Designing Microneedle Patch for Prophylaxis of Postoperative Atrial Fibrillation.

Postoperative atrial fibrillation (POAF) is a common complication following cardiac surgery, which often occurs within 30 postoperative days, especially peaking at 2-3 days. Antiarrhythmic medications such as amiodarone are recommended in clinical practice for the prophylaxis and treatment of POAF. However, conventional oral administration is hindered due to delayed drug action and high risks of systemic toxicity, and emerging localized delivery strategies suffer from a limited release duration (less than 30 days). Herein, we develop a microneedle (MN) patch for localized delivery of amiodarone to the atria in a "First Rapid and Then Sustained" dual-release mode. Specifically, this patch is composed of a needle array integrated with an amiodarone-loaded reservoir for a sustained and steady release for over 30 days; and an amiodarone-containing coating film deposited on the needle surface via the Langmuir-Blodgett technique for a rapid release at the first day. Upon this design, only one MN patch enables a higher drug accumulation in the atrial tissue at the first day than oral administration and simultaneously remains therapeutical levels for over 30 days, despite at a significantly reduced drug dosage (5.08 mg in total versus ∼10 mg per day), thereby achieving ideal preventive effects and safety in a rat model. Our findings indicate that this MN device provides a robust and efficient delivery platform for long-term prophylaxis of POAF.

Soft-tissue sound-speed-aware ultrasound-CT registration method for computer-assisted orthopedic surgery.

Ultrasound (US) has been introduced to computer-assisted orthopedic surgery for bone registration owing to its advantages of nonionizing radiation, low cost, and noninvasiveness. However, the registration accuracy is limited by US image distortion caused by variations in the acoustic properties of soft tissues. This paper proposes a soft-tissue sound-speed-aware registration method to overcome the above challenge. First, the feature enhancement strategy of multi-channel overlay is proposed for U2-net to improve bone segmentation performance. Secondly, the sound speed of soft tissue is estimated by simulating the bone surface distance map for the update of US-derived points. Finally, an iterative registration strategy is adopted to optimize the registration result. A phantom experiment was conducted using different registration methods for the femur and tibia/fibula. The fiducial registration error (femur, 0.98 ± 0.08 mm (mean ± SD); tibia/fibula, 1.29 ± 0.19 mm) and the target registration error (less than 2.11 mm) showed the high accuracy of the proposed method. The experimental results suggest that the proposed method can be integrated into navigation systems that provide surgeons with accurate 3D navigation information.

Advances in Polymeric Micelles: Responsive and Targeting Approaches for Cancer Immunotherapy in the Tumor Microenvironment.

In recent years, to treat a diverse array of cancer forms, considerable advancements have been achieved in the field of cancer immunotherapies. However, these therapies encounter multiple challenges in clinical practice, such as high immune-mediated toxicity, insufficient accumulation in cancer tissues, and undesired off-target reactions. To tackle these limitations and enhance bioavailability, polymer micelles present potential solutions by enabling precise drug delivery to the target site, thus amplifying the effectiveness of immunotherapy. This review article offers an extensive survey of recent progress in cancer immunotherapy strategies utilizing micelles. These strategies include responsive and remodeling approaches to the tumor microenvironment (TME), modulation of immunosuppressive cells within the TME, enhancement of immune checkpoint inhibitors, utilization of cancer vaccine platforms, modulation of antigen presentation, manipulation of engineered T cells, and targeting other components of the TME. Subsequently, we delve into the present state and constraints linked to the clinical utilization of polymeric micelles. Collectively, polymer micelles demonstrate excellent prospects in tumor immunotherapy by effectively addressing the challenges associated with conventional cancer immunotherapies.

Minimally Invasive Valve Replacement for Late Tricuspid Regurgitation After Left-Sided Valve Surgery.

