Optical biosensors - Illuminating the path to personalized drug dosing
Introduction
Personalized medicine is the contemporary approach towards disease management and treatment which forsakes conventional one-size-fits-all models for bespoke medicines tailored to the individual. Its rise to prominence was brought forth by the knowledge generated through the Human Genome Project (Carrasco-Ramiro et al., 2017). The growing molecular understanding of diseases has not only improved diagnostic strategies but has also informed us of the subtle variations in the way different people respond to medicines. This should hardly come as a surprise; sex differences in digoxin toxicity, for instance, were reported as early as 1964 (Rodensky and Wasserman, 1964). Today, we are better equipped to understand the molecular mechanisms underlying inter- and intra-patient variations, such as sex (Farkouh et al., 2020; Madla et al., 2021), metabolic enzymes polymorphism (Ahmed et al., 2016), gut microbiota (McCoubrey et al., 2021; Zimmermann et al., 2019), and the time of administration (Zaki et al., 2019). Progress towards tailor-made medicines is faster than ever due in part to political interest and pressure, with the 2015 Precision Medicine Initiative launched by the Obama administration (Fox, 2015) one key example of this.
Personalized medicine encompasses numerous concepts, including patient-centric dose design and personalized dosing. Advances in 3D printing technologies have enabled the fabrication of precise doses for any given individual (Capel et al., 2018; Elbadawi et al., 2020; Eleftheriadis et al., 2021; Goyanes et al., 2019; Melocchi et al., 2021; Seoane-Viaño et al. 2021a, 2021b). To determine the optimal dose to be administered, a means of determining the patient's drug serum concentration is necessary. This can be achieved through therapeutic drug monitoring (TDM). TDM is the clinical practice of measuring the extent to which a patient has been exposed to a therapeutic agent, known as the exposure parameter, to adjust subsequent doses and optimize dosing regimens (Ates et al., 2020). Different exposure parameters may be used for different types of drugs, such as the trough concentration (for antiepileptics or antivirals), peak concentration (for concentration-dependent antibiotics), and the area under time-concentration curve (AUC) (for immunosuppressants) (Buclin et al., 2020). These exposure parameters are interpreted using dosing adaptation algorithms derived from pharmacokinetic-pharmacodynamic (PK-PD) models, which are in turn built from population studies on the inter- and intra-patient pharmacokinetic variability for the specific drug (Jelliffe et al., 2020; Stillhart et al., 2020; Vinarov et al., 2021). As these existing PK-PD models are representative of an average patient rather than an individual, dose adjustments through present-day TDM practices are not truly personalized (Ates et al., 2020). A tailored dosage regimen will require continuous or frequent monitoring of the aforementioned exposure parameters to both construct an individualized PK-PD model for each patient and accurately evaluate the patient's drug exposure. However, at present, TDM practices require the invasive sampling of blood, which can be an unpleasant experience when done routinely. Additionally, blood samples are analyzed using expensive chromatographic or immunoassay-based machines, at times in a centralized laboratory. These result in long turnaround times, high instrumentation costs and intensive skilled labor requirements (Ates et al., 2020). Prompt and routine TDM is consequently unfeasible, limiting its present-day use to narrow therapeutic index (NTI) drugs (i.e. drugs with a small gap between their therapeutic and toxic concentrations).
Indeed, TDM possesses immense potential that largely remains untapped (Garzón et al., 2019). Knowledge of drug serum concentrations through TDM allow clinicians and pharmacist to adjust the next scheduled dose, ensuring that drug concentrations are kept within the therapeutic window. As such, adverse and occasionally fatal side effects are avoided, and the Time in Therapeutic Range (TTR) can be maximized to improve patient outcomes. In this way, TDM may also help to mitigate intra and/or inter-patient variability. If its application is extended beyond NTI drugs, the amplification of these benefits will likely see reduced drug wastage and reduced hospitalization due to avoidable drug overdoses. Routine TDM practices for antibiotics may also help to tackle the pressing issue of antimicrobial resistance by obviating sub-therapeutic doses.
