Challenges encountered in dermatologic drug development.

Few truly new drugs are developed primarily for the treatment of dermatologic diseases. We discuss challenges and special considerations of dermatology drug development which contribute to this relative absence of novel drugs in dermatology. The issues considered are: a) the economic potential of dermatologic drugs including the potential return on investment (ROI); b) the benefit-to-risk ratio for treatments of skin disease; c) the relative absence of surrogate end points for topically applied drugs; d) drug penetration and vehicles; e) shelf life, stability, emulsifiers, preservatives; f ) contact irritancy, contact allergy, contact photoallergy and photocarcinogenicity; g) drugs with more than one active; h) semi-quantitative or soft primary end points; i) inadequate basic knowledge of pathophysiology of skin diseases. Of the many challenges, we conclude it is the low economic potential or ROI available with skin disease treatments which inhibits the creation of novel therapies for dermatologic disease.

Tissue-engineered skin. Current status in wound healing.

Tissue-engineered skin is a significant advance in the field of wound healing and was developed due to limitations associated with the use of autografts. These limitations include the creation of a donor site which is at risk of developing pain, scarring, infection and/or slow healing. A number of products are commercially available and many others are in development. Cultured epidermal autografts can provide permanent coverage of large area from a skin biopsy. However, 3 weeks are needed for graft cultivation. Cultured epidermal allografts are available immediately and no biopsy is necessary. They can be cryopreserved and banked, but are not currently commercially available. A nonliving allogeneic acellular dermal matrix with intact basement membrane complex (Alloderm) is immunologically inert. It prepares the wound bed for grafting allowing improved cultured allograft 'take' and provides an intact basement membrane. A nonliving extracellular matrix of collagen and chondroitin-6-sulfate with silicone backing (Integra) serves to generate neodermis. A collagen and glycosaminoglycan dermal matrix inoculated with autologous fibroblasts and keratinocytes has been investigated but is not commercially available. It requires 3 to 4 weeks for cultivation. Dermagraft consists of living allogeneic dermal fibroblasts grown on degradable scaffold. It has good resistance to tearing. An extracellular matrix generated by allogeneic human dermal fibroblasts (TransCyte) serves as a matrix for neodermis generation. Apligraf is a living allogeneic bilayered construct containing keratinocytes, fibroblasts and bovine type I collagen. It can be used on an outpatient basis and avoids the need for a donor site wound. Another living skin equivalent, composite cultured skin (OrCel), consists of allogeneic fibroblasts and keratinocytes seeded on opposite sides of bilayered matrix of bovine collagen. There are limited clinical data available for this product, but large clinical trials are ongoing. Limited data are also available for 2 types of dressing material derived from pigs: porcine small intestinal submucosa acellular collagen matrix (Oasis) and an acellular xenogeneic collagen matrix (E-Z-Derm). Both products have a long shelf life. Other novel skin substitutes are being investigated. The potential risks and benefits of using tissue-engineered skin need to be further evaluated in clinical trials but it is obvious that they offer a new option for the treatment of wounds.

Recombinant human platelet-derived growth factor gel speeds healing of acute full-thickness punch biopsy wounds.

BACKGROUND: Recombinant human platelet derived growth factor-BB gel (PDGF gel) has been shown to be effective in the treatment of diabetic neuropathic ulcers. It is also being used off-label to speed wound healing of flaps, grafts, and wounds from Mohs micrographic surgery. OBJECTIVE: The purpose of the study was to compare the rate of healing in wounds treated with PDGF gel and with wounds treated with conventional therapy (antibiotic ointment). METHODS: A double-blind controlled study of 7 healthy volunteers was performed. With a 4-mm skin punch biopsy instrument, two full-thickness wounds were made on each arm of each volunteer. Fourteen wounds treated with PDGF gel were compared with 14 wounds treated with antibiotic ointment. Healing was evaluated by visual determination of the global percentage healed and wound depth. RESULTS: Wounds treated with PDGF gel showed a significantly faster rate of healing on each of the initial 6 follow-up visits. The greatest difference was on day 10 when PDGF-treated wounds were 71% healed compared with 28% for antibiotic-treated wounds (P =.0005). At days 22 and 24, 92.9% and 100% of the PDGF gel-treated wounds were healed, compared with 50% and 57%, respectively (P =.0313 and P =.0313), in the antibiotic ointment group. By day 29, both PDGF gel and antibiotic-treated wounds were healed. PDGF also decreased wound depth compared with wounds treated with antibiotic ointment at days 8 and 10 with P values <.0313 and <.0020, respectively. CONCLUSION: We conclude that PDGF gel speeds healing of acute full-thickness wounds compared with antibiotic ointment.

