Hemodynamic evaluation of biomaterial-based surgery for Tetralogy of Fallot using a biorobotic heart, in silico, and ovine models.

Tetralogy of Fallot is a congenital heart disease affecting newborns and involves stenosis of the right ventricular outflow tract (RVOT). Surgical correction often widens the RVOT with a transannular enlargement patch, but this causes issues including pulmonary valve insufficiency and progressive right ventricle failure. A monocusp valve can prevent pulmonary regurgitation; however, valve failure resulting from factors including leaflet design, morphology, and immune response can occur, ultimately resulting in pulmonary insufficiency. A multimodal platform to quantitatively evaluate the effect of shape, size, and material on clinical outcomes could optimize monocusp design. This study introduces a benchtop soft biorobotic heart model, a computational fluid model of the RVOT, and a monocusp valve made from an entirely biological cell-assembled extracellular matrix (CAM) to tackle the multifaceted issue of monocusp failure. The hydrodynamic and mechanical performance of RVOT repair strategies was assessed in biorobotic and computational platforms. The monocusp valve design was validated in vivo in ovine models through echocardiography, cardiac magnetic resonance, and catheterization. These models supported assessment of surgical feasibility, handling, suturability, and hemodynamic and mechanical monocusp capabilities. The CAM-based monocusp offered a competent pulmonary valve with regurgitation of 4.6 ± 0.9% and a transvalvular pressure gradient of 4.3 ± 1.4 millimeters of mercury after 7 days of implantation in sheep. The biorobotic heart model, in silico analysis, and in vivo RVOT modeling allowed iteration in monocusp design not now feasible in a clinical environment and will support future surgical testing of biomaterials for complex congenital heart malformations.

Soft robotic platform for progressive and reversible aortic constriction in a small-animal model.

Our understanding of cardiac remodeling processes due to left ventricular pressure overload derives largely from animal models of aortic banding. However, these studies fail to enable control over both disease progression and reversal, hindering their clinical relevance. Here, we describe a method for progressive and reversible aortic banding based on an implantable expandable actuator that can be finely tuned to modulate aortic banding and debanding in a rat model. Through catheterization, imaging, and histologic studies, we demonstrate that our platform can recapitulate the hemodynamic and structural changes associated with pressure overload in a controllable manner. We leveraged soft robotics to enable noninvasive aortic debanding, demonstrating that these changes can be partly reversed because of cessation of the biomechanical stimulus. By recapitulating longitudinal disease progression and reversibility, this animal model could elucidate fundamental mechanisms of cardiac remodeling and optimize timing of intervention for pressure overload.

National registry insights on genetic aortopathies and thoracic endovascular aortic interventions.

