Enhancing Single Photon Emission Purity via Design of van der Waals Heterostructures.

Quantum emitters are essential components of quantum photonic circuitry envisioned beyond the current optoelectronic state-of-the-art. Two dimensional materials are attractive hosts for such emitters. However, the high single photon purity required is rarely realized due to the presence of spectrally degenerate classical light originating from defects. Here, we show that design of a van der Waals heterostructure effectively eliminates this spurious light, resulting in purities suitable for a variety of quantum technological applications. Single photon purity from emitters in monolayer WSe2 increases from 60% to 92% by incorporating this monolayer in a simple graphite/WSe2 heterostructure. Fast interlayer charge transfer quenches a broad photoluminescence background by preventing radiative recombination through long-lived defect bound exciton states. This approach is generally applicable to other 2D emitter materials, circumvents issues of material quality, and offers a path forward to achieve the ultrahigh single photon purities ultimately required for photon-based quantum technologies.

Immune Potentiation of PLGA Controlled-Release Vaccines for Improved Immunological Outcomes.

With the emergence of SARS-CoV-2 and the continued emergence of new infectious diseases, there is a need to improve and expand current vaccine technology. Controlled-release subunit vaccines provide several benefits over current vaccines on the market, including the use of less antigen and fewer boost doses. Previously, our group reported molecules that alter NF-κB signaling improved the vaccine's performance and improved adjuvant-related tolerability. In this report, we test how these immune potentiators will influence responses when included as part of a controlled-release poly(lactic-co-glycolic) vaccine formulation. Murine in vivo studies revealed that SN50 and honokiol improved antibody levels at early vaccine time points. Microparticles with SN50 produced strong antibody levels over a longer period compared to microparticles without SN50. The same particles also increased T-cell activity. All of the immune potentiators tested further promoted Th2 humoral responses already exhibited by the control CpG OVA microparticle formulation. Overall, under controlled-release conditions, immune potentiators enhance the existing effects of controlled-release formulations, making it a potentially beneficial additive for controlled-release vaccine formulations.

Atomic Defect Quantification by Lateral Force Microscopy.

Atomic defects in two-dimensional (2D) materials impact electronic and optoelectronic properties, such as doping and single photon emission. An understanding of defect-property relationships is essential for optimizing material performance. However, progress in understanding these critical relationships is hindered by a lack of straightforward approaches for accurate, precise, and reliable defect quantification on the nanoscale, especially for insulating materials. Here, we demonstrate that lateral force microscopy (LFM), a mechanical technique, can observe atomic defects in semiconducting and insulating 2D materials under ambient conditions. We first improve the sensitivity of LFM through consideration of cantilever mechanics. With the improved sensitivity, we use LFM to locate atomic-scale point defects on the surface of bulk MoSe2. By directly comparing LFM and conductive atomic force microscopy (CAFM) measurements on bulk MoSe2, we demonstrate that point defects observed with LFM are atomic defects in the crystal. As a mechanical technique, LFM does not require a conductive pathway, which allows defect characterization on insulating materials, such as hexagonal boron nitride (hBN). We demonstrate the ability to observe intrinsic defects in hBN and defects introduced by annealing. Our demonstration of LFM as a mechanical defect characterization technique applicable to both conductive and insulating 2D materials will enable routine defect-property determination and accelerate materials research.

Validating the Use of Conductive Atomic Force Microscopy for Defect Quantification in 2D Materials.

Defects significantly affect the electronic, chemical, mechanical, and optical properties of two-dimensional (2D) materials. Thus, it is critical to develop a method for convenient and reliable defect quantification. Scanning transmission electron microscopy (STEM) and scanning tunneling microscopy (STM) possess the required atomic resolution but have practical disadvantages. Here, we benchmark conductive atomic force microscopy (CAFM) by a direct comparison with STM in the characterization of transition metal dichalcogenides (TMDs). The results conclusively demonstrate that CAFM and STM image identical defects, giving results that are equivalent both qualitatively (defect appearance) and quantitatively (defect density). Further, we confirm that CAFM can achieve single-atom resolution, similar to that of STM, on both bulk and monolayer samples. The validation of CAFM as a facile and accurate tool for defect quantification provides a routine and reliable measurement that can complement other standard characterization techniques.

Data-driven discovery of innate immunomodulators via machine learning-guided high throughput screening.

