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Dr. Eppell's Research: An Annotated Bibliography
Zypman, F. R. & Eppell, S. J. (1997). Electrostatic tip-surface interaction in scanning force
microscopy: A convenient expression useful for arbitrary tip and sample geometries. Journal
of Vacuum Science, 15(6), 1853-1860.
Eppell and colleagues describe a method of determining the electric fields surrounding individual
protein molecules using the Atomic Force Microscope. The AFM uses a microscopic "diving
board" called a cantilever with a needle on the end, much like the needle on a old record player.
As the needle moves across the surface, the cantilever bends up and down, and this data is
recorded to produce an image of the surface. Eppell describes here how the interactions between
the needle and the surface can be used to map out the electric fields surrounding large molecules
such as proteins. The electric fields around proteins reveal important information about the way
that the protein molecules attach to one another. This information is essential to the design of new
orthopedic biomaterials (materials used for bone and joint replacement) and a better
understanding of conditions such as osteoarthritis.
Todd, B. A., Eppell, S. J. & Zypman, F. R. (2001). Squeezing out hidden force information
from scanning force microscopes. Applied Physics Letters, 79(12), 1888-1890.
Eppell and colleagues describe some difficulties in attempting to measure the electric fields around
protein molecules. As the needle is brought close to the protein, the needle is repelled and the
cantilever bends upwards. Then, the cantilever suddenly snaps to the surface and sticks there.
This "snap-to-contact" phenomenon occurs within milliseconds, during which all of the information
about the electric fields must be measured. Here, the authors describe how to overcome these
difficulties by making faster, more frequent measurements of the cantilever's position, and using
complicated mathematical techniques. These techniques are necessary to further research on the
nature of the bonds between molecules of collagen protein, which is the primary building block of
many biological tissues such as bone, tendon, cartilage, and skin. Knowledge of collagen's
structure will lead to stronger new biomaterials and diagnostic techniques for conditions such as
osteoporosis.
Todd B. A., Eppell, SJ. (2004). Probing the limits of the Derjaguin approximation with
scanning force microscopy. Langmuir, 20 (12), 4892–4897.
In this article, Dr. Eppell and a colleague from the Case Biomedical Engineering department
measured the attractive forces between an AFM probe and a specialized type of granite. The
primary results of this experiment showed the limitations of a mathematical approximation,
Derjaguin's approximation, at a non-typical boundary. The failures were reduced by replacing the
old approximation technique with a different integration technique. This experiment demonstrated
the limitations of an approximation used in Dr. Eppell's reseach.
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Zypman Niechonski, F. R. & Eppell, S. J. (2000). U.S. Patent No. 6,145,374. Washington,
DC: U.S. Patent and Trademark Office.
This patent received by Eppell and a colleague is for the technique of measuring the electric fields
surrounding a sample molecule (such as a collagen protein) using an Atomic Force Microscope.
The patented technique involves a method of taking frequent samples of the cantilever position
and using mathematical analyses to extract information from the collected data. The patent shows
that Eppell's technique, which is central to his research in developing new orthopedic biomaterials,
is unique and cutting-edge.
Eppell, S. J., Tong, W., Katz, J. L., Kuhn, L. J. & Glimcher, M. J. (2001). Shape and size of
isolated bone mineralites measured using atomic force microscopy. Journal of Orthopaedic
Research, 19(6), 1027-1034.
Bone is primarily composed of collagen and mineral. In this paper, Eppell and colleagues have
measured the shape and size of the mineral components in mature bovine bone tissue. From this
data, the group began to build three-dimensional molecular models of bone tissue. The
advancements made in the research behind this paper is important for two reasons. First, it
illustrates how Eppell's lab has advanced the utility of ATM beyond imaging and toward
quantitative analysis. Secondly, the data from this paper translates directly into practical
application in designing joint replacement implants.
