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The delivery of particulate vaccines and drugs to human skin with a practical, hand-held shock tube-based system
Abstract
A unique form of powdered vaccine and drug delivery has been developed. The principle behind the concept is to accelerate
vaccine and drug particles, using a gas flow, so that they attain sufficient velocities to enter the skin and achieve a pharmaceutical
effect. This paper presents the Contoured Shock Tube (CST), configured to deliver particles to the skin with a narrow and
controlled velocity distribution and uniform spatial distribution. The gas and particle flows of a prototype CST are explored
experimentally and compared with Computational Fluid Dynamics (CFD) calculations. Some key steps in converting the prototype
into a practical hand-held vaccine and drug delivery system are discussed. The ability of this system to deliver particles
to the skin is illustrated by sample penetration data into excised human tissue.
... Powder injectors are non-invasive drug delivery systems that have received much attention because the drug delivery is painless and the chances of spreading of autoimmune and communicable diseases are none. Needleless drug delivery devices [5][6][7][8][9][10][11][12][13][14] use a shock tube to deliver painkillers, contraceptives, genetic material and insulin, which are frequently used treatments. Often, these devices involve a contoured shock tube with pressurized gas filled in first the compartment sealed by a diaphragm [5][6][7][8][9][10][11]. ...
... Needleless drug delivery devices [5][6][7][8][9][10][11][12][13][14] use a shock tube to deliver painkillers, contraceptives, genetic material and insulin, which are frequently used treatments. Often, these devices involve a contoured shock tube with pressurized gas filled in first the compartment sealed by a diaphragm [5][6][7][8][9][10][11]. In such devices, the drug particles are placed on the surface of the diaphragm facing the pressurized gas. ...
... The velocity, density and size of the drug particle were the main parameters governing drug particle penetration. Kendal [10] studied particle flow in a contoured shock tube using particle image velocimetry, which captured 500 m/s velocity of gold particles with a diameter of 1 µm. A unified penetration model predicted the particle penetration of 20-30 µm, which matched with experiments. ...
This paper presents the design optimization of diaphragms for a micro-shock tube-based drug delivery device. The function of the diaphragm is to impart the required velocity and direction to the loosely held drug particles on the diaphragm through van der Waals interaction. The finite element model-based studies involved diaphragms made up of copper, brass and aluminium. The study of the influence of material and geometric parameters serves as a vital tool in optimizing the magnitude and direction of velocity distribution on the diaphragm surface. Experiments carried out using a micro-shock tube validate the final deformed shape of the diaphragms determined from the finite element simulation. The diaphragm yields a maximum velocity of 335 m/s for which the maximum deviation of the velocity vector is 0.62°. Drug particles that travel to the destination target tissue are simulated using the estimated velocity distribution and angular deviation. Further, a theoretical model of penetration helps in the prediction of the drug particle penetration in the skin tissue like a target, which is found to be 0.126 mm. The design and calibration procedure of a micro-shock tube device to alter drug particle penetration considering the skin thickness and property are presented.
... An electric gene gun uses a high voltage (HV) to vaporize water droplets; the expanding gas is used to achieve the acceleration of microparticles (Christou et al., 1990). A gas gene gun releases a high pressure gas to accelerate the micro-particles (or microparticles loaded ground slide) to a sufficient velocity to breach the barrier of the target (Zhou, 2000;Kendall, 2002;Liu, 2007;Zhang et al., 2013). ...
... In this case, golden particles of 1-3 mm and 2-5 mm diameters have been fired and penetration depths of 150 and 200 mm have been obtained in a mouse liver, under 1300 psi operating pressure. Kendall (2002) has reported a contoured shock tube which is shown in Figure 8. In this case, the compressed gas will pressurize the membrane, and the micro-particle will be accelerated by a shock wave as the gas pressure rises to the point where the membrane ruptures. ...
... Driver Nozzle Figure 8. The schematic diagram of contoured shock tube [reproduced from Kendall (2002)]. DOI: 10.3109/10717544.2013.864345 ...
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.
... An electric gene gun uses a high voltage (HV) to vaporize water droplets; the expanding gas is used to achieve the acceleration of microparticles (Christou et al., 1990). A gas gene gun releases a high pressure gas to accelerate the micro-particles (or microparticles loaded ground slide) to a sufficient velocity to breach the barrier of the target (Zhou, 2000;Kendall, 2002;Liu, 2007;Zhang et al., 2013). ...
... In this case, golden particles of 1-3 mm and 2-5 mm diameters have been fired and penetration depths of 150 and 200 mm have been obtained in a mouse liver, under 1300 psi operating pressure. Kendall (2002) has reported a contoured shock tube which is shown in Figure 8. In this case, the compressed gas will pressurize the membrane, and the micro-particle will be accelerated by a shock wave as the gas pressure rises to the point where the membrane ruptures. ...
... Driver Nozzle Figure 8. The schematic diagram of contoured shock tube [reproduced from Kendall (2002)]. DOI: 10.3109/10717544.2013.864345 ...
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 delivery systems.
... A typical NFJI system creates a high velocity microjet with a velocity greater than 100 m/s to penetrate the skin surface. This high velocity microjet may be created due to the momentum transfer between a piston driven by mechanical or electrical actuators or by direct actuation like lasers [4][5][6][7][8][9][10] or shock waves [11,12]. The energy possessed by a compressed spring [13][14][15][16][17][18][19][20][21] or an expanding gas or air [22][23][24][25][26][27][28][29] is the energy source for mechanical actuators, whereas electrical actuators use Lorentz force [30][31][32][33][34] or piezoelectric [35,36] energy to move the piston. ...
... A major limitation in the development of a valid mathematical model on the interaction of a high-velocity microjet with a penetrated medium is the lack of understanding of the relevant parameters. Previous studies have investigated parameters that could influence the characteristics of a propelled microjet [11,14,15,[19][20][21][25][26][27][28]32,36,37,40,41,43,44,[46][47][48][49], but only a few studies investigated the mechanical properties of the penetrated medium. These studies focused on the Young's modulus of the medium [44,50] while little or no thought was given to other parametric aspects like porosity or the effect of layer junctions on penetration and dispersion characteristics. ...
Needle-free jet injection systems are characterized by the increased drug delivery efficacy over conventional needle-based injection systems and have become a viable alternative. The majority of previous studies have investigated underlying mechanisms of needle-free jet injection systems with an emphasis on the fluid dynamics of the propelled microjet without considering the influence of an injected medium on the penetration and dispersion of the microjet. Unlike the injected fluid introduced directly into a target region of the skin tissue through a hollow needle, the fluid microjet produced by a needle-free injector has to work through multiple skin tissue layers and interfaces having different mechanical properties. Here we evaluated injection characteristics in two hydrogel media having similar stiffness controlled precisely but different pore size and hence different fracture toughness. High-speed imaging data showed that the fracture toughness of the medium influenced the penetration mechanism of the injected microjet, whereas viscoelastic and poroelastic characteristics of the medium determined the final attainable injection profiles. The injection profiles were also dependent on the type and depth of the interface between the layers of two media, where tight and loose interfaces can have different effects on the distribution of injected drug as the injected fluid prefers the path having the least resistance. Our findings would improve the present understanding of needle-free jet injection systems and could help to develop more effective drug delivery systems.
... Shockwaves have been extensively used for various medical procedures like extracorporeal lithotripsy [11], treatment of avascular necrosis [12], accelerated bone fracture healing [13], angiogenesis [14] and tendinitis [15]. The use of shockwaves as a driving force for transdermal drug delivery has proved to be effective because of their ability to accelerate the drug particles to high velocities so that they can penetrate the skin [16][17][18][19][20][21].Shockwaves have also been demonstrated to generate high velocity projectiles for delivering nucleic acids into living cells [22][23][24][25]. However, the use of either compressed air bottles [16][17][18], ignition of detonable mixtures [20][21][22][23][24][25] or operation of bulky and expensive instruments [19] to generate shockwaves, make these techniques undesirable. ...
