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Wound Healing
And
The Use of Regranex ®
By: Susan McCarty


Introduction

Diabetic wound care is a large portion of diabetic care in today's society. This is due to the large number of diabetics who receive a wound or ulcer throughout the course of their disease. The body heals itself through a process known as wound repair. Wound repair is the attempt of the body or organism to restore mechanical integrity, barrier/protective functions, and limited mobility to the damaged or injured area. This article will concentrate on the process of healing by secondary infection or by the body itself, as this is usually the first attempt of doctors in wound healing.

What happens, however, when an ulcer does not heal? Doctors can now use growth hormones in the treatment of chronic diabetic ulcers. Recently, the Food and Drug Administration approved the use of the growth hormone becaplermin, trade name Regranex ® in the treatment of chronic diabetic ulcers. This article will also look at how Regranex ® works, and its safety and efficacy in the treatment of diabetic ulcers. Finally, a case study will be presented in which Regranex ® was used in the treatment of a chronic lower extremity wound. Wound Prevalence

Approximately 16 million people in the United States have Diabetes Mellitus, or diabetes. Of this 16 million, 15% will develop a diabetic ulcer (a lesion or opening on the surface of the skin caused by loss of tissue directly related to the underlying pathology of diabetes) throughout the course of their disease. About 30% of these ulcers become chronic, full-thickness ulcers, despite good ulcer care. Ulcer care constitutes a large portion of "health care dollars" in the United States.

One cause of ulcers is pressure. Pressure slows down, and in some cases even stops, the flow of blood to an area of the body. This problem typically occurs in areas where the skin and underlying tissue is stretched over a bony prominence. Rees, et. al., stated that:

"patients with pressure ulcers often have prolonged and expensive hospitalizations. The mean length of stay for a patient with a primary diagnosis of pressure ulcer was nearly five times greater than that of patients without pressure ulcers in one cross sectional study. [This] translates into significant costs: the mean hospital charge for patients with a primary diagnosis of pressure ulcer was nearly $22,000 in 1992. The same study found that patients with a secondary diagnosis of pressure ulcer incurred an average of $11,000 in additional hospital charges."

T.J. Wieman's article published in 1998, states that the "results of a recent study based on claims data, indicate that the total payments for treatments of lower extremity ulcers average $2297 per patient per ulcer and can exceed $4500 per ulcer episode." A study by Halpin-Landry, et. al., indicates that not only are foot problems among the most common indicators for hospitalization of patients with diabetes, but also that they consume more that $1 billion annually in health care costs.

Skin Physiology

Skin is our greatest weapon against infection and bacteria. It provides us with a protective barrier, helps maintain and establish hemostasis (the arrest of bleeding), provides temperature regulation, helps to produce Vitamin D, allows us sensation, and excretes waste products. The skin protects us by preventing water loss and by preventing microorganisms and other foreign substances from entering the body. Hemostasis is accomplished through the constriction of superficial blood vessels. Temperature regulation is important because chemical reactions within the body can be affected by even slight temperature changes. Temperature is regulated in two ways, 1) the dilation or constriction of blood vessels, and 2) the evaporation of sweat from the surface of the skin.

Vitamin D is not actually produced by the skin; however, the skin plays an important role in the production of Vitamin D. The skin produces a precursor chemical which is converted to Vitamin D when exposed to ultraviolet light. Vitamin D is necessary to stimulate calcium and phosphate uptake in the intestine. The skin allows for sensation because there are receptors in the skin that can detect pain, heat, cold, and pressure. We can also feel the movement of the hair that covers the skin as it responds to changes in temperature. The final function of the skin is the excretion or removal of waste products from the body through sweat. Sweat plays a larger role in temperature regulation than in excretion. Only a small amount of waste products, such as uric acid, are excreted through sweat; however, it is known that the skin does play a role in excretion.

The skin is comprised of two distinct layers, the epidermis and the dermis. The epidermis is the protective, superficial or uppermost layer that we see. The dermis is comprised of the underlying structures and is responsible for the skin's strength and elasticity. The subcutaneous tissue, mostly made up of adipose or fat tissue, lies beneath the dermis, and is considered a functional part of the skin.

The epidermis, or outside layer of the skin, varies in thickness depending upon its location and its function. For example, the skin of the heel is very thick and tough, while the skin of an eyelid is thin and sensitive. The epidermis consists of many layers of keratinized or hard, stratified squamous epithelium. Epithelium is the purely cellular layer that covers all free surfaces of the body, inside and out. Stratified squamous epithelium is made up of layers of flattened, scale-like cells, which grow hard as they mature. It is these cells which form our skin and provide protective functions.

