Utilizing multiscale engineered biomaterials to examine TGF-ß-mediated myofibroblastic differentiation.

Cells integrate many mechanical and chemical cues to drive cell signalling responses. Because of the complex nature and interdependency of alterations in extracellular matrix (ECM) composition, ligand density, mechanics, and cellular responses it is difficult to tease out individual and combinatorial contributions of these various factors in driving cell behavior in homeostasis and disease. Tuning of material viscous and elastic properties, and ligand densities, in combinatorial fashions would enhance our understanding of how cells process complex signals. For example, it is known that increased ECM mechanics and transforming growth factor beta (TGF-ß) receptor (TGF-ß-R) spacing/clustering independently drive TGF-ß signalling and associated myofibroblastic differentiation. However, it remains unknown how these inputs orthogonally contribute to cellular outcomes. Here, we describe the development of a novel material platform that combines microgel thin films with controllable viscoelastic properties and DNA origami to probe how viscoelastic properties and nanoscale spacing of TGF-ß-Rs contribute to TGF-ß signalling and myofibroblastic differentiation. We found that highly viscous materials with non-fixed TGF-ß-R spacing promoted increased TGF-ß signalling and myofibroblastic differentiation. This is likely due to the ability of cells to better cluster receptors on these surfaces. These results provide insight into the contribution of substrate properties and receptor localisation on downstream signalling. Future studies allow for exploration into other receptor-mediated processes.

Biomaterials for Hemostasis.

Uncontrolled bleeding is a major problem in trauma and emergency medicine. While materials for trauma applications would certainly find utility in traditional surgical settings, the unique environment of emergency medicine introduces additional design considerations, including the need for materials that are easily deployed in austere environments. Ideally, these materials would be available off the shelf, could be easily transported, and would be able to be stored at room temperature for some amount of time. Both natural and synthetic materials have been explored for the development of hemostatic materials. This review article provides an overview of classes of materials used for topical hemostats and newer developments in the area of injectable hemostats for use in emergency medicine.

Using Virtual Technology for Fear of Medical Procedures: A Systematic Review of the Effectiveness of Virtual Reality-Based Interventions.

BACKGROUND: Innovations in virtual reality (VR) technologies have improved the adaptability of its use in therapeutic settings, and VR has shown to be a promising treatment for fear of medical procedures, with research increasing in this area in recent years. PURPOSE: This review aims to collate evidence for the impact of VR on fear of medical procedures. METHODS: CENTRAL (Cochrane), MEDLINE, EMBASE, and PsychINFO databases were searched up to October 2020. A mix of experimental and case-control studies were included for review, which evaluated the effectiveness of VR for fear, anxiety, and pain of medical procedures for people with needle phobia, dental phobia, claustrophobia of medical scans, and burn wound care anxiety. Risk of bias (RoB) was assessed by Cochrane and ROBINS-I tools. RESULTS: Twenty-eight studies were selected. Some studies included mixed participant groups of young people adults. The interventions varied, with VR used for distraction, hypnosis, or exposure. These were shown to be effective for reducing fear of medical procedures. However, effectiveness for blood-injection-injury phobias and burn wound care patients was unclear. CONCLUSIONS: Evidence on the effectiveness of VR suggests that it does decrease fear of medical procedures in some situations. However, the RoB assessment illustrated a poor quality of studies across those included in this review, limiting the ability to draw firm general conclusions from the study findings. There is a need for further research exploring the use of VR technologies in the management of anxiety in physical health care settings.

Mechanical properties of tissue formed in vivo are affected by 3D-bioplotted scaffold microarchitecture and correlate with ECM collagen fiber alignment.