OBJECTIVE: Thoracic endovascular aortic repair (TEVAR) in patients with genetic aortopathies (GA) is controversial, given concerns of durability. We describe characteristics and outcomes after TEVAR in patients with GA. METHODS: All patients undergoing TEVAR between 2010 and 2023 in the Vascular Quality Iniatitive were identified and categorized as having a GA or not. Demographics, baseline, and procedural characteristics were compared among groups. Multivariable logistic regression was used to evaluate the independent association of GA with postoperative outcomes. Kaplan-Meier methods and multivariable Cox regression analyses were used to evaluate 5-year survival and 2-year reinterventions. RESULTS: Of 19,340 patients, 304 (1.6%) had GA (87% Marfan syndrome, 9% Loeys-Dietz syndrome, and 4% vascular Ehlers-Danlos syndrome). Compared with patients without GA, patients with GA were younger (50 years [interquartile range, 37-72 years] vs 70 years [interquartile range, 61-77 years]), more often presented with acute dissection (28% vs 18%), postdissection aneurysm (48% vs 17%), had a symptomatic presentation (50% vs 39%), and were less likely to have degenerative aneurysms (18% vs 47%) or penetrating aortic ulcer (and intramural hematoma) (3% vs 13%) (all P < .001). Patients with GA were more likely to have prior repair of the ascending aorta/arch (open, 56% vs 11% [P < .001]; endovascular, 5.6% vs 2.1% [P = .017]) or the descending thoracic aorta (open, 12% vs 2% [P = .007]; endovascular, 8.2% vs 3.6% [P = .011]). No significant differences were found in prior abdominal suprarenal repairs; however, patients with GA had more prior open infrarenal repairs (5.3% vs 3.2%), but fewer prior endovascular infrarenal repairs (3.3% vs 5.5%) (all P < .05). After adjusting for demographics, comorbidities, and disease characteristics, patients with GA had similar odds of perioperative mortality (4.6% vs 7.0%; adjusted odds ratio [aOR], 1.1; 95% confidence interval [CI], 0.57-1.9; P = .75), any in-hospital complication (26% vs 23%; aOR, 1.24; 95% CI, 0.92-1.6; P = .14), or in-hospital reintervention (13% vs 8.3%; aOR, 1.25; 95% CI, 0.84-1.80; P = .25) compared with patients without GA. However, patients with GA had a higher likelihood of postoperative vasopressors (33% vs 27%; aOR, 1.44; 95% CI, 1.1-1.9; P = .006) and transfusion (25% vs 23%; aOR, 1.39; 95% CI, 1.03-1.9; P = .006). The 2-year reintervention rates were higher in patients with GA (25% vs 13%; adjusted hazard ratio, 1.99; 95% CI, 1.4-2.9; P < .001), but 5-year survival was similar (81% vs 74%; adjusted hazard ratio, 1.02; 95% CI, 0.70-1.50; P = .1). CONCLUSIONS: TEVAR for patients with GA seemed to be safe initially, with similar odds for in-hospital complications, in-hospital reinterventions, and perioperative mortality, as well as similar hazards for 5-year mortality compared with patients without GA. However, patients with GA had higher 2-year reintervention rates. Future studies should assess long-term durability after TEVAR compared with the recommended open repair to appropriately weigh the risks and benefits of endovascular treatment in patients with GA.

Surgeon volume and outcomes following thoracic endovascular aortic repair for blunt thoracic aortic injury.

OBJECTIVE: Thoracic endovascular aortic repair (TEVAR) for blunt thoracic aortic injury (BTAI) at high-volume hospitals has previously been associated with lower perioperative mortality, but the impact of annual surgeon volume on outcomes following TEVAR for BTAI remains unknown. METHODS: We analyzed Vascular Quality Initiative (VQI) data from patients with BTAI that underwent TEVAR between 2013 and 2023. Annual surgeon volumes were computed as the number of TEVARs (for any pathology) performed over a 1-year period preceding each procedure and were further categorized into quintiles. Surgeons in the first volume quintile were categorized as low volume (LV), the highest quintile as high volume (HV), and the middle three quintiles as medium volume (MV). TEVAR procedures performed by surgeons with less than 1-year enrollment in the VQI were excluded. Using multilevel logistic regression models, we evaluated associations between surgeon volume and perioperative outcomes, accounting for annual center volumes and adjusting for potential confounders, including aortic injury grade and severity of coexisting injuries. Multilevel models accounted for the nested clustering of patients and surgeons within the same center. Sensitivity analysis excluding patients with grade IV BTAI was performed. RESULTS: We studied 1321 patients who underwent TEVAR for BTAI (28% by LV surgeons [0-1 procedures per year], 52% by MV surgeons [2-8 procedures per year], 20% by HV surgeons [≥9 procedures per year]). With higher surgeon volume, TEVAR was delayed more (in <4 hours: LV: 68%, MV: 54%, HV: 46%; P < .001; elective (>24 hours): LV: 5.1%; MV: 8.9%: HV: 14%), heparin administered more (LV: 80%, MV: 81%, HV: 87%; P = .007), perioperative mortality appears lower (LV: 11%, MV: 7.3%, HV: 6.5%; P = .095), and ischemic/hemorrhagic stroke was lower (LV: 6.5%, MV: 3.6%, HV: 1.5%; P = .006). After adjustment, compared with LV surgeons, higher volume surgeons had lower odds of perioperative mortality (MV: 0.49; 95% confidence interval [CI], 0.25-0.97; P = .039; HV: 0.45; 95% CI, 0.16-1.22; P = .12; MV/HV: 0.50; 95% CI, 0.26-0.96; P = .038) and ischemic/hemorrhagic stroke (MV: 0.38; 95% CI, 0.18-0.81; P = .011; HV: 0.16; 95% CI, 0.04-0.61; P = .008). Sensitivity analysis found lower adjusted odds for perioperative mortality (although not significant) and ischemic/hemorrhagic stroke for higher volume surgeons. CONCLUSIONS: In patients undergoing TEVAR for BTAI, higher surgeon volume is independently associated with lower perioperative mortality and postoperative stroke, regardless of hospital volume. Future studies could elucidate if TEVAR for non-ruptured BTAI might be delayed and allow stabilization, heparinization, and involvement of a higher TEVAR volume surgeon.

