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Review of MEMS-based drug delivery and dosing systems
Sensors and Actuators A 134 (2007) 555–564
Review
Review of MEMS-based drug delivery and dosing systems Nan-Chyuan Tsai ∗ , Chung-Yang Sue Department of Mechanical Engineering, National Cheng Kung University, No. 1, Ta-Hsueh Road, Tainan 701, Taiwan Received 24 February 2006; received in revised form 7 June 2006; accepted 8 June 2006 Available online 17 July 2006
Abstract Micro-dosing/drug delivery control system is a bio-chip in practice. It is mostly developed by Micro-electro-mechanical Systems (MEMS) technology. In micro-dosing or drug delivery control systems, the driving power source with driving methodology and bio-compatibility are the two key issues that a great deal of researchers are truly interested in. Since the micro-dosing and drug delivery systems are applied on human bodies, there inevitably exist inherent limitations. Our study is aimed at driving technology review from all aspects. Comparisons are made to unveil the advantages and shortcomings of different driving designs. In addition, bio-compatibility is addressed and discussed, especially upon the currently-used and potential bio-materials in bio-MEMS. © 2006 Elsevier B.V. All rights reserved. Keywords: MEMS; Micro-dosing systems; Bio-chip; Bio-compatibility
Contents 1. 2.
3. 4.
∗
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Micro pumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Mechanical micro pumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Electrostatic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Piezoelectric . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. Thermo-pneumatic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4. Shape memory alloy (SMA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.5. Bimetallic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.6. Ionic conductive polymer film (ICPF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Non-mechanical micro pumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Magnetohydrodynamic (MHD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Electrohydrodynamic (EHD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.3. Electroosmotic (EO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.4. Chemical. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.5. Osmotic-type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.6. Capillary-type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.7. Electrowetting (EW) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.8. Bubble-type Micro pump . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bio-compatibility of MEMS materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Corresponding author. Tel.: +886 6 2757575x62137; fax: +886 6 2369567. E-mail address: [email protected] (N.-C. Tsai).
0924-4247/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.sna.2006.06.014
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1. Introduction In general, drugs or chemical agents have to retain a certain degree of concentrations so that desired therapeutic effect can be achieved. Drug concentration below or above the designed limits might cause intoxication or trivial therapy. Controlled drug delivery technology was ever studied back in early 1970s. In last decade, the micro bio-technologies increasingly attract the researchers’ attention especially in bio-medical control engineering. Micro-drug delivery [1–8] therefore tends to be incorporated with newly-well-developed MEMS fabrication technology [9–13] and gradually applied in medical fields. Certain physical or chemical properties of doses are quite commonly used to control drug delivery, such as bio-dissolution, bio-compatibility, sensitivity to PH value, temperature, etc. For example, traditionally the wall thickness, of the starch layer of a capsule, plays a crucial role to control how later to indeed activate the dosing effect after the capsule is swallowed down by patients. A micro-dosing system or micro-scale drug delivery system, in fact, consists of micro pumps, micro sensors, micro fluid channels and necessary related circuits. It is mainly aimed at serious chronic disease, such as diabetes, melancholia, malignant lymphoma, etc., or abrupt life threats, such as heart attack, stroke, septicaemia and so on. With the automatic dosing system being active, the patients are prevented from sudden death or irregular/incorrect taking medicine. Based on the real-time measurement from micro sensors, the appropriate and effective amount of dose will be precisely calculated by the controller and released by micro actuators/mechanisms in time. Since the micro-dosing control systems and drug delivery are employed on human bodies, it has to preserve inevitable limitations for the sake of safety and anti-infections. Namely the driving voltage level is one of key constrains as the microdosing systems are to be designed. Usually the driving power is expected to be restricted in low electrical energy consumption. In addition, bio-compatibility and high resolution, with respect to drug concentration, are both required technically commonly. 2. Micro pumps The driving devices or so called micro pumps, to dispense drugs or therapeutic agents into the human bodies, have been a key component to be well designed and fabricated. In general, high volumetric flow rate and high resolution are both of great importance. The generated pressure head is usually the performance index of flow rate. The other essential concerns on micro-dosing/drug delivery systems are reliability, bio-compatibility and power consumption. Technically, micro pumps are basically categorized into two types: mechanical and non-mechanical. Mechanical type needs a physical actuator or mechanism to perform pumping function. On the other hand, the non-mechanical type of pumps has to transform certain available non-mechanical energy into kinetic momentum so that the fluid in micro channels can be driven. Non-mechanical pumps can be further categorized into electrical, chemical, magnetic, surface-tension-driving micro pumps, etc.
Fig. 1. Reciprocating pump.
2.1. Mechanical micro pumps Although peristaltic, reciprocating and rotary pumps all ever show up in literatures on micro mechanical driving systems, the reciprocating type, whose typical structure is depicted in Fig. 1, relatively is always the majority as mechanical pumps are employed. The most popular of them applied in MEMS are, namely electrostatic, piezoelectric, thermo-pneumatic, bimetallic, shape memory alloy (SMA) and ionic conductive polymer film (ICPF). 2.1.1. Electrostatic The membrane of the electrostatic micro pump [14–16] will be forced towards either one direction as the two opposite electrostatic plates, located on both sides, are applied by appropriate controlled voltages (as shown in Fig. 2). This is the well-known Columbus Law. On the other hand, the deformed membrane will be recovered if the applied voltages are shut off. The chamber volume inside the micro pump is thus changed alternatively by every half cycle of periodical switching of applied voltage. The fluid in reservoir is forced to flow in the micro channels due to pressure difference induced by the membrane momentum. The electrostatic force applied on the electrostatic plate can be described as follows: F=
dW 1 εAV 2 = dx 2 x2
(1)
where F is the electrostatic attraction force, W the energy stored, ε the dielectric constant, A the electrode area, X the electrode spacing and V is the applied voltage. Zengerle et al. reported an electrostatic micro pump with check valves [14]. The reported micro pump consists of a silicon membrane. The maximum pressure reached 31 kPa. The maximum volumetric flow rate was 850 l/min. The advantage of electrostatic pump is that it can simultaneously mix a vari-
Fig. 2. Electrostatic micro pump.
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Fig. 5. Thermo-pneumatic micro pump. Fig. 3. Piezoelectric effects.
ety of dose up and then convey the finished fluid into micro channels. The major shortcomings of electrostatic pumps are structure complexity and high applied voltages required. 2.1.2. Piezoelectric The concept to apply piezoelectric driving device is that the corresponding voltage is induced by exerting pressure upon certain types of material such as quartz. The schematic diagram is shown in Fig. 3. Therefore, if a coating of piezoelectric material is deposited onto a membrane, the induced voltage will result in a certain degree of deformation that behaves like a push plate to expel the fluid out of the chamber of a micro pump (as shown in Fig. 4). The electric signal of this type of micro pumps [17–21] is electrical charge instead of voltage or current. Up to 200 V driving voltage is required to generate a useful deformation. These two drawbacks make piezoelectric pumps less popular in driving applications of MEMS. Koch et al. proposed a typical piezoelectric micro pump [17]. The reported micro pump consists of a silicon membrane with maximum pressure reaching 1.8 kPa. The maximum volumetric flow rate is 0.12 l/min as 600 Vpp sinusoidal driving voltage is applied. Piezoelectric micro pumps can be operated at relatively high frequencies but the required induced voltage has to be high up to a certain level. 2.1.3. Thermo-pneumatic The chamber, full of air inside, of a thermo-pneumatic micro pump is expanded and compressed periodically by a pair of heater and cooler as shown in Fig. 5. The periodic change in volume of chamber provides the membrane with a regular momentum to result in fluid flow-out. The pressure drop in chamber induced by volume increase is shown in Eq. (2). The thermo-pneumatic type of micro pumps [22–24] generates relatively large induced pressure and displacement of membrane. However, on the other hand, the driving power
Fig. 4. Piezoelectric micro pump.
