Contenu connexe Similaire à Etd 0712105 122345 Similaire à Etd 0712105 122345 (20) Etd 0712105 1223453. (Patch Clamp)
(pipette)
(Voltage clamp)
(action
potential)
(Soft lithography)
ICP(
)
I
4. ABSTRACT
Patch clamp is a well-developed lelectrophysiological recording
technique used to study ion channel function and regulation. The
conventional method of performing patch clamp technique employs a glass
micropipette onto the cell by manual manipulation. Despite this technique
is extremely sensitive and information-rich, but requires a highly-skilled
operator and is limited in throughput. Voltage clamp that determine the
behavior of the ion channel conductances responsible for the generation of
the action potential is the another method to record the flow of ionic current
across the cell membrance. The method is held a constant membrane
potential while the ionic current flowing through the membrane is measured.
The thesis presents cell-platforms and etcing pores on silicon by using
soft lithography and etching technique insteading of conventional glass
micropipette recording method. we successfully demonstrated practicability
of the process by the cells adhered on the platform and the etching pores on
the silicon chip by using ICP. The less laborious manipulation time saving
and high sampling throughput will be expected .In the future, we can
automatically real time controlled and changed in response to the cell’s
physiologic characteristics measured by ionic channel activities.
Keyword MEMS Patch clamp Voltage Clamp Soft lithography ICP
II
7. ……………………………………………………………………I
…………………………………………………………..……….
……………………………………………………………………..….
………………………………………………………………..……….
…………………………………………………………………….
…………………………………………………………………...…
…………………………….…………………………………..1
1-1 ………………………………..………………………………….1
1-2 ………………………………………………..…….1
1-3 …………………………..……………………….2
1-4 ………………….…………………………………………..3
1-5 ……………………………………………………………...4
1-6 ………………………………………………………..…….9
…………………………...10
2-1 ………………………………………….10
2-1-1 ………………………………………….……….10
2-1-2 …………………………………………………..13
2-1-3 …………………………..………15
2-1-4 (Voltage Clamp)……………………….……………17
2-2 ………………………………19
2-2-1 (HTS) ………………………..20
V
8. 2-2-1-1 AVIVA Biosciences Corp Axon Instruments,Inc…………..20
2-2-1-2 Cytocentrics CCS(Reutlingen ,Germany)…………………22
2-2-1-3 Flyion GmbH (Tubingen , Germany)……………………...24
2-2-1-4 Ionworks HT –Molecular Devices corp.(Sunnyvale ,USA).25
2-2-1-5 Sophion Biosciences(Ballerup,Demark)…………………..26
……………….….……………………….30
3-1 ………………….….……………………………..30
3-2 ………………………….….…………………………..31
3-2-1 (Clean)…………………………….……………………...31
3-2-2 (Oxidation)…………………….…….……………………34
3-2-3 ( Photolithography)……………………………………….35
3-3 (Soft lithography)……………………………………………39
3-3-1 …………………………………………………..39
3-3-2 ………………………………………………………39
3-3-3 …………………………………………………43
3-4 (TMAH )………………………………………...46
3-4-1 …………………………………………………46
3-4-2 ……………………………………………………46
3-5 ( ,ICP)…………………………..47