... The use of shockwaves as a driving force for transdermal drug delivery has proved to be effective because of their ability to accelerate the drug particles to high velocities so that they can penetrate the skin [16][17][18][19][20][21].Shockwaves have also been demonstrated to generate high velocity projectiles for delivering nucleic acids into living cells [22][23][24][25]. However, the use of either compressed air bottles [16][17][18], ignition of detonable mixtures [20][21][22][23][24][25] or operation of bulky and expensive instruments [19] to generate shockwaves, make these techniques undesirable. Also, many of the techniques result in the accumulation of waste and production of harmful by-products during the detonation of mixtures. ...
Background
Needle-free, painless and localized drug delivery has been a coveted technology in the area of biomedical research. We present an innovative way of trans-dermal vaccine delivery using a miniature detonation-driven shock tube device. This device utilizes~2.5 bar of in situ generated oxyhydrogen mixture to produce a strong shockwave that accelerates liquid jets to velocities of about 94 m/s.
Method
Oxyhydrogen driven shock tube was optimized for efficiently delivering vaccines in the intradermal region in vivo. Efficiency of vaccination was evaluated by pathogen challenge and host immune response. Expression levels of molecular markers were checked by qRT-PCR.
Results
High efficiency vaccination was achieved using the device. Post pathogen challenge with Mycobacterium tuberculosis, 100% survival was observed in vaccinated animals. Immune response to vaccination was significantly higher in the animals vaccinated using the device as compared to conventional route of vaccination.
Conclusion
A novel device was developed and optimized for intra dermal vaccine delivery in murine model. Conventional as well in-house developed vaccine strains were used to test the system. It was found that the vaccine delivery and immune response was at par with the conventional routes of vaccination. Thus, the device reported can be used for delivering live attenuated vaccines in the future.
Electronic supplementary material
The online version of this article (10.1186/s13036-017-0088-x) contains supplementary material, which is available to authorized users.
... According to Kendall et al, the impact parameter (ρrv) required for particles to breach the sc ranges from 7-12 (kg/mÁs) and is a function of particle density (ρ), radius (r) and velocity (v). [18] Generally, particles less than 100 μm in diameter have been reported as pain-free, while particles smaller than 20 μm were unable to penetrate into the epidermis [20]. If the overall amount of powder per injection is kept below 1-2 mg, bleeding can be almost entirely avoided [16]. ...
... ± 0.4˚C) was not different from the pure TMDD freeze-concentrate, and therefore the same lyophilisation program was used. The observed particle diameters and the calculated impact factors for TMDD (10.1 kg/mÁs) and TMDD-CRM 197 (11.5 kg/mÁs) fall within the recommended range for pain-free intradermal powder injection [16,20]. ...
Powder-injectors use gas propulsion to deposit lyophilised drug or vaccine particles in the epidermal and sub epidermal layers of the skin. We prepared dry-powder (Tg = 45.2 ± 0.5°C) microparticles (58.1 μm) of a MenY-CRM197 glyconjugate vaccine (0.5% wt.) for intradermal needle-free powder injection (NFPI). SFD used ultrasound atomisation of the liquid vaccine-containing excipient feed, followed by lyophilisation above the glass transition temperature (Tg’ = − 29.9 ± 0.3°C). This resulted in robust particles (density~ 0.53 ±0.09 g/cm³) with a narrow volume size distribution (mean diameter 58.1 μm, and span = 1.2), and an impact parameter (ρvr ~ 11.5 kg/m·s) sufficient to breach the Stratum corneum (sc). The trehalose, manitol, dextran (10 kDa), dextran (150 kDa) formulation, or TMDD (3:3:3:1), protected the MenY-CRM197 glyconjugate during SFD with minimal loss, no detectable chemical degradation or physical aggregation. In a capsular group Y Neisseria meningitidis serum bactericidal assay (SBA) with human serum complement, the needle free vaccine, which contained no alum adjuvant, induced functional protective antibody responses in vivo of similar magnitude to the conventional vaccine injected by hypodermic needle and syringe and containing alum adjuvant. These results demonstrate that needle-free vaccination is both technically and immunologically valid, and could be considered for vaccines in development.
... Delivery of DNA in situ using high-pressure helium gas has been reported (Williams et al. 1991). Various other methods have been developed using different principles (Bellhouse et al. 1997;Dmirty et al. 2005;Jagadeesh et al. 2001;Kendall 2002Kendall , 1999Menezes et al. 2008Menezes et al. , 2005Mutsumi et al. 2008). Furthermore, modification of these techniques for biomedical application such as drug delivery has been a major challenge. ...
... The noise level associated with the membrane rupture is also quite high. A complicated silencer is therefore required in clinical use (Kendall 2002). ...
Shockwaves are essentially non-linear waves that propagate at supersonic speeds. Such disturbances occur in steady transonic or supersonic flows, during explosions, earthquakes, hydraulic jumps and lightning. Rapid movement of piston in a tube filled with gas generates a shock wave. Any sudden release of energy (within few μs) will invariably result in the formation of shock waves since they are one of the efficient mechanisms of energy dissipation observed in nature. The dissipation of mechanical, nuclear, chemical, and electrical energy in a limited space will usually result in the formation of a shock wave. Because of the dissipative nature of shock waves they invariably need a medium both for generation as well as for propagation.
... Later it was modified by Bellhouse et al for human treatment with particle accelerated by entrainment in a supersonic gas flow (1) . Recently, Kendall designed different systems and studied them both experimentally and numerically to make it more convenient for clinical use (1,2,3,4,5) . ...
... The performance of the contoured shock tube has been studied extensively (3,4) . For proper delivery of drug particle it is important to deliver it with a uniform velocity and spatial distribution something which the previous devices failed to provide. ...
In recent years a unique drug delivery system named as the transdermal drug delivery system has been developed which can deliver drug particles to the human skin without using any external needle. The solid drug particles are accelerated by means of high speed gas flow through a shock tube imparting enough momentum so that particles can penetrate through the outer layer of the skin. Different systems have been tried and tested in order to make it more convenient for clinical use. One of them is the contoured shock tube system (CST). The contoured shock tube consists of a classical shock tube connected with a correctly expanded supersonic nozzle. A set of bursting membrane are placed upstream of the nozzle section which retains the drug particle as well as initiates the gas flow (act as a diaphragm in a shock tube). The key feature of the CST system is it can deliver particles with a controllable velocity and spatial distribution. The flow dynamics of the contoured shock tube is analyzed numerically using computational fluid dynamics (CFD). To validate the numerical approach pressure histories in different sections on the CST are compared with the experimental results. The key features of the flow field have been studied and analyzed in details. To investigate the performance of the CST system flow behavior through the shock tube under different operating conditions are also observed.
... Recently Kendall et al. has designed different systems for transdermal powdered drug delivery and studied them both numerically and experimentally [4][5][6][7][8][9][10]. The earliest of them was the convergentdivergent supersonic nozzle system (CDSN). ...
... The main components of the contoured shock tube (CST) along with it's working principle has been discussed in details by Kendall et al. [6,9]. Still a brief description is given in this section for convenience. ...
