Functional Hydrogels Integration in 3D Printed Microarchitectures for the Production of Magnetically Controlled Microdevices for Targeted Drug Delivery

Two of the most crucial topics in modern medicine are drug administration routes and their relative pharmacokinetics inside human body. Virtually all conventional delivery methodologies are based on the non-selective distribution of the active substance in the whole body, mediated by blood circulation. Consequently, a relevant fraction of the drug reaches non-target parts of the body, lowering thus administration efficacy and amplifying negative side-effects. To overcome these problematics, advanced administration strategies based on targeted delivery have been recently developed [1]. In these approaches, drugs are released in controlled amounts by specifically tailored smart materials. A promising class of such materials is constituted by functionalized hydrogels. Release from these biocompatible materials can be controlled through a variety of approaches [2]. For example, smart hydrogels can be tailored to release drugs only under specific conditions of pH, temperature ... In this way, release rate and timing can be efficiently tuned by controlling the structure and the chemistry of the hydrogels.<br/><br/>On the other side, a possible key to improve spatial control over release can be the use of magnetically controlled microrobots [3]. These remotely controlled devices are able to perform different tasks in-vivo, including for example cell transport [4] and medicine delivery applications [5]. For the latter, they can be coated with drug releasing materials and wirelessly guided inside human body to perform administration only in close proximity of the target organ. Moreover, magnetic field is harmless for humans, allowing a limited invasivity of the microrobots in conjunction with a great manipulation precision.<br/><br/>In this context, we describe the realization of magnetically guidable microdevices integrating smart hydrogel layers specifically tailored to perform controlled drug release. The microdevices are obtained employing additive manufacturing, specifically microstereolithography, in combination with wet metallization. This approach is highly scalable and flexible and can yield micrometric sized objects at relatively low cost. To allow actuation, a magnetic layer is applied by means of wet metallization on the 3D printed devices. The same technique is employed also to deposit a gold layer to make the surface biocompatible. Finally, the surface is coated with the hydrogels and drug release performances are evaluated in-vitro. Following this manufacturing strategy, we are able to obtain hard-soft hybrid microrobots able to combine the high magnetic properties typical of ferromagnetic alloys with the shape customizability typical of 3D printing and the drug releasing properties of hydrogels.<br/><br/>Two different strategies are investigated to control the drug release from the hydrogel. In the first, an alginate hydrogel is modified with click chemistry, binding the drug to the biopolymer chains by mean of a pH cleavable bond. In this way, release takes place only when the device reaches the part of the body presenting the correct pH range. An example of possible application of this method may be drug release in well-defined zones of the gastrointestinal apparatus, which is characterized by different pH levels according to the tract considered. In the second approach, two different hydrogel couples (alginate and chitosan or alginate and poly(allylamine) hydrochloride) are sequentially deposited following a layer-by-layer technique. In this way, drug release can be tuned by increasing the diffusion path in the material. This approach, even though not targeted as the first, is less complicate and more applicable to different types of drugs.<br/> <br/>[1] M.W. Tibbitt et al., J. Am. Chem. Soc. 138, 704 (2016)<br/>[2] K.S. Soppimath et al., Drug Dev. Ind. Pharm. 28(8), 957 (2002)<br/>[3] J.J. Abbott, IEEE Robot. Autom. Mag. 14, 92 (2007)<br/>[4] R. Bernasconi et al., Mater. Horiz. 5, 699 (2018)<br/>[5] S. Fusco, Adv. Healthcare Mater. 2(7), 1037 (2013)