A Comprehensive Review Of Topical Agents

By Jonathan Moore, DPM, MS, A. Patti Smith, MD, and John S. Steinberg, DPM

The wound is in constant evolution. Changes arise and you need to be able to respond accordingly in your treatment course. Indeed, understanding the biochemical dynamics of wound healing is vital for proper product selection (see “Understanding The Phases Of Wound Healing” on page 42). The challenge to the practitioner is to have the knowledge base with which to sort through the thousands of topical agents and dressings available today.

Insights On Topical Agents With Collagen
Let’s start out with a discussion of the biologic topical agents that contain collagen. Collagen hastens wound healing and works best when you apply it in the woven sheet format.
1. Kollagen (BioCore). These products are 100 percent non-denatured bovine collagen type I in proper configuration specific to skin tissue.
2. Medifil (BioCore). Of these products, you can use Medifil particles for draining, undermined, tunneled, infected or contaminated deep cavity wounds. Medifil pads are for deep cavity draining wounds. You may use Medifil gel to help treat dry, tunneled, superficial, minimally draining wounds.
3. Skin Temp (BioCore). Skin Temp (porous collagen sheets attached to a nonadherent backing) is also indicated for dry, superficial draining wounds.

4. Fibracol (Johnson and Johnson). Fibracol is a non-adherent, collagen-based dressing (90 percent) that is combined with calcium alginate (10 percent). It’s indicated for moderate to heavy exudative wounds, ulcers or dehisced incisions. It helps maintain a moist wound environment while allowing exudative transmission to prevent maceration.
5. Collagen Wound Gel (Johnson and Johnson). NU-GEL promotes natural autolysis by rehydrating and softening necrotic tissue while providing a moist wound environment.
6. Collagen Dressings. Another option is hyCure, a 96 percent type I collagen. It’s a hydrolyzed protein powder that forms a gel in the wound bed. It acts as a wound filler and exudate absorber.
7. Oasis (Healthpoint). Oasis offers a sterile wound covering to support tissue regeneration in partial thickness wounds. It provides a tissue-engineered collagen matrix derived from porcine small intestine submucosa (SIS). Oasis has a one-year shelf life and is available in single thickness, fenestrated sheets.

What About Hyaluronic Acid?
Hyaluronic acid is another biologic topical agent you should consider. Hyaff (ConvaTec) is an ester of hyaluronic acid (60 percent). As an essential component of the wound matrix, hyaluronic acid facilitates growth and movement of fibroblasts as well as controlling hydration. Use it for closure of sinuses and improved healing of indolent neuropathic ulcers. Hyalofill F is a non-woven fleece-like material. Hyalofill R is a rope-like material. You can use either of these as topical wound dressings, creating a hydrophilic gel rich in hyaluronic acid.

A Helpful Primer On Bioengineered Tissues
• Apligraf (Novartis). With Apligraf, you get bilayered, bioengineered tissue, consisting of four components: extracellular matrix, fibroblasts, keratinocytes and a stratum corneum on an organized bovine type I collagen base. Human neonatal derived fibroblasts and kerotinocytes produce multiple growth factors to stimulate wound healing. Supplied in a circular 7.5-cm disk, Apligraf is partly transparent, pliant and can be stored up to five days at room temperature.
• Dermagraft (Smith and Nephew). How does Dermagraft work? Essentially, you have neonatal dermal fibroblasts cultured on a bioabsorbable mesh that produces a living active tissue containing dermal matrix proteins and cytokines. Dermagraft has a normal ratio of collagen type III to type I glycosaminoglycans (GAGs) and many growth factors. Dermagraft is FDA-approved for treating full-thickness diabetic foot ulcers. The product is cryopreserved for storage and can be stored for up to three days from the time of shipping.
• Transcyte (Advanced Tissue Sciences). Transcyte consists of human dermal tissue cells combined with a synthetic epidermal layer. It offers an alternative to cadaver skin for treating patients with third-degree burns.
• Epicel (Genzyme Biosurgery). Also called cultured epidermal replacement, Epicel is indicated for deep dermal or full thickness wounds requiring skin graft. Cells are harvested and cultivated, producing keratinocyte sheets available as cultured epithelial autografts (CEA).

