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Biosensors have become integrated into our lives. Current technology requires biosensors not only to have high sensitivity but also to have high specificity for one target, while repelling all other molecules and materials in the biological medium. These goals are met by surfaces that combine a biorecognition element and a high‐quality antifouling layer. In this review, we largely focus on polymer brushes that are grafted from the surface, as these are known to exhibit excellent antifouling properties. We also discuss how to functionalize these with biorecognition elements. Based on the current research on antifouling brushes, we recommend using poly(2‐hydroxypropylmethacrylamide) (HPMAA) and/or poly(carboxybetainemethacrylamide) (CBMAA) brushes, with a thickness between 20–30 nm. Furthermore, we note the importance of high polymer chain densities in such brushes and highlight that a proper comparison requires, among others, similar pre‐treatments. These antifouling brushes are biospecific after receptors are integrated with efficient coupling strategies. Here the opportunities and limitations of frequently used approaches of antifouling polymer brushes within biosensors are highlighted. Also, with the resulting combination of high specificity and low (bio‐)chemical noise levels, we envision an increase in the incorporation of novel polymer brushes for the development of stable biospecific sensors. Modern biosensors offer high sensitivity but often struggle with long‐term stability and selectivity for specific targets. Antifouling polymer brushes help enhance both stability and selectivity. In this review, we compare recent antifouling coatings, their design parameters, and how they are integrated with biorecognition elements for improved biosensor performance. We also explore their current applications in the sensing field.

In this paper, we present the development of a photonic biosensor device for cancer treatment monitoring as a complementary diagnostics tool. The proposed device combines multidisciplinary concepts from the photonic, nano-biochemical, micro-fluidic and reader/packaging platforms aiming to overcome limitations related to detection reliability, sensitivity, specificity, compactness and cost issues. The photonic sensor is based on an array of six asymmetric Mach Zender Interferometer (aMZI) waveguides on silicon nitride substrates and the sensing is performed by measuring the phase shift of the output signal, caused by the binding of the analyte on the functionalized aMZI surface. According to the morphological design of the waveguides, an improved sensitivity is achieved in comparison to the current technologies (<5000 nm/RIU). This platform is combined with a novel biofunctionalization methodology that involves material-selective surface chemistries and the high-resolution laser printing of biomaterials resulting in the development of an integrated photonics biosensor device that employs disposable microfluidics cartridges. The device is tested with cancer patient blood serum samples. The detection of periostin (POSTN) and transforming growth factor beta-induced protein (TGFBI), two circulating biomarkers overexpressed by cancer stem cells, is achieved in cancer patient serum with the use of the device.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic has once more emphasized the urgent need for accurate and fast point-of-care (POC) diagnostics for outbreak control and prevention. The main challenge in the development of POC in vitro diagnostics (IVD) is to combine a short time to result with a high sensitivity, and to keep the testing cost-effective. In this respect, sensors based on photonic integrated circuits (PICs) may offer advantages as they have features such as a high analytical sensitivity, capability for multiplexing, ease of miniaturization, and the potential for high-volume manufacturing. One special type of PIC sensor is the asymmetric Mach–Zehnder Interferometer (aMZI), which is characterized by a high and tunable analytical sensitivity. The current work describes the application of an aMZI-based biosensor platform for sensitive and multiplex detection of anti-SARS-CoV-2 antibodies in human plasma samples using the spike protein (SP), the receptor-binding domain (RBD), and the nucleocapsid protein (NP) as target antigens. The results are in good agreement with several CE-IVD marked reference methods and demonstrate the potential of the aMZI biosensor technology for further development into a photonic IVD platform.

