Convergence of regenerative medicine and synthetic biology to develop standardized and validated models of human diseases with clinical relevance

In order to progress beyond currently available medical devices and implants, the concept of tissue engineering has moved into the centre of biomedical research worldwide. The aim of this approach is not to replace damaged tissue with an implant or device but rather to prompt the patient's own tissue to enact a regenerative response by using a tissue-engineered construct to assemble new functional and healthy tissue. More recently, it has been suggested that the combination of Synthetic Biology and translational tissue-engineering techniques could enhance the field of personalized medicine, not only from a regenerative medicine perspective, but also to provide frontier technologies for building and transforming the research landscape in the field of in vitro and in vivo disease models.

Preliminary investigations into the use of a functionalised polymer to reduce diffusion in Fricke gel dosimeters

Purpose A modification of the existing PVA-​FX hydrogel has been made to investigate the use of a functionalised polymer in a Fricke gel dosimetry system to decrease Fe3+ diffusion. Methods The chelating agent, xylenol orange, was chem. bonded to the gelling agent, polyvinyl alc. (PVA) to create xylenol orange functionalised PVA (XO-​PVA)​. A gel was created from the XO-​PVA (20​% w​/v) with ferrous sulfate (0.4 mM) and sulfuric acid (50 mM)​. Results This resulted in an optical d. dose sensitivity of 0.014 Gy-​1, an auto-​oxidn. rate of 0.0005 h-​1, and a diffusion rate of 0.129 mm2 h-​1; an 8​% redn. compared to the original PVA-​FX gel, which in practical terms adds approx. 1 h to the time span between irradn. and accurate read-​out. Conclusions Because this initial method of chem. bonding xylenol orange to polyvinyl alc. has inherently low conversion, the improvement on existing gel systems is minimal when compared to the drawbacks. More efficient methods of functionalising polyvinyl alc. with xylenol orange must be developed for this system to gain clin. relevance.

The use of a synthetic prostaglandin e1 analogue (misoprostol) as an adjunct to pancreatic enzyme replacement in cystic fibrosis

Eleven cystic fibrosis children (mean age, 9.6 years) were chosen at random to participate in a study to observe the effects of concurrently stimulating gastric/duodenal bicarbonate secretion and inhibiting gastric acid secretion, using a methylated prostaglandin E1 analogue in patients with pancreatic insufficiency and taking pancreatic enzymes. Percentage fat absorption in 3-day stool collections were calculated before and after commencing therapy with misoprostol, 400 μg/day in divided doses. We found a significant reduction in fat output (14.7 ± 11.7 versus 7.5 ± 3.5 g/day, p < 0.05) in the study group as a whole and a significant reduction in steatorrhoeic level as a percentage of fat intake in all of the patients with abnormal base-line collections (23.1% versus 9.2% p < 0.002). We conclude that misoprostol should be considered in cystic fibrosis patients with steatorrhoea as a means of improving nutrient absorption. © 1988 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

The use of a synthetic prostaglandin-E1 analog (misoprostol) as an adjunct to pancreatic-enzyme replacement in cystic-fibrosis

Eleven cystic fibrosis children (mean age, 9.6 years) were chosen at random to participate in a study to observe the effects of concurrently stimulating gastric/duodenal bicarbonate secretion and inhibiting gastric acid secretion, using a methylated prostaglandin E1 analogue in patients with pancreatic insufficiency and taking pancreatic enzymes. Percentage fat absorption in 3-day stool collections were calculated before and after commencing therapy with misoprostol, 400 μg/day in divided doses. We found a significant reduction in fat output (14.7 ± 11.7 versus 7.5 ± 3.5 g/day, p < 0.05) in the study group as a whole and a significant reduction in steatorrhoeic level as a percentage of fat intake in all of the patients with abnormal base-line collections (23.1% versus 9.2%, p < 0.002). We conclude that misoprostol should be considered in cystic fibrosis patients with steatorrhoea as a means of improving nutrient absorption.

