Improving nanoparticle superlattice stability with deformable polymer gels.

The self-assembly of colloidal nanoparticles into ordered superlattices typically uses dynamic interactions to govern particle crystallization, as these non-permanent bonds prevent the formation of kinetically trapped, disordered aggregates. However, while the use of reversible bonding is critical in the formation of highly ordered particle arrangements, dynamic interactions also inherently make the structures more prone to disassembly or disruption when subjected to different environmental stimuli. Thus, there is typically a trade-off between the ability to initially form an ordered colloidal material and the ability of that material to retain its order under different conditions. Here, we present a method for embedding colloidal nanoparticle superlattices into a polymer gel matrix. This encapsulation strategy physically prevents the nanoparticles from dissociating upon heating, drying, or the introduction of chemicals that would normally disrupt the lattice. However, the use of a gel as the embedding medium still permits further modification of the colloidal nanoparticle lattice by introducing stimuli that deform the gel network (as this deformation in turn alters the nanoparticle lattice structure in a predictable manner). Moreover, encapsulation of the lattice within a gel permits further stabilization into fully solid materials by removing the solvent from the gel or by replacing the solvent with a liquid monomer that can be photopolymerized. This embedding method therefore makes it possible to incorporate ordered colloidal arrays into a polymer matrix as either dynamic or static structures, expanding their potential for use in responsive materials.

Nanocomposite tectons as unifying systems for nanoparticle assembly.

Nanocomposite tectons (NCTs) are nanocomposite building blocks consisting of nanoparticle cores functionalized with a polymer brush, where each polymer chain terminates in a supramolecular recognition group capable of driving particle assembly. Like other ligand-driven nanoparticle assembly schemes (for example those using DNA-hybridization or solvent evaporation), NCTs are able to make colloidal crystal structures with precise particle organization in three dimensions. However, despite the similarity of NCT assembly to other methods of engineering ordered particle arrays, the crystallographic symmetries of assembled NCTs are significantly different. In this study, we provide a detailed characterization of the dynamics of hybridizations through universal (independent of microscopic details) parameters. We perform rigorous free energy calculations and identify the persistence length of the ligand as the critical parameter accounting for the differences in the phase diagrams of NCTs and other assembly methods driven by hydrogen bond hybridizations. We also report new experiments to provide direct verification for the predictions. We conclude by discussing the role of non-equilibrium effects and illustrating how NCTs provide a unification of the two most successful strategies for nanoparticle assembly: solvent evaporation and DNA programmable assembly.

Sequential Bone Scintigraphy and the Evolution of Warfarin-Mediated Calcific Uremic Arteriolopathy.

Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is a complex syndrome of deranged mineral metabolism and vascular calcification leading to tissue ischemia that primarily occurs in end-stage renal disease (ESRD) patients on maintenance hemodialysis (HD). We report a case illustrating a temporal relationship between long-term warfarin anticoagulation and development of CUA in a patient with pre-dialysis chronic kidney disease (CKD) who progressed to ESRD. Serial 99mTc-methylene diphosphonate bone scintigraphy documented the evolution of metastatic CUA over a 5-month period following HD initiation. Given the temporality demonstrated here via imaging, we speculate that warfarin's influence on vitamin K-dependent matrix Gla protein function coupled with risk factors associated with ESRD led to the development of metastatic CUA.

Macroscopic materials assembled from nanoparticle superlattices.

Nanoparticle assembly has been proposed as an ideal means to program the hierarchical organization of a material by using a selection of nanoscale components to build the entire material from the bottom up. Multiscale structural control is highly desirable because chemical composition, nanoscale ordering, microstructure and macroscopic form all affect physical properties1,2. However, the chemical interactions that typically dictate nanoparticle ordering3-5 do not inherently provide any means to manipulate structure at larger length scales6-9. Nanoparticle-based materials development therefore requires processing strategies to tailor micro- and macrostructure without sacrificing their self-assembled nanoscale arrangements. Here we demonstrate methods to rapidly assemble gram-scale quantities of faceted nanoparticle superlattice crystallites that can be further shaped into macroscopic objects in a manner analogous to the sintering of bulk solids. The key advance of this method is that the chemical interactions that govern nanoparticle assembly remain active during the subsequent processing steps, which enables the local nanoscale ordering of the particles to be preserved as the macroscopic materials are formed. The nano- and microstructure of the bulk solids can be tuned as a function of the size, chemical makeup and crystallographic symmetry of the superlattice crystallites, and the micro- and macrostructures can be controlled via subsequent processing steps. This work therefore provides a versatile method to simultaneously control structural organization across the molecular to macroscopic length scales.

Reinforcing Supramolecular Bonding with Magnetic Dipole Interactions to Assemble Dynamic Nanoparticle Superlattices.

