Nanocomposite Hydrogel Synthesis using Ultrasonication

Nanocomposite hydrogels or nanogels are multi-functional 3D structures with high efficacies as drug carriers and controlled-release drug delivery systems. Ultrasonication promotes the dispersion of nano-sized, polymeric hydrogel particles as well as the subsequent inclusion/incorporation of nanoparticles into these polymer structures.

Ultrasonic Synthesis of Nanogels

Ultrasonic probe-type homogenizer UP400St for the dispersion and synthesis of nanocomposite hydrogels or nanogels.Nanocomposite hydrogels are three-dimensional material structures and can be designed to exhibit specific features, which makes them potent drug carriers and controlled-release drug delivery systems. Ultrasonication promotes the synthesis of functionalized nano-sized particles as well as the subsequent inclusion/incorporation of nanoparticles in three-dimensional polymeric structures. As ultrasonically synthesized nanogels can entrap bioactive compounds inside their nanoscale core, these nano-sized hydrogels offer great functionalities.
Nanogels are aqueous dispersion of hydrogel nanoparticles, which are physically or chemically cross-linked as hydrophilic polymer network. As high-performance ultrasound is highly efficient in producing nano-dispersions, probe-type ultrasonicators are a crucial tool for the fast and reliable production of nanogels with superior functionalities.

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Ultrasonic cavitation promotes the cross-linking and polymerization during hydrogel and nanogel (nanocomposite hydrogel) synthesis. Ultrasonic dispersion facilitates the uniform distribution of nanomaterials for hybrid hydrogel fabrication.

Ultrasonicator UIP1000hdT with glass reactor for nanocomposite hydrogel synthesis

Functionalities of Ultrasonically Produced Nanogels

  • excellent colloidal stability and the large specific surface area
  • can be densely packed with nanoparticles
  • allow to combine hard and soft particles in hybrid core/shell nanogel
  • high hydration potential
  • promoting bioavailability
  • high swelling / de-swelling properties



 
Ultrasonically synthesized nanogels are used in numerous applications and industries, e.g.

  • for pharmaceutical and medical applications: e.g. drug carrier, antibacterial gel, antibacterial wound dressing
  • in biochemistry and biomedicine for gene delivery
  • as adsorbent/biosorbent in chemical and environmental applications
  • in tissue engineering as hydrogels can mimic the physical, chemical, electrical, and biological properties of many native tissue

Case Study: Zinc Nanogel Synthesis via Sonochemical Route

Schematic flowchart for the synthesis of ZnO NPs and Carbopol/ZnO hybrid nanoparticle gel. In the study, the ultrasonicator UP400St was used for ZnO nanoparticle precipitation and nanogel formation. (adapted from Ismail et al., 2021)ZnO hybrid nanoparticles can be stabilized in a Carbopol gel via a facile ultrasonic process: Sonication is used to drive the precipitation of zinc nanoparticles, which are subsequently ultrasonically crosslinked with Carbopol to form a nano-hydrogel.
Ismail et al. (2021) precipitated zinc oxide nanoparticles via a facile sonochemical route. (Find the protocol for the sonochemical synthesis of ZnO nanoparticles here).
Subsequently, the nanoparticles were used to synthesize the ZnO nanogel. Therefore, the produced ZnO NPs were rinsed with double deionized water. 0.5 g of Carbopol 940 was dissolved in 300 mL of doubled deionized water, followed by addition of the freshly washed ZnO NPs. Since Carbopol is naturally acidic, the solution requires a neutralisation of the pH value, otherwise it would not thicken. Thus, the mixture had undergone continuous sonication using the Hielscher ultrasonicator UP400S with an amplitude of 95 and a cycle of 95% for 1 h. Then, 50 mL of trimethylamine (TEA) as a neutralizing agent (raising the pH to 7) was added dropwise under continuous sonication until the formation of the ZnO white gel occurred. The thickening of the Carbopol started when the pH was near to a neutral pH .
The research team explains the extraordinarily positive effects of ultrasonication on nanogel formation by enhanced particle-particle interaction. Ultrasonically initiated molecular agitation of the constituents in the reaction mixture enhances the thickening process promoted by the polymer-solvent interactions. Additionally, sonication promotes the dissolving of Carbopol. In addition, ultrasound wave irradiation enhances the polymer–ZnO NPs interaction and improves the viscoelastic properties of the prepared Carbopol/ZnO hybrid nanoparticles gel.
The schematic flowchart above shows the synthesis of ZnO NPs and Carbopol/ZnO hybrid nanoparticle gel. In the study, the ultrasonicator UP400St was used for ZnO nanoparticle precipitation and nanogel formation. (adapted from Ismail et al., 2021)

