A mechanical-assisted post-bioprinting strategy for challenging bone defects repair.

Bioprinting that can synchronously deposit cells and biomaterials has lent fresh impetus to the field of tissue regeneration. However, the unavoidable occurrence of cell damage during fabrication process and intrinsically poor mechanical stability of bioprinted cell-laden scaffolds severely restrict their utilization. As such, on basis of heart-inspired hollow hydrogel-based scaffolds (HHSs), a mechanical-assisted post-bioprinting strategy is proposed to load cells into HHSs in a rapid, uniform, precise and friendly manner. HHSs show mechanical responsiveness to load cells within 4 s, a 13-fold increase in cell number, and partitioned loading of two types of cells compared with those under static conditions. As a proof of concept, HHSs with the loading cells show an enhanced regenerative capability in repair of the critical-sized segmental and osteoporotic bone defects in vivo. We expect that this post-bioprinting strategy can provide a universal, efficient, and promising way to promote cell-based regenerative therapy.

Predictors of short-term survival in cardiac valvular surgery patients with intra-aortic balloon pump implantation.

BACKGROUND: Intro-aortic balloon pump (IABP) is widely used in cardiac surgery patients nowadays. This study aimed to analyze the predictor of short-term survival in cardiac valvular surgery patients with intra-aortic balloon pump implantation. METHODS: This was a retrospective study and a total of 102 cardiac valvular surgery patients who received intra-aortic balloon pump implantation were consecutively included. We retrospectively collected the baseline characteristics and short-term outcomes. Baseline characteristics were compared between survivors with non-survivors, and logistic regression was performed to identify predictors for short-term mortality. RESULTS: Among all the patients, there were 71 (69.6%) patients successfully weaned from IABP and survived to discharge, the other 31 (30.4%) patients failed to wean from IABP and died within the first 30 days after surgery. When compared with non-survivors, survivors had a higher proportion of males (62% vs 32.3%, p = 0.006), a lower rate of Atrial fibrillation (38% vs 62%, p < 0.03). After IABP implantation, vasoactive drug use was significantly lower in survivors compared with non-survivors, and survivors showed significant improvements in cardiac function and urine volume. Univariate and multivariate logistic regression analysis indicated that atrial fibrillation and combined use of continuous renal replacement therapy (CRRT) were significant independent predictors for short-term mortality. CONCLUSION: Timely implantation of IABP can improve patients' cardiac and renal function and reduce the dosage of vasoactive drugs. Atrial fibrillation and combined use of CRRT are independent predictors for short-term mortality in patients who underwent cardiac valvular surgery with IABP implantation.

M2b macrophages protect against doxorubicin induced cardiotoxicity via alternating autophagy in cardiomyocytes.

OBJECTIVE: Doxorubicin (DOX) is an anthracycline antibiotic which is widely used for the treatment of various cancers, while the dose-related cardiotoxicity limits its potential therapeutic application. The underlying mechanism of DOX induced cardiotoxicity is complex and remains elusive. Our previous studies have shown that M2b macrophage plays an important role in reducing inflammation due to ischemic reperfusion injury in the myocardium. The purpose of this study was to investigate the potential protective role of M2b macrophages in DOX induced cardiotoxicity. METHODS: In vivo, we conducted DOX induced cardiac injury in C57BL/6 mice and treated them with M2b macrophages. Then, the mice were examined by echocardiography. The heart specimens were harvested for histological examination, transmission electron microscope analysis, and autophagy molecules evaluation. In vitro, HL-1 cardiac cell lines treated with DOX were cocultured with or without M2b macrophages. Then, Autophagy related genes and protein expression were assessed by real-time quantitative PCR and western blot; cell proliferation was assessed by cell counting kit-8. RESULTS: We found that M2b macrophages can improve cardiac function and alleviate cardiac injury in DOX induced cardiac injury mice. M2b macrophages can enhance cardiac autophagy levels both in vivo and in vitro in DOX induced cardiac injury model. In addition, this protective effect can be blocked by an autophagy inhibitor. CONCLUSION: Our study shows that M2b macrophages can help attenuate the DOX induced cardiotoxicity by regulating the autophagy level of cardiomyocytes.

