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In Brief

A wound is a disruption of normal anatomic structure and function thatresults from pathologic processes that begin internally or externally to theinvolved organ(s). Wounds can be caused accidentally or intentionally orbe the result of a disease process. Wound healing is a dynamic interactiveprocess that begins at the moment of wounding and involves solublemediators, many cell types, and extracellular matrices. Wound healing canno longer be thought of as a generic term but rather a series of carefullyregulated, interrelated processes. These processes including coagulation,inflammation, deposition and differentiation of extracellular matrix, fibro-plasia, epithelialization, contraction, and remodeling are initiated at thetime of wounding and proceed through repair. Unencumbered, theseprocesses follow a specific time sequence or chronologic order. Althoughthe timing of the various processes is usually orderly, they are not mutu-ally exclusive, and there is a varying overlap in time.

Clinically, categorization of wounds as acute or chronic has been basedon the timeliness of healing. The use of a dynamic healing trajectory orhealing time curve allows a complete evaluation of wound healing.Healing trajectories provide information about the whole continuum ofthe wound healing processes. In the past, it was thought that, if onedebrided a wound of nonviable tissue and repaired it in a physiologicmanner, the normal phases of wound healing should proceed without dif-ficulty. However, it is clear that many local and systemic factors can causedisturbances in the repair processes and be reflected by a slowed woundhealing trajectory. Conversely, we now have the ability to begin interven-tions that go beyond optimization of the wound healing environment toaccelerate healing and maximize the healing trajectory.

Wounds have been with man from his prehistoric beginnings. Surgicaloperations that resulted in wounds were performed as long ago as 100centuries. In every ancient culture from Mesopotamia, Egypt, and India tothe Roman, Byzantine, and Arabic periods, wounds and wound healingwere discussed. Later during the Middle Ages and the Renaissance, con-cepts of debridement and gentle handling of tissue were discussed.Because wounds have been with mankind since the beginning, the scopeof these wounds and their repair in terms of prevalence and costs must beconsidered. Each year in the United States alone, there are 50,000,000

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surgical operations performed, and more than $7 billion spent on woundcare products.

The process of acute wound healing allows the most clarity for under-standing the various cellular processes and the soluble messengers ormediators that orchestrate cell-cell and cell-matrix interaction. Acutewound healing is a highly regulated sequence of cellular, humoral, andmolecular events that are activated at the time of injury and result in atime-dependent but predictable and orderly pattern of repair. Immediatelyafter injury, hemostasis and coagulation occur to prevent exsanguination.Signaling pathways initiated at the time of tissue injury such as theeicosanoid products of arachidonic acid metabolism and active oxygenradicals such as nitric acid may be considered as primary mediators ofacute wound healing. Wound cytokines may then be considered as sec-ondary mediators or messengers. The inflammatory process normally fol-lows coagulation, first with an influx of polymorphonuclear leukocytesfollowed by a wave of monocytes that eventually differentiate into tissuemacrophages. The macrophage secretes additional cytokines to attractand proliferate fibroblasts. These fibroblasts synthesize collagen andother extracellular matrix molecules. The processes of epithelializationand contraction are also controlled by cytokines such as platelet-derivedgrowth factor (PDGF), transforming growth factor beta (TGFβ1), basicfibroblast growth factor (bFGF), and keratinocyte growth factor.Angiogenesis restores blood supply to the wound by a budding or sprout-ing mechanism that forms new blood vessels and acute granulation tissue.Numerous tissue growth factors (such as vascular endothelial growth fac-tor and bFGF) play central regulatory roles in neovascularization and sub-sequent tissue repair. Collagen, the major protein component of connec-tive tissue, is secreted, cross-linked, and remodeled to finalize the repairprocess. These activities appear to be controlled by a series of mediatorsof which TGFβ plays a pivotal role. Ideally, the summation of these vari-ous processes occurs efficiently with the optimum recovery in tissuestrength and function in a minimum amount of time.

A chronic wound is one that has failed to proceed through an orderlyand timely process to produce anatomic and functional integrity or hasproceeded through the processes without establishing a sustained anatom-ic and functional result. Chronic wounds such as pressure ulcers, venousstasis ulcers, diabetic neuropathic ulcers, and ischemic ulcers are charac-terized by one or more persistent inflammatory stimuli: repeat trauma,ischemia, or bacterial contamination. This leads to an ongoing proin-flammatory stimulus instead of a self-limited proinflammatory stimulus,

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as in acute wounds. In addition to elevated proinflammatory cytokines,the chronic wound has increased protease activity, decreased levels of nat-ural tissue inhibitors to metalloproteinases, and diminished growth factoractivity. Degradation of the growth factors and their receptors limits theprogression of the wound healing cascade by eliminating its mediators.Progression through the wound healing scheme is thereby impaired; thetrajectory is slowed, and the wound fails to heal.

