drug delivery systems - university of minnesotamicrosensors for intrathecal, insulin, and other drug...

Introduction to BioMEMS & Medical Microdevices

Drug Delivery Systems Companion lecture to the textbook: Fundamentals of BioMEMS and Medical Microdevices, by Prof. Steven S. Saliterman, http://saliterman.umn.edu/

Steven S. Saliterman

Star Tribune February 12, 2012

Image courtesy of MicroCHIPS, photo by Dana Lipp


Classification of Micropumps

Li, Tao et al.. Compact, power-efficient architecture using microvalves and microsensors for intrathecal, insulin, and other drug delivery systems. Advanced Drug Delivery Reviews 64 (2012) 1639-1649


Mechanical Displacement Micropump

These use the motion of a solid (such as a gear or diaphragm) or a fluid to generate the pressure difference needed to move fluid.

They need a physical actuator for the pumping and they have moving parts.

Type include piezoelectric, electrostatic, thermo pneumatic, electromagnetic, bimetallic, Ion Conductive Polymer Films (ICPF)and Shape Memory Alloy (SMA) . Li, Tao et al.. Compact, power-efficient architecture using microvalves and

microsensors for intrathecal, insulin, and other drug delivery systems. Advanced Drug Delivery Reviews 64 (2012) 1639-1649


Mechanical Displacement Micropump

Tsai, NC and CY Sue. Review of MEMS-based drug delivery and dosing systems. Sensors and Actuators A 134 (2007) 555-564


What are the Left Heart Analogies?

Actuator ? Inlet Chamber? Inlet Valve? Main Chamber? Outlet Valve? Outlet Vessel?


Answers…

Actuator: Smooth Muscle Inlet Chamber: Left Atrium Inlet Valve: Mitral Valve Main Chamber: Left Ventricle Outlet Valve: Aortic Valve Outlet Vessel: Aorta


Electrostatic Micropump

These use electrostatic forces in their actuation mechanism. The pressure difference induced by the membrane deflection in the pump chamber forces fluid in the reservoir to flow in the microchannels.

The electrostatic force is defined as “the electrical force of attraction and repulsion induced by an electric field” where like charges repel, unlike charges attract.

Electrostatic actuator has only a small stroke and the deflection of the diaphragm can be easily controlled by the applied voltage.

Low power consumption and fast response . Well suited for peristaltic pumping.



Electrostatic Micropump



Peristaltic Pumping Action

Patrascu, M., et al. Flexible, electrostatic microfluidic based on thin film fabrication. Sensors and Actuators A 186(2012) 249-256


Piezoelectric Micropump

Piezoelectric mechanism finds common use in the reciprocating micropumps of drug delivery and other biomedical applications.

Main advantages of piezoelectric actuators include large actuation force, fast response and simple structure.

Fabrication is complex as is processing of piezoelectric materials.

Disadvantage of the comparatively high actuation voltage and small stroke volume.



Implantable Microport System

Geipel, A., et al. 2008. Design of an implantable active microport system for patient specific drug release. Biomedical Microdevices 10, no. 4:469-478.

Concept of an active microport


The Piezoelectric Pump

Schematic cross section of the piezoelectric micropump with a close-up of the valve geometry

Three-phase actuation scheme of the micropump



Micropump Chip

Photograph of the two membrane silicon micropump chip (a) and REM-picture of the valve lip (b).



Active Microport Design & Prototype

(a) Cross-sectional drawing of the active microport design visualizing the embedded fluidic elements, and the integration of a silicon micropump chip and a pressure sensor.

(b) Photograph of a prototype of the active microport system.



Thermopneumatic Micropump

A chamber full of air is periodically and alternately expanded and compressed by a pair of heater and cooler.

The periodic change in the volume of the chamber gives the membrane a regular momentum so fluid can flow out.

This type generates relatively large induced pressure and membrane displacement.

Two disadvantages are the need for the driving power to be maintained at a constant and specific level and the slow response.

The thermo-pneumatic actuation has a thermally induced volume change and/or phase change of fluids sealed in a cavity with at least one compliant wall



Thermopneumatic Pump



Shape Memory Alloy Micropump

SMAs are metals that show two unique properties such as pseudo elasticity and Shape Memory (SM).

The diaphragm of SMA micropumps is made mostly of Titanium/Nickel alloy (TiNi)

Transformation between two solid phases: the austenite phase (at high temperatures) and the marten-site phase (at low temperatures).

Considerable forces are generated if subjected to mechanical constraint while returning to the pre-deformed shape.

High force-to-volume ratio, ability to recover large transformation stress and strain upon heating and cooling processes, high damping capacity, chemical resistance and biocompatibility.



SMA Micropump



Bimetallic Micropump

Bimetallic actuation functions differently on different Coefficients of Thermal Expansion (CTE) of materials.

The diaphragm of bimetallic micropump is made of two different metals having different CTEs.

Bonding mechanism of dissimilar materials and their subjection to temperature changes induce thermal stresses because the coefficients of the metals differ, providing a means for actuation.

