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The Role of Growth Factors in Wound Healing

Greenhalgh, David G. MD

The Journal of Trauma: Injury, Infection, and Critical Care: July 1996 - Volume 41 - Issue 1 - p 159-167
Review Article
Free

Growth factors have many activities that make them attractive agents for stimulating tissue repair. Growth factors attract cells into the wound, stimulate their proliferation, and have profound influence on extracellular matrix deposition. Since developing the ability to mass-produce these cytokines by recombinant techniques, hundreds of studies have demonstrated that growth factors can augment all aspects of tissue repair in normal and impaired healing models. After demonstrating that growth factors augment healing, investigators have started to detect and measure growth factors in wounds and have found that wounding initiates the expression of various growth factors. Impaired healing has also been linked to altered growth factor production. These findings have prompted great interest in the use of growth factors to augment clinical healing. Preliminary clinical trials have not produced the results expected. Growth factor treatment has occasionally led to statistically significant improvements in tissue repair, but whether the results are clinically significant can be debated. It appears that to be cost effective, clinical trials must focus on targeting growth factors for specific types of impaired healing. Although growth factors have not been the panacea that was originally expected, they have the potential for making significant clinical improvements when targeted for specific problem wounds.

From the Shriners Burn Institute and Department of Surgery, University of Cincinnati, Cincinnati, Ohio.

Address for reprints: David G. Greenhalgh, MD, Shriners Burn Institute, 3229 Burnet Ave., Cincinnati, OH 45229.

Key Words: Growth factors, Cytokines, Wound healing, Clinical trials, Platelet-derived growth factor, Fibroblast growth factor, Epidermal growth factor, Transforming growth factor-alpha, Transforming growth factor-

Why do wounds heal? How does the body know that tissue is damaged? While the transmission of pain and other sensations tell the brain that a wound has occurred, wounds still heal in tissues lacking sensation. Without the ability to communicate, one might suppose that a wound would not heal. Cells communicate with each other through the use of specific molecules that are usually proteins. Proteins that are used for cellular communication are called "cytokines." Cytokines are secreted in minute quantities from one cell and then bind to a cellular receptor to induce a response in the recipient cell. When a protein is released into the blood stream, cells are affected in areas distant to the original cell in what is called an "endocrine" response. When a cell secretes a protein to stimulate a nearby cell, the response is called a "paracrine" interaction. Proteins can be released from a cell that bind to its own receptors in an "autocrine" response. Finally, certain cytokines remain attached to the cell membrane and the interaction involves one cell to another through direct cell contact ("juxtacrine" interaction).

Growth factors are a subclass of cytokines that specifically stimulate the proliferation of cells. [1] While all of this class of cytokines act as mitogens, their name may be misleading, since most growth factors have other functions. In essence, growth factors have the ability to affect all aspects of the cellular phenotype. Recently, a great deal has been learned about the intracellular mechanisms of how growth factors cause phenotypic changes in cells. Although the molecular mechanisms of growth factor actions are beyond the scope of this paper and are covered in other reviews, [2-9] a few simplified mechanistic points may be made. The binding of growth factors to cell surface receptors leads to the initiation of specific cell transduction pathways. In addition to binding growth factors, many receptors must form dimers as a requirement for cell transduction. Most growth factors activate tyrosine kinases that are attached to the receptor. The receptor-associated tyrosine kinase then activates a series of other kinases that initiate a specific signal transduction pathway. Phospholipase C is often involved in growth factor signal transduction. Activation of intracellular kinases may also activate "G proteins" (members of the guanine nucleotide regulatory proteins), which in turn, activate the inositol phospholipid pathway. The inositol pathway activates diacylglycerol, which activates protein kinase C. Protein kinase C leads to changes in gene expression through such molecules as c-fos and transcription factor AP1 /c-jun. The inositol pathway may also lead to changes in intracellular calcium concentrations. Ultimately, changes in gene expression lead to new protein synthesis, changes in cellular activity or proliferation. As studies progress, greater details will be ascertained about the cell transduction pathways of growth factors.

