Size-Dependent Deformation of Nanocrystalline Pt Nanopillars

We report the synthesis, mechanical properties, and deformation mechanisms of polycrystalline, platinum nanocylinders of grain size d = 12 nm. The number of grains across the diameter, D/d, was varied from 5 to 80 and 1.5 to 5 in the experiments and molecular dynamics simulations, respectively. An abrupt weakening is observed at a small D/d, while the strengths of large nanopillars are similar to bulk. This “smaller is weaker” trend is opposite to the “smaller is stronger” size effect in single crystalline nanostructures. The simulations demonstrate that the size-dependent behavior is associated with the distinct deformation mechanisms operative in interior versus surface grains

Review of the current TB human infection studies for use in accelerating TB vaccine development: A meeting report

Tools to evaluate and accelerate tuberculosis (TB) vaccine development are needed to advance global TB control strategies. Validated human infection studies for TB have the potential to facilitate breakthroughs in understanding disease pathogenesis, identify correlates of protection, develop diagnostic tools, and accelerate and de-risk vaccine and drug development. However, key challenges remain for realizing the clinical utility of these models, which require further discussion and alignment amongst key stakeholders. In March 2023, the Wellcome Trust and the International AIDS Vaccine Initiative (IAVI) convened international experts involved in developing both TB and Bacillus Calmette-Guerin (BCG) human infection studies (including mucosal and intradermal challenge routes) to discuss the status of each of the models and the key enablers to move the field forward. This report provides a summary of the presentations and discussion from the meeting. Discussions identified key issues, including demonstrating model validity, to provide confidence for vaccine developers, which may be addressed through demonstration of known vaccine effects, e.g. BCG vaccination in specific populations, and by comparing results from field efficacy and human infection studies. The workshop underscored the importance of establishing safe and acceptable studies in high-burden settings, and the need to validate more than one model to allow for different scientific questions to be addressed as well as to provide confidence to vaccine developers and regulators around use of human infection study data in vaccine development and licensure pathways

Renal clearable catalytic gold nanoclusters for in vivo disease monitoring

Ultra-small gold nanoclusters (AuNCs) have emerged as agile probes for in vivo imaging, as they exhibit exceptional tumour accumulation and efficient renal clearance properties. However, their intrinsic catalytic activity, which can enable increased detection sensitivity, has yet to be explored for in vivo sensing. By exploiting the peroxidase-mimicking activity of AuNCs and the precise nanometer size filtration of the kidney, we designed multifunctional protease nanosensors that respond to disease microenvironments to produce a direct colorimetric urinary readout of disease state in less than 1 h. We monitored the catalytic activity of AuNCs in collected urine of a mouse model of colorectal cancer where tumour-bearing mice showed a 13-fold increase in colorimetric signal compared to healthy mice. Nanosensors were eliminated completely through hepatic and renal excretion within 4 weeks after injection with no evidence of toxicity. We envision that this modular approach will enable rapid detection of a diverse range of diseases by exploiting their specific enzymatic signatures

