Asymmetric Mach-Zehnder Interferometric Biosensing for Quantitative and Sensitive Multiplex Detection of Anti-SARS-CoV-2 Antibodies in Human Plasma.

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.

Formation of Polyrotaxane Particles via Template Assembly.

In this study, we report a versatile method to assemble tunable poly(ethylene glycol) (PEG)-based polyrotaxane (PRX) particles and capsules. By threading α-cyclodextrins (αCDs) onto PEG chains physically adsorbed onto template particles and subsequently dissolving the templates, PRX replica particles and hollow capsules are formed. This approach overcomes issues related to CD steric hindrance, and also reduces the multiple processing steps often associated with PRX-based particle formation. By simple variation of the molecular weight and end-group functionality of the PEG, we show that the rate of particle degradation as well as the stability of the particles can be tuned. We also demonstrate the loading and release of model (drug) compounds, achieving burst and controlled release of the compounds. It is envisaged that this approach will provide a flexible platform for the engineering of a diverse range of PRX-based particles, enabling PRX materials to be further explored in various applications.

Nanoparticles assembled via pH-responsive reversible segregation of cyclodextrins in polyrotaxanes.

Supramolecular polymers with monomers bound together by secondary interactions, such as polyrotaxanes (PRXs), consisting of alpha cyclodextrin (αCD) threaded onto poly(ethylene glycol) (PEG), have attracted interest as a result of their ability to overcome physical limitations present in conventional, covalently structured polymers. Herein, we describe the formation of pH-responsive supramolecular assemblies from carboxyethylester bearing αCD and PEG PRXs. These PRXs were formed using PEG of Mw 20 kDa and a threading degree of 28%. Upon charge neutralisation the threaded αCDs co-localise, resulting in aggregation of the PRXs and the formation of a suspension by self-assembly. This process is shown to be reversible and possible via the mobility of CDs along the PEG guest chain. As a result of the inherent properties of PRXs, such as enhanced multivalent interactions and degradation, these responsive supramolecular polymers are expected to be of interest in fields where PRX-based materials have already found application, including paints, self-healing materials, surface coatings, and polymer therapeutics.

Morphology change and improved efficiency in organic photovoltaics via hexa-peri-hexabenzocoronene templates.

The morphology of the active layer in organic photovoltaics (OPVs) is of crucial importance as it greatly influences charge generation and transport. A templating interlayer between the electrode and the active layer can change active layer morphology and influence the domain orientation. A series of amphiphilic interface modifiers (IMs) combining a hydrophilic polyethylene-glycol (PEG) oligomer and a hydrophobic hexabenzocoronene (HBC) were designed to be soluble in PEDOT:PSS solutions, and surface accumulate on drying. These IMs are able to self-assemble in solution. When IMs are deposited on top of a poly(3,4-ethylenedioxythiophene) poly(styrenesulfonate) (PEDOT:PSS) film, they induce a morphology change of the active layer consisting of discotic fluorenyl-substituted HBC (FHBC) and [6,6]-phenyl C61-butyric acid methyl ester (PCBM). However, when only small amounts (0.2 wt %) of IMs are blended into PEDOT:PSS, a profound change of the active layer morphology is also observed. Morphology changes were monitored by grazing incidence wide-angle X-ray scattering (GIWAXS), transmission electron microscopy (TEM), TEM tomography, and low-energy high-angle angular dark-field scanning transmission electron microscopy (HAADF STEM). The interface modification resulted in a 20% enhancement of power conversion efficiency.

Self-assembled stimuli-responsive polyrotaxane core-shell particles.

Thermodynamically assembled core-shell nanocarriers are potential candidates for drug delivery applications due to their submicrometer size and the ability to load drugs into their hydrophobic core. Herein, we describe the formation of core-shell particles that consist of noncovalent polymers, that is, polyrotaxanes (PRXs), that form an α-cyclodextrin (αCD) core surrounded by a corona of low-fouling poly(ethylene glycol) (PEG). The PRX core-shell particles are able to sequester small organic molecules, such as pyrene and calcein, releasing these small molecules during degradation. The small, cellular peptide, glutathione, was used to degrade the particles through the reductive cleavage of disulfide bonds that stabilize the individual PRX polymers. Cleavage of a single bond allows for the degradation of the supramolecular-polymer, making these PRX core-shell particles highly responsive. Furthermore, these particles demonstrate negligible cytotoxicity in mammalian cells, making them promising carriers for future drug delivery research.