Assembling superparamagnetic particles into ordered lattices is an attractive means of generating new magnetically responsive materials, and is commonly achieved by tailoring interparticle interactions as a function of the ligand coating. However, the inherent linkage between the collective magnetic behavior of particle arrays and the assembly processes used to generate them complicates efforts to understand and control material synthesis. Here, we use a synergistic combination of a chemical force (hydrogen bonding) and magnetic dipole coupling to assemble polymer-brush coated superparamagnetic iron oxide nanoparticles, where the relative strengths of these interactions can be tuned to reinforce one another and stabilize the resulting superlattice phases. We find that we can precisely control both the dipole-dipole coupling between nanoparticles and the strength of the ligand-ligand interactions by modifying the interparticle spacing through changes to the polymer spacer between the hydrogen bonding groups and the nanoparticles' surface. This results in modulation of the materials' blocking temperature, as well as the stabilization of a unique superlattice phase that only exists when magnetic coupling between particles is present. Using magnetic interactions to affect nanoparticle assembly in conjunction with ligand-mediated interparticle interactions expands the potential for synthesizing predictable and controllable nanoparticle-based magnetic composites.

Dictating Nanoparticle Assembly via Systems-Level Control of Molecular Multivalency.

Nanoparticle assembly can be controlled by multivalent binding interactions between surface ligands, indicating that more precise control over these interactions is important to design complex nanoscale architectures. It has been well-established in natural materials that the arrangement of different molecular species in three dimensions can affect the ability of individual supramolecular units to coordinate their binding, thereby regulating the strength and specificity of their collective molecular interactions. However, in artificial systems, limited examples exist that quantitatively demonstrate how changes in nanoscale geometry can be used to rationally modulate the thermodynamics of individual molecular binding interactions. As a result, the use of nanoscale design features to regulate molecular bonding remains an underutilized design handle to control nanomaterials synthesis. Here we demonstrate a polymer-coated nanoparticle material where supramolecular bonding and nanoscale structure are used in conjunction to dictate the thermodynamics of their multivalent interactions, resulting in emergent bundling of supramolecular binding groups that would not be expected on the basis of the molecular structures alone. Additionally, we show that these emergent phenomena can controllably alter the superlattice symmetry by using the mesoscale particle arrangement to alter the thermodynamics of the supramolecular bonding behavior. The ability to rationally program molecular multivalency via a systems-level approach therefore provides a major step forward in the assembly of complex artificial structures, with implications for future designs of both nanoparticle- and supramolecular-based materials.

Multistimuli Responsive Nanocomposite Tectons for Pathway Dependent Self-Assembly and Acceleration of Covalent Bond Formation.

Nanocomposite tectons (NCTs) are a recently developed building block for polymer-nanoparticle composite synthesis, consisting of nanoparticle cores functionalized with dense monolayers of polymer chains that terminate in supramolecular recognition groups capable of linking NCTs into hierarchical structures. In principle, the use of molecular binding to guide particle assembly allows NCTs to be highly modular in design, with independent control over the composition of the particle core and polymer brush. However, a major challenge to realize an array of compositionally and structurally varied NCT-based materials is the development of different supramolecular bonding interactions to control NCT assembly, as well as an understanding of how the organization of multiple supramolecular groups around a nanoparticle scaffold affects their collective binding interactions. Here, we present a suite of rationally designed NCT systems, where multiple types of supramolecular interactions (hydrogen bonding, metal complexation, and dynamic covalent bond formation) are used to tune NCT assembly as a function of multiple external stimuli including temperature, small molecules, pH, and light. Furthermore, the incorporation of multiple orthogonal supramolecular chemistries in a single NCT system makes it possible to dictate the morphologies of the assembled NCTs in a pathway-dependent fashion. Finally, multistimuli responsive NCTs enable the modification of composite properties by postassembly functionalization, where NCTs linked by covalent bonds with significantly enhanced stability are obtained in a fast and efficient manner. The designs presented here therefore provide major advancement for the field of composite synthesis by establishing a framework for synthesizing hierarchically ordered composites capable of complicated assembly behaviors.

Assembling Ordered Crystals with Disperse Building Blocks.

Conventional colloidal crystallization techniques typically require low dispersity building blocks in order to make ordered particle arrays, resulting in a practical challenge for studying or scaling these materials. Nanoparticles covered in a polymer brush therefore may be predicted to be challenging building blocks in the formation of high-quality particle superlattices, as both the nanoparticle core and polymer brush are independent sources of dispersity in the system. However, when supramolecular bonding between complementary functional groups at the ends of the polymer chains are used to drive particle assembly, these "nanocomposite tectons" can make high quality superlattices with polymer dispersities as large as 1.44 and particle diameter relative standard deviations up to 23% without any significant change to superlattice crystallinity. Here we demonstrate and explain how the flexible and dynamic nature of the polymer chains that comprise the particle brush allows them to deform to accommodate the irregularities in building block size and shape that arise from the inherent dispersity of their constituent components. Incorporating "soft" components into nanomaterials design therefore offers a facile and robust method for maintaining good control over organization when the materials themselves are imperfect.