The epidermis serves as a selective barrier to protect the body from toxins and bacteria. The deepest epidermal layer is known as the basal layer. This layer is the source of cells for the natural regeneration of the four overlying layers of epidermis. Regeneration requires a successive process of cell removal and replacement or regrowth. In order for skin cells to be removed, there must be new cells underneath to take their place. The basal layer provides these new cells. The four overlying layers of epidermis are generated in a process called cell maturation. These layers are the prickle-cell layer (or stratum, meaning layer, spinosum), the granular layer (or stratum granulosum), the clear layer (or stratum lucidum), and the horny layer (or stratum cornium). Together these five layers of the epithelium provide a semi-permeable and protective layer over the dermis.15 Figure I of the Appendix illustrates the skin's layers.

The basal layer constantly makes new cells. As these cells mature, they are pushed up a layer to the prickle-cell layer. As they migrate, they become the cells of this layer. The basal layer continues to make new cells, which pushes the cells of the prickle-cell layer into the granular layer. The cells take on the characteristics of this layer as well. More new cells are added to the basal layer, moving the granular layer cells into the clear layer. This layer is called stratum lucidum, or the clear layer, because here the cells lose everything inside them (i.e. nucleus, mitochondria, etc) except fluid, and so are partially see-through. Again, more new cells are added to the basal layer, shifting the cells of the clear layer into the horny layer. It is in this layer that the cells are keratinized or made hard by the addition of hormones. In this last and uppermost layer, the cells begin their protective function. As the cells die, they are sloughed off and replaced by cells beneath them. The entire process takes about 15 - 30 days.

The dermis combines both cellular and fibrous elements and so, provides the skin with its structure and strength. With its visco-elastic structure, the dermis defines the characteristics of the skin. The dermis is built on a complex structure of collagen (the major protein of connective tissue) and elastin (an elastic protein in connective tissue) consisting of two layers, the papillary dermis and the reticular dermis. The papillary dermis is the superficial dermal layer and consists of the undulating interconnection of the dermis and the epidermis. This connection contains a rich supply of blood vessels, nerves, and nerve endings.

The reticular dermal layer consists of a layer of connective tissue in which fibroblasts (cells which make collagen fibers) are contained within a matrix of collagen, elastin, and proteoglycans (a blood group substance that occurs in the extracellular matrix of connective tissue). It is this layer which supports the dermal appendages - the hair follicles and sweat glands. The squamous epithelium of the sweat gland ducts and hair follicle crypts serves as an important source of epidermal regeneration.

The subcutaneous tissue is below the reticular dermis. It contains many cellular elements, such as adipose or fat cells, fibroblasts, histiocytes (macrophages present in connective tissue), plasma cells, lymphocytes, and mast cells, which are also important in the healing and protective functions of the body. The layers of the skin provide our body not only with a barrier to injury, but also with the necessary vessels for wound healing. The skin provides the first healing attempts of the body in the event of an injury by tightening vessels to control bleeding and by providing itself with the cells necessary to build more or new skin. As such, the layers of the skin each play a part in the process of wound healing.

Wound Etiology

One of the most common types of ulcer found among today's diabetic population is a pressure ulcer. A pressure ulcer is a "breakdown of skin and underlying tissues caused by constant pressure and inadequate oxygenation." Pressure interrupts the flow of blood to an area of the body, typically over a bony prominence, such as the elbow. Table I indicates areas of the body where pressure sores or ulcers can occur. If pressure in these areas remains constant or is unrelieved, the decrease or lack of blood flow (known as ischemia) will cause tissue breakdown.

Table 1. Areas Pressure Sores Can Occur

Heel Spine of Scapula
Elbow Lateral Femoral Condyle
Lateral Malleoulus Lateral Humerus
Sacrum Collar Bone
Occiput Patella
Toes Lateral Orbits

According to Halpin-Landry et. al., diabetic patients have many complications, all of which can contribute to and cause chronic skin ulcers. These complications include sensory and motor neuropathy; lower extremity peripheral vascular disease; impaired host defenses against infection; and delayed wound repair. Motor neuropathy is a generic term for any diabetes-related disorder of the peripheral nervous system, autonomic nervous system, or cranial nerves. It is the most common of the chronic complications of diabetes and involves dulling of the sensations of pain, temperature, and pressure especially in the lower legs and feet. Thus, the three most frequent etiological mechanisms involved in the formation of diabetic ulcers are ischemia, neuropathy, and infection.

lschemia occurs when inadequate perfusion (the flow of blood per unit volume of tissue) leads to cellular death. In the diabetic foot, the distal popliteal artery (found behind the knee) and the tibial artery (found on the front of the lower leg) are most often involved in ischemic changes. lschemic changes mean that there is a decrease in blood flow to the muscles and bone in the area supplied by that artery or vessel. This puts the area at risk for breakdown because it is blood that brings the chemicals and immune cells that are involved in healing to the area.

Neuropathy occurs when a disturbance in metabolism caused by hyperglycemia (increased levels of blood glucose) leads to reduced blood flow and consequent nerve damage. When sensory nerve fibers become damaged, the body's normal vaso-constrictive impulses are impaired, leading to hyperemia (the presence of an increased amount of blood in a part or organ) and to osteoarthropathy (a disorder affecting bones and joints).

