Fabrication of Spheroidal Microparticles from Biodegradable Polymers for Drug Delivery Application.

This work describes the novel fabrication of biodegradable prolate spheroids from poly(lactic-co-glycolic acid) (PLGA) polymers via oil-in-water (O/W) and water-in-oil-in-water (W/O/W) emulsion solvent evaporation methods. Droplet deformation and breakup in mechanically-mixed emulsions are governed by competing viscous and interfacial tension forces that shear the drop apart and hold it together, respectively. The size and shape of fabricated spheroids were manipulated through controlling fabrication process parameters that modulated the viscous and interfacial forces on droplets in the emulsion. These parameters included polyvinyl alcohol, tris(hydroxymethyl)aminomethane and hydrochloric acid (aqueous phase pH) concentrations in the aqueous phase, the mechanical stir speed, the oil-to-aqueous phase volume ratio, the use of acetone and dichloromethane as oil phase solvents, PLGA concentration in the oil phase and PLGA polymer characteristics such as co-monomer ratio, end group and molecular weight. The presented data show that low viscosity ratios and low interfacial tension caused by basic aqueous phase pH, acetone as a co-solvent and hydrophilic polymer side chains and end groups are all conditions that favor the formation of spheroidal particles. Low interfacial tension determined the ability to stretch droplets and form spheroids as well as the aspect ratio of formed particles. However, droplet breakup in the emulsification stage was also critically important; fast stir rates and high continuous phase viscosity led to smaller initial droplet sizes that were unable to be stretched. The polydispersity of fabricated particles was evaluated; low tris concentrations, fast stir rates and high lactic acid concentrations led to monodisperse particle distributions. The flexibility of the described techniques were demonstrated via the loading of a variety of therapeutics including paclitaxel, lovastatin and bovine serum albumin, as well as imaging agents including 6-carboxyfluorescein and cadmium sulfide fluorescent nanospheres into PLGA prolate spheroids. Loaded paclitaxel released faster from spheroid particles than from spheres of the same volume. Non-spherical particles may increase the efficiency of targeted drug delivery carriers in localizing and adhering to the blood vessel wall over spherical particles of the same volume. This technique has the advantages of simplicity in setup, high particle yield and adaptability to a wide range of biodegradable polymers and therapeutics.Ph.D.Chemical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/91458/1/mjhesli_1.pd

Biom Biostat Int J

CC999999/Intramural CDC HHS/United States2016-06-17T00:00:00Z27331197PMC491222

A medical device-grade T1 and ECV phantom for global T1 mapping quality assurance - the T1_1 Mapping and ECV Standardization in cardiovascular magnetic resonance (T1MES) program

$\textbf{Background:}$ T$_1$ mapping and extracellular volume (ECV) have the potential to guide patient care and serve as surrogate end-points in clinical trials, but measurements differ between cardiovascular magnetic resonance (CMR) scanners and pulse sequences. To help deliver T$_1$ mapping to global clinical care, we developed a phantom-based quality assurance (QA) system for verification of measurement stability over time at individual sites, with further aims of generalization of results across sites, vendor systems, software versions and imaging sequences. We thus created T1MES: The T1 Mapping and ECV Standardization Program. $\textbf{Methods:}$ A design collaboration consisting of a specialist MRI small-medium enterprise, clinicians, physicists and national metrology institutes was formed. A phantom was designed covering clinically relevant ranges of T$_1$ and T$_2$ in blood and myocardium, pre and post-contrast, for 1.5 T and 3 T. Reproducible mass manufacture was established. The device received regulatory clearance by the Food and Drug Administration (FDA) and Conformité Européene (CE) marking. $\textbf{Results:}$ The T1MES phantom is an agarose gel-based phantom using nickel chloride as the paramagnetic relaxation modifier. It was reproducibly specified and mass-produced with a rigorously repeatable process. Each phantom contains nine differently-doped agarose gel tubes embedded in a gel/beads matrix. Phantoms were free of air bubbles and susceptibility artifacts at both field strengths and T$_1$ maps were free from off-resonance artifacts. The incorporation of high-density polyethylene beads in the main gel fill was effective at flattening the $B_1$ field. T$_1$ and T$_2$ values measured in T1MES showed coefficients of variation of 1 % or less between repeat scans indicating good short-term reproducibility. Temperature dependency experiments confirmed that over the range 15-30 °C the short-T$_1$ tubes were more stable with temperature than the long-T$_1$ tubes. A batch of 69 phantoms was mass-produced with random sampling of ten of these showing coefficients of variations for T$_1$ of 0.64 ± 0.45 % and 0.49 ± 0.34 % at 1.5 T and 3 T respectively. $\textbf{Conclusion:}$ The T1MES program has developed a T$_1$ mapping phantom to CE/FDA manufacturing standards. An initial 69 phantoms with a multi-vendor user manual are now being scanned fortnightly in centers worldwide. Future results will explore T$_1$ mapping sequences, platform performance, stability and the potential for standardization.This project has been funded by a European Association of Cardiovascular Imaging (EACVI part of the ESC) Imaging Research Grant, a UK National Institute of Health Research (NIHR) Biomedical Research Center (BRC) Cardiometabolic Research Grant at University College London (UCL, #BRC/ 199/JM/101320), and a Barts Charity Research Grant (#1107/2356/MRC0140). G.C. is supported by the National Institute for Health Research Rare Diseases Translational Research Collaboration (NIHR RD-TRC) and by the NIHR UCL Hospitals Biomedical Research Center. J.C.M. is directly and indirectly supported by the UCL Hospitals NIHR BRC and Biomedical Research Unit at Barts Hospital respectively. This work was in part supported by an NIHR BRC award to Cambridge University Hospitals NHS Foundation Trust and NIHR Cardiovascular Biomedical Research Unit support at Royal Brompton Hospital London UK

