An MD&DI May 1998 Column
Current research encompasses almost every conceivable organ system and function.
The earliest attempts to make artificial organs focused on reproducing the mechanical functions of the body. The kidneys were basically just a blood filter, and the heart simply a four-chambered pump. The first artificial kidney was an external device larger than the human torso. In 1982, William Devries of the University of Utah implanted the first completely artificial heart, the Jarvik-7. Although recipient Barney Clark survived only 112 days, the interest in artificial organs lived on.
Artificial skin is perhaps the most mature specialty in the development of artificial organs. Photo courtesy of Integra Lifesciences (Plainsboro, NJ)
Researchers today are realizing that mechanical mimicry alone cannot always succeed in duplicating the intricacies of human organs. Regulatory and endocrine organs, for example, are exceedingly complex in their functions and interactions with other systems. Rather than synthesize all of these functions from scratch, some researchers have concentrated their efforts on growing and manipulating human cells, using artificial templates or biological scaffolds. Other research seeks to develop hybrid devices that are part organic and part synthetic, combining living cells with constructed devices or engineered materials. And still other research is geared toward improving basic mechanical models.
Hepatix, Inc. (La Jolla, CA), is among those companies that are developing organic-synthetic hybrid technologies. The company's ELAD (extracorporeal liver assist device) is touted as the first artificial liver and the first medical device to incorporate immortalized human hepatocytes. The ELAD consists of two parts: the Bioassist System, which pumps the blood, and the ELAD cartridge, which contains the cloned (immortal) human hepatocytes that assume liver function. In design, the ELAD works much like a traditional kidney dialysis machine. In practice, it does much more. The cloned liver cells not only filter toxins from the plasma but also secrete albumin proteins and clotting factors like a normal liver.
Even though human cells are used, tissue types do not require matching. Immune response is prevented by a semipermeable membrane that separates the ELAD's cells from the patient's blood cells and immunoglobins. Smaller molecules, like toxins and nutrients, can pass through the membrane. These blood toxins are filtered out, while the nutrients from the patient's own sera can sustain the artificial liver cells indefinitely.
ELAD therapy is intended for patients with fulminant hepatic failure. Hepatix president C. Richard Piazza envisions the device as a bridge to recovery or transplant. "Unlike kidneys, the liver has self-regenerative properties," he says. "If the damage is not too extensive, the ELAD can assume some of the liver's functions while it recuperates." The ELAD may also expedite recovery of posttransplant liver recipients. Phase I clinical trials were successful, and a bridge to a pivotal clinical trial scheduled for this June should determine if Hepatix will meet its year 2000 target date to market the device.
For clinics and hospitals, donated blood has always been in high demandand often in short supply. The threat of disease transmission further underscores the need for an alternative supply. To capture this potentially large market, many companies are scrambling to develop an artificial blood substitute. Although the blood performs myriad functions in the body, most research concentrates on duplicating its oxygen-transport capabilities. For surgical or emergent patients, providing oxygen to the body is obviously of paramount concern.
Development of a blood substitute has followed two basic avenues. Companies like Alliance Pharmaceuticals (San Diego) believe perfluorocarbons (PFCs) hold the key to augmenting blood supplies. PFCs are chemically inert but can dissolve oxygen in large quantities. Alliance presented a dramatic demonstration by immersing a mouse in a beaker of its LiquiVent PFC solution and showing that it could survive by breathing the oxygen-rich liquid.
Other companies are focusing their efforts on hemoglobin, the natural oxygen-carrying molecule in red blood cells. Unfortunately, purified hemoglobin in its native form cannot be used by the body and, furthermore, exhibits renal toxicity. The challenge lies in developing an altered form of hemoglobin.
Baxter Healthcare Corp. (Deerfield, IL) is leading the race to market such a product with its HemAssist (diaspirin cross-linked hemoglobin, or DCLHb). Baxter uses outdated blood-bank supplies as a source for its hemoglobin. Filtration and viral inactivation minimize the possibility of disease transmission. HemAssist and other blood substitutes also make blood typing and cross-matching unnecessary.
