By Kathy Dix
Products to Assist Healing
The Science of Wound Healing
Wounds come in a variety of shapes and sizes, and can be either chronic or acute. Their diversity means that each wound must be approached with consideration for its own unique characteristics and how best to heal the patient. This may involve more than treatment of the wound itself — it may require treatment of an underlying condition or comorbidity.
Gerald Lazarus, MD, professor of dermatology and director of the Johns Hopkins Wound Center, says that it’s important to address the whole patient. Accurate diagnosis is first and foremost, he points out. “You may say it’s a venous ulcer, because the veins are shot and there’s edema, but they may also have arterial disease.”
It can be easy to misdiagnose the cause of an ulcer; one 20-year old female from Bermuda presented with venous ulcers, but had systemic lupus erythematosus. “One must consider, ‘Is there a serious underlying disease?’” Lazarus says.
“A key issue in wounds is that all wounds contain bacteria. We have our chronic difficulty in deciding if the wound is infected — trying to decide if bacteria are pertinent. A swab from the middle of a filthy wound is useless. We take tissue at the rim of the ulcer, submit it to the lab where it is ground and cultured, and most of the time we have a pretty reasonable idea of what we’re looking for,” he says. “With the emergence of resistance, it’s critical to ensure you have the right organism before you start throwing antibiotics at it. Gentamycin cream basically breeds resistance. Many topical antibiotics will cause contact dermatitis around the wound and that slows wound healing.”
Not only that, but the wound may become redder and result in the addition of some other treatment, because healthcare workers assume the inflammation is from an infection. “Is it in- flamed from infection, from the underlying disease, or because of an allergy to the medicine? The most common allergen in the United States is Neosporin, causing contact dermatitis. Bacitracin is up to No. 6 or No. 7,” he observes.
“The promiscuous use of oral and topical antibiotics is inappropriate, because what you’re doing is selecting for resistant organisms. You do not give antibiotics indiscriminately by mouth or vein until you know what the organism is. A number of topical drugs will not do the trick because the patient may become allergic to them, or there may be penetration problems. You’re asking a lot of a topical prep to go through a necrotic bucket of dead tissue to get to the bugs at the bottom. There must also be adequate debridement. Get the necrotic tissue out of there; otherwise it doesn’t heal,” Lazarus says.
If a wound is chronic, one method is to make it acute to restart the healing process. Get a good “base,” he recommends, debriding all dead tissue, thereby reducing it to an acute wound, and allow the healing process to begin.
“The care of wounds is in its clinical infancy,” Lazarus observes. But the basics have been established. “Look for underlying disease, quantify ability of infection, clearly debride, and keep the wound moist and treat with adequate doses of antibiotics for significant organisms,” he concludes.
Products to Assist Healing
NovaCal Pharmaceuticals is working to address wound healing, developing a new class of non-antibiotic, direct-acting therapies to prevent and treat serious bacterial and fungal infections. Aganocides are patterned after the small-molecule chemicals that white blood cells naturally produce to kill microbes and biological invaders. One of the company’s lead aganocides, NVC-101, is currently in Phase II trials for the treatment of infections associated with chronic wounds, and NovaCal has an additional antimicrobial compound, NVC-422, currently in preclinical development for a variety of applications.
Says Behzad Khosrovi, PhD, vice president of research and development for NovaCal, “A major problem (and source of differing opinion) in modern wound care is the issue of antibiotic resistance, making widespread use of antibiotics undesirable. However, many topical anti-infectives such as povidone-iodine, chlorhexidine, and hydrogen peroxide that efficiently kill microbes can be toxic to the treated tissue; they can prevent wounds from decreasing in size and ultimately inhibit healing. One question in this area that NovaCal is working to address: Can we circumvent these problems based on mechanisms used by the body’s own immune cells?”
NovaCal’s novel antimicrobials are based on mechanisms used by the body’s own immune cells, neutrophils and macrophages, which clear infections by the process of phagocytosis. Aganocide compounds are designed to attack and kill the bacteria directly by destroying cell walls, proteins, and nucleic acids.