has to be constantly retained above a certain level. In addition, slower response is also another drawback. V P = E βT − (2) V where P is the pressure change, E the modulus of elasticity, β the thermal expansion coefficient, T the temperature increase, and V/V is the volume change percentage. Jeong and Yang designed a micro pump [22] with a diaphragm in wave shape. The maximum generated pressure reached 2.5 kPa. The maximum flow rate reached 14 l/min at 4 Hz when the input voltage and duty ratio are 8 V and 40%, respectively. The relatively complicated structure and slow response are two major shortcomings of thermo-pneumatic types. Since air cooling is mostly used in this type of micro pumps, its low efficiency and slow response prevent it from being applied in high frequency operations Fig. 5. 2.1.4. Shape memory alloy (SMA) The diaphragm of SMA micro pumps [25–28] is popularly made of material titanium/nickel alloy (TiNi). SMA inherits a useful particular feature: being capable of restoring its original shape right after the heating/cooling cycle. Hence it is referred to as Shape Memory Alloy. SMA starts in Martensite phase and transforms into Austensite phase after being heated. This phase transformation results in shape deformation that is utilized as the actuating force upon the diaphragm of a micro SMA pump shown in Fig. 6. Xu et al. presented the structure of a typical micro SMA pump [25]. Its overall size is about 10 mm × 20 mm × 1.4 mm. The volumetric flow rate and back pressure of the pump are around 340 l/min and 100 kPa, respectively. The advantages of micro SMA pumps includes: linearity retained during deflection of the diaphragm, high stress
Fig. 6. SMA micro pump.
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Fig. 7. Bimetallic micro pump.
(>200 MPa) and long operation cycle. However, it needs particular SMA materials and relatively high power consumption is economically concerned. 2.1.5. Bimetallic A bimetallic micro diaphragm, shown in Fig. 7 is constituted by two different metals that exhibit appreciably distinct deformation degrees as being heated [29–30]. The deflection of a diaphragm, made of bimetallic materials, is induced against thermal alternation, as long as the two chosen materials possess adequately discriminative thermal expansion factors. Zhan et al. reported a silicon-based bimetallic membrane, for a specific micro pump [29]. They deposit a layer of aluminum, 10 m thick, on the silicon substrate to constitute a micro driving diaphragm. The overall size of the micro pump is about 6 mm × 6 mm × 1 mm. The flow rate and maximum back pressure are approximately 45 l/min and 12 kPa, respectively, while 5.5 V driving voltage, at 0.5 Hz, is applied. The required voltage is relatively low, compared to other types of micro pumps, but it is not suitable at all to operate at high frequencies. 2.1.6. Ionic conductive polymer film (ICPF) The core layer of ICPF is made of a sort of perfluorosulfonic acid polymer [31,32]. Physically, it looks like a “sandwich” diaphragm since two thin films are deposited upon two sides of the polymer. These two deposited films, with high electrical conductivity such as gold, basically serve as the metal electrodes. With one end fixed, the ICPF diaphragm can be controlled to bend in direction of either upside or downside as long as an appropriate pair of voltages is applied at the electrodes. Fig. 8
Fig. 8. Bending action of an ICPF.
Fig. 9. ICPF micro pump (Courtesy of [22]).
shows this bending movement just like a cantilever plate usually behaves. Guo and Fukuda developed an ICPF device [31] shown in Fig. 9. The size of this pump is 13 mm in diameter and 23 mm in length. The flow rate of this pump is about 4.5–37.8 l/min as 1.5 V driving voltage is applied. ICPF has quite a few superiorities such as low driving voltage, quick response, and biocompatibility. Besides, it can work in aqueous environments. The major shortcoming is weak repeatability in batch fabrication. 2.2. Non-mechanical micro pumps Non-mechanical micro pumps generally need sorts of mechanisms that can convert non-mechanical energy into kinetic momentum. In general, non-mechanical pumps do not need physical actuation components so that geometry design and fabrication of this type of pumps are both relatively simpler. However, its driving effect and performance, such as back pressure, flow rate, rise time of response and maximum stroke/deformation, are inferior, if compared with mechanical micro pumps. 2.2.1. Magnetohydrodynamic (MHD) Lorentz force is the driving source, perpendicular both to electric field and magnetic field, for the types of MHD micro pumps [33–36]. The working fluid has to be chosen to have conductivity 1 s/m or higher, in addition to externally providing electric and magnetic fields. Its schematic force fields and relations are shown in Fig. 10. Jang and Lee presented this type of device, MHD micro pump [33] shown in Fig. 11, with
Fig. 10. Force fields of MHD (Courtesy of [33]).
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moved in a specific direction. Though this type of pumps only requires driving voltage, 40–60 V, a relatively complicated 3D overall geometry is needed to ensure sufficient degree of electro-chemical reactions. More details on this type of micro pumps can be referred in [37–41].
experimental analysis. The performance of the MHD device was investigated by varying the applied voltage from 10 to 60 V while the magnetic flux density was retained at 0.19 T. The working fluid was chosen to be sea water. The electric conductivity of working fluids is extremely higher (4 s/m) than that of working fluids of the EHD micro pump where the electric conductivity ranges from 10−12 to 10−6 s/m. The maximum flow rate reached to 63 l/min as the driving current was retained at 1.8 mA. The maximum pressure head, 18 mm H2 O, from inlet to outlet was obtained if the driving current was set and retained at 38 mA. The most attractive feature of MHD micro pump is the flow can be bi-directional. In addition, the structure and fabrication process are relatively simple. The uncommon drawback is that quite a few bubbles, due to ionization, might be generated.
2.2.3. Electroosmotic (EO) The fluid, with electric conductivity feature, is driven by appropriately exerting an external electrical field upon the channel walls that are naturally charged. The voltage potential is induced at the interface between the silica capillary walls and electrolyte solution, as shown in Fig. 13. In general, the inner wall of silica capillary, such as glass that carries a lot of anion “SiO− ” on its surface, is deprotonated and thus the associate electrolyte liquid against the walls is thus protonated. If an external electric field is appropriately applied at the electrodes, located at the longitudinal ends of microchannel, the fluid will be driven towards the cathode due to Coulomb force. This is overall so called “Electro-osmotic Flow”. Chen et al. reported an EO flow micro pump [41]. The pump can generate a maximum pressure of 0.33 atm and a maximum flow rate of 15 l/min at 1 kV. No actual mechanical actuator is needed for EO pumps. The major shortcomings are high voltage required and electrically conductive solution well prepared. More details on this type of micro pumps can be referred in [42–44].
2.2.2. Electrohydrodynamic (EHD) The electric body force density F៝ that results from an applied electric field with magnitude E is given as follows [38]: 1 2 ∂ε 1 ៝ ៝ ៝ ៝ F = qE + P∇ · E − E ∇ε + ∇ E2 ρ (3) 2 2 ∂ρ T
2.2.4. Chemical The most common feature of electro-chemical micro pumps [45,46] is the generation of bubbles by electrolysis. In addition to the chemical reaction mechanism, the other key component is a bubble reservoir, filled with redox electrolyte solution. The reaction of electrolysis can be roughly described by:
where q is the charge density, ε the fluid permittivity, ρ the fluid density, T the fluid temperature and P៝ is the polarization vector. Darabi et al. reported an Electrohydrodynamic (EHD) Ion-drag micro pump [37] with dimensions 19 mm × 32 mm × 1.05 mm. The driving momentum is a combination of electrical field, dielectrophoretic force, dielectric force and electrostrictive force. The chosen working fluid has to perform conductivity ranging from 10−12 to 10−6 s/m. The particles in dielectric fluid are charged by the applied electrical field so that the fluid is conveyed by induced electrostrictive forces, shown in Fig. 12. The electric field is developed by a pair of electrodes: an emitter and a collector. The ionized molecules are thus
Anode :
Bohm et al. [1] presented an electro-chemical pump for micro-dosing system (as shown in Fig. 14). The rate of bubble generation is about 0.02 nl/s. The advantages of chemical micro pump are relatively simple structure and easier to be integrated with other microfluidic devices. The drawback, depending on bubble generation rate, is that the born bubbles might partially
Fig. 12. EHD micro pump (Courtesy of [37]).
