Fischell Department of Bioengineering Research Works

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Decrease of resistance to air flow with nasal strips as measured with the airflow perturbation device
(Springer Nature, 2004-10-22) Wong, Lily S; Johnson, Arthur T
Nasal strips are used by athletes, people who snore, and asthmatics to ease the burden of breathing. Although there are some published studies that demonstrate higher flow with nasal strips, none had directly measured the effect of the strips on nasal resistance using the airflow perturbation device (APD). The APD is an inexpensive instrument that can measure respiratory resistance based on changes in mouth pressure and rate of airflow. This study tested forty-seven volunteers (14 men and 33 women), ranging in age from 17 to 51. Each volunteer was instructed to breathe normally into the APD using an oronasal mask with and without nasal strips. The APD measured respiratory resistance during inhalation, exhalation, and an average of the two. Results of a paired mean t-test comparing nasal strip against no nasal strip were statistically significant at the p = 0.05 level. The Breathe Right™ nasal dilator strips lowered nasal resistance by an average of 0.5 cm H20/Lps from an average nasal resistance of 5.5 cm H20/Lps. Nasal strips reduce nasal resistance when measured with the APD. The effect is equal during exhalation and during inhalation.
Maximum static inspiratory and expiratory pressures with different lung volumes
(Springer Nature, 2006-05-05) Lausted, Christopher G; Johnson, Arthur T; Scott, William H; Johnson, Monique M; Coyne, Karen M; Coursey, Derya C
Maximum pressures developed by the respiratory muscles can indicate the health of the respiratory system, help to determine maximum respiratory flow rates, and contribute to respiratory power development. Past measurements of maximum pressures have been found to be inadequate for inclusion in some exercise models involving respiration. Maximum inspiratory and expiratory airway pressures were measured over a range of lung volumes in 29 female and 19 male adults. A commercial bell spirometry system was programmed to occlude airflow at nine target lung volumes ranging from 10% to 90% of vital capacity. In women, maximum expiratory pressure increased with volume from 39 to 61 cmH2O and maximum inspiratory pressure decreased with volume from 66 to 28 cmH2O. In men, maximum expiratory pressure increased with volume from 63 to 97 cmH2O and maximum inspiratory pressure decreased with volume from 97 to 39 cmH2O. Equations describing pressures for both sexes are: Pe/Pmax = 0.1426 Ln( %VC) + 0.3402 R2 = 0.95 Pi/Pmax = 0.234 Ln(100 - %VC) - 0.0828 R2 = 0.96 These results were found to be consistent with values and trends obtained by other authors. Regression equations may be suitable for respiratory mechanics models.
A finite element model for protein transport in vivo
(Springer Nature, 2007-06-28) Sadegh Zadeh, Kouroush; Elman, Howard C; Montas, Hubert J; Shirmohammadi, Adel
Biological mass transport processes determine the behavior and function of cells, regulate interactions between synthetic agents and recipient targets, and are key elements in the design and use of biosensors. Accurately predicting the outcomes of such processes is crucial to both enhancing our understanding of how these systems function, enabling the design of effective strategies to control their function, and verifying that engineered solutions perform according to plan. A Galerkin-based finite element model was developed and implemented to solve a system of two coupled partial differential equations governing biomolecule transport and reaction in live cells. The simulator was coupled, in the framework of an inverse modeling strategy, with an optimization algorithm and an experimental time series, obtained by the Fluorescence Recovery after Photobleaching (FRAP) technique, to estimate biomolecule mass transport and reaction rate parameters. In the inverse algorithm, an adaptive method was implemented to calculate sensitivity matrix. A multi-criteria termination rule was developed to stop the inverse code at the solution. The applicability of the model was illustrated by simulating the mobility and binding of GFP-tagged glucocorticoid receptor in the nucleoplasm of mouse adenocarcinoma. The numerical simulator shows excellent agreement with the analytic solutions and experimental FRAP data. Detailed residual analysis indicates that residuals have zero mean and constant variance and are normally distributed and uncorrelated. Therefore, the necessary and sufficient criteria for least square parameter optimization, which was used in this study, were met.The developed strategy is an efficient approach to extract as much physiochemical information from the FRAP protocol as possible. Well-posedness analysis of the inverse problem, however, indicates that the FRAP protocol provides insufficient information for unique simultaneous estimation of diffusion coefficient and binding rate parameters. Care should be exercised in drawing inferences, from FRAP data, regarding concentrations of free and bound proteins, average binding and diffusion times, and protein mobility unless they are confirmed by long-range Markov Chain-Monte Carlo (MCMC) methods and experimental observations.