Although ahead of the pack, Baxter is only one in a crowded field of competitors. Northfield Laboratories (Evanston, IL) received FDA clearance for Phase III clinical trials of its Polyheme. Hemosol, Inc. (Etobicoke, ON, Canada), hopes that its Hemolink blood substitute will have treatment indications for anemia as well as surgery and emergency medicine. Biopure Corp. (Cambridge, MA) taps the larger but perhaps less marketable bovine hemoglobin supply. Biopure's purification techniques reportedly make its Hemopure pathogen free, but after the recent "mad cow" disease scare it may take a great deal of marketing acumen to overcome popular concerns.
Rather than using a natural source of hemoglobin, Somatogen (Boulder, CO) is using recombinant DNA technology to genetically engineer new varieties. J. William Freytag, Somatogen's vice president of technology, expects that recombinant hemoglobins will ultimately dominate the market, noting that "every animal product that hit first was followed by a recombinant genetic version." Somatogen is reportedly conducting a Phase II study of its Optro oxygenating therapeutic solution in a cardiopulmonary bypass setting, where it would be used to increase the amount of patient blood that could be withdrawn before surgery for postsurgical reinfusion.
While some researchers are trying to enhance the blood's capacity for carrying oxygen, others are working just to get oxygen to the blood in the first place. At the McGowan Center for Artificial Organs, a branch of the University of Pittsburgh Medical Center, a team of researchers led by cardiothoracic surgeon Brack Hattler, MD, and bioengineer William Federspiel, PhD, has developed what is essentially a temporary implantable synthetic lung. The device, known as an intravenous membrane oxygenator (IMO), is designed to rest directly within the vena cava system, oxygenating the blood as it returns to the heart before reaching the natural lungs.
The intravenous membrane oxygenator rests within the vena cava system, oxygenating blood as it returns to the heart (McGowan Center for Artificial Organs, Pittsburgh).
"The IMO basically consists of a bundle of hollow-fiber membranes that can be inserted through a peripheral vein in the leg and guided up to reside within the inferior vena cava, superior vena cava, and right atrium," explains Federspiel. "In an average-size adult, that's a vessel length of about 40 cm." Oxygen enters the membranes through an external tube and diffuses into the blood through the microporous fiber walls. CO2 diffuses from the blood into the gas stream and exits through a second tube. A third tube activates an intraaortic-type balloon, located at the center of the membrane bundle, that actively draws blood across the membrane surface by inflating and deflating 60 to 160 times per minute.
The balloon is critical to achieving efficient gas transfer within the obvious space limitations. As Federspiel explains, the rate of gas exchange for any diffusion device is directly proportional to the active surface area. A lung, for example, presents about 100 m2 of surface area, while a traditional blood oxygenator works with about 24 m2. The most Federspiel expects to get without obstructing blood flow is 0.5 to 0.6 m2. "So right off the bat, we have a lot less surface area, and we have to be more efficient," he says. "The way we do that is through a concept we refer to as active mixing. We have an intraaortic-type balloon within the fiber bundle, and we pulse that balloon, which introduces additional mixing within the blood stream, directly improving the rate of gas transfer to and from the artificial lung device."
Blood substitutes such as these made from diaspirin cross-linked hemoglobin (DCLHb) make blood typing and cross-matching unnecessary (Baxter Healthcare, Deerfield, IL).
Federspiel points out that the real impediment to gas transfer is not the membrane fiber itself but rather the diffusional boundary layers in the blood stream. Basically, when fluid flows across a stationary surface, fluid elements immediately adjacent to the surface experience a proportional decrease in velocity, eventually becoming stagnant at zero distance. "By adding more motion to the blood flow," he says, "you make those stagnant regions as thin as possible, improving the rate of gas transfer." Active mixing allows the device to remain small enough to permit blood to return to the heart unobstructed; in fact, the cross-sectional area of the fiber bundle is only about 75% of the cross section of the blood vessel. Most of the energy the blood needs to flow through the bundle is provided by the device itselfnot by the cardiovascular system.