Sensory neuropathy causes loss of the sensory network's protective functions. Precursors to sensory neuropathy include numbness, tingling, and pain. Distal sensory neuropathy, common in the diabetic patient, results in progressive distal-to-proximal (bottom-to-top) loss of sensation in both lower extremities. A major concern with sensory neuropathy is that patients are unable to feel pain and therefore, will not compensate for plantar pressure by changing their gait pattern to avoid injury.

Motor neuropathy impairs functioning of the intrinsic muscles of the affected body part. For example, when the foot is initially affected, the metatarsals flex and the toes draw up into a "claw" position. This creates pressure points beneath the metatarsal heads and over the dorsum and tips of the toes. Both sensory and motor neuropathies can occur at the same time. As such, the deformities caused by the motor neuropathy are not felt due to the diminished sensory awareness caused by the sensory neuropathy. This places the affected area at increased risk of ulceration.

Infection occurs as the neuropathy and vascular disease associated with diabetes creates opportunities for microbial invasions. Microbial invasion can be deadly for a diabetic because the patient's usual inflammatory response may be blunted. If infection of a diabetic ulcer is suspected, a culture should be taken to identify the organism or organisms that are actually causing the infection. Then, antibiotic therapy should then be targeted specifically at the infection-causing organism. An ulcer with tendon, muscle, or bone exposure is at an increased risk of developing deep infection and has a higher incidence of delayed healing time.

In addition to the extrinsic and intrinsic risk of factors (see Table 2 below), which contribute to diabetic ulcer, there are "mechanisms of injury" that also contribute to the formation of an ulcer. Mechanical forces such as stress and shear are a large threat to the high-risk patient. "Mechanical stress may be easily understood as a pressure force: high intensity (as with penetrating injury), moderate intensity (the impact of walking), or low intensity (the rub of an uncomfortable shoe). "8 The mechanical stresses that most often effect diabetic patients are low to moderate intensity stress.

Table 2. Risk Factors

Intrinsic Risk FactorsExtrinsic Risk Factors
Male sex

Long-standing duration of diabetes

Diabetic retinopathy

Impaired visual acuity

Diabetic neuropathy

Cardiovascular disease

Microangiopathy

Macroangiopathy

Lower extremity neuropathy

Peripheral vascular disease

Foot deformity

Limited joint mobility

Previous foot ulcers

Advanced age

Obesity

Poor glucose

Current or recent foot trauma

Inappropiate foot care

Cigarette Smoking

Inadequate knowledge of diabetes management

Noncompliance with the diabetes management plan

Mechanical stress can be an important consideration regarding the diabetic foot. Most foot problems begin with the formation of a callus over structural deformities. The callus then sustains excess pressure, because the diabetic patient is often unable to feel that greater pressure than normal is being placed on that area. If the patient with diabetic neuropathy continues to walk on the callused areas, "underlying hemorrhage" often results, which leads to the formation of an abscess and eventually, ulcerations Just prior to ulceration, the area becomes red in color and "mushy" to the touch. An example of how this might feel is an overripe orange. The peel is intact, but the fruit is extra soft to the touch.

Shearing occurs when superficial tissues slide over deeper tissues. Some sliding of tissues is normal. However, once healing has taken place, a scar is left behind, which then inhibits this normal sliding motion. Inhibition of sliding causes tissues to be torn apart because scar tissue cannot dissipate the normal shearing forces. This, in turn causes a re-opening of the ulceration. Figure 2 of the Appendix shows the shearing forces that affect a person lying in bed.

Wound Healing

Once a wound is apparent, i.e. tissue breakdown is apparent, a person's body attempts to repair the breach of skin integrity. There are four strategies that surgeons and the body use to heal. The first strategy is primary closure or closure by sutures (stitches). The second is delayed primary closure or closure by sutures following a delay specifically to allow drainage to occur. Third is secondary intention healing or letting the body heal itself through scabbing and contracture. The final strategy is closure with skin flaps and/or grafts done by surgeons. In its attempts to heal itself through secondary intention, the body utilizes three stages of healing, the Inflammatory Stage, the Proliferation Stage, and the Maturation or Remodeling Stage. Key cellular events in wound healing are inflammation, proliferation, matrix synthesis and degradation, and angiogenesis (the formation of new blood vessels). They are diagramed in Figure 3 of the Appendix.

The Inflammation Stage is the initial reaction to any breach in skin integrity. Tissue injury causes disruption of blood vessels, leading to a rapid extravasation (movement out of the blood vessel and into the tissue) of cellular and plasma components into the wound, including blood.10 While the body is re-establishing hemostasis through the formation of a fibrin clot, the platelets congregating at the site of injury release other chemical substances, including growth factors. These growth factors bring about the constriction of the severed blood vessels to stop the bleeding. At the same time, the growth factors also cause dilation of local blood vessels (those blood vessels not directly involved in the injury), making them more porous. Dilation of local vessels causes a rise in the local temperature, which leads to an increase in blood flow and extravasation. As a result, edema or swelling ensues, pressing on local nerve endings and causing pain. This sequence produces the clinical signs of inflammation - redness, edema, increased skin temperature, and pain. If the inflammatory stage is reduced the wound healing is prolonged.

