US-12618826-B2 - Multi-chip packaging of integrated circuits and flow cells for nanopore sequencing

US12618826B2US 12618826 B2US12618826 B2US 12618826B2US-12618826-B2

Abstract

A nanopore-based sequencing system includes a plurality of nanopore-based sequencing chips. Each of the nanopore-based sequencing chips comprises a plurality of nanopore sensors. The system comprises at least one flow cell coupled to at least one of the plurality of nanopore-based sequencing chips, wherein the flow cell coupled to the at least one of the plurality of nanopore-based sequencing chips comprises one or more fluidic flow channels that allow a fluid external to the system to flow on top of the nanopore-based sequencing chip and out of the system. The system further comprises a printed circuit board electrically connected to the plurality of nanopore-based sequencing chips.

Inventors

Yuri Mitnick
Xu Ouyang
Janusz B. Wojtowicz

Assignees

Roche Sequencing Solutions, Inc.

Dates

Publication Date: 20260505
Application Date: 20240312

Claims (11)

1 . A nanopore-based sequencing device, comprising: a printed circuit board; a plurality of nanopore-based sequencing chips disposed on the printed circuit board, wherein the plurality of nanopore-based sequencing chips are electrically connected to the printed circuit board, wherein each of the nanopore-based sequencing chips comprises a plurality of nanopore sensors, each nanopore sensor configured to support a membrane and a nanopore that is inserted into the membrane, wherein each nanopore has a pore diameter suitable for nucleotide sequencing, wherein all the nanopores have the same pore diameter; and a flow cell disposed on the printed circuit board and over the plurality of nanopore-based sequencing chips, wherein the flow cell, when disposed over the plurality of nanopore-based sequencing chips, is configured to form a serpentine fluidic flow path that is configured to allow a fluid to flow over the plurality of nanopore-based sequencing chips along a serpentine path.
2 . The nanopore-based sequencing device of claim 1 , wherein the flow cell comprises a fluid inlet and a fluid outlet.
3 . The nanopore-based sequencing device of claim 1 , wherein the flow cell comprises a molded pliable material or glass material.
4 . The nanopore-based sequencing device of claim 1 , further comprising a plurality of bond wires, and wherein the printed circuit board further comprises a plurality of metal connectors, and wherein the plurality of bond wires electrically connect at least one of the plurality of nanopore-based sequencing chips to at least some of the plurality of metal connectors, and wherein the plurality of bond wires arch upwards and do not touch one another.
5 . The nanopore-based sequencing device of claim 1 , wherein the plurality of nanopore-based sequencing chips are embedded in the printed circuit board, and wherein the printed circuit board further comprises a plurality of metal connectors, and wherein at least one of the plurality of metal connectors has a portion that lies flat on a top surface of the printed circuit board and that lies flat on a top surface of one of the plurality of nanopore-based sequencing chips, and wherein the at least one of the plurality of metal connectors is electrically connected to the one of the plurality of nanopore-based sequencing chips.
6 . The nanopore-based sequencing device of claim 1 , wherein the printed circuit board comprises a plurality of cavities, and wherein the at least one of the plurality of nanopore-based sequencing chips is positioned right-side up and below the printed circuit board such that the plurality of nanopore sensors of the nanopore-based sequencing chip are exposed by one of the plurality of cavities.
7 . The nanopore-based sequencing device of claim 1 , wherein each of the nanopore-based sequencing chips comprises a plurality of banks, wherein each bank comprises a plurality of nanopore sensors.
8 . The nanopore-based sequencing device of claim 1 , wherein each of the nanopore-based sequencing chips are made from a discrete piece of silicon.
9 . A nanopore-based sequencing device, comprising: a printed circuit board; a plurality of nanopore-based sequencing chips disposed on the printed circuit board, wherein the plurality of nanopore-based sequencing chips are electrically connected to the printed circuit board, wherein each of the nanopore-based sequencing chips comprises a plurality of nanopore sensors, each nanopore sensor configured to support a membrane and a nanopore that is inserted into the membrane, wherein each nanopore has a pore diameter suitable for nucleotide sequencing, wherein all the nanopores have the same pore diameter; and a flow cell disposed on the printed circuit board and over the plurality of nanopore-based sequencing chips.
10 . The nanopore-based sequencing device of claim 9 , wherein each of the nanopore-based sequencing chips comprises a plurality of banks, wherein each bank comprises a plurality of nanopore sensors.
