Laser-engineered dissolving microneedles for active transdermal delivery of nadroparin calcium

There is an urgent need to replace the injection currently used for low molecular weight heparin (LMWH) multidose therapy with a non- or minimally invasive delivery approach. In this study, laser-engineered dissolving microneedle (DMN) arrays fabricated from aqueous blends of 15% w/w poly(methylvinylether-co-maleic anhydride) were used for the first time in active transdermal delivery of the LMWH nadroparin calcium (NC). Importantly, an array loading of 630 IU of NC was achieved without compromising the array mechanical strength or drug bioactivity. Application of NC-DMNs to dermatomed human skin (DHS) using the single-step 'poke and release' approach allowed permeation of approximately 10.6% of the total NC load over a 48-h study period. The cumulative amount of NC that permeated DHS at 24 h and 48 h attained 12.28 ± 4.23 IU/cm and 164.84 ± 8.47 IU/cm , respectively. Skin permeation of NC could be modulated by controlling the DMN array variables, such as MN length and array density as well as application force to meet various clinical requirements including adjustment for body mass and renal function. NC-loaded DMN offers great potential as a relatively low-cost functional delivery system for enhanced transdermal delivery of LMWH and other macromolecules. © 2012 Elsevier B.V. All rights reserved.

On the application of genetic algorithms for optimising composites against impact loading

A genetic algorithm (GA) was adopted to optimise the response of a composite laminate subject to impact. Two different impact scenarios are presented: low-velocity impact of a slender laminated strip and high-velocity impact of a rectangular plate by a spherical impactor. In these cases, the GA's objective was to, respectively, minimise the peak deflection and minimise penetration by varying the ply angles.

The GA was coupled to a commercial finite-element (FE) package LS DYNA to perform the impact analyses. A comparison with a commercial optimisation package, LS OPT, was also made. The results showed that the GA was a robust, capable optimisation tool that produced near optimal designs, and performed well with respect to LS OPT for the more complex high-velocity impact scenario tested.

Effect of offset web holes on web crippling strength of cold-formed steel channel sections under end-two-flange loading condition

A combination of experiments and non-linear finite element analyses are used to investigate the effect of offset web holes on the web crippling strength of cold-formed steel channel sections under the end-two-flange (ETF) loading condition; the cases of both flanges fastened and unfastened to the support are considered. The web holes are located at the mid-depth of the sections, with a horizontal clear distance of the web holes to the near edge of the bearing plate. Finite element analysis results are compared against the laboratory test results; good agreement was obtained in terms of both strength and failure modes. A parametric study was then undertaken to investigate both the effect of the position of holes in the web and the cross-section sizes on the web crippling strength of the channel sections. It was demonstrated that the main factors influencing the web crippling strength are the ratio of the hole depth to the depth of the web, and the ratio of the distance from the edge of the bearing to the flat depth of the web. Design recommendations in the form of web crippling strength reduction factors are proposed in this study.

1-D constitutive model for evolution of stress-induced R-phase and localized Lüders-like stress-induced martensitic transformation of super-elastic NiTi wires

NiTi alloys have been widely used in the applications for micro-electro-mechanical-systems (MEMS), which often involve some precise and complex motion control. However, when using the NiTi alloys in MEMS application, the main problem to be considered is the degradation of functional property during cycling loading. This also stresses the importance of accurate prediction of the functional behavior of NiTi alloys. In the last two decades, a large number of constitutive models have been proposed to achieve the task. A portion of them focused on the deformation behavior of NiTi alloys under cyclic loading, which is a practical and non-negligible situation. Despite of the scale of modeling studies of the field in NiTi alloys, two experimental observations under uniaxial tension loading have not received proper attentions. First, a deviation from linearity well before the stress-induced martensitic transformation (SIMT) has not been modeled. Recent experiments confirmed that it is caused by the formation of stress-induced R phase. Second, the influence of the well-known localized Lüders-like SIMT on the macroscopic behavior of NiTi alloys, in particular the residual strain during cyclic loading, has not been addressed. In response, we develop a 1-D phenomenological constitutive model for NiTi alloys with two novel features: the formation of stress-induced R phase and the explicit modeling of the localized Lüders-like SIMT. The derived constitutive relations are simple and at the same time sufficient to describe the behavior of NiTi alloys. The accumulation of residual strain caused by R phase under different loading schemes is accurately described by the proposed model. Also, the residual strain caused by irreversible SIMT at different maximum loading strain under cyclic tension loading in individual samples can be explained by and fitted into a single equation in the proposed model. These results show that the proposed model successfully captures the behavior of R phase and the essence of localized SIMT.

