Localized Delivery of Small Hydrophilic Drugs using Polyelectrolyte Multilayered Thin Films

Technology:
My research involves the economic, scalable, and efficient technology of layer-by-layer (LBL) deposition, which involves alternating polyanions and polycations to build up thin films that contain small hydrophilic antibiotics such as gentamicin. The thin films utilize a unique breed of polycations known as poly(β-amino esters), which although relatively stable in the solid-state, undergo hydrolytic degradation upon contact with aqueous environment (e.g. in vivo). The films are engineered to erode in top-down fashion such that the elution of encapsulated drug can be precisely tuned. Ultimately, this work can be coupled to the greater effort of including proteins and hydrophobic molecules in the thin films in order to achieve complex, sequential, or “smart” release profiles of the film contents.

Application:
As the baby boomer generation begins to increase the demand for orthopedic implants, our technology can find excellent use in the near future. By applying our thin films directly to the orthopedic implants, we can envision that a single surgery could provide the prosthesis, painkillers, anti-inflammatories, antibiotics, and growth factors all in one. Why is this awesome? First, there will be no wait time where the patient has to live without a hip while the implant site is disinfected. Second, this means that there is no second surgery, which in turn reduces hospital bills. Third, there will be no need for future doses of drugs since the release schedule of the film can be “pre-programmed” to take care of the patient’s needs. This is convenient for patients since it removes the human error in dosage when the drugs are delivered by hand. Finally, the amounts of each drug used can be significantly reduced since the delivery is localized to the site of infection, which also becomes a cost-saving benefit.

Problem:
Sustained delivery of gentamicin 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 the film. 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 48 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.

Proposed Solutions:
1. 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.
2. Making use of a gentamicin pro-drug, this antibiotic can be linked to a charged polymeric backbone using degradable bonds. The bonds would be engineered to break upon submersion in specific ambient conditions. The long polymer backbone, which is incapable of diffusing out of the film before it has sufficiently eroded, will tether the drug to a specific layer within the film.

Pictures/Figures will be added as this research develops.