Structurally constrained and pathology-aware convolutional transformer generative adversarial network for virtual histology staining of human coronary optical coherence tomography images.

Significance: There is a significant need for the generation of virtual histological information from coronary optical coherence tomography (OCT) images to better guide the treatment of coronary artery disease (CAD). However, existing methods either require a large pixel-wise paired training dataset or have limited capability to map pathological regions. Aim: The aim of this work is to generate virtual histological information from coronary OCT images, without a pixel-wise paired training dataset while capable of providing pathological patterns. Approach: We design a structurally constrained, pathology-aware, transformer generative adversarial network, namely structurally constrained pathology-aware convolutional transformer generative adversarial network (SCPAT-GAN), to generate virtual stained H&E histology from OCT images. We quantitatively evaluate the quality of virtual stained histology images by measuring the Fréchet inception distance (FID) and perceptual hash value (PHV). Moreover, we invite experienced pathologists to evaluate the virtual stained images. Furthermore, we visually inspect the virtual stained image generated by SCPAT-GAN. Also, we perform an ablation study to validate the design of the proposed SCPAT-GAN. Finally, we demonstrate 3D virtual stained histology images. Results: Compared to previous research, the proposed SCPAT-GAN achieves better FID and PHV scores. The visual inspection suggests that the virtual histology images generated by SCPAT-GAN resemble both normal and pathological features without artifacts. As confirmed by the pathologists, the virtual stained images have good quality compared to real histology images. The ablation study confirms the effectiveness of the combination of proposed pathological awareness and structural constraining modules. Conclusions: The proposed SCPAT-GAN is the first to demonstrate the feasibility of generating both normal and pathological patterns without pixel-wisely supervised training. We expect the SCPAT-GAN to assist in the clinical evaluation of treating the CAD by providing 2D and 3D histopathological visualizations.

Clinical characteristics and outcomes of patients requiring prolonged mechanical circulatory support after high-risk percutaneous coronary intervention.

BACKGROUND: There are limited data on the clinical characteristics and outcomes of patients who require prolonged mechanical circulatory support (MCS) after Impella-supported high-risk percutaneous coronary intervention (HR-PCI). AIMS: The aim of this study is to describe the contemporary clinical characteristics, outcomes, and predictors associated with prolonged MCS support after assisted HR-PCI. METHODS: Patients enrolled in the prospective, multicentre, clinical endpoint-adjudicated PROTECT III study who had undergone HR-PCI using Impella were evaluated. Patient and procedural characteristics and outcomes for those who received prolonged MCS beyond the duration of their index procedure were compared to those in whom MCS was successfully weaned and explanted at the conclusion of the index PCI. RESULTS: Among 1,155 patients who underwent HR-PCI with Impella between 2017 and 2020 and had sufficient data to confirm the duration of Impella support, 16.5% received prolonged MCS (mean duration 25.2±31.1 hours compared with 1.8±5.8 hours for those who only received intraprocedural MCS). Patients receiving prolonged support presented with more urgent indications (e.g., acute coronary syndromes [ACS], lower ejection fraction [EF], elevated baseline heart rate and lower systolic blood pressure). Use of the Impella CP, intraprocedural complications, periprocedural complications and in-hospital mortality were all more common amongst the prolonged MCS group. Prolonged MCS was associated with increased rates of major adverse cardiovascular and cerebrovascular events, cardiovascular death, and all-cause mortality at 90-day follow-up. CONCLUSIONS: Patients receiving prolonged MCS after Impella-supported HR-PCI presented with more ACS, reduced EF and less favourable haemodynamics. Additionally, they were more likely to experience intraprocedural and periprocedural complications as well as increased in-hospital and post-discharge mortality.

Atherosclerotic three-layer nanomatrix vascular sheets for high-throughput therapeutic evaluation.

