The concepts herein are based upon the comparison of the two FDA approved chronic wound-healing products, Apligraf and Dermagraft, against CHIFIX’s Fibromate Wound Healing Kit. It will be demonstrated that all 3 of the Regenerative Medicine technologies heal chronic wounds by the same biological mechanisms. However, The advantages of utilizing the Fibromate Kit will show that its has a two year shelf life and can be stored at room temperature, and will be 1/3 the cost.
DERMAGRAFT, marketed by Advanced BioHealing Inc.features neonatal dermal fibroblasts cultured in vitro onto a biodegradable polyglactin mesh. The graft secretes structural protein and growth factors into the 3 dimensional scaffold. Dermagraft is then frozen for storage. To prolong its shelf life up to six months it must be stored at -75% C. Most wound treatment centers would not ordinarily have such storage refrigeration. It is approved for diabetic foot ulcers. Its mode of action is to assist in restoring the dermal bed allowing wounds to heal when implanted into adequately prepared diabetic foot ulcers. There is no indication that that neonatal fibroblast cells become incorporated directly into the wound. That would constitute a probable immunological event. The probable healing effect is from the growth factors and healing molecules that the fibroblsts supply to the wound-bed. Its cost is $1500.
APLIGRAF has a twenty year research history. It was developed by Organogenesis Inc. was approved for marketing by the FDA in 1999. Marketed by Novartis, Apligraf features human foreskin fibroblasts attached to a bovine collagen matrix on one side and human keratinocytes attached to the opposite side. Both cell types are culture from neonatal foreskin. This live tissue is delivered to the clinician in a 10% carbon dioxide bag. Immediately after being received Apligraf must be stored in a 37-degree incubator until use. It must be used within 10 days of delivery. The therapy consists of simply placing the Apligraf onto the ulcer. A nonadherent primary dressing is applied, followed by the cotton gauss dressing folded as a bolster to immobilize the graft. Nowhere in Apligraf’s literature is there a claim that any part of the original graft tissue becomes incorporated into the healing wound. There is a mention that the healing is promoted by the addition of dermal collagen and the presence of the fibroblasts. Each Apligraf application cost between $1000 and $1200, and there has been in some more refractory cases additional treatments in order to obtain the ideal therapeutic results.
THE FIBROMATE WOUND HEALING KIT THE ACTIVE COMPONENTS AND THEIR ACTIVITIES
Since this blog was written almost a decade ago there has been expanded research using fetal skin cells in Phase I and II clinical trials showing possible scarless healing potential of these cells. In the future the technology presented below will change. Our concept would apply fetal cells directly to the wound site. We would set up a culture technology for these fetal cells and utilize the cellular fibronectin and extracellular matrix molecules (ECM) derived from them. The clinical applications for these fetal derived molecules would be the same as proposed below
DOXYCYCLINE: Chronic wounds contain colonies of bacteria and virus. Also within wound exudates are elastases, collagenases, and metalloproteinases. These proteases play a significant role in the problem of why wounds become chronic and do not heal. This issue must be addressed before the sequential therapy can be initiated. Doxycycline applied locally to the wound bed for several minutes can inactivate these destructive proteases, and have an antibiotic effect on the bacterium and viruses.
CELLULAR FIBRONECTIN: This extraordinary matrix protein is seen to orchestrate a myriad of biological and physiological activities that are essential to wound healing. At this juncture we are obliged to clear up any confusion regarding the differences of plasma fibronectin and cellular fibronectin. Plasma fibronectin is synthesized exclusively in liver hepatocytes, remains soluble, as an important blood plasma protein with several blood related functions. Its role in wound healing is critical as it is involved with fibrinogen and other plasma proteins in creating the blood clot and a provisional matrix. Cellular fibronectin is synthesized seemingly in all cells as part of their internal structure, basement membranes, and is secreted into to extracellular space to become a prominent member of the ECM. Cellular fibronectin is the first molecule that is synthesized by migrating fibroblasts in response to chemotractic signals from the wound site and is laid down over the provisional matrix and forms its own insoluble matrix. This is then followed by the sequential activities of the extracellular matrix molecules (ECM), growth factors and cytokines that are intimately involved with the insoluble fibronectin matrix which allows cell migration followed by the synthesis of the structural molecules that shall remodel and restore the wound site. Cellular fibronectin has been shown to be 150 times as adhesive as plasma fibronectin. Until CHIFYX (formerly FIBROGENEX) perfected the purification technologies for cellular fibronectin, only plasma fibronectin was available for research and clinical trials. A small clinical trial for chronic healing had limited success with plasma fibronectin in 1988. Many researchers have mistakenly equated these two quite functionally different molecules. From an evolutionary stand point cellular fibronectin is at least 1/2 billion year older than plasma fibronectin. Cellular is found in the earliest most primitive metazoan animals. Plasma fibronectin came into existence with more advanced metazoan animals that had circulatory systems later in evolution. Fibronectin has also been shown to enhance angiogenesis which is critical in wound healing. There may be an additional dividend by the use of our Cellular Fibronectin in the wound bed as this remarkable molecule has shown to bind and attenuate the effects of various viruses and microorganism. (References upon request.)