Fig. 13. EO flow and double layer.
Fig. 11. MHD micro pump (Courtesy of [33]).
Cathode :
2H2 O → 4H+ + 4e− + O2 (g) 2H2 O + 2e− → 2OH− + H2 (g)
(4)
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Fig. 17. MFA structure (Courtesy of [50]). Fig. 14. Electro-chemical pump (Courtesy of [1]).
Fig. 15. Osmotic actuator (Courtesy of [22]).
collapse and become water as long as the chemical reaction in Eq. (4) is reversed due to any possible reasons. Hence, the releasing of drug is not completely reliable and not ensured to retain steady. 2.2.5. Osmotic-type With particularly selected osmotic driving agent inside the chamber to provide concentration difference for working fluidic molecules across the diaphragm, the working fluid, outside the chamber, naturally moves towards the low density zone. The inertia force of the moving flow directly transfers a kinetic momentum upon an actuation diaphragm. The osmotic force is thus generated as long as the fluid, carrying drug particles, diffuses into an osmotic diaphragm shown in Fig. 15. Though this type of micro pumps needs no external power (mechanical or electrical) it suffers from low flow rate and low response with long time delay. Moreover, the semi-permeable diaphragm might depart from the substrate after a certain period of time. Su and Lin presented a water-powered micro drug delivery system [47–48] as shown in Fig. 16. The major advantage of
this actuator is no additional electrical power needed at all, but its flow rate is too slow, below 0.2 l/h, to be efficiently used in most bio-chips. 2.2.6. Capillary-type Fig. 17 presents a Micro Fluidic Accumulator (MFA) that is driven by capillary phenomenon [49,50]. MFA is mainly composed of quite many hydrophobic micro capillaries that can be controlled by valves to make inlet/outlet exposed in atmosphere [51]. If the pressure in the main micro channel is escalated, the fluid will be conveyed into all capillaries that tentatively act together as a reservoir. The fluid can be quantatively released by changing the outlet fluidic resistance. The maximum flow rate was reported about 7.2 l/min, that is far below the level usually required in bio-chips. 2.2.7. Electrowetting (EW) Electrowetting (EW) is the application of exerting electrostatic force to control the surface tension between two layers of material that could be solid/liquid or liquid/liquid as long as they are immiscible and explicitly two-phased. EW operates in two approaches: continuous and digital. Digital EW is mostly applied to control the surface tension between solid-phase electrode and liquid-phase droplet as shown in Fig. 18. The contact angle, θ, is decreased if an external control voltage is applied on the electrode and therefore the liquid droplet tends to get flattened. The relation among contact angle, surface tension and applied voltage can be described by Lippmann–Young equation as follows [52]: cos θ = cos θ0 +
1 CV 2 γls 2
(5)
where θ is the contact angle, θ 0 the equilibrium contact angle at V = 0 V, γ ls the liquid–solid interfacial tension and C is the specific capacitance of the dielectric layer.
Fig. 16. Water-powered drug delivery (Courtesy of [48]).
Fig. 18. Digital electrowetting.
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Fig. 19. Continuous electrowetting (Courtesy of [53]).
Fig. 20. EW micro pump (Courtesy of [53]).
Continuous EW is usually applied to adjust the surface tension between two immiscible liquids such as liquid-phased metal (e.g., mercury) and electrolyte. Its interface is referred to as “electric double layer” as shown in Fig. 19. Due to protonation effect on the mercury surface, the electric potential between right end of mercury droplet and the cathode of electrode pair is higher than the counter electric potential on the left side. The surface tension difference beside a mercury droplet thus pushes the droplet toward right, like a stone rolls down from hill. Yun et al. presented a continuous EW micro pump [53] as shown in Fig. 20. The volumetric flow rate reaches up to 70 l/min at driving voltage 2.3 V and power consumption of 170 W. The maximum pressure is about 800 Pa by applying voltage 2.3 V with frequency 25 Hz. 2.2.8. Bubble-type Micro pump Tsai and Lin reported a bubble pump [54] consisting of a pair of diffuser and nozzle and a reaction chamber. As shown in Fig. 21, the bubbles are generated by heating process. The
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bubbles are expanded and collapsed in volume, periodically by a controlled voltage input. The volume change in chamber is incorporated with the diffuser/nozzle mechanism that is used to determine the direction of fluidic flow. The maximum value of the flow rate of the bubble-type micro pump is 5 l/min as the applied voltage was exerted periodically at 250 Hz with 10% duty cycle and power consumption 1 W. The most attractive feature of bubble-type micro pump is that two or more kinds of doses can be thus mixed up during the expanding/collapsing cycles. This kind of pumps always needs to be heated so that its application scope is limited in case heating process is not allowed or preferred. In general, micro pumps can be divided into mechanical and non-mechanical ones by discrimination of active mechanisms. Most mechanical pump consists of valves and actuating membrane so that fatigue and reliability are the main design concerns. On the other hand, non-mechanical micro pumps mostly cannot achieve sufficient flow rate, driving pressure head and fast response. Table 1 is to compare their major characteristics in maximum pressure, flow rate and applied voltage. 3. Bio-compatibility of MEMS materials MEMS-based micro-dosing/drug delivery devices can be either implanted or just placed under the skin. A key issue for both cases to be seriously taken into account is bio-compatibility. Even with special surface treatment [55–57], the MEMS devices can still be treated as an external intruder and attacked by immunization system. As time goes by, a fouled or corruptive medical device thus becomes malfunction. Hence, more rigorous biocompatibility and bio-stability requirements have to be fulfilled. A common index for bio-compatibility is called Foreign Body Giant Cells (FBGC) density that can be usually used to evaluate the feasibility of designed devices and materials. Secondly, in addition to bio-compatibility, a certain degree of toxicity to tissues is strictly forbidden and this has to be counted in at the very beginning to assign a specific material. Another concern is to reduce the mechanical stress induced by the micro pumps dynamics by all means. Recently, polymer-MEMS becomes more and more popular mainly because it has a very low stiffness and inherently provides adequate flexibility. Currently, polymer material, such as Poly Methyl Methacrylate (PMMA), PolyDimethylsiloxane ( PDMS), SU-8 photo resist, or Parylene C, is
Fig. 21. A bubble pump (Courtesy of [54]).