Purpose: Musculoskeletal soft tissues possess highly aligned extracellular collagenous networks that provide structure and strength. Such an organization dictates tissue-specific mechanical properties but can be difficult to replicate by engineered biological substitutes. Nanofibrous electrospun scaffolds have demonstrated the ability to control cell-secreted collagen alignment, but concerns exist regarding their scalability for larger and anatomically relevant applications. Additive manufacturing processes, such as melt extrusion-based 3D-Bioplotting, allow fabrication of structurally relevant scaffolds featuring highly controllable porous microarchitectures.Materials and Methods: In this study, we investigate the effects of 3D-bioplotted scaffold design on the compressive elastic modulus of neotissue formed in vivo in a subcutaneous rat model and its correlation with the alignment of ECM collagen fibers. Polycaprolactone scaffolds featuring either 100 or 400 µm interstrand spacing were implanted for 4 or 12 weeks, harvested, cryosectioned, and characterized using atomic-force-microscopy-based force mapping.Results: The compressive elastic modulus of the neotissue formed within the 100 µm design was significantly higher at 4 weeks (p < 0.05), but no differences were observed at 12 weeks. In general, the tissue stiffness was within the same order of magnitude and range of values measured in native musculoskeletal soft tissues including the porcine meniscus and anterior cruciate ligament. Finally, a significant positive correlation was noted between tissue stiffness and the degree of ECM collagen fiber alignment (p < 0.05) resulting from contact guidance provided by scaffold strands.Conclusion: These findings demonstrate the significant effects of 3D-bioplotted scaffold microarchitectures in the organization and sub-tissue-level mechanical properties of ECM in vivo.

The VPS34 PI3K negatively regulates RAB-5 during endosome maturation.

The GTPase Rab5 and phosphatidylinositol-3 phosphate [PI(3)P] coordinately regulate endosome trafficking. Rab5 recruits Vps34, the class III phosphoinositide 3-kinase (PI3K), to generate PI(3)P and recruit PI(3)P-binding proteins. Loss of Rab5 and loss of Vps34 have opposite effects on endosome size, suggesting that our understanding of how Rab5 and PI(3)P cooperate is incomplete. Here, we report a novel regulatory loop whereby Caenorhabditis elegans VPS-34 inactivates RAB-5 via recruitment of the TBC-2 Rab GTPase-activating protein. We found that loss of VPS-34 caused a phenotype with large late endosomes, as with loss of TBC-2, and that Rab5 activity (mice have two Rab5 isoforms, Rab5a and Rab5b) is increased in Vps34-knockout mouse embryonic fibroblasts (Vps34 is also known as PIK3C3 in mammals). We found that VPS-34 is required for TBC-2 endosome localization and that the pleckstrin homology (PH) domain of TBC-2 bound PI(3)P. Deletion of the PH domain enhanced TBC-2 localization to endosomes in a VPS-34-dependent manner. Thus, PI(3)P binding of the PH domain might be permissive for another PI(3)P-regulated interaction that recruits TBC-2 to endosomes. Therefore, VPS-34 recruits TBC-2 to endosomes to inactivate RAB-5 to ensure the directionality of endosome maturation.

Are all rural placements created equal? A national study of placement experiences among multidisciplinary health students.

OBJECTIVE: Members of the National Rural Health Student Network have expressed concerns that the quality and accessibility of rural placements might vary between health degrees. This study compared a range of placement factors between health student disciplines. DESIGN: Cross-sectional survey. SETTING: An online survey tool was distributed in 2016 by the National Rural Health Student Network and its Rural Health Clubs to the National Rural Health Student Network's 10 218 members in all Australian states and territories. PARTICIPANTS: Responses were received from 897 health students (9% response rate). Participants were from the disciplines of medicine, dentistry, nursing, midwifery or an allied health degree. MAIN OUTCOME MEASURES: Bivariate analysis between medical and non-medical students relating to the support received for rural placements: support provided to help students coordinate their placement; assistance with financial costs; mental health support; social support; and student orientation regarding both the placement's health service and community. RESULT: Compared with medical students, non-medical students were more likely to have coordinated the majority of their placement themselves, but were less likely to have had control over their placement location or to have received financial support, mental health support, social support, a health service orientation or a community orientation. CONCLUSION: Among National Rural Health Student Network members, those studying health degrees other than medicine had significantly less rural placement support in all examined domains when compared with medical students.

Study of Poly(N-isopropylacrylamide-co-acrylic acid) (pNIPAM) Microgel Particle Induced Deformations of Tissue-Mimicking Phantom by Ultrasound Stimulation.