In vitro atherosclerosis models are essential to evaluate therapeutics before in vivo and clinical studies, but significant limitations remain, such as the lack of three-layer vascular architecture and limited atherosclerotic features. Moreover, no scalable 3D atherosclerosis model is available for making high-throughput assays for therapeutic evaluation. Herein, we report an in vitro 3D three-layer nanomatrix vascular sheet with critical atherosclerosis multi-features (VSA), including endothelial dysfunction, monocyte recruitment, macrophages, extracellular matrix remodeling, smooth muscle cell phenotype transition, inflammatory cytokine secretion, foam cells, and calcification initiation. Notably, we present the creation of high-throughput functional assays with VSAs and the use of these assays for evaluating therapeutics for atherosclerosis treatment. The therapeutics include conventional drugs (statin and sirolimus), candidates for treating atherosclerosis (curcumin and colchicine), and potential gene therapy (miR-146a-loaded liposomes). The high efficiency and flexibility of the scalable VSA functional assays should facilitate drug discovery and development for atherosclerosis.

Randomized trial of an oblique versus standard fluoroscopic-guided micropuncture technique for femoral arterial access: The Micropuncture-CFA trial.

BACKGROUND: The anterior-posterior fluoroscopic guidance (the AP technique) is a standard method for common femoral artery (CFA) access, but the rate of CFA access with ultrasound vs. the AP technique was not significantly different. We have shown an oblique fluoroscopic guidance (the oblique technique) with a micropuncture needle (MPN) resulted in CFA access in 100 % of patients. The outcome of the oblique vs. AP technique is unknown. We compared the utilities of the oblique vs. AP technique for CFA access with a MPN in patients undergoing coronary procedures. METHODS: A total of 200 patients were randomized to the oblique vs. AP technique. Using the oblique technique, a MPN was advanced to the mid pubis in the 20° ipsilateral right-or left anterior oblique view with fluoroscopic guidance and the CFA was punctured. In the AP technique, a MPN was advanced to the mid femoral head in the AP view with fluoroscopic guidance and the CFA was punctured. The primary endpoint was the rate of successful access to the CFA. RESULTS: The rates of first pass and CFA access were higher with the oblique vs. AP technique (82 % vs. 61 %, and 94 % vs. 81 %, respectively; P < 0.01). The number of needle punctures was lower with the oblique vs. AP technique (1.1 ± 0.39 vs. 1.4 ± 0.78, respectively; P < 0.01). In high CFA bifurcations, the rate of CFA access was higher with the oblique vs. AP technique (76 % vs. 52 %, respectively; P < 0.01). Vascular complications were lower with the oblique vs. AP technique (1 % vs. 7 %, respectively; P < 0.05). CONCLUSIONS: Our data suggest that the oblique technique, compared with the AP technique, significantly increased the rates of first pass and access to the CFA, and decreased the number of punctures and vascular complication. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03955653.

Multilevel Assessment of Stent-Induced Inflammation in the Adjacent Vascular Tissue.

A recent U.S. Food and Drug Administration report presented the currently available scientific information related to biological response to metal implants. In this work, a multilevel approach was employed to assess the implant-induced and biocorrosion-related inflammation in the adjacent vascular tissue using a mouse stent implantation model. The implications of biocorrosion on peri-implant tissue were assessed at the macroscopic level via in vivo imaging and histomorphology. Elevated matrix metalloproteinase activity, colocalized with the site of implantation, and histological staining indicated that stent surface condition and implantation time affect the inflammatory response and subsequent formation and extent of neointima. Hematological measurements also demonstrated that accumulated metal particle contamination in blood samples from corroded-stetted mice causes a stronger immune response. At the cellular level, the stent-induced alterations in the nanostructure, cytoskeleton, and mechanical properties of circulating lymphocytes were investigated. It was found that cells from corroded-stented samples exhibited higher stiffness, in terms of Young's modulus values, compared to noncorroded and sham-stented samples. Nanomechanical modifications were also accompanied by cellular remodeling, through alterations in cell morphology and stress (F-actin) fiber characteristics. Our analysis indicates that surface wear and elevated metal particle contamination, prompted by corroded stents, may contribute to the inflammatory response and the multifactorial process of in-stent restenosis. The results also suggest that circulating lymphocytes could be a novel nanomechanical biomarker for peri-implant tissue inflammation and possibly the early stage of in-stent restenosis. Large-scale studies are warranted to further investigate these findings.

