Quartz Crystal Microbalance: Basics and Applications in Biology

Abstract

The quartz crystal microbalance (QCM) technique refers to a bioanalytical approach capable of monitoring adsorption reactions at the solid–liquid interface with the help of thumbnail‐sized piezoelectric quartz crystals that perform resonant shear oscillations of nanometre amplitude. Shifts of its resonance frequency report on mass deposition on the crystal surface with sub‐microgram sensitivity. The device is typically used to study and quantify non‐covalent biomolecular interactions of the ligand‐receptor type. When the crystal surface is, for instance, functionalised with antibodies, the resulting biosensor captures target molecules or microorganisms from solution and indicates the associated mass change. Growing adherent animal cells on the crystal surface provides a convenient, non‐invasive and label‐free approach to follow changes in cellular micromechanics and adhesion state under physiological conditions. This article provides a brief introduction into the physical basics of the technology and highlights its major applications as well as limitations.

Key Concepts

  • The quartz crystal microbalance (QCM) is a simple, cost‐effective, mass sensing technique based on the resonant oscillation of a piezoelectric quartz crystal.
  • The resonance frequency of the crystal (typically 5 to 10 MHz) is measured as a function of time, and it reports on the presence of a foreign mass film on the crystal surface and any changes with time.
  • When a rigid mass is deposited on the crystal surface, the device has demonstrated a mass sensitivity in the sub‐microgram range.
  • For non‐rigid films, the QCM returns information on the viscoelastic properties of the load material.
  • The QCM operates label‐free and non‐invasively with a maximum shear displacement that is commonly set below 1 nm amplitude.
  • The QCM is used to monitor biomolecular interactions such as those between antigen–antibody, enzyme–substrate or ligand–receptor with one binding partner immobilised upon the resonator surface while the other one is present in the incubation fluid.
  • When used as a growth substrate for adherent eukaryotic cells, the QCM reports on cell attachment, spreading and proliferation upon the resonator surface in real time.
  • Based on its sensitivity for the viscoelastic properties of the load material, the device is capable of monitoring changes in cellular micromechanics when adherent mammalian cells are grown on the resonator.

Keywords: quartz crystal microbalance; biomolecular interaction analysis; cell‐based assays; biosensor; label‐free; cytomechanics; molecular recognition; whole‐cell biosensor; shear‐wave resonator; viscoelasticity; resonance frequency

Figure 1. Schematic illustration of the electromechanical coupling in piezoelectric quartz resonators with evaporated gold electrodes on either side (centre). (a) Unit cell of quartz (SiO2) in resting state with the centre of positive and negative polarisation cancelling each other. (b) Mechanical shear stress along the y‐axis induces the charge centres to displace and create a potential difference between the surface electrodes, a phenomenon called direct piezoelectric effect. (c) Schematic of a quartz resonator with evaporated gold electrodes in resting state. (d) An external electric field applied via the surface electrodes causes a mechanical strain within the piezoelectric material via the polarisation dipoles, a phenomenon called inverse piezoelectric effect. The orientation and amplitude of the electric field determine the direction and amplitude of the mechanical displacement.
Figure 2. Time‐resolved shift in resonance frequency for a QCM‐based immunosensor detecting Human Salivary Amylase (HAS). (i) Pre‐immobilisation of the capture antibody on the resonator surface. (ii) Rinsing with buffer to remove unbound antibodies. (iii) Incubation with a sample containing the target molecule HAS (red). (iv) Rinsing with buffer to remove unbound target molecules. (v) Incubation with a second antibody binding to HAS for signal amplification. (vi) Rinsing with buffer. Reproduced with permission from Della Ventura, (2017). © Elsevier.
Figure 3. Time‐dependent frequency shift during a QCM‐based assay monitoring lipase activity. Initially, a lipid film is predeposited on the resonator surface producing a frequency shift of app. 50 Hz. Addition of lipase at t = 8 min induces hydrolysis of the lipid film and a corresponding increase in resonance frequency indicating that lipase‐mediated digestion of the lipid film was rapid and complete in less than five minutes. Reproduced with permission from Joyce et al. . © RSC Publishing.
Figure 4. (a) Time‐dependent frequency shift during attachment and spreading of initially suspended cells. Each curve represents a different number of cells seeded at time zero with seeding densities in the range of 0 – 1.5 × 106 cm−2 (upper to the lower curve). The maximum frequency shift is indicated by Δfmax for a given seeding density. (b) Time‐dependent changes of the resonance frequency when confluent cell monolayers were exposed to Cytochalasin D (5 μM) at t = 25 min. Fluorescence micrographs after staining the actin cytoskeleton by fluorescence‐labelled phalloidin confirm the degradation of actin filaments: (i) before exposure to 5 μM Cytochalasin D and (ii) after 50 min of exposure.
Figure 5. Simulated conductance spectra G(f) for QCM resonators around their fundamental resonance (here: 5 MHz). The spectra are characterised by the frequency of maximum conductance f(Gmax) and the bandwidth w of the resonance curve. Thus, any material deposition on the resonator surface is described by two parameters. The red curve represents a blank and unloaded resonator; the blue curve represents the quartz after deposition of a rigid mass film and the green curve stands for the resonator after a viscoelastic film has been deposited on the resonator. Using two descriptors of the shear oscillation allows for a clear distinction between mass and viscous loading.
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Further Reading

Oberleitner M (2017) Label‐free and Multi‐parametric Monitoring of Cell‐based Assays with Substrate‐embedded Sensors. Cham: Springer‐Verlag.

Steinem C and Janshoff A (2007) Springer Series on Chemical Sensors and Biosensors: Piezoelectric Sensors. Heidelberg: Springer‐Verlag.

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Ruckdäschel, Simone, Kade, Christian, and Wegener, Joachim(Jan 2019) Quartz Crystal Microbalance: Basics and Applications in Biology. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0028178]