Synthetic biology: enormous possibility, exaggerated perils
(Springer Nature, 2008-04-25) Russ, Zachary N
The following essay was written by a freshman undergraduate student majoring in Bioengineering at the University of Maryland, Mr. Zachary Russ. Mr. Russ was one of 94 students who submitted a 1000 to 1200 word essay to the 3rd Annual Bioethics Essay Contest sponsored by the Institute of Biological Engineering (IBE). A group of professionals in Biological Engineering assessed and ranked the essays in a blinded process. Five semi-finalists were invited to present their essays at a session at the annual meeting of IBE in Chapel Hill, NC on March 8, 2008. Five judges scored the presentations at the annual meeting and selected Mr. Russ's contribution as the overall winner (1st Place). Below is his essay.
Testing limits to airflow perturbation device (APD) measurements
(Springer Nature, 2008-10-31) Lopresti, Erika R; Johnson, Arthur T; Koh, Frank C; Scott, William H; Jamshidi, Shaya; Silverman, Nischom K
The Airflow Perturbation Device (APD) is a lightweight, portable device that can be used to measure total respiratory resistance as well as inhalation and exhalation resistances. There is a need to determine limits to the accuracy of APD measurements for different conditions likely to occur: leaks around the mouthpiece, use of an oronasal mask, and the addition of resistance in the respiratory system. Also, there is a need for resistance measurements in patients who are ventilated. Ten subjects between the ages of 18 and 35 were tested for each station in the experiment. The first station involved testing the effects of leaks of known sizes on APD measurements. The second station tested the use of an oronasal mask used in conjunction with the APD during nose and mouth breathing. The third station tested the effects of two different resistances added in series with the APD mouthpiece. The fourth station tested the usage of a flexible ventilator tube in conjunction with the APD. All leaks reduced APD resistance measurement values. Leaks represented by two 3.2 mm diameter tubes reduced measured resistance by about 10% (4.2 cmH2O·sec/L for control and 3.9 cm H2O·sec/L for the leak). This was not statistically significant. Larger leaks given by 4.8 and 6.4 mm tubes reduced measurements significantly (3.4 and 3.0 cm cmH2O·sec/L, respectively). Mouth resistance measured with a cardboard mouthpiece gave an APD measurement of 4.2 cm H2O·sec/L and mouth resistance measured with an oronasal mask was 4.5 cm H2O·sec/L; the two were not significantly different. Nose resistance measured with the oronasal mask was 7.6 cm H2O·sec/L. Adding airflow resistances of 1.12 and 2.10 cm H2O·sec/L to the breathing circuit between the mouth and APD yielded respiratory resistance values higher than the control by 0.7 and 2.0 cm H2O·sec/L. Although breathing through a 52 cm length of flexible ventilator tubing reduced the APD measurement from 4.0 cm H2O·sec/L for the control to 3.6 cm H2O·sec/L for the tube, the difference was not statistically significant. The APD can be adapted for use in ventilated, unconscious, and uncooperative patients with use of a ventilator tube and an oronasal mask without significantly affecting measurements. Adding a resistance in series with the APD mouthpiece has an additive effect on resistance measurements, and can be used for qualitative calibration. A leak size of at least the equivalent of two 3.2 mm diameter tubes can be tolerated without significantly affecting APD measurements.
