Currently, kinetic data is either collected under steady‐state conditions in flow or by generating time‐series data in batch. Batch experiments are generally considered to be more suitable for the generation of kinetic data because of the ability to collect data from many time points in a single experiment. Now, a method that rapidly generates time‐series reaction data from flow reactors by continuously manipulating the flow rate and reaction temperature has been developed. This approach makes use of inline IR analysis and an automated microreactor system, which allowed for rapid and tight control of the operating conditions. The conversion/residence time profiles at several temperatures were used to fit parameters to a kinetic model. This method requires significantly less time and a smaller amount of starting material compared to one‐at‐a‐time flow experiments, and thus allows for the rapid generation of kinetic data.
By partially retracting microneedles after insertion and other methods to overcome flow resistance of dense dermal tissue, protocols can be designed for hollow microneedles to microinfuse fluid at therapeutically relevant rates.
Purpose
This study tested the hypothesis that hollow microneedles can infuse solutions containing soluble molecules, nanoparticles, and microparticles into sclera in a minimally invasive manner.
Methods
Individual hollow microneedles were inserted into, but not across, human cadaver sclera and aqueous solutions containing sulforhodamine or fluorescently-tagged nanoparticles or microparticles were infused into sclera at constant pressure. The infused volume of fluid was measured and imaged histologically as a function of scleral thickness, infusion pressure, needle retraction depth and the presence of spreading enzymes (hyaluronidase and collagenase).
Results
Individual hollow microneedles were able to insert into sclera. Fluid infusion was extremely slow after microneedle insertion into the sclera without retraction, but partial retraction of the microneedle over a distance of 200–300 μm enabled infusion of 10–35 μl of fluid into the tissue. Scleral thickness and infusion pressure had insignificant effects on fluid delivery. Nanoparticle suspensions were also delivered into sclera, but microparticles were delivered only in the presence of hyaluronidase and collagenase spreading enzymes, which suggested the role of scleral glycosaminoglycans and collagen fibers as rate-limiting barriers.
Conclusion
This study shows that hollow microneedles can infuse solutions into the sclera for minimally invasive delivery of soluble molecules, nanoparticles and microparticles.
An automated multitrajectory optimization platform with continuous online infrared (IR) monitoring is presented. The production rate of a Paal−Knorr reaction is maximized within a constrained temperature and residence time design space. The automated platform utilizes a microreactor system to carry out optimizations with low material requirements and implements a micro IR flow cell for continuous online monitoring of reaction conversion. The approach to steady state at each set of reaction conditions is assessed continuously before the objective function is evaluated and reactor conditions move to the next set point. Several optimization algorithms are tested for their performance on a complex objective terrain. Each function comes to agreement on the optimal conditions but requires a significantly different number of experiments to reach the final conditions. Additionally, multiple objective functions are compared to analyze the trade-off between production rate and conversion.
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