Optimization of a jet-propelled particle injection system for the uniform transdermal delivery of...

ARTICLE

Optimization of a Jet-propelled Particle InjectionSystem for the Uniform Transdermal Deliveryof Drug/Vaccine

Yi Liu, Mark A.F. Kendall

Oxford Institute of Biomedical Engineering, Department of Engineering Science, University

of Oxford, Oxford OX2 6PE, UK; telephone: 01865-274740; fax: 01865-274752;

e-mail: [email protected]

Received 26 September 2006; accepted 18 December 2006

Published online 10 January 2007 in Wiley InterScience (www.interscience.wiley.com
). DOI 10.1002/bit.21324
ABSTRACT: A jet-propelled particle injection system, thebiolistics, has been developed and employed to acceleratemicro-particles for transdermal drug delivery. We haveexamined a prototype biolistic device employing a conver-ging–diverging supersonic nozzle (CDSN), and found thatthe micro-particles were delivered with a wide velocity range(200–800 m/s) and spatial distribution. To provide a con-trollable system for transdermal drug delivery, we present acontoured shock-tube (CST) concept and its embodimentdevice. The CST configuration utilizes a quasi-steady, quasi-one dimensional and shock-free supersonic flow to deliverthe micro-particles with an almost uniform velocity (themean velocity and the standard deviation, 699� 4.7 m/s)and spatial distribution. The transient gas and particledynamics in both prototype devices are interrogated withthe validated computational fluid dynamics (CFD)approach. The predicted results for static pressure and Machnumber histories, gas flow structures, particle velocity dis-tributions and gas–particle interactions are presented andinterpreted. The implications for clinical uses are discussed.

Biotechnol. Bioeng. 2007;97: 1300–1308.

� 2007 Wiley Periodicals, Inc.

KEYWORDS: drug delivery; jet; macromolecules; particle;protein; skin; transdermal

Introduction

Skin represents the largest and most easily accessible organof the body and its use for topical and systemic delivery ofdrugs has been reviewed (Barry, 2001, 2004; Cross andRoberts, 2004; Naik et al., 2000; Thomas and Finnin, 2004).The advantages of the transdermal drug delivery include:therapeutic benefits such as sustained delivery of drugs, andhence reduced systemic side effects; reducing the typical

Correspondence to: Yi Liu

Contract grant sponsor: Chiron Vaccines

1300 Biotechnology and Bioengineering, Vol. 97, No. 5, August 1, 2007

dosing schedule, hence generating the potential forimproved patient compliance; and avoidance of the first-pass metabolism effect for drugs with poor oral bioavail-ability. Additionally, the transdermal route represents aconvenient, patient-friendly option for drug delivery withthe potential for flexibility, easily allowing dose changesaccording to patient needs and the capacity for self-regulation of dosing by the patient.

Although the skin represents a suitable target for drugdelivery, the functional properties that enable it to act as anexcellent barrier also serve to limit the access of drugs intoand across the epidermis (Barry, 2001; Thomas and Finnin,2004). The skin portrays an extraordinary evolutionary feat.Structurally, it consists of an epidermis of columnarepithelium and a dermis of fibrous connective tissue. Notonly does it physically encapsulate the organism and providea multifunctional interface with the surrounding environ-ments, but it is also perpetually engaged in the assembly of ahighly efficient homeostatic barrier to the outward loss ofwater (Barry, 2004). In so doing, it furnishes a membranethat is equally adept at limiting molecular transport bothfrom and into the body. To overcome this barrier function,for the purpose of transdermal drug delivery, has been anecessarily challenge for pharmaceutical scientists, and onethat boasts significant progress.

With the recent focus on the delivery of new protein-based and DNA-based therapeutic macromolecules gener-ated by modern biotechnology, a variety of tactics has beenexploited and utilized to overcome the skin barrier, such as,iontophoresis, electroporation, sonophoresis, micro-needle,and particle bombardment techniques, as reviewed exten-sively in literatures (Cross and Roberts, 2004; Mehier-Humbert and Guy, 2005).

� 2007 Wiley Periodicals, Inc.

In particular, particle-mediated drug delivery using highvelocity acceleration of gold particles coated with geneticmaterials was originally developed to facilitate genetictransformation of targeted tissues. This technique, alsoreferring to gene gun, has since applied to variousapplications and proved to be a versatile method and highefficacy for transdermal drug delivery (Bauer et al., 2006;Davidson et al., 2000; Shefi et al., 2006; Sohn et al., 2001).The delivery of a drug or protein, for instance, can promoteeffective and rapid healing of the injured tissue for the localtreatment of chronic wounds (Davidson et al., 2000). It isalso concluded that optimization of ballistic parameters canresult in synthesis of functional protein (Sohn et al., 2001).However, the application area of such technology has beenlimited by the current design of gene guns used for theparticle acceleration. Even with distinct advantages as aresearch tool for the in vivo study, the technique in itscurrent form needs to be further optimized for clinical use(Bauer et al., 2006). The currently available gene guns,including the stand-alone PDS-1000 and the popular hand-held Helios (both commercially available from Bio-Rad,Hercules, CA) that are powered by pulses of highlypressurized Helium gas, deliver particles with limitedaccuracy and reproducibility. In addition, the tissue targetedby a Helios gun may be damaged by the high-speed gas jetemerging from the gun nozzle (Shefi et al., 2006).

In University of Oxford, we have been developing aneedle-free jet-propelled particle injection system, thebiolistic system, to overcome the barrier properties of theskin for particle transdermal delivery (Bellhouse et al., 1994;Kendall, 2002; Kendall et al., 1999; Liu, 2006; Liu andKendall, 2004; Liu et al., 2002; Quinlan et al., 2001). Aschematic diagram of a commercially variable, hand-heldbiolistic system, configured for clinical use, is shown inFigure 1.

This new technology provides a unique means to delivermicro-particle formulation of drugs into the human skin ormucosal tissue with a specially designed conical nozzle(Kendall et al., 1999; Liu and Kendall, 2004). The system,shown in Figure 1, employs a conical converging–diverging

Figure 1. A schematic diagram of commercially variable, hand-held biolistic

system. [Color figure can be seen in the online version of this article, available at

www.interscience.wiley.com.]

supersonic nozzle (CDSN). For convenience, we shall referthis biolistic system as the CDSN system, and the systembased on a contoured shock-tube (CST) design (Kendall,2002; Liu et al., 2002; Hardy, 2003; Truong, 2005), as theCST system. Prototype devices have shown to be clinicallyeffective, needle-free, pain-free and applicable to a largenumber of macromolecular drugs, particularly therapeuticprotein and vaccines (Burkoth and Bellhouse, 1999; Chenet al., 2002; Dean et al., 2003; Swain and Heydenburg Fuller,2000).

In this study, we employ an advanced computational fluiddynamics (CFD) methodology to gain a more completeunderstanding of the flow physics, with the emphasis onthe device optimization to achieve a controllable particledelivery. The CDSN Biolistic System section starts a briefdescription of the biolistic system under concern, followedby a presentation of numerical approach in NumericalMethod section. The gas and particle characteristics of theCDSN biolistic device are provided in GAS/ParticleDynamics of the CDSN System section, with an aim tonumerically elucidate the basic characteristics of the biolisticsystem. The particle velocity and spatial distribution areexamined and interpreted. Contoured Shock-Tube Conceptand the CST System section presents a new CST designconcept and its embodiment, CST device. The capability ofuniformly delivering particles by means of the CST system isnumerically interrogated and demonstrated. Finally, weconclude with the main remarks.

The CDSN Biolistic System

The pivotal internal components of the CDSN biolisticsystem are a helium micro-cylinder, a drug cassette and aCDSN. Key aspects of the concept and its embodimentdevice are described (Kendall, 2002; Liu and Kendall, 2004),hence only a brief description is provided here. The heliumgas is stored in the micro-cylinder at a pressure of 1–6 MPa.Upon activation, the released helium ruptures diaphragmsof the cassette, generating a shock wave, which propagatesdown the nozzle and initiates an unsteady gas flow, as in aclassical shock-tube theory with consideration of areachange (Chisnell, 1957; Smith, 1966). Later, a sustained gasflow from the micro-cylinder is established. In the course ofthese processes, micro-particles are entrained in the gas flowand accelerated through the nozzle to the skin target. As thegas–particle flow impinges on the skin target, gas is deflectedaway and exhausted through the vented silencer. The micro-particles, with their higher inertia, breach the stratumcorneum, thereby targeting specific cells of interest in thehuman skin.

