Two-dimensional materials like graphene and molybdenum disulfide (MoS2) have emerged as promising candidates for pH sensing due to their exceptional electronic properties, high surface-to-volume ratio, and tunable surface chemistry. These materials enable highly sensitive ion detection, making them ideal for ion-sensitive field-effect transistors (ISFETs) that operate based on the Nernstian response. Their biocompatibility further enhances their suitability for medical applications, such as continuous pH monitoring in physiological environments.

The working principle of pH sensors using 2D materials relies on the surface charge modulation induced by hydrogen ion (H⁺) concentration changes in the surrounding medium. Functionalized graphene and MoS2 exhibit pH-dependent conductivity due to protonation and deprotonation of surface functional groups. When integrated into an ISFET architecture, these materials act as the sensing channel, where the gate potential is directly influenced by the electrolyte pH. The resulting shift in the transistor’s transfer characteristics correlates with the pH value, following the Nernst equation:

ΔV = (2.303 * kT / q) * ΔpH

where ΔV is the threshold voltage shift, k is the Boltzmann constant, T is temperature, q is the elementary charge, and ΔpH is the change in pH. For an ideal Nernstian response, the sensitivity is approximately 59 mV/pH at room temperature. However, functionalized 2D materials often surpass this limit due to their enhanced surface reactivity. For example, oxygenated graphene derivatives demonstrate sensitivities exceeding 70 mV/pH, attributed to additional charge-transfer mechanisms at defect sites.

Functionalization plays a critical role in optimizing pH response. Graphene oxide (GO) and reduced graphene oxide (rGO) are commonly used due to their abundant oxygen-containing groups (e.g., carboxyl, hydroxyl, epoxy), which directly interact with H⁺ ions. Similarly, MoS2 can be chemically modified with thiol or amine groups to enhance pH sensitivity. The choice of functional group affects both the dynamic range and selectivity. For instance, carboxyl-rich surfaces exhibit higher sensitivity in acidic pH ranges, while amine-functionalized surfaces perform better in alkaline conditions.

ISFET designs incorporating 2D materials typically employ a back-gated or liquid-gated configuration. In back-gated devices, the 2D material is deposited on an insulated substrate, and a reference electrode controls the electrolyte potential. Liquid-gated designs, on the other hand, immerse the channel directly in the analyte solution, with the gate voltage applied through a reference electrode. The latter configuration improves sensitivity by minimizing interfacial resistance. Key performance metrics include response time, drift, and hysteresis. High-quality, defect-engineered 2D materials exhibit response times under one second and minimal drift over prolonged use, making them suitable for real-time monitoring.

Biocompatibility is a crucial consideration for medical applications. Graphene and MoS2 are inherently biocompatible, but surface modifications must be carefully selected to prevent cytotoxicity. For example, non-covalent functionalization with biocompatible polymers like polyethylene glycol (PEG) preserves the electronic properties while improving stability in physiological fluids. Additionally, encapsulation strategies using inert materials such as silicon nitride or parylene can prevent degradation and ion leakage in vivo. Studies have confirmed that properly passivated 2D material-based pH sensors maintain functionality in biological media for extended periods without inducing inflammatory responses.

Medical applications of these sensors include gastrointestinal monitoring, wound healing assessment, and intracellular pH measurement. Unlike biosensors that target specific biomolecules, pH sensors provide a general measure of acidity or alkalinity, which is critical for diagnosing conditions like acidosis or alkalosis. For example, implantable graphene-based ISFETs have been tested for continuous gastric pH monitoring, demonstrating stability in highly corrosive environments. Similarly, flexible MoS2 sensors integrated into wound dressings enable real-time tracking of infection-related pH changes.

Challenges remain in achieving long-term stability and reproducibility. Factors such as material inhomogeneity, environmental interference, and reference electrode drift can affect performance. Advanced fabrication techniques, including atomic layer deposition (ALD) for uniform passivation and machine learning for signal calibration, are being explored to address these issues.

In summary, 2D material-based pH sensors leverage the unique properties of graphene and MoS2 to achieve high sensitivity, fast response, and excellent biocompatibility. ISFET designs utilizing these materials follow Nernstian principles while surpassing conventional limits through surface engineering. Their medical applicability is broad, provided that stability and biocompatibility are carefully optimized. Future advancements in material functionalization and device integration will further enhance their reliability for clinical use.

The following table summarizes key properties of graphene and MoS2 for pH sensing:

Material Functional Groups Sensitivity (mV/pH) Response Time Biocompatibility
Graphene Oxide Carboxyl, Hydroxyl 70-90 <1 s High (with passivation)
MoS2 Thiol, Amine 50-75 <2 s High (with PEG coating)

These values are derived from experimental studies and highlight the trade-offs between sensitivity and response dynamics. The development of 2D material pH sensors continues to advance, driven by their potential for precision medical diagnostics and environmental monitoring.