Zero-Length Cross-Linked HA Hydrogels for Stable, Easy Injection
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Solution Overview
Problem
Current hydrogel synthesis strategies for dermal fillers face challenges in achieving stable, elastic properties while maintaining ease of injection through fine gauge needles, as they often result in hydrolyzed HA chains and introduction of small molecule linkers under basic conditions.
Innovation Solution
Cross-linking hyaluronic acid (HA) with zero-length cross-linking agents like EDC at neutral pH, optionally with NHS, to form hydrogels, which can include additional biocompatible polymers such as elastin, and incorporating active agents, with a method involving buffered solutions and dialysis to remove by-products.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If HA-based fillers are made highly viscous to exhibit desirable stability properties in vivo, then stability is improved, but ease of injection through fine gauge needles deteriorates
Solution Approach 1:
The patent applies parameter changes by adjusting the molecular weight distribution of hyaluronic acid and modifying cross-linking density to achieve optimal balance between stability and injectability. Specifically, using high molecular weight HA (average MW ≥ 1,000,000 g/mol) and controlling cross-linking parameters enables the filler to maintain stability while reducing viscosity for easier injection.
Solution Approach 2:
The patent employs composite materials by combining hyaluronic acid with complementary polymers or proteins to create a multi-component filler system. This composite approach allows the formulation to exhibit both stable in vivo properties and improved rheological characteristics for ease of injection, as the composite structure can be engineered to balance these competing requirements.
2Strength
If cross-linking is performed under basic conditions using small molecules, then cross-linking is achieved, but HA chains hydrolyze into shorter fragments and small molecule linkers are introduced
Solution Approach 1:
The patent applies parameter changes by shifting from basic conditions to neutral or slightly acidic pH for cross-linking, and using zero-length cross-linking agents instead of small molecule linkers. This changes the chemical parameters of the cross-linking process to prevent HA chain hydrolysis while maintaining effective cross-linking, thereby preserving molecular weight and avoiding introduction of small molecule linkers.
Solution Approach 2:
The patent uses zero-length cross-linking agents that form stable cross-links without leaving persistent small molecule linkers in the final product. These cross-linking agents act temporarily during the cross-linking process but do not remain as permanent structural components, thus avoiding the problem of small molecule linker accumulation while maintaining cross-linking strength.
3Object-affected harmful factors
If human-derived collagen filler compositions are used, then allergic reaction risk is reduced, but degradation rate increases
Solution Approach 1:
The patent employs composite materials by combining hyaluronic acid with complementary polymers or proteins to create a multi-component filler system. This composite approach allows the formulation to exhibit both stable in vivo properties and improved rheological characteristics for ease of injection, as the composite structure can be engineered to balance these competing requirements.
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 resulting hydrogels exhibit improved rheological properties, high molecular weight retention, and reduced extrusion forces, making them suitable for soft tissue augmentation with enhanced stability and comfort during injection.
Implementation Method 1
Cross-linking hyaluronic acid (HA) with zero-length cross-linking agents like EDC at neutral pH
Implementation Method 2
HA has the ability to bind to large amounts of water, making it an excellent volumizer of soft tissues
Data Source
AI summary
Disclosed herein are cohesive soft tissue fillers, for example, dermal and subdermal fillers, based on hyaluronic acids and optionally including proteins. In one aspect, hyaluronic acid-based compositions described herein include zero-length cross-linked moieties and optionally at least one active agent. The present hyaluronic acid-based compositions have enhanced flow characteristics, hardness, and persistence compared to known hyaluronic acid-based compositions. Methods and processes of preparing such hyaluronic acid-based compositions are also provided.