The effect of ultrasound-assisted thrombolysis studied in blood-on-a-chip.

BACKGROUND: Thromboembolism, which leads to pulmonary embolism and ischemic stroke, remains one of the main causes of death. Ultrasound-assisted thrombolysis (UAT) is an effective thrombolytic method. However, further studies are required to elucidate the mechanism of ultrasound on arterial and venous thrombi. METHODS: We employed the blood-on-a-chip technology to simulate thrombus formation in coronary stenosis and deep vein valves. Subsequently, UAT was conducted on the chip to assess the impact of ultrasound on thrombolysis under varying flow conditions. Real-time fluorescence was used to assess thrombolysis and drug penetration. Finally, scanning electron microscopy and immunofluorescence were used to determine the effect of ultrasound on fibrinolysis. RESULTS: The study revealed that UAT enhanced the thrombolytic rate by 40% in the coronary stenosis chip and by 10% in the deep venous valves chip. This enhancement is attributed to the disruption of crosslinked fibrin fibers by ultrasound, leading to increased urokinase diffusion within the thrombus and accumulation of plasminogen on the fibrinogen α chain. Moreover, the acceleration of the dissolution rate of thrombi in the venous valve chip by ultrasound was not as significant as that in the coronary stenosis chip. CONCLUSION: These findings highlight the differential impact of ultrasound on thrombolysis under various flow conditions and emphasize the valuable role of the blood-on-a-chip technology in exploring thrombolysis mechanisms.

Usefulness of aliasing phenomenon for diagnosing venous valve stenosis of arteriovenous fistula in a hemodialysis patient.

We present venous valve stenosis, which is an uncommon cause of arteriovenous fistula (AVF) dysfunction. Owing to the thin structure in echography, venous valves are challenging to observe; however, we have found that the aliasing phenomenon is useful for diagnosing venous valve stenosis.

Surgical repair of a special category of arteriovenous fistula outflow stenosis caused by venous valve hyperplasia.

OBJECTIVE: This study evaluated a special category of arteriovenous fistula outflow stenosis caused by venous valve hyperplasia and explored the effectiveness of surgical repair in dealing with this kind of stenosis. STUDY DESIGN: This retrospective cohort study was conducted from February 2016 to January 2020 in our center. Patients with arteriovenous fistula dysfunction, including flow rate insufficiency, venous hypertension, thrombosis, and aneurysm dilation enlargement, were selected. Stenosis lesions presenting with venous valve hyperplasia were selected after ultrasound screening. All patients underwent surgical repair and were followed up every 6 months after surgery. RESULTS: Forty-three patients (median age, 54.5 ± 11.2 years; 65.1% men) were included. All procedures were technically successful. Based on intraoperative exploration, 56.5% were reconstructed via autologous vein patch, 17.4% of patients were reconstructed with end-to-end reconstruction after cutting the stenotic segment, 13.0% of cases simply had the valve resected, and 13.0% of cases involved a longitudinal incision and transverse suture. All patients returned to routine dialysis the following day and avoided catheter insertion. The mean follow-up time was 22.5 ± 14.0 (range, 1.3-49.8) months. The patency rates at 2 and 4 years were 92.2% and 79.0%, respectively. Valves harvested from patients were analyzed via Masson staining and immunohistochemical staining, indicating collagen fiber and myofibroblast hyperplasia in outflow venous valve hyperplasia (OVVH). CONCLUSIONS: Outflow venous valve hyperplasia can lead to fistula dysfunction. Ultrasound is the main method to diagnosis OVVH. Special surgical repair can preserve valuable vascular resources and relieve stenosis, is safe and effective, and has a high patency rate.

The perplexity of catheter-directed thrombolysis for deep venous thrombosis: the approaches play an important role.

