If you compare a syringe of Juvéderm Voluma XC to a syringe of Restylane Refyne, you are looking at two products made from the same base molecule — hyaluronic acid (HA) — that behave very differently once injected. One provides structural lift for the cheeks. The other flexes with dynamic movement around the mouth. The difference is not the ingredient. It is the engineering.
Understanding how HA fillers are manufactured, what cross-linking actually does, and why properties like G-prime and cohesivity matter helps patients ask better questions and gives providers a framework for choosing the right product for each anatomical area.
What Hyaluronic Acid Is — and Why It Needs Help
Hyaluronic acid is a polysaccharide — a long-chain sugar molecule — found naturally in human skin, joints, eyes, and connective tissue. A single gram of HA can bind up to six liters of water, which is why it provides the skin with hydration, volume, and structural support.
But natural HA has a half-life of less than three days in tissue. The body breaks it down rapidly using an enzyme called hyaluronidase. If you injected pure, unmodified HA into the skin, it would be absorbed within days — useless as a filler.
The solution is cross-linking: chemically bonding individual HA chains together to form a three-dimensional network that resists degradation. This is the foundational technology behind every modern HA dermal filler.
Cross-Linking: The Core Technology
The most commonly used cross-linking agent in FDA-approved HA fillers is 1,4-butanediol diglycidyl ether (BDDE). BDDE forms covalent bonds between HA chains, creating a gel network that resists enzymatic breakdown and mechanical deformation.
How BDDE cross-linking works
HA fermentation. The starting material is HA produced by bacterial fermentation of Streptococcus equi — identical in molecular structure to human HA regardless of species or source.
Cross-linking reaction. BDDE is added to the HA solution under alkaline conditions (pH > 7). The epoxy groups at both ends of the BDDE molecule react with hydroxyl groups on the HA chains, forming stable ether bonds that link separate HA strands together.
Gel formation. The cross-linked HA becomes a cohesive, viscoelastic hydrogel — a three-dimensional network that behaves as both a liquid and a solid depending on the forces applied to it.
Purification. Unreacted BDDE is removed. Residual BDDE levels must be minimized because the compound is cytotoxic in its unreacted form. Reputable manufacturers ensure only trace amounts remain in the final product — typically less than 2 parts per million.
Cross-linking degree matters
The degree of cross-linking — how many bonds connect the HA chains — directly affects gel properties:
- Higher cross-linking creates a denser, firmer gel with greater resistance to deformation. These gels provide more structural lift but are harder to inject and may feel firmer under the skin.
- Lower cross-linking creates a softer, more malleable gel that integrates more easily into tissue but provides less lift and may have shorter duration.
However, cross-linking is not the only variable. The total degree of modification (DoM) includes both cross-links and "pendant" modifications — where BDDE bonds to only one HA strand, leaving the other end free. Pendant modifications minimally affect gel firmness but can increase swelling and the risk of foreign-body reactions.
Manufacturing Technologies: NASHA, Vycross, OBT, and Beyond
After cross-linking, each manufacturer uses proprietary technology to process the gel into its final form. This is where the major product families diverge.
NASHA (Non-Animal Stabilized Hyaluronic Acid) — Restylane Family
NASHA technology, developed by Q-Med (now Galderma), was the first HA filler manufacturing process. After cross-linking, the gel block is pushed through screens of various sizes to create particles. Products are differentiated by particle size:
| Product | Particle Concentration | G' (Pa) | Primary Use |
|---|---|---|---|
| Restylane Silk | ~200,000 particles/mL | 416 | Lips, fine lines |
| Restylane-L | ~100,000 particles/mL | 701 | Moderate wrinkles, folds |
| Restylane Lyft | ~8,000 particles/mL | 799 | Cheeks, hands, deep volume |
NASHA products are particulate — they consist of discrete gel particles suspended in a carrier fluid. This gives them high G-prime (firmness) but lower cohesivity. They tend to hold their shape well and provide good lift, making them suitable for structural support in areas like the cheeks, chin, and jawline.
Vycross — Juvéderm Family
Vycross technology, developed by Allergan (now AbbVie), mixes HA of different molecular weights — both high and low — before cross-linking. The result is a tightly packed, homogeneous gel:
| Product | HA Concentration | G' (Pa) | Primary Use |
|---|---|---|---|
| Juvéderm Volbella XC | 15 mg/mL | Low (~45) | Lips, fine lines |
| Juvéderm Vollure XC | 17.5 mg/mL | Moderate (~115) | Moderate wrinkles |
| Juvéderm Voluma XC | 20 mg/mL | Higher (~210) | Cheeks, mid-face volume |
| Juvéderm Volux XC | 23.5 mg/mL | Highest (~320) | Jawline, chin |
Vycross products are non-particulate (monophasic) — a smooth, homogeneous gel with higher cohesivity than NASHA products. They integrate more uniformly into tissue and tend to spread less, which can mean less post-injection swelling in some patients. The range of HA concentrations and cross-linking densities across the Vycross line allows product selection matched to anatomical needs.