Hydrogel-forming microneedle arrays exhibit antimicrobial properties:potential for enhanced patient safety

We describe, for the first time, the microbial characterisation of hydrogel-forming polymeric microneedle arrays and the potential for passage of microorganisms into skin following microneedle penetration. Uniquely, we also present insights into the storage stability of these hydroscopic formulations, from physical and microbiological viewpoints, and examine clinical performance and safety in human volunteers. Experiments employing excised porcine skin and radiolabelled microorganisms showed that microorganisms can penetrate skin beyond the stratum corneum following microneedle puncture. Indeed, the numbers of microorganisms crossing the stratum corneum following microneedle puncture were greater than 105 cfu in each case. However, no microorganisms crossed the epidermal skin. When using a 21G hypodermic needle, more than 104 microorganisms penetrated into the viable tissue and 106 cfu of Candida albicans and Staphylococcus epidermidis completely crossed the epidermal skin in 24 h. The hydrogel-forming materials contained no microorganisms following de-moulding and exhibited no microbial growth during storage, while also maintaining their mechanical strength, apart from when stored at relative humidities of 86%. No microbial penetration through the swelling microneedles was detectable, while human volunteer studies confirmed that skin or systemic infection is highly unlikely when polymeric microneedles are used for transdermal drug delivery. Since no pharmacopoeial standards currently exist for microneedle-based products, the exact requirements for a proprietary product based on hydrogel-forming microneedles are at present unclear. However, we are currently working towards a comprehensive specification set for this microneedle system that may inform future developments in this regard.

Characterization of physio-chemical processes and hydration kinetics in concretes containing supplementary cementitious materials using electrical property measurements

The current study monitors both the short- and long-term hydration characteristics of concrete using discretized conductivity measurements from initial gauging, through setting and hardening, the latter comprising both the curing and post-curing periods. In particular, attention is directed to the near-surface concrete as it is this zone which protects the steel from the external environment and has a major influence on durability, performance and service-life. A wide range of concrete mixes is studied comprising both plain Portland cement concretes and concretes containing fly-ash and ground granulated blast furnace slag. The parameter normalised conductivity was used to identify four distinct stages in the hydration process and highlight the influence of supplementary cementitious materials (SCM) on hydration and hydration kinetics. A relationship has been presented to account for the temporal decrease in conductivity, post 10-days hydration. The testing procedure and methodology presented lend itself to in-situ monitoring of reinforced concrete structures. (c) 2013 Elsevier Ltd. All rights reserved.

Optimized process for the inclusion of carbon nanotubes in elastomers with improved thermal and mechanical properties

The effects of addition of reinforcing carbon nanotubes (CNTs) into hydrogenated nitrile-butadiene rubber (HNBR) matrix on the mechanical, dynamic viscoelastic, and permeability properties were studied in this investigation. Different techniques of incorporating nanotubes in HNBR were investigated in this research. The techniques considered were more suitable for industrial preparation of rubber composites. The nanotubes were modified with different surfactants and dispersion agents to improve the compatibility and adhesion of nanotubes on the HNBR matrix. The effects of the surface modification of the nanotubes on various properties were examined in detail. The amount of CNTs was varied from 2.5 to 10 phr in different formulations prepared to identify the optimum CNT levels. A detailed analysis was made to investigate the morphological structure and mechanical behavior at room temperature. The viscoelastic behavior of the nanotube filler elastomer was studied by dynamic mechanical thermal analysis (DMTA). Morphological analysis indicated a very good dispersion of the CNTs for a low nanotube loading of 3.5 phr. A significant improvement in the mechanical properties was observed with the addition of nanotubes. DMTA studies revealed an increase in the storage modulus and a reduction in the glass-transition temperature after the incorporation of the nanotubes. Further, the HNBR/CNT nanocomposites were subjected to permeability studies. The studies showed a significant reduction in the permeability of nitrogen gas. Copyright © 2011 Wiley Periodicals, Inc.

Influence of nanoclays on mechanical and barrier properties of hydrogenated acrylonitrile butadiene rubber nanocomposites

In this research, two different methods have been investigated for optimising the preparation of hydrogenated acrylonitrile butadiene rubber/clay nanocomposites. Commercially available organoclay (Cloisite 20A) has been considered for the preparation of rubber nanocomposites. A detailed analysis has been made to investigate the morphological structure and mechanical behaviour at room temperature and at elevated temperature. Also the influence of organoclays on permeability has been studied. Structural analysis indicates very good dispersion for a low loading of 5 parts per hundred (phr) amount of nanoclays. Significant improvements in mechanical properties have been observed with the addition of organoclays at both room and elevated temperatures. Even with the low level of addition of nanoclays, there was a remarkable reduction in permeability. © Institute of Materials, Minerals and Mining 2011.