An octyl-2-cyanoacrylate formulation speeds healing of partial-thickness wounds.

BACKGROUND: Occlusive dressings have been known to accelerate the rate of healing. Every year new dressings are being introduced in the marketplace. OBJECTIVE: The purpose of this study was to evaluate the effect of a new octyl-2-cyanoacrylate liquid dressing as compared to two over-the-counter bandages on partial-thickness wounds. Performance parameters were epithelialization, erythema, scab formation, material adherence, hemostasis, and infection. METHOD: Eight pigs with a total of 645 partial-thickness wounds were assigned to one of the following treatments: liquid dressing, standard bandage, hydrocolloid bandage, or untreated air exposed. RESULT: The liquid bandage enhanced the rate of epithelialization and was the only treatment to provide complete hemostasis, reduced scab formation, and did not induce an irritant response (erythema) or infection. CONCLUSION: The liquid bandage is an easy to use material that stops bleeding (instantaneous hemostasis) while enhancing healing of partial-thickness wounds.

The pig as a model for human wound healing.

The medical literature describes numerous in vitro and in vivo wound-healing models. The selection of an animal model depends on a number of factors including availability, cost, ease of handling, investigator familiarity, and anatomical/functional similarity to humans. Small mammals are frequently used for wound healing studies, however, these mammals differ from humans in a number of anatomical and physiological ways. Anatomically and physiologically, pig skin is more similar to human skin. The many similarities between man and pig would lead one to believe that the pig should make an excellent animal model for human wound healing. The purpose of this paper is to review the existing literature for evidence of this supposition and determine how well the various models correlate to human wound healing. Studies of wound dressings, topical antimicrobials, and growth factors are examined. Over 180 articles were utilized for this comparative review. Our conclusion is that the porcine model is an excellent tool for the evaluation of therapeutic agents destined for use in human wounds.

Chronic venous insufficiency and venous leg ulceration.

UNLABELLED: Venous ulcers are the most common form of leg ulcers. Venous disease has a significant impact on quality of life and work productivity. In addition, the costs associated with the long-term care of these chronic wounds are substantial. Although the exact pathogenic steps leading from venous hypertension to venous ulceration remain unclear, several hypotheses have been developed to explain the development of venous ulceration. A better understanding of the current pathophysiology of venous ulceration has led to the development of new approaches in its management. New types of wound dressings, topical and systemic therapeutic agents, surgical modalities, bioengineered tissue, matrix materials, and growth factors are all novel therapeutic options that may be used in addition to the "gold standard," compression therapy, for venous ulcers. This review discusses current aspects of the epidemiology, pathophysiology, clinical presentation, diagnostic assessment, and current therapeutic options for chronic venous insufficiency and venous ulceration. (J Am Acad Dermatol 2001;44:401-21.) LEARNING OBJECTIVE: At the conclusion of this learning activity, participants should be familiar with the 3 main types of lower extremity ulcers and should improve their understanding of the epidemiology, pathogenesis, risk factors, clinical presentation, diagnostic assessment, and current therapies for chronic venous insufficiency and venous ulcers.

Moist wound healing with occlusive dressings: a clinical focus.

The concept of moist wound healing, which is facilitated by the application of occlusive dressings, dates back to 1615 BC, and the technique is currently supported by a relatively large volume of data. It is clear that occlusive dressings are in many cases associated with more rapid reepithelialization, a reduced risk of infection, and more rapid wound healing than the alternatives. Nevertheless, many clinicians have been slow to accept this therapeutic technique. This article traces the history of moist wound healing from its earliest inception, examines the theoretical mechanisms of its effect, and explores its advantages and disadvantages. It also reviews the literature supporting the use of occlusive dressings in a variety of wound settings and examines the possible reasons behind the apparent reluctance on the part of the medical community to accept a potentially valuable therapy.