Late severe tricuspid regurgitation after left-sided valve surgery can negatively affect long-term prognosis and quality of life. Because of extensive surgical trauma and poor right heart function, perioperative mortality after reoperation for tricuspid regurgitation historically remained high. A number of minimally invasive techniques were adopted at our center recently, including endoscopy-assisted right minithoracotomy, vacuum-assisted single femoral venous drainage without dissecting or snaring vena cava, direct right atriotomy through pericardium, and the beating-heart technique. Moreover, the tricuspid valves were replaced with bioprostheses in the majority of those patients at our center. The midterm outcomes of minimally invasive bioprosthetic tricuspid valve replacement were favorable.

Suppression of microRNA-155 exerts an anti-inflammatory effect on CD4+ T cell-mediated inflammatory response in the pathogenesis of atherosclerosis.

In the current study, we aimed to investigate the effects of miR-155 on CD4+ T cell-mediated immune response in the pathogenesis of atherosclerosis. CD34+ hematopoietic stem cells, CD4+ T lymphocytes, endothelial cells (ECs), and vascular smooth muscle cells (VSMCs) were harvested from the same donor. Knockdown of miR-155 in the CD4+ T cells was achieved by lentiviral transfection, whereas control RNA-transfected or untransfected lymphocytes were used as controls. The transfected CD4+ T cells were activated by incubating with oxidized low-density lipoprotein-treated dendritic cells. The proliferative capacities, phenotype distribution, and cytokine secretion profiles of the activated CD4+ T cells from different groups were evaluated. The activated lymphocytes were used to treat ECs co-cultivated with VSMCs. The ability of the CD4+ T cells to induce the apoptosis of the ECs and to promote the proliferation of the VSMCs was investigated. Inhibition of miR-155 was found to significantly reduce the proliferation rate of the transfected CD4+ T cells. CD4+ T lymphocytes transfected with the miR-155 inhibitor showed increased populations of T helper type 2 and regulatory T cells, as well as more production of anti-inflammatory cytokines. MiR-155 knockdown was also shown to significantly hamper the ability to CD4+ T cells to induce EC apoptosis and to promote the growth of VSMCs. Our data suggested that inhibition of miR-155 in CD4+ T cells could slow down the formation of atherosclerotic plaques. These results lay the groundwork for future research on the therapeutic potential of miR-155 against atherosclerosis-associated cardiovascular diseases.

Postoperative hypothermia after total aortic arch replacement in acute type A aortic dissection-multivariate analysis and risk identification for postoperative hypothermia occurrence.

BACKGROUND: Postoperative hypothermia (PH) is a common physiological abnormality associated with increased morbidity and mortality after non-cardiac surgery. The incidence, risk factors of PH and its impact on early outcomes after total aortic arch replacement are not clear. METHODS: We conducted a retrospective cohort study in patients with acute type A aortic dissection who underwent total arch replacement from January 2013 to December 2016 at our institution. Basic variables, procedural and postoperative early outcomes were collected. Univariate and multivariate statistical analysis were performed for statistical interpretation. The early outcomes were compared between patients with or without PH. RESULTS: A total of 300 patients (age 53.8±11.5 years, female 63, 21.0%) with acute type A aortic dissection underwent total arch replacement. Forty-four patients (14.7%) developed PH. The independent risk factors of PH are age and the intraoperative lowest bladder temperature. There is no significant difference in major postoperative morbidity and mortality between patients with or without PH. CONCLUSIONS: The incidence of PH after total arch replacement in acute type A aortic dissection is relatively low. The independent risk factors of PH in this population include age and the intraoperative lowest bladder temperature. With comprehensive rewarming strategy upon arrival at the ICU, the PH is easy to be corrected, and the adverse effect of transient PH on early outcomes after arch surgery is minimal.

The assembly of protein-templated gold nanoclusters for enhanced fluorescence emission and multifunctional applications.

