Cross-Spray ESI Derivatization for Sensitive Analyte Detection

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Solution Overview

Problem

Current mass spectrometry techniques face challenges in achieving sensitive detection of analytes from complex biological matrices, particularly for low-abundance analytes or those present in limited sample quantities, due to issues like matrix effects, contamination, and peak broadening caused by dopants in the eluent, which hinder high-throughput analysis.

Innovation Solution

A method involving two electrospray ionization sources, one for the analyte and another for a derivatization reagent or dopand, where the streams are intermixed in gaseous form to enhance sensitivity and avoid contamination, using a cross spray configuration to form a derivatized analyte for analysis by mass spectrometry.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If dopand is added to the LC-MS eluent to enhance sensitivity, then sensitivity for analyte detection is improved, but the ion source becomes contaminated over time

Engineering Contradiction:

ImprovesensitivityVSAvoidion source contamination

Core Design Contradiction:

Measurement precisionVSObject-generated harmful factors

Solution Approach 1:

The system separates the dopant delivery from the main eluent stream by using a post-column infusion approach. The dopant is introduced separately through a secondary flow path that merges with the eluent after the chromatographic column, preventing dopant accumulation in the ion source while maintaining sensitivity enhancement in the detection region.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

A post-column infusion system acts as an intermediary mechanism to deliver the dopant to the analyte stream. This intermediary approach allows the dopant to be introduced at a controlled location downstream of the chromatographic separation, enabling sensitivity enhancement without permanent ion source contamination.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Measurement precision

If dopand is infused in the eluent to enhance analyte detection, then sensitivity is improved, but chromatographic peak width is extended

Engineering Contradiction:

ImprovesensitivityVSAvoidpeak sharpness

Core Design Contradiction:

Measurement precisionVSManufacturing precision

Solution Approach 1:

The dopant is introduced after chromatographic separation is complete, rather than during the separation process. This preliminary action timing ensures that the chromatographic peaks maintain their sharpness and narrow width characteristics, while the dopant enhances detection sensitivity in the post-separation detection phase.

Inventive Principle:

Principle #10Preliminary action

3Measurement precision

If reactants for derivatization are infused before the ion source, then analyte detection sensitivity is improved, but the risk of contamination of the analyte ESI emitter increases

Engineering Contradiction:

Improvedetection sensitivityVSAvoidESI emitter contamination

Core Design Contradiction:

Measurement precisionVSObject-generated harmful factors

Solution Approach 1:

The derivatization reagent is extracted from the main eluent stream and delivered separately through a post-column infusion system. This separation prevents the reagent from contacting and contaminating the ESI emitter, while still allowing the derivatization reaction to occur in the detection region to enhance analyte sensitivity.

Inventive Principle:

Principle #2Taking out (Extraction)

4Measurement precision

If DMSO is added to enhance peptide signal sensitivity, then sensitivity is improved, but cleaning of HPLC system tubings is required when switching solvents

Engineering Contradiction:

Improvepeptide signal sensitivityVSAvoidsystem maintenance complexity

Core Design Contradiction:

Measurement precisionVSEase of manufacture

Solution Approach 1:

The DMSO-containing dopant stream is segmented from the main HPLC eluent flow path. By using a separate post-column infusion line for dopant delivery, the main HPLC system tubings are protected from DMSO exposure, eliminating the need for extensive cleaning when switching between different solvent systems.

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 approach allows for accurate and sensitive detection of analytes with improved peak sharpness and reduced contamination, enabling efficient high-throughput analysis of diverse analytes in biological samples.

Implementation Method 1

ESI (electrospray ionization) is a technique used in mass spectrometry to produce ions using an electrospray in which a high voltage is applied to a liquid to create an aerosol or a gas

Methodology Applied

Scientific EffectElectrospray ionization: Electrohydrodynamics

Implementation Method 2

Intermixing the first and the second analytical flow stream for forming a mixture or a derivatized analyte of interest

Methodology Applied

Scientific EffectDiffusion: Diffusion

Implementation Method 3

each of the first analytical flow stream and the second analytical flow stream is comprised in gaseous form or aerosol

Methodology Applied

Scientific EffectConvection: Convection

Data Source

PatentUS20230314444A1Detection of an analyte of interest by cross spray ESI mass spectrometry

Publication Date: 2023.10.05 ROCHE DIAGNOSTICS OPERATIONS INC

AI summary

The present invention relates to a method, a diagnostic system, a dopand and the use thereof for the enhancement of detection of an analyte of interest by Cross Spray ESI mass spectrometry.