Apatite-Polymer Composites for the Controlled Dual Delivery of BMP-2 and BMP-6 for Bone Tissue Engineering

The release of growth factors from tissue engineering scaffolds provides signals that influence the migration, differentiation, and proliferation of cells. The incorporation of a drug delivery platform that is capable of tunable release will give tissue engineers greater versatility in the direction of tissue regeneration. We have prepared a novel composite of two biomaterials with proven track records - apatite and poly(lactic-co-glycolic acid) (PLGA) – as a drug delivery platform with promising controlled release properties. These composites have been tested in the delivery of a model protein, bovine serum albumin (BSA), as well as therapeutic proteins, recombinant human bone morphogenetic protein-2 (rhBMP-2) and rhBMP-6. The controlled release strategy is based on the use of a polymer with acidic degradation products to control the dissolution of the basic apatitic component, resulting in protein release. Therefore, any parameter that affects either polymer degradation or apatite dissolution can be used to control protein release. We have modified the protein release profile systematically by varying the polymer molecular weight, polymer hydrophobicity, apatite loading, apatite particle size, and other material and processing parameters. Biologically active rhBMP-2 was released from these composite microparticles over 100 days, in contrast to conventional collagen sponge carriers, which were depleted in approximately 2 weeks. The released rhBMP-2 was able to induce elevated alkaline phosphatase and osteocalcin expression in pluripotent murine embryonic fibroblasts. To augment tissue engineering scaffolds with tunable and sustained protein release capabilities, these composite microparticles can be dispersed in the scaffolds in different combinations to obtain a superposition of the release profiles. We have loaded rhBMP-2 into composite microparticles with a fast release profile, and rhBMP-6 into slow-releasing composite microparticles. An equi-mixture of these two sets of composite particles was then injected into a collagen sponge, allowing for dual release of the proteins from the collagenous scaffold. The ability of these BMP-loaded scaffolds to induce osteoblastic differentiation in vitro and ectopic bone formation in a rat model is being investigated. We anticipate that these apatite-polymer composite microparticles can be extended to the delivery of other signalling molecules, and can be incorporated into other types of tissue engineering scaffolds.

Experimental and theoretical study of the infrared spectra of BrHI- and BrDI-

Gas phase vibrational spectra of BrHI- and BrDI- have been measured from 6 to 17 mum (590-1666 cm-1) using tunable infrared radiation from the free electron laser for infrared experiments in order to characterize the strong hydrogen bond in these species. BrHI-.Ar and BrDI-.Ar complexes were produced and mass selected, and the depletion of their signal due to vibrational predissociation was monitored as a function of photon energy. Additionally, BrHI- and BrDI- were dissociated into HBr (DBr) and I- via resonant infrared multiphoton dissociation. The spectra show numerous transitions, which had not been observed by previous matrix studies. New ab initio calculations of the potential-energy surface and the dipole moment are presented and are used in variational ro-vibrational calculations to assign the spectral features. These calculations highlight the importance of basis set in the simulation of heavy atoms such as iodine. Further, they demonstrate extensive mode mixing between the bend and the H-atom stretch modes in BrHI- and BrDI- due to Fermi resonances. These interactions result in major deviations from simple harmonic estimates of the vibrational energies. As a result of this new analysis, previous matrix-isolation spectra assignments are reevaluated. (C) 2004 American Institute of Physics.

Nonlinear system identification using particle swarm optimisation tuned radial basis function models

A novel particle swarm optimisation (PSO) tuned radial basis function (RBF) network model is proposed for identification of non-linear systems. At each stage of orthogonal forward regression (OFR) model construction process, PSO is adopted to tune one RBF unit's centre vector and diagonal covariance matrix by minimising the leave-one-out (LOO) mean square error (MSE). This PSO aided OFR automatically determines how many tunable RBF nodes are sufficient for modelling. Compared with the-state-of-the-art local regularisation assisted orthogonal least squares algorithm based on the LOO MSE criterion for constructing fixed-node RBF network models, the PSO tuned RBF model construction produces more parsimonious RBF models with better generalisation performance and is often more efficient in model construction. The effectiveness of the proposed PSO aided OFR algorithm for constructing tunable node RBF models is demonstrated using three real data sets.

Particle swarm optimization aided orthogonal forward regression for unified data modeling

We propose a unified data modeling approach that is equally applicable to supervised regression and classification applications, as well as to unsupervised probability density function estimation. A particle swarm optimization (PSO) aided orthogonal forward regression (OFR) algorithm based on leave-one-out (LOO) criteria is developed to construct parsimonious radial basis function (RBF) networks with tunable nodes. Each stage of the construction process determines the center vector and diagonal covariance matrix of one RBF node by minimizing the LOO statistics. For regression applications, the LOO criterion is chosen to be the LOO mean square error, while the LOO misclassification rate is adopted in two-class classification applications. By adopting the Parzen window estimate as the desired response, the unsupervised density estimation problem is transformed into a constrained regression problem. This PSO aided OFR algorithm for tunable-node RBF networks is capable of constructing very parsimonious RBF models that generalize well, and our analysis and experimental results demonstrate that the algorithm is computationally even simpler than the efficient regularization assisted orthogonal least square algorithm based on LOO criteria for selecting fixed-node RBF models. Another significant advantage of the proposed learning procedure is that it does not have learning hyperparameters that have to be tuned using costly cross validation. The effectiveness of the proposed PSO aided OFR construction procedure is illustrated using several examples taken from regression and classification, as well as density estimation applications.

