Developing Polyelectrolyte Multilayer Films for Releasing Multiple Therapeutic Agents

It is estimated that a million joint replacements are performed worldwide every year, with approximately 50% of them taking place in the United States. As the average lifespan continues to rise, the need for such procedures is expected to increase at a rapid pace. Unfortunately, due to surgical and implant-related complications including serious issues of bone and joint infection, about 10% of such joint replacements eventually fail and require a replacement, in which the patient may undergo more than two additional surgeries; such revisions cost over $1 billion annually in the U.S. The prevention of infection with subsequent re-growth of healthy bone tissue at and around the implant surface are key elements for the success of these procedures. Strategies to promote osseointegration of implant material and bone tissue after removing infection are of significant interest in the long term for the permanent incorporation and anchoring of bone tissue with the implant such that the two cannot become easily separated under mechanical loading and stress. Currently, the standard of care in cases of implant related infections is gentamicin sulfate antibiotic therapy via PMMA beads along with IV antibiotics and subsequently implanting a new prosthesis via a revision arthroplasty. No therapy is administered to promote re-growth of bone tissue, which results in longer rehabilitation times and can lead to skeletal defects, severe functional impairment and morbidity, particularly in older patients.

Bone morphogenetic proteins (BMPs) are some of the most potent growth factors for bone tissue formation and stimulate rapid healing of tissue around the implant, with decreased inflammation and more complete bone remodeling over shorter time periods. Vascular endothelial growth factor (VEGF) can act synergistically with BMP to further enhance bone formation through the rapid remodeling of surrounding vascular networks to increase blood flow to the implant site. To induce this synergism the timing and quantity of VEGF and BMP delivery is critical. In terms of in vivo delivery, common biodegradable polymeric drug delivery systems are unsuitable due to the need to process the polymers at low pH, high temperature and harsh solvent conditions. Direct injection of growth factor to a site would lead to the immediate breakdown and resorption of the protein before it could begin to exhibit desired results. The complex requirements for antibiotic and growth factor therapy necessitate the development of a delivery system as part of the implant structure that is able to locally deliver precise amounts of therapy over varying time scales while maintaining efficacy.

We are interested in the use of a novel polyelectrolyte multilayer (PEM) assembly approach to generate thin films on implants that allow programmed localized delivery of growth factors, along with antibiotics, to the tissue surrounding the implant. These fragile biologics can be easily introduced into LbL films, non-covalently and under physiological conditions, without alteration of their biological properties. In addition, it is possible to achieve nanometer scale precision over the composition and the internal structure of the resultant multi-component films to facilitate sophisticated levels of spatial, temporal or active control over the release of therapeutics. Orthopedic implant surfaces are a compelling application as the film can be coated on to complex implant geometries in a conformal manner for sequential and controlled delivery of growth factors and antibiotics. This approach has the potential of making joint replacement surgery a convenient one-step solution.