The innate immune response is vital for the success of prophylactic vaccines and immunotherapies. Control of signaling in innate immune pathways can improve prophylactic vaccines by inhibiting unfavorable systemic inflammation and immunotherapies by enhancing immune stimulation. In this work, we developed a machine learning-enabled active learning pipeline to guide in vitro experimental screening and discovery of small molecule immunomodulators that improve immune responses by altering the signaling activity of innate immune responses stimulated by traditional pattern recognition receptor agonists. Molecules were tested by in vitro high throughput screening (HTS) where we measured modulation of the nuclear factor κ-light-chain-enhancer of activated B-cells (NF-κB) and the interferon regulatory factors (IRF) pathways. These data were used to train data-driven predictive models linking molecular structure to modulation of the NF-κB and IRF responses using deep representational learning, Gaussian process regression, and Bayesian optimization. By interleaving successive rounds of model training and in vitro HTS, we performed an active learning-guided traversal of a 139 998 molecule library. After sampling only ∼2% of the library, we discovered viable molecules with unprecedented immunomodulatory capacity, including those capable of suppressing NF-κB activity by up to 15-fold, elevating NF-κB activity by up to 5-fold, and elevating IRF activity by up to 6-fold. We extracted chemical design rules identifying particular chemical fragments as principal drivers of specific immunomodulation behaviors. We validated the immunomodulatory effect of a subset of our top candidates by measuring cytokine release profiles. Of these, one molecule induced a 3-fold enhancement in IFN-ß production when delivered with a cyclic di-nucleotide stimulator of interferon genes (STING) agonist. In sum, our machine learning-enabled screening approach presents an efficient immunomodulator discovery pipeline that has furnished a library of novel small molecules with a strong capacity to enhance or suppress innate immune signaling pathways to shape and improve prophylactic vaccination and immunotherapies.

Atomic Force Microscopy Methods to Measure Tumor Mechanical Properties.

Atomic force microscopy (AFM) is a popular tool for evaluating the mechanical properties of biological materials (cells and tissues) at high resolution. This technique has become particularly attractive to cancer researchers seeking to bridge the gap between mechanobiology and cancer initiation, progression, and treatment resistance. The majority of AFM studies thus far have been extensively focused on the nanomechanical characterization of cells. However, these approaches fail to capture the complex and heterogeneous nature of a tumor and its host organ. Over the past decade, efforts have been made to characterize the mechanical properties of tumors and tumor-bearing tissues using AFM. This has led to novel insights regarding cancer mechanopathology at the tissue scale. In this Review, we first explain the principles of AFM nanoindentation for the general study of tissue mechanics. We next discuss key considerations when using this technique and preparing tissue samples for analysis. We then examine AFM application in characterizing the mechanical properties of cancer tissues. Finally, we provide an outlook on AFM in the field of cancer mechanobiology and its application in the clinic.

Next-Generation Adjuvants: Applying Engineering Methods to Create and Evaluate Novel Immunological Responses.

Adjuvants are a critical component of vaccines. Adjuvants typically target receptors that activate innate immune signaling pathways. Historically, adjuvant development has been laborious and slow, but has begun to accelerate over the past decade. Current adjuvant development consists of screening for an activating molecule, formulating lead molecules with an antigen, and testing this combination in an animal model. There are very few adjuvants approved for use in vaccines, however, as new candidates often fail due to poor clinical efficacy, intolerable side effects, or formulation limitations. Here, we consider new approaches using tools from engineering to improve next-generation adjuvant discovery and development. These approaches will create new immunological outcomes that will be evaluated with novel diagnostic tools. Potential improved immunological outcomes include reduced vaccine reactogenicity, tunable adaptive responses, and enhanced adjuvant delivery. Evaluations of these outcomes can leverage computational approaches to interpret "big data" obtained from experimentation. Applying engineering concepts and solutions will provide alternative perspectives, further accelerating the field of adjuvant discovery.

Discovery of New States of Immunomodulation for Vaccine Adjuvants via High Throughput Screening: Expanding Innate Responses to PRRs.

Stimulation of the innate immune system is crucial in both effective vaccinations and immunotherapies. This is often achieved through adjuvants, molecules that usually activate pattern recognition receptors (PRRs) and stimulate two innate immune signaling pathways: the nuclear factor kappa-light-chain-enhancer of activated B-cells pathway (NF-κB) and the interferon regulatory factors pathway (IRF). Here, we demonstrate the ability to alter and improve adjuvant activity via the addition of small molecule "immunomodulators". By modulating signaling activity instead of receptor binding, these molecules allow the customization of select innate responses. We demonstrate both inhibition and enhancement of the products of the NF-κB and IRF pathways by several orders of magnitude. Some modulators apply generally across many receptors, while others focus specifically on individual receptors. Modulators boost correlates of a protective immune responses in a commercial flu vaccine model and reduced correlates of reactogenicity in a typhoid vaccine model. These modulators have a range of applications: from adjuvanticity in prophylactics to enhancement of immunotherapy.