Polymer encapsulation of magnesium to control biodegradability and biocompatibility

Clinical utility of biodegradable magnesium implants is undermined by the untimely degradation of these materials in vivo. Their high corrosion rate leads to loss of mechanical integrity, peri–implant alkalization and localised accumulation of hydrogen gas. Biodegradable coatings were produced on pure magnesium using RF plasma polymerisation. A monoterpene alcohol with known anti-inflammatory and antibacterial properties was used as a polymer precursor. The addition of the polymeric layer was found to reduce the degradation rate of magnesium in simulated body fluid. The in vitro studies indicated good cytocompatibility of non-adherent THP–1 cells and mouse macrophage cells with the polymer, and the polymer coated sample. The viability of THP–1 cells was significantly improved when in contact with polymer encapsulated magnesium compared to unmodified samples. Collectively, these results suggest plasma enhanced polymer encapsulation of magnesium as a suitable method to control degradation kinetics of this biomaterial.

New encapsulating materials for implantable devices

Synthetic, natural, or composite, biomaterials occupy a key position in the management of disease and support continuous advancement of health care. Clinical utility of many permanent and biodegradable implants can be significantly improved via surface modification. Here, we discuss a novel polymer material developed from essential oil-based monoterpene alcohol using plasma polymerisation. The developed coatings are cytocompatible and limit adhesion and proliferation of a variety of pathogens. The coating can also be used to control degradation behaviour of resorbable materials, such as magnesium.

Complex permittivity measurements of RF plasma polymerized polyterpenol organic thin films employing split post dielectric resonator

In the fields of organic electronics and biotechnology, applications for organic polymer thin films fabricated using low-temperature non-equilibrium plasma techniques are gaining significant attention because of the physical and chemical stability of thin films and the low cost of production. Polymer thin films were fabricated from non-synthetic terpinen-4-ol using radiofrequency polymerization (13.56 MHz) on low loss dielectric substrates and their permittivity properties were ascertained to determine potential applications for these organic films. Real and imaginary parts of permittivity as a function of frequency were measured using the variable angle spectroscopic ellipsometer. The real part of permittivity (k) was found to be between 2.34 and 2.65 in the wavelength region of 400–1100 nm, indicating a potential low-k material. These permittivity values were confirmed at microwave frequencies. Dielectric properties of polyterpenol films were measured by means of split post dielectric resonators (SPDRs) operating at frequencies of 10 GHz and 20 GHz. Permittivity increased for samples deposited at higher RF energy – from 2.65 (25 W) to 2.83 (75 W) measured by a 20-GHz SPDR and from 2.32 (25 W) to 2.53 (100 W) obtained using a 10-GHz SPDR. The error in permittivity measurement was predominantly attributed to the uncertainty in film thickness measurement.

Effect of iodine doping on surface and optical properties of polyterpenol thin films

This study presents the effect of iodine doping on optical and surface properties of polyterpenol thin films deposited from non-synthetic precursor by means of plasma polymerisation. Spectroscopic ellipsometry studies showed iodine doping reduced the optical band gap from 2.82 eV to 1.50 eV for pristine and doped samples respectively. Higher levels of doping notably reduced the transparency of films, an issue if material is considered for applications that require high transparency. Contact angle studies demonstrated higher hydrophilicity for films deposited at increased doping levels, results confirmed by XPS Spectroscopy and FTIR. Doping had no significant effect on the surface profile or roughness of the film.

