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Über dieses Buch

This thesis presents a theoretical and experimental approach for the rapid fabrication, optimization and testing of holographic sensors for the quantification of pH, organic solvents, metal cations, and glucose in solutions.

Developing non-invasive and reusable diagnostics sensors that can be easily manufactured will support the monitoring of high-risk individuals in any clinical or point-of-care setting. Sensor fabrication approaches outlined include silver-halide chemistry, laser ablation and photopolymerization. The sensors employ off-axis Bragg diffraction gratings of ordered silver nanoparticles and localized refractive index changes in poly (2-hydroxyethyl methacrylate) and polyacrylamide films. The sensors exhibited reversible Bragg peak shifts, and diffracted the spectrum of narrow-band light over the wavelength range λpeak ≈ 495-1100 nm. Clinical trials of glucose sensors in the urine samples of diabetic patients demonstrated that they offer superior performance compared to commercial high-throughput urinalysis devices. Lastly, a generic smartphone application to quantify colorimetric tests was developed and tested for both Android and iOS operating systems. The sensing platform and smartphone application may have implications for the development of low-cost, reusable and equipment-free point-of-care diagnostic devices.

Inhaltsverzeichnis

Frontmatter

Chapter 1. Point-of-Care Diagnostics

Abstract
Rapid tests that are low-cost and portable are the first line of defence in healthcare systems. Dipstick and lateral-flow are the two universal assay formats as they are lightweight and compact, and provide qualitative results without external instrumentation. However, existing formats have limitations in the quantification of analyte concentrations. Hence, the demand for sample preparation, improved sensitivity and user-interface has challenged the commercial products. Recently, capabilities, sensors and readout devices were expanded to multiplexable assays platforms, which might transcend the capabilities of existing design format of diagnostic tests. This chapter outlines the evolution of diagnostic devices and current trends in the development of qualitative and quantitative sensing devices for applications in healthcare, veterinary medicine, environmental monitoring and food safety. The chapter also discusses design parameters for diagnostics, their functionalisation to increase the capabilities and the performance, emerging sensing platforms and readout technologies. The factors which limit the emerging rapid diagnostics to become commercial products are also discussed.
Ali Kemal Yetisen

Chapter 2. Fundamentals of Holographic Sensing

Abstract
Optical devices that reversibly respond to external stimuli can provide fast, quantitative, visual colorimetric readouts in real-time. They may consist of bioactive recognition elements that can transmit the signal through a transducer embedded within the system. Responsive photonic structures may have applications in chemical, biological and physical sensors for medical diagnostics, veterinary screening, environmental monitoring, pharmaceutical bioassays, optomechanical sensing and security applications. This chapter provides an overview of the fabrication of optical devices, and highlights holography as a practical approach for the rapid construction of optical sensors that operate in the visible spectrum and near infrared. It begins with describing the fundamentals of holography and origins of holographic sensors. The chapter also explains the principle of operation of these devices and discusses the design parameters that affect the readouts. The principles of laser light interference during sensor fabrication and photochemical patterning are discussed. Furthermore, computational readout simulations of a generic holographic sensor through a finite element method are demonstrated. Studied design parameters include optical effects due to lattice spacing, nanoparticle (NP) size and concentration, number of stacks, their distribution, and lattice deficiencies within the sensor. Computational simulations allow designing holographic sensors with predictive optical characteristics.
Ali Kemal Yetisen

Chapter 3. Holographic pH Sensors

Abstract
Dynamic photonic structures can be modulated by changing the periodic structure and/or the index of refraction. These dynamic photonic structures allow responsive capability for sensing external stimuli to control the properties of light and act as optical transducers. Dynamic optical systems operating in the visible and near-infrared region offer promise for designing adaptive materials and sensors. Such devices have been prepared by microfabrication, self-assembly or a combination of both. However, achieving the attributes of a narrow-band response with a wide operating range to construct optical sensors in a few steps in hydrophilic polymers still remains a challenge. This chapter describes the construction of holographic pH sensors by silver chemistry and laser ablation induced in situ size reduction of Ag0 NPs in hydrogel matrices using Denisyuk reflection holography. The holographic sensor consists of chemical-stimuli responsive hydrogels with reversible narrow-band tuneability using Ag0 NPs that are organised in density-concentrated 3D regions. The optical characteristics of these sensors were investigated by analysing the distribution of the mean diameter of Ag0 NPs, effective refractive indices of patterned polymer-NP regions, and angular-resolved measurements. The clinical utility of the sensor for the quantification of pH in artificial urine was demonstrated. The chapter also shows strategies for fabricating holographic flakes and paper-based holographic sensors.
Ali Kemal Yetisen