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Table 1 Comparison of micro pumps Working principle (type/actuator)
V (V)
Qmax (l/min)
Pmax (MPa)
Structure
Year
Me/electrostatic Me/electrostatic Me/piezoelectric Me/piezoelectric Me/piezoelectric Me/piezoelectric Me/piezoelectric Me/thermo-pneumatic Me/thermo-pneumatic Me/thermo-pneumatic Me/SMA Me/SMA Me/SMA Me/SMA Me/bimetallic Me/bimetallic Me/ICPF Non-Me/MHD Non-Me/MHD Non-Me/MHD Non-Me/EHD Non-Me/EHD Non-Me/EO Non-Me/EO Non-Me/EO Non-Me/electro-chemical Non-Me/electro-chemical Non-Me/osmotic Non-Me/capillary Non-Me/electrowetting
200 200 600 110 190 350 250 8 n/a 15 n/a 0.6 n/a 8 5.5 16 1.5 60 4 6.6 300 700 1000 2000 5000 4.5 1.5 0 0 2.3
850 30 0.12 13.33 1500 1900 550 14 9 44 340 50 50 700 44 43 37.8 63 2.88 18.3 n/a 14 15 3.6 1.75 0.024 0.08 0.0033 7.2 70
0.31 0.02 0.002 0.35 0.001 0.012 0.009 0.0025 0.016 0.0038 0.1 0.0042 0.0005 n/a 0.107 n/a n/a 0.1037 n/a n/a 0.0007 0.0025 0.0334 2.026 11 0.11 0.0235 n/a 0.0065 0.0008
Si–Si Plastics-metals Si–Si–Si Si–pyrex Si–Si Plastics-metals Glass–Si–glass Glass–Si–glass Glass–Si Polymer Si–Si Si–Si Si–Si–Si Acryl Si–Si Si–Si n/a Si–Si Glass–glass Glass–Si–glass Ceramic–alumina Si–Si Glass–glass Fused-silica capillary Fused-silica capillary Si–Si PDMS–glass PDMS–PDMS Si–Si Si–Si–glass
1995 [14] 2001 [16] 1998 [17] 1999 [18] 2002 [19] 1999 [20] 1994 [21] 2000 [22] 2004 [23] 1994 [24] 2001 [25] 1997 [26] 1998 [27] 2004 [28] 1996 [29] 1996 [30] 1997 [31] 2000 [33] 2003 [35] 2000 [36] 2002 [37] 1990 [38] 2002 [42] 2001 [43] 2005 [44] 2004 [45] 2003 [46] 2004 [48] 2003 [50] 2002 [53]
Table 2 Bio-compatibility materials for MEMS Materials
Bio-compatibility
Characteristic
Application
PDDA PDMS SU-8 (PR) PMMA ICPF TiN alloy Au Al2 O3 Pt Ti
Good Good Good Good Very good Good Good Very good Good Good
Porous material Ultra-thin active layer Thick-PR (high aspect ratio) Simply fabrication (hot embossing) Difficult to fabrication (replica or modeling) Shape memory effect Simply fabrication (low resistivity) Brittle Simply fabrication (low resistivity) Simply fabrication
Reduce toxicity of nano particle Osmotic membrane (soft lithography) Microfluidic structure Microfluidic structure Sensor actuator Actuator Electrode connection Microfluidic structure Temperature sensor heater Heater
gradually proven to possess relatively better bio-compatibility and flexibility. They have the potential to be upgraded to be officially applied in biomedical MEMS devices. Table 2 lists a summary of bio-MEMS materials from the viewpoint of application fields and their main characteristics. 4. Conclusion The applied voltage is essentially a key constraint factor for micro-dosing/drug delivery driving power. In other words, the micro pumps have to be limited by low applied voltage, say from 5 to 12 V. Since the micro-dosing and drug delivery systems cannot tolerate any potential detrimental influence from
driving forces, the electrostatic micro pumps and piezoelectric micro pumps have to be usually ruled out because of high driving voltage required. EHD and MHD micro pumps have to be incorporated with working fluid with a certain degree of electric conductivity. This would narrow down the application fields, particularly in bio-chips. Bubble-type and other non-mechanical micro pumps need no physical actuation components but its effectiveness, due to long time delay and slow response, are much devalued. The type of SMA micro pumps suffers from a relatively low flow rate and insufficient bio-compatibility. In addition to applied voltage and driving methodology, the other crucial issue for micro-dosing driving power is the degree of biocompatibility. It would become extremely sensitive and deter-
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minative especially for implanting-oriented biological applications. In comparison, ICPF micro pumps possess the most advantages of long stroke, low driving voltage, qualified flexibility and bio-compatibility. Bimetallic micro pumps have the superiority on high flow rate and pressure head. If the associated flexibility and bio-compatibility can be further improved, they would become more competitive. References [1] S. Bohm, B. Timmer, W. Olthuis, P. Bergveld, A closed-loop controlled electrochemically actuated micro-dosing system, J. Micromech. Microeng. 10 (2000) 498–504. [2] A. Manz, N. Graber, H.M. Widmer, Miniaturized total chemical analysis systems: a novel concept for chemical sensing, Sens. Actuators B 1 (1990) 244–248. [3] T.S.J. Lammerink, M. Elwenspoek, J.H.J. Fluitman, Integrated microliquid dosing system, IEEE Micro Electro Mech. Syst. (1993) 254– 259. [4] D. Maillefer, H.V. Lintel, G.R. Mermet, R. Hirschi, A high-performance silicon micropump for an implantable drug delivery system, in: Prcoceedings of IEEE MEMS ’99, 1999, pp. 212–215. [5] L. Gao, S. Mantell, D. Polla, Implantable medical drug delivery systems using micro-electro-mechanical systems technology, in: First IEEE-EMBS Special Topic Conference on Microtechnologies in Medicine and Biology, 2000, pp. 487–490. [6] S.L. Tao, M.W. Lubeley, T.A. Desai, Bioadhesive poly(methyl methacrylate) microdevices for controlled drug delivery, J. Control. Rel. 88 (2003) 215–228. [7] F.E.H. Tay, W.O. Choong, H. Liu, G.L. Xu, An intelligent micro-fluidic system for drug delivery, in: Proceedings of IEEE MEMS ’2000, 2000, pp. 70–75. [8] D. Reynaerts, J. Peirs, H.V. Brussel, An implantable drug-delivery system based on shape memory alloy micro-actuation, Sens. Actuators A: Phys. 61 (1997) 488–562. [9] G.T.A. Kovas, N.I. Maluf, K.E. Petersen, Bulk micromachining of silicon, Proc. IEEE 86 (1998) 1536–1551. [10] J.M. Bustillo, R.T. Howe, R.S. Muller, Surface micromachining for microelectromechanical systems, Proc. IEEE 86 (1998) 1552–1574. [11] P.R. Choudhury, Handbook of Microlithography, Micromachining and Microfabrication, SPIE Press, 1997, pp. 1–2. [12] M. Madou, Fundamentals of Microfabrication, second ed., CRC Press, New York, 2002. [13] Gregory T.A. Kovacs, Micromachined Transducers Sourcebook, McGrawHill, New York, 1998. [14] R. Zengerle, J. Ulrich, S. Kluge, M. Richter, A. Richter, A bidirectional silicon micropump, Sens. Actuators A: Phys. 50 (1995) 81–86. [15] R. Zengerle, M. Richter, H. Sandmaier, A micro membrane pump with electrostatic actuation, in: Proceedings of IEEE, Micro Electro Mechanical System, 1992, pp. 19–24. [16] C. Cabuz, W.R. Herb, E.I. Cabuz, S.T. Lu, The dual diaphragm pump, in: Proceedings of the IEEE MEMS ’2001, 2001, pp. 519–522. [17] M. Koch, N. Harris, A.G.R. Evans, N.M. White, A. Brunnschweiler, A novel micromachined pump based on thick-film piezoelectric actuation, Sens. Actuators A: Phys. 70 (1998) 98–103. [18] M. Didier, V.L. Harald, R.M. Gilles, H. Roland, High-performance silicon micropump for an implantable drug delivery system, in: Proceedings of the IEEE MEMS 99, 1999, pp. 541–546. [19] C.G.J. Schabmueller, M. Koch, M.E. Mokhtari, A.G.R. Evans, A. Brunnschweiler, H. Sehr, Self-aligning gas/liquid micropump, J. Micromech. Microeng. 12 (2000) 420–424. [20] S. Bohm, W. Olthuis, P. Bergveld, A plastic micropump constructed with conventional techniques and materials, Sens. Actuators A 77 (1999) 223–228. [21] V. Gass, B.H. Vanderschoot, S. Jeanneret, N.F. Derooij, Integrated flow regulated silicon micropump, Sens. Actuators A 43 (1994) 335–338.
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Biographies Nan-Chyuan Tsai was born in Taiwan in 1963. He received his BS degree from National Cheng Kung University in 1986 and MS degree in mechanical engineering and electrical engineering from PENN STATE University in 1991 and 1993, respectively. In 1995 he received his PhD degree in mechanical engineering from PENN STATE University. He has been an assistant professor at National Cheng Kung University since 2003. His research interests include MEMS/NEMS technology, mechatronics, control engineering, active magnetic bearings and bio-chip applications. Chung-Yang Sue was born in Taiwan in 1980. He received his BS degree from Kun Shan University in 2003 and MS degree from National Cheng Kung University 2005 both in mechanical engineering. He is about to earn his PhD degree in the field of bio-MEMS technologies at National Cheng Kung University. His research interests include design, fabrication and experiments of MEMS/NEMS sensors and actuators.
