Ultrasonic Polymerization of Hydrogels: Protocol and Scale-Up

Ultrasound-induced polymerization offers a radical-free, initiator-free approach to synthesizing hydrogels from water-soluble vinyl monomers and macromonomers. This methodology exploits the sonochemical generation of radicals via cavitation and is ideally suited for biomedical applications where initiator residues must be avoided.

Hydrogels are three-dimensional, hydrophilic polymer networks capable of retaining substantial amounts of water while maintaining structural integrity — an attribute arising from crosslinked polymer chains. Their physicochemical properties — swelling behavior, mechanical strength, and biocompatibility — make them highly attractive for biomedical applications, including drug delivery, tissue engineering, and wound healing.

The Advantage of Ultrasonic Hydrogel Polymerization

Traditionally, hydrogel synthesis relies on thermal, photochemical, or chemical crosslinking; however, ultrasonic hydrogel synthesis is gaining significant traction as the sonication method offers a simple reagent-free, tunable, and greener approach. Ultrasonic hydrogel synthesis uses acoustic cavitation to promote polymerization and physical or chemical crosslinking without the need for external initiators. Notably, ultrasonication can also facilitate in situ nanoparticle dispersion or initiate radical reactions in aqueous media, making it a versatile tool for crafting multifunctional or nanocomposite hydrogels under mild conditions.

The video clip above demonstrates the ultrasonic synthesis of a hydrogel using the sonicator UP50H and a low molecular weight gelator. The result is a self-healing supramolecular hydrogel. (Study and movie: Rutgeerts et al., 2019)
 

Biocompatible Hydrogels with Sonication

In the quest for biocompatible hydrogels that can be formed cleanly, safely, and on-demand, traditional polymerization strategies often fall short. The work by Cass and colleagues presents an effective solution to this problem: a clean, initiator-free method for hydrogel synthesis using low-frequency ultrasound.

Their study explores the sonochemical polymerization of various water-soluble monomers, but one formulation stood out as particularly efficient and robust: a 5% dextran methacrylate (Dex-MA) solution in 70% glycerol-water, polymerized under ultrasound at a moderate intensity of 56 W/cm². Remarkably, this system yielded a fully formed hydrogel in just 6.5 minutes, achieving a monomer-to-polymer conversion of 72% — the highest among all formulations tested.

Acoustic Cavitation: The working principle of this method is based on a phenomenon as powerful as it is transient: acoustic cavitation. When subjected to power ultrasound, microscopic bubbles form and collapse violently in the liquid medium, generating localized hotspots where temperatures may briefly exceed 5000 Kelvin. These conditions induce homolytic cleavage of solvent molecules, producing a burst of reactive radicals. Unlike conventional polymerization, which depends on external initiators or heat, ultrasound delivers both the energy and the radicals needed to initiate polymerization — without exceeding physiologically relevant bulk temperatures.

Co-Solvent: The choice of glycerol as a co-solvent was not incidental. Beyond increasing the viscosity of the solution — a critical factor for enhancing cavitation intensity — glycerol itself acts as a radical co-donor. Its hydroxyl groups are known to produce relatively stable secondary radicals, thereby increasing radical lifetimes and promoting chain propagation. Additionally, the viscous glycerol-rich environment helps trap nascent polymer chains, reducing their solubility and shielding them from ultrasonic degradation, which can occur in more dilute aqueous systems.

Ultrasonic Polymerization: To characterize the progression of polymerization, the researchers used infrared spectroscopy, tracking the depletion of vinyl groups on Dex-MA over time. The characteristic absorption at 1635 cm⁻¹ — indicative of C=C double bonds — diminished rapidly during sonication, while the ester carbonyl stretch at 1730 cm⁻¹ remained constant, serving as an internal reference. These data confirmed not only rapid vinyl conversion but also a high degree of crosslinking, as evidenced by low swelling ratios and robust gel structures.

Analysis: Scanning electron microscopy further revealed the evolution of the gel’s microstructure. In early stages, the network featured large, open pores, but with continued sonication, these filled in with a denser secondary structure. By 15 minutes, the hydrogel displayed a homogeneously crosslinked morphology with tightly interconnected pores—a hallmark of well-formed biomedical gels.

Result: When compared to hydrogels produced with thermal free-radical initiators, the differences were striking. Although similar conversions could be achieved thermally, the resulting networks were more porous, less uniform, and exhibited higher swelling ratios—signs of a looser crosslinking architecture. Moreover, the thermal process required nitrogen purging, chemical additives, and higher temperatures, whereas the ultrasonic approach functioned at ambient temperature of just 37°C.