Transdermal powdered drug delivery is a recent concept which has been proposed as an alternative of the conventional drug delivery systems. The idea is to accelerate the drug particles behind a moving shock inside the shock tube so that particles can gain enough momentum to penetrate the outer layer of the skin (stratum corneum) and have a pharmaceutical effect. The drugs are delivered in a powdered form. While delivering the particles to the skin two important issues have to be taken care of. The particles should be delivered with uniform velocity and with spatial distri- bution. To fulfill these requirements different systems have been tried and tested . Among different systems the contoured shock tube (CST) system is the one to be mentioned. CST system can successfully produce uniform velocity and also with spatial distribution. However, future application of this system demands flexibility and capability to accommodate a wide range of drugs and doses. This paper aims at numerical investigation of particle transportation through the contoured shock tube. Computation fluid dynamics (CFD) has been used to model the flow field and analyze it in details. The unsteady DPM (discrete phase model) is adopted to model the particle transportation. The drug correlation proposed by Igra et al. is used instead of the standard drag correlation to predict the particle movement through the flow filed. The gas and particle dynamics inside the shock tube is closely monitored and analyzed. The effect of different particle features in the transportation process is also investigated.
... One promising method is the use of pressure pulse to permeabilize cells. (Frairia et al. 2003;Kendall 2002;Kodama et al. 2000;Kodama et al. 2002Kodama et al. , 2003Koshiyama et al. 2006;Lee et al. 2000) The majority of research on shock-induced cell permeabilization has been conducted using energy sources based on either laser-ablation or gas-driven shock-tubes. Due to system limitations this research has resulted in low transfection rates of dyes. ...
This paper describes a new system for pressure-induced cell transfection. The system generates pressure pulses from a microchip that contains a small quantity of nanothermite material and an electrical igniter. The pressure output from the nanothermite reaction is coupled to the biological target through a PDMS membrane and a tube filled with gelatin. The system generates pressure pulses in the range of 10-40MPa. It has been used to transfect primary cells with 99% transfection rate and cell survival. It has also been used to transfect cell lines (Hela, HL-60, and HT-29). In all cases survival was >99%, and transfection rate in Hela, HL60 and HT-29 was up to 37 60 and 30% respectively. In addition, the system has been shown to transfect intact spinal cords and arteries from chicken (St 30) with no noticeable damage.
... In the former, the specimen impact velocity provides the microsphere's kinetic energy upon impact. In the latter, the skin impact velocity [10] may be utilized in a theoretical penetration model [28] to estimate the tissue depth reached by the penetrating microsphere [9,10,29]. Future studies of projectile gene and drug delivery may achieve greater efficacy by including the present work's quantification of C D in such penetration models. The "standard drag curve" for spheres illustrates vs. in subsonic, incompressible flow [30]. ...
The acceleration of microparticles to supersonic velocities is required for microscopic ballistic testing, a method for understanding material characteristics under extreme dynamic conditions, and for projectile gene and drug delivery, a needle-free administration technique. However, precise aerodynamic effects upon supersonic microsphere motion at sub-300 Reynolds numbers have not been quantified. We derive drag coefficients for microspheres traveling in air at subsonic, transonic, and supersonic velocities from the measured trajectories of microspheres launched by laser-induced projectile acceleration. Moreover, the observed drag effects on microspheres in atmospheric (760 Torr) and reduced pressure (76 Torr) are compared with existing empirical data and drag coefficient models. We find that the existing models adequately predict the drag coefficient for subsonic microspheres, while rarefaction effects cause a discrepancy between the model and empirical data in the supersonic regime. These results will improve microsphere flight modeling for high-precision microscopic ballistic testing and projectile gene and drug delivery.
... Nozzle pressure ratio and exit diameter were investigated to have great effects on shock flows at the nozzle exit. Kendall et al. [23][24][25] performed experimental studies to investigate particle dynamic through contoured shock tubes by particle image velocimetry (PIV) and Schlieren visualization. e velocity and propagation of shock wave were obtained and discussed in detail. ...
Microshock tubes are always used to induce shock waves and supersonic flows in aerospace and medical engineering fields. A needle-free drug delivery device including a microshock tube and an expanded nozzle is used for delivering solid drug powders through the skin surface without any injectors or pain. Therefore, to improve the performance of needle-free drug delivery devices, it is significantly important to investigate shock waves and particle-gas flows induced by microshock tubes. Even though shock waves and multiphase flows discharged from microshock tubes have been studied for several decades, the characteristics of unsteady particle-gas flows are not well known to date. In the present studies, three microshock tube models were used for numerical simulations. One microshock tube model with closed end was used to observe the reflected shock wave and flow characteristics behind it. The other two models are designed with a supersonic nozzle and a sonic nozzle at the exit of the driven section, respectively, to investigate particle-gas flows induced by different nozzles. Discrete phase method (DPM) was used to simulate unsteady particle-gas flows and the discrete random walk model was chosen to record the unsteady particle tracking. Numerical results were obtained for comparison with those from experimental pressure measurement and particle visualization. Shock wave propagation was observed to agree well with experimental results from numerical simulations. Particles were accelerated at the exit of microshock tube due to the reservoir pressure induced by reflected shock wave. Both sonic and supersonic nozzles were underexpanded at the end of microshock tubes. Particle velocity was calculated to be smaller than gas velocity, which results from larger drag of injected particles.
... Particles can either be initially positioned in the course of the flow using stationary mounts or directly injected into the flow. For instance, Kendall et al. devised a hand-held contoured shock tube where particles, instead of being mounted on a sabot, were directly enclosed between two diaphragms designed to burst under light-gas pressure (73), as depicted in Figs. 4a. ...
High-velocity microparticle impacts are relevant to many fields from space exploration to additive manufacturing and can be used to help understand the physical and chemical behaviors of materials under extreme dynamic conditions. Recent advances in experimental techniques for single microparticle impacts have allowed fundamental investigations of dynamical responses of wide-ranging samples including soft materials, nano-composites, and metals, under strain rates up to 108 s-1. Here we review experimental methods for high-velocity impacts spanning 15 orders of magnitude in projectile mass and compare method performances. Next, we present a review of recent studies using the laser-induced particle impact test technique comprising target, projectile, and synergistic target-particle impact response. We conclude by presenting the future perspectives in the field of high-velocity impact.
... In space, high-and hyper-velocity micro-debris and micrometeorites, while also a subject of study, pose a threat to equipment and personnel integrity [1][2][3][4]. On earth, high-velocity microparticle impact can be, for instance, utilized for therapeutic purposes in the field of biolistics [5] or to build metallic coatings via the cold spray method [6]. While macroscale projectile impacts have been studied using well established experimental tools, such as light-gas guns, optical methods are gaining interest in the field of micro-particle impacts. ...
The study of high-velocity microparticles is important to a wide range of both space and terrestrial applications. In space, high- and hyper-velocity micro-debris and micrometeorites, while also a subject of study, pose a threat to equipment and personnel integrity [1–4]. On earth, high-velocity microparticle impact can be, for instance, utilized for therapeutic purposes in the field of biolistics [5] or to build metallic coatings via the cold spray method [6]. While macroscale projectile impacts have been studied using well established experimental tools, such as light-gas guns, optical methods are gaining interest in the field of micro-particle impacts.
... High velocity impact of microparticles is fundamental to many fields from additive manufacturing [1] and needleless drug delivery [2] to spacecraft protection against micro-debris and interstellar dust collection [3][4][5][6]. Dust sensors and collectors have been implemented in many missions to study high-and hyper-velocity dusts [6][7][8][9]. ...