Poly(N-isopropylacrylamide) (pNIPAm) microgels (microgels) are colloidal particles that have been used extensively for biomedical applications. Typically, these particles are synthesized in the presence of an exogenous cross-linker, such as N,N'-methylenebis(acrylamide) (BIS); however, recent studies have demonstrated that pNIPAm microgels can be synthesized in the absence of an exogenous cross-linker, resulting in the formation of ultralow cross-linked (ULC) particles, which are highly deformable. Microgel deformability has been linked in certain cases to enhanced bioactivity when ULC microgels are used for the creation of biomimetic particles. We hypothesized that ultrasound stimulation of microgels would enhance particle deformation and that the degree of enhancement would negatively correlate with the degree of particle cross-linking. Here, we demonstrate in tissue-mimicking phantoms that using ultrasound insonification causes deformations of ULC microgel particles. Furthermore, the amount of deformation depends on the ultrasound excitation frequency and amplitude and on the concentration of ULC microgel particles. We observed that the amplitude of deformation increases with increasing ULC microgel particle concentration up to 2.5 mg/100 mL, but concentrations higher than 2.5 mg/100 mL result in reduced amount of deformation. In addition, we observed that the amplitude of deformation was significantly higher at 1 MHz insonification frequency. We also report that increasing the degree of microgel cross-linking reduces the magnitude of the deformation and increases the optimal concentration required to achieve the largest amount of deformation. Stimulated ULC microgel particle deformation has numerous potential biomedical applications, including enhancement of localized drug delivery and biomimetic activity. These results demonstrate the potential of ultrasound stimulation for such applications.

Platelet mechanosensing of substrate stiffness during clot formation mediates adhesion, spreading, and activation.

As platelets aggregate and activate at the site of vascular injury to stem bleeding, they are subjected to a myriad of biochemical and biophysical signals and cues. As clot formation ensues, platelets interact with polymerizing fibrin scaffolds, exposing platelets to a large range of mechanical microenvironments. Here, we show for the first time (to our knowledge) that platelets, which are anucleate cellular fragments, sense microenvironmental mechanical properties, such as substrate stiffness, and transduce those cues into differential biological signals. Specifically, as platelets mechanosense the stiffness of the underlying fibrin/fibrinogen substrate, increasing substrate stiffness leads to increased platelet adhesion and spreading. Importantly, adhesion on stiffer substrates also leads to higher levels of platelet activation, as measured by integrin αIIbß3 activation, α-granule secretion, and procoagulant activity. Mechanistically, we determined that Rac1 and actomyosin activity mediate substrate stiffness-dependent platelet adhesion, spreading, and activation to different degrees. This capability of platelets to mechanosense microenvironmental cues in a growing thrombus or hemostatic plug and then mechanotransduce those cues into differential levels of platelet adhesion, spreading, and activation provides biophysical insight into the underlying mechanisms of platelet aggregation and platelet activation heterogeneity during thrombus formation.

Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial.

BACKGROUND & AIMS: Simeprevir is an oral, once-daily inhibitor of hepatitis c virus (HCV) protease NS3/4A. We investigated the safety and efficacy of simeprevir with peg-interferon α-2a and ribavirin (PR) in a randomized, double-blind, placebo-controlled, phase 3 trial of patients with HCV genotype 1 infection who relapsed after previous interferon-based therapy. METHODS: Patients were assigned randomly (2:1) to groups given simeprevir (150 mg, once daily) and PR (n = 260) or placebo and PR (n = 133) for 12 weeks. Patients then were given PR alone for 12 or 36 weeks (simeprevir group, based on response-guided therapy criteria) or 36 weeks (placebo group). RESULTS: Simeprevir and PR was significantly superior to placebo and PR; rates of sustained virologic response 12 weeks after planned end of treatment (SVR12) were 79.2% vs 36.1%, respectively (43.8% difference; 95% confidence interval, 34.6-53.0; P < .001). Among patients given simeprevir, 92.7% met the response-guided therapy criteria and were eligible to complete PR at week 24; of these, 83.0% achieved SVR12. HCV RNA was undetectable at week 4 in 77.2% of patients given simeprevir and 3.1% given placebo. On-treatment failure and relapse rates were lower among patients given simeprevir and PR than those given placebo and PR (3.1% vs 27.1%, and 18.5% vs 48.4%, respectively). Patients given simeprevir did not have adverse events beyond those that occurred in patients given PR alone. Most adverse events were grades 1/2; the prevalence of anemia and rash was similar in both groups. Patients in both groups reported similar severity of fatigue and functional impairments during the study, but duration was reduced among patients given simeprevir. CONCLUSIONS: In a phase 3 trial of patients who had relapsed after interferon-based therapy, the addition of simeprevir to PR was generally well tolerated, with an SVR12 rate of 79.2%. Most patients (92.7%) receiving simeprevir were able to shorten therapy to 24 weeks. ClinicalTrials.gov number: NCT01281839.

Ultrasoft microgels displaying emergent platelet-like behaviours.