The contact of the clotting system with membrane phospholipids (a lipid -a substance extracted from animal or vegetable cells -- containing phosphorus) initiates the intrinsic clotting cascade, which leads to the formation of the fibrin clot. The fibrin clot is made up of coagulated blood and discharged platelet contents and, most importantly, fibronectin, an adhesive protein present in plasma and serum. Fibronectin attaches itself to form a provisional matrix, which has a greater number of potential binding sites for migrating leukocytes and connective tissue cells, which are necessary for healing.

Once hemostasis is established, cellular and chemical tools to repair the wound and fight infection are delivered to the wound site. The infiltrating neutrophils (a mature white blood cell formed by bone and released into the blood stream) cleanse the wound of bacteria and foreign particles, which are then extruded with the eschar (a thick crust of slough which develops following a burn or other skin injury) or phagocytosed (ingested and digested) by macrophages. The chemicals and hormones, such as cytokine and chemokine, released by the activated neutrophils promote the recruitment of the macrophages into the area to help cleanse the wound through its phagocytic properties. As the wound site is being cleaned, the activated macrophages and platelets begin to secrete a combination of growth factors that initiate the healing process.

With this release of growth factors, the second phase of healing - the Proliferation Stage -- begins at the wound site. It is important to remember that sometimes the Proliferation and Inflammation Stages can and do occur at the same time within the wound. This means there is no clear-cut separation of these phases of healing. During the Proliferation stage of wound healing, intracellular signaling molecules from macrophages, endothelial cells, and platelets attract dermal fibroblasts (spindle-shaped cells capable of forming collagen fibers) in order to resurface the wound, which is essential to protect against fluid loss and infection. The macrophage produces a wide array of cytokines (hormone-like cells which regulate the intensity and duration of immune responses) and growth factors that can modulate the healing process. This phase of healing is marked by angiogenesis (the formation of new blood vessels), fibroblast proliferation and migration, and rapid collagen matrix synthesis. This phase of healing can last two to six weeks or more, depending of the extent and size of the wound.

Angiogenesis consists of the growth of new capillary blood vessels from pre-existing vessels in areas previously unoccupied by vascular tissue. Angiogenesis most likely occurs due to the production of the growth hormone's vascular permeability factor/ vascular endothelial growth factor (VPFNEGF) by macrophages. These molecules, acting together, direct the formation of new blood vessels in the wound. Angiogenesis begins as cell movement, in that intact vessels are stimulated by angiogenic factors to permit the egress and migration of capillary endothelial cells (the cells that form the capillary walls) toward the injury site. Following this movement, endothelial proliferation of capillary cells is stimulated to connect and bind together the vessels and to fill in if they do not quite reach. Angiogenesis is an important part of wound healing, since it is these vessels that support the granulation tissue as it moves across the wound.

At the same time that vessels are entering the wound site, they are accompanied by mesenchymal (relating to primordial embryonic connective tissue) cells, which are fibroblastic in nature. These cell are instrumental in providing the first true extracellular matrix (the surrounding substance within which something is contained or embedded outside the cells) at the wound site. Granulation tissue, macrophages, fibroblasts, and blood vessels move into the wound at the same time. The macrophages provide a continuing source of growth factors necessary to stimulate fibroblasia (formation of collagen fiber cells) and angiogenesis. The fibroblasts produce the new extracellular matrix necessary to support cell in-growth, while the blood vessels carry oxygen and nutrients to sustain cell metabolism's Eventually covering the wound bed, granulation tissue has a red, granular appearance gained from the new capillaries that migrate into the wound with the new tissue. Granulation tissue has a characteristic randomized or flowing appearance as far as cellular and collagen fiber orientation are concerned. This suggests that tensile forces are not distributed in an organized fashion at the wound site.

In partial or scraping injuries to the skin, epithelial migration over the denuded surface begins almost immediately from both the wound margins and the many epidermal appendages, which serve as reservoirs of epidermal cells. Most Of us have noticed that when we have a scratch that it takes only a couple of minutes for any bleeding the stop. Within a period of one to two days, the scratch is covered by a scab. On some occasions, the scab falls off or is scratched off. The area beneath the scab is smaller than the original area. This process continues until the wound edges are reunited and knitted back together. All that may be left is a slight scar to mark the injury.

In deep skin injuries, the epidermis can only resurface from the margins, and full-thickness injuries require a collagenous (producing or containing collagen), granulation tissue base before successful resurfacing can occur. The migration of epidermis involves several different events. Keratinocytes (cells of living epidermis that produce keratin) or basal cells at the wound edge differentiate and move out over the denuded collagenous substrate of the wound bed. Cells at the migrating tip express proteins, which may facilitate migration. Behind this tip, there is a proliferating center where there is a progressive accumulation of new basement membrane material under the migrating sheet.