This paper presents a novel approach to launch single microparticles at high velocities under low vacuum conditions. In an all-optical table-top method, microparticles with sizes ranging from a few microns to tens of microns are accelerated to supersonic velocities depending on the particle mass. The acceleration is performed through a laser ablation process and the particles are monitored in free space using an ultra-high-speed multi-frame camera with nanosecond time resolution. Under low vacuum, we evaluate the current platform performance by measuring particle velocities for a range of particle types and sizes, and demonstrate blast wave suppression and drag reduction under vacuum. Showing an impact on polyethylene, we demonstrate the capability of the experimental setup to study materials behavior under high-velocity impact. The present method is relevant to space applications, particularly to rendezvous missions where velocities range from tens of m/s to a few km/s, as well as to a wide range of terrestrial applications including impact bonding and impact-induced erosion.
... High velocity impact of microparticles is fundamental to many fields from additive manufacturing [1] and needleless drug delivery [2] to spacecraft protection against micro-debris and interstellar dust collection [3][4][5][6]. Dust sensors and collectors have been implemented in many missions to study high-and hyper-velocity dusts [6][7][8][9]. ...
This paper presents a novel approach to launch single microparticles at high velocities under low vacuum conditions. In an all-optical table-top method, microparticles with sizes ranging from a few microns to tens of microns are accelerated to supersonic velocities depending on the particle mass. The acceleration is performed through a laser ablation process and the particles are monitored in free space using an ultra-high-speed multi-frame camera with nanosecond time resolution. Under low vacuum, we evaluate the current platform performance by measuring particle velocities for a range of particle types and sizes, and demonstrate blast wave suppression and drag reduction under vacuum. Showing an impact on polyethylene, we demonstrate the capability of the experimental setup to study materials behavior under high-velocity impact. The present method is relevant to space applications, particularly to rendezvous missions where velocities range from tens of m/s to a few km/s, as well as to a wide range of terrestrial applications including impact bonding and impact-induced erosion.
... Among the skin surrogates widely used to simulate the mechanical properties of soft tissues, agarose is one of the most used due to its transparency which allows the optical quantification of injections [20,[27][28][29][30][31]. The surrogates were prepared by diluting agarose powder (Om-niPur agarose, CAS No. 9012-36-6.), in deionised water, with an agarose concentration of 1%wt. ...
We have used high speed imaging to capture the fast dynamics of two injection methods. The first one and perhaps the oldest known is based on solid needles and used for dermal pigmentation, popularly known as tattooing. The second is a novel needle-free microjet injector based on thermocavitation. Injections in agarose gel skin surrogates were made with both methods and ink formulations having different fluidic properties. Water, a glycerin–water mixture, and commercial inks were used with both injectors to understand better end-point injection. The agarose deformation process due to the solid needle injection helped establish an assessment of penetration potential by using the dimensionless penetration strength quantity. We found that microjet injections are superior than solid injections in terms of energy and volumetric delivery efficiencies per injection for three different liquids. The microjet injector could reduce the environmental impact of used needles and benefit millions of people using needles for medical and cosmetic use.
... The Lorentz and piezoelectric actuators could provide electronic control over the injection speed. Recently, lasers [28][29][30] and shockwaves [31,32] have been used to pressurize the injected fluid. ...
Needle-free injectors can be used to achieve non-invasive drug delivery by impregnating biological barriers. They are considered as the future of drug delivery and therapeutic applications. The history of needle-free injectors dates back to the 1940s and these devices have been constantly evolving since then. Their operating principles and applications have been improved over the years. Herein, we review the current engineering mechanisms and clinical aspects of needle-free microjet injectors. The present study focuses on using engineering approaches to deal with various factors that affect the penetration and dispersion characteristics of the microjet.
... Among the skin surrogates used to simulate the mechanical properties of soft tissues, agarose is one of the most popular due to its transparency, which allows the optical quantification of injections. 24,29,[33][34][35][36] The surrogates were prepared by diluting agarose powder (OmniPur agarose, CAS No. 9012-36-6), in deionized water, with an agarose concentration of 1% wt. The solution was heated up 45 s in microwave at full power. ...
High speed imaging was used to capture the fast dynamics of two injection methods. The first one and perhaps the oldest known, is based on solid needles and used for dermal pigmentation, or tattooing. The second, is a novel needle-free micro-jet injector based on thermocavitation. We performed injections in agarose gel skin surrogates, and studied both methods using ink formulations with different fluidic properties to understand better the end-point injection. Both methods were used to inject water and a glycerin-water mixture. Commercial inks were used with the tattoo machine and compared with the other liquids injected. The agarose gel was kept stationary or in motion at a constant speed, along a plane perpendicular to the needle. The agarose deformation process due to the solid needle injection was also studied. The advantages and limitations of both methods are discussed, and we conclude that micro-jet injection has better performance than solid injection when comparing several quantities for three different liquids, such as the energy and volumetric delivery efficiencies per injection, depth and width of penetrations. A newly defined dimensionless quantity, the penetration strength, is used to indicate potential excessive damage to skin surrogates. Needle-free methods, such as the micro-jet injector here presented, could reduce the environmental impact of used needles, and benefit the health of millions of people that use needles on a daily basis for medical and cosmetic use.
... We also note, that R = 21 MPa for 10 wt% gelatin is comparable to high strain rate (2000-3000 s -1 ) strength measurements of 10 wt% gelatin by Kwan and Subhash, which were on the order of 2-6 MPa and increased with strain rate (Kwon and Subhash, 2010). In a comparable study, using a shock tube-based system for microparticle acceleration, Kendall analyzed penetration data in human skin in view of the Poncelet model and found a similar resistance value of the order of 10 7 Pa (Kendall, 2002). The reason for the scatter in the penetration data (shown for instance in Fig. 3(b)) is unclear. ...
The high-velocity impact response of gelatin and synthetic hydrogel samples is investigated using a laser-based microballistic platform for launching and imaging supersonic micro-particles. The micro-particles are monitored during impact and penetration into the gels using a high-speed multi-frame camera that can record up to 16 images with nanosecond time resolution. The trajectories are compared with a Poncelet model for particle penetration, demonstrating good agreement between experiments and the model for impact in gelatin. The model is further validated on a synthetic hydrogel and the applicability of the results is discussed. We find the strength resistance parameter in the Poncelet model to be two orders of magnitude higher than in macroscopic experiments at comparable impact velocities. The results open prospects for testing high-rate behavior of soft materials on the microscale and for guiding the design of drug delivery methods using accelerated microparticles.
... Shock wave attenuation and particles acceleration are the two aspects of shock-particle interaction. Particles acceleration driven by shock wave is an important process encountered in many technological and engineering applications, including fuel air explosive dispersal, needle-free injection, supersonic cold spraying and aerosol fire extinguishing ( Kendall, 2002;Lee et al., 2015;Liu and Kendall, 2006;Quinlan et al., 2001;Yaogang et al., 2007;Zhang et al., 2001 ). The acceleration or dispersion results directly determine the success of the above-mentioned applications. ...
... In recent times Kendall et al. have designed a number of systems and studied them both numerically and experimentally [4][5][6][7][8][9][10]. He concluded that the performance of contoured shock tube is far better than the other devices. ...
... Results showed that total pressure loss and large nozzle area ratio lead to gas and particle flow non-uniformities generated by oblique shock waves. M. A. F. Kendall [2] also operated experimental study and CFD simulation on a CST model. The CST system delivered particles with a narrow and controlled velocity range and a uniform spatial distribution. ...
Recently, the needle-free delivery system has been widely used in medical fields due to its convenience in delivering drug particles into human body without any external needles. In order to penetrate through the outer layer of the skin, drug particles need to obtain enough momentum, which is achieved by accelerating drug particles in a Contoured Shock Tube (CST). The CST consists of a micro shock tube with two diaphragms and an expanded supersonic nozzle. In the present study, experimental studies were carried out by pressure measurement. Six high sensitive pressure transducers were used for recording pressure changes as the shock wave moved through different locations along walls in the test section. From which, data on shock wave propagation could be obtained. Different diaphragm pressure ratios were conducted to demonstrate effects of initial diaphragm pressure ratios on shock wave propagation. Shilieren visualization was also performed to observe shock wave propagation and shock wave structure in the present experimental shock tube model. The characteristic of the internal flow and shock wave system have been studied and analyzed in details in the present shock tube model.