Large-Area Periodic Arrays of Atomically Flat Single-Crystal Gold Nanotriangles Formed Directly on Substrate Surfaces.

The advancement of nanoenabled wafer-based devices requires the establishment of core competencies related to the deterministic positioning of nanometric building blocks over large areas. Within this realm, plasmonic single-crystal gold nanotriangles represent one of the most attractive nanoscale components but where the formation of addressable arrays at scale has heretofore proven impracticable. Herein, a benchtop process is presented for the formation of large-area periodic arrays of gold nanotriangles. The devised growth pathway sees the formation of an array of defect-laden seeds using lithographic and vapor-phase assembly processes followed by their placement in a growth solution promoting planar growth and threefold symmetric side-faceting. The nanotriangles formed in this high-yield synthesis distinguish themselves in that they are epitaxially aligned with the underlying substrate, grown to thicknesses that are not readily obtainable in colloidal syntheses, and present atomically flat pristine surfaces exhibiting gold atoms with a close-packed structure. As such, they express crisp and unambiguous plasmonic modes and form photoactive surfaces with highly tunable and readily modeled plasmon resonances. The devised methods, hence, advance the integration of single-crystal gold nanotriangles into device platforms and provide an overall fabrication strategy that is adaptable to other nanomaterials.

Enhancing the Purity of Deterministically Placed Quantum Emitters in Monolayer WSe2.

We present a method utilizing an applied electrostatic potential for suppressing the broad defect bound excitonic emission in two-dimensional materials (2DMs) which otherwise inhibits the purity of strain induced single photon emitters (SPEs). Our heterostructure consists of a WSe2 monolayer on a polymer in which strain has been deterministically introduced via an atomic force microscope (AFM) tip. We show that by applying an electrostatic potential, the broad defect bound background is suppressed at cryogenic temperatures, resulting in a substantial improvement in single photon purity demonstrated by a 10-fold reduction of the correlation function g(2)(0) value from 0.73 to 0.07. In addition, we see a 2-fold increase in the intensity of the SPEs as well as the ability to activate/deactivate the emitters at certain wavelengths. Finally, we present an increase in the operating temperature of the SPE up to 110 K, a 50 K increase when compared with the results when no electrostatic potential is present.

Emergent Moiré Phonons Due to Zone Folding in WSe2-WS2 Van der Waals Heterostructures.

Bilayers of 2D materials offer opportunities for creating devices with tunable electronic, optical, and mechanical properties. In van der Waals heterostructures (vdWHs) where the constituent monolayers have different lattice constants, a moiré superlattice forms with a length scale larger than the lattice constant of either constituent material regardless of twist angle. Here, we report the appearance of moiré Raman modes from nearly aligned WSe2-WS2 vdWHs in the range of 240-260 cm-1, which are absent in both monolayers and homobilayers of WSe2 and WS2 and in largely misaligned WSe2-WS2 vdWHs. Using first-principles calculations and geometric arguments, we show that these moiré Raman modes are a consequence of the large moiré length scale, which results in zone-folded phonon modes that are Raman active. These modes are sensitive to changes in twist angle, but notably, they occur at identical frequencies for a given small twist angle away from either the 0-degree or 60-degree aligned heterostructure. Our measurements also show a strong Raman intensity modulation in the frequency range of interest, with near 0 and near 60-degree vdWHs exhibiting a markedly different dependence on excitation energy. In near 0-degree aligned WSe2-WS2 vdWHs, a nearly complete suppression of both the moiré Raman modes and the WSe2 A1g Raman mode (∼250 cm-1) is observed when exciting with a 532 nm CW laser at room temperature. Temperature-dependent reflectance contrast measurements demonstrate the significant Raman intensity modulation arises from resonant Raman effects.

Room-Temperature Oxygen Transport in Nanothin BixOySez Enables Precision Modulation of 2D Materials.