A multi-targeting bionanomatrix coating to reduce capsular contracture development on silicone implants.

BACKGROUND: Capsular contracture is a critical complication of silicone implantation caused by fibrotic tissue formation from excessive foreign body responses. Various approaches have been applied, but targeting the mechanisms of capsule formation has not been completely solved. Myofibroblast differentiation through the transforming growth factor beta (TGF-ß)/p-SMADs signaling is one of the key factors for capsular contracture development. In addition, biofilm formation on implants may result chronic inflammation promoting capsular fibrosis formation with subsequent contraction. To date, there have been no approaches targeting multi-facted mechanisms of capsular contracture development. METHODS: In this study, we developed a multi-targeting nitric oxide (NO) releasing bionanomatrix coating to reduce capsular contracture formation by targeting myofibroblast differentiation, inflammatory responses, and infections. First, we characterized the bionanomatrix coating on silicon implants by conducting rheology test, scanning electron microcsopy analysis, nanoindentation analysis, and NO release kinetics evaluation. In addition, differentiated monocyte adhesion and S. epidermidis biofilm formation on bionanomatrix coated silicone implants were evaluated in vitro. Bionanomatrix coated silicone and uncoated silicone groups were subcutaneously implanted into a mouse model for evaluation of capsular contracture development for a month. Fibrosis formation, capsule thickness, TGF-ß/SMAD 2/3 signaling cascade, NO production, and inflammatory cytokine production were evaluated using histology, immunofluorescent imaging analysis, and gene and protein expression assays. RESULTS: The bionanomatrix coating maintained a uniform and smooth surface on the silicone even after mechanical stress conditions. In addition, the bionanomatrix coating showed sustained NO release for at least one month and reduction of differentiated monocyte adhesion and S. epidermidis biofilm formation on the silicone implants in vitro. In in vivo implantation studies, the bionanomatrix coated groups demonstrated significant reduction of capsule thickness surrounding the implants. This result was due to a decrease of myofibroblast differentiation and fibrous extracellular matrix production through inhibition of the TGF-ß/p-SMADs signaling. Also, the bionanomatrix coated groups reduced gene expression of M1 macrophage markers and promoted M2 macrophage markers which indicated the bionanomatrix could reduce inflammation but promote healing process. CONCLUSIONS: In conclusion, the bionanomatrix coating significantly reduced capsular contracture formation and promoted healing process on silicone implants by reducing myfibroblast differentiation, fibrotic tissue formation, and inflammation. A multi-targeting nitric oxide releasing bionanomatrix coating for silicone implant can reduce capsular contracture and improve healing process. The bionanomatrix coating reduces capsule thickness, α-smooth muscle actin and collagen synthesis, and myofibroblast differentiation through inhibition of TGF-ß/SMADs signaling cascades in the subcutaneous mouse models for a month.

Toward reliable calcification detection: calibration of uncertainty in object detection from coronary optical coherence tomography images.

Significance: Optical coherence tomography (OCT) has become increasingly essential in assisting the treatment of coronary artery disease (CAD). However, unidentified calcified regions within a narrowed artery could impair the outcome of the treatment. Fast and objective identification is paramount to automatically procuring accurate readings on calcifications within the artery. Aim: We aim to rapidly identify calcification in coronary OCT images using a bounding box and reduce the prediction bias in automated prediction models. Approach: We first adopt a deep learning-based object detection model to rapidly draw the calcified region from coronary OCT images using a bounding box. We measure the uncertainty of predictions based on the expected calibration errors, thus assessing the certainty level of detection results. To calibrate confidence scores of predictions, we implement dependent logistic calibration using each detection result's confidence and center coordinates. Results: We implemented an object detection module to draw the boundary of the calcified region at a rate of 140 frames per second. With the calibrated confidence score of each prediction, we lower the uncertainty of predictions in calcification detection and eliminate the estimation bias from various object detection methods. The calibrated confidence of prediction results in a confidence error of ∼ 0.13 , suggesting that the confidence calibration on calcification detection could provide a more trustworthy result. Conclusions: Given the rapid detection and effective calibration of the proposed work, we expect that it can assist in clinical evaluation of treating the CAD during the imaging-guided procedure.