Amputation Rates and Associated Social Determinants of Health in the Most Populous US Counties.

Importance: Social Determinants of Health (SDOH) have been found to be associated with health outcome disparities in patients with peripheral artery disease (PAD). However, the association of specific components of SDOH and amputation has not been well described. Objective: To evaluate whether individual components of SDOH and race are associated with amputation rates in the most populous counties of the US. Design, Setting, and Participants: In this population-based cross-sectional study of the 100 most populous US counties, hospital discharge rates for lower extremity amputation in 2017 were assessed using the Healthcare Cost and Utilization Project State Inpatient Database. Those data were matched with publicly available demographic, hospital, and SDOH data. Data were analyzed July 3, 2022, to March 5, 2023. Main outcome and Measures: Amputation rates were assessed across all counties. Counties were divided into quartiles based on amputation rates, and baseline characteristics were described. Unadjusted linear regression and multivariable regression analyses were performed to assess associations between county-level amputation and SDOH and demographic factors. Results: Amputation discharge data were available for 76 of the 100 most populous counties in the United States. Within these counties, 15.3% were African American, 8.6% were Asian, 24.0% were Hispanic, and 49.6% were non-Hispanic White; 13.4% of patients were 65 years or older. Amputation rates varied widely, from 5.5 per 100 000 in quartile 1 to 14.5 per 100 000 in quartile 4. Residents of quartile 4 (vs 1) counties were more likely to be African American (27.0% vs 7.9%, P < .001), have diabetes (10.6% vs 7.9%, P < .001), smoke (16.5% vs 12.5%, P < .001), be unemployed (5.8% vs 4.6%, P = .01), be in poverty (15.8% vs 10.0%, P < .001), be in a single-parent household (41.9% vs 28.6%, P < .001), experience food insecurity (16.6% vs 12.9%, P = .04), or be physically inactive (23.1% vs 17.1%, P < .001). In unadjusted linear regression, higher amputation rates were associated with the prevalence of several health problems, including mental distress (ß, 5.25 [95% CI, 3.66-6.85]; P < .001), diabetes (ß, 1.73 [95% CI, 1.33-2.15], P < .001), and physical distress (ß, 1.23 [95% CI, 0.86-1.61]; P < .001) and SDOHs, including unemployment (ß, 1.16 [95% CI, 0.59-1.73]; P = .03), physical inactivity (ß, 0.74 [95% CI, 0.57-0.90]; P < .001), smoking, (ß, 0.69 [95% CI, 0.46-0.92]; P = .002), higher homicide rate (ß, 0.61 [95% CI, 0.45-0.77]; P < .001), food insecurity (ß, 0.51 [95% CI, 0.30-0.72]; P = .04), and poverty (ß, 0.46 [95% CI, 0.32-0.60]; P < .001). Multivariable regression analysis found that county-level rates of physical distress (ß, 0.84 [95% CI, 0.16-1.53]; P = .03), Black and White racial segregation (ß, 0.12 [95% CI, 0.06-0.17]; P < .001), and population percentage of African American race (ß, 0.06 [95% CI, 0.00-0.12]; P = .03) were associated with amputation rate. Conclusions and Relevance: Social determinants of health provide a framework by which the associations of environmental factors with amputation rates can be quantified and potentially used to guide interventions at the local level.