Progressive Medical utilizes the Provant Wound Closure System with its injured workers who have wounds that have not healed using other systems. Progressive Medical manages the care of injured workers and their relationship with insurers, and is a national provider of cost containment services and products such as Provant, which was developed by Regenesis Biomedical.
The Provant system uses sensation-free radiofrequency signals to penetrate directly into the wound bed. The radiofrequency signals promote the growth of certain cells, along with necessary growth factors, in the soft tissue that are critical for wound healing. Research has shown that specific cells respond to varying radiofrequency signals in much the same way they would to pharmaceutical products. The device is lightweight, portable and easy for patients to use without supervision. This enables patients to treat themselves, which reduces their need to physically go to the physician’s office for clinical care.
The Science of Wound Healing
Virginia Rybski, a molecular biologist, is vice president of corporation development for Regenesis Biomedical. The science of wound healing, she observes, still has room for improvement. “There are three distinct sequential phases of wound healing: inflammatory phase, proliferative phase, and maturational phase. The inflammatory phase is characterized by inflammation and hemostasis. When the injury occurs to the skin, the cell membranes release vasoconstrictor proteins to help limit immediate hemorrhage, then the capillaries dilate to allow inflammatory cells to migrate to the wound. Platelets are the first cells to respond to a wound site. They release chemokines to help with clot formation. Next, neutrophils are attracted to the wound site when the complement cascade is activated by platelet degranulation. Neutrophils help kill bacteria and remove foreign debris from the wound. Later, leukocytes and macrophages respond to the wound site. Macrophages produce and secrete numerous types of proteins. These include collagenases that debride the wound, interleukins and tumor necrosis factor (TNF) that stimulate fibroblasts (produce collagen) and promote angiogenesis, and transforming growth factor (TGF) that stimulates keratinocytes. This step marks the transition into the proliferative phase.
“The proliferative phase includes epithelialization, angiogenesis, granulation tissue formation, and collagen deposition. Epithelialization — the regrowth of the epidermis — occurs early in wound repair. If the basement membrane remains intact between the epidermis and the dermis, the epithelial cells migrate upwards in the normal pattern to heal the wound. The epithelial progenitor cells remain intact below the wound and the normal layers of epidermis are restored in two to three days. If the basement membrane has been destroyed, similar to a second- or third-degree burn, then the wound is re-epithelialized from the normal cells in the periphery and from the skin appendages. Angiogenesis, stimulated by the protein TNF-alpha, is marked by endothelial cell migration and capillary formation. The new capillaries deliver nutrients to the wound and help maintain the granulation tissue bed. The migration of capillaries into the wound bed is critical for proper wound healing. The granulation phase and tissue deposition require nutrients supplied by the capillaries, and failure for this to occur results in a chronically unhealed wound. The final part of the proliferative phase is granulation tissue formation. Fibroblasts differentiate and produce ground substance and then collagen. The ground substance is deposited into the wound bed; collagen is then deposited as the wound undergoes the final phase of repair.
“The final phase of wound healing is the maturational phase. The wound undergoes contraction, ultimately resulting in a smaller amount of apparent scar tissue. The entire process is a dynamic continuum with an overlap of each phase and continued remodeling. The wound reaches maximal strength at one year, with a tensile strength that is 80 percent of normal skin. Collagen deposition continues for a prolonged period, but the net increase in collagen deposition plateaus after 21 days.”
Chronic wounds are wounds that do not heal within the first 30 days — unlike acute wounds — and do not respond to standard wound care practices. “Some researchers believe that all chronic wounds are infected,” Rybski says.
“There are numerous advanced treatment methods for chronic, non-healing wounds. These can be segmented into three main categories: pharmaceutical agents, wound dressings, and medical devices. Pharmaceutical agents include antibiotics; however, a recent systematic review of antimicrobial agents has concluded that systemic or topical antimicrobials are not generally indicated for the management of chronic wound infections. However, there may be some value in the prophylactic use of topical antimicrobials for the initial management of acute cellulitis. There is also a pharmaceutical agent containing platelet-derived growth factor (PDGF) called Regranex®, by Johnson & Johnson, which helps wounds granulate, as well as various agents to enzymatically debride wounds, such as Accuzme by Healthpoint, and ointments that contain trypsin, Balsam Peru, and Castor Oil that act as enzyme debriders, epithelial agents and pain reducers, such as Meander® by Healthpoint.”
