The quartz crystal microbalance (QCM) is a simple, cost effective, high-resolution mass sensing technique, based upon the piezoelectric effect. As a methodology, the QCM evolved a solution measurement capability in largely analytical chemistry and electrochemistry applications due to its sensitive solution-surface interface measurement capability. The technique possesses a wide detection range. At the low mass end, it can detect monolayer surface coverage by small molecules or polymer films. At the upper end, it is capable of detecting much larger masses bound to the surface. These can be complex arrays of biopolymers and biomacromolecules, even whole cells. In addition, the QCM can provide information about the energy dissipating properties of the bound surface mass. Another important and unique feature of the technique is the ability to measure mass and energy dissipation properties of films while simultaneously carrying out electrochemistry on solution species or upon film systems bound to the upper electrode on the oscillating quartz crystal surface. These measurements can describe the course of electropolymerization of a film or can reveal ion or solute transport within a film during changes in the film environment or state, including the oxidation state for an electroactive film driven by the underlying surface potential. The past decade has witnessed an explosive growth in the application of the QCM technique to the study of a wide range of molecular systems at the solution-surface interface, in particular, biopolymer and biochemical systems. In this report, we start with a brief historical and technical overview. Then we discuss the application of the QCM technique to measurements involving micellar systems, self-assembling monolayers and their phase transition behavior, molecularly imprinted polymers, chemical sensors, films formed using the layer-by-layer assembly technique, and biopolymer films and point out the utility of the electrochemical capabilities of the technique to characterizing film properties, especially electroactive polymer films. We also describe the wide range of surface chemistries and attachment strategies used by investigators to bring about surface attachment and multi-layer interactions of these thin film systems. Next we review the wide range of recent applications of the technique to: studies of complex biochemical and biomimetic systems, the creation of protein and nucleic acid biosensors, studies of attached living cells and whole cell biosensor applications. Finally, we discuss future technical directions and applications of the QCM technique to areas such as drug discovery.

The quartz crystal microbalance (QCM) was used to monitor endothelial cell (EC) adhesion on the gold surface of an oscillating quartz crystal contained in a QCM device. A number of parameters were investigated. First, we observed differential QCM O‐ring toxicities for ECs. Second, appropriate conditions for cell culture and QCM cell environment were identified that can eliminate large‐scale frequency oscillations in the measurements. These artifacts are not due to added cells but originate in the time‐dependent evaporation of water. Having eliminated these artifacts, we then demonstrated that the measured steady‐state crystal frequency shift, Δf, and motional resistance shift, ΔR, were determined by the number of firmly attached ECs requiring trypsinization from the crystal surface. Last, following steady‐state attachment of ECs, the EC growth stimulation by fibroblast growth factor was monitored in a continuous fashion by measuring f and R values over a 72 h. period. We observed the Δf values to increase in a way that reflected the increase in EC number bound to the QCM surface. Following addition of ECs to the QCM, the time‐dependent increase in ΔR can be interpreted in terms of increase by the ECs of the energy dissipation properties of the solution at the solution‐gold surface interface. This effect is due to their rapid surface attachment and the elaboration of their cytoskeletal properties. These results indicate that the QCM technique can be used for the study of EC attachment and growth and suggest its potential for the real time study of per unit surface area cell mass distribution dynamics and viscoelastic properties and the cells' responses to stresses or perturbations brought about using biologically active molecules.

The quartz crystal microbalance (QCM) technique has been applied to the real time monitoring of endothelial cell (EC) adhesion and spreading on the QCM gold surface. We previously showed that the measured QCM Δf and ΔR shifts were due to cells adhering to the gold crystal surface, requiring proteolytic enzyme treatment to be removed from the surface, in order for the Δf and ΔR shifts to return to zero. In the present report, we demonstrate the quantitative dependence and saturation of the measured Δf and ΔR shifts on the number of firmly attached ECs as measured by electronic counting of the cells. We demonstrate through a light microscope simulation experiment that the different Δf and ΔR regions of the QCM temporal response curve correspond to the incident ECs contacting the surface, followed by their adhesion and spreading, which reflect cellular mass distribution and cytoskeletal viscoelasticity changes. Also, we demonstrate that the dose response curve of Δf and ΔR values versus attached EC number is more sensitive and possesses less scatter for the hydrophilically treated surface compared to the native gold surface of the QCM. For both surfaces, a Δf and ΔR versus trypsinized, attached EC number plot 1 h post‐seeding exhibits a sigmoid curve shape whereas a similar plot 24 h post‐seeding exhibits a hyperbolic curve shape. This number dependence suggests cell‐cell cooperativity in the initial cell adhesion and spreading processes. These QCM data and our interpretation are corroborated by differences in cell appearance and spreading behavior we observed for ECs in a light microscope fluorescence simulation experiment of the cell density effect. For a stably attached EC monolayer at 24 h post‐addition, steady‐state Δf and ΔR values are higher and exhibit saturation behavior for both the hydrophilically treated gold surface as compared to the untreated surface. The steady‐state 24 h Δf and ΔR values of stably attached ECs are shifted from the 1 h attached ECs. The 24 h values are characteristic of a more energy‐dissipative structure. This is consistent with the time‐dependent elaboration of surface contacts in anchorage‐dependent ECs via the attachment of intregrins to underlying extracellular matrix. It is also in agreement with the known energy dissipation function of the ECs that cover the interior of blood vessels and are exposed to continuous pulsatile blood flow.