Liu, Z., Smith, B. N., Kahn, H., Bakkarini, R. & Eppell, S. J. (2006). Mechanical Testing of
Hydrated Collagen Nanofibrils Using MEMS Technology. 2006 6th IEEE Conference on
Nanotechnology, IEEE-NANO 2006, 1, 177-180.
Eppell, and colleagues detail a microelectromechanical system (MEMS), a simple machine on the
scale of micrometers, that measures physical properties of microscopic collagen fibers. This
MEMS device allows for individual collagen fibers to be stressed multiple times under different
loadings. The results from these tests lead to the conclusion that collagen fibers would break if
fatigued or stressed in cycles. This is significant, because the data gathered will allow others to
create better models of bones to understand how they fracture and break. This research also
gives bone substitute manufacturers a quantitative value to compare to their new substitutes.
Eppell, S., Smith, B., Kahn, H. & Ballarini, R. (2006). Nano measurements with microdevices: mechanical properties of hydrated collagen fibrils. JOURNAL OF THE ROYAL
SOCIETY INTERFACE, 3(6), 117-121.
Eppell and colleagues designed a MEMS to measure properties of organic fibers on the nanometer
scale. Previous measuring devices for organic materials could only go down to the micrometer.
This however is too large for nanometer sized fibers like collagen. The newly created MEMS
device could test collagen fibers that are on the nanometer scale. The MEMS implementation
described in this article is significant because it is the first time MEMS is used to measure
properties of nanometer scale fibers. The research also proved that MEMS devices are a reliable
way to test nanometer scale fibers which were previously were unable to be tested.
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Graham, J. S., Vomund, A. N., Phillips, C. L. & Grandbois, M. (2004). Structural changes in
human type I collagen fibrils investigated by force spectroscopy. Experimental Cell Research,
299(2), 335-342.
Graham and his colleagues research is the one of the first attempt to get measurements of the
properties of an individual collagen fibers. Before this measurements of the fibers were based on
bone structures that were made up of these fibers. This experiment used AFM to measure a
collagen fiber while it was being subjected to a constant force. However the AFM did not have the
ability make all the measurements that the MEMS device created by Eppell and his colleagues,
mainly the ability to cycle the loads on the fiber. The data gathered in this research is significant
because it shows the same phenomenon that Eppell and his colleagues MEMS device measured.
This gave assurance that the new properties measured with the MEMS device would also be valid.
Shen, Z. L., Dodge, M. R., Kahn, H., Ballarini, R. & Eppell, S. J. (2008). Stress-strain
experiments on individual collagen fibrils. Biophysical Journal, 95(8), 3956-3963.
This paper contains mechanical measurements of the stress-strain curve of type I collagen fibrils.
Analysis of these results suggest that the stress-strain behavior of collagen fibrils is dictated by
global characteristic dimensions as well as internal structure. This data and conclusion is
important to Dr. Eppell's research because knowing the mechanical properties of these tissues will
allow researchers to better gauge the abilities and limitations of such structures.
Katz, J. L., Misra, A., Spencer, P., Wang, Y., Bumrerraj, S., Nomura, T., Eppell, S. J., et
al. (2007). Multiscale mechanics of hierarchical structure/property relationships in calcified
tissues and tissue/material interfaces. Materials Science and Engineering, 27(3), 450-468.
This paper considers both microscopic material properties of calcified tissues (i.e. bone) as well as
of the boundaries that form between such tissues and implanted biomaterials. It combines the sets
of data mathematically in order to take into account the effects of scale while modeling these
tissues and the tissue/biomaterial boundaries. The importance of scale in properly modeling the
mechanical behavior of bone shows the significance of Dr. Eppell’s research on collagen, a
microscopic component of bone. The importance of understanding the components of bone in
order to understand the mechanical properties of bone and make effective synthetic bone material
with similar properties is one aspect driving Dr. Eppell’s research.
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Eppell, S., Longsworth, J., Tong, W., McMasters, J., Chooi, W-T., & Baskin, J. (2007).
