Technology for hemophilia offers hope for chronic wounds
System also can produce platelet-derived growth factor
New technology now approved in Canada and Europe seems to hold much promise for increased effectiveness in treatment of acute surgical and chronic dermal wounds.
The CryoSeal system provides equipment and sterile disposable containers for rapid automated harvesting of adhesive and clotting proteins from blood plasma to produce cryoprecipitated antihemophiliac factor (AHF), a blood product for intravenous treatment of hemophilia. U.S. marketing of the CryoSeal system for this indication is awaiting Food and Drug Administration 510(k) approval, which is expected within the next few months. Once FDA approval of this indication is achieved, the product’s manufacturer, ThermoGenesis Corp. of Rancho Cordova, CA, will make parallel applications for two more indications for the system: production of autologous fibrin glue (AFG) and production of an autologous concentrated platelet-derived growth factor (APDGF) solution for treatment of chronic wounds such as diabetic, decubitus, and venous stasis skin ulcers.
One machine, three functions
The CryoSeal System is a thermodynamic micromanufacturing device that can harvest and concentrate therapeutic components from a patient’s own blood. The same CryoSeal device is used for all indications, but each indication requires a different software program and disposable container. The desired material is harvested into the containers. For example, to produce AHF, a technician would put the appropriate disposable container into the machine and activate the corresponding program algorithm in the software. The machine then works with that disposable container to harvest the desired proteins. To make AFG, the technician uses a disposable container called the CP-2 and activates the algorithm for fibrin glue. The machine harvests the fibrinogen protein and thrombin into separate chambers of that disposable disposable container. Production of APDGF requires use of the third software function and third disposable container for the machine. The source material in each case is plasma. In each application, harvesting the desired blood components from the patient’s blood takes a little less than an hour.
According to Philip H. Coelho, CEO of ThermoGenesis, the FDA approved the first PDGF product in 1998, containing PDGF beta beta. The product, which comes in a gel form, was approved for treatment of diabetic ulcers and has a growth factor produced by the recombinant manufacturing process. "They’re basically just growing a growth factor that exists in everyone’s body," Coelho says. "Our solution is to harvest multiple platelet-derived growth factors from the patient’s own platelet-rich blood plasma and concentrate them, and then bring them to these chronic dermal wound sites for palliative treatment. Using the exact same machine with a slightly different software program, we can get highly concentrated solutions of multiple platelet-derived growth factors including PDGF beta beta." Coelho says these growth factors have been demonstrated to be critical to the endothelial cell growth required to cover chronic dermal wounds.
"Most of these wounds are a result of decreasing vasculature underneath — the blood simply isn’t getting to the site — so you need to concentrate them and bring them topically to the wound site," he notes. "All of these treatments for chronic wounds require repeated treatments daily for weeks to heal them."
Product used for hemostasis, wound glue
Cryoprecipitated AHF is normally prepared by blood banks in a labor-intensive two- to four-day process. About 70% of the 1.1 million units of cryoprecipitated AHF now manufactured annually by blood banks and sold to hospitals is used "off label" by U.S. surgeons to stop bleeding and to augment or replace sutures. In this usage, the fibrinogen content of cryoprecipitated AHF is combined with the enzyme thrombin to make a two-part adhesive for surgical hemostasis.
The typical AHF manufacturing process uses five pieces of equipment: a blast freezer, a storage freezer, a 4-degree C centrifuge, an expresser, and a 4-degree C refrigerator. The production cycle involves a lot of handling because the product must be moved from one machine to another in a complicated and error-prone process to manufacture the product from a single unit of blood. CryoSeal products may provide a safer approach to producing therapeutic doses of proteins, enzymes, and growth factors.
The CryoSeal System is a compact, floor-standing unit about the size of a trash compactor, within which a disposable container processes plasma to concentrate therapeutic doses of fibrinogen, factor VIII, fibronectin, and PDGF from a single donor unit of blood plasma. For its use in making AFG, special applicators are provided that allow the surgeon to precisely administer the autologous fibrin glue to the internal wound site to control surface bleeding, bond tissues, and augment or replace sutures.
