Laminar Flow Microfluidic Concentration Gradient for Lipophilic Drug Screening

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Solution Overview

Problem

Existing methods for determining biological responses in target-based drug discovery, such as dilution assays, face limitations in concentration resolution and are not suitable for lipophilic substances due to the use of an oil phase, which restricts the range of usable compounds and targets.

Innovation Solution

A method involving the introduction of a soluble candidate substance into a laminar flow of buffer liquid to form a dispersed concentration profile, followed by directing this flow into a detection channel where a target is introduced to create a combined concentration profile, allowing for optical scanning of the candidate substance's concentrations to detect biological responses without an oil phase, enabling continuous scanning and broader applicability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If an oil phase is used to generate microdroplets, then discrete concentration profiles can be formed, but lipophilic candidate substances or targets cannot be used due to diffusion into the oil

Engineering Contradiction:
Improverange of usable compoundsVSAvoiddiffusion into oil phase
Core Design Contradiction:
Adaptability or versatilityVSObject-generated harmful factors

Solution Approach 1:

The invention extracts and removes the oil phase from the microdroplet generation system, replacing it with an aqueous-based segmented flow system. This elimination of the oil phase removes the harmful diffusion effect that prevented use of lipophilic compounds, while still achieving discrete microdroplet formation through alternative hydrodynamic mechanisms at a T-junction or flow focusing geometry.

Inventive Principle:
Principle #2Taking out (Extraction)

Solution Approach 2:

The invention changes the fundamental parameter of the continuous phase from oil-based to aqueous-based buffer liquid. This parameter change transforms the system from one that causes diffusion of lipophilic substances into one that is compatible with all types of compounds, including lipophilic ones, while maintaining the ability to generate discrete concentration profiles through controlled flow segmentation.

Inventive Principle:
Principle #35Parameter changes

2Measurement precision

If microdroplets are used to segment concentration profile, then discrete mean concentrations are obtained, but the resolution in terms of different concentrations is limited by the number of microdroplets

Engineering Contradiction:
Improveconcentration resolutionVSAvoidnumber of microdroplets required
Core Design Contradiction:
Measurement precisionVSDevice complexity

Solution Approach 1:

The invention replaces the mechanical segmentation approach (creating discrete microdroplets) with a continuous flow approach that generates a continuous concentration gradient. Instead of relying on the number of discrete droplets to achieve concentration resolution, the system uses controlled diffusion and flow dynamics to create a continuous spectrum of concentrations that can be scanned optically, thereby achieving high resolution without increasing device complexity.

Inventive Principle:
Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The invention transitions from a discrete one-dimensional segmentation (individual microdroplets with discrete concentrations) to a continuous spatial gradient along the flow channel. By creating a continuous concentration profile that varies along the length of the channel, the system achieves high concentration resolution through spatial distribution rather than through increasing the number of discrete units.

Inventive Principle:
Principle #17Another dimension (Dimensionality change)

3Measurement precision

If continuous flow is used to deliver candidate substance and target, then the system is simple, but concentration resolution is limited without segmentation

Engineering Contradiction:
Improveconcentration resolutionVSAvoidflow control mechanism
Core Design Contradiction:
Measurement precisionVSDevice complexity

Solution Approach 1:

The invention introduces segmentation of the continuous flow into discrete flow segments or slugs using a T-junction or flow focusing geometry. This segmentation creates distinct zones of candidate substance and buffer liquid that can be precisely controlled in terms of length, frequency, and concentration, thereby achieving high concentration resolution while maintaining relatively simple device architecture without requiring complex control mechanisms.

Inventive Principle:
Principle #1Segmentation

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

This method provides enhanced concentration resolution and allows for the use of lipophilic substances, enabling the detection of biological responses across a wide range of concentrations, improving the efficiency and scope of target-based drug discovery assays.

Implementation Method 1

The laminar flow of buffer liquid causes the pulse-shaped initial concentration profile of the solute in the solvent to change its profile due to Taylor-Aris-dispersion into a Gaussian-shaped dispersed concentration profile

Methodology Applied
Scientific EffectTaylor-Aris dispersion: Diffusion

Implementation Method 2

optically scanning the at least one half of the combined concentration profile contained in the buffer liquid held in the detection channel to detect at the various concentrations of the candidate substance solute

Methodology Applied
Scientific EffectOptical scanning: Absorption Spectroscopy

Data Source

PatentEP2965082B1Method and system for determining a biological response of a target to a soluble candidate substance
Publication Date: 2016.12.28 F HOFFMANN LA ROCHE & CO AG
  • EP2965082B1 patent drawing

AI summary

A method for determining a biological response of a target (41, 42) to a soluble candidate substance comprises the steps: introducing a soluble candidate substance into a laminar flow of a buffer liquid (2) to form a candidate substance solute (3) having an initial concentration profile (31); dispersing the initial concentration profile (31) to form a dispersed concentration profile (32); directing the dispersed concentration profile (32) into a detection channel (12) to form a final symmetrical concentration profile (33) therein; introducing a target into the detection channel (12) to obtain a combined concentration profile comprising a constant target concentration profile overlying the final symmetrical concentration profile (33); holding in the detection channel (12) at least one half of the combined concentration profile; and optically scanning the combined concentration profile to detect an optical signal representative of the biological response of the target to the soluble candidate substance.