Wound healing and inflammation: from acute inflammation to the mature scar

Acute inflammation: the vascular and cellular response

Inflammation is the response of vascularised living tissue to injury, and its job is to deliver leucocytes and plasma proteins to the site of damage. The cardinal signs — rubor, calor, tumor, dolor and functio laesa — are the visible face of two sequences. The vascular phase begins with a few seconds of arteriolar vasoconstriction, then vasodilatation driven by histamine, nitric oxide and prostaglandins (hence redness and heat), then increased permeability of post-capillary venules as endothelial cells contract and gaps open between them under histamine, bradykinin, leukotrienes, C3a and C5a. Protein-rich fluid leaks out as an exudate — specific gravity above about 1.020, high protein, cells — as distinct from the low-protein transudate of raised hydrostatic or reduced oncotic pressure, and the slowing of flow (stasis) brings leucocytes to the vessel wall.

The cellular phase belongs first to the neutrophil. Margination along the endothelium is followed by rolling on selectins (E- and P-selectin on the endothelium, L-selectin on the leucocyte), firm adhesion when integrins on the neutrophil are activated by chemokines and bind ICAM-1 and VCAM-1, transmigration between endothelial cells (diapedesis, using PECAM-1), and chemotaxis along gradients of C5a, leukotriene B₄, IL-8 and bacterial peptides. At the target the neutrophil recognises opsonised particles (IgG Fc and C3b), engulfs them into a phagosome and kills them by oxygen-dependent mechanisms — the NADPH oxidase respiratory burst producing superoxide and, through myeloperoxidase, hypochlorous acid — and by oxygen-independent lysozyme, defensins and lactoferrin. Chronic granulomatous disease, with its defective NADPH oxidase, shows what happens without the burst. Neutrophils predominate for the first 24–48 hours and then die by apoptosis; monocytes arrive from about 48 hours and mature into macrophages, which clear the debris and direct what comes next.

The four phases of healing

Wound healing is acute inflammation with a constructive ending. The phases overlap, but each has a dominant cell and a timetable the exam expects you to know.

Tensile strength lags behind collagen content because early collagen is poorly cross-linked. A healing wound has only a few per cent of normal strength in the first week, about 20% at three weeks, and plateaus at roughly 70–80% of unwounded skin after about three months; it never reaches 100%. That curve explains why laparotomy sutures must hold for weeks (and why slowly absorbed or non-absorbable material is used for fascia), why scars stretch when subjected to early tension, and why incisional hernias declare themselves months after the operation.

Primary, secondary and tertiary intention

Primary intention

The edges are apposed with sutures, staples, glue or tape. Minimal granulation tissue forms, epithelial continuity is restored within 24–48 hours and the scar is narrow. It needs a clean wound with little tissue loss and no tension.

Secondary intention

The wound is left open to fill with granulation tissue from the base, contract from the edges by myofibroblast activity, and epithelialise from the margins. Slower, with a broader and often depressed scar, but the method of choice for infected, contaminated or tissue-deficient wounds and for abscess cavities.

Tertiary (delayed primary) intention

A contaminated or doubtful wound is cleaned, debrided and left open for a few days — typically three to five — then closed once it is clearly clean and granulating. Used for heavily contaminated lacerations, war wounds, some bites and after a relook laparotomy.

What impairs healing

Healing fails when the wound cannot be perfused, cannot be kept clean, or cannot build collagen. The exam likes the local–systemic split.

• Local: infection (more than about 10⁵ organisms per gram of tissue, or β-haemolytic streptococcus at any count), foreign body or necrotic tissue, haematoma or seroma, poor perfusion (arterial disease, venous hypertension, oedema, tension, tight sutures), previous irradiation, repeated trauma or shear, desiccation, and a mobile joint beneath the wound.
• Systemic: advancing age; diabetes (microangiopathy, neuropathy, glycation of proteins, impaired neutrophil function); malnutrition — especially protein, vitamin C (scurvy, from failed hydroxylation), vitamin A, zinc and copper; smoking (nicotine vasoconstriction, carbon monoxide, impaired fibroblast and neutrophil function); obesity; corticosteroids, which suppress inflammation, fibroblast proliferation and collagen synthesis (vitamin A partly reverses this), chemotherapy and other immunosuppressants; uraemia, jaundice, anaemia and hypoxia; hypothermia; hypothyroidism; and inherited connective-tissue disorders such as Ehlers–Danlos syndrome.

