Coupled Diffusion-Binding-Deformation Modelling for Phase-Transition Microneedles-Based Drug Delivery.

Phase-transition microneedles (PTMNs)-based transdermal drug delivery (TDD) is gaining popularity due to its non-invasiveness and ability to deliver a wide range of drugs. PTMNs absorb interstitial skin fluid (ISF) and transport drugs from microneedle (MNs) domain to the skin without polymer dissolution. To establish PTMNs for practical use, one needs to understand and optimise the key parameters governing drug transport mechanisms to achieve controlled drug delivery. In addressing this point, we have developed a coupled diffusion-binding-deformation model to understand the effect of physicochemical parameters (e.g., swelling capacity, drug binding) of MN and skin mechanical properties on overall drug transport behaviour. The contact mechanics at the MN and skin interface is introduced to account for the resistive force exerted by the deformed skin to MN swelling. The model is validated with the reported data of in vitro insulin delivery using polyvinyl alcohol (PVA) MN. The drug binding parameters are estimated from the fitting of the cumulative release of insulin within 6 hours of MN insertion. To predict the in vivo data of insulin delivery using the PVA MN, one-compartment model of drug pharmacokinetics is incorporated. It is shown in the paper that the model is able to predict the final insulin concentration in blood and in good agreement with the reported experimental data. The proposed model is concluded to be a tool for the predictive design and development of PTMNs-based TDD systems.

Barium Oxide Doped Magnesium Silicate Nanopowders for Bone Fracture Healing: Preparation, Characterization, Antibacterial and In Vivo Animal Studies.

Magnesium silicate (MgS) nanopowders doped with barium oxide (BaO) were prepared by sol-gel technique, which were then implanted into a fracture of a tibia bone in rats for studying enhanced in vivo bone regeneration. The produced nanopowders were characterized using X-ray diffraction (XRD), Fourier transform infrared spectra (FTIR), scanning electron microscope with energy-dispersive X-ray spectrometry (SEM-EDX) and transmission electron microscope (TEM). Mechanical and bactericidal properties of the nanopowders were also determined. Increased crystallinity, particle diameter and surface area were found to decrease after the BaO doping without any notable alterations on their chemical integrities. Moreover, elevated mechanical and antibacterial characteristics were recognized for higher BaO doping concentrations. Our animal studies demonstrated that impressive new bone tissues were formed in the fractures while the prepared samples degraded, indicating that the osteogenesis and degradability of the BaO containing MgS samples were better than the control MgS. The results of the animal study indicated that the simultaneous bone formation on magnesium biomaterial silicate and barium MgS with completed bone healing after five weeks of implantations. The findings also demonstrated that the prepared samples with good biocompatibility and degradability could enhance vascularization and osteogenesis, and they have therapeutic potential to heal bone fractures.

Decentralized systems for the treatment of antimicrobial compounds released from hospital aquatic wastes.

In many developing countries, untreated hospital effluents are discharged and treated simultaneously with municipal wastewater. However, if the hospital effluents are not treated separately, they pose concerning health risks due to the possible transport of the antimicrobial genes and microbes in the environment. Such effluent is considered as a point source for a number of potentially infectious microorganisms, waste antimicrobial compounds and other contaminants that could promote antimicrobial resistance development. The removal of these contaminants prior to discharge reduces the exposure of antimicrobials to the environment and this should lower the risk of superbug development. At an effluent discharge site, suitable pre-treatment of wastewater containing antimicrobials could maximise the ecological impact with potentially reduced risk to human health. In addressing these points, this paper reviews the applications of decentralized treatment systems toward reducing the concentration of antimicrobials in wastewater. The most commonly used techniques in decentralized wastewater treatment systems for onsite removal of antimicrobials were discussed and evidence suggests that hybrid techniques should be more useful for the efficient removal of antimicrobials. It is concluded that alongside the cooperation of administration departments, health industries, water treatment authorities and general public, decentralized treatment technology can efficiently enhance the removal of antimicrobial compounds, thereby decreasing the concentration of contaminants released to the environment that could pose risks to human and ecological health due to development of antimicrobial resistance in microbes.

