Krystyn Van Vliet - Faculty highlight Krystyn Van Vliet
MIT associate professor brings a materials scientist's understanding to biochemical behavior in stem cells and organ tissue.
Denis Paiste | Materials Processing Center
March 18, 2015
With joint appointments in the departments of Materials Science and Engineering and Biological Engineering,
MIT Associate Professor Krystyn J. Van Vliet brings a
materials scientist's understanding of mechanical triggers for
biochemical behavior. Although her group studies many non-biological
materials that also show this coupling between chemistry and mechanics,
biological cells and tissues are especially complex. She studies stem
cells from the central nervous system and from bone marrow, as well as
tissues from the brain, heart, and liver.
In recent work, Van Vliet's group has shown that three biophysical
markers — size, mechanical stiffness, and how much the nucleus inside
the cell moves around — can accurately identify stem cells in a mixed
group of cells; engineered polymers that can mimic the response of human
tissue to high rates of loading; and established that measurements of
cell fluidity, a mechanical property that ranges from 0 to 1, can detect
cell responses to different chemical triggers such as salinity or
physical triggers such as temperature.
Stem cells hold promise for a procedure known as cellular therapy, in
which a person's own stem cells can fight disease or repair tissue
damage — regrowing bone, for example. Alternatively, the cells can be
used as factories to produce key chemicals that are collected to act as
the medicine. The challenge, Van Vliet says, is that stem cells
naturally occur in small numbers in our bodies. "Roughly 1 in 100,000 of
the cells that are in our bone marrow are actually the bone
marrow-derived stem cells," she explains. "The rest are other cell
types; so it's called a rare cell type."
Although a stem cell line can be grown, or expanded, in the lab from
100 cells to a million cells, a common problem is that over time the
cells change properties. "Instead of them all being stem cells, after
several generations of growing in the lab, some of them are stem cells,
but many of them are not. So if you want to use them for human therapy,
how do you sort out the cells that are still stem cells? You want to do
that in a way that you don't have to, ideally, touch the cells or put
any other proteins or particles on them to enable the separation. So we
sought a method of what's called 'label-free sorting,'" Van Vliet says.
Separating stem cells
In a 2014 paper, Van
Vliet and colleagues demonstrated that sought-after bone marrow stem
cells could be separated from a large group of cells using a
spiral-shaped inertial microfluidic device and sorted by function based
on a combination of three identifying characteristics: small cell
diameter, low cell stiffness and high nuclear-membrane fluctuations. "We
measured those three properties as well as several other properties,
but only those three properties together, that triplet of properties,
distinguished a stem cell from a non-stem cell," Van Vliet explains.
"We don't have to label the cells, we don't have to put any particles
on them, or any fluorescent antibodies on them. Just on the basis of
these three physical and mechanical properties, we can say, this
fraction of cells grown in the lab are still the stem cells, that you
can put back in a human," Van Vliet adds. The study used human cells but
tested them in mice.
MIT biological engineering graduate student Frances Liu is
continuing stem cell research through the Singapore-MIT Alliance for
Research and Technology (SMART) BioSystems and Micro-mechanics (BioSyM)
group, of which Van Vliet is lead principal investigator. While the Van
Vliet group's expertise is in mechanical characterization of cells,
SMART colleague and fellow MIT Professor Jongyoon Han provided
his expertise in microfluidics. "We put those two approaches together
and developed this approach," Van Vliet explains.
"Even though we now can separate the cells into different categories,
there's so much we don't how know about them in terms of how are they
different, why are they different, what happens when you put them back
in the body? What happens if you expose them to different environments
in the lab in terms of what chemicals they produce, what functions they
take on," Van Vliet says. "All of that work needs to be figured out in
order to find material environments where you can expand these cells to
large number without accidentally or inadvertently changing their
biological properties. And that's part of what Frances is working on."
Based on their findings with the bone marrow stem cells —
specifically, cells called mesenchymal stromal cells — clinical trials
are underway in Singapore at various hospitals. "We have pending
clinical trials to use these subsets of cells that we've isolated on the
basis of their biophysical markers for specific repair processes to
affect different diseases," Van Vliet says. Research scientist Zhiyong
Poon, a member of the team who lives in Singapore, is taking the lead on
using the Van Vliet group's engineering approaches to advance the
clinical trial goals.
"It's exciting. This project took five years to make sure we fully
understood the system and could really engineer the separation of the
cells, but it is very gratifying to see that it's already moving toward
clinical trials," Van Vliet says. "These are engineers, like myself,
learning how to interact with clinicians and help design studies that
make this useful, including needing to redesign, for example, the
instruments you're using, so they can be used for human trials. It's not
a quick progression of the ideas in the lab to the ideas in the clinic,
but we've made good progress."
