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More than 90% of surgical patients develop postoperative adhesions, and the incidence of hospital re-admissions can be as high as 20%. Current adhesion barriers present limited efficacy due to difficulties in application and incompatibility with minimally invasive interventions. To solve this clinical limitation, we developed an injectable and sprayable shear-thinning hydrogel barrier (STHB) composed of silicate nanoplatelets and poly(ethylene oxide). We optimized this technology to recover mechanical integrity after stress, enabling its delivery though injectable and sprayable methods. We also demonstrated limited cell adhesion and cytotoxicity to STHB compositions in vitro. The STHB was then tested in a rodent model of peritoneal injury to determine its efficacy preventing the formation of postoperative adhesions. After two weeks, the peritoneal adhesion index was used as a scoring method to determine the formation of postoperative adhesions, and STHB formulations presented superior efficacy compared to a commercially available adhesion barrier. Histological and immunohistochemical examination showed reduced adhesion formation and minimal immune infiltration in STHB formulations. Our technology demonstrated increased efficacy, ease of use in complex anatomies, and compatibility with different delivery methods, providing a robust universal platform to prevent postoperative adhesions in a wide range of surgical interventions.

The replacement of small-diameter arteries remains an unmet clinical need. Here we investigated the cellular remodeling of fibrotic conduits as vascular grafts. The formation of fibrotic conduit around subcutaneously implanted mandrels involved not only fibroblasts but also the trans-differentiation of inflammatory cells such as macrophages into fibroblastic cells, as shown by genetic lineage tracing. When fibrotic conduits were implanted as vascular grafts, the patency was low, and many fibrotic cells were found in neointima. Decellularization and anti-thrombogenic coating of fibrotic conduits produced highly patent autografts that remodeled into neoarteries, offering an effective approach to obtain autografts for clinical therapy. While autografts recruited mostly anti-inflammatory macrophages for constructive remodeling, allogenic DFCs had more T cells and pro-inflammatory macrophages and lower patency. Endothelial progenitors and endothelial migration were observed during endothelialization. Cell infiltration into DFCs was more efficient than decellularized arteries, and infiltrated cells remodeled the matrix and differentiated into smooth muscle cells (SMCs). This work provides insight into the remodeling of fibrotic conduits, autologous DFCs and allogenic DFCs, and will have broad impact on using fibrotic matrix for regenerative engineering.

BackgroundVascular grafts are widely used as a treatment in coronary artery bypass surgery, hemodialysis, peripheral arterial bypass and congenital heart disease. Various types of synthetic and natural materials were experimented to produce tissue engineering vascular grafts. In this study, we investigated in vivo tissue engineering technology in miniature pigs to prepare decellularized autologous extracellular matrix-based grafts that could be used as vascular grafts for small-diameter vascular bypass surgery.MethodsAutologous tissue conduits (3.9 mm in diameter) were fabricated by embedding Teflon tubings in the subcutaneous pocket of female miniature pigs (n = 8, body weight 25-30 kg) for 4 weeks. They were then decellularized by CHAPS decellularization solution. Heparin was covalently-linked to decellularized tissue conduits by Sulfo-NHS/EDC. We implanted these decellularized, completely autologous extracellular matrix-based grafts into the carotid arteries of miniature pigs, then sacrificed the pigs at 1 or 2 months after implantation and evaluated the patency rate and explants histologically.ResultsAfter 1 month, the patency rate was 100% (5/5) while the inner diameter of the grafts was 3.43 ± 0.05 mm (n = 5). After 2 months, the patency rate was 67% (2/3) while the inner diameter of the grafts was 2.32 ± 0.14 mm (n = 3). Histological staining confirmed successful cell infiltration, and collagen and elastin deposition in 2-month samples. A monolayer of endothelial cells was observed along the inner lumen while smooth muscle cells were dominant in the graft wall.ConclusionA completely autologous acellular conduit with excellent performance in mechanical properties can be remodeled into a neoartery in a minipig model. This proof-of-concept study in the large animal model is very encouraging and indicates that this is a highly feasible idea worthy of further study in non-human primates before clinical translation.