Numerical Method

In this study, the governing equations of multi-species gasphase (Reynolds average Navier–Stokes equations, togetherwith an additional species transport equation) are solved by

Liu and Kendall: Uniform Transdermal Delivery of Drug/Vaccine 1301

Biotechnology and Bioengineering. DOI 10.1002/bit

a commercial finite-volume-method based software, Fluent(Fluent Inc., Lebanon, NH). In order to capture the mainfeatures of the unsteady motion of the shock wave process, acoupled explicit solver is employed. Time integration isexplicitly performed. A multi-stage (Runge-Kutta) timestepping algorithm is employed to achieve the desiredtemporal accuracy. An overall second order accuracy issatisfied both spatially and temporally.

The trajectory of the particle is obtained by solving theparticle equation of motion. The transient gas flow and itsinteraction with particles are modeled simultaneously andinteractively. The particle motion equation, aided by thedrag correlation, is advanced in time with gas flowsimulation.

The detailed mathematical equations and physical modelcan be found in the published references (Liu, 2006; Liuet al., 2002). This numerical approach has been validatedwith studies of a number of similar shock-tube basedparticle injection systems (Liu, 2006; Liu and Costigan,2005; Liu and Kendall, 2004; Liu et al., 2002), particularly inwhich different drag correlations of Igra and Takayama(1993), Henderson (1976), and Kurian and Das (1997) have,respectively, been assessed. The results presented in thisarticle are obtained with the drag correlation of Igra andTakayama, which shows the best agreements with experi-mental measurements in those applications.

Figure 2. Comparisons between simulated and experimental measured pres-

sure (a), and Mach number histories (b), and simulated strain rate contours at a time of

354 m after diaphragm rupture (c). [Color figure can be seen in the online version of this

article, available at www.interscience.wiley.com.]

Radial position (m)

Vel

ocity

(m

/s)

0.000 0.001 0.002 0.003 0.004 0.005 0.0060

200

400

600

800

1000

1200

Figure 3. Simulated particle velocity profile at 10 mm downstream of the nozzle

exit. [Color figure can be seen in the online version of this article, available at www.

interscience.wiley.com.]

GAS/Particle Dynamics of the CDSN System

For a better perception of the gas and particle dynamics ofthe CDSN system, we have performed CFD simulation of theCDSN, the simplest mode of the system (Liu and Kendall,2004).

Figure 2 presents static pressure and Mach numberhistories, and two-dimensional contour plots of train rate ata time of 354 mm after diaphragm rupture. A time of zeromarks the instantaneous rupture of diaphragm. Timehistories for representative static pressures (Fig. 2a), andthe Mach number at the centre of the nozzle exit (Fig. 2b) arecompared with experimental measurements. The Machnumber traces are quite oscillatory due to the interaction ofthe supersonic flow and the presence of a relatively largePitot probe. However, one can see that the trends and levelof key flow regions are in good agreement with themeasurements.

The main features of gas flow, including: the oblique-shock systems, as a result of an over-expanded nozzleoperation condition; the flow separation due to the obliqueshocks interaction with the boundary layer, are demon-strated in Figure 2c, which is comparable with the corres-ponding Schlieren photograph (Kendall et al., 1999). Theparticles will be delivered by this shock-persist, separated jetflow within the CDSN system.

Figure 3 shows the simulated particle velocity profilealong radial position at 10 mm downstream of the nozzleexit. It is clearly seen that the particles are distributed within


DOI 10.1002/bit

a high-velocity gas core area of less than 6–8 mm indiameter. The oblique shock system and resulting separationof the supersonic gas flow (shown in Fig. 2c) have asignificant effect on the performance of the supersonicnozzle in the drug delivery, as illustrated. The numericalresults agree well with the DGV images in terms of theparticle velocity magnitude and distributions (Quinlanet al., 2001).

