Regenerative
medicine researchers at Wake Forest
Baptist Medical Center have addressed a major challenge in the quest to build
replacement kidneys in the lab. Working with human-sized pig kidneys, the scientists
developed the most successful method to date to keep blood vessels in the new
organs open and flowing with blood. The work is reported in journal Technology.
“Until now, lab-built kidneys have been rodent-sized and have functioned for
only one or two hours after transplantation because blood clots developed,”
said Anthony Atala, M.D., director and professor at the Wake Forest Institute for Regenerative Medicine
and a senior author on the study. “In our
proof-of-concept study, the vessels in a human-sized pig kidney remained open during
a four-hour testing period. We are now conducting a longer-term study to determine
how long flow can be maintained.”
If proven successful, the new method to more effectively coat the vessels with
cells (endothelial) that keep blood flowing smoothly, could potentially be
applied to other complex organs that scientists are working to engineer, including
the liver and pancreas.
The current research is part of a long-term project to use pig kidneys to make support
structures known as “scaffolds” that could potentially be used to build replacement
kidneys for human patients with end-stage renal disease. Scientists first remove
all animal cells from the organ – leaving only the organ structure or “skeleton.”
A patient’s own cells would then be placed in the scaffold, making an organ
that the patient theoretically would not reject.
The cell removal process leaves behind an intact network of blood vessels that can
potentially supply the new organ with oxygen. However, scientists working to
repopulate kidney scaffolds with cells have had problems coating the vessels
and severe clotting has generally occurred within a few hours after
transplantation.
The Wake Forest Baptist scientists took a two-pronged approach to address this
problem. First, they evaluated four different methods of introducing new cells
into the main vessels of the kidney scaffold. They found that a combination of infusing
cells with a syringe, followed by a period of pumping cells through the vessels
at increasing flow rates, was most effective.
Next, the research team coated the scaffold’s vessels with an antibody designed
to make them more “sticky” and to bind endothelial cells. Laboratory and
imaging studies -- as well as tests of blood flow in the lab – showed that cell
coverage of the vessels was sufficient to support blood flow through the entire
kidney scaffold.
The final test of the dual-approach was implanting the scaffolds in pigs
weighing 90 to 110 pounds. During a four-hour testing period, the vessels
remained open.
“Our cell seeding method, combined with the antibody, improves the attachment
of cells to the vessel wall and prevents the cells from being detached when blood
flow is initiated,” said In Kap Ko, Ph.D., lead author and instructor in
regenerative medicine at Wake Forest Baptist.
The scientists said a long-term examination is necessary to sufficiently
conclude that blood clotting is prevented when endothelial cells are attached
to the vessels.
The scientists said if the new method is proven successful in the long-term, the
research brings them an important step closer to the day when replacement
kidneys can be built in the lab.
“The results are a promising indicator that it is possible to produce a fully functional
vascular system that can deliver nutrients and oxygen to engineered kidneys, as
well as other engineered organs,” said Ko.
Using pig kidneys as scaffolds for human patients has several advantages,
including that the organs are similar in size and that pig heart valves –
removed of cells – have safety been used in patients for more than three decades.
This study was supported, in part, by Telemedicine and Advanced Technology
Research Center at the U.S. Army Medical Research and Materiel Command.
Co-researchers
were Mehran Abolbashari, M.D., Jennifer Huling, B.S., Cheil Kim, M.D., Ph.D.,
Sayed-Hadi Mirmalek-Sani, Ph.D., Mahmoudreza Moradi, M.D., Giuseppe Orlando,
M.D., John D. Jackson, Ph.D., Tamer Aboushwareb, M.D., Shay Soker, Ph.D., and
Anthony Atala, M.D., all with Wake Forest Baptist.
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Media Relations
Karen Richardson: krchrdsn@wakehealth.edu, 336-716-4453