Microchannel system for rate-controlled, sequential, and pH-responsive drug delivery.

Controlled delivery of drug at a constant rate, in a sequential order, or responsive to environment conditions has been pursued for a long time to enhance the efficacy of therapeutic molecules and to minimize side effects of highly potent drugs. However, achieving such delicately-controlled delivery of a drug molecule is non-trivial and still remains a challenge. We propose the use of microchannels to control the rate, sequence, and pH-responsiveness of drug delivery for high precision and predictability. In this study, we introduce elementary drug delivery units consisting of micro-reservoirs and microchannels that have variations in their lengths, widths, numbers, and straightness. The release study demonstrates that the release rates of model drugs can be modulated by the design of microchannels. Finite element modeling of drug release predicts the performance of the drug delivery units with high accuracy. The possibility of sequential drug delivery is also demonstrated using biodegradable polymer plug in microchannels. Finally, pH-responsive delivery of drugs in microfluidic units is also discussed and demonstrated via cell viability tests. STATEMENT OF SIGNIFICANCE: In this work, we developed microchannel-based drug delivery devices whose release rate could be accurately calculated and controlled by design of microchannel geometry. Although there have been many advances in microfabricated drug delivery systems, in particular, reservoir-based systems, no systematic investigation has been made to utilize the release channels. In our work, an equivalent electrical circuit concept was applied to the microfluidic systems for more detailed design and analysis. A microfluidic channel was regarded as an electrical resistor; their diffusion/electrical flux could be tuned with geometric factors such as length, width, a number of channel/resistor and their connections. Furthermore, from delivery rate control using channel geometry, multifunctional channel-based release systems for sequential and pH-responsive were demonstrated.

Spatially discrete thermal drawing of biodegradable microneedles for vascular drug delivery.

Spatially discrete thermal drawing is introduced as a novel method for the fabrication of biodegradable microneedles with ultra-sharp tip ends. This method provides the enhanced control of microneedle shapes by spatially controlling the temperature of drawn polymer as well as drawing steps and speeds. Particular focus is given on the formation of sharp tip ends of microneedles at the end of thermal drawing. Previous works relied on the fracture of polymer neck by fast drawing that often causes uncontrolled shapes of microneedle tips. Instead, this approach utilizes the surface energy of heated polymer to form ultra-sharp tip ends. We have investigated the effect of such temperature control, drawing speed, and drawing steps in thermal drawing process on the final shape of microneedles using biodegradable polymers. XRD analysis was performed to analyze the effect of thermal cycle on the biodegradable polymer. Load-displacement measurement also showed the dependency of mechanical strengths of microneedles on the microneedle shapes. Ex vivo vascular tissue insertion and drug delivery demonstrated microneedle insertion to tunica media layer of canine aorta and drug distribution in the tissue layer.

Curved biodegradable microneedles for vascular drug delivery.

Curved biodegradable microneedles for application to the outer surface of blood vessels are produced to enhance drug delivery to vascular tissues suffering from hyperplasia or atherosclerosis. Spatially discrete thermal drawing and post-annealing processes are employed to fabricate microneedles on a curved surface. Insertion of microneedles into arteries in vivo and ex vivo is demonstrated, and their mechanical properties and drug-delivery function are studied.