Three dimensional (3D) printing, which consists in the conversion of digital images into a 3D physical model, is a promising and versatile field that, over the last decade, has experienced a rapid ...development in medicine. Cardiovascular medicine, in particular, is one of the fastest growing area for medical 3D printing. In this review, we firstly describe the major steps and the most common technologies used in the 3D printing process, then we present current applications of 3D printing with relevance to the cardiovascular field. The technology is more frequently used for the creation of anatomical 3D models useful for teaching, training, and procedural planning of complex surgical cases, as well as for facilitating communication with patients and their families. However, the most attractive and novel application of 3D printing in the last years is bioprinting, which holds the great potential to solve the ever-increasing crisis of organ shortage. In this review, we then present some of the 3D bioprinting strategies used for fabricating fully functional cardiovascular tissues, including myocardium, heart tissue patches, and heart valves. The implications of 3D bioprinting in drug discovery, development, and delivery systems are also briefly discussed, in terms of in vitro cardiovascular drug toxicity. Finally, we describe some applications of 3D printing in the development and testing of cardiovascular medical devices, and the current regulatory frameworks that apply to manufacturing and commercialization of 3D printed products.
This study was designed to study the behavior of a stent deployed inside human stenotic aortic valves.
Endovascular valved stent (VS) implantation is a promising new therapy for patients with severe ...calcific aortic stenosis (AS). The precise characteristics of stent deployment in humans have been poorly studied so far.
Thirty-five patients with severe AS were included in the study. Sixteen patients (46%) had bicuspid aortic valves. A self-expandable stent specifically designed for VS implantation was deployed intraoperatively inside the aortic valve before surgical aortic valve replacement.
In tricuspid aortic valves, the shape of stent deployment was circular, triangular, or elliptic in 68%, 21%, or 11%, respectively. Noncircular stent deployment was frequent in bicuspid aortic valves (the elliptic deployment being the rule 79%), and stent underdeployment was constant. The incidence of gaps between the stent external surface and the aortic valve did not differ between tricuspid and bicuspid valves (58% vs. 43%; p = 0.49). Sharp calcific excrescences protruding inside the stent lumen were present in 3 cases (9%). Ex vivo study of a homemade VS confirmed that the regularity of the coaptation line of the leaflets was critically dependent on the presence or the absence of stent misdeployment.
Stent misdeployment was constant in bicuspid valves and occurred in one-third of cases of tricuspid valves. Premature failure of implanted VS (secondary to valve distortion or traumatic injury to the leaflets by calcific excrescences) might be an important concern in the future.
No significant time-dependent loss was observed after initiating the support (Figure 1A), with the average drop in high-molecular-weight multimer ratio (relative to baseline) reaching 0.97 ± 0.34, ...0.88 ± 0.15, and 0.98 ± 0.01 at 5, 30, 60, and 180 min for all patients (repeated analysis of variance, p > 0.05). All of the membranes demonstrated cells of an endothelial phenotype, confirmed by immunohistochemical positive labeling for vascular endothelial cadherin (data not shown) and the...
