Only a century ago, complicated and incomplete healing after injury was the rule rather than the exception. Surgeons had little choice but to accept draining wounds and invasive infections. New means of aiding healing and preventing infections have been developed. To use them efficiently, knowledge of the basic mechanisms of healing is required.
Forms of Healing
Surgeons customarily divide types of wound healing into first and second “intention.”
Role of Tissue Hypoxia
Impaired perfusion and oxygenation are the most frequent causes of healing failure. Oxygen is required for successful inflammation, bacterial-killing angiogenesis, epithelialization, and matrix (collagen) deposition. The critical oxygenases involved have Km values for oxygen of about 20 mm Hg and maximums of about 200 mm Hg, which means that their reaction rates are governed by PaO2 and blood perfusion throughout the entire physiologic range. The PaO2 of wound fluid in human incisional wounds is about 30–40 mm Hg, implying that these enzymes normally function just beyond half capacity. Wound PaO2 is depressed by blood volume deficiency, catecholamine infusion, or cold. On the other hand wound fluid PaO2 can be raised above 100 mm Hg by improved perfusion and breathing of oxygen. Human healing is profoundly influenced by local blood supply, vasoconstriction, and all other factors that govern perfusion and blood oxygenation.
Cardiopulmonary diseases affect wound healing, but vasoconstriction due to sympathetic nervous system activity is the principal background clinical problem. Prevention or resolution of problems can be achieved by turning off sympathetic activity by correcting blood volume deficits, alleviating pain, and avoiding hypothermia. Wounds in highly vascularized tissues (eg, head, anus) heal rapidly and are remarkably resistant to infection.
Impaired Healing in Disorders of Inflammation
The growth signals and lytic enzymes released by inflammatory cells are necessary for repair. Excessive and inadequate inflammatory responses can pose problems. Failure to heal is common in patients taking anti-inflammatory corticosteroids, immune suppressants, or cancer chemotherapeutic agents and whose inflammatory responses are blunted. Open wounds suffer more than primarily healing ones. The inhibiting effect of these agents diminishes as their effect on inflammation lessens. The clinical corollary is that administration is less harmful after the third day than on the first. Healing impaired by inadequate inflammation, especially that due to corticosteroids, can be accelerated by vitamin A systemically or locally. Experimentally, this appears to pertain to diabetics as well. In experiments, some of the growth factors have also had this effect.
Inflammation may also be excessive. A major excess of inflammation (eg, in response to endotoxin) can excite inflammatory cells to produce cytolytic cytokines and excessive proteinases with the consequence of lysis of newly formed tissue. In gram-negative wound infections or septic shock, granulation tissue may not develop or it may even be lysed.
Massive injuries give rise to large inflammatory reactions, and cytokines from large but otherwise uncomplicated wounds can produce systemic symptoms. Extensive wounds can produce large amounts of lactate that must be reconverted to glucose in the liver — a process that contributes to the hypermetabolism of trauma. High levels of lactate also enhance oxidant production and loss of cell function.
Debridement of damaged tissue and early immobilization of fractures minimize the above effects. Stimulation of the reticuloendothelial system, major amounts of injured tissue, and failure to debride can produce the SIRS even in the absence of infection.
Effect of Malnutrition
Malnutrition impairs healing, since healing depends on cell replication, specific organ function (liver, heart, lungs), and matrix synthesis. Weight loss and protein depletion have been shown experimentally to be risk factors for poor healing. Nevertheless, healing may be normal in patients who have lost weight over a long period as opposed to a short but severe loss. Deficient healing is seen mainly in patients with acute malnutrition (ie, in the weeks just before or after an injury or operation). Even a few days of starvation measurably impairs healing, and an equally short period of repletion can reverse the deficit. Wound complications increase in severe malnutrition. A period of preoperative corrective nutrition is generally helpful for patients who have recently lost 10% or more of their body weight.