MiR-146a encapsulated liposomes reduce vascular inflammatory responses through decrease of ICAM-1 expression, macrophage activation, and foam cell formation.

Vascular insults can create an inflammatory cascade involving endothelial cell, smooth muscle cell, and macrophage activation which can eventually lead to vascular disease such as atherosclerosis. Several studies have identified microRNA 146a's (miR-146a) anti-inflammatory potential based on its role in regulating the nuclear factor kappa beta (NF-κß) pathway. Therefore, in this study, we introduced exogenous miR-146a encapsulated by liposomes to lipopolysaccharide (LPS) stimulated vascular cells and macrophages to reduce inflammatory responses. First, the miR-146a encapsulated liposomes showed uniform size (radius 96.4 ± 4.22 nm) and round shape, long term stability (at least two months), high encapsulation efficiency (69.73 ± 0.07%), and were well transfected to human aortic endothelial cells (HAECs), human aortic smooth muscle cells (SMCs), and human differentiated monocytes (U937 cells). In addition, we demonstrated that miR-146a encapsulated liposomes reduced vascular inflammation responses in HAECs and SMCs through inhibition of ICAM-1 expression and decreased monocyte adhesion. In macrophages, miR-146a liposome treatment demonstrated decreased production of proinflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß), as well as reduced oxidized low-density lipoprotein (ox-LDL) uptake and foam cell formation. Thus, based on these results, miR-146a encapsulated liposomes may be promising for reducing vascular inflammation by targeting its multiple associated mediators.

Pro-Healing Nanomatrix-Coated Stent Analysis in an In Vitro Vascular Double-Layer System and in a Rabbit Model.

Cardiovascular stent technologies have significantly improved over time. However, their optimal performance remains limited by restenosis, thrombosis, inflammation, and delayed re-endothelialization. Current stent designs primarily target inhibition of neointimal proliferation but do not promote functional arterial healing (pro-healing) in order to restore normal vascular reactivity. The endothelial lining that does develop with current stents appears to have loose intracellular junctions. We have developed a pro-healing nanomatrix coating for stents that enhances healing while limiting neointimal proliferation. This builds on our prior work evaluating the effects of the pro-healing nanomatrix coating on cultures of vascular endothelial cells (ECs), smooth muscle cells (SMCs), monocytes, and platelets. However, when a stent is deployed in an artery, multiple vascular cell types interact, and their interactions affect stent performance. Thus, in our current study, an in vitro vascular double-layer (VDL) system was used to observe stent effects on communication between different vascular cell types. Additionally, we assessed the pro-healing ability and vascular cell interactions after stent deployment in the VDL system and in a rabbit model, evaluating the nanomatrix-coated stent compared to a commercial bare metal stent (BMS) and a drug eluting stent (DES). In vitro results indicated that, in a layered vascular structure, the pro-healing nanomatrix-coated stent could (1) improve endothelialization and endothelial functions, (2) regulate SMC phenotype to reduce SMC proliferation and migration, (3) suppress inflammation through a multifactorial manner, and (4) reduce foam cell formation, extracellular matrix remodeling, and calcification. Consistent with this, in vivo results demonstrated that, compared with commercial BMS and DES, this pro-healing nanomatrix-coated stent enhanced re-endothelialization with negligible restenosis, inflammation, or thrombosis. Thus, these findings indicate the unique pro-healing features of this nanomatrix stent coating with superior efficacy over commercial BMS and DES.

