A New Approach To Using Growth Factors In Wound Healing

There has been a plethora of advances, especially within the last several years, for the treatment of chronic wounds. One of the more notable advancements is the use of autologous platelet-derived growth factors. Not only have platelet-derived growth factors gained notoriety in specialties such as orthopedic, maxillofacial and plastic surgery, the technology is increasingly being recognized as an important modality for accelerating healing in chronic wounds.1-3 Human epidermal growth factor (EGF) has been shown to enhance wound healing in diabetic ulcers.4 Researchers have used various names to describe autologous platelet derived growth factors, including: APC+ (autologous platelet concentrate); PRP (platelet rich plasma); PC (platelet concentrate); and PG (platelet gel). However, while these terms are often interchanged in the literature, they are not necessarily clinically and biologically equivalent. In order to fully appreciate the impact of autologous platelet-derived growth factors, one must have a strong understanding of the wound healing process (see “Understanding The Nature Of Wound Healing” below). Ongoing research continues to identify, investigate and explain more growth factors, their cellular mechanisms and the ways they interact with other proteins to affect the healing of both hard and soft tissue types. Some of the complex interaction and function of platelet-derived growth factors have been reported in the literature. The use of platelet concentrates has enhanced osseous repair of bone grafts.2 Degranulation (release of growth factors from the alpha granules) of the platelet at the wound site is known to initiate and enhance the healing cascade. Reviewing The Benefits Of Autologous Platelet Concentrate By processing the patient’s own blood to derive a platelet concentrate, the surgeon can then use this autograft to treat both hard and soft tissue wounds. One may apply autologous platelet concentrate to an osteotomy site or combine it with a bone graft to fill a large defect and/or accelerate and enhance soft tissue wound healing. Kevy and Jacobson, from the Center for Blood Research Laboratories, have shown that platelets concentrated with the SmartPReP™ system (Harvest Technologies) maintain normal functionality and are not activated or damaged during the separation process.7 They also reported that as platelet concentration increases, so does the concentration of growth factors released from those platelets. Autologous platelet concentrate prepared with the SmartPReP resulted in four to six times greater concentration of platelets than normal baseline platelet levels. While there are other methods to process a patient’s blood in order to make a platelet concentrate, Kevy and Jacobson have shown that the SmartPReP system results in a greater platelet yield, greater platelet concentration and increased growth factor levels than these in other devices.7 How APC+ Differs From Procuren And Regranex Some wound care clinicians have drawn the erroneous conclusion that using autologous platelet concentrate is similar to using Procuren® or that it is like using a recombinant growth factor preparation such as Regranex®. However, unlike a single growth factor recombinant preparation, APC+ results in the release of a multiplicity of growth factors synergistically working together in the wound site to enhance healing. It is not limited to a single regeneration pathway, but provides a more complete biologic event that is able to affect the entire healing cascade. Procuren is a manufactured pharmaceutical material of extracted wound healing proteins that is suspended and diluted in a biological carrier. The product is devoid of all cellular components and their receptor sites. Although blood is drawn from the patient to produce Procuren and it is processed at a remote laboratory, there is no similarity between autologous platelet concentrate and Procuren or other recombinant single growth factor preparations. How To Prepare And Utilize APC+ There may be advanced technology behind the SmartPReP system but it is simple to use for office-based practices and very time efficient. Prior to wound debridement, one would draw 20 ccs of blood from the patient. (Other systems require you to take large amounts of blood ranging from 60 to 300 ccs.) You would proceed to put the blood into the sterile centrifuge container and then place it into the machine. It takes about 14 minutes to process the APC+. The platelet concentrate is re-suspended in a small amount of platelet poor plasma. One can then use the recovered APC+ at any time over the next six to eight hours since it is not activated until you place it into the wound. Using the Harvest double