Optical biosensors have emerged as powerful tools for label-free biomarker detection, offering real-time, high-sensitivity analysis with minimal sample preparation. Among the most widely used techniques are surface plasmon resonance (SPR), localized surface plasmon resonance (LSPR), and interferometry. These methods exploit the interaction of light with plasmonic materials or waveguide structures to detect molecular binding events, making them invaluable in drug discovery, clinical diagnostics, and biomedical research.

Surface plasmon resonance operates by exciting collective oscillations of free electrons at the interface between a metal film and a dielectric medium. When polarized light strikes a thin gold or silver film under total internal reflection conditions, it generates an evanescent wave that couples with surface plasmons, resulting in a sharp dip in reflected light intensity at a specific resonance angle. Binding of biomolecules to the sensor surface alters the local refractive index, shifting the resonance angle, which is measured in real time. SPR provides exceptional sensitivity, with detection limits reaching picomolar concentrations for proteins. The technique is widely used in kinetic studies of biomolecular interactions, such as antibody-antigen binding or receptor-ligand dynamics, providing insights into association and dissociation rates.

Localized surface plasmon resonance differs from SPR in that it relies on nanostructured metal particles rather than planar films. Gold or silver nanoparticles exhibit LSPR when their conduction electrons oscillate in resonance with incident light, producing a distinct absorption peak. The peak position is highly sensitive to changes in the local dielectric environment caused by molecular adsorption. LSPR sensors offer advantages such as simpler optical setups and compatibility with miniaturized devices. By engineering nanoparticle size, shape, and composition, the plasmonic response can be tuned for specific applications. For instance, anisotropic structures like nanorods or nanostars exhibit enhanced sensitivity due to stronger local field confinement at sharp tips.

Interferometric biosensors measure phase shifts induced by biomolecular binding on waveguide surfaces. Common configurations include Mach-Zehnder and Young interferometers, where a sensing arm is functionalized with biorecognition elements while a reference arm remains inert. As light propagates through the waveguide, binding events alter the effective refractive index, causing a phase difference between the two arms. Interferometry achieves exceptional sensitivity, capable of detecting sub-nanometer thickness changes in adsorbed layers. Silicon nitride and silicon dioxide are frequently used as waveguide materials due to their low optical loss and compatibility with microfabrication processes.

Plasmonic materials play a critical role in the performance of optical biosensors. Gold is the most widely used metal due to its chemical stability and strong plasmonic response in the visible to near-infrared range. Silver offers higher sensitivity but is prone to oxidation, limiting its practical use. Recent advancements include bimetallic structures, such as gold-silver core-shell nanoparticles, which combine the stability of gold with the enhanced plasmonic properties of silver. Alternative materials like aluminum and copper are being explored for cost-effective solutions, particularly in UV plasmonics. Two-dimensional materials such as graphene have also been integrated with plasmonic sensors to enhance sensitivity through charge transfer interactions.

Waveguide design is another key factor influencing sensor performance. Single-mode waveguides provide high sensitivity but require precise alignment, while multimode waveguides offer robustness at the expense of resolution. Photonic crystal waveguides, with their periodic dielectric structures, enable strong light confinement and enhanced light-matter interaction. Slot waveguides, featuring narrow low-index regions between high-index rails, concentrate the optical field in the sensing region, improving detection limits. Advances in fabrication techniques, such as electron-beam lithography and nanoimprinting, have enabled the production of complex waveguide geometries with nanometer-scale precision.

In drug discovery, optical biosensors are indispensable for high-throughput screening of compound libraries. SPR platforms are routinely used to characterize drug-target interactions, providing binding affinity and kinetic data critical for lead optimization. Fragment-based drug discovery benefits from the ability to detect weak interactions with low molecular weight compounds. LSPR sensors integrated with microfluidics enable rapid screening of multiple analytes in parallel, reducing reagent consumption and assay time. Interferometric sensors are employed in studying membrane proteins, where their label-free nature preserves native conformation and function.

Despite their advantages, optical biosensors face challenges in refractive index sensitivity and multiplexing. Refractive index changes caused by nonspecific binding or bulk solution effects can obscure signals from target analytes. Surface functionalization strategies, such as polyethylene glycol (PEG) coatings, help mitigate fouling and improve specificity. Multiplexing remains technically demanding due to crosstalk between adjacent sensing channels. Spatial and spectral multiplexing approaches, including wavelength-division and imaging-based detection, are being developed to address this limitation.

Smartphone-compatible optical sensors represent a significant advancement in point-of-care diagnostics. By leveraging the built-in camera and processing power of smartphones, these devices democratize access to advanced biosensing. SPR and LSPR sensors have been miniaturized using compact light sources like LEDs and diffraction gratings for wavelength analysis. Smartphone cameras capture intensity or colorimetric changes, which are processed through dedicated apps. Examples include attachments that measure LSPR shifts in nanoparticle solutions or interferometric sensors using the phone's flash as a light source. These systems have been applied to detect biomarkers for diseases such as malaria, HIV, and COVID-19, demonstrating detection limits comparable to laboratory instruments.

Recent innovations focus on improving sensor robustness and scalability. Plasmonic metasurfaces, with engineered subwavelength structures, enable unprecedented control over light-matter interactions. Hybrid systems combining plasmonics with photonic crystals or dielectric resonators enhance sensitivity while reducing noise. Machine learning algorithms are being employed to analyze complex sensor data, improving accuracy in multiplexed detection. The integration of optical biosensors with wearable devices opens new possibilities for continuous health monitoring.

The field continues to evolve with the development of novel materials and fabrication techniques. As optical biosensors become more accessible and versatile, their impact on healthcare, pharmaceuticals, and life sciences will expand, driving innovations in personalized medicine and global health.