MILESTONE REACHED IN WORK TO BUILD REPLACEMENT KIDNEY IN THE LAB.
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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