Catalytic nanomaterials for amplified biosensing

Accurate, timely, and sensitive diagnosis is the first step in appropriately treating disease. The development of diagnostics that can be used in non-hospital and point-of-care (PoC) settings is key for democratizing access to disease diagnosis and treatment when it is most effective. The application of PoC diagnostics in early disease detection is often limited due to insufficient sensitivity for the short time frames and limited resources available in these settings. To overcome these challenges, this thesis presents the synthesis, characterization, and application of catalytic nanomaterials for signal amplification and enhanced sensitivity in PoC diagnostic platforms. The nanomaterials developed here span a broad size regime from 1.5 nm clusters of atoms to 300 nm diameter particles and have been demonstrated for use in both in vitro and in vivo biosensing platforms. The platinum and gold nanomaterials exhibited robust and efficient peroxidase-like activity in their ability to oxidize chromogenic substrates in the presence of hydrogen peroxide to generate additional colored signals that could be used for amplification of disease detection, even after exposure to harsh conditions such as elevated temperatures. The larger catalytic nanomaterials were employed as extraordinarily stable and highly amplifying labels in a simple paper-based lateral flow assay (LFA). The nanocatalyst-labeled LFA surpassed the sensitivities of both commercial and published reports to date for paper-based detection of p24, one of the earliest and most conserved biomarkers of HIV. The smaller catalytic nanoclusters were efficiently renally cleared and were deployed in a modular nanosensor platform to monitor disease-associated protease activity in vivo. Catalytic activity of cleared gold nanoclusters in collected urine provided a simple, sensitive, and rapid colorimetric urinary readout of disease state. The clinical utility of both platforms presented here was investigated through detection of acute phase HIV in clinical human plasma samples using the nanocatalyst-labeled LFA, and successful non-invasive detection of tumors in a mouse model of colorectal cancer using the protease-nanosensors with colorimetric urinary readout. This thesis demonstrates the broad applicability and versatility of catalytic nanoparticle amplification for use in disease detection. A pipeline for further development of both sensing platforms for detection of other biomolecules at the PoC is presented.Open Acces

Renal clearable catalytic gold nanoclusters for in vivo disease monitoring

Ultrasmall gold nanoclusters (AuNCs) have emerged as agile probes for in vivo imaging, as they exhibit exceptional tumour accumulation and efficient renal clearance properties. However, their intrinsic catalytic activity, which can enable an increased detection sensitivity, has yet to be explored for in vivo sensing. By exploiting the peroxidase-mimicking activity of AuNCs and the precise nanometre-size filtration of the kidney, we designed multifunctional protease nanosensors that respond to disease microenvironments to produce a direct colorimetric urinary readout of the disease state in less than one hour. We monitored the catalytic activity of AuNCs in the collected urine of a mouse model of colorectal cancer in which tumour-bearing mice showed a 13-fold increase in colorimetric signal compared to healthy mice. The nanosensors were eliminated completely through hepatic and renal excretion within four weeks of injection with no evidence of toxicity. We envision that this modular approach will enable the rapid detection of a diverse range of diseases by exploiting their specific enzymatic signatures.National Institute of Environmental Health Sciences (Grant P30-ES002109)NIH/NIGMS (Grant T32-GM008313

Platinum Nanocatalyst Amplification: Redefining the Gold Standard for Lateral Flow Immunoassays with Ultrabroad Dynamic Range

Paper-based lateral flow immunoassays (LFIAs) are one of the most widely used point-of-care (PoC) devices; however, their application in early disease diagnostics is often limited due to insufficient sensitivity for the requisite sample sizes and the short time frames of PoC testing. To address this, we developed a serum-stable, nanoparticle catalyst-labeled LFIA with a sensitivity surpassing that of both current commercial and published sensitivities for paper-based detection of p24, one of the earliest and most conserved biomarkers of HIV. We report the synthesis and characterization of porous platinum core–shell nanocatalysts (PtNCs), which show high catalytic activity when exposed to complex human blood serum samples. We explored the application of antibody-functionalized PtNCs with strategically and orthogonally modified nanobodies with high affinity and specificity toward p24 and established the key larger nanoparticle size regimes needed for efficient amplification and performance in LFIA. Harnessing the catalytic amplification of PtNCs enabled naked-eye detection of p24 spiked into sera in the low femtomolar range (<i>ca</i>. 0.8 pg·mL^–1) and the detection of acute-phase HIV in clinical human plasma samples in under 20 min. This provides a versatile absorbance-based and rapid LFIA with sensitivity capable of significantly reducing the HIV acute phase detection window. This diagnostic may be readily adapted for detection of other biomolecules as an ultrasensitive screening tool for infectious and noncommunicable diseases and can be capitalized upon in PoC settings for early disease detection