Glioblastoma multiforme (GBM) is a particularly malignant form of brain cancer. It grows rapidly and is essentially always fatal. Even after surgery, a GBM patient’s median survival time is approximately one year. GBM also has a track record of being resistant to the best efforts of medical science and, as a result, there have been relatively few significant advances in GBM treatment over the last 25 years.

SEAS professors George T. Gillies and Joseph A. C. Humphrey, in partnership with Dr. William Broaddus at Virginia Commonwealth University (VCU), are determined to put an end to this deadlock. GBM thwarts the efforts of surgeons because it spreads diffusely within brain tissue. While surgeons can remove the larger tumors, they cannot hope to locate and excise each individual cell. Chemotherapy is a promising alternative, but there are obstacles. Therapeutic agents are often defeated by the blood/brain barrier, which protects the central nervous system from harm, thereby typicially

making intravenous injections and oral medications ineffective.

To overcome this problem, the team has turned to specially designed catheters. After inserting the catheter into the brain, physicians could deliver chemotherapy directly to the tumor and the area surrounding it. Since brain tissue is surprisingly porous, they could bathe the affected tissue with a therapeutic agent that would serve to destroy or neutralize the cancerous cells.

“This line of work has taken on a life of its own here and at other institutions over the past few years, following the appearance of promising new agents, one of which is now undergoing phase III trials,” notes Gillies. “Now that there are agents that people believe will be effective, more than ever there’s a strong incentive to create an effective delivery mechanism.”

Building a new catheter

Gillies’ and Humphrey’s project builds on research on new catheter designs that Gillies, Broaddus and their colleagues have pursued over the last 20 years. Gillies was instrumental in creating an innovative, double-tube catheter that alleviates one of the main problems in delivering therapeutic agents directly into brain tissue: trapped air. If air is pushed into the brain, it can cause uneven distribution of the agent within the targeted tissues.

Gillies, Broaddus and their colleagues in industry have also

developed a catheter with three microcoils at its tip that should enable it to be guided magnetically to a specific location. In certain versions of this catheter, controlling the temperature of the microcoils is critical to prevent their burning out and damaging adjacent tissue. Gillies turned to Humphrey for his expertise in fluid dynamics to ensure that the microcoils receive an adequate flow of coolant while the catheter is being maneuvered to its target location.

Humphrey’s knowledge of fluid dynamics, heat, and mass transfer is also critical if a protocol for GBM therapy is to be established. “We have to be able to design the catheter to provide a precise flow pattern,” Gillies says. “In order to do this, we have to understand exactly how fluid moves through the brain.”

For most of the preliminary work, they use a surrogate material for brain tissue that is based on agarose gel. It has strikingly similar mechanical properties to the brain, enabling Humphrey to evaluate the flow patterns of a variety of neurocatheters. “One advantage of agarose gel is that it is translucent,” Humphrey explains. “You can see the flow pattern when you use a dye. This makes it relatively straightforward, for instance, to measure flow and mass transfer patterns as a function of time and space.”

The physical model also enables Humphrey to validate the code for the computer models he has constructed with his graduate student, Josh Smith. “This is complex but essential work if we are to deliver therapeutic agents with precision,” Humphrey says. “We are using new calculation techniques, genetic algorithms, and in-house code that we’ve developed to optimize catheter design.”

Collaboration in progress

Gillies’ and Humphrey’s effort to develop a new method of drug delivery epitomizes the

interdisciplinary and highly collaborative nature of much groundbreaking work in engineering and the medical sciences. Gillies and Humphrey themselves hold joint appointments. Gillies is a member of the biomedical engineering and the mechanical and aerospace engineering departments at U.Va., and the Department of Neurosurgery at VCU. Humphrey, who chairs mechanical and aerospace engineering, also has an appointment in biology at U.Va.

Their work is being advanced by contributions from researchers at a series of academic and private institutions. They include several colleagues of Broaddus at VCU, faculty members from the University of Minnesota, the University of Toronto and the University of California at Davis, and scientists from NexGen Medical Systems Inc. and elsewhere in industry.

The project also has attracted significant student participation. Over 20 undergraduates have completed senior theses on issues related to catheters, and Gillies and Humphrey both have supported graduate students to assist with the research. “This experience produces students with a very unique set of skills,” Humphrey points out. “They are people who can solve mechanical problems and think in biological and clinical terms.”

While treating GBM is currently an important motivator of their research, the catheter designs they develop may also permit the delivery of cell therapies and gene vectors for neurodegenerative diseases such as Parkinson’s and Alzheimer’s, as well as the treatment of diabetic lesions elsewhere in the body. “In essence, we’re working to expand the options available to interventional radiologists, vascular surgeons and neurosurgeons,” Gillies says. “And in the process, we hope to save lives.”

The research seeks to optimize the flow patterns inside perfusion sleeve catheters, a general type of which is shown here in a cross-sectional view. The purple regions represent a clotted thrombus on the inside wall of the blood vessel. The catheter is inserted into the blood vessel and the tip is extended a short distance past the thrombus. A balloon is inflated outward from the catheter wall, forming a loose seal against the thrombus, thus blocking the flow of blood past it. However, internal channels within the catheter allow the bloodstream (red arrows) to bypass the blocked area and then re-emerge from the catheter near the tip. This keeps tissues downstream from the thrombus oxygenated. Meanwhile, a separate set of internal channels allows a therapeutic agent (blue arrows) to flow through the catheter and exit directly onto the thrombus, bathing it fully and accelerating its break-up. The work now under way seeks to use sophisticated fluid dynamical analysis and experiments to model the flows and thereby give biomedical engineers new tools for designing these types of perfusion sleeve catheters.