Corinne S. Lengsfeld

Manipulation of particle size distribution of poly(l-lactic acid) nanoparticles with a jet-swirl nozzle during precipitation with a compressed antisolvent

Abstract The precipitation with a compressed-fluid antisolvent (PCA) process is a useful technique for producing biodegradable polymer microparticles for controlled drug delivery applications. Based on the mechanism that particles precipitate from a gaseous jet rather than atomized liquid droplets, we have designed and manufactured a nozzle capable of producing nanoscale poly( l -lactic acid) (PLLA) particles during PCA processing. A key design feature of the nozzle is the combination of a swirl flow and a micro-mixing swirl chamber to optimize gas-like mixing between the solvent and compressed antisolvent. Increasing the power input into the swirl chamber from 1.9×106 to 6.5×109 W/m3 acts to enhance the degree of mixing occurring within the confines of the swirl chamber. This is shown by a reduction in jet mixing length from 2627±14 to 0 μm and a decrease in the average particle diameter of 100 000 M.W. PLLA from 1430±90 to 193±20 nm (volume weighted diameter). Nozzles designed to optimize gas-like mixing are inherently different from conventional PCA spray nozzles, and allow production of nanoscale PLLA particles with a sharper size distribution than previously attainable.

In vitro and in vivo evaluation of the effects of PLA microparticle crystallinity on cellular response

Previous research suggests that crystallinity of poly(L-lactide) P(L)LA microparticles can influence surface free energy, which in turn might influence biocompatibility. This work studies the cellular response to P(L)LA microparticles of different crystallinity both in vitro and in vivo. Following incubation with P(L)LA microparticles, the in vitro production of reactive oxygen intermediates (ROI) was measured as a marker of cellular response. In both fluorescence and chemiluminescence experiments to measure ROI, a small effect of microparticle crystallinity on NR8383 AM response was observed. Microparticles of higher crystallinity elicited a smaller inflammatory response compared to lower crystallinity particles. Compared to the elevated inflammatory response induced by zymosan, the response to all P(L)LA microparticles tested was practically negligible. Results from in vivo experiments further supported conclusions that P(L)LA microparticles elicit minimal inflammatory response. Following acute exposure to P(L)LA microparticles in guinea-pig lungs, the inflammatory response was not significantly different from the response observed when sterile saline was administered. In contrast to the in vitro experiments, there were not apparent differences in cellular responses to microparticles of different crystallinity.

Dissolution and partitioning behavior of hydrophobic ion-paired compounds.

AbstractPurpose. This study was conducted to determine the effects of counterion hydrophobicity on organic/aqueous partition coefficients for hydrophobic ion paired (HIP) complexes. Furthermore, the coupled dissolution and reverse ion-exchange kinetics for dissolution of HIP complexes into aqueous electrolyte solutions were measured and mathematically modeled. Methods. HIP complexes of model drugs tacrine and l-phenylephrine were formed using linear sodium alkylsulfates and bis (2-ethylhexyl sodium sulfosuccinate). Equilibrium partition coefficients between chloroform and aqueous solutions for the complexes and the kinetics of dissolution of the complexes in buffered aqueous solutions were measured. Results. The chloroform/aqueous partition coefficients for l-phenylephrine/bis (2-ethylhexyl sodium sulfosuccinate) complexes decrease with increasing molar surface tension increment of salts added to the aqueous solution. The logarithm of the partition coefficient for a homologous series of alkyl sulfate complexes decreases as the hydrophilic-lipophilic balance number increases. Dissolution of HIP complexes in deionized water shows first order kinetics, whereas dissolution in aqueous electrolyte solutions shows biphasic kinetics. A kinetic model explains these dissolution rates. Conclusions. Solubility and dissolution rates for HIP complexes depend on the hydrophobic-lipophilic balance number of the organic counter ion as well as on the electrolyte composition of aqueous solutions. Reverse ion-exchange kinetics are sufficiently slow to allow HIP complexes to be considered simple prodrugs.

Encapsulating DNA within Biodegradable Polymeric Microparticles

In order for genetic medicines to become viable commercial products, the active form of the drug (e.g., DNA) must be able to reach the site of action and remain there long enough to accomplish its intended function. Encapsulation of plasmid DNA into biodegradable microspheres is one approach towards solving this challenge. This review describes the primary methods for satisfactorily entrapping intact DNA into biodegradable polymeric matrices. In particular, the materials, processes, and equipment required for each encapsulation method are described in detail. The resulting microspheres could be used for parenteral, oral, and inhalation therapy.

