Preliminary pharmacokinetics and patient experience of jet-injected dexmedetomidine in healthy adults.

Jet injection is a drug delivery system without a needle. A compressed liquid drug formulation pierces the skin, depositing the drug into the subcutaneous or intramuscular tissues. We investigated the pharmacokinetics and patient experience of dexmedetomidine administered using jet injection in six healthy adult study participants. This needleless jet injection device was used to administer dexmedetomidine 0.5 µg/kg to the subcutaneous tissues overlying the deltoid muscle. Serum concentrations of dexmedetomidine were assayed at approximately 5 minutes, 15 minutes, 30 minutes, 1 hour and 4 hours after administration. Pharmacokinetic interrogation of concentration time profiles estimated an absorption half time for jet-injected dexmedetomidine of 21 minutes (coefficient of variation 69.4%) with a relative bioavailability assumed unity. In our samples the measured median peak (range) concentration was 0.164 µg/l (0.011-0.325 µg/l), observed in the sample taken at a median (range) of 13.5 minutes (11-30 minutes). The Richmond agitation sedation scale was used to assess the sedative effect, and scored 0 (alert and calm) or -1 (drowsy) in all participants. Five of the six participants stated they would prefer jet injection to needle injection in the future and one had no preference. The findings suggest that the use of a larger dose (>2 µg/kg) would be required to achieve the clinically relevant target concentration of 1 µg/l necessary to achieve deeper sedation (Richmond agitation sedation scale ≤3).

Large volume subcutaneous delivery using multi-orifice jet injection.

Needle-free jet injection is an alternative drug delivery technique that uses the liquid drug itself to penetrate through the skin. This technology is not only a promising alternative to hypodermic needles but also has the potential to replace intravenous delivery with rapid, needle-free subcutaneous delivery for large-volume treatments. In this work we propose a parallelised, 'multi-orifice' approach to overcome the volume constraints of subcutaneous tissue. We present a prototype multi-orifice nozzle with up to seven orifices and use this nozzle to perform injections into samples of ex vivo porcine tissue. These injections demonstrated the rapid (<0.15 s) delivery of up to 2 mL into the tissue using both three and seven orifices. Delivery success (measured as the percentage of fluid deposited in the tissue relative to the total volume that left the device) was very similar when using three versus seven injection orifices. A computational fluid dynamic model of multi-orifice jet injection is also presented. This model predicts that jet production is largely unaffected as the spacing between orifices is changed from 3 mm to 48 mm. This finding is supported by measurements of the speed, volume, and shape of the jets produced by the prototype nozzle that showed very similar jets were produced through all seven orifices. These findings demonstrate the feasibility of multi-orifice jet injection for needle-free delivery of large volumes. This promising technique has the potential to improve patient experience and reduce healthcare costs in large volume parenteral delivery applications.

Rotatable Orifice for Needle-Free Jet Injection.

This research explores a new development in orifice technology for needle-free jet injection. The premise lies in the ability to control the angle at which the drug is delivered into the tissue to increase the lateral dispersion of the drug. Towards this aim, a spherical orifice that can rotate to adjust the injection angle is explored. This work tests the design and feasibility of the spherical orifice, its housing, and the orifice seats. The results show that the most successful way to create a fluid seal within the housing was to use an o-ring to create a fluid seal at the inlet side of the sphere and an extended brass seat on the outlet side of the sphere. This allowed jet speeds up to approximately 123 m/s through a 0.2 mm orifice machined into 9.5 mm diameter brass sphere. Jet speeds large enough to penetrate porcine tissue were reached at jet angles of 0° to 50° relative to the base of the injector. Although the jets successfully penetrated the tissue, the amount of fluid delivered varied depending on the injection angle. With a shallow angle injection, the fluid retention rate (the percentage of the ejected fluid from the injector which the tissue sample retained) was on average 44%. When the spherical orifice was at its maximum angle, the injection achieved an average fluid retention rate of 22%. At its widest angle, lateral dispersion of the drug also increased by approximately 40%, in comparison to conventional needles and traditional perpendicular jet injection. In summary, a spherical orifice needle-free injection system successfully produced high-speed jets and delivered liquid into porcine tissue at injection angles from 0° to 50°, demonstrating the feasibility of this technique that offers unique advantages over typical orifice plates and conventional needles.Clinical Relevance-A rotatable nozzle can be used to control the angle of needle-free drug delivery.

Measurement of Blood Dilution during Lancet-Free Blood Sampling.

