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Karp, Jeffrey

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Karp

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Jeffrey

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Karp, Jeffrey
Author's Publications: search.filters.isAuthorOfPublication.09340134-0f29-46f3-bf1e-702ccf81903f

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Now showing 1 - 10 of 21
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    Emerging Trends in Micro- and Nanoscale Technologies in Medicine: From Basic Discoveries to Translation
    (American Chemical Society (ACS), 2017) Alvarez, Mario M.; Aizenberg, Joanna; Analoui, Mostafa; Andrews, Anne M.; Bisker, Gili; Boyden, Edward S.; Kamm, Roger D.; Karp, Jeffrey; Mooney, David; Oklu, Rahmi; Peer, Dan; Stolzoff, Michelle; Strano, Michael S.; Trujillo-de Santiago, Grissel; Webster, Thomas J.; Weiss, Paul; Khademhosseini, Ali
    We discuss the state of the art and innovative micro- and nano- scale technologies that are finding niches and opening up new opportunities in medicine, particularly in diagnostic and therapeutic applications. We take the design of point-of-care applications and the capture of circulating tumor cells as illustrative examples of the integration of micro- and nanotechnologies into solutions of diagnostic challenges. We describe several novel nanotechnologies that enable imaging cellular structures and molecular events. In therapeutics, we describe the utilization of micro- and nanotechnologies in applications including drug delivery, tissue engineering, and pharmaceutical development/testing. In addition, we discuss relevant challenges that micro- and nanotechnologies face in achieving cost-effective and widespread clinical implementation as well as forecasted applications of micro- and nanotechnologies in medicine.
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    Author Correction: Towards an arthritis flare-responsive drug delivery system
    (Nature Publishing Group UK, 2018) Joshi, Nitin; Yan, Jing; Levy, Seth; Bhagchandani, Sachin; Slaughter, Kai V.; Sherman, Nicholas E.; Amirault, Julian; Wang, Yufeng; Riegel, Logan; He, Xueyin; Rui, Tan Shi; Valic, Michael; Vemula, Praveen; Miranda, Oscar R.; Levy, Oren; Gravallese, Ellen M.; Aliprantis, Antonios; Ermann, Joerg; Karp, Jeffrey
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    Harnessing single-cell genomics to improve the physiological fidelity of organoid-derived cell types
    (BioMed Central, 2018) Mead, Benjamin E.; Ordovas-Montanes, Jose; Braun, Alexandra P.; Levy, Lauren E.; Bhargava, Prerna; Szucs, Matthew J.; Ammendolia, Dustin A.; MacMullan, Melanie A.; Yin, Xiaolei; Hughes, Travis; Wadsworth, Marc H.; Ahmad, Rushdy; Rakoff-Nahoum, Seth; Carr, Steven A.; Langer, Robert; Collins, James; Shalek, Alex K.; Karp, Jeffrey
    Background: Single-cell genomic methods now provide unprecedented resolution for characterizing the component cell types and states of tissues such as the epithelial subsets of the gastrointestinal tract. Nevertheless, functional studies of these subsets at scale require faithful in vitro models of identified in vivo biology. While intestinal organoids have been invaluable in providing mechanistic insights in vitro, the extent to which organoid-derived cell types recapitulate their in vivo counterparts remains formally untested, with no systematic approach for improving model fidelity. Results: Here, we present a generally applicable framework that utilizes massively parallel single-cell RNA-seq to compare cell types and states found in vivo to those of in vitro models such as organoids. Furthermore, we leverage identified discrepancies to improve model fidelity. Using the Paneth cell (PC), which supports the stem cell niche and produces the largest diversity of antimicrobials in the small intestine, as an exemplar, we uncover fundamental gene expression differences in lineage-defining genes between in vivo PCs and those of the current in vitro organoid model. With this information, we nominate a molecular intervention to rationally improve the physiological fidelity of our in vitro PCs. We then perform transcriptomic, cytometric, morphologic and proteomic characterization, and demonstrate functional (antimicrobial activity, niche support) improvements in PC physiology. Conclusions: Our systematic approach provides a simple workflow for identifying the limitations of in vitro models and enhancing their physiological fidelity. Using adult stem cell-derived PCs within intestinal organoids as a model system, we successfully benchmark organoid representation, relative to that in vivo, of a specialized cell type and use this comparison to generate a functionally improved in vitro PC population. We predict that the generation of rationally improved cellular models will facilitate mechanistic exploration of specific disease-associated genes in their respective cell types. Electronic supplementary material The online version of this article (10.1186/s12915-018-0527-2) contains supplementary material, which is available to authorized users.
