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.

Assessment of virtual design and manufacturing techniques for fibre reinforced composite materials

Virtual tools are commonly used nowadays to optimize product design and manufacturing process of fibre reinforced composite materials. The present work focuses on two areas of interest to forecast the part performance and the production process particularities. The first part proposes a multi-physical optimization tool to support the concept stage of a composite part. The strategy is based on the strategic handling of information and, through a single control parameter, is able to evaluate the effects of design variations throughout all these steps in parallel. The second part targets the resin infusion process and the impact of thermal effects. The numerical and experimental approach allowed the identificationof improvement opportunities regarding the implementation of algorithms in commercially available simulation software.

Serviceability behaviour of fibre reinforced polymer reinforced concrete beams

El uso de materiales compuestos de matriz polimérica (FRP) emerge como alternativa al hormigón convencionalmente armado con acero debido a la mayor resistencia a la corrosión de dichos materiales. El presente estudio investiga el comportamiento en servicio de vigas de hormigón armadas con barras de FRP mediante un análisis teórico y experimental. Se presentan los resultados experimentales de veintiséis vigas de hormigón armadas con barras de material compuesto de fibra de vidrio (GFRP) y una armada con acero, todas ellas ensayadas a flexión de cuatro puntos. Los resultados experimentales son analizados y comparados con algunos de los modelos de predicción más significativos de flechas y fisuración, observándose, en general, una predicción adecuada del comportamiento experimental hasta cargas de servicio. El análisis de sección fisurada (CSA) estima la carga última con precisión, aunque se registra un incremento de la flecha experimental para cargas superiores a las de servicio. Esta diferencia se atribuye a la influencia de las deformaciones por esfuerzo cortante y se calcula experimentalmente. Se presentan los aspectos principales que influyen en los estados límites de servicio: tensiones de los materiales, ancho máximo de fisura y flecha máxima permitida. Se presenta una metodología para el diseño de dichos elementos bajo las condiciones de servicio. El procedimiento presentado permite optimizar las dimensiones de la sección respecto a metodologías más generales.

Simulation of delamination in composites under quasi-static and fatigue loading using cohesive zone models

Es desenvolupa una eina de disseny per l'anàlisi de la tolerància al dany en composites. L'eina pot predir el inici i la propagació de fisures interlaminars. També pot ser utilitzada per avaluar i planificar la necessitat de reparar o reemplaçar components durant la seva vida útil. El model desenvolupat pot ser utilitzat tan per simular càrregues estàtiques com de fatiga. El model proposat és un model de dany termodinàmicament consistent que permet simular la delaminació en composites sota càrregues variables. El model es formula dins el context de la Mecànica del Dany, fent ús dels models de zona cohesiva. Es presenta un metodologia per determinar els paràmetres del model constitutiu que permet utilitzar malles d'elements finits més bastes de les que es poden usar típicament. Finalment, el model és també capaç de simular la delaminació produïda per càrregues de fatiga.

Conductive elastomeric composites

Conductive elastic materials are formed by distributing conductive particles within an elastic polymer. We consider a novel composite based on dendritic nickel particles that exhibit remarkably strong negative piezoresistivity with an increase in conductivity of up to 10 orders of magnitude with strains of the order of 0.2. A vital factor for the conductivity of conductive elastomers is the concentration of conductive fillers and many aspects can be understood in terms of percolation theory. In this system the concentration of particles within the composite does not change with strain, yet due to the shape of the particles, the concentration of electrical contacts between the particles does change. We have developed a new model based on the concentration of contact sites, rather than particles which enables us to successfully model this remarkable strain-dependence of conductivity.

Infrared actuation in aligned polymer-nanotube composites

Rubber composites containing multiwalled carbon nanotubes have been irradiated with near-infrared light to study their reversible photomechanical actuation response. We demonstrate that the actuation is reproducible across differing polymer systems. The response is directly related to the degree of uniaxial alignment of the nanotubes in the matrix, contracting the samples along the alignment axis. The actuation stroke depends on the specific polymer being tested; however, the general response is universal for all composites tested. We conduct a detailed study of tube alignment induced by stress and propose a model for the reversible actuation behavior based on the orientational averaging of the local response. The single phenomenological parameter of this model describes the response of an individual tube to adsorption of low-energy photons; its experimentally determined value may suggest some ideas about such a response.

