Team designs computer model to
predict pathways of blood vessels
Model may have applications for treatment of
heart disease, diabetes and cancer
by Andrew Shurtleff
Skalak, professor and chairman of biomedical engineering (left),
and research associate Shayn Peirce are two members of the
U.Va. research team that developed a complex computer model
for accurately predicting how and where new blood vessels
will form. Their findings were published Feb. 6 in FASEB,
the journal of the Federation of American Societies for Experimental
team of U.Va. researchers has developed a complex computer model
that can accurately predict how and where new blood vessels will
form in response to two different stimuli: changes in blood pressure
and the delivery of a growth protein.
Their results — believed to be the first in the emerging
field of systems biology — hold promise for future developments
in the treatment of chronic heart disease and diabetes through
angiogenesis, or the growth of new blood vessels. The results
also could be used in the development of treatments for cancer
that involve shutting off the blood supply to cancerous tissue.
Their method — using a complex, quantitative, predictive
model — also has the potential to speed up the development
of new medical treatments and should be of interest to the pharmaceutical
and medical-device industries.
“Large pharmaceutical companies are investing heavily in
computational systems biology, and our study indicates they are
on the right track,” said Thomas C. Skalak, professor of
biomedical engineering and principal investigator. “Quantitative
biology holds the key to the medical discoveries of the future.”
The U.Va. team’s findings will be released Feb. 6 in the
online edition of FASEB Journal, published for the Federation
of American Societies for Experimental Biology, at www.faseb.org.
An illustration of their work will appear on the cover of the
journal’s print edition in April.
“To our knowledge, this is the first time that a computer
model of a complex biological system has accurately predicted
how a network of new blood vessels will grow in response to specific
stimuli,” Skalak said. “Experimental observation verified
our in silico results.”
Skalak, past president of the Biomedical Engineering Society,
and U.Va. research scientists Shayn M. Peirce and Eric J. Van
Giesen conducted the computational bioengineering research and
co-authored the FASEB Journal article.
The U.Va. researchers set out to answer two questions: 1) How
are blood vessels assembled on a cell-by-cell basis in mammals?
and 2) How do the responses of individual cells to environmental
stress or injury affect the construction of single blood vessels
and networks of blood vessels? Their goal was to better understand
how a living, multicellular system grows and adapts to various
stimuli and, ultimately, to be able to engineer vascular tissue
systems by harnessing natural mechanisms.
The research team built on the work of Hungarian-born mathematician
John Louis von Neumann, borrowing his “Cellular Automaton”
theory, and used Uri Wilensky’s NetLogo simulation software,
developed at Northwestern University’s Center for Connected
Learning and Computer-Based Modeling, to build a complex computer
model that mimics blood-vessel growth in mammals.
They also drew on 50 rules of cellular behavior published by other
researchers for elements of their model. But no one had pulled
all the pieces together in the same way to answer those questions.
The U.Va. researchers created a complex, “multicellular
simulation” in mammalian tissue, integrating data from thousands
of individual cells, including the endothelial cells and smooth-muscle
cells needed to build the blood-vessel walls. Among the 50 factors
the model considers for each cell as it interacts with other cells
are varied rates of cellular growth and cellular migration in
space and over time. The model also takes into account the dynamic
environment of the surrounding tissue, which influences the pace
and direction of blood-vessel construction.
The researchers’ model predicted that an increase in blood
pressure would stimulate cells to build blood vessels with a larger
diameter, increasing the delivery of oxygen through an expanded
blood flow; and that the delivery of a growth protein would stimulate
cells to build longer blood vessels, extending the reach of the
blood flow through an expanded network of blood vessels.
This research into microvascular remodeling has multiple applications
in the fields of tissue engineering, developmental biology and
reparative medicine, according to Skalak. In particular, the results
may contribute to the development of processes to help the body
heal itself after heart disease or traumatic injury, or help with
the creation of in vitro systems to grow new tissue to replace
that lost to injury or disease.
In addition, the U.Va. team is investigating the impact of other
stimuli on blood vessel growth, on vascular cells and on matrix
proteins, which are involved in cellular and tissue cohesion.
The U.Va. research is funded in part by the National Institutes
of Health and by the Whitaker Foundation, a private, nonprofit
foundation based in Rosslyn, which is dedicated to improving human
health through support for biomedical engineering.