Valvular heart disease is currently treated with mechanical valves, which benefit from longevity, but are burdened by chronic anticoagulation therapy, or with bioprosthetic valves, which have reduced thromboembolic risk, but limited durability. Tissue engineered heart valves have been proposed to resolve these issues by implanting a scaffold that is replaced by endogenous growth, leaving autologous, functional leaflets that would putatively eliminate the need for anticoagulation and avoid calcification. Despite the diversity in fabrication strategies and encouraging results in large animal models, control over engineered valve structure-function remains at best partial. This study aimed to overcome these limitations by introducing double component deposition (DCD), an electrodeposition technique that employs multi-phase electrodes to dictate valve macro and microstructure and resultant function. Results in this report demonstrate the capacity of the DCD method to simultaneously control scaffold macro-scale morphology, mechanics and microstructure while producing fully assembled stent-less multi-leaflet valves composed of microscopic fibers. DCD engineered valve characterization included: leaflet thickness, biaxial properties, bending properties, and quantitative structural analysis of multi-photon and scanning electron micrographs. Quasi-static ex-vivo valve coaptation testing and dynamic organ level functional assessment in a pressure pulse duplicating device demonstrated appropriate acute valve functionality.

After many decades of improvements in mechanical circulatory assist devices (CADs), blood damage remains a serious problem during support contributing to variety of adverse events, and consequently affecting patient survival and quality of life. The mechanisms of cumulative cell damage in continuous-flow blood pumps are still not fully understood despite numerous in vitro, in vivo, and in silico studies of blood trauma. Previous investigations have almost exclusively focused on lethal blood damage, namely hemolysis, which is typically negligible during normal operation of current generation CADs. The measurement of plasma free hemoglobin (plfHb) concentration to characterize hemolysis is straightforward, however sublethal trauma is more difficult to detect and quantify since no simple direct test exists. Similarly, while multiple studies have focused on thrombosis within blood pumps and accessories, sublethal blood trauma and its sequelae have yet to be adequately documented or characterized. This review summarizes the current understanding of sublethal trauma to red blood cells (RBCs) produced by exposure of blood to flow parameters and conditions similar to those within CADs. It also suggests potential strategies to reduce and/or prevent RBC sublethal damage in a clinically-relevant context, and encourages new research into this relatively uncharted territory.

Multilaboratory in vitro blood damage testing was performed on a simple nozzle model to determine how different flow parameters and blood properties affect device-induced hemolysis and to generate data for comparison with computational fluid dynamics-based predictions of blood damage as part of an FDA initiative for assessing medical device safety. Three independent laboratories evaluated hemolysis as a function of nozzle entrance geometry, flow rate, and blood properties. Bovine blood anticoagulated with acid citrate dextrose solution (2–80 h post-draw) was recirculated through nozzle-containing and paired nozzle-free control loops for 2 h. Controlled parameters included hematocrit (36 ± 1.5%), temperature (25°C), blood volume, flow rate, and pressure. Three nozzle test conditions were evaluated (n = 26–36 trials each): (i) sudden contraction at the entrance with a blood flow rate of 5 L/min, (ii) gradual cone at the entrance with a 6-L/min blood flow rate, and (iii) sudden-contraction inlet at 6 L/min. The blood damage caused only by the nozzle model was calculated by subtracting the hemolysis generated by the paired control loop test. Despite high intralaboratory variability, significant differences among the three test conditions were observed, with the sharp nozzle entrance causing the most hemolysis. Modified index of hemolysis (MIHnozzle) values were 0.292 ± 0.249, 0.021 ± 0.128, and 1.239 ± 0.667 for conditions i–iii, respectively. Porcine blood generated hemolysis results similar to those obtained with bovine blood. Although the interlaboratory hemolysis results are only applicable for the specific blood parameters and nozzle model used here, these empirical data may help to advance computational fluid dynamics models for predicting blood damage.

Objective: Anticoagulation may be a challenge in coronavirus disease 2019 (COVID-19) extracorporeal membrane oxygenation due to endothelial injury and dysregulation of coagulation, which may increase the risk of thrombotic and bleeding complications. This report was created to describe the authors' single institutional experience, with emphasis on the high rate of intracranial hemorrhage for the first 10 patients with COVID-19 placed on venovenous extracorporeal membrane oxygenation (VV ECMO). Design: Case series, retrospective analysis. Setting: Single institution. Participants: Ten patients. Interventions: None. Measurements and Main Results: Patient characteristics, mortality, stroke rate, and length of stay data were collected in all patients. In addition, laboratory values of D-dimer and C-reactive protein and standard measurements of prothrombin and activated partial thromboplastin time were collected on all patients. Ten patients, each confirmed with COVID-19 via reverse transcription-polymerase chain reaction, were supported on VV ECMO for acute respiratory distress syndrome (ARDS) for a mean duration of 9.4 § 7 days. Four of 10 patients had hemorrhagic strokes, 3 of which resulted in death. At 30 days after initiation of VV ECMO, a total of 7 survivors included 6 patients discharged from the hospital and 1 patient who remained in the intensive care unit. Conclusions: In this small study of 10 patients, intracranial hemorrhage was a common complication, resulting in a high rate of death. The authors urge caution in the anticoagulation management of VV ECMO for patients with severe ARDS and COVID-19 patients. Close monitoring of all hematologic parameters is recommended during ECMO support while awaiting larger, multicenter studies to examine the best practice.