Contoured Shock-Tube Concept andthe CST System

For the powder injection concept to be optimized for a rangeof applications in transdermal drug delivery, systempreferably should deliver micro-particles to the skin witha narrow and controllable velocity range and uniformspatial distribution. This can be achieved with the optimaldesign of a CST instead, termed the CST system. During theparticle delivery, the CST system is designed to accom-modate correctly expanded compression waves, rather toform the oblique shock waves as in the CDSN system, with acontoured supersonic nozzle.

The Contoured Shock-Tube

The prototype CST configuration is illustrated schematicallyin Figure 4b and the principles of operation are described inthe space-time (x� t) diagram in Figure 4a.

Axial Po

Tim

e (µ

s)

-60.0- 40.0- 20.000.0

50.0

100.0

150.0

200.0

4

Unsteadyexpansion

Reflected (u+a)w ave

I I

Diaphragm

10 mm

S

a

b

Figure 4. Configuration (a) and space-time (x� t ) (b) of the prototype CST syst

www.interscience.wiley.com.]

The CST consists of a shock tube and a correctly expandeddiverging nozzle. Similar to the CDSN system, the operationcommences with the diaphragm rupture. The rupture ofdiaphragm initiates a classic shock-tube flow, where aprimary shock (PS) wave propagates along the shock tube,processing the quiescent gas (air at atmospheric pressure) inRegion 1 (marked in Fig. 4b) to Region 2. Simultaneously,an unsteady expansion wave propagates upstream intoRegion 4 (mixture of air and helium gas at rupturepressure). This expansion wave expands and accelerates thedriver gas to Region 3, where the velocity matches that inRegion 2. Also labeled in Figure 4b is a typical trajectory ofthe particle cloud, entrained and accelerated in the unsteadyexpansion and further accelerated by the gas in Region 3.

The functions of the shock tube are to allow the PS andcontact surface (CS) to form and increase the separationbetween the PS and particle cloud. The divergent nozzle iscoupled to the shock tube to further accelerate helium to acorrectly expanded supersonic exit condition throughunsteady expansion. The particles are further acceleratedto a uniform exit velocity and distributed over a largerimpart area.

The CST system need to be optimized such that the bulkof the particle cloud is accelerated in a quasi-steadysupersonic flow (QSSF) and not in the starting process,which can be achieved by the choice of system geometry, gasspecies and operating conditions. The upstream terminationboundary of the particle delivery window is defined by thereflected expansion wave. Practical constraints of the hand-held device limit the device length, and the duration of the

sition (mm).0 20.0 40.0 60.0

1

23PSCS

Startingprocess

Particle cloud trajectory

SS

Particles

Nozzlehock-tube

em. [Color figure can be seen in the online version of this article, available at



Figure 5. Time sequence of simulated contour plots of the gas pressure. [Color figure can be seen in the online version of this article, available at www.interscience.wiley.

com.]

QSSF within which the particles are to be entrained.Therefore, an emphasis is placed upon gaining new insightsinto the nozzle starting process and the gas–particleinteractions for this CST configuration.

GAS–Particle Dynamics of the CST Configuration

Figure 5 presents a sequence of contour plots of staticpressure. Key flow features, such as the propagation of thePS, the CS, the unsteady expansion waves and the secondaryshock (SS), are shown from times of 98–164 ms afterdiaphragm rupture. In particular, the CS is clearly seen at atime of 98 ms when the supersonic gas flow undergoes theunsteady expansion in the nozzle. At a time of 185 ms, thetermination of the starting process within the CSTconfiguration is shown. The solution becomes essentiallytime independent, that is, the QSSF is then established with amore uniform gas flow properties, which are preferable formicro-particle acceleration.

The particle delivery window has already been terminatedat a time of 255 ms, that is, the end of the QSSF. From thistime onwards, a pair of oblique shocks near the nozzle exitare formed due to the nozzle working in an over-expansioncondition. Unlike the CDSN system, all the particles aredesigned to be delivered within the uniform QSSF regionbefore the presence of the oblique shocks, as illustrated inFigure 8 later.