Ideally, the outcome of wound healing would be the reestablishment ofthe status quo before wounding. This can occur only through the processof regeneration, which unfortunately occurs only in lower vertebrates.Chronic wounds heal slower than normal acute wounds, whereas the tra-jectory for fetal wounds appears to be accelerated. The prenatal healingresponse is faster and more efficient than adult repair and produces newtissue rather than scar. Most of the healing processes are modified in thefetus; coagulation produces less PDGF and TGFβ than in the adult.Inflammation is essentially absent, with minimal production of TGFβ.This results in a more organized extracellular matrix that requires lessgranulation tissue formation and essentially no remodeling. There aremajor differences in the extracellular matrix of the fetal wound, with morehyaluronic acid, and in the humoral mediators, with very little TGFβ.These differences result in fetal wounds that heal rapidly and withoutscarring. In terms of a wound healing trajectory, the fetal wound healingcurve is to the “left” of healing adult wounds. If regeneration occurred inwounds above the lower vertebrates, it would result in the “ideal” woundhealing trajectory. Therefore, the trajectory of fetal wound healing isabout as close to “ideal” as we have to study human healing.

It is clear from the differences of acute wound healing, chronic woundhealing, and fetal wound healing that the evaluation of the outcome ofhealing can be measured versus time. The acute wound healing trajectoryis, in reality, an integration of multiple time-dependent processes. The endresult trajectory is a compromise between the processes as they wouldproceed in a vacuum and the way they proceed in the organism whenexposed to systemic and local deterrents to healing. The compromised tra-jectory has been suggested to be “normal” wound healing. “Normal” heal-ing and “impaired” healing can be viewed on a continuum and are a com-promise from “ideal” healing. In an attempt to accelerate wound healing,conceptually the healing process moves in the direction of the “ideal.”This essentially shifts the healing curve or trajectory to the left. Any localor systemic deterrent to wound healing processes would shift the trajec-tory to the right toward “impaired” healing.


There are both systemic and local deterrents to wound healing; allimpair the repair processes and shift the trajectory to the right. Systemiccauses include diabetes mellitus, decreased perfusion, hypoxia, renal fail-ure, corticosteroids, immune deficiency, cancer, and radiation. Each ofthese affect specific cellular processes and/or humoral mediators. Localfactors are also important. Necrotic tissue, high bacterial levels, ischemia,hematoma, foreign bodies, and dead space can all result in healing impair-ment. More than 105 bacteria per gram of tissue has been shown to affectadversely every process in the wound healing scheme.

The goal is to “normalize” or “idealize” the wound healing trajectory.There are several ways the surgeon can optimize wound healing and/orneutralize the deterrents to healing that tend to shift the trajectory to theright. Obviously, diabetes requires meticulous medical control, perfusionto the wound part must be maximized, and other systemic causes must beoptimized to the greatest degree possible. Vitamin A can neutralize thedetrimental effects on healing because of corticosteroids. Local detrimen-tal factors can usually be eliminated completely or diminished greatly bythe surgeon. Judicious debridement can remove necrotic or devascular-ized tissue. A combination of debridement, irrigation, and topical antibac-terials can decrease tissue bacterial levels and establish “bacterial bal-ance” within the wound. Limb revascularization can eliminate or reduceischemia and hypoxia. Surgical technique as taught in the Halstedian tra-dition can minimize hematomas, foreign bodies, and dead space. All ofthese maneuvers will aid in shifting the healing trajectory to the left toaccelerate the processes of repair.

Once a wound is optimized mechanically to close or to allow sponta-neous closure, other strategies have been developed to optimize the cellu-lar and molecular environment. Until now, most of these advances havebeen aimed at chronic wounds because they are thought to have impairedhealing. Because chronic wounds have decreased levels of essentialcytokine growth factors, attempts to shift the healing trajectory to the leftwith the application of exogenous growth factors have been made over thepast 10 years. Clinical trials of topical recombinant growth factors toaccelerate healing of diabetic neuropathic foot ulcers, pressure ulcers, andvenous stasis ulcers have been reported, with varying degrees of success.It is obvious that substances that are chemotactic to inflammatory cellssuch as neutrophils and macrophages or mitogenic to cells such as fibro-blasts, endothelial cells, and keratinocytes should benefit wound healing.Not only have trials been performed with single growth factors such asPDGF-BB, bFGF, TGFβ2, epidermal growth factor, interleukin-1β, granu-


locyte macrophage-colony stimulating factor, and insulin-like growth fac-tor-1 but combinations of factors and sequential application of factorshave been attempted also. Newer strategies attempt to combine exogenousgrowth factors and protease inhibitors to maximize the healing trajectory.Another way to optimize the molecular and cellular environment is withthe use of active dressings and skin substitutes. Combinations of cells,extracellular matrix, and growth factors attempt to reeducate the wound torepair itself though bioengineering. Effecting immediate permanent func-tional wound closure is the goal of these products. If this strategy wereeffective routinely, this would shift the trajectory markedly to the left.Although limited success of these bioengineered products has beenreported, like the exogenous growth factor therapy, uniform success is notyet achievable.