Radial basis function classifier construction using particle swarm optimisation aided orthogonal forward regression

We develop a particle swarm optimisation (PSO) aided orthogonal forward regression (OFR) approach for constructing radial basis function (RBF) classifiers with tunable nodes. At each stage of the OFR construction process, the centre vector and diagonal covariance matrix of one RBF node is determined efficiently by minimising the leave-one-out (LOO) misclassification rate (MR) using a PSO algorithm. Compared with the state-of-the-art regularisation assisted orthogonal least square algorithm based on the LOO MR for selecting fixednode RBF classifiers, the proposed PSO aided OFR algorithm for constructing tunable-node RBF classifiers offers significant advantages in terms of better generalisation performance and smaller model size as well as imposes lower computational complexity in classifier construction process. Moreover, the proposed algorithm does not have any hyperparameter that requires costly tuning based on cross validation.

Induced random fields in the LiHoxY1-xF4 quantum ising magnet in a transverse magnetic field

The LiHoxY1-xF4 magnetic material in a transverse magnetic field Bxx̂ perpendicular to the Ising spin direction has long been used to study tunable quantum phase transitions in a random disordered system. We show that the Bx-induced magnetization along the x̂ direction, combined with the local random dilution-induced destruction of crystalline symmetries, generates, via the predominant dipolar interactions between Ho3+ ions, random fields along the Ising ẑ direction. This identifies LiHoxY1-xF4 in Bx as a new random field Ising system. The random fields explain the rapid decrease of the critical temperature in the diluted ferromagnetic regime and the smearing of the nonlinear susceptibility at the spin-glass transition with increasing Bx and render the Bx-induced quantum criticality in LiHoxY1-xF4 likely inaccessible.

Supramolecular structures of enzyme clusters

The structural characterization of subtilisin mesoscale clusters, which were previously shown to induce supramolecular order in biocatalytic self-assembly of Fmocdipeptides, was carried out by synchrotron small-angle X-ray, dynamic, and static light scattering measurements. Subtilisin molecules self-assemble to form supramolecular structures in phosphate buffer solutions. Structural arrangement of subtilisin clusters at 55 degrees Centigrade was found to vary systematically with increasing enzyme concentration. Static light scattering measurements showed the cluster structure to be consistent with a fractal-like arrangement, with fractal dimension varying from 1.8 to 2.6 with increasing concentration for low to moderate enzyme concentrations. This was followed by a structural transition around the enzyme concentration of 0.5 mg mL-1 to more compact structures with significantly slower relaxation dynamics, as evidenced by dynamic light scattering measurements. These concentration-dependent supramolecular enzyme clusters provide tunable templates for biocatalytic self-assembly.

Tuning thermal properties and microphase separation in aliphatic polyester ABA copolymers

Four alkyl substituted β-lactones were investigated as monomers in ring opening polymerisation to produce a family of poly(3-hydroxyalkanoate)s. Homopolymers were synthesised using a robust aluminium salen catalyst, resulting in polymers with low dispersity (Đ < 1.1) and predictable molecular weights. ABA triblock copolymers were prepared using poly(L-lactic acid) as the A block and the aforementioned poly(3-hydroxyalkanoate) as the B block via a sequential addition method. Characterisation of these copolymers determined they were well controlled with low dispersities and predictable molecular weight. DSC analysis determined copolymers prepared from β-butyrolactone or β-valerolactone yielded polymers with tunable and predictable thermal properties. Copolymers prepared from β-heptanolactone yielded a microphase separated material as indicated by SAXS, with two distinct Tgs. The polymers could be readily cast into flexible films and their improved tensile properties were explored.

Enantiomeric conformation controls rate and yield of photoinduced electron transfer in DNA sensitized by Ru(II) Dipyridophenazine complexes

Photosensitized oxidation of guanine is an important route to DNA damage. Ruthenium polypyridyls are very useful photosensitizers as their reactivity and DNA-binding properties are readily tunable. Here we show a strong difference in the reactivity of the two enantiomers of [Ru(TAP)2(dppz)]2+, by using time-resolved visible and IR spectroscopy. This reveals that the photosensitized one-electron oxidation of guanine in three oligonucleotide sequences proceeds with similar rates and yields for bound delta-[Ru(TAP)2(dppz)]2+, whereas those for the lambda enantiomer are very sensitive to base sequence. It is proposed that these differences are due to preferences of each enantiomer for different binding sites in the duplex.