Complete genomic sequence analysis of infectious bronchitis virus Ark DPI strain and its evolution by recombination
(2008-12-22) Ammayappan, Arun; Upadhyay, Chitra; Gelb, Jack Jr.; Vakharia, Vikram N
An infectious bronchitis virus Arkansas DPI (Ark DPI) virulent strain was sequenced, analyzed and compared with many different IBV strains and coronaviruses. The genome of Ark DPI consists of 27,620 nucleotides, excluding poly (A) tail, and comprises ten open reading frames. Comparative sequence analysis of Ark DPI with other IBV strains shows striking similarity to the Conn, Gray, JMK, and Ark 99, which were circulating during that time period. Furthermore, comparison of the Ark genome with other coronaviruses demonstrates a close relationship to turkey coronavirus. Among non-structural genes, the 5'untranslated region (UTR), 3C-like proteinase (3CL pro) and the polymerase (RdRp) sequences are 100% identical to the Gray strain. Among structural genes, S1 has 97% identity with Ark 99; S2 has 100% identity with JMK and 96% to Conn; 3b 99%, and 3C to N is 100% identical to Conn strain. Possible recombination sites were found at the intergenic region of spike gene, 3'end of S1 and 3a gene. Independent recombination events may have occurred in the entire genome of Ark DPI, involving four different IBV strains, suggesting that genomic RNA recombination may occur in any part of the genome at number of sites. Hence, we speculate that the Ark DPI strain originated from the Conn strain, but diverged and evolved independently by point mutations and recombination between field strains.
Microbial nar-GFP cell sensors reveal oxygen limitations in highly agitated and aerated laboratory-scale fermentors
(Springer Nature, 2009-01-15) Garcia, Jose R; Cha, Hyung J; Rao, Govind; Marten, Mark R; Bentley, William E
Small-scale microbial fermentations are often assumed to be homogeneous, and oxygen limitation due to inadequate micromixing is often overlooked as a potential problem. To assess the relative degree of micromixing, and hence propensity for oxygen limitation, a new cellular oxygen sensor has been developed. The oxygen responsive E. coli nitrate reductase (nar) promoter was used to construct an oxygen reporter plasmid (pNar-GFPuv) which allows cell-based reporting of oxygen limitation. Because there are greater than 109 cells in a fermentor, one can outfit a vessel with more than 109 sensors. Our concept was tested in high density, lab-scale (5 L), fed-batch, E. coli fermentations operated with varied mixing efficiency – one verses four impellers. In both cases, bioreactors were maintained identically at greater than 80% dissolved oxygen (DO) during batch phase and at approximately 20% DO during fed-batch phase. Trends for glucose consumption, biomass and DO showed nearly identical behavior. However, fermentations with only one impeller showed significantly higher GFPuv expression than those with four, indicating a higher degree of fluid segregation sufficient for cellular oxygen deprivation. As the characteristic time for GFPuv expression (approx 90 min.) is much larger than that for mixing (approx 10 s), increased specific fluorescence represents an averaged effect of oxygen limitation over time and by natural extension, over space. Thus, the pNar-GFPuv plasmid enabled bioreactor-wide oxygen sensing in that bacterial cells served as individual recirculating sensors integrating their responses over space and time. We envision cell-based oxygen sensors may find utility in a wide variety of bioprocessing applications.
Mapping the moral boundaries of biological engineering
(Springer Nature, 2009-05-08) Russ, Zachary N
The following essay was written by a sophomore undergraduate student majoring in Bioengineering at the University of Maryland, Mr. Zachary Russ. Mr. Russ was one of 174 students who submitted a 1000–1200 word essay to the 4th Annual Bioethics Contest sponsored by the Institute of Biological Engineering (IBE). A group of professionals in Biological Engineering assessed and ranked the essays in a blinded process. Five semi-finalists were invited to present their essays at a session at the annual meeting of IBE in Santa Clara, CA on March 21, 2009. Five judges scored all the presentation at the annual meeting and selected Mr. Russ's contribution as the overall winner (1st Place).