Multi-Scale Reconstruction of Undersampled Spectral-Spatial OCT Data for Coronary Imaging Using Deep Learning.

Coronary artery disease (CAD) is a cardiovascular condition with high morbidity and mortality. Intravascular optical coherence tomography (IVOCT) has been considered as an optimal imagining system for the diagnosis and treatment of CAD. Constrained by Nyquist theorem, dense sampling in IVOCT attains high resolving power to delineate cellular structures/features. There is a trade-off between high spatial resolution and fast scanning rate for coronary imaging. In this paper, we propose a viable spectral-spatial acquisition method that down-scales the sampling process in both spectral and spatial domain while maintaining high quality in image reconstruction. The down-scaling schedule boosts data acquisition speed without any hardware modifications. Additionally, we propose a unified multi-scale reconstruction framework, namely Multiscale-Spectral-Spatial-Magnification Network (MSSMN), to resolve highly down-scaled (compressed) OCT images with flexible magnification factors. We incorporate the proposed methods into Spectral Domain OCT (SD-OCT) imaging of human coronary samples with clinical features such as stent and calcified lesions. Our experimental results demonstrate that spectral-spatial down-scaled data can be better reconstructed than data that are down-scaled solely in either spectral or spatial domain. Moreover, we observe better reconstruction performance using MSSMN than using existing reconstruction methods. Our acquisition method and multi-scale reconstruction framework, in combination, may allow faster SD-OCT inspection with high resolution during coronary intervention.

Subcutaneous Administration of a Nitric Oxide-Releasing Nanomatrix Gel Ameliorates Obesity and Insulin Resistance in High-Fat Diet-Induced Obese Mice.

Nitric oxide (NO) is a gaseous signaling molecule, which plays crucial roles in various biological processes, including inflammatory responses, metabolism, cardiovascular functions, and cognitive function. NO bioavailability is reduced with aging and cardiometabolic disorders in humans and rodents. NO stimulates the metabolic rate by increasing the mitochondrial biogenesis and brown fat activation. Therefore, we propose a novel technology of providing exogenous NO to improve the metabolic rate and cognitive function by promoting the development of brown adipose tissue. In the present study, we demonstrate the effects of the peptide amphiphiles-NO-releasing nanomatrix gel (PANO gel) on high-fat diet-induced obesity, insulin resistance, and cognitive functions. Eight-week-old male C57BL/6 mice were subcutaneously injected in the brown fat area with the PANO gel or vehicle (PA gel) every 2 weeks for 12 weeks. The PANO gel-injected mice gained less body weight, improved glucose tolerance, and decreased fasting serum insulin and leptin levels compared with the PA gel-injected mice. Insulin signaling in the muscle, liver, and epididymal white adipose tissue was improved by the PANO gel injection. The PANO gel reduced inflammation, increased lipolysis in the epididymal white adipose tissue, and decreased serum lipids and liver triglycerides. Interestingly, the PANO gel stimulated uncoupled protein 1 gene expression in the brown and beige fat tissues. Furthermore, the PANO gel increased the cerebral blood flow and improved learning and memory abilities. Our results suggest that using the PANO gel to supply exogenous NO is a novel technology to treat metabolic disorders and cognitive dysfunctions.

Nitric oxide releasing nanomatrix gel treatment inhibits venous intimal hyperplasia and improves vascular remodeling in a rodent arteriovenous fistula.