Observation of two-magnon bound states in the spin-1 anisotropic Heisenberg antiferromagnetic chain system NiCl2-4SC(NH2)(2)

Results of systematic tunable-frequency ESR studies of the spin dynamics in NiCl2-4SC(NH2)(2) (known as DTN), a gapped S = 1 chain system with easy-plane anisotropy dominating over the exchange coupling (large-D chain), are presented. We have obtained direct evidence for two-magnon bound states, predicted for S = 1 large-D spin chains in the fully spin-polarized (FSP) phase. The frequency-field dependence of the corresponding excitations was calculated using the set of parameters obtained earlier [S.A. Zvyagin, et al., Phys. Rev. Lett. 98 (2007) 047205]. Very good agreement between the calculations and the experiment was obtained. It is argued that the observation of transitions from the ground to two-magnon bound states might indicate a more complex picture of magnetic interactions in DTN, involving a finite in-plane anisotropy. (C) 2007 Elsevier B.V. All rights reserved.

Optical and dielectric relaxor behaviour of Ba(Zr(0.25)Ti(0.75))O(3) ceramic explained by means of distorted clusters

In this work, Ba(Zr(0.25)Ti(0.75))O(3) ceramic was prepared by solid-state reaction. This material was characterized by x-ray diffraction and Fourier transform Raman spectroscopy. The temperature dependent dielectric properties were investigated in the frequency range from 1 kHz to 1 MHz. The dielectric measurements indicated a diffuse phase transition. The broadening of the dielectric permittivity in the frequency range as well as its shifting at higher temperatures indicated a relaxor-like behaviour for this material. The diffusivity and the relaxation strength were estimated using the modified Curie-Weiss law. The optical properties were analysed by ultraviolet-visible (UV-vis) absorption spectroscopy and photoluminescence (PL) measurements at room temperature. The UV-vis spectrum indicated that the Ba(Zr(0.25)Ti(0.75))O(3) ceramic has an optical band gap of 2.98 eV. A blue PL emission was observed for this compound when excited with 350 nm wavelength. The polarity as well as the PL property of this material was attributed to the presence of polar [TiO(6)] distorted clusters into a globally cubic matrix.

Electrospinning of Hyperbranched Poly-L-Lysine/Polyaniline Nanofibers for Application in Cardiac Tissue Engineering

Electrospun polyaniline nanofibers are one of the most promising materials for cardiac tissue engineering due to their tunable electroactive properties. Moreover, the biocompatibility of polyaniline nanofibes can be improved by grafting of adhesive peptides during the synthesis. In this paper, we describe the biocompatible properties and cardiomyocytes proliferation on polyaniline electrospun nanofibers modified by hyperbranched poly-L-lysine dendrimers (HPLys). The microstructure characterization of the HPLys/polyaniline nanofibers was carried out by scanning electron microscopy (SEM). It was observed that the application of electrical current stimulates the differentiation of cardiac cells cultured on the nanofiber scaffolds. Both electroactivity and biocompatibility of the HPLys based nanofibers suggest the use this material for culture of cardiac cells and opens the possibility of using this material as a biocompatible electroactive 3-D matrix in cardiac tissue engineering.

Effects of hydroxyl group distribution on the reactivity, stability and optical properties of fullerenols

We investigate the impact of hydroxyl groups on the properties of C(60)(OH)(n) systems, with n = 1, 2, 3, 4, 8, 10, 16, 18, 24, 32 and 36 by means of first-principles density functional theory calculations. A detailed analysis from the local density of states has shown that adsorbed OH groups can induce dangling bonds in specific carbon atoms around the adsorption site. This increases the tendency to form polyhydroxylated fullerenes (fullerenols). The structural stability is analyzed in terms of the calculated formation enthalpy of each species. Also, a careful examination of the electron density of states for different fullerenols shows the possibility of synthesizing single molecules with tunable optical properties.

Controlled Drug Release from Ureasil-Polyether Hybrid Materials

Flexible, transparent, and insoluble urea-cross-linked polyether-siloxane hybrids presenting a tunable drug delivery pattern were prepared using the sol-gel method from PEO (poly(ethylene oxide)) and PPO (poly(propylene oxide)) functionalized at both chain ends with triethoxysilane. Different polyether chain lengths were used to control the urea/siloxane (named ureasil) node density, flexibility, and swellability of the hybrid network. We herein demonstrate that the drug release from swellable hydrophilic ureasil-PEO hybrids can be sustained for some days, whereas that from the unswellable ureasil-PPO hybrids can be sustained for some weeks. This outstanding feature conjugated with the biomedically safe formulation of the ureasil cross-linked polyether-siloxane hybrid widens their scope of application to include the domain of soft and implantable drug delivery devices.

Trajectory of neutron-neutron-C-18 excited three-body state

The trajectory of the first excited Efimov state is investigated by using a renormalized zero-range three-body model for a system with two bound and one virtual two-body subsystems. The approach is applied to n-n-C-18, where the n-n virtual energy and the three-body ground state are kept fixed. It is shown that such three-body excited state goes from a bound to a virtual state when the n-C-18 binding energy is increased. Results obtained for the n-C-19 elastic cross-section at low energies also show dominance of an S-matrix pole corresponding to a bound or virtual Efimov state. It is also presented a brief discussion of these findings in the context of ultracold atom physics with tunable scattering lengths. (C) 2008 Elsevier B.V. All rights reserved.