The Future Of Wound Care

Wound healing involves a coordinated series of events involving specialized cells, polypeptide growth factors, proteinases and proteinase inhibitors, as well as nutritional factors. Initially after a wound is created, the body seals off or reduces blood flow into the area and neutrophils migrate to the site to secrete toxic superoxide and other highly reactive molecules to sterilize and induce a general inflammation.

In the next phase of healing, this inflammatory response is suppressed while macrophages and fibroblasts migrate into the injury to secrete specific growth factors and to begin the process of rebuilding tissue. The fibroblasts are stimulated to produce new collagen, proteoglycans and other extracellular matrix components, and new blood vessels are formed by capillary endothelial cells.

Non-viable tissue is removed, cell migration and new blood vessel formation are facilitated, and remodeling is accomplished through the action of specific proteinases (MMP or matix metalloproteinase). These proteinases are controlled through the action of specific inhibitors (TIMP or tissue inhibitor of metalloproteinase). Overall, many of the activities involved in wound healing have been shown to be controlled by specific growth factors secreted by cells involved in the process or liberated during the early stages of clot formation.

THE PRESENT
The modern wound healing theory is that optimal healing is based on maintaining a moist wound environment containing all the factors necessary for healing to proceed. The purpose of a wound dressing is to provide a protective environment for tissue healing. An optimal wound dressing should:1

Maintain the proper humidity at the wound surface

Control fluid (wound exudate)
Be easy to apply and remove
Allow air and water vapor to escape or enter
Provide thermal insulation
Provide a barrier to contamination
Be non-toxic
Conform to the wound surface
Modern wound care practices aim to optimize wound healing through the use of select nutritional and growth factors which bring an additional trait for an optimal wound dressing.

Provide an enriched wound environment
Wound dressings used for acute and chronic wound care consist of a wide range of natural and synthetic materials2, 3 . These dressings, used singly or in combinations, can provide many of the characteristics of optimum wound dressings in terms of protection of the wound from contamination and management of wound fluids.

In addition to the management of wound fluid and contamination, many modern wound dressings are developed to create an environment to optimize wound healing underneath the dressing. This is accomplished through the application of nutritional factors such as copper and zinc, botanicals such as aloe vera, and sterilants or odor control agents. For example, the combination of moisture management and nutrient copper supplementation in the form of the GraftCyteÔ product line became available for cosmetic and dermatological wound care in 1997.

Tissue glues have received considerable interest as a speedy and safe equivalent to sutures. In the studies reported, their use resulted in significantly quicker closure with equivalent cosmetic results to traditional sutures9-13.

The importance of growth factors to wound healing has been discussed above and a number of factors (epidermal growth factor (EGF), transforming growth factor (TGF), and platelet derived growth factor (PDGF)) have been the subject of intensive investigation16-18. 1998 saw the introduction of a long awaited growth factor product in the wound care field. This was the first commercially available human growth factor (PDGF, Regranex® Gel, J&J) which was approved by the FDA for topical application to chronic wounds.

THE FUTURE
What might the future practice of wound care involve? Integration of the protective and fluid handling properties of modern synthetic dressings with direct application of factors to enhance the wound environment is the most likely scenario. These "interactive" dressings and treatments would allow the physician to intervene in a positive and stimulatory way in the healing process rather than just protecting the wound and letting nature take its course.

The recent approval of Regranex® Gel provides the first commercially available product to allow the practicing clinician to supplement the wound with a natural factor, which initiates and ultimately controls part of the process. The increasing availability of dressings and treatments which provide micronutrients and other factors will help provide the building blocks and cellular tools to further enhance wound healing.

One of the most exciting approaches to manipulation of the wound healing process involves the application of modern molecular biology techniques to the proven participation of growth factors in the healing process. There are several approaches to the addition of growth factors to damaged tissue involving genetic technology. This can be through either the genetic modification of cells and their subsequent introduction to the wound or direct in vivo introduction of the genes to the wound. Genetic methodology has the advantage that a constant, regulated source of the growth factors will result.

Skin is an ideal target organ for genetically modified cells, as the turn over of skin cells will eliminate the modified cells as part of the normal healing process. Genetically modified keratinocytes have been prepared by the insertion of a plasmid containing the TGFb 1 or EGF gene. These genetically modified keratinocytes were shown to release high levels of the corresponding growth factor to wounds19, 20. In a similar manner, genetically modified human keratinocytes over-expressing PDGF-AA were used as the epidermal part of a composite skin graft. The composite graft composed of the genetically modified keratinocytes performed significantly better than control grafts in an animal model21.

Direct transfection with genes coding for growth factors is also a promising therapy. Topical application or transfection with a plasmid containing the gene for aFGF has been shown to significantly increase the closure and breaking strength of experimental wound 22 as has particle transfer of the human EGF gene23.

The entry to the field of artificial human skin is another promising technology to be applied to dermatology and cosmetic surgery. These products hold the promise of an unlimited source of replacement skin (full or partial thickness) for reconstructive and cosmetic purposes. No longer will skin have to be recycled from another site nor will the clinician and patient have to wait for new skin to cover a defect. Additional advantages of these products is that they serve an additional role as "biological" bandages which possess many of the attributes of an optimum wound dressing. Of course, the obvious combination of genetically modified cellular components to artificial skin replacements brings together the ability to manipulate the healing process with the instant coverage provided by artificial skin.

