Numerous approaches have been taken to miniaturizing fluorescence sensing, which is a key capability for micro-total-analysis systems. This critical, comprehensive review focuses on the optical hardware required to attenuate excitation light while transmitting fluorescence. It summarizes, evaluates, and compares the various technologies, including filtering approaches such as interference filters and absorption filters and filterless approaches such as multicolor sensors and light-guiding elements. It presents the physical principles behind the different architectures, the state-of-the-art micro-fluorometers and how they were microfabricated, and their performance metrics. Promising technologies that have not yet been integrated are also described. This information will permit the identification of methods that meet particular design requirements, from both performance and integration perspectives, and the recognition of the remaining technological challenges. Finally, a set of performance metrics are proposed for evaluating and reporting spectral discrimination characteristics of integrated devices in order to promote side-by-side comparisons among diverse technologies and, ultimately, to facilitate optimized designs of micro-fluorometers for specific applications.
We describe the design, fabrication, and performance of a class of simple handheld fluorometers. The devices consist of a sensor along with an integrated optical filter packaged in a handheld format. The sensor is a differential active pixel sensor with in-pixel correlated double sampling fabricated in a 0.5-mu m 2-poly 3-metal complementary metal-oxide semiconductor process and has a readout noise of 175.3 muV, reset noise of 360 muV, dynamic range of 59 dB, and conversion gain of 530 nV/e(-) . The filter is a high rejection chromophore embedded in a polymer film which is cast onto the chip. We show the results of bioassays utilizing two different single color fluorometers constructed by using the chromophores 2-(2'-hydroxy 5'-methylphenyl) benzotriazole and Sudan II with long-pass wavelengths of 400 nm and 540 nm, respectively. The bioassays measures metabolic activity and viability of biological cells, which are useful for cytotoxicity and pathogen detection applications.
We describe a capacitance sensor array that has been incorporated into a lab-on-CMOS system for applications in monitoring cell viability. This paper presents analytical models, calibration results, and measured experimental results of the biosensor. The sensor has been characterized and exhibits a sensitivity of 590 kHz/fF. We report results from benchtop tests and in vitro experiments demonstrating on-chip tracking of cell adhesion as well as monitoring of cell viability. Human ovarian cancer cells were cultured on chip, and measured capacitance responses were validated by comparison with images from photomicrographs of the chip surface. Analysis was performed to quantify cell proliferation and adhesion, and responses to live cells were estimated to be 100 aF/cell.
We report on several techniques that have been pursued in our laboratories for packaging complementary metaloxide semiconductor (CMOS) sensors for use in biological environments, such as cell medium. These techniques are suited for single CMOS die ranging from 1.5 x 1.5 mm 2 to 3 x 3 mm 2 in area. The first method consisted of creating high aspect ratio structures from negative-tone photocurable resins to simultaneously encapsulate wirebonds from the chip to a ceramic package and create a cell culture well. The second technique used a photolithographically defined barrier on the die to allow the use of non-photocurable resins as encapsulants. The third method consisted of re-routing the die padframe using photolithographically defined, planar leads to a much larger padframe; this will allow the chip to be integrated with microfluidic networks. Finally, we show a method in which the encapsulant was also used as an optical filter and as a base for integrating more complex structures.
We report on the breakdown characteristics of a single-photon avalanche diode structure fabricated in a 0 5 m single-well CMOS process. This paper features two mechanisms for reducing perimeter breakdown. The first mechanism consists of using the lateral diffusion of adjacent n-wells to reduce the electric field at the diode's periphery, and the second makes use of a poly-silicon gate over the high field regions to modulate the electric field. We studied each technique independently as well as their combined effect on the devices' avalanche profiles. In addition to marked alterations in the current-voltage curves near and above breakdown, the diodes' breakdown voltages were increased by more than 4 V, indicating that perimeter breakdown was curtailed.We verified this assertion through a self-consistently solved 2-D numerical model based on Poisson's equation and the hole and electron current continuity equations coupled with rate equations for carrier generation due to impact ionization. The model revealed spatial maxima of the charge generation rates, thereby indicating regions susceptible to breakdown. Our investigation revealed that in native diodes, the generation rate peaked at the perimeter and near the junction's surface, suggesting perimeter breakdown. Conversely, in devices where suppression techniques were used, the region of maximum generation spread laterally and away from the surface, indicating full volumetric breakdown was achieved.
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