Due to the ongoing miniaturization of semiconductor devices, there is a significant interest in the surface modification of silicon. In this perspective, organic monolayers directly bound to oxide-free silicon are interesting candidates as they can easily be implemented in the existing technology for fabrication of silicon-based micro- and nanostructured devices. The direct covalent linkage (Si–C bond) to the silicon surface creates a well-defined organic monolayer-silicon interface and makes these monolayers thermally and chemically very robust. Moreover, because an intervening SiO2 layer is essentially absent, direct electronic coupling between any organic functionality and the silicon substrate is possible, which provides an opportunity to enhance the device performance compared to SiO2-covered devices. As a result these monolayers have great potential in the field of biosensing and optoelectronic devices. At the start of this work we delineated the factors that still limited this potential, with the aim to push the barriers forward. First of all, the oxide-free monolayer-silicon interface typically has a limited long-term stability. Furthermore, because many functional groups are reactive towards a H-Si surface, only a few robust functional monolayers had been described in literature. In addition, only a limited number of patterning routes for this type of monolayers had been reported. Since these three issues hamper the development and fabrication of functional hybrid organic monolayer-silicon devices, the fundamental work presented in this thesis focused on solving the abovementioned problems. After a general introduction in Chapter 1, a new and very mild method to produce covalently bound organic monolayers on hydrogen-terminated Si from 1-alkynes is described in Chapter 2. Because monolayer formation even occurs at room temperature in the dark, i.e. without any external activation, this is the mildest method reported thus far. Since at the same time this method yields the highest quality yet reported for organic monolayers on Si, as indicated by water contact angles, infrared reflection absorption spectroscopy (IRRAS) and X-ray photoelectron spectroscopy (XPS), this has become the new standard for making such monolayers. To pinpoint the precise origin of this self-assembly process, we compared the reactivity of 1-alkenes and 1-alkynes towards H-Si(111) in Chapter 3. As follows from the development of the static water contact angle during reaction, 1-alkynes are considerably more reactive towards H-Si(111) than 1-alkenes, which is attributed to the higher nucleophilicity of 1-alkynes, a better stabilization of the β-radical, and a lower energy barrier for H-abstraction (Figure 1). In practice the higher reactivity of 1-alkynes will further extend the range of functional groups that can be attached directly onto H-Si, and will lead to an easier and more reproducible preparation of oxide-free monolayers on Si. In Chapter 4 we studied the influence of the different linkages to the Si surface (Si–C–C versus Si–C=C) on the final monolayer structure. For this purpose organic monolayers were prepared from 1-alkenes and 1-alkynes with chain lengths from C12 to C18. Although the static contact angles were similar for all monolayers, ellipsometry, ATR-IR and quantitative XPS revealed a higher packing density, higher ordering and smaller tilt angles with respect to the surface normal for the alkenyl monolayers. As expected, the surfaces coverages for alkyl monolayers was determined to be 50-55%, but for the alkenyl monolayers it increased with the chain length from 55% for C12 to as high as 65% for C18, and thus starts to approach the theoretical maximum of 69% for long alkyl (and alkenyl) monolayers on HSi(111). Following Chapter 4, in Chapter 5 molecular modeling experiments and composite highquality G3 calculations were combined to clarify the observed structural differences of alkyl and alkenyl monolayers on Si(111). It was found that due to the smaller Van der Waals radius of the Si–C=C linkage and the larger exothermicity of the reaction substitution percentages > 50% become feasible. In combination with the oxidationinhibiting nature of the Si–C=C linkage, this significantly increases the chance of successful implementation of organic monolayers on oxide-free silicon into molecular electronic and biosensor devices. In Chapter 6 the benefits of 1-alkynes were put into practice and well-defined acid fluoride-terminated monolayers, without any sign of upside-down attachment, were prepared on Si(111). These acid fluoride monolayers were used as a platform for reactive microcontact printing (CP) with an n-hexadecylamine-inked PDMS stamp, and yield within a minute well-defined 5 m N-hexadecylamide dots on the surface (Figure 2). The high and selective reactivity of the acid fluorides towards primary amines even allowed printing of functionalized oligo-DNA, which was still accessible for hybridization. Since this indirect printing approach also preserves the oxide-free and well-defined monolayer silicon interface, it is a highly promising technique for the production of new hybrid biosensor and molecular electronic devices. In Chapter 7, photothermal laser patterning of nonfunctional and functional organic monolayers on oxide-free silicon is described with feature sizes down to 100 nm. With a focused laser beam the silicon substrate surface is locally heated, initiating the thermal decomposition of the organic monolayer. Because this process is highly nonlinear in the applied laser power density, sub-wavelength patterning of the organic monolayers was feasible. A variety of multifunctional patterns can be obtained, depending on the starting monolayer, and the possibility of back-filling of the laser-written lines with a new functionality. The flexibility in pattern design, the high writing speeds, and the feasibility for patterning inside complex device geometries, like in microfluidic channels, make photothermal laser patterning a promising technique in the fabrication of new small-scale biosensor and molecular electronic devices. Because a thorough understanding of the charge transport mechanisms through organic monolayers on oxide-free silicon is essential for their implementation in new electronic devices, Chapter 8 describes the electronic characterization of alkyl and alkenyl monolayers on moderately and highly doped n-Si(111) substrates. For the first time it is shown that the electric behavior of monolayers is dependent on the doping of the silicon: on moderately doped n-Si charge transport through the junction is a minority-carrier process at reverse and low forward bias, and is controlled by series resistance at higher forward bias, and thus the alkyl and alkenyl monolayers exhibited nearly identical electrical properties. However, when using highly doped n-Si as substrate, the internal barrier is smaller and thus charge transport though the junction is majority-carrier controlled and sensitive for the type of monolayer in the junctions. It is proposed that the double bond in the alkenyl monolayers increases the coupling between the organic monolayer and the Si substrate, enhancing the contact conductance, which in turn increases the current density at a given bias. Chapter 9 describes the preparation of two bent-core liquid crystalline monolayers on HSi and the characterization thereof. The monolayer thickness, as determined with X-ray reflectivity, ellipsometry and ATR-IR, corresponded well with the layer spacing of these molecules in the liquid crystalline smectic phase, suggesting that even when covalently bound to a surface the mesogens retain their liquid crystalline ordering properties. Due to the similarity of ordering in the monolayer and ordering in the liquid crystalline bulk, these monolayers can be used as thin alignment layers for switchable smectic liquid crystalline materials. Finally, Chapter 10 discusses several outstanding mechanistic and application-oriented issues and provides recommendations for further research.