Protein-templated gold nanoclusters have attracted attention in fluorescence imaging due to their simple synthesis and good biocompatibility. However, limitations still exist such as poor colloid stability and undesirable fluorescence intensity. Here we describe the self-assembly of keratin-templated gold nanoclusters via a simple and mild preparation process, including keratin-templated synthesis of gold nanoclusters (AuNCs@Keratin), silver ions modification of AuNCs@Keratin (AuNCs-Ag@Keratin), and gadolinium ions-induced aggregation of AuNCs-Ag@Keratin (AuNCs-Ag@Keratin-Gd). It was demonstrated that the AuNCs-Ag@Keratin-Gd obtained an enhanced fluorescence intensity (6.5 times that of AuNCs@Keratin), high colloid stability for more than 4 months, and good biocompatibility. Moreover, the AuNCs-Ag@Keratin-Gd holds promise in multifunctional applications such as near-infrared (NIR) fluorescence imaging, magnetic resonance (MR) imaging, and redox-responsive drug delivery, extending the applicability of fluorescent gold nanoclusters, especially in biomedical fields. STATEMENT OF SIGNIFICANCE: Assembly-induced fluorescence enhancement has been rarely reported on as it relates to the protein-templated gold nanoclusters (AuNCs). In this work, self-assembly of protein-templated AuNCs was developed for enhanced fluorescence intensity and multifunctional applications, including bioimaging and responsive drug delivery. A cysteine-rich protein, keratin, was utilized as the template to synthesize AuNCs, which underwent silver ion modification and gadolinium ion-induced aggregation. The silver modification of the keratin-templated AuNCs facilitated the formation of a dense aggregate after gadolinium ion-induced assembly, thus generating an enhanced fluorescence intensity. Such a mechanism was confirmed by fluorescence correlation spectroscopy analysis. We believe that this work will extend the applicability of the fluorescent gold nanoclusters, especially in biomedical fields, and provided an effective approach for the mechanism analysis of the assembly-induced fluorescence enhancement via fluorescence correlation spectroscopy.

Engineering human ventricular heart tissue based on macroporous iron oxide scaffolds.

Myocardial infarction (MI) is a primary cardiovascular disease threatening human health and quality of life worldwide. The development of engineered heart tissues (EHTs) as a transplantable artificial myocardium provides a promising therapy for MI. Since most MIs occur at the ventricle, engineering ventricular-specific myocardium is therefore more desirable for future applications. Here, by combining a new macroporous 3D iron oxide scaffold (IOS) with a fixed ratio of human pluripotent stem cell (hPSC)-derived ventricular-specific cardiomyocytes and human umbilical cord-derived mesenchymal stem cells, we constructed a new type of engineered human ventricular-specific heart tissue (EhVHT). The EhVHT promoted expression of cardiac-specific genes, ion exchange, and exhibited a better Ca2+ handling behaviors and normal electrophysiological activity in vitro. Furthermore, when patched on the infarcted area, the EhVHT effectively promoted repair of heart tissues in vivo and facilitated the restoration of damaged heart function of rats with acute MI. Our results show that it is feasible to generate functional human ventricular heart tissue based on hPSC-derived ventricular myocytes for the treatment of ventricular-specific myocardium damage. STATEMENT OF SIGNIFICANCE: We successfully generated highly purified homogenous human ventricular myocytes and developed a method to generate human ventricular-specific heart tissue (EhVHT) based on three-dimensional iron oxide scaffolds. The EhVHT promoted expression of cardiac-specific genes, ion exchange, and exhibited a better Ca2+ handling behaviors and normal electrophysiological activity in vitro. Patching the EhVHT on the infarct area significantly improved cardiac function in rat acute MI models. This EhVHT has a great potential to meet the specific requirements for ventricular damages in most MI cases and for screening drugs specifically targeting ventricular myocardium.

Controlled-releasing hydrogen sulfide donor based on dual-modal iron oxide nanoparticles protects myocardial tissue from ischemia-reperfusion injury.