In this paper, we report on a fluorescent and colorimetric system for measuring the dilution of capillary blood released by a needle-free jet injector. Jet injection uses a high-speed liquid jet to penetrate tissue, and in the process can release capillary blood that can be collected for performing blood tests. In this way, blood sampling can be performed without the use of a lancet. However, any injectate that mixes with the collected blood dilutes the sample and may significantly impact subsequent analyses. By adding the fluorescent marker indocyanine green to the injected liquid, the fraction of injectate mixed into the collected blood can be measured. The incorporation of colorimetry allows our system to also correct for the impact of hematocrit on fluorescence. The results from this system show that it can determine the dilution of blood that has been diluted by up to 10 %, the upper limit of dilution typically observed in lancet-free blood sampling via jet injection.Clinical Relevance- Blood samples can be collected by jet injection without significant dilution, avoiding the need for lancing.

Minimally invasive capillary blood sampling methods.

INTRODUCTION: Whole blood samples, including arterial, venous, and capillary blood, are regularly used for disease diagnosis and monitoring. The global Covid-19 pandemic has highlighted the need for a more resilient screening capacity. Minimally invasive sampling techniques, such as capillary blood sampling, are routinely used for point of care testing in the home healthcare setting and clinical settings such as the Intensive Care Unit with less pain and wounding than conventional venepuncture. AREAS COVERED: In this manuscript, we aim to provide a overview of state-of-the-art of techniques for obtaining samples of capillary blood. We first review both established and novel methods for releasing blood from capillaries in the skin. Next, we provide a comparison of different capillary blood sampling methods based on their mechanism, testing site, puncture size, cost, wound geometry, healing, and perceptions of pain. Finally, we overview established and new methods for enhancing capillary blood collection. EXPERT OPINION: We expect that microneedles will prove to be a preferred option for paediatric blood collection. The ability of microneedles to collect a capillary blood sample without pain will improve paediatric healthcare outcomes. Jet injection may prove to be a useful method for facilitating both blood collection and drug delivery.

Jet-Induced Blood Release From Human Fingertips: A Single-Blind, Randomized, Crossover Trial.

BACKGROUND: Lancet pricks are often poorly received by individuals with diabetes; jet injection may allow lancet-free blood sampling. We examine whether the technique of jet injection can release sufficient blood from the fingertip to enable measurement of blood glucose concentration. In addition, we assess the effect of jet shape and cross-sectional area on fluid release, blood dilution, and perceived pain. METHODS: A randomized, single-blind, crossover study was conducted on 20 healthy volunteers who received interventions on four fingertips: a lancet prick, and jet injection of a small quantity of saline solution through three differently shaped and sized nozzles. Released fluid volume, blood concentration, and glucose concentration were assessed immediately after the intervention. Pain perception and duration, and any skin reactions, were evaluated both immediately and 24 hours after the intervention. RESULTS: Jet injection released sufficient blood from the fingertip to conduct a glucose measurement. A slot-shaped nozzle released the most blood, although less than a lancet, with slightly higher pain. The blood glucose levels estimated from the extracted fluid showed a mean absolute percentage error of 25%. There was no consistent evidence that a jet injection leads to different skin reactions at the intervention site relative to a lancet prick. CONCLUSIONS: Fingertip penetration by jet injection can release a volume of fluid sufficient for blood glucose measurement. Jet injection with a slot-shaped nozzle and/or a nozzle with larger outlet area helps to release more fluid. This technique may enable blood sampling, glucose concentration measurement, and insulin delivery to be performed in a single device.

Jet-Induced Tissue Disruption for Blood Release.

OBJECTIVE: Needle-free jet injection is a drug delivery technique that uses the momentum of the fluid drug to break through the skin. This technique has recently also been applied to blood release, aiming to collect samples from capillaries in the skin without needing a lancet prick. This work provides new information about the wound geometry and tissue disruption caused by shallow jet injection with circular-shaped and slot-shaped jets. METHODS: We use histological analysis to compare the disruption of tissue, including blood vessels, caused by lancet-pricking and jet injection with a circular-shaped jet and a lancet-inspired slot-shaped jet. RESULTS: Intradermal injection into porcine skin using a slot-shaped jet disrupted more vascular endothelium in the tissue than a circular-shaped jet and did so at a smaller penetration depth with smaller wound volume. Our results suggest that shallow jet injections may have the potential to release more capillary blood than a lancet prick. CONCLUSION: These findings demonstrate that a reversible jet injector might be used in diabetes management as a device to release and collect blood samples, in addition to being used to deliver insulin. SIGNIFICANCE: Tissue disruption is crucial to consider when using jet injection to deliver drugs and release capillary blood.