... Supersonic gas-solid suspension flows are always associated with lots of complex physics [3]. The flow field will experience additional forces like Drag /Basset /Magnus /Saffman force and other gradient-related forces due to the appearance of solid particles [4]. Many experimental investigations show that some physical phenomena like particle-turbulence interaction, particle-mean fluid interaction, inter-particle collisions and particle-wall interaction can affect solid particles motion [5][6][7]. ...
A considerable deal of work has been carried out to get an insight into the gas-solid suspension flows and to specify the particle motion and its influence on the gas flow field. In this paper an attempt is made to develop an analytical model to study the effect of nozzle inlet/exit pressure ratio, particle/gas loading and the particle diameter effect on gas-solid suspension flow. The effect of the particle/gas loading on the mass flow, Mach number, thrust coefficient and static pressure variation through the nozzle is analyzed. The results obtained show that the presence of particles seems to reduce the strength of the shock wave. It is also found that smaller the particle diameter is, bigger will be the velocity as bigger particle will have larger slip velocity. The suspension flow of smaller diameter particles has almost same trend as that of single phase flow with ideal gas as working fluid. Depending on the ambient pressure, the thrust coefficient is found to be higher for larger particle/gas loading or back pressure ratio.
... We also note, that R = 21 MPa for 10 wt% gelatin is comparable to high strain rate (2000-3000 s -1 ) strength measurements of 10 wt% gelatin by Kwan and Subhash, which were on the order of 2-6 MPa and increased with strain rate (Kwon and Subhash, 2010). In a comparable study, using a shock tube-based system for microparticle acceleration, Kendall analyzed penetration data in human skin in view of the Poncelet model and found a similar resistance value of the order of 10 7 Pa (Kendall, 2002). The reason for the scatter in the penetration data (shown for instance in Fig. 3(b)) is unclear. ...
We report photoacoustic measurements of the quasi-longitudinal speed of sound along different crystallographic directions in the energetic molecular crystal cyclotrimethylene trinitramine (RDX). Measurements in (100)-oriented RDX were made using two complimentary techniques to probe acoustic frequencies from 0.5 to 15 GHz to resolve large discrepancies in reported sound speed values measured using different techniques and frequency ranges. In impulsive stimulated light scattering (ISS), two laser beams were crossed at various angles in a sample to generate coherent acoustic waves with well-defined wavevectors. Picosecond acoustic interferometry (PAI) measurements were conducted in which a laser pulse heated a thin metal transducer layer coated on the sample surface to generate a broadband acoustic wave-packet that propagated into the sample. Time-dependent coherent Brillouin scattering of probe light from the acoustic waves revealed frequencies in the 0.5–3.5 GHz range in ISS measurements and at ∼15 GHz in the PAI measurements, yielding the speed of sound in each case. Our ISS results are in agreement with previous ultrasonic and ISS measurements at kilo- and megahertz frequencies. Our PAI results yielded a 15 GHz sound speed essentially equal to those at megahertz frequencies in contrast to an earlier report based on Brillouin light scattering measurements. The lack of acoustic dispersion over six orders of magnitude in frequency indicates that there is no relaxation process that significantly couples to acoustic waves in RDX at acoustic frequencies up to 15 GHz.
... The PowderJect delivery system is a case in point, which has been applied to exploit the microparticle gene transfer treatment. 7,8 In most cases, these delivery systems are based on the principle that biocompatible microparticles loaded with genes can be accelerated to a sufficient velocity so as to penetrate the barrier function of the target tissue and thereby achieve gene delivery. 9,10 However, cell and tissue damages are particular problems for these microparticle delivery systems, which are discussed further later. ...
A set of well-defined experiments has been carried out to explore whether microneedles (MNs) can enhance the penetration depths of microparticles moving at high velocity such as those expected in gene guns for delivery of gene-loaded microparticles into target tissues. These experiments are based on applying solid MNs that are used to reduce the effect of mechanical barrier function of the target so as to allow delivery of microparticles at less imposed pressure as compared with most typical gene guns. Further, a low-cost material, namely, biomedical-grade stainless steel microparticle with size ranging between 1 and 20 μm, has been used in this study. The microparticles are compressed and bound in the form of a cylindrical pellet and mounted on a ground slide, which are then accelerated together by compressed air through a barrel. When the ground slide reaches the end of the barrel, the pellet is separated from the ground slide and is broken down into particle form by a mesh that is placed at the end of the barrel. Subsequently, these particles penetrate into the target. This paper investigates the implications of velocity of the pellet along with various other important factors that affect the particle delivery into the target. Our results suggest that the particle passage increases with an increase in pressure, mesh pore size, and decreases with increase in polyvinylpyrrolidone concentration. Most importantly, it is shown that MNs increase the penetration depths of the particles. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
Background
Needle-free jet injection (NFJI) systems enable a controlled and targeted delivery of drugs into skin tissue. However, a scarce understanding of their underlying mechanisms has been a major deterrent to the development of an efficient system. Primarily, the lack of a suitable visualization technique that could capture the dynamics of the injected fluid–tissue interaction with a microsecond range temporal resolution has emerged as a main limitation. A conventional needle-free injection system may inject the fluids within a few milliseconds and may need a temporal resolution in the microsecond range for obtaining the required images. However, the presently available imaging techniques for skin tissue visualization fail to achieve these required spatial and temporal resolutions. Previous studies on injected fluid–tissue interaction dynamics were conducted using in vitro media with a stiffness similar to that of skin tissue. However, these media are poor substitutes for real skin tissue, and the need for an imaging technique having ex vivo or in vivo imaging capability has been echoed in the previous reports.
Methods
A near-infrared imaging technique that utilizes the optical absorption and fluorescence emission of indocyanine green dye, coupled with a tissue clearing technique, was developed for visualizing a NFJI in an ex vivo porcine skin tissue.
Results
The optimal imaging conditions obtained by considering the optical properties of the developed system and mechanical properties of the cleared ex vivo samples are presented. Crucial information on the dynamic interaction of the injected liquid jet with the ex vivo skin tissue layers and their interfaces could be obtained.
Conclusions
The reported technique can be instrumental for understanding the injection mechanism and for the development of an efficient transdermal NFJI system as well.
Injections into or through the skin are common drug or vaccine administration routes, which can be achieved with conventional needles, microneedles, or needle-free jet injections (NFJI). Understanding the transport mechanism of these injected fluids is critical for the development of effective drug administration devices. NFJI devices are distinct from traditional injection techniques by their route and time scale, which relies on a propelled microjet with sufficient energy to penetrate the skin surface and deliver the drug into the targeted region. The injected fluid interacts with multiple skin tissue layers and interfaces, which implies that the corresponding injection profile is dependent on their mechanical properties. In this study, we address the lack of fundamental knowledge on the impact of these interfaces on the injection profiles of NFJI devices.Graphical abstract
High-velocity microparticle impacts are relevant to many fields from space exploration to additive manufacturing and can be used to help understand the physical and chemical behaviors of materials under extreme dynamic conditions. Recent advances in experimental techniques for single microparticle impacts have allowed fundamental investigations of dynamical responses of wide-ranging samples including soft materials, nano-composites, and metals, under strain rates up to 10 8 s-1. Here we review experimental methods for high-velocity impacts spanning 15 orders of magnitude in projectile mass and compare method performances. This review aims to present a comprehensive overview of high-velocity microparticle impact techniques to provide a reference for researchers in different materials testing fields and facilitate experimental design in dynamic testing for a wide range of impactor sizes, geometries, and velocities. Next, we review recent studies using the laser-induced particle impact test platform comprising target, projectile, and synergistic target-particle impact response, hence demonstrating the versatility of the method with applications in impact protection and additive manufacturing. We conclude by presenting the future perspectives in the field of high-velocity impact.
