Generic, label-free and immobilization-free biosensing in nL liquids with Terahertz waves

Terahertz (0.3-3.0 THz, 1.0?0.1 mm, 0.1-1 kJ/mol) electromagnetic radiation has low photon energy to directly probe weak chemical bonds. A (bio-)molecule interacts with solvents by means of weak chemical bonds, which is expressed in the formation of a hydration shell. The hydration shell is correlated with the biomolecules' surface properties, conformation, and rigidity. Therefore it is possible to detect and quantify biomolecular processes based on the solution's dielectric response at Terahertz frequencies. In order to overcome challenges related to limited THz source power, high water absorption and sample size, a micro-fabricated sensor was produced, which consists of a capillary container filled with liquid, integrated into a THz waveguide. Innovative sensor designs led to outstanding performance: label-free and immobilization-free detection of concentration, conformation, binding and cell physiology at nM-uM-mM concentrations, requiring only 4 nL volume of sample. The proof-of-concept experiments show the technique's feasibility for PCR, protein crystallization, binding assays, cell analysis. The technique enables to drastically reduce sample consumption ([nL]* [n/u/mM]), does not require sample treatment as it is truly label-free and immobilization-free, and it could be fully automated (lab-on-a-chip, high throughput). The technique could lead to a new generation of analytical instrumentation for pharmaceutical, medical diagnostic and biotechnology industries.