ANALOG MULTISTABLE FLOW-CONTROLLER FOR PORTABLE DELIVERY SYSTEMS

ANALOG MULTISTABLE FLOW-CONTROLLER FOR PORTABLE DELIVERY SYSTEMS T. Goettsche *, H. Ernst *, R.Gronmaier *, M. Reichen *, J. Kohnle *, S. Messner *, H. Sandmaier *+** HSG-IMIT, Wilhelm-Schickard-Str. 1, 7852 Villingen-Schwenningen, Germany *, IZFM-Lehrstuhl für Mikrosystemtechnik, University of Stuttgart, Breitscheidstraße 2, 7174 Stuttgart, Germany ** Thorsten.Goettsche@hsg-imit.de, Herbert.Ernst@hsg-imit.de, Roland.Gronmaier@hsg-imit.de, Joerg.Kohnle@hsg-imit.de, Stephan.Messner@hsg-imit.de, Hermann.Sandmaier@hsg-imit.de ABSTRACT The development of a flow-controller that is adequate to be implemented as stand-alone component in a portable drug delivery system is presented in this paper. Changing the fluidic resistance of a variable flow restrictor in an analog multistable manner allows an energy optimized operation even in implantable systems. Working with unfiltered, particle contaminated liquid did not noticeably affect the dosing behavior. All parts in contact with the dosed media are implimented as low cost disposable parts obviating cleaning issues and facilitating product approval. The proposed disposable flow restrictor measures 6x6x2mm 3, the overall dimensions of the entire, geometrically not yet optimised system, including the actuation unit, measures 5x5x23mm 3, still providing room for the implementation of other components, e.g. a reservoir, into the same housing. KEY WORDS medical devices, micro-dosage, particle-tolerant, standalone system INTRODUCTION Advances in drug development and medical long-term therapy require precise dosing systems to reliably handle flow rates of liquids in the range of milliliter per hour down to few microliter per day. In the past, numerous approaches have made the attempt to take advantage of MEMS (Micro-Electro-Mechanical-Systems) technology to meet the strong demands on miniaturization. This has been of significant importance for portable drug-delivery systems. In this context, various components have been developed such as flow restrictors, microvalves or micropumps [1]-[5]. Facing the need to allow flexible therapies adjustable to the patients varying demands comparatively complex systems, often with an increased energy consumption, have been tested. Known problems of microtechnology - as there are its demand on reliable interfaces to the macroscopic environment and its fault liability when not operated under laboratory conditions - remained unsolved. Especially particles that are omnipresent under standard conditions most often impeded the application of microfluidic systems in the field of medical dosage with the associated significant safety issues. drug refill port = septum A: Commercially established systems: Constant pressure reservoir fluidic resistor. drug refill port = septum B: HSG-IMIT system 1999: Constant pressure reservoir fluidic resistor silicon microvalve. drug refill port = septum pressurized reservoir pressurized reservoir C: HSG-IMIT approach 22: pressurized reservoir constant flow resistance constant flow resistance binary valve analogous adjustable flow resistance outlet to catheter Constant pressure reservoir regulable capillary as multistable valve outlet to catheter outlet to catheter Fig.1: Principal sketch of implantable drug delivery systems Typical passive systems that are currently on the market apply a controlled pressure across a defined fluidic resistor (Fig.1, A) to deliver controlled amounts of liquid. 458-129 78

To allow the treatment of a wider range of diseases, theses systems need to become more flexible, controllable and accurate. Some established systems switch between individual fluidic resistors [6],[7]. In previous systems controllable membrane valves have been pursued (Fig.1, B) [2],[3]. Conducting long term measurements under conditions as they are expected in the intended applications, particles tended to accumulate in the sealing regions of these valves (Fig.2) leading to increased leakage rates as well as irregularities in the flow behavior [4]. trapped particles sealing surface inlet opening of silicon membrane valve Fig.2: Trapped particles on the sealing surface of a silicon membrane-valve [2]. To overcome these problems and to meet the latest requirements of drug flow control we recently presented a novel approach with an increased system-level integration and decreased system complexity (Fig.1, C) [8]. Here, the basic idea is to manipulate the cross section of a channel over its complete length (Fig.3). Applying a fluid driving pressure across the channel and an additional external control pressure onto the elastic channel structure i.e. the capillary system - the resulting flow rate through the channel is actively controlled. Compared