Post-deposition ageing reactions of plasma derived polyterpenol thin films

Owing to the structural flexibility, uncomplicated processing and manufacturing capabilities, plasma polymers are the subject of active academic as well as industrial research. Polymer thin films prepared from non-synthetic monomers combine desirable optical and physical properties with biocompatibility and environmental sustainability. However, the ultimate expediency and implementation of such materials will dependent on the stability of these properties under varied environmental conditions. Polyterpenol thin films were manufactured at different deposition powers. Under ambient conditions, the bulk of ageing occurred within first 150h after deposition and was attributed to oxidation and volumetric relaxation. Films observed for further 12 months showed no significant changes in thickness or refractive index. Thermal degradation behaviour indicated thermal stability increased for the films manufactured at higher RF powers. Annealing the films to 405°C resulted in full degradation, with retention between 0.29 and 0.99%, indicating films' potential as sacrificial material.

Fabrication and characterization of plasma polymer thin films from monoterpene alcohols for applications in organic electronics and biotechnology

After more than twenty years of basic and applied research, the use of nanotechnology in the design and manufacture of nanoscale materials is rapidly increasing, particularly in commercial applications that span from electronics across renewable energy areas, and biomedical devices. Novel polymers are attracting significant attention for they promise to provide a low−cost high−performance alternative to existing materials. Furthermore, these polymers have the potential to overcome limitations imposed by currently available materials thus enabling the development of new technologies and applications that are currently beyond our reach. This work focuses on the development of a range of new low−cost environmentally−friendly polymer materials for applications in areas of organic (flexible) electronics, optics, and biomaterials. The choice of the monomer reflects the environmentally−conscious focus of this project. Terpinen−4−ol is a major constituent of Australian grown Melaleuca alternifolia (tea tree) oil, attributed with the oil's antimicrobial and anti−inflammatory properties. Plasma polymerisation was chosen as a deposition technique for it requires minimal use of harmful chemicals and produces no hazardous by−products. Polymer thin films were fabricated under varied process conditions to attain materials with distinct physico−chemical, optoelectrical, biological and degradation characteristics. The resultant materials, named polyterpenol, were extensively characterised using a number of well−accepted and novel techniques, and their fundamental properties were defined. Polyterpenol films were demonstrated to be hydrocarbon rich, with variable content of oxygen moieties, primarily in the form of hydroxyl and carboxyl functionalities. The level of preservation of original monomer functionality was shown to be strongly dependent on the deposition energy, with higher applied power increasing the molecular fragmentation and substrate temperature. Polyterpenol water contact angle contact angle increased from 62.7° for the 10 W samples to 76.3° for the films deposited at 100 W. Polymers were determined to resist solubilisation by water, due to the extensive intermolecular and intramolecular hydrogen bonds present, and other solvents commonly employed in electronics and biomedical processing. Independent of deposition power, the surface topography of the polymers was shown to be smooth (Rq <0.5 nm), uniform and defect free. Hardness of polyterpenol coatings increased from 0.33 GPa for 10 W to 0.51 GPa for 100 W (at 500 μN load). Coatings deposited at higher input RF powers showed less mechanical deformation during nanoscratch testing, with no considerable damage, cracking or delamination observed. Independent of the substrate, the quality of film adhesion