“There are a wide variety of wound dressings that are used for various types of wounds,” Rybski continues. “Amorphous hydrogels vary in thickness and viscosity and may help facilitate autolytic debridement of necrotic tissue. Care must be taken not to apply hydrogels to periwound skin as they may cause maceration. Hydrogel dressings contain up to 95 percent water and thus cannot absorb much exudates, so they are used in dry wounds such as pressure ulcers, skin tears, surgical wounds, and radiation burns. Hydrocolloid dressings are occlusive and do not allow water, oxygen, or bacteria into the wound. This may help angiogenesis and granulation and even lower the pH of the wound bed to prevent bacterial growth, but they should not be used in the wound in infected. Alginate dressings absorb moderate-to-high amounts of wound drainage and may be used in infected and non-infected draining-type wounds. The alginate forms a gel when it comes in contact with fluid and may absorb up to 20 times its weight in fluid. As such they should not be used in dry wounds. Composite dressings — containing multiple layers — may be used in wounds with minimal to heavy exudates, healthy granulation tissue, and necrotic tissue; however, they should not be used if the patient has frail or dehydrated skin. Transparent films are flexible sheets of polyurethane coated with an adhesive so that the caregiver can easily monitor the wound bed through the film, however they should not be used in areas where there is a high friction level, such as with the buttocks or sacrum. Films also are semi-occlusive and trap moisture, creating a moist wound environment. Silver dressings have become available, since silver interferes with bacterial electron transport system and inhibits the multiplication of the bacteria. However, to achieve this, silver ions have to be able to enter a cell, so the chemical bonding of silver with a sulphonamide antimicrobial — sulphadiazine — has resulted in the development of a safe broad-spectrum agent for topical use. In this formulation, silver is released slowly from the transport medium in concentrations that are selectively toxic to microorganisms such as bacteria and fungi. This type of silver product has been used successfully in the management of acute and chronic wounds. Products that can sustain the interaction of silver with microorganisms in the exuding wound are likely to be more effective in preventing/controlling local infection as potentially more silver ions will be available to enter bacterial cells. This assumes that the concentration of silver in the solution is both correct and maintained.”
She adds, “Medical devices used to treat post-surgical chronic wounds include KCI’s Wound VAC® based on negative pressure therapy (NPT) and Regenesis Biomedical’s Provant® Wound Closure System based on cell proliferation induction (CPI). Negative pressure therapy requires the insertion of a special sponge dressing into the wound bed, covering it with a transparent film to create a vacuum seal, and then applying suction pressure to remove exudates and to draw the wound edges closer together.
A skilled clinician is required to apply the VAC to the patient’s wound and the patient remains tethered to the medical device for 22 out of 24 hours of every day. Cell proliferation induction therapy works non-invasively directly through any type of intact dressing, compression hose, cast, or Unna boot and delivers a pulse and modulated radiofrequency energy to recruit the skin cells into an active growth and replication process called mitosis. Since CPI is an adjunctive therapy, it gives the clinician the most flexibility in treatment options — moist or dry wounds/infected or non-infected wounds — and is so easy to administer that patients can treat themselves under a physician’s care. Compared to the VAC, Provant is about half the cost, is sensation-free for patients and healing rates are equivalent.”
The National Healing Corporation (NHC) accounts for more than 20 percent of the nation’s managed wound healing centers. In 2004, NHC became an official partner of the Wound Healing Research Program at The Ohio State University in Columbus. Jack E. Lighton, DO, FACOS, CWS, is a member of the physician’s advisory panel for NHC.
“The difference between acute vs. chronic wounds is 30 days,” he says. “Most acute wounds, such as contusions, lacerations, and abrasions, heal without any complications, and require only cleansing and protection. If, however, the wound doesn’t heal within 30 days, this would be considered a chronic, non-healing wound. Chronic, non-healing wounds would suggest a serious underlying disease process such as diabetes, poor arterial blood supply to the area of the wound, or an immuno-compromised or malnourished patient. The underlying conditions that contribute to the non-healing wound need to be identified and corrected in order for the healing process to take place.”
