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Fall 2007

New Surgery Program Explores Bioengineering

Surgeons are adept at finding clever ways to reconstruct diseased tissue, but there are limits to what they can do. For the past 20 years, bioengineers and clinicians have been experimenting with the production of surrogate tissues to replace those that cannot be surgically repaired.

UCSF is moving a step closer to realizing that ambition with the addition of biochemist Valerie Weaver, Ph.D., to the UCSF Department of Surgery faculty. Weaver will direct a new laboratory within the department, the Center for Bioengineering and Tissue Regeneration, that will meld the individual talents of researchers at UCSF and surrounding institutions such as UC Berkeley and Lawrence Berkeley National Laboratory (LBNL). By drawing on the expertise of chemical, mechanical and biomedical engineers; developmental and cellular biologists; biochemists; and stem cell experts, Weaver and her colleagues hope to catalyze a wave of translational research.

Surgeons constantly bump up against the limitations of current tissue engineering, according to Weaver. Veins stripped from a leg for use in coronary bypass surgery, for example, quickly become damaged from the force of blood pumping through vessels that, in the leg, do not have to withstand such pressures.

"We're still novices at trying to reconstruct tissues," said Weaver, who previously served on the faculty of the University of Pennsylvania Institute for Medicine and Engineering and completed postdoctoral fellowships at LBNL and the Institute for Biological Sciences of the National Research Council of Canada in Ottawa.

"Too often the field has underestimated basic cell biological problems," said Weaver. "We can make something that looks like a duck, walks like a duck, but isn't a duck."

Weaver sees UCSF, with its history of groundbreaking work in cellular and developmental biology, as especially fertile ground for the new center. She envisions close collaborations with the UCSF Biomedical Engineering Group under Sara Nelson, Ph.D., and the Department of Cell and Tissue Biology program headed by Susan Fisher, Ph.D. UC Berkeley experts in nanotechnology will also work with the center.

Weaver's 12-person laboratory will make its core research facilities available to other investigators on the UCSF campus. The equipment will include a traction force microscope and rheometers that measure the physical properties of tissue, an atomic force microscope for mapping physical cell and tissue stiffness on the nanoscale, and two- and three-dimensional (2-D and 3-D) bioreactors for exerting controlled mechanical forces of precise duration and magnitudes. Weaver will mentor residents and junior faculty from other departments who want to learn to use the equipment and will advise them on their projects.

Weaver's own area of expertise lies in culturing cells in three-dimensional structures. She focuses on the molecular basis for how tissue organization regulates cell differentiation. "Somehow, the structure of a tissue and its surrounding extracellular matrix informs the cell what to do," said Weaver. Increasingly scientists are realizing that differentiation involves a complex interplay between the physical and chemical organization of the surrounding matrix of tissue. Within this extracellular matrix, forces are sensed and exerted.

Tumor cells, for example, don't just reproduce quickly, they lose their normal cell and tissue organization. Weaver and her colleagues have conducted experiments that explore why tumors and other diseased tissues often become stiff. When a breast tumor is palpated, explained Weaver, what is felt are not just the tumor cells, but the extracellular structure (stroma) surrounding them. This stiffness is probably due to molecular changes in the extracellular matrix as well as infiltrating fluid. Recent animal studies conducted by a postdoctoral fellow and graduate student working with Weaver at the University of Pennsylvania demonstrated a particularly intriguing preliminary finding: increasing matrix stiffness promoted malignant transformation of the breast, while inhibiting the stiffness of the stroma significantly inhibited tumor formation.

This work has implications for many other diseases, according to Weaver. A fibrotic liver may be losing the differentiated function of its cells specifically because of the stiffening of the surrounding tissues. Spinal cord regeneration is another area where complex intracellular signals can influence cell function. Researchers now know that spinal cord nerves can regenerate after injury; the problem is making sure that the surrounding tissues provide a proper "welcome mat," letting the nerve cells know that the environment is hospitable. If the surrounding environment is not right, nerves do not regenerate. It is possible that those positive signals could be provided by applying a biomedical material to the injured site.

Another handicap to tissue regeneration is the medium in which materials are typically tested, said Weaver. Usually the culture is two-dimensional, but in the body, the tissue must survive in a three-dimensional matrix that involves different sets of forces. According to Weaver, attempts to regenerate bone cells have been more successful when conducted by seeding a three-dimensional scaffold with osteocytes. It is likely that other cells, such as those that form heart valves, blood vessels and cartilage, could be more successfully grown in a three-dimensional environment that more closely resembles the one the cells will occupy within the human body. Defined, three-dimensional systems could also be used to encourage stem cells to propagate along specific lineages. The center is also investigating new biomaterials for use in the surgical environment.

Ongoing collaborations include work with Jennifer Leach of the University of Maryland and Joyce Wong of Boston University on recombinant protein biogels and a collaboration with David Kaplan of Tufts University on the use of purified and recombinant silks—a form of protein already used in the surgical environment.

For more information, please contact Valerie Weaver, Ph.D., at weaverv@surgery.ucsf.edu or (415) 476-3826.

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