@article{sheridan_nellenbach_pandit_byrnes_hardy_lutz_moiseiwitsch_scull_mihalko_levy_et al._2024, title={Clot-Targeted Nanogels for Dual-Delivery of AntithrombinIII and Tissue Plasminogen Activator to Mitigate Disseminated Intravascular Coagulation Complications}, volume={6}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.4c00162}, abstractNote={Disseminated intravascular coagulation (DIC) is a pathologic state that follows systemic injury and other diseases. Often a complication of sepsis or trauma, DIC causes coagulopathy associated with paradoxical thrombosis and hemorrhage. DIC upregulates the thrombotic pathways while simultaneously downregulating the fibrinolytic pathways that cause excessive fibrin deposition, microcirculatory thrombosis, multiorgan dysfunction, and consumptive coagulopathy with excessive bleeding. Given these opposing disease phenotypes, DIC management is challenging and includes treating the underlying disease and managing the coagulopathy. Currently, no therapies are approved for DIC. We have developed clot-targeted therapeutics that inhibit clot polymerization and activate clot fibrinolysis to manage DIC. We hypothesize that delivering both an anticoagulant and a fibrinolytic agent directly to clots will inhibit active clot polymerization while also breaking up pre-existing clots; therefore, reversing consumptive coagulopathy and restoring hemostatic balance. To test this hypothesis, we single- and dual-loaded fibrin-specific nanogels (FSNs) with antithrombinIII (ATIII) and/or tissue plasminogen activator (tPA) and evaluated their clot preventing and clot lysing abilities in vitro and in a rodent model of DIC. In vivo, single-loaded ATIII-FSNs decreased fibrin deposits in DIC organs and reduced blood loss when DIC rodents were injured. We also observed that the addition of tPA in dual-loaded ATIII-tPA-FSNs intensified the antithrombotic and fibrinolytic mechanisms, which proved advantageous for clot lysis and restoring platelet counts. However, the addition of tPA may have hindered wound healing capabilities when an injury was introduced. Our data supports the benefits of delivering both anticoagulants and fibrinolytic agents directly to clots to reduce the fibrin load and restore hemostatic balance in DIC.}, journal={ACS NANO}, author={Sheridan, Anastasia and Nellenbach, Kimberly and Pandit, Sanika and Byrnes, Elizabeth and Hardy, Grace and Lutz, Halle and Moiseiwitsch, Nina and Scull, Grant and Mihalko, Emily and Levy, Jerrold and et al.}, year={2024}, month={Jun} }
 @article{nellenbach_mihalko_nandi_koch_shetty_moretti_sollinger_moiseiwitsch_sheridan_pandit_et al._2024, title={Ultrasoft platelet-like particles stop bleeding in rodent and porcine models of trauma}, volume={16}, ISSN={["1946-6242"]}, DOI={10.1126/scitranslmed.adi4490}, abstractNote={Uncontrolled bleeding after trauma represents a substantial clinical problem. The current standard of care to treat bleeding after trauma is transfusion of blood products including platelets; however, donated platelets have a short shelf life, are in limited supply, and carry immunogenicity and contamination risks. Consequently, there is a critical need to develop hemostatic platelet alternatives. To this end, we developed synthetic platelet-like particles (PLPs), formulated by functionalizing highly deformable microgel particles composed of ultralow cross-linked poly ( N -isopropylacrylamide) with fibrin-binding ligands. The fibrin-binding ligand was designed to target to wound sites, and the cross-linking of fibrin polymers was designed to enhance clot formation. The ultralow cross-linking of the microgels allows the particles to undergo large shape changes that mimic platelet shape change after activation; when coupled to fibrin-binding ligands, this shape change facilitates clot retraction, which in turn can enhance clot stability and contribute to healing. Given these features, we hypothesized that synthetic