BACKGROUND: Hydrogen sulfide (H2S) has shown promising therapeutic benefits in reversing a variety of pathophysiological processes in cardiovascular system, including myocardial ischemia-reperfusion (IR) injury. However, the achievement of controlled and sustained release of H2S has been a technical bottleneck that limits the clinical application of the gas molecule. METHODS: The current study describes the development of mesoporous iron oxide nanoparticles (MIONs) which were loaded with diallyl trisulfide (DATS), a H2S donor compound, and calibrated by stimulated Raman scattering/transient absorption. RESULTS: The synthesized MIONs were characterized with excellent mesoporosity and a narrow size distribution, which enabled them to slow down the release of H2S to a suitable rate and prolong the plateau period. The controlled-release feature of DATS-MIONs resulted in little adverse effect both in vitro and in vivo, and their protective effect on the heart tissue that underwent IR injury was observed in the mouse model of myocardial ischemia. The rapid biodegradation of DATS-MIONs was induced by Kupffer cells, which were specialized macrophages located in the liver and caused limited hepatic metabolic burden. CONCLUSION: The sustained-release pattern and excellent biocompatibility make DATS-MIONs a promising H2S donor for research and medical purposes.

Donor heart preservation with a novel long-term and slow-releasing hydrogen sulfide system.

Cardiac transplantation has been limited by the inability to long preserve donor hearts safely. Hydrogen sulfide (H2S) has been recognized as an important gasotransmitter exerting potent cardioprotection from ischemia/reperfusion injury (I/R). Herein we investigated the cardioprotective effects of a novel long-term and slow-releasing H2S system, namely DATS-MSN, in heart preservation solution using a heart transplantation models. The release of H2S from DATS-MSN was slow and continuous in the University of Wisconsin solution (UW), correspondingly, DATS-MSN application demonstrated superior cardioprotective effects over the control and traditional H2S donors after 6 h heart preservation and 1 h reperfusion, associated with greater allograft performance including left ventricular developed pressure (LVDP) and dP/dt max, reduced plasmic CK-MB and troponin I levels, inhibited myocardial inflammation, increased antioxidant enzyme activities, preserved mitochondria structure and function, and decreased cardiomyocyte apoptosis index. Also, DATS-MSN application presented significant superiority in long-term allografts survival and function after 8 weeks of transplantation. In the in vitro experiments, cardiomyocytes injury from hypoxia was found to be relived with the treatment of DATS-MSN by anti-inflammatory effects via TLR4/NLRP3 pathway. The present work provides a long-term releasing H2S donor compatibly applied in the donor heart preservation, and preliminary explores its underlying mechanisms.

Recent Progress in Isolation and Detection of Extracellular Vesicles for Cancer Diagnostics.

Extracellular vesicles (EVs) are emerging as one of the many new and promising biomarkers for liquid biopsy of cancer due to their loading capability of some specific proteins and nucleic acids that are closely associated with cancer states. As such, the isolation and detection of cancer-derived EVs offer important information in noninvasive diagnosis of early-stage cancer and real-time monitoring of cancer development. In light of the importance of EVs, over the last decade, researchers have made remarkable innovations to advance the development of EV isolation and detection methods by taking advantage of microfluidics, biomolecule probes, nanomaterials, surface plasmon, optics, and so on. This review introduces the basic properties of EVs and common cancer-derived EV ingredients, and provides a comprehensive overview of EV isolation and detection strategies, with emphasis on liquid biopsies of EVs for cancer diagnostics.

Frosted Slides Decorated with Silica Nanowires for Detecting Circulating Tumor Cells from Prostate Cancer Patients.

Developing low-cost and highly efficient nanobiochips are important for liquid biopsies, real-time monitoring, and precision medicine. By in situ growth of silica nanowires on a commercial frosted slide, we develop a biochip for effective circulating tumor cells (CTCs) detection after modifying epithelial cell adhesion molecule antibody (anti-EpCAM). The biochip shows the specificity and high capture efficiency of 85.4 ± 8.3% for prostate cancer cell line (PC-3). The microsized frosted slides and silica nanowires allow enhanced efficiency in capture EpCAM positive cells by synergistic topographic interactions. And the capture efficiency of biochip increased with the increase of silica nanowires length on frosted slide. The biochip shows that micro/nanocomposite structures improve the capture efficiency of PC-3 more than 70% toward plain slide. Furthermore, the nanobiochip has been successfully applied to identify CTCs from whole blood specimens of prostate cancer patients. Thus, this frosted slide-based biochip may provide a cheap and effective way of clinical monitoring of CTCs.

