Drug loading and release of Tobramycin from hydroxyapatite coated fixation pins.

This paper evaluates the loading and release properties of Tobramycin incorporated by adsorptive loading from a solution into plasma sprayed and biomimetically coated Hydroxyapatite (HA) fixation pins. The aim of this study is to contribute towards designing a functional implant surface offering local release of the antibiotic agent to prevent post-surgical infections. Cathodic arc deposition is used to coat stainless steel fixation pins with a bioactive, anatase phase dominated, TiO2 coating onto which a HA layer is grown biomimetically. The loading and release properties are evaluated by studying the subsequent release of Tobramycin using high performance liquid chromatography and correlated to the differences in HA coating microstructure and the physical conditions under loading. The results from these studies show that a dual loading strategy consisting of a solution temperature of 90 °C and a pressure of 6 bar during a loading time of 5 min release a sufficient amount of Tobramycin to guarantee the inhibition of Staphylococcus aureus up to 2 days for plasma sprayed HA coatings and for 8 days for biomimetic coatings. The present study emphasizes the advantages of the nanoporous structure of biomimetically deposited HA over the more dense structure of plasma sprayed HA coatings in terms of antibiotic incorporation and subsequent sustained release and provides a valuable outline for the design of implant surfaces aiming for a fast-loading and controlled, local drug administration.

Co-loading of bisphosphonates and antibiotics to a biomimetic hydroxyapatite coating.

We have incorporated bisphosphonates and antibiotics simultaneously into a biomimetic hydroxyapatite implant coating aiming to use the interaction between drug-molecules and hydroxyapatite to enable local release of the two different substances to obtain a dual biological effect. A sustained release over for 43 h of antibiotics (cephalothin) was achieved without negative interference from the presence of the bisphosphonate (clodronate) which, in turn, successfully bonded to the coating surface. To our knowledge, this is the first study that indicates the possibility to simultaneously incorporate both antibiotics and bisphosphonates to an implant coating, a strategy that is believed to improve implant stability and reduce implant-related infections.

Bisphosphonate incorporation in surgical implant coatings by fast loading and co-precipitation at low drug concentrations.

The objectives of the present work was to evaluate the possibility for fast loading by soaking of bisphosphonates (BPs) into hydroxylapatite (HA) implant coatings biomimetically grown on crystalline TiO(2) surfaces, and also investigate the influence of different BP loading concentrations in a buffer during co-precipitation of a calcium phosphate containing layer onto these surfaces. The co-precipitation method created coatings that contained BPs throughout most of the coating layer, but the presence of BPs in the buffer hindered the formation of a bulk HA-layer, thus resulting in very thin coatings most likely consisting of islands built up by a calcium phosphate containing BPs. The coatings biomimetically grown on TiO(2) surfaces, were shown to consist of crystalline HA. Soaking of these coatings during 15 min only in a low BPs concentration containing buffer yielded a concentration on the coating surface of the same order of magnitude as obtained with soaking during 60 min in significantly higher concentrated buffers. This could be of advantage during surgery since the operating surgeon could make a fast decision whether or not to include the drugs in the coating based on the need of the particular patient at hand. The BPs present on the surface of the fast-loaded HA coatings were found to be strongly bound, something which should be beneficial for in vivo use. Both the co-precipitation method and the fast loading by soaking method investigated here are promising techniques for loading of BPs onto surgical implants. The simplicity of both methods is an advantage since implants can have spatially complicated structures.

Multifunctional implant coatings providing possibilities for fast antibiotics loading with subsequent slow release.

The possibility to fast-load biomimetic hydroxyapatite coatings on surgical implant with the antibiotics Amoxicillin, Gentamicin sulfate, Tobramycin and Cephalothin has been investigated in order to develop a multifunctional implant device offering sustained local anti-bacterial treatment and giving the surgeon the possibility to choose which antibiotics to incorporate in the implant at the site of surgery. Physical vapor deposition was used to coat titanium surfaces with an adhesion enhancing gradient layer of titanium oxide having an amorphous oxygen poor composition at the interface and a crystalline bioactive anatase TiO(2) composition at the surface. Hydroxyapatite (HA) was biomimetically grown on the bioactive TiO(2) to serve as a combined bone in-growth promoter and drug delivery vehicle. The coating was characterized using scanning and transmission electron microscopy, X-ray diffraction and X-ray photoelectron spectroscopy. The antibiotics were loaded into the HA coatings via soaking and the subsequent release and antibacterial effect were analyzed using UV spectroscopy and examination of inhibition zones in a Staphylococcus aureus containing agar. It was found that a short drug loading time of 15 min ensured antibacterial effects after 24 h for all antibiotics under study. It was further found that the release processes of Cephalothin and Amoxicillin consisted of an initial rapid drug release that varied unpredictably in amount followed by a reproducible and sustained release process with a release rate independent of the drug loading times under study. Thus, implants that have been fast-loaded with drugs could be stored for ~10 min in a simulated body fluid after loading to ensure reproducibility in the subsequent release process. Calculated release rates and measurements of drug amounts remaining in the samples after 22 h of release indicated that a therapeutically relevant dose could be achieved close to the implant surface for about 2 days. Concluding, the present study provides an outline for the development of a fast-loading slow-release surgical implant kit where the implant and the drug are separated when delivered to the surgeon, thus constituting a flexible solution for the surgeon by offering the choice of quick addition of antibiotics to the implant coating based on the patient need.