The recent adjunctive catheter-directed thrombolysis (ATTRACT) trial rose a controversy about the treatment effect of catheter-directed thrombolysis (CDT) in deep venous thrombosis (DVT). In fact, most studies including the ATTRACT trial did not perform subgroup analysis of catheterization approaches. Different approaches would confound the conclusions. Therefore, a single-center retrospective analysis was performed to compare the differences between the antegrade (AGA) and retrograde (RGA) approaches. Total 217 DVT patients treated with CDT were enrolled from January 2010 to December 2017, with mean age of 55.3 years (67 received antegrade approach, 150 received retrograde approach). The clot burden reduction by segment was evaluated. The mean access establishment time and thrombolytic time were compared. The patency of the iliofemoral vein at 6 months was evaluated. The rate of PTS, quality of life and venous insufficiency were assessed at 1 year. AGA group showed better thrombolytic effect in popliteal and femoral vein than RGA group. The rate of iliofemoral clot burden reduction in RGA group was mostly at Grade II, while most were at Grade III in AGA group. The retrograde approach showed better thrombolysis effect in iliofemoral DVT than popliteal to iliac DVT. The RGA group reported longer mean access establishment time (5.4 ± 1.8 vs 27.0 ± 7.5 min, p < 0.001) and thrombolytic time (6.9 ± 1.5 days vs 6.8 ± 1.5 days, p = 0.586). At 6 months, RGA group had a lower rate of femoral vein patency (52.0% vs 89.6%, p < 0.001) and a higher rate of venous insufficiency (52.0% vs 29.9%, p < 0.001), compared with AGA group. Although there was no difference in the rate of PTS, the RGA group showed higher Villalta scores in the free and mild PTS. The antegrade approach was preferably recommended over the retrograde approach for CDT treatment.

Microengineered Human Vein-Chip Recreates Venous Valve Architecture and Its Contribution to Thrombosis.

Deep vein thrombosis (DVT) and its consequences are lethal, but current models cannot completely dissect its determinants-endothelium, flow, and blood constituents-together called Virchow's triad. Most models for studying DVT forego assessment of venous valves that serve as the primary sites of DVT formation. Therefore, the knowledge of DVT formed at the venous cusps has remained obscure due to lack of experimental models. Here, organ-on-chip methodology is leveraged to create a Vein-Chip platform integrating fully vascularized venous valves and its hemodynamic, as seen in vivo. These Vein-Chips reveal that vascular endothelium of valve cusps adapts to the locally disturbed microenvironment by expressing a different phenotype from the regions of uniform flow. This spatial adaptation of endothelial function recreated on the in vitro Vein-Chip platform is shown to protect the vein from thrombosis from disturbed flow in valves, but interestingly, cytokine stimulation reverses the effect and switches the valve endothelium to becoming prothrombotic. The platform eventually modulates the three factors of Virchow's triad and provides a systematic approach to investigate the determinants of fibrin and platelet dynamics of DVT. Therefore, this Vein-Chip offers a new preclinical approach to study venous pathophysiology and show effects of antithrombotic drug treatment.

Search for an Optimal Design of a Bioprosthetic Venous Valve: In silico and in vitro Studies.

OBJECTIVE/BACKGROUND: Valve incompetence is a progressive disease of the venous system that may eventually lead to venous hypertension, pain, and ulcers. There is a need for a venous valve prosthesis to replace incompetent valves. Computational and experimental investigations on venous valve design and associated haemodynamics will undoubtedly advance prosthesis design and treatments. Here, the objective is to investigate the effect of venous valve on the fluid and solid mechanics. The hypothesis is that there exists a valve geometry that maximises leaflet shear stress (LSS) but minimises leaflet intramural stress (LIS; i.e., minimise stress ratio = LIS/LSS). METHODS: To address the hypothesis, fully dynamic fluid-structure interaction (FSI) models were developed. The entire cycle of valve opening and closure was simulated. The flow validation experiments were conducted using a stented venous valve prosthesis and a pulse duplicator flow loop. RESULTS: Agreement between the output of FSI simulations and output of pulse duplicator was confirmed. The maximum flow rates were within 6% difference, and the total flow during the cycle was within 10% difference. The simulated high stress ratio region at the leaflet base (five times the leaflet average) predicted the disease location of the vast majority of explanted venous valves reported in clinical literature. The study found that the reduced valve height and leaflet dome shape resulted in optimal performance to provide the lowest stress ratio. CONCLUSION: This study proposes an effective design of venous prostheses and elaborates on the correlations of venous valve with clinical observations.