improved with RF power, suggesting these coatings are likely to be more stable and less susceptible to wear. Independent of fabrication conditions, polyterpenol thin films were optically transparent, with refractive index approximating that of glass. Refractive index increased slightly with deposition power, from 1.54 (10 W) to 1.56 (100 W) at 500 nm. The optical band gap values declined with increasing power, from 2.95 eV to 2.64 eV, placing the material within the range for semiconductors. Introduction of iodine impurity reduced the band gap of polyterpenol, from 2.8 eV to 1.64 eV, by extending the density of states more into the visible region of the electromagnetic spectrum. Doping decreased the transparency and increased the refractive index from 1.54 to 1.70 (at 500 nm). At optical frequencies, the real part of permittivity (k) was determined to be between 2.34 and 2.65, indicating a potential low-k material. These permittivity values were confirmed at microwave frequencies, where permittivity increased with input RF energy – from 2.32 to 2.53 (at 10 GHz ) and from 2.65 to 2.83 (at 20 GHz). At low frequencies, the dielectric constant was determined from current−voltage characteristics of Al−polyterpenol−Al devices. At frequencies below 100 kHz, the dielectric constant varied with RF power, from 3.86 to 4.42 at 1 kHz. For all samples, the resistivity was in order of 10⁸−10⁹ _m (at 6 V), confirming the insulating nature of polyterpenol material. In situ iodine doping was demonstrated to increase the conductivity of polyterpenol, from 5.05 × 10⁻⁸ S/cm to 1.20 × 10⁻⁶ S/cm (at 20 V). Exposed to ambient conditions over extended period of time, polyterpenol thin films were demonstrated to be optically, physically and chemically stable. The bulk of ageing occurred within first 150 h after deposition and was attributed to oxidation and volumetric relaxation. Thermal ageing studies indicated thermal stability increased for the films manufactured at higher RF powers, with degradation onset temperature associated with weight loss shifting from 150 ºC to 205 ºC for 10 W and 100 W polyterpenol, respectively. Annealing the films to 405 °C resulted in full dissociation of the polymer, with minimal residue. Given the outcomes of the fundamental characterisation, a number of potential applications for polyterpenol have been identified. Flexibility, tunable permittivity and loss tangent properties of polyterpenol suggest the material can be used as an insulating layer in plastic electronics. Implementation of polyterpenol as a surface modification of the gate insulator in pentacene-based Field Effect Transistor resulted in significant improvements, shifting the threshold voltage from + 20 V to –3 V, enhancing the effective mobility from 0.012 to 0.021 cm²/Vs, and improving the switching property of the device from 10⁷ to 10⁴. Polyterpenol was demonstrated to have a hole transport electron blocking property, with potential applications in many organic devices, such as organic light emitting diodes. Encapsulation of biomedical devices is also proposed, given that under favourable conditions, the original chemical and biological functionality of terpinen−4−ol molecule can be preserved. Films deposited at low RF power were shown to successfully prevent adhesion and retention of several important human pathogens, including P. aeruginosa, S. aureus, and S. epidermidis, whereas films deposited at higher RF power promoted bacterial cell adhesion and biofilm formation. Preliminary investigations into in vitro biocompatibility of polyterpenol demonstrated the coating to be non−toxic for several types of eukaryotic cells, including Balb/c mice macrophage and human monocyte type (HTP−1 non-adherent) cells. Applied to magnesium substrates, polyterpenol encapsulating layer significantly slowed down in vitro biodegradation of the metal, thus increasing the viability and growth of HTP−1 cells. Recently, applied to varied nanostructured titanium surfaces, polyterpenol thin films successfully reduced attachment, growth, and viability of P. aeruginosa and S. aureus.