Federspiel expects the IMO to be used initially as a support device for people with acute respiratory failure and reversible lung damagenot chronic conditions. In particular, the device would be indicated for patients who do not respond to a standard ventilator within 2448 hours. It would be inserted percutaneously and then removed after about two weeks. Future applications, however, could extend far beyond that. "We expect that as we improve performance and improve biocompatibility and start gaining success with implantation over that two-to-three-week period, we will look toward a version of the device that could be used as a longer-term support or as a bridge to transplant," Federspiel says. Currently, the Pittsburgh team is in the process of forming a start-up to commercialize the IMO. Clinical trials could begin by late 1999 or early 2000.
Some tissues challenge medicine not with their complexity of function but with their inability to regrow. Cartilage, for example, typically does not regenerate after it has been damaged. Rather than use wholly synthetic materials, researchers are now investigating ways to grow cartilage outside the body. Genzyme Tissue Repair (Cambridge, MA) and Telios (San Diego) are working on using a patient's own chondrocytes to grow replacement cartilage for subsequent transplantation. Autologous transplants have several inherent benefits. Because they come directly from the patient, for example, they eliminate the need to match tissue types and present no danger of disease transmission from donor to recipient. Moreover, because cartilage replacement is often elective surgery, the patient can afford the time it takes to culture the tissue.
Both the Genzyme and Telios engineering processes begin by harvesting a portion of healthy cartilage from the patient. With Genzyme's Carticel (autologous cultured chondrocytes), a biopsy of healthy cartilage cells is expanded to millions of cells by technicians at the company's Cambridge facility. After enough cells are grown, they are shipped back to the surgeon, who then fills in the cartilage defect with the new cells and sutures a periosteal patch over the site. Once implanted, the cells produce hyaline cartilage, which is more durable than the soft fibrocartilage produced by alternative treatments. "Hyaline cartilage forms a more natural, longer-lasting repair than is possible with other types of treatments," explains Jean George, vice president of sales and marketing for Genzyme. Carticel has been used worldwide in more than 1500 transplants to date, and orthopedic surgeons report that 86% of patients receiving it continue to show improvement after two years. "Good long-term clinical outcomes for patients are the real benefit," adds George. Carticel was granted FDA approval for repair of knee cartilage last August.
The Telios approach uses the harvested cells to seed an "articular cartilage regeneration template," a collagen device composed of two layers. Healthy cells are dispersed into the first porous layer, where they grow to form new cartilage once the template is transplanted back into the patient. The second, denser layer is designed to prevent the ingrowth of scar tissue that often accompanies cartilage replacement. Telios and Johnson & Johnson are collaborating to develop the technology, but so far the research has been limited to animal studies.
Both types of cartilage replacement are intended for acute or repetitive trauma damage to the knees. Indications for damaged articular cartilage of the patella, ankle, shoulder, and hip are also being pursued. Replacement of cartilage damaged by osteoarthritis or other degenerative diseases requires further research.
Widespread clinical applications may still be years away, but researchers are making great strides in getting severed nerves to grow. Peripheral nerves will innately regenerate but at an exceedingly slow rate (less than 1 mm per day). The problem is that they seem to lack instructions on how to reconnect themselves when severed. Without treatment, the ends can form a useless, tangled mass called an end-bulb neuroma. Present therapies to repair severed nerves involve suturing the two ends or using a graft harvested from another part of the body. Suturing is only possible when the gap is short (a few millimeters), and using a graft means that the harvest site will lose innervation.
Although traditional surgery and medicine have met with limited success, material sciences have given rise to new treatment strategies. Guides made from collagen or biodegradable polymers show promise in facilitating organized nerve growth. Basically just tubes that connect the two severed ends, these nerve guides lay down a path for the severed ends to find each other. The guides also serve as a pipeline for diffusion of growth and development factors that stimulate proper regeneration.
