There is a strong need for biomedical implant coatings which can act to deliver the appropriate therapeutics, including sensitive biologic drugs, to localized areas in the body with a level of precision and control. The current state-of-art for drug-coated implants is essentially limited to those which elute a single drug over a given time period, usually with a drug release profile based on the rate of diffusion of the drug component from the thin film coating or the rate of degradation of a homogeneous bulk polymer. In either case, it is not possible to introduce complex release profiles such as the sequential release or two or more drugs utilizing standard methods;yet there are many situations in which more than one therapeutic is needed, and must be introduced at different times during the lifetime of the implant. Furthermore, it is considerably more difficult to deliver pH or solvent sensitive recombinant protein drugs or growth factors often needed for implant applications using traditional degradable polymers such as PLGA, which can expose the drug to low pH and harsh processing conditions. The primary aim of this work is to utilize the enabling nanofabrication tool of electrostatic multilayer assembly to create coatings one nanoscale layer at a time by alternating drugs with degradable polyions such that complex, multicomponent, sequential or graduated release of drugs takes place from implant surfaces in a layer-by-layer fashion. This method is simple, low cost, and allows infinite tuning of film composition using an alternate electrostatic assembly process, resulting in films that degrade under biological conditions to release series of drugs layers at a time.
Specific Aims i nclude the control of degradable polyion composition, multilayer film assembly conditions, and manipulation of nanometer scale structure of the thin films to ensure delivery in inverse order to construction of the film. In vitro cell culture studies of release of antibacterial agents and growth factors will be used to determine efficacy and optimal dose levels of these systems. Animal models that include a small animal large scale rabbit study will be used to determine efficacy of antibacterial, growth factor, and combination coatings that delivery 2 or 3 agents will be performed. A large animal goat model that better replicates human bone mechanics will be performed on the most promising nanoscale coatings. Preservation of sensitive biologic drug efficacy will be key to these studies. This novel approach has several important high- impact applications, including coatings of stents, sutures, bone and other surgical implants. The focus of this work will be on orthopedic implants, an area where the controlled delivery of multiple therapeutics could eliminate additional surgeries and promote rapid healing. We will investigate the coating of prostheses with therapeutic quantities of antibiotics, angipgenic factors, and bone morphogenetic growth factors that can be released sequentially to enable disinfection of the joint area, bone healing and growth respectively. The concept of highly controlled, passive coatings on implants is both commercially feasible and disruptive, and promises molecular level control of delivery from the device surface, which should lead to broader applications for a number of implant devices.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG029601-04
Application #
7795798
Study Section
Special Emphasis Panel (ZRG1-BCMB-L (50))
Program Officer
Rossi, Winifred K
Project Start
2007-03-01
Project End
2012-02-29
Budget Start
2010-04-01
Budget End
2011-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$417,965
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Morton, Stephen W; Shah, Nisarg J; Quadir, Mohiuddin A et al. (2014) Osteotropic therapy via targeted layer-by-layer nanoparticles. Adv Healthc Mater 3:867-75
Min, Jouha; Braatz, Richard D; Hammond, Paula T (2014) Tunable staged release of therapeutics from layer-by-layer coatings with clay interlayer barrier. Biomaterials 35:2507-17
Shah, Nisarg J; Hyder, Md Nasim; Quadir, Mohiuddin A et al. (2014) Adaptive growth factor delivery from a polyelectrolyte coating promotes synergistic bone tissue repair and reconstruction. Proc Natl Acad Sci U S A 111:12847-52
Shah, Nisarg J; Hyder, Md Nasim; Moskowitz, Joshua S et al. (2013) Surface-mediated bone tissue morphogenesis from tunable nanolayered implant coatings. Sci Transl Med 5:191ra83
Hong, Jinkee; Alvarez, Luis M; Shah, Nisarg J et al. (2012) Multilayer thin film coatings capable of extended programmable drug release: application to human mesenchymal stem cell differentiation. Drug Deliv Transl Res 2:375-83
Hong, Jinkee; Shah, Nisarg J; Drake, Adam C et al. (2012) Graphene multilayers as gates for multi-week sequential release of proteins from surfaces. ACS Nano 6:81-8
Costa, Eunice; Lloyd, Margaret M; Chopko, Caroline et al. (2012) Tuning smart microgel swelling and responsive behavior through strong and weak polyelectrolyte pair assembly. Langmuir 28:10082-90
Shah, Nisarg J; Hong, Jinkee; Hyder, Md Nasim et al. (2012) Osteophilic multilayer coatings for accelerated bone tissue growth. Adv Mater 24:1445-50
Macdonald, Mara L; Samuel, Raymond E; Shah, Nisarg J et al. (2011) Tissue integration of growth factor-eluting layer-by-layer polyelectrolyte multilayer coated implants. Biomaterials 32:1446-53
Shukla, Anita; Fuller, Renee C; Hammond, Paula T (2011) Design of multi-drug release coatings targeting infection and inflammation. J Control Release 155:159-66

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