Granulation tissue, characteristic of wound repair, is a transient structure. The term granulation tissue comes from the fact that is appears in open, excisional (cut out or removed) wounds with an irregular surface due to the presence of new capillary vessels. As new collagen is accumulated in the interstitium (a small gap in the substance of an organ or tissue), cells are gradually replaced by collagen. Collagen fiber bundles become thicker and take on more specific orientations along lines of stress.

The increase of collagen fibers within a wound signifies the Remodeling or Maturation Phase. This phase gives the visible sign, by way of a scar, that a wound is almost fully healed. The initial scar is red in appearance. This coloring fades as the scar matures, a process that may take up to a year. A mature scar fills the wound completely, is faded in color, is avascular (without blood vessels) and aneural (without nerves or nerve endings). As such, scar tissue is histologically (relating to structure relative to function) distinguishable from surrounding tissue because it does not reflect normal tissue architecture or biomechanics.

However, the scar is recognized as a repair site because it takes anywhere from months to years to accomplish the necessary organization of connective tissue and rearrangement of collagen fiber bundles within the scar tissue. The extent of scarring depends upon the site of injury, the organ (including the skin) injured, the genetic background of the person injured, the nature of the injury, and wound care therapy. Scars continue to be marked by elevated matrix turnover (collagen and connective tissue are constantly being replaced) throughout life.14 A normal scar will only take up as much space as the wound itself, if not less secondary to wound contracture.

Throughout the healing process, growth factors in the body are secreted into the wound. These growth factors are more than growth-promoting molecules, because they are capable of eliciting a broad spectrum of biological effects on target cells, including chemotaxis (the movement of cells or organisms in response to chemicals) and the accumulation of the extracellular matrix.

The body utilizes several growth factors during the healing process. Some of these hormones accelerate, some mediate, while others inhibit the healing process. Transforming growth factors, epidermal growth factors, and fibroblast growth factors are just a few of the hormones the body can use during the healing process. It appears that all three have similar properties during the healing process, so just transforming growth factors will be explained extensively. Transforming growth factors (TGF), such as TGFPI, TGFP2, and TGFP3, work with other genetically related molecules to occupy a key role in the direct and indirect mediation of proliferation, chemotaxis, and metabolism of the extracellular matrix in both normal and pathologic processes.

Transforming growth factor P has also been shown to have chemoattractant properties for fibroblasts and macrophages, and plays a central role in regulating the accumulation of extracellular matrix.

Granulation tissue appears to be significantly enhanced by TGFP treatment and so does the quality of the wound. Studies have shown that TGFP may be useful as an accelerator of wound repair in patients with both normal and impaired healing. In acutely injured tissue, gatherings or clusters of platelets release TGFP and Platelet Derived Growth Factor (PDGF) whose chemoactic (relating to the movement of cells in response to chemicals) activity causes, in part, the influx of neutrophils (mature white blood cells formed by bone marrow). Subsequent to this influx, monocytes (a leukocyte or cell found in circulating blood), and activated macrophages are recruited. Figure 4 of the Appendix explains how PDGF works in the healing of a wound.

Platelet derived growth factor (PDGF) is also a potent chemoactic agent for fibroblasts and osteoblasts (cells which form bone). In in-vivo studies, PDGF increased the quantity of granulation tissue, along with an overall increase in the number of fibroblasts and in the total collagen present in a wound. Recently, recombinant PDGF has been approved for the treatment of diabetic foot ulcers.

Regranex ®

It is important to remember at this point that the diabetic patient does not respond to injury as a normal patient (one without Diabetes) responds to the same or a similar injury. Diabetes Mellitus is a systemic disease, which not only invades, but also effects, every cell of the body. When injured, the diabetic patient will experience a delay in healing. This delayed response creates an increased opportunity for infection to set in, especially in the case of an ulcer or other break in the skin.

Usually, a diabetic ulcer can and does heal on its own. However, sometimes an ulcer becomes chronic and the body cannot heal the ulcer without help from doctors and/or medications. It is for a chronic ulcer that a doctor prescribes or turns to growth factors to help the ulcer heal.

The growth factor that has been approved for use in diabetic ulcers is commonly known as Regranex ® . It gained the approval of the Food and Drug Administration (FDA) in December 1997. Regranex ® is available to patients through prescription only. The active ingredient in Regranex ® @ is becaplermin, a growth factor that stimulates the migration of cells to the wound, and thus speeds healing, when used in addition to good wound care. The wound requires an adequate blood supply for favorable results.

Becaplermin is made using recombinant DNA technology. The genes for human Platelet Derived Growth Factor (PDGF) is inserted into yeast, which then makes the growth factor becaplermin. Regranex ® , or Becaplermin gel, is used on lower extremity diabetic ulcers that extend into the subcutaneous tissue or beyond.