3-5-1 ………………………………………………………48
3-5-2 ………………………..………………………..50
3-5-3 ……………………………………………………52
VI
9. ……………………………………………………….55
4-1 ………………………………………………………………….55
4-2 TMAH ………………………………………………………58
4-3 ICP ……………………………………………………...…...61
……………………………………………….…67
5-1 ………………………………………………………………….…67
5-2 ……………………………………………………………….67
…………………………………………………………………...69
………………………………………………………………………
VII
10. 1 ……………………………………………….….28
2 …………………………………………………29
3 …………………………………………………………54
VIII
11. 1.1 [2] …………………………………...…..………3
1.2 Nanion 5
1.3 PDMS 6
1.4 PDMS 6
1.5 7
1.6 MCA 7
1.7 …………………………………………8
1.8 sidewall 8
2.1 [15] ……………………………...………………..11
2.2
2.3 ………..…………12
2.4 …………………………………………………….13
2.5 …………………………………….14
2.6 - …………………………………………15
2.7 (Patch Clamp)[6,18,19] ………………………………..16
2.8 …………………………………....………18
2.9 [20] ………………………….………18
2.10 (A) (B) [21] ………..20
2.11 SealChip16…………………………………………………...……20
TM
2.12 PatchXpress ………………………………………………21
2.13 CytoPatchTM 23
IX
12. 2.14 CytoPatchTM SEM 23
2.15 CytoPatch Site 23
2.16 Flyion 24
2.17 Flyscreen 8500………………………………………………….24
2.18 Ionworks HT ………………………….26
2.19 QPatch 16TM QPatch HT…………………………………….27
3.1 ……………………………………….30
3.2 ………………………………………..31
3.3 NDL (Wet bench)………………………33
3.4 (a) (Oxidation Furnace)
(b) …………………………….35
3.5 (a) (b) (c) ……36
3.6 NDL(a) (Track)
(b) (Aligner) ……………………………….38
3.7 ………………………………………41
3.8 OM (a)
(b) 42
3.9 (a) 16µm 1.6µm (b) 20µm
1.6µm © 30µm 1.6µm …………42
3.10 DSPC 45
3.11 (a) SH-(CH2)11COOH
PDMS substrate (b)substrate
SH-(CH2)11COOH (c) substrate DSPC
(d) 12 substrate DSPC
X
13. DSPC …………………………………………45
3.12 ………………………………47
3.13 TMAH Si ……………………………………………..47
3.14 NDL (a) (ICP)
(b) (Sputter) ………………………………………48
3.15 51
3.16 53
3.17 ICP ………………………………54
4.1
4.2
µm
µm
………………………
4.3
µm …………………………
4.4 (a)
(b)
18µm x36µm ……………………57
4.5
18x18µm 2 ……………………………...……….57
4.6 (a) 27µm x54µm
(b) 37umx74um
(c) 38µm
XI
14. (d) 38µm ……………………………………57
4.7 TMAH (5wt%) (a)
(b) BOE SiO2 ( 760µm) ………58
4.8 TMAH (25wt%) (a)
(b) BOE SiO2 ( 760µm) ………59
4.9 ………………………………
4.10
…………………………
4.11
……………………………………
4.12 (a) (b) …………………………………………62
4.12 (c) (d) ……………………63
4.13 ……………………..63
4.14 IC (dummy) ………………...………64
4.15 (a)
(b) …………………………………………………..64
4.16 …………………………………………………………65
4.17 SEM ……………………………………..…..65
4.18 …………………………...……………….66
XII
15. (Micro – Electro – Mechanical – Systems
MEMS ) (Bio-MEMS)
(Biochip)
1959 · (Richard
Feynmann,1918~1988) “There is plenty of room at the
bottom”[1]
(Micro-Electro-Mechanical-System, MEMS)
(Batch)
1
16. MEMS
-
?
(Silicon chip) (glass)
DNA
resting membrane potential
(Polarization)
depolarize
2
17. 2.1 [2]
(Patch clamp)
3
19. [4]
1952 (Hodgkin) (Huxley) (Katz)
(voltage-clamp)
[5]
1976 Erwin Neher Bert Sakmann
single channel recording or patch
clamprecording
1991 [6]
2002 Sophion APATCHI-1
[7]
2002 (Munich University) 奈
(Center of Nanoscience) Niels Fertig
(Planar micro structured quartz chip) 1.2
(Xenopus oocytes) (cell-attached mode)