Impact of Lesion Morphology on Durability After Angioplasty of Failed Arteriovenous Fistulas in Hemodialysis Patients.

PURPOSE: To investigate if morphological patterns of arteriovenous fistula (AVF) venous lesions affect primary patency after percutaneous transluminal angioplasty (PTA). METHODS: From July 2014 to June 2015, 262 patients underwent PTA for failed AVFs. A total of 104 patients were excluded owing to (1) calcification or AVF occlusion precluding ultrasound examination, (2) central venous or arterial lesions, and (3) no follow-up, leaving 158 patients (mean age 71±12; 96 men) for analysis. More than half of the patients had one or more previous PTAs for the failed AVF. Prior to PTA the stenotic lesions were assessed using ultrasonography to determine stenotic patterns at the minimum lumen area site and to evaluate the flow volume in the brachial artery. Three stenotic patterns were identified: intimal hyperplasia (IH) stenosis (n=110), shrinking lumen stenosis (n=32), and venous valve-related stenosis (n=16). The main outcome measure was primary patency after PTA estimated using Kaplan-Meier analysis. Predictors for loss of primary patency were determined using a multivariate Cox proportional hazards model; the results are presented as the adjusted hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Median follow-up after PTA was 6.3 months (interquartile range 3.3, 10.5). The 6-month primary patency estimates were 56%±5% in the IH group, 40±9% in the shrinking lumen group, and 100% in the valve stenosis group (IH vs shrinking, p=0.013; IH vs valve, p=0.003). In multivariate analysis, shrinking lumen morphology had a negative impact on primary patency (HR 2.05, 95% CI 1.25 to 3.36, p=0.005), while venous valve-related stenosis had a positive impact (HR 0.19, 95% CI 0.04 to 0.79, p=0.023). Flow volume (10-mL/min increments; HR 0.97, 95% CI 0.96 to 0.99, p=0.004) and history of PTA (HR 1.66, 95% CI 1.06 to 2.60, p=0.029) were also independently associated with primary patency after PTA. CONCLUSION: The patterns of AVF stenosis as determined by ultrasound can affect the outcome of treatment with balloon dilation.

Extrathoracic subclavian-axillary vein location and morphological features over the first rib for pacemaker and defibrillator lead implantation.

BACKGROUND: We aimed to describe the variations of extrathoracic subclavian-axillary vein location and its morphology over the first rib by venography in order to facilitate venous puncture using fluoroscopic landmarks without contrast venography, and evaluate the success rate of punctures, which is made with our method. METHODS: Patients who had undergone de novo lead implantation with the help of prepuncture venography between 2011 and 2015 were enrolled. For detection of the segmental location of the axillary vein, the zones were defined (Zone 1: Posterior, Zone 2: Lateral, Zone 3: Medial) at the first rib by fluoroscopy. Additionally, patients, who underwent venous puncture with our method after January 2017, were evaluated in terms of puncture success. RESULTS: Four hundred thirty-three patients who had prepuncture contrast venography for defibrillator or pacemaker lead implantation in 2011-2015 were analyzed. The most common position of the axillary vein was found to be over zone 2 (91%) while the zone 1 location was 8.5% and the zone 3 was 0.5%. Venous valves were detected on the first rib in 98 patients. After January 2017, venous puncture using fluoroscopic landmarks was performed to 171 patients. The punctures were successfully performed over zone 2 with our method in 90.7% of the patients. CONCLUSIONS: The most common radioanatomic position of the extrathoracic subclavian-axillary vein was observed at zone 2 according to our method and the probability of presence of venous valve over the first rib is 22%. Additionally, the success rate of puncture using fluoroscopic landmarks over zone 2 was 90.7%.

The influence of age on valve disease in patients with varicose veins analysed by transmission electron microscopy and stereology.