Mechanics of pH-responsive hydrogel capsules.

While soft hydrogel nano- and microstructures hold great potential for therapeutic treatments and in vivo applications, their nanomechanical characterization remains a challenge. In this paper, soft, single-component, supported hydrogel films were fabricated using pendant-thiol-modified poly(methacrylic acid) (PMASH). The influence of hydrogel architecture on deformation properties was studied by fabricating films on particle supports and producing free-standing capsules. The influence of the degree of thiol-based cross-linking on the mechanical properties of the soft hydrogel systems (core-shell and capsules) was studied using a colloidal-probe (CP) AFM technique. It was found that film mechanical properties, stability, and capsule swelling could be finely tuned by controlling the extent of poly(methacrylic acid) thiol modification. Furthermore, switching the pH from 7.4 to 4.0 led to film densification due to increased hydrogen bonding. Hydrogel capsule systems were found to have stiffness values ranging from 0.9 to 16.9 mN m(-1) over a thiol modification range of 5 to 20 mol %. These values are significantly greater than those for previously reported PMASH planar films of 0.7-5.7 mN m(-1) over the same thiol modification range (Best et al., Soft Matter 2013, 9, 4580-4584). Films on particle substrates had comparable mechanical properties to planar films, demonstrating that while substrate geometry has a negligible effect, membrane and tension effects may play an important role in capsule force resistance. Further, when transitioning from solid-supported films to free-standing capsules, simple predictions of shell stiffness based on modulus changes found for supported films are not valid. Rather, additional effects like diameter increases (geometrical changes) as well as tension buildup need to be taken into account. These results are important for research related to the characterization of soft hydrogel materials and control over their mechanical properties.

Formation and degradation of layer-by-layer-assembled polyelectrolyte polyrotaxane capsules.

We report the preparation of degradable capsules via layer-by-layer assembly using polyelectrolyte (PE) polyrotaxanes (PRXs). The PRX capsules were prepared by the sequential deposition of PRXs onto silica particles followed by the dissolution of the silica cores. The colloidal stability of the PRX capsules that are formed depends on the salt/buffer solution used in the assembly process. Various salt/buffer combinations were examined to avoid aggregation of the core-shell particles during PRX assembly and core dissolution. Using appropriate assembly conditions, we prepared colloidally stable, robust capsules. PRX capsules consisting of eight layers of PE PRXs had a wall thickness of ~15 nm. The degradation of the PRX capsules was demonstrated through the disassembly of the PE PRXs using glutathione, which cleaves the disulfide bonds linking the end-capping groups of the PE PRXs. Given the supramolecular noncovalent structure of PRXs and their adjustable properties, it is expected that PRXs will be used as building blocks for assembling advanced capsules with unique and tailored properties.

Modular click assembly of degradable capsules using polyrotaxanes.

A modular approach for the formation of degradable capsules using polyrotaxanes (PRXs) is described. The PRXs consist of α-cyclodextrin (αCD) and poly(ethylene glycol) (PEG), which are both biologically benign and the main degradation products of the capsules. The PRXs were equipped with three alkyne groups at their ends and could be successfully grafted to azide-functionalized silica particles (2.76 µm diameter) using azide-alkyne click chemistry. The assembled PRXs were then cross-linked using a degradable linker. The cross-linked structure was sufficiently robust to allow the formation of capsules after dissolving the template silica particles. The formation of capsules of ca. 2 µm diameter was verified by optical microscopy, TEM, and AFM imaging. The capsules were loaded with the chemotherapy drug doxorubicin (DOX) by conjugating it to the threaded αCDs via their free OH groups, while maintaining degradability of the capsules. Alkyne moieties at the surface of the cross-linked PRX architecture were available for further functionalization of the capsules, as is demonstrated by clicking on fluorescent PEG moieties. The DOX-loaded capsules were degraded within 90 min at 37 °C upon exposure to a 5 mM solution of glutathione in water.

