Will nano-engineered implants set kidney patients free?
Conventional dialysis, in which a patient’s blood is pumped through an external filter to drain out accumulating toxins, is far from ideal for the 1.4 million people with kidney disease worldwide whose lives depend on it. The common regimen of three half-day blood-cleansing sessions per week removes, on average, just 17 percent of the toxins that a healthy kidney would clear, so that only one-third of all dialysis patients survive more than five years of treatment.
Nanotechnology could offer an alternative, according to nephrologist William Fissell at the University of Michigan. He and colleagues are working on nano-pore membranes that could enable dialysis to be miniaturized into implantable devices that provide round-the-clock clearance of toxins, untethering dialysis patients from bulky pumps and clinics. “This is a fundamentally liberating technology,” says Fissell.
Fissell and colleague Shuvo Roy, a biomedical engineer at the Cleveland Clinic Foundation, claim to have solved half of the challenge: engineering nano-membranes that are efficient enough to support a compact, low-power implant. The team secured a patent for the concept earlier this year. However, engineering pores with the required selectivity–pores that drain away the worst toxins without robbing the body of critical proteins such as albumin, blood clotting factors, and antibodies–is proving to be tougher than expected.
As currently practiced, dialysis is a crude procedure. Patients are hooked up intravenously to a powerful pump that circulates their blood through a cartridge of porous plastic fibers. Fluids, dissolved toxins, and salts pass through the fibers and are discarded, while the proteins and blood cells caught in the sieve are supplemented with electrolyte before returning to the patient. The filter’s poor fluid dynamics are a function of their imprecision: filter manufacturing produces a wide range of pores, so to avoid having too many large pores, which would suck out valuable proteins, the fibers must be manufactured with a preponderance of very small pores. The machine’s pump makes up the difference, forcing blood through these inefficient sieves.
In contrast, Fissell and Roy etch pores into ultrathin wafers of silicon with lithographic precision. The result is a homogenous array of pores, each capable of flow rates several orders of magnitude higher than the average pore in a conventional filter. The pores mimic the exquisitely precise yet efficient diaphragms that filter blood in a human kidney, resembling a panel of Venetian blinds, says Fissell.
Current prototypes contain roughly 10,000 pores per square millimeter, according to Fissell. Next-generation membranes, now being engineered, will have more than 100,000 pores or slits per square millimeter and provide more than 10 times the flow. An implanted device carrying several hundred square centimeters of this next-generation membrane should, Fissell estimates, filter at least 30 milliliters of blood per minute at average blood pressures–about one-third of normal kidney function. The implant would be tucked under the skin; small fluid bags worn externally could receive the ultrafiltrate and supply replacement electrolytes.
Controlling what goes through the slits, however, remains a problem. While even the largest blood toxins easily slide through the membrane’s slits, experiments with prototypes suggest that the smallest of the valuable proteins, albumin, will also drain through. Dextran, a complex sugar used as a surrogate for albumin in filtration tests, flies right through the prototype pores, despite measuring roughly 40 nanometers in diameter, which is three to four times wider than the pores. Fissell thinks that the dextran, a long-chain molecule normally scrunched up like a wad of paper, stretches out when it encounters the slit pores and snakes through–something that a protein chain like albumin might also do.
Fissell’s team is testing whether the kidney sorts not only by size but also by generating electrical charges that repel protein chains, which are also charged. They’re modeling various chemical modifications to introduce charges on the surface of the silicon pores.
To make the system practical will require rendering the membranes biocompatible. Unmodified silicon strongly attracts proteins, and thus a silicon nano-pore membrane would rapidly clog if implanted in the body. Fissell’s colleague at the University of Michigan, David Humes, has initiated animal studies with the nano membranes to identify surface treatments or alternative membrane materials that will prevent clogging in implants.
Humes hopes to use the membranes to fashion a more sophisticated version of the implant that would contain living kidney cells–analogous to his “bioartificial” Renal Assist Device that’s currently in phase two clinical trials (see “Saving Lives with Living Machines,” July/August 2003). In an implantable version of the bio-artificial kidney, nano-pore membranes would protect the live kidney cells from immune cells and antibodies, which have thwarted most bio-artificial organ implants to date. The live kidney cells, in turn, would improve the function of the implant by reabsorbing and returning to the bloodstream some of the fluids and salts that pass through the nano-pore membrane. Eventually, bio-artificial implants that recover fluids and salts and divert the remaining ultrafiltrate to the bladder might even eliminate the need for external electrolyte and ultrafiltrate bags.
UCLA Medical School nephrologist Allen Nissenson, who has worked extensively to support the development of portable dialysis devices, says it remains to be seen if the University of Michigan researchers can squeeze their filtration systems into a package small and robust enough for implantation. But he says their goal to more precisely emulate the function of the kidney is right on–and a welcome alternative to the incremental improvements in more conventional technologies that have dominated dialysis developments for the past 20 years. Innovations that “more closely mimic the way natural kidneys function are really the cutting edge for the future of therapy,” he says.
Fissell’s 30 milliliters per minute of filtration would provide more than 30 percent of normal kidney function–a huge improvement, according to William Harmon, director of nephrology at Children’s Hospital in Boston. It’s an “important threshold,” he says, above which many symptoms of kidney disease would fade: “If you’re at 30 percent you’re doing quite well.”