About Us
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It is well-known that three-dimensional (3D) culture closely mimics cell interaction in vivo and enhances cell viability and function compared to 2D (monolayer) culture. Over the years, we have been employing different methods to construct the spheroidal structure of therapeutic cells, including mesenchymal stem cells (MSCs), hepatocytes, islets, and fibroblasts.
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In our lab, traditional hanging drop and micropatterned plate-based techniques are frequently utilized to construct spheroids with a size below 200 μm. Meanwhile, we demonstrated that the methylcellulose-based fabrication technique is highly suitable for spheroids of large sizes (200-500 μm) because this is a rapid and efficient method and can maintain high cell viability.
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To further enhance cell therapy outcomes, therapeutic drug depots are incorporated with cells in heterospheroid (hybrid spheroid) structures. We have proved the advantages of these systems in various diseases of murine models, including acute liver injury, colitis, and islet transplantation. We are continuously developing organoid-like heterospheroids with complex compositions to improve cell therapy and to serve for drug screening.
Our lab advances drug delivery technologies to elevate the safety, precision, and therapeutic power of cell-based treatments. By engineering functional nanoparticles, microparticles, and hybrid biomaterials, we create systems that optimize the interaction of therapeutics with their biological environment, enhancing targeted delivery, sustained action, and cell viability. Through this particle-enabled approach, we aim to drive innovation in regenerative medicine and expand the clinical impact of next-generation cellular therapies.
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Cell transplantations, especially pancreatic islet transplantation (PIT), provide a viable option to treat difficult-to-cure diseases, including organ failures. However, there are many challenges in these approaches and the main challenge is the immune rejection of transplanted cells/tissues. Over the years, we have been developing various strategies to overcome this issue. One of our effective approaches is surface modification of therapeutic cells (i.e., pancreatic islets, PI) with biomaterials, aiming to escape immune recognition.
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In the first papers, we reported the islet surface modifications with various biocompatible polyethylene glycol (PEG) structures, including linear PEG, multi-armed PEG, and PEG-dendron. Also, we synthesized heparin derivative with DOPA moieties, enabling its chemical conjugation to the islet surface. In addition, we used the layer-by-layer (LbL) technique to anchor various molecules on the cells. We showed that combining polymer-based surface modifications and daily systemically administered low-dose immunosuppressive drugs (i.e., FK506 and MR-1 antibody) induced synergistic effects on inhibiting immune recognition and activation. As a result, the survival of transplanted PI significantly improved as compared to without surface modification and drug treatment alone.
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To eliminate the need for systemic immunosuppression, we fabricated “cell-particle hybrids” of PI with drug-eluting nano-/microparticles. Initially, we synthesized DOPA-PEG-PLGA NPs and conjugated them onto the islet surface. The auto-polymerization of DOPA enables multilayer coating of the cells with these NPs. However, the deposited drug amount on islets was very low, which later inspired us to develop a method to anchor particles with bigger sizes. Motivated by polydopamine (PD) chemistry, we first coated microparticles with a thin PD layer to achieve tissue-adhesive properties. Using this approach, we were the first group to report the conjugation of microparticles to PI to escape immune activation. The result of significant improvement in islet survival time after microparticle conjugation was highly encouraging.
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We realize that the conjugation of particles on the cell surface provides many benefits. Motivated by this, we developed the method named “Surface-Triggered In situ Gelation (STIG)”. In this method, we first conjugated PD-CaCO3 microparticles onto cells, then immersed them in an alginate solution containing D-(+)-gluconic acid-δ-lactone (GDL). The sustained hydrolysis of GDL facilitates controlled release of Ca2+ from particles, thus, enabling progressive propagation of alginate hydrogel from the surface of cells. The gel layer thickness can be easily controlled by the time of incubation. Our islet transplantation results showed that alginate encapsulation of islets induced a high rate of islet tolerance in a murine model, without the need for immunosuppression.