Practice management for academic dermatology departments.

Practice management in the academic medical center (AMC) is different than in other environments. Practice is only a part of the practitioner's mission within an AMC. Practice revenue will be subject to a tax or overhead by both the school and the department. Contract and practice guidelines cannot be tailored to the needs of the dermatology practice, because contracts and guidelines are negotiated globally for all of the practices within the AMC. Personnel, on which the practice depends, may report to hospitals and clinics rather than to the practice's management. Even control of the practice's manager may be diluted by a dual or "dotted line" reporting relationship between the department manager and the school practice manager. Although more constraints exist within the AMC, there are some strategic and operational choices that affect a practice's success. Among these are: (1) selection of services offered; (2) creation of satellites; (3) stimulation of faculty effort; (4) enhancement of faculty billing knowledge; and (5) creation of a "tie" between staff and the practice.

Tissue-engineered skin (Apligraf) in the healing of patients with epidermolysis bullosa wounds.

BACKGROUND: At present, wound treatment of inherited epidermolysis bullosa (EB) is only supportive. OBJECTIVE: To determine the safety and clinical effects of tissue-engineered skin (Apligraf; Organogenesis Inc, Canton, Mass) in the healing of wounds of patients with different types of EB. DESIGN: An open-label uncontrolled study of 15 patients with EB treated with tissue-engineered skin. Each patient received tissue-engineered skin on up to 2 wounds on each of 3 clinic visits: day 1, week 6, and week 12. They were evaluated 7 (+/- 3) days and 6 weeks after each round of treatment. A quality-of-life survey was administered during week 6. SETTING: University of Miami, Miami, Fla. PATIENTS: Volunteers with EB. MAIN OUTCOME MEASURE: Safety and wound healing. RESULTS: A total of 69 different acute wounds received tissue-engineered skin at the day-1 (24 wounds), week-6 (23 wounds), and week-12 (22 wounds) visits. Overall, 63 wounds (79%) were found healed at the day-7 visit. Of the acute wounds, 82% (51/62) were healed 6 weeks after being treated, 75% (27/36) after 12 weeks, and 79% (11/14) after 18 weeks. Nine chronic wounds were also treated. Four were healed at 6 weeks; however, 7 were still open at the last clinic visit (week 18). There were no signs of rejection or clinical infection and no adverse events related to the tissue-engineered skin. The quality of life for most patients improved after treatment. Compared with patients' recollection of wounds treated with standard dressings, healing was faster and less painful. CONCLUSION: In this series of patients, tissue-engineered skin induced very rapid healing, was not clinically rejected, and was devoid of adverse effects. It was felt by the patients and families to be more effective than conventional dressings for EB wounds.

The effects of topical transforming growth factor-beta2 and anti-transforming growth factor-beta2,3 on scarring in pigs.

BACKGROUND: Transforming growth factor-b2 (TGF-b2) has been implicated in the inflammatory response and subsequent scarring during wound healing. OBJECTIVE: The experiment was designed to study the effects of a topical application of TGF-b2 and mouse monoclonal anti-TGF-b2,3 neutralizing antibody (anti TGF-b2,3) on the development of fibrosis during healing. METHODS: Sixteen full-thickness excision wounds were made in the paravertebral and thoracic area of four domestic pigs. On day 0, three wounds each were treated with: a) 5 mg of TGF-b2, b) 5 mg of 2% methylcellulose (mc), or c) 1.2 mg of anti-TGF-b2,3. As a vehicle for treatment of each wound methylcellulose 2% was used. Four wounds served as the untreated air-exposed control. Wounds were biopsied and the tissue sectioned and stained with hematoxylin and eosin on days 7, 14, and 45. Three blinded observers evaluated the wound specimens. RESULTS: Using computer-aided point count stereology on days 7, 14, and 45, we found a statistically significant increase (p <.05) in the number of nucleated cells in the TGF-b2-treated wounds as compared to the other control wounds. Wounds treated with anti-TGF-b2,3 had significantly (p <.05) fewer nucleated cells on days 7,14, and 45. Microscopically, the TGF-b2-treated wounds had a larger scar area as compared to anti-TGF-b2,3 and controls. CONCLUSION: Treating wounds with an antibody directed against TGF-b2 might be a useful clinical approach to reduce fibrosis.