Blood Collection from The Porcine Ear Using a Jet Injector.

We present a new lancet-free method of capillary blood collection for the measurement of blood glucose concentration using a needle-free jet injector. This technique is tested on living animals and directly compared to the current best practice, lancet prick. Shallow jet injection into porcine outer-ear was performed using a portable needle-free jet injector with a slot-shaped nozzle. The jet injections presented used about 25 µL of injectate to penetrate porcine skin to about 1.4 mm, which is within the WHO standards for capillary blood sampling. The blood and fluid released by the jet injections and lancet pricks was collected. The volume and colour of these samples were analysed. The results demonstrate that jet injection is a feasible technique for the collection of capillary blood, despite the small volume of blood samples retrieved from all four pigs. Jet injection may be used in the future to retrieve capillary blood samples from human fingertips.

Subcutaneous nicotine delivery via needle-free jet injection: A porcine model.

Subcutaneous delivery of nicotine was performed using a novel electrically-operated needle-free jet injector, and compared to hypodermic needle delivery in a porcine model. Nicotine was delivered as a single, one-milligram dose into the abdominal skin, formulated as a 50 microliter aqueous solution. Plasma levels of nicotine and cotinine, its main metabolite, were then monitored over 2 h, following which the injection site was excised for histological examination. No irritation or tissue damage were found at the injection sites, and the jet-injected nicotine exhibited comparable absorption into the systemic circulation to that injected using a conventional needle and syringe. The needle-free jet injection of nicotine is a promising and well tolerated method. The data presented from this porcine model will support a first in human trial towards a new promising nicotine replacement therapy.

Viscous Heating Assists Jet Formation During Needle-Free Jet Injection of Viscous Drugs.

OBJECTIVE: Jet injectors use a high-pressure liquid jet to pierce the skin and deliver drug into underlying tissues. This jet is formed through a short, narrow orifice; the geometry of the orifice and the properties of the fluid affect the nature of the flow. We aimed to discover information about the turbulent and viscous processes that contribute to pressure loss and flow patterns during jet injection. METHODS: We used computational fluid dynamics methods and experimental observation to investigate the effects of nozzle geometry, fluid viscosity, and viscous heating on jet production. We experimentally verified the temperature change of the jet during ejection, using an infrared camera. RESULTS: Our models accurately predict the average jet speed produced for two example nozzle geometries over two orders of magnitude of viscosity. The models reveal the previously unreported importance of viscous heating in the formation of the jet. Temperatures >65 °C were predicted at the edge of the flow as a result of viscous heating. These caused a significant local reduction in viscosity and effectively allowed the fluid to lubricate itself. Our experiments confirmed changes in mean jet temperature of up to 2.5 °C, which are similar to those predicted by our model (∼2.8 °C). CONCLUSION: These results reveal the importance of the viscous heating properties of a fluid in the formation of high-speed jets for drug delivery. SIGNIFICANCE: This property is crucial to consider when formulating new drugs for needle-free jet injection.

Laterally Dispersing Nozzles for Needle-assisted Jet Injection.

Most transdermal drug delivery systems are designed to inject drugs through the skin in a direction normal to the skin surface. However, in some applications, such as local anaesthesia, it is desirable to disperse the drug in a direction parallel to the surface of the skin. In this paper we present nozzles for needle-assisted jet injection that are designed to laterally disperse the fluid drug at a chosen depth in tissue. These nozzles were manufactured by laser machining holes in the walls of 0.57 mm (24 G) hypodermic needles, and sealing the ends of the needles. An existing controllable jet injection system was used to test the nozzles. High-speed video recordings were taken to examine the shape of the high-speed jets emitted from the orifices, and jet injections into post mortem porcine tissue were performed to evaluate the resulting dispersion pattern. These injections demonstrated the ability of these nozzles to achieve a widely spread dispersion at a depth of 3 mm to 4 mm in tissue. We observed that the widest dispersion occurred at the same depth as the orifices, and dispersion was greater in the direction of the jets. Further investigation, including an in vivo study, is now required to evaluate whether this technique can reduce the time, cost or pain associated with transdermal local anaesthetic delivery.

Power-efficient controlled jet injection using a compound ampoule.

