Publications by authors named "Shannon Tsai"

10 Publications

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Leveraging the modularity of biomaterial carriers to tune immune responses.

Adv Funct Mater 2020 Nov 11;30(48). Epub 2020 Sep 11.

Fischell Department of Bioengineering, 8278 Paint Branch Drive, College Park, MD 20742, USA; Robert E. Fischell Institute for Biomedical Devices, 8278 Paint Branch Drive, College Park, MD 20742, USA; United States Department of Veterans Affairs, VA Maryland Health Care System, 10. N Green Street, Baltimore, MD 21201, USA; United States Department of Veterans Affairs, VA Maryland Health Care System, 10. N Green Street, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Cancer Center, 22 South Greene Street, Baltimore, MD 21201, USA.

Biomaterial carriers offer modular features to control the delivery and presentation of vaccines and immunotherapies. This tunability is a distinct capability of biomaterials. Understanding how tunable material features impact immune responses is important to improve vaccine and immunotherapy design, as well as clinical translation. Here we discuss the modularity of biomaterial properties as a means of controlling encounters with immune signals across scales - tissue, cell, molecular, and time - and ultimately, to direct stimulation or regulation of immune function. We highlight these advances using illustrations from recent literature across infectious disease, cancer, and autoimmunity. As the immune engineering field matures, informed design criteria could support more rational biomaterial carriers for vaccination and immunotherapy.
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http://dx.doi.org/10.1002/adfm.202004119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939076PMC
November 2020

Altering Antigen Charge to Control Self-Assembly and Processing of Immune Signals During Cancer Vaccination.

Front Immunol 2020 6;11:613830. Epub 2021 Jan 6.

Fischell Department of Bioengineering, University of Maryland, College Park, MD, United States.

Biomaterial delivery systems offer unique potential to improve cancer vaccines by offering targeted delivery and modularity to address disease heterogeneity. Here, we develop a simple platform using a conserved human melanoma peptide antigen (Trp2) modified with cationic arginine residues that condenses an anionic toll-like receptor agonist (TLRa), CpG, into polyplex-like nanoparticles. We reasoned that these structures could offer several useful features for immunotherapy - such as tunable loading, co-delivery of immune cues, and cargo protection - while eliminating the need for synthetic polymers or other complicating delivery systems. We demonstrate that Trp2/CpG polyplexes can readily form over a range of Trp2:CpG ratios and improve antigen uptake by primary antigen presenting cells. We show antigen loading can be tuned by interchanging Trp2 peptides with defined charges and numbers of arginine residues. Notably, these polyplexes with greater antigen loading enhance the functionality of Trp-2 specific T cells and in a mouse melanoma model, decrease tumor burden and improve survival. This work highlights opportunities to control the biophysical properties of nanostructured materials built from immune signals to enhance immunotherapy, without the added complexity or background immune effects often associated with synthetic carriers.
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http://dx.doi.org/10.3389/fimmu.2020.613830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815530PMC
June 2021

An Optical Method for Quantitatively Determining the Surface Free Energy of Micro- and Nanoparticles.

Anal Chem 2019 10 13;91(20):12819-12826. Epub 2019 Sep 13.

Department of Mechanical Engineering , University of Hawaii at Manoa , Honolulu , Hawaii 96822 , United States.

Surface free energy (SFE) of micro- and nanoparticles plays a crucial role in determining the hydrophobicity and wettability of the particles. To date, however, there are no easy-to-use methods for determining the SFE of particles. Here, with the application of several inexpensive, easy-to-use, and commonly available lab procedures and facilities, including particle dispersion, settling/centrifugation, pipetting, and visible-light spectroscopy, we developed a novel technique called the maximum particle dispersion (MPD) method for quantitatively determining the SFE of micro- and nanoparticles. We demonstrated the versatility and robustness of the MPD method by studying nine representative particles of various chemistries, sizes, dimensions, and morphologies. These are triethoxycaprylylsilane-coated zinc oxide nanoparticles, multiwalled carbon nanotubes, graphene nanoplatelets, molybdenum(IV) sulfide flakes, neodymium(III) oxide nanoparticles, two sizes of zeolites, poly(vinylpolypyrrolidone), and polystyrene microparticles. The SFE of these micro- and nanoparticles was found to cover a range from 21 to 36 mJ/m. These SFE values may find applications in a broad spectrum of scientific disciplines including the synthesis of these nanomaterials, such as in liquid-phase exfoliation. The MPD method has the potential to be developed into a standard, low-cost, and easy-to-use method for quantitatively characterizing the SFE and hydrophobicity of particles at the micro- and nanoscale.
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http://dx.doi.org/10.1021/acs.analchem.9b02507DOI Listing
October 2019

Improving Vaccine and Immunotherapy Design Using Biomaterials.

Trends Immunol 2018 02 14;39(2):135-150. Epub 2017 Dec 14.

