| Autor: |
Lykins WR; University of California Berkeley-University of California San Franciso Graduate Program in Bioengineering, San Francisco, California 94118, United States.; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California 94143, United States., Hansen ME; University of California Berkeley-University of California San Franciso Graduate Program in Bioengineering, San Francisco, California 94118, United States.; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California 94143, United States., Sun X; Department of Medicine, University of California San Francisco, San Francisco, California 94143, United States., Advincula R; Department of Medicine, University of California San Francisco, San Francisco, California 94143, United States., Finbloom JA; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California 94143, United States., Jain AK; Sun Pharma Advanced Research Company, Vadodara 390010, India., Zala Y; Sun Pharma Advanced Research Company, Vadodara 390010, India., Ma A; Department of Medicine, University of California San Francisco, San Francisco, California 94143, United States., Desai TA; University of California Berkeley-University of California San Franciso Graduate Program in Bioengineering, San Francisco, California 94118, United States.; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California 94143, United States. |
| Abstrakt: |
Oral protein delivery technologies often depend on encapsulating or enclosing the protein cargo to protect it against pH-driven degradation in the stomach or enzymatic digestion in the small intestine. An emergent methodology is to encapsulate therapeutics in microscale, asymmetric, planar microparticles, referred to as microdevices. Previous work has shown that, compared to spherical particles, planar microdevices have longer residence times in the GI tract, but it remains unclear how specific design choices (e.g., material selection, particle diameter) impact microdevice behavior in vivo. Recent advances in microdevice fabrication through picoliter printing have expanded the range of device sizes that can be fabricated in a rapid manner. However, relatively little work has explored how device size governs their behavior in the intestinal environment. In this study, we probe the impact of geometry of planar microdevices on their transit and accumulation in the murine GI tract. Additionally, we present a strategy to label, image, and quantify these distributions in intact tissue in a continuous manner, enabling a more detailed understanding of device distribution and transit kinetics than previously possible. We show that smaller particles (194.6 ± 7 μm.diameter) tend to empty from the stomach faster than midsize (293.2 ± 7 μm.diameter) and larger devices (440.9 ± 9 μm.diameter) and that larger devices distribute more broadly in the GI tract and exit slower than other geometries. In general, we observed an inverse correlation between device diameter and GI transit rate. These results inform the future design of drug delivery systems, using particle geometry as an engineering design parameter to control device accumulation and distribution in the GI tract. Additionally, our image analysis process provides greater insight into the tissue level distribution and transit of particle populations. Using this technique, we demonstrate that microdevices act and translocate independently, as opposed to transiting in one homogeneous mass, meaning that target sites will likely be exposed to devices multiple times over the course of hours post administration. This imaging technique and associated findings enable data-informed design of future particle delivery systems, allowing orthogonal control of transit and distribution kinetics in vivo independent of material and cargo selection. |