The implementation extremely simple with large forces generated but the deflection of a diaphragm is only can be achieved by thermal alternation.

The key advantage is that bimetallic micropumps require relatively low voltages than the other types of micropumps.

Their main disadvantage is their unsuitability to high-frequency operation.



Bimetallic Micropump



Ionic-Conductive Micropump

Polymer MEMS actuators that can be actuated in aqueous environments with large deflection.

They are actuated by stress gradient from the ionic movement due to an electric field.

Composed of polyelectrolyte film with both sides chemically plated with platinum.

The two films have high electrical conductivity. One diaphragm-end is fixed. An ICPF diaphragm can be controlled by

bending it upside or downside in certain value of voltages applied to the electrodes within a certain duration.



Ionic-Conductive Micropump Continued…

The presence of an electric field causes the ions in both sides of the polymer molecule chain to move to the cathode.

Simultaneously, each ion with a positive charge will take some water molecules and move towards the cathode. The ionic movement causes the cathode to expand and the anode to shrink.

The presence of an alternating voltage signal will bend the films alternately.

ICPF actuators have advantages such as low driving voltage, quick response and biocompatibility. They can work in aqueous environments.



Ionic-Conductive Polymer Film



Non-Mechanical Pumps

Electrokinetic micropumps often use an electric field to pull ions within the pumping channel, in turn dragging along the bulk fluid by momentum transfer due to viscosity.

Magneto kinetic micropumps typically use Lorentz force on the bulk fluid to drive microchannel flow.

Dynamic pumps do not usually have valves; they obtain directionality from the direction of the applied force.



Electrokinetic Microfluidic Pump

Aram J. Chung, Donn Kim, and David Erickson. 2008. Electrokinetic microfluidic devices for rapid, low power drug delivery in autonomous microsystems. Lab on a Chip - Miniaturization for Chemistry & Biology 8, no. 2:330-338.

(a) Schematic representative section of an electroactive microwell drug delivery system. Inset: cross sectional view. (b) Fabricated and assembled device with electrical leads connected to thin copper wires.


System Operation

System operation. (a) Stage 1: to electrochemically dissolve the membrane a potential is applied between the two upper electrodes. (b) Stage 2: after dissolution to eject the contents, the potentials applied between the upper electrode and the lower one on the PDMS. (c) Magnified view of microchip from above looking at the region near the membrane. Pale yellow regions (membrane and C-shape gold features) are gold where the polyimide layer was etched. (d) An example of gold–PDMS bottom substrate.



Ejection from the Microwells

Time lapse illustrating repulsion the ejection of 1.9 mm fluorescent polystyrene microsphere particles from an electroactive microwell. (a) After dissolution of the membrane, the fluorescent particles can be seen in the well. White lines outline the gold electrodes features. (b)–(f) frames taken every 2 s (total of 10 s) after application of a 4.0 V potential.



Video of Ejection



Dispersion & Front Velocity

(a) Dispersion radius vs. time for different applied potentials. (b) Instantaneous front velocity as a function of time.



Time to Empty & Power Load

Time required to completely empty the contents of the microwell as a function of applied potential.

(a) Average power load during ejection process. (b) Total energy consumed to completely empty

the well using the times above. The line through the data points in this Figure represents a quadratic best fit.



Electric Fields & Streamlines

Computed electric field lines in electroactive microwell.

Finite element simulations of the transport process. (a) Transport streamlines for pure electroosmosis. (b) Streamlines when all electrokinetic effects are

considered. Color contours show applied potential ranging from blue (ground) to red (maximum potential).



Video of Recirculation of Flow



Time-Dependent Species Transport

Finite element analysis of time-dependent species transport. Images show cut view of species concentration every 5 s up to 25 s after the ejection process (a) electroosmosis only (b) electrophoresis and electroosmosis.



Radius vs Time Results

Plot comparing experimental and numerical results on the 3.5 V case.



Other Non-Mechanical Micropumps

Magneto Hydro Dynamic (MHD) Micropumps.

Electro Hydrodynamic Micropumps (EHD). Electro-Osmotic Micropumps (EO) DC Electro-Osmotic (DCEO) Micropumps. AC Electro-osmotic (ACEO) Micropumps. Electrowetting (EW) Micropumps. Bubble-type Micropumps. Electrochemical Micropumps


Microneedles & Transdermal Delivery



Opening Schemes

Roxhed, Niclas, Patrick Griss, and Goran Stemme. 2008. Membrane-sealed hollow microneedles and related administration schemes for transdermal drug delivery. Biomedical Microdevices 10, no. 2:271-279.


Fabrication



Membrane Bursting Pressure



Pre & Post Gold Membrane Removal



Post Insertion & Evaporation Test



Summary

Chip Reservoir Drug Delivery Systems. Mechanical Displacement Pumping.

Electrostatic Piezoelectric Thermopneumatic Shape Memory Alloy Bimetallic Ion Conductive

Non-Mechanical Micropumps. Electrokinetic

Microneedles.

drug delivery systems - university of minnesotamicrosensors for intrathecal, insulin, and other drug...

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