to previous systems, the main advantages of the presented concept are to be seen in the fundamentally different influence of trapped particles on the flow behaviour and the optimization of the energy consumption when actuated in a multistable manner. In this context multistable indicates that energy is only needed to adjust the flow rate rather than to maintain a flow-rate. While the feasibility of this operating principle has been shown [4], this paper reports on the successful integration of the multistable flow-controller in a miniaturized stand-alone device. Figure 3: Schematic sketch of a channel with variable cross-section. A cover is positioned onto capillary channel. One or both components may be elastic, the flow resistance of the device can then be changed by deforming the elastic component. THEORETICAL APPROACH To get an impression of the elastic behavior of the capillary structure under a given load, extensive numerical simulations were performed using ANSYS [9]. The availability of pertinent material data proved to be very problematic as stress-strain tests of elastomers are usually not performed for strains below 1%. Calculations with approximated material models showed, that plastic deformations are avoidable by an appropriate choice of the elastomer. Furthermore, the simulations demonstrated the change of cross sectional area against the internal and external exerted pressures onto the channel structure. Fig.4 gives an exemplary impression of the expected elastomer deformation. The correlation between reduction of channel height and resulting channel width for the targeted channel-geometry is plotted in Fig.5. The expected resulting flow through the device of 1ml/day (completely undeformed channel) down to 1ml/day was calculated following [1] and is plotted in Fig.5. Fig.4: Simulated exemplary deformation of an elastic channel when compressed by a rigid cover. 79

flow-rate [ml/day] 12 1 8 6 4 2 118 113 18 13 98 93 88 83 78 73 68 channel height [µm] flow-rate channel width channel length 12 mm initial channel height 118 µm Initial channel width 5 µm Material PDMS (Sylgard 186) controlled liquid unfiltered water Temperature 25 C 5 4 3 2 1 channel width [µm] Fig.5: Change of flow-rate due to compression of the capillary described in the table. SETUP FOR THE PROOF OF PRINCIPLE AND RELATED MEASUREMENTS In order to achieve a reversibly deformable channel cross section at least one component, the channel structure itself or its cover, need to be elastic. For reasons of availability, in a proof of principle, channels, anisotropically etched in <1>-silicon, were covered with the elastomer Da/Pro 862-C-4.. In a first test setup, the fluidic seal between the channel structure and its elastomer cover was achieved by applying an initial pneumatic pressure onto the elastic cover, no adhesives or bonding techniques were applied (see Fig. 6). The controlled application of force onto the test structure resulted in a controlled reduction of the channel s cross section and thus a controlled variation of the fluidic resistance. Area load to press elastomer into channel-structure Inlet Polymer cover of the capillaries Meander-shaped silicon capillary Outlet Polymer sealing of the fluidic connections Fig.6: Laboratory setup for the realization of capillary valves in a proof of principle. 1,4 1,2 1,8,6,4,2 resulting flow 7:12 7:4 8:9 8:38 time [hh:mm] applied pressure 3,5 3 2,5 2 1,5 1,5 pressure applied to elastomer [bar] channel length 85 mm initial channel height 49 µm initial upper channel width 41,5 µm material silicon covered by Da/Pro 862-C-4 controlled liquid unfiltered water temperature 25 C diff. pressure across capillary 2.5 bar (36.25 psi) Fig.7: In a proof of principle, the flow rate was manipulated repeatedly over a period of days by stepwise changing the pressure on the elastomer. Fig.7 describes the capillary chip that was used for these experiments and shows promising results of a long-term test with good reproducability. In this experiment, a differential pressure of 2,5bar was applied to generate a flow that was measured using thermal flow sensors [12]. Increasing the pneumatic pressure onto the elastomer cover in defined steps resulted in a directly correlated reduction of the flow-rate as shown in figure 7. Choosing other geometries for the flow channel and other differential pressures, the flow range is easily adjustable to the respective applications needs. REALIZATION AS STAND-ALONE DEVICE Disposable fluidic cartridge: Cleaning issues are a major concern in devices used in direct contact with drugs or analytes in medical devices. In particular for portable drug delivery devices, safety issues and cost effectiveness are of high importance for the success on the market. To prevent the necessity of cleaning, individual parts that are in contact with the dosed liquid should preferably be implemented as disposable parts. Using a photolithographically processed master in SU-8, the presented capillary structure was fabricated by means of soft lithography in PDMS (Poly- Di-Methyl-Siloxane). Before the final curing of the PDMS, a second layer of PDMS was assembled onto the first layer to achieve a fluidically sealed monolithic capillary chip. Fig.7 depicts this capillary chip the layout of which has already been described in Fig.5. Figure 7 show the sealed PDMS capillaries, the structures are filled 71

