Research: Engineering News
New Life on the Cold Front: Research in mechanical engineering aims to extend the medical uses of cryo engineering
Extreme cold can destroy or preserve, depending on how it is used. In medicine it is used both ways—to kill cancerous tissue, or to preserve healthy tissue for implanting—and key strides could be made in both areas through new research at Carnegie Mellon.
Yoed Rabin is at the center of the work. Rabin directs the Biothermal Technology Lab in Mechanical Engineering, where he has a busy agenda. Over the past year Rabin won grants from the National Institutes of Health totaling $2.6 million to pursue four distinct lines of research in cryosurgery and cryopreservation.
Rabin says the grants are noteworthy because "cryo is not a glamorous new field; not the type that usually attracts a lot of funding. It has been practiced for many years, so it tends to be seen as a 'mature' field, when in fact there is still much more to be done."
For instance, he points out, our ability to preserve tissues at ultra-low temperatures is limited, where cryopreservation is the only method for long-term preservation. We can store body fluids such as blood, and some small and less complex tissues like corneas—but not blood vessels of significant size, or entire organs such as hearts and livers. Such organs can only be kept viable for a few hours by mildly chilling them. This is why transplant surgery depends on matching the right donor with the right recipient on a very short notice, and within a limited shipping time/traveling distance, then rushing the organ and patient to the surgery site. This process puts an enormous pressure and limitations on the practice of transplantation medicine.
If cryopreservation were extended to more complex and larger tissues, more transplants would be possible and we could think of building comprehensive tissue and organ banks for a very wide range of treatments, similar in concept to blood banks for example. That's one goal that Rabin and his team are working toward. Another is improving the precision of cryosurgery, with tools that range from a "flight simulator" for training surgeons to cutting-edge sensors to display freezing effects in real time. Some of the R&D is fast-track and some longer term, but Rabin says it all has one common theme—"it is cool technology."
No Ice, No Fractures, Please
One trick in preservation is to arrest decay by bringing tissues down to minus-130°C or below without letting ice crystals form. When the water inside or between cells turns to ice, it triggers a sequence of events which eventually leads to cell death. One effect that kills cells is the expansion of water upon freezing, rupturing cell membranes, and another effect is that body solutions become toxic when a significant amount of water is removed in the form of ice. Although blood can be used for transfusion even if many of the cells are lost to ice damage, organs can't absorb high cell loss in critical places and still function. Rabin taps a window in his office: "You want to vitrify the tissue. Make it solid but not crystalline, like glass." This can be done by adding cryo-protective agents (CPAs), which inhibit icing. The trouble is, CPAs have toxic effects. A popular one, DMSO, "was developed as a paint stripper in the early 1950s and may become very toxic to the tissue," Rabin says. Thus a core problem in cryo-cooling is finding ways to add CPAs in amounts that are low enough to not poison the tissue, yet high enough to be effective in affecting ice formation. New and exotic chemicals called synthetic ice blockers are now being developed, but they too have limitations. So with one NIH grant, says Rabin, "the concept we are testing is to mix ice blockers with the CPA, to see if we can use less CPA and get the results we want."
The other big obstacle to preserving organs is macro-fracture. As cooling or thawing proceeds through tissue, the temperature gradients can induce forces that leave structural damage. While the majority of individual cells may survive it, tissue or organ functionality may not. An expert in such fracture, Rabin is using a second NIH grant to develop a much-needed instrument, a "cryomacroscope" for observing how macro-fractures develop in test specimens.
"I got frustrated by cryobiologists asking me, 'How did this happen?', and I had to speculate by reasoning backward from the results," he says. "We want a movie that shows structural changes in progress, with time and temperature data embedded." Using fiber optics, a scanning mirror and other hardware and software, his MechE team is constructing a prototype system to deliver that result. Says Rabin, "We hope to have a fully computerized system within a year."
Learning and Sensing
Rabin has a passion for his specialty. "I've always been fascinated by heat transfer," he admits. He has done cutting-edge work in heat transfer in biological systems since the early 1990s, first as a graduate student in Israel, then at Pittsburgh's Allegheny General Hospital, where he began building networks of research partners among physicians and biologists while developing surgical devices. At Carnegie Mellon since 2000, beyond his research interest, Rabin is developing new teaching methods in the area of thermal sciences, ranging from hands-on lab activities to thermal design. In recognition of those efforts, he also won teaching awards for "Best Class" and "Professor of the Year" in MechE, and his teaching interests show up in another NIH project.
In cryosurgery, icing is good. The goal is simply to freeze and kill cancer tumors. Slender cryoprobes delivering liquid nitrogen are inserted into the affected area, such as the prostate in men or the breast in women. Targeting and control are crucial to freeze all of the diseased tissue without harming nearby healthy tissue. In previous work Rabin has developed computer-based "planning algorithms" to suggest optimum placement of probes for a given target geometry. But good surgeons, he notes, will want to try improving on what the algorithms suggest.
Hence the flight simulator as a learning tool, a project in collaboration with Kenji Shimada of MechE. "If the computer said 'put the cryoprobes here,' the clinician can say, 'Let's try this instead.' A 3-D visualization will then tell you if the outcome would be better or worse. You can play with different scenarios, and learn to develop intuition"—before trying anything on a patient. Rabin talks about the challenges of getting a very complex simulation and visualization to "run in an acceptable time for the learner" on standard computing resources. Still, he concludes, "We're building a toolkit with a clear path of development along an established line of research. We can see it becoming a product."
And his ultimate cryosurgery product would allow on-the-fly control during surgery itself. It's a grain-of-rice sized wireless temperature sensor and transmitter. An array of these, pre-embedded around the target region, would show the progress of the freeze front.
Such small sensors don't yet exist. Developing them represents a collaborated effort with Carnegie Mellon's experts in microelectronics fabrication and wireless communication—Gary Fedder and Jeyanandh Paramesh of ECE. The goal for the two-year NIH grant period is just "proof of concept," yet Rabin says he's already heard from a customer. "A company developing a device for hyperthermia"—killing unwanted cells with extreme heat rather than cold—"was hoping the sensors were close to ready. They need them and there are no alternatives."
In Yoed Rabin's view, that reflects the general eagerness of many people for new advances in cryosurgery and cryopreservation. "We're talking about improving the quality of life, possibly extending life expectancy," he says, while distancing his effort from whole-body freezing—a much debatable practice commonly known as cryonics. "Within my lifetime, I want to see our work touching people."
By Mike Vargo
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