Sorting Out The Growth Factor Promoters
While growth factors can play a key role in wound healing (see “An Essential Update On Growth Factors” on page 45), you may also use growth factor promoters to help facilitate successful treatment outcomes. Here are a few to consider.
1. Panafil ointment (Healthpoint). Panafil is an enzymatic debriding-healing ointment containing papain-urea copper-chlorophyllin complex. Copper reduces fibrin formation and enhances structural integrity of the deposited collagen. Chlorophyllin stimulates fibroblasts and keratinocyte proliferation and migration while the papain-urea component provides mild debridement of devitalized necrotic tissue.
2. Biafine WDE (Medix Pharmaceuticals Americas, Inc.). The active ingredient, trolamine/sodium alginate, recruits macrophages to the wound site, impacting all phases of wound healing. It also assists in autolytic debridement and provides moist wound healing. You can use it for radiation burns and skin breakdown.
3. Zinc oxide. Zinc is a co-factor or component of more than 300 enzymes needed for wound repair. Deficiencies result in poor healing and decreased wound tensile strength. Zinc oxide (not zinc sulfate) has been found to enhance re-epithelialization, decreasing inflammation and bacterial growth. You can apply zinc oxide topically or in a compressive bandage.

What Are The Best Options For Wound Fluid Regulation?
Drying agents run the gamut from Mesalt to calcium alginates and foam dressings. In regard to their makeup and indications …
• Mesalt (Direct Medical). Hypertonic NaCl impregnated gauze uses oncotic pressure to promote a unidirectional movement of fluids, necrotic exudate and debris away from the wound. You can use it to treat infected, draining wounds or to treat the macerated margins of a wound site.
• Multidex (DeRoyal). Provided in a powder or gel form, maltodextrin absorbs exudative wound fluid and creates a protective coating over the wound, thus controlling odor and decreasing the amount of exudate. The polydisaccharide, hyaluronic acid is the most abundant component in the gel matrix. You can use Multidex on a variety of infected and non-infected wounds, ranging from dermal ulcers and donor sites to diabetic ulcers and second-degree burns.
• Foam dressings (Allevyn, Mepilex, Biopatch, Polyderm and Lyofoam). Made of hydrophilic polyurethane foam, these dressings help decrease maceration and can assist in healing heavily exudating wounds, especially during the inflammatory phase of wound healing.
• Hydrofiber (Aquacel, ConvaTec). Methylcellulose fibers adsorb exudative fluids to create a soft, comforming absorbent dressing. Using Aquacel helps maintain a moist wound environment, aids in autolytic debridement and is easily removed with little or no damage to newly formed tissue. You can use these products to manage exuding, chronic wounds (such as pressure ulcers) and acute wounds (such as abrasions and incisions).
• Calcium alginates (Kalginate, Algicell, AlgiSite, Curosorb, Hyperion, Maxorb, Melgisorb, Sorbsan and many others). These products are sterile, non-woven dressings with thick fibers (derived from seaweed) absorbing many times their weight while maintaining their integrity after absorption. They are available as pads or rope dressings, and you can use them for highly exudative wounds.
• PolyMem. The polyurethane membrane matrix wicks away exudate (10x weight). The membrane contains a cleanser, moisturizer and super absorbent starch co-polymer. The mild cleaner, F-68 Surfactant, is activated by moisture and then is gradually released into the wound bed. Since there is a reduced adherence of debris to healthy tissue, you’ll find the product loosens eschar and necrotic tissue, supports autolytic debridement and keeps the wound bed clean throughout the entire wound healing process. You can use it to help treat a variety of conditions, ranging from diabetic and venous statis ulcers to burns and post-operative wounds.

Getting A Handle On Drying Beads And Absorbent Agents
• Iodosorb Gel (Healthpoint). This product contains hydrophilic beads made into an ointment containing 0.9 percent iodine. The beads absorb wound exudates, swell and then release iodine to provide an antibacterial dressing. This dressing is indicated for infected, wet, sloughing wounds, and can be changed daily or up to three times weekly. The low level of iodine provides an antibacterial effect without causing cytotoxicity.
• Debrisan (Pharmacia and Upjohn Ltd.). Debrisan consists of sterile, pale yellow dextranomer beads that use capillary action suction pressure (up to 200mmHg) to absorb and trap bacteria, and cellular debris in the spaces between the beads. It reduces local tissue edema and controls odor formation. You can use Debrisan to treat small wounds containing soft yellow slough, including infected surgical or post-traumatic wounds, pressure sores and leg ulcers.