BACKGROUND: The aim of this study was to investigate the influence of age on the ultrastructure of venous valve morphology in patients with C2 classified chronic venous disorders according to the CEAP classification. PATIENTS AND METHODS: The study population consisted of 16 consecutive patients with varicose veins (C2). The mean age was 49.8 years (30-66). The (pre-) terminal valve including the vessel wall was harvested within the proximal 2 centimetres of the great saphenous vein. The mean thickness (volume-to-surface ratio = V/S ratio) of elastin, collagen, endothelium and of the entire valve was determined. A blinded morphologist performed the examination by transmission electron microscopy and stereology. Analyses by Pearson's product moment correlation, Kendall's tau and Spearman's rank correlation were performed to investigate whether there is a correlation between age and the ultrastructural morphology. RESULTS: Stereological analysis of the valves demonstrated a mean V/S ratio (signifying a thickness estimation) for elastin of 0.87 µm3/µm2, for collagen of 18.0 µm3/µm2, for endothelium of 0.65 µm3/µm2, and for the entire valve of 25.2 µm³/µm². Statistical analyses showed no statistically significant correlation between age and the ultrastructural morphology in this patient group. CONCLUSIONS: The ultrastructural morphology of the venous valves in chronic venous disorders may not depend on age in patients presenting with C2 disease. This conclusion may or may not apply to all C classes as we investigated a homogenous group of patients with C2 limbs.

Proof-of-Concept Evaluation of the SailValve Self-Expanding Deep Venous Valve System in a Porcine Model.

PURPOSE: To evaluate the SailValve, a new self-expanding deep venous valve concept based on a single polytetrafluoroethylene cusp floating up and down in the bloodstream like a sail, acting as a flow regulator and allowing minimal reflux to reduce thrombogenicity. METHODS: Both iliac veins of 5 pigs were implanted with SailValve devices; the first animal was an acute pilot experiment to show the feasibility of accurately positioning the SailValve via a femoral access. The other 4 animals were followed for 2 weeks (n=2) or 4 weeks (n=2) under a chronic implantation protocol. Patency and valve function were evaluated directly in all animals using ascending and descending phlebography after device placement and at termination in the chronic implant animals. For reasons of clinical relevance, a regimen of clopidogrel and calcium carbasalate was administered. Histological analysis was performed according to a predefined protocol by an independent pathologist. RESULTS: Deployment was technically feasible in all 10 iliac veins, and all were patent directly after placement. No perioperative or postoperative complications occurred. Ascending phlebograms in the follow-up animals confirmed the patency of all valves after 2 or 4 weeks. Descending phlebograms showed full function in 5 of 8 valves. Limited reflux was seen in 1 valve (4-week group), and the function in the remaining 2 valves (2-week group) was insufficient because of malpositioning. No macroscopic thrombosis was noted on histology. Histology in the follow-up groups revealed a progressive inflammatory reaction to the valves. CONCLUSION: This animal study shows the potential of the SailValve concept with sufficient valve function after adequate positioning and no (thrombogenic) occlusions after short-term follow-up. Future research is essential to optimize valve material and long-term patency.

The sex prevalence of lower limb varicose vein networks.