Systolic blood pressure time in target range and long-term outcomes in patients with ischemic cardiomyopathy.

BACKGROUND: The relationship between the degree of systolic blood pressure (SBP) control and outcomes remains unclear in patients with ischemic cardiomyopathy (ICM). Current control metrics may not take into account the potential effects of SBP fluctuations over time on patients. METHODS: This study was a post-hoc analysis of the surgical treatment of ischemic heart failure trial which enrolled 2,136 participants with ICM. Our SBP target range was defined as 110 to 130 mm Hg and the time in target range (TTR) was calculated by linear interpolation. RESULTS: A total of 1,194 patients were included. Compared with the quartile 4 group (TTR 77.87%-100%), the adjusted hazard ratios and 95% confidence intervals of all-cause mortality were 1.32 (0.98-1.78) for quartile 3 group (TTR 54.81%-77.63%), 1.40 (1.03-1.90) for quartile 2 group (TTR 32.59%-54.67%), and 1.53 (1.14-2.04) for quartile 1 group (TTR 0%-32.56%). Per 29.28% (1-SD) decrement in TTR significantly increased the risk of all-cause mortality (1.15 [1.04-1.26]). Similar results were observed in the cardiovascular (CV) mortality and the composite outcome of all-cause mortality plus CV rehospitalization, and in the subgroup analyses of either coronary artery bypass grafting or medical therapy, and different baseline SBP. CONCLUSIONS: In patients with ICM, the higher TTR was significantly associated with decreased risk of all-cause mortality, CV mortality and the composite outcome of all-cause mortality plus CV rehospitalization, regardless of whether the patient received coronary artery bypass grafting or medical therapy, and the level of baseline SBP. TTR may be a surrogate metric of long-term SBP control in patients with ICM.

Machine Learning-Based Risk Model for Predicting Early Mortality After Surgery for Infective Endocarditis.

Background The early mortality after surgery for infective endocarditis is high. Although risk models help identify patients at high risk, most current scoring systems are inaccurate or inconvenient. The objective of this study was to construct an accurate and easy-to-use prediction model to identify patients at high risk of early mortality after surgery for infective endocarditis. Methods and Results A total of 476 consecutive patients with infective endocarditis who underwent surgery at 2 centers were included. The development cohort consisted of 276 patients. Eight variables were selected from 89 potential predictors as input of the XGBoost model to train the prediction model, including platelet count, serum albumin, current heart failure, urine occult blood ≥(++), diastolic dysfunction, multiple valve involvement, tricuspid valve involvement, and vegetation >10 mm. The completed prediction model was tested in 2 separate cohorts for internal and external validation. The internal test cohort consisted of 125 patients independent of the development cohort, and the external test cohort consisted of 75 patients from another center. In the internal test cohort, the area under the curve was 0.813 (95% CI, 0.670-0.933) and in the external test cohort the area under the curve was 0.812 (95% CI, 0.606-0.956). The area under the curve was significantly higher than that of other ensemble learning models, logistic regression model, and European System for Cardiac Operative Risk Evaluation II (all, P<0.01). This model was used to develop an online, open-access calculator (http://42.240.140.58:1808/). Conclusions We constructed and validated an accurate and robust machine learning-based risk model to predict early mortality after surgery for infective endocarditis, which may help clinical decision-making and improve outcomes.

Synthetic Extracellular Matrices as a Toolbox to Tune Stem Cell Secretome.

The application of stem cell-derived secretome in regenerative therapies offers the key advantage that instead of the stem cells, only their effective paracrine compounds are in vivo delivered. Ideally, the secretome can be steered by the culture conditions of the stem cells. So far, most studies use stem cells cultured on stiff plastic substrates, not representative of their native 3D environment. In this study, cells are cultured inside synthetic polyisocyanide (PIC)-based hydrogels, which are minimal, tailorable, and highly reproducible biomimetic matrices. Secretome analysis of human adipose-derived stem cells (multiplex, ELISA) displays that matrix manipulation is a powerful tool to direct the secretome composition. As an example, cells in nonadherent PIC gels secrete increased levels of IL-10 and the conditioned media from 3D culture accelerate wound closure. In all, our PIC-based approach opens the door to dedicated matrix design to engineer the secretome for custom applications.