Performance comparison of nylon and an absorbable suture material (Polyglactin 910) in the closure of punch biopsy sites.

The ability to close biopsy sites primarily without the need for removing sutures is obvious. However, it was unclear whether absorbable sutures could be used for this purpose. We prospectively studied 10 healthy volunteers on whom one 3 mm punch biopsy was performed on each arm. In each subject two sutures were compared for closure of the biopsy sites, polyglactin 910 and nylon. Our primary goal was to compare absorbable and nonabsorbable sutures in the closure of punch biopsy sites. Each site was closed with one simple percutaneous suture. The sites were evaluated at 2 weeks and 6 months for redness, infection, dehiscence, scar hypertrophy, and patient satisfaction. We found no statistically significant difference between the two suture materials in any of the above parameters. Therefore we conclude that absorbable sutures are a good alternative in the primary closure of skin biopsy sites.

Skin grafting.

No longer an option of last resort, skin grafting has become a technique that is routinely and sometimes preferentially considered as skin replacement for burns, chronic ulcers, and skin defects after cutaneous surgical procedures. When selected as the best alternative for wound closure, autologous skin grafts are commonly considered the gold standard. Availability of autologous grafts is a major obstacle, however, and the search for a manufactured skin replacement has continued. In cases in which autologous grafts cannot be performed, skin substitutes have become an attractive alternative.

Causes and effects of the chronic inflammation in venous leg ulcers.

The pathogenesis of venous leg ulcers is multifactorial. In this review article new physiological, molecular and cellular abnormalities in venous ulcers related to the chronic inflammation are presented and discussed. Venous hypertension causes disturbed microcirculation and pathological changes of the capillaries, which eventually locks the condition in a self-amplifying, detrimental cascade with persistent elevated levels and activities of pro-inflammatory cytokines and proteases preventing progress into a healing phase. As a consequence fibroblasts senescence and become less responsive to growth factors the older the ulcers become. Current data imply there is no deficiency but rather an unfavorable distribution of growth factors in venous ulcers. An imbalance in proteolytic enzymes and their endogenous inhibitors is a common finding in chronic venous leg ulcers. Variation in disease severity and concomitant ailments in this heterogeneous patient group may explain the contradictory results in the literature. Thus, to advance the areas of research further, longitudinal studies involving larger number of patients are required to identify the major pathogenic factors.

The use of tissue-engineered skin (Apligraf) to treat a newborn with epidermolysis bullosa.

BACKGROUND: Inherited epidermolysis bullosa (EB) is a mechanobullous disorder. The Dowling-Meara variant, a subtype of EB, is characterized by widespread blister formation that may include the oral cavity and nails. Many patients with the Dowling-Meara phenotype are at increased risk of sepsis and death during infancy. The treatment of EB is generally supportive. The tissue-engineered skin used (Apligraf) is a bilayered human skin equivalent developed from foreskin. It is the only Food and Drug Administration-approved skin equivalent of its kind. It is approved for the treatment of venous ulcers of the lower extremities. It has also been used to treat acute wounds, such as graft donor sites and cancer excision sites. OBSERVATION: To our knowledge, we describe the first case in which a newborn with EB, Dowling-Meara variant, was treated with bilayered tissue-engineered skin. The areas treated with the tissue-engineered skin healed faster than the areas treated with conventional therapy. Most of the areas treated with tissue-engineered skin have remained healed, without developing new blisters. These areas appear to be more resistant to trauma. CONCLUSIONS: Our early success with tissue-engineered skin in this patient may have a significant impact on the future treatment of neonates with EB simplex. Future studies are needed to determine if the beneficial effects of tissue-engineered skin are reproducible in other neonates with EB simplex and in patients of all ages with different subtypes of EB.

