Dynamic control of needle-free jet injection Jeanne C. Stachowiak a , Thomas H. Li a , Anubhav Arora b , Samir Mitragotri b , Daniel A. Fletcher c, ⁎ a University of California, Berkeley, Department of Mechanical Engineering, United States b University of California, Santa Barbara, Department of Chemical Engineering, United States c University of California, Berkeley, Department of Bioengineering, United States abstract article info Article history: Received 9 May 2008 Accepted 9 January 2009 Available online 21 January 2009 Keywords: Needle-free delivery Transdermal Jet injector Piezoelectric Dynamic control Many modern pharmaceutical therapies such as vaccines and macromolecular drugs benefit from transdermal delivery. Conventional transdermal drug delivery via hypodermic needles causes pain, non- compliance, and potential contamination. Alternative transdermal strategies that deliver drugs in a quick, reliable, painless, and inexpensive way are needed. Jet injectors, which deliver drugs through the skin using a high-speed stream of liquid propelled by compressed springs or gasses, provide a needle-free method of trandermal drug delivery. However, poor reliability as well as painful bruising and bleeding characterize these devices, due in part to the high and constant jet velocity with which drugs are delivered. Toward improved reliability and reduced pain, we have developed a jet injector capable of dynamic control of jet velocity during a single injection pulse. Using this device, we demonstrate that temporal control of jet velocity leads to independent control of penetration depth, by adjusting time at high velocity, and delivered dose, by adjusting time at low velocity, in model materials. This dynamic control of jet velocity creates the potential for better control of needle-free injections, as demonstrated through injection studies on whole ex vivo human skin samples. © 2009 Published by Elsevier B.V. 1. Introduction Transdermal drug delivery is advantageous for administration of therapeutic agents that do not survive ingestion, such as many vaccines and macromolecular drugs. Recently, a growing number of pharmaceutical therapies, including insulin therapy for diabetic patients, rely on macromolecules, which often fail to survive ingestion and also exhibit low rates of diffusion through the skin and other tissues [1,2] This trend has led to a focus on the development of appropriate transdermal delivery strategies. Additionally, a diverse and demanding set of requirements for transdermal drug delivery arises from specific applications of drug delivery. Patients requiring frequent and often self-administered drug doses need a simple, convenient, highly precise, and pain-free transdermal delivery strategy [2]. In developing nations, simple, inexpensive, and contam- ination-free transdermal delivery routes are needed for vaccine delivery [1]. In the case of a large-scale infection pandemic, appropriate transdermal vaccination or therapeutic strategies must be inexpensive, highly rapid, and contamination-free [3]. Since their invention in the mid 19th century, hypodermic needles and syringes have served as the primary strategy for transdermal drug delivery. While effective and precise, these devices can cause pain, require a trained operator, create large volumes of medical waste, lead to contamination if reused, and are prohibitively expensive in some developing world settings. These shortcomings have motivated the recent development of several diverse alternative strategies [1,3,4] including iontophoresis [5,6] sonophoresis, microneedle delivery [7,8], chemical permeation enhancement [9], particle injection [10], and jet injection [4,11–16]. Initially developed in the 1940s, jet injectors rely on compressed springs or gasses to propel liquid streams to velocities sufficient for skin penetration in the absence of needles. Due to concerns over cross-contamination due to splash back [17], poor reliability of dose and depth of delivery [11,18], and complaints of painful bruising and bleeding [4,19], jet injectors have not gained wide acceptance. The lack of reliability associated with jet injectors is thought to arise partly from the failure of current devices to respond to the large variations in the mechanical properties of the skin [11]. Additionally, the large dose sizes [4] (tens to hundreds of microliters) and nozzle diameters (100–500 μm) used in these devices likely worsen the reliability problem by causing splash back of the drug from the skin and may be responsible for pain. A likely cause of the difficulty encountered by conventional jet injectors in controlling the depth and dose of drug delivery arises from their use of a single jet velocity [11], as depicted schematically in Fig. 1A. Liquid jets from these devices have been shown to deposit fluid into the skin in three stages: (i) a penetration stage in which the maximum injection depth is defined, followed by (ii) a stagnation event where the fluid begins to build up at the maximum injection depth and (iii) a constant depth dispersion stage during which fluid (drug) is absorbed by the penetrated tissue surfaces [12–14]. The skin Journal of Controlled Release 135 (2009) 104–112 ⁎ Corresponding author. ⁎608B Stanley Hall #1762, Berkeley, CA 94720, United States. Tel.: +1 510 643 5624; fax: +1 510 642 5835. E-mail address: fletch@berkeley.edu (D.A. Fletcher). 0168-3659/$ – see front matter © 2009 Published by Elsevier B.V. doi:10.1016/j.jconrel.2009.01.003 Contents lists available at ScienceDirect Journal of Controlled Release journal homepage: www.elsevier.com/locate/jconrel