@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{scull_aligwekwe_rey_koch_nellenbach_sheridan_pandit_sollinger_pierce_flick_et al._2024, title={Fighting fibrin with fibrin: Vancomycin delivery into coagulase-mediated <i>Staphylococcus aureus</i> biofilms via fibrin-based nanoparticle binding}, volume={6}, ISSN={["1552-4965"]}, DOI={10.1002/jbm.a.37760}, abstractNote={Abstract Staphylococcus aureus skin and soft tissue infection is a common ailment placing a large burden upon global healthcare infrastructure. These bacteria are growing increasingly recalcitrant to frontline antimicrobial therapeutics like vancomycin due to the prevalence of variant populations such as methicillin‐resistant and vancomycin‐resistant strains, and there is currently a dearth of novel antibiotics in production. Additionally, S. aureus has the capacity to hijack the host clotting machinery to generate fibrin‐based biofilms that confer protection from host antimicrobial mechanisms and antibiotic‐based therapies, enabling immune system evasion and significantly reducing antimicrobial efficacy. Emphasis is being placed on improving the effectiveness of therapeutics that are already commercially available through various means. Fibrin‐based nanoparticles (FBNs) were developed and found to interact with S. aureus through the clumping factor A (ClfA) fibrinogen receptor and directly integrate into the biofilm matrix. FBNs loaded with antimicrobials such as vancomycin enabled a targeted and sustained release of antibiotic that increased drug contact time and reduced the therapeutic dose required for eradicating the bacteria, both in vitro and in vivo. Collectively, these findings suggest that FBN‐antibiotic delivery may be a novel and potent therapeutic tool for the treatment of S. aureus biofilm infections.}, journal={JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A}, author={Scull, Grant and Aligwekwe, Adrian and Rey, Ysabel and Koch, Drew and Nellenbach, Kimberly and Sheridan, Ana and Pandit, Sanika and Sollinger, Jennifer and Pierce, Joshua G. and Flick, Matthew J. 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{moiseiwitsch_nellenbach_downey_boorman_brown_guzzetta_2023, title={Influence of Fibrinogen Concentrate on Neonatal Clot Structure When Administered Ex Vivo After Cardiopulmonary Bypass}, volume={137}, ISSN={0003-2999}, url={http://dx.doi.org/10.1213/ANE.0000000000006357}, DOI={10.1213/ANE.0000000000006357}, abstractNote={
            BACKGROUND:
            Bleeding is a serious complication of cardiopulmonary bypass (CPB) in neonates. Blood product transfusions are often needed to adequately restore hemostasis, but are associated with significant risks. Thus, neonates would benefit from other effective, and safe, hemostatic therapies. The use of fibrinogen concentrate (FC; RiaSTAP, CSL Behring, Marburg, Germany) is growing in popularity, but has not been adequately studied in neonates. Here, we characterize structural and degradation effects on the neonatal fibrin network when FC is added ex vivo to plasma obtained after CPB.