Assessing Educational Needs of FIRST Robotics

This project is aimed at assessing the educational needs of students new to the FIRST Robotics Competition (FRC) and developing a set of requirements for an educational website. Using data collected by surveying students and mentors from the FRC community, this project provides recommendations for an online robotics learning resource designed to improve the retention rates of the competition through a support system for FRC Rookie teams

Self-Reconfigurable Modular Robot

Natural disasters wreak havoc on populated areas around the world, in these situations quick informative responses are imperative to saving lives. Human involvement in these circumstances is strictly regulated for fear of increasing the number of affected persons. Therefore, there exists a demand for a fast, robust, dynamic robotic solution. The goal of this project was to design and build a self-reconfigurable modular robot for search and rescue applications. The MQP team investigated previous work and collaborated on three new innovative ideas. From these ideas, using an evaluation matrix, one specific design was chosen. These metrics required that each module move independently, identify and connect with other modules, and travel as a collective system. The chosen design is small, individually mobile, and capable of collaborated motion and dynamic system configuration. The rigorous constraints, small module size and untethered operation, necessitated an innovative design and required strategic placement of the internal components. Two different connection mechanisms, one magnetic and the other mechanical were researched, designed, and prototyped as viable methods for module connection. A final module was fabricated and individual module mobility was validated. A switchable permanent magnet connection mechanism was realized and developed for module integration

Plasma protein corona modulates the vascular wall interaction of drug carriers in a material and donor specific manner.

The nanoscale plasma protein interaction with intravenously injected particulate carrier systems is known to modulate their organ distribution and clearance from the bloodstream. However, the role of this plasma protein interaction in prescribing the adhesion of carriers to the vascular wall remains relatively unknown. Here, we show that the adhesion of vascular-targeted poly(lactide-co-glycolic-acid) (PLGA) spheres to endothelial cells is significantly inhibited in human blood flow, with up to 90% reduction in adhesion observed relative to adhesion in simple buffer flow, depending on the particle size and the magnitude and pattern of blood flow. This reduced PLGA adhesion in blood flow is linked to the adsorption of certain high molecular weight plasma proteins on PLGA and is donor specific, where large reductions in particle adhesion in blood flow (>80% relative to buffer) is seen with ∼60% of unique donor bloods while others exhibit moderate to no reductions. The depletion of high molecular weight immunoglobulins from plasma is shown to successfully restore PLGA vascular wall adhesion. The observed plasma protein effect on PLGA is likely due to material characteristics since the effect is not replicated with polystyrene or silica spheres. These particles effectively adhere to the endothelium at a higher level in blood over buffer flow. Overall, understanding how distinct plasma proteins modulate the vascular wall interaction of vascular-targeted carriers of different material characteristics would allow for the design of highly functional delivery vehicles for the treatment of many serious human diseases

Adhesion of sLe^a–coated PS spheres or anti-ICAM-coated PLGA spheres to activated HUVEC under various flow conditions.

<p>(A) Adhesion of 5 µm sLe^a–coated PS spheres in laminar whole blood and buffer flows to activated HUVEC at 200 s⁻¹ for 7 human subjects. N = 2 (distinct trials) for each blood bar. (B) Average adhesion of 5 µm anti-ICAM-coated PLGA spheres to activated HUVEC from laminar buffer, plasma, or whole blood flow of three low PLGA binding donors at 200 s⁻¹. Laminar flow was run for 5 min. Particle concentration in flow  = 5e5 spheres/mL. sLe^a density  = 1,800+/−200 sites/µm² (SEM) and anti-ICAM-1 density  = 3500+/−500 sites/µm² (SEM). #  =  Not significant with respect to the whole blood trial. N = 3 distinct trials (donors) for the plasma and blood flow assays.</p