Plug-Based Microfluidics for Membrane Protein Crystallization

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Solution Overview

Problem

Current microfluidic technologies for protein crystallization are expensive, incompatible with organic solvents, and inefficient for handling membrane proteins due to their high viscosity and low surface tension, making rapid and economical crystallization challenging.

Innovation Solution

A plug-based microfluidic system that uses fluorinated carrier fluids and spacers to control surface chemistry and prevent merging of aqueous plugs, allowing for scalable, economical, and direct testing of diffraction quality of crystals, suitable for protein crystallization and other biochemical assays.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If combinatorially mixing chips are used for high throughput screening, then productivity is improved, but device complexity and cost increase

Engineering Contradiction:

Improvehigh throughput screening capabilityVSAvoidcomplexity of combinatorially mixing chips

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The system segments the crystallization screening process into discrete aqueous plugs flowing through microchannels, with each plug representing an independent reaction unit. This segmentation enables high throughput screening while maintaining relatively simple device architecture compared to integrated combinatorially mixing chips.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

A fluorinated carrier fluid acts as an intermediary medium to transport aqueous plugs through the microfluidic device. This carrier fluid enables plug flow and reaction conditions while simplifying the overall system design compared to complex integrated mixing chips.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If combinatorially mixing chips are used, then productivity is improved, but manufacturing cost increases

Engineering Contradiction:

Improvescreening throughputVSAvoidmanufacturing cost of chips

Core Design Contradiction:

ProductivityVSEase of manufacture

Solution Approach 1:

The system uses simple microchannels with discrete aqueous plugs rather than complex integrated mixing structures, significantly reducing manufacturing cost while maintaining high throughput screening capability.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The microfluidic device uses inexpensive materials and simple structures that can be easily manufactured or replaced, reducing overall system cost compared to expensive integrated combinatorially mixing chips.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

3Ease of operation

If conventional microfluidic structures are used, then handling is simplified, but compatibility with membrane proteins is lost

Engineering Contradiction:

Improveease of handlingVSAvoidcompatibility with membrane proteins

Core Design Contradiction:

Ease of operationVSAdaptability or versatility

Solution Approach 1:

The system changes the physical parameters of the carrier fluid by using fluorinated compounds with specific surface tension and viscosity properties. These parameter changes enable the system to handle membrane proteins in detergent solutions while maintaining ease of operation through plug flow.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The fluorinated carrier fluid serves as an intermediary that is compatible with both the microfluidic structure and membrane protein detergent solutions, enabling handling of challenging samples while maintaining operational simplicity.

Inventive Principle:

Principle #24Intermediary (Mediator)

4Loss of substance

If minimal reagent volumes are used, then loss of substance is reduced, but measurement precision becomes more difficult

Engineering Contradiction:

Improvereagent consumptionVSAvoiddiffraction quality testing

Core Design Contradiction:

Loss of substanceVSMeasurement precision

Solution Approach 1:

The system segments reactions into individual aqueous plugs, each containing minimal reagent volumes that reduce waste. The segmented plug structure allows for efficient use of scarce membrane protein samples while maintaining sufficient volume for diffraction quality testing.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The system replaces traditional mechanical handling methods with microfluidic plug flow, enabling precise control of minimal reagent volumes while maintaining measurement precision through the confined geometry of the microchannels.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

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

Enables rapid and economical manipulation of reactions on a sub-femtoliter to milliliter scale, facilitating the crystallization of proteins and biomolecules with minimal reagents, and allows for the monitoring of kinetics and reaction products without the need for sophisticated equipment.

Implementation Method 1

the use of fluorinated carrier fluid can provide protection of plugs and control of the surface chemistry

Methodology Applied

Scientific EffectSurface tension: Surface Tension

Implementation Method 2

enables rapid and economical manipulation of reactions on the sub-femtoliter to milliliter scale

Methodology Applied

Scientific EffectDiffusion: Diffusion

Implementation Method 3

A plug-based microfluidic system that uses fluorinated carrier fluids and spacers to control surface chemistry

Methodology Applied

Scientific EffectAdvection: Advection

Data Source

PatentUS11853087B2Microfluidic system

Publication Date: 2023.12.26 UNIVERSITY OF CHICAGO

AI summary

The present invention provides microfluidic technology enabling rapid and economical manipulation of reactions on the femtoliter to microliter scale.