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IntroductionPrimary pulmonary vein stenosis (PVS) is a rare congenital heart disease that proves to be a clinical challenge due to the rapidly progressive disease course and high rates of treatment complications. PVS intervention is frequently faced with in-stent restenosis and persistent disease progression despite initial venous recanalization with balloon angioplasty or stenting. Alterations in wall shear stress (WSS) have been previously associated with neointimal hyperplasia and venous stenosis underlying PVS progression. Thus, the development of patient-specific three-dimensional (3D)in vitromodels is needed to further investigate the biomechanical outcomes of endovascular and surgical interventions. MethodsIn this study, deidentified computed tomography images from three patients were segmented to generate perfusable phantom models of pulmonary veins before and after catheterization. These 3D reconstructions were 3D printed using a clear resin ink and used in a benchtop experimental setup. Computational fluid dynamic (CFD) analysis was performed on modelsin silicoutilizing Doppler echocardiography data to represent thein vivoflow conditions at the inlets. Particle image velocimetry was conducted using the benchtop perfusion setup to analyze WSS and velocity profiles and the results were compared with those predicted by the CFD model. ResultsOur findings indicated areas of undesirable alterations in WSS before and after catheterization, in comparison with the published baseline levels in the healthyin vivotissues that may lead to regional disease progression. DiscussionThe established patient-specific 3Din vitromodels and the developedin vitro–in silicoplatform demonstrate great promise to refine interventional approaches and mitigate complications in treating patients with primary PVS. 

Abstract Nanomedicine technologies are being developed for the prevention, diagnosis, and treatment of cardiovascular disease (CVD), which is the leading cause of death worldwide. Before delving into the nuances of cardiac nanomedicine, it is essential to comprehend the fundamental sex‐specific differences in cardiovascular health. Traditionally, CVDs have been more prevalent in males, but it is increasingly evident that females also face significant risks, albeit with distinct characteristics. Females tend to develop CVDs at a later age, exhibit different clinical symptoms, and often experience worse outcomes compared to males. These differences indicate the need for sex‐specific approaches in cardiac nanomedicine. This Perspective discusses the importance of considering sex in the safety and therapeutic efficacy of nanomedicine approaches for the prevention, diagnosis, and treatment of CVD. 

Abstract Adhesive tissue engineering scaffolds (ATESs) have emerged as an innovative alternative means, replacing sutures and bioglues, to secure the implants onto target tissues. Relying on their intrinsic tissue adhesion characteristics, ATES systems enable minimally invasive delivery of various scaffolds. This study investigates development of the first class of 3D bioprinted ATES constructs using functionalized hydrogel bioinks. Two ATES delivery strategies, in situ printing onto the adherend versus printing and then transferring to the target surface, are tested using two bioprinting methods, embedded versus air printing. Dopamine‐modified methacrylated hyaluronic acid (HAMA‐Dopa) and gelatin methacrylate (GelMA) are used as the main bioink components, enabling fabrication of scaffolds with enhanced adhesion and crosslinking properties. Results demonstrate that dopamine modification improved adhesive properties of the HAMA‐Dopa/GelMA constructs under various loading conditions, while maintaining their structural fidelity, stability, mechanical properties, and biocompatibility. While directly printing onto the adherend yields superior adhesive strength, embedded printing followed by transfer to the target tissue demonstrates greater potential for translational applications. Together, these results demonstrate the potential of bioprinted ATESs as off‐the‐shelf medical devices for diverse biomedical applications. 

Abstract Vascular cell overgrowth and lumen size reduction in pulmonary vein stenosis (PVS) can result in elevated PV pressure, pulmonary hypertension, cardiac failure, and death. Administration of chemotherapies such as rapamycin have shown promise by inhibiting the vascular cell proliferation; yet clinical success is limited due to complications such as restenosis and off‐target effects. The lack of in vitro models to recapitulate the complex pathophysiology of PVS has hindered the identification of disease mechanisms and therapies. This study integrated 3D bioprinting, functional nanoparticles, and perfusion bioreactors to develop a novel in vitro model of PVS. Bioprinted bifurcated PV constructs are seeded with endothelial cells (ECs) and perfused, demonstrating the formation of a uniform and viable endothelium. Computational modeling identified the bifurcation point at high risk of EC overgrowth. Application of an external magnetic field enabled targeting of the rapamycin‐loaded superparamagnetic iron oxide nanoparticles at the bifurcation site, leading to a significant reduction in EC proliferation with no adverse side effects. These results establish a 3D bioprinted in vitro model to study PV homeostasis and diseases, offering the potential for increased throughput, tunability, and patient specificity, to test new or more effective therapies for PVS and other vascular diseases. 

Abstract 3D bioprinting is revolutionizing the fields of personalized and precision medicine by enabling the manufacturing of bioartificial implants that recapitulate the structural and functional characteristics of native tissues. However, the lack of quantitative and noninvasive techniques to longitudinally track the function of implants has hampered clinical applications of bioprinted scaffolds. In this study, multimaterial 3D bioprinting, engineered nanoparticles (NPs), and spectral photon‐counting computed tomography (PCCT) technologies are integrated for the aim of developing a new precision medicine approach to custom‐engineer scaffolds with traceability. Multiple CT‐visible hydrogel‐based bioinks, containing distinct molecular (iodine and gadolinium) and NP (iodine‐loaded liposome, gold, methacrylated gold (AuMA), and Gd₂O₃) contrast agents, are used to bioprint scaffolds with varying geometries at adequate fidelity levels. In vitro release studies, together with printing fidelity, mechanical, and biocompatibility tests identified AuMA and Gd₂O₃NPs as optimal reagents to track bioprinted constructs. Spectral PCCT imaging of scaffolds in vitro and subcutaneous implants in mice enabled noninvasive material discrimination and contrast agent quantification. Together, these results establish a novel theranostic platform with high precision, tunability, throughput, and reproducibility and open new prospects for a broad range of applications in the field of precision and personalized regenerative medicine. 

The design and fabrication of 3D printed ATESs within vivoadhesion and application potential, shape design capability, as well as accessible and convenient fabrication and application process. 

Vascular restenosis is a major complication in recanalized arteries. Nanoparticles (NPs) have shown great promise as delivery systems in advancing strategies to treat such vascular anomalies. By enabling precise targeting, NPs can overcome the challenges of low drug efficacy and off-target effects. Here we present a biomimetic in vitro platform comprised of 3D bioprinting, nanomaterials, and perfusion technologies, to study the use of NP targeting to address endothelial overgrowth. We bioprinted 3D vascular channels at high fidelity, using gelatin methacrylate as bioink, with artery-like stiffness. Human endothelial cells (ECs) were used to endothelialize the printed channels. GFP-labelled superparamagnetic iron oxide NPs (SPIONs), loaded with the Rapamune anti-proliferative drug, were perfused through the bifurcated artery model at physiological rate. Computational modeling predicted greatest level of alterations in wall shear stress in the conduit’s junction with the artery, identifying this region prone to restenosis. A neodymium disc magnet was embedded in the printed tissue to attract the therapeutic SPIONs to the region of high risk. In vitro dynamic culture was conducted for 2 wks. We assessed cell viability, proliferation, and function using AlamarBlue and immunohistochemistry. Results showed significant targeted effect of NP delivery in reducing EC overgrowth. This platform enables design of precise targeting of therapeutics to treat a variety of cardiovascular diseases at a high spatial and temporal control.