Oxygen conductors and transporters are important to several consequential renewable energy technologies, including fuel cells and syngas production. Separately, monolayer transition-metal dichalcogenides (TMDs) have demonstrated significant promise for a range of applications, including quantum computing, advanced sensors, valleytronics, and next-generation optoelectronics. Here, we synthesize a few-nanometer-thick BixOySez compound that strongly resembles a rare R3m bismuth oxide (Bi2O3) phase and combine it with monolayer TMDs, which are highly sensitive to their environment. We use the resulting 2D heterostructure to study oxygen transport through BixOySez into the interlayer region, whereby the 2D material properties are modulated, finding extraordinarily fast diffusion near room temperature under laser exposure. The oxygen diffusion enables reversible and precise modification of the 2D material properties by controllably intercalating and deintercalating oxygen. Changes are spatially confined, enabling sub-micrometer features (e.g., pixels), and are long-term stable for more than 221 days. Our work suggests few-nanometer-thick BixOySez is a promising unexplored room-temperature oxygen transporter. Additionally, our findings suggest that the mechanism can be applied to other 2D materials as a generalized method to manipulate their properties with high precision and sub-micrometer spatial resolution.

Stacking-dependent optical properties in bilayer WSe2.

The twist angle between the monolayers in van der Waals heterostructures provides a new degree of freedom in tuning material properties. We compare the optical properties of WSe2 homobilayers with 2H and 3R stacking using photoluminescence, Raman spectroscopy, and reflectance contrast measurements under ambient and cryogenic temperatures. Clear stacking-dependent differences are evident for all temperatures, with both photoluminescence and reflectance contrast spectra exhibiting a blue shift in spectral features in 2H compared to 3R bilayers. Density functional theory (DFT) calculations elucidate the source of the variations and the fundamental differences between 2H and 3R stackings. DFT finds larger energies for both A and B excitonic features in 2H than in 3R, consistent with experimental results. In both stacking geometries, the intensity of the dominant A1g Raman mode exhibits significant changes as a function of laser excitation wavelength. These variations in intensity are intimately linked to the stacking- and temperature-dependent optical absorption through resonant enhancement effects. The strongest enhancement is achieved when the laser excitation coincides with the C excitonic feature, leading to the largest Raman intensity under 514 nm excitation in 2H stacking and at 520 nm in 3R stacked WSe2 bilayers.

IgG Immune Complexes Inhibit Naïve T Cell Proliferation and Suppress Effector Function in Cytotoxic T Cells.

Elevated levels of circulating immune complexes are associated with autoimmunity and with worse prognoses in cancer. Here, we examined the effects of well-defined, soluble immune complexes (ICs) on human peripheral T cells. We demonstrate that IgG-ICs inhibit the proliferation and differentiation of a subset of naïve T cells but stimulate the division of another naïve-like T cell subset. Phenotypic analysis by multi-parameter flow cytometry and RNA-Seq were used to characterize the inhibited and stimulated T cells revealing that the inhibited subset presented immature features resembling those of recent thymic emigrants and non-activated naïve T cells, whereas the stimulated subset exhibited transcriptional features indicative of a more differentiated, early memory progenitor with a naïve-like phenotype. Furthermore, we show that while IgG1-ICs do not profoundly inhibit the proliferation of memory T cells, IgG1-ICs suppress the production of granzyme-ß and perforin in cytotoxic memory T cells. Our findings reveal how ICs can link humoral immunity and T cell function.

Direct-Write of Nanoscale Domains with Tunable Metamagnetic Order in FeRh Thin Films.

We have directly written nanoscale patterns of magnetic ordering in FeRh films using focused helium-ion beam irradiation. By varying the dose, we pattern arrays with metamagnetic transition temperatures that range from the as-grown film temperature to below room temperature. We employ transmission electron microscopy, X-ray diffraction, and temperature-dependent transport measurements to characterize the as-grown film, and magneto-optic Kerr effect imaging to quantify the He+ irradiation-induced changes to the magnetic order. Moreover, we demonstrate temperature-dependent optical microscopy and conductive atomic force microscopy as indirect probes of the metamagnetic transition that are sensitive to the differences in dielectric properties and electrical conductivity, respectively, of FeRh in the antiferromagnetic (AF) and ferromagnetic (FM) states. Using density functional theory, we quantify strain- and defect-induced changes in spin-flip energy to understand their influence on the metamagnetic transition temperature. This work holds promise for in-plane AF-FM spintronic devices, by reducing the need for multiple patterning steps or different materials, and potentially eliminating interfacial polarization losses due to cross material interfacial spin scattering.

Small Molecule NF-κB Inhibitors as Immune Potentiators for Enhancement of Vaccine Adjuvants.

