## 3 History of PCEM Development
### Instrument 1--Biomolecular Interaction Detection (BIND) Scanner  
In 2002, the first PC biosensor introduced by SRU company (SRU Biosystems) was designed for high-throughput microplate-based detection of protein-protein and protein-small molecule interactions, using a PC with resonant reflection in the near-infrared (NIR) spectral range [49, 51]. Shortly afterwards, a PC biosensor microplate reader was introduced that incorporated a linear array of optical fibers with illumination/detection heads that could read all the wells in one row (e.g., \(y\) direction) of a 96-well microplate at one time [46]. The illumination/detection heads were installed beneath the microtiter plate, which sits upon a motion stage that could translate the plate in an orthogonal dimension (e.g., \(x\) direction) to scan the entire microplate in \(\sim\)15 s. This mode enabled serial re-scanning of the microplate to generate kinetic data for the biomolecular interaction taking place in all the wells. The PC biosensor resonant PWV was determined at each location with this linear scan mode. Subsequently, the first-generation label-free PC biosensor imaging system was introduced and named the \"Biomolecular Interaction Detection\" (BIND) Scanner (Instrument 1, Figure 2A) [12, 47, 50]. The optical fiber-based illumination/detection approach was replaced by free space illumination of the bottom surface of the PC biosensor with a broadband light source, and the collection of reflected light into an imaging spectrometer, which was able to rapidly acquire a spatial PWV map by scanning a large sensor surface area. Following the light path of the system, the incoming light beam was divided by a beam splitter, directed to the PC biosensor surface, magnified by an optional objective lens, and, finally, projected into the imaging spectrometer via a narrow entrance slit. The illumination source in this instrument was a white light lamp or a broadband light-emitting diode (LED) in the NIR spectral range, and the detector was a CCD camera. In a single CCD image (Figure 2A, bottom-right inset), the reflectance spectra of several hundred independent locations in one line that spans the PC were gathered at one time. To construct a 2D PWV image, a scanning stage translated the PC across the illumination line in small spatial increments.  
The first generation of scanning PC imaging instruments (BIND Scanner) was developed into a commercially available product and utilized in many life science research applications [38; 39; 40; 41; 43; 50; 80; 82; 83]. For example, it has been reported in [83] that assessing combined enhanced fluorescence and label-free biomolecular detection on the same PC surface. The sensitivity of the PC biosensor has been examined in detail in [80]. The PWS image shown in Figure 2B illustrates the detection of a microarray of Protein A printed on the biosensor surface to form the letters 'NSG' (Nano Sensors Group, University of Illinois at Urbana-Champaign) [50]. Cytotoxicity screening of Bangladesh medicinal plant extracts has been performed with pancreatic cancer cells (Panc-1) using the BIND Scanner. As shown in Figure 2C, the untreated control group and two representative plant extracts, Petunia punctata Paxton (_P. punctate_) and Anisoptera glabra Kurz (_A. glabra_), demonstrate different cellular activities (apoptosis and proliferation) on the biosensor surfaces [41]. The imaging instrument was sufficient for observing large populations of cells with \(\sim\)9 \(\upmu\)m spatial resolution, so that cells with large surface attachment footprints could be observed, although the system lacked sufficient resolution for observing intra-cell attachment dynamics.