Chapter 4. Holographic Metal Ion Sensors

Abstract
The quantification of metal ions has applications in medical diagnostics, veterinary screening and environmental monitoring. This chapter describes the development of a holographic metal ion sensor through photopolymerisation. In contrast to the nanoparticles (NPs) in silver halide chemistry, porphyrin molecules were chosen for the construction of metal NP-free holographic sensors. A porphyrin derivative with acrylate groups was synthesised to crosslink 2-hydroxyethyl methacrylate monomers. The porphyrin derivative also served as the light-absorbing material and cation chelating agent. A single pulse of a Nd:YAG laser (λ = 532 nm, 6 ns, 350 mJ) in Denisyuk reflection holography mode allowed formation of Bragg diffraction gratings within the porphyrin cross-linked polymer matrix. Holographic sensors had a reversible narrow-band tuneability within the visible spectrum to report on organic solvents in water as a proof of concept, and concentrations of metal cations such as Cu2+ and Fe2+ in aqueous media. The quantification of Cu2+ ions has a potential application in the diagnosis of Wilson’s disease, a genetic disorder in which copper accumulates in the tissues. Similarly, the measurement of Fe2+ ions may help the diagnosis of hemochromatosis, hemolytic anemia, paroxysmal nocturnal hemoglobinemia, and impaired biliary clearance.
Ali Kemal Yetisen

Chapter 5. Holographic Glucose Sensors

Abstract
Rapid glucose sensors have applications in the screening, diagnosis and monitoring of diabetes at point of care. This chapter demonstrates the design, fabrication and clinical trial of reusable holographic glucose sensors. Holographic sensors comprised boronic acid derivative functionalised acrylamide matrices, which consisted of Bragg diffraction gratings that colorimetrically report on the concentration of glucose in aqueous solutions. The optical properties of the sensor were designed and characterised by computational analysis. The sensors were fabricated by combining the advantages of multi-beam interference and in situ size reduction of silver metal (Ag0) nanoparticles (NPs) by single-pulse laser writing. Fully-quantitative narrow-band (monochromatic) readouts were attained through spectrophotometry. The advantages of holographic sensors over other sensing mechanisms are (i) reusability, (ii) amenable to mass manufacturing through laser writing, (iii) readouts in visible as well as near-infrared regions of the spectrum, and (v) reproducibility to sense glucose concentrations up to 400 mM using a low sample volume (<500 μl). Interference due to other metabolites such as lactate and fructose was also evaluated. Trials of the sensor in the urine samples of diabetic patients demonstrated that the sensor had improved performance as compared to Multistix® 10 SG read by CLINITEK Status®, while having comparable performance with fully-automated Dimension® Clinical Chemistry System. Holographic glucose sensors may have clinical applicability for diabetes screening or diagnosis of bacterial urinary tract infections.
Ali Kemal Yetisen

Chapter 6. Mobile Medical Applications

Abstract
The development of medical smartphone applications (apps) can allow quantification of rapid diagnostics at point-of-care and enable clinical data collection in real time. Mobile medical apps can reduce the erroneous subjective readouts, and create a standard readout platform with connectivity options at low cost. This chapter demonstrates the development of an app algorithm that utilises the camera of the Android and iPhone smartphones to read colorimetric tests. This smartphone app can be used with dipsticks, lateral-flow and flow-through assays as well as aqueous colorimetric tests that are typically read by spectrophotometers or microplate readers. The mobile app was designed to provide on-site quantitative screening when rapid diagnosis is needed. The utility of the smartphone app was demonstrated through quantifying pH, the concentrations of protein and glucose in commercial urine test strips, which had linear responses in the ranges of 5.0–9.0, 15–100 and 50–300 mg/dL, respectively. The app can be adapted for semi-quantitative analysis of commercial colorimetric tests, rendering it an inexpensive and accessible alternative to more costly commercial readers.
Ali Kemal Yetisen

Chapter 7. The Prospects for Holographic Sensors

Abstract
The development of rapid and low-cost optical sensors can enable monitoring of high-risk individuals at point of care. This thesis described the design, fabrication and optimisation of holographic pH, divalent metal cation, and glucose sensors. Holographic sensing is an emerging analytical platform that allows semi-quantitative colorimetric readouts by eye and fully-quantitative results by spectrophotometry. They have the added advantage of being rapidly fabricated using laser light and having precise control over the optical characteristics as compared to other optical sensors. This chapter discusses potential areas of research in (i) fabricating holographic sensors, (ii) functionalising the hydrogel matrices to increase the capabilities and the performance, (iii) multiplexing holographic sensors through microfluidics, and (iv) extracting quantitative readouts via smartphone and wearable devices. Additionally, this chapter identifies the gaps within the field, outlines the strategies to overcome the perceived limitations of holographic sensors, and includes challenges to scaling up and commercialisation.
Ali Kemal Yetisen
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