Team Member Role(s) Profile
Paul Banaszkiewicz Paul Banaszkiewicz Section Editor
Zak Zakareya Gamie Segment Author
  • Wound healing remains a challenging clinical problem. Wound infection and breakdown remain a frequent cause of morbidity and mortality. It is important as orthopaedic surgeons to have a comprehensive understanding of the physiology and pathophysiology of wound healing to minimise wound healing complications. Wound healing involves different cell populations, the extracellular matrix and the action of mediators such as growth factors and cytokines. Although the process of healing is continuous, it may be arbitrarily split into three phases: 

(1) inflammation

(2) proliferation

(3) wound remodelling with scar tissue formation.

  • Wound healing involves a complex series of events including cell division, chemotaxis, neovascularisation, and the formation and maturation of scar tissue. It is regulated by a number of mediators that includes cytokines, inflammatory cells and growth factors.

Primary healing

  • This wound is closed within 12–24 hours of its creation.

Delayed primary healing

  • The wound is closed after a few days having been left open to prevent infection. After 3–4 days local recruitment of phagocytic cells destroy contaminated tissue.

Secondary healing

  • This occurs in a wound with extensive loss of soft tissue secondary to trauma or severe burns. There is an ingrowth of granulation tissue from the wound margin, accumulation of extracellular matrix and the laying down of collagen.
  • These are essentially open, full thickness wounds closed by wound contracture and epithelialisation.
  • It can be divided into three important phases:1,2
  1. The inflammatory phase
  2. The proliferative phase
  3. The maturation phase


Figure 1. Phases of wound healing

The inflammatory phase of wound healing (1–3 days)

  • The inflammatory phase of wound healing is characterised by platelet accumulation, coagulation and the formation of a fibrin plug (which consists of platelets embedded in a meshwork of mainly polymerised fibrinogen (fibrin), fibronectin, vitronectin, and thrombospondin), increased permeability of the vessels adjacent to the wound, and leukocyte migration into the wound bed.
  • During this phase the role of polymorphonuclear leukocytes (PMNLs), monocytes, and macrophages (tissue equivalent of the monocyte) are attracted to the wound site within 24–48 hours of injury by a number of chemoattractants including transforming growth factor β (TGF-β) and complement components.
  • T-cells also have a role in wound healing as growth factor producing cells and immunological effector cells.3 A number of cytokines, which are synthesised by T-helper (Th) lymphocytes have a profound influence in mediating the physiological response to tissue injury. The two major subsets of Th lymphocytes are the Th1 and Th2 cells, which are characterised by the presence of cell surface glycoprotein receptor cluster of differentiation 4 (CD4). CD8+ cells are involved in more specific cell targeting.
  • Th1 cells secrete tumour necrosis factor (TNF), interferon gamma (IFN-γ), interleukin (IL)-1 and IL-2, which are key mediators of cellular immunity.
  • Th2 cells secrete IL-4, IL-5, IL-6, IL-10 and IL-13, which are key mediators of the humoral immune system, and are predominantly responsible for stimulating the synthesis and release of antibodies from mature B-lymphocytes.
  • Th3 cells are a minor subset of Th lymphocytes which secrete TGF-β and IL-10, and mediate a dampening of the overall immune response by inhibiting the action of other Th cells.
  • An increased presence of T-cells and imbalances between CD4 and CD8 cells has been reported in chronic wound healing problems such as venous or diabetic ulcers.4

The proliferative phase of wound healing (3–10 days)

  • The proliferative phase of wound healing involves a combination of four individual processes which take place simultaneously.
  • Fibroplasia and angiogenesis within the wound bed collectively form both the granulation tissue matrix as well as the delicate new blood vessels which supply the developing tissue with essential nutrients.
  • Re-epithelialisation restores the cutaneous barrier, and finally contraction of the wound by myofibroblasts reduces the wound size along with the resulting scar tissue.
  • This process is also associated with a gradual decline in the number of pro-inflammatory cells associated with the early stages of the wound healing.

The matrix deposition and remodelling phase of wound healing (weeks to months)

  • Matrix deposition and remodelling constitutes the longest phase in the wound healing process. It typically takes place over a period of months, as granulation tissue progressively devascularises and the collagen within the scar tissue undergoes dynamic remodelling.4,5
  • Achieving equilibrium between collagen formation and degradation is extremely important in this process. There is sequential deposition of collagen, first type 3 and then type 1, and their hydroxylation peaks at around week 3. Collagen provides tensile strength, securing the matrix and scar tissue in situ, whereas collagenases degrade collagen in order to maintain the extracellular matrix. Together collagen synthesis and collagenolysis determine the functional strength of the scar tissue.
  • The wound continues to contract with a maximal tensile strength about 60% of the previously unwounded skin.


Figure 2. Timing, main events and duration of phases



  • 1. Parkin J, Cohen B. An overview of the immune system. Lancet 2001; 357(9270): 1777–1789.
  • 2. Howgate DJ, et al. The potential adverse effects of aromatase inhibitors on wound healing: in vitro and in vivo evidence. Expert Opin Drug Safety 2009; 8(5): 523–535.
  • 3. Strbo N, Yin N, Stojadinovic O. Innate and adaptive immune responses in wound epithelialization. Adv Wound Care 2014; 3(7): 492–501.
  • 4. Loots MA, et al. Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. J Invest Dermatol 1998; 111(5): 850–857.
  • 5. Clark R. The molecular and cellular biology of wound repair. Springer Science & Business Media, 2013.