Corneal Collagen Crosslinking Using Sugars Under Low-Oxygen Conditions

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Solution Overview

Problem

Existing corneal crosslinking methods, such as the Dresden protocol, face challenges due to cytotoxic effects on stromal keratocytes and endothelium cells, require epithelial removal, and are oxygen-dependent, limiting their effectiveness in reshaping the cornea for conditions like keratoconus and myopia.

Innovation Solution

A method involving the use of ribose and UV-A light or a femtosecond laser for crosslinking corneal tissues, which accelerates glycation-mediated crosslinking without oxygen dependence, allowing for corneal stiffening or flattening through mechanical loading.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If riboflavin-mediated CxL is performed using the Dresden protocol, then corneal crosslinking is achieved, but cytotoxic effects occur on stromal keratocytes and endothelium cells

Engineering Contradiction:

Improvecrosslinking effectivenessVSAvoidcytotoxic effects on cells

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent removes riboflavin and oxygen from the crosslinking system, replacing them with sugar-based crosslinking agents that do not produce cytotoxic ROS. This extraction of harmful components eliminates cell damage while preserving crosslinking effectiveness.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent uses sugars (glucose, fructose, sucrose) as temporary crosslinking agents that are metabolically compatible and non-toxic. These sugars serve their crosslinking function and are then naturally metabolized by the cornea, avoiding long-term cytotoxicity.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

2Productivity

If epithelium removal is performed to enable R5P absorption, then crosslinking efficiency is improved, but tissue invasion and complexity increase

Engineering Contradiction:

Improvecrosslinking efficiencyVSAvoidprocedure complexity

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The patent employs sugars that can penetrate the intact corneal epithelium through natural transport mechanisms. The cornea's own metabolic systems facilitate sugar uptake and utilization, eliminating the need for surgical epithelium removal while maintaining crosslinking efficiency.

Inventive Principle:

Principle #25Self-service

3Reliability

If oxygen is supplied for riboflavin activation, then crosslinking reaction proceeds, but harmful ROS generation increases

Engineering Contradiction:

Improvecrosslinking reaction efficiencyVSAvoidROS generation

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent extracts oxygen from the crosslinking reaction system, using sugars that can undergo Maillard reaction and form crosslinks under anaerobic or low-oxygen conditions. This eliminates the source of harmful ROS generation while maintaining crosslinking effectiveness.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent converts the normally harmful oxidative pathway into a beneficial reductive glycation pathway. By using sugar-based crosslinking under low-oxygen conditions, the system achieves crosslinking through a mechanism that is inherently less harmful to corneal tissues.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

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

Achieves significant corneal stiffening or flattening, with biomechanical properties comparable to traditional methods, and potential for non-invasive vision correction, as demonstrated by increased equilibrium modulus and sustained diopter changes.

Implementation Method 1

illuminating the tissue with any one or more of UV-A light or a femtosecond laser, the illuminating being performed under conditions sufficient to give rise to crosslinking within the tissue

Methodology Applied

Scientific EffectPhotochemical reaction: Photopolymerisation

Implementation Method 2

Riboflavin-mediated CxL halts the progression of keratoconus by introducing intra and intermolecular chemical bond formation within the collagen fibril-comprised stromal extracellular matrix (ECM)

Methodology Applied

Scientific EffectGlycation: Chemical Bonding

Data Source

PatentUS20250381274A1Methods for crosslinking of collagenous tissue

Publication Date: 2025.12.18 THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK

AI summary

Methods of crosslinking collagenous tissue include contacting the tissue with a sugar; and illuminating the tissue with any one or more of UV-A light or a femtosecond laser, the illuminating being performed under conditions sufficient to give rise to crosslinking within the tissue is a method of treating a tissue of a cornea. Method of treating a tissue of a cornea include restricting oxygen replenishment of the tissue; contacting the tissue with a sugar; and illuminating the tissue with at least one of UV-A light or a femtosecond laser, the illuminating being performed under conditions sufficient to give rise to crosslinking within the tissue. Methods of treating a collagenous tissue include contacting the tissue with a sugar; and illuminating the tissue with any one or more of UV-A light or a femtosecond laser, the illuminating being performed under conditions sufficient to give rise to crosslinking within the tissue.