• Iodoflex (Healthpoint). This absorbent agent is a sheet form of Iodosorb. An iodine-based ointment containing sterile, yellow-brown microspheres (beads) forms a three-dimensional network of cadexomer, a chemically modified starch, and two layers of gauze fabric, which facilitate transportation and application. Iodoflex is highly absorbent while also providing a moist wound environment. You can use Iodoflex to help treat chronic leg ulcers complicated with infection, slough or heavy drainage. Other absorbent agents include Medipore, Tiell, Mepore and Exu-dry.

A Brief Overview Of Moisturizing Agents And Wet Dressings
• Hydrogels (amorphous, impregnated gauze, sheets) include Aquasorb, Duoderm Gel, SAF-gel, Curasol, Intrasite Gel, Granugel, Nu-Gel and many others. These products are cross-linked polymer gels or sheets that provide absorption, desloughing and debriding. These commonly used and relatively inexpensive products are often the mainstay in maintaining a moist wound environment. Hydrogels have replaced saline-moistened gauze in many instances.

• Hydrocolloids (pastes, powders, and sheets) include Comfeel, Duoderm, Tegasorb and many more. These products feature gelatin or pectin (absorptive polymers) in an adhesive matrix. Semi-hydrated granules change into a gel during wound exudate absorption. You may find hydrocolloids useful for both dry necrotic wounds with minimal exudate, and for clean granulating wounds. Occlusive sheets do not allow bacteria, water or oxygen into the wound bed and can aid in angiogenesis and granulation. When the dressing is changed every two to three days, be aware that breakdown of the product produces a residue and a slight odor. This should not be confused with infection.
• TenderWet dressings (Medline Industries, Inc). These dressings are polyacrylate pads saturated with Ringer’s solution that you can pack into a deep wound bed. Polyacrylate attracts large protein molecules found in wound debris. As proteinatous exudate enters the pad, Ringer’s solution is released into the wound bed. Combining hydration with absorption, you’ll find that this dressing also provides some debridement for up to 24 hours.

Assessing Topical Antibacterials
The silver ion rapidly kills microbes by blocking the cell respiration pathway. The efficacy of microbe killing is based not only on the amount of silver ion present, but also the amount of silver radicals generated. Silver ion alone is not cytotoxic. Cytotoxicity occurs when the ion complexes with the delivery systems, as in silver-nitrate and silver-sulfadiazine. Silver also increases wound surface calcium, which stimulates epithelialization.
1. Silvadene Cream 1%. It has broad antimicrobial activity for gram negative and gram positive organisms, and yeast. You can use this product adjunctively for treating and preventing wound sepsis in patients with burns and ulcerations. This is a sulfa derivative, so be aware of possible allergies. Silvadene is a pro-inflammatory product and causes an inflammatory exudate with increased wound drainage generated by the sulfadiazine complex. Be aware that combining Silvadene with papain-containing debriding agents causes inhibition of the enzymatic activity, and should be avoided.
2. Acticoat (burns) and Acticoat 7 (wounds). The products consist of two layers of a nanocrystaline silver coated mesh enclosing a single layer of an apertured, non-woven fabric. Acticoat is indicated as an antimicrobial barrier for burns, wounds and graft sites. The product has activity against a wide range of gram-positive and negative bacteria. You moisten the dressing with sterile water (not saline) as the chloride in saline combines with the silver ion to precipitate as silver chloride. Then trim the dressing to size and apply it to the area, making sure the darker blue surface is directly on the skin. Cover it with a secondary dressing and change it every three days for burns and every seven days for wounds.
Other silver-based topicals include Arglaes (a non-cytotoxic film dressing with ionic silver) and Silver Nitrate (which is used to create hemostasis in debrided wound areas and to “burn” hypergranulation tissue caused by repetitive trauma at wet wound sites).
In regard to other helpful topical antibiotics, there are Mefenide (sulfanylon) and Bactroban (mupirocin calcium cream 2%). In particular, Bactroban inhibits bacterial protein synthesis and shows little risk of resistance if properly prescribed. In studies, researchers have shown that Bactroban is equal in efficacy to cephalexin. Disadvantages include possible inhibition of re-epithelialization and wound maceration.
Other intriguing topicals include the Triple Antibiotic ointment (polymyxin B sulfate, bacitracin zinc, neomycin), which can help minimize scars and decrease infection risk.