(mammalian) (whole-cell mode)
Nanion [8]
1.2 Nanion
5
20. 2002 (Yale) Kathryn PDMS
(Polydimethysiloxane)( 3-3-3 )
(pipette) 10 (GigaSeal)
1.3 Axon Instruments [9]
1.3 PDMS
PDMS 2004 (University of California)
Rigo Pantoja PDMS
1.4 [10]
1.4 PDMS
6
21. 2002 (Swiss Federal Institute of Technology)
(Institute of Microelectronics and Microsystems) Lehnert
(Hamburg) Evotec OAI AG Netzer
(SiO2) (micronozzle) 1.5
[11]
1.5
2003 Masato TANABE
MCA (Micro Channel Array) 1.6
[12]
1.6 MCA
7
22. 2004 (Lehigh University) Santosh Pandey
(current transport model)
1.7[13]
1.7
2004 , (Sensor and Actuator)
J.Seo PDMS (sidewall)
(lateral) 1.8 [14]
1.8 sidewall
8
23. (Voltage clamp)
- (Voltage Clamp)
(BioMEMS) (Patch-on-a-chip)
(Soft lithography)
9
24. (Patch Clamp)
(Lipid)
(lipid bilayer) 2.1 [15]
1~2 2~6 nm 12 nm
10
25. 2.2 [15]
(glycoprotein)
(integral protein)
(peripheral protein) 2.2 [16]
2.2
11
26. (channels) (pores)
2.3 [17]
(1) (Transport protein)
(2) (Channel protein)
(3) (Carrier protein)
(Channel protein) (Carrier proteins)
Energy
(Simple diffusion)
(Diffusuion) (Active transport)
2.3
12
27. diffusion
passive transport active transport
1. voltage gating
Outside
Na+
(Gate closed) (Gate open)
Inside
2.4
13
28. 2. ligand gating
ligand
acetylcholine acetylcholine channel
0.65
2.5
acetylcholine
2.5
(2)
ATP
14
29. (sodium -
potassium pump 2.6
+
3-Na
Outside 2-k+
ATPase
Inside
3-Na+
+
2-K
ATP ADP+Pi
2.6
1976 ‧ (Erwin Neher) ‧
(Bert Sakmann) single channel
recording or patch clamp recording pipette
1~2 2.7
15
30. [6,18,19]
rectangular voltage-clamp steps
2.7 (Patch clamp)[6,18,19]
(Patch clamp recording) (1)
(2)
(3)
(cell attached)
(4) (whole cell recording) (Inside-out patch)
(secondary messengers)
(5)
intracellular recording (6)
(Fluorescence microscope)
Ca++
16
31. 2-1-4 (Voltage Clamp)
R ohms,
Ω (Conductance
G) siemens S (G=1/R)
17
34. 2.10 (A) (B) [21]
2-2-1 (HTS)
(High -
throughput screening)
2-2-1-1 AVIVA Biosciences Corp Axon Instruments,Inc
SealChip16 AVIVA
2.11 [22] 90% 10 ( gigaseal)
75% (whole cell patch-clamp )
whole-cell 15 15 MΩ
(membrane resistance) 200MΩ
2.11 SealChip16
20
35. SealChip16 Axon Instrument PatchXpress
TM
2.12 16 SealChip16
16 1µm 4.5mm
TM
2.12 PatchXpress
PatchXpress SealChip
1. whole cell patch-clamp
2. 16
3. 16 gigaseal whole cell
patch-clamp (access resistence)
4.
50µl
5. 16 2000
6.
21
36. 2-2-1-2 Cytocentrics CCS(Reutlingen ,Germany)
Cytocentrics CCS CytoPatchTM
(focused ion beam)
CytoPatchTM
200 [21]
Cytocentering
gigaseal 2.13 (SiO2) CytoPatchTM chip
5 2 .14
CytoPatchTM chip SEM CytoPatchTM
cytocentring CytoPatchTM
CytoPatch Site 2.15 CytoPatch Automat
1~50 CytoPatch sites Multi
Channel Systems npi electronic
22
37. 2.13 CytoPatchTM
2.14 CytoPatchTM SEM
2.15 CytoPatch Site
23
38. 2-2-1-3 Flyion GmbH (Tubingen , Germany)
Flyion Gmbh
2.16 [23]
Flyscreen 8500 1~6
2.17
Flyion
2.16 Flyion
2.17 Flyscreen 8500
24
39. 2-2-1-4 Ionworks HT –Molecular Devices corp.
