Systems and methods for rapidly changing the solution environment around sensors

a sensor and solution environment technology, applied in the field of systems and methods for rapid and programmable delivery of aqueous streams to sensors, can solve the problems of affecting the development of hts platforms, ignoring significant drug activity of existing hts drug discovery systems targeting ion channels, and avoiding detection of false drugs

Inactive Publication Date: 2006-04-13
CELLECTRICON
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0054] Thus, the system can, for example, be used to characterize if an ion channel or receptor antagonists is a competitive or non-competetive inhibitor. The systems and methods according to the invention also can be used for toxicology screens, e.g., by monitoring cell viability in response to varying kinds or doses of compound, or in diagnostic screens. The method can also be used to internalize drugs, in the cell cytoplasm, for example, using electroporation to see if a drug effect is from interaction with a cell membrane bound outer surface receptor or target or through an intracellular receptor or target. It should be obvious to those of skill in the art that the systems according to the invention can be used in any method in which an object would benefit from a change in solution environment, and that such methods are encompassed within the scope of the instant invention.

Problems solved by technology

However, existing HTS drug discovery systems targeting ion channels generally miss significant drug activity because they employ indirect methods, such as raw binding assays or fluorescence-based readouts.
Although as many as ten thousand drug leads can be identified from a screen of a million compounds, identification of false positives and false negatives can still result in a potential highly therapeutic blockbuster drug being ignored, and in unnecessary and costly investments in false drug leads.
However, patch clamp methods generally have not been the methods of choice for developing HTS platforms.

Method used

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  • Systems and methods for rapidly changing the solution environment around sensors
  • Systems and methods for rapidly changing the solution environment around sensors
  • Systems and methods for rapidly changing the solution environment around sensors

Examples

Experimental program
Comparison scheme
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example 1

Microfabrication of a Substrate

[0252]FIG. 19 shows examples of microchannels fabricated in silicon by deep reactive ion etching in SF6. Masks for photolithography were produced using standard e-beam writing on a JEOL JBX-5DII electron beam lithography system (medium reflective 4″ chrome masks and Shipley UV5 resists, 50 keV acc. voltage, dose 15 μC / cm−2, exposure current 5 nA). The resist was spin coated at 2000 rpm for 60 s giving 250 nm of resist and soft baked for 10 minutes at 130° C. on a hotplate before exposure. The pattern was post exposure baked for 20 minutes in an oven at 130° C. and developed for 60 s in Shipley MF24-A, rinsed in DI water and etched in a reactive ion etcher (Plasmatherm RIE m-95, 30 s, 50 W, 250 mTorr, 10 ccm O2). The chrome was etched for 1-2 minutes in Balzers chrome etch #4, the mask was stripped of the remaining resist using Shipley 1165 remover and rinsed in acetone, isopropanol and DI water. A 3″, [100], two sides polished, low N-doped Silicon waf...

example 2

Re-Sensitization of Patch-Clamped Cells Using Microfluidic-Based Buffer Superfusion and Cell Scanning

[0256] Microchannels were molded in a polymer, polydimethylsiloxane (PDMS), which were then sealed irreversibly onto a glass coverslip to form an enclosed channel having four walls.

[0257] The procedure used is the following:

[0258] (1) A silicon master used for molding PDMS was fabricated by first cleaning the wafer to ensure good adhesion to the photoresist, followed by spin coating a layer (˜50 am) of negative photoresist (SU 8-50) onto the wafer. This layer of negative photoresist was then soft baked to evaporate the solvents contained in the photoresist. Photolithography with a mask aligner was carried out using a photomask having the appropriate patterns that were prepared using e-beam writing. The exposed wafer was then baked and developed by washing away the unexposed photoresist in an appropriate developer (e.g. propylene glycol methyl ether acetate).

[0259] (2) This develo...

example 3

Rapid Scanning of A Patch-Clamped Cell Across Interdigitated Streams of Ligands and Buffer for HTS Applications

[0269] One preferred embodiment for implementing HTS using the current invention is to scan a patch-clamped cell rapidly across interdigitated streams of buffer and ligands, with each ligand stream corresponding to a different drug. In these applications, as discussed above, both the flow rate of the fluids exiting the microchannels and the scan rate of the patch-clamped cell are important FIGS. 21A-D show the response of patch-clamped whole cells after being scanned across the outlets of a 7-channel structure. The width of each channel is 100 μm, the thickness is 50 μm, and the interchannel spacing is 25 μm. This 7-channel structure is identical to that shown in FIG. 16B. The procedure used for fabricating the microchannels and for patch clamping are identical to that described in Example 2 (see above). The patch clamped cell used was a PC-12 cell, which was placed betwee...

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Abstract

The invention provides microfluidic systems for altering the solution environment around a nanoscopic or microscopic object, such as a sensor, and methods for using the same. The invention can be applied in any sensor technology in which the sensing element needs to be exposed rapidly, sequentially, and controllably, to a large number of different solution environments whose characteristics may be known or unknown.

Description

FIELD OF THE INVENTION [0001] The invention relates to systems and methods for rapid and programmable delivery of aqueous streams to a sensor, such as a cell-based biosensor. In particular, the invention provides methods and systems for high throughput patch clamp analysis. BACKGROUND OF THE INVENTION [0002] Ion-channels are important therapeutic targets. Neuronal communication, heart function, and memory all critically rely upon the function of ligand-gated and voltage-gated ion-channels. In addition, a broad range of chronic and acute pathophysiological states in many organs such as the heart, gastrointestinal tract, and brain involve ion channels. Indeed, many existing drugs bind receptors directly or indirectly connected to ion-channels. For example, anti-psychotic drugs interact with receptors involved in dopaminergic, serotonergic, cholinergic and glutamatergic neurotransmission. [0003] Because of the importance of ion-channels as drug targets, there is a need for methods whic...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12Q1/02C12M1/34C12M1/42C12N5/07C12N5/071G01N21/27G01N27/416G01N33/543G01N37/00
CPCB01L3/0293G01N33/554B01L3/502715B01L3/50273B01L2200/027B01L2200/0636B01L2200/10B01L2300/0627B01L2300/0636B01L2300/0645B01L2300/0816B01L2300/0829B01L2300/0867B01L2300/087B01L2300/0874B01L2300/14B01L2400/0487B82Y5/00B82Y10/00B82Y20/00G01N33/15G01N33/48728G01N33/54366G01N33/5438B01L3/5027C12M3/00C12Q1/02
Inventor CHIU, DANIELORWAR, OWEJARDEMARK, KENTKARLSSON, MATTIASOLOFSSON, JESSICAPIHL, JOHANSINCLAIR, JON
Owner CELLECTRICON
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