Stabilized Hyaluronic Acid Hydrogels with Low-Molecular-Weight Extractables
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Solution Overview
Problem
Existing hyaluronan-based soft tissue fillers face issues with rapid in vivo degradation due to enzymatic and chemical degradation, leading to the formation of low molecular weight fragments that can cause inflammatory reactions and require harsh crosslinking conditions, which may compromise biocompatibility and safety.
Innovation Solution
A sterile hydrogel composition comprising crosslinked hyaluronan with a low content of extractable hyaluronan below 200 kDa, using endogenous linkers like thiol groups to form disulfide bonds under mild conditions, ensuring high biocompatibility and resistance to degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chemical crosslinking agents like BDDE are used to stabilize hyaluronan, then resistance to degradation is improved, but genotoxic effects and foreign body reactions occur
Solution Approach 1:
The patent uses transglutaminase as an enzymatic intermediary to catalyze crosslinking between hyaluronan molecules and glutamine-containing peptides. This enzymatic mediator enables stable crosslinking without requiring toxic chemical agents like BDDE, thus achieving degradation resistance while avoiding genotoxic effects
Solution Approach 2:
The patent changes the crosslinking mechanism from chemical reactions (using BDDE) to enzymatic reactions (using transglutaminase). This parameter change in the crosslinking method allows for stable hyaluronan networks without the harmful side effects of chemical crosslinking agents
2Productivity
If harsh crosslinking conditions (high temperature, alkaline pH) are applied, then crosslinking efficiency is improved, but hyaluronan degradation occurs
Solution Approach 1:
The patent changes the reaction conditions from harsh chemical crosslinking (high temperature, extreme pH) to mild enzymatic crosslinking (physiological temperature, neutral pH). The transglutaminase enzyme remains active under these mild conditions, achieving efficient crosslinking without hyaluronan degradation
Solution Approach 2:
The patent replaces the mechanical/chemical crosslinking system (requiring high energy input) with a biological enzymatic system. The transglutaminase enzyme provides the necessary catalytic activity under mild conditions, substituting the need for harsh physical and chemical parameters
3Reliability
If low molecular weight hyaluronan fragments are formed, then degradation resistance is reduced, but inflammatory reactions are triggered
Solution Approach 1:
The patent uses the natural substrate specificity of transglutaminase to selectively crosslink hyaluronan without generating harmful low molecular weight fragments. The enzymatic reaction pathway is designed to maintain polymer integrity, converting the potential harm of degradation into the benefit of stable, non-inflammatory crosslinked structures
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 composition provides improved biocompatibility and resistance to degradation, allowing for larger doses and wider applications, including cosmetic uses, while minimizing inflammatory reactions and maintaining molecular weight integrity.
Implementation Method 1
using endogenous linkers like thiol groups to form disulfide bonds under mild conditions
Data Source
AI summary
Sterile hydrogel composition comprising crosslinked hyaluronan, wherein the amount of extractable hyaluronan having a molecular weight of less than 200 kDa is less than 15 wt. % relative to the total amount of hyaluronan.