Background and Aims Valve interstitial cells (VICs) undergo a transition to intermediate state cells before ultimately transforming into the osteogenic cell population, which is a pivotal cellular process in calcific aortic valve disease (CAVD). Herein, this study successfully delineated the stages of VIC osteogenic transformation and elucidated a novel key regulatory role of lumican (LUM) in this process. Methods Single-cell RNA-sequencing (scRNA-seq) from nine human aortic valves was used to characterize the pathological switch process and identify key regulatory factors. The in vitro , ex vivo , in vivo , and double knockout mice were constructed to further unravel the calcification-promoting effect of LUM. Moreover, the multi-omic approaches were employed to analyse the molecular mechanism of LUM in CAVD. Results ScRNA-seq successfully delineated the process of VIC pathological transformation and highlighted the significance of LUM as a novel molecule in this process. The pro-calcification role of LUM is confirmed on the in vitro , ex vivo , in vivo level, and ApoE−/−//LUM−/− double knockout mice. The LUM induces osteogenesis in VICs via activation of inflammatory pathways and augmentation of cellular glycolysis, resulting in the accumulation of lactate. Subsequent investigation has unveiled a novel LUM driving histone modification, lactylation, which plays a role in facilitating valve calcification. More importantly, this study has identified two specific sites of histone lactylation, namely, H3K14la and H3K9la, which have been found to facilitate the process of calcification. The confirmation of these modification sites' association with the expression of calcific genes Runx2 and BMP2 has been achieved through ChIP-PCR analysis. Conclusions The study presents novel findings, being the first to establish the involvement of lumican in mediating H3 histone lactylation, thus facilitating the development of aortic valve calcification. Consequently, lumican would be a promising therapeutic target for intervention in the treatment of CAVD. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the impact of the donor−recipient BMI ratio on the survival outcomes of heart transplant recipients. Methods: A retrospective analysis was conducted on 641 heart transplant patients who underwent surgery between September 2008 and June 2021. The BMI ratio (donor BMI divided by recipient BMI) was calculated for each patient. Kaplan−Meier survival analysis and Cox proportional hazards regression were performed to evaluate survival rates and determine the hazard ratio (HR) for mortality. Results: Significant differences were found in donor age and donor−recipient height ratio between the BMI ratio groups. The BMI ratio ≥ 1 group had a higher mean donor age (37.27 ± 10.54 years) compared to the BMI ratio < 1 group (34.72 ± 11.82 years, p = 0.008), and a slightly higher mean donor−recipient height ratio (1.02 ± 0.06 vs. 1.00 ± 0.05, p = 0.002). The Kaplan−Meier survival analysis indicated that the survival rate in the BMI ratio ≥ 1 group was significantly lower than in the BMI ratio < 1 group. Cox multivariate analysis, adjusted for confounding factors, revealed a HR of 1.50 (95% CI: 1.08−2.09) for mortality in patients with a BMI ratio ≥ 1. No significant differences were observed in ICU stay, postoperative hospitalization days, or total mechanical ventilation time between the groups. Conclusion: A higher donor−recipient BMI ratio was associated with an increased risk of mortality in heart transplant recipients. [ABSTRACT FROM AUTHOR]

Background and purposeMaternal cigarette smoking increases the risk of cardiovascular disease in offspring. Recently, we have demonstrated that perinatal nicotine exposure alters heart development and increases heart susceptibility to ischemia/reperfusion (I/R) injury in rat offspring. The present study tested the hypothesis that DNA methylation plays a key role in the nicotine-induced development of heart ischemia-sensitive phenotype in offspring.Experimental approachNicotine was administered to pregnant rats via subcutaneous osmotic minipumps from gestational day 4 until postnatal day 10. After birth, the postnatal offspring were treated with the DNA methylation inhibitor, 5-aza-2'-deoxycytidine (5-Aza) or saline from postnatal day 3 to day 10. Experiments were conducted in 1 month old offspring.Key resultsPerinatal nicotine increased I/R-induced left ventricular (LV) injury, and decreased post-ischemic recovery of the LV function and coronary flow rate in both male and female offspring. Nicotine differentially increased DNMT3a expression and global DNA methylation levels in LV tissues. Treatment with 5-Aza inhibited nicotine-induced an increase in DNMT3a and global DNA methylation, and blocked the nicotine-induced increase in I/R injury and dysfunction in the heart. In addition, nicotine attenuated protein kinases Cε and large-conductance Ca(2+)-activated K(+) (BKca) channel β1 subunit protein abundances in the heart, which were reversed by 5-Aza treatment.Conclusions and implicationsThe present findings provide novel evidence that the increased DNA methylation plays a causal role in nicotine-induced development of heart ischemic sensitive phenotype, and suggest a potential therapeutic target of DNA demethylation for the fetal programming of heart ischemic disease later in life.

Small-diameter synthetic vascular grafts have high failure rate due to primarily surface thrombogenicity, and effective surface chemical modification is critical to maintain the patency of the grafts. In this study, we engineered a small-diameter, elastic synthetic vascular graft with off-the-shelf availability and anti-thrombogenic activity. Polycarbonate-urethane (PCU), was electrospun to produce nanofibrous grafts that closely mimicked a native blood vessel in terms of structural and mechanical strength. To overcome the difficulty of adding functional groups to PCU, we explored various surface modification methods, and determined that plasma treatment was the most effective method to modify the graft surface with functional amine groups, which were subsequently employed to conjugate heparin via end-point immobilization. In addition, we confirmed in vitro that the combination of plasma treatment and end-point immobilization of heparin exhibited the highest surface density and correspondingly the highest anti-thrombogenic activity of heparin molecules. Furthermore, from an in vivo study using a rat common carotid artery anastomosis model, we showed that plasma-heparin grafts had higher patency rate at 2weeks and 4weeks compared to plasma-control (untreated) grafts. More importantly, we observed a more complete endothelialization of the luminal surface with an aligned, well-organized monolayer of endothelial cells, as well as more extensive graft integration in terms of vascularization and cell infiltration from the surrounding tissue. This work demonstrates the feasibility of electrospinning PCU as synthetic elastic material to fabricate nanofibrous vascular grafts, as well as the potential to endow desired functionalization to the graft surface via plasma treatment for the conjugation of heparin or other bioactive molecules.Statement of significanceVascular occlusion remains the leading cause of death all over the world, despite advances made in balloon angioplasty and conventional surgical intervention. Currently, autografts are the gold-standard grafts used to treat vascular occlusive disease. However, many patients with vascular occlusive disease do not have autologous vascular graft available. Therefore, there is a widely recognized need for a readily available, functional, small-diameter vascular graft (inner diameter of