Vascular access is the lifeline for hemodialysis patients and the single most important component of the hemodialysis procedure. Arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis patients, but nearly 60% of AVFs created fail to successfully mature due to early intimal hyperplasia development and poor outward remodeling. There are currently no therapies available to prevent AVF maturation failure. First, we showed the important regulatory role of nitric oxide (NO) on AVF development by demonstrating that intimal hyperplasia development was reduced in an overexpressed endothelial nitric oxide synthase (NOS3) mouse AVF model. This supported the rationale for the potential application of NO to the AVF. Thus, we developed a self-assembled NO releasing nanomatrix gel and applied it perivascularly at the arteriovenous anastomosis immediately following rat AVF creation to investigate its therapeutic effect on AVF development. We demonstrated that the NO releasing nanomatrix gel inhibited intimal hyperplasia formation (more than 70% reduction), as well as improved vascular outward remodeling (increased vein diameter) and hemodynamic adaptation (lower wall shear stress approaching the preoperative level and less vorticity). Therefore, direct application of the NO releasing nanomatrix gel to the AVF anastomosis immediately following AVF creation may enhance AVF development, thereby providing long-term and durable vascular access for hemodialysis.

A New Method to Optimize Stent Deployment by High-Definition Intravascular Ultrasound.

OBJECTIVES: Optimal stent deployment by intravascular ultrasound (IVUS) improves outcome, but it can only be achieved in 50% of patients. We investigated the feasibility and effect of a new method of stent optimization on optimal stent deployment. METHODS: IVUS analyses of 168 coronary segments were performed after angiography-guided stenting (AGS) and stent optimization in 29 patients (30 lesions). Minimum stent area (MSA), stent volume index (SVI), lumen area, external elastic membrane (EEM), and plaque burden (PB) were measured. Stent optimization included post-stent dilation with a balloon sized by high-definition (HD)-IVUS to the distal reference EEM diameter for stent underexpansion or malapposition, and stenting of PB >50% or edge dissection. RESULTS: After AGS, stent deployment was suboptimal in 77% of patients. After stent optimization, MSA and SVI were significantly larger than AGS. Adequate stent expansion - defined as MSA ≥5.4 mm² or ≥90% of distal reference lumen area - was significantly higher after stent optimization vs AGS (87% vs 56%, respectively; P=.02). Optimal stent deployment - a composite of adequate stent expansion, no malapposition, PB <50% at the stent edges, and no edge dissection - was markedly higher after stent optimization vs AGS (87% vs 35%, respectively; P<.01). CONCLUSION: After stent deployment and postdilation, stent results were suboptimal in two-thirds of patients. This simple online stent optimization by HD-IVUS was feasible and resulted in optimal stent deployment in the majority of patients. Randomized studies are warranted to compare the rate of optimal stent deployment and outcomes of this strategy vs other techniques.

Recent advances in nanomaterials for therapy and diagnosis for atherosclerosis.

Atherosclerosis is a chronic inflammatory disease driven by lipid accumulation in arteries, leading to narrowing and thrombosis. It affects the heart, brain, and peripheral vessels and is the leading cause of mortality in the United States. Researchers have strived to design nanomaterials of various functions, ranging from non-invasive imaging contrast agents, targeted therapeutic delivery systems to multifunctional nanoagents able to target, diagnose, and treat atherosclerosis. Therefore, this review aims to summarize recent progress (2017-now) in the development of nanomaterials and their applications to improve atherosclerosis diagnosis and therapy during the preclinical and clinical stages of the disease.

Endothelium-Mimicking Nanomatrix Coating to Enhance Endothelialization after Left Atrial Appendage Closure Device Implantation.