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    A Bio-Inspired Swellable Microneedle Adhesive for Mechanical Interlocking with Tissue
    (2013) Yang, Seung Yun; O'Cearbhaill, Eoin D.; Sisk, Geoffroy Courcelle; Park, Kyeng Min; Cho, Woo Kyung; Villiger, Martin; Bouma, Brett; Pomahac, Bohdan; Karp, Jeffrey
    Achieving significant adhesion to soft tissues while minimizing tissue damage poses a considerable clinical challenge. Chemical-based adhesives require tissue-specific reactive chemistry, typically inducing a significant inflammatory response. Staples are fraught with limitations including high-localized tissue stress and increased risk of infection, and nerve and blood vessel damage. Here, inspired by the endoparasite Pomphorhynchus laevis which swells its proboscis to attach to its host’s intestinal wall, we have developed a biphasic microneedle array that mechanically interlocks with tissue through swellable microneedle tips, achieving ~ 3.5 fold increase in adhesion strength compared to staples in skin graft fixation, and removal force of ~ 4.5 N/cm2 from intestinal mucosal tissue. Comprising a poly(styrene)-block-poly(acrylic acid) swellable tip and non-swellable polystyrene core, conical microneedles penetrate tissue with minimal insertion force and depth, yet high adhesion strength in their swollen state. Uniquely, this design provides universal soft tissue adhesion with minimal damage, less traumatic removal, reduced risk of infection and delivery of bioactive therapeutics.
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    Self-assembled hydrogel fibers for sensing the multi-compartment intracellular milieu
    (Nature Publishing Group, 2014) Vemula, Praveen Kumar; Kohler, Jonathan E.; Blass, Amy; Williams, Miguel; Xu, Chenjie; Chen, Lynna; Jadhav, Swapnil R.; John, George; Soybel, David I.; Karp, Jeffrey
    Targeted delivery of drugs and sensors into cells is an attractive technology with both medical and scientific applications. Existing delivery vehicles are generally limited by the complexity of their design, dependence on active transport, and inability to function within cellular compartments. Here, we developed self-assembled nanofibrous hydrogel fibers using a biologically inert, low-molecular-weight amphiphile. Self-assembled nanofibrous hydrogels offer unique physical/mechanical properties and can easily be loaded with a diverse range of payloads. Unlike commercially available E. coli membrane particles covalently bound to the pH reporting dye pHrodo, pHrodo encapsulated in self-assembled hydrogel-fibers internalizes into macrophages at both physiologic (37°C) and sub-physiologic (4°C) temperatures through an energy-independent, passive process. Unlike dye alone or pHrodo complexed to E. coli, pHrodo-SAFs report pH in both the cytoplasm and phagosomes, as well the nucleus. This new class of materials should be useful for next-generation sensing of the intracellular milieu.
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    Affinity flow fractionation of cells via transient interactions with asymmetric molecular patterns
    (Nature Publishing Group, 2013) Bose, Suman; Singh, Rishi; Hanewich-Hollatz, Mikhail; Shen, Chong; Lee, Chia-Hua; Dorfman, David; Karp, Jeffrey; Karnik, Rohit
    Flow fractionation of cells using physical fields to achieve lateral displacement finds wide applications, but its extension to surface molecule-specific separation requires labeling. Here we demonstrate affinity flow fractionation (AFF) where weak, short-range interactions with asymmetric molecular patterns laterally displace cells in a continuous, label-free process. We show that AFF can directly draw neutrophils out of a continuously flowing stream of blood with an unprecedented 400,000-fold depletion of red blood cells, with the sorted cells being highly viable, unactivated, and functionally intact. The lack of background erythrocytes enabled the use of AFF for direct enumeration of neutrophils by a downstream detector, which could distinguish the activation state of neutrophils in blood. The compatibility of AFF with capillary microfluidics and its ability to directly separate cells with high purity and minimal sample preparation will facilitate the design of simple and portable devices for point-of-care diagnostics and quick, cost-effective laboratory analysis.
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    Performance-enhanced mesenchymal stem cells via intracellular delivery of steroids
    (Nature Publishing Group, 2014) Ankrum, James A.; Dastidar, Riddhi G.; Ong, Joon Faii; Levy, Oren; Karp, Jeffrey
    Inadequate immunomodulatory potency of mesenchymal stem cells (MSC) may limit their therapeutic efficacy. We report glucocorticoid steroids augment MSC expression and activity of indoleamine-2,3-dioxygenase (IDO), a primary mediator of MSC immunomodulatory function. This effect depends on signaling through the glucocorticoid receptor and is mediated through up-regulation of FOXO3. Treatment of MSCs with glucocorticoids, budesonide or dexamethasone, enhanced IDO expression following IFN-γ stimulation in multiple donors and was able to restore IDO expression in over-passaged MSCs. As IDO enhancement was most notable when cells were continuously exposed to budesonide, we engineered MSC with budesonide loaded PLGA microparticles. MSC efficiently internalized budesonide microparticles and exhibited 4-fold enhanced IDO activity compared to budesonide preconditioned and naïve MSC, resulting in a 2-fold improvement in suppression of stimulated peripheral blood mononuclear cells in an IDO-dependent manner. Thus, the augmentation of MSC immune modulation may abrogate challenges associated with inadequate potency and enhance their therapeutic efficacy.