Near-infrared ratiometric probe with a self-immolative spacer for rapid and sensitive detection of alkaline phosphatase activity and imaging in vivo.

Alkaline phosphatase (ALP), an enzyme that catalyzes the hydrolysis of phosphate groups, is closely associated with many diseases, including bone disease, prostate cancer, and diabetes. Thus, new assays for ALP detection in live cells are needed to better understand its role in related biological processes. In this study, we constructed a novel near-infrared ratiometric fluorescent probe for detecting ALP activity with high sensitivity. The probe uses a new self-immolative mechanism that can achieve a rapid response (within 10 min) to ALP, detected as a spectral shift (from 580 to 650 nm). This method effectively avoids issues related to instrument variability, and the near-infrared fluorescence emission (650 nm) makes it more suitable for biological detection. Moreover, the high sensitivity (14-fold enhancement of the fluorescence ratio F650/F580) and low detection limit (0.89 U L-1) for ALP allows the probe to be adapted to complex biological environments. The assay was successfully performed using serum samples with a linear range of ALP of up to 150 U L-1. We used the developed probe to detect and image endogenous ALP in cells with satisfactory results, and we successfully used the probes to detect changes in endogenous ALP levels in zebrafish caused by drug-induced organ damage.

A near-infrared fluorescent probe for the ratiometric detection and living cell imaging of ß-galactosidase.

ß-Galactosidase (ß-gal) has captured the attention of biologists, chemists, and medical researchers as an important biomarker for cell senescence and primary ovarian cancer. Therefore, many fluorescent probes with visible light emission have been developed for the detection and imaging of ß-gal in living cells. However, near-infrared (NIR) ratiometric probes are more suitable for bioimaging because near-infrared light can effectively avoid the interference of autofluorescence and the ratiometric approach can improve sensitivity and accuracy of the detection. In this work, we designed an NIR ratiometric probe (TMG) for the highly sensitive detection of ß-gal. Using a spontaneous degradation mechanism based on the ICT effect, the change in ratio (F650/F580) exhibited a prominent ß-gal-dependent performance and proved a strong linear response to the activity of ß-gal at an enzyme concentration between 0 and 200 U L-1, with a limit of detection as low as 0.86 U L-1, and the response speed is much faster than the same type of probes previously reported. The probe also revealed an excellent biocompatibility and a large Stokes shift. Moreover, fluorescence microscopy imaging experiments confirmed that this probe could be successfully used for the detection of endogenous ß-gal in living cells. Graphical abstract.

Synthetic Extracellular Matrices with Nonlinear Elasticity Regulate Cellular Organization.

One of the promises of synthetic materials in cell culturing is that control over their molecular structures may ultimately be used to control their biological processes. Synthetic polymer hydrogels from polyisocyanides (PIC) are a new class of minimal synthetic biomaterials for three-dimensional cell culturing. The macromolecular lengths and densities of biofunctional groups that decorate the polymer can be readily manipulated while preserving the intrinsic nonlinear mechanics, a feature commonly displayed by fibrous biological networks. In this work, we propose the use of PIC gels as cell culture platforms with decoupled mechanical inputs and biological cues. For this purpose, different types of cells were encapsulated in PIC gels of tailored compositions that systematically vary in adhesive peptide (GRGDS) density, polymer length, and concentration; with the last two parameters controlling the gel mechanics. Both cancer and smooth muscle cells grew into multicellular spheroids with proliferation rates that depend on the adhesive GRGDS density, regardless of the polymer length, suggesting that for these cells, the biological input prevails over the mechanical cues. In contrast, human adipose-derived stem cells do not form spheroids but rather spread out. We find that the morphological changes strongly depend on the adhesive ligand density and the network mechanics; gels with the highest GRGDS densities and the strongest stiffening response to stress show the strongest spreading. Our results highlight the role of the nonlinear mechanics of the extracellular matrix and its synthetic mimics in the regulation of cell functions.