Sustained release from mesoporous nanoparticles: evaluation of structural properties associated with release rate.

We present here a detailed study of the controlled release of amino acid derived amphiphilic molecules from the internal pore structure of mesoporous nanoparticle drug delivery systems with different structural properties; namely cubic and hexagonal structures of various degrees of complexity. The internal pore surface of the nanomaterials presented has been functionalised with amine moieties through a one pot method. Release profiles obtained by Alternating Ionic Current measurements are interpreted in terms of specific structural and textural parameters of the porous nanoparticles such as pore geometry and connectivity. Results indicate that diffusion coefficients are lower by as much as four orders of magnitude in 2-dimensional structures in comparison to 3-dimensional mesoporous solids. A fast release in turn is observed from mesocaged materials AMS-9 and AMS-8 where the presence of structural defects is thought to lead to a slightly lower diffusion coefficient in the latter. Amount of pore wall functionalisation and number of binding sites on the model drug are found to have little effect on the drug release rate.

Finite element analysis of the release of slowly dissolving drugs from cylindrical matrix systems.

Drug release from matrix systems of cylindrical shape is analyzed in detail by using the finite element method. The model used combines the Noyes-Whitney and diffusion equations, and thus takes the effects of a finite dissolution rate into account. The model is valid for all drug solubilities and dissolution rates, and allows accurate predictions of the drug release to be made. Anisotropic drug transport that may result from the manufacturing process is properly accounted for. Model calculations show that a finite dissolution rate may affect the release profile significantly, producing an initial delay. The equivalence between anisotropic release and isotropic release from a matrix with different dimensions is demonstrated. Comparisons are made with the predictions of a recently proposed pseudo-steady state (PSS) analysis of drug release from cylindrical matrices [Y. Zhou, J. S. Chu, T. Zhou, X. Y. Wu, Modeling of dispersed-drug release from two-dimensional matrix tablets, Biomaterials 26 (2005) 945-952]. This comparison reveals that important discrepancies exist between the numerical and analytical results, which are attributed to the simplifying assumption made in the PSS analysis that the region containing solid drug remains cylindrical in shape throughout the release process. The proposed model is shown to describe experimental release data well.

Bone response to a novel Ti-Ta-Nb-Zr alloy.

Commercially pure titanium (cp-Ti) is regarded as the state-of-the-art material for bone-anchored dental devices, whereas the mechanically stronger alloy (Ti-6Al-4V), made of titanium, aluminum (Al) and vanadium (V), is regarded as the material of choice for high-load applications. There is a call for the development of new alloys, not only to eliminate the potential toxic effect of Al and V but also to meet the challenges imposed on dental and maxillofacial reconstructive devices, for example. The present work evaluates a novel, dual-stage, acid-etched, Ti-Ta-Nb-Zr alloy implant, consisting of elements that create low toxicity, with the potential to promote osseointegration in vivo. The alloy implants (denoted Ti-Ta-Nb-Zr) were evaluated after 7 days and 28 days in a rat tibia model, with reference to commercially pure titanium grade 4 (denoted Ti). Analyses were performed with respect to removal torque, histomorphometry and gene expression. The Ti-Ta-Nb-Zr showed a significant increase in implant stability over time in contrast to the Ti. Further, the histological and gene expression analyses suggested faster healing around the Ti-Ta-Nb-Zr, as judged by the enhanced remodeling, and mineralization, of the early-formed woven bone and the multiple positive correlations between genes denoting inflammation, bone formation and remodeling. Based on the present experiments, it is concluded that the Ti-Ta-Nb-Zr alloy becomes osseointegrated to at least a similar degree to that of pure titanium implants. This alloy is therefore emerging as a novel implant material for clinical evaluation.

Characterization of the drug release process by investigation of its temperature dependence.

Temperature-dependent drug release from disintegrating tablets made of NaCl-containing agglomerated micronized cellulose (AMC) granules has been studied to characterize the release process. Release measurements on tablets compacted at three different compaction pressures; 50, 100, and 200 MPa, were performed at seven different temperatures; 6, 23, 33, 43, 50, 55, and 63 degrees C using the recently developed alternating ionic current method. Tablets compacted at different compaction pressures showed similar release rates. The release process was found to be diffusion-controlled, and the activation energy of the diffusion coefficient was comparable to that obtained for diffusion in pure water. The results show that the AMC granules in contact with water swell to a size and shape that is only slightly affected by their compaction history and the ion diffusion operates mainly within liquid-filled pores within the AMC granules. By using the temperature dependence of the release process, it was possible to reach this conclusion without any assumptions concerning the number and radii of the granules into which the tablets disintegrated. Further, the magnitude of the effective diffusion coefficient was found to be approximately 7.5 x 10(-10) cm(2)/s, which is approximately four orders of magnitude lower than for unhindered diffusion of Na(+) and Cl(-) in water but similar to the diffusion coefficient for protons and OH(-) ions in microcrystalline cellulose.

