Diganta Bhusan Das

Influence of array interspacing on the force required for successful microneedle skin penetration: theoretical and practical approaches.

Insertion behaviour of microneedle (MN) arrays depends upon the mechanical properties of the skin and, MN geometry and distribution in an array. In addressing this issue, this paper studies MN array insertion mechanism into skin and provides a simple quantitative basis to relate the insertion force with distance between two MNs. The presented framework is based on drawing an analogy between a beam on an elastic foundation and mechanism of needle insertion, where insertion force is separated into different components. A theoretical analysis indicates that insertion force decreases as interspacing increases. For a specified skin type, insertion force decreased from 0.029 to 0.028 N/MN when interspacing at MN tip was increased from 50 μm (350 μm at MN base) to 150 μm (450 μm at MN base). However, dependence of insertion force seems to decrease as the interspacing is increased beyond 150 μm. To assess the validity of the proposed model, a series of experiments was carried out to determine the force required for skin insertion of MN. Experiments performed at insertion speed of 0.5 and 1.0 mm/s yielded insertion force values of 0.030 and 0.0216 N, respectively, for 30 μm interspacing at MN base (330 μm interspacing at tip) and 0.028 and 0.0214 N, respectively, for 600 μm interspacing at MN base (900 μm interspacing at tip). Results from theoretical analysis and finite element modelling agree well with experimental results, which show MN interspacing only begins to affect insertion force at low interspacing (<150 μm interspacing at MN base). This model provides a framework for optimising MN devices, and should aid development of suitable application method and determination of force for reliable insertion into 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.

A finite volume model for the hydrodynamics of combined free and porous flow in sub-surface regions

Abstract In this paper, a finite volume model for the 3-D analysis of sub-surface water flow is described. The model is applied to simulate groundwater hydrodynamics in domains representing combined free flow and porous sections. The free flow section is isotropic, while the porous section is assumed to be a saturated and anisotropic medium with a constant porosity. The Navier–Stokes equations are used to simulate the free flow regime, while the porous flow is modelled by the Darcy equation. The governing equations of motion for each sub-domain are linked through the imposition of suitable matching conditions at the free/porous flow interface. At the exit from the domain, ‘no boundary condition’ is imposed to avoid forcing of any artificial condition on the flow system. This is guided by previously published work that recommends this approach for obtaining realistic simulations for complex flow systems. Results presented in this paper show that depending on pressure distribution, underground flow circulation inside the porous domain may occur. It is also shown that the direction of the porous flow may reverse at the interface, with the flow front reversal and the circulation centre moving away from their initial positions with time.

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.

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

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Glass capillary microfluidics for production of monodispersed poly (dl-lactic acid) and polycaprolactone microparticles: Experiments and numerical simulations

HYPOTHESIS Droplet size in microfluidic devices is affected by wettability of the microfluidic channels. Three-dimensional countercurrent flow focusing using assemblies of chemically inert glass capillaries is expected to minimize wetting of the channel walls by the organic solvent. EXPERIMENTS Monodispersed polycaprolactone and poly(lactic acid) particles with a diameter of 18-150 μm were produced by evaporation of solvent (dichloromethane or 1:2 mixture of chloroform and toluene) from oil-in-water or water-in-oil-in-water emulsions produced in three-dimensional flow focusing glass capillary devices. The drop generation behaviour was simulated numerically using the volume of fluid method. FINDINGS The numerical results showed good agreement with high-speed video recordings. Monodispersed droplets were produced in the dripping regime when the ratio of the continuous phase flow rate to dispersed phase flow rate was 5-20 and the Weber number of the dispersed phase was less than 0.01. The porosity of polycaprolactone particles increased from 8 to 62% when 30 wt% of the water phase was incorporated in the organic phase prior to emulsification. The inner water phase was loaded with 0.156 wt% lidocaine hydrochloride to achieve a sustained drug release. 26% of lidocaine was released after 1 h and more than 93% of the drug was released after 130 h.

Microneedles for drug delivery: trends and progress.

Abstract In recent years, there has been a surge in the research and development of microneedles (MNs), a transdermal delivery system that combines the technology of transdermal patches and hypodermic needles. The needles are in the hundreds of micron length range and therefore allow relatively little or no pain. For example, biodegradable MNs have been researched in the literature and have several advantages compared with solid or hollow MNs, as they produce non-sharp waste and can be designed to allow rapid or slow release of drugs. However, they also pose a disadvantage as successful insertion into the stratum corneum layer of the skin relies on sufficient mechanical strength of the biodegradable material. This review looks at the various technologies developed in MN research and shows the rapidly growing numbers of research papers and patent publications since the first invention of MNs (using time series statistical analysis). This provides the research and industry communities a valuable synopsis of the trends and progress being made in this field.

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.

Microneedle Assisted Micro-Particle Delivery from Gene Guns: Experiments Using Skin-Mimicking Agarose Gel

A set of laboratory experiments has been carried out to determine if micro-needles (MNs) can enhance penetration depths of high-speed micro-particles delivered by a type of gene gun. The micro-particles were fired into a model target material, agarose gel, which was prepared to mimic the viscoelastic properties of porcine skin. The agarose gel was chosen as a model target as it can be prepared as a homogeneous and transparent medium with controllable and reproducible properties allowing accurate determination of penetration depths. Insertions of various MNs into gels have been analysed to show that the length of the holes increases with an increase in the agarose concentration. The penetration depths of micro-particle were analysed in relation to a number of variables, namely the operating pressure, the particle size, the size of a mesh used for particle separation and the MN dimensions. The results suggest that the penetration depths increase with an increase of the mesh pore size, because of the passage of large agglomerates. As these particles seem to damage the target surface, then smaller mesh sizes are recommended; here, a mesh with a pore size of 178 μm was used for the majority of the experiments. The operating pressure provides a positive effect on the penetration depth, that is it increases as pressure is increased. Further, as expected, an application of MNs maximises the micro-particle penetration depth. The maximum penetration depth is found to increase as the lengths of the MNs increase, for example it is found to be 1272 ± 42, 1009 ± 49 and 656 ± 85 μm at 4.5 bar pressure for spherical micro-particles of 18 ± 7 μm diameter when we used MNs of 1500, 1200 and 750 μm length, respectively.

Potential of microneedle-assisted micro-particle delivery by gene guns: a review

Abstact Context: Gene guns have been used to deliver deoxyribonucleic acid (DNA) loaded micro-particle and breach the muscle tissue to target cells of interest to achieve gene transfection. Objective: This article aims to discuss the potential of microneedle (MN) assisted micro-particle delivery from gene guns, with a view to reducing tissue damage. Methods: Using a range of sources, the main gene guns for micro-particle delivery are reviewed along with the primary features of their technology, e.g. their design configurations, the material selection of the micro-particle, the driving gas type and pressure. Depending on the gene gun system, the achieved penetration depths in the skin are discussed as a function of the gas pressure, the type of the gene gun system and particle size, velocity and density. The concept of MN-assisted micro-particles delivery which consists of three stages (namely, acceleration, separation and decoration stage) is discussed. In this method, solid MNs are inserted into the skin to penetrate the epidermis/dermis layer and create holes for particle injection. Several designs of MN array are discussed and the insertion mechanism is explored, as it determines the feasibility of the MN-based system for particle transfer. Results: This review suggests that one of the problems of gene guns is that they need high operating pressures, which may result in direct or indirect tissue/cells damage. MNs seem to be a promising method which if combined with the gene guns may reduce the operating pressures for these devices and reduce tissue/cell damages. Conclusions: There is sufficient potential for MN-assisted particle develivery systems.