Blood clots (90%) originate from the left atrial appendage (LAA) in non-valvular atrial fibrillation patients and are a major cause of embolic stroke. Long-term anticoagulation therapy has been used to prevent thrombus formation, but its use is limited in patients at a high risk for bleeding complications. Thus, left atrial appendage closure (LAAC) devices for LAA occlusion are well-established as an alternative to the anticoagulation therapy. However, the anticoagulation therapy is still required for at least 45 days post-implantation to bridge the time until complete LAA occlusion by neoendocardium coverage of the device. In this study, we applied an endothelium-mimicking nanomatrix to the LAAC device membrane for delivery of nitric oxide (NO) to enhance endothelialization, with the goal of possibly being able to reduce the duration of the anticoagulation therapy. The nanomatrix was uniformly coated on the LAAC device membranes and provided sustained release of NO for up to 1 month in vitro. In addition, the nanomatrix coating promoted endothelial cell proliferation and reduced platelet adhesion compared to the uncoated device membranes in vitro. The nanomatrix-coated and uncoated LAAC devices were then deployed in a canine LAA model for 22 days as a pilot study. All LAAC devices were not completely covered by neoendocardium 22 days post-implantation. However, histology image analysis showed that the nanomatrix-coated LAAC device had thicker neoendocardium coverage compared to the uncoated device. Therefore, our in vitro and in vivo results indicate that the nanomatrix coating has the potential to enhance endothelialization on the LAAC device membrane, which could improve patient outcomes by shortening the need for extended anticoagulation treatment.

Recent Progress in in vitro Models for Atherosclerosis Studies.

Atherosclerosis is the primary cause of hardening and narrowing arteries, leading to cardiovascular disease accounting for the high mortality in the United States. For developing effective treatments for atherosclerosis, considerable efforts have been devoted to developing in vitro models. Compared to animal models, in vitro models can provide great opportunities to obtain data more efficiently, economically. Therefore, this review discusses the recent progress in in vitro models for atherosclerosis studies, including traditional two-dimensional (2D) systems cultured on the tissue culture plate, 2D cell sheets, and recently emerged microfluidic chip models with 2D culture. In addition, advanced in vitro three-dimensional models such as spheroids, cell-laden hydrogel constructs, tissue-engineered blood vessels, and vessel-on-a-chip will also be covered. Moreover, the functions of these models are also summarized along with model discussion. Lastly, the future perspectives of this field are discussed.

Evaluation of Viscoelastic Properties, Blood Coagulation, and Cellular Responses of a Temperature-Sensitive Gel for Hemostatic Application.

Hemorrhagic blood loss from traumatic injury is the leading cause of death in severe accidents and combat injuries. Treating and stopping blood loss in a timely and effective manner is essential for the survival of the patient. Currently, QuikClot and dry fibrin sealant dressing are well-known approaches for hemostatic treatment. However, these dressings have limitations in slowing blood loss such as being brittle, low blood absorption, and a poor sealant of the injury site. Temperature-sensitive gels may have potential as a platform for delivery of coagulation factors to improve hemostasis and wound sealing in the treatment of traumatic injuries. Here, we developed a temperature-sensitive triblock copolymer (poly ethylene oxide (PEO)-poly propylene oxide (PPO)-poly ethylene oxide (PEO)) containing fibrinogen to promote blood coagulation through gel formation at body temperature. This temperature sensitive solution-to-gel (sol-gel) transition does not require cross-linking agents or UV photoinitiation. We determined that 22 wt % (weight percent) copolymers with and without fibrinogen was the maximum concentration for sol-gel transition at body temperature. Rheology results further confirmed this sol-gel transition of 22 wt % copolymers at body temperature. We showed that fibrinogen itself promoted blood coagulation. Additionally, 22 wt % copolymer with fibrinogen successfully demonstrated stable blood coagulation within the gel compared to 22 wt % copolymer without fibrinogen. Twenty-two weight percent copolymers with and without fibrinogen also exhibited excellent biocompatibility based on cell viability, proliferation, and morphology analysis. In addition, treatment of 22 wt % copolymers did not stimulate pro-inflammatory TNF-α production from differentiated human monocytes. Our results suggest that 22 wt % of a temperature-sensitive copolymer gel containing fibrinogen has great potential as a hemostatic agent stimulating coagulation and providing immediate wound coverage for protection through a sol-gel transition at body temperature.

Effects of Crushed Ticagrelor Versus Eptifibatide Bolus Plus Clopidogrel in Troponin-Negative Acute Coronary Syndrome Patients Undergoing Percutaneous Coronary Intervention: A Randomized Clinical Trial.