Mechanically stimulating cell functions
Another study led by research scientist Anna Jagielska focused on
stem cells from the central nervous system. "The stem cells that Anna
studied are also very sensitive to their environment and to their
mechanical cues and their chemical cues, but their goal when they
differentiate is to produce myelin, this protein that insulates your
neurons so that your nervous system works correctly. There we have a
disease context, where there are several conditions such as multiple
sclerosis in which the stem cells fail to differentiate and take on the
correct functions," Van Vliet explains. "We're trying to understand what
are the mechanical cues and the chemical cues that retard that
differentiation or inhibit that differentiation, and then how could we
engineer the environment so that the cells do what we want, which is to
properly insulate the axons (nerve fibers). There are many different
stem cell types in the body in adults or in neo-natal animals, and so
they all have different possible functions."
Jagielska was lead author of a paper with
colleagues from the University of Cambridge in England and the Dresden
University of Technology in Germany. "Since we discovered and showed for
the first time that these central nervous system stem cells were
mechanosensitive, it's going to be a few years before we translate this
understanding to clinical applications," Van Vliet says. "But we're
making very rapid progress in growing this interdisciplinary team, and
Anna has done a great job with that."
Polymers as tissue simulants
Another area of research the Van Vliet group is pursuing is
developing polymer-based materials that mimic human tissue for use as
experimental substitutes for tissue from the brain, heart, and liver.
MIT biological engineering graduate student Bo Qing is
studying brain tissue from mice and rats to establish the necessary
properties for synthetic material and then designing and testing
synthetic materials. The work is supported by the U.S. Army Research
Lab, which developed some of the materials considered, through the
Institute for Soldier Nanotechnologies.
"If we're going to develop either computational models or
experimental models of how the brain responds to high rates of
mechanical loading in an accident or a blast wave or a bullet, you need
to develop materials that will not degrade, be stable under lab
conditions, but also mechanically recapitulate the impact response of
the brain tissue," Van Vliet explains. Qing conducts a special type of
indentation tests on the tissues and the engineered polymer gels.
"Surprisingly, there are not much data out there on the response of the
brain tissue to the kinds of experiments we do, which is called impact
indentation. ... Bo is generating some of the first data on the brain
tissue for these length scales and deformation rates, and then using the
same experiments to understand how engineered materials dissipate
Qing is working with polydimethylsiloxane-based (PDMS) gels, which
are stretchy and transparent. "It's a polymer for which we can easily
control properties such as its stiffness by just varying the
crosslinker-to-base ratio that we had when we make these polymers," Qing
says. "We can tune the composition of the materials that we build into
the final system, in order to tune the energy dissipation properties
upon impact. Understanding the tunability of the engineered polymers
allows us also to simulate the properties of specific biological
A May 2013 paper examined
indentation impacts on rodent heart and liver tissue and compared
cross-linked PDMS gels for their ability to mimic the response of
natural tissue. It identified specific gel compositions that closely
matched the impact response of heart tissue.
"We could make a very, very complicated material that looked just
like brain tissue, had multiple layers to it, white and gray matter, but
that's not really the point," Van Vliet explains. "The point is to make
as simple a material as you can to mimic the mechanical behavior of
interest so that you can then manufacture a lot of it at scale."
Moving from the lab to the market, manufacturing any material at an
industrial scale can present several challenges. To address this issue
for a specific set of so-called "critical" materials, Van Vliet is
collaborating with Elsa A. Olivetti, the Thomas Lord Assistant Professor
of Materials Science and Engineering, and the MIT Portugal Program.
They are studying how best to recover discarded electronic devices and
track their critical materials content. MIT graduate student Patrick
Ford of the Engineering Systems Division and Department of Materials
Science and Engineering is co-advised by Olivetti and Van Vliet, and is
leading that work in Van Vliet's Laboratory for Material Chemomechanics this semester.
"It's a very neat opportunity for a case study on how materials are
used in a particular technology we all use, and how those materials
might be used or recovered differently in the future," Van Vliet
says. "This builds on Elsa's expertise in technical and economic aspects
of materials recycling, and my interest in the global supply chains for
some of the materials we use in today's most advanced technologies."
"Portugal is a smaller, more homogeneous country than the U.S., and
also follows E.U. and national targets for material recovery, so you can
look at how they handle recycling of electronic devices with a very
high level of specificity," Van Vliet adds. "We're taking apart those
electronic devices such as smartphones here at MIT, characterizing the
material in them and understanding how they make it through the supply
chain in Portugal. A lot of the work we are doing is to develop
materials or technologies that eventually you want to see adopted in
industry and scaled up. Most of the time when engineers design new
materials or new devices, they don't think much about where the
materials come from in the world or how they're processed in order to
reach their lab, but that becomes a problem when you start to produce
any device at scale."
Many renewable energy technologies, such as solar cells or electric
and hybrid car batteries, rely on key materials that are not stable in
either their supply or their availability to manufacturers. When key
supplies become disrupted, those materials become "critical." That puts
the burden on engineers to give more consideration to sourcing issues.
"If you need a particular material that has very special properties,
which is often the case in most of my lab-scale research and
development, can you design the device so you can get that material out
afterwards and reuse it, if not for that application, then for other
applications?" Van Vliet asks. "It's a challenging problem. It's one
that we're very interested in from both a technical point of view as
well as a policy point of view."