Ultrasonically produced nanogel loaded with zinc oxide nanoparticles.

ZnO NPs synthesized by the chemical precipitation method under the effect of ultrasonication, where (a) is in the aqueous solution, and (b) is ultrasonically dispersed into a stable Carbopol-based hydrogel.
(study and picture: Ismail et al., 2021)

Case Stuy: Ultrasonic Preparation of Poly(methacrylic acid)/Montmorillonite (PMA/nMMT) Nanogel

Khan et al. (2020) demonstrated the successful synthesis of a poly(methacrylic acid)/Montmorillonite (PMA/nMMT) nanocomposite hydrogel via ultrasound-assisted redox polymerization. Typically, 1.0 g of nMMT was dispersed in 50 mL of distilled water with ultrasonication for 2 h to form a homogeneous dispersion. Sonication improves the dispersion of clay, resulting in enhanced mechanical properties and adsorption capacity of the hydrogels. Methacrylic acid monomer (30 mL) was added dropwise to the suspension. Initiator ammonium persulfate (APS) (0.1 M) was added to the mixture followed by 1.0 mL of TEMED accelerator. The dispersion was vigorously stirred for 4 h at 50°C by a magnetic stirrer. The resulting viscous mass was acetone-washed and desiccated for 48 h at 70°C in an oven. The resulting product was ground and stored in a glass bottle. Different nanocomposite gels were synthesized by varying the nMMT in quantities of 0.5, 1.0, 1.5, and 2.0 g. The nanocomposite hydrogels prepared using 1.0 g of nMMT depicted better adsorption results than the rest of composites and was therefore used for further adsorption investigation.
The SEM-EDX micrographs on the right show the elemental and structural analysis of the nanogels consisting in montmorillonite (MMT), nano-montmorillonite (nMMT), poly(methacrylic acid)/nano-montmorillonite (PMA/nMMT), and amoxicillin (AMX)- and diclofenac (DF)-loaded PMA/nMMT. The SEM micrographs recorded at a magnification of 1.00 KX along with the EDX of

  • montmorillonite (MMT),
  • nano-montmorillonite (nMMT),
  • poly(methacrylic acid)/nano-montmorillonite (PMA/nMMT),
  • and amoxicillin (AMX)- and diclofenac (DF)-loaded PMA/nMMT.

It is observed that raw MMT owes a layered sheet structure showing the presence of larger grains. After modification, the sheets of MMT are exfoliated into tiny particles, which may be due to the elimination of Si2+ and Al3+ from the octahedral sites. The EDX spectrum of nMMT exhibits a high percentage of carbon, which may primarily be due to the surfactant utilized for modification as the main constituent of CTAB (C19H42BrN) is carbon (84%). PMA/nMMT displays a coherent and near-co-continuous structure. Further, no pores are visible, which depicts the complete exfoliation of nMMT into the PMA matrix. After sorption with the pharmaceutical molecules amoxicillin (AMX) and diclofenac (DF), changes in the PMA/nMMT morphology are observed. The surface becomes asymmetric with an increase in the rough texture.
Use and functionalities of clay-based nano-sized hydrogels: Clay-based hydrogel nanocomposites are envisioned to be potential super adsorbents for the uptake of inorganic and/or organic contaminants from an aqueous solution due to the combining characteristics of both clays and polymers, such as biodegradability, biocompatibility, economic viability, abundance, high specific surface area, three-dimensional network, and swelling / de-swelling properties.
(cf. Khan et al., 2020)

Ultrasonically synthesized nanogels loaded with various nanoparticles such as nano-montmorillonite clay.

