Coronary Arterial Dynamics and Atherogenesis

While documented risk factors (e.g., hypertension, diabetes, etc.) for atherosclerosis are systemic in nature, atherosclerotic plaques appear in a heterogeneous distribution in the vasculature. This heterogeneity is thought to be related in part to the fact that the plaques tend to develop in areas of disturbed blood flow such as bifurcations and curvatures. Moreover, the coronary arteries, which also experience the added mechanical deformations of cyclic flexing, stretching, and twisting due to their tethering to a beating heart, are particularly susceptible to atherogenesis. This suggests that both fluid-induced (shear) and deformation-induced (mural) stress contribute to location specific susceptibility or protection from disease. We hypothesized that local variations in shear and mural stress associated with dynamic motion of arterial segments influence the distribution of early markers of atherogenesis. To test this hypothesis, we utilized our unique, well-established, and validated ex vivo vascular perfusion system in a combined experimental / computational study. Pairs of freshly-harvested porcine arterial segments were perfused ex vivo under normal hemodynamic conditions. One of the paired segments was exposed to coronary levels of either cyclic axial stretching, flexure, or twist. Post-perfusion tissue processing provided the extent and spatial distribution of early markers of atherogenesis, including endothelial permeability, apoptosis, and proliferation. Finite element analysis and computational fluid dynamics techniques were used to estimate the mural and shear stress distributions, respectively, for reconstructed models of each experimentally perfused segment. Quantitative correlations between biological marker and mechanical stress distributions were determined using multiple linear regression analysis. Vessel segments exposed to cyclic axial stretch and flexure showed significant increases in both permeability and apoptosis. In addition, we demonstrated that all three deformations generated complex, non-uniform distributions of both biologic endpoints and mechanical stresses. These distributions displayed a high degree of specimen-to-specimen variability which was attributed to the highly variable vessel geometries. Several specific mechanical stress measures, both mural and shear, were shown to be associated with cellular atherogenic marker distribution. Future work should be aimed at more fully elucidating the molecular mechanism linking mechanical stress in the tissue to these cellular based responses

Plasmonic nanoparticles assemblies templated by helical bacteria and resulting optical activity

Plasmonic nanoparticles (NPs) adsorbing onto helical bacteria can lead to formation of NP helicoids with micron scale pitch. Associated chiroptical effects can be utilized as bioanalytical tool for bacterial detection and better understanding of the spectral behavior of helical self‐assembled structures with different scales. Here, we report that enantiomerically pure helices with micron scale of chirality can be assembled on Campylobacter jejuni, a helical bacterium known for severe stomach infections. These organisms have right‐handed helical shapes with a pitch of 1–2 microns and can serve as versatile templates for a variety of NPs. The bacteria itself shows no observable rotatory activity in the visible, red, and near‐IR ranges of electromagnetic spectrum. The bacterial dispersion acquires chiroptical activity at 500–750 nm upon plasmonic functionalization with Au NPs. Finite‐difference time‐domain simulations confirmed the attribution of the chiroptical activity to the helical assembly of gold nanoparticles. The position of the circular dichroism peaks observed for these chiral structures overlaps with those obtained before for Au NPs and their constructs with molecular and nanoscale chirality. This work provides an experimental and computational pathway to utilize chiroplasmonic particles assembled on bacteria for bioanalytical purposes.Gold nanoparticles assemble onto the surface of helical bacterium, Campylobacter jejuni, producing right‐handed helices with a pitch of 1–2 microns. The bacterial dispersion acquires chiroptical activity at 500–750 nm that matches the calculated chiroplasmonic spectra. This study provides a pathway to utilize chiroplasmonic particles for monitoring shape dynamics of bacteria and identification of helical bacteria in complex microbiomes.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155927/1/Supporting_information_Chirality_Manuscript_2020.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155927/2/chir23225_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155927/3/chir23225.pd

Antimicrobial Microwebs of DNA–Histone Inspired from Neutrophil Extracellular Traps

Neutrophil extracellular traps (NETs) are decondensed chromatin networks released by neutrophils that can trap and kill pathogens but can also paradoxically promote biofilms. The mechanism of NET functions remains ambiguous, at least in part, due to their complex and variable compositions. To unravel the antimicrobial performance of NETs, a minimalistic NET‐like synthetic structure, termed “microwebs,” is produced by the sonochemical complexation of DNA and histone. The prepared microwebs have structural similarity to NETs at the nanometer to micrometer dimensions but with well‐defined molecular compositions. Microwebs prepared with different DNA to histone ratios show that microwebs trap pathogenic Escherichia coli in a manner similar to NETs when the zeta potential of the microwebs is positive. The DNA nanofiber networks and the bactericidal histone constituting the microwebs inhibit the growth of E. coli. Moreover, microwebs work synergistically with colistin sulfate, a common and a last‐resort antibiotic, by targeting the cell envelope of pathogenic bacteria. The synthesis of microwebs enables mechanistic studies not possible with NETs, and it opens new possibilities for constructing biomimetic bacterial microenvironments to better understand and predict physiological pathogen responses.Microwebs with bacteria trapping and killing functions are designed to mimic neutrophil extracellular traps—an immune defense weapon to fight against invading pathogens. The composition–structure–function relationship of the synthetic structure is discussed, and the collaborative action between microwebs and antibiotics allows better elimination of pathogenic bacteria, Escherichia coli.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149216/1/adma201807436-sup-0001-S1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149216/2/adma201807436_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149216/3/adma201807436.pd

Diverse Applications of Nanomedicine

The design and use of materials in the nanoscale size range for addressing medical and health-related issues continues to receive increasing interest. Research in nanomedicine spans a multitude of areas, including drug delivery, vaccine development, antibacterial, diagnosis and imaging tools, wearable devices, implants, high-throughput screening platforms, etc. using biological, nonbiological, biomimetic, or hybrid materials. Many of these developments are starting to be translated into viable clinical products. Here, we provide an overview of recent developments in nanomedicine and highlight the current challenges and upcoming opportunities for the field and translation to the clinic. \ua9 2017 American Chemical Society

Improved diagnostic prediction of the pathogenicity of bloodstream isolates of Staphylococcus epidermidis.