A unified view on the effect of fibers and loading on sfrc creep through linear projection to latent structures

Creep of Steel Fiber Reinforced Concrete (SFRC) under flexural loads in the cracked state and to what extent different factors determine creep behaviour are quite understudied topics within the general field of SFRC mechanical properties. A series of prismatic specimens have been produced and subjected to sustained flexural loads. The effect of a number of variables (fiber length and slenderness, fiber content, and concrete compressive strength) has been studied in a comprehensive fashion. Twelve response variables (creep parameters measured at different times) have been retained as descriptive of flexural creep behaviour. Multivariate techniques have been used: the experimental results have been projected to their latent structure by means of Principal Components Analysis (PCA), so that all the information has been reduced to a set of three latent variables. They have been related to the variables considered and statistical significance of their effects on creep behaviour has been assessed. The result is a unified view on the effects of the different variables considered upon creep behaviour: fiber content and fiber slenderness have been detected to clearly modify the effect that load ratio has on flexural creep behaviour.

Graded/Gradient Porous Biomaterials

Biomaterials include bioceramics, biometals, biopolymers and biocomposites and they play important roles in the replacement and regeneration of human tissues. However, dense bioceramics and dense biometals pose the problem of stress shielding due to their high Young's moduli compared to those of bones. On the other hand, porous biomaterials exhibit the potential of bone ingrowth, which will depend on porous parameters such as pore size, pore interconnectivity, and porosity. Unfortunately, a highly porous biomaterial results in poor mechanical properties. To optimise the mechanical and the biological properties, porous biomaterials with graded/gradient porosity, pores size, and/or composition have been developed. Graded/gradient porous biomaterials have many advantages over graded/gradient dense biomaterials and uniform or homogenous porous biomaterials. The internal pore surfaces of graded/gradient porous biomaterials can be modified with organic, inorganic, or biological coatings and the internal pores themselves can also be filled with biocompatible and biodegradable materials or living cells. However, graded/gradient porous biomaterials are generally more difficult to fabricate than uniform or homogenous porous biomaterials. With the development of cost-effective processing techniques, graded/gradient porous biomaterials can find wide applications in bone defect filling, implant fixation, bone replacement, drug delivery, and tissue engineering.

Effects of particle/matrix interface and strengthening mechanisms on the mechanical properties of metal matrix composites

A randomly distributed multi-particle model considering the effects of particle/matrix interface and strengthening mechanisms introduced by the particles has been constructed. Particle shape, distribution, volume fraction and the particles/matrix interface due to the factors including element diffusion were considered in the model. The effects of strengthening mechanisms, caused by the introduction of particles on the mechanical properties of the composites, including grain refinement strengthening, dislocation strengthening and Orowan strengthening, are incorporated. In the model, the particles are assumed to have spheroidal shape, with uniform distribution of the centre, long axis length and inclination angle. The axis ratio follows a right half-normal distribution. Using Monte Carlo method, the location and shape parameters of the spheroids are randomly selected. The particle volume fraction is calculated using the area ratio of the spheroids. Then, the effects of particle/matrix interface and strengthening mechanism on the distribution of Mises stress and equivalent strain and the flow behaviour for the composites are discussed.

Hydrogel-Forming Microneedles Prepared from ‘‘Super Swelling’’ Polymers Combined with Lyophilised Wafers for Transdermal Drug Delivery

We describe, for the first time, hydrogel-forming microneedle arrays prepared from "super swelling" polymeric compositions. We produced a microneedle formulation with enhanced swelling capabilities from aqueous blends containing 20% w/w Gantrez S-97, 7.5% w/w PEG 10,000 and 3% w/w Na2CO3 and utilised a drug reservoir of a lyophilised wafer-like design. These microneedle-lyophilised wafer compositions were robust and effectively penetrated skin, swelling extensively, but being removed intact. In in vitro delivery experiments across excised neonatal porcine skin, approximately 44 mg of the model high dose small molecule drug ibuprofen sodium was delivered in 24 h, equating to 37% of the loading in the lyophilised reservoir. The super swelling microneedles delivered approximately 1.24 mg of the model protein ovalbumin over 24 h, equivalent to a delivery efficiency of approximately 49%. The integrated microneedle-lyophilised wafer delivery system produced a progressive increase in plasma concentrations of ibuprofen sodium in rats over 6 h, with a maximal concentration of approximately 179 µg/ml achieved in this time. The plasma concentration had fallen to 71±6.7 µg/ml by 24 h. Ovalbumin levels peaked in rat plasma after only 1 hour at 42.36±17.01 ng/ml. Ovalbumin plasma levels then remained almost constant up to 6 h, dropping somewhat at 24 h, when 23.61±4.84 ng/ml was detected. This work represents a significant advancement on conventional microneedle systems, which are presently only suitable for bolus delivery of very potent drugs and vaccines. Once fully developed, such technology may greatly expand the range of drugs that can be delivered transdermally, to the benefit of patients and industry. Accordingly, we are currently progressing towards clinical evaluations with a range of candidate molecules.