Several studies have been performed to determine the clinical safety and efficacy of becaplermin gel (rhPDGF-BB) since 1997. All of the studies promote a regimen of good ulcer care in addition to the use of Regranex ® . Treatment continued for 20 weeks in the studies or until complete ulcer healing was achieved. In most studies, patients were considered treatment failures if the ulcer did not show approximately 20-30% reduction from baseline after 8-1 0 weeks of standard treatment. To determine whether the ulcer extends into subcutaneous tissue, a staging system has been developed by medical professionals to describe the severity of ulcers. Ulcers are described as a Stage I (an area of redness) up to a Stage 4, which is a loss of skin with extensive damage to bone or muscle. Table 3 in the Appendix describes the stages of an ulcer.

A study by Rees, et. al., compared the efficacy of becaplermin gel with that of a placebo gel in the treatment of chronic full thickness pressure ulcers. This study's efficacy evaluations were based upon the functional assessment of the ulcer (completely healed versus less than completely healed), the ulcer's volume measurements, and the ulcer's area measurements. Efficacy results indicate that those groups treated with becaplermin gel observed a greater incidence of healing compared to the placebo gel-treated group.

Rees, et. al., found that the once daily treatment of chronic pressure ulcers with becaplermin gel significantly increased the incidence of complete healing and greater than/equal to 90% healing; whereas none of the patients treated with the placebo gel achieved complete healing by the end of the study. Although all four treatment groups showed a significant improvement compared with baseline evaluations, the results suggest the becaplermin gel treatment brings about greater ease of wound closure. This may subsequently decrease the need for flap surgery and allow for a more simple procedure requiring a few stitches placed for wound edge approximation, performed at bedside rather than extensive surgical procedures.

Rees, et. al., conclusions suggest that within a comprehensive wound management program setting, becaplermin gel once daily increases the incidence of complete healing and greater than/equal to 90% healing in patients with full thickness pressure ulcers. The increased incidence of healing may "potentially reduce the costs associated with pressure ulcer treatment." There are currently no available studies which have evaluated whether the use of Regranex ® will or has decreased the cost of ulcer care, but it seems likely that faster, more complete healing would reduce overall costs associated with ulcer care. Further studies in this area of wound management are warranted.

A study by Janice Smiell examined the clinical safety of becaplermin gel. In her article, Smiell calls upon two clinical studies which were conducted to determine whether becaplermin was systemically absorbed following daily application to full thickness lower extremity diabetic ulcers. Both studies found that plasma PDGF-BB concentrations (composed of both endogenous PDGF-BB - originating within the organism and becaplermin) remained near baseline levels. Based on the results of these two studies and those of non-clinical studies, there is minimal potential for becaplermin gel to elicit any adverse systemic reactions. Similar results were noted following skin irritancy and sensitization tests.

Safety assessments were based on the incidence of adverse events, discontinuation due to adverse event, clinical laboratory data, physical examination, vital signs, and cardiovascular-related adverse events. An adverse event is something that was either not present at baseline, or if present at baseline, increased in severity as the study progressed. Treatment-emergent adverse events are adverse events that newly appeared or worsened in severity following initiation of therapy. Disorders commonly associated with chronic diabetic ulcer, such as infection, cellulitis, and osteomyelitis, were the adverse events that most frequently led to discontinuation of treatment.

Overall, in the six studies Smiell reviewed, a total of 357 out of 538 (66%) patients from all six studies treated with any concentration of becaplermin gel reported at least one treatment-emergent adverse event. The most commonly reported adverse events were infection, cellulitis, skin ulceration (at untreated sites), pain, and osteomyelitis. Overall, patients receiving good ulcer care alone had a higher incidence of adverse events than those in other treatment groups. Those patients treated with good ulcer care alone showed the shortest time before the occurrence of an infection-related adverse event, while those treated with either the placebo or becaplermin had similar times to the first occurrence of an infection-related adverse event. Adverse events were deemed serious if they were fatal, immediately life-threatening, permanently or significantly disabling, or were neoplastic (pertaining to an abnormal tissue growth).

Based on the results of these six studies, Smiell concluded that becaplermin gel is safe and well tolerated by patients. "Becaplermin gel's safety," she stated, "most likely stems from the negligible systemic absorption of topically applied [Regranex ® ] and the rapid metabolism of parenterally [referring to the introduction of a substance subcutaneously] administered becaplermin." As such, becaplermin "appears to be a safe therapy for the treatment of lower extremity diabetic ulcers.

A third study by Wieman and Smiell was conducted to compare the efficacy and safety of two concentrations of becaplermin gel (30 and 100 pg/g) with that of a placebo gel. Again, once daily application of becaplermin or placebo gel was combined with a regimen of good wound care. Good wound care included initial and ongoing sharp debridement (removal of dead tissue and callus by a scalpel) of the ulcer, twice-daily moist saline dressing changes, off-loading of pressure from the affected area, and if present, control of infection.