With an estimated 440,000 active cases occurring each year, medical device associated infections pose a significant burden on the US healthcare system, costing about $9.8 billion in 2013. Staphylococcus epidermidis is the most common cause of these device-associated infections, which typically involve isolates that are multi-drug resistant and possess multiple virulence factors. S. epidermidis is also frequently a benign contaminant of otherwise sterile blood cultures. Therefore, tests that distinguish pathogenic from non-pathogenic isolates would improve the accuracy of diagnosis and prevent overuse/misuse of antibiotics. Attempts to use multi-locus sequence typing (MLST) with machine learning for this purpose had poor accuracy (~73%). In this study we sought to improve the diagnostic accuracy of predicting pathogenicity by focusing on phenotypic markers (i.e., antibiotic resistance, growth fitness in human plasma, and biofilm forming capacity) and the presence of specific virulence genes (i.e., mecA, ses1, and sdrF). Commensal isolates from healthy individuals (n = 23), blood culture contaminants (n = 21), and pathogenic isolates considered true bacteremia (n = 54) were used. Multiple machine learning approaches were applied to characterize strains as pathogenic vs non-pathogenic. The combination of phenotypic markers and virulence genes improved the diagnostic accuracy to 82.4% (sensitivity: 84.9% and specificity: 80.9%). Oxacillin resistance was the most important variable followed by growth rate in plasma. This work shows promise for the addition of phenotypic testing in clinical diagnostic applications

Synthesis of Antimicrobial Chiral Cerium Oxide Nanoparticles

The rapid emergence of antibiotic resistant bacteria is an increasingly worrying global health challenge. In recent years, attention has been turned to the development of next-generation antibiotics, including antimicrobial nanomaterials. Nanoparticles are an attractive alternative to traditional antibiotics due to the various antibacterial mechanisms and physical characteristics associated with these materials. This project presents a facile synthesis method for the creation of chiral cerium oxide nanoparticles with varying amino acid ligands. These nanoparticles exhibit a wide range of intriguing physiochemical properties, such as antimicrobial activity, sintering at standard conditions, and possible chiromagnetism. We believe the variety of interesting properties associated with these nanoparticles makes them an exciting material for future exploration.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/176723/1/Honors_Capstone_Report_Antimicrobial_Chiral_Ceria_Nanoparticles_-_Brendan_Knittle.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/176723/2/Honors_Capstone_Poster_Antimicrobial_Chiral_Ceria_Nanoparticles_-_Brendan_Knittle.pd

Stretchable, Nano‐Crumpled MXene Multilayers Impart Long‐Term Antibacterial Surface Properties

Abstract Infections are a significant risk to patients who receive medical implants, and can often lead to implant failure, tissue necrosis, and even amputation. So far, although various surface modification approaches are proposed for prevention and treatment of microbial biofilms on indwelling medical devices, most are too expensive/complicated to fabricate, unscalable, or limited in durability for clinical use. Here, this work presents a new bottom‐up design for fabricating scalable and durable nano‐patterned coatings with dynamic topography for long‐term antibacterial effects. This work shows that MXene layer‐by‐layer (LbL) self‐assembled coatings—with finely tunable crumpled structures with nanometer resolution and excellent mechanical durability—can be successfully fabricated on stretchable poly(dimethylsiloxane) (PDMS). The crumpled MXene coating with sharp‐edged peaks shows potent antibacterial effects against Staphylococcus aureus and Escherichia coli. In addition, this work finds that on‐demand dynamic deformation of the crumpled coating can remove ≥99% of adhered bacterial cells for both species, resulting in a clean surface with restored functionality. This approach offers improved practicality, scalability, and antibacterial durability over previous methods, and its flexibility may lend itself to many types of biomaterials and implantable devices

Chiral chromatography and surface chirality of carbon nanoparticles

Chiral carbon nanoparticles (CNPs) represent a rapidly evolving area of research for optical and biomedical technologies. Similar to small molecules, applications of CNPs as well as fundamental relationships between their optical activity and structural asymmetry would greatly benefit from their enantioselective separations by chromatography. However, this technique remains in its infancy for chiral carbon and other nanoparticles. The possibility of effective separations using high performance liquid chromatography (HPLC) with chiral stationary phases remains an open question whose answer can also shed light on the components of multiscale chirality of the nanoparticles. Herein, we report a detailed methodology of HPLC for successful separation of chiral CNPs and establish a path for its future optimization. A mobile phase of water/acetonitrile was able to achieve chiral separation of CNPs derived from L- and D-cysteine denoted as L-CNPs and D-CNPs. Molecular dynamics simulations show that the teicoplanin-based stationary phase has a higher affinity for L-CNPs than for D-CNPs, in agreement with experiments. The experimental and computational findings jointly indicate that chiral centers of chiral CNPs are present at their surface, which is essential for the multiple applications of these chiral nanostructures and equally essential for interactions with biomolecules and circularly polarized photons.….Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/175242/1/chir23507.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/175242/2/chir23507_am.pd