Needle-free jet injectors are non-invasive systems having intradermal drug delivery capabilities. At present, they revolutionize the next phase of drug delivery and therapeutic applications in the medical industry. An efficiently designed injection chamber can reduce the energy consumption required to achieve the maximum penetration depth in skin tissue. In this study, the authors explored the effect of various geometrical parameters using a computational fluid dynamics tool. Peak stagnation pressure during the initial phase of the injection procedure was considered as the quantifier for comparison because of its proportional relationship with the initial penetration depth during the injection process. Peak stagnation pressure indicates the maximum energy transformation that could happen between the microjet and skin tissues for an injection procedure. The results of this study indicated a tradeoff that exists between the attainable density and velocity of the microjet on the skin surface with variation in nozzle diameter; the optimum nozzle diameter was found to be within 200-250 μm under the present conditions. The authors also observed a discrepancy in the peak stagnation pressure value for lower filling ratios with variation in chamber diameter; hence, filling ratio of at least 50% was recommended for such systems. Furthermore, a 150% increase in the peak stagnation pressure was obtained with an angle of entry of 10°. In general, this study could provide valuable insights into the effect of geometrical parameters in the fluid dynamics characteristics of propelled microjets from the nozzle of a needle-free jet injector. Such information could be useful for the design of a mechanically driven needle-free jet injector having limited control over the energizing mechanism.
Emerging micro-scale medical devices are showing promise, whether in delivering drugs or extracting diagnostic biomarkers from skin. In progressing these devices through animal models towards clinical products, understanding the mechanical properties and skin tissue structure with which they interact will be important. Here, through measurement and analytical modelling, we advanced knowledge of these properties for commonly used laboratory animals and humans (~30 g to ~150 kg). We hypothesised that skin’s stiffness is a function of the thickness of its layers through allometric scaling, which could be estimated from knowing a species’ body mass. Results suggest that skin layer thicknesses are proportional to body mass with similar composition ratios, inter- and intra-species. Experimental trends showed elastic moduli increased with body mass, except for human skin. To interpret the relationship between species, we developed a simple analytical model for the bulk elastic moduli of skin, which correlated well with experimental data. Our model suggest that layer thicknesses may be a key driver of structural stiffness, as the skin layer constituents are physically and therefore mechanically similar between species. Our findings help advance the knowledge of mammalian skin mechanical properties, providing a route towards streamlined micro-device research and development onto clinical use.
Recently a needle-free drug delivery device as an innovative injection device has been widely used in medical fields. Drug powders induced with the high momentum by a moving shock wave can be directly delivered into skin layers. The main component of this device is a contoured shock tube, which consists of a micro shock tube and an expanded nozzle. Drug powders and gas flows are induced by a moving shock wave generated in the micro shock tube and accelerated in the expanded nozzle. The most difficult operation is that the momentum of drug powders should be strictly controlled. In present experimental studies, a micro shock tube was designed to investigate the shock wave propagation. A sonic or a supersonic nozzle installed at the exit of the micro shock tube was studied to observe the particle acceleration. Different diaphragms for initializing incident shock waves were investigated as well. Particle tracking velocimetry (PTV) measurement was carried out to investigate the motion of solid particles. In order to visualize the shock wave propagation, Schlieren visualization method was also carried out. The primary incident shock wave and the reflected shock wave induced by the closed end of the driven section were clearly observed.
Delivery of macromolecules is primarily achieved by the use of hypodermic needles, which have several disadvantages including accidental needlesticks, pain, and needle phobia. These limitations have led to extensive research and development of alternative methods for drug and vaccine delivery across the skin, without the use of needles. Jet injectors are one such class of needle-free devices, which have been used to deliver both liquid and solid drug and vaccine formulations. In spite of their availability for research and clinical use for the past several decades, these devices have had limited acceptance. The mechanism of operation of these devices, the enhanced skin penetration of drugs, device design parameters, applications, and safety concerns for these two types of injection devices are described. Current developments in the field have also been discussed.
Needle-free vaccine delivery methods have the potential for pain-free, improved immunogenicity vaccination by delivering directly into the skin. Herein we give a brief overview of approaches for this and subsequently provide a detailed description of the Nanopatch approach. This work details the design, hypothesized mode of action, and the immune responses generated from this method. Additionally, the potential for eliminating the cold chain in vaccines is discussed, and the potential long-term implications of these devices. These are explained in the context of the field of microneedles, which have not otherwise been able to achieve the performance of the Nanopatch.
Recently, micro shock tubes have been widely used in the medical engineering. The needle-free drug delivery device which mainly consists of a micro shock tube and an expanded nozzle has been produced to inject drug powders into human and animal bodies without any sharp metal needles. The drug powders were delivered by obtaining high momentum, which can be done by accelerating drug powders in the micro shock tube and supersonic nozzle. The particle-gas flows are induced by the incident shock wave developing by rupturing the diaphragm in the micro shock tube and again accelerated in the supersonic nozzle. The momentum of injected drug particles should be strictly controlled otherwise patients will suffer from skin injury or hurt. Even though micro shock tubes have been investigated in the past several decades, the detailed studies on particle-gas flows in the micro shock tube were rare to date due to the micro size and difficult experimental operation on micro shock tubes. In this paper, the experimental and numerical studies were carried out on investigating particle-gas flows in a designed micro shock tube. Particle tracking velocimetry (PTV) was performed to calculated particle average velocity at the exit of the supersonic nozzle. The nozzle flows were analyzed by obtaining instantaneous particle fields. The particle number density ratio was also investigated in the test section. The numerical simulations were performed by calculating unsteady Naver-Stokes equations on compressible flows and using fully implicit finite volume schemes. Discrete phase model (DPM) was used for simulating particle-gas flows in the micro shock tube. Particle diameter and density were varied to investigate their effects on the particle-gas flows. Unsteady particle-gas flows and shock wave propagation were obtained in details in the micro shock tube for present experimental and numerical studies.
Recently, micro shock tubes have been widely used in various fields such as aerospace, combustion and medical science. Needle-free drug delivery device is a typical example of the application of the micro shock tube used in the field of medical science. Compared to the macro shock tube, the flow viscosity and micro scale effects considerably influence the shock wave propagation in the micro shock tube, which makes shock wave behaviors significant difference from the theoretical prediction. Boundary layers which develop behind the moving shock wave attenuate the shock wave propagation as well. Additionally, the gas-particle flows are also shown the different characteristics compared to the single gas flow in the micro shock tube. Particles are induced by the shock wave inside the micro shock tube and accelerated in the supersonic nozzle. Supersonic flows and particle velocity make experimental studies difficult to be performed in the micro shock tube. Even though micro shock tubes have been studied for decades, shock flow characteristics and particle dynamics inside the micro shock tube are not well known to date. For the present study, pressure measurements and optical visualization have been carried out in a micro shock tube. Static pressure measurements were used for investigating the shock wave propagation in the driven section, and Pitot pressure measurements were used for obtaining flow characteristics at the exit of nozzles. Two high sensitive pressure transducers were used for recording pressure changes as the shock wave moved through pressure transducers and the shock Mach number was calculated. Particle tracking velocimetry was conducted to analyze particle-gas two-phase flows. Particle distribution and velocity were obtained in the present experiment study.