Healing of Specialized Tissues
The axon then regenerates from the nerve cell through the rejoined sheaths, advancing as much as 1 mm/d. Unfortunately, because individual neural sheaths have no means of seeking out their original distal ends, the axon sheaths reconnect randomly, and motor nerve axons may regenerate in vain into a sensory distal sheath and end organ. The functional result of neural regeneration, therefore, is more satisfactory in the purer peripheral nerves and in nerves rejoined by microscopic surgical techniques. This is currently one of the forefronts of surgical research.
The rate of repair varies from one part of the intestine to the other in proportion to vascularity. Drugs such as fluorouracil limit lysis and in experimental conditions appear to prevent the early loss of strength in colonic wounds.
Though the surgeon aims for primary healing in anastomoses, much of the healing actually occurs by second intention in both sutured and stapled anastomoses. Fine surgical technique is more likely to promote primary repair.
Adhesions are wrongly assumed to be an almost inevitable consequence of abdominal surgery. The most powerful stimuli to adhesions is ischemic tissue because ischemic tissues attract a new blood supply that takes the form of vascularized adhesions, abscesses, foreign bodies.
Simple peritoneal defects are less likely to cause adhesions. When severe trauma, large defects, infection, ischemia, or foreign bodies are added, the process becomes more intense. Trauma and inflammation excite plasma leaks and deposition of fibrin. If allowed to remain, the fibrin increases the volume of ischemic tissue. Exogenous plasminogen activator has decreased the occurrence of adhesions in experimental circumstances, but side effects discourage its clinical use.
Attempts to prevent adhesions by suturing peritoneal defects usually worsen the problem by causing local ischemia and suture granulomas. Starch powder used in most surgical gloves as a lubricant was a great improvement over talc, but severe peritoneal (as well as pericardial, pleural, and meningeal) inflammatory reactions due to starch and leading to adhesions are well documented. Evidence indicates that lymphocytes participate in healing more so in colon wounds than in wounds of other tissues. Immunologic contribution is proportionately greater.
Bone healing is controlled by many of the same mechanisms that control soft tissue healing. It, too, occurs in three morphologic stages: an inflammatory stage, a reparative stage, and a remodeling stage. The duration of each stage varies depending on the location, nature of the fracture.
Injury (fracture) leads to hematoma formation from the damaged blood vessels of the periosteum, endosteum, and surrounding tissues. Within hours, an inflammatory infiltrate of neutrophils, macrophages is recruited into the hematoma as in soft tissue injuries. Monocytes and granulocytes debride and digest necrotic tissue and debris, including bone, on the fracture surface. This process continues for days to weeks depending on the amount of necrotic tissue.
During the reparative stage, the hematoma is gradually replaced by specialized granulation tissue that has the power to form bone. This tissue, known as callus, develops from both sides of the fracture and is composed of fibroblasts, endothelial cells, and bone-forming cells (chondroblasts, osteoblasts). The extent to which callus forms from the medulla, the periosteum, or cortical bone depends upon the site of fracture, the degree of immobilization, and the type of bone injured. As macrophages (osteoclasts) phagocytose the hematoma and injured tissue, fibroblasts (osteocytes) deposit a collagenous matrix, and chondroblasts deposit proteoglycans in a process called enchondral bone formation. This step, prominent in some bones, is then converted to bone as osteoblasts condense on hydroxyapatite crystals on specific points on the collagen fibers. Endothelial cells form a vasculature characteristic of bone with an end result analogous to reinforced concrete. Eventually the fibrovascular callus is completely replaced by new bone.
Bone healing also depends on blood supply. Upon injury, the ends of fractured bone become avascular. Osteocyte and vessel lacunae become vacant for several millimeters from the fracture. New blood vessels must sprout from preexisting ones and migrate into the area of injury. As new blood vessels cross the bone ends, they are preceded by osteoclasts just as macrophages precede them in soft tissue repair. In bone, this unit is called the “cutting cone” because it literally bores its way through bone in the process of connecting with other vessels. Excessive movement of the bone ends during this revascularization stage will break the delicate new vessels and delay healing.
