Piezoelectric control of needle-free transdermal drug delivery

https://doi.org/10.1016/j.jconrel.2007.08.017Get rights and content

Abstract

Transdermal drug delivery occurs primarily through hypodermic needle injections, which cause pain, require a trained administrator, and may contribute to the spread of disease. With the growing number of pharmaceutical therapies requiring transdermal delivery, an effective, safe, and simple needle-free alternative is needed. We present and characterize a needle-free jet injector that employs a piezoelectric actuator to accelerate a micron-scale stream of fluid (40–130 μm diameter) to velocities sufficient for skin penetration and drug delivery (50–160 m/s). Existing jet injectors, powered by compressed springs and gases, are not widely used due to painful injections and poor reliability in skin penetration depth and dose. In contrast, our device offers electronic control of the actuator expansion rate, resulting in direct control of jet velocity and thus the potential for more precise injections. We apply a simple fluid-dynamic model to predict the device response to actuator expansion. Further, we demonstrate that injection parameters including expelled volume, jet pressure, and penetration depth in soft materials vary with actuator expansion rate, but are highly coupled. Finally, we discuss how electronically-controlled jet injectors may enable the decoupling of injection parameters such as penetration depth and dose, improving the reliability of needle-free transdermal drug delivery.

Introduction

Development of new therapeutic drugs offers promise for the treatment of many diseases, but effective and efficient delivery of drugs remains a significant challenge. Large molecule and protein-based drugs and vaccinations typically are administered via hypodermic needle since they cannot be absorbed through the skin or taken orally [1]. The requirement for trained health professionals, fear of needles, and the negative physiological impact of large and infrequent doses has motivated the development of alternative methods for delivering liquids through the skin that maintain therapeutic dosing simply and painlessly. Recent developments in the field of transdermal drug delivery [2] include iontophoresis [3], sonophoresis, microneedles [4], and chemical permeation enhancers [5], as well as renewed interest in jet injectors [1], [6], [7], [8], [9]. Jet injectors, which propel liquids at speeds sufficient to penetrate skin without needles, were initially developed in the 1940s. Despite the great need for needle-free injection methods, jet injectors have remained largely underused due to concerns over potential cross contamination due to splash-back [10], unreliability of dose and depth of delivery [11], [12], and painful bruising and bleeding [13], [14]. It has been argued that the lack of reliability arises primarily from the inability of current devices to respond to variations in skin mechanical properties [11] and is exacerbated by the large dose sizes (tens to hundreds of microliters) and nozzle diameters (100–500 μm) employed by conventional injectors [13], which also likely contribute to the problems of splash-back and pain.

A jet injector device that is capable of delivering electronically-controlled doses may offer improved consistency and reduced pain. We present and characterize a new needle-free microjet injector powered by the rapid expansion of a piezoelectric actuator that offers electronic control of fluid displacement. Neither conventional jet injectors powered by springs and compressed air, nor our previous bubble-driven device [15], [16], have offered electronic control of the injection speed. A recent report has demonstrated that fluid jets generated by piezoelectric actuators are capable of skin penetration and delivery of insulin into animals [17]. However, this work did not demonstrate electronic variation of the actuator expansion rate, a key enabling feature of our device. Further, the physical mechanisms of fluid pressurization, jet formation, and material penetration by an electronically-controlled jet injector are at present unclear. A precise understanding of these mechanisms is a critical next step toward the effective clinical application of piezoelectric powered needle-free transdermal drug delivery devices and is the focus of this paper.

Our new device offers electronic control of the actuator expansion rate over nearly an order of magnitude to achieve higher speeds and larger doses than previously reported, and the device is instrumented for the detection of jet velocity (strobe microscopy), actuator and plunger motion (laser-based motion tracking), and jet impact force (miniature load cell). We utilize experimental and computational methods to evaluate the efficacy of our device and the degree to which electronic control of the actuator expansion rate facilitates control of the injection characteristics (expelled volume, pressure, penetration depth). We show that our piezoelectric microjet is capable of propelling fluid jets of small diameter (40–130 μm) and volume (50–650 nL) to high speeds (60–160 m/s) and high impact pressures (0.3–3 MPa) capable of penetrating materials that model the elastic properties of the skin. We conclude with a discussion of the potential for achieving more reliable jet injection through the use of electronically-controlled actuators.

Section snippets

Device

Our piezoelectric-driven needle-free injector, which we refer to as the piezoelectric microjet, consisted of a conventional syringe fitted with a micro-nozzle and completely filled with liquid. The syringe plunger was placed in mechanical contact with a conventional piezoelectric multi-layer actuator (Fig. 1A). Glass syringes with an inner diameter of 1.457 mm and 100 μL capacity were used (Hamilton, Reno, NV). Micro-nozzles were fabricated using a micropipette puller (Sutter Instruments,

Results and discussion

Our piezoelectric microjet uses the rapid expansion of a piezoelectric actuator to displace the plunger of a conventional syringe, generating a high-speed liquid jet of small diameter (30–130 μm) capable of penetrating soft materials. We evaluated electronic control of this drug delivery device by (i) demonstrating control of jet velocity with the piezoelectric actuator; (ii) examining and modeling the effect of device parameter variation on the jet velocity; (iii) characterizing the dependence

Conclusions

We have presented a piezoelectric microjet injector with electronic control over actuator expansion, which is capable of penetrating soft tissue model materials. The behavior of the injector system agrees qualitatively with the predictions of a simple fluid-dynamic model, which considers fluid compressibility, plunger inertia, and mass loss. We have shown that by controlling actuator expansion, we are able to gain significant dependent control over injection characteristics such as jet

Acknowledgements

The authors gratefully acknowledge Professor Samir Mitragotri and Giovanni Nisato for useful discussions as well as Philips Semiconductor (NXP) and StrataGent Life Sciences for generous financial support. J.C.S. gratefully acknowledges fellowship support from the NSF Graduate Research Fellowship Program and from the ARCS Foundation.

Disclosure: D.A.F is a stockholder in StrataGent.

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