Review
Review of MEMS-based drug delivery and dosing systems Nan-Chyuan Tsai ∗ , Chung-Yang Sue Department of Mechanical Engineering, National Cheng Kung University, No. 1, Ta-Hsueh Road, Tainan 701, Taiwan Received 24 February 2006; received in revised form 7 June 2006; accepted 8 June 2006 Available online 17 July 2006
Abstract Micro-dosing/drug delivery control system is a bio-chip in practice. It is mostly developed by Micro-electro-mechanical Systems (MEMS) technology. In micro-dosing or drug delivery control systems, the driving power source with driving methodology and bio-compatibility are the two key issues that a great deal of researchers are truly interested in. Since the micro-dosing and drug delivery systems are applied on human bodies, there inevitably exist inherent limitations. Our study is aimed at driving technology review from all aspects. Comparisons are made to unveil the advantages and shortcomings of different driving designs. In addition, bio-compatibility is addressed and discussed, especially upon the currently-used and potential bio-materials in bio-MEMS. © 2006 Elsevier B.V. All rights reserved. Keywords: MEMS; Micro-dosing systems; Bio-chip; Bio-compatibility
Contents 1. 2.
3. 4.
∗
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Micro pumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Mechanical micro pumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Electrostatic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Piezoelectric . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. Thermo-pneumatic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4. Shape memory alloy (SMA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.5. Bimetallic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.6. Ionic conductive polymer film (ICPF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Non-mechanical micro pumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Magnetohydrodynamic (MHD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Electrohydrodynamic (EHD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.3. Electroosmotic (EO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.4. Chemical. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.5. Osmotic-type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.6. Capillary-type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.7. Electrowetting (EW) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.8. Bubble-type Micro pump . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bio-compatibility of MEMS materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Corresponding author. Tel.: +886 6 2757575x62137; fax: +886 6 2369567. E-mail address: [email protected] (N.-C. Tsai).
0924-4247/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.sna.2006.06.014
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1. Introduction In general, drugs or chemical agents have to retain a certain degree of concentrations so that desired therapeutic effect can be achieved. Drug concentration below or above the designed limits might cause intoxication or trivial therapy. Controlled drug delivery technology was ever studied back in early 1970s. In last decade, the micro bio-technologies increasingly attract the researchers’ attention especially in bio-medical control engineering. Micro-drug delivery [1–8] therefore tends to be incorporated with newly-well-developed MEMS fabrication technology [9–13] and gradually applied in medical fields. Certain physical or chemical properties of doses are quite commonly used to control drug delivery, such as bio-dissolution, bio-compatibility, sensitivity to PH value, temperature, etc. For example, traditionally the wall thickness, of the starch layer of a capsule, plays a crucial role to control how later to indeed activate the dosing effect after the capsule is swallowed down by patients. A micro-dosing system or micro-scale drug delivery system, in fact, consists of micro pumps, micro sensors, micro fluid channels and necessary related circuits. It is mainly aimed at serious chronic disease, such as diabetes, melancholia, malignant lymphoma, etc., or abrupt life threats, such as heart attack, stroke, septicaemia and so on. With the automatic dosing system being active, the patients are prevented from sudden death or irregular/incorrect taking medicine. Based on the real-time measurement from micro sensors, the appropriate and effective amount of dose will be precisely calculated by the controller and released by micro actuators/mechanisms in time. Since the micro-dosing control systems and drug delivery are employed on human bodies, it has to preserve inevitable limitations for the sake of safety and anti-infections. Namely the driving voltage level is one of key constrains as the microdosing systems are to be designed. Usually the driving power is expected to be restricted in low electrical energy consumption. In addition, bio-compatibility and high resolution, with respect to drug concentration, are both required technically commonly. 2. Micro pumps The driving devices or so called micro pumps, to dispense drugs or therapeutic agents into the human bodies, have been a key component to be well designed and fabricated. In general, high volumetric flow rate and high resolution are both of great importance. The generated pressure head is usually the performance index of flow rate. The other essential concerns on micro-dosing/drug delivery systems are reliability, bio-compatibility and power consumption. Technically, micro pumps are basically categorized into two types: mechanical and non-mechanical. Mechanical type needs a physical actuator or mechanism to perform pumping function. On the other hand, the non-mechanical type of pumps has to transform certain available non-mechanical energy into kinetic momentum so that the fluid in micro channels can be driven. Non-mechanical pumps can be further categorized into electrical, chemical, magnetic, surface-tension-driving micro pumps, etc.
Fig. 1. Reciprocating pump.
2.1. Mechanical micro pumps Although peristaltic, reciprocating and rotary pumps all ever show up in literatures on micro mechanical driving systems, the reciprocating type, whose typical structure is depicted in Fig. 1, relatively is always the majority as mechanical pumps are employed. The most popular of them applied in MEMS are, namely electrostatic, piezoelectric, thermo-pneumatic, bimetallic, shape memory alloy (SMA) and ionic conductive polymer film (ICPF). 2.1.1. Electrostatic The membrane of the electrostatic micro pump [14–16] will be forced towards either one direction as the two opposite electrostatic plates, located on both sides, are applied by appropriate controlled voltages (as shown in Fig. 2). This is the well-known Columbus Law. On the other hand, the deformed membrane will be recovered if the applied voltages are shut off. The chamber volume inside the micro pump is thus changed alternatively by every half cycle of periodical switching of applied voltage. The fluid in reservoir is forced to flow in the micro channels due to pressure difference induced by the membrane momentum. The electrostatic force applied on the electrostatic plate can be described as follows: F=
dW 1 εAV 2 = dx 2 x2
(1)
where F is the electrostatic attraction force, W the energy stored, ε the dielectric constant, A the electrode area, X the electrode spacing and V is the applied voltage. Zengerle et al. reported an electrostatic micro pump with check valves [14]. The reported micro pump consists of a silicon membrane. The maximum pressure reached 31 kPa. The maximum volumetric flow rate was 850 l/min. The advantage of electrostatic pump is that it can simultaneously mix a vari-
Fig. 2. Electrostatic micro pump.
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Fig. 5. Thermo-pneumatic micro pump. Fig. 3. Piezoelectric effects.
ety of dose up and then convey the finished fluid into micro channels. The major shortcomings of electrostatic pumps are structure complexity and high applied voltages required. 2.1.2. Piezoelectric The concept to apply piezoelectric driving device is that the corresponding voltage is induced by exerting pressure upon certain types of material such as quartz. The schematic diagram is shown in Fig. 3. Therefore, if a coating of piezoelectric material is deposited onto a membrane, the induced voltage will result in a certain degree of deformation that behaves like a push plate to expel the fluid out of the chamber of a micro pump (as shown in Fig. 4). The electric signal of this type of micro pumps [17–21] is electrical charge instead of voltage or current. Up to 200 V driving voltage is required to generate a useful deformation. These two drawbacks make piezoelectric pumps less popular in driving applications of MEMS. Koch et al. proposed a typical piezoelectric micro pump [17]. The reported micro pump consists of a silicon membrane with maximum pressure reaching 1.8 kPa. The maximum volumetric flow rate is 0.12 l/min as 600 Vpp sinusoidal driving voltage is applied. Piezoelectric micro pumps can be operated at relatively high frequencies but the required induced voltage has to be high up to a certain level. 2.1.3. Thermo-pneumatic The chamber, full of air inside, of a thermo-pneumatic micro pump is expanded and compressed periodically by a pair of heater and cooler as shown in Fig. 5. The periodic change in volume of chamber provides the membrane with a regular momentum to result in fluid flow-out. The pressure drop in chamber induced by volume increase is shown in Eq. (2). The thermo-pneumatic type of micro pumps [22–24] generates relatively large induced pressure and displacement of membrane. However, on the other hand, the driving power
Fig. 4. Piezoelectric micro pump.
