Invasive Surgical Implantation Research Articles

Talaromyces marneffei endocarditis initially detected by Next Generation Sequencing: A case report

BackgroundTalaromyces marneffei (T. marneffei) is a thermal dimorphic fungus, which can cause lung or blood stream infection in patients, often life-threatening. However, endocarditis caused by T. marneffei has not been reported. For elderly patients with implanted cardiac devices or artificial valves, the prevention and treatment of infective endocarditis should not be ignored. MethodsThis is a descriptive study of a T. marneffei endocarditis by joint detection of cardiac ultrasound examination, peripheral blood DNA metagenomics Next Generation Sequencing (mNGS), and in vitro culture. ResultsWe describe an 80-year-old female patient with an unusual infection of T. marneffei endocarditis. After intravenous drip of 0.2 g voriconazole twice a day for antifungal treatment, the patient showed no signs of improvement and their family refused further treatment. ConclusionInfective endocarditis is becoming more and more common in the elderly due to the widely use of invasive surgical procedures and implantation of intracardiac devices. The diagnosis and treatment of T. marneffei endocarditis is challenging because of its rarity. Here, we discussed a case of T. marneffei endocarditis, and emphasized the role of mNGS in early diagnosis, which is of great significance for treatment and survival rate of patients.

Millimetric devices for nerve stimulation: a promising path towards miniaturization.

Nerve stimulation is a rapidly developing field, demonstrating positive outcomes across several conditions. Despite potential benefits, current nerve stimulation devices are large, complicated, and are powered via implanted pulse generators. These factors necessitate invasive surgical implantation and limit potential applications. Reducing nerve stimulation devices to millimetric sizes would make these interventions less invasive and facilitate broader therapeutic applications. However, device miniaturization presents a serious engineering challenge. This review presents significant advancements from several groups that have overcome this challenge and developed millimetric-sized nerve stimulation devices. These are based on antennas, mini-coils, magneto-electric and opto-electronic materials, or receive ultrasound power. We highlight key design elements, findings from pilot studies, and present several considerations for future applications of these devices.

Using a Convolutional Neural Network to Classify Subvocalized Letters Collected from the Brain by EEG

Communication is essential to human behavior. Individuals with amyotrophic lateral sclerosis and severe traumatic brain injury encounter enormous challenges in communicating via speaking, writing or typing with others. Such lack of communication severely limits their independence and quality of life. Recent research employing invasive and expensive surgical implants of neuroprosthesis shows some degree of success in reconstructing language or images. However, these procedures are not user-friendly and not available for all affected individuals. To address these limitations, the researcher created a convolutional neural network model to classify individually thought letters – