Multiscale analysis of human tissue engineered matrices for next generation heart valve applications.

Human tissue-engineered matrices (hTEMs) have been proposed as a promising approach for in situ tissue engineered heart valves (TEHVs). However, there is still a limited understanding on how ECM composition in hTEMs develops over tissue culture time. Therefore, we performed a longitudinal hTEM assessment by 1) multiscale evaluation of hTEM composition during culture time (2, 4, 6-weeks), using (immuno)histology, biochemical assays, and mass spectrometry (LC-MS/MS); 2) analysis of protein pathways involved in ECM development using gene set enrichment analysis (GSEA); and 3) assessment of hTEM mechanical characterization using uniaxial tensile testing. Finally, as a proof-of-concept, TEHVs manufactured using 6-weeks hTEM samples were tested in a pulse duplicator. LC-MS/MS confirmed the tissue culture time-dependent increase in ECM proteins observed in histology and biochemical assays, revealing the most abundant collagens (COL6, COL12), proteoglycans (HSPG2, VCAN), and glycoproteins (FN, TNC). GSEA identified the most represented protein pathways in the hTEM at 2-weeks (mRNA metabolic processes), 4-weeks (ECM production), and 6-weeks (ECM organization and maturation). Uniaxial mechanical testing showed increased stiffness and stress at failure, and reduction in strain over tissue culture time. hTEM-based TEHVs demonstrated promising in vitro performance at both pulmonary and aortic pressure conditions, with symmetric leaflet coaptation and no stenosis. In conclusion, ECM protein abundance and maturation increased over tissue culture time, with consequent improvement of hTEM mechanical characteristics. These findings suggest that longer tissue culture impacts tissue organization, leading to an hTEM that may be suitable for high-pressure applications. STATEMENT OF SIGNIFICANCE: It is believed that the composition of the extracellular matrix (ECM) in the human tissue engineered matrices (hTEM) may favor tissue engineered heart valve (TEHV) remodeling upon implantation. However, the exact protein composition of the hTEM, and how this impacts tissue mechanical properties, remains unclear. Hence, we developed a reproducible rotation-based tissue culture method to produce hTEM samples. We performed a longitudinal assessment using different analytical techniques and mass spectrometry. Our data provided an in-depth characterization of the hTEM proteome with focus on ECM components, their development, and how they may impact the mechanical properties. Based on these results, we manufactured functional hTEM-based TEHVs at aortic-like condition in vitro. These outcomes pose an important step in translating hTEM-based TEHVs into clinics and in predicting their remodeling potential upon implantation.

[Artificial intelligence in cardiac surgery]. / Künstliche Intelligenz in der Herzchirurgie.

Less than 10 years ago a breakthrough was made in the world of computer science and artificial intelligence (AI) with the application of deep neural networks, which initially found little attention in medicine. In 2017 the first high-ranking publications on the medical application of AI were published. The potential of AI became known to many both in clinical medicine as well as in clinical and biomedical research. At the end of 2019 a phase of upheaval is occurring: first concepts for regulatory procedures have appeared, a large number of start-ups but also established companies are endeavoring to introduce AI-based medical devices into the market. This article discusses the basic principles for understanding AI-based medical devices as well as an overview of current AI-based solutions specific to cardiac surgery.

Cardiovascular tissue engineering: From basic science to clinical application.

Valvular heart disease is an increasing population health problem and, especially in the elderly, a significant cause of morbidity and mortality. The current treatment options, such as mechanical and bioprosthetic heart valve replacements, have significant restrictions and limitations. Considering the increased life expectancy of our aging population, there is an urgent need for novel heart valve concepts that remain functional throughout life to prevent the need for reoperation. Heart valve tissue engineering aims to overcome these constraints by creating regenerative, self-repairing valve substitutes with life-long durability. In this review, we give an overview of advances in the development of tissue engineered heart valves, and describe the steps required to design and validate a novel valve prosthesis before reaching first-in-men clinical trials. In-silico and in-vitro models are proposed as tools for the assessment of valve design, functionality and compatibility, while in-vivo preclinical models are required to confirm the remodeling and growth potential of the tissue engineered heart valves. An overview of the tissue engineered heart valve studies that have reached clinical translation is also presented. Final remarks highlight the possibilities as well as the obstacles to overcome in translating heart valve prostheses into clinical application.

Development of a Novel Human Cell-Derived Tissue-Engineered Heart Valve for Transcatheter Aortic Valve Replacement: an In Vitro and In Vivo Feasibility Study.

Transcatheter aortic valve replacement (TAVR) is being extended to younger patients. However, TAVR-compatible bioprostheses are based on xenogeneic materials with limited durability. Off-the-shelf tissue-engineered heart valves (TEHVs) with remodeling capacity may overcome the shortcomings of current TAVR devices. Here, we develop for the first time a TEHV for TAVR, based on human cell-derived extracellular matrix and integrated into a state-of-the-art stent for TAVR. The TEHVs, characterized by a dense acellular collagenous matrix, demonstrated in vitro functionality under aortic pressure conditions (n = 4). Next, transapical TAVR feasibility and in vivo TEHV functionality were assessed in acute studies (n = 5) in sheep. The valves successfully coped with the aortic environment, showing normal leaflet motion, free coronary flow, and absence of stenosis or paravalvular leak. At explantation, TEHVs presented full structural integrity and initial cell infiltration. Its long-term performance proven, such TEHV could fulfill the need for next-generation lifelong TAVR prostheses.

Organ Chips: Quality Assurance Systems in Regenerative Medicine.

A class of novel therapies leverages regenerative cell types in disease microenvironments. This complex interplay challenges established good manufacturing practices, as standards and analytical tools to measure regenerative potency are missing. That is, we can build the product right, but we do not know if we are building the right product. Here, we suggest that organ-chips, biomimetic in vitro phenotyping platforms, can serve as key quality assurance systems in regenerative medicine.

Delayed two-step free wall rupture of the right and left ventricular wall after myocardial infarction.

We present a 68-year-old female who suffered extensive complications after severe myocardial infarction (MI) in the circumflex (CX) territory. At 24 hours after the initial event, the patient presented with a covered right ventricular free wall rupture (FWR) which was followed by a rupture of the left posterior wall ten days later. We report here on a rare case of delayed two-step biventricular FWR after severe MI in the CX territory.

Relative concentrations of haemostatic factors and cytokines in solvent/detergent-treated and fresh-frozen plasma.

BACKGROUND: Indications, efficacy, and safety of plasma products are highly debated. We compared the concentrations of haemostatic proteins and cytokines in solvent/detergent-treated plasma (SDP) and fresh-frozen plasma (FFP). METHODS: Concentrations of the following parameters were measured in 25 SDP and FFP samples: fibrinogen (FBG), factor (F) II, F V, F VII, F VIII, F IX, F X, F XIII, von Willebrand factor (vWF), D-Dimers, ADAMTS-13 protease, tumour necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, IL-8, and IL-10. RESULTS: Mean FBG concentrations in SDP and FFP were similar, but in FFP, the range was larger than in SDP (P<0.01). Mean F II, F VII, F VIII, F IX, and F XIII levels did not differ significantly. Higher concentrations of F V (P<0.01), F X (P<0.05), vWF (P<0.01), and ADAMTS-13 (P<0.01) were found in FFP. With the exception of F VIII and F IX, the range of concentrations for all of these factors was smaller (P<0.05) in SDP than in FFP. Concentrations of TNF-α, IL-8, and IL-10 (all P<0.01) were higher in FFP than in SDP, again with a higher variability and thus larger ranges (P<0.01). CONCLUSIONS: Coagulation factor content is similar for SDP and FFP, with notable exceptions of less F V, vWF, and ADAMTS-13 in SDP. Cytokine concentrations (TNFα, IL-8, and IL-10) were significantly higher in FFP. The clinical relevance of these findings needs to be established in outcome studies.

Sternal plate closure: indications, surgical procedure and follow-up.

OBJECTIVES: Titanium plate osteosynthesis (Synthes) is an alternative option for sternal closure. The indications and time point of application are still debated. This study investigated the application and feasibility of this technique after median sternotomy. METHODS: Forty-one patients (29 M/12F, mean age 63 ± 17 years) received the plate system for complicated sternal conditions. Indications, intraoperative course and postoperative follow-up were assessed. RESULTS: Sternal deformity was present in 5 % (2/41), sternal fractures in 17 % (7/41), bone defect in 12 % (5/41), wire loosening in 39 % (16/41) and pseudoarthrosis in 27 % (11/41). 54 % (22/41) of patients showed concomitant sternal infection. Two intraoperative complications were noted: mammary artery injury (1 patient), pleural injury (1 patient). At discharge the patients reported no pain (90 %, 37/41) or only occasional discomfort (10 %, 4/41). Postoperative complications were subcutaneous hematoma in 12 % (5/41), seroma in 12 % (5/41) and sternal reinfection in 7 % (3/41). 12 % (5/41) showed occasional discomfort and 7 % (3/41) had persistent pain leading to plate removal. CONCLUSION: The Titanium Sternal Fixation System is comfortable and easy to use. It can be used to treat a wide spectrum of indications, especially for pseudoarthrosis, an entity which has not yet received sufficient attention.

Predictors of adverse neurological outcome following cardiac surgery.

INTRODUCTION: Stroke is a debilitating complication of cardiac surgery. Many intraoperative and postoperative factors predict the likelihood of post-cardiac surgery stroke. We evaluated preoperative parameters, seeking correlations with adverse neurological outcome following cardiac surgery. We investigated the possibility of preoperative carotid ultrasonography to select patients for carotid endarterectomy pre- or intraoperatively. METHODS: We conducted a retrospective analysis of 61 patients who suffered stroke post-cardiac surgery from 2003 to 2006. Data was collected for patient and disease characteristics, preoperative status, intraoperative events and postoperative course. Postoperative neurological complications were subdivided into three groups: mild/temporary events, moderate events such as seizures, and severe events such as stroke. A mild/temporary event was defined as a focal neurological deficit of less than 24 hours in duration. RESULTS: A total of 2,226 cardiac cases were retrospectively evaluated. The frequency of stroke was 61 patients (2.7 percent). The mean age of these patients was 63.7 +/- 7.4 years, and 40 (65.6 percent) were males. Logistic EuroSCORE, left ventricular ejection fraction (as determined by two-dimensional echocardiogram) and aortic cross-clamp time were significantly correlated with postoperative neurological complications, with a p-value of less than 0.05 for all subgroups. There was a significant correlation between the presence of preoperative carotid disease (as proven by pre- and postoperative carotid ultrasonography) and postoperative neurological events (p-value equals 0.033). However, atrial fibrillation did not correlate with postoperative stroke. CONCLUSION: The stage of cardiac disease (risk factor level, ejection fraction and presence of carotid stenosis) correlates with stroke and may predict an adverse neurological outcome.

"When Aneurysm Ain't Aneurysm": sinus of Valsalva aneurysm mimicked by healed abscess cavity under the aortic valve.

In a 70-year-old patient with severe aortic valve stenosis, preoperative standard imaging (transthoracic echocardiography and angiography) detected an unclear subannular cavity structure. Initially interpreted as an aneurysm of Valsalva, the structure was identified intraoperatively as a huge chronic abscess cavity and exclusion was carried out by pericardial patch plasty. This case draws attention to the importance of a differential diagnosis of an abscess due to infective endocarditis in cases of unclear subannular structures rashly diagnosed as aneurysm of Valsalva.