has to be constantly retained above a certain level. In addition, slower response is also another drawback. V P = E βT − (2) V where P is the pressure change, E the modulus of elasticity, β the thermal expansion coefficient, T the temperature increase, and V/V is the volume change percentage. Jeong and Yang designed a micro pump [22] with a diaphragm in wave shape. The maximum generated pressure reached 2.5 kPa. The maximum flow rate reached 14 l/min at 4 Hz when the input voltage and duty ratio are 8 V and 40%, respectively. The relatively complicated structure and slow response are two major shortcomings of thermo-pneumatic types. Since air cooling is mostly used in this type of micro pumps, its low efficiency and slow response prevent it from being applied in high frequency operations Fig. 5. 2.1.4. Shape memory alloy (SMA) The diaphragm of SMA micro pumps [25–28] is popularly made of material titanium/nickel alloy (TiNi). SMA inherits a useful particular feature: being capable of restoring its original shape right after the heating/cooling cycle. Hence it is referred to as Shape Memory Alloy. SMA starts in Martensite phase and transforms into Austensite phase after being heated. This phase transformation results in shape deformation that is utilized as the actuating force upon the diaphragm of a micro SMA pump shown in Fig. 6. Xu et al. presented the structure of a typical micro SMA pump [25]. Its overall size is about 10 mm × 20 mm × 1.4 mm. The volumetric flow rate and back pressure of the pump are around 340 l/min and 100 kPa, respectively. The advantages of micro SMA pumps includes: linearity retained during deflection of the diaphragm, high stress
Fig. 6. SMA micro pump.
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Fig. 7. Bimetallic micro pump.
(>200 MPa) and long operation cycle. However, it needs particular SMA materials and relatively high power consumption is economically concerned. 2.1.5. Bimetallic A bimetallic micro diaphragm, shown in Fig. 7 is constituted by two different metals that exhibit appreciably distinct deformation degrees as being heated [29–30]. The deflection of a diaphragm, made of bimetallic materials, is induced against thermal alternation, as long as the two chosen materials possess adequately discriminative thermal expansion factors. Zhan et al. reported a silicon-based bimetallic membrane, for a specific micro pump [29]. They deposit a layer of aluminum, 10 m thick, on the silicon substrate to constitute a micro driving diaphragm. The overall size of the micro pump is about 6 mm × 6 mm × 1 mm. The flow rate and maximum back pressure are approximately 45 l/min and 12 kPa, respectively, while 5.5 V driving voltage, at 0.5 Hz, is applied. The required voltage is relatively low, compared to other types of micro pumps, but it is not suitable at all to operate at high frequencies. 2.1.6. Ionic conductive polymer film (ICPF) The core layer of ICPF is made of a sort of perfluorosulfonic acid polymer [31,32]. Physically, it looks like a “sandwich” diaphragm since two thin films are deposited upon two sides of the polymer. These two deposited films, with high electrical conductivity such as gold, basically serve as the metal electrodes. With one end fixed, the ICPF diaphragm can be controlled to bend in direction of either upside or downside as long as an appropriate pair of voltages is applied at the electrodes. Fig. 8
Fig. 8. Bending action of an ICPF.
Fig. 9. ICPF micro pump (Courtesy of [22]).
shows this bending movement just like a cantilever plate usually behaves. Guo and Fukuda developed an ICPF device [31] shown in Fig. 9. The size of this pump is 13 mm in diameter and 23 mm in length. The flow rate of this pump is about 4.5–37.8 l/min as 1.5 V driving voltage is applied. ICPF has quite a few superiorities such as low driving voltage, quick response, and biocompatibility. Besides, it can work in aqueous environments. The major shortcoming is weak repeatability in batch fabrication. 2.2. Non-mechanical micro pumps Non-mechanical micro pumps generally need sorts of mechanisms that can convert non-mechanical energy into kinetic momentum. In general, non-mechanical pumps do not need physical actuation components so that geometry design and fabrication of this type of pumps are both relatively simpler. However, its driving effect and performance, such as back pressure, flow rate, rise time of response and maximum stroke/deformation, are inferior, if compared with mechanical micro pumps. 2.2.1. Magnetohydrodynamic (MHD) Lorentz force is the driving source, perpendicular both to electric field and magnetic field, for the types of MHD micro pumps [33–36]. The working fluid has to be chosen to have conductivity 1 s/m or higher, in addition to externally providing electric and magnetic fields. Its schematic force fields and relations are shown in Fig. 10. Jang and Lee presented this type of device, MHD micro pump [33] shown in Fig. 11, with
Fig. 10. Force fields of MHD (Courtesy of [33]).
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moved in a specific direction. Though this type of pumps only requires driving voltage, 40–60 V, a relatively complicated 3D overall geometry is needed to ensure sufficient degree of electro-chemical reactions. More details on this type of micro pumps can be referred in [37–41].
experimental analysis. The performance of the MHD device was investigated by varying the applied voltage from 10 to 60 V while the magnetic flux density was retained at 0.19 T. The working fluid was chosen to be sea water. The electric conductivity of working fluids is extremely higher (4 s/m) than that of working fluids of the EHD micro pump where the electric conductivity ranges from 10−12 to 10−6 s/m. The maximum flow rate reached to 63 l/min as the driving current was retained at 1.8 mA. The maximum pressure head, 18 mm H2 O, from inlet to outlet was obtained if the driving current was set and retained at 38 mA. The most attractive feature of MHD micro pump is the flow can be bi-directional. In addition, the structure and fabrication process are relatively simple. The uncommon drawback is that quite a few bubbles, due to ionization, might be generated.
2.2.3. Electroosmotic (EO) The fluid, with electric conductivity feature, is driven by appropriately exerting an external electrical field upon the channel walls that are naturally charged. The voltage potential is induced at the interface between the silica capillary walls and electrolyte solution, as shown in Fig. 13. In general, the inner wall of silica capillary, such as glass that carries a lot of anion “SiO− ” on its surface, is deprotonated and thus the associate electrolyte liquid against the walls is thus protonated. If an external electric field is appropriately applied at the electrodes, located at the longitudinal ends of microchannel, the fluid will be driven towards the cathode due to Coulomb force. This is overall so called “Electro-osmotic Flow”. Chen et al. reported an EO flow micro pump [41]. The pump can generate a maximum pressure of 0.33 atm and a maximum flow rate of 15 l/min at 1 kV. No actual mechanical actuator is needed for EO pumps. The major shortcomings are high voltage required and electrically conductive solution well prepared. More details on this type of micro pumps can be referred in [42–44].
2.2.2. Electrohydrodynamic (EHD) The electric body force density F៝ that results from an applied electric field with magnitude E is given as follows [38]: 1 2 ∂ε 1 ៝ ៝ ៝ ៝ F = qE + P∇ · E − E ∇ε + ∇ E2 ρ (3) 2 2 ∂ρ T
2.2.4. Chemical The most common feature of electro-chemical micro pumps [45,46] is the generation of bubbles by electrolysis. In addition to the chemical reaction mechanism, the other key component is a bubble reservoir, filled with redox electrolyte solution. The reaction of electrolysis can be roughly described by:
where q is the charge density, ε the fluid permittivity, ρ the fluid density, T the fluid temperature and P៝ is the polarization vector. Darabi et al. reported an Electrohydrodynamic (EHD) Ion-drag micro pump [37] with dimensions 19 mm × 32 mm × 1.05 mm. The driving momentum is a combination of electrical field, dielectrophoretic force, dielectric force and electrostrictive force. The chosen working fluid has to perform conductivity ranging from 10−12 to 10−6 s/m. The particles in dielectric fluid are charged by the applied electrical field so that the fluid is conveyed by induced electrostrictive forces, shown in Fig. 12. The electric field is developed by a pair of electrodes: an emitter and a collector. The ionized molecules are thus
Anode :
Bohm et al. [1] presented an electro-chemical pump for micro-dosing system (as shown in Fig. 14). The rate of bubble generation is about 0.02 nl/s. The advantages of chemical micro pump are relatively simple structure and easier to be integrated with other microfluidic devices. The drawback, depending on bubble generation rate, is that the born bubbles might partially
Fig. 12. EHD micro pump (Courtesy of [37]).