Graphical abstract
Recently, an innovative drug delivery system has been developed to deliver drug particles to the human shin without using any external needles. In order to obtain enough momentum, drug particles are accelerated by means of high speed gas produced in a Contoured Shock Tube (CST), so that particles can penetrate through the outer layer of the skin. The CST system consists of a classical shock tube with two diaphragms and an expanded supersonic nozzle. Schlieren visualization technique was used to observe shock waves in a CST of needle-free drug delivery system. The visualization of density gradient between the front and the behind of the shock wave is obtained from 2D density stratified flow in the shock tube. The structure and propagation of Shock waves were obviously observed in present schlieren images. In the pressure measurement, six high sensitive pressure transducers are used to record the pressure change as the shock wave moves through the test section, from which data on shock wave propagation was obtained.
Transdermal and topical drug delivery, with minimal tissue damage has been an area of vigorous research for a number of years. Our research team has initiated the development of an effective method for delivering drug particles across the skin (transdermal) for systemic circulation, and to localized (topical) areas. The device consists of a microparticle acceleration system based on laser ablation that can be integrated with endoscopic surgical techniques. A layer of microparticles is deposited on the surface of a thin metal foil. The rear side of the foil is irradiated with a laser beam, which generates a shockwave that travels through the foil. When the shockwave reaches the end of the foil, it is reflected as an expansion wave and causes instantaneous deformation of the foil in the opposite direction. Due to this sudden deformation, the microparticles are ejected from the foil at very high speeds, and therefore have sufficient momentum to penetrate soft body tissues. We have demonstrated this by successfully delivering cobalt particles 3 μm in diameter into gelatin models that represent soft tissue with remarkable penetration depth.
A liquid jet injector is a biomedical device intended for drug delivery. Medication is delivered through a fluid stream that penetrates the skin. This small diameter liquid stream is created by a piston forcing a fluid column through a nozzle. These devices can be powered by springs or compressed gas. In this study, a CFD simulation is carried out to investigate the fluid mechanics and performance of needle free injectors powered specifically by compressed air. The motion of the internal mechanisms of the injector which propels a liquid jet through an orifice is simulated by the moving boundary method and the fluid dynamics is modeled using LES/VOF techniques. In this paper, numerical results are discussed by comparing the fluid stagnation pressures of the liquid jet with previously published experimental measurements obtained using a custom-built prototype of the air-powered needle free liquid injector. Performance plots as a function of various injector parameters are presented and explained.
We report a biolistic technology platform for physical delivery of particle formulations of drugs or vaccines using parallel arrays of microchannels, which generate highly collimated jets of particles with high spatial resolution. Our approach allows for effective delivery of therapeutics sequentially or concurrently (in mixture) at a specified target location or treatment area. We show this new platform enables the delivery of a broad range of particles with various densities and sizes into both in vitro and ex vivo skin models. Penetration depths of ∼1 mm have been achieved following a single ejection of 200 μg high-density gold particles, as well as 13.6 μg low-density polystyrene-based particles into gelatin-based skin simulants at 70 psi inlet gas pressure. Ejection of multiple shots at one treatment site enabled deeper penetration of ∼3 mm in vitro, and delivery of a higher dose of 1 mg gold particles at similar inlet gas pressure. We demonstrate that particle penetration depths can be optimized in vitro by adjusting the inlet pressure of the carrier gas, and dosing is controlled by drug reservoirs that hold precise quantities of the payload, which can be ejected continuously or in pulses. Future investigations include comparison between continuous versus pulsatile payload deliveries. We have successfully delivered plasmid DNA (pDNA)-coated gold particles (1.15 μm diameter) into ex vivo murine and porcine skin at low inlet pressures of ∼30 psi. Integrity analysis of these pDNA-coated gold particles confirmed the preservation of full-length pDNA after each particle preparation and jetting procedures. This technology platform provides distinct capabilities to effectively deliver a broad range of particle formulations into skin with specially designed high-speed microarray ejector nozzles.
Technologies and strategies for cutaneous vaccination have been evolving significantly during the past decades. Today, there is evidence for increased efficacy of cutaneously delivered vaccines allowing for dose reduction and providing a minimally invasive alternative to traditional vaccination. Considerable progress has been made within the field of well-established cutaneous vaccination strategies: Jet and powder injection technologies, microneedles, microporation technologies, electroporation, sonoporation, and also transdermal and transfollicular vaccine delivery. Due to recent advances, the use of cutaneous vaccination can be expanded from prophylactic vaccination for infectious diseases into therapeutic vaccination for both infectious and non-infectious chronic conditions. This review will provide an insight into immunological processes occurring in the skin and introduce the key innovations of cutaneous vaccination technologies.
Copyright © 2015. Published by Elsevier Ltd.
The powdered injection system (PowderJect) is a novel needle-free medical device for the delivery of drug and vaccines. The underlying principle is to harness energy from compressed Helium gas to accelerate a pre-measured dose of the drug and vaccines in micro-particle form to appropriate velocity in order to penetrate the outer layer of skin or mucosal tissue to achieve a pharmacological effect. One of PowderJect developments is the Venturi system, using the venturi effect to entrain micron-sized drug particles into an established quasi-steady supersonic jet flow (QSSJF) and accelerate them towards the targets. In this paper, computational fluid dynamics (CFD) is utilized to simulate the complete operation of the prototype Venturi system. The key features of the gas dynamics and gas-particle interaction are discussed. © 2005 by the American Institute of Aeronautics and Astronautics, Inc. All rights reserved.
Transdermal and topical drug delivery with minimal tissue damage has been an area of vigorous research for years. Our research team has initiated the development of an effective method for delivering drug particles across the skin (transdermal) for systemic circulation, and to localized (topical) areas. The device consists of a laser ablation based micro-particle acceleration system that can be integrated with endoscopic surgical techniques. We have successfully delivered 3μm size cobalt particles into gelatin models that represent soft tissue with remarkable penetration depth.
A unique biolistic method of vaccination is operated by accelerating particulate vaccines with a high-speed gas jet generated by a convergent-divergent conical nozzle to sufficient momentum to penetrate the outer layer of human skin. The targeted cells elicit an immunological response. In this paper, Computational Fluid Dynamics (CFD) is utilized to simulate the operation of a prototype biolistics delivery system. The key features of transient gas dynamics and gas-particle interaction are discussed.
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. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
The present study focuses on numerical simulation of the gas-solid suspension flow in a supersonic nozzle. The EulerLagrange approach using a Discrete Phase Model (DPM) has been used to solve the compressible Navier-Stokes equations. A fully implicit finite volume scheme has been employed to discretize the governing equations. Based upon the present CFD results, the particle loading effect on gas-solid suspension flow was investigated. The results show that the presence of particles has a big influence on the gas phase behavior. The structure of shock train, the separation point, and the vortex of the backflow are all related to particle loading. As the particle loading increases the flow characteristics behave differently such as 1) the strength of shock train decreases, 2) the separation point moves toward the nozzle exit, 3) the number and strength of vortex increase, 4) the strength of first shock also increases while the other pseudo shocks decreases. The change of gas flow behavior in turn affects the particle distribution. The particles are concentrated at the shear layers separated from the upper wall surface.
The biolistic approach of DNA/drug delivery was applied to deliver liquid DNA into living cells. The liquid DNA to be delivered was deposited as a drop on a thin aluminum foil and the posterior surface of the foil was ablated using an Nd:YAG laser. The ablation launched a shock wave through the foil. A part of this shock wave was transmitted to the drop, and a part was reflected back into the foil as an expansion wave. The wave motions caused the drug droplet to accelerate and acquire a sufficiently high velocity in the forward direction. A part of the propelled DNA droplet, on impacting the surface of a soft, living target, entered the target cells, accomplishing the drug delivery. The technique was tested on E-coli bacteria by delivering a plasmid DNA pUC119 into the bacterial cells. A few bacterial colonies could be transformed by this method of DNA delivery.