Association of stroke or death with severity of carotid lesion calcification in patients undergoing carotid artery stenting.

OBJECTIVE: Carotid artery stenting (CAS) for heavily calcified lesions is controversial due to concern for stent failure and increased perioperative stroke risk. However, the degree to which calcification affects outcomes is poorly understood, particularly in transcarotid artery revascularization (TCAR). With the precipitous increase in TCAR use and its expansion to standard surgical-risk patients, we aimed to determine the impact of lesion calcification on CAS outcomes to ensure its safe and appropriate use. METHODS: We identified patients in the Vascular Quality Initiative who underwent first-time transfemoral CAS (tfCAS) and TCAR between 2016 and 2021. Patients were stratified into groups based on degree of lesion calcification: no calcification, 1% to 50% calcification, 51% to 99% calcification, and 100% circumferential calcification or intraluminal protrusion. Outcomes included in-hospital and 1-year composite stroke/death, as well as individual stroke, death, and myocardial infarction outcomes. Logistic regression was used to evaluate associations between degree of calcification and these outcomes. RESULTS: Among 21,860 patients undergoing CAS, 28% patients had no calcification, 34% had 1% to 50% calcification, 35% had 51% to 99% calcification, and 3% had 100% circumferential calcification/protrusion. Patients with 51% to 99% and circumferential calcification/protrusion had higher odds of in-hospital stroke/death (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.02-1.6; P = .034; OR, 1.9; 95% CI, 1.1-2.9; P = .004, respectively) compared with those with no calcification. Circumferential calcification was also associated with increased risk for in-hospital myocardial infarction (OR, 3.5; 95% CI, 1.5-8.0; P = .003). In tfCAS patients, only circumferential calcification/protrusion was associated with higher in-hospital stroke/death odds (OR, 2.0; 95% CI, 1.2-3.4; P = .013), whereas for TCAR patients, 51% to 99% calcification was associated with increased odds of in-hospital stroke/death (OR, 1.5; 95% CI, 1.1-2.2; P = .025). At 1 year, circumferential calcification/protrusion was associated with higher odds of ipsilateral stroke/death (12.4% vs 6.6%; hazard ratio, 1.64; P = .002). CONCLUSIONS: Among patients undergoing CAS, there is an increased risk of in-hospital stroke/death for lesions with >50% calcification or circumferential/protruding plaques. Increasing severity of carotid lesion calcification is a significant risk factor for stroke/death in patients undergoing CAS, regardless of approach.

A Tunable Soft Silicone Bioadhesive for Secure Anchoring of Diverse Medical Devices to Wet Biological Tissue.

Silicone is utilized widely in medical devices for its compatibility with tissues and bodily fluids, making it a versatile material for implants and wearables. To effectively bond silicone devices to biological tissues, a reliable adhesive is required to create a long-lasting interface. BioAdheSil, a silicone-based bioadhesive designed to provide robust adhesion on both sides of the interface is introduced here, facilitating bonding between dissimilar substrates, namely silicone devices and tissues. The adhesive's design focuses on two key aspects: wet tissue adhesion capability and tissue-infiltration-based long-term integration. BioAdheSil is formulated by mixing soft silicone oligomers with siloxane coupling agents and absorbents for bonding the hydrophobic silicone device to hydrophilic tissues. Incorporation of biodegradable absorbents eliminates surface water and controls porosity, while silane crosslinkers provide interfacial strength. Over time, BioAdheSil transitions from nonpermeable to permeable through enzyme degradation, creating a porous structure that facilitates cell migration and tissue integration, potentially enabling long-lasting adhesion. Experimental results demonstrate that BioAdheSil outperforms commercial adhesives and elicits no adverse response in rats. BioAdheSil offers practical utility for adhering silicone devices to wet tissues, including long-term implants and transcutaneous devices. Here, its functionality is demonstrated through applications such as tracheal stents and left ventricular assist device lines.