(Sunnyvale , USA)
Ionwork HT 48 8
384 (well)
voltage gating
2.18 [24]
96 384 12
HTS
Amphotericin B (
perforated patch) (co-factor)
whole-cell 1GΩ
(seal resistance) 100MΩ
HT 48 headstage
headstage
25
40. state-dependent block desensitising
ligand gating
2.18 Ionworks HT
2-2-1-5 Sophion Biosciences(Ballerup,Demark)
Sophion Biosciences
Apatchi-1TM QPatch 16TM QPatch HT
2.19 [25] 16 48
gigaseal
26
41. 2.19 QPatch 16TM QPatch HT
N/A Not available
27
42. Whole-cell Whole-cell
Institution Chip Cell positioning Gigaseal rate Status
access recording rate
Affymax Galss,laser drilling Suction N/A N/A N/A N/A
Patch
AVIVA >75% , 15min
Galss with modified >90% , >1GΩ Suction Xpress and
Biosciences , Suction Ra<15MΩ;
surface dielectrophoresis (loss<1%) Seal chip
Axon Instruments Rm>200MΩ
available
Axon Instruments PDMS,molding Suction ~50% Suction ~50% N/A
Various substrates , laser
CeNeS drilling , and other, Suction N/A N/A N/A N/A
methods
Under
Cytocentrics CCS Quartz glass Suction N/A N/A N/A
development
Si3N4 membrane Under
Cytion Electrophoresis N/A N/A N/A
supported by a Si Chip development
IonWork HT
Plastic chip laser 60-80% , 6min
Essen Instrument, Perforated and
drilling, with a glass Suction 20-250MΩ Ra=10-15MΩ
Molecular Devices patch PatchPlate
coating Rm=10MΩ
available
Glass chip, gold NPC 16
Nanion
ion-etched track Suction 30-50% Suction 30-50% , 30min under
Technologies
followed by wet etching development
Qpatch 16
Silicon chip, etching
Fluid channel and 96
Sophion Biosciences with biocompatible N/A Suction N/A
,Suction under
coating
development
PDMS, molding Xenopus occyte
Yale University Suction N/A N/A N/A
13% , gigaseal
28
43. Man u f a c t u r e r Produts Substrate/Seal Description/Throughput Amplifiers/Source Costs per chip per Status partners
website data point
r e f e r e n c ee
Axon Instruments Inc PatchXpressTM planar patch 16 channel Sealchip, 16 channel range$140-180<$3. available/Aviva
Union City, CA,USA 7000A glass chip/ 16 channel washout head, parallel/Axon 8/dp BioSciences
G Seal 1 channel dispenser
20000 dp/day
Cytocentrics CCS CytoPatchTM planar patch modular instrument, with up to 20 $8<$3.2/dp β-test inQ3 03/
GmbH Reutlingen , Automat quartz chip/ up to 20 patch calmp channels,switched BionChip, MultiChannel
Germany G Seal sites mode parallel Systems,
2000 dp/stie/day(if fast operation/npi NMI, npi electronic, no
acting compounds) electronic and Multi sales/
40000 dp/day with 20 Channel Systems commercialization
sites/unit partner
lFlyion GmbH FlyScreen glass micropipette single channel Flip Tip® up to 6 independent Fliptips®A-$3 available in Europe
®
Tubingen, Germany 8500 embedded in plastic dispenser with 2 channels channels/HEKA Fliptips®L-$4 /HEKA,Tecan, Manz
jacket(Flip Tip)/ (functions) 3-6Flip Tip <$1.6/dp Automation no sales /
G Seal recordings positions commercializtion partner