Transapical transcatheter aortic valve replacement for aortic regurgitation with a second-generation heart valve.

OBJECTIVE: To report on the Chinese multicenter study of the J-Valve transcatheter heart valve for treatment of predominant aortic regurgitation. METHODS: Transapical transcatheter aortic valve replacement with the J-Valve for treating high-risk severe aortic regurgitation was performed in 43 patients in 3 Chinese centers. The study was registered with the Chinese Clinical Trial Registry (ChiCTR-OPC-15006354). Procedural results and clinical outcomes up to 1-year were analyzed using Valve Academic Research Consortium 2 criteria. RESULTS: All patients (mean age, 73.9 ± 5.7 years) were considered at prohibitive or high risk for surgical valve replacement (logistic European System for Cardiac Operative Risk Evaluation, 20.0% to 44.4%; mean, 25.5% ± 5.3%) after evaluation by an interdisciplinary heart team. Transapical implantation was successful in 42 patients (97.7%). The 1-year outcomes included all-cause mortality (4.7%), disabling stroke (2.3%), new permanent pacemaker (4.7%), and valve-related reintervention (7.0%). At the 1-year follow-up, postprocedural paravalvular regurgitation was none/trace in 30 of 39 patients and mild in 8 of 39 patients, and the mean transvalvular gradient after valve implantation was favorable at 10.4 ± 4.5 mm Hg. CONCLUSIONS: After an initial demonstration of feasibility, this multicenter study shows that the J-Valve transcatheter heart valve system is a reasonable option for patients with predominant aortic regurgitation.

Implantable and Biodegradable Macroporous Iron Oxide Frameworks for Efficient Regeneration and Repair of Infracted Heart.

The construction, characterization and surgical application of a multilayered iron oxide-based macroporous composite framework were reported in this study. The framework consisted of a highly porous iron oxide core, a gelatin-based hydrogel intermediary layer and a matrigel outer cover, which conferred a multitude of desirable properties including excellent biocompatibility, improved mechanical strength and controlled biodegradability. The large pore sizes and high extent of pore interconnectivity of the framework stimulated robust neovascularization and resulted in substantially better cell viability and proliferation as a result of improved transport efficiency for oxygen and nutrients. In addition, rat models with myocardial infraction showed sustained heart tissue regeneration over the infract region and significant improvement of cardiac functions following the surgical implantation of the framework. These results demonstrated that the current framework might hold great potential for cardiac repair in patients with myocardial infraction.

Bioinspired Pollen-Like Hierarchical Surface for Efficient Recognition of Target Cancer Cells.

The efficient recognition and isolation of rare cancer cells holds great promise for cancer diagnosis and prognosis. In nature, pollens exploit spiky structures to realize recognition and adhesion to stigma. Herein, a bioinspired pollen-like hierarchical surface is developed by replicating the assembly of pollen grains, and efficient and specific recognition to target cancer cells is achieved. The pollen-like surface is fabricated by combining filtering-assisted assembly and soft lithography-based replication of pollen grains of wild chrysanthemum. After modification with a capture agent specific to cancer cells, the pollen-like surface enables the capture of target cancer cells with high efficiency and specificity. In addition, the pollen-like surface not only assures high viability of captured cells but also performs well in cell mixture system and at low cell density. This study represents a good example of constructing cell recognition biointerfaces inspired by pollen-stigma adhesion.

A Strategy for Precise Treatment of Cardiac Malignant Neoplasms.