Soft robotics-enabled large animal model of HFpEF hemodynamics for device testing.

Heart failure with preserved ejection fraction (HFpEF) is a major challenge in cardiovascular medicine, accounting for approximately 50% of all cases of heart failure. Due to the lack of effective therapies for this condition, the mortality associated with HFpEF remains higher than that of most cancers. Despite the ongoing efforts, no medical device has yet received FDA approval. This is largely due to the lack of an in vivo model of the HFpEF hemodynamics, resulting in the inability to evaluate device effectiveness in vivo prior to clinical trials. Here, we describe the development of a highly tunable porcine model of HFpEF hemodynamics using implantable soft robotic sleeves, where controlled actuation of a left ventricular and an aortic sleeve can recapitulate changes in ventricular compliance and afterload associated with a broad spectrum of HFpEF hemodynamic phenotypes. We demonstrate the feasibility of the proposed model in preclinical testing by evaluating the hemodynamic response of the model post-implantation of an interatrial shunt device, which was found to be consistent with findings from in silico studies and clinical trials. This work addresses several of the limitations associated with previous models of HFpEF, such as their limited hemodynamic fidelity, elevated costs, lengthy development time, and low throughput. By showcasing exceptional versatility and tunability, the proposed platform has the potential to revolutionize the current approach for HFpEF device development and selection, with the goal of improving the quality of life for the 32 million people affected by HFpEF worldwide.

Soft robotic platform for controlled, progressive and reversible aortic constriction in a small animal model.

Our understanding of cardiac remodeling processes due to left ventricular pressure overload derives largely from animal models of aortic banding. However, these studies fail to simultaneously enable control over disease progression and reversal, hindering their clinical relevance. Here, we describe a method for controlled, progressive, and reversible aortic banding based on an implantable expandable actuator that can be finely controlled to modulate aortic banding and debanding in a rat model. Through catheterization, imaging, and histologic studies, we demonstrate that our model can recapitulate the hemodynamic and structural changes associated with pressure overload in a controllable manner. We leverage the ability of our model to enable non-invasive aortic debanding to show that these changes can be partly reversed due to cessation of the biomechanical stimulus. By recapitulating longitudinal disease progression and reversibility, this model could elucidate fundamental mechanisms of cardiac remodeling and optimize timing of intervention for pressure overload.

The association between diabetes mellitus and its management with outcomes following endovascular repair for descending thoracic aortic aneurysm.

OBJECTIVE: Prior literature is conflicted regarding the effect of diabetes mellitus (DM) on outcomes after endovascular repair of aortic aneurysms. In this study, we aimed to examine the association between DM and outcomes after thoracic endovascular aneurysm repair (TEVAR) for thoracic aortic aneurysm (TAA). METHODS: We identified patients who underwent TEVAR for TAA of the descending thoracic aorta in the Vascular Quality Initiative between 2014 and 2022. We created two cohorts, DM and nonDM, based on the patient's preoperative DM status, and secondarily substratified patients with DM by management strategy: dietary management, noninsulin medications, and insulin therapy cohorts. Outcomes included perioperative and 5-year mortality, in-hospital complications, indications for repair, and 1-year sac dynamics, which were analyzed with multivariable cox regression, multivariable logistic regression, and χ2 tests, respectively. RESULTS: We identified 2637 patients, of which 473 (18%) had DM preoperatively. Among patients with DM, 25% were diet controlled, 54% noninsulin medications, and 21% insulin therapy. Within patients who underwent TEVAR for TAA, the proportions of ruptured presentation were higher in the dietary-managed (11.1%) and insulin-managed (14.3%) cohorts relative to noninsulin therapy (6.6%) and those without DM (6.9%). After multivariable regression analysis, we found that DM was associated with similar perioperative mortality (odds ratio, 1.14; 95% confidence interval [CI], 0.70-1.81) and 5-year mortality compared with patients without DM (hazard ratio, 1.15; 95% CI, 0.91-1.48). Furthermore, all in-hospital complications were comparable between patients with DM and patients without DM. Compared with patients without DM, dietary management of DM was significantly associated with higher adjusted perioperative mortality (OR, 2.16; 95% CI, 1.03-4.19) and higher 5-year mortality (hazad ratio, 1.50; 95% CI, 1.03-2.20), although this was not the case for other DM subgroups. All cohorts displayed similar 1-year sac dynamics, with sac regression occurring in 47% of patients without DM vs 46% of patients with DM (P = .27). CONCLUSIONS: Preoperatively, patients with DM who underwent TEVAR had a higher proportion of ruptured presentation when treated with diet or insulin medications than when treated with noninsulin medications. After TEVAR for descending TAA, DM was associated with a similar risk of perioperative and 5-year mortality as nonDM. In contrast, dietary therapy for DM was associated with significantly higher perioperative mortality and 5-year mortality.