In addition to the standard treatment — debridement, evaluating and documenting adequate arterial profusion, and special dressings — there are other options. “Bio-engineered tissue may be required for certain wounds to obtain closure. Off-loading, or removing pressure or friction from the wound, is also very important and must be addressed,” he says.
“Current research emphasizes the importance of not using common substances that we used in the past such as betadine, peroxide, and dakins solution, which are known to inhibit or destroy new cell growth,” he points out.
Orthopedic surgeon Daniel Sparks, MD, has completed a two-year study on Skin Renu Plus, a proprietary formula from Health Renu Medical that decreased the incidence of wound complications, including infection, by 66 percent. Further, he noted that 77 percent of the 203 subjects had decreased scarring and shorter healing time after surgery. Skin Renu Plus is a topical formula that helps promote healing by providing nutrients to the wound and by applying an anti-bacterial layer directly to the wound site.
“Treatment after wound closure is focused on the prevention of complications that are known to disrupt the healing sequence, thus resulting in a ‘chronic’ wound,” observes Sparks.
“These complicating factors include:
- Loss of blood supply to the wounded area
- Retention of foreign material
- Loss of tissue resulting in incomplete wound closure
- Sepsis (wound infection)
“By far, the most common cause of acute wounds becoming chronic is the development of septic or infected wounds. Many protocols, therefore, incorporate various strategies for eliminating/suppressing infectious agents to minimize the number of wounds that progress to the chronic state,” he adds. “Skin Renu Plus and Derm All Gel applied as a pre-dressing over acute wounds provide an environment of bacteriostatic fatty acids and bactericidal trepinens that greatly enhance the body’s natural defenses against acute wound sepsis. Application of these products along with time-honored management of acute wounds will result in a minimum of wounds that progress to a chronic healing state.
“There are various wound care programs incorporating many different techniques to obtain the same goal, but no one program has signifi- cantly outperformed the others. Basic wound care principles along with nutritional and antibacterial support is still the gold standard of wound management,” he says.
Jean M. deLeon, MD, is associate medical director of rehabilitation services and wound care, medical director of the outpatient wound care center, and director of the wound care team at Baylor Specialty Hospital in Dallas, which has a comprehensive wound care program that treats patients with wounds resulting from diabetes, pressure, peripheral vascular disease, trauma, infection, or surgery.
“The trauma causing a wound may be chemical, thermal, electrical, or mechanical in etiology. ‘Chronic’ does not always indicate a long period of time. For instance, pressure ulcers can develop very quickly and be treated in a timely fashion, but still can be considered chronic due to the difficulty in reversing the underlying cause (pressure),” she says.
“The goal of many treatments of the past was to dry the wound. Research, however, dating back to the 50s, demonstrated the benefit of a moist wound environment. Normal saline gauze wet-to-dry dressings two to three times a day is still a standard of care at many institutions. The wound care community continues to educate on the benefit of a moist wound environment,” continues deLeon.
“The question of how to finance the use of more technologically advanced dressings will always be a never-ending discussion. Dressing prices can range from less than a dollar to over a thousand dollars for one dressing. The purchase or rental of the modalities adds an even higher cost,” she adds.
Giuseppina Benincasa-Feingold, MD, is the assistant director of pediatric emergency medicine at Our Lady of Mercy Medical Center in the Bronx, N.Y., and is medical advisor to the International Hyperbarics Association, Inc. The association is an educational and charitable organization focusing on the needs of the hyperbaric community.
Benincasa-Feingold is the medical director of three facilities in New Jersey, New York, and Connecticut, where hyperbaric oxygen therapy (HBOT) is offered to enhance the body’s natural healing process. “I treat both acute and chronic wounds in a 2.4 atmosphere,” relates Benincasa- Feingold. “They are not always treated with hyperbaric oxygen therapy, although we in the HBOT world think they should be. A lot of tissue loss can be prevented with HBOT. A majority of wounds that are chronic are because of poor circulation, and are usually found in the lower extremities. You find a high incidence of them among people with emphysema, cardiac disease, smokers, etc., so the blood supply is very poor and enough nutrients are not being brought in. I try to encourage patients to stop smoking, which would help to improve circulation and promote healing. However, HBOT remains a great tool to use for these cases and should be used more for acute injuries.”