Growth factors have the potential to improve wound healing through several mechanisms. First, growth factors have chemotactic activities that attract inflammatory cells and fibroblasts into the wound. Second, growth factors act as mitogens to stimulate cellular proliferation. Third, growth factors can stimulate angiogenesis, the ingrowth of new blood vessels. Fourth, growth factors have a profound effect on the production and degradation of the extracellular matrix. Finally, growth factors influence the synthesis of cytokines and growth factors by neighboring cells.

There currently are scores of growth factors that have been identified. A brief summary of some of the more common growth factors will be reviewed. The names of growth factors are frequently misleading because they may have little relation to their major actions. Most growth factors were named by the original cell that they were found to stimulate, the cell of original isolation, or with the specific assay in which they were identified. Growth factors are usually grouped into "families" based on structural and functional similarities.

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PLATELET-DERIVED GROWTH FACTOR (PDGF)

One of the earlier growth factors to be discovered was PDGF, a growth factor that is a product of not only platelets but macrophages and many other cell types. PDGF must exist as a dimer consisting of either A and/or B chains (AA, AB, or BB). [10,11] The most common form in the human platelet is the AB form (70% AB, 30% BB). [12] Like many growth factors, abnormal PDGF regulation and feedback may lead to cell transformation. The B chain has been found to be the c-sis proto-oncogene and is very similar to the transforming protein produced by the simian sarcoma virus. There are two specific PDGF receptors: alpha and beta. [13] The alpha receptor can bind all three isoforms (AA, AB, or BB). The beta receptor binds the BB homodimer with high affinity, the AB with lower affinity, and does not bind AA. The differential binding contributes to the varying effects of the different isoforms on cellular function. PDGF is chemotactic for fibroblasts, smooth muscle cells, and possibly monocytes, and neutrophils. PDGF is a mitogen (increases proliferation) for smooth muscle cells and fibroblasts. It also has profound effects on the extracellular matrix. [10,11] At least two other proteins fit in the PDGF family. Vascular endothelial growth factor (VEGF) is a growth factor that has homology with PDGF and is a potent angiogenic factor. [14]

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FIBROBLAST GROWTH FACTOR (FGF)

There are currently at least nine members of the fibroblast growth factor family. [15] Many of these growth factors have heparin-binding capabilities. There are four known FGF receptors that contain tyrosine kinase activities (FGFR-1, FGFR-2, FGFR-3, and FGFR-4). [16] Another membrane protein binds FGFs but lacks kinase activity. The first two members of the FGF growth factor family to be discovered were acidic and basic FGF (aFGF or FGF-1, and bFGF or FGF-2, respectively). The majority of the healing studies have involved these two growth factors. Acidic and basic FGF have profound angiogenic activities in addition to being mitogenic for fibroblasts. One of the more recently discovered fibroblast growth factors, keratinocyte growth factor (KGF or FGF-7), has been found to have profound stimulatory effects on keratinocyte growth. [17]

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TRANSFORMING GROWTH FACTOR-beta (TGF-beta)

One of the most interesting growth factors has been transforming growth factor-beta, which currently consists of five isoforms. [18] Only three isoforms are found in humans. TGF-beta is secreted as a high molecular weight latent dimer complex. [19] The latent form must be activated before producing an effect. TGF-beta is also bound by several proteins, such as alpha2 -macroglobulin, which further regulate the growth factor activity. There are three well-characterized TGF-beta receptors (types I, II, and III) and at least three more less well-described receptors (types IV, V, and VI). [19] The best characterized growth factor is TGF-beta1, which has been found to have multiple effects, depending on the cell type and the environment. TGF-beta1 is a very potent stimulant for collagen deposition and inhibits collagen breakdown. [18] Studies have demonstrated that if TGF-beta1 is blocked, then scar production may be decreased. [20] Interestingly, TGF-beta3 may actually inhibit scar formation on its own. [21] TGF-beta1 is also very important for the regulation of inflammation. Animals deficient in TGF-beta1 die from an overwhelming inflammatory response. [22] TGF-beta is also important for down-regulating the growth of many cell types and has been found to be involved in cancer formation when it is not properly regulated.