Autologous fibrin glue contains the adhesive and/or clotting proteins fibrinogen, fibronectin, von Willebrand’s Factor, factor VIII, and clot stabilizing proteins, as well as platelet-derived growth factors. ThermoGenesis says its AFG is competitive with commercial fibrin glues derived from blood plasma pooled from thousands of donors.
Pooled plasma raises concern over pathogens
Because of the concern of viral contamination from the source-pooled plasma, it was only in May 1998 that the FDA granted its first clearance to Baxter Corp. for production of a pooled-plasma commercial fibrin glue. Patients who have wounds or other medical conditions that require proteins, enzymes, or growth factors taken from pooled plasma (typically made from a pool of 10,000 donors) for treatment have legitimate concerns regarding the contamination of such products by bloodborne viruses (e.g., HIV, hepatitis A-H, etc.), bacteria (e.g., Staphylococcus aureus, Yersinia enterocolitica, etc.) and prions (e.g., Creutzfeldt-Jakob disease).
Recent technologies that manufacture these same proteins, enzymes, and growth factors through recombinant production processes rather than pooled plasma have their own manufacturing and allergic reaction safety risks. "Any time we administer any kind of blood products or by-products, there’s a danger of allergic reaction," says Iris Gatchell, RN, a cardiovascular intensive care unit nurse at Memorial Hospital in Greenville, SC. "If you can get the patient’s own body to produce something that they need, there’s no doubt in my mind you’ll cut down on reactions."
Commercial fibrin glues have traditionally used bovine-derived thrombin in their kits to initiate clot formation. Bovine-derived thrombin is both readily available and inexpensive. With the emergence of Creutzfeldt-Jakob disease (CJD) and nvCJD, however, the European community has prohibited the use of bovine-derived thrombin in commercial fibrin glues.
ThermoGenesis expects sales of the CryoSeal system with the AFG disposable could occur in Europe as early as fiscal year 2000. Nevertheless, formal clinical trials and FDA clearance will be required to market the product for this application in the United States. The company expects to move into parallel clinical trials for the AFG and APDGF product indications in fiscal year 1999, with market launch outside the United States in late fiscal year 2000.
One of the principal investigators in the clinical trials will be Paul O’Dell, MD, otolaryngologist and professor and chairman of otolaryngology at the University of Ottawa, Canada, who has tried the CryoSeal system for fibrin glue.
"We’ve just done a few patients with it and are in the process of setting up appropriate clinical trials," O’Dell says. "My involvement with it was to try it out to see if there were any problems in delivering it or any problems associated with it, which there weren’t." Three other Canadian doctors will join O’Dell as principal investigators in the clinical trials.
O’Dell comments that "the problem with the commercial [fibrin glue] products is that they are very expensive. The reason for trying CryoSeal is that it’s cost-effective, and with it being the patient’s own product, there is no risk of transmitting any of the known infections." He adds that though the patient may spend two or three extra hours in the preassessment unit where the blood work is done prior to surgery, "down the road, the advantage is that if we can glue these wounds closed and don’t need to use a drain, the patients may be able to go home right after their surgeries, so that their stay in hospital will be greatly shortened."
The regulatory process has taken about two and a half years so far. "The biggest step is behind us because we’ve fully characterized all those proteins," Coelho says. "We don’t need to do that again. We merely have to demonstrate efficacy for new claims. Basically, the FDA is concerned with safety and efficacy. They want to assure the public that medical claims are supported by the scientific evidence submitted. It’s really truth in advertising in a lot of ways. You can’t say our product is useful for a surgical glue or platelet growth factor for treatment of dermal ulcers until you can demonstrate this efficacy in clinical trials. That’s something I don’t begrudge at all. The FDA is playing an extremely useful role in health care, forming a barrier or filter that lets only the products that really work get through."
For more information, contact Philip Coelho, ThermoGenesis Corp., 3146 Gold Camp Drive, Rancho Cordova, CA 95670-6022. Telephone: (916) 858-5105. World Wide Web: http://www.thermogenesis.com.
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