Cross-Linked HA Hydroxyapatite Gel for Controlled Degradation
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Solution Overview
Problem
Existing hyaluronic acid-based materials face challenges with poor in-vivo stability, enzymatic degradation, and lack of controlled degradation resistance, spatial swelling behavior, rheological properties, mechanical stability, biocompatibility, and reduced side-effects.
Innovation Solution
A composite material is produced by cross-linking hyaluronic acid in multiple steps and adding hydroxyapatite in multiple stages, resulting in a gel with dispersed hydroxyapatite particles having varying degrees of association within the HA matrix, providing improved properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If hyaluronic acid is chemically modified to improve in-vivo stability, then stability is improved, but complexity of modification process increases
Solution Approach 1:
The patent applies preliminary action by pre-crosslinking hyaluronic acid with BDDE before adding hydroxyapatite particles. This preliminary crosslinking step creates a stable HA matrix that prevents enzymatic degradation, and then hydroxyapatite is incorporated into this pre-formed network. The crosslinking reaction is initiated by raising pH to above 11, allowing the HA to be modified in advance before final assembly with the ceramic particles.
2Ease of manufacture
If hydroxyapatite is added in single step to hyaluronic acid gel, then manufacturing is simple, but homogeneous distribution of particles is difficult to achieve
Solution Approach 1:
The patent applies segmentation by dividing the hydroxyapatite addition into multiple sequential steps. First, hydroxyapatite particles are added to the hyaluronic acid solution before crosslinking occurs. After crosslinking is complete and the gel structure is formed, additional hydroxyapatite particles are added to the finished gel. This segmented approach ensures homogeneous distribution throughout the matrix while maintaining manufacturing feasibility.
3Strength
If cross-linking of hyaluronic acid is performed to improve mechanical stability, then mechanical strength is improved, but control over degradation rate becomes difficult
Solution Approach 1:
The patent applies parameter changes by systematically varying the concentration of BDDE crosslinker (from 0.1% to 10% relative to HA), the pH level during crosslinking (maintained above 11), and the amount of hydroxyapatite added in two different steps. These parameter adjustments allow precise control over the degree of crosslinking and particle distribution, thereby controlling both mechanical strength and degradation rate. The dual-step hydroxyapatite addition further fine-tunes the degradation profile.
4Reliability
If multiple cross-linking agents are used to achieve desired gel properties, then gel performance is improved, but manufacturing complexity increases
Solution Approach 1:
The patent applies the taking out principle by isolating and using a single crosslinking agent, BDDE (1,4-butanediol diglycidyl ether), rather than combining multiple crosslinkers. This extraction of the crosslinking function to a single well-characterized reagent simplifies the manufacturing process while maintaining gel performance. The BDDE crosslinker is used in controlled amounts with precise pH control, eliminating the need to manage multiple crosslinking reactions simultaneously.
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 composite material exhibits enhanced stability, controlled degradation, and improved rheological and mechanical properties, while maintaining biocompatibility, suitable for cosmetic, medical, and pharmaceutical applications.
Implementation Method 1
combining in an aqueous medium hyaluronic acid or a salt thereof, a cross-linking agent, and conducting a cross-linking reaction
Implementation Method 2
incorporating a second portion of hydroxyapatite into the so-formed gel
Data Source
AI summary
Provided herein are the compositions and methods of manufacturing of injectable gels of cross-linked hyaluronic acid associated to a varying degree with hydroxyapatite.