NEW TECHNOLOGY MAKINGS TISSUES , SOMEDAY MAY ORGANS
A new instrument could
someday build replacement human organs the way electronics are assembled today:
with precise picking and placing of parts.
In this case, the
parts are not resistors and capacitors, but 3-D microtissues containing
thousands to millions of living cells that need a constant stream of fluid to
bring them nutrients and to remove waste. The new device is called 'BioP3' for
pick, place, and perfuse. A team of researchers led by Jeffrey Morgan, a Brown
University bioengineer, and Dr. Andrew Blakely, a surgery fellow at Rhode
Island Hospital and the Warren Alpert Medical School, introduces BioP3 in a new
paper in the journal Tissue Engineering Part C.
Because it allows
assembly of larger structures from small living microtissue components, Morgan
said, future versions of BioP3 may finally make possible the manufacture of
whole organs such as livers, pancreases, or kidneys.
"For us it's
exciting because it's a new approach to building tissues, potentially organs,
layer by layer with large, complex living parts," said Morgan, professor
of molecular pharmacology, physiology and bBiotechnology. "In contrast to
3-D bioprinting that prints one small drop at a time, our approach is much
faster because it uses pre-assembled living building parts with functional
shapes and a thousand times more cells per part."
Morgan's research has
long focused on making individual microtissues in various shapes such as
spheres, long rods, donut rings and honeycomb slabs. He uses a novel
micromolding technique to direct the cells to self-assemble and form these
complex shapes. He is a founder of the Providence startup company MicroTissues
Inc., which sells such culture-making technology.
Now, the new paper
shows, there is a device to build even bigger tissues by combining those living
components.
"This project was
particularly interesting to me since it is a novel approach to large-scale
tissue engineering that hasn't been previously described," Blakely said.
The BioP3 prototype
The BioP3, made mostly
from parts available at Home Depot for less than $200, seems at first glance to
be a small, clear plastic box with two chambers: one side for storing the living
building parts and one side where a larger structure can be built with them.
It's what rests just above the box that really matters: a nozzle connected to
some tubes and a microscope-like stage that allows an operator using knobs to
precisely move it up, down, left, right, out and in.
The plumbing in those
tubes allows a peristaltic pump to create fluid suction through the nozzle's
finely perforated membrane. That suction allows the nozzle to pick up, carry
and release the living microtissues without doing any damage to them, as shown
in the paper.
Once a living
component has been picked, the operator can then move the head from the picking
side to the placing side to deposit it precisely. In the paper, the team shows
several different structures Blakely made including a stack of 16 donut rings
and a stack of four honeycombs. Because these are living components, the
stacked microtissues naturally fuse with each other to form a cohesive whole
after a short time.
Because each honeycomb
slab had about 250,000 cells, the stack of four achieved a proof-of-concept,
million-cell structure more than 2 millimeters thick.
That's not nearly
enough cells to make an organ such as a liver (an adult's has about 100 billion
cells), Morgan said, but the stack did have a density of cells consistent with
that of human organs. In 2011, Morgan's lab reported that it could make
honeycomb slabs 2 centimeters wide, with 6 million cells each. Complex stacks
with many more cells are certainly attainable, Morgan said.
If properly nurtured,
stacks of these larger structures could hypothetically continue to grow, Morgan
said. That's why the BioP3 keeps a steady flow of nutrient fluid through the
holes of the honeycomb slabs to perfuse nutrients and remove waste. So far, the
researchers have shown that stacks survive for days.
In the paper the team
made structures with a variety of cell types including H35 liver cells, KGN
ovarian cells, and even MCF-7 breast cancer cells (building large tumors could
have applications for testing of chemotherapeutic drugs or radiation
treatments). Different cell types can also be combined in the microtissue
building parts. In 2010, for example, Morgan collaborated on the creation of an
artificial human ovary unifying three cell types into a single tissue.
Improvements underway
Because version 1.0 of
the BioP3 is manually operated, it took Blakely about 60 minutes to stack the
16 donut rings around a thin post, but he and Morgan have no intention of
keeping it that way.
In September, Morgan
received a $1.4-million, three-year grant from the National Science Foundation
in part to make major improvements, including automating the movement of the
nozzle to speed up production.
"Since we now
have the NSF grant, the Bio-P3 will be able to be automated and updated into a
complete, independent system to precisely assemble large-scale, high-density
tissues," Blakely said.
In addition, the grant
will fund more research into living building parts -- how large they can be
made and how they will behave in the device over longer periods of time. Those
studies include how their shape will evolve and how they function as a stack.
"We are just at
the beginning of understanding what kinds of living parts we can make and how
they can be used to design vascular networks within the structures,"
Morgan said. "Building an organ is a grand challenge of biomedical
engineering. This is a significant step in that direction."
Brown has sought a
patent on the BioP3.
In addition to Blakely
and Morgan, the paper's other authors are biology graduate student Kali Manning
and Anubhav Tripathi, profesor of engineering, who co-directs Brown's Center
for Biomedical Engineering with Morgan.
The National
Institutes of Health (grant T32 GM065085-09) and the NSF (grant CBET-1428092)
have supported the research.
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