Enabling effective learning, curriculum delivery reform at the University of Denver

The Engineering Department at the University of Denver (USA) has received a Sturm Program Development Award for reform of its curricula. Specifically they have: (1) changed the learning environment from predominately teacher centered to student centered; (2) implemented a quality based grading method that allows students to know what is expected of them and to actually take part in the procedure; (3) created more studio type classrooms with current technology to facilitate learning and demonstrate state of the art engineering methods and procedures; and (4) blended engineering topics with English topics in an integrated freshman sequence.

Mechanical modeling of carbonic anhydrase motion in simple channels

The difference in potential energy generated by molecular confinement arising from molecular length has a potential application to separation technology. However, the design and optimization of an integrated microfluidic device to detect and separate chemically similar molecules will require computational techniques capable of predicting the energy storage (or release) associated with conformational change. To this end we developed midlevel modeling approach for the prediction of macromolecular motion in a confinement channel using finite element analysis and stochastic methods. As a proof of concept, we investigated the mechanical behavior of a carbonic anhydrase molecule where the molecule was modeled as a beam network constructed by the backbone carbon atoms. Each pair of the adjacent atoms form an elastic beam that bears both axial and shear stresses. The molecular conformation and associated dynamic behavior of the reconstructed molecule were investigated via two protocols: (1) compression of the mol...

OPTIMIZATION OF MICRO-TEXTURED SURFACES FOR TURBINE VANE IMPINGEMENT COOLING

Gas turbine engines are challenged to operate at higher efficiencies, leading to turbine inlet temperatures that exceed turbine material limits. Increased internal cooling efficiency enables higher temperature operation, reduces cooling air injection into the core flow, and mitigates performance penalties from thermal mixing and total pressure loss. Micro Cooling Concepts has developed a turbine vane cooling concept that provides enhanced internal impingement cooling effectiveness via the use of micro-textured impingement surfaces (i.e., grooves and fins). The current effort employs computational models, in conjunction with optimization techniques, to explore the optimal design of these micro-textured surfaces. A computational fluid dynamics model of the vane leading edge was utilized to compute the flow in the vane interior and the temperature distribution in the vane material. A gradient-based optimization routine, implemented in Matlab, varied geometric parameters in an independent manner to minimize the maximum metal temperature in the vane material volume. Four separate design spaces were explored: grooves and fins (both shrouded and unshrouded). It was determined that the shrouded fins and fin design outperformed all others. The maximum external convective free stream temperature obtained was 2600 K while the maximum internal vane temperature remained below 1219 K.Copyright

DNA hydrodynamic degradation controlled by kolomogorov length scales in pipe flow

Strict US Food and Drug Administration regulations on contamination levels for DNA therapeutics acceptable for human use complicate the manufacturing process. This study aims to improve therapeutic production through the investigation of the molecular effects of hydrodynamic forces encountered during processing. Results suggest that the strain rate and residence time were not solely responsible for degradation within the system. Instead, turbulent flows at the entrance or developing flow regions dominate especially when the Kolmogorov length scale approaches the stretched molecular length scale. We specifically suggest this for linear genomic DNA and supercoiled plasmid DNA when the ratio of the molecular length to the Kolmogorov length scale must remain smaller than unity to minimize loss of the desired structure. These findings suggest that bioprocessing systems should design expansions and contractions to minimize recirculation and turbulent mixing zones, although, not always possible, careful attention should be paid to pipe surface roughness to ensure that turbulent eddies are not generated in low Reynolds number flows.

Understanding EHDA and Protein Stability

Therapeutic proteins can be difficult to work with due to the fact that each protein has properties and functions that are unique. These exclusive properties are in part due to the proteins three-dimensional shape (secondary and tertiary structure). This shape is determined by bends in the amino acid sequence generated by electrostatic interactions, hydrogen bonds, and hydrophobic-hydrophilic interactions between neighboring amino acids. These bonding interactions are weak and can be severed by chemical or physical forces. Thus, therapeutic proteins can be denatured during manufacture and by methods used to deliver them to the body.Copyright