Probing multivalent interactions in a synthetic host-guest complex by dynamic force spectroscopy.

Multivalency is present in many biological and synthetic systems. Successful application of multivalency depends on a correct understanding of the thermodynamics and kinetics of this phenomenon. In this Article, we address the stability and strength of multivalent bonds with force spectroscopy techniques employing a synthetic adamantane/ß-cyclodextrin model system. Comparing the experimental findings to theoretical predictions for the rupture force and the kinetic off-rate, we find that when the valency of the complex is increased from mono- to di- to trivalent, there is a transition from quasi-equilibrium, with a constant rupture force of 99 pN, to a kinetically dependent state, with loading-rate-dependent rupture forces from 140 to 184 pN (divalent) and 175 to 210 pN (trivalent). Additional binding geometries, parallel monovalent ruptures, single-bound divalent ruptures, and single- and double-bound trivalent ruptures are identified. The experimental kinetic off-rates of the multivalent complexes show that the stability of the complexes is significantly enhanced with the number of bonds, in agreement with the predictions of a noncooperative multivalent model.

Gradient-driven motion of multivalent ligand molecules along a surface functionalized with multiple receptors.

The kinetics of multivalent (multisite) interactions at interfaces is poorly understood, despite its fundamental importance for molecular or biomolecular motion and molecular recognition events at biological interfaces. Here, we use fluorescence microscopy to monitor the spreading of mono-, di- and trivalent ligand molecules on a receptor-functionalized surface, and perform multiscale computer simulations to understand the surface diffusion mechanisms. Analogous to chemotaxis, we found that the spreading is directional (along a developing gradient of vacant receptor sites) and is strongly dependent on ligand valency and concentration of a competing monovalent receptor in solution. We identify multiple surface diffusion mechanisms, which we call walking, hopping and flying. The study shows that the interfacial behaviour of multivalent systems is much more complex than that of monovalent ones.

Targeting of cancer cells using click-functionalized polymer capsules.

Targeted delivery of drugs to specific cells allows a high therapeutic dose to be delivered to the target site with minimal harmful side effects. Combining targeting molecules with nanoengineered drug carriers, such as polymer capsules, micelles and polymersomes, has significant potential to improve the therapeutic delivery and index of a range of drugs. We present a general approach for functionalization of low-fouling, nanoengineered polymer capsules with antibodies using click chemistry. We demonstrate that antibody (Ab)-functionalized capsules specifically bind to colorectal cancer cells even when the target cells constitute less than 0.1% of the total cell population. This precise targeting offers promise for drug delivery applications.

Methodology for the qualitative screening of parallel arrays of potential Am3+ ligands using a photographic film.

A screening method for parallel Am(3+) ligand libraries is presented. The method makes use of alpha-radiation in combination with a photographic film to detect the complexed Am(3+). After screening and development of the film spots of varying intensities are obtained. The intensities of the spots correspond with the amount of complexed Am(3+). This allows a fast discrimination between the Am(3+) complexation efficiencies of ligands from large libraries. Depending on the exposure time of the film, activities as small as 5Bq (241)Am can be detected. Using internal standards a semi-quantitative assessment can be performed.

In the pursuit for better actinide ligands: an efficient strategy for their discovery.

