Single-molecule detection is one of the fundamental challenges of modern biology. Such experiments often use labels that can be expensive, difficult to produce, and for small analytes, might perturb the molecular events being studied. Analyte size plays an important role in determining detectability. Here we use laser-frequency locking in the context of sensing to improve the signal-to-noise ratio of microtoroid optical resonators to the extent that single nanoparticles 2.5 nm in radius, and 15.5 kDa molecules are detected in aqueous solution, thereby bringing these detectors to the size limits needed for detecting the key macromolecules of the cell. Our results, covering several orders of magnitude of particle radius (100 nm to 2 nm), agree with the ‘reactive’ model prediction for the frequency shift of the resonator upon particle binding. This confirms that the main contribution of the frequency shift for the resonator upon particle binding is an increase in the effective path length due to part of the evanescent field coupling into the adsorbed particle. We anticipate that our results will enable many applications, including more sensitive medical diagnostics and fundamental studies of single receptor–ligand and protein–protein interactions in real time.

Recently exosomes have attracted interest due to their potential as cancer biomarkers. We report the real-time, label-free sensing of single exosomes in serum using microtoroid optical resonators. We use this approach to assay the progression of tumors implanted in mice by specifically detecting low concentrations of tumor-derived exosomes. Our approach measures the adsorption of individual exosomes onto a functionalized silica microtoroid by tracking changes in resonant frequency of the microtoroid. When exosomes land on the microtoroid, they perturb its refractive index in the evanescent field and thus shift its resonance frequency. Through digital frequency locking, we are able to rapidly track these shifts with accuracies of better than 10 attometers (one part in 1011). Samples taken from tumor-implanted mice from later weeks generated larger frequency shifts than those from earlier weeks. Analysis of these shifts shows a distribution of unitary steps, with the maximum step having a height of ∼1.2 fm, corresponding to an exosome size of 44 ± 4.8 nm. Our results demonstrate the development of a minimally invasive tumor “biopsy” that eliminates the need to find and access a tumor.

Sensitive and rapid label-free biological and chemical sensors are needed for a wide variety of applications including early disease diagnosis and prognosis, the monitoring of food and water quality, as well as the detection of bacteria and viruses for public health concerns and chemical threat sensing. Whispering gallery mode optical resonator based sensing is a rapidly developing field due to the high sensitivity and speed of these devices as well as their label-free nature. Here, we describe the history of whispering gallery mode optical resonator sensors, the principles behind detection, the latest developments in the fields of biological and chemical sensing, current challenges toward widespread adoption of these devices, and an outlook for the future. In addition, we evaluate the performance capabilities of these sensors across three key parameters: sensitivity, selectivity, and speed.

Clean sport competition is of significant concern to many governments and sporting organizations. Highly sensitive and rapid sensors are needed to improve the detection of performance enhancing drugs in sports as athletes take diuretics to dilute the concentration of drugs in their urine and microdose under the detectable limits of current sensors. Here we demonstrate, using frequency locked microtoroid optical resonators, a three order of magnitude improvement in detection limit over the current gold standard, mass spectrometry, for the common performance enhancing drug, human chorionic gonadotropin (hCG). hCG, also known as the pregnancy hormone, was detected both in simulated urine and in the urine of pregnant donors at a concentration of 1 and 3 femtomolar, respectively. We anticipate that the sensitivity provided by frequency locked optical microcavities can enable a new standard in anti-doping research.The use of performance enhancing drugs during athletic events is prohibited by the World Anti-Doping Association (WADA). To monitor the use of these drugs, anti-doping drug tests are routinely performed during athletic events 1,2 . These tests can detect minute quantities of chemicals from bodily fluids, such as blood or urine. Mass spectrometry is currently the gold standard 3,4 for detecting various doping agents; however, it can have insufficient limits of detection 5 , requires a trained operator, involves specialized enzymes, 6,7 and can be expensive, costing in excess of 100 dollars per assay.