Background After a loading dose of ticagrelor, the rate of high on-treatment platelet reactivity remains elevated, which increases periprocedural myocardial infarction and injury. This indicates that faster platelet inhibition with crushed ticagrelor (CTIC) or eptifibatide is needed to reduce high on-treatment platelet reactivity. The efficacy of CTIC versus eptifibatide bolus plus clopidogrel is unknown. Methods and Results A total of 100 P2Y12 naïve, troponin-negative patients with acute coronary syndrome were randomized to CTIC (180 mg) versus eptifibatide bolus (180 µg/kg×2 intravenous boluses) plus clopidogrel (600 mg) at the time of percutaneous coronary intervention. High on-treatment platelet reactivity was markedly higher with CTIC versus eptifibatide bolus plus clopidogrel (42% versus 0%; P<0.001) at 30 minutes and persisted up to 2 hours (12% versus 0%; P=0.01, respectively). Platelet aggregation by adenosine diphosphate dropped faster from baseline with eptifibatide bolus plus clopidogrel versus CTIC (0.5 versus 2 hours, respectively) and was higher with CTIC versus eptifibatide bolus plus clopidogrel at 0.5, 2, and 4 hours after loading dose (53±12% versus 1.3±2%; 35±11% versus 0.34±1.0%; and 23±9% versus 3.5±2%, respectively; P<0.001). Eptifibatide bolus plus clopidogrel, but not CTIC, significantly inhibited platelet aggregation induced by thrombin-receptor activating peptide. Periprocedural myocardial infarction and injury was higher with CTIC versus eptifibatide bolus plus clopidogrel (48% versus 28%, respectively; P=0.035). Post-percutaneous coronary intervention hemoglobin levels were not different between groups. Conclusions Eptifibatide bolus plus clopidogrel led to faster and more potent platelet inhibition than CTIC and reduced periprocedural myocardial infarction and injury in troponin-negative acute coronary syndrome patients undergoing percutaneous coronary intervention, with no significant hemoglobin drop after percutaneous coronary intervention. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02925923.

Risk of Major Adverse Cardiovascular Events and Major Hemorrhage Among White and Black Patients Undergoing Percutaneous Coronary Intervention.

Background Data on racial disparities in major adverse cardiovascular events (MACE) and major hemorrhage (HEM) after percutaneous coronary intervention are limited. Factors contributing to these disparities are unknown. Methods and Results PRiME-GGAT (Pharmacogenomic Resource to Improve Medication Effectiveness-Genotype-Guided Antiplatelet Therapy) is a prospective cohort. Patients aged ≥18 years undergoing percutaneous coronary intervention were enrolled and followed for up to 1 year. Racial disparities in risk of MACE and HEM were assessed using an incident rate ratio. Sequential cumulative adjustment analyses were performed to identify factors contributing to these disparities. Data from 919 patients were included in the analysis. Compared with white patients, black patients (n=203; 22.1% of the cohort) were younger and were more likely to be female, to be a smoker, and to have higher body mass index, lower socioeconomic status, higher prevalence of diabetes mellitus and moderate to severe chronic kidney disease, and presentation with acute coronary syndrome and to undergo urgent percutaneous coronary intervention. The incident rates of MACE (34.1% versus 18.2% per 100 person-years, P<0.001) and HEM (17.7% versus 10.3% per 100 person-years, P=0.02) were higher in black patients. The incident rate ratio was 1.9 (95% CI, 1.3-2.6; P<0.001) for MACE and 1.7 (95% CI, 1.1-2. 7; P=0.02) for HEM. After adjustment for nonclinical and clinical factors, black race was not significantly associated with outcomes. Rather, differences in socioeconomic status, comorbidities, and coronary heart disease severity were attributed to racial disparities in outcomes. Conclusions Despite receiving similar treatment, racial disparities in MACE and HEM still exist. Opportunities exist to narrow these disparities by mitigating the identified contributors.