Ionic liquids offer greener route to collagen extraction and advanced materials

Collagen, the protein that gives skin and leather their strength, has long been extracted with acids, alkalis or enzymes, but those methods can damage the molecule’s delicate triple-helix structure and create substantial environmental burdens. A new review published in the journal Collagen and Leather argues that ionic liquids, a class of salts that melt below 100 degrees Celsius, could change that. The authors, led by Kai Wang and Jian Sun, survey recent advances showing that ionic liquids can dissolve collagen from skins and tanned leather under mild conditions, preserve its natural molecular architecture, and simultaneously serve as versatile ingredients in collagen-based drugs, scaffolds, sensors and leather finishes.

The case for ionic liquids rests on chemistry. Collagen’s triple helix, in which three parallel polypeptide chains intertwine, is stabilised by hydrogen bonds, ionic bonds and van der Waals forces. That stability is exactly what makes collagen hard to separate from tissue. Ionic liquids, composed of asymmetric cations and anions, disrupt those intermolecular bonds and replace them with new, reversible interactions, allowing the collagen chains to move freely and dissolve. Molecular dynamics simulations show that ionic liquid anions bind strongly to collagen functional groups, reorienting the hydrogen bond network and stripping away the hydrophilic environment that normally stabilises the protein. The authors also invoke the Hofmeister series, the classical ranking of ions by their ability to destabilise proteins, to explain why some anions, such as sulfate, disrupt collagen more aggressively than more hydrophilic ones.

Not all ionic liquids perform equally. A bibliographic analysis cited in the review finds that imidazolium-based liquids dominate collagen research from skins, accounting for roughly 67 percent of studies, followed by ammonium and phosphonium variants; phosphonium liquids make up only about 8 percent, partly because they form insoluble precipitates with proteins in aqueous two-phase systems. Within the imidazolium family, chain length matters. Short-chain variants with four or fewer carbons in the cation side chain represent around 59 percent of relevant research, prized for low viscosity and excellent solubility. Longer chains increase hydrophobicity: molecular docking calculations show binding energies between collagen peptides and imidazolium cations strengthening from -2.6 to -3.1 kilocalories per mole as the alkyl chain grows from butyl to decyl, with hydrophobic interactions that can ultimately destabilise the protein.

Anion choice is equally decisive. In comparative experiments highlighted in the review, 1-butyl-3-methylimidazolium acetate preserved the collagen helix better than its chloride counterpart, because the moderately electronegative acetate ion forms stable hydrogen bonds with amino and hydroxyl groups without shredding the helical scaffold, whereas chloride promotes stronger electrostatic interactions and partial peptide bond cleavage. Acetate also outperformed tetrafluoroborate, delivering nearly twice the extraction efficiency, since the bulky spherical tetrafluoroborate ion suffers steric hindrance. Raising the concentration of acetate-type liquids from 10 to 30 percent increased collagen solubility by more than 30 percent, although the review cautions that higher concentrations can cut collagen’s thermal denaturation temperature by 0.26 to 7.63 degrees Celsius.

Concrete extraction studies back the efficiency claims. Using a deep eutectic solvent of urea and lactic acid, researchers extracted up to 6 percent collagen from cod skin, outperforming conventional acetic acid treatment while eliminating acid-base neutralisation and reducing wastewater treatment costs. A separate cowhide study reported extraction rates reaching 37 percent with ionic liquid systems, with infrared spectroscopy suggesting a better-preserved triple helix than acid or pepsin samples. Perhaps most striking, a citric acid, xylitol and water deep eutectic solvent applied to blue shark skin, supported by computational modelling, yielded the equivalent of 18 tons of collagen per 100 tons of dry raw material, nearly double conventional acid-base methods, with life cycle assessment pointing to lower wastewater discharge, energy use and pollutant concentrations.

Recyclability strengthens the economic case. In one tuna skin study, a triple-phase system built on choline-based ionic liquids and the surfactant Triton X-100 recovered type I collagen with recovery rates for choline dihydrogen citrate and the surfactant remaining above 87.5 percent after three reuse cycles. Choline dihydrogen citrate itself delivered a collagen yield of 16.61 percent, while ultrasound-assisted deep eutectic extraction from sturgeon skin reached 24 percent. The review also situates ionic liquids among emerging alternatives such as supercritical fluid extraction, which achieved 13.8 percent from cod skin but demands pressures above 80 atmospheres, and ultrasound-assisted extraction, which is efficient but can damage collagen under harsh conditions. Both, the authors note, face higher operating costs than ionic liquid routes.

