Programmable ion-sensitive transistor interfaces. III. Design considerations, signal generation, and sensitivity enhancement.

We report on factors that affect DNA hybridization detection using ion-sensitive field-effect transistors (ISFETs). Signal generation at the interface between the transistor and immobilized biomolecules is widely ascribed to unscreened molecular charges causing a shift in surface potential and hence the transistor output current. Traditionally, the interaction between DNA and the dielectric or metal sensing interface is modeled by treating the molecular layer as a sheet charge and the ionic profile with a Poisson-Boltzmann distribution. The surface potential under this scenario is described by the Graham equation. This approximation, however, often fails to explain large hybridization signals on the order of tens of mV. More realistic descriptions of the DNA-transistor interface which include factors such as ion permeation, exclusion, and packing constraints have been proposed with little or no corroboration against experimental findings. In this study, we examine such physical models by their assumptions, range of validity, and limitations. We compare simulations against experiments performed on electrolyte-oxide-semiconductor capacitors and foundry-ready floating-gate ISFETs. We find that with weakly charged interfaces (i.e., low intrinsic interface charge), pertinent to the surfaces used in this study, the best agreement between theory and experiment exists when ions are completely excluded from the DNA layer. The influence of various factors such as bulk pH, background salinity, chemical reactivity of surface groups, target molecule concentration, and surface coatings on signal generation is studied. Furthermore, in order to overcome Debye screening limited detection, we suggest two signal enhancement strategies. We first describe frequency domain biosensing, highlighting the ability to sort short DNA strands based on molecular length, and then describe DNA biosensing in multielectrolytes comprising trace amounts of higher-valency salt in a background of monovalent saline. Our study provides guidelines for optimized interface design, signal enhancement, and the interpretation of FET-based biosensor signals.

Programmable ion-sensitive transistor interfaces. I. Electrochemical gating.

Electrochemical gating is the process by which an electric field normal to the insulator electrolyte interface shifts the surface chemical equilibrium and further affects the charge in solution [Jiang and Stein, Langmuir 26, 8161 (2010)]. The surface chemical reactivity and double-layer charging at the interface of electrolyte-oxide-semiconductor (EOS) capacitors is investigated. We find a strong pH-dependent hysteresis upon dc potential cycling. Varying salinity at a constant pH does not change the hysteretic window, implying that field-induced surface pH regulation is the dominant cause of hysteresis. We propose and investigate this mechanism in foundry-made floating-gate ion-sensitive field-effect transistors, which can serve as both an ionic sensor and an actuator. Termed the chemoreceptive neuron metal-oxide-semiconductor (CνMOS) transistor, it features independently driven control gates (CGs) and sensing gates (SGs) that are capacitively coupled to an extended floating gate (FG). The SG is exposed to fluid, the CG is independently driven, and the FG is capable of storing charge Q(FG) of either polarity. Asymmetric capacitive coupling between the CG and SG to FG results in intrinsic amplification of the measured surface potential shifts and influences the FG charge injection mechanism. This modified SG surface condition was monitored through transient recordings of the output current, performed under alternate positive and negative CG pulses. Transient recordings revealed a hysteresis where the current was enhanced under negative pulsing and reduced after positive pulsing. This hysteresis effect is similar to that observed with EOS capacitors, suggesting a field-dependent surface charge regulation mechanism at play. At high CG biases, nonvolatile charge Q(FG) tunneling into the FG occurs, which creates a larger field and tunes the pH response and the point of zero charge. This mechanism gives rise to surface programmability. In this paper we describe the operational principles, tunneling mechanism, and role of electrolyte composition under field modulation. The experimental findings are then modeled by a Poisson-Boltzmann formulation with surface pH regulation. We find that surface ionization constants play a dominant role in determining the pH tuning effect. In the following paper [K. Jayant et al., Phys. Rev. E 88, 012802 (2013)] we extend the dual-gate operation to molecular sensing and demonstrate the use of Q(FG) to achieve manipulation of surface-adsorbed DNA.

Programmable ion-sensitive transistor interfaces. II. Biomolecular sensing and manipulation.

The chemoreceptive neuron metal-oxide-semiconductor transistor described in the preceding paper is further used to monitor the adsorption and interaction of DNA molecules and subsequently manipulate the adsorbed biomolecules with injected static charge. Adsorption of DNA molecules onto poly-L-lysine-coated sensing gates (SGs) modulates the floating gate (FG) potential ψ(O), which is reflected as a threshold voltage shift measured from the control gate (CG) V(th_CG). The asymmetric capacitive coupling between the CG and SG to the FG results in V(th_CG) amplification. The electric field in the SG oxide E(SG_ox) is fundamentally different when we drive the current readout with V(CG) and V(ref) (i.e., the potential applied to the CG and reference electrode, respectively). The V(CG)-driven readout induces a larger E(SG_ox), leading to a larger V(th_CG) shift when DNA is present. Simulation studies indicate that the counterion screening within the DNA membrane is responsible for this effect. The DNA manipulation mechanism is enabled by tunneling electrons (program) or holes (erase) onto FGs to produce repulsive or attractive forces. Programming leads to repulsion and eventual desorption of DNA, while erasing reestablishes adsorption. We further show that injected holes or electrons prior to DNA addition either aids or disrupts the immobilization process, which can be used for addressable sensor interfaces. To further substantiate DNA manipulation, we used impedance spectroscopy with a split ac-dc technique to reveal the net interface impedance before and after charge injection.