Fig. 13. EO flow and double layer.
Fig. 11. MHD micro pump (Courtesy of [33]).
Cathode :
2H2 O → 4H+ + 4e− + O2 (g) 2H2 O + 2e− → 2OH− + H2 (g)
(4)
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Fig. 17. MFA structure (Courtesy of [50]). Fig. 14. Electro-chemical pump (Courtesy of [1]).
Fig. 15. Osmotic actuator (Courtesy of [22]).
collapse and become water as long as the chemical reaction in Eq. (4) is reversed due to any possible reasons. Hence, the releasing of drug is not completely reliable and not ensured to retain steady. 2.2.5. Osmotic-type With particularly selected osmotic driving agent inside the chamber to provide concentration difference for working fluidic molecules across the diaphragm, the working fluid, outside the chamber, naturally moves towards the low density zone. The inertia force of the moving flow directly transfers a kinetic momentum upon an actuation diaphragm. The osmotic force is thus generated as long as the fluid, carrying drug particles, diffuses into an osmotic diaphragm shown in Fig. 15. Though this type of micro pumps needs no external power (mechanical or electrical) it suffers from low flow rate and low response with long time delay. Moreover, the semi-permeable diaphragm might depart from the substrate after a certain period of time. Su and Lin presented a water-powered micro drug delivery system [47–48] as shown in Fig. 16. The major advantage of
this actuator is no additional electrical power needed at all, but its flow rate is too slow, below 0.2 l/h, to be efficiently used in most bio-chips. 2.2.6. Capillary-type Fig. 17 presents a Micro Fluidic Accumulator (MFA) that is driven by capillary phenomenon [49,50]. MFA is mainly composed of quite many hydrophobic micro capillaries that can be controlled by valves to make inlet/outlet exposed in atmosphere [51]. If the pressure in the main micro channel is escalated, the fluid will be conveyed into all capillaries that tentatively act together as a reservoir. The fluid can be quantatively released by changing the outlet fluidic resistance. The maximum flow rate was reported about 7.2 l/min, that is far below the level usually required in bio-chips. 2.2.7. Electrowetting (EW) Electrowetting (EW) is the application of exerting electrostatic force to control the surface tension between two layers of material that could be solid/liquid or liquid/liquid as long as they are immiscible and explicitly two-phased. EW operates in two approaches: continuous and digital. Digital EW is mostly applied to control the surface tension between solid-phase electrode and liquid-phase droplet as shown in Fig. 18. The contact angle, θ, is decreased if an external control voltage is applied on the electrode and therefore the liquid droplet tends to get flattened. The relation among contact angle, surface tension and applied voltage can be described by Lippmann–Young equation as follows [52]: cos θ = cos θ0 +
1 CV 2 γls 2
(5)
where θ is the contact angle, θ 0 the equilibrium contact angle at V = 0 V, γ ls the liquid–solid interfacial tension and C is the specific capacitance of the dielectric layer.
Fig. 16. Water-powered drug delivery (Courtesy of [48]).
Fig. 18. Digital electrowetting.
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Fig. 19. Continuous electrowetting (Courtesy of [53]).
Fig. 20. EW micro pump (Courtesy of [53]).
Continuous EW is usually applied to adjust the surface tension between two immiscible liquids such as liquid-phased metal (e.g., mercury) and electrolyte. Its interface is referred to as “electric double layer” as shown in Fig. 19. Due to protonation effect on the mercury surface, the electric potential between right end of mercury droplet and the cathode of electrode pair is higher than the counter electric potential on the left side. The surface tension difference beside a mercury droplet thus pushes the droplet toward right, like a stone rolls down from hill. Yun et al. presented a continuous EW micro pump [53] as shown in Fig. 20. The volumetric flow rate reaches up to 70 l/min at driving voltage 2.3 V and power consumption of 170 W. The maximum pressure is about 800 Pa by applying voltage 2.3 V with frequency 25 Hz. 2.2.8. Bubble-type Micro pump Tsai and Lin reported a bubble pump [54] consisting of a pair of diffuser and nozzle and a reaction chamber. As shown in Fig. 21, the bubbles are generated by heating process. The
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bubbles are expanded and collapsed in volume, periodically by a controlled voltage input. The volume change in chamber is incorporated with the diffuser/nozzle mechanism that is used to determine the direction of fluidic flow. The maximum value of the flow rate of the bubble-type micro pump is 5 l/min as the applied voltage was exerted periodically at 250 Hz with 10% duty cycle and power consumption 1 W. The most attractive feature of bubble-type micro pump is that two or more kinds of doses can be thus mixed up during the expanding/collapsing cycles. This kind of pumps always needs to be heated so that its application scope is limited in case heating process is not allowed or preferred. In general, micro pumps can be divided into mechanical and non-mechanical ones by discrimination of active mechanisms. Most mechanical pump consists of valves and actuating membrane so that fatigue and reliability are the main design concerns. On the other hand, non-mechanical micro pumps mostly cannot achieve sufficient flow rate, driving pressure head and fast response. Table 1 is to compare their major characteristics in maximum pressure, flow rate and applied voltage. 3. Bio-compatibility of MEMS materials MEMS-based micro-dosing/drug delivery devices can be either implanted or just placed under the skin. A key issue for both cases to be seriously taken into account is bio-compatibility. Even with special surface treatment [55–57], the MEMS devices can still be treated as an external intruder and attacked by immunization system. As time goes by, a fouled or corruptive medical device thus becomes malfunction. Hence, more rigorous biocompatibility and bio-stability requirements have to be fulfilled. A common index for bio-compatibility is called Foreign Body Giant Cells (FBGC) density that can be usually used to evaluate the feasibility of designed devices and materials. Secondly, in addition to bio-compatibility, a certain degree of toxicity to tissues is strictly forbidden and this has to be counted in at the very beginning to assign a specific material. Another concern is to reduce the mechanical stress induced by the micro pumps dynamics by all means. Recently, polymer-MEMS becomes more and more popular mainly because it has a very low stiffness and inherently provides adequate flexibility. Currently, polymer material, such as Poly Methyl Methacrylate (PMMA), PolyDimethylsiloxane ( PDMS), SU-8 photo resist, or Parylene C, is
Fig. 21. A bubble pump (Courtesy of [54]).