PLPs could enhance clotting in trauma models and promote healing after clotting. We first assessed PLP activity in vitro and found that PLPs selectively bound fibrin and enhanced clot formation. In murine and porcine models of traumatic injury, PLPs reduced bleeding and facilitated healing of injured tissue in both prophylactic and immediate treatment settings. We determined through biodistribution experiments that PLPs were renally cleared, possibly enabled by ultrasoft particle properties. The performance of synthetic PLPs in the preclinical studies shown here supports future translational investigation of these hemostatic therapeutics in a trauma setting.}, number={742}, journal={SCIENCE TRANSLATIONAL MEDICINE}, author={Nellenbach, Kimberly and Mihalko, Emily and Nandi, Seema and Koch, Drew W. and Shetty, Jagathpala and Moretti, Leandro and Sollinger, Jennifer and Moiseiwitsch, Nina and Sheridan, Ana and Pandit, Sanika and et al.}, year={2024}, month={Apr} }
 @article{chee_mihalko_nellenbach_sollinger_huang_hon_pandit_cheng_brown_2023, title={Wound‐triggered shape change microgels for the development of enhanced biomimetic function platelet‐like particles}, volume={112}, ISSN={1549-3296 1552-4965}, url={http://dx.doi.org/10.1002/jbm.a.37625}, DOI={10.1002/jbm.a.37625}, abstractNote={Abstract}, number={4}, journal={Journal of Biomedical Materials Research Part A}, publisher={Wiley}, author={Chee, Eunice and Mihalko, Emily and Nellenbach, Kimberly and Sollinger, Jennifer and Huang, Ke and Hon, Mason and Pandit, Sanika and Cheng, Ke and Brown, Ashley}, year={2023}, month={Oct}, pages={613–624} }
 @article{mihalko_sandry_mininni_nellenbach_deal_daniele_ghadimi_levy_brown_2021, title={Fibrin-modulating nanogels for treatment of disseminated intravascular coagulation}, volume={5}, ISSN={2473-9529 2473-9537}, url={http://dx.doi.org/10.1182/bloodadvances.2020003046}, DOI={10.1182/bloodadvances.2020003046}, abstractNote={Abstract}, number={3}, journal={Blood Advances}, publisher={American Society of Hematology}, author={Mihalko, Emily P. and Sandry, Megan and Mininni, Nicholas and Nellenbach, Kimberly and Deal, Halston and Daniele, Michael and Ghadimi, Kamrouz and Levy, Jerrold H. and Brown, Ashley C.}, year={2021}, month={Jan}, pages={613–627} }
 @article{mihalko_nellenbach_krishnakumar_moiseiwitsch_sollinger_cooley_brown_2021, title={Fibrin‐specific <scp>poly(N‐isopropylacrylamide)</scp> nanogels for targeted delivery of tissue‐type plasminogen activator to treat thrombotic complications are well tolerated in vivo}, volume={7}, ISSN={2380-6761 2380-6761}, url={http://dx.doi.org/10.1002/btm2.10277}, DOI={10.1002/btm2.10277}, abstractNote={Abstract}, number={2}, journal={Bioengineering & Translational Medicine}, publisher={Wiley}, author={Mihalko, Emily P. and Nellenbach, Kimberly and Krishnakumar, Manasi and Moiseiwitsch, Nina and Sollinger, Jennifer and Cooley, Brian C. and Brown, Ashley C.}, year={2021}, month={Dec} }
 @article{krissanaprasit_key_froehlich_pontula_mihalko_dupont_andersen_kjems_brown_labean_2021, title={Multivalent Aptamer‐Functionalized Single‐Strand RNA Origami as Effective, Target‐Specific Anticoagulants with Corresponding Reversal Agents}, volume={10}, ISSN={2192-2640 2192-2659}, url={http://dx.doi.org/10.1002/adhm.202001826}, DOI={10.1002/adhm.202001826}, abstractNote={Abstract}, number={11}, journal={Advanced Healthcare Materials}, publisher={Wiley}, author={Krissanaprasit, Abhichart and Key, Carson M. and Froehlich, Kristen and Pontula, Sahil and Mihalko, Emily and Dupont, Daniel M. and Andersen, Ebbe S. and Kjems, Jørgen and Brown, Ashley C. and LaBean, Thomas H.}, year={2021}, month={Apr} }