Analysis of recent segmental duplications in the bovine genome
(Springer Nature, 2009-12-01) Liu, George E; Ventura, Mario; Cellamare, Angelo; Chen, Lin; Cheng, Ze; Zhu, Bin; Li, Congjun; Song, Jiuzhou; Eichler, Evan E
Duplicated sequences are an important source of gene innovation and structural variation within mammalian genomes. We performed the first systematic and genome-wide analysis of segmental duplications in the modern domesticated cattle (Bos taurus). Using two distinct computational analyses, we estimated that 3.1% (94.4 Mb) of the bovine genome consists of recently duplicated sequences (≥ 1 kb in length, ≥ 90% sequence identity). Similar to other mammalian draft assemblies, almost half (47% of 94.4 Mb) of these sequences have not been assigned to cattle chromosomes. In this study, we provide the first experimental validation large duplications and briefly compared their distribution on two independent bovine genome assemblies using fluorescent in situ hybridization (FISH). Our analyses suggest that the (75-90%) of segmental duplications are organized into local tandem duplication clusters. Along with rodents and carnivores, these results now confidently establish tandem duplications as the most likely mammalian archetypical organization, in contrast to humans and great ape species which show a preponderance of interspersed duplications. A cross-species survey of duplicated genes and gene families indicated that duplication, positive selection and gene conversion have shaped primates, rodents, carnivores and ruminants to different degrees for their speciation and adaptation. We identified that bovine segmental duplications corresponding to genes are significantly enriched for specific biological functions such as immunity, digestion, lactation and reproduction. Our results suggest that in most mammalian lineages segmental duplications are organized in a tandem configuration. Segmental duplications remain problematic for genome and assembly and we highlight genic regions that require higher quality sequence characterization. This study provides insights into mammalian genome evolution and generates a valuable resource for cattle genomics research.
Assembly complexity of prokaryotic genomes using short reads
(2010-01-12) Kingsford, Carl; Schatz, Michael C; Pop, Mihai
Background: De Bruijn graphs are a theoretical framework underlying several modern genome assembly programs, especially those that deal with very short reads. We describe an application of de Bruijn graphs to analyze the global repeat structure of prokaryotic genomes. Results: We provide the first survey of the repeat structure of a large number of genomes. The analysis gives an upper-bound on the performance of genome assemblers for de novo reconstruction of genomes across a wide range of read lengths. Further, we demonstrate that the majority of genes in prokaryotic genomes can be reconstructed uniquely using very short reads even if the genomes themselves cannot. The non-reconstructible genes are overwhelmingly related to mobile elements (transposons, IS elements, and prophages). Conclusions: Our results improve upon previous studies on the feasibility of assembly with short reads and provide a comprehensive benchmark against which to compare the performance of the short-read assemblers currently being developed.
Assessing the benefits of using mate-pairs to resolve repeats in de novo short-read prokaryotic assemblies
(2011-04-13) Wetzel, Joshua; Kingsford, Carl; Pop, Mihai
Background: Next-generation sequencing technologies allow genomes to be sequenced more quickly and less expensively than ever before. However, as sequencing technology has improved, the difficulty of de novo genome assembly has increased, due in large part to the shorter reads generated by the new technologies. The use of mated sequences (referred to as mate-pairs) is a standard means of disambiguating assemblies to obtain a more complete picture of the genome without resorting to manual finishing. Here, we examine the effectiveness of mate-pair information in resolving repeated sequences in the DNA (a paramount issue to overcome). While it has been empirically accepted that mate-pairs improve assemblies, and a variety of assemblers use mate-pairs in the context of repeat resolution, the effectiveness of mate-pairs in this context has not been systematically evaluated in previous literature. Results: We show that, in high-coverage prokaryotic assemblies, libraries of short mate-pairs (about 4-6 times the read-length) more effectively disambiguate repeat regions than the libraries that are commonly constructed in current genome projects. We also demonstrate that the best assemblies can be obtained by ‘tuning’ mate-pair libraries to accommodate the specific repeat structure of the genome being assembled - information that can be obtained through an initial assembly using unpaired reads. These results are shown across 360 simulations on ‘ideal’ prokaryotic data as well as assembly of 8 bacterial genomes using SOAPdenovo. The simulation results provide an upper-bound on the potential value of mate-pairs for resolving repeated sequences in real prokaryotic data sets. The assembly results show that our method of tuning mate-pairs exploits fundamental properties of these genomes, leading to better assemblies even when using an off -the-shelf assembler in the presence of basecall errors. Conclusions: Our results demonstrate that dramatic improvements in prokaryotic genome assembly quality can be achieved by tuning mate-pair sizes to the actual repeat structure of a genome, suggesting the possible need to change the way sequencing projects are designed. We propose that a two-tiered approach - first generate an assembly of the genome with unpaired reads in order to evaluate the repeat structure of the genome; then generate the mate-pair libraries that provide most information towards the resolution of repeats in the genome being assembled - is not only possible, but likely also more cost-effective as it will significantly reduce downstream manual finishing costs. In future work we intend to address the question of whether this result can be extended to larger eukaryotic genomes, where repeat structure can be quite different.