SEM-EDX micrographs of (a) MMT, (b) nMMT, (c) PMA/nMMT, and (d) AMX- and (e) DF-loaded nanocomposite hydrogels. The nanogels were prepared using ultrasonication.
(study and pictures: ©Khan et al. 2020)

High Performance Ultrasonicators for Hydrogel and Nanogel Production

High Performance Ultrasonicators for Hydrogel and Nanogel Production
Hielscher Ultrasonics manufactures high-performance ultrasonic equipment for the synthesis of hydrogels and nanogels with superior functionalities. From small and mid-size R&D and pilot ultrasonicators to industrial systems for commercial hydrogel manufacturing in continuous mode, Hielscher Ultrasonics has the right ultrasonic processor to cover your requirements for hydrogel / nanogel production.

Firwat Hielscher Ultrasonics?

  • héich Effizienz
  • Staat-vun-der-Konscht Technologie
  • Zouverlässegkeet & Robustheet
  • batch & an der Schlaang
  • fir all Volumen
  • intelligent Software
  • smart features (e.g., data protocolling)
  • einfach a sécher ze bedreiwen
  • niddereg Ënnerhalt
  • CIP (clean-in-place)

D'Tabell hei drënner gëtt Iech eng Indikatioun vun der geschätzter Veraarbechtungskapazitéit vun eisen Ultraschaller:

Batch VolumeDuerchflossrateRecommandéiert Apparater
1 bis 500 ml10 bis 200 ml/minUP100H
10 bis 2000 ml20 bis 400 ml/minUP200Ht, UP 400 St
0.1 bis 20L02 bis 4 l/minUIP2000hdT
10 bis 100 l2 bis 10 l/minUIP4000hdT
15 bis 150 l3 bis 15 l/minUIP6000hdT
na10 bis 100 l/minUIP16000
naméi groussStärekoup vun UIP16000

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In the short clip above, the ultrasonicator UP50H is used to form a hydrogel using a low molecular weight gelator. The result is a self-healing supramolecular hydrogels.
(Study and movie: Rutgeerts et al., 2019)
Ultrasonic Dispersion of silica nanoparticles into hydrogel: The Hielscher ultrasonic homogenizer UP400St disperses silica nanoparticles rapid and efficiently into a uniform nanogel with multi-functionalities.

Ultrasonic Dispersion of Nanoparticles in Hydrogel using the ultrasonicator UP400St

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Protocol for Sonochemical Synthesis of ZnO Nanoparticles

ZnO NPs were synthesized using the chemical precipitation method under the effect of ultrasound irradiation. In a typical procedure, zinc acetate dihydrate (Zn(CH3COO)2·2H2O) as a precursor, and an ammonia solution of 30–33% (NH3) in an aqueous solution (NH4OH) as a reducing agent, were used. The ZnO nanoparticles were produced by dissolving the appropriate amount of zinc acetate in 100 mL of deionized water to produce 0.1 M of a zinc ions solution. Subsequently, the zinc ions solution was subjected to ultrasonic wave irradiation using a Hielscher UP400S (400 W, 24 kHz, Berlin, Germany) at an amplitude of 79% and a cycle of 0.76 for 5 min at a temperature of 40 ◦C. Then, the ammonia solution was added dropwise to the zinc ions solution under the effect of the ultrasonic waves. After few moments, the ZnO NPs began to precipitate and grow, and the ammonia solution was continuously added until the complete precipitation of ZnO NPs occurred.
The obtained ZnO NPs were washed using deionized water several times and were left out to settle down. Posteriorly, the obtained precipitate was dried at room temperature.
(Ismail et al., 2021)

What are Nanogels?