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EPIDERMAL GROWTH FACTOR (EGF)

One of the first growth factors to be identified was epidermal growth factor. The discovery led to the Nobel Prize for Stanley Cohen. EGF stimulates the proliferation and migration of all types of epithelial cells. [23] EGF has also been found to be important for the healing of the gut mucosa and may have protective and healing effects for ulcers. [24] Transforming Growth Factor-alpha (a completely different growth factor than TGF-beta) has a very similar action and structure as EGF; however, TGF-alpha may be more potent than EGF. [25] These two growth factors (plus other members of the family) bind to the EGF receptor and initiate the signal transduction pathway described above. A mutated form of the EGF receptor that lacks the extracellular component is the oncogene v-erb-B. [26] The loss of the extracellular binding site leads to a loss of negative feedback, chronic receptor activation, and malignant transformation.

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INSULIN-LIKE GROWTH FACTORS (IGF-I, IGF-II)

The insulin-like growth factors are similar in structure to proinsulin and have considerable overlapping functions. IGF-I (also known as somatomedin C) has profound effects on stimulating growth, especially the secondary growth characteristics of adolescence. [27] It also is very important in promoting protein synthesis. The current studies suggest that the anabolic mechanisms of growth hormone act through increases in serum levels of IGF-I. IGF-I also increases the proliferation of many cell types, including fibroblasts; however, it frequently needs to be combined with another growth factor such as PDGF or FGF. [28] IGF-II is felt to be more active in fetal growth; however, it has been found to have similar effects as IGF-I and can also improve healing. [29] The IGF-I receptor has a structure that resembles the alpha/beta dimer structure of the insulin receptor. The IGF-II receptor has a totally different structure and has been found to be identical to the mannose-6-phosphate (M6P) receptor. Insulin, IGF-I, and IGF-II preferentially bind their own receptor but can bind to either of the other types of receptors. [30] Interestingly, the IGF-II/M6P receptor also binds mannose moieties on latent TGF-beta and may play a role in activating TGF-beta. [31]

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EXPRESSION OF GROWTH FACTORS IN WOUNDS

After discovering that growth factors had the potential to augment tissue repair, many investigators returned to the wound in an attempt to detect and quantify growth factors during the healing process. The determination of the regular sequence of growth factor expression in the wound is helpful for several reasons. First, the normal sequence of growth factor expression will lead to a better understanding of the regulation of the normal healing process. Second, alterations in growth factor expression or response to growth factors may explain why specific wounds have impaired healing. Third, by understanding which growth factors are important for the healing process, one may have a greater understanding of how to treat problem wounds. Fourth, learning how growth factors are down-regulated during wound maturation might give insights to controlling excessive scar formation. Finally, many pathologic processes, such as pulmonary fibrosis, [32] cirrhosis, [33] atherosclerosis, [34] and many others, involve excessive healing. This "healing to excess" leads to the fibrotic changes observed in many disease states. Understanding the role of growth factors in this process may help with the understanding of the final pathway of multiple disease processes.

Initial studies measured growth factors in wound fluids. Cromack et al. were the first group to measure a growth factor in a subcutaneous wound chamber placed in a rat. [35] They found that TGF-beta levels increased initially after wounding and then gradually declined with wound closure. Three methodologies have since been used as a source of human wound fluid or tissue. Fluid collected from drains placed in mastectomy wounds has been used for several studies. [36,37] Others have collected fluid from split-thickness donor sites [38,39] or chronic wound ulcers [40] covered with a film dressing. Finally, porus polytetrafluoroethylene chambers have been placed in the subcutaneous tissues. [41] PDGF, TGF-alpha, and TGF-beta were all found to be increased in wound fluids, while EGF and bFGF were found by some and not by others. [36,37]

Many studies have not only measured the amount of growth factors in wound fluid but also the proteinases that destroy the cytokines. Bennett and Schultz have found that the amount of proteinases found in mastectomy wounds was relatively low. [40] These wounds healed without problems. Chronic, nonhealing ulcers, however, were found to have increased levels of matrix metalloproteinases (MMPs), the proteinases that break down extracellular matrix proteins such as collagen. [40] Other investigators have also found increased levels after wounding. [42-44] Our laboratory has demonstrated induction of MMP1 and MMP3 in burn wounds. [45] One must recognize that net growth factor levels in a wound result from the balance of synthesis and degradation. Increased growth factor degradation resulting from increased proteinase activity also appears to contribute to altered tissue repair.