Hylacross — Earlier Juvéderm Products
Juvéderm Ultra and Ultra Plus use Hylacross technology, an earlier generation that uses only high-molecular-weight HA with high cross-linking and cohesivity. These products have intermediate G' values and remain widely used for nasolabial folds and lip augmentation.
OBT (Optimal Balance Technology) — Restylane Refyne, Kysse, Defyne
OBT is Galderma's newer technology that creates flexible, lower-G' gels designed for dynamic facial areas. The key differentiator is not just firmness but flexibility — measured by xStrain, the ability of a gel to deform under stress and return to its original shape:
| Product | G' (Pa) | xStrain (%) | Primary Use |
|---|---|---|---|
| Restylane Refyne | 70 | 1,442 | Fine lines, dynamic areas |
| Restylane Kysse | 160 | 908 | Lips |
| Restylane Defyne | 271 | 761 | Deep folds, dynamic areas |
For comparison, NASHA products have xStrain values of 7–19% — they resist deformation strongly but do not flex. OBT products can deform up to 1,442% before yielding, making them appropriate for areas of constant facial movement.
Other Technologies
- Cohesive Polydensified Matrix (CPM) — Belotero Balance uses varying densities of cross-linking within the same gel, creating zones of different firmness. This allows the gel to integrate smoothly at multiple tissue depths.
- RHA (Resilient Hyaluronic Acid) — The RHA Collection (Revance Therapeutics, now Crown Laboratories) is designed to mimic the natural HA in skin, with minimal chemical modification and high resilience to stretching. RHA products are FDA-approved for dynamic wrinkles and folds.
- Preserved Network (PN) Technology — Teoxane's Teosyal range uses a manufacturing process that preserves a natural HA network during cross-linking, maintaining high elasticity alongside firmness. The technology aims to retain more of HA's natural viscoelastic properties while still achieving clinical duration.
Emerging: Self-Crosslinking HA
A newer category under development uses self-crosslinking hyaluronic acid (SC-HA), which eliminates the need for chemical cross-linkers like BDDE entirely. SC-HA uses modified HA conjugates with gallol (catechol) moieties that form cross-links through oxidation in vivo — after injection, the gel cross-links itself through exposure to the body's active oxygen. Early-stage research published in MDPI Polymers (2024) demonstrates viable gel formation and biocompatibility, but no SC-HA filler has received FDA approval as of mid-2026. This technology could eventually address the BDDE residual safety question at its source, though clinical data remains limited.
G-Prime (G'): The Stiffness Metric
G-prime (written G') is the elastic modulus — a measure of how much a gel resists deformation and bounces back when force is applied. It is measured in pascals (Pa) using a rheometer.
Practical translation:
- High G' (400–800+ Pa): Firm gels that hold shape and provide structural lift. Best for deep placement — cheeks, chin, jawline, nose. Examples: Restylane Lyft, Restylane-L.
- Moderate G' (100–300 Pa): Mid-range gels that balance lift and flexibility. Best for moderate wrinkles and folds. Examples: Juvéderm Voluma XC, Restylane Defyne.
- Low G' (<100 Pa): Soft, spreadable gels that integrate into superficial tissue. Best for fine lines, lips, under-eyes. Examples: Juvéderm Volbella XC, Restylane Refyne.
G' is important, but it is not the whole story. Two fillers with similar G' values can behave differently depending on their cohesivity, swelling factor, and manufacturing technology.
Cohesivity and Swelling Factor
Cohesivity
Cohesivity describes how well the gel holds together as a unit. A highly cohesive gel maintains its shape as a single mass after injection. A less cohesive gel may fragment into smaller pieces.
- High cohesivity (Vycross, Hylacross): The gel stays together, providing uniform tissue expansion and less risk of visible lumps. But it may spread more from the injection site.
- Low cohesivity (NASHA): Particulate gels that may be more palpable but resist migration and maintain position well.
Swelling factor
All HA fillers absorb water after injection — this is the hydrophilic nature of HA. The degree of swelling varies by product:
- Higher swelling (Hylacross products): Draws in more water, which can provide additional volumization but also increases the risk of post-injection edema, particularly in areas prone to puffiness like the under-eyes.
- Lower swelling (NASHA products): Less water uptake means more predictable immediate results but may require slightly more product to achieve the same volumization.
How All of This Affects You
For patients
When your injector chooses a product, they are balancing these properties against your anatomy:
- Cheeks and mid-face: High G', high cohesivity products (Juvéderm Voluma XC, Restylane Lyft) for structural lift.
- Lips: Moderate to low G', high flexibility (Restylane Kysse, Juvéderm Volbella XC) for natural movement.
- Nasolabial folds and dynamic wrinkles: Flexible products (Restylane Defyne, Restylane Refyne) that move with facial expression.
- Under-eyes (tear troughs): Low G', low swelling products to minimize puffiness and visible product.
The same "filler" — HA with BDDE cross-linking — can produce very different results depending on which specific product is used and where it is placed. Choosing an injector who understands rheology and selects products based on anatomical requirements, not just brand loyalty, is a significant factor in outcome quality.
For providers
Product selection should be driven by the rheological demands of the anatomical area, not marketing materials:
- Match G' to depth. Deep, structural placement requires firm gels. Superficial placement requires soft gels. Placing a high-G' product superficially creates visible ridges and Tyndall effect.