Fischell Department of Bioengineering, University of Maryland, 8228 Paint Branch Drive, College Park, MD 20742, USA; Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Cancer Center, 22 South Greene Street, Baltimore, MD 21201, USA; United States Department of Veteran Affairs, 10 North Greene Street, Baltimore, MD 21201, USA. Electronic address:

Polymers, lipids, scaffolds, microneedles, and other biomaterials are rapidly emerging as technologies to improve the efficacy of vaccines against infectious disease and immunotherapies for cancer, autoimmunity, and transplantation. New studies are also providing insight into the interactions between these materials and the immune system. This insight can be exploited for more efficient design of vaccines and immunotherapies. Here, we describe recent advances made possible through the unique features of biomaterials, as well as the important questions for further study.
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http://dx.doi.org/10.1016/j.it.2017.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914493PMC
February 2018

The toxin biliatresone causes mouse extrahepatic cholangiocyte damage and fibrosis through decreased glutathione and SOX17.

Hepatology 2016 09 20;64(3):880-93. Epub 2016 May 20.

Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Unlabelled: Biliary atresia, the most common indication for pediatric liver transplantation, is a fibrotic disease of unknown etiology affecting the extrahepatic bile ducts of newborns. The recently described toxin biliatresone causes lumen obstruction in mouse cholangiocyte spheroids and represents a new model of biliary atresia. The goal of this study was to determine the cellular changes caused by biliatresone in mammalian cells that ultimately lead to biliary atresia and extrahepatic fibrosis. We treated mouse cholangiocytes in three-dimensional (3D) spheroid culture and neonatal extrahepatic duct explants with biliatresone and compounds that regulate glutathione (GSH). We examined the effects of biliatresone on SOX17 levels and determined the effects of Sox17 knockdown on cholangiocytes in 3D culture. We found that biliatresone caused disruption of cholangiocyte apical polarity and loss of monolayer integrity. Spheroids treated with biliatresone had increased permeability as shown by rhodamine efflux within 5 hours compared with untreated spheroids, which retained rhodamine for longer than 12 hours. Neonatal bile duct explants treated with the toxin showed lumen obstruction with increased subepithelial staining for α-smooth muscle actin and collagen, consistent with fibrosis. Biliatresone caused a rapid and transient decrease in GSH, which was both necessary and sufficient to mediate its effects in cholangiocyte spheroid and bile duct explant systems. It also caused a significant decrease in cholangiocyte levels of SOX17, and Sox17 knockdown in cholangiocyte spheroids mimicked the effects of biliatresone.

Conclusion: Biliatresone decreases GSH and SOX17 in mouse cholangiocytes. In 3D cell systems, this leads to cholangiocyte monolayer damage and increased permeability; in extrahepatic bile duct explants, it leads to disruption of the extrahepatic biliary tree and subepithelial fibrosis. This mechanism may be important in understanding human biliary atresia. (Hepatology 2016;64:880-893).
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http://dx.doi.org/10.1002/hep.28599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992464PMC
September 2016

Stiffening hydrogels for investigating the dynamics of hepatic stellate cell mechanotransduction during myofibroblast activation.

Sci Rep 2016 Feb 24;6:21387. Epub 2016 Feb 24.

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.

Tissue fibrosis contributes to nearly half of all deaths in the developed world and is characterized by progressive matrix stiffening. Despite this, nearly all in vitro disease models are mechanically static. Here, we used visible light-mediated stiffening hydrogels to investigate cell mechanotransduction in a disease-relevant system. Primary hepatic stellate cell-seeded hydrogels stiffened in situ at later time points (following a recovery phase post-isolation) displayed accelerated signaling kinetics of both early (Yes-associated protein/Transcriptional coactivator with PDZ-binding motif, YAP/TAZ) and late (alpha-smooth muscle actin, α-SMA) markers of myofibroblast differentiation, resulting in a time course similar to observed in vivo activation dynamics. We further validated this system by showing that α-SMA inhibition following substrate stiffening resulted in attenuated stellate cell activation, with reduced YAP/TAZ nuclear shuttling and traction force generation. Together, these data suggest that stiffening hydrogels may be more faithful models for studying myofibroblast activation than static substrates and could inform the development of disease therapeutics.
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http://dx.doi.org/10.1038/srep21387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764908PMC
February 2016

Microfluidic immunocapture of circulating pancreatic cells using parallel EpCAM and MUC1 capture: characterization, optimization and downstream analysis.

Lab Chip 2014 May 28;14(10):1775-84. Epub 2014 Mar 28.

Department of Biomedical Engineering, College of Engineering, Cornell University, Ithaca, NY 14853, USA.