Osteomyelitis originates most often in ischemic bone fragments. Hyperoxygenation hastens fracture healing and aids in the cure (and potentially the prevention) of osteomyelitis. Acute or chronic hypoxia slows bone repair. Applications of electrical currents maintain its progress.
Once the fracture has been bridged, the new bone remodels in response to the mechanical stresses upon it, with restoration to normal or near-normal strength. During this process, as in soft tissue, preexisting bone and its vascular network are simultaneously removed and replaced. Increased bone turnover may be detected as long as 6–9 years after injury.
Fibroblasts, chondroblasts, and osteoblasts in healing fractures are derived from surrounding primitive mesenchyme. The origin of the mesenchyme is less clear. It seems to arise from muscle, fascia, periosteum, endothelium, marrow, even from circulating stem cells, as well as directly from fibrous tissue. The differentiation of these mesenchymal cells into bone-forming cells appears to be governed by specific growth factors such as bone morphogenetic protein, TGF, IGF-1, GM-CSF, and PDGF, all of which stimulate proliferation and induce the differentiation of osteoblasts in cell culture. BMP (which belongs to the TGF supergene family) appears to be the most specific for bone and is found in large quantity in bone matrix. BMP induces ectopic bone formation in the absence of preexisting bone and induces cartilage formation in vivo.
Bone repair may occur through primary or secondary intention. Primary repair can occur only when the fracture is stable and aligned and its surfaces closely apposed. This is the goal of rigid plate fixation of fractures. When these conditions are met, capillaries can grow across the fracture and rapidly reestablish a vascular supply. Little or no callus forms. Secondary repair with callus formation is more common.
Bone repair can be manipulated. Electrical currents applied directly (through implanted electrodes) or induced by external alternating electromagnetic fields accelerate repair by inducing new bone formation in much the same way as small piezoelectric currents produced by mechanical deformation of intact bone controls remodeling along lines of stress. The technique of electrical stimulation has been used successfully to treat nonunion of bone (where new bone formation between bone ends fails, often requiring long periods of bed rest). BMP-impregnated implants have accelerated bone healing in animals and have been used with encouraging results to treat large bony defects and nonunions.
The Ilizarov technique, linear distraction osteogenesis, can lengthen bones, stimulate bone growth across a defect. The Ilizarov device is an external fixator attached to the bones through metal pins or wires. A surgical break is created and then slowly pulled apart (1 mm/d) or slowly reangulated. The vascular supply and subsequent new bone formation migrate along with the moving segment of bone.
Synthetic nonabsorbable sutures are generally inert, retain strength (do not fracture) longer than wire. However, their handling characteristics are not as good as those of silk, and they must usually be knotted at least four times, resulting in large amounts of retained foreign body. Multifilament plastic sutures are just as apt to become infected and migrate to the surface as silk sutures. Monofilament plastic, like wire, will not harbor bacteria. Nylon monofilament is extremely nonreactive, but it is difficult to tie. Monofilament polypropylene is intermediate in these properties. Plastic sutures are required for cardiovascular work because they are not absorbed. Vascular anastomoses to prosthetic vascular grafts rely indefinitely on the strength of sutures; therefore, use of absorbable sutures may lead to aneurysm formation. Even monofilament sutures will “spit.” However, this disadvantage is generally confined to sizes of 00 and larger.
Synthetic absorbable sutures are strong, have predictable rates of loss of tensile strength, incite a minimal inflammatory reaction, and have special usefulness in gastrointestinal, urologic, gynecologic surgery. Compared with catgut, polyglycolic acid and polyglactin retain tensile strength longer in gastrointestinal anastomoses. Polydioxanone sulfate and polyglycolate are monofilament and lose about half their strength in 50 days, thus solving the problem of premature breakage in fascial closures. Poliglecaprone 25 is a newer monofilament synthetic suture with faster reabsorption, retaining 50% tensile strength at 7 days, and 0% at 21 days. This suture is suitable for soft tissue approximation but is not intended for fascial closure.
Tapes are the skin closure of choice for clean or contaminated wounds. They minimize the probability of infection by not connecting the skin surface to the wound dead space. They cannot be used on actively bleeding wounds or wounds with complex surfaces, such as those in the perineum.