OBJECTIVE: To determine the sex prevalence of lower limb varicose networks fed by reflux of the great saphenous vein (GSV), anterior accessory saphenous vein (AASV), and small saphenous vein singularly or in combination. METHODS: We scanned by the means of the same color Doppler ultrasound protocol 3000 lower limbs in 1500 consecutive patients, affected by symptomatic chronic venous insufficiency from 2013 to 2023. Limbs with normal venous function, incomplete scans, or that were affected by post-thrombotic syndrome, pelvic reflux, isolated perforator reflux, venous malformation, phlebolymphedema and Clinical, Etiological, Anatomical, Pathophysiological clinical class C5 and C6 were excluded from the final analysis. RESULTS: Overall, 1072 patients-252 (23.5%) males and 820 (76.5%) females (P < .0001) matched for age (P = .692)-were included in the study for a total of 1956 limbs affected by primary chronic venous insufficiency, clinical class C2 to C4. The main finding was the significant prevalence of varicose networks fed by reflux of the AASV alone (odds ratio [OR], 1.96; 95% confidence interval [CI], 1.26-3.06; P = .001) or combined with GSV (OR, 1.84; 95% CI, 1.34-2.52; P = .0002) in females. In contrast, GSV insufficiency alone was significantly prevalent in males (OR, 0.54; 95% CI, 0.43-0.68; P < .0001). No significant sex differences regarding SSV reflux were detected. Moreover, we considered the presence of competent terminal valve (TV+) at the level of the saphenofemoral junction, which resulted more significantly present in female (OR, 1.57; 95% CI, 1.12-2.19; P = .0083); to the contrary incompetent terminal valve (TV-) was more common in males (OR, 0.64; 95% CI, 0.46-0.89; P = .0083). Finally, considering reflux in the AASV territory in the presence of a TV+, a strong prevalence in females was detected (OR, 2.28; 95% CI, 1.48-3.52; P = .0002), whereas males developed reflux along the GSV when a concomitant TV- was present (OR, 0.62; 95% CI, 0.41-0.94; P = .0244). CONCLUSIONS: The analysis of the lower limb varicose networks highlights that reflux along the AASV alone, in presence of a TV+ at the junction or coupled with GSV insufficiency, is more prevalent in females. In contrast, GSV resulted the main trunk feeding varicose veins in males, in particular when a TV- was detected. Our findings suggest that females could be more prone to developing varicose veins with an ascending mechanism, whereas in males the descending one seems to be more common.

Long-Term Efficacy of Ultrasound-Guided Percutaneous Transluminal Angioplasty for Arteriovenous Fistula Outflow Stenosis Caused by Venous Valve.

Introduction: Venous valve-related stenosis (VVRS) is an uncommon type of failure of arteriovenous fistula among patients with end-stage renal disease (ESRD). There is a paucity of data on the long-term efficacy of ultrasound-guided percutaneous transluminal angioplasty (PTA) for VVRS. Methods: ESRD patients who underwent PTA because of VVRS between January 2017 and December 2021 at the First Affiliated Hospital of Chongqing Medical University were enrolled. Patients were classified into three cohorts (cohort1, VVRS located within 3 cm of the vein adjacent to the anastomosis; cohort2, VVRS located over 3 cm away from the anastomosis; cohort3, multiple stenoses). The patency rates were assessed by the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate Cox analyses were performed to identify the risk factors. Results: A total of 292 patients were enrolled, including 125 (42.8%), 111 (38.0%), and 56 (19.2%) patients in cohort1, cohort2, and cohort3, respectively. The median follow-up was 34.8 months. The 6-month, 1-year, 2-year, and 3-year primary patency rates were 86.0%, 69.4%, 47.5%, and 35.3%, respectively. The secondary patency rates were 94.5%, 89.4%, 75.5%, and 65.3%, respectively. Cohort1 showed a relatively better primary patency compared to cohort2 and cohort3. The secondary patency rates were comparable in the three cohorts. Duration of dialysis and VVRS type were potential factors associated with primary patency. Conclusions: This study showed acceptable long-term primary and secondary patency rates after PTA for VVRS in ESRD patients, especially for those with VVRS located within 3 cm of the vein adjacent to the anastomosis.

Endovenous valve transfer for chronic deep venous insufficiency.

OBJECTIVES: The aims of the study were to test the safety and efficacy of a custom-made endovenous valve transfer stent, and delivery system in animals and humans. METHODS: The internal jugular veins of 16 sheep, weighing 45-55 kg, were used. A segment of vein with venous valve was enclosed circumferentially with a barbed stent. This segment from the internal jugular vein was introduced and deployed remotely into the contralateral internal jugular vein. Harvesting occurred acutely (one sheep) and at 1, 3, and 6 months postoperatively (five sheep per group). Operative competence testing, histological and scanning electron microscopic (SEM) examinations were performed. Four males with recalcitrant ulcers (mean age of 22 years) had axillary veins transferred from the popliteal vein and were followed for a mean of 3.8 years. RESULTS: At harvest, all the transferred valves were competent, with no evidence of thrombosis, tilting, endoleak, or migration with normal macroscopic and SEM findings. Although only 50% of the ulcers completely healed in humans, the remainder were improved, with all valves being competent and patent. CONCLUSIONS: Endovenous valve transfer with a custom-made circumferential stent produces near perfect results in sheep and encouraging results in a small pilot study.