          }, number={3}, journal={Anesthesia & Analgesia}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Moiseiwitsch, Nina and Nellenbach, Kimberly A. and Downey, Laura A. and Boorman, David and Brown, Ashley C. and Guzzetta, Nina A.}, year={2023}, month={Jan}, pages={682–690} }
 @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{londoño-zuluaga_jameel_gonzalez_nellenbach_brown_yang_lucia_2022, title={A Unique Crustacean-Based Chitin Platform to Reduce Self-Aggregation of Polysaccharide Nanofibers}, volume={10}, ISSN={2079-6439}, url={http://dx.doi.org/10.3390/fib10100087}, DOI={10.3390/fib10100087}, abstractNote={Every year, over 8 million tons of crustacean shells are discarded. However, there exists an opportunity for valorizing the chitin and calcium carbonate part of the composition of the shells. Our study revealed crustacean chitin reduces self-aggregation effects. It was shown that crustacean-based nanofibers alone or added to cellulose offer unprecedented reductions in viscosity even after drying to produce foams impossible for cellulose. Polysaccharide nanofibers suffer from increased viscosity from strong hydrogen bonding addressed by the incorporation of crustacean-based nanofibers. The ability of the nanocomposite to overcome self-aggregation and collapse was attributed to organized chitin nanofiber morphology in the crustacean matrix. As a result of enhanced surface area from reduced fiber aggregation, the chitin/crustacean-cellulose blend was tested for a biomedical application requiring a high surface area: coagulation. Preliminary experiments showed the crustacean matrices, especially those containing calcium carbonate, induced blood clotting when 35 s. A materials platform is proposed for bio-based nanofiber production overcoming intractable and difficult-to-address self-aggregation effects associated with polysaccharides.}, number={10}, journal={Fibers}, publisher={MDPI AG}, author={Londoño-Zuluaga, Carolina and Jameel, Hasan and Gonzalez, Ronalds and Nellenbach, Kimberly and Brown, Ashley and Yang, Guihua and Lucia, Lucian}, year={2022}, month={Oct}, pages={87} }
 @article{wang_sun_vallabhuneni_pawlowski_vahabi_nellenbach_brown_scholle_zhao_kota_2022, title={On-demand, remote and lossless manipulation of biofluid droplets}, volume={9}, ISSN={2051-6347 2051-6355}, url={http://dx.doi.org/10.1039/D2MH00695B}, DOI={10.1039/d2mh00695b}, abstractNote={To minimize exposure of healthcare workers and clinical laboratory personnel to infectious liquids, we designed biofluid manipulators for on-demand handling of liquid droplets, in-plane or out-of-plane, in a remote and lossless manner.}, number={11}, journal={Materials Horizons}, publisher={Royal Society of Chemistry (RSC)}, author={Wang, Wei and Sun, Jiefeng and Vallabhuneni, Sravanthi and Pawlowski, Benjamin and Vahabi, Hamed and Nellenbach, Kimberly and Brown, Ashley C. and Scholle, Frank and Zhao, Jianguo and Kota, Arun K.}, year={2022}, pages={2863–2871} }
 @article{nellenbach_brown_2022, title={Platelet-mimicking procoagulant nanoparticles: Potential strategies for mitigating blood shortages}, volume={4}, ISSN={["1538-7836"]}, DOI={10.1111/jth.15720}, abstractNote={Bleeding can be a lifethreating event following trauma or surgery. Many factors can increase a patient's likelihood of severe bleeding, including the use of anticoagulants or having hereditary clotting disorders or thrombocytopenia. In a hospital setting, transfusion of donor blood products, including red blood cells, platelets, and/or fibrinogen concentrates, are used as a first line of defense to mitigate bleeding.1 Because of their critical roles in hemostasis, transfusion of platelets is particularly important for stopping uncontrolled bleeding. However, donor platelets have a short shelf life of approximately 5 to 7 days under standard storage conditions. The use of coldstored platelets is gaining popularity as a means to enhance platelet shelflife, but cold storage can cause platelet lesions and has not yet been widely adopted.2 Additionally, no matter the storage conditions used for platelets, because they are derived from human donors, platelet supply is dependent on donor availability and willingness, which often leads to shortages. This limitation has been particularly striking in the past year because