Teaching the principle of biological optimization
(Springer Nature, 2013-02-20) Johnson, Arthur T
Among the important principles in biology that should be taught in biological engineering educational programs is the principle of optimization, what it means, why it is important, and how it comes about. This material can be presented at numerous levels throughout the curriculum. Understanding of this principle can lead biological engineers to expect it in many, if not all, biological system applications. Understanding optimization in biological systems can help understand the predictive power of evolutionary principles and what to expect from living things incorporated in designs.
MMP-2 mediates local degradation and remodeling of collagen by annulus fibrosus cells of the intervertebral disc
(Springer Nature, 2013-04-27) Rastogi, Anshu; Kim, Hyunchul; Twomey, Julianne D; Hsieh, Adam H
Degeneration of the intervertebral disc (IVD) is characterized by marked degradation and restructuring of the annulus fibrosus (AF). Although several matrix metalloproteinases (MMPs) have been found to be more prevalent in degenerate discs, their coordination and function within the context of the disease process are still not well understood. In this study, we sought to determine whether MMP-2 is associated with degenerative changes in the AF and to identify the manner by which AF cells use MMP-2. Two established animal models of disc degeneration, static compression and transannular needle puncture of rodent caudal discs, were examined for MMP-2 immunopositivity. With lentiviral transduction of an shRNA expression cassette, we screened and identified an effective shRNA sequence for generating stable RNA interference to silence MMP-2 expression in primary rat AF cells. Gelatin films were used to compare gelatinase activity and spatial patterns of degradation between transduced cells, and both noninfected and nonsense shRNA controls. The functional significance of MMP-2 was determined by assessing the ability for cells to remodel collagen gels. Both static compression and 18-g annular puncture of rodent caudal discs stimulated an increase in MMP-2 activity with concurrent lamellar disorganization in the AF, whereas 22-g and 26-g needle injuries did not. To investigate the functional role of MMP-2, we established lentivirus-mediated RNAi to induce stable knockdown of transcript levels by as much as 88%, and protein levels by as much as 95% over a 10-day period. Culturing transduced cells on gelatin films confirmed that MMP-2 is the primary functional gelatinase in AF cells, and that MMP-2 is used locally in regions immediately around AF cells. In collagen gels, transduced cells demonstrated an inability to remodel collagen matrices. Our study indicates that increases in MMP-2 observed in human degenerate discs are mirrored in experimentally induced degenerative changes in rodent animal models. AF cells appear to use MMP-2 in a very directed fashion for local matrix degradation and collagen remodeling. This suggests that MMP-2 may have a functionally significant role in the etiology of degenerative disc disease and could be a potential therapeutic target.