Translation of Polymeric Microneedles for Treatment of Human Diseases: Recent Trends, Progress, and Challenges.

The ongoing search for biodegradable and biocompatible microneedles (MNs) that are strong enough to penetrate skin barriers, easy to prepare, and can be translated for clinical use continues. As such, this review paper is focused upon discussing the key points (e.g., choice polymeric MNs) for the translation of MNs from laboratory to clinical practice. The review reveals that polymers are most appropriately used for dissolvable and swellable MNs due to their wide range of tunable properties and that natural polymers are an ideal material choice as they structurally mimic native cellular environments. It has also been concluded that natural and synthetic polymer combinations are useful as polymers usually lack mechanical strength, stability, or other desired properties for the fabrication and insertion of MNs. This review evaluates fabrication methods and materials choice, disease and health conditions, clinical challenges, and the future of MNs in public healthcare services, focusing on literature from the last decade.

Mathematical Modelling, Simulation and Optimisation of Microneedles for Transdermal Drug Delivery: Trends and Progress.

In the last two decades, microneedles (MNs) have received significant interest due to their potential for painless transdermal drug delivery (TDD) and minimal skin damage. MNs have found applications in a range of research and development areas in drug delivery. They have been prepared using a variety of materials and fabrication techniques resulting in MN arrays with different dimensions, shapes, and geometries for delivery of a variety of drug molecules. These parameters play crucial roles in determining the drug release profiles from the MNs. Developing mathematical modelling, simulation, and optimisation techniques is vital to achieving the desired MN performances. These will then be helpful for pharmaceutical and biotechnological industries as well as professionals working in the field of regulatory affairs focusing on MN based TDD systems. This is because modelling has a great potential to reduce the financial and time cost of both the MNs' studies and manufacturing. For example, a number of robust mathematical models for predicting the performance of the MNs in vivo have emerged recently which incorporate the roles of the structural and mechanical properties of the skin. In addressing these points, this review paper aims to highlight the current status of the MN modelling research, in particular, the modelling, simulation and optimisation of the systems for drug delivery. The theoretical basis for the simulation of MN enhanced diffusion is discussed within this paper. Thus, this review paper provides a better understanding of the modelling of the MN mediated drug delivery process.

Glucose diffusivity in cell-seeded tissue engineering scaffolds.

OBJECTIVE: To determine the effective glucose diffusion coefficient in cell-seeded porous scaffolds to understand the importance of nutrient diffusion in tissue engineering bioreactors. RESULTS: Cell growth changed the morphological structure of the scaffolds decreasing the effective pore space and, inevitably, decreasing the effective glucose diffusivity in the chosen scaffolds, namely, collagen, poly(L-lactide) and poly(caprolactone) scaffolds from 3.7 × 10(-9) to 3.2 × 10(-9) m(2)/s, 1.4 × 10(-10) to 9.1 × 10(-11) m(2)/s and 1.8 × 10(-10) to 1.3 × 10(-10) m(2)/s, respectively. CONCLUSIONS: The presence of cells over time during cell culture reduces the mobility of glucose. The results can predict the glucose concentration profiles in thick engineered tissues.

Lidocaine carboxymethylcellulose with gelatine co-polymer hydrogel delivery by combined microneedle and ultrasound.