the COVID19 pandemic has led to an unprecedented blood product storage. In fact, in 2022, for the first time, the American Red Cross declared a “blood crisis” and implored eligible donors to give blood.3 Furthermore, although risk of disease transmission is low because of current screening standards for donorderived products, this risk is still not zero.4 Finally, although platelets are a key therapeutic tool in the hospital setting, in emergency situations outside of a hospital, it is not practical to carry platelets or other blood products; therefore, many patients suffering traumatic bleeding have delays in critical treatment that could prevent morbidity and mortality.5 Overall, these limitations highlight that a great need exists to identify an alternative to natural platelets to treat bleeding. Ideally, this alternative should be readily available, have a long shelf life, have storage conditions that are amenable to use in emergency medicine, and perform in an equivalent manner to natural platelets. The creation of artificial platelets to meet these design goals has been an active area of research in recent years, and a new study by Sekhon et al. has demonstrated the creation of plateletmimicking procoagulant nanoparticles (PPNs) that have advanced platelet function compared with prior designs.6 Here, we discuss the implications for these new findings in the field of synthetic platelet design.}, journal={JOURNAL OF THROMBOSIS AND HAEMOSTASIS}, author={Nellenbach, Kimberly and Brown, Ashley C.}, year={2022}, month={Apr} }
 @article{nellenbach_kyu_guzzetta_brown_2021, title={Differential sialic acid content in adult and neonatal fibrinogen mediates differences in clot polymerization dynamics}, volume={5}, ISSN={["2473-9537"]}, DOI={10.1182/bloodadvances.2021004417.}, abstractNote={Neonates possess a molecular variant of fibrinogen, known as fetal fibrinogen, characterized by increased sialic acid, a greater negative charge, and decreased activity compared with adults. Despite these differences, adult fibrinogen is used for the treatment of bleeding in neonates, with mixed efficacy. To determine safe and efficacious bleeding protocols for neonates, more information on neonatal fibrin clot formation and the influence of sialic acid on these processes is needed. Here, we examine the influence of sialic acid on neonatal fibrin polymerization. We hypothesized that the increased sialic acid content of neonatal fibrinogen promotes fibrin B:b knob-hole interactions and consequently influences the structure and function of the neonatal fibrin matrix. We explored this hypothesis through analysis of structural properties and knob:hole polymerization dynamics of normal and desialylated neonatal fibrin networks and compared them with those formed with adult fibrinogen. We then characterized normal neonatal fibrin knob:hole interactions by forming neonatal and adult clots with either thrombin or snake-venom thrombin-like enzymes that preferentially cleave fibrinopeptide A or B. Sialic acid content of neonatal fibrinogen was determined to be a key determinant of resulting clot properties. Experiments analyzing knob:hole dynamics indicated that typical neonatal fibrin clots are formed with the release of more fibrinopeptide B and less fibrinopeptide A than adults. After the removal of sialic acid, fibrinopeptide release was roughly equivalent between adults and neonates, indicating the influence of sialic acid on fibrin neonatal fibrin polymerization mechanisms. These results could inform future studies developing neonatal-specific treatments of bleeding.}, number={23}, journal={BLOOD ADVANCES}, author={Nellenbach, Kimberly and Kyu, Alexander and Guzzetta, Nina and Brown, Ashley C.}, year={2021}, month={Dec}, pages={5202–5214} }
 @article{moiseiwitsch_nellenbach_guzzetta_brown_downey_2021, title={Ex Vivo and In Vivo Evaluation of Fibrinogen Concentrate to Mitigate Post-Surgical Bleeding in Neonates}, volume={138}, ISSN={["1528-0020"]}, DOI={10.1182/blood-2021-153823}, abstractNote={Abstract}, journal={BLOOD}, author={Moiseiwitsch, Nina and Nellenbach, Kimberly A. and Guzzetta, Nina A. and Brown, Ashley C. and Downey, Laura}, year={2021}, month={Nov} }