Efficacy and safety were determined in a manner similar to that done in the studies by Smiell and Rees, et. al. For efficacy evaluation, the area of the target ulcer was measured (length multiplied by width) and each ulcer was given a functional assessment score based on whether the wound was completely closed without drainage or need of dressing (scored as 1) or less than 100% closed with drainage and requiring a dressing (scored as 2). In cases in which the target ulcer was debrided, length and width were measured after debridement. Other efficacy measurements included ulcer volume and ulcer area as determined by planimetric (a radiographic image of a selected plane by means of curved motion of the x-ray) analyses of acetate tracings. The primary efficacy criterion was the percentage or incidence of complete healing (given a functional assessment score of 1) among the patients. A secondary efficacy criterion was the time required to achieve complete healing.

The study by Wieman and Smiell found that treatment with becaplermin gel 100pg/g significantly increased the incidence of complete healing compared with placebo gel. There was, however, no statistical difference in the incidence of complete healing between those patients receiving the lower concentration, becaplermin gel 30 pg/g, and those patients receiving the placebo gel. It was noted in this study that compliance with a non-weight bearing regimen was positively associated with complete healing.

Wieman and Smiell concluded that "becaplermin is the first and only growth factor to date to demonstrate a statistically significant effect in a phase II clinical trail." This study found that becaplermin gel 100 pg/g, coupled with debridement yielded a higher incidence of healing than placebo gel and debridement. It was also found that, not only the did the use of becaplermin gel 100 pg/g increase the incidence of complete healing, but it also reduced the time to complete healing of lower extremity neuropathic ulcers in diabetic patients. The incidence of ulcer recurrence was approximately 30% in all treatment groups. This demonstrates that the durability of the healed ulcers was comparable in all treatment groups.

Regranex ® , however, is not used as a "miracle healer" in ulcer care. It is used as an adjunct to good wound care. Good wound care involves off-loading or decreasing pressure on the wound, maintaining a moist wound environment to promote wound healing, adequate nutrition and hydration of the patient to promote healing and to prevent complications, initial and ongoing sharp debridement, and systemic treatment of any wound-related infection.

When using Regranex ® , there is a standardized procedure to apply becaplermin gel. The first step is for the patient or caregiver to wash their hands. Next, medical personnel should debride the wound as needed. Once the wound has been debrided, it is necessary to measure the wound's length and width. This is important because becaplermin gel is measured from a tube for application based on the length and width of the wound. The measurement can be recorded in either inches or centimeters. Once the Regranex ® has been measured out onto a clean, firm, non-absorbent surface, it should be applied once daily to a clean wound bed. The measured quantity is spread over the wound in a thin continuous layer using a cotton swab or tongue depressor. The wound is covered with a moist saline dressing. The moist dressing must be kept within the boundaries of the wound so the surrounding healthy tissue does not become effected. The moist dressing is covered with a dry gauze pad and a gauze bandage is wrapped snugly over the pad and secured with adhesive tape. Tape should be applied only to the gauze and not the skin. After twelve hours, the dressing is removed and the wound is gently cleansed using saline solution or water. No a second application of Regranex ® is done at this time. A new moist dressing is applied, covered with a dry gauze pad, wrapped with a gauze bandage and secured with tape. The tube of Regranex ® is kept in a refrigerator until the patient is finished using it. Figure 5, found in the Appendix, depicts the application of Regranex ® described above. The pictures of Figure 5 make it easy for both patients and caregivers to follow the appropriate application steps.

Regranex ® is contraindicated in patients who have a known hypersensitivity to any component of this product (e.g. parabens or chemicals with two substitutions linked to opposite carbons in the benzene ring) or who have known neoplasm(s) at the site or sites of application. Because becaplermin is a "non-sterile, low bioburden" preserved product, it should not be used in wounds that are closed by primary intention or by sutures. Patients must be reminded that Regranex ® is for external use only.

It is not known at this time if Regranex ® gel interacts with other topical medications applied to the ulcer site. The use of Regranex ® with other topical drugs has not yet been studied. Therefore, caution should be used when applying Regranex ® and other topical medications to the same ulcer site. It is also unknown whether Regranex ® gel causes fetal harm when administered to a pregnant woman, nor is it known if it can affect a woman's reproductive capacity. Due to these unknown factors, Regranex ® should be given to pregnant women only if clearly indicated. It is also unknown whether becaplermin is excreted in human breast milk. As such, caution should be exercised if becaplermin is prescribed and administered to nursing women, because many drugs are secreted in human milk. At this time, the safety and effectiveness of Regranex ® gel in pediatric patients below the age of 16 years has not yet been established.

More clinical studies with Regranex ® are warranted at this time, especially in the fields of pediatrics and pregnant women. Regranex ® has been shown, however, to positively impact the healing of diabetic neuropathic ulcers. It is clinically safe and effective when used in conjunction with good wound care.