Soft robotic patient-specific hydrodynamic model of aortic stenosis and ventricular remodeling.

Aortic stenosis (AS) affects about 1.5 million people in the United States and is associated with a 5-year survival rate of 20% if untreated. In these patients, aortic valve replacement is performed to restore adequate hemodynamics and alleviate symptoms. The development of next-generation prosthetic aortic valves seeks to provide enhanced hemodynamic performance, durability, and long-term safety, emphasizing the need for high-fidelity testing platforms for these devices. We propose a soft robotic model that recapitulates patient-specific hemodynamics of AS and secondary ventricular remodeling which we validated against clinical data. The model leverages 3D-printed replicas of each patient's cardiac anatomy and patient-specific soft robotic sleeves to recreate the patients' hemodynamics. An aortic sleeve allows mimicry of AS lesions due to degenerative or congenital disease, whereas a left ventricular sleeve recapitulates loss of ventricular compliance and diastolic dysfunction (DD) associated with AS. Through a combination of echocardiographic and catheterization techniques, this system is shown to recreate clinical metrics of AS with greater controllability compared with methods based on image-guided aortic root reconstruction and parameters of cardiac function that rigid systems fail to mimic physiologically. Last, we leverage this model to evaluate the hemodynamic benefit of transcatheter aortic valves in a subset of patients with diverse anatomies, etiologies, and disease states. Through the development of a high-fidelity model of AS and DD, this work demonstrates the use of soft robotics to recreate cardiovascular disease, with potential applications in device development, procedural planning, and outcome prediction in industrial and clinical settings.

Distal embolic protection use during transfemoral carotid artery stenting is associated with improved in-hospital outcomes.