EXTRACELLULAR MATRIX (ECM): These molecules are a complex of structural proteins, such as collagens, laminins, and growth factors. This composite is purified from the same human foreskin fibroblasts that the cellular fibronectin is purified from. It is recognized that the growth factors and the matrix molecules are the major players in wound healing. Applying these human derived proteins to the wound bed recreates the potential for natural healing.
BIODEGRADABLE BARRIER: CHIFYX recently developed a biodegradable barrier that has a 510 K, FDA approval. ALL OF THE CONSTITUENTS OF THE FIBROMATE KIT ARE IN A STERILE, FREEZED DRIED STATE, THAT IS RECONSTITUTED BEFORE USE. IT CAN BE STORED FOR OVER 2 YEARS.
Dermagraft and Apligraf, as of this date, do heal chronic wounds more effectively than other therapies. In the papers describing the clinical trials for Apligraf, there are conjectures that the healing effectiveness of the therapy is possibly due to this product’s cellular and matrix components, biological effects of occlusion, a possible graft take with vascularization, or through some unknown mechanism. No matter how Apligraf works, when the wound is healed there is no trace of the original products seen in the healed tissue. Therefore, it would seem that most if not all the components are superfluous as far as being incorporated in the wound itself. Since Apligragf does not seem to cause an immune response to the wound itself nor to the patient internal systems, the intact cells and the bovine collagen barrier probably are not invasive to the wound site. Bovine collagen and non- autologous cells have been known to cause immunological effects when applied as grafts. There is also a question of how long the foreskin fibroblasts and the keratinocyte are able to remain vital. Further, the 10 day critical time period for usage is problematical for clinicians. Dermagraft probably works similarly to Apligraf, wherein there is no implantation of the cells nor mesh.
We have designed The Fibromate Kit and therapy to have as little superfluous material as possible. The structural molecules therein are not known to cause immunological effects. The structural molecules in the kit should be effective because they will become incorporated into the wound site. The Doxycycline completes its activities within several minutes and is washed out of the wound. The Cellular Fibronectin will adhere to the wound bed within a minute. The special biodegradable barriers with its adsorbed ECM molecules are placed onto the cellular fibronectin prepared wound bed. It contains ECM molecules in superabundance that should assist the healing progression. The rationale of our proposed therapy is based upon the premise that recreates as closely as possible the natural way that the body endeavors to heal. We recognize that there are various surgical techniques and diagnostic evaluations that clinicians render before proceeding with their treatment protocols. Because of the different philosophies of individual clinicians we have intentionally not made any references to this aspect of the application of the therapy. An example would be debridment of the wound before initiating further treatment.
CLINICAL TRIAL PROPOSAL We envision a small pilot initial clinical trial under a hospital IRB approval for Venous Ulcers that should have about 12 to 15 patients and be conducted at one or two Wound Healing Centers. The trials would be designed to obtain sufficient data that could be used in designing a larger FDA trial. The results of this initial trial should take no more than 3 months to ascertain whether this new technology is working. The first and foremost question is that of the safety and effectiveness of the proposed therapy. Further, the trial should be able to ascertain how often the therapy should be utilized and how frequently the bandages should be changed. The initial trial should not be double-blinded. The small trial will have the advantage of less costs and should provide sufficient information to proceed with a larger trial