Laser resurfacing: usual and unusual complications.

The use of the carbon dioxide laser for skin resurfacing was initially described in 1989. 1 Since that time, several reports have shown it to be highly effective in the treatment of photodamaged skin and acne scarring. 2,3,4,5 Advances in laser technology have simplified the procedure and minimized adverse sequelae. Laser skin resurfacing has become a very popular technique, and recently several patient series have been published on the use of different resurfacing lasers to treat photodamaged skin. 3,4 However, very little has been written about its complications. Adequate patient selection, sound medical judgement, proper training with experience and knowledge of skin physiology and wound care are important factors for successful outcomes. Interested physicians across a broad range of subspecialties have expressed concern about the rate of adverse outcomes and management of complications. We report seven representative cases of complications referred to our dermatology clinics from outside physicians, in the hope of educating clinicians regarding the usual and unusual side effects of this procedure.

Behavior of tissue-engineered skin: a comparison of a living skin equivalent, autograft, and occlusive dressing in human donor sites.

OBJECTIVE: To compare the behavior of a tissue-engineered living skin equivalent (LSE) with an autograft in acute donor site wounds. DESIGN: Paired-comparison, randomized control trial. SETTING: A university dermatology service. PATIENTS: Three donor sites were created on the anterior thigh of each of 20 patients requiring split-thickness skin grafts. INTERVENTION: For each patient, the donor sites were randomly assigned to be treated with meshed LSE, meshed autograft, or a polyurethane film (PUF) occlusive dressing. Blood and biopsy samples were taken for immunologic and histological studies. MAIN OUTCOME MEASURES: Toxic effects or clinically apparent rejection, humoral and cellular immune responses, clinical take, healing time, pain, and 1-month histological appearance. RESULTS: There was no toxic effect or clinically apparent rejection of LSE. Results of humoral and cellular studies were unchanged from baseline. The average time to healing for LSE with clinical take was 7.3 days (SD, +/- 0.8 days); for autograft, 7.6 days (SD, +/- 1.1 days); and for PUF, 9.5 days (SD, +/- 1.8 days). The difference between LSE or autograft and PUF was statistically significant at the .001 level. Pain was experienced by 1 patient, no patients, and 10 patients at the LSE, autograft, and PUF sites, respectively. Histologically, LSE had the thickest epidermis (P = .02), PUF had the greatest degree of fibrosis (P = .02), and autograft had the least degree of increased inflammation (P = .004) and vascularity (P = .01). CONCLUSIONS: In acute donor site wounds, LSE appeared to clinically take and to be a safe and usable form of tissue therapy.

Collagen fiber orientation as quantified by small angle light scattering in wounds treated with transforming growth factor-beta2 and its neutalizing antibody.

The purpose of this study was determine quantitative differences in collagen fiber orientation in a wound healing model in the presence of transforming growth factor-beta2 and anti-transforming growth factor-beta2,3 antibody. Full-thickness wounds were made in the paravertebral area of two young pigs. Wounds were treated once, topically, with either transforming growth factor-beta2 or anti-transforming growth factor-beta2 antibody, or with methylcellulose gel. Control wounds were left untreated. Tissue biopsies were obtained from each wound on days 7, 14 and 46 post wounding. Tissue sections were stained with hematoxylin and eosin, and collagen fiber preferred orientation was quantified using small angle light scattering. Our results indicated that wounds treated with transforming growth factor-beta2 and anti-transforming growth factor-beta2,3 antibody had a significantly higher degree of orientation of collagen fibers than normal unwounded skin on days 7, 14 and 46 (p < 0.001). Transforming growth factor-beta2- treated wounds had a higher degree of orientation of collagen fibers than control wounds on days 7 and 14 (p < 0.001), and control wounds displayed a higher degree of orientation than wounds treated with anti-transforming growth factor-beta2,3 and normal unwounded skin at all time points (p < 0.001). These results suggest that differences in the dermal collagen degree of orientation correlate with scarring, and show that small angle light scattering can be used quantitatively to assess differences in the collagen fiber architecture of dermal wounds.