 @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{pearce_nellenbach_smith_brown_haider_2021, title={Modeling and Parameter Subset Selection for Fibrin Polymerization Kinetics with Applications to Wound Healing}, volume={83}, ISSN={0092-8240 1522-9602}, url={http://dx.doi.org/10.1007/s11538-021-00876-6}, DOI={10.1007/s11538-021-00876-6}, abstractNote={During the hemostatic phase of wound healing, vascular injury leads to endothelial cell damage, initiation of a coagulation cascade involving platelets, and formation of a fibrin-rich clot. As this cascade culminates, activation of the protease thrombin occurs and soluble fibrinogen is converted into an insoluble polymerized fibrin network. Fibrin polymerization is critical for bleeding cessation and subsequent stages of wound healing. We develop a cooperative enzyme kinetics model for in vitro fibrin matrix polymerization capturing dynamic interactions among fibrinogen, thrombin, fibrin, and intermediate complexes. A tailored parameter subset selection technique is also developed to evaluate parameter identifiability for a representative data curve for fibrin accumulation in a short-duration in vitro polymerization experiment. Our approach is based on systematic analysis of eigenvalues and eigenvectors of the classical information matrix for simulations of accumulating fibrin matrix via optimization based on a least squares objective function. Results demonstrate robustness of our approach in that a significant reduction in objective function cost is achieved relative to a more ad hoc curve-fitting procedure. Capabilities of this approach to integrate non-overlapping subsets of the data to enhance the evaluation of parameter identifiability are also demonstrated. Unidentifiable reaction rate parameters are screened to determine whether individual reactions can be eliminated from the overall system while preserving the low objective cost. These findings demonstrate the high degree of information within a single fibrin accumulation curve, and a tailored model and parameter subset selection approach for improving optimization and reducing model complexity in the context of polymerization experiments.}, number={5}, journal={Bulletin of Mathematical Biology}, publisher={Springer Science and Business Media LLC}, author={Pearce, Katherine J. and Nellenbach, Kimberly and Smith, Ralph C. and Brown, Ashley C. and Haider, Mansoor A.}, year={2021}, month={Mar} }
 @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{roosa_muhamed_young_nellenbach_daniele_ligler_brown_2021, title={Synthesis of sonicated fibrin nanoparticles that modulate fibrin clot polymerization and enhance angiogenic responses}, volume={204}, ISSN={0927-7765}, url={http://dx.doi.org/10.1016/j.colsurfb.2021.111805}, DOI={10.1016/j.colsurfb.2021.111805}, abstractNote={Chronic wounds can occur when the healing process is disrupted and the wound remains in a prolonged inflammatory stage that leads to severe tissue damage and poor healing outcomes. Clinically used treatments, such as high density, FDA-approved fibrin sealants, do not provide an optimal environment for native cell proliferation and subsequent tissue regeneration. Therefore, new treatments outside the confines of these conventional fibrin bulk gel therapies are required. We have previously developed flowable, low-density fibrin nanoparticles that, when coupled to keratinocyte growth factor, promote cell migration and epithelial wound closure in vivo. Here, we report a new high throughput method for generating the fibrin nanoparticles using probe sonication, which is less time intensive than the previously reported microfluidic method, and investigate the ability of the sonicated fibrin nanoparticles (SFBN) to promote clot formation and cell migration in vitro. The SFBNs can form a fibrin gel when combined with fibrinogen in the absence of exogenous thrombin, and the polymerization rate and fiber density in these fibrin clots is tunable based on SFBN concentration. Furthermore, fibrin gels made with SFBNs support cell migration in an in vitro angiogenic sprouting assay, which is relevant for wound healing. In this report, we show that SFBNs may be a promising wound healing therapy that can be easily produced and delivered in a flowable formulation.}, journal={Colloids and Surfaces B: Biointerfaces}, publisher={Elsevier BV}, author={Roosa, Colleen A. and Muhamed, Ismaeel and Young, Ashlyn T. and Nellenbach, Kimberly and Daniele, Michael A. and Ligler, Frances S. and Brown, Ashley C.}, year={2021}, month={Aug}, pages={111805} }
