with reference to structure and function - from its
microscopic crystalline structure to its biological activity.
that closely resembles the
structure of bones and is populated by bone cells, endothelial cells, and nerve
cells that are capable of self-organization into functional components of bone
new 'bone in a dish' technology is being used to closely study various disease
processes, including the initiation and progression of bone cancer
, as well as for developing therapies for bone injury.
"What is remarkable is that researchers in
our field have become used to cultivating cells within a protein mixture to
approximate how cells live in the body. But this is the first time anyone has
been able to embed cells in minerals, which is what characterizes the bone
said Dr. Luiz E. Bertassoni, who led the study.
The study has been published in Nature Communications
, a constituent
journal of the Nature Publishing Group.
The study was led by Dr. Luiz E. Bertassoni,
DDS, PhD, who is an Associate Professor at the Oregon Health & Science
University (OHSU) in Portland, Oregon, USA. He holds joint appointments at the Department of
Restorative Dentistry, the OHSU Center for Regenerative Medicine, Department of Biomedical Engineering and the Cancer Early Detection Advanced Research Center
(CEDAR) at the Knight Cancer
Other team members included Dr. Greeshma Thrivikraman Nair, PhD, who is a postdoctoral fellow at the
OHSU School of Dentistry and Avathamsa Athirasala, BTech, MS, who is a PhD student in Bertassoni's
How was the 'Bone in a Dish' Constructed?
The new technology, which resembles a
miniaturized 'bone in a dish,' requires just 72 hours for preparing and
becoming functional. It was constructed by mixing human stem cells with a solution of collagen
- a common protein available abundantly, which
is an essential component of bone tissue matrix. The collagen proteins become
linked together, forming a gel, consisting of a mesh-like network in which the
stem cells become embedded. This gel containing embedded stem cells was then
exposed to a solution containing dissolved calcium and phosphate, which are
essential minerals present in bone.
Another essential component of this mixture
was osteopontin, which is a phosphorylated sialic acid-rich non-collagenous protein
present in bone matrix. Osteopontin slows down the process of crystal
by binding to the calcium and phosphate molecules. This binding
also reduces cellular toxicity caused by these minerals. The whole mixture
percolates through the spongy collagen matrix and the minerals gradually form
ordered layers of crystals that resemble actual bone.
"We can reproduce the architecture of bone
down to a nanometer scale,"
says Bertassoni. "Our model goes through the same biophysical process of formation that
How was the 'Bone in a Dish' Technology Used to Study Disease Models?
The stem cells embedded within the
mineralized collagen matrix developed into fully functional bone cells,
osteoblasts and osteocytes, without the need for any additional nutrients or
growth factors. Subsequently, these cells developed the capacity to connect and
communicate with neighboring cells. Thus, the artificially engineered bone-like
structure provided a microenvironment similar to that present in actual bone,
which was ideal for the growth and differentiation of the stem cells into bone
cells. This microenvironment also allowed nerve cells and endothelial cells to
thrive and develop interconnected networks within the mineralized structure.
The engineered bone was evaluated in vivo
in a mouse model of prostate cancer.
The mineralized structure was
implanted beneath the skin of mice and in due course, blood vessels developed
from the embedded stem cells, which interconnected with the natural blood
vasculature of the mice. Upon injection of prostate cancer cells within the
vicinity of the mineralized bone implant, it was observed that the tumor growth
was three times higher than in control mice that didn't have the mineralized
What are the Potential Applications of the 'Bone in a Dish' Technology?
The major application of the new technology
will be in the area of disease modeling. For example, this technology will be
ideal for closely studying bone function, bone regeneration, as well as various
aspects of cancer such as initiation, growth, and metastasis. In fact, this
novel technology could potentially transform the field of Regenerative Medicine
by replacing the need for autologous bone transplants,
currently used to regenerate injured bone.
The research team is planning to engineer a
new variant of the mineralized artificial bone with embedded bone marrow cells
to study various aspects of leukemia
, such as initiation, development and
metastasis. Moreover, they are in the process of testing the artificially
engineered bone as a replacement for damaged bone in animal models.
The research was funded by the National Institute of
Dental and Craniofacial Research of the National Institutes of Health (NIH),
the American Academy of Implant Dentistry Foundation, the OHSU-PSU
Collaboration Project Seed Funding, the OHSU Knight Cancer Institute,
the Pacific Northwest National Laboratory (PNNL) under the US Department
of Energy (DOE), and the National Science Foundation, USA.