 @article{todd_bharadwaj_nellenbach_nandi_mihalko_copeland_brown_stabenfeldt_2021, title={Platelet‐like</scp> particles reduce <scp>coagulopathy‐related</scp> and neuroinflammatory pathologies <scp>post‐experimental</scp> traumatic brain injury}, volume={109}, ISSN={1552-4973 1552-4981}, url={http://dx.doi.org/10.1002/jbm.b.34888}, DOI={10.1002/jbm.b.34888}, abstractNote={Abstract}, number={12}, journal={Journal of Biomedical Materials Research Part B: Applied Biomaterials}, publisher={Wiley}, author={Todd, Jordan and Bharadwaj, Vimala N. and Nellenbach, Kimberly and Nandi, Seema and Mihalko, Emily and Copeland, Connor and Brown, Ashley C. and Stabenfeldt, Sarah E.}, year={2021}, month={Jun}, pages={2268–2278} }
 @article{nandi_mihalko_nellenbach_castaneda_schneible_harp_deal_daniele_menegatti_barker_et al._2021, title={Synthetic Platelet Microgels Containing Fibrin Knob B Mimetic Motifs Enhance Clotting Responses}, volume={4}, ISSN={2366-3987 2366-3987}, url={http://dx.doi.org/10.1002/adtp.202100010}, DOI={10.1002/adtp.202100010}, abstractNote={Abstract}, number={5}, journal={Advanced Therapeutics}, publisher={Wiley}, author={Nandi, Seema and Mihalko, Emily and Nellenbach, Kimberly and Castaneda, Mario and Schneible, John and Harp, Mary and Deal, Halston and Daniele, Michael and Menegatti, Stefano and Barker, Thomas H. and et al.}, year={2021}, month={Mar} }
 @article{chee_nandi_nellenbach_mihalko_snider_morrill_bond_sproul_sollinger_cruse_et al._2020, title={Nanosilver composite pNIPAm microgels for the development of antimicrobial platelet‐like particles}, volume={108}, ISSN={1552-4973 1552-4981}, url={http://dx.doi.org/10.1002/jbm.b.34592}, DOI={10.1002/jbm.b.34592}, abstractNote={Abstract}, number={6}, journal={Journal of Biomedical Materials Research Part B: Applied Biomaterials}, publisher={Wiley}, author={Chee, Eunice and Nandi, Seema and Nellenbach, Kimberly and Mihalko, Emily and Snider, Douglas B. and Morrill, Landon and Bond, Andrew and Sproul, Erin and Sollinger, Jennifer and Cruse, Glenn and et al.}, year={2020}, month={Feb}, pages={2599–2609} }
 @article{nandi_sommerville_nellenbach_mihalko_erb_freytes_hoffman_monroe_brown_2020, title={Platelet-like particles improve fibrin network properties in a hemophilic model of provisional matrix structural defects}, volume={577}, ISSN={0021-9797}, url={http://dx.doi.org/10.1016/j.jcis.2020.05.088}, DOI={10.1016/j.jcis.2020.05.088}, abstractNote={Following injury, a fibrin-rich provisional matrix is formed to stem blood loss and provide a scaffold for infiltrating cells, which rebuild the damaged tissue. Defects in fibrin network formation contribute to impaired healing outcomes, as evidenced in hemophilia. Platelet-fibrin interactions greatly influence fibrin network structure via clot contraction, which increases fibrin density over time. Previously developed hemostatic platelet-like particles (PLPs) are capable of mimicking platelet functions including binding to fibrin fibers, augmenting clotting, and inducing clot retraction. In this study, we aimed to apply PLPs within a plasma-based in vitro hemophilia B model of deficient fibrin network structure to determine the ability of PLPs to improve fibrin structure and wound healing responses within hemophilia-like abnormal fibrin network formation. PLP impact on structurally deficient clot networks was assessed via confocal microscopy, a micropost deflection model, atomic force microscopy and an in vitro wound healing model of early cell migration within a provisional fibrin matrix. PLPs improved clot network density, force generation, and stiffness, and promoted fibroblast migration within an in vitro model of early wound healing under hemophilic conditions, indicating that PLPs could provide a biomimetic platform for improving wound healing events in disease conditions that cause deficient fibrin network formation.}, journal={Journal of Colloid and Interface Science}, publisher={Elsevier BV}, author={Nandi, Seema and Sommerville, Laura and Nellenbach, Kimberly and Mihalko, Emily and Erb, Mary and Freytes, Donald O. and Hoffman, Maureane and Monroe, Dougald and Brown, Ashley C.}, year={2020}, month={Oct}, pages={406–418} }
