Surface-Mediated Bone Tissue Morphogenesis from Tunable Nanolayered Implant Coatings.
ABSTRACT The functional success of a biomedical implant critically depends on its stable bonding with the host tissue. Aseptic implant loosening accounts for more than half of all joint replacement failures. Various materials, including metals and plastic, confer mechanical integrity to the device, but often these materials are not suitable for direct integration with the host tissue, which leads to implant loosening and patient morbidity. We describe a self-assembled, osteogenic, polymer-based conformal coating that promotes stable mechanical fixation of an implant in a surrogate rodent model. A single modular, polymer-based multilayered coating was deposited using a water-based layer-by-layer approach, by which each element was introduced on the surface in nanoscale layers. Osteoconductive hydroxyapatite (HAP) and osteoinductive bone morphogenetic protein-2 (BMP-2) contained within the nanostructured coating acted synergistically to induce osteoblastic differentiation of endogenous progenitor cells within the bone marrow, without indications of a foreign body response. The tuned release of BMP-2, controlled by a hydrolytically degradable poly(β-amino ester), was essential for tissue regeneration, and in the presence of HAP, the modular coating encouraged the direct deposition of highly cohesive trabecular bone on the implant surface. In vivo, the bone-implant interfacial tensile strength was significantly higher than standard bioactive bone cement, did not fracture at the interface, and had long-term stability. Collectively, these results suggest that the multilayered coating system promotes biological fixation of orthopedic and dental implants to improve surgical outcomes by preventing loosening and premature failure.
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ABSTRACT: In developing new generations of coatings for medical devices and tissue engineering scaffolds, there is a need for thin coatings that provide controlled sequential release of multiple therapeutics while providing a tunable approach to time dependence and the potential for sequential or staged release. Herein, we demonstrate the ability to develop a self-assembled, polymer-based conformal coating, built by using a water-based layer-by-layer (LbL) approach, as a dual-purpose biomimetic implant surface that provides staggered and/or sustained release of an antibiotic followed by active growth factor for orthopedic implant applications. This multilayered coating consists of two parts: a base osteoinductive component containing bone morphogenetic protein-2 (rhBMP-2) beneath an antibacterial component containing gentamicin (GS). For the fabrication of truly stratified composite films with the customized release behavior, we present a new strategy-implementation of laponite clay barriers-that allows for a physical separation of the two components by controlling interlayer diffusion. The clay barriers in a single-component GS system effectively block diffusion-based release, leading to approximately 50% reduction in bolus doses and 10-fold increase in the release timescale. In a dual-therapeutic composite coating, the top GS component itself was found to be an effective physical barrier for the underlying rhBMP-2, leading to an order of magnitude increase in the release timescale compared to the single-component rhBMP-2 system. The introduction of a laponite interlayer barrier further enhanced the temporal separation between release of the two drugs, resulting in a more physiologically appropriate dosing of rhBMP-2. Both therapeutics released from the composite coating retained their efficacy over their established release timeframes. This new platform for multi-drug localized delivery can be easily fabricated, tuned, and translated to a variety of implant applications where control over spatial and temporal release profiles of multiple drugs is desired.Biomaterials 12/2013; 35(8). DOI:10.1016/j.biomaterials.2013.12.009 · 8.31 Impact Factor
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ABSTRACT: The innate immune system consists of functionally specialized "modules" that are activated in response to a particular set of stimuli via sensors located on the surface or inside the tissue cells. These cells screen tissues for a wide range of exogenous and endogenous danger/damage-induced signals with the aim to reject or tolerate them and maintain tissue integrity. In this line of thinking, inflammation evolved as an adaptive tool for restoring tissue homeostasis. A number of diseases are mediated by a maladaptation of the innate immune response, perpetuating chronic inflammation and tissue damage. Here, we review recent evidence on the cross talk between innate immune sensors and development of rheumatoid arthritis, osteoarthritis, and aseptic loosening of total joint replacements. In relation to the latter topic, there is a growing body of evidence that aseptic loosening and periprosthetic osteolysis results from long-term maladaptation of periprosthetic tissues to the presence of by-products continuously released from an artificial joint.Journal of Long-Term Effects of Medical Implants 01/2014; 24(4):297-317.
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ABSTRACT: We report on the assembly of multi-layered polyelectrolyte thin films containing an immobilized enzyme to perform conversion of externally administered prodrugs and achieve delivery of the resulting therapeutics to adhering cells. Towards this goal, multi-layered coatings were assembled using poly(sodium styrene sulfonate) and poly(allylamine hydrochloride). Activity of the incorporated enzyme was quantified as a function of the assembly conditions, position of the enzyme within the multi-layered architecture, concentration of the enzyme in the adsorption solution, and concentration of the administered prodrug. Biocatalytic coatings exhibited sustained levels of enzymatic activity over at least one week of incubation in physiological buffers without signs of loss of activity of the enzyme. Developed enzyme-containing polymer films afforded zero-order release of the in situ synthesized cargo with kinetics of synthesis (nM per hour) covering at least 3 orders of magnitude. Internalization of the synthesized product by adhering cells was visualized using a fluorogenic enzyme substrate. Therapeutic utility of biocatalytic coatings was demonstrated using a myoblast cell line and a prodrug for the anti-proliferative agent, 5-fluorouridine. Taken together, this work presents a novel approach to delivery of small molecule drugs using multi-layered polymer thin films with utility in surface-mediated drug delivery, assembly of therapeutic implantable devices, and tissue engineering.Nanoscale 03/2014; 6(8). DOI:10.1039/c3nr05999e · 6.74 Impact Factor