Current Insights On Growth Factor Therapy

Recent advances with growth factor therapy have created more possibilities for wound care. These authors review currently available modalities and emerging treatments, and survey the literature on the effectiveness of growth factor therapy for chronic wounds. The future of growth factor therapy in wound care is advancing rapidly. There is also increasing evidence in the literature to support the efficacy of growth factors in wounds, particularly chronic wounds, and how they can help facilitate desired healing outcomes. With advances in research over the past decades, physicians and researchers have teamed together to isolate and identify the disruption(s) in the sequence of wound healing that lead to chronic wounds. Upon a closer examination of the phases of wound healing on the cellular level, it is clear that cytokines, particularly growth factors, play significant roles. The direct functions of growth factors exert an effect or effects on multiple processes during wound healing. By looking at the phases of wound healing which are catalysts for the production of growth factors and are also stimulated by the growth factors, one can gain insight into how direct or indirect application of growth factors can help heal chronic wounds. A Guide To The Wound Healing Continuum Wound healing proceeds through three phases: inflammation, fibroplasia and maturation.1-4 Beginning with an initial injury, the inflammatory phase ensues after a brief introductory period of immediate vasoconstriction replaced by vasodilation. This vasodilation serves as a pipeline and funnels the unfolding inflammatory cascade. During this time, platelet-derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factor α and transforming growth factor ß (TGF-ß) are released from the alpha granules of platelets secondary to degranulation.2-4 As the inflammatory phase tapers around the sixth day after the injury has occurred, fibroblastic proliferation begins. During proliferation, present fibroblasts stimulate angiogenesis and other circulating, sensitive growth factors.1-4 While fibroplasia wanes around the third week after the injury, fibroblasts persist into maturation. Maturation comprises collagen production and can last up to two years or more.2-4 Aside from the context of the phases of wound healing, the process of wound healing may further be distinguished or categorized as acute or chronic. In the normal sequence of acute wound healing, the phases not only overlap but are also mutually dependent. On the contrary, chronic wounds persist primarily in the inflammatory phase. In effect, the link to fibroplasia fails. Understanding The Roles Of Growth Factors Proliferating capillaries bring oxygen and micronutrients to growing tissues and remove metabolic waste products. All types of chronic wounds, including diabetic foot infections (DFUs), are insufficient in their ability to generate angiogenesis (neovascularization).5 One may apply angiogenic stimulators to DFUs to speed neovascularization. Angiogenesis is essential for wound healing. In 2002, Loots and colleagues found that fibroblasts extracted from diabetic ulcers demonstrated “retarded” healing and are often frozen in an inert state that requires debridement or the external application of (isolated) growth factors.6 Isolated growth factors include PDGF, EGF, insulin-like growth factor (IGF), transforming growth factor (TGF), keratinocyte growth factor (KGF) and fibroblast growth factor (FGF). The more familiar growth factors, PDGF, TGF and EGF, are initially present in wounds following injury. Platelet-derived growth factors (PDGFs) are produced from platelets, macrophages, endothelial cells and smooth muscle cells.1-4 They act to stimulate fibroblastic proliferation, chemotaxis and collagen metabolism as well as the activation of neutrophils, macrophages and angiogenesis. In regard to TGF-ß, it is derived from platelets, neutrophils, lymphocytes and macrophages. These TGF-ß growth factors induce fibroblastic proliferation, chemotaxis, collagen metabolism and angiogenesis (indirectly), and act on other growth factors indirectly. Epidermal growth factors are secreted by platelets, monocytes and macrophages as well as salivary/ lacrimal/duodenal glands. Additionally, EGFs are found in urine, milk and plasma.1 The EGFs, which bind to receptors on epidermal cells, keratinocytes and fibroblasts, stimulate endothelial cells, epithelial cell growth, fibroblastic proliferation, neovascularization and granulation tissue formation.1,7 In regard to TGF-α, which are often grouped with EGF due to similar function, they are activated by macrophages, platelets and keratinocytes as well as other tissues.1 Insulin-like growth factors (IGF-1), produced by the liver, plasma and fibroblasts as stimulated by human growth hormone, function to stimulate synthesis of sulfated proteoglycans, collagen and fibroblast proliferation.1 Basic fibroblast growth factors (BFGF) are released by macrophages, the brain and the pituitary along with other tissues. The BFGFs function to stimulate fibroblasts, endothelial cells and keratinocytes, in addition to the processes of