Given its benefits, it is impetuous to disregard the notion of enabling timely, routine and affordable TDM practices. Optical biosensors could hold the key to unlocking the full potential of TDM (Garzón et al., 2019). A biosensor is a device that employs specific biological elements (such as enzymes, antibodies, aptamers) and/or biochemical reactions to detect specific chemical analytes through the quantification of optical, thermal, electrical or piezoelectric signals (Elbadawi et al., 2021; Nagel et al., 1992). Optical biosensors use the interaction of light (electromagnetic radiation/waves) with matter to measure the concentration of a species. The interaction can be measured through adsorption, scattering (absorbing and re-emitting the light), refractive index changes and fluorescence (Chen and Wang, 2020). Optical sensors have already been established as a staple of the healthcare industry, ranging from traditional sensors such as pulse oximeters to modern photoplethysmograms for heart rate monitoring in wearable devices such as the Apple Watch and Fitbit. Today, optical biosensors continue to evolve in many applications, including food safety (Scognamiglio et al., 2014), pathogen detection (Yoo and Lee, 2016), cancer diagnosis (Balaji and Zhang, 2017), environmental monitoring (Halilović et al., 2019; Liu et al., 2019), DNA sensing (Lan et al., 2019), and blood glucose monitoring (Mendosa, 2000). Indeed, optical biosensors are steadily permeating nearly every aspect of our lives. Consequently, its implementation into practices with stricter regulatory requirement, such as TDM, becomes increasingly likely.
In the following review, we provide an overview of the key advances in optical biosensors for drug detection and quantification, and discuss their potential to enable routine and cost-effective TDM. In particular, we discuss the overarching principles that underpin various optical biosensors and critically review recent examples with potential for clinical translation. We examine the pros and cons of optical biosensors, including the technical and regulatory challenges that must be addressed to permit their translation into clinical practice.
Section snippets
Visualizing the molecular world: the overarching principles
Optical biosensors share a common set of working components. Foremost, to capture the analyte of interest, a bio-recognition element is necessary. This can be organic such as enzymes, antibodies, aptamers, cells, or tissues (Chen and Wang, 2020), or inorganic such as molecularly imprinted polymers (MIPs) (Uzun and Turner, 2016). Interactions between the bio-recognition element and the analyte lead to a signal through interactions with light, which can originate from a light source such as a
Surveying the current state of optical biosensors
Optical biosensors have had a long-standing presence in the healthcare sector. Lateral flow immunoassays or immunochromatographic test strips are perhaps the earliest forms of optical biosensors. These include home pregnancy test kits and most recently, SARS-CoV-2 diagnostic kits (Udugama et al., 2020). Here, biorecognition molecules are conjugated with colored compounds (e.g. gold nanoparticles) and migrate across the test strip via capillary action (Koczula and Gallotta, 2016). Antibodies
Strengths of optical biosensors
Optical biosensors offer an assortment of advantages that continue to spur research into their application in TDM. Foremost, optical biosensors boast high sensitivity, having been demonstrated to be capable of measuring analytes in femtomolar concentrations (Muneer et al., 2020a). Such sensitivity makes optical biosensors suitable for measuring serum concentrations of highly potent drugs that are administered in very small doses, such as levothyroxine (dose ~50–100 μg). Electrochemical
Looking towards the future
Technological advancements in the field of materials engineering, biotechnology and nanotechnology continue to contribute significantly towards the vision of routine TDM powered by optical biosensors. Improvements to molecularly imprinted polymers and new aptamer formats, such as xeno nucleic acid-based aptamers, offer solutions to existing stability issues (Eremeeva et al., 2019; Kupai et al., 2017). New optical biosensing configurations continue to emerge with increasing sensitivity and
Conclusion
Optical biosensors show great promise in revolutionizing TDM practices and facilitating the transition into a new era of personalized medicine. Complemented by the bespoke medicine fabrication capabilities of 3D printing, the archaic one-size-fit-all model will eventually be superseded by precision dosing, and accordingly improved patient outcomes. Optical biosensors afford high sensitivity, efficiency, portability and potential affordability, that make them capable of becoming key clinical and
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The authors thank the Engineering and Physical Sciences Research Council (EPSRC), UK for their financial support (EP/R513143/1 and EP/S00900/1).
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