Figure 6 shows the simulated Mach number history at thenozzle exit, with PS, CS, and SS, respectively, labeled. Unlike


the CDSN system (as shown in Fig. 2), the complex obliqueshock structure and resulting separation are not presented.Also shown is an analysis Mach number obtained withquasi-2D shock relations. It is demonstrated that shocks,compression, expansion waves, and interactions betweenwaves and the boundary layer are reasonably captured by theemployed numerical method. The predicted QSSF durationfor the particle delivery is about 50 ms.

The closer examination of the gas flow properties in theQSSF is achieved at a time of 205 ms after diaphragm rupture(labeled in Fig. 6), shown in Figure 7, in the form of the gasdensity and velocity contours.

In contrast to the CDSN system, the correctly expandedsupersonic nozzle flow provides a quasi-steady, quasi-onedimensional uniform gas flow. Consequently, the micro-particles are accelerated with a more uniform velocity at thesame axial position. Figure 8, respectively, displays theparticles velocity map at a range of times after diaphragmrupture. Comparing to the gas flow counterparts, we can seethat the micro-particles are accelerated by a transient quasi-one dimensional gas flow (Region 3, marked in Figure 4b),initiated by the primary shock.

Figure 9a plots the calculated particle trajectories throughthe CST as a function of velocity and time, where A, B, and Cdenote the starting, the end, and 10 mm downstream of thediverging nozzle, respectively. The velocity plots clearlyshow that the particles are accelerated to uniform velocity inthe shock-tube up to A as designed. The particles haveobtained a further increase of about 100 m/s with the

DOI 10.1002/bit

Time(µs)

Mac

h N

umbe

r0 50 100 150 200 250 300

0.0

0.5

1.0

1.5

2.0

2.5

CFD Simulation1D analysisC.S.

P.S.S.S.

t=205µs

Figure 6. Mach number history at the center of the nozzle exit plane. [Color figure can be seen in the online version of this article, available at www.interscience.wiley.com.]

t = 98 µs

520510

Verlocity (m/s)

365360355350345340335330325320

Verlocity (m/s)a

b

coupled correctly expanded nozzle (from A to B), and aredistributed to a large area. The time plots give the timehistory of the particle movement along the axial position.

The particle velocity distributions along the radius at 10mm downstream of the nozzle exit (representing the actualdistance of the target in the biolistic drug delivery, marked Cat Fig. 9a) are drawn in Figure 9b. The corresponding meanvelocity of sampled micro-particles is 699.1 m/s, with aremarkably lower standard deviation of 4.68 m/s for allparticles over a delivery duration, which demonstrates thatmicro-particles have been delivered with a desired uni-formity by the CST configuration. In contrast, the meanvelocity for CDSN system (shown in Fig. 3) is 798.1 m/s,with the standard deviation of 113.68 m/s at a single time of354 ms after diaphragm rupture. Indeed, it has beendemonstrated experimentally and numerically that theparticles were delivered with a wide range of velocity (200–800 m/s) during the whole particle delivery process (Liu andKendall, 2004).

Figure 7. Simulated contour plots of the gas density and velocity magnitude.

[Color figure can be seen in the online version of this article, available at www.in-

terscience.wiley.com.]

GAS–Particle-Target Interactions of the Pre-ClinicalDevice

This CST configuration is further embodied in the hand-held biolistic device. Figure 10 shows a hand-held CSTbiolistic embodiment. In contrast to the clinical deliverysystem, as shown in Figure 1, the CST configuration ofFigure 4a is employed instead.

650640630620610600590580570560

Verlocity (m/s)

t = 205µs

600590580570560550540530520510

Verlocity (m/s)

t = 185µs

500490480470460450440430

t = 164µs

c

d

Figure 8. Time sequence of calculated particle velocity map. [Color figure can

be seen in the online version of this article, available at www.interscience.wiley.com.]



Axial Position (m)

Vel

oci

ty (

m/s

)

Tim

e(µ

s)

0 0.02 0.04 0.06 0.08 0.10

200

400

600

800

0

50

100

150

200

250

300

350

Velocity

Time

CBA

Radial position (m)

Vel

ocity

(m/s

)

0 0.0005 0.001 0.0015 0.002 0.0025 0.003 0.0035 0.0040

100

200

300

400

500

600

700

a

b

Figure 9. Calculated particle trajectories (a), and velocity profile at 10 mm downstream of the nozzle exit (b). [Color figure can be seen in the online version of this article,

available at www.interscience.wiley.com.]