Biomechanical and functional variation in rat sciatic nerve following cuff electrode implantation
(Springer Nature, 2014-04-23) Restaino, Stephen M; Abliz, Erkinay; Wachrathit, Kelliann; Krauthamer, Victor; Shah, Sameer B
Nerve cuff electrodes are commonly and successfully used for stimulating peripheral nerves. On the other hand, they occasionally induce functional and morphological changes following chronic implantation, for reasons not always clear. We hypothesize that restriction of nerve mobility due to cuff implantation may alter nerve conduction. We quantified acute changes in nerve-muscle electrophysiology, using electromyography, and nerve kinematics in anesthetized Sprague Dawley rat sciatic nerves during controlled hindlimb joint movement. We compared electrophysiological and biomechanical response in uncuffed nerves and those secured within a cuff electrode using analysis of variance (ANOVA) and regression analysis. Tethering resulting from cuff implantation resulted in altered nerve strain and a complex biomechanical environment during joint movement. Coincident with biomechanical changes, electromyography revealed significantly increased variability in the response of conduction latency and amplitude in cuffed, but not free, nerves following joint movement. Our findings emphasize the importance of the mechanical interface between peripheral nerves and their devices on neurophysiological performance. This work has implications for nerve device design, implantation, and prediction of long-term efficacy.
Chitosan to Connect Biology to Electronics: Fabricating the Bio-Device Interface and Communicating Across This Interface
(MDPI, 2014-12-24) Kim, Eunkyoung; Xiong, Yuan; Cheng, Yi; Wu, Hsuan-Chen; Liu, Yi; Morrow, Brian H.; Ben-Yoav, Hadar; Ghodssi, Reza; Rubloff, Gary W.; Shen, Jana; Bentley, William E.; Shi, Xiaowen; Payne, Gregory F.
Individually, advances in microelectronics and biology transformed the way we live our lives. However, there remain few examples in which biology and electronics have been interfaced to create synergistic capabilities. We believe there are two major challenges to the integration of biological components into microelectronic systems: (i) assembly of the biological components at an electrode address, and (ii) communication between the assembled biological components and the underlying electrode. Chitosan possesses a unique combination of properties to meet these challenges and serve as an effective bio-device interface material. For assembly, chitosan’s pH-responsive film-forming properties allow it to “recognize” electrode-imposed signals and respond by self-assembling as a stable hydrogel film through a cathodic electrodeposition mechanism. A separate anodic electrodeposition mechanism was recently reported and this also allows chitosan hydrogel films to be assembled at an electrode address. Protein-based biofunctionality can be conferred to electrodeposited films through a variety of physical, chemical and biological methods. For communication, we are investigating redox-active catechol-modified chitosan films as an interface to bridge redox-based communication between biology and an electrode. Despite significant progress over the last decade, many questions still remain which warrants even deeper study of chitosan’s structure, properties, and functions.
Enhancing anti-tumor immunity through local gene delivery to lymph nodes
(Springer Nature, 2015-11-04) Dold, Neil M; Jewell, Christopher M
Biodegradable polymer carriers offer attractive features for therapeutic cancer vaccines including delivery of multiple vaccine components, efficient internalization, and sustained release of adjuvants and tumor-associated antigens (TAAs). We previously demonstrated that local delivery of depots containing nucleic acid-based toll-liked receptor agonists (TLRas) to lymph nodes (LNs) potently enhances antigen-specific T cell immunity. Building on this work, we hypothesized that local LN delivery of microparticles loaded with TAA-encoding plasmid DNA (pDNA) and TLRas might drive strong local expression and presentation of antigen by LN-resident antigen presenting cells. These effects could help drive more potent and effective CD8+ T cell functions that slow or stop tumor growth.
Mechanism of pH-dependent activation of the sodium-proton antiporter NhaA
(2016) Huang, Yandong; Chen, Wei; Dotson, David L.; Beckstein, Oliver; Shen, Jana
Escherichia coli NhaA is a prototype sodium-proton antiporter, which has been extensively characterized by X-ray crystallography, biochemical and biophysical experiments. However, the identities of proton carriers and details of pH-regulated mechanism remain controversial. Here we report constant pH molecular dynamics data, which reveal that NhaA activation involves a net charge switch of a pH sensor at the entrance of the cytoplasmic funnel and opening of a hydrophobic gate at the end of the funnel. The latter is triggered by charging of Asp164, the first proton carrier. The second proton carrier Lys300 forms a salt bridge with Asp163 in the inactive state, and releases a proton when a sodium ion binds Asp163. These data reconcile current models and illustrate the power of state-of-the-art molecular dynamics simulations in providing atomic details of proton-coupled transport across membrane, which is challenging to elucidate by experimental techniques.
