Fully Integrated Ultra-thin Intraoperative Micro-imager for Cancer Detection Using Upconverting Nanoparticles.

PURPOSE: Intraoperative detection and removal of microscopic residual disease (MRD) remain critical to the outcome of cancer surgeries. Today's minimally invasive surgical procedures require miniaturization and surgical integration of highly sensitive imagers to seamlessly integrate into the modern clinical workflow. However, current intraoperative imagers remain cumbersome and still heavily dependent on large lenses and rigid filters, precluding further miniaturization and integration into surgical tools. PROCEDURES: We have successfully engineered a chip-scale intraoperative micro-imager array-without optical filters or lenses-integrated with lanthanide-based alloyed upconverting nanoparticles (aUCNPs) to achieve tissue imaging using a single micro-chip. This imaging platform is able to leverage the unique optical properties of aUCNPs (long luminescent lifetime, high-efficiency upconversion, no photobleaching) by utilizing a time-resolved imaging method to acquire images using a 36-by-80-pixel, 2.3 mm [Formula: see text] 4.8 mm silicon-based electronic imager micro-chip, that is, less than 100-µm thin. Each pixel incorporates a novel architecture enabling automated background measurement and cancellation. We have validated the performance, spatial resolution, and the background cancellation scheme of the imaging platform, using resolution test targets and mouse prostate tumor sample intratumorally injected with aUCNPs. To demonstrate the ability to image MRD, or tumor margins, we evaluated the imaging platform in visualizing a single-cell thin section of the injected prostate tumor sample. RESULTS: Tested on USAF resolution targets, the imager is able to achieve a resolution of 71 µm. We have also demonstrated successful background cancellation, achieving a signal-to-background ratio of 8 when performing ex vivo imaging on aUCNP-injected prostate tumor sample, improved from originally 0.4. The performance of the imaging platform on single-cell layer sections was also evaluated and the sensor achieved a signal-to-background ratio of 4.3 in resolving cell clusters with sizes as low as 200 cells. CONCLUSION: The imaging system proposed here is a scalable chip-scale ultra-thin alternative for bulky conventional intraoperative imagers. Its novel pixel architecture and background correction scheme enable visualization of microscopic-scale residual disease while remaining completely free of lenses and filters, achieving an ultra-miniaturized form factor-critical for intraoperative settings.

PM-IRRAS and DFT investigation of the surface orientation of new Ir piano-stool complexes attached to Au(111).

Surface immobilization of organometallic catalysts is a promising approach to developing new catalytic systems that combine molecular catalysts with heterogenous surfaces to probe surface mechanisms. The orientation of the catalyst relative to the surface is one important parameter that must be considered in such hybrid systems. In this work, we synthesize three new sulfide-modified Ir piano-stool complexes with sulfide-modified bipyridine and phenylpyridine ligands for the attachment to Au(111) surfaces. Self-assembled monolayers made from (Cp*Ir(2,2'-bipyridine-4-sulfide)Cl)2[Cl]2 (C1m) and [Cp*Ir(2-phenylpyridine-4-sulfide)Cl]2 (C2m) were characterized by combining polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS) with DFT calculations of the minimum energy orientations of the complexes on the surface. We find that the bipyridine and phenylpyridine ligands are oriented at between 73-77° relative to the surface normal, irrespective of the orientation of the other ligands. Additionally, DFT and PM-IRRAS support that there is no orientation preference for C1m and C2m, with both orientations present on the surface.

Synthesis, structure and reactivity of µ3-SnH capped trinuclear nickel cluster.

Treatment of the trichlorotin-capped trinuclear nickel cluster, [Ni3(dppm)3(µ3-Cl)(µ3-SnCl3)], 1, with 4 eq. NaHB(Et)3 yields a µ3-SnH capped trinuclear nickel cluster, [Ni3(dppm)3(µ3-H)(µ3-SnH)], 2 [dppm = bis(diphenylphosphino)methane]. Single-crystal X-ray diffraction, nuclear magnetic resonance (NMR) spectroscopy, and computational studies together support that cluster 2 is a divalent tin hydride. Complex 2 displays a wide range of reactivity including oxidative addition of bromoethane across the Sn center. Addition of 1 eq. iodoethane to complex 2 releases H2 (g) and generates an ethyltin-capped nickel cluster with a µ3-iodide, [Ni3(dppm)3(µ3-I)(µ3-Sn(CH2CH3))], 4. Notably, insertion of alkynes into the Sn-H bond of 2 can be achieved via addition of 1 eq. 1-hexyne to generate the 1-hexen-2-yl-tin-capped nickel cluster, [Ni3(dppm)3(µ3H)(µ3-Sn(C6H11))], 5. Addition of H2 (g) to 5 regenerates the starting material, 2, and hexane. The formally 44-electron cluster 2 also displays significant redox chemistry with two reversible one-electron oxidations (E = -1.3 V, -0.8 V vs. Fc0/+) and one-electron reduction process (E = -2.7 V vs. Fc0/+) observed by cyclic voltammetry.

A Dicopper Platform that Stabilizes the Formation of Pentanuclear Coinage Metal Hydride Complexes.

Reduction of a dicopper(II) bis(hydroxide) complex with silanes in the presence of external copper or silver cations results in the formation of multinuclear hydride clusters, which were characterized by a variety of NMR spectroscopic experiments and X-ray crystallography. In particular, the pentanuclear complexes adopt an unusual planar "bow tie" configuration. The copper hydride complexes are efficient catalysts for the dehydrogenation of formic acid to H2 and CO2 .