Nanogels or nanocomposite hydrogels are a type of hydrogel that incorporates nanoparticles, usually in the range of 1-100 nanometers, into their structure. These nanoparticles can be organic, inorganic, or a combination of both.
Nanogels are formed through a process known as crosslinking, which involves the chemical bonding of polymer chains to form a three-dimensional network. Since the formation of hydrogels and nanogels requires thorough mixing in order to hydrate the polymeric structure, to promote the crosslinking and to incorporate the nanoparticles, ultrasonication is a highly efficacious technique for the production of hydrogels and nanogels. Hydrogel and nanogel networks are capable of absorbing large amounts of water, making nanogels highly hydrated and thus suitable for a wide range of applications such as drug delivery, tissue engineering, and biosensors.
Nanogel hydrogels are typically composed of nanoparticles, such as silica or polymer particles, that are dispersed throughout the hydrogel matrix. These nanoparticles can be synthesized through various methods, including emulsion polymerization, inverse emulsion polymerization, and sol-gel synthesis. These polymerization and sol-gel syntheses benefit greatly from ultrasonic agitation.
Nanocomposite hydrogels, on the other hand, are composed of a combination of a hydrogel and a nanofiller, such as clay or graphene oxide. The addition of the nanofiller can improve the mechanical and physical properties of the hydrogel, such as its stiffness, tensile strength, and toughness. Here, the powerful dispersion capacities of sonication facilitate the uniform and stable distribution of nanoparticles into the hydrogel matrix.
Overall, nanogel and nanocomposite hydrogels have a wide range of potential applications in fields such as biomedicine, environmental remediation, and energy storage due to their unique properties and functionalities.

Applications of Nanogel for Medical Treatments

Type of Nanogel Drug Disease Activity References
PAMA-DMMA nanogels Doxorubicin CancerIncrease in the release rate as the pH value decreased. Higher cytotoxicity at pH 6.8 in cell-viability studiesDu et al. (2010)
Chitosan-based nanogels decorated with hyaluronatePhotosensitizers like tetra-phenyl-porphyrin-tetra-sulfonate (TPPS4), tetra-phenyl-chlorin-tetra-carboxylate (TPCC4), and chlorin e6 (Ce6)Rheumatic disordersRapidly taken up (4 h) by the macrophages and accumulated in their cytoplasm and organellesSchmitt et al. (2010)
PCEC nanoparticles in Pluronic hydrogels LidocaineLocal anesthesiaProduced long-lasting infiltration anaesthesia of about 360 minYin et al. (2009)
Poly(lactide-co-glycolic acid) and chitosan nanoparticle dispersed in HPMC and Carbopol gel Spantide IIAllergic contact dermatitis and other skin inflammatory disordersNanogelinncreases potential for the percutaneous delivery of spantide IIPunit et al. (2012)
pH-sensitive polyvinyl pyrrolidone-poly (acrylic acid) (PVP/PAAc) nanogels PilocarpineMaintain an adequate concentration of the pilocarpine at the site of action for prolonged period of timeAbd El-Rehim et al. (2013)
Cross-linked poly (ethylene glycol) and polyethylenimine OligonucleotidesNeurodegenerative diseasesEffectively transported across the BBB. The transport efficacy is further increased when the surface of the nanogel is modified with transferrin or insulinVinogradov et al. (2004)
Cholesterol bearing pullulan nanogelsRecombinant murine interleukine-12Tumor immunotherapySustained release nanogelFarhana et al. (2013)
Poly(N-isopropylacrylamide) and chitosanHyperthermia cancer treatment and targeted drug deliveryThermosensitive magnetically modalizedFarhana et al. (2013)
Cross-linked branched network of polyethyleneimine and PEG Polyplexnanogel Fludarabine CancerElevated activity and reduced cytotoxicityFarhana et al. (2013)
Biocompatible nanogel of cholesterol-bearing pullulanAs artificial chaperoneTreatment of Alzheimer’s diseaseInhibit aggregation of amyloid β-proteinIkeda et al. (2006)
DNA nanogel with photo cross-linkingGenetic materialGene therapyControlled delivery of plasmid DNALee et al. (2009)
Carbopol/zinc oxide (ZnO) hybrid nanoparticle gelZnO nanoparticlesAntibacterial activity, bacterial inhibitor Ismail et al. (2021)

Table adapted from Swarnali et al., 2017


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