A study that combines microneedles (MNs) and sonophoresis pre-treatment was explored to determine their combined effects on percutaneous delivery of lidocaine from a polymeric hydrogel formulation. Varying ratios of carboxymethylcellulose and gelatine (NaCMC/gel ranges 1:1.60-1:2.66) loaded with lidocaine were prepared and characterized for zeta potential and particle size. Additionally, variations in the formulation drying techniques were explored during the formulation stage. Ex vivo permeation studies using Franz diffusion cells measured lidocaine permeation through porcine skin after pre-treatment with stainless steel MNs and 20 kHz sonophoresis for 5-and 10-min durations. A stable formulation was related to a lower gelatine mass ratio because of smaller mean particle sizes and high zeta potential. Lidocaine permeability in skin revealed some increases in permeability from combined MN and ultrasound pre-treatment studies. Furthermore, up to 4.8-fold increase in the combined application was observed compared with separate pre-treatments after 30 min. Sonophoresis pre-treatment alone showed insignificant enhancement in lidocaine permeation during the initial 2 h period. MN application increased permeability at a time of 0.5 h for up to ∼17 fold with an average up to 4 fold. The time required to reach therapeutic levels of lidocaine was decreased to less than 7 min. Overall, the attempted approach promises to be a viable alternative to conventional lidocaine delivery methods involving painful injections by hypodermic needles. The mass transfer effects were fairly enhanced and the lowest amount of lidocaine in skin was 99.7% of the delivered amount at a time of 3 h for lidocaine NaCMC/GEL 1:2.66 after low-frequency sonophoresis and MN treatment.

Delivery of large molecular protein using flat and short microneedles prepared using focused ion beam (FIB) as a skin ablation tool.

Many studies have been reported in the literature on the effects of various geometries and lengths of microneedles (MNs) on transdermal drug delivery using a variety of drug molecules. In particular, sharp-tipped MNs have been used to disrupt the top layer of the skin, namely, stratum corneum (SC). It has also been shown that short- and flat-tipped MNs can pierce the SC and they have the potential to increase drug permeability. However, there is little work that explores MNs as a skin ablative tool with a view to increasing skin permeability. To address this point, well-defined small patterns (size of individual pattern 10-20 µm) on the tip of flat MN (tip radius of individual MN ∼250 µm) were created and their effects evaluated on the permeability of bovine serum albumin (BSA), which is chosen as a model drug of high molecular weight. The patterns on the tip of flat MN act as rough surfaces (e.g. like sand paper) which when applied on the surface of the skin ablate the SC layer. Focused ion beam (FIB) has been used as the fabrication technique for the MNs. The permeability data are then compared with the other data for flat- and sharp-tipped MN. The permeability data from passive diffusion experiments are used as the reference case. The exact number of MNs or patterns in the flat and patterned MN patches is not considered as important as they have not been designed to pierce the skin. However, this is an important consideration in the case of sharp MNs as they pierce and create cavities in the skin. It is found that the delivery of BSA with the fabricated flat and patterned MNs gave similar but somewhat lower drug permeation profile in comparison to the sharp MNs. Passive diffusion showed no permeation, as would be expected due to the large size of the chosen molecule.

A new paradigm for numerical simulation of microneedle-based drug delivery aided by histology of microneedle-pierced skin.

Microneedle (MN) is a relatively recent invention and an efficient technology for transdermal drug delivery (TDD). Conventionally, mathematical models of MNs drug delivery define the shape of the holes created by the MNs in the skin as the same as their actual geometry. Furthermore, the size of the MN holes in the skin is considered to be either the same or a certain fraction of the length of the MNs. However, the histological images of the MN-treated skin indicate that the real insertion depth is much shorter than the length of the MNs and the shapes may vary significantly from one case to another. In addressing these points, we propose a new approach for modeling MN-based drug delivery, which incorporates the histology of MN-pierced skin using a number of concepts borrowed from image processing tools. It is expected that the developed approach will provide better accuracy of the drug diffusion profile. A new computer program is developed to automatically obtain the outline of the MNs-treated holes and import these images into computer software for simulation of drug diffusion from MN systems. This method can provide a simple and fast way to test the quality of MNs design and modeling, as well as simulate experimental studies, for example, permeation experiments on MN-pierced skin using diffusion cell. The developed methodology is demonstrated using two-dimensional (2D) numerical modeling of flat MNs (2D). However, the methodology is general and can be implemented for three dimensional (3D) MNs if there is sufficient number of images for reconstructing a 3D image for numerical simulation. Numerical modeling for 3D geometry is demonstrated by using images of an ideal 3D MN. The methodology is not demonstrated for real 3D MNs, as there are not sufficient numbers of images for the purpose of this paper.

Potential of combined ultrasound and microneedles for enhanced transdermal drug permeation: a review.

Transdermal drug delivery (TDD) is limited by the outer layer of the skin, i.e., the stratum corneum. Research on TDD has become very active in the recent years and various technologies have been developed to overcome the resistance of the stratum corneum to molecular diffusion. In particular, researchers have started to consider the possibility of combining the TDD technologies in order to have further increase in drug permeability. Both microneedles (MNs) and ultrasound are promising technologies. They achieve enhancement in drug permeation via different mechanisms and therefore give a good potential for combining with each other. This review will focus on discussing the potential of this combinational technique along with other important issues, e.g., the mechanisms of ultrasound and MNs as it is and these mechanisms which are coupled via the two systems (i.e. MNs and ultrasound). We discuss the possible ways to achieve this combination as well as how this combination would increase the permeability. Some of the undeveloped (weaker) research areas of MNs and sonophoresis are also discussed in order to understand the true potential of combining the two technologies when they are developed further in the future. We propose several hypothetical combinations based on the possible mechanisms involved in MNs and ultrasound. Furthermore, we carry out a cluster analysis by which we determine the significance of this combinational method in comparison with some other selected combinational methods for TDD (e.g., MNs and iontophoresis). Using a time series analysis tool (ARIMA model), the current trend and the future development of combined MNs and ultrasound are also analysed. Overall, the review in this paper indicates that combining MNs and ultrasound is a promising TDD method for the future.

Effect of force of microneedle insertion on the permeability of insulin in skin.

Many experiments conducted in the literature have investigated the effect of microneedles (MNs) on insulin permeation across skin. There are also a number of articles that deal with the effect of MN insertion force in skin. However, there is little known on quantifying the relationship between the effect of MN insertion force and the amount of insulin permeated for given MNs. This issue is addressed in this article. MNs of 1100 µm and 1400 µm are used to conduct in vitro permeability experiments on porcine skin, using insulin. Histological images of MN treated skin are obtained from a microtome and the viscoelastic properties of the skin sample are measured using a rheometer. An in-house insertion force device is utilized that can reproducibly apply a specified force on MNs for a set period of time using compressed air. It is deduced that when porcine skin was pretreated with an applied force of 60.5 N and 69.1 N, the resultant amount of insulin permeated was approximately 3 µg and 25 µg over a 4-hour period for the MNs used. The amount of MN force applied to porcine skin was shown to be related to the amount of insulin permeated. An increase in insertion force increase the amount of insulin permeated. It was also demonstrated that using insufficient force may have reduced or prevented the amount of insulin passing through the skin, regardless of the geometry of the MNs.

Permeability enhancement for transdermal delivery of large molecule using low-frequency sonophoresis combined with microneedles.

Transdermal drug delivery is limited by the high resistance of skin towards diffusion of high-molecular-weight drugs. This is mainly because of the fact that the outer layer of the skin, that is the stratum corneum, can prevent diffusion of molecules whose molecular weight is greater than 500 Da. Sonophoresis can be used to enhance the permeability of the skin. However, in the delivery of large molecules, ultrasound alone cannot provide sufficient permeability enhancement. In addressing this issue, we propose optimised ultrasound combined with microneedles to further increase the permeation rates. In this paper, we use porcine ear skin to simulate human skin and treat the skin samples with both ultrasound and microneedles. Further, bovine serum albumin (BSA) is used as a model of larger molecular weight molecule. Our results show that the permeability of BSA is increased to 1 µm/s with the combination of 1.5 mm microneedles patch and 15-W ultrasound output which is about 10 times higher than the permeability obtained in passive diffusion. Diffusion with only microneedles or ultrasound pre-treatment is also tested. The maximum permeability from microneedles and ultrasound treatment reached 0.43 and 0.4 µm/s, respectively.

Potential of biodegradable microneedles as a transdermal delivery vehicle for lidocaine.