2,2'-Oxybis[1,3-bis-(4-meth-oxy-phen-yl)-2,3-di-hydro-1H-benzo[d][1,3,2]di-aza-borole].

In the title compound, C40H36B2N4O5, the B-O-B bond angle is 132.75 (13) and the dihedral angle between the benzodiazborole rings is 73.02 (5)°. In the crystal, weak C-H⋯O inter-actions link the mol-ecules.

A 25 micron-thin microscope for imaging upconverting nanoparticles with NIR-I and NIR-II illumination.

Rationale: Intraoperative visualization in small surgical cavities and hard-to-access areas are essential requirements for modern, minimally invasive surgeries and demand significant miniaturization. However, current optical imagers require multiple hard-to-miniaturize components including lenses, filters and optical fibers. These components restrict both the form-factor and maneuverability of these imagers, and imagers largely remain stand-alone devices with centimeter-scale dimensions. Methods: We have engineered INSITE (Immunotargeted Nanoparticle Single-Chip Imaging Technology), which integrates the unique optical properties of lanthanide-based alloyed upconverting nanoparticles (aUCNPs) with the time-resolved imaging of a 25-micron thin CMOS-based (complementary metal oxide semiconductor) imager. We have synthesized core/shell aUCNPs of different compositions and imaged their visible emission with INSITE under either NIR-I and NIR-II photoexcitation. We characterized aUCNP imaging with INSITE across both varying aUCNP composition and 980 nm and 1550 nm excitation wavelengths. To demonstrate clinical experimental validity, we also conducted an intratumoral injection into LNCaP prostate tumors in a male nude mouse that was subsequently excised and imaged with INSITE. Results: Under the low illumination fluences compatible with live animal imaging, we measure aUCNP radiative lifetimes of 600 µs - 1.3 ms, which provides strong signal for time-resolved INSITE imaging. Core/shell NaEr0.6Yb0.4F4 aUCNPs show the highest INSITE signal when illuminated at either 980 nm or 1550 nm, with signal from NIR-I excitation about an order of magnitude brighter than from NIR-II excitation. The 55 µm spatial resolution achievable with this approach is demonstrated through imaging of aUCNPs in PDMS (polydimethylsiloxane) micro-wells, showing resolution of micrometer-scale targets with single-pixel precision. INSITE imaging of intratumoral NaEr0.8Yb0.2F4 aUCNPs shows a signal-to-background ratio of 9, limited only by photodiode dark current and electronic noise. Conclusion: This work demonstrates INSITE imaging of aUCNPs in tumors, achieving an imaging platform that is thinned to just a 25 µm-thin, planar form-factor, with both NIR-I and NIR-II excitation. Based on a highly paralleled array structure INSITE is scalable, enabling direct coupling with a wide array of surgical and robotic tools for seamless integration with tissue actuation, resection or ablation.

A Molecular Imaging "Skin A Time-resolving Intraoperative Imager for Microscopic Residual Cancer Detection Using Enhanced Upconverting Nanoparticles.

Optimal cancer therapy requires targeted and individualized treatment of all tumor cells, including both gross and microscopic disease. Intraoperatively hard to visualize and often left behind, microscopic foci of residual cancer cells significantly increase the risk of cancer recurrence and treatment failure rates. Fluorescently-tagged targeted molecular labels are employed to guide surgery, but conventional fluorescent intraoperative imagers suffer from lack of sensitivity and maneuverability, limiting practicality in small tumor cavities owing to their cumbersome sizes driven by optics. This work does away with conventional lenses and filters and introduces an optics-free molecular imaging "skin" consisting of only a $25\mu \mathrm{m}$ thin CMOS contact imager that synergistically integrates the long emission lifetimes of upconverting nanoparticles (UCNP) combined with upconversion to use a time domain approach to acquire the image coupled with infrared illumination allowing deep tissue penetration and elimination of autofluorescence. Using this strategy, we are able to visualize UCNPs at fluences (W/cm2) compatible with intraoperative use, opening the door to visualize targeted areas with microscopic sensitivity and facilitate residual microscopic disease detection during surgery, and laying the groundwork for precision post-operative radiation.

Low irradiance multiphoton imaging with alloyed lanthanide nanocrystals.

Multiphoton imaging techniques that convert low-energy excitation to higher energy emission are widely used to improve signal over background, reduce scatter, and limit photodamage. Lanthanide-doped upconverting nanoparticles (UCNPs) are among the most efficient multiphoton probes, but even UCNPs with optimized lanthanide dopant levels require laser intensities that may be problematic. Here, we develop protein-sized, alloyed UCNPs (aUCNPs) that can be imaged individually at laser intensities >300-fold lower than needed for comparably sized doped UCNPs. Using single UCNP characterization and kinetic modeling, we find that addition of inert shells changes optimal lanthanide content from Yb3+, Er3+-doped NaYF4 nanocrystals to fully alloyed compositions. At high levels, emitter Er3+ ions can adopt a second role to enhance aUCNP absorption cross-section by desaturating sensitizer Yb3+ or by absorbing photons directly. Core/shell aUCNPs 12 nm in total diameter can be imaged through deep tissue in live mice using a laser intensity of 0.1 W cm-2.