Nanolayer multi-agent scaled delivery from implant surface

Abstract

One of the important problems in the field of orthopedic medicine is the ability to create a stable bone-materials interface with an implant, particularly when faced with the difficult condition of bone infection. Only recently have we come to understand the significance of addressing infection during the bone wound healing process; however, to apply this understanding toward an effective treatment requires the ability to deliver exacting amounts of therapeutics of different types over the appropriate timeframes in and around the implant. This task must be accomplished while maintaining the mechanical integrity of the implant materials and allowing for bone integration on their surfaces. Here we present a novel, particularly enabling next-generation implant solution for both eradication of an established biofilm within the bone cavity and accelerated bone repair via the controlled delivery of antibiotic and growth factor in sequence from stable nanometer scale coatings on the implant surface. Infection is by far the most common reason for complications, which often lead to complete removal of implants (74.3%). Infection significantly increases morbidity, and places huge financial burdens on the patient and the healthcare system-projected to exceed $1.62 billion/year by 2020. Because infection is much more common in implant replacement surgeries, these issues greatly impact long-term patient care for a continually growing part of the population. For revision arthroplasty of an infected prosthesis, a prolonged and expensive twostage procedure requiring two surgical steps and a 6-8 week period of joint immobilization exists as today's gold standard. A single-stage revision is preferred as an alternative; however, traditional bulk polymer systems such as bone cement cannot load sufficient amounts of therapeutic to eradicate existing infection, are insufficient or infeasible for the release of sensitive biologic drugs that considerably aid in bone regeneration, and lead to substandard mechanical properties and retarded bone repair. To address these issues, we created conformal, programmable, and degradable dual therapy coatings (~500 nm thick) in a layer-by-layer fashion using the enabling nanofabrication tool of electrostatic multilayer assembly. The nanolayered construct allows large loadings of each drug, thus enabling ultrathin film coatings to carry sufficient treatment and precise independent control of release kinetics and loading for each therapeutic agent in an infected implant environment. The coating architecture was adapted to allow early release of antibiotics contained in top layers sufficient to eliminate infection, followed by sustained release above the MIC over several weeks; whereas, the underlying BMP-2 growth factor layers enabled a long-term sustained release of BMP-2, which induced more significant and mechanically competent bone formation than a short-term burst release. In rats, the successful growth factor-mediated osteointegration of the multilayered implants with the host tissue improved bone-implant interfacial strength by impressive amounts (15-fold) when compared with the bare implant control, and yields a mechanical bond 17-fold higher than that created with the use of clinically available bioactive bone cement. Here we focused on dual delivery of an antibiotic and a growth factor owing to the urgent need for enhanced infection-reducing and tissue-integrating strategies in orthopedic applications, but the excellent modularity of multilayers for incorporation and release of diverse therapeutics suggests this approach should be also applicable to different implant applications such as vascular graft and artificial heart implants for which the risks of infection are often ignored. Our findings demonstrate the potential of this layered release strategy to introduce a durable implant solution, ultimately an important step forward in the design of biomedical implant release coatings for multiple medical applications. In addition to focusing on multi-therapeutic multilayer coatings for macroscale implants and scaffolds, I have also extended the work to understand release properties of the therapeutic agents, guided by predictive mathematical modeling of the release mechanisms involved in polyelectrolyte multilayer films and cell uptakes based on the principles of polymer physics and molecular and cellular biology. The potential impact of this work is substantial: introduce the next-generation biomaterials and implantable devices, save billions of dollars in the healthcare cost, and directly benefit the rapidly growing current and future generations of patients relying on medical device.