We compare the charge transport characteristics of heavy doped p- and n-Si-alkyl chain/Hg junctions. Photoelectron spectroscopy (UPS, IPES and XPS) results for the molecule-Si band alignment at equilibrium show the Fermi level to LUMO energy difference to be much smaller than the corresponding Fermi level to HOMO one. This result supports the conclusion we reach, based on negative differential resistance in an analogous semiconductor-inorganic insulator/metal junction, that for both p- and n-type junctions the energy difference between the Fermi level and LUMO, i.e., electron tunneling, controls charge transport. The Fermi level-LUMO energy difference, experimentally determined by IPES, agrees with the non-resonant tunneling barrier height deduced from the exponential length-attenuation of the current.

Electronic transport across n-Si-alkyl monolayer/Hg junctions is, at reverse and low forward bias, independent of alkyl chain-length from 18 down to 1 or 2 carbons! This and further recent results indicate that electron transport is minority, rather than majority carrier-dominated, occurs via generation and recombination, rather than (the earlier assumed) thermionic emission and, as such is rather insensitive to interface properties. The (m)ethyl results show that binding organic molecules directly to semiconductors provides semiconductor/metal interface control options, not accessible otherwise.

The worldwide antibiotic crisis has led to a renewed interest in phage therapy. Since time immemorial phages control bacterial populations on Earth. Potent lytic phages against bacterial pathogens can be isolated from the environment or selected from a collection in a matter of days. In addition, phages have the capacity to rapidly overcome bacterial resistances, which will inevitably emerge. To maximally exploit these advantage phages have over conventional drugs such as antibiotics, it is important that sustainable phage products are not submitted to the conventional long medicinal product development and licensing pathway. There is a need for an adapted framework, including realistic production and quality and safety requirements, that allowsa timely supplying of phage therapy products for ‘personalized therapy’ or for public health or medical emergencies. This paper enumerates all phage therapy product related quality and safety risks known to the authors, as well as the tests that can be performed to minimize these risks, only to the extent needed to protect the patients and to allow and advance responsible phage therapy and research.