Shock wave research was traditionally developed as an element of high-speed gas dynamics supporting supersonic flights and atmospheric reentry of space vehicles. However, recently its scope has expanded to the comprehensive interpretation of shock wave phenomena in nature and the artificial world. In particular, many aspects of volcanoes’s explosive eruptions are closely related to shock wave dynamics. One hypothesis proposes that during asteroid impact events that took place millions of years ago underwater shock waves played a decisive role in mass extinction of marine creatures. Shock waves have been successfully applied to medical therapy. Extracorporeal shock wave lithotripsy (ESWL) was a wonderful success in noninvasive removal of urinary tract stones. Recently, shock wave therapy was further developed for the revascularization of cerebral embolism, drug delivery, and other interesting therapeutic methods. This review provides an overview of the state-of-the-art interdisciplinary applications of shock wave research to geophysics and medicine.
Transdermal powdered drug delivery involves the propulsion of solid drug particles into the skin by means of high-speed gas-particle flow. The fluid dynamics of this technology have been investigated in devices consisting of a convergent-divergent nozzle located downstream of a bursting membrane, which serves both to initiate gas Row (functioning as the diaphragm of a shock tube) and to retain the drug particles before actuation. Pressure surveys of Row in devices with contoured nozzles of relatively low exit-to-throat area ratio and a conical nozzle of higher area ratio have indicated a starting process of approximately 200 mus typical duration, followed by a quasi-steady supersonic flow. The velocity of drug particles exiting the contoured nozzles was measured at up to 1050 m/s, indicating that particle acceleration took place primarily in the quasi-steady flow. In the conical nozzle, which had larger exit area ratio, the quasi-steady nozzle flow was found to be overexpanded, resulting in a shock system within the nozzle. Particles were typically delivered by these nozzles at 400 m/s, suggesting that the starting process and the quasi-steady shock processed flow are both responsible for acceleration of the particle pag load. The larger exit area of the conical nozzle tested enables drug delivery over a larger target disc, which may be advantageous.
This paper describes a single equation of motion which, in its most general form, describes penetration by a forming, stretching, eroding jet. In various specialized forms it describes penetration by pre-formed rods and compact projectiles. One specialized form reduces to the classical jet penetration formula according to which penetration into a semi-infinite target is proportional to the square root of the ratio of the jet and target densities. However, in the present theory, a correction for target hardness is automatically included. The equation is derived and certain solutions are illustrated by comparisons with experimental data.
This paper describes an experimental study of the starting process in a reflected-shock tunnel, and compares the results with numerical calculations reported previously (Smith 1962). It is shown that an unsteady expansion wave dominates the transient flow, and the shock-wave system plays a minor role. The effects of initial pressure in the nozzle were investigated, and the behaviour of the secondary shock wave was noted. It was found that initial pressures larger even than the steady-flow static pressure can be tolerated without prolonging the starting process, despite the presence of a strong secondary shock wave. Other analyses, based on the ‘steady-state’ model of the starting process, are discussed and shown to give an unrealistic description of the flow field.
The mechanical parameters, work of fracture, ultimate breaking strength and elongation at fracture, were determined from the stress-strain characteristics of normal human stratum corneum conditioned in various physicochemical environments. These biomechanical properties were found to be highly dependent on the conditioning relative humidity (RH) and solvent extraction history. Over the increasing 0 to 100% RH range, untreated stratum corneum breaking strength decreased 85%, while the work of fracture increased 600%. Elongation at fracture increased from 20% at 0% RH to 190% at 100% RH. Ether extraction increased the magnitude of the breaking strength at all RH's while having little influence on RH dependence of the % elongation at fracture as compared to untreated. Sequential ether-water extraction significantly decreased the fracture elongation at the higher RH's while breaking strengths were less dependent on RH than untreated. The lower extensibility of the ether-water treated samples relative to ether extracted or untreated is consistent with the suggested role of water soluble materials being responsible for the water binding necessary for membrane flexibility. The mechanism for the influence of ether extraction on the breaking strength remains unclear.
Particle Image Ve-locimetry The starting process in a hypersonic nozzle
- M C Willert
M, Willert C, Kompenhans J (1998) Particle Image Ve-locimetry. Springer Smith CE (1966) The starting process in a hypersonic nozzle. J Fluid Mechanics 24:625–641
Micro-particle penetration to the oral mucosa
- Kendall Maf Tj
- Bellhouse
- Bj
TJ, Kendall MAF, Bellhouse BJ (2001) Micro-particle penetration to the oral mucosa. In: ASME Bioeng. Conf., Snowbird, UT, USA, June 27–30
Studies of shock wave propagation in gas–particle mixtures
- J Das
J, Das HK (1997) Studies of shock wave propagation in gas–particle mixtures. In: Houwing AFP, Paull A (eds) Shock Waves. Panther Publishing & Printing, Australia, pp 953–958
Unsteady Flow Phe-nonoma in Shock-Tube Nozzles
- Amman
- Ho
- Reichenbach
Amman HO, Reichenbach H (1973) Unsteady Flow Phe-nonoma in Shock-Tube Nozzles. In: Bershader D, Griffith W (eds) Recent Developments in Shock Tube Research: Proceedings of the Ninth International Shock Tube Sym-posium, Stanford University Press, Stanford, pp 96–112
Stratum corneum properties I. Influence of relative humidity on nor-mal and extracted stratum corneum
- Rh Bothwell
- Jw
- Douglas
- Ab
RH, Bothwell JW, Douglas AB (1971) Stratum corneum properties I. Influence of relative humidity on nor-mal and extracted stratum corneum. Journal of Investiga-tive Dermatology 56:72–78
The ballistic delivery of high-density, high-velocity micro-particles into excised human skin
- Mitchell Tj Maf
- Hardy Mp
- Bellhouse
- Bj
MAF, Mitchell TJ, Hardy MP, Bellhouse BJ (2001b) The ballistic delivery of high-density, high-velocity micro-particles into excised human skin. In: ASME Bioeng. Conf., Snowbird, UT, USA, June 27–30
Transdermal ballistic delivery of micro-particles: investi-gation into skin penetration Comparison of the Transdermal Ballistic Delivery of Micro-Particles into Human and Porcine Skin
- Maf
- Wrighton-Smith Pj
- Bellhouse
- Bj
MAF, Wrighton-Smith PJ, Bellhouse BJ (2000b) Transdermal ballistic delivery of micro-particles: investi-gation into skin penetration. In: World Congress on Med. Phys. and Biomed. Eng., Chicago, IL, USA, July Kendall MAF, Carter FV, Mitchell TJ, Bellhouse BJ (2001a) Comparison of the Transdermal Ballistic Delivery of Micro-Particles into Human and Porcine Skin. In: 23rd Intl. Conf. of IEEE Engineering in Medicine and Biology Society, Is-tanbul, October 25–28
The gas–particle dynamics of a high-speed needle-free drug delivery system
- Maf
- Quinlan
- Nj
- Thorpe
- Sj
- Rw Ainsworth
- Bj
MAF, Quinlan NJ, Thorpe SJ, Ainsworth RW, Bell-house BJ (1999) The gas–particle dynamics of a high-speed needle-free drug delivery system. In: Ball CJ, Hillier R, Roberts CT (eds) Shock Waves. University of Southamp-ton, pp 605–610