Characterization of jets for impulsively-started needle-free jet injectors: Influence of fluid properties
Graphical abstract
Introduction
Routine administration of vaccines via hypodermic syringes is known to cause mild to severe anxiety in patients with needle-phobia (trypanphobia), and affects approximately one in ten patients in the US [1,2]. More grave, however, are needle-stick injuries for health professionals and patient cross-contamination due to needle re-use in developing nations [3,4]. The 2002 World Health Report [5] from the World Health Organization (WHO) indicated that 2 million health-care workers are subject to needle-stick injuries each year, which causes nearly 40% of all cases of Hepatitis B and C in health-care workers, whilst the financial cost of treating needle-stick injury is estimated at up to $3,000 per incident [6,7]. The Safe Injection Global Network (SIGN) and Global Vaccine Action Plan (GVAP) of the WHO have therefore recommended supporting the development of needle-free injection technologies [8,9], noting that they reduce the risk of spreading infection.
Needle-free injection is a form of drug delivery through the skin without the use of hypodermic needles and syringes. There are different forms of needle-free injection [10,11], such as micro-needle patches specifically for intradermal (ID) delivery, powder-based ballistic delivery and jet injectors, which rely on a high-speed jet to puncture the skin. The predominant use of needle-free jet injectors in the past has been for subcutaneous (SC) and intramuscular (IM) delivery [[11], [12], [13], [14]], but are now being explored for intradermal (ID) delivery, as documented in recent clinical trials [[15], [16], [17], [18], [19], [20]].
The basic operating premise of jet injection is that a high upstream pressure, typically created using either a spring or compressed gas mechanism, forces a jet at high-speed, Vjet~ , from a narrow orifice, D0~ . Studies with both commercial and custom devices in the literature have primarily been in-vitro [[21], [22], [23], [24], [25], [26], [27]] or ex-vivo [[28], [29], [30], [31], [32], [33], [34]] and typically consider large doses in the milliliter range, but some novel approaches including piezoelectrics [35], lasers [[36], [37], [38], [39]] and explosives [40] are now also exploring delivery in the nanoliter range. While most of these studies have focused on low-viscosity fluids, the injectable drug market includes concentrated solutions with potentially high viscosities (μ ≳ 200 mPa.s) [41,42], indicating the need to address the influence of fluid viscosity. In addition, the advent of novel nucleic acid vaccines [[43], [44], [45]] necessitates an assessment of the effect of rheological profile on injection. With regards to hydrodynamic considerations, refs [46,47] are of particular relevance; A mechanical force balance was derived in Ref. [46], accounting for viscous losses through a discharge coefficient. This model compared favorably to experimental data for the piston displacement, however, non-Newtonian solutions were not explicitly considered. In addition, the recent study of [47] reports on CFD simulations of flow in the orifice region, which again gave good agreement with experimental data for jet speeds. This latter paper also addresses the issue of viscosity reduction due to heating caused by the high shear rates in the orifice region, which has important implications for non-Newtonian fluids as well.
In this paper, we focus specifically on the effect of fluid viscosity and rheological properties for impulsively-started jets using a spring mechanism. We use a single device and orifice size paired with different spring constants to study the influence of fluid properties, and characterize the jet performance with (i) jet speed, (ii) impact force, and (iii) delivery efficiency in ex-vivo tissues. In light of the observations of [47], a key factor in our analysis is the nature of the fluid, i.e. Newtonian vs. non-Newtonian.
Section snippets
Injection device
For this study we used the Bioject ID Pen, which is a streamlined spring-powered jet injector device originally designed for injection of 0.1 mL. The device, shown in Fig. 1(a) is comprised of a spring housed in an upper chamber which is cocked by manually extending the arm on the outside of the chamber. A cartridge, shown in Fig. 1(b), pre-loaded with fluid is then inserted into the front end of the device and locked in place by rotation. The injection is then triggered manually by pressing on
Jet start-up observations
The total jetting time depends upon both the volume expelled and fluid viscosity, but typically lasts between 20 and 80 ms. Of this, the first 2–3 ms is herein referred to as the ‘start-up’ phase during which the impulsive action of the spring-piston causes a rapid pressure rise in the liquid inside the cartridge, and an interplay between compression of the plunger tip and unsteady fluid motion through the orifice. After this, the plunger achieves an approximately linear motion, which is
Conclusions
We have conducted a broad study of the effect of fluid properties in spring-actuated jet injection. The primary quantitative measurements were jet speed, impact force, and injection efficiency. For jet speed, which was derived by direct displacement using high-speed video, we found that the speed diminishes from m/s for water ( Pa.s) down to m/s for glycerol ( Pa.s). However, for the non-Newtonian fluids, with a wide range of low-shear viscosities (
Acknowledgments
This work was financially supported by Inovio Pharmaceuticals and National Science Foundation via award number NSF-CBET-1749382.
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2021, Computers in Biology and MedicineCitation Excerpt :Here, to study the behaviour of jet injectors at extremes of fluid properties, we used two Newtonian liquids: water (ultrapure milliQ) and glycerine (Macron Fine Chemicals). The initial peak-pressure (∼106 Pa) [9,23,27] is strong enough to shake the entire jet injector assembly and therefore the jet injector is fixed onto an opto-mechanic rail system at the time of injection. To further reduce error in plunger displacement, we also log the shaking of jet injector using a multi-point tracking method and subtract it from plunger displacement profile as shown in our previous work [9].