While measuring growth factors in wound fluids is interesting, these "overflow" secretions may not totally reflect what is occurring in the wound. Several investigators have attempted to localize growth factors in healing wounds. EGF, TGF-alpha, PDGF, TGF-beta, IGF-I, IGF-II, and bFGF have all been found in wounds. [46-53] Other investigators have also found growth factor receptors, such as the EGF and PDGF receptors, in close association with their growth factors. [54-57] Using in situ hybridization, the cells in the wound that produce the growth factors have also been identified. [54-56]

One goal of several laboratories has been to examine mechanisms of altered healing. One hypothesis is that impaired healing results from altered growth factor expression or utilization. Delayed expression of KGF, IGF-II, and VEGF has been found in wounds of diabetic mice with delayed healing compared to nondiabetic litter mates. [58-60] TGF-beta1 was also found to be decreased after treating animals with doxorubicin. [61] Finally, a different approach has been developed to elucidate the role of growth factors in tissue repair. The ability has been developed for targeted disruption of genes that produce growth factors. "Knockout" mice have been developed lacking all types of proteins. Studies have been performed that examine tissue repair in mice lacking the ability to produce TGF-beta1. [62] These animals did die from an overwhelming inflammatory response that suggests that TGF-beta1 is essential for the regulation of inflammation. It was expected that these animals would have abnormal healing, but surprisingly, these animals healed well until they developed the overwhelming inflammatory response. It was found that other growth factors (TGF-beta2, PDGF-A, PDGF-B, and inflammatory cytokines) were augmented in these animals. [62] The findings suggest a redundancy in the actions of growth factors that allows for normal tissue repair in the absence of single cytokine.

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ANIMAL STUDIES SUPPORTING THE ROLE OF GROWTH FACTORS IN WOUND HEALING

Growth factors have been found to improve healing in almost all kinds of wounds. [63-75] Because of the hundreds of studies, only a few principles related to the effects of growth factors on healing will be covered. The degree of improvement, while statistically significant, has not been profound in animals that are otherwise healthy. The focus of several laboratories have been to try to examine the role of growth factors in impaired wound healing. Most healing occurs without problems unless there is some form of host impairment such as diabetes, malnutrition, infection, or after treatment with steroids, chemotherapy agents, or radiation. Growth factors have improved healing in animals impaired with diabetes, [76-80] malnutrition, [81] infection, [82] hypoxia, [83-85] or after treatment with chemotherapy agents, [86] steroids, [87-89] and radiation. [90] Growth factors appear to shift the rate of healing in these delayed models towards that of normal animals. The mechanisms of improvement are not entirely clear but several forms of impairment result from a decrease in the proliferation of inflammatory cells or a delay in the "inflammatory phase" of wound healing. Steroids, radiation, and chemotherapy are designed to kill rapidly proliferating cells. Growth factors appear to act as local stimulators of cell proliferation and appear to "over-ride" the inhibitory actions of cytotoxic drugs.

Other strategies have been developed to increase the effectiveness of growth factors. Since multiple growth factors with different activities are present in the wound, laboratories have focused on determining whether growth factor combinations can enhance healing to a greater extent than a single growth factor. The rationale behind doing such studies is that in vitro studies suggest that more than one growth factor may be required for a cell to enter the cell cycle. For instance, quiescent cells that are treated with either PDGF, FGF, or IGF-I alone did not enter the cell cycle; however, when PDGF or FGF was given followed by the addition of IGF-I, proliferation occurred. [28] Studies in diabetic mice support the use of both PDGF and IGF-II to enhance healing beyond that of the individual growth factors. [91] Lynch et al. have also demonstrated that PDGF and IGF-I have synergistic actions in different models of tissue repair. [92-95] Hennessey et al. found a similar additive effect when adding insulin to EGF. [96] Another rationale for using growth factor combinations is that healing involves different cell types. The use of PDGF to stimulate fibroblast growth with the addition of TGF-alpha to stimulate epidermal growth has also proved to improve healing beyond that of the individual growth factors. [97]