(scalable) 300-1000
dp/day
Molecular Devices IonWorksTMHT planar patch 384 PatchPlate at 1536 48 channel range $ 145-200 per available/ lower
Corp Sunnyvale, plastic chip/ spacing(~14 L/well),12 parallel/proprietary patch throughut
CA,USA Avg.~150MΩ seal channel dispenser 3000 development plate,<$2.0/dp IonworksTMAPC target
dp/day launch Q1 04
Nanion Technologies NPC©1(Port-a- planar patch 1, or 16 channel chips 1 channel ©
NPC 1-$10 NPC©in -test,target
©
GmbH Munich , Patch) glass chip perfusion (scalable) 1 channel sequential/HEKA 16 NPC 16-$100 launch Q4 03/
Germany NPC©16s(sequ cartidge/G seal dispenser channel parallel <$2.5/dp for HEKA,Dagan, Tecan,
ential) NPC©1-50 dp/day (asynchronous)/Dagan NPC©16 Bruxton,
NPC©16p(paral NPC©16s-200 dp/day No sales/
lel) NPC© 16p-2000 dp/day commercializtion partner
TM
Sophion Bioscience QPatch 16 planar patch QpatchTM16-16channel- 16 and 96 channel QPatchTM16-$100< QPatchTM16 in -test
A/S Ballerup , QPatchTM96 silicon chip/ 250-1200 dp/day parallel $2.5/dp targen
Denmark G seal QpatchTM96-96channel- (asynchronous)/propri launch Q3 03/CRL,no
1500-7000dp/day 4/8 etary development sales/ commercialization
channel dispenser partner
29
46. 奈
( NDL)
NDL (Clean room) ( Wet Bench )
RCA 3.3 RCA
1965 RCA 1970
RCA
RCA
CARO DHF SC-1 SC-2
(1)CARO
RCA 若
hydrophobic
3 硫 1 120- 130 硫
(2)DHF
hydrophobic
(D.I.water) (rinse)
32
47. (3)SC-1
Standard clean 1 SC-1 5
1 30 1 29
70 - 80 SC-1
(4)SC-2
Standard clean 2 SC-2 6
1 30 1 37
70 - 80 SC-2
留
3.3 NDL (Wet bench)
33
48. (Oxidation)
(oxidation) (SiO2)
(mask)
SiO2 10~20Å
SiO2 600
(thermal oxidation)
SiO2 56
SiO2 Wet Oxidation
Dry Oxidation
Si s + O2(g →SiO2 s ( 3.1)
Si s +2H2O g →SiO2 s + 2H2 g ( 3.2)
34
49. SiO2
SiO2
Si SiO2
3.4(a) ( )
1092 3.4(b)
50Å
度
(a) (b)
3.4 (a) (Oxidation Furnace) (b)
( Photolithography)
35
50. (Exposure)
(Development)
(a) (b) (c)
3.5 (a) (b) (c)
(DehydrationBake) Priming (Soft bake) (Hard Bake)
(1)
(2)
(Hexamethyldisilazane, HMDS)
36
51. (3)
(Spincoating)
(5)
(6)
(Standing wave)
(7)
37
52. (8)
NDL
(Track) (Aligner) 3.6
(a) (b)
3.6 NDL(a) (Track) (b)
(Aligner)
38
53. (surface coating)
(plasma treatment) (self-assembly monolayer
SAM) LB (Langmuir-Blodgett film)
microcontact printing CP replica molding REM
microtransfer molding TM micromolding
in capillaries MIMIC solvent-assisted micromolding
SAMIM phase-shift photolitography [28]
(microcontact printing) ,
留 (substrate)
( 3.7)
39
54. (a) RCA
(b) 1092 2
0.9µm SiO2
(c)
(d) BOE (Buffer Oxide Etch) 50nm/min 20
SiO2
(e) 90 TMAH 0.9µm/min 0.5~4
(f)BOE .
(g) (E-Beam) (Cr) (Au)
500Å 1500Å
40
55. (a) (e)
TMAH
(b) (f)
(c) (g)
(d)
3.7
3.8(a) 3.7(b)
(OM)
3.9(a~c) (Alpha-step)
1.6 m 16 m 20 m 30 m
41
56. (a) (b)
3.8 OM (a) (b)
度
度
度 度
(a) (b)
度
度
(c)
3.9 (a) 16µm 1.6µm (b) 20µm 1.6µm (c)
30µm 1.6µm
42
57. 3-3-3
PDMS (Stamp)
(substrate)
PDMS(Polydimethysiloxane)
Dow Corning (Sylgard 184