reepithelialization, matrix deposition, wound contraction and angiogenesis.1 Keratinocyte growth factors, produced by fibroblasts, have their effect on epithelial cell proliferation and collagen synthesis as influenced by IGF.1 Vascular endothelial growth factor (VEGF) primarily support angiogenesis.4,8 What The Literature Reveals About Becaplermin Introduced over 10 years ago, becaplermin (Regranex®, Johnson and Johnson), a recombinant human PDGF-ßß (rhPDGF-ßß), remains the only FDA approved growth factor for use in wound healing. Becaplermin has stood the test of time and is now a commonly employed therapy for the treatment of DFUs.9 It is approved for use in neuropathic, diabetic ulcers demonstrating extension into the subcutaneous tissues with adequate pedal blood supply.2-4,8,10 The efficacy of becaplermin is enhanced when one combines it with sharp debridement and good clinical practices.11 Researchers have suggested other uses including venous ulcerations, pressure sores, non-healing amputation sites and wound bed preparation for grafting, but none of these uses are approved by the FDA.3,12 In a phase 3, randomized, placebo-controlled, double-blind study published by Wieman and colleagues, they report a 43 percent incidence of wound closure in chronic diabetic ulcers treated with 100µg/g of becaplermin and a 32 percent reduction in the overall time to heal for a length of 86 days.13 Over time, research on becaplermin has continued with varying supportive data. In their 2000 study, Embil and associates found a 21 percent rate of ulcer recurrence over a span of six months with once a day application of rhPDGF on full thickness diabetic ulcerations.14 The mean healing time for the 57.5 percent of ulcers achieving complete closure was 63 days, roughly nine weeks. When assessing the effectiveness of rhPDGF in the treatment of diabetic foot ulcers, Margolis and colleagues not only found that diabetic ulcers receiving rhPDGF were more likely to heal but also noted less relative risk in regard to future amputations of the affected limb.15 The relative risk translates to about 35 percent less for individuals who received rhPDGF therapy. Upon assessing the determinants and estimation of healing times in diabetic foot ulcers, Zimny and colleagues discovered that “the fastest course of healing determined by the daily wound radius reduction was achieved in the neuropathic foot ulcer group between the first and seventh week.”16 Furthermore, they observed a linear relationship between wound radius and healing time with a 0.045 mm daily reduction in the radius of diabetic neuropathic ulcers.16 Zimny and colleagues noted these findings in the absence of growth factor therapy. When considering the application of growth factor therapy, Steed reported in 2006 that a greater percentage of rhPDGF-treated lower extremity ulcers healed than placebo counterparts with notable differences after six weeks.17 In addition, wound area reduction was greater in the rhPDGF-treated group with researchers seeing appreciable differences after the third week with a median reduction of 98.8 percent versus 82.1 percent in ulcers receiving placebo. What About Other Growth Factor Applications? Since the approval of becaplermin, newly marketed growth factor applications have emerged. One such application targeted for topical use is Procuren (Cytomedix), which relies on freshly drawn blood that is spun down with isolated growth factors or proteins that podiatric physicians can apply to the wound bed.8,18 Currently, this modality is only FDA regulated, not approved.18 Other systems that emphasize whole blood derivatives include the use of autogenous platelet applications through products such as Symphony™ (DePuy), autologous platelet concentrate (APC), platelet rich plasma (PRP) and platelet gel such as AutoloGel™ (Cytomedix).18-21 Researchers have found that autologous blood-derived growth factors similar to FGF, PDGF and VEGF play a role in wound healing. A number of different processes are utilized in providing this therapy. For example, the AutoloGel System utilizes the patient’s own blood. After separating plasma and platelets from the red blood cells, the liquid platelet rich plasma is enriched with proprietary ingredients. Then it is agitated and forms a gel that one can apply to the wound. The gel releases multiple growth factors and also provides a cellular matrix for new tissue growth.22 In 2006, Driver and colleagues demonstrated healing with PRP (AutoloGel) in a median of 45 days for the most common size of diabetic foot ulcers (<7.0 cm2 in area and <2.0 cm3 in volume) in comparison to 85 days for the control group.21 A Closer Look At Growth Factors In Combination Therapy Another means of growth factor application is the use of combination therapy. In current studies and trials, researchers have looked at the wound healing potential(s) gained from applying a combination of growth factors or substrates to the wound bed either simultaneously or sequentially. In their 2002 report, Loots and colleagues found that they achieved the highest stimulatory response of fibroblasts from diabetic ulcers with the combination of PDGF with IGF-1, EGF