Abnormal scarring

Hypertrophic scar

A raised, red, itchy scar that stays within the boundaries of the original wound. It appears within weeks of injury, typically after wounds under tension, across flexures or in deep burns, in any skin type, and tends to regress over one to two years. It responds to pressure garments, silicone gel or sheeting, massage and intralesional steroid, and excision with correction of the cause (tension, a contracture) is reasonable. Histology shows organised collagen bundles parallel to the surface and abundant myofibroblasts.

Keloid

Scar tissue that extends beyond the original wound margins into normal skin, often appearing months after injury — sometimes after trivial trauma such as ear piercing or acne — and continuing to grow; it does not regress. It is commoner in darker skin, runs in families, and favours the earlobe, presternal area, deltoid and upper back. Histology shows thick, haphazard, hyalinised collagen bundles with an excess of type III. Excision alone recurs in most cases, so it is combined with intralesional steroid, pressure, silicone or adjuvant radiotherapy.

Other patterns to recognise: contracture (shortening across a joint or orifice from unopposed contraction, prevented by splinting and early grafting), atrophic and stretched scars, and Marjolin's ulcer — squamous cell carcinoma arising in a chronic wound, burn scar or osteomyelitis sinus, classically decades later, with a poor prognosis once it breaches the poorly lymphatic scar tissue that initially contains it.

Chronic inflammation and granulomas

Chronic inflammation is prolonged inflammation in which active inflammation, tissue destruction and attempted repair proceed together. It follows acute inflammation that cannot resolve — persistent infection, retained foreign material, inadequate drainage — or arises de novo in autoimmune disease, prolonged exposure to toxic agents and certain infections. The cells are lymphocytes, plasma cells and macrophages rather than neutrophils, with angiogenesis and fibrosis; the clinical correlates are chronic ulcers, fistulae, sinus tracts and the strictures of Crohn's disease.

A granuloma is a specific form of chronic inflammation: a focal collection of activated macrophages with an epithelioid appearance, often fused into multinucleate giant cells and surrounded by a cuff of lymphocytes, formed when a stimulus cannot be digested — a T-cell-mediated (type IV hypersensitivity) response. Caseating granulomas with central necrosis are the hallmark of tuberculosis; non-caseating granulomas occur in sarcoidosis, Crohn's disease, foreign-body reactions to suture or talc, fungal infection, leprosy and syphilis. Langhans giant cells with their horseshoe of nuclei are typical of tuberculosis, foreign-body giant cells have haphazard nuclei, and Touton cells are seen in xanthomas and fat necrosis.

Wound classification and surgical site infection

NICE NG125 (Surgical site infections: prevention and treatment) sets out the principles the exam draws on. Before surgery: patients shower or bathe with soap the day before or on the day; hair is not removed routinely and, when it must be, electric clippers with a single-use head are used on the day — never razors, which abrade the skin and raise infection rates; antibiotic prophylaxis is given as a single intravenous dose on starting anaesthesia (earlier when a tourniquet will be inflated) for clean surgery involving a prosthesis or implant, for clean-contaminated and for contaminated surgery, and not routinely for clean non-prosthetic surgery; nasal decolonisation with mupirocin and a chlorhexidine body wash is considered where Staphylococcus aureus is a likely cause. In theatre: surgical hand decontamination, sterile gowns and gloves, skin antisepsis with an alcohol-based chlorhexidine preparation as first choice (aqueous chlorhexidine next to a mucous membrane, povidone-iodine where chlorhexidine is contraindicated), maintenance of normothermia, oxygenation and perfusion, and glycaemic control; triclosan-coated sutures may be considered; diathermy for the skin incision and routine wound irrigation are not recommended as ways of reducing infection. Afterwards: aseptic non-touch technique for dressing changes, sterile saline for cleaning during the first 48 hours, after which the patient may shower; tap water for a wound that has been opened; no topical antimicrobials on wounds healing by primary intention; and an established infection is treated by opening and draining the wound with an antibiotic chosen for the likely organisms.