 @article{mihalko_brown_2019, title={Clot Structure and Implications for Bleeding and Thrombosis}, volume={46}, ISSN={0094-6176 1098-9064}, url={http://dx.doi.org/10.1055/s-0039-1696944}, DOI={10.1055/s-0039-1696944}, abstractNote={Abstract}, number={01}, journal={Seminars in Thrombosis and Hemostasis}, publisher={Georg Thieme Verlag KG}, author={Mihalko, Emily and Brown, Ashley C.}, year={2019}, month={Oct}, pages={096–104} }
 @article{tang_su_huang_dinh_wang_vandergriff_hensley_cores_allen_li_et al._2018, title={Targeted repair of heart injury by stem cells fused with platelet nanovesicles}, volume={2}, ISSN={2157-846X}, url={http://dx.doi.org/10.1038/s41551-017-0182-x}, DOI={10.1038/s41551-017-0182-x}, abstractNote={Stem cell transplantation, as used clinically, suffers from low retention and engraftment of the transplanted cells. Inspired by the ability of platelets to recruit stem cells to sites of injury on blood vessels, we hypothesized that platelets might enhance the vascular delivery of cardiac stem cells (CSCs) to sites of myocardial infarction injury. Here, we show that CSCs with platelet nanovesicles fused onto their surface membranes express platelet surface markers that are associated with platelet adhesion to injury sites. We also find that the modified CSCs selectively bind collagen-coated surfaces and endothelium-denuded rat aortas, and that in rat and porcine models of acute myocardial infarction the modified CSCs increase retention in the heart and reduce infarct size. Platelet-nanovesicle-fused CSCs thus possess the natural targeting and repairing ability of their parental cell types. This stem cell manipulation approach is fast, straightforward and safe, does not require genetic alteration of the cells, and should be generalizable to multiple cell types. The attachment of platelet nanovesicles to the surface of cardiac stem cells increases the retention of the cells delivered to the heart and reduces infarct size in rat and pig models of acute myocardial infarction.}, number={1}, journal={Nature Biomedical Engineering}, publisher={Springer Science and Business Media LLC}, author={Tang, Junnan and Su, Teng and Huang, Ke and Dinh, Phuong-Uyen and Wang, Zegen and Vandergriff, Adam and Hensley, Michael T. and Cores, Jhon and Allen, Tyler and Li, Taosheng and et al.}, year={2018}, month={Jan}, pages={17–26} }
 @article{mihalko_brown_2017, title={Material Strategies for Modulating Epithelial to Mesenchymal Transitions}, volume={4}, ISSN={2373-9878 2373-9878}, url={http://dx.doi.org/10.1021/acsbiomaterials.6b00751}, DOI={10.1021/acsbiomaterials.6b00751}, abstractNote={Epithelial to mesenchymal transitions (EMT) involve the phenotypic change of epithelial cells into fibroblast-like cells. This process is accompanied by the loss of cell-cell contacts, increased extracellular matrix (ECM) production, stress fiber alignment, and an increase in cell mobility. While essential for development and wound repair, EMT has also been recognized as a contributing factor to fibrotic diseases and cancer. Both chemical and mechanical cues, such as tumor necrosis factor alpha, NF-κB, Wnt, Notch, interleukin-8, metalloproteinase-3, ECM proteins, and ECM stiffness can determine the degree and duration of EMT events. Additionally, transforming growth factor beta is a primary driver of EMT and, interestingly, can be activated through cell-mediated mechanoactivation. In this review, we highlight recent findings demonstrating the contribution of mechanical stimuli, such as tissue and material stiffness, in driving EMT. We then highlight material strategies for controlling EMT events. Finally, we discuss drivers of the similar process of endothelial to mesenchymal transition (EndoMT) and corresponding material strategies for controlling EndoMT.}, number={4}, journal={ACS Biomaterials Science & Engineering}, publisher={American Chemical Society (ACS)}, author={Mihalko, Emily P. and Brown, Ashley C.}, year={2017}, month={Apr}, pages={1149–1161} }