Successful Phase I clinical trials have prompted Integra LifeSciences (Plainsboro, NJ) to expand the testing of its peripheral-nerve regeneration conduit. The bioabsorbable collagen tube has been shown capable of closing 2-cm nerve gaps with restoration of function. Additional preliminary studies indicate that the product could bridge gaps of up to 5 cm. Larger clinical studies are under way in three European centers.
This regeneration conduit helps severed nerve endings find each other.
A combination of this technology with others may ultimately hold the key for clinical nerve regeneration. Medical researchers have shown that electric fields, certain auxiliary cell types, and biochemical stimuli can enhance neuron growth. Christine E. Schmidt, PhD, assistant professor of chemical engineering at the University of Texas at Austin, is working to improve current techniques. Schmidt thinks that the technology to repair small defects is close, but the ultimate goal is to reconnect much larger nerve gaps. "Nerves definitely need the physical guidance of the tubes," she says, "but the properties of the material used is a complex issue." When trying to reconnect longer spans of nerve, "organization of the individual axons will most likely be biochemically driven by growth factors and other stimuli," Schmidt explains.
Another difficulty with using neural guidance tubes is that the resulting nerve tissue typically exhibits less myelination, which plays an important role in proper signal transmission. Normally, Schwann cells wrap themselves around the nerve fibers to form the myelin sheath. Seeding the nerve guides with Schwann cells to promote myelination is also being researched at some institutes.
THE ARTIFICIAL BODY
Some current research into artificial organs represents new ways of considering old bioengineering problems. The artificial pancreas, for example, has long been the subject of intensive research, thanks to the large market that would be served by such a device. The traditional model seeks to combine a permanent glucose monitor with some sort of insulin-delivery device. But some biotech firms are taking a different tack. For example, Islet Technology, Inc. (North Oaks, MN), is developing a process for encapsulating healthy pancreatic islets to permit implantation. Encapsulation would allow diffusion of small molecules like glucose and insulin but prevent passage of larger immunogenic molecules. Islet Technology president and CEO Bill Drake likens the encapsulation material to a chain-link fence. "I envision glucose as the size of marbles and immunoglobins as basketballs," he explains.
Cadaver or autogenous bone grafts could become a thing of the past if Interpore International (Irvine, CA) continues to have success with its Pro Osteon bone graft substitute made from processed sea coral. The processing technique converts the coral to hydroxyapatite, the same mineral found in human bone. The resulting product is nonimmunogenic and is easily sculpted by surgeons for various implant applications. The geometrical structure is similar to that of human cancellous bone. As Interpore president David Mercer explains, "The patient's own osteoblasts are attracted to and grow into the hydroxyapatite graft." Conservationists need not worry. "Less than 1% of the world's coral supply will ever be used for grafts," reassures Mercer.
Artificial skin may be the most mature specialty in the development of artificial organs, and there is definitely no lack of players in this crowded field. Organogenesis (Canton, MA) hopes to stand out from the pack by positioning its Apligraf as entirely natural skin. Organogenesis believes that Apligraf is the first living manufactured organunlike competing products, which are made from collagen or protein matrices. According to Carol Hausner, director of investor and public relations, "Our organotypic cell-culture technique actually achieves the three-dimensional organization of living skin." Hausner, who refers to Apligraf as "skin in a dish," also notes that the living tissue product has the added benefit of being able to actively contribute to the wound-healing process.
Research continues in trying to find artificial substitutes for almost every organ in the human body. Many systems are external, like kidney dialysis and liver-assist machines. Some organslike the eyesrequire electronic and optic technology that we can grasp conceptually but not yet command. Although fully implantable organs are still mostly science fiction, the technology is rapidly making that fiction our future.
Gary Woo is a freelance writer based in Woodland Hills, CA.