Bayesian synthetic likelihood

Having the ability to work with complex models can be highly beneficial, but the computational cost of doing so is often large. Complex models often have intractable likelihoods, so methods that directly use the likelihood function are infeasible. In these situations, the benefits of working with likelihood-free methods become apparent. Likelihood-free methods, such as parametric Bayesian indirect likelihood that uses the likelihood of an alternative parametric auxiliary model, have been explored throughout the literature as a good alternative when the model of interest is complex. One of these methods is called the synthetic likelihood (SL), which assumes a multivariate normal approximation to the likelihood of a summary statistic of interest. This paper explores the accuracy and computational efficiency of the Bayesian version of the synthetic likelihood (BSL) approach in comparison to a competitor known as approximate Bayesian computation (ABC) and its sensitivity to its tuning parameters and assumptions. We relate BSL to pseudo-marginal methods and propose to use an alternative SL that uses an unbiased estimator of the exact working normal likelihood when the summary statistic has a multivariate normal distribution. Several applications of varying complexity are considered to illustrate the findings of this paper.

Plasma polymer and biomolecule modification of 3-D scaffolds for tissue engineering

Plasma polymerization was used to coat a melt electrospun polycaprolactone scaffold to improve cell attachment and organization. Plasma polymerization was performed using an amine containing monomer, allylamine, which then allowed for the subsequent immobilization of biomolecules i.e. heparin and fibroblast growth factor-2. The stability of the plasma polymerized amine-coating was demonstrated by X-ray photoelectron spectroscopy analysis and imaging time-of-flight secondary ion mass spectrometry revealed that a uniform plasma amine-coating was deposited throughout the scaffold. Based upon comparison with controls it was evident that the combination scaffold aided cell ingress and the formation of distinct fibroblast and keratinocyte layers.

What are the driving factors influencing the size distribution of airborne synthetic clay particles emitted from a jet milling process?

In the field of workplace air quality, measuring and analyzing the size distribution of airborne particles to identify their sources and apportion their contribution has become widely accepted, however, the driving factors that influence this parameter, particularly for nanoparticles (< 100 nm), have not been thoroughly determined. Identification of driving factors, and in turn, general trends in size distribution of emitted particles would facilitate the prediction of nanoparticles’ emission behavior and significantly contribute to their exposure assessment. In this study, a comprehensive analysis of the particle number size distribution data, with a particular focus on the ultrafine size range of synthetic clay particles emitted from a jet milling machine was conducted using the multi-lognormal fitting method. The results showed relatively high contribution of nanoparticles to the emissions in many of the tested cases, and also, that both surface treatment and feed rate of the machine are significant factors influencing the size distribution of the emitted particles of this size. In particular, applying surface treatments and increasing the machine feed rate have the similar effect of reducing the size of the particles, however, no general trend was found in variations of size distribution across different surface treatments and feed rates. The findings of our study demonstrate that for this process and other activities, where no general trend is found in the size distribution of the emitted airborne particles due to dissimilar effects of the driving factors, each case must be treated separately in terms of workplace exposure assessment and regulations.

Free energy calculations of the interactions of c-Jun-based synthetic peptides with the c-Fos protein

The c-Fos–c-Jun complex forms the activator protein 1 transcription factor, a therapeutic target in the treatment of cancer. Various synthetic peptides have been designed to try to selectively disrupt the interaction between c-Fos and c-Jun at its leucine zipper domain. To evaluate the binding affinity between these synthetic peptides and c-Fos, polarizable and nonpolarizable molecular dynamics (MD) simulations were conducted, and the resulting conformations were analyzed using the molecular mechanics generalized Born surface area (MM/GBSA) method to compute free energies of binding. In contrast to empirical and semiempirical approaches, the estimation of free energies of binding using a combination of MD simulations and the MM/GBSA approach takes into account dynamical properties such as conformational changes, as well as solvation effects and hydrophobic and hydrophilic interactions. The predicted binding affinities of the series of c-Jun-based peptides targeting the c-Fos peptide show good correlation with experimental melting temperatures. This provides the basis for the rational design of peptides based on internal, van der Waals, and electrostatic interactions.

Rational design of 3D dendritic TiO2 nanostructures with favorable architectures

Controlling the morphology and size of titanium dioxide (TiO2) nanostructures is crucial to obtain superior photocatalytic, photovoltaic, and electrochemical properties. However, the synthetic techniques for preparing such structures, especially those with complex configurations, still remain a challenge because of the rapid hydrolysis of Ti-containing polymer precursors in aqueous solution. Herein, we report a completely novel approach-three- dimensional (3D) TiO2 nanostructures with favorable dendritic architectures-through a simple hydrothermal synthesis. The size of the 3D TiO2 dendrites and the morphology of the constituent nano-units, in the form of nanorods, nanoribbons, and nanowires, are controlled by adjusting the precursor hydrolysis rate and the surfactant aggregation. These novel configurations of TiO2 nanostructures possess higher surface area and superior electrochemical properties compared to nanoparticles with smooth surfaces. Our findings provide an effective solution for the synthesis of complex TiO2 nano-architectures, which can pave the way to further improve the energy storage and energy conversion efficiency of TiO 2-based devices.