Efforts to create platelet-like structures for the augmentation of haemostasis have focused solely on recapitulating aspects of platelet adhesion; more complex platelet behaviours such as clot contraction are assumed to be inaccessible to synthetic systems. Here, we report the creation of fully synthetic platelet-like particles (PLPs) that augment clotting in vitro under physiological flow conditions and achieve wound-triggered haemostasis and decreased bleeding times in vivo in a traumatic injury model. PLPs were synthesized by combining highly deformable microgel particles with molecular-recognition motifs identified through directed evolution. In vitro and in silico analyses demonstrate that PLPs actively collapse fibrin networks, an emergent behaviour that mimics in vivo clot contraction. Mechanistically, clot collapse is intimately linked to the unique deformability and affinity of PLPs for fibrin fibres, as evidenced by dissipative particle dynamics simulations. Our findings should inform the future design of a broader class of dynamic, biosynthetic composite materials.

A European single centre experience of management of hepatitis C virus genotype 4 infection with pegylated-interferon and ribavirin.

New direct acting antiviral agents are revolutionising hepatitis C virus (HCV) treatment. However, to date limited clinical trial data exists for outcomes in genotype 4 (GT4) HCV patients. GT4 HCV is more common in Africa, the Middle East, and Asia, and limited data exists to date for outcomes in Europe. We report the first "real-life" sustained virological response (SVR) outcomes using pegylated interferon and ribavirin for HCV GT4 in the UK, and the largest European single centre cohort. HCV GT4 patients treated at a London, UK centre between 2002 and 2014 were assessed for SVR outcomes. Patient age, sex, region of origin, co-infection with HIV, pre-treatment liver biopsy histological assessment, genotype subtyping, treatment duration, and dose reductions were compared against SVR outcomes on univariate analysis. Multivariate analysis was performed on results with P < 0.1. A total of 118 patients were treated with HCV GT4 during the study period, 57 achieved SVR (48%). On univariate analysis age ≥45 (P < 0.0001), high viral load (P < 0.0001), Ishak staging 5-6 (P < 0.0001), and non-Egyptian Africans (P = 0.0059) were all negatively associated with SVR. Eastern Europeans appeared to have higher SVR (P < 0.0001). Using multivariate correlation viral load (P = 0.0005); Ishak staging (P = 0.0031) and age (P = 0.0003) were associated with SVR but not country of origin (P = 0.0645). Outcomes with pegylated interferon and ribavirin for HCV GT4 in this "real-life" setting were sub-optimal especially in the context of newer regimens. Patients with older age, high viral loads, and advanced disease need prioritisation for alternative treatments.

Ultrasoft, highly deformable microgels.

Microgels are colloidally stable, hydrogel microparticles that have previously been used in a range of (soft) material applications due to their tunable mechanical and chemical properties. Most commonly, thermo and pH-responsive poly(N-isopropylacrylamide) (pNIPAm) microgels can be fabricated by precipitation polymerization in the presence of the co-monomer acrylic acid (AAc). Traditionally pNIPAm microgels are synthesized in the presence of a crosslinking agent, such as N,N'-methylenebisacrylamide (BIS), however, microgels can also be synthesized under 'crosslinker free' conditions. The resulting particles have extremely low (<0.5%), core-localized crosslinking resulting from rare chain transfer reactions. AFM nanoindentation of these ultralow crosslinked (ULC) particles indicate that they are soft relative to crosslinked microgels, with a Young's modulus of ∼10 kPa. Furthermore, ULC microgels are highly deformable as indicated by a high degree of spreading on glass surfaces and the ability to translocate through nanopores significantly smaller than the hydrodynamic diameter of the particles. The size and charge of ULCs can be easily modulated by altering reaction conditions, such as temperature, monomer, surfactant and initiator concentrations, and through the addition of co-monomers. Microgels based on the widely utilized, biocompatible polymer polyethylene glycol (PEG) can also be synthesized under crosslinker free conditions. Due to their softness and deformability, ULC microgels are a unique base material for a wide variety of biomedical applications including biomaterials for drug delivery and regenerative medicine.

Preparation and Characterization of Hydrogels Fabricated From Chitosan and Poly(vinyl alcohol) for Tissue Engineering Applications.

