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9. Gelatin methacryloyl inverted colloidal crystal scaffolds as artificial liver platform

Author

Shirahama, Hitomi, Cho Nam-Joon, and Interdisciplinary Graduate School (IGS)

Subjects
Engineering::Bioengineering [DRNTU]
Abstract

Artificial organs are vital for drug development since preclinical animal testing has a limitation in human toxicity prediction, occasionally leading to severe damages. In particular the liver which is an organ that serves the functions in drug metabolism and detoxification, would play a critical role in toxicity screening when reconstructed in vitro. However, primary hepatocytes lose their functions when seeded onto plain substrates, and maintaining the functions ex vivo has been challenging. One of the cues found in liver tissue engineering to keep hepatocyte phenotype is the structural dimensionality; three-dimensional (3D) culture systems which emulate the liver microenvironment, provide enhanced cell-cell interactions and cell-material interactions compared to those in two-dimensions, resulting in prolonged of hepatocyte functions. Therefore, in-vivo-like platforms that mimic the liver microstructure have been in high demand. The overall goal of this dissertation is to create a liver-mimicking platform that can aid in maintaining hepatic functions. Besides cells, the liver is composed of extracellular matrices (ECM) with highly-ordered, porous structure. On the other hand, fabrication of such ECM-based highly-ordered scaffold has been challenging. Problems lie in high viscosity and in slow crosslinking of the aqueous protein solutions for building complex configuration. In this thesis, the material chosen for the platform is a photocrosslinkable protein, gelatin methacryloyl (GelMA). Gelatin is a hydrolyzed form of collagen, which is the main component of the liver structure. While preserving biological advantages of collagen/gelatin, the functionalized gelatin can be crosslinked in minutes in the presence of ultraviolet light and a photoinitiator. Furthermore, aqueous solutions of GelMA are much less viscous than the parent materials. However, the synthesis method has not been optimized in a systematic manner, leaving room for improvement. The first work presented in this thesis is to revamp GelMA synthesis through finding appropriate buffer systems and reaction conditions such as pH, molarity, temperature, and time. The second part of the thesis work entails characterizing the physical properties of GelMA hydrogels with a simplified model. Rheological experiments on mechanical stiffness, swelling measurements in size and mass, and enzymatic degradation experiments were carried out for comprehensive characterization. Finally, a liver-mimicking hydrogel platform was developed, possessing highly-ordered pores and interconnections. Protein-based inverted colloidal crystal (ICC) scaffolds were fabricated with GelMA and a sacrificial polymer lattice. The use of GelMA enabled easy infiltration into the lattices at a high protein concentration and fast crosslinking. Liver model cells, Huh7.5 cells, in GelMA ICC scaffolds attached well to the surface of GelMA ICC and formed 3D cell constructs with cell multi layers during a culture period of high viability. Relative to GelMA plain surface, cells in GelMA ICC exhibited higher hepatic functions. The results demonstrate the potential of GelMA ICC to be an artificial liver platform – that can maintain hepatic functions and foresee human drug toxicity – and would be contributive to drug discovery and development. Doctor of Philosophy (IGS)

Published
2018

11. Scaffold-Mediated Sustained, Non-viral Delivery of miR-219/miR-338 Promotes CNS Remyelination

Author

Milbreta, Ulla, primary, Lin, Junquan, additional, Pinese, Coline, additional, Ong, William, additional, Chin, Jiah Shin, additional, Shirahama, Hitomi, additional, Mi, Ruifa, additional, Williams, Anna, additional, Bechler, Marie E., additional, Wang, Jun, additional, ffrench-Constant, Charles, additional, Hoke, Ahmet, additional, and Chew, Sing Yian, additional

Published
2019
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15. Scaffold-Mediated Sustained, Non-viral Delivery of miR-219/miR-338 Promotes CNS Remyelination