Mechanical effects of plant cell wall enzymes on xyloglucan/cellulose composites

Xyloglucan-acting enzymes are believed to have effects on type I primary plant cell wall mechanical properties. In order to get a better understanding of these effects, a range of enzymes with different in vitro modes of action were tested against cell wall analogues (bio-composite materials based on Acetobacter xylinus cellulose and xyloglucan). Tomato pericarp xyloglucan endo transglycosylase (tXET) and nasturtium seed xyloglucanase (nXGase) were produced heterologously in Pichia pastoris. Their action against the cell wall analogues was compared with that of a commercial preparation of Trichoderma endo-glucanase (EndoGase). Both 'hydrolytic' enzymes (nXGase and EndoGase) were able to depolymerise not only the cross-link xyloglucan fraction but also the surface-bound fraction. Consequent major changes in cellulose fibril architecture were observed. In mechanical terms, removal of xyloglucan cross-links from composites resulted in increased stiffness (at high strain) and decreased visco-elasticity with similar extensibility. On the other hand, true transglycosylase activity (tXET) did not affect the cellulose/xyloglucan ratio. No change in composite stiffness or extensibility resulted, but a significant increase in creep behaviour was observed in the presence of active tXET. These results provide direct in vitro evidence for the involvement of cell wall xyloglucan-specific enzymes in mechanical changes underlying plant cell wall re-modelling and growth processes. Mechanical consequences of tXET action are shown to be complimentary to those of cucumber expansin.

Evaluating forecasts of the evolution of the cloudy boundary layer using diurnal composites of radar and lidar observations

Observations of boundary-layer cloud have been made using radar and lidar at Chilbolton, Hampshire, UK. These have been compared with output from 7 different global and regional models. Fifty-five cloudy days have been composited to reveal the mean diurnal variation of cloud top and base heights, cloud thickness and liquid water path of the clouds. To enable like-for-like comparison between model and observations, the observations have been averaged on to the grid of each model. The composites show a distinct diurnal cycle in observed cloud; the cloud height exhibits a sinusoidal variation throughout the day with a maximum at around 1600 and a minimum at around 0700 UTC. This diurnal cycle is captured by six of the seven models analysed, although the models generally under-predict both cloud top and cloud base heights throughout the day. The two worst performing models in terms of cloud boundaries also have biases of around a factor of two in liquid water path; these were the only two models that did not include an explicit formulation for cloud-top entrainment.

Effects of drugs that potentiate GABA on extinction of positively-reinforced operant behaviour

Extinction following positively reinforced operant conditioning reduces response frequency, at least in part through the aversive or frustrative effects of non-reinforcement. According to J.A. Gray's theory, non-reinforcement activates the behavioural inhibition system which in turn causes anxiety. As predicted, anxiolytic drugs including benzodiazepines affect the operant extinction process. Recent studies have shown that reducing GABA-mediated neurotransmission retards extinction of aversive conditioning. We have shown in a series of studies that anxiolytic compounds that potentiate GABA facilitate extinction of positively reinforced fixed-ratio operant behaviour in C57B1/6 male mice. This effect does not occur in the early stages of extinction, nor is it dependent on cumulative effects of the compound administered. Potentiation of GABA at later stages has the effect of increasing sensitivity to the extinction contingency and facilitates the inhibition of the behaviour that is no longer required. The GABAergic hypnotic, zolpidem, has the same selective effects on operant extinction in this procedure. The effects of zolpidem are not due to sedative action. There is evidence across our series of experiments that different GABA-A subtype receptors are involved in extinction facilitation and anxiolysis. Consequently, this procedure may not be an appropriate model for anxiolytic drug action, but it may be a useful technique for analysing the neural bases of extinction and designing therapeutic interventions in humans where failure to extinguish inappropriate behaviours can lead to pathological conditions such as post-traumatic stress disorder.