Endovenous thermal ablation of superficial truncal veins and compression therapy result in symptom relief in venous valve aplasia.

Venous valve aplasia (or valvular rarefication) is a rare cause of chronic venous insufficiency. In the present report, we have described the case of a 33-year-old man with severe symmetric lower leg edema and heaviness and pain in both lower legs. Duplex ultrasound demonstrated severe venous insufficiency in the superficial and deep venous system of both legs. Further imaging examinations supported the diagnosis of venous valvular aplasia. Treatment consisted of endovenous thermal ablation of the great saphenous vein and small saphenous vein as well as consistent compression therapy, resulting in a marked reduction of his leg edema, heaviness, and pain.

Numerical simulation and experimental validation of thrombolytic therapy for patients with venous isomer and normal venous valves.

Thrombus is an extremely dangerous factor in the human body that can block the blood vessel. Once thrombosis happens in venous of lower limbs, local blood flow is impeded. This leads to venous thromboembolism (VTE) and even pulmonary embolism. In recent years, venous thromboembolism has frequently occurred in a variety of people, and there is no effective treatment for patients with different venous structures. For the patients with venous isomer with single valve structure, we establish a coupled computational model to simulate the process of thrombolysis with multi-dose treatment schemes by considering the blood as non-Newtonian fluid. Then, the corresponding in vitro experimental platform is built to verify the performance of the developed mathematical model. At last, the effects of different fluid models, valve structures and drug doses on thrombolysis are comprehensively studied through numerical and experimental observations. Comparing with the experimental results, the relative error of blood boosting index (BBI) obtained from non-Newtonian fluid model is 11% smaller than Newtonian fluid. In addition, the BBI from venous isomer is 1300% times stronger than patient with normal venous valve while the valve displacement is 500% times smaller. As consequence, low eddy current and strong molecular diffusion near the thrombus in case of isomer promote thrombolysis rate up to 18%. Furthermore, the 80 µM dosage of thrombolytic drugs gets the maximum thrombus dissolution rate 18% while the scheme of 50 µM doses obtains a thrombolysis rate of 14% in case of venous isomer. Under the two administration schemes for isomer patients, the rates from experiments are around 19.1% and 14.9%, respectively. It suggests that the proposed computational model and the designed experiment platform can potentially help different patients with venous thromboembolism to carry out clinical medication prediction.

Persistent right venous valve as a cause of fetal and neonatal pathology from prenatal to postnatal periods: a case report and review.

Background: Neonatal cyanosis is a clinical manifestation of hypoxemia and is usually pathological. Persistent right venous valve (PRVV) is a rare cause of cyanosis in newborns and can cause prenatal abnormalities, the clinical significance of which varies depending on the severity of the abnormality. There have been few reports on the intrauterine detection of these abnormalities and their follow-up during infancy. Here, we report a case of PRVV causing supravalvular tricuspid valve (TV) obstruction and secondary right ventricle (RV) hypoplasia. This case is unique in terms of its early prenatal detection, distinct cardiac anomalies, and successful surgery that reversed the symptoms, and the findings offer insights into the diagnosis and management of such rare cardiac conditions. Case Description: We report a case of a newborn diagnosed with PRVV at 31 weeks of gestation at our center. There was no underlying family history of congenital heart disease. Prenatal sonography identified an echogenic membrane in the right atrium, suggesting TV obstruction and subsequent RV hypoplasia. After birth, the neonate suffered hypoxia with decreased arterial oxygen saturation (SaO2). Minimally invasive surgery successfully corrected the membrane. Postoperative SaO2 improved immediately. Three months later, follow-up echocardiography revealed normalized TV and RV dimensions. The patient demonstrated steady progress without any complications. We also reviewed previous cases of PRVV before and after birth and summarized the sonographic and clinically relevant features. Conclusions: Although PRVV is typically considered as a benign structure, it may lead to significant clinical complications, particularly in fetuses and neonates. The precise identification of its variant forms and related flow patterns is crucial to inform decisions regarding patient management.