We present a new mechanism for achieving needle free jet injection that significantly reduces the power required to perform a given injection. Our 'compound ampoule' produces two phases of jet speed under a constant force input by changing the effective piston area part-way through the injection. In this paper we define the benefits associated with a compound ampoule, relative to those of the conventional single piston design, by developing expressions for the power and energy required to perform an injection. We demonstrate that a compound ampoule can reduce the maximum input power required to perform a jet injection to less than one fifth of that previously required, enabling motors of less than half the mass to perform the same injection. We then detail the development of a prototype compound ampoule injector. Results from testing of this prototype demonstrate the function of a compound ampoule and verify the expected reduction in the required power and energy. Injections into post mortem porcine tissue confirm that our compound ampoule prototype can achieve the delivery of 1 mL of liquid into post-mortem tissue at least as effectively as a conventional ampoule. This approach will advance progress toward light-weight and power-efficient needle-free jet injectors for transdermal drug delivery.

The effect of jet speed on large volume jet injection.

Jet injection presents a promising alternative to needle and syringe injection for transdermal drug delivery. The controllability of recently-developed jet injection devices now allows jet speed to be modulated during delivery, and has enabled efficient and accurate delivery of volumes up to 0.3 mL. However, recent attempts to inject larger volumes of up to 1 mL using the same methods have highlighted the different requirements for successful delivery at these larger volumes. This study aims to establish the jet speed requirements for delivery of 1 mL of liquid using a controllable, voice coil driven injection device. Additionally, the effectiveness of a two-phase jet speed profile is explored (where jet speed is deliberately decreased toward the end of the injection) and compared to the constant jet speed case. A controllable jet injection device was developed to deliver volumes of 1 mL of liquid at jet speeds >140 m/s. This device was used to deliver a series of injections into post-mortem porcine tissue in single and two-phase jet speed profiles. Single-phase injections were performed over the range 80 m/s to 140 m/s. Consistent delivery success (>80% of the liquid delivered) was observed at a jet speed of 130 m/s or greater. Consistent penetration into the muscle layer coincided with delivery success. Two-phase injections of 1 mL were performed with a first phase volume of 0.15 mL, delivered at 140 m/s, while the injection of the remainder of fluid was delivered at a second phase speed that was varied over the range 60 m/s to 120 m/s. Ten two-phase injections were performed with a second phase speed of 100 m/s producing a mean delivery volume of 0.8 mL ±â€¯0.2 mL, while the single-phase injections at 100 m/s achieved a mean delivery volume of 0.4 mL ±â€¯0.3 mL. These results demonstrate that a reduced jet speed can be used in the later stages of a 1 mL injection to achieve delivery success at a reduced energy cost. We found that a jet speed approaching 100 m/s was required following initial penetration to successfully deliver 1 mL, whereas speeds as low as 50 m/s have been used for volumes of <0.3 mL. These findings provide valuable insight into the effect of injection volume and speed on delivery success; this information is particularly useful for devices that have the ability to vary jet speed during drug delivery.

High-speed X-ray analysis of liquid delivery during jet injection.

The effect of varying velocity during jet injection on the dispersion of fluid into tissue is investigated using a custom-built X-ray imaging system. Injections are performed into ex-vivo porcine abdominal tissue using a voice coil actuated injection device. Single velocity and two-phase velocity injections reveal the complex nature of the dispersion of the fluid jet in layered tissue and highlight the effects of changing the jet velocity following the initial penetration of the liquid into the tissue.

A device for controlled jet injection of large volumes of liquid.

We present a needle-free jet injection device controllably actuated by a voice coil and capable of injecting up to 1.3 mL. This device is used to perform jet injections of ~900 µL into porcine tissue. This is the first time that delivery of such a large volume has been reported using an electronically controllable device. The controllability of this device is demonstrated with a series of ejections where the desired volume is ejected to within 1 % during an injection at a predetermined jet velocity.

A compound ampoule for large-volume controllable jet injection.

We present a new design for a needle-free injector ampoule, using two concentric pistons to pressurize the fluid during the injection. The smaller, inner piston is used to provide an initial high-velocity piercing jet; it then engages the outer piston to deliver the remaining drug via a low-velocity jet. The goal of this design is to enable needle-free delivery of relatively large volumes to controlled depths in tissue, a task impractical with conventional ampoules and actuators. We demonstrate this concept by constructing a 1.2mL ampoule, measuring the jet velocity it produces in free air, and performing a set of injections into post-mortem porcine tissue. The ampoule smoothly produces the two desired phases of an injection, with a smooth transition of jet velocity as the two pistons engage. The injection is able to penetrate porcine skin to a controlled depth and deliver fluid to the subcutaneous and/or intramuscular layers, though further investigation is required to ensure that all of the fluid delivered can be retained at the desired depth.