Perhaps the most intriguing aspect of this work is the observation that polymerization can continue even after ultrasound is stopped. The gel continued to cure and increase in strength over a 30-minute period following cessation of sonication. This suggests that persistent radical species or intermediate structures formed during sonication may continue to propagate polymer chains in the absence of further energy input — a behavior with potentially useful implications for in vivo applications.

Learn more about the advantages of ultrasonic hydrogel production!

Protocol: Ultrasonic Synthesis of Dextran Methacrylate (Dex-MA) Hydrogel using a Sonicator

To synthesize a covalently crosslinked Dex-MA hydrogel, high-intensity, low-frequency ultrasound is coupled into a glycerol/water solution. Temperature and ultrasound energy density are precisely controlled.
Below, we give you the instructions for the ultrasonic hydrogel synthesis at lab scale, which can be linearly scaled-up to large quantities.

Equipment and Materials

Equipment

• Hielscher UP200Ht Ultrasonic Processor (200 W, 26 kHz)
• Sonotrode S26d2 (tip diameter: 2 mm; recommended for small-scale volumes)
• Jacketed reaction vessel (50 mL), compatible with magnetic stirrer
• Circulating water bath (thermostatically controlled at 37°C)
• Temperature probe PT100 (included in the scope of delivery of the UP200Ht)
• Magnetic stirrer
• Analytical balance (±0.1 mg)
• Vacuum oven or lyophilizer

Chemicals

• Dextran Methacrylate (Dex-MA), ~20% methacrylation
• Glycerol, ≥99.5% (anhydrous)
• Deionized water

All reagents should be of analytical grade. Avoid oxygen-rich environments; degas solvents if possible.

Step-by-Step Procedure: Ultrasonic Hydrogel Polymerization

1. Preparation of Polymerization Mixture
   • Weigh 0.75 g of Dex-MA into a 50 mL jacketed reaction vessel.
   • Add 10.5 g glycerol and 3.75 g deionized water.
   • Stir the mixture magnetically at room temperature (~22 °C) for 5–10 minutes to dissolve Dex-MA completely. A slightly viscous, homogeneous solution should result.
   • Preheat the water bath to 37 °C and connect it to the jacketed vessel to maintain constant temperature.
2. Setup of Sonicator
   • Mount the S26d2 sonotrode to the UP200Ht and ensure a tight coupling.
   • Immerse the tip of the sonotrode into the reaction mixture. Avoid touching the vessel walls or bottom.
   • Place the temperature probe in the solution close to the sonotrode but not in direct contact. This allows you to use the integrated temperature control of the sonicator.
   • Set amplitude to 100%.
3. Ultrasonic Polymerization
   • Start stirring at 100–200 rpm to maintain gentle homogenization.
   • Begin sonication at the appropriate amplitude setting to deliver ~56 W/cm² for 6.5 minutes.
   • Maintain solution temperature at 37°C throughout. If the mixture begins to heat, increase the coolant flow or add ice to the water bath.
   • Gelation typically begins within 5–6 minutes. Viscosity will increase sharply.
   • If gelation occurs before 6.5 min, stop sonication to avoid excessive crosslinking or degradation.
4. Post-Processing and Purification
   • Immediately transfer the gel into 200 mL deionized water under vigorous stirring to leach out unreacted monomer and glycerol.
   • Stir for 30 minutes, then decant supernatant or filter.
   • Repeat washing 3 additional times using warm water (~60 °C) for improved diffusion.
   • Dry the gel under vacuum at 60°C for 8 hours, or lyophilize for porous structures.

 
The Result: A Biocompatible Hydrogel
You should obtain a transparent, robust hydrogel with high conversion (~70–75%), excellent crosslinking, and minimal residual monomer. The hydrogel will resist dissolution in water and exhibit a uniform structure upon drying.

 
Notes for Optimum Process Control

The Scale-Up: Linear and Simple with Sonication

In a field that increasingly demands precision, purity, and scalability, this ultrasonic method offers a compelling alternative. It is spatially controllable, tunable in real time, and compatible with continuous processing using modern ultrasonic inline systems.
Sonicators by Hielscher Ultrasonics deliver exact amplitudes and scale linearly from laboratory to production scale—making them ideal for translating such hydrogel systems into real-world therapeutic and diagnostic applications.

Design, Manufacturing and Consulting – Quality Made in Germany

Hielscher ultrasonicators are well-known for their highest quality and design standards. Robustness and easy operation allow the smooth integration of our ultrasonicators into industrial facilities. Rough conditions and demanding environments are easily handled by Hielscher ultrasonicators.

Hielscher Ultrasonics is an ISO certified company and put special emphasis on high-performance ultrasonicators featuring state-of-the-art technology and user-friendliness. Of course, Hielscher ultrasonicators are CE compliant and meet the requirements of UL, CSA and RoHs.

The table below gives you an indication of the approximate processing capacity of our ultrasonicators: