Functionalized hydrogel coated microdevices may be potential candidates for targeted drug delivery

This article is a part of our University Technology Exposure Program. The program aims to recognize and reward innovation from engineering students and researchers across the globe.

Medicine relies on the use of pharmacologically active agents to treat the disease and is effective in the manner by which it is administered or delivered. Drug delivery mechanisms can affect drug pharmacokinetics, absorption, distribution, metabolism, duration of the therapeutic effect, excretion, and toxicity. In recent times, chemical engineers and pharmacology experts have carried out research to solve the issues with conventional drug delivery approaches that are based on the non-selective distribution of the active substance in the human body. In traditional drug delivery methodology, most of the drug is unused, meaning that a higher dosage must be provided to achieve active concentration in the target organ. 

Several smart delivery approaches have been discussed in the past couple of years based on nanometric structures to travel the body system until they reach the organ, and designed polymers to control the release of the drug. The materials used in the polymer-based drug release approach are polypyrrole, hydrogel-based chitosan, or alginate which are designed for release in the presence of thermal stimuli, pH variations, or electric fields. Another promising drug delivery technique is based on the implementation of controlled release materials with wirelessly controlled small-scale devices such as micro and nanorobots [1]. Various actuation methods such as chemical, light, and ultrasound have been proposed, however magnetic actuation has been widely adopted. A team of experts in the field of chemical and materials engineering has carried out work to develop chemically tailored hydrogels that are able to release drugs at a defined pH interval on existing magnetically controlled microdevices [2].

Guidelines for device design

In the paper titled, “3D integration of pH-cleavable drug-hydrogel conjugates on magnetically driven smart microtransporters,” we proposed a drug delivery approach based on the existing microdevices, manufactured with the combination of microstereolithography and wet metallization technique to allow easy and versatile production. The three main guidelines for the manufacturing of the devices are– biocompatibility, magnetic actuality, and hydrogel loading optimization. Several features are needed to satisfy these requirements: the microdevices exhibit a chemically inert surface, a suitable metallic coating that reacts to the presence of a magnetic field, and a scaffold structure to accommodate enough hydrogel mass. 

Production steps for hydrogel coated microrobots: [a] Wet metallization; [b] Device dipping in RhB dissolved in alginate solution (in ultrasound bath); [c] Device dipping in functionalized alginate solution (in ultrasound bath); [d] Hydrogel dipping in CaCl2 water solution; [e] Final coated devices [Image Credit: Research Paper]

We decided to use the 3D printed magnetically steerable microscaffolds developed by R. Bernasconi et. al. [3] that were originally developed for cell transportation; however, their high surface area and biocompatibility help them to be used as a multipurpose platform. “Their porous structure can be used to accommodate a large quantity of hydrogel with respect to their volume,” the research explains. “Furthermore, pores allow tuning the release, as the drug incorporated inside the device diffuses out in more time with respect to the drug in the hydrogel layers at the surface.”

As shown in the figure above, the surface is deposited with four metallic layers– a copper layer, a CoNiP layer to impart magnetic characteristics, a NiP layer, and an Au layer to provide biocompatibility. After this, two types of Rhodamine B (RhB) loaded hydrogels were deposited on these devices to obtain the drug-releasing microrobots. According to figure c, RhB is dissolved in the alginate solution (M-NB), while in figure d. the RhB is chemically bound to the structure of the alginate with an ester or an amide bond (M-B). In the first case (figure i), the RhB release from alginate takes place via diffusion and starts immediately in the presence of a concentration gradient. On the other hand (figure j), in the M-B devices, the drug is bound to the alginate chain via a cleavable link that can be dissolved in a predefined pH range.

Production steps for hydrogel coated microrobots: [i] Final coated samples for non-functionalized hydrogels [j] For functionalized hydrogels [Image Credit: Research Paper]

“This renders the release insensitive to concentration gradients and makes possible drug delivery only when the device reaches an environment characterized by the correct pH."

Experimentation of the drug delivery method

To improve the performance of the drug delivery method, two strategies were investigated– the synthesis of an ester bond-based cleavable linker and an amide bond-based cleavable linker. To achieve high performance, the team functionalized alginate in order to create a pH-sensitive linker between the polymeric network and the drug molecules. Once the team proved that alginate hydrogel systems can successfully be functionalized with cleavable bonds and applied to magnetically steerable microdevices, the RhB release was investigated. 

“Considering the results, it is evident that functionalized hydrogel-coated microdevices may be potential candidates to perform targeted drug delivery in environments where pH differences are present,” the team concludes. “The functional microtransporters described in the present work are particularly promising for in-vivo applications in environments where pH differences are present, like the digestive apparatus.”

The research paper was published in Elsevier’s Materials & Design journal in the year 2020 under open-access terms.

References

[1] ] E. Mauri, S. Papa, M. Masi, P. Veglianese, F. Rossi, Novel functionalization strategies to improve drug delivery from polymers, Expert Opin. Drug Deliv. 14 (2017) 1305–1313

[2] Bernasconi, R., Mauri, E., Rossetti, A., Rimondo, S., Suriano, R., Levi, M., et al. (2021). 3D integration of pH-cleavable drug-hydrogel conjugates on magnetically driven smart microtransporters. Mater. Des. 197, 109212. doi:10.1016/j.matdes.2020.109212.

[3] R. Bernasconi, F. Cuneo, E. Carrara, G. Chatzipirpiridis, M. Hoop, X. Chen, B.J. Nelson, S. Pané, C. Credi, M. Levi, L. Magagnin, Hard-magnetic cell microscaffolds from electroless coated 3D printed architectures, Mater. Horizons. 5 (2018) 699–707, https:// doi.org/10.1039/C8MH00206A 

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