Nanophase load Bearing Bone Substitute Material Designed for the Osteoclast. Microscopy
andMicroanalysis, 13(Suppl. 02), 42-43.
This short article authored by Dr. Eppell is an extended abstract of a paper presented at
Microscopy and Microanalysis 2007 in Ft. Lauderdale, Florida, USA, August 5 – August 9, 2007. It
details his goal of designing resorbable synthetic bone material that can be implanted and then
resorbed via the healthy processes involved in natural bone remodeling. Osteoclasts, the cells
responsible for resorbing bone during remodeling, will need to respond to the synthetic bone in the
same way they respond to normal bone. A goal of Eppell’s research, according to this article, is to
synthetically reproduce the extracellular matrix of bone so that osteoclasts will respond properly to
this implanted matrix.
Tong, W. & Eppell, S. J. (2002). Control of surface mineralization using collagen fibrils. J.
Biomed Mater Res, 61(3), 346-353.
A major problem with joint replacement implants is maintaining the interface between the bone and
implant surfaces. After implantation, it is necessary for the bone to grow on the material surface, or
else the implant will fail and will require further surgery. Implants are given mineral covering to
induce bone cells to grow after implantation. The shape and pattern of surface mineralization is
important in facilitating bone growth. Eppell and his colleagues used collagen fibers to control the
pattern of mineralization, and have shown that this process is more effective because it mimics
natural physiological processes. Surface mineralization using collagen fiber can reduce the rate of
device failure in clinical application.
Gosh, P. K., Vasanji, A., Murugesan, G., Eppell, S. J., Graham, L. M. & Fox, P. L. (2002).
Membrane microviscosity regulates endothelial cell motility. Nature Cell Biology, 4, 894-900.
Endothelial cells comprise the thin layer of cells that line blood vessels. This article shows that
certain proteins and molecules can alter an endothelial cell’s motility, or active movement, by
changing the surface properties of the cell and hence the signaling between cell surfaces.
Endothelial cell motility is crucial to wound healing in blood vessels. This past research of Eppell’s
is relevant to his current research because of the wound healing application that could arise from a
better understanding of the collagen molecule, which the body lays down in order to form scars
and mend damage. A better understanding of the signaling between collagen fibers and the
nerves that need to grow through the scar tissue in order to properly heal the patient, a signaling
akin to the signaling that occurs in endothelial cells, could result in treatments that can enhance
the functionality of scar tissue as a result of more effective wound healing.
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Marchant R. E., Barb M. D., Shainoff J. R., Eppell S. J., Wilson D. L., Siedlecki C. A. (1997)
Three dimensional structure of human fibrinogen under aqueous conditions visualized by
atomic force microscopy. Thromb Haemost, 77(6), Pg. 1048-51.
The research done for this article is about fibrogen, which is used to make up a protein called fibrin
that is involved in blood clotting. The protein's interactions with different layers are incompletely
understood by the medical community because it is difficult to image them under aqueous
conditions. In this article the researchers use a technique similar to Eppell's involving AFM to
generate three-dimensional molecular-scale images. These results show the importance of
hydration on protein structure and properties that affect surface-dependent interactions.
Park, P. S. & Palczewski, K. (2005). Imaging G protein–coupled receptor islands. Nature
Chemical Biology, 1(4), 184-185.
A new frontier in biological imaging is Near-field Scanning Optical Microscopy (NSOM), where
individual cell surface proteins may be imaged in real time. In this article, a group successfully
imaged the arrangement and interactions among cell surface proteins. Such protein interaction has
not been viewed until the cutting-edge NSOM technique had been developed. Dr. Eppell's
manages an NSOM facilty in Case's BME department, which has been severely underutilized due
to a lack of funding for personel. He plans to use this facility imaging of bone cells surface
receptors. A better understanding of the biomolecular interactions of bone cells will help in making
smarter designs for implant surfaces to facilitate bone growth. The NSOM facility may be used to
study numerous types of cells in other areas of research.