MEMS FOR DRUG DISCOVERY APPLICATIONS

Transcription

1 MEMS FOR DRUG DISCOVERY APPLICATIONS Dr. Sue Mantell Dr. David Markus Dr. Shayne Zurn Jia Zhou Luigi Ottoboni Departments of Mechanical and Electrical Engineering University of Minnesota Minneapolis, MN September, 1999 Sponsor: Affymax Research Institute

2 Problem Statement many possible biomolecules Combinatorial Chemistry combinatorial chemistry: synthesize many new compounds Need a rapid low cost method to identify effective drugs Q: How can we screen the new drugs? Q: Where is there a hit?

3 MEMS As A Screening Tool batch fabrication low cost disposable rapid testing many sensors

4 Approach Vibrating Structures cantilever bridge Challenges fabrication surface chemistry sensitivity operation in a fluid Principle: Frequency shift when new compounds attached to the biomolecule +Δm ω

5 Overview Design Details Surface Treatment Performance Measures Device Performance Current Focus Overview of Performance in Liquid Conclusion

6 Design Details gold surface 1000µm 300 µm SU8 dam 2.765µm Au (0.5 µm) Ti (0.1 µm) Insulator (0.5 µm) Platinum (0.1 µm) PZT (0.4 µm) Platinum (0.1 µm) PZT (0.4 µm) Platinum (0.15 µm) Ti (0.015 µm) Insulator (0.5 µm) Two layers PZT, for sensing and actuating

7 Cross Section of Cantilever

8 SEM Picture Cantilever

9 SEM Picture Cantilever Vibrating

10 SEM Picture Cantilever Vibrating

11 Cantilever Vibration

12 SEM Picture Bridge

13 SEM Picture Bridge With Dam

14 SEM Picture Dam

15 Hysteresis Loop Top PZT Sample: su201

16 Hysteresis Loop Bottom PZT Sample: su201

17 Surface Treatment 1. 4-step SAM Biotin Blocker Avidin Gold 2. 1-step Avidin BCIP Avidin-Biotin: strong protein -ligand bond Blocker: prevent non -specific bonding BCIP: verification of avidin, amplify response

18 Performance Measures Resonant Frequency Resonant Frequency Shift Q factor

19 Resonance Frequency: Cantilever Plate W=mass density per unit area E= composite modulus b=width ν=poisson s ratio

20 Resonance Frequency: Bridge Plate W=mass density per unit area E= composite modulus b=width ν=poisson s ratio

21 Resonance Frequency Shift: Mass Of Biomolecules molecule weight = 1.7 e-20 g/mol molecule density= mol/µm 2 weight/area = e-16 g/µm 2

22 Resonance Frequency Shift: Theoretical Shift in Frequency in Air w 1 = weight / area of plate = g/µm 2 w 2 = weight / area of plate and biomolecules = g/µm 2 If biomolecules on both sides, shift = %

23 Quality Factor Definition: The quality factor, along with the resonance frequency, is an important parameter that affects the responsiveness expectable from the feedback circuit.

24 Measurement Of Q Root-mean-square amplitude curve as a function of frequency for a one-dimensional oscillator with damping g. An example of an experimental diagram

25 Data: Resonant Frequency in Air Devices without surface treatment Devices with surface treatment

26 Cantilevers Without Biomolecules Total in sample: 28 cantilevers

27 Bridges Without Biomolecule Total in sample: 35 bridges

28 Effect Of Adding Biomolecule 2-step process, bridge design ± ± ±0

29 Independent Measure of Performance Avidin Biotin with Fluorescein Frequency Shift vs. Shift in Fluorescence

30 Summary of Performance With Biomolecule: Cantilevers 4-step Process 13 devices tested 5 devices shifted down 7 devices shifted up -1.1% average down shift

31 Summary of Performance With Biomolecule: Bridges 4-step Process 13 devices tested 6 devices shift down 5 devices shifted up -0.65% average down shift 2-step Process 9 devices tested 5 devices shift down 0 devices shifted up -1.47% average down shift

32 Current Focus Performance in a Liquid Secondary Verification of Avidin mass or Thickness Packaging

33 Frequency Shift in Liquid The resonance frequencies in water are much lower than in air, due to the mass of water dragged along with the cantilever. The motion of the lever affects a layer of fluid which is approximately half a wavelength λ n thick: L λ n /2 t Source: Weigert et al., Frequency shifts of cantilevers vibrating in various media, 1996

34 Theoretical Model K R Mbeam Mfluid Schematic of cantilever oscillating in a fluid. The virtual mass of the cantilever includes an induced mass caused by the fluid being carried along. Viscous damping must also be considered to determine the resonant frequency and width.

35 Calculation Of Q In Liquid From theoretical model:

36 Liquid Influence Frequency Quality factor Both resonance frequencies and quality factors drop down when the beams are immersed in the liquid. Source: Walters et al., Short Cantilevers for atomic force microscopy, 1996

37 Liquid Test(1)

38 Liquid Test(2)

39 Liquid Test(3)

40 Concepts for Liquid Test Channel Inlet Glass Outlet

41 Concepts for Liquid Test Reservoir 1

42 Concepts for Liquid Test Reservoir 2 Drop in Liquid O Ring

43 Conclusions Bridge devices are more repeatable Device sensitivity is adequate Future Work New set of bridge devices nearly completed Additional verification of surface treatment and sensitivity required Complete study of performance in a liquid

44 Resonance Frequency: Finite Element Model

45 Behavior in Liquid: Damping Force K R Mbeam Mfluid β water =3*10-8

46 Behavior in Liquid: Finite Element Results middle node Middle-node displacement β water

47 Conclusions Resonance frequencies have been predicted with analytical and numerical models Shift in resonance frequency due to added biomolecule has been evaluated Behavior in liquid has been studied Results from analytical and numerical (Finite Element) approaches have a good agreement Experiments performed in a related work confirm the obtained results