And, she says, “15 percent to 20 percent of patients in need of wound care should go for HBOT, but most doctors don’t know about it and are not aware of its broad use and benefits. Wound treatment hasn’t changed all that much. The traditional treatment is with antibiotics, but in severe cases an amputation is done, which costs much more, when HBOT could have prevented the loss of a limb.”
Decubitus ulcers are a particular bugbear for wound healers. “Prolonged pressure causes ischemia, which leads to tissue necrosis. The tissue closest to the bone is typically the first tissue to undergo necrosis. Therefore, visible discoloration of the skin may actually be an indicator of underlying subcutaneous fat and muscle necrosis. Pressure ulcers are classified as stages according to the degree of tissue damage. The other key factors involved in the development of pressure ulcers include shear, friction, moisture, impaired nutrition, immobility, impaired sensation, and advanced age,” says deLeon.
“The Omnibus Budget Reconciliation Act 1987 led to a mandate for hospitalized and institutionalized patients to receive regular assessment, preventive measures, and treatment of pressure ulcers. The National Pressure Ulcer Advisory Panel 1989 devised a universal pressure ulcer staging system (Stage I, II, III, IV). In 1994, the Agency for Healthcare Policy and Research (AHCPR) published Guidelines for Treatment of Pressure Ulcers. On Dec. 6, 1999, President Clinton signed the Healthcare Research and Quality Act. AHCPR is now known as the Agency for Healthcare Research and Quality,” she adds.
“The AHCPR Guidelines for Treatment of Pressure Ulcers were designed to help clinicians in the prevention, diagnosis, treatment, and management of pressure ulcers. The basic recommendations include the use of a Risk Assessment Tool; a multidisciplinary approach to management; the use of specialty beds and mattresses for pressure relief; moist wound healing strategies (dressings designed to maintain a continuously moist clean wound bed); nutritional assessment and continued monitoring and support ( maximize protein intake, and use of antioxidants); management of bacteria and infection with topical dressings, modalities, debridement, and medications; and the need for educational programs on pressure ulcers.”
The best practice for treating this type of wound — also known as a pressure ulcer — is, first, removal of the pressure, also known as “off-loading.” “This is accomplished through the use of specialized beds, air fluid mattresses, and special cushions for wheelchair-bound patients,” Lighton says. “Many elderly patients have lost significant amounts of protective fat over bony prominences and therefore are very susceptible to breakdowns of tissue due to pressure. If pressure is not removed, the ulcer will not heal. It is also important to evaluate the patient’s nutritional status. Many of these patients are nutritionally depleted, and correction of their low serum proteins is necessary for wound healing.” “Treating them with antibiotics along with oxygen therapy are the best practices,” says Benincasa-Feingold.
“Treatment of decubitus ulcers in the United States adds a $1 billion financial burden to a healthcare system already stressed by cost overrun,” Sparks says. “Prevention and effective and timely treatment protocols would obviously benefit the entire healthcare industry as well as save financial resources.
“For many years now, the mainstay of decubitus ulcer treatment has been prevention. Protocols, seminars, research projects, and facility awareness programs abound throughout the healthcare industry. Given the lack of success in even the most high-tech and sophisticated treatment programs, prevention has gained the high road in managing decubitus ulcers. When decubitus ulcers do occur, they are managed as chronic wounds requiring intense and expensive interventions,” he adds.
“What does prevention require? It requires vigilance in following preventive protocols such as the following:
- Pressure applied to an area of the body is the cause of decubitus ulcers and relief of pressure will prevent the occurrence of these wounds
- Turning -- repositioning patients when sitting or lying down is the mainstay of prevention
- Skin must be kept clean and healthy
The healthier the skin, the greater its resistance to pressure breakdown,” Sparks says. The products Sparks tested can be applied once or twice per day to the body, he notes, “especially areas most at risk for decubitus ulcers, as a body shield to improve skin health and combat the microbial and frictional forces that promote decubitus formation.”