UV-assisted punching for fabrication of biocompatible microgel shapes for applications in drug delivery

wide range of micro-and nano- carriers entrapping active pharmaceutical ingredients to improve their delivery are described today. Amongst these, hydrogel based carriers are of particular interest for the delivery of biomacromolecules, as they provide a water-rich environment in addition to a protective polymeric matrix for these compounds. The use of replication based top-down microfabrication techniques to precisely configure the shape and size of these micro- and nanocarriers is becoming increasingly popular. This is due to the high degree of control offered by these techniques as opposed to the more established bottom-up techniques which mainly produce polydisperse spherical carriers. Recent studies have successfully demonstrated that carrier shape and size play a significant role in carrier flow, bioadhesion, internalization and interaction with biological membranes. Thus, this work explored the microfabrication of shape-specific hydrogel based carriers for oral and intravenous drug delivery.
UV-assisted punching was developed as a novel two-step microfabrication technique that allows for the fabrication of biocompatible poly(ethylene glycol)-based hydrogel micro-carriers termed as “microgel shapes”. UV-assisted punching is a facile, temperature ambient and solventless method that allows for the fabrication of individual microgel shapes by mechanical punching with a robust thermoplastic stamp. Furthermore, it allows for a process integrated incorporation of biomacromolecules. In the current work, microgel shapes targeted towards oral drug delivery were initially fabricated in circular, elliptical, square and rod-like geometries with a carrier length/diameter of 100 μm and a height of 25 μm. For each of the geometries, successful incorporation of a fluorescently labelled model biomacromolecule was demonstrated by fluorescence microscopy. In vitro release studies were performed to quantify the macromolecular content and the release profile associated with the produced microgel shapes.
After establishment of UV-assisted punching as a fabrication method, process optimizations with use of alternate materials for thermoplastic stamps were performed. A versatile use of different thermoplastic stamps in UV-assisted punching for microgel shape fabrication was demonstrated.
Furthermore, an evaluation of thermoplastic stamps in native, degassed and plasma activated conditions was conducted to assess its correlation on stamp wetting and microgel shape yield.
Finally, a step-wise downscaling of microgel shape size for all the aforementioned geometries was carried out to obtain carriers with a length/diameter of 8 μm and a height of 2 μm relevant for intravenous applications. Biocompatibility of the developed carriers was demonstrated through hemocompatibility and cell viability assays. Moreover, successful process integrated loading of the microgel shapes with model enzyme and the retention of its activity post-loading to obtain microreactors was demonstrated.
Overall, microgel shapes in various geometries with lengths/diameters ranging from 100 – 8 μm and a heights ranging from 25 – 2 μm were successfully fabricated by UV-assisted punching. Furthermore, a process integrated loading of biomacromolecules was demonstrated.