Two-Year Results of a First-In-Human Study in Patients Surgically Implanted With a Bioprosthetic Venous Valve, the VenoValve in Patients With Severe Chronic Venous Insufficiency.

OBJECTIVE: Two-year follow-up results from a first-in-human study of patients implanted with the VenoValve are evaluated for supporting the long-term clinical safety and performance of the device. BACKGROUND: Chronic Venous Insufficiency (CVI) involves improper functioning of lower limb vein valves and inability of these valves to move blood back towards the heart. CVI symptoms include swelling, varicose veins, pain, and leg ulcers. Currently, there is no cure for this condition and treatment options are limited. This study provides 2-year outcomes for 8 patients who were implanted with the bioprosthetic VenoValve for treating severe CVI with deep venous reflux measured at the mid-popliteal vein. The 6-month and 1-year results were previously published. METHODS: Eleven patients with C5 & C6 CVI were implanted with VenoValve into the midthigh femoral vein and followed for 2 years. Assessed clinical outcomes include device-related adverse events, reflux time, disease severity, and pain scores. RESULTS: All 11 implant procedures were successful. Two-year follow-up data was obtained for 8 subjects: 1 patient died of non-device related causes, 1 was lost to follow-up, and 1 refused to follow-up due to the COVID-19 pandemic. No device-related adverse events occurred between the first and second years of follow-up. Reported 2-year clinical performance outcomes included significant decreases in mean reflux times of the mid-popliteal vein (61%), and significant improvements in mean scores for disease severity rVCSS (56%) and VAS pain (87%). CONCLUSIONS: Results from this study support long-term safety and effectiveness of the VenoValve for improving CVI severity by reducing reflux and thereby venous pressures in the lower extremities. With limited treatments for valvular incompetence involved in severe, deep venous CVI, the device may be considered as a novel therapy. A pivotal trial in the United States is currently being conducted to assess the device in a larger number of patients.

Glutaraldehyde fixation of venous valve tissue: A benchmark for alternative fixation methods.

OBJECTIVE: Bioprosthetic venous valves have yet to achieve long-term patency due to issues with calcification following implantation that is influenced by current xenograft fixation methods, most notably glutaraldehyde. The goal of this study was to investigate the effects of glutaraldehyde fixation on the functional properties of venous tissue to establish a benchmark for the evaluation of alternative fixation methods. METHODS: The degree of crosslinking was evaluated by determining shrink temperature and the stability of tissue with pronase and collagenase digestion. RESULTS: Glutaraldehyde fixation of venous tissue was confirmed by a significant difference in the shrink temperature between fresh and glutaraldehyde treated samples. Significant differences in the amount of tissue remaining following digestion were observed for venous versus cardiac tissue. CONCLUSIONS: This study demonstrates the importance of tissue-specific evaluation in the development of alternative xenograft fixation methods to improve outcomes with bioprosthetic venous valves.

In silico analyses of blood flow and oxygen transport in human micro-veins and valves.

BACKGROUND: Almost 95% of the venous valves are micron scale found in veins smaller than 300µm diameter. The fluid dynamics of blood flow and transport through these micro venous valves and their contribution to thrombosis is not yet well understood or characterized due to difficulty in making direct measurements in murine models. OBJECTIVE: The unique flow patterns that may arise in physiological and pathological non-actuating micro venous valves are predicted. METHODS: Computational fluid and transport simulations are used to model blood flow and oxygen gradients in a microfluidic vein. RESULTS: The model successfully recreates the typical non-Newtonian vortical flow within the valve cusps seen in preclinical experimental models and in clinic. The analysis further reveals variation in the vortex strengths due to temporal changes in blood flow. The cusp oxygen is typically low from the main lumen, and it is regulated by systemic venous flow. CONCLUSIONS: The analysis leads to a clinically-relevant hypothesis that micro venous valves may not create a hypoxic environment needed for endothelial inflammation, which is one of the main causes of thrombosis. However, incompetent micro venous valves are still locations for complex fluid dynamics of blood leading to low shear regions that may contribute to thrombosis through other pathways.