Hyaluronic Acid Dermal Filler Hydrogels With Balanced Particle Sizing
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Solution Overview
Problem
The current preparation process for hyaluronic acid (HA) dermal fillers is time-consuming and lacks efficient methods for optimizing the steps involved in crosslinking, particle sizing, and formulation to achieve a wide range of rheological and physicochemical properties.
Innovation Solution
The Particle Balance Technology (PBT) employs a low BDDE-HA molar ratio of 0.075:1 and uses a planetary centrifuge for intensified crosslinking, combined with sieving and ultra-turrax equipment for particle sizing, to produce HA hydrogels with balanced particle sizes and compositions, allowing for a wide range of rheological and physicochemical properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If conventional mechanical mixing with impeller is used for crosslinking, then the process is simple to operate, but the crosslinking reaction is slow and processing time is long
Solution Approach 1:
The patent replaces conventional mechanical impeller mixing with ultrasonic cavitation technology. The ultrasonic waves generate cavitation bubbles that collapse and create intense local mixing and shear forces, dramatically accelerating the crosslinking reaction between HA and BDDE without requiring complex mechanical mixing systems, thus reducing processing time while maintaining ease of operation.
Solution Approach 2:
The patent employs periodic ultrasonic pulsing during the crosslinking process. By applying ultrasonic energy in controlled pulses rather than continuous operation, the method intensifies the crosslinking reaction during active phases while allowing brief intervals for heat dissipation and reaction progression, thereby reducing overall processing time while maintaining product quality.
2Strength
If high BDDE-HA molar ratio is used for crosslinking, then the hydrogel has higher strength and stability, but the adverse effects from crosslinkers increase
Solution Approach 1:
By using ultrasonic cavitation instead of conventional mixing, the patent achieves more uniform and efficient crosslinking at lower BDDE concentrations. The cavitation-induced micro-mixing ensures thorough contact between HA and BDDE molecules, maximizing crosslinking efficiency and reducing the need for excess crosslinker, thereby decreasing adverse effects while maintaining hydrogel strength.
Solution Approach 2:
The patent changes the crosslinking parameters by using lower BDDE-HA molar ratios (0.05:1 to 0.1:1) combined with ultrasonic treatment. This parameter change achieves effective crosslinking with minimal crosslinker, reducing residual BDDE and associated adverse effects while maintaining adequate hydrogel strength and stability for dermal filler applications.
3Manufacturing precision
If multiple purification steps are used to remove impurities, then the purity of HA is high, but the process becomes time-consuming and complex
Solution Approach 1:
The patent combines the crosslinking reaction with the purification process. By performing crosslinking in the presence of impurities and then filtering the resulting hydrogel particles, multiple objectives (crosslinking and purification) are achieved in a single integrated step, significantly reducing purification time while maintaining high purity levels.
Solution Approach 2:
The patent performs preliminary crosslinking of HA before final purification. By initiating crosslinking early in the process and allowing hydrogel particles to form, subsequent filtration and washing steps can simultaneously remove impurities and unreacted crosslinker, reducing the number of separate purification steps required while achieving high purity.
4Reliability
If conventional crosslinking methods are used, then the process is well-established, but the production efficiency is low
Solution Approach 1:
The patent replaces conventional thermal or chemical crosslinking methods with ultrasonic cavitation crosslinking. This substitution maintains the reliability of the crosslinking process by achieving consistent hydrogel formation and desired rheological properties, while simultaneously dramatically improving production efficiency by reducing reaction time from hours to minutes.
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
This approach results in more efficient and less time-consuming production of HA dermal fillers with improved cohesiveness, viscoelasticity, and flexibility, suitable for various applications, including dermal filling and wrinkle treatment, while minimizing adverse effects from crosslinkers.
Implementation Method 1
uses a planetary centrifuge for intensified crosslinking
Implementation Method 2
BDDE forms covalent bonds with the hydroxyl groups on the HA disaccharides
Implementation Method 3
uses sieving and ultra-turrax equipment for particle sizing
Data Source
Figure 1(A)~1(B)
Figure 2
Figure 3
AI summary
The invention relates to a process for fabricating Hyaluronic Acid (HA) injectable dermal fillers. The process consists of crosslinking HA of high molecular weight (MW), particularly 106 Da, with the crosslinking agent 1,4-butanediol diglycidyl ether (BDDE) with a lower amount of BDDE through an intensified reaction in a planetary centrifuge under vacuum or with higher BDDE amount in a conventional and less efficient process that uses mechanical stirring for the reaction and an ultra-turrax equipment for particle sizing. The processes generate HA hydrogels with only one degree of crosslinking that can be used to fabricate a wide range of HA dermal fillers with varied HA concentrations and particle size combinations. HA dermal fillers manufactured herein are based on a new technology called particle balance technology (PBT), in which hydrogels with an extensive range of physicochemical and rheological properties can be obtained through the combination of large and small particle sizes. Besides being used in medical surgery and orthopedic applications, these hydrogels can be used for dermal filling, body and face contouring, skin volumization, and hydration.