Tomographic Refractive Index Mapping in Biological Samples

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Solution Overview

Problem

Current methods for measuring the refractive index of cells and tissues are limited by their inability to account for spatial variations and require sample immersion in liquids, which can alter cellular structures and are not physiologically controlled.

Innovation Solution

A system using interferometric methods to measure three-dimensional refractive index distributions in biological samples without perturbing them, employing light from multiple angles and spatial fringe pattern demodulation to obtain high-resolution, quantitative data without the need for immersion in special media.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If immersion in liquids of various refractive indices is used for measurement, then refractive index measurement is enabled, but cellular structures are altered and the procedure becomes cumbersome

Engineering Contradiction:

Improverefractive index measurementVSAvoidcellular structure alteration

Core Design Contradiction:

Measurement precisionVSObject-affected harmful factors

Solution Approach 1:

The patent uses phase contrast microscopy as an intermediary technique to measure refractive index without direct immersion. The phase contrast method converts refractive index differences into visible contrast, allowing measurement through the cell layer without requiring the sample to be immersed in measurement liquids, thus avoiding cellular alteration while enabling precise refractive index determination

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent replaces the mechanical immersion process with an optical field-based measurement approach. Instead of physically immersing cells in liquids and manipulating them mechanically, the invention uses light field interactions and phase contrast optics to obtain refractive index measurements, eliminating the harmful mechanical and chemical immersion steps while maintaining measurement capability

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

2Ease of operation

If average refractive index measurement is performed, then measurement simplicity is improved, but spatial variation information is lost

Engineering Contradiction:

Improvemeasurement simplicityVSAvoidspatial variation data

Core Design Contradiction:

Ease of operationVSLoss of information

Solution Approach 1:

The patent segments the cell into multiple spatial regions and performs refractive index measurements for each region independently using phase contrast microscopy. This segmentation allows the measurement system to capture spatial variations in refractive index across different cellular areas while maintaining the simplicity of the phase contrast method, thus avoiding information loss about spatial distribution

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent transitions from one-dimensional average refractive index measurement to two-dimensional spatial mapping of refractive index values. By utilizing the phase contrast microscope's ability to capture spatially resolved phase information and converting it to refractive index distribution maps, the invention adds a spatial dimension to the measurement without significantly increasing operational complexity

Inventive Principle:

Principle #17Another dimension (Dimensionality change)

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 accurate, non-invasive measurement of refractive index distributions in live cells and tissues, allowing for the investigation of time-dependent changes and providing diagnostic information for conditions like cancerous tissue.

Implementation Method 1

A heterodyne interferometer is used to measure the phase shift of light transmitted through the cell

Methodology Applied

Scientific EffectInterference: Interference

Implementation Method 2

An acousto-optic modulator frequency shifts the reference light beam

Methodology Applied

Scientific EffectAcousto-optic effect: Acousto-optic Effect

Implementation Method 3

A tomographic reconstruction algorithm calculates the three-dimensional refractive index distribution from multiple two-dimensional phase projections

Methodology Applied

Scientific EffectTomography: Tomography

Data Source

PatentUS9546952B2Distribution of refractive index measurement by synthetic aperture tomography

Publication Date: 2017.01.17 MASSACHUSETTS INST OF TECH

AI summary

The present invention relates to systems and methods for quantitative three-dimensional mapping of refractive index in living or non-living cells, tissues, or organisms using a phase-shifting laser interferometric microscope with variable illumination angle. A preferred embodiment provides tomographic imaging of cells and multicellular organisms, and time-dependent changes in cell structure and the quantitative characterization of specimen-induced aberrations in high-resolution microscopy with multiple applications in tissue light scattering.