Endothelial progenitor cells (EPCs) are involved in vasculogenesis and cardiovascular diseases. However, the phenotype of circulating EPCs remains elusive but they are more often described as CD34
...KDR
. The aim of the study was to extensively characterize circulating potential vasculogenic stem cell candidates in two populations of patients with cardiovascular disease by powerful multidimensional single cell complementary cytometric approaches (mass, imaging and flow). We identified cellular candidates in one patient before and after bioprosthetic total artificial heart implantation and results were confirmed in healthy peripheral and cord blood by mass cytometry. We also quantified cellular candidates in 10 patients with different COVID-19 severity. Both C-TAH implantation and COVID-19 at critical stage induce a redistribution of circulating CD34
and CD19
sub-populations in peripheral blood. After C-TAH implantation, circulating CD34
progenitor cells expressed c-Kit stem marker while specific subsets CD34
CD133
CD45
c-Kit
KDR
were mobilized. KDR was only expressed by CD19
B-lymphocytes and CD14
monocytes subpopulations in circulation. We confirmed by mass cytometry this KDR expression on CD19
in healthy peripheral and cord blood, also with a VE-cadherin expression, confirming absence of endothelial lineage marker on CD34
subtypes. In COVID-19, a significant mobilization of CD34
c-Kit
KDR
cells was observed between moderate and critical COVID-19 patients regardless CD133 or CD45 expression. In order to better evaluate EPC phenotype, we performed imaging flow cytometry measurements of immature CD34
KDR
cells in cord blood and showed that, after elimination of non-circular events, those cells were all CD19
. During COVID-19, a significant mobilization of CD19
KDR
per million of CD45
cells was observed between moderate and critical COVID-19 patients regardless of CD34 expression. CD34
c-Kit
cells are mobilized in both cardiovascular disease described here. KDR cells in peripheral blood are CD19 positive cells and are not classic vasculogenic stem and/or progenitor cells. A better evaluation of c-Kit and KDR expressing cells will lead to the redefinition of circulating endothelial progenitors.Graphical abstract Central illustration figure. Multidimensional proteomic approach of endothelial progenitors demonstrate expression of KDR restricted to CD19 cells. Endothelial progenitor cells (EPCs) are involved in cardiovascular diseases, however their phenotype remains elusive. We elucidated here EPCs phenotype by a deep characterization by multidimensional single cell complementary cytometric approaches after Bioprosthetic total artificial heart implantation and during COVID-19. We showed a redistribution of circulating CD34
and CD19
sub-populations in both situations. None of the immature cell population expresses KDR. Mobilized CD34
expressed c-Kit. Imaging flow cytometry demonstrated that CD34
KDR
cells, after elimination of non-circular events, are all CD19
. Our results suggest a new definition of circulating EPCs and emphasize involvement of CD19 cells in cardiovascular disease.
Abstract The Aeson® total artificial heart (A-TAH) has been developed as a total heart replacement for patients at risk of death from biventricular failure. We previously described endothelialization ...of the hybrid membrane inside A-TAH probably at the origin of acquired hemocompatibility. We aimed to quantify vasculogenic stem cells in peripheral blood of patients with long-term A-TAH implantation. Four male adult patients were included in this study. Peripheral blood mononuclear cells were collected before A-TAH implantation (T0) and after implantation at one month (T1), between two and five months (T2), and then between six and twelve months (T3). Supervised analysis of flow cytometry data confirmed the presence of the previously identified Lin−CD133+CD45− and Lin−CD34+ with different CD45 level intensities. Lin−CD133+CD45−, Lin−CD34+CD45− and Lin−CD34+CD45+ were not modulated after A-TAH implantation. However, we demonstrated a significant mobilization of Lin−CD34+CD45dim (p = 0.01) one month after A-TAH implantation regardless of the expression of CD133 or c-Kit. We then visualized data for the resulting clusters on a uniform manifold approximation and projection (UMAP) plot showing all single cells of the live Lin− and CD34+ events selected from down sampled files concatenated at T0 and T1. The three clusters upregulated at T1 are CD45dim clusters, confirming our results. In conclusion, using a flow cytometry approach, we demonstrated in A-TAH-transplanted patients a significant mobilization of Lin−CD34+CD45dim in peripheral blood one month after A-TAH implantation.Using a flow cytometry approach, we demonstrated in A-TAH transplanted patients a significant mobilization of Lin−CD34+CD45dim in peripheral blood one month after A-TAH implantation. This cell population could be at the origin of newly formed endothelial cells on top of hybrid membrane in Carmat bioprosthetic total artificial heart.
Objectives
To assess the value of effective regurgitant orifice (ERO) in predicting outcome after edge-to-edge transcatheter mitral valve repair (TMVR) for secondary mitral regurgitation (SMR) and ...identify the optimal cut-off for patients’ selection.