with ink for reasons of visualization. The entire fluidic chip measures 6x6x2mm 3. Fig.8: Fluidic seal monolithic capillary structures in PDMS, filled with ink. Left picture: top view; right picture: cut through the filled channels. The capillary chip is mounted inside an exchangeable cartridge that is shown in Fig.9. oscillations in a frequency range of 9kHz to apply driving forces of up to.5n and self-locking forces of around 1N. With an specifically designed spindle-lever transmission, a transmission ratio of 5:1 is achieved resulting in forces of up to 2N with a displacement of up to 1mm and a resolution at the interface to the cartridge below 1µm (Fig.9 and 1). At a driving voltage of 6V to 8V, around.5 Joule are consumed per actuation, i.e. per change of flow rate. When maintaining a constant flow rate, which is the case during the main period in typical applications, no energy is consumed. Elliptec Resonant Actuator area for application of pressure standarized fluidic ports free space for further miniaturization or components capillary chip Fig.9: Changeable cartridge; metric dimensions. By means of a changeable cartridge, the controller device itself (see fig. 12) is applicable for a wide range of dosing applications. The capillary structure implemented in the cartridge can be custom-specifically designed according to virtually any flow regime. Even a complete shut-off of flow without consumption of energy seams feasible and is matter of current evaluations. For later applications with a defined chip design, the main cartridge can be further miniaturized. A monolithic fabrication of the whole cartridge containing individual capillary structures would further simplify the system. Depending on the individual application and the liquid to be dosed, a wide range of materials for this cartridge is possible. Self-locking actuation unit: Backed by numerical analysis experiments have shown that, depending on the used elastomer, several tens of Newtons are necessary to achieve satisfactory changes in cross-sectional channel area, i.e. satisfactory changes in flow-rate. On the market available actuators, that confer forces in this range (mostly based on piezo-stacks) and exhibit displacements of up to 5µm, are comparatively large in size and require voltages of up to 1V and are too expensive for this application. A promising alternative was identified with a piezo-driven actuator of Elliptec AG, Germany [11]. This actuator uses resonant Fig.1: Self-locking spindle-lever transmission assembled on the ground plate of the flow-controller. transmission wheel to generate the required compression forces position independent application of force onto cartridge lever for force transmission slot for insertion of individual disposable cartridge with fluidic structures Fig.11: Self-locking spindle-lever transmission assembled on the ground plate of the flow-controller. Implementation in a stand-alone flow controller with changeable fluidic cartridges: Implementing the actuation unit (Fig.9,1) and the changeable cartridge into a single housing and using the capillary chip, a flow-controller capable of controlling flow rates in the range from 1ml/day down to 1 ml/day was demonstrated. The actual entire device measures 5x5x23mm 3 with sufficient space inside the housing to implement further components, e.g. a reservoir for the liquid to be dosed (Fig.1,11). Depending on the applied fluidic pressure and the design of the capillary structure in the exchangeable cartridge, the range of 711