There has been an increasing interest in applying biotechnology in formulating and characterising new and innovative drug delivery methods, e.g., drug-loaded biodegradable microneedles within the area of transdermal delivery technology. Recently, microneedles have been proposed for use in pain management, e.g., post-operative pain management through delivery of a local anaesthetic, namely, lidocaine. Lidocaine is a fairly common, marketed prescription-based, local anaesthetic pharmaceutical, applied for relieving localised pain and lidocaine-loaded microneedles have been explored. The purpose of this review is to evaluate the properties of biodegradable polymers that may allow the preparation of microneedle systems, methods of preparing them and pharmacokinetic conditions in considering the potential use of lidocaine for delivery through the skin.

Optimizing microneedle arrays to increase skin permeability for transdermal drug delivery.

Improving drug permeability in the skin is one of the most important issues for designing new methods of transdermal drug delivery. Consequently, many techniques have been proposed to effectively deliver drugs across the stratum corneum. The microneedle is a new technology to enhance transdermal delivery of high-molecular-weight drugs. This technique combines the concepts of transdermal drug delivery across the skin with patches and hypodermic injections. The microneedles have been shown experimentally to increase the skin permeability by orders of magnitude in vitro for a range of drugs that differ in molecular size and weight. Recently, other questions appeared while using these microneedles, such as how to reduce needle diameters by which the hole is produced to be as small as possible to exclude bacteria and other foreign particles. Another issue is how to correlate the skin thickness and microneedle length with the skin permeability. In this work, we have developed an optimization framework for improving skin permeability to drugs by using microneedle arrays, which considers different classifications of skin thickness arising from different races, sex groups, ages, and anatomical regions. To know the optimum design of these microneedles, the effect of the microneedle geometry (e.g., number of microneedles, microneedle radius) on skin should be determined. In this work, the optimization algorithm is presented. The outcome of this work will be used to suggest optimum microneedle designs based on the parameters of interest.

Optimizing microneedle arrays for transdermal drug delivery: extension to non-square distribution of microneedles.

The technology of fabricating microneedle arrays to deliver high molecular weight drugs across skin in a minimally invasive manner is receiving increasing attention. Microneedle arrays with different geometries have been manufactured using materials such as glass, polymer, metal, etc. However, a framework that can identify the optimum designs of these arrays seems to be lacking. This is important since by optimizing the microneedles dimensions (e.g., surface area of the patch, microneedle radius, etc.) the permeability of drugs in skin can be increased. To address this issue, this study presents an optimization framework for transdermal delivery of high molecular weight drug from microneedle. The optimization process is based on determining an optimization function (g) for various microneedles patterns (e.g., square, diamond, triangular, etc.). We argue that higher the value of g is the higher the drug permeability in skin is. The outputs of the developed framework have allowed us to identify the optimum design of both solid and hollow microneedles. In particular, the results have been used to predict skin permeability of high molecular weight using microneedle system. Also, optimum designs based on different classifications of skin thickness (e.g., race, age, etc.) for transdermal delivery of drugs are suggested.

Modelling transdermal delivery of high molecular weight drugs from microneedle systems.

In the past few years, a number of microneedle designs have been proposed for transdermal drug delivery of high molecular weight drugs. However, most of them do not increase the drug permeability in skin significantly. In other cases, designs developed based on certain criteria (e.g. strength of the microneedles) have failed to meet other criteria (e.g. drug permeability in skin, throughputs of the drugs, etc.). It is obvious therefore that in order to determine the 'optimum' design of these microneedles, the effect of different factors (e.g. length of the microneedle, surface area of the patch, etc.) along with various transport properties of drug transport behaviour using microneedles should be determined accurately. Appropriate mathematical models for drug transport from these systems into skin have the potential to resolve some of these issues. To address this, a parametric analysis for transdermal delivery of a high molecular weight drug from a microneedle is presented in this paper. The simulations have allowed us to identify the significance of various factors that influence the drug delivery while designing microneedle arrays. A scaling analysis is also done which shows the functional dependence of drug concentration on other variables of skin and microneedle arrays.