Other investigators have examined the combination of growth factors, and proteins that normally bind and regulate the actions of that growth factor. Adding IGF-I with one of its binding proteins (IGFBP-1) further augmented tissue repair. [98,99] Another strategy is to use growth factors in combination with other types of therapies that have the potential to augment tissue repair. Mustoe et al. have demonstrated that growth factors combined with hyperbaric oxygen may have an additive effect in the treatment of hypoxic wounds. [84]

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CLINICAL STUDIES

Since their discovery, the goal has been to utilize growth factors for enhancing all forms of clinical tissue repair. It is important to remember that the use of growth factors is not always appropriate for all types of wounds. In other words, growth factors should target specific problems. The initial hopes of adding growth factors to "BandAids" (trademark of Johnson and Johnson, New Brunswick, NJ) are currently not appropriate. Growth factors are expensive so BandAids could cost in the range of $10 to 20 each. We know that small wounds heal very well without treatment, so adding growth factors would be impractical. Growth factor treatment should also be appropriate for the specific type of wound. Adding growth factors to enhance granulation tissue formation in burn patients, for instance, would be inappropriate, since excessive granulation tissue would lead to increased scarring. The goal, instead, is to rapidly excise and graft the burn, and minimize scar formation. Growth factors could have the potential to lead to complications such as excessive scar formation and theoretically malignant transformation. Fortunately, no cancers nor excessive scarring have developed from the application of growth factors.

Rational use of growth factors should be based on several principles:

1. Growth factors should enhance tissue repair to a degree that is not only statistically significant but also clinically significant. In most instances, healing proceeds rapidly in healthy individuals, so research efforts should concentrate on clinically significant healing problems such as in diabetes, malnutrition, infection, or after treatment with steroids, chemotherapy agents, or radiation.

2. The enhancement should not lead to "excessive healing" or scar formation.

3. The risks of using growth factors should be minimal.

4. Growth factors should act only at the wound and not elsewhere in the body.

5. Growth factor use should be cost effective.

6. Applicability should be easy enough to make growth factor use practical.

Up to now, clinical studies have focused on two types of wounds:

1. Chronic nonhealing cutaneous ulcers.

2. Split-thickness donor sites.

Chronic nonhealing cutaneous ulcers lead to profound morbidity for the patient with a significant cost to society. These wounds include pressure sores, diabetic ulcers, venous statis ulcers, and various other types of chronic wounds. Treatment of these chronic wounds has involved two sources of growth factors: "natural products" and "recombinant" growth factors. Since platelets contain high concentrations of growth factors, they were one of the first sources used for healing studies. Knighton et al. were the first to publish the use of "platelet-derived wound healing formula" [100] and since then, several groups have demonstrated the potential efficacy of platelet releasates in treating problem wounds. [101-103] Platelet releasates, however, have not always led to successful enhancement in tissue repair. [104,105] The technique of isolating autologous platelets for their growth factors has been marketed in several centers around the country. The concept of having a center that deals solely with problem wounds has certainly improved care, although the question of the regulation of these products still needs to be addressed.

Another method of obtaining "natural" growth factors is through the application of sheets of cultured cells, usually keratinocytes, onto the wound. Cultured cells release their own cytokines and thus have the potential to enhance tissue repair. Cultured cells have the potential advantage of being able to release growth factors for prolonged periods (as long as the cells remain viable). Most studies have utilized cultured keratinocytes and have had varied success. [106-108] Current evidence suggests that keratinocytes co-cultured with fibroblasts may enhance the quantities of growth factors produced and lead to a greater potential for augmenting healing. [109] The paracrine interaction between the cells appears to cause a synergistic enhancement in cytokine production.

Techniques are now available for the mass-production of purified "recombinant" growth factors. Several biotechnology companies were formed in the 1980s to try to market all types of growth factors. Several clinical studies have been initiated and several completed to examine the efficacy of growth factors in chronic, nonhealing skin wounds. These studies do fit many of the criteria for utilizing growth factors since they tend to alleviate chronic problems that plague these patients. The shortening in the length of hospitalization is the major way that growth factors are cost effective for the treatment of chronic, nonhealing wounds. Healing these wounds would also allow for these patients to return to work more rapidly and thus further benefit society.