Mesoporous silica-based nanomaterials for drug delivery: evaluation of structural properties associated with release rate.

We present here a study of the controlled release of amino acid-derived amphiphilic molecules from the internal pore structure of mesoporous nanoparticle drug delivery systems with different structural properties, namely cubic and hexagonal structures of various degrees of complexity. The internal pore surface of the nanomaterials presented has been functionalised with amine moieties through a one-pot method. Release profiles obtained by conductivity measurements are interpreted in terms of specific structural and textural parameters of the porous nanoparticles, such as pore geometry and connectivity. Results indicate that diffusion coefficients are lower by as much 4 orders of magnitude in two-dimensional structures in comparison to three-dimensional mesoporous solids. A fast release in turn is observed from mesocaged materials AMS-9 and AMS-8, where the presence of structural defects is thought to lead to a slightly lower diffusion coefficient in the latter. We conclude that the use of single or mixed phases of these porous systems can be utilized to provide sustained release over long time periods and expect their use in a variety of formulations.

Proton absorption in as-synthesized mesoporous silica nanoparticles as a structure-function relationship probing mechanism.

A new method to investigate the effect of pore geometry on diffusion processes in mesoporous silica nanoparticles and other types of micro- and mesoporous structures is put forward. The method is based on the study of proton diffusion from a liquid surrounding the mesoporous particles into the particle pore system. The proton diffusion properties are assessed for a variety of as-synthesized mesoporous nano- and microparticles with two-dimensional and three-dimensional connectivity. Results show that the diffusion coefficients are higher for the proton absorption process than for the release of surfactant template molecules, and that they overall follow the same trend with the more complex three-dimensional mesocaged particles showing the highest diffusion coefficients. The pore geometry (cylindrical pores versus cage-type pores) and structure connectivity are found to play a key role for the effects observed. The results put forward in the present work should offer a valuable tool in the development of porous nanomaterials in a range of applications including the use as catalysis and separation enhancers in the petrochemical industry, as scaffolds for hydrogen storage, and as drug delivery vehicles for sustained release and gene transfection.

In vitro characterization of bioactive titanium dioxide/hydroxyapatite surfaces functionalized with BMP-2.

Poor implant fixation and bone resorption are two of the major challenges in modern orthopedics and are caused by poor bone/implant integration. In this work, bioactive crystalline titanium dioxide (TiO(2))/hydroxyapatite (HA) surfaces, functionalized with bone morphogenetic protein 2 (BMP-2), were evaluated as potential implant coatings for improved osseointegration. The outer layer consisted of HA, which is known to be osteoconductive, and may promote improved initial bone attachment when functionalized with active molecules such as BMP-2 in a soaking process. The inner layer of crystalline TiO(2) is bioactive and ensures long-term fixation of the implant, once the hydroxyapatite has been resorbed. The in vitro response of mesenchymal stem cells on bioactive crystalline TiO(2)/HA surfaces functionalized with BMP-2 was examined and compared with the cell behavior on nonfunctionalized HA layers, crystalline TiO(2) surfaces, and native titanium oxide surfaces. The crystalline TiO(2) and the HA surfaces showed to be more favorable than the native titanium oxide surface in terms of cell viability and cell morphology as well as initial cell differentiation. Furthermore, cell differentiation on BMP-2-functionalized HA surfaces was found to be significantly higher than on the other surfaces indicating that the simple soaking process can be used for incorporating active molecules, promoting fast bone osseointegration to HA layers.

A mechanistic study of the formation of mesoporous structures from in situ AC conductivity measurements.

The purpose of this work is to study the kinetics of self-assembly in the formation mechanism of anionic templated mesoporous solids (AMS-n) during the first few seconds of the synthesis as well as to demonstrate the use of alternating ion current (AIC) conductivity measurements to follow the self-assembly in complex hybrid systems. The formation of different AMS-n caged-type mesostructures through the delayed addition of the silica source is demonstrated and explained in terms of the interaction between the co-structure-directing agent (CSDA) and the oppositely charged surfactant headgroup regions. Our findings, supported by transmission electron microscopy, 29Si magic angle spinning nuclear magnetic resonance (MAS NMR) spectroscopy, dynamic light scattering (DLS) measurements, and powder X-ray diffraction suggest that the interaction of the CSDA with the surfactant headgroup occurs within seconds after its addition to the synthesis gel leading to interaction between the polymerizing CSDAs and the oppositely charged micelle and to an increase in the micelle-CSDA aggregate size. Both DLS and AIC measurements agree that this process occurs within the first 1000 s after addition of the CSDA to the synthesis gel at room temperature. In addition to the mechanistic study it was found that the intermediate materials are comprised of a three-layer entity. Time-dependent 29Si MAS NMR studies reveal that an organo-silica layer forms around the micelles prior to a condensed outer inorganic shell of silica.