Author

Milbreta, Ulla, Lin, Junquan, Pinese, Coline, Ong, William, Chin, Jiah Shin, Shirahama, Hitomi, Mi, Ruifa, Williams, Anna, Bechler, Marie E., Wang, Jun, ffrench-Constant, Charles, Hoke, Ahmet, and Chew, Sing Yian

Abstract

The loss of oligodendrocytes (OLs) and subsequently myelin sheaths following injuries or pathologies in the CNS leads to debilitating functional deficits. Unfortunately, effective methods of remyelination remain limited. Here, we present a scaffolding system that enables sustained non-viral delivery of microRNAs (miRs) to direct OL differentiation, maturation, and myelination. We show that miR-219/miR-338 promoted primary rat OL differentiation and myelination in vitro. Using spinal cord injury as a proof-of-concept, we further demonstrate that miR-219/miR-338 could also be delivered non-virally in vivousing an aligned fiber-hydrogel scaffold to enhance remyelination after a hemi-incision injury at C5 level of Sprague-Dawley rats. Specifically, miR-219/miR-338 mimics were incorporated as complexes with the carrier, TransIT-TKO (TKO), together with neurotrophin-3 (NT-3) within hybrid scaffolds that comprised poly(caprolactone-co-ethyl ethylene phosphate) (PCLEEP)-aligned fibers and collagen hydrogel. After 1, 2, and 4 weeks post-treatment, animals that received NT-3 and miR-219/miR-338 treatment preserved a higher number of Olig2+oligodendroglial lineage cells as compared with those treated with NT-3 and negative scrambled miRs (Neg miRs; p < 0.001). Additionally, miR-219/miR-338 increased the rate and extent of differentiation of OLs. At the host-implant interface, more compact myelin sheaths were observed when animals received miR-219/miR-338. Similarly within the scaffolds, miR-219/miR-338 samples contained significantly more myelin basic protein (MBP) signals (p < 0.01) and higher myelination index (p < 0.05) than Neg miR samples. These findings highlight the potential of this platform to promote remyelination within the CNS.

Published
2024
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19. Macromol. Biosci. 3/2016

Author

Kim, Myung Hee, primary, Kumar, Supriya K., additional, Shirahama, Hitomi, additional, Seo, Jeongeun, additional, Lee, Jae-Ho, additional, Zhdanov, Vladimir P., additional, and Cho, Nam-Joon, additional

Published
2016
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30. Lycopodium Spores: A Naturally Manufactured, Superrobust Biomaterial for Drug Delivery.

Author

Mundargi, Raghavendra C., Potroz, Michael G., Park, Soohyun, Park, Jae Hyeon, Shirahama, Hitomi, Lee, Jae Ho, Seo, Jeongeun, and Cho, Nam‐Joon

Subjects
CLUB mosses, BIOMATERIALS, DRUG delivery systems, ENCAPSULATION (Catalysis), MACROMOLECULES, PARTICLE size distribution, SPORES
Abstract

Herein, the exploration of natural plant-based 'spores' for the encapsulation of macromolecules as a drug delivery platform is reported. Benefits of encapsulation with natural 'spores' include highly uniform size distribution and materials encapsulation by relatively economical and simple versatile methods. The natural spores possess unique micromeritic properties and an inner cavity for significant macromolecule loading with retention of therapeutic spore constituents. In addition, these natural spores can be used as advanced materials to encapsulate a wide variety of pharmaceutical drugs, chemicals, cosmetics, and food supplements. Here, for the first time a strategy to utilize natural spores as advanced materials is developed to encapsulate macromolecules by three different microencapsulation techniques including passive, compression, and vacuum loading. The natural spore formulations developed by these techniques are extensively characterized with respect to size uniformity, shape, encapsulation efficiency, and localization of macromolecules in the spores. In vitro release profiles of developed spore formulations in simulated gastric and intestinal fluids have also been studied, and alginate coatings to tune the release profile using vacuum-loaded spores have been explored. These results provide the basis for further exploration into the encapsulation of a wide range of therapeutic molecules in natural plant spores. [ABSTRACT FROM AUTHOR]

Published
2016
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