A novel method for the efficient discovery of new types of minor actinide (MA) ligands is based on the unique combination of "tea bag" split pool combinatorial chemistry and screening based on the inherent radioactivity of the complexed cations. Four multicoordinating Am(3+) chelating groups, such as CMPO (diphenylcarbamoylmethyl)phosphine oxide), PICO (picolinamide), DGA (N,N'-dimethyldiglycoldiamide), and MPMA (N-methyl-N-phenylmalonamide), on a trityl platform immobilized on TentaGelS served as a model library for the development of the screening method. This model library was screened under various conditions (i.e., 0.001 M < or = [HNO3] < or = 3 M, NaNO3 < or = 4 M, and [Eu] < or = 10 x [ligand]) showing competitive extraction of the four ligands. Other libraries of 9 and 72 members were synthesized by functionalization of the trityl platform with ligating groups that are composed of four building blocks (including at least one amide and one (phosphoric) hydrazone moiety). The screening of these two libraries resulted in the discovery of two multicoordinate ligands that contain ligating groups previously not known to complex Am(3+). Both are N-isopropyl amides terminated with a p-methoxyphenyl hydrazide (A2B1C1D10 K(D(Am)) = 2197) or a p-nitrophenyl hydrazide (A2B1C1D11 K(D(Am)) =1989) moiety, respectively. They are more efficient than the immobilized tritylCMPO ligand (K(D(Am)) = 1280) at 3 M HNO3. This method has the advantages of a high analytical sensitivity and the direct comparison of the extraction results. The method also allows the competitive screening of multiple nuclides which can be quantified by their radioactive emission spectrum.

Development of a disposable mercury ion-selective optode based on trityl-picolinamide as ionophore.

A disposable ion-selective optode for mercury based on trityl-picolinamide (T-Pico) as neutral ionophore was developed. The sensing layer consist of plasticised PVC incorporating T-Pico as a selective ionophore for Hg2+, ETH 5418 as a chromoionophore, and potassium tetrakis[3,5-bis(trifluoromethyl)phenyl] borate as lipophilic salt. The measurement principle is based on an ion-exchange mechanism. When the optode membrane is introduced into a water sample for 5 min, there is a colour change from red to blue, depending on the mercury concentration (pH 4.7), making it possible to use the absorbance at 665 nm as the analytical signal. The optode membrane response to Hg2+ was not fully reversible; however, it reveals a very good selectivity to many cations including alkali, alkaline earth, transition, and heavy metal ions. The detection limit for Hg2+ is 5.0x10(-7) M at pH 4.7. The response characteristics of the sensor including dynamic range, reproducibility, response time, and lifetime are discussed in detail. This sensor was used for the determination of mercury in environmental water samples with satisfactory recovery.

Multicoordinate ligands for actinide/lanthanide separations.

In nuclear waste treatment processes there is a need for improved ligands for the separation of actinides (An(III)) and lanthanides (Ln(III)). Several research groups are involved in the design and synthesis of new An(III) ligands and in the confinement of these and existing An(III) ligands onto molecular platforms giving multicoordinate ligands. The preorganization of ligands considerably improves the An(III) extraction properties, which are largely dependent on the solubility and rigidity of the platform. This tutorial review summarizes the most important An(III) ligands with emphasis on the preorganization strategy using (macrocyclic) platforms.

Obstacles to adherence in living with type-2 diabetes: an international qualitative study using meta-ethnography (EUROBSTACLE).

Quantitative studies failed to determine variables which consistently explain adherence or non-adherence to treatment recommendations. Qualitative studies identified issues such as the quality of the health provider-health receiver relationship and the patient's health beliefs. According to these findings, 39 focus groups of 246 people living with type-2 diabetes were conducted in seven European countries, assessing health beliefs, communication with caregivers and problems encountered in adhering to treatment regimens. Meta-ethnography was later applied to make a qualitative meta-analysis. Obstacles to adherence are common across countries, and seem to be related less to issues of the health-care system and more to patient's knowledge about diabetes, beliefs and attitudes and the relationship with health-care professionals. The resulting key themes are course of diabetes, information, person and context, body awareness and relationship with the health care provider. Meta-ethnography is a feasible tool for the meta-analysis of multilingual qualitative data and leads to a richer account.

A novel heteroditopic terpyridine-pincer ligand as building block for mono- and heterometallic Pd(II) and Ru(II) complexes.