OBJECTIVE: Despite current guidelines recommending the use of distal embolic protection during transfemoral carotid artery stenting (tfCAS) to prevent periprocedural stroke, there remains significant variation in the routine use of distal filters. We sought to assess in-hospital outcomes in patients undergoing tfCAS with and without embolic protection using a distal filter. METHODS: We identified all patients undergoing tfCAS in the Vascular Quality Initiative from March 2005 to December 2021 and excluded those who received proximal embolic balloon protection. We created propensity score-matched cohorts of patients who underwent tfCAS with and without attempted placement of a distal filter. Subgroup analyses of patients with failed vs successful filter placement and failed vs no attempt at filter placement were performed. In-hospital outcomes were assessed using log binomial regression, adjusted for protamine use. Outcomes of interest were composite stroke/death, stroke, death, myocardial infarction (MI), transient ischemic attack (TIA), and hyperperfusion syndrome. RESULTS: Among 29,853 patients who underwent tfCAS, 28,213 (95%) had a filter attempted for distal embolic protection and 1640 (5%) did not. After matching, 6859 patients were identified. No attempted filter was associated with significantly higher risk of in-hospital stroke/death (6.4% vs 3.8%; adjusted relative risk [aRR], 1.72; 95% confidence interval [CI], 1.32-2.23; P < .001), stroke (3.7% vs 2.5%; aRR, 1.49; 95% CI, 1.06-2.08; P = .022), and mortality (3.5% vs 1.7%; aRR, 2.07; 95% CI, 1.42-3.020; P < .001). In a secondary analysis of patients who had failed attempt at filter placement vs successful filter placement, failed filter placement was associated with worse outcomes (stroke/death: 5.8% vs 2.7%; aRR, 2.10; 95% CI, 1.38-3.21; P = .001 and stroke: 5.3% vs 1.8%; aRR, 2.87; 95% CI, 1.78-4.61; P < .001). However, there were no differences in outcomes in patients with failed vs no attempted filter placement (stroke/death: 5.4% vs 6.2%; aRR, 0.99; 95% CI, 0.61-1.63; P = .99; stroke: 4.7% vs 3.7%; aRR, 1.40; 95% CI, 0.79-2.48; P = .20; death: 0.9% vs 3.4%; aRR, 0.35; 95% CI, 0.12-1.01; P = .052). CONCLUSIONS: tfCAS performed without attempted distal embolic protection was associated with a significantly higher risk of in-hospital stroke and death. Patients undergoing tfCAS after failed attempt at filter placement have equivalent stroke/death to patients in whom no filter was attempted, but more than a two-fold higher risk of stroke/death compared with those with successfully placed filters. These findings support current Society for Vascular Surgery guidelines recommending routine use of distal embolic protection during tfCAS. If a filter cannot be placed safely, an alternative approach to carotid revascularization should be considered.

Dynamic actuation enhances transport and extends therapeutic lifespan in an implantable drug delivery platform.

Fibrous capsule (FC) formation, secondary to the foreign body response (FBR), impedes molecular transport and is detrimental to the long-term efficacy of implantable drug delivery devices, especially when tunable, temporal control is necessary. We report the development of an implantable mechanotherapeutic drug delivery platform to mitigate and overcome this host immune response using two distinct, yet synergistic soft robotic strategies. Firstly, daily intermittent actuation (cycling at 1 Hz for 5 minutes every 12 hours) preserves long-term, rapid delivery of a model drug (insulin) over 8 weeks of implantation, by mediating local immunomodulation of the cellular FBR and inducing multiphasic temporal FC changes. Secondly, actuation-mediated rapid release of therapy can enhance mass transport and therapeutic effect with tunable, temporal control. In a step towards clinical translation, we utilise a minimally invasive percutaneous approach to implant a scaled-up device in a human cadaveric model. Our soft actuatable platform has potential clinical utility for a variety of indications where transport is affected by fibrosis, such as the management of type 1 diabetes.

Racial and ethnic disparities in 3-year outcomes following infrainguinal bypass for chronic limb-threatening ischemia.