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    Mesenchymal Stem Cells: Immune Evasive, Not Immune Privileged
    (Springer Science and Business Media LLC, 2014-02-23) Ankrum, James A.; Ong, Joon Faii; Karp, Jeffrey
    The diverse immunomodulatory properties of mesenchymal stem/stromal cells (MSCs) may be exploited for treatment of a multitude of inflammatory conditions. MSCs have long been reported to be hypoimmunogenic or 'immune privileged'; this property is thought to enable MSC transplantation across major histocompatibility barriers and the creation of off-the-shelf therapies consisting of MSCs grown in culture. However, recent studies describing generation of antibodies against and immune rejection of allogeneic donor MSCs suggest that MSCs may not actually be immune privileged. Nevertheless, whether rejection of donor MSCs influences the efficacy of allogeneic MSC therapies is not known, and no definitive clinical advantage of autologous MSCs over allogeneic MSCs has been demonstrated to date. Although MSCs may exert therapeutic function through a brief 'hit and run' mechanism, protecting MSCs from immune detection and prolonging their persistence in vivo may improve clinical outcomes and prevent patient sensitization toward donor antigens.
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    Quantification of Mesenchymal Stem Cell (MSC) Delivery to a Target Site Using In Vivo Confocal Microscopy
    (Public Library of Science, 2013) Mortensen, Luke J.; Levy, Oren; Phillips, Joseph P.; Stratton, Tara; Triana, Brian; Ruiz, Juan P.; Gu, Fangqi; Karp, Jeffrey; Lin, Charles
    The ability to deliver cells to appropriate target tissues is a prerequisite for successful cell-based therapy. To optimize cell therapy it is therefore necessary to develop a robust method of in vivo cell delivery quantification. Here we examine Mesenchymal Stem Cells (MSCs) labeled with a series of 4 membrane dyes from which we select the optimal dye combination for pair-wise comparisons of delivery to inflamed tissue in the mouse ear using confocal fluorescence imaging. The use of an optimized dye pair for simultaneous tracking of two cell populations in the same animal enables quantification of a test population that is referenced to an internal control population, thereby eliminating intra-subject variations and variations in injected cell numbers. Consistent results were obtained even when the administered cell number varied by more than an order of magnitude, demonstrating an ability to neutralize one of the largest sources of in vivo experimental error and to greatly reduce the number of cells required to evaluate cell delivery. With this method, we are able to show a small but significant increase in the delivery of cytokine pre-treated MSCs (TNF-α & IFN-γ) compared to control MSCs. Our results suggest future directions for screening cell strategies using our in vivo cell delivery assay, which may be useful to develop methods to maximize cell therapeutic potential.
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    Quantitative assessment of barriers to the clinical development and adoption of cellular therapies: A pilot study
    (SAGE Publications, 2014) Davies, Benjamin M; Rikabi, Sarah; French, Anna; Pinedo-Villanueva, Rafael; Morrey, Mark E; Wartolowska, Karolina; Judge, Andrew; MacLaren, Robert E; Mathur, Anthony; Williams, David J; Wall, Ivan; Birchall, Martin; Reeve, Brock; Atala, Anthony; Barker, Richard W; Cui, Zhanfeng; Furniss, Dominic; Bure, Kim; Snyder, Evan Y; Karp, Jeffrey; Price, Andrew; Carr, Andrew; Brindley, David A
    There has been a large increase in basic science activity in cell therapy and a growing portfolio of cell therapy trials. However, the number of industry products available for widespread clinical use does not match this magnitude of activity. We hypothesize that the paucity of engagement with the clinical community is a key contributor to the lack of commercially successful cell therapy products. To investigate this, we launched a pilot study to survey clinicians from five specialities and to determine what they believe to be the most significant barriers to cellular therapy clinical development and adoption. Our study shows that the main concerns among this group are cost-effectiveness, efficacy, reimbursement, and regulation. Addressing these concerns can best be achieved by ensuring that future clinical trials are conducted to adequately answer the questions of both regulators and the broader clinical community.