A palladium-catalyzed Stille coupling reaction was employed as a versatile method for the synthesis of a novel terpyridine-pincer (3, TPBr) bridging ligand, 4'-{4-BrC6H2(CH2NMe2)2-3,5}-2,2':6',2' '-terpyridine. Mononuclear species [PdX(TP)] (X = Br, Cl), [Ru(TPBr)(tpy)](PF6)2, and [Ru(TPBr)2](PF6)2, synthesized by selective metalation of the NCNBr-pincer moiety or complexation of the terpyridine of the bifunctional ligand TPBr, were used as building blocks for the preparation of heterodi- and trimetallic complexes [Ru(TPPdCl)(tpy)](PF6)2 (7) and [Ru(TPPdCl)2](PF6)2 (8). The molecular structures in the solid state of [PdBr(TP)] (4a) and [Ru(TPBr)2](PF6)2 (6) have been determined by single-crystal X-ray analysis. Electrochemical behavior and photophysical properties of the mono- and heterometallic complexes are described. All the above di- and trimetallic Ru complexes exhibit absorption bands attributable to (1)MLCT (Ru --> tpy) transitions. For the heteroleptic complexes, the transitions involving the unsubstituted tpy ligand are at a lower energy than the tpy moiety of the TPBr ligand. The absorption bands observed in the electronic spectra for TPBr and [PdCl(TP)] have been assigned with the aid of TD-DFT calculations. All complexes display weak emission both at room temperature and in a butyronitrile glass at 77 K. The considerable red shift of the emission maxima relative to the signal of the reference compound [Ru(tpy)2]2+ indicates stabilization of the luminescent 3MLCT state. For the mono- and heterometallic complexes, electrochemical and spectroscopic studies (electronic absorption and emission spectra and luminescence lifetimes recorded at room temperature and 77 K in nitrile solvents), together with the information gained from IR spectroelectrochemical studies of the dimetallic complex [Ru(TPPdSCN)(tpy)](PF6)2, are indicative of charge redistribution through the bridging ligand TPBr. The results are in line with a weak coupling between the {Ru(tpy)2} chromophoric unit and the (non)metalated NCN-pincer moiety.

Social support in diabetes: a systematic review of controlled intervention studies.

Systematic, computerized search in Medline, the Cochrane Library, Eric, PsychINFO and Embase files, 1980-2003, selecting descriptions of prospective intervention trials with good methodological design, testing effects of social support interventions on health outcomes in primary and outpatient care for type 2 diabetes. Six controlled trials were reviewed. They defined, modified, and measured social support in various ways, and scored outcomes with varying measures. Gender differences and the right amount of support seem important. Promising new forms of social support: group consultations (better HbA1c and lifestyle), Internet or telephone-based peer support (improved perceived support, increased physical activity, respectively), and social support groups (improved knowledge and psychosocial functioning). No improved diabetes control by classic forms of support, e.g. from spouse (but weight loss in women) and family and friends (no differences). It is tentatively concluded that this review supports the hypothesis that specific social support interventions affect patient self-care and diabetes outcomes. New forms of social support may be discussed and incorporated in the work of diabetes teams, and offered to patients as new possibilities to help them adjust to a life with (type 2) diabetes and make information-based decisions. Only in the group consultations study, diabetes control was protected. More well-designed research testing the effects of specific social support interventions on patient self-care, lifestyle adaptations, and outcomes of diabetes care, is warranted.

Provider-patient interaction in diabetes care: effects on patient self-care and outcomes. A systematic review.

A systematic review of the research literature using Medline, Embase, Psyclit/Psycinfo and the Cochrane Library files 1980 through 2001, identified only eight publications based on well-designed studies involving randomised controlled trials (RCTs)--testing the effects of modification of provider-patient interaction and provider consulting style on patient diabetes self-care and diabetes outcomes, in general practice or hospital outpatient settings. Review of these publications leads to the tentative conclusion that focusing on patient behaviour--directly enhancing patient participation i.e. by assistant-guided patient preparation for visits to doctors, empowering group education, group consultations, or automated telephone management--is more effective than focusing on provider behaviour to change their consulting style into a more patient-centred one. The latter proves hard to sustain, needs intensive support, and is not very effective in improving patient self-care and health outcomes when executed alone. Patient behaviour focused interventions show good efficacy and efficiency, and improve patient self-care and diabetes outcomes. More well-designed intervention studies focusing on enhancing patient participation in primary and hospital outpatient diabetes care are needed.