silicone elastomer) (Curing agent) 10:1
PDMS (1)
(2)
22 dyne/cm2
PDMS
PDMS 3.10
SH-(CH2)11COOH PDMS
PDMS
PDMS 60 PDMS
SH-(CH2)11COOH SH-(CH2)11COOH
硫 硫
(Van der
Waals force) self-assembled monolayers,
SAM COOH
43
58. (a) (b)
3.10 (a) PDMS (b) PDMS
( )
DSPC 12
DSPC
PC(phosphorylcholine) [29]
SH-(CH2)11COOH 硫-硫
undecyl
cholinyl COOH
3.10 ( 3.11)
44
59. 3.10 DSPC
PDMS PDMS
SH-(CH2)11COOH
DSPC
DSPC
3.11 (a) SH-(CH2)11COOH PDMS substrate
(b)substrate SH-(CH2)11COOH (c) substrate DSPC
(d) 12 substrate DSPC DSPC
45
60. (TMAH )
TMAH (Tetramethyl ammonium hydroxide (CH3)4NOH
)) (Etch mask)
(SiO2) TMAH 110°C
IC
3-4-1
TMAH
SiO2
(111) (100) 54.74° [30]
(Etching Stop) TMAH
SiO2 3µm
46
61. 3.12 3.13
54.74 ゚
3um
3.12
(µm)
Si
TMAH Si (hr)
3.13 TMAH Si
Dry Etching Plasma Etching
NDL
Inductively Coupled Plasma ICP 3.14(a)
47
62. (a) (b)
3.14 NDL (a) (ICP) (b) (Sputter)
3-5-1
(Plasma)
(Radical) (Partially Ionized Gas)
48
63. 若
(DC) (RF)
(1) (2)
(Secondary Electron) (DC)
(RF)
49
64. 3-5-2
Physical Chemical
(undercut)
SF6 (g)+e- → Sx Fy(g)+ Sx Fy + F-(g)+e- ………………..….……………..(3-1 )
Si+ F-1 → Si- nF………………………………..…….……………….(3-2 )
Si-nF→SiFx (adsorb)…………………………………….………...……..(3-3 )
SiFx(adsorb) →SiF4(g)………………………………...……………….….(3-4 )
50
65. 3-15 ICP load-lock
1000 W 13.56 MHz RF 30W 13.56 MHz RF
(backside
helium cooling)
[31]
3.15
51
66. 3-5-3
NDL
(Sputter)( 3.14(b))
3
3.17
(a)
(b)
(c)
52
67. (d)
(e) ICP
(f)
(g)
(h)
(i) , ICP
(j)
3.16
53
68. 參數
Forward Power (W) 6
RF Generator
Reflect Power (W) 1
Forward Power (W) 1200
ICP Generator
Reflect Power (W) 10
DC Bias (V) 35
SF6 flow rate (sccm) 100
O2 flow rate (sccm) 9
C4F8 flow rate (sccm) 0
Ar flow rate (sccm) 0
Chamber Pressure (mtorr) 9.8
APC Controller
Valve position (Deg) 61.7
CRYO Temperature ) -100
Pressure (Torr) 15
Helium cooling
Flow Meter (sccm) 11.3
(µm/min)
Si
ICP
3.17 ICP
54
69. human CD34+
Progenitor Cell 0.1M PBS (Phosphate Buffered Saline)
10.9 Na2HPO4 3.2 NaH2PO4 90 NaCl 1000 Distilled
water pH 7.2 Trypan blue
4.1
( 1.6 m) 4.2(a)
4.2(b) 4.2(c) 7 m 8 m
4.3-5
55
70. (a) (b)
(c)
4.2 (a) (b)
7x7µm 2 (c) 8x8µm 2 (
)
(a) (b)
µm
56
71. (a) (b)
4.4 (a) (b)
18µm x36µm
4.5 18x18µm 2
(a) (b) (c) (d)
4.6 (a) 27µm x54µm (b) 37umx74um (c) 38µm
(d) 38µm
57
72. 若
TMAH
TMAH (5wt% 25wt%)
( )
4.7(a) 4.8(a)
4.7(b) 4.8(b) BOE (Buffer Oxide
Etch) SiO2 (Etch
mask)
(a) (b)
4.7 TMAH (5wt%) (a) (b) BOE SiO2
( 760µm)
58
73. (a) (b)
4.8 TMAH (25wt%) (a) (b) BOE SiO2
( 760µm)
Wm Wo
z
Wo 3 m
Wm 710 m
Wo=Wm- 2 z …………………………………………
Wm
z
Wo
59
75. 4-3 ICP
ICP ICP
(RF)
留 留
留
61
76. (1)
4.12(a)
4 m ICP
4.12(b) 4 m
15 m 4.12(c-d)
(a) (b)
4.12 (a) (b)
62
77. (c) (d)
4.12 (c) (d)
4.13
63
78. 4.14 IC (dummy)
(2)
(a) (b)
4.15 (a) (b)
64
79. (3)
4.16
4.17 4.18
3.19 m
4.17 SEM
65
81. 若
(series resistance)
(electrical couple)
; Bosch ICP
seal resistance
67
82. ICP
(Micro-pump)(
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