 @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{nellenbach_nandi_peeler_kyu_brown_2020, title={Neonatal Fibrin Scaffolds Promote Enhanced Cell Adhesion, Migration, and Wound Healing In Vivo Compared to Adult Fibrin Scaffolds}, volume={13}, ISBN={1865-5033}, ISSN={1865-5025 1865-5033}, url={http://dx.doi.org/10.1007/s12195-020-00620-5}, DOI={10.1007/s12195-020-00620-5}, abstractNote={Fibrin scaffolds are often utilized to treat chronic wounds. The monomer fibrinogen used to create such scaffolds is typically derived from adult human or porcine plasma. However, our previous studies have identified extensive differences in fibrin network properties between adults and neonates, including higher fiber alignment in neonatal networks. Wound healing outcomes have been linked to fibrin matrix structure, including fiber alignment, which can affect the binding and migration of cells. We hypothesized that fibrin scaffolds derived from neonatal fibrin would enhance wound healing outcomes compared to adult fibrin scaffolds. Fibrin scaffolds were formed from purified adult or neonatal fibrinogen and thrombin then structural analysis was conducted via confocal microscopy. Human neonatal dermal fibroblast attachment, migration, and morphology on fibrin scaffolds were assessed. A murine full thickness injury model was used to compare healing in vivo in the presence of neonatal fibrin, adult fibrin, or saline. Distinct fibrin architectures were observed between adult and neonatal scaffolds. Significantly higher fibroblast attachment and migration was observed on neonatal scaffolds compared to adults. Cell morphology on neonatal scaffolds exhibited higher spreading compared to adult scaffolds. In vivo significantly smaller wound areas and greater epidermal thickness were observed when wounds were treated with neonatal fibrin compared to adult fibrin or a saline control. Distinctions in neonatal and adult fibrin scaffold properties influence cellular behavior and wound healing. These studies indicate that fibrin scaffolds sourced from neonatal plasma could improve healing outcomes compared to scaffolds sourced from adult plasma.}, number={5}, journal={Cellular and Molecular Bioengineering}, publisher={Springer Science and Business Media LLC}, author={Nellenbach, Kimberly and Nandi, Seema and Peeler, Christopher and Kyu, Alexander and Brown, Ashley C.}, year={2020}, month={May}, pages={393–404} }
 @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{nandi_mohanty_nellenbach_erb_muller_brown_2020, title={Ultrasound Enhanced Synthetic Platelet Therapy for Augmented Wound Repair}, volume={6}, ISSN={2373-9878 2373-9878}, url={http://dx.doi.org/10.1021/acsbiomaterials.9b01976}, DOI={10.1021/acsbiomaterials.9b01976}, abstractNote={Native platelets perform a number of functions within the wound healing process, including interacting with fibrin fibers at the wound site to bring about retraction after clot formation. Clot retraction improves clot stability and enhances the function of the fibrin network as a provisional matrix to support cellular infiltration of the wound site, thus facilitating tissue repair and remodeling after hemostasis. In cases of traumatic injury or disease, platelets can become depleted and this process disrupted. To that end, our lab has developed synthetic platelet-like particles (PLPs) that recapitulate the clot retraction abilities of native platelets through a Brownian-wrench driven mechanism that drives fibrin network densification and clot retraction over time, however, this Brownian-motion driven process occurs on a longer time scale than native active actin/myosin-driven platelet-mediated clot retraction. We hypothesized that a combinatorial therapy comprised of ultrasound stimulation of PLP motion within fibrin clots would facilitate a faster induction of clot retraction on a more platelet-mimetic time scale and at a lower dosage than required for PLPs acting alone. We found that application of ultrasound in combination with a subtherapeutic dosage of PLPs resulted in increased clot density and stiffness, improved fibroblast migration in vitro and increased epidermal thickness and angiogenesis in vivo, indicating that this combination therapy has potential to facilitate multiphase pro-healing outcomes. Additionally, while these particular studies focus on the role of ultrasound in enhancing specific interactions between fibrin-binding synthetic PLPs embedded within fibrin networks, these studies have wide applicability in understanding the role of ultrasound stimulation in enhancing multi-scale colloidal interactions within fibrillar matrices.