We have developed and optimized a microfluidic device platform for the capture and analysis of circulating pancreatic cells (CPCs) and pancreatic circulating tumor cells (CTCs). Our platform uses parallel anti-EpCAM and cancer-specific mucin 1 (MUC1) immunocapture in a silicon microdevice. Using a combination of anti-EpCAM and anti-MUC1 capture in a single device, we are able to achieve efficient capture while extending immunocapture beyond single marker recognition. We also have detected a known oncogenic KRAS mutation in cells spiked in whole blood using immunocapture, RNA extraction, RT-PCR and Sanger sequencing. To allow for downstream single-cell genetic analysis, intact nuclei were released from captured cells by using targeted membrane lysis. We have developed a staining protocol for clinical samples, including standard CTC markers; DAPI, cytokeratin (CK) and CD45, and a novel marker of carcinogenesis in CPCs, mucin 4 (MUC4). We have also demonstrated a semi-automated approach to image analysis and CPC identification, suitable for clinical hypothesis generation. Initial results from immunocapture of a clinical pancreatic cancer patient sample show that parallel capture may capture more of the heterogeneity of the CPC population. With this platform, we aim to develop a diagnostic biomarker for early pancreatic carcinogenesis and patient risk stratification.
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http://dx.doi.org/10.1039/c4lc00041bDOI Listing
May 2014

Detection of circulating pancreas epithelial cells in patients with pancreatic cystic lesions.

Gastroenterology 2014 Mar 13;146(3):647-51. Epub 2013 Dec 13.

Gastroenterology Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Hematogenous dissemination is thought to be a late event in cancer progression. We recently showed in a genetic model of pancreatic ductal adenocarcinoma that pancreas cells can be detected in the bloodstream before tumor formation. To confirm these findings in humans, we used microfluidic geometrically enhanced differential immunocapture to detect circulating pancreas epithelial cells in patient blood samples. We captured more than 3 circulating pancreas epithelial cells/mL in 7 of 21 (33%) patients with cystic lesions and no clinical diagnosis of cancer (Sendai criteria negative), 8 of 11 (73%) with pancreatic ductal adenocarcinoma, and in 0 of 19 patients without cysts or cancer (controls). These findings indicate that cancer cells are present in the circulation of patients before tumors are detected, which might be used in risk assessment.
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http://dx.doi.org/10.1053/j.gastro.2013.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4514438PMC
March 2014

Chitosan adsorption on hydroxyapatite and its role in preventing acid erosion.

J Colloid Interface Sci 2012 Nov 7;385(1):235-43. Epub 2012 Jul 7.

Department of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA 19104, United States.

Polymer adsorption onto an artificial saliva (AS) layer is investigated using quartz-crystal microbalance with dissipation (QCM-D) and chitosan as the model polymer. QCM-D is utilized in an innovative manner to monitor in situ adsorption of chitosan (CH) onto a hydroxyapatite (HA) coated crystal and to examine the ability of the adsorbed layer to "protect" the HA upon sequential exposure to acidic solutions. After deposition of a thin AS layer (16 nm), the total thickness on the HA substrate increases to 37 nm upon exposure to CH at pH 5.5 for 10 min. Correspondingly, the surface charge changes from negative (i.e., AS) to positive, consistent with the adsorption the polycationic CH onto or into the AS layer. Upon exposure to an oxidizing agent, the chitosan cross-links and collapses as noted by a decrease in thickness to 10 nm and an increase in the shear modulus by an order of magnitude. Atomic force microscopy (AFM) is used to determine the surface morphology and RMS roughness of the coated and HA surfaces after citric acid challenges. Both physisorbed and cross-linked chitosan are demonstrated to limit and prevent the erosion of HA, respectively.
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http://dx.doi.org/10.1016/j.jcis.2012.06.074DOI Listing
November 2012

Deciphering diatom biochemical pathways via whole-cell proteomics.

Aquat Microb Ecol 2009 Jun;55(3):241-253

Medicinal Chemistry Department, University of Washington, Box 335351, Seattle, Washington 98195, USA.

Diatoms play a critical role in the oceans' carbon and silicon cycles; however, a mechanistic understanding of the biochemical processes that contribute to their ecological success remains elusive. Completion of the Thalassiosira pseudonana genome provided 'blueprints' for the potential biochemical machinery of diatoms, but offers only a limited insight into their biology under various environmental conditions. Using high-throughput shotgun proteomics, we identified a total of 1928 proteins expressed by T. pseudonana cultured under optimal growth conditions, enabling us to analyze this diatom's primary metabolic and biosynthetic pathways. Of the proteins identified, 70% are involved in cellular metabolism, while 11% are involved in the transport of molecules. We identified all of the enzymes involved in the urea cycle, thereby describing the complete pathway to convert ammonia to urea, along with urea transporters, and the urea-degrading enzyme urease. Although metabolic exchange between these pathways remains ambiguous, their constitutive presence suggests complex intracellular nitrogen recycling. In addition, all C(4) related enzymes for carbon fixation have been identified to be in abundance, with high protein sequence coverage. Quantification of mass spectra acquisitions demonstrated that the 20 most abundant proteins included an unexpectedly high expression of clathrin, which is the primary structural protein involved in endocytic transport. This result highlights a previously overlooked mechanism for the inter- and intra-cellular transport of nutrients and macromolecules in diatoms, potentially providing a missing link to organelle communication and metabolite exchange. Our results demonstrate the power of proteomics, and lay the groundwork for future comparative proteomic studies and directed analyses of specifically expressed proteins and biochemical pathways of oceanic diatoms.
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http://dx.doi.org/10.3354/ame01284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761042PMC
June 2009
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