All wound healing consists of an integrated sequence of events involving specialized cells, growth factors, proteinases and proteinase inhibitors, and nutritional factors. Current medical practice for wound care is based on maintaining a protected moist wound environment. Future directions for wound care will be based on the ability to manipulate the wound environment with micronutrients, growth factors, and living cells. These enhanced wound care strategies should lead to faster and more aesthetically pleasing results in our hair transplants, in both the donor and recipient areas.

REFERENCES
Szycher M, Lee SJ.: Modern wound dressings: a systematic approach to wound healing. J Biomater Appl 1992; 7: 142-213.
Hanna JR, Giacopelli JA.: A Review of Wound Healing and Wound Dressing Products. The Journal of Foot and Ankle Surgery 1997; 36: 2-14.
Hess CT.: Wound Care Products: A Directory. Ostomy/Wound Management 1994; 40: 70-94.
Williams R, L, Armstrong D, G.: Wound healing . New modalities for a new millennium. Clinics In Podiatric Medicine And Surgery 1998; 15: 117-28.
Falanga V, Margolis D, Alvarez O, Auletta M, Maggiacomo F, Altman M, et al.: Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Human Skin Equivalent Investigators Group [see comments]. Archives Of Dermatology 1998; 134: 293-300.
Sorensen J, C.: Living skin equivalents and their application in wound healing. Clinics In Podiatric Medicine And Surgery 1998; 15: 129-37.
Duinslaeger L, A, Verbeken G, Vanhalle S, Vanderkelen A.: Cultured allogeneic keratinocyte sheets accelerate healing compared to Op-site treatment of donor sites in burns. Journal Of Burn Care And Rehabilitation 1997; 18: 545-51.
Elson ML. Soft Tissue Augmentation with Allogeneic Human Tissue Matrix. Cosmetic Dermatology 1998; 11: 24-28.
Shigemitsu T, Majima Y.: The utilization of a biological adhesive for wound treatment: comparison of suture, self-sealing sutureless and cyanoacrylate closure in the tensile strength test. International Ophthalmology 1996; 20: 323-8.
Singer A, J, Hollander J, E, Valentine S, M, Turque T, W, McCuskey C, F, Quinn J, V.: Prospective, randomized, controlled trial of tissue adhesive (2-octylcyanoacrylate) vs standard wound closure techniques for laceration repair. Stony Brook Octylcyanoacrylate Study Group. Academic Emergency Medicine 1998; 5: 94-9.
Qureshi A, Drew P, J, Duthie G, S, Roberts A, C, Monson J, R.: n-Butyl cyanoacrylate adhesive for skin closure of abdominal wounds: preliminary results. Annals Of The Royal College Of Surgeons Of England 1997; 79: 414-5.
Quinn J, Wells G, Sutcliffe T, Jarmuske M, Maw J, Stiell I, et al.: A randomized trial comparing octylcyanoacrylate tissue adhesive and sutures in the management of lacerations [see comments]. JAMA 1997; 277: 1527-30.
Maw J, L, Quinn J, V, Wells G, A, Ducic Y, Odell P, F, Lamothe A, et al.: A prospective comparison of octylcyanoacrylate tissue adhesive and suture for the closure of head and neck incisions. Journal Of Otolaryngology 1997; 26: 26-30.
Mendez-Eastman S.: Negative pressure wound therapy. Plastic Surgical Nursing 1998; 18: 27-9, 33-7.
Genecov D, G, Schneider A, M, Morykwas M, J, Parker D, White W, L, Argenta L, C.: A controlled subatmospheric pressure dressing increases the rate of skin graft donor site reepithelialization. Annals Of Plastic Surgery 1998; 40: 219-25.
Robinson C, J.: Growth factors: therapeutic advances in wound healing. Annals Of Medicine 1993; 25: 535-8.
Falanga V.: Growth factors and wound healing. Dermatologic Clinics 1993; 11: 667-75.
Meyer-Ingold W.: Wound therapy: growth factors as agents to promote healing. Trends In Biotechnology 1993; 11: 387-92.
Ghahary A, Tredget E, E, Chang L, J, Scott P, G, Shen Q.: Genetically modified dermal keratinocytes express high levels of transforming growth factor-beta1. Journal Of Investigative Dermatology 1998; 110: 800-5.
Rosenthal F, M, Cao L, Tanczos E, Kopp J, Andree C, Stark G, B, et al.: Paracrine stimulation of keratinocytes in vitro and continuous delivery of epidermal growth factor to wounds in vivo by genetically modified fibroblasts transfected with a novel chimeric construct. In Vivo 1997; 11: 201-8.
Eming S, A, Medalie D, A, Tompkins R, G, Yarmush M, L, Morgan J, R.: Genetically modified human keratinocytes overexpressing PDGF-A enhance the performance of a composite skin graft. Human Gene Therapy 1998; 9: 529-39.
Sun L, Xu L, Chang H, Henry F, A, Miller R, M, Harmon J, M, et al.: Transfection with aFGF cDNA improves wound healing. Journal Of Investigative Dermatology 1997; 108: 313-8.
Andree C, Swain W, F, Page C, P, Macklin M, D, Slama J, Hatzis D, et al.: In vivo transfer and expression of a human epidermal growth factor gene accelerates wound repair. Proceedings Of The National Academy Of Sciences Of The United States Of America 1994; 91: 12188-92.
New Medicines as an Adjunct to Surgery