To interrogate the effects of the silencer configuration andimpingement region, we have performed the simulation ofgas–particles flow impact on the skin target for the completeoperation of the hand-held CST device. The resulting

Figure 10. A hand-held CST biolistic device. [Color figure can be seen in the

online version of this article, available at www.interscience.wiley.com.]


particle impact velocity distributions are plotted inFigure 11.

The impact velocities for the hand-held CST biolisticsystem are found lower than those in the free jet (shown in

Radial position (m)

Impa

ctve

loci

ty(m

/s)

0 0.0005 0.001 0.0015 0.002 0.0025 0.003 0.0035 0.0040

100

200

300

400

500

600

700

Figure 11. Calculated particle impact velocity profile. [Color figure can be seen

in the online version of this article, available at www.interscience.wiley.com.]

DOI 10.1002/bit

Figure 12. Calculated contour plots of the gas velocity (a) and density (b). [Color

figure can be seen in the online version of this article, available at www.interscience.

wiley.com.]

Fig. 9b) due to the presence of the silencer and theimpingement region.

To illustrate the effects of the gas flow on the micro-particle acceleration, Figure 12 presents the simulatedcontour plots of gas velocity magnitude and density at theQSSF. One can see that a quasi-one dimensional uniform gasflow has been established for the micro-particle delivery inthe hand-held CST system. Also shown is the normal-shocklike standing-off shock wave in the impingement region ofthe target, which is responsible for the decrease of theparticle impact velocity magnitude and uniformity (themean velocity� the standard deviation, 504.5� 64.46 m/s).

In general, it is demonstrated that the micro-particleshave been delivered and impacted the target with a moreuniform velocity range and spatial distribution by the hand-held CST biolistic system, compared to the CDSN device.Therefore, the use of the CST device gives the technique ofbiolistic delivery a new capability in a controllable fashionand targeted with a high precision.

These simulations provide a valuable guideline for thedesign, evaluation and optimization of transdermal drugdelivery system. The particle impact inputs lend necessaryinformation for further studies on physiological transporta-tion (such as lymphatic system) and biological effects(Ohhashi et al., 2005). The controllable biolistic systemfurnishes a unique means for biomedical research on topics,for example, the rate and extent of protein absorption, andthe role of the lymphatic system in the transport of proteindrugs to the systemic circulation. With the CST biolisticsystem, for instance, the DNA-coated micro-gold particlescan be accurately delivered into Langerhans cells (antigenpresenting cells, residing in the epidermal layer of the skin,typically at a depth of 20–60 mm) for a more quantitativeinspection in complex biological systems.

Conclusions

A needle-free jet-propelled particle injection system, thebiolistics, has been developed to overcome the skin barrierfor transdermal drug delivery. A CFD approach has beenemployed to gain a more complete understanding of theflow physics of the CDSN and CST system.

Firstly, transient gas and particle dynamics within theprototype CDSN biolistic devices were examined. Thecalculations revealed that an over-expanded supersonicnozzle condition has led to gas and micro-particle flow non-uniformities generated by an oblique shock wave systemalong with associated flow separation within the QSSF(798� 113.7 m/s, at a time of 354 ms alone).

To achieve a controllable particle delivery system, the CSTdesign concept and its embodiment, CST device, arepresented. In the simplest CST configuration, a quasi-steady, quasi-one dimensional uniform gas flow is provided.As a result, all the micro-particles are accelerated in the freejet with an almost uniform velocity (699� 4.7 m/s).

Consequently, the CFD simulations are conducted for thehand-held CST biolistic system, and demonstrate the micro-particles to be delivered with a more uniform velocity andspatial distribution (505� 64.5 m/s). However, the particleimpact velocity magnitude and uniformity are decreased,compared to those obtained from the free jet simulation ofthe simplest CST configuration. This is due to the presenceof the silencer and the impingement region.

This collaborative research was supported by Chiron Vaccines (pro-

prietor of PowderJect Pharmaceuticals plc.). Professor Brian J. Bell-

house is acknowledged for his fruitful discussions.

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