Case Study

Mrs. "X," as the patient will be called, was a 56 year old female who was admitted to the hospital in September 1999 with a 4 inch long by 2 inch wide wound on the anterior or front of the left lower leg. Mrs. X reported receiving the injury in October 1998 when she fell down the steps in front of her apartment. "My leg went between the steps," she stated, "and ... was scraped." The patient cared for the injury at home without success. Prior to admittance to the hospital, the patient was actively involved in the community.

Upon admittance to the hospital, the patient's wound was assessed by the Physical Therapy staff. There was no drainage from the wound, nor was there any odor to indicate an active infection of the wound. The anterior tibialis (a muscle which pulls the toes up) tendon was visible in the center of the wound. There was black, necrotic or dead tissue on the tendon and along the right side of the tendon. There was also yellow slough along the inside edges of the wound and on the tendon. Mrs. X's doctor ordered whirlpool therapy with sharp debridement as needed, followed by wet-to-dry dressing, changed 2 times daily. A wet-to-dry dressing is one that is applied wet or moist and removed when it is dry. This technique is used to remove slough and necrotic tissue from a wound.

After about two weeks of this therapy twice a day, five times per week, the patient's wound was still not responding to treatment. At this time, the doctor ordered Regranex ® gel to be added to the patient's regimen of therapy. Regranex ® was applied during the morning treatment after the patient received whirlpool and sharp debridement, according to its instructions. Mrs. X's afternoon therapy session was changed from wound care to ambulation training and stretching, secondary to the flexor-withdrawal reflex pattern that the patient acquired while hospitalized.

Three days after beginning Regranex ® treatment, granulation tissue was noted at the top and bottom edges of the wound. Wound color had improved significantly. The development of granulation tissue was a positive event in the treatment of this wound given its history. Treatment continued, including whirlpool, sharp debridement, and Regranex ® application.

Due to the chronic nature of the wound, granulation was slow to occur and slow to fill in the entire wound bed. About 2 weeks after beginning Regranex ® , granulation tissue was migrating over the exposed tendon. Regranex ® application continued until the end of November, when the entire wound bed showed viable granulation tissue and the doctor felt that there was sufficient granulation tissue to support a skin graft to the area. The patient was prepared for surgery, the graft was placed and wound care therapy was discontinued to allow the graft to "take" or attach itself to the wound. Several weeks following the skin grafting, the doctor determined that the graft was stable and intact and the patient was discharged home. Prior to discharge, Mrs. X was instructed in the care of the graft site.

In the above case study, the patient was not diabetic. The doctor in charge of her care decided to use Regranex ® due to the chronic nature of the wound. The wound bed at the time of the patient's admittance had no viable granulation tissue. The use of Regranex ® stimulated the growth of granulation tissue, which allowed for the placement of a skin graft.

Conclusion

Regranex ® was designed to stimulate the healing cascade of an ulcer or wound. Numerous studies have been done which have proven that Regranex ® does, in fact, stimulate healing in a wound. This new product has been found to be applicable in the treatment of diabetic ulcers. Diabetic patients are more prone to receive chronic ulcers due to the nature of their disease. Because Diabetes Mellitus is a systemic disorder, all cells and tissues are affected. Delayed healing in the diabetic patient means that the natural process may become stalled or unable to continue on its own. Regranex ® , with its active ingredient of becaplermin, a human-derived growth factor, is used to stimulate the healing process. Regranex ® is not meant to replace good skin care for the diabetic, but to help the diabetic heal in the event of a chronic neuropathic ulcer.

APPENDIX

Figure 1. Epidermis, Dermis, and Subcutaneous Tissue



Figure 2. Patient in semi-recumbent position and the forces of friction and shear



Figure 3. Uninterupted Wound Repair Diagram



Figure 4. Placelet Derived Growth Factor and How its Properties Effect Wound Healing



Table 3. Pressure Ulcer Classifications

Stage 1 Observable pressure-related alteration of intact skin whose indicators as compared to adjacent or opposite area on the body may include changes in one or more of the following: skin temperature (warmth or coolness), tissue consistency (firm of boggy feel), and /or sensation (pain, itching). The ulcer appears as a defined area of persistent redness in lightly pigmented skin, whereas in darker skin tones, the ulcer may appear with persistent red, blue, or purple hues.
Stage 2 Partial-thickness skin loss involving epidermis and/or dermis. The ulcer is superficial and presents as an abrasion, blister, or shallow crater.
Stage 3 Full-thickness skin loss involving damage or necrosis of subcutaneous tissue that may extend down to, but not through underlying fascia (tissue). The ulcer presents clinically as a deep crater with or without undermining of adjacent tissue.
Stage 4 Full-thickness skin loss with extensive destruction, tissue necrosis, or damage to muscle, bone, or supporting structures (e.g. tendon, joint capsule).



Figure 5. How to Apply Regranex ®



References

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