A Lifetime of Proving Them Wrong: Robert Langer and the Development of “Bioartificial” Tissues

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“They said it wouldn’t work” has been a galvanizing challenge to Robert Langer, Sc.D., throughout his long and astonishingly productive career. Langer has been a pioneer in the creation of biomaterials for drug delivery, and more recently in laying the foundations for the development of engineered tissues, including those in development for treatment of renal disease. He delivered a state of the art” plenary lecture here during Kidney Week in Philadelphia.

As a young man wanting to put his chemical engineering skills to some creative use, Langer approached Judah Folkman, a cancer researcher whom Langer had heard “sometimes hired unusual people.” Folkman was in the early days of seeking angiogenesis inhibitors as antitumor agents, and it fell to Langer to prospect for candidates in bovine cartilage, which is largely devoid of blood vessels. This, he said, led to long hours scraping clean the thigh bones of “most of the cows in the Northeast.”

Most significantly, this early work led him to make fundamental advances in polymer chemistry, designing polymers that could hold, and equally importantly slowly release, large molecules such as proteins. The chemistry establishment was skeptical such a feat was possible. But he showed them wrong, creating polymers with high “tortuosity,” full of large pores that twisted throughout the structure. He published his initial landmark results in Nature, in 1976. The polymer was used to deliver candidate angiogenesis inhibitors for in vivo testing. That research led, three decades later, to Nexavar and Torisel for renal cancer, and Avastin for colorectal cancer.

A different challenge was to develop polymers that would dissolve in a controlled fashion when placed in the body. Dissolvable sutures existed prior to his work, but the rate and pattern of dissolution was poorly controlled. By thinking long and hard, and experimenting relentlessly, he came up with a material that overcame these limitations. And by altering the ratio of the two subunits in the polymer, he could change the rate of dissolution, and therefore the release of anything within it, making the polymer perfect for implanted drug delivery systems.

The polymer is currently used to deliver carmustine in situ after resection of glioblastoma multiforme, killing remaining tumor cells with fewer side effects than systemic chemotherapy. The therapy was approved by the FDA in 1996, only after, as Langer told it, 15 years of grant reviewers explaining why each new advance along the way had no chance of working. The achievement was rewarding in several respects, he said. The treatment triples survival at one year, and quintuples it at two years. In addition, his many postdocs who perfected the system over the years now hold major positions in industry and academia across the country. The reviewers? Not so much, he said.

A major focus of Langer’s work in recent years has been the development of biodegradable scaffolds for direct implantation in vivo, around which cells can grow. He noted that when tissue progenitor cells are injected directly into the body, “not much happens,” because of the absence of the appropriate context in which to grow. But with a scaffold to provide spatial clues, cartilage cells direct their growth to take on the shape of the scaffold, which then dissolves, leaving pure animal (or human) tissue.

“We still have a good deal of work ahead of us,” he cautioned, noting that strength of the new tissue is limited, making the repair of sports injuries, for instance, a still-unrealized goal. But early work indicates the potential: a remodeled ear for a soldier with a war injury, a new chest wall for a boy with a congenital deformation. A related approach is now under development for spinal cord injury repair, with preliminary results that, judging by a video of a treated rat, are nothing short of astonishing.

“It is my hope that engineering approaches such as these can play a role in nephrology,” Langer concluded.

That challenge has been taken up by several researchers, including David Humes, MD, professor of internal medicine at the University of Michigan. In an interview with Kidney News, Langer described the development of a bioartificial kidney as “a new frontier.” Of the two central functions of the kidney, dialysis handles only one: filtration clearance. The other, which combines reabsorption with metabolic and synthetic capacities, is the role of the tubule, and it is replacing the tubule to which Humes has devoted many years of research.

“The field has advanced considerably,” Humes said. He spearheaded a successful phase II trial of an extracorporeal tubule cell cartridge for acute kidney disease, which cut mortality in half. But as other treatment strategies emerged, that application has become less important.

For the last several years, Humes has been developing “a compact, wearable device” that can be combined with peritoneal dialysis for end stage renal disease. The tubule cells in the device are bathed in peritoneal fluid to keep them healthy. “The concept of a fully functional, bioartificial, wearable kidney has now been conceptually formulated,” he said, “and a proof of concept has been made in a large animal model.” Miniaturization would allow the device to be implanted, but that remains “a number of years away.”

Still further away is the replication of the tissue architecture of the kidney itself, which integrates the clearance and reabsorption functions in a compact and efficient package. “That is the ultimate challenge,” he said, but one that is orders of magnitude harder than sculpting cartilage. Tubules have at least 10 segments with different functions; cells of the right type might be injected under computer control into a dissolvable matrix, Hume speculated, but would still need the appropriate vasculature and innervation. “That would be a tour de force.”

“The extracorporeal systems are here already,” he said, but remain in the lab, awaiting both further development and a commercial rationale that would support that development. “It is difficult to add any costly component to the system in ESRD, unless there is a cost savings that can be identified.” Decreasing a patient’s dependence on dialysis centers might provide the financial savings that would justify the cost of the system, he suggested.