Staples, whether for internal use or skin closure, are mainly steel-tantalum alloys that incite a minimal tissue reaction. The technique of staple placement is different from that of sutures, but the same basic rules pertain. There are no real differences in the healing that follows suture or stapled closures. Stapling devices tend to minimize errors in technique, but at the same time they do not offer a feel for tissue and have limited ability to accommodate to exceptional circumstances. Staples are preferable to sutures for skin closure, since they do not provide a conduit for contaminating organisms. Staples are not, however, preferable to skin tapes.
Chronically unhealed wounds, especially on the lower extremity, are common in the setting of vascular, immunologic, and neurologic disease. Venous ulcers, largely of the lower leg, reflect poor perfusion, perivascular leakage of plasma into tissue. This is the result of venous hypertension produced by incompetent venous valves. Most venous ulcers will heal if the venous congestion and edema are relieved by bed rest, compression stockings, surgical procedures that eliminate incompetent feeding vessels.
Arterial or ischemic ulcers, which tend to occur on the lateral ankle or foot, are best treated by revascularization. Hyperbaric oxygen, which provides a temporary source of enhanced oxygenation that stimulates angiogenesis, is an effective though expensive alternative when revascularization is not possible. Useful information can be obtained by transcutaneous oximetry. Tissues with a low PaO2 will not heal spontaneously. However, if oxygen tension can be raised into a relatively normal range by oxygen administration even intermittently, the lesion will probably respond to oxygen therapy.
Sensory loss, especially of the feet, leads to ulceration. Bony deformities due to fractures, the so-called Charcot deformity, are difficult problems. Ulcers in patients with diabetes mellitus may have two causes. Patients with neuropathic ulcers usually have good circulation, their lesions will heal if protected from trauma by bed rest, special shoes, or splints. Recurrences are common, however. Diabetics with ischemic disease, whether they have neuropathy or not, are at risk for gangrene, and they frequently require amputation when revascularization is not possible. Insulin dressings have been advocated. More recently, intermittent warming has been helpful.
In pyoderma gangrenosum, granulomatous inflammation with or without arteritis kills skin and subcutaneous skin, possibly by a mechanism involving excess cytokine release. These ulcers are associated with inflammatory bowel disease and certain types of arthritis and chondritis. Corticosteroids or other anti-inflammatory drugs are helpful. However, anti-inflammatory corticosteroids can also contribute to poor healing by inhibiting cytokine release. In these cases, topical or systemic vitamin A restores the inflammatory mechanism and may induce healing of the lesions. Distinguishing between these possibilities in patients with inflammatory bowel disease may be difficult.
Infection may contribute to the lack of healing of chronic ulcers or may be a complication. The bacteria are usually mixed and staphylococci are commonly present. Antibiotics should be part of initial therapy in most cases. However, antibiotics are a secondary concern to enhanced vulnerability.
The most important means of achieving optimal healing after operation is good surgical technique. Many cases of healing failure are due to technical errors. Tissue should be protected from drying and contamination. The surgeon should use fine instruments; should perform clean, sharp dissection; and should make minimal, skillful use of electrocautery, ligatures, and sutures. All of these precautions contribute to the most important goal of surgical technique — gentle handling of tissue. Even the best ligature or suture is a foreign body that may strangulate tissue if tied tightly. The skillful operator who uses sutures minimally and gently will be rewarded with the best results. Good hemostasis is a laudable objective, but excessive sponging, electrocautery, and tying of small vessels are traumatic and invite infection.
As with many surgical techniques, the exact method of wound closure may be less important than how well it is performed. The tearing strength of sutures in fascia is no greater than 3–4 kg. There is little reason for use of sutures of greater strength than this. Excessively tight closure strangulates tissue and leads to hernia formation and infection.
If surgeons could foresee the future, dehiscence (undesired spontaneous separation of wound edges) would be none, since techniques to prevent it are well known. The surgeon can choose the techniques to meet the needs and risks of the individual wound. The most common technical causes of dehiscence are infection and excessively tight sutures.