}, number={5}, journal={ACS Biomaterials Science & Engineering}, publisher={American Chemical Society (ACS)}, author={Nandi, Seema and Mohanty, Kaustav and Nellenbach, Kimberly and Erb, Mary and Muller, Marie and Brown, Ashley C.}, year={2020}, month={Apr}, pages={3026–3036} }
 @article{nandi_sproul_nellenbach_erb_gaffney_freytes_brown_2019, title={Platelet-like particles dynamically stiffen fibrin matrices and improve wound healing outcomes}, volume={7}, ISSN={2047-4830 2047-4849}, url={http://dx.doi.org/10.1039/C8BM01201F}, DOI={10.1039/c8bm01201f}, abstractNote={PLPs increase fibrin stiffness, promote cell migration, and improve healing outcomes.}, number={2}, journal={Biomaterials Science}, publisher={Royal Society of Chemistry (RSC)}, author={Nandi, Seema and Sproul, Erin P. and Nellenbach, Kimberly and Erb, Mary and Gaffney, Lewis and Freytes, Donald O. and Brown, Ashley C.}, year={2019}, pages={669–682} }
 @article{nellenbach_guzzetta_brown_2018, title={Analysis of the structural and mechanical effects of procoagulant agents on neonatal fibrin networks following cardiopulmonary bypass}, volume={16}, ISSN={1538-7836}, url={http://dx.doi.org/10.1111/jth.14280}, DOI={10.1111/jth.14280}, abstractNote={Essentials The standard of care (SOC) for treating neonatal bleeding is transfusion of adult blood products. We compared neonatal clots formed with cryoprecipitate (SOC) to two procoagulant therapies. The current SOC resulted in clots with increased stiffness and decreased fibrinolytic properties. Procoagulant therapies may be a viable alternative to SOC treatment for neonatal bleeding.}, number={11}, journal={Journal of Thrombosis and Haemostasis}, publisher={Elsevier BV}, author={Nellenbach, K. and Guzzetta, N.A. and Brown, A.C.}, year={2018}, month={Nov}, pages={2159–2167} }
 @article{chester_kathard_nortey_nellenbach_brown_2018, title={Viscoelastic properties of microgel thin films control fibroblast modes of migration and pro-fibrotic responses}, volume={185}, ISSN={0142-9612}, url={http://dx.doi.org/10.1016/j.biomaterials.2018.09.012}, DOI={10.1016/j.biomaterials.2018.09.012}, abstractNote={Cell behavior is influenced by the biophysical properties of their microenvironments, and the linear elastic properties of substrates strongly influences adhesion, migration, and differentiation responses. Because most biological tissues exhibit non-linear elastic properties, there is a growing interest in understanding how the viscous component of materials and tissues influences cell fate. Here we describe the use of microgel thin films with controllable non-linear elastic properties for investigating the role of material loss tangent on cell adhesion, migration, and myofibroblastic differentiation, which have implications in fibrotic responses. Fibroblast modes of migration are dictated by film loss tangent; high loss tangent induced ROCK-mediated amoeboid migration while low loss tangent induced Rac-mediated mesenchymal cell migration. Low loss tangent films were also associated with higher levels of myofibroblastic differentiation. These findings have implications in fibrosis and indicate that slight changes in tissue viscoelasticity following injury could contribute to early initiation of fibrotic related responses.}, journal={Biomaterials}, publisher={Elsevier BV}, author={Chester, Daniel and Kathard, Rahul and Nortey, Jeremy and Nellenbach, Kimberly and Brown, Ashley C.}, year={2018}, month={Dec}, pages={371–382} }
 @article{nellenbach_brown_2017, title={Peptide Mimetic Drugs for Modulating Thrombosis and Hemostasis}, volume={78}, ISSN={0272-4391 1098-2299}, url={http://dx.doi.org/10.1002/ddr.21407}, DOI={10.1002/ddr.21407}, abstractNote={ABSTRACT}, number={6}, journal={Drug Development Research}, publisher={Wiley}, author={Nellenbach, Kimberly and Brown, Ashley C.}, year={2017}, month={Aug}, pages={236–244} }