Although most efforts to optimize the cellular and molecular milieu ofthe wound have been aimed at chronic wounds, there have been recentattempts to shift the acute wound healing trajectory more towards the“ideal.” Realizing the sigmoid-shaped curve of gain in breaking strengthis a compromise, attempts have been made to shorten the inflammatory orlag phase of healing, accelerate the proliferative phase of healing, andmodulate the remodeling phase of healing. Injection of TGFβ1 or TGFβ2accelerates the proliferative phase of healing by stimulating fibroblastsdirectly to synthesize collagen. Injecting proinflammatory cytokines intoareas of proposed incisions before actual wounding eliminates the “lag”in healing and simulates the inflammatory phase of healing before theincision is made. Recent attention to fascial healing instead of dermalhealing has demonstrated that fascial repair has a more rapid trajectorythan skin. Major intra-abdominal operations such as hepatectomy canimpair fascial healing; this impairment can be returned to normal with theaddition of TGFβ2 to the fascial repair.

Gene therapy is being evaluated to replace missing or deficient proteinsin wounds. Although cells can be transfected and will produce the proteinencoded by the gene, expression levels have not been adequate to pro-duce, in a reliable manner, the clinical effect. In addition, the levels arefurther lowered by wound proteases. One way to overcome the low levelsand short time of action is to devise vectors with polymer coatings,microspheres, or synthetic matrices for prolonged DNA delivery. Whenthis occurs, gene therapy may become part of the armamentarium toattempt to achieve “ideal” healing.

Wound healing is not always a self-contained result of a series of eventswith a defined endpoint. Overhealing or proliferative scar formation can


result from any wound and in every organ system. In terms of the woundhealing trajectory, proliferative scarring is not so much a problem on thetime abscissa as it is a problem of the amount of healing on the ordinate. Inexcessive healing or proliferative scarring, it is as if the equilibrium pointbetween collagen deposition and lysis is never reached. There are sugges-tions that the processes of coagulation, inflammation, angiogenesis, fibro-plasia, contraction, and remodeling may be different in wounds, resultingin proliferative scars. Epidermal regeneration does not play a major role inscar production. Increases in the time and/or intensity of inflammation areassociated with proliferative scarring and may result in later changes inangiogenesis and fibroplasia. The key cytokine released during inflamma-tion that may trigger many cell-cell and cell-matrix interactions that lead toproliferative scarring is TGFβ. It appears that over-expression or dysregu-lated activation of TGFβ may lead to fibrosis and scar formation. With therecent description of an animal model for explanted human proliferativescars, it has been shown that the isoforms of TGFβ, specifically TGFβ1 andTGFβ2, can increase fibroblast kinetics, stimulate fibroblast synthesis ofcollagen I and collagen III, and increase the size of the proliferative scars.Neutralizing antibodies to TGFβ1 and TGFβ2 can abrogate or reverse thosechanges. The action of TGFβ2 in the pathogenesis of proliferative scarringmay be to downregulate fibroblast apoptosis or programmed cell death.

Most treatment of proliferative scarring has been disappointing. However,with the recent recognition of the importance of TGFβ isoforms in fibro-genesis, new treatments are being investigated. Interferon α-2b downregu-lates collagen synthesis in burn scars because of its ability to antagonizeTGFβ gene regulation and production. Other attempts to decrease the effectsof TGFβ include decorin, mannose-6-phosphate, and tamoxifen. If success-ful in models of integumentary proliferative scarring, these anti-TGFβ agentscould be used in other fibrotic conditions such as Dupuytren’s contracture,periprosthetic capsular contracture, adhesions, cirrhosis, glomerulonephritis,or glial scarring in the central nervous system.

Wounds have been with mankind since the beginning. The evolution ofhealing may not have kept pace with modern technology. The degree ofinflammation and fibrosis necessary in prehistoric times may be excessivetoday. The lessons learned from fetal wound healing and recent attemptsto control proliferative scarring suggest that this is true. The wound heal-ing trajectory that today’s surgeon considers “normal” may indeed beimpaired. By understanding the biologic features of wound healing, thesurgeon can collaborate with other medical specialists and basic scientiststo develop approaches to maximize healing trajectories.