11 . The nanopore-based sequencing device of claim 9 , wherein each of the nanopore-based sequencing chips are made from a discrete piece of silicon.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 17/457,843, filed Dec. 5, 2021, which is a continuation of U.S. patent application Ser. No. 16/394,962, filed Apr. 4, 25, 2019, which is a continuation of International Application No. PCT/EP2017/077107, filed Oct. 24, 2017, which claims priority to U.S. Provisional Application No. 62/413,336, filed Oct. 26, 2016, each of which is herein incorporated by reference in its entirety. BACKGROUND OF THE INVENTION Advances in micro-miniaturization within the semiconductor industry in recent years have enabled biotechnologists to begin packing traditionally bulky sensing tools into smaller and smaller form factors, onto so-called biochips. It would be desirable to develop techniques for biochips that make them more robust, efficient, and cost-effective. BRIEF DESCRIPTION OF THE INVENTION In a first aspect, the present invention provides a nanopore-based sequencing system, comprising a plurality of nanopore-based sequencing chips, each of the nanopore-based sequencing chips comprising a plurality of nanopore sensors; at least one flow cell coupled to at least one of the plurality of nanopore-based sequencing chips, wherein the flow cell coupled to the at least one of the plurality of nanopore-based sequencing chips comprises one or more fluidic flow channels that allow a fluid external to the system to flow on top of the nanopore-based sequencing chip and out of the system; and a printed circuit board electrically connected to the plurality of nanopore-based sequencing chips. The at least one flow cell may be coupled to at least two of the plurality of nanopore-based sequencing chips and at least one flow cell may be connected to an inlet, an outlet, and a fluidic pump. The one or more fluidic flow channels may direct fluid to flow across a chip-to-chip boundary, wherein the chip-to-chip boundary is a boundary between the at least two of the plurality of nanopore-based sequencing chips. The chip-to-chip boundary may be hermetically sealed, for example by dicing side walls of the at least two of the plurality of nanopore-based sequencing chips to be substantially vertical and flat; placing the side walls of the at least two of the plurality of nanopore-based sequencing chips such that the side walls are butted against each other; and depositing a hermetic sealing material on the side walls. The chip-to-chip boundary may also be hermetically sealed by bonding the at least two of the plurality of nanopore-based sequencing chips onto the at least one flow cell. The at least one flow cell may comprises a molded pliable material or a glass material. At least one of the plurality of nanopore-based sequencing chips may comprise a bonding surface bonding to the at least one flow cell, wherein the bonding surface does not include circuitry or other components. The nanopore-based sequencing system or instrument may further comprise a plurality of bond wires, wherein the printed circuit board may further comprise a plurality of metal connectors, and the plurality of bond wires may electrically connect at least one of the plurality of nanopore-based sequencing chips to at least some of the plurality of metal connectors, and the plurality of bond wires may arch upwards and do not touch one another. The nanopore-based sequencing system may further comprise an encapsulation layer covering the plurality of bond wires. The plurality of nanopore-based sequencing chips may be embedded in the printed circuit board, and the printed circuit board may further comprise a plurality of metal connectors, and at least one of the plurality of metal connectors may have a portion that lies flat on a top surface of the printed circuit board and that lies flat on a top surface of one of the plurality of nanopore-based sequencing chips, and the at least one of the plurality of metal connectors may be electrically connected to the one of the plurality of nanopore-based sequencing chips. The system or instrument may further comprise an encapsulation layer, wherein the portion that lies flat on the top surface of the printed circuit board and that lies flat on the top surface of the one of the plurality of nanopore-based sequencing chips is covered by the encapsulation layer. The printed circuit board may comprise a plurality of cavities, and the at least one of the plurality of nanopore-based sequencing chips may be positioned right-side up and below the printed circuit board such that the plurality of nanopore sensors of the nanopore-based sequencing chip are exposed by one of the plurality of cavities. Then, the at least one flow cell is embedded in a well formed by the one of the plurality of cavities and the at least one of the plurality of nanopore-based sequencing chips. In a second aspect, the present invention provides a method of integrating a nanopore-based sequencing system, comprising: coupling at least one flow cell to at least on