COVID-19-related coagulopathy is a known complication of SARS-CoV-2 infection and can lead to intracranial hemorrhage (ICH), one of the most feared complications of extracorporeal membrane oxygenation (ECMO). We sought to evaluate the incidence and etiology of ICH in patients with COVID-19 requiring ECMO. Patients at two academic medical centers with COVID-19 who required venovenous-ECMO support for acute respiratory distress syndrome (ARDS) were evaluated retrospectively. During the study period, 33 patients required ECMO support; 16 (48.5%) were discharged alive, 13 died (39.4%), and 4 (12.1%) had ongoing care. Eleven patients had ICH (33.3%). All ICH events occurred in patients who received intravenous anticoagulation. The ICH group had higher C-reactive protein (P ¼ 0.04), procalcitonin levels (P ¼ 0.02), and IL-6 levels (P ¼ 0.05), lower blood pH before and after ECMO (P < 0.01), and higher activated partial thromboplastin times throughout the hospital stay (P < 0.0001). ICH-free survival was lower in COVID-19 patients than in patients on ECMO for ARDS caused by other viruses (49% vs. 79%, P ¼ 0.02). In conclusion, patients with COVID-19 can be successfully bridged to recovery using ECMO but may suffer higher rates of ICH compared to those with other viral respiratory infections.

Bench-top in vitro hemolysis testing is a fundamental tool during the design and regulatory safety evaluation of blood-contacting medical devices. While multiple published experimental protocols exist, descriptions of the test loop reservoir remain ambiguous. A critical fixture within the circuit, there is no readily available blood reservoir that ensures thorough mixing and complete air evacuation: two major factors which can affect results. As part of the Food and Drug Administration (FDA) Critical Path Initiative, we developed a three-piece reservoir consisting of a 3D-printed base, a plastic clamp set, and a medical-grade blood bag. This simple, reusable, and cost-effective design was used successfully in the hemolysis assessment of FDA benchmark nozzles and prototype rotary blood pumps, and may be useful as an integral component to any in vitro blood circulation loop.

Extracorporeal membrane oxygenation (ECMO) is rarely utilized in patients with severe pulmonary hypertension (PH) as a bridge to lung transplantation. In this study we assess the blood biocompatibility of the integrated Centrimag® Novalung ® ECMO system (veno arterial) in an acute model of PH. Severe PH (≥ 2/3 systemic) was induced in eight ovines through progressive ligation of the main pulmonary artery. System performance, platelet activation, thromboelastography parameters, fibrinogen, plasma free hemoglobin, and total plasma protein were measured at initiation, 3 and 6 hrs of support in the ECMO (N=4) and sham (N=4) groups. A stable ECMO flow (2.2 ± 0.1 L/min), low trans-membrane pressure gradient and steady blood O2 and CO2 levels were maintained. Platelet activation was low (< 4%) in both the groups whereas platelet responsiveness to agonist (platelet activating factor) was reduced in the sham group when compared to the ECMO group. There were no differences in the TEG parameters, fibrinogen concentration, plasma free hemoglobin (< 10 mg/dL) and plasma total protein between the two groups. The findings of low levels of platelet activation and plfHb suggest adequate blood biocompatibility of the integrated Centrimag® Novalung® circuit use for short term support in a model of PH.

Ventricular assist devices (VADs) have significantly impacted the treatment of adult cardiac failure, but few options exist for pediatric patients. This has motivated our group to develop an implantable magnetically levitated rotodynamic VAD (PediaFlow®) for 3–20 kg patients. The second prototype design of the PediaFlow (PF2) is 56% smaller than earlier prototypes, and achieves 0.5–1.5 L/min blood flow rates. In vitro hemodynamic performance and hemolysis testing were performed with analog blood and whole ovine blood, respectively. In vivo evaluation was performed in an ovine model to evaluate hemocompatibility and end-organ function. The in vitro normalized index of hemolysis was 0.05–0.14 g/L over the specified operating range. In vivo performance was satisfactory for two of the three implanted animals. A mechanical defect caused early termination at 17 days of the first in vivo study, but two subsequent implants proceeded without complication and electively terminated at 30 and 70 days. Serum chemistries and plasma free hemoglobin were within normal limits. Gross necropsy revealed small, subclinical infarctions in the kidneys of the 30 and 70 day animals (confirmed by histopathology). The results of these experiments, particularly the biocompatibility demonstrated in vivo encourage further development of a miniature magnetically levitated VAD for the pediatric population. Ongoing work including further reduction of size will lead to a design freeze in preparation for of clinical trials.