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Joshua Moskowitz Chemical
Engineering Grad Student
B.S. in
Materials Science and
Engineering, Cornell University '07
Hometown: Nashua, NH |
Engineering a layer-by-layer (LbL) film for the extended release of
antibiotics
The Technology:
My research involves the economic, scalable, and efficient
technology of layer-by-layer (LBL) deposition. Specifically, I am
interested in using electrostatics to build films with alternating
polyanionic and polycationic species. The films will be functionalized
by incorporating both gentamicin—a small, hydrophilic antibiotic—and a
unique breed of polycations known as poly(β-amino esters). The latter
are polymers that are relatively stable in the solid-state, but undergo
rapid hydrolytic degradation upon contact with physiological environment
(i.e. in vivo). The films are engineered to erode in top-down fashion
such that the elution of contained drug can be precisely tuned.
Ultimately, this work with antibiotics will be coupled to similar
systems incorporating proteins and analgesics in order to achieve a
complex, sequential, and hence “smart” release profile of the film
contents.
The Application:
As the baby boomer generation begins to increase the demand for
orthopedic implants, our technology can find excellent use in the near
future. Rough numbers for infection rates in total knee arthroplasty and
total hip arthroplasty are about 1 in 200 for primary surgeries and grow
to 10% for first revisions. Second revisions increase even more
drastically. Through my conversations with orthopedic surgeons Dr. Mitch
Harris and Dr. Scott Martin (Brigham and Women’s Hospital), there would
be a major market for these films on all revision arthroplasties as well
as primary arthroplasties in high risk cases (e.g. patient is diabetic
and obese). By applying our thin films directly to surface of orthopedic
implants, we envision that a single surgery could locally provide the
patient with painkillers, anti-inflammatories, antibiotics, and growth
factors all in one and with optimized dosage profiles. The goal is to
drastically reduce the heightened infection rates in revision
arthroplasties and high risk cases. The importance of this work relates
to the consequences of infection. Infected patients end up getting
crushed with two more surgeries (to remove infected implant, disinfect
the area, and re-implant a new prosthesis), steep hospital bills, a
drawn out period of immobility, and potential for permanent limb damage
and death.
The Research Problem:
Sustained delivery of gentamicin from LbL films is difficult because
it is a small, hydrophilic molecule. When placed in aqueous solution, we
currently find that the gentimicin will readily diffuse out of these
films. Specifically, there are two domains of release: first, there is a
“burst” release where a large fraction of the deposited gentamicin
leaves the film within the first few hours, and this is followed by a
slower release of the remaining fraction as the film erodes. Release
durations beyond 24 hours are very difficult to achieve using our
current method of layering the gentamicin directly into the film.
Antibiotic delivery will need to reach a 2—6 week duration for any
practical application.
The Proposed Solution:
Encapsulate gentamicin inside of much larger vesicles which are not
as capable of diffusion within the film. The vesicles can be engineered
with a charged surface so that they can be conveniently layered into the
LBL superstructure. Hence, the drug is effectively “locked in place” and
will need to wait until the film has sufficiently eroded before release.
This method has its challenges rooted in optimizing the encapsulation
efficiency, antibiotic efficacy, and delivery timeline for use in
orthopedic applications. Along the way, my goal is to discover the
different variables that can be adjusted to precisely tune the dosage
and delivery of gentamicin.

Upper left: growth curve for
(LPEI/PSS)[(CHI/HA)5(Liposome/HA)1]n as determined
by profilometry. Notation defined below.
Lower Left: loading of liposomes by mass into
(LPEI/PSS)[(CHI/HA)5(Liposome/HA)1]n as determined
by liquid scintillation counting. This graph corresponds to liposomes
with no drug loading. Recent measurements suggest that the n = 20 film
would have incorporated approximately 4 µg/cm2 of gentamicin sulfate.
Assuming a 1 cm diffusion length away from the substrate surface, this
would be 40x greater than the minimum inhibitory concentration of
gentamicin against S. aureus—the most common bacteria associated with
bone infection.
Upper Right: liposomes are stabilized with
poly L-lysine (PLL) to give them a robust polymer shell such that they
keep their structure when being layered into the films. As fabricated,
the liposomes are negatively charged. The graph shows that by increasing
the mixing ratio in favor of polymer, the liposomes go from naked with a
negative zeta potential to polymer-stabilized with a positive zeta
potential.
Lower Right: This graph shows the activity of
gentamicin-loaded liposomes against S. aureus. The liposome
concentrations are an over-estimate to their true value suggesting that
their activity may be even more favorable than shown here.* The
minimum inhibitory concentration appears to be between 39 and 78 µg.
Coupling this information with the graph in the lower left, we should be
able to build films that are efficacious against this bacteria in vitro.
* The over-estimate is due to the fact that
gentamicin loaded liposomes are prepared initially with an excess of
gentamicin. This excess must be dialyzed out and the assumption above is
that liposome loss during dialysis is negligible. It has been
experimentally determined that there is about a 2% loss of liposomes due
to dialysis.
Notation for films:
(X/Y)n
X = Polymer 1
Y = Polymer 2 of opposite charge
(X/Y) = Bi-layer of X/Y
n = number of bilayers
Materials:
LPEI—Linear poly(ethyleneimine)
PSS—Poly(styrene sulfonate)
CHI—Chitosan
HA—Hyaluronan (or hyaluronic acid)
Liposomes—Prepared with a 69.5 to 30 to 0.5 mass ratio of
dioleoylphosphatidylethanolamine (DOPE), n-glutaryl-DOPE, and
C16-poly(ethylene glycol)-ceramide. The glutaryl component provides
negative charge and the poly(ethylene glycol) component prevents
aggregation of liposomes.
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