Clinical characteristics and risk factors associated with mortality in calcific uremic arteriolopathy.

BACKGROUND: Calcific uremic arteriolopathy (CUA) is an often-fatal condition in dialysis patients. The clinical descriptions and treatments of CUA patients have been confined mostly to case reports. We report a comprehensive characterization of CUA and its associated diagnosis, treatment patterns, and outcome. METHODS: An internet-based registry collected information about CUA in dialysis patients. Univariate analysis using Cox proportional hazards models estimated hazard ratios of the association between clinical characteristics, laboratory values, and treatments with all-cause mortality. RESULTS: A total of 117 CUA patients had adequate information for analysis. The majority of patients (56.7%) were diagnosed clinically, with only 32.5% biopsied. Debridement was undertaken in 42.6% of cases. Intravenous sodium thiosulfate (STS) was initiated in 54.7% of patients; most received ≥ 12.5 g of STS (98.3%) for < 3 months (79.7%). Mean parathyroid hormone (PTH) and phosphorus (P) were 459 ± 492 pg/mL and 6.3 ± 2.1 mg/dL, respectively. A total of 24 patients (21.6%, of 111 with information) died, with a median survival time of 2.9 months. In univariate analysis, higher mortality was observed in patients with cardiovascular disease (CVD; HR = 10.47; 95% CI 1.40-78.38), those taking warfarin at time of diagnosis (HR = 2.74; 95% CI 1.16-6.51), and those who had both diabetes (DM) and CVD and who were taking warfarin (HR = 13.41; 95% CI 1.66-109.29). CONCLUSIONS: In real-world clinical practice, there is substantial variability in the diagnosis and treatment of CUA. There is usually only modest derangement of bone and mineral parameters at the time of diagnosis. Death is common. The presence of CVD and use of warfarin may influence clinical outcome after diagnosis of CUA.

Self-Assembling Nanocomposite Tectons.

The physical characteristics of composite materials are dictated by both the chemical composition and spatial configuration of each constituent phase. A major challenge in nanoparticle-based composites is developing methods to precisely dictate particle positions at the nanometer length scale, as this would allow complete control over nanocomposite structure-property relationships. In this work, we present a new class of building blocks called nanocomposite tectons (NCTs), which consist of inorganic nanoparticles grafted with a dense layer of polymer chains that terminate in molecular recognition units capable of programmed supramolecular bonding. By tuning various design factors, including the particle size and polymer length, we can use the supramolecular interactions between NCTs to controllably alter their assembly behavior, enabling the formation of well-ordered body-centered cubic superlattices consisting of inorganic nanoparticles surrounded by polymer chains. NCTs therefore present a modular platform that enables the construction of composite materials where the composition and three-dimensional arrangement of different constituents within the composite can be independently controlled.

Paraganglioma mimicking a pancreatic neoplasm.

CONTEXT: Paragangliomas are rare tumours of neural crest origin. Extra-adrenal pancreatic paragangliomas are exceptionally rare. CASE REPORT: A 66-year-old man with abdominal pain was noted to have a complex pancreatic head and uncinate process mass on imaging. He underwent complete resection by pancreaticoduodenectomy with final pathology confirming a 6 cm paraganglioma without evidence of metastases. On histology the tumour was arising from the retroperitoneum and abutting the pancreas. The patient was disease free at 14-month follow-up. CONCLUSION: Pancreatic paragangliomas represent in many cases the retroperitoneal extension of a paraganglioma into the pancreas rather than a true pancreatic neoplasm. Although generally benign, the risk of malignant transformation justifies aggressive management.

Elevated FGF23 levels are associated with impaired calcium-mediated suppression of PTH in ESRD.

CONTEXT: The positive association of elevated fibroblast growth factor-23 (FGF23) with PTH levels in the setting of secondary hyperparathyroidism is paradoxical to the purported effects of FGF23 to suppress PTH secretion. OBJECTIVE: We used dynamic calcium-mediated suppression of PTH levels in hemodialysis (HD) patients to determine the relationship between FGF23 levels and parathyroid gland function. DESIGN: HD patients with elevated PTH were washed out of vitamin D analogs and/or calcimimetics and then exposed them to a high-calcium dialysate bath designed to suppress PTH. SETTING: The study was conducted at an outpatient HD unit of an academic medical center. PARTICIPANTS: Eighteen maintenance HD patients with elevated PTH levels participated in the study. MAIN OUTCOME MEASURES: Ionized calcium (iCa), PTH, and FGF23 levels were measured during HD. The slope of the relationship between iCa and PTH (a marker of parathyroid gland mass) and the iCa level required for a 50% reduction in PTH were determined, and the association of these with FGF23 levels was determined. RESULTS: Increased baseline log FGF23 levels were associated with putative alterations in gland mass as estimated by significantly shallower slopes of the iCa/PTH suppression curves (P = 0.0004), but there was no association between FGF23 and calcium sensing as measured by ionized Ca associated with a 50% suppression of PTH (P = 0.38). FGF23 levels decreased significantly during HD, but this change was not correlated with decrements in either renal phosphate or PTH. CONCLUSIONS: High FGF23 levels may be a marker for parathyroid gland hyperplasia in HD patients. Acute reductions in neither PTH nor renal phosphate during dialysis correlated with PTH suppression.