The search for new and effective agents to treat many different hair loss problems has been intensified by the increase in hair biology research taking place worldwide, from university-academic institutions to the pharmaceutical companies, all with a desire to profit from marketing such drugs which have been termed, "cosmeceuticals." Millions of men and women of every race suffer from various forms of alopecia, the most common being AGA, where DHT aggravates genetically programmed scalp hair follicles, resulting in short, fine, miniaturized hairs.

There is a great need for drug therapies which specifically attack the metabolic pathways involved in the balding process. This section will describe the most recently approved products for AGA, along with some in clinical trial development that may be used either alone or as an adjunct to surgical interventions.1

5a-REDUCTASE INHIBITORS

In this category there are the structural steroid competitive inhibitors that chemically resemble the substrate, testosterone, and bind to the active site of the enzyme so that DHT is not formed. Propecia (finasteride) has recently been FDA approved in the USA for men with AGA. Propecia is a specific 5a-reductase type II enzyme inhibitor, and does not bind to the AR, and is therefore not called an "anti-androgen", but an androgen inhibitor.

The pharmokinetics of finasteride reveal that after a 1 mg dose serum concentration of DHT decreases by 65% in 24 hours. Serum concentrations of testosterone and estradiol increase about 15% but remain within normal limits. Prostate concentrations of testosterone increase about sixfold2. Finasteride is well absorbed in the GI tract, metabolized in the liver and excreted in urine and feces, with a half-life of 5 to 6 hours. Small nanogram levels of the drug are detectable in human semen, but are not thought to have any consequence in women who are exposed by sexual contact.

Three double-blind multi-center trials were conducted in men ages 18 to 41 years and the results of these trials have been presented as abstracts3, 4. In combined results from two of the trials, 1553 men with mild to moderate male AGA of the vertex took finasteride 1 mg/day or a placebo orally for one year. After three months of treatment, the men who took finasteride were more satisfied with the appearance of their hair. At the end of 1 year, in a circle on the vertex scalp, a one inch diameter mean baseline hair count was 876. Patients who took the drug had an average of 107 more hairs than those who took the placebo. Hair counts were maintained for up to 24 months in the men who continued to take the drug4. A third study in 326 men with mild to moderate frontal hair loss found that after one year, finasteride treated men had statistically significantly higher hair counts in their frontal scalp. Approximately 50% of treated men and 30% of those who took placebo thought the appearance of their hair had improved. Hair regrowth was not reported in older men taking 5 mg finasteride (Proscar), perhaps because it was not indicated in those trials to make observations on the scalp.

Adverse events described with 5 mg finasteride (Proscar) in a small percent of older men were loss of: libido and erection, ejaculatory dysfunction, hypersensitivity reactions, gynecomastia and severe myopathy2. Finasteride 1mg causes a 30 to 50% decrease in prostate specific antigen (PSA) in clinical trials in men 18 to 41 years old. The decreased libido, erectile dysfunction or a decreased volume of ejaculate have been reported in less than 2% of patients, which in reality is between 0.5% to 1% when compared against placebo and these effects are reversible when the drug is discontinued.

Finasteride has teratogenic effects in animals when taken in high doses, causing genitourinary abnormalities in male offspring. The concentration of the drug in semen of men who took 1 mg/day was much lower than the concentration associated with teratogenic effects in monkeys. Merck warns that women who are, or who may become pregnant should not have exposure to finasteride orally or by exposure of handling crushed or broken tablets, due to possible adverse effects on the male fetus. Finasteride is not indicated for use in women at the present time. There have been no published benefits for the use of finasteride in post-menopausal women thus far.

Dutasteride (GI198745, GlaxoWellcome) is a dual 5a-reductase inhibitor blocking both type I and II isoenzymes, which is currently in clinical trial studies around the USA for males with AGA. It is structurally similar to the parent structure of finasteride, maintaining the 4-aza structure of the steroid nucleus. However on the 21-carbon position is a tri-fluorophenyl group which renders the molecule to be electronegative and perhaps gives it greater affinity for both the type I and II isoenzyme forms of 5a-reductase5. Therefore, this drug is similar to finasteride in structure, but different in that it competitively inhibits both forms of the 5a-reductase type I and II isoenzymes, whereas, finasteride is just specific for inhibiting type II 5a-reductase. Dutasteride is known to inhibit >90% serum DHT levels in 24 hours after oral administration, and because of this greater ability to inhibit DHT, it is thought that it may be more effective in promoting hair growth, as well as treating acne. The results of clinical trials are pending.

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