OBJECTIVE: Black and Hispanic patients have had higher rates of chronic limb-threatening ischemia (CLTI) and experienced worse perioperative outcomes after lower extremity bypass compared with White patients. The underlying reasons for these disparities have remained unclear, and data on 3-year outcomes are limited. Therefore, we examined the differences in 3-year outcomes after open infrainguinal bypass for CLTI stratified by race/ethnicity and explored the potential factors contributing to these differences. METHODS: We identified all CLTI patients who had undergone primary open infrainguinal bypass in the Vascular Quality Initiative registry from 2003 to 2017 with linkage to Medicare claims through 2018 for the 3-year outcomes. Our primary outcomes were the 3-year rates of major amputation, reintervention, and mortality. We also recorded the 30-day major adverse limb events (MALE) defined as major amputation or reintervention. We used Kaplan-Meier estimation methods and multivariable Cox regression analyses to evaluate the outcomes stratified by race/ethnicity and identify contributing factors. RESULTS: Of the 7108 patients with CLTI, 5599 (79%) were non-Hispanic White, 1053 (15%) were Black, 48 (1%) were Asian, and 408 (6%) were Hispanic patients. Compared with White patients, Black patients had higher rates of 3-year major amputation (Black vs White, 32% vs 19%; hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.7-2.2), reintervention (Black vs White, 61% vs 57%; HR, 1.2; 95% CI, 1.1-1.3), and 30-day MALE (Black vs White, 8.1% vs 4.9%; HR, 1.3; 95% CI, 1.2-1.4) but lower mortality (Black vs White, 38% vs 42%; HR, 0.9; 95% CI, 0.8-0.99). Hispanic patients also experienced higher rates of amputation (Hispanic vs White, 27% vs 19%; HR, 1.6; 95% CI, 1.3-2.0), reintervention (Hispanic vs White, 70% vs 57%; HR, 1.4; 95% CI, 1.2-1.6), and MALE (Hispanic vs White, 8.7% vs 4.9%; HR, 1.5; 95% CI, 1.3-1.7. However, mortality was similar between the two groups (Hispanic vs White, 38% vs 42%; HR, 0.88; 95% CI, 0.76-1.0). The low number of Asian patients prevented a meaningful assessment of amputation (Asian vs White, 20% vs 19%; HR, 0.93; 95% CI, 0.44-2.0), reintervention (Asian vs White, 55% vs 57%; HR, 0.79; 95% CI, 0.51-1.2), MALE (Asian vs White, 8.5% vs 4.9%; HR, 0.71; 95% CI, 0.46-1.1), or mortality (Asian vs White, 36% vs 42%; HR, 0.83; 95% CI, 0.52-1.3). In the adjusted analyses, the association of Black race and Hispanic ethnicity with amputation and reintervention was explained by differences in the demographic characteristics (ie, age, sex) and baseline comorbidities (ie, tobacco use, diabetes, renal disease). CONCLUSIONS: Compared with White patients, Black and Hispanic patients had higher 3-year major amputation and reintervention rates. However, mortality was lower for Black patients than for the White patients and similar between Hispanic and White patients. Disparities in amputation and reintervention were partly attributable to differences in demographic characteristics and the higher prevalence of comorbidities in Black and Hispanic patients with CLTI. Future work is necessary to determine whether interventions to improve access to care and reduce the burden of comorbidities in these populations will confer limb salvage benefits.

Synthesis and characterization of model compounds of the lysine tyrosyl quinone cofactor of lysyl oxidase.

4-n-Butylamino-5-ethyl-1,2-benzoquinone (1(ox)) has been synthesized as a model compound for the LTQ (lysine tyrosyl quinone) cofactor of lysyl oxidase (LOX). At pH 7, 1(ox) has a lambda(max) at 504 nm and exists as a neutral o-quinone in contrast to a TPQ (2,4,5-trihydroxyphenylalanine quinone) model compound, 4, which is a resonance-stabilized monoanion. Despite these structural differences 1(ox) and 4 have the same redox potential (ca. -180 mV vs SCE). The structure of the phenylhydrazine adduct of 1(ox) (2) is reported, and 2D NMR spectroscopy has been used to show that the position of nucleophilic addition is at C(1). UV-vis spectroscopic pH titration of phenylhydrazine adducts of 1(ox) and 4, 2, and 11, respectively, reveals a similar red shift in lambda(max) at alkaline pH with the same pK(a) (approximately 11.8). In contrast, the red shift in lambda(max) at acidic pH conditions yields different pK(a) values (2.12 for 2 vs -0.28 for 11), providing a means to distinguish LTQ from TPQ. Reactions between in situ generated 4-ethyl-1,2-benzoquinone and primary amines give a mixture of products, indicating that the protein environment must play an essential role in LTQ biogenesis by directing the nucleophilic addition of the epsilon-amino group of a lysine residue to the C(4) position of a putative dopaquinone intermediate. Characterization of a 1,6-adduct between an o-quinone and butylamine (3-n-butylamino-5-ethyl-1,2-benzoquinone, 13) confirms the assignment of LTQ as a 1,4-addition product.