Adjuvants are added to vaccines to enhance the immune response and provide increased protection against disease. In the last decade, hundreds of synthetic immune adjuvants have been created, but many induce undesirable levels of proinflammatory cytokines including TNF-α and IL-6. Here we present small molecule NF-κB inhibitors that can be used in combination with an immune adjuvant to both decrease markers associated with poor tolerability and improve the protective response of vaccination. Additionally, we synthesize a library of honokiol derivatives identifying several promising candidates for use in vaccine formulations.

Twist Angle-Dependent Atomic Reconstruction and Moiré Patterns in Transition Metal Dichalcogenide Heterostructures.

Van der Waals layered materials, such as transition metal dichalcogenides (TMDs), are an exciting class of materials with weak interlayer bonding, which enables one to create so-called van der Waals heterostructures (vdWH). One promising attribute of vdWH is the ability to rotate the layers at arbitrary azimuthal angles relative to one another. Recent work has shown that control of the twist angle between layers can have a dramatic effect on TMD vdWH properties, but the twist angle has been treated solely through the use of rigid-lattice moiré patterns. No atomic reconstruction, that is, any rearrangement of atoms within the individual layers, has been reported experimentally to date. Here, we demonstrate that vdWH of MoSe2/WSe2 and MoS2/WS2 at twist angles ≤1° undergo significant atomic level reconstruction leading to discrete commensurate domains divided by narrow domain walls, rather than a smoothly varying rigid-lattice moiré pattern as has been assumed in prior experimental work. Using conductive atomic force microscopy (CAFM), we show that TMD vdWH at small twist angles exhibit large domains of constant conductivity. The domains in samples with R-type stacking are triangular, whereas the domains in samples with H-type stacking are hexagonal. Transmission electron microscopy provides additional evidence of atomic reconstruction in MoSe2/WSe2 structures and demonstrates the transition between a rigid-lattice moiré pattern for large angles and atomic reconstruction for small angles. We use density functional theory to calculate the band structures of the commensurate reconstructed domains and find that the modulation of the relative electronic band edges is consistent with the CAFM results and photoluminescence spectra. The presence of atomic reconstruction in TMD heterostructures and the observed impact on nanometer-scale electronic properties provide fundamental insight into the behavior of this important class of heterostructures.

Synthesis of High-Quality Monolayer MoS2 by Direct Liquid Injection.

We report the synthesis of high-quality single monolayer MoS2 samples using a novel technique that utilizes direct liquid injection (DLI) for the delivery of precursors. The DLI system vaporizes a liquid consisting of a selected precursor dissolved in a solvent into small, micron-sized droplets in an expansion chamber maintained at a selected temperature and pressure, before delivery to the deposition chamber. We demonstrate the synthesis of monolayer MoS2 on SiO2/Si substrates using the DLI technique with film quality superior to exfoliated samples or those grown by traditional tube furnace chemical vapor deposition (CVD) methods. Photoluminescence measurements of DLI monolayers exhibit consistently brighter emission, narrower line width, and higher emission energy than their exfoliated and CVD counterparts. Conductive atomic force microscopy identifies a defect density of 8.3 × 1011/cm2 in DLI MoS2, lower than the measured density in CVD material and nearly an order of magnitude improvement over the exfoliated MoS2 investigated under the same conditions. The DLI method is directly applicable to many other van der Waals materials, which require the use of challenging low vapor pressure precursors, to the growth of alloys, and sequential growths of dissimilar materials leading to van der Waals heterostructures.

Continuous Wave Sum Frequency Generation and Imaging of Monolayer and Heterobilayer Two-Dimensional Semiconductors.

We report continuous-wave second harmonic and sum frequency generation from two-dimensional transition metal dichalcogenide monolayers and their heterostructures with pump irradiances several orders of magnitude lower than those of conventional pulsed experiments. The high nonlinear efficiency originates from above-gap excitons in the band nesting regions, as revealed by wavelength-dependent second order optical susceptibilities quantified in four common monolayer transition metal dichalcogenides. Using sum frequency excitation spectroscopy and imaging, we identify and distinguish one- and two-photon resonances in both monolayers and heterobilayers. Data for heterostructures reveal responses from constituent layers accompanied by nonlinear signal correlated with interlayer transitions. We demonstrate spatial mapping of heterogeneous interlayer coupling by sum frequency and second harmonic confocal microscopy on heterobilayer MoSe2/WSe2.