Methods
Using the EuroSMR (European Registry of Transcatheter Repair for Secondary Mitral Regurgitation) registry, that included patients undergoing edge-to-edge TMVR for SMR between November 2008 and January 2019 in 8 experienced European centres, we assessed the optimal ERO threshold associated with mortality in SMR patients undergoing TMVR, and compared characteristics and outcomes of patients according to baseline ERO.
Results
Among 1062 patients with severe SMR and ERO quantification by proximal isovelocity surface area method in the registry, ERO was < 0.3 cm
2
in 575 patients (54.1%), who were more symptomatic at baseline (NYHA class ≥ III: 91.4% vs. 86.9%, for ERO < vs. ≥ 0.3 cm
2
;
P
= 0.004). There was no difference in all-cause mortality at 2-year follow-up according to baseline ERO (28.3% vs. 30.0% for ERO < vs. ≥ 0.3 cm
2
,
P
= 0.585). Both patient groups demonstrated significant improvement of at least one NYHA class (61.7% and 73.8%,
P
= 0.002), resulting in a prevalence of NYHA class ≤ II at 1-year follow-up of 60.0% and 67.4% for ERO < vs. ≥ 0.3 cm
2
, respectively (
P
= 0.05).
Conclusion
All-cause mortality at 2 years after TMVR does not differ if baseline ERO is < or ≥ 0.3 cm
2
, and both groups exhibit relevant clinical improvements. Accordingly, TMVR should not be withheld from patients with ERO < 0.3 cm
2
who remain symptomatic despite optimal medical treatment, if TMVR appropriateness was determined by experienced teams in dedicated valve centres.
The CARMAT-Total Artificial Heart (C-TAH) is designed to provide heart replacement therapy for patients with end-stage biventricular failure. This report details the reliability and efficacy of the ...autoregulation device control mechanism (auto-mode), designed to mimic normal physiologic responses to changing patient needs. Hemodynamic data from a continuous cohort of 10 patients implanted with the device, recorded over 1,842 support days in auto-mode, were analyzed with respect to daily changing physiologic needs. The C-TAH uses embedded pressure sensors to regulate the pump output. Right and left ventricular outputs are automatically balanced. The operator sets target values and the inbuilt algorithm adjusts the stroke volume and beat rate, and hence cardiac output, automatically. Auto-mode is set perioperatively after initial postcardiopulmonary bypass hemodynamic stabilization. All patients showed a range of average inflow pressures of between 5 and 20 mm Hg during their daily activities, resulting in cardiac output responses of between 4.3 and 7.3 L/min. Operator adjustments were cumulatively only required on 20 occasions. This report demonstrates that the C-TAH auto-mode effectively produces appropriate physiologic responses reflective of changing patients’ daily needs and represents one of the unique characteristics of this device in providing almost physiologic heart replacement therapy.
To determine hemostasis perturbations, including von Willebrand factor (VWF) multimers, after implantation of a new bioprosthetic and pulsatile total artificial heart (TAH).
Preclinical study
...Single-center biosurgical research laboratory.
Female Charolais calves, 2-to-6 months old, weighing 102-to-122 kg.
Surgical implantation of TAH through a mid-sternotomy approach.
Four of 12 calves had a support duration of several days (4, 4, 8, and 10 days), allowing for the exploration of early steps of hemostasis parameters, including prothrombin time; coagulation factor levels (II, V, VII+X, and fibrinogen); and platelet count. Multimeric analysis of VWF was performed to detect a potential loss of high-molecular weight (HMW) multimers, as previously described for continuous flow rotary blood pumps. Despite the absence of anticoagulant treatment administered in the postoperative phase, no signs of coagulation activation were detected. Indeed, after an immediate postsurgery decrease of prothrombin time, platelet count, and coagulation factor levels, most parameters returned to baseline values. HMW multimers of VWF remained stable either after initiation or during days of support.