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Table 1 Comparison of micro pumps Working principle (type/actuator)
V (V)
Qmax (l/min)
Pmax (MPa)
Structure
Year
Me/electrostatic Me/electrostatic Me/piezoelectric Me/piezoelectric Me/piezoelectric Me/piezoelectric Me/piezoelectric Me/thermo-pneumatic Me/thermo-pneumatic Me/thermo-pneumatic Me/SMA Me/SMA Me/SMA Me/SMA Me/bimetallic Me/bimetallic Me/ICPF Non-Me/MHD Non-Me/MHD Non-Me/MHD Non-Me/EHD Non-Me/EHD Non-Me/EO Non-Me/EO Non-Me/EO Non-Me/electro-chemical Non-Me/electro-chemical Non-Me/osmotic Non-Me/capillary Non-Me/electrowetting
200 200 600 110 190 350 250 8 n/a 15 n/a 0.6 n/a 8 5.5 16 1.5 60 4 6.6 300 700 1000 2000 5000 4.5 1.5 0 0 2.3
850 30 0.12 13.33 1500 1900 550 14 9 44 340 50 50 700 44 43 37.8 63 2.88 18.3 n/a 14 15 3.6 1.75 0.024 0.08 0.0033 7.2 70
0.31 0.02 0.002 0.35 0.001 0.012 0.009 0.0025 0.016 0.0038 0.1 0.0042 0.0005 n/a 0.107 n/a n/a 0.1037 n/a n/a 0.0007 0.0025 0.0334 2.026 11 0.11 0.0235 n/a 0.0065 0.0008
Si–Si Plastics-metals Si–Si–Si Si–pyrex Si–Si Plastics-metals Glass–Si–glass Glass–Si–glass Glass–Si Polymer Si–Si Si–Si Si–Si–Si Acryl Si–Si Si–Si n/a Si–Si Glass–glass Glass–Si–glass Ceramic–alumina Si–Si Glass–glass Fused-silica capillary Fused-silica capillary Si–Si PDMS–glass PDMS–PDMS Si–Si Si–Si–glass
1995 [14] 2001 [16] 1998 [17] 1999 [18] 2002 [19] 1999 [20] 1994 [21] 2000 [22] 2004 [23] 1994 [24] 2001 [25] 1997 [26] 1998 [27] 2004 [28] 1996 [29] 1996 [30] 1997 [31] 2000 [33] 2003 [35] 2000 [36] 2002 [37] 1990 [38] 2002 [42] 2001 [43] 2005 [44] 2004 [45] 2003 [46] 2004 [48] 2003 [50] 2002 [53]
Table 2 Bio-compatibility materials for MEMS Materials
Bio-compatibility
Characteristic
Application
PDDA PDMS SU-8 (PR) PMMA ICPF TiN alloy Au Al2 O3 Pt Ti
Good Good Good Good Very good Good Good Very good Good Good
Porous material Ultra-thin active layer Thick-PR (high aspect ratio) Simply fabrication (hot embossing) Difficult to fabrication (replica or modeling) Shape memory effect Simply fabrication (low resistivity) Brittle Simply fabrication (low resistivity) Simply fabrication
Reduce toxicity of nano particle Osmotic membrane (soft lithography) Microfluidic structure Microfluidic structure Sensor actuator Actuator Electrode connection Microfluidic structure Temperature sensor heater Heater
gradually proven to possess relatively better bio-compatibility and flexibility. They have the potential to be upgraded to be officially applied in biomedical MEMS devices. Table 2 lists a summary of bio-MEMS materials from the viewpoint of application fields and their main characteristics. 4. Conclusion The applied voltage is essentially a key constraint factor for micro-dosing/drug delivery driving power. In other words, the micro pumps have to be limited by low applied voltage, say from 5 to 12 V. Since the micro-dosing and drug delivery systems cannot tolerate any potential detrimental influence from
driving forces, the electrostatic micro pumps and piezoelectric micro pumps have to be usually ruled out because of high driving voltage required. EHD and MHD micro pumps have to be incorporated with working fluid with a certain degree of electric conductivity. This would narrow down the application fields, particularly in bio-chips. Bubble-type and other non-mechanical micro pumps need no physical actuation components but its effectiveness, due to long time delay and slow response, are much devalued. The type of SMA micro pumps suffers from a relatively low flow rate and insufficient bio-compatibility. In addition to applied voltage and driving methodology, the other crucial issue for micro-dosing driving power is the degree of biocompatibility. It would become extremely sensitive and deter-
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minative especially for implanting-oriented biological applications. In comparison, ICPF micro pumps possess the most advantages of long stroke, low driving voltage, qualified flexibility and bio-compatibility. Bimetallic micro pumps have the superiority on high flow rate and pressure head. If the associated flexibility and bio-compatibility can be further improved, they would become more competitive. References [1] S. Bohm, B. Timmer, W. Olthuis, P. Bergveld, A closed-loop controlled electrochemically actuated micro-dosing system, J. Micromech. Microeng. 10 (2000) 498–504. [2] A. Manz, N. Graber, H.M. Widmer, Miniaturized total chemical analysis systems: a novel concept for chemical sensing, Sens. Actuators B 1 (1990) 244–248. [3] T.S.J. Lammerink, M. Elwenspoek, J.H.J. Fluitman, Integrated microliquid dosing system, IEEE Micro Electro Mech. Syst. (1993) 254– 259. [4] D. Maillefer, H.V. Lintel, G.R. Mermet, R. Hirschi, A high-performance silicon micropump for an implantable drug delivery system, in: Prcoceedings of IEEE MEMS ’99, 1999, pp. 212–215. [5] L. Gao, S. Mantell, D. Polla, Implantable medical drug delivery systems using micro-electro-mechanical systems technology, in: First IEEE-EMBS Special Topic Conference on Microtechnologies in Medicine and Biology, 2000, pp. 487–490. [6] S.L. Tao, M.W. Lubeley, T.A. Desai, Bioadhesive poly(methyl methacrylate) microdevices for controlled drug delivery, J. Control. Rel. 88 (2003) 215–228. [7] F.E.H. Tay, W.O. Choong, H. Liu, G.L. Xu, An intelligent micro-fluidic system for drug delivery, in: Proceedings of IEEE MEMS ’2000, 2000, pp. 70–75. [8] D. Reynaerts, J. Peirs, H.V. Brussel, An implantable drug-delivery system based on shape memory alloy micro-actuation, Sens. Actuators A: Phys. 61 (1997) 488–562. [9] G.T.A. Kovas, N.I. Maluf, K.E. Petersen, Bulk micromachining of silicon, Proc. IEEE 86 (1998) 1536–1551. [10] J.M. Bustillo, R.T. Howe, R.S. Muller, Surface micromachining for microelectromechanical systems, Proc. IEEE 86 (1998) 1552–1574. [11] P.R. Choudhury, Handbook of Microlithography, Micromachining and Microfabrication, SPIE Press, 1997, pp. 1–2. [12] M. Madou, Fundamentals of Microfabrication, second ed., CRC Press, New York, 2002. [13] Gregory T.A. Kovacs, Micromachined Transducers Sourcebook, McGrawHill, New York, 1998. [14] R. Zengerle, J. Ulrich, S. Kluge, M. Richter, A. Richter, A bidirectional silicon micropump, Sens. Actuators A: Phys. 50 (1995) 81–86. [15] R. Zengerle, M. Richter, H. Sandmaier, A micro membrane pump with electrostatic actuation, in: Proceedings of IEEE, Micro Electro Mechanical System, 1992, pp. 19–24. [16] C. Cabuz, W.R. Herb, E.I. Cabuz, S.T. Lu, The dual diaphragm pump, in: Proceedings of the IEEE MEMS ’2001, 2001, pp. 519–522. [17] M. Koch, N. Harris, A.G.R. Evans, N.M. White, A. Brunnschweiler, A novel micromachined pump based on thick-film piezoelectric actuation, Sens. Actuators A: Phys. 70 (1998) 98–103. [18] M. Didier, V.L. Harald, R.M. Gilles, H. Roland, High-performance silicon micropump for an implantable drug delivery system, in: Proceedings of the IEEE MEMS 99, 1999, pp. 541–546. [19] C.G.J. Schabmueller, M. Koch, M.E. Mokhtari, A.G.R. Evans, A. Brunnschweiler, H. Sehr, Self-aligning gas/liquid micropump, J. Micromech. Microeng. 12 (2000) 420–424. [20] S. Bohm, W. Olthuis, P. Bergveld, A plastic micropump constructed with conventional techniques and materials, Sens. Actuators A 77 (1999) 223–228. [21] V. Gass, B.H. Vanderschoot, S. Jeanneret, N.F. Derooij, Integrated flow regulated silicon micropump, Sens. Actuators A 43 (1994) 335–338.
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Biographies Nan-Chyuan Tsai was born in Taiwan in 1963. He received his BS degree from National Cheng Kung University in 1986 and MS degree in mechanical engineering and electrical engineering from PENN STATE University in 1991 and 1993, respectively. In 1995 he received his PhD degree in mechanical engineering from PENN STATE University. He has been an assistant professor at National Cheng Kung University since 2003. His research interests include MEMS/NEMS technology, mechatronics, control engineering, active magnetic bearings and bio-chip applications. Chung-Yang Sue was born in Taiwan in 1980. He received his BS degree from Kun Shan University in 2003 and MS degree from National Cheng Kung University 2005 both in mechanical engineering. He is about to earn his PhD degree in the field of bio-MEMS technologies at National Cheng Kung University. His research interests include design, fabrication and experiments of MEMS/NEMS sensors and actuators.