In this study, we report on the preparation, characterization, and cytocompatibility of hydrogels for biomedical applications made from two different molecular weights of chitosan (CS) blended with poly(vinyl alcohol) (PVA) and chemically cross-linked with tetraethyl orthosilicate (TEOS) followed by freeze-drying. A series of CS-PVA hydrogels were synthesized with different amounts of chitosan (1%, 2%, and 3% by weight). The structure of these CS-PVA hydrogels was characterized by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The hydrogel samples were also characterized for tensile strength, contact angle, swelling behavior, and degradation at physiological body temperature. Their physicochemical properties, biocompatibility, and cell viability when cultured with human dermal fibroblasts were assessed using alamarBlue and live/dead assays and compared to optimize their functionality. SEM analysis showed that the concentration and molecular weight of the chitosan component affected the pore size. Furthermore, the contact angle decreased with increasing chitosan content, indicating that chitosan increased its hydrophilic properties. The in vitro degradation study revealed a nonlinear time-dependent relationship between chitosan concentration or molecular weight, and the rate of degradation was affected by the pore size of the hydrogel. All of the CS-PVA hydrogels exhibited good cell proliferation, particularly with the high molecular weight chitosan samples.

Wound-triggered shape change microgels for the development of enhanced biomimetic function platelet-like particles.

Platelets play a pivotal role in hemostasis and wound healing and conditional shape change is an important component of platelet functionality. In normal circumstances, platelets travel through the circulatory system in an inactive rounded state, which enables platelets to easily move to vessel walls for attachment. When an injury occurs, platelets are prompted by molecules, such as thrombin, to shift into a stellate shape and increase exposure of fibrin-binding receptors. When active, platelets promote hemostasis and clot retraction, which enhances clot stability and promotes healing. However, in conditions where platelets are depleted or hyporeactive, these functions are diminished and lead to inhibited hemostasis and healing. To treat platelet depletion, our group developed platelet-like particles (PLPs) which consist of highly deformable microgels coupled to fibrin binding motif. However, first generation PLPs do not exhibit wound-triggered shape change like native platelets. Thus, the objective of these studies was to develop a PLP formulation that changes shape when prompted by thrombin. To create thrombin-sensitive PLPs (TS-PLPs), we incorporated a thrombin-cleavable peptide into the microgel body and then evaluated PLP properties before and after exposure to thrombin including morphology, size, and in vitro clot retraction. Once thrombin-prompted shape change ability was confirmed, the TS-PLPs were tested in vivo for hemostatic ability and subsequent wound healing outcomes in a murine liver trauma model. We found that TS-PLPs exhibit a wound-triggered shape change, induce significant clot retraction following exposure to thrombin and promote hemostasis and healing in vivo after trauma.

Clot-Targeted Nanogels for Dual-Delivery of AntithrombinIII and Tissue Plasminogen Activator to Mitigate Disseminated Intravascular Coagulation Complications.

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.

Evidence of a Sjögren's disease-like phenotype following COVID-19 in mice and humans.

Sjögren's Disease (SjD) is a systemic autoimmune disease characterized by lymphocytic inflammation of the lacrimal and salivary glands (SG), dry eyes and mouth, and systemic symptoms. SARS-CoV-2 may trigger the development or progression of autoimmune diseases. To test this, we used a mouse model of SARS-CoV-2 infection and convalescent patients' blood and SG in order to understand the development of SjD-like autoimmunity after infection. First, SARS-CoV-2-infected human angiotensin-converting enzyme 2 (ACE2) transgenic mice exhibited decreased salivation, elevated antinuclear antibodies (ANA), and lymphocytic infiltration in the lacrimal and SG. The sera from patients with COVID-19 sera showed increased ANA (i.e., anti-SSA [Sjögren's-syndrome-related antigen A]/anti-Ro52 and anti-SSB [SS-antigen B]/anti-La). Male patients showed elevated anti-SSA compared with female patients, and female patients exhibited diverse ANA patterns. SG biopsies from convalescent COVID-19 patients were microscopically similar to SjD SG with focal lymphocytic infiltrates in 4 of 6 patients and 2 of 6 patients exhibiting focus scores of at least 2. Lastly, monoclonal antibodies produced in recovered patients blocked ACE2/spike interaction and cross-reacted with nuclear antigens. Our study shows a direct association between SARS-CoV-2 and SjD. Hallmark features of SjD-affected SGs were histologically indistinguishable from convalescent COVID-19 patients. The results implicate that SARS-CoV-2 could be an environmental trigger for SjD.

Elucidating the combinatorial effect of substrate stiffness and surface viscoelasticity on cellular phenotype.