Malignant pheochromocytoma metastasis to the breast shown on I-123 MIBG scan.

A 36-year-old woman was referred to our department for I-123 metaiodobenzylguanidine (MIBG)-SPECT/CT scan 3 years after surgical excision of pheochromocytoma. She was referred due to recurrence of her symptoms as well as raised urinary catecholamines. Review of I-123 MIBG scan revealed multiple MIBG-avid metastatic lesions. Most of these were bony lesions, however, there were also 2 soft tissue lesions in the left breast. She subsequently underwent ultrasound-guided fine-needle aspiration of the left breast lesions. Fine-needle aspiration revealed cytologic changes consistent with pheochromocytoma. There has only been 1 previous reported case of pheochromocytoma metastasizing to the breast. This is the first case in which the metastasis was detected by I-123 MIBG scan.

Resolution of SLE-related soft-tissue calcification following haematopoietic stem cell transplantation.

BACKGROUND: Calciphylaxis and calcinosis can both cause severe morbidity and mortality in patients with systemic lupus erythematosus (SLE). Haematopoietic stem cell transplantation (HSCT) has been successfully used to treat patients with refractory SLE. It was hypothesized that in calciphylaxis and calcinosis, ongoing inflammatory activity contributes to the calcium deposition in the media of small arteries, as well as perivascular and periarticular tissues. We report three patients whose soft-tissue calcification syndromes dramatically resolved after undergoing HSCT. METHODS: Three patients referred for refractory SLE underwent HSCT at a tertiary care medical center. SLE serologies and clinical features before and after HSCT were recorded. RESULTS: Despite receiving >6 months of intravenous cyclophosphamide (CYC), three SLE patients showed signs of persistent lupus activity, including severe soft-tissue calcification. The first patient was on haemodialysis and developed severe calciphylaxis with large ulcers and tissue necrosis. The second patient had calcinosis, with palpable crystals extruding from ulcers. The third patient had calcinosis characterized by subcutaneous nodules and plaques. Because prior conventional therapies had failed, the three were treated with high-dose CYC, anti-thymocyte globulin and HSCT. They have been followed post-HSCT for 26-38 months, with excellent clinical responses, including sustained resolution of skin abnormalities. CONCLUSIONS: The successful treatment of advanced calcium deposition by aggressive immune ablation underscores the contribution of SLE-mediated inflammation to soft-tissue calcification syndromes.

CT coronary angiography predicts the outcome of percutaneous coronary intervention of chronic total occlusion.

BACKGROUND: The success rate of percutaneous coronary intervention (PCI) of chronic total occlusions (CTO) is relatively low. Further evaluation of CTO lesion with CT coronary angiography (CT-CA) may help to better select patients that would benefit from percutaneous revascularization. We aimed to test the possible association between failed PCI and transluminal calcification of CTO as assessed by CT-CA. METHODS: Patients with CTO awaiting PCI were scanned with a 16-slice CT. A cardiologist and a radiologist assessed transluminal calcification of CTO lesions on CT images while an interventional cardiologist at a core laboratory assessed conventional variables of invasive fluoroscopic coronary angiography (FCA) associated with failed PCI of CTO. The significance of CT and FCA variables in association with failed PCI were analyzed. RESULTS: In a cohort of 39 patients with 43 CTO lesions, 24 lesions were successfully revascularized. Transluminal calcification > or =50% as assessed on CT-CA was strongly associated with failed PCI (odds ratio [OR] of PCI success = 0.10, 95% confidence interval [CI]: 0.02-0.47, P = 0.003). Blunt stump as seen on FCA was also associated with failed PCI (OR of PCI success = 0.24, 95% CI: 0.07-0.86, P = 0.029). There was no significant evidence to support that the duration of CTO, presence of side branch and bridging collaterals, and the absence of microchannels as assessed with FCA were associated with failed PCI. On multivariate analysis, transluminal calcification > or =50% on CT-CA was the only significant predictor of failed PCI. CONCLUSIONS: Heavy transluminal calcification as assessed with CT-CA is an independent predictor of failed PCI of CTO. CT-CA may have a role in the work-up of CTO patients prior to PCI.