Tanned leather poses a harder problem than raw skin, because chromium(III) introduced during chrome tanning forms stable coordination cross-links with carboxyl groups on collagen side chains. Any extraction method must therefore break both hydrogen bonds and metal-collagen coordination bonds. Ionic liquid anions can compete with collagen carboxylates for chromium binding, weakening the cross-links. One team dissolved collagen from tanning solid waste with 1-allyl-3-methylimidazolium chloride, whose cation and chloride anion interact with the amino and carboxylate groups to separate microfibrils. Another developed a targeted homogeneous separation process using tetra-n-butylammonium hydroxide, recovering 72.4 percent of collagen from chrome-tanned waste at ambient temperature while sharply reducing chromium leaching. A related synergistic dissolution and regeneration system retained the triple-helix conformation and achieved a 51.22 percent recovery rate.

Beyond extraction, the review catalogues how ionic liquids upgrade collagen materials. In drug delivery, choline acetate acts as a plasticiser in collagen-poly(vinyl alcohol) films that sustain the release of the antibiotic ciprofloxacin, its cation binding electrostatically to collagen while its anion rewires the hydrogen bond network to curb swelling. A lactobionic acid-arginine ionic liquid self-assembles with collagen peptides into spherical nanoparticles that stabilise the triple helix and improve transdermal penetration. In tissue engineering, triethanolamine acetate dissolves collagen at a mild 30 degrees Celsius for bone-filler beads, while 1-ethyl-3-methylimidazolium acetate helps form hydrogels with exceptional strength, toughness and fatigue resistance, with tunable pore structure and shortened gelation times when paired with microbial transglutaminase.

Flexible sensors and leather finishing round out the applications. Collagen films blended with ionic liquids such as choline dihydrogen phosphate show increased conductivity from mobile ions and hydrogen-bond-mediated channels, supporting resistive touch and force sensors that retain biocompatibility and controlled biodegradability. Collagen fiber materials soaked in 1-butyl-3-methylimidazolium hexafluorophosphate serve as dielectric layers in capacitive pressure sensors sensitive enough to monitor wrist pulses and vocal cord vibrations. In tanneries, an imidazolium dihydrogen phosphate pretreatment raised dye absorption by 5 to 24 percent over conventional methods by modifying the hydration layer on tanned surfaces without disrupting fibril cross-links, and 1-butyl-3-methylimidazolium chloride pretreatment turned insulating leather into a conductive substrate for multi-stimuli colour-changing devices.

The authors are candid about limitations. Conventional imidazolium and phosphonium liquids can destabilise collagen at higher structural levels, show poor biodegradability and low biocompatibility, and some, including 1-butyl-3-methylimidazolium chloride, disrupt the triple helix and inhibit fibril formation, a concern for biomedical use. Their response is a push toward biocompatible ionic liquids built from choline derivatives, amino acids, fatty acids and non-nutritive sweeteners, coupled with machine learning models that predict viscosity, toxicity and extraction performance to shortcut the screening of ionic combinations. Whether the technology moves from laboratory benches into tanneries, the authors argue, will depend on cost control, large-scale process development and full life cycle assessments of the kind already pointing in ionic liquids’ favour.

Subject of Research: Use of ionic liquids for extracting collagen from skins and leather and for functionalising collagen-based materials

Article Title: Ionic liquids promote extraction of collagen from skins/leather and application of collagen-based materials

Article References: Wang, K., Luo, X., Zhao, W., Bao, Y., Pang, X., & Sun, J. (2026). Ionic liquids promote extraction of collagen from skins/leather and application of collagen-based materials. Collagen and Leather, 8(1), Article 37. https://doi.org/10.1186/s42825-026-00259-4

Image Credits: AI Generated

DOI: 10.1186/s42825-026-00259-4

Keywords: ionic liquids, collagen, collagen extraction, deep eutectic solvents, leather industry, green chemistry, drug delivery, tissue engineering, flexible sensors, triple helix, chrome-tanned leather, biocompatible solvents