Surgeons often must operate patients who have impaired wound healing. In these cases, closures must be stronger. A more secure closure begins with a running or mattress absorbable suture in the posterior sheath, joint capsule, or submucosa. The closure is continued with simple buried retention sutures through the fascia in which the farthest point of penetration is at least 1 cm from the wound edge. When the tension is placed this far back, the fascial fibers closer to the wound that become weakened by postinjury collagen lysis are not expected to provide critical support. The lytic effect extends for about 5 mm to each side of the wound edge. The skin is preferably closed with adhesive strips unless bleeding from the wound or an uneven surface makes adherence of the strips precarious, in which case staples are the next choice. With this fascial closure, the skin can easily be left open for delayed primary or secondary closure. Subcutaneous tissues rarely need to be sutured closed.
In all closures, sutures should be placed as far apart as possible consistent with approximation of tissue. Sutures placed too tightly, too close together obstruct blood supply to the wound. In most cases of dehiscence, suture material cuts through tissue. Broken or untied sutures are found less often.
It is useful to assess wound risk in advance, so that the proper choice of closure can be made easily.
Poor apposition of surrounding tissues (pelvic anastomosis, unreduced fracture, unclosed dead space)
Factors that increase collagen synthesis
Delayed primary closure is a technique by which the subcutaneous portion of the wound is left open for 4–5 days and then closed with skin tapes. During the delay period, angiogenesis and healing start, and bacteria are cleared from the wound. The success of this method depends on the ability of the surgeon to detect minor signs of infection. Merely leaving the wound open for 4 days does not guarantee that it will not become infected. Some wounds (eg, fibrin-covered or inflamed wounds) should not be closed but should be left open for secondary closure.
The appearance of delayed wound infection — weeks to years after operation — emphasizes that all wounds are contaminated and that the line between apparent infection and apparent normal repair is a fine one. A minor setback such as a period of cardiac failure or of malnutrition will often allow infection to become established. Most frequently, however, poor tissue perfusion and oxygenation of the wound during the postoperative period weaken host resistance. Regulation of perfusion is due—more than anything — to sympathetic nervous activity. The instigators of vasoconstriction are cold, pain, hypovolemia, beta-blockers, cigarette smoking, and hypoxemia. Recent tests show that special efforts to remove or limit these factors reduce the wound infection rate by more than half. Maintenance of normothermia and blood volume is particularly important. Appropriate assurance that peripheral perfusion is adequate is best obtained from peripheral tissues rather than urine output, central venous pressure, or wedge pressure — none of which correlate with peripheral wound tissue oxygenation. What does correlate with tissue oxygenation is the capillary refill time on the forehead or patella, which should be less than 2 seconds and 5 seconds, respectively; or true thirst and eye globe turgor (which should match the observer’s). Collagen deposition is increased also by the addition of oxygen breathing (nasal prongs or light mask) but only in well-perfused patients. Unfortunately, there are as yet no convenient clinical means of measuring wound PaO2 that can be done routinely.
Postoperative care of the wound also involves cleanliness, protection from trauma, and maximal support of the patient. Even closed wounds can be infected by surface contamination, particularly within the first 3 days. Bacteria gain entrance most easily through suture tracts. If a wound is likely to be traumatized or contaminated, it should be protected during this time. Such protection may require special dressings such as occlusive sprays or repeated cleansings as well as dressings.
Some mechanical stress enhances healing. Even fracture callus formation is greater if slight motion is allowed. Patients should move and stress their wounds a little. Early ambulation and return to normal activity are, in general, good for repair.
Surgical technique must be clean, gentle, and skillful. Postoperatively, wound care includes maintenance of nutrition, blood volume, and oxygenation. Although wound healing is in many ways a local phenomenon, ideal care of the wound is essentially ideal care of the patient.
Although localized collections in the chest and abdominal cavities often require drainage, wounds rarely do. Routine use of drains is more harmful than helpful. If drainage of reapproximated wounds that have been opened due to infection is needed, it should be done with vacuum-assisted techniques.