syringe applicator, you’ll see the APC+ form a gel via activation with a calcium chloride/thrombin mixture upon applying it to the wounds. What One Office-Based Study Revealed We recently conducted an office-based study to gauge the effectiveness of APC+ grafting for treating chronic wounds. We employed the SmartPReP system in addition to standard wound care protocols for debridement, offloading and topical applications of hydrocolloids. The study involved 16 patients with a total of 17 chronic wounds. Patients were only included in this study if they had failed to have any reduction in wound size after four weeks of standard wound care modalities. Wounds that were included in this patient mix were diabetic ulcers, decubitis ulcers, venous stasis ulcers and complicated surgical wound dehiscence. After the initial assessment of each patient, we measured and photographed the wounds. Patients with infected wounds were not included in the study. After thorough and complete debridement of the wound, we placed an autologous platelet gel graft on the wound bed. After allowing several seconds for the gel to set, we proceeded to apply petrolatum impregnated gauze onto the graft and subsequently added several layers of gauze dressing to cover this area. Patients were instructed to leave the dressing undisturbed for a minimum of five days and preferably one week. Afterward, we removed the dressings, re-evaluated the wounds and photographed them. We then instructed the patients to apply a topical hydrocolloid daily to keep the wound moist and to cover it with another gauze dressing. Patients were asked to return between the 10th and 14th day after the initial autologous platelet graft for additional treatments with platelet concentrates if necessary. We continued this protocol until complete epithelialization was achieved. No patient was deemed to have reached the endpoint until he or she had complete wound closure. The treatment with APC+ resulted in successful wound closure in 16 out of the 17 chronic wounds. There was a 94 percent success of epithelialization. One of the patients had a recurrence of a sub-first metatarsal head ulceration due to noncompliance. The number of APC+ applications ranged from one to five. In addition to the results table (see “How The Patients Fared In The Study” below), here are three individual case studies that help illustrate the results one would normally see in using autologous platelet grafting. Case Study One: Getting Closure On Large, Non-Infected Wounds A 72-year-old African-American male initially presented to the clinic with two large, non-infected chronic wounds on the heel of the right foot and the lateral aspect of the right heel. The patient had well-controlled diabetes with a recent blood sugar of 111g/dl and appeared well-nourished and oriented. The patient said he had stepped on a small object when he went out to get the newspaper. He believed it was a small pebble or stone that was inside of his shoe. Unfortunately, he wasn’t able to feel the presence of the pebble or stone because of his diabetic peripheral neuropathy. He consequently developed ulceration on the plantar lateral aspect of his right heel. He said the ulceration occurred approximately 90 days prior to his initial visit. He initially treated himself with hydrogen peroxide, but ended up in the hospital several weeks later with osteomyelitis of the right calcaneus in addition to cellulitis. The patient remained hospitalized for 45 days. During this time, he had a partial calcanectomy with extensive debridement to treat the osteomyelitis. Unfortunately, the incision used to perform the calcanectomy also dehisced and became a chronic wound in addition to the original ulceration. In addition to the standard wound care protocol, the patient had 40 hyperbaric oxygen treatments and VAC therapy. The physical examination revealed a palpable doris pedis and posterior tibial pulse. The patient had two large, mildly draining wounds. The plantar lateral heel ulceration measured 31 mm x 9 mm with a depth of 5 mm. This wound had a granular wound base and was not infected. The second wound, on the lateral aspect of the right heel, had dimensions of 50 mm x 11 mm with a depth of 16 mm. This wound was deep with involuted skin edges and exposed bone. The patient underwent five APC+ tissue grafts. The wound beds and margins were extensively debrided to ensure removal of all necrotic tissue and the development of a freely bleeding surface. We proceeded to apply APC+ and covered the graft with a non-adherent dressing and an outer layer of gauze. The wound on the plantar aspect of the heel was completely epithelialized and healed on 12/23/02, less than two months after the initial treatment. Case Study Two: Treating Post-Op