obtainable flow rates is adjustable to individual applications. As illustrated in figure 13 the exchange process of the cartridges is comparatively simple. While a guidance eliminates the risk of faulty insertion, a snap-in mechanic reversibly locks the cartridge inside the flowcontroller housing. alternating, stepwise closing of the capillaries and subsequent abrupt opening to their original shape. Viscoelastic behaviour of the elastomer (PDMS) is known to result in a time dependent increase in flow when abruptly opening the capillaries and thus releasing the material tension. As was found during the experiments, viscoelastic effects of the elastomer are negligible which is in good agreement with prevalent numerical investigations [9]. 6 55 5 45 4 35 3 25 2 1 11 12 13 14 15 time [s] Fig.12: Implementation of the self-locking actuation unit and insertion slot for the changeable cartridge in a transparent housing of PMMA; metric dimensions (mm). Fig.14: Exemplary flow rates, realized by stepwise actuation of the self-locking actuation unit. 7 6 5 4 3 2 1 365 385 45 425 445 time [s] Fig.15: Repeatedly opening and closing of the analogous adjustable capillary channel in a stepwise manner. Fig.13: Illustration of the replacement procedure of the changeable cartridge containing the individual fluidic structures. MEASUREMENTS For the characterization of the multistable flow-controller, a differential pressure of 1bar was applied to the dosed fluid across the removable cartridge. As can be extracted from Fig. 14 to 16 flow rates between 2 and 65ml/day were reproducibly adjusted. During the measurement shown in Fig.1, flow-rates were kept constant for 6s without interim adjustment of the actuator position. Within this time, no significant changes in flow rate were observed. Figures15 and 16 show results obtained while 7 6 5 4 3 2 1 37 375 38 385 39 395 time [s] Fig.16: Flow behaviour during abrupt opening the capillaries to their original shape. 712

DISCUSSION & CONCLUSION Previously realized flow-controllers use discrete valves to control liquid flows. Especially in applications with highest demands on accuracy in the range of few ml/day down to µl/day, particles, that are omnipresent in fluids, despite filtering, tend to accumulate, raise leakage rates and strongly influence the dosing behaviour. The issue of clogging has in the past been addressed using various approaches, such as multiple sealing lips or flexible materials, yet it cannot be prevented completely. The novel multistable flow controller addresses this problem. Due to the laminar flow regime inside the device, the tendency to accumulate particles is minimized. Furthermore, particles do not tend to increase, as is the case for membrane-valve controlled systems, but reduce the flow in the closed state, a failure mode favourable in drug delivery systems. This safety aspect facilitates medical applications. In the measurements that have been performed with the current capillary cartridge, flow rates in the between 2 and 65ml/day were reproducibly achieved. No viscoelastic material behavior was observable, indicating the usability of the approach for mid- to long-term application. Different variants of the exchangeable capillary cartridges allow a wide range of adjustable flow-rates, even a complete zero flow-rate (shut-off), is considered to be realistic. Due to the strongly time dependent behaviour of elastomers and the associated actuation intervals for the presented system in the range of several seconds, limitations for the novel flow controller are applications that require fast switching times below or in the range of a second. Currently established microvalves typically possess one or two stable states. Depending on the applied selflocking actuation mechanism. The presented flowcontroller on the other hand can be operated in multiple stable states making it a valuable tool for low power applications such as mobile drug delivery systems. For the latter type of system the approach is currently being explored in more detail, targeting disposable, energy efficient and precise drug delivery systems. REFERENCES [1] Cousseau et al., Improved micro regulator for drug delivery systems, IEEE MEMS, Interlaken, Switzerland, 21. [2] Strobelt et al., Energy optimized valves with low leakage rates, 5th Micro-Fluidics Symposium IMECE 2, Orlando, USA, 2. [3] Waibel et al., Highly integrated autonomous microdosage system, Sensors and Actuators, A13, 23, 225-23. [4] Ernst et al., Microvalves for implantable microdosage systems, IEEE EMBS-BMES, Houston, USA, 22. [5] Nguyen, Dötzel, Mikropumpen der Entwicklungsstand im Überblick, F&M, 19, Carl Hanser Verlag, München, 21. [6] http://www.fluidigm.com [7] Unger et al., Monolithic Microfabricated Valves and Pumps by Multilayer Soft Lithography, Science, Vol. 288, 2. [8] German Patent Pending DE 1254312.7, HSG- IMIT, 22. [9] Spieth, Simulation of the flow- and elastomercharacteristics of a variable, microfluidic flow resistance, diploma thesis, Institute for Micro- and Information Technology (HSG-IMIT), Villingen-Schwenningen, Germany, 23. [1] Nguyen, Wereley, Fundamentals and applications of microfluidics (Artech House Publishers, Boston, London, 22) [11] http://www.elliptec.com [12] M. Ashauer et al., Thermal Flow Sensor for Liquids and Gases based on Combinations of Two Principles, Sensors and Actuators, A 73, 1999, 7-13 713