Coagulation parameters and platelet count recovery in the postoperative phase of the Carmat TAH (Camat SA, Velizy Villacoublay Cedex, France) implantation in calves, in the absence of anticoagulant treatment and associated with the absence of decrease in HMW multimers of VWF, is in line with early hemocompatibility that is currently being validated in human clinical studies.
OBJECTIVES
The Carmat bioprosthetic total artificial heart (TAH) contains bioprosthetic blood-contacting surfaces, and is designed for orthotopic cardiac replacement. In preparation for clinical ...studies, we evaluated the TAH performance and its effects on end-organ function in an animal model.
METHODS
Twelve female Charolais calves, 2–3 months of age and weighing 102–122 kg, were implanted with the TAH through a mid-sternotomy to ensure an adequate anatomic fit. The intended support duration was 4–10 days. Haematological values, creatinine, bilirubin and lactate levels were measured and mean arterial and central venous pressure, central venous oxygen saturation and TAH parameters were monitored.
RESULTS
The calves were placed in a cage immediately postoperatively, and extubated on postoperative day 1 in most cases. Average support duration was 3 days, with 4 of 12 calves supported for 4, 4, 8 and 10 days. The initial procedures were used to refine surgical techniques and postoperative care. Pump output ranged from 7.3 to 10 l/min. Haemodynamic parameters and blood analysis were within acceptable ranges. No device failures occurred. No anticoagulation was used in the postoperative phase. The calves were euthanized in case of discomfort compromising the animal well-being, such as respiratory dysfunction, severe blood loss and cerebral dysfunction. Device explant analysis showed no thrombus formation inside the blood cavities. Histological examination of kidneys showed isolated micro-infarction in 2/12 animals; brain histology revealed no thromboembolic depositions.
CONCLUSION
The Carmat bioprosthetic TAH implanted in calves up to 10 days provided adequate blood flow to organs and tissues. Low levels of haemolysis and no visible evidence of thromboembolic depositions in major organs and device cavities, without the use of anticoagulation, may indicate early-phase haemocompatibility of the TAH.
The Carmat bioprosthetic total artificial heart (C-TAH) is a biventricular pump developed to minimize drawbacks of current mechanical assist devices and improve quality of life during support. This ...study aims to evaluate the safety of the hybrid membrane, which plays a pivotal role in this artificial heart. We investigated in particular its blood-contacting surface layer of bovine pericardial tissue, in terms of mechanical aging, risks of calcification, and impact of the hemodynamics shear stress inside the ventricles on blood components. Hybrid membranes were aged in a custom-designed endurance bench. Mechanical, physical and chemical properties were not significantly modified from 9 months up to 4 years of aging using a simulating process. Exploration of erosion areas did not show risk of oil diffusion through the membrane. Blood contacting materials in the ventricular cavities were subcutaneously implanted in Wistar rats for 30 days as a model for calcification and demonstrated that the in-house anti-calcification pretreatment with Formaldehyde-Ethanol-Tween 80 was able to significantly reduce the calcium concentration from 132 μg/mg to 4.42 μg/mg (p < 0.001). Hemodynamic simulations with a computational model were used to reproduce shear stress in left and right ventricles and no significant stress was able to trigger hemolysis, platelet activation nor degradation of the von Willebrand factor multimers. Moreover, explanted hybrid membranes from patients included in the feasibility clinical study were analyzed confirming preclinical results with the absence of significant membrane calcification. At last, blood plasma bank analysis from the four patients implanted with C-TAH during the feasibility study showed no residual glutaraldehyde increase in plasma and confirmed hemodynamic simulation-based results with the absence of hemolysis and platelet activation associated with normal levels of plasma free hemoglobin and platelet microparticles after C-TAH implantation. These results on mechanical aging, calcification model and hemodynamic simulations predicted the safety of the hybrid membrane used in the C-TAH, and were confirmed in the feasibility study.
Biomedical engineering; Bioengineering; Biophysics; Cardiology; Haematology; Total artificial heart; Bioprosthetic; Carmat; Hemocompatibility
PDF