Wound Dehiscence The patient, a 64-year-old male, developed a wound dehiscence after tarsal tunnel decompression surgery on the left ankle. The patient was in relatively good health and was neither diabetic nor immunocompromised. He was referred to a hospital-based wound care center and had 54 hyperbaric oxygen treatments in addition to standard wound care protocols and treatments. The wound failed to heal. Upon our physical examination, we noted that the wound measured 35 mm x 14 mm x 3 mm. There was surrounding redness and pain with palpation. A deep tissue culture grew out Klebsiella pneumoniae. Appropriate antibiosis cleared the infection in one week. The wound bed was fibrinous and poorly granulated, which was the result of heavy colonization. Once the infection had resolved, the patient presented to the clinic for extensive wound debridement, which required local anesthetization and a subsequent application of APC+ graft. After three autologous grafts with APC+, the patient’s wound closed in 35 days. Case Study Three: Treating A Heel Ulcer On A Bedridden Patient With Diabetes The patient had an original complaint of a diabetic ulcer on the left heel. She had been bedridden and did not have proper padding to reduce pressure on her heels. Upon the physical examination, we measured the wound initially at 3.1 cm x 1.3 cm x 2 mm. While there were no palpable pulses, the wound was not infected and had only mild drainage. We extensively debrided the wound beds and margins to ensure removal of all necrotic tissue and the development of a freely bleeding surface. We proceeded to apply APC+ and subsequently covered the graft with a non-adherent dressing and an outer layer of gauze. This wound was successfully closed with two APC+ treatments in 21 days. In Conclusion Clinically, when it comes to using APC+, the results have been impressive. We achieved a 94 percent success rate in this series of chronic wounds, with the criteria for success being complete epithelialization. Not only has this technology repeatedly proved itself with closure and epithelialization in different types of wounds, there are certain economic benefits as well in the most difficult refractory cases. While this technology is simple to use and is effective in an office-based setting, one may anticipate huge savings of the healthcare dollar once this technology becomes more available. In addition to further implementation of this technology into the wound care arena, it is my opinion that widespread use of this technology will become commonplace in other aspects of podiatric surgery. APC+ will enhance and accelerate bone healing in osteotomies (i.e., common procedures like bunionectomies) and augment bone grafting techniques. It is also very likely to prove useful in a myriad of other podiatric situations. Investigation has begun on the use of growth factors in tendinopathies and degenerative processes in joints. Indeed, this technology may greatly change the way podiatric surgeons view and manage many different clinical pathologies. Dr. Barrett is a Fellow of the American College of Foot and Ankle Surgeons and is board-certified in podiatric orthopedics. He is the Director of Surgical Training at the Institute of Peripheral Nerve Surgery and is the Research Director for the Houston Podiatric Foundation. Editor’s Note: For a related article, see “Expert Tips On Wound Bed Preparation” in the July issue of Podiatry Today or check out the archives at www.podiatrytoday.com.
 

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References 1. Marx RE. Platelet Rich Plasma Growth Factor Enhancement for Bone Graft. Oral Surgery, Oral Medicine, Oral Pathology, Vol. 85, #6, June 1998. 2. Marx RE. Platelet-Rich Plasma: A Source of Multiple Autologous Growth Factors for Bone Grafts. Tissue Engineering Applications in Maxillofacial Surgery and Periodontics. P.71-72. 1999 Quintessence Publishing Co., Inc., Chicago, Ill. 3. Whitman DH, Berry RL and Green DM. Platelet Gel: An Autologous Alternative to Fibrin Glue with Applications in Oral and Maxillofacial Surgery. Journal of Oral Maxillofacial Surgery Vol. 55:1294-1299, 1997. 4. Tsang MW, et. al. Human Epidermal Growth Factor Enhances Healing of Diabetic Foot Ulcers. Diabetes Care, Vol. 26, #6, June 2003. 5. Adler SC, Kent K. Enhancing Wound Healing With Growth Factors. Facial Plast Surg Clin N Am 10 (2002) 129-146. 6. Clark RAF. The Molecular and Cellular Biology of Wound Repair, 2nd Edition, Kluwer Academic/Plenum Publishers, New York, 1998. 7. Kevy S, Jacobson M. Preparation of Growth Factor Enriched Autologous Platelet Gel. Presented at the Society for Biomaterials; 27th Annual Meeting, April 2001. Additional Reference 8. Gogia, PP. Clinical Wound Management. SLACK Inc. Thorofare, NJ, 1995.