The prevalence of cardiac malignant neoplasms in the general population has been shown to be significant higher than what was previously estimated, yet their treatment has remained difficult and effective therapies are lacking. In the current study, we developed a novel thermotherapy in which PEG-functionalized carbon nanotubes were injected into the tumor regions to assist in the targeted delivery of infrared radiation energy with minimal hyperthermic damage to the surrounding normal tissues. In a mouse model of cardiac malignant neoplasms, the injected carbon nanotubes could rapidly induce coagulative necrosis of tumor tissues when exposed to infrared irradiation. In accordance, the treatment was also found to result in a restoration of heart functions and a concomitant increase of survival rate in mice. Taken together, our carbon nanotube-based thermotherapy successfully addressed the difficulty facing conventional laser ablation methods with regard to off-target thermal injury, and could pave the way for the development of more effective therapies against cardiac malignant neoplasms.

Efficient Capture of Cancer Cells by Their Replicated Surfaces Reveals Multiscale Topographic Interactions Coupled with Molecular Recognition.

Cell-surface topographic interactions can direct the design of biointerfaces, which have been widely used in isolation of circulating tumor cells or fundamental cell biological research. By using three kinds of cancer cell-replicated surfaces with differentiated structures, we uncover that multiscale-cooperative topographic interactions (at both nanoscale and microscale) coupled with molecular recognition enable efficient and specific isolation of cancer cells. The cell replicas precisely inherit the structural features from the original cancer cells, providing not only preferable structures for matching with cancer cells but also a unique platform to interrogate whether certain cancer cells can optimally match with their own replicated surfaces. The results reveal that cancer cells do not show preferential recognitions to their respective replicas, while the capture agent-modified surfaces with hierarchical structures exhibit improved cancer cell capture efficiencies. Two levels of topographic interactions between cancer cells and cell replica surfaces exist. Nanoscale filopodia on cancer cells can topographically interact with different nanostructures on replica surfaces. In addition, microscale concave/convex on surfaces provide suitable sites for trapping cancer cells. This study may promote smart design of multiscale biofunctional materials that can specifically recognize cancer cells.

Light-Triggered Specific Cancer Cell Release from Cyclodextrin/Azobenzene and Aptamer-Modified Substrate.

Cell adhesion behaviors of stimuli-responsive surfaces have attracted significant attention for their potential biomedical applications. Distinct from temperature and pH stimuli, photoswitching avoids the extra input of thermal energy or chemicals. Herein, we designed a novel reusable cyclodextrin (CD)-modified surface to realize photoswitched specific cell release utilizing host-guest interactions between CD and azobenzene. The azobenzene-grafted specific cell capture agent was assembled onto the CD-modified surface to form a smart surface controlling cell adhesion by light radiation. After UV light irradiation, the azobenzene switched from trans- to cis-isomers, and the cis-azobenzene was not recognized by CD due to the unmatched host-guest pairs; thus, the captured MCF-7 cells could be released. Light-triggered specific cancer cell release with high efficiency may afford a smart surface with significant potential applications for the isolation and analysis of circulating tumor cells.

Photoswitched Cell Adhesion on Azobenzene-Containing Self-Assembled Films.

Stimuli-responsive surfaces that can regulate and control cell adhesion have attracted much attention for their great potential in diverse biomedical applications. Unlike for pH- and temperature-responsive surfaces, the process of photoswitching requires no additional input of chemicals or thermal energy. In this work, two different photoresponsive azobenzene films are synthesized by chemisorption and electrostatic layer-by-layer (LbL) assembly techniques. The LbL film exhibits a relatively loose packing of azobenzene chromophores compared with the chemisorbed film. The changes in trans/cis isomer ratio of the azobenzene moiety and the corresponding wettability of the LbL films are larger than those of the chemisorbed films under UV light irradiation. The tendency for cell adhesion on the LbL films decreases markedly after UV light irradiation, whereas adhesion on the chemisorbed films decreases only slightly, because the azobenzene chromophores stay densely packed. Interestingly, the tendency for cell adhesion can be considerably increased on rough substrates, the roughness being introduced by use of photolithography and inductively coupled plasma deep etching techniques. For the chemisorbed films on rough substrates, the amount of cells that adhere also changes slightly after UV light irradiation, whereas, the amount of cells that adhere to LbL films on rough substrates decreases significantly.