or FGF.6 Overall, the simultaneous combination of PDGF with IGF-1 yielded a more significant difference in fibroblast response in comparison to the control of a double dose of PDGF. Earlier this year, Liu and colleagues published a report that BFGF therapy in conjunction with chondroitin 6-sulfate (CS) and heparin (HP) delivered in a controlled release environment resulted in a higher degree of wound closure than CS-BFGF alone when they applied the combination to a full thickness wound bed in diabetic mice.23 Furthermore, they noted a BFGF dose-dependent increase in the thickness of regenerated epithelium. In 2003, researchers of a randomized, double-blind, controlled trial looked at the healing effectiveness of human epithelial growth factor (hEGF) in diabetic ulcers. Tsang, et al., related a reduction in the median time to heal in wounds treated with a 0.04% hEGF solution for a median of six weeks.24 Additionally, 95.3 percent of ulcers in this subset achieved complete healing during the median of six weeks. In the 2006 publication of a prospective, open-label crossover study, Hong and colleagues examined the efficacy of a recombinant EGF biologically identical to human EGF in healing Wagner grade II and III diabetic ulcers. The researchers noted that this modality achieved 76 percent complete wound healing with a mean time to healing of 46 days, roughly six weeks.25 When they reassessed patients in six months, they found no recurrences among those patients who had healed. What Does The Future Hold? Future applications may include Repifermin (Human Genome Sciences), a recombinant human keratinocyte growth factor (KGF)-2 that selectively promotes the proliferation and migration of cultured keratinocytes.26 This member of the FGF family reportedly stimulates granulation tissue production. In 2001, Robson and colleagues executed the first phase 2 trial on rhKGF-2 and documented its effect on healing chronic venous ulcers.26 This randomized, double-blind, placebo-controlled, multicenter study examined the efficacy of the first genomics-derived drug. They found a significant disparity between the combined- rhKGF-2 treatment groups and placebos. In looking at other plausible future application of fibroblasts in wound care, Xiaobing and colleagues observed complete closure of 30 chronic wounds within a four-week time frame with daily applications of recombinant bovine fibroblast growth factor (rbFGF).27 In an abbreviated “pilot study” of eight patients undergoing topical application of fresh, de-epithelialized, fibroblast allografts for diabetic foot ulcers, Han and colleagues observed granulation tissue formation as well as epithelialization, even in the presence of exposed bone, following a single application. They achived 100 percent closure with this modality in a mean of 18.1 days.28 Advanced therapies such as growth factors are more expensive in comparison to off the shelf standard of care products. Therefore, many practitioners have been skeptical and slow to utilize these options. However, hospitalization and infections are key cost drivers in wound care. Drug costs do not impact cost-effective ratios the way adverse outcomes do. Advanced therapies in wound care may have short-term expense but could help facilitate long-term gains. It is important to consider advanced therapies and modalities in chronic wound care because physicians know that a prevented ulcer does not become infected, a prevented infection does not require hospitalization, and a successfully treated infection will not require amputation. Also bear in mind that shorter ulcer duration yields less exposure to infection. The primary goal of fewer infections will yield large savings due to fewer hospital days and fewer admissions. Therapies that promote rapid and complete healing, and reduce the need for expensive surgical procedures would impact these costs substantially.29 In Conclusion In light of increasingly positive research findings, it is hopeful that future applications of topical growth factors will prove promising not only in helping to expedite wound healing but also in yielding long-term strength, integrity and viability to newly epithelialized tissue. More importantly, the effective transformation of chronic wounds through debridement in conjunction with growth factor therapy may become orthodox in wound healing, thereby generating healing in wounds that would otherwise remain stagnant in the face of sharp debridement alone. Dr. Toney is a Fellow of the Center for Lower Extremity Ambulatory Research (CLEAR) at Dr. William M. Scholl College of Podiatric Medicine at Rosalind Franklin University of Medicine in Chicago. She is a Research Fellow at the National Center for Limb Preservation at Advocate Lutheran General Hospital in Niles, Ill. Dr. Driver is the Director of Clinical Research for CLEAR and an Associate Professor of Surgery at Dr. William M. Scholl College of Podiatric Medicine. She is the Chief of the National Center for Limb Preservation at Advocate Lutheran General Hospital in Niles, Ill. Dr. Driver is a Fellow of the American College of Foot and Ankle Surgeons.

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