A Quick Review Of Antiseptics
Povidone-iodine, acetic acid, hydrogen peroxide and Dakin’s solution (sodium hypochlorite) are cytotoxic to human fibroblasts. Collagen synthesis and granulation tissue formation are inhibited. Even though cytotoxicity exists, these products have their place in the clinical setting of severe aerobic and anaerobic infection. You can use acetic acid (0.25%), iodine (10%), hydrogen peroxide (50%) or dilute dakins solution to flush the wound site to lessen the bacterial load. After approximately 15 minutes, you wash out the antiseptic with saline. Single daily treatments or multiple daily treatments have been used for short periods. In regard to the specific antiseptics …
• Betadine (povidone-iodine 10%). Controversy exists concerning the overall wound cytotoxicity of Betadine. Betadine promotes wound healing by killing bacteria and is available as a solution, cream and ointment. However, be aware that Betadine scrubs have additional detergents that are more detrimental to the wound healing process and should be avoided. Betadine solution, cream and ointment do not have the detergent and have lesser cytotoxicity levels.
• Iodosorb. This is the only wound gel known to inhibit bacterial growth while absorbing exudate. Pure iodine can cause toxicity in wounds over prolonged periods of time and is generally contraindicated. However, when it comes to the form of iodosorb ointment (0.9% iodine), no significant wound impairment has been noted.
• Zinc oxide. Studies on zinc have shown beneficial results in wound healing with acceleration of the re-epithelialization process and an antibacterial effect. Zinc oxide activates endogenous zinc-dependent matrix metalloproteinases, augments expression of endogenous growth factors and facilitates keratinocyte migration.
• Panafil (chlorophyllin copper complex). This copper complex promotes the formation of strong granulation tissue by reducing hemagglutination; supporting blood flow of O2 and nutrients to the cells; reduces excessive fibrin formation; and removes fibrin that acts to shield bacterium. Copper protects tissues from the effects of superoxide radicals and is essential for collagen formation, crosslinking and maturation.

The Inside Scoop On Enzymatic Debriding Agents
• Papain-urea (Accuzyme, Panafil (Healthpoint)). Papain-urea is a serine protease that selectively degrades cysteine amino acid residues. Urea facilitates the proteolytic process by disrupting hydrogen sulfide bonds to unfold protein molecules, and thereby exposes the active sites for papain enzymatic debridement. The combination of papain and urea is twice as effective as papain alone. Healthy cells quickly metabolize urea to provide a relative level of protection from papain debridement. Be aware that some patients may develop pain with papain-enzymatic debridement because of an innate pro-inflammatory response as well as a response to degradative products in the wound bed. In Panafil, chlorophyllin decreases potential pain generation by blocking the agglutination of erythrocytes.
• Santyl (Smith and Nephew). Collagenase, derived from Clostridium histolyticum bacteria, is a water-soluble proteinase that specifically attaches to and degrades collagen. This can facilitate rapid debridement and healing of chronic wounds. Necrotic tissue is anchored to the wound by strands of collagen. Unless these fibers are broken, debridement cannot take place. Collagenase converts collagen into a gelatinous form that undergoes degradation by lesser enzymes. Thick, hard eschar often has collagen buried deeply at the base. These wounds require scoring (pie-cutting) for collagenase products to interact with and degrade the underlying collagen.

In Conclusion
The many products discussed above represent an attempt to summarize the key categories of topical wound agents. While this listing is certainly quite extensive unto itself, it is only a partial compilation when you consider the expansive growth and sheer number of products that are rapidly entering the market today. Staying on top of the latest advances in wound care may be difficult, but it it truly essential in order to provide appropriate, effective treatment for our patients.

Dr. Moore is a Diabetic Foot Fellow at the University of Texas Health Science Center (UTHSCA) in San Antonio, Texas.
Dr. Smith is the Medical Director at the Hyperbaric and Wound Care Center of the Texas Diabetes Institute, and is an Assistant Professor at UTHSCA.
Dr. Steinberg is the Medical Director of the Podiatry Clinic at the Texas Diabetes Institute, and is an Assistant Professor at UTHSCA.



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4. Product information materials and Internet corporate sites for Healthpoint, Novartis, Smith and Nephew, Johnson and Johnson, Biocore, ConvaTec, Advanced Tissue Sciences, Genzyme Biosurgery, Human Genome Sciences, Ortho-McNeil, Immunex, Medix, Direct Medical, DeRoyal, Pharmacia, Upjohn and Medline.

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