Thiol-Modified Hyaluronan Hydrogel Without External Crosslinkers

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Solution Overview

Problem

Existing hyaluronan-based dermal fillers face issues with rapid in vivo degradation due to enzymatic and chemical degradation, leading to safety concerns and limitations in dosage, and require harsh reaction conditions for crosslinking, which can degrade the molecular weight and cause adverse effects.

Innovation Solution

A thiol-modified hyaluronan with disulfide crosslinks formed by oxidation, using amino acid residues with basic side chains and conjugated terminal amino-thiols, eliminating the need for external crosslinking agents and allowing for controlled rheological properties and extended residence time.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If chemical crosslinking agents (BDDE, DVS) are used to improve resistance to degradation, then stability and durability are improved, but genotoxic effects and safety risks increase

Engineering Contradiction:

Improveresistance to degradationVSAvoidgenotoxic effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention extracts and eliminates the harmful external crosslinking agents (BDDE, DVS) from the system by using endogenous thiol groups naturally present in hyaluronan for crosslinking, thereby removing the source of genotoxic effects while maintaining crosslinking functionality

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The hyaluronan molecules perform self-crosslinking through their own thiol groups without requiring external crosslinking agents, making the system self-sufficient and eliminating harmful foreign substances from the formulation

Inventive Principle:

Principle #25Self-service

2Productivity

If harsh reaction conditions (alkaline pH, high temperature) are applied to achieve adequate crosslinking, then crosslinking efficiency is improved, but molecular weight decreases due to hydrolytic degradation

Engineering Contradiction:

Improvecrosslinking efficiencyVSAvoidmolecular weight

Core Design Contradiction:

ProductivityVSManufacturing precision

Solution Approach 1:

The invention changes the reaction parameters from harsh conditions (alkaline pH, high temperature) to mild physiological conditions (neutral pH, room temperature) by utilizing the natural thiol-disulfide oxidation reaction, thereby achieving crosslinking without molecular weight degradation

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention substitutes the chemical crosslinking mechanism requiring harsh conditions with a biochemical oxidation mechanism (thiol to disulfide) that proceeds under mild conditions, replacing the need for extreme pH and temperature control

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

3Duration of action of moving object

If conventional crosslinking methods are used to extend residence time, then duration of action is improved, but viscosity increases and biocompatibility decreases

Engineering Contradiction:

Improveresidence timeVSAvoidadverse effects

Core Design Contradiction:

Duration of action of moving objectVSObject-affected harmful factors

Solution Approach 1:

The invention maintains homogeneity by using the same hyaluronan material for both the base polymer and crosslinking functionality, ensuring uniform biocompatibility throughout the formulation without introducing heterogeneous foreign substances

Inventive Principle:

Principle #33Homogeneity

Solution Approach 2:

The thiol groups on hyaluronan self-crosslink to extend residence time without requiring external agents, thereby prolonging duration of action while maintaining biocompatibility through endogenous components only

Inventive Principle:

Principle #25Self-service

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

The thiol-modified hyaluronan compositions exhibit lower viscosity, enabling higher concentrations and prolonged in vivo residence time, with improved biocompatibility and reduced adverse effects, facilitating safer and more effective soft tissue filler applications.

Implementation Method 1

a crosslinked polymer, wherein the crosslinked polymer is an oxidation product of the thiol-modified hyaluronan

Methodology Applied

Scientific EffectOxidation: Oxidation

Data Source

PatentUS12428499B2Thiol-modified hyaluronan and hydrogel comprising the crosslinked hyaluronan

Publication Date: 2025.09.30 CROMA PHARMA GMBH

AI summary

A thiol-modified hyaluronan, wherein the thiol-modified hyaluronan comprises a plurality of modification groups with a thiol-group in the hyaluronan side-chains, wherein the modification group comprises an amino acid residue with basic side chain and a conjugated terminal naturally occurring amino-thiol as well as a sterile hydrogel composition comprising a crosslinked polymer, wherein the crosslinked polymer is an oxidation product of the thiol-modified hyaluronan and uses of the composition.