of macrophages, fibroblasts, and lymphocytes. Granulation tissue is abundant in blood capillaries and type 3 collagen fibers. Epidermal stem cells at the wound margins proliferate to renew the epidermis at the wound site. Secretion of collagenase facilitates clot degradation. Wound contraction occurs as collagen synthesis increases and pulls the wound edges together. This process is facilitated by myofibroblasts.

© AMBOSS

**Maturation phase of wound healing**
Scar tissue formation occurs as type I collagen replaces type III collagen in the connective tissue. The scar tissue is covered by epidermis, but it lacks melanocytes and skin appendages such as hair follicles or cutaneous sweat glands.

© AMBOSS

Wound healing complications

Scar formation

Occurs when initial injury cannot be repaired solely by cell regeneration
Cells that cannot be regenerated (e.g., due to chronic injury or because acute injury is too severe) are replaced by connective tissue.
After 3 months, 70–80% of tensile strength is regained. [2]
Maximum strength of scar tissue is approx. 80% of that of unwounded skin. [2]

Excessive scar

Dysregulation of the wound healing process during the proliferative stage and maturation stage leads to excess fibroblast replication and collagen deposition.
Molecular mechanisms
[3]
[4]
[5]
[6][7][8]

Increased production of:

Certain isoforms of transforming growth factor-beta (primary mediator)

Connective tissue growth factor

Platelet-derived growth factor

Tissue inhibitors of metalloproteinases

Decreased production of:

Basic fibroblast growth factor

Metalloproteinases (e.g., collagenase)

Interleukin-10

Hypertrophic scar

Cutaneous condition characterized by high fibroblast proliferation and collagen production that leads to a raised scar that does not grow beyond the boundaries of the original lesion.
See “Hypertrophic scars.”

Keloid

Skin lesions caused by high fibroblast proliferation and collagen production in excessive tissue response to typically small skin injuries
Lesions grow beyond the original wound margins, leading to a ”claw-like” appearance.
See “Keloid scars.”

Contracture

Excessive proliferation in myofibroblasts during proliferative and maturation phases leads to contraction of the wound.
Excessive contraction can reduce the functionality of the injured limbs or organs.
Wounds that cross a joint (e.g., on the hands and fingers) are at high risk for causing functional deficits from contracture. Periodic exercise of the involved limb can help preserve normal function.

References

Stadelmann WK, Digenis AG, Tobin GR. "Physiology and healing dynamics of chronic cutaneous wounds". Am J Surg. 176(2A Suppl). :26S-38S. (1998)
Thiruvoth F, Mohapatra D, Sivakumar D, Chittoria R, Nandhagopal V. "Current concepts in the physiology of adult wound healing". Plastic and Aesthetic Research. 2(5). :250. (2015)
Zhu Z, Ding J, Tredget EE. "The molecular basis of hypertrophic scars.". Burns & trauma. 4. :2. (2016)
Leivonen SK, Lazaridis K, Decock J, et al. "TGF-β-elicited induction of tissue inhibitor of metalloproteinases (TIMP)-3 expression in fibroblasts involves complex interplay between Smad3, p38α, and ERK1/2.". PloS one. 8(2). :e57474. (2013)
Shah M, Foreman DM, Ferguson MW. "Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring.". J Cell Sci. 108 ( Pt 3). :985-1002. (1995)
Schultz GS, Chin GA, Moldawer L, et al. "Principles of Wound Healing". StatPearls. (2011)
Köse O, Waseem A. "Keloids and hypertrophic scars: are they two different sides of the same coin?". Dermatol Surg. 34(3). :336-46. (2008)
Verhaegen PD, van Zuijlen PP, Pennings NM, et al. "Differences in collagen architecture between keloid, hypertrophic scar, normotrophic scar, and normal skin: An objective histopathological analysis.". Wound Repair Regen. 17(5). :649-56