Cells maintain tensional homeostasis by monitoring the mechanics of their microenvironment. In order to understand this mechanotransduction phenomenon, hydrogel materials have been developed with either controllable linear elastic or viscoelastic properties. Native biological tissues, and biomaterials used for medical purposes, often have complex mechanical properties. However, due to the difficulty in completely decoupling the elastic and viscous components of hydrogel materials, the effect of complex composite materials on cellular responses has largely gone unreported. Here, we characterize a novel composite hydrogel system capable of decoupling and individually controlling both the bulk stiffness and surface viscoelasticity of the material by combining polyacrylamide (PA) gels with microgel thin films. By taking advantage of the high degree of control over stiffness offered by PA gels and viscoelasticity, in terms of surface loss tangent, of microgel thin films, it is possible to study the influence that bulk substrate stiffness and surface loss tangent have on complex fibroblast responses, including cellular and nuclear morphology and gene expression. This material system provides a facile method for investigating cellular responses to complex material mechanics with great precision and allows for a greater understanding of cellular mechanotransduction mechanisms than previously possible through current model material platforms.

On-demand, remote and lossless manipulation of biofluid droplets.

The recent global outbreaks of epidemics and pandemics have shown us that we are severely under-prepared to cope with infectious agents. Exposure to infectious agents present in biofluids (e.g., blood, saliva, urine etc.) poses a severe risk to clinical laboratory personnel and healthcare workers, resulting in hundreds of millions of hospital-acquired and laboratory-acquired infections annually. Novel technologies that can minimize human exposure through remote and automated handling of infectious biofluids will mitigate such risk. In this work, we present biofluid manipulators, which allow on-demand, remote and lossless manipulation of virtually any liquid droplet. Our manipulators are designed by integrating thermo-responsive soft actuators with superomniphobic surfaces. Utilizing our manipulators, we demonstrate on-demand, remote and lossless manipulation of biofluid droplets. We envision that our biofluid manipulators will not only reduce manual operations and minimize exposure to infectious agents, but also pave the way for developing inexpensive, simple and portable robotic systems, which can allow point-of-care operations, particularly in developing nations.

Plasma-Induced Diallyldimethylammonium Chloride Antibacterial Hernia Mesh.

A hernia is a pathological condition caused by a defect or opening in the muscle wall, which leads to organs pushing through the opening or defect. Hernia recurrence, seroma, persistent pain, tissue adhesions, and wound infection are common complications following hernia repair surgery. Infection after hernia mesh implantation is the third major complication leading to hernia recurrence. In order to reduce the incidence of late infections, we developed a polypropylene mesh with antibacterial properties. In this study, knitted polypropylene meshes were exposed to radio-frequency plasma to activate their surfaces. The antibacterial monomer diallyldimethylammonium chloride (DADMAC) was then grafted onto the mesh surface using pentaerythritol tetraacrylate as the cross-linker since it is able to engage all four functional groups to form a high-density cross-linked network. The subsequent antibacterial performance showed a 2.9 log reduction toward Staphylococcus aureus and a 0.9 log reduction for Escherichia coli.

Fibrin-modulating nanogels for treatment of disseminated intravascular coagulation.

Disseminated intravascular coagulation (DIC) is a pathological coagulopathy associated with infection that increases mortality. In DIC, excessive thrombin generation causes symptoms from formation of microthrombi to multiorgan failure; bleeding risks can also be a concern because of clotting factor consumption. Different clinical events lead to DIC, including sepsis, trauma, and shock. Treatments for thrombotic episodes or bleeding presentation in DIC oppose each other, thus creating therapeutic dilemmas in management. The objective of this study was to develop fibrin-specific core-shell nanogels (FSNs) loaded with tissue-type plasminogen activator (tPA) to treat the microcirculatory complications of DIC, which would facilitate targeted clot dissolution to manage microthrombi and the potential consumptive coagulopathy that causes bleeding. FSNs enhance formation of actively polymerizing clots by crosslinking fibrin fibers, but they can also target preexisting microthrombi and, when loaded with tPA, facilitate targeted delivery to lyse the microthrombi. We hypothesized that this dual action would simultaneously address bleeding and microthrombi with DIC to improve outcomes. In vivo, tPA-FSNs decreased the presentation of multiorgan microthrombi, recovered platelet counts, and improved bleeding outcomes in a DIC rodent model. When incorporated with human DIC patient plasma, tPA-FSNs restored clot structure and clot growth under flow. Together, these data demonstrate that a fibrinolytic agent loaded into fibrin-targeting nanogels could improve DIC outcomes.