- Consider cohesivity in mobile areas. Highly cohesive gels may migrate in areas of constant movement. Particulate or lower-cohesivity products tend to stay where placed.
- Account for swelling. If a patient is prone to edema (common around the eyes), choose a low-swelling product and counsel them about expected post-treatment appearance.
- Understand reversibility. Highly cross-linked gels are more resistant to hyaluronidase dissolution. If you anticipate the need for correction (e.g., first-time filler patients), a lower cross-linking density may offer more forgiving management.
Hyaluronic Acid Beyond Aesthetics
The same molecule that provides volume and hydration in dermal fillers plays a critical role in veterinary medicine. Hyaluronic acid is a major component of synovial fluid in joints, and intra-articular HA injections have been used to treat osteoarthritis in horses and dogs for decades.
FDA-approved veterinary HA products include Legend (hyaluronate sodium, Boehringer Ingelheim) and NexHA (Vetoquinol), both approved for the treatment of joint dysfunction in horses due to non-infectious synovitis associated with equine osteoarthritis. These products are regulated by FDA's Center for Veterinary Medicine (CVM) under New Animal Drug Applications (NADAs), a separate pathway from the Center for Drug Evaluation and Research (CDER) approval process that governs human dermal fillers. The science underlying both applications — HA's viscoelastic properties, biocompatibility, and anti-inflammatory effects — is the same. For veterinary HA product regulation, joint therapy protocols, and animal-health drug guidance, VetMedGuide covers veterinary medicine and animal-health regulation, including veterinary device classification and veterinary drug approval pathways.
The Bottom Line
All HA fillers start from the same molecule. What makes them different is the engineering: how they are cross-linked, processed, and formulated. Cross-linking degree determines durability and firmness. Manufacturing technology (NASHA, Vycross, OBT, CPM, RHA) determines whether a filler is particulate or smooth, firm or flexible, cohesive or spreadable. G' quantifies stiffness. Cohesivity describes structural integrity. Swelling factor predicts water absorption.
These are not marketing distinctions — they are material science properties that directly affect clinical outcomes. Patients benefit from understanding that "hyaluronic acid filler" is not a single product but a category of engineered materials, each designed for specific anatomical demands. Providers benefit from selecting products based on rheological properties rather than brand familiarity alone.
Sources
- Edsman K, Nord LI, Ohrlund A, et al. "Gel Properties of Hyaluronic Acid Dermal Fillers." Dermatologic Surgery. 2012;38(7 Pt 2):1170-1179. https://pubmed.ncbi.nlm.nih.gov/22909086/
- Ohrlund A, Winlof P, Bromee T, Prygova I. "Differentiation of NASHA and OBT Hyaluronic Acid Gels According to Strength, Flexibility, and Associated Clinical Significance." Journal of Drugs in Dermatology. 2024;23(1):1332. https://jddonline.com/articles/differentiation-of-nasha-and-obt-hyaluronic-acid-gels-according-to-strength-flexibility-and-associated-clinical-significance-S1545961624P1332X
- de la Guardia C, et al. "Rheologic and Physicochemical Characteristics of Hyaluronic Acid Fillers: Overview and Relationship to Product Performance." Facial Plastic Surgery. 2022;38(2):116-123. https://pmc.ncbi.nlm.nih.gov/articles/PMC9188840/
- Kablik J, Monheit GD, Yu L, Chang G, Gershkovich J. "Comparative Physical Properties of Hyaluronic Acid Dermal Fillers." Dermatologic Surgery. 2009;35(Suppl 1):302-312. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1524-4725.2008.01046.x
- Tezel A, Fredrickson GH. "The Science of Hyaluronic Acid Dermal Fillers." Journal of Cosmetic and Laser Therapy. 2008;10:35-42.
- Guarise C, et al. "Comparative Physicochemical Analysis among 1,4-Butanediol Diglycidyl Ether Cross-Linked Hyaluronic Acid Dermal Fillers." MDPI Polymers. 2021;13(19):2739. https://pmc.ncbi.nlm.nih.gov/articles/PMC8482174/
- Mesoestetic, "What Is Cross-Linked Hyaluronic Acid and Why Is It Used in Aesthetic Medicine?" https://www.mesoestetic.com/blog/cross-linked-hyaluronic-acid
- U.S. FDA, "Dermal Fillers (Soft Tissue Fillers)." https://www.fda.gov/medical-devices/aesthetic-cosmetic-devices/dermal-fillers-soft-tissue-fillers
- Boehringer Ingelheim Animal Health, "LEGEND (hyaluronate sodium) Prescribing Information." https://animalhealth.boehringer-ingelheim.com/equine/joint-health/legend
- Vetoquinol USA, "NexHA (hyaluronate sodium) Injectable Solution." https://usanexha.com
- Virbac, "Hyaluronic Acid: Molecular Mechanisms and Therapeutic Trajectory." https://vet-pl.virbac.com/files/live/sites/virbac-b2b-pl/files/pictures/Mobility/Movoflex%20product%20page/Hyaluronic%20acid.pdf