Lipid tethering of breast tumor cells enables real-time imaging of free-floating cell dynamics and drug response
(Impact Journals, 2016-02-08) Chakrabarti, Kristi R.; Andorko, James I.; Whipple, Rebecca A.; Zhang, Peipei; Sooklal, Elisabeth L.; Martin, Stuart S.; Jewell, Christopher M.
Free-floating tumor cells located in the blood of cancer patients, known as circulating tumor cells (CTCs), have become key targets for studying metastasis. However, effective strategies to study the free-floating behavior of tumor cells in vitro have been a major barrier limiting the understanding of the functional properties of CTCs. Upon extracellular-matrix (ECM) detachment, breast tumor cells form tubulin-based protrusions known as microtentacles (McTNs) that play a role in the aggregation and re-attachment of tumor cells to increase their metastatic efficiency. In this study, we have designed a strategy to spatially immobilize ECM-detached tumor cells while maintaining their free-floating character. We use polyelectrolyte multilayers deposited on microfluidic substrates to prevent tumor cell adhesion and the addition of lipid moieties to tether tumor cells to these surfaces through interactions with the cell membranes. This coating remains optically clear, allowing capture of high-resolution images and videos of McTNs on viable free-floating cells. In addition, we show that tethering allows for the real-time analysis of McTN dynamics on individual tumor cells and in response to tubulin-targeting drugs. The ability to image detached tumor cells can vastly enhance our understanding of CTCs under conditions that better recapitulate the microenvironments they encounter during metastasis.
Reprogramming the Local Lymph Node Microenvironment Promotes Tolerance that Is Systemic and Antigen Specific
(Cell Press, 2016-09-13) Tostanoski, Lisa H.; Chiu, Yu-Chieh; Gammon, Joshua M.; Simon, Thomas; Andorko, James I.; Bromberg, Jonathan S.; Jewell, Christopher M.
Many experimental therapies for autoimmune diseases, such as multiple sclerosis (MS), aim to bias T cells toward tolerogenic phenotypes without broad suppression. However, the link between local signal integration in lymph nodes (LNs) and the specificity of systemic tolerance is not well understood. We used intra-LN injection of polymer particles to study tolerance as a function of signals in the LN microenvironment. In a mouse MS model, intra-LN introduction of encapsulated myelin self-antigen and a regulatory signal (rapamycin) permanently reversed paralysis after one treatment during peak disease. Therapeutic effects were myelin specific, required antigen encapsulation, and were less potent without rapamycin. This efficacy was accompanied by local LN reorganization, reduced inflammation, systemic expansion of regulatory T cells, and reduced T cell infiltration to the CNS. Our findings suggest that local control over signaling in distinct LNs can promote cell types and functions that drive tolerance that is systemic but antigen specific.
Engineering Cell Surfaces with Polyelectrolyte Materials for Translational Applications
(MDPI, 2017-01-28) Zhang, Peipei; Bookstaver, Michelle L.; Jewell, Christopher M.
Engineering cell surfaces with natural or synthetic materials is a unique and powerful strategy for biomedical applications. Cells exhibit more sophisticated migration, control, and functional capabilities compared to nanoparticles, scaffolds, viruses, and other engineered materials or agents commonly used in the biomedical field. Over the past decade, modification of cell surfaces with natural or synthetic materials has been studied to exploit this complexity for both fundamental and translational goals. In this review we present the existing biomedical technologies for engineering cell surfaces with one important class of materials, polyelectrolytes. We begin by introducing the challenges facing the cell surface engineering field. We then discuss the features of polyelectrolytes and how these properties can be harnessed to solve challenges in cell therapy, tissue engineering, cell-based drug delivery, sensing and tracking, and immune modulation. Throughout the review, we highlight opportunities to drive the field forward by bridging new knowledge of polyelectrolytes with existing translational challenges.

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