Several papers reported that patients had a chronic wound for months before entering the study and then healed in the matter of weeks. Several confounding factors make the interpretation of these studies difficult. Clinical trials have demonstrated that there is a significant "placebo effect" for patients entered into studies for chronic wounds. Relatively rapid healing occurred in many patients treated with placebo. It appears that when a patient believes that another potential cure exists for their chronic wound, they are willing to take better care of their wounds. Another problem with these clinical studies is that the uniformity of the study wounds is difficult to control. Patients with chronic wounds have all types of underlying illnesses. It is difficult to compare the healing of a pressure sore in an otherwise healthy, young paraplegic, with an elderly, malnourished, diabetic, incontinent nursing home patient. Although growth factors may reduce the time required for healing, they do not alter the underlying pathology that led to the chronic wound. Most venous stasis ulcers, for instance, can be healed by relieving the venous hypertension by simply elevating the extremity. Unfortunately, these ulcers have a high recurrence rate because venous hypertension returns as soon as the patient walks, a necessary activity for returning home and to work. The high recurrence rate of chronic wounds needs to be addressed.

Recent studies have demonstrated that several growth factors, including PDGF, FGF, EFG, and TGF-beta2 each have the potential for enhancing healing in patients with chronic wounds. [110-115] Most of the studies have focused on pressure sores and have demonstrated that growth factor treatment results in statistically significant or nearly statistically significant improvement in the rate of wound closure. [111-114] Steed et al. recently published the results of a multicenter study that examined the effects of PDGF on the healing of lower extremity diabetic ulcers. [115] After treatment with PDGF, approximately twice the number of wounds healed when compared with placebo treatment. Not all growth factors have been effective. Falanga et al. was unable to augment healing in venous stasis ulcers using EGF, [116] Robson et al. found no effects from treating pressure sores with interleukin-1, [117] and Mazue et al. had equivocal results with basic FGF. [118] The reasons why a growth factor has no effect in a clinical trial needs to be addressed. Although the growth factor may indeed have no biologic effect, other reasons may explain equivocal results. The delivery system, dose, dosing schedule, or duration of effect may not be appropriate. The preliminary studies do suggest that at least some growth factors have the potential to accelerate the closure of at least some chronic skin wounds. More rapid healing would be highly cost effective by allowing for shorter periods of hospitalization. As of yet, no recombinant growth factor has been approved by the Food and Drug Administration for the treatment of any type of wound.

The other category of clinical growth factor trial has involved the attempts to enhance reepithelialization of split-thickness skin graft donor sites. Donor sites have several advantages for clinical trials. The depth and size of the wound can be standardized, and different but separate wounds on the same patient can be used for comparisons of different treatments. In other words, the patient serves as his or her own control. Studies can also be performed in otherwise healthy patients, avoiding the confounding issues seen in the chronic wound population. The time to reepithelialization can be relatively easy to document and compare between different centers, thus making multicenter trials less complicated. These advantages were borne out, since several of the first growth factor studies involved donor sites.

Brown et al. published the first study suggesting that EGF had the potential to improve healing of burn wound donor sites. [119] They found that the topical application of EGF produced a modest improvement in the time required for healing of these split-thickness donor sites. In essence, healing was reduced by approximately 1 day. This study was repeated in normal volunteers by Cohen et al. who found no difference in the rate of epithelial closure. [120] Greenhalgh and Riemen examined the role of basic FGF in improving donor site healing in children with small burns and found no difference in the rate of closure. [121] Barbul also suggested that there may be a modest improvement in healing in donor sites treated with topical interleukin-1. [122] All these studies suggested that, although there was possible statistical improvement in some of the studies, the amount of improvement was not clinically significant. Most small donor sites can be treated in the outpatient setting and the difference of a day or so does not justify the use and expense of growth factors.

The studies that did reveal a potentially valuable improvement was in Herndon's systemic growth hormone studies. [123,124] Where previous studies involved patients with relatively minor burns, Herndon's group examined patients with burn wounds large enough to require multiple donor site reharvests. With a larger burn and greater wound burden, healing is probably impaired to the point that growth factors can make a more clinically significant improvement. Herndon found that patients treated with growth hormone, a hormone that increased serum levels of IGF-I, had a significant decrease in length of stay because they were repeatedly able to reharvest the donor sites days earlier for multiple grafting procedures. These findings are important because the use of topical growth factors in patients with small burns and small donor sites probably is not of clinical relevance since most of these patients can heal their donor sites quickly and frequently can be treated as outpatients. Those patients who may benefit from topical growth factors will be those who have extensive burns and thus require multiple reharvests of their donor sites. Shortening the time for donor site reharvest by even a few days would add up to a significantly shortened hospital stay and reduced cost when multiple grafting procedures are required.

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GROWTH FACTORS AND SCAR CONTROL

A great deal has been learned about the factors that "turn on" tissue repair. Surprisingly little is known about what "turns off" the healing process or controls the extent of scar formation. Growth factors undoubtedly play a role in wound maturation and scar formation. A few facts are known. In burn wounds, the longer the wound remains open, the greater the scarring that results. [125] It appears that the longer the wound is exposed to the environment (foreign tissue and invading organisms), the more pronounced the inflammatory response. The prolonged inflammation probably leads to excessive growth factor production and excessive collagen deposition. It also appears that covering the wound with an epithelium leads to down-regulation of the inflammatory response and thus reduces the scarring potential. Eisinger has described an "epithelial-derived factor" that can decrease fibroblast proliferation. [126]

A few growth factors have been found to play a role in scar formation. The most evidence suggests that TGF-beta, especially TGF-beta1 and TGF-beta2, may be the key regulators of collagen deposition in excessive scar formation. [21,127,128] Shah et al. demonstrated that giving a blocking antibody to TGF-beta1 led to reduced scar formation. [20] Ferguson also states that TGF-beta3 may actually reduce scar formation. [21] The cytokines that appear to a major candidate for down-regulating collagen production and reducing scar formation are interferons gamma and alpha2b (IFN-gamma and IFN-alpha2b). [129-131] Clinical trials with intralesional IFN-gamma [132] and IFN-alpha2b [131,133] led to significant decreases in keloid and hypertrophic scar formation. A great deal more needs to be understood about the regulation of scar formation.

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GROWTH FACTOR USE IN OTHER TISSUES

Growth factors have the potential to assist healing in other tissues in the body. An active area of research includes the use of growth factors to enhance healing in eyes. Growth factors also play a key role in healing in the gastrointestinal tract. These cytokines, especially EGF and FGF have the potential to enhance the healing of peptic ulcer disease. The role of growth factors in bone tendon healing has also been studied. Many of these areas of tissue repair will be affected by clinical trials in the near future.

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FUTURE USE OF GROWTH FACTORS

A great deal of knowledge has been gained since the first discoveries of growth factors. The suspicions that growth factors can improve healing have been borne out, but the initial excitement has faded. The extent of healing augmentation in healthy individuals may or may not be statistically significant, but it clearly is not clinically significant. The focus has appropriately shifted to trials involving chronic, nonhealing wounds or in patients with large burns. Unfortunately, the initial enthusiasm of the several biotechnology firms has also waned. Several companies have given up the investigation and production of growth factors for augmenting tissue repair. Clearly, the use of growth factors will not be appropriate for a majority of patients. There are still a select population, however, who have markedly impaired healing problems. Most surgeons have experienced dealing with a patient on chronic steroids who requires emergent surgery. These patients often develop complications from their altered healing. Healing failures not only manifest by wound dehiscence but also minor anastomotic leaks that lead to the complications of sepsis and multiple organ failure. Prevention of healing failures in these high-risk patients should lead to improved survival and reduced medical costs. In the future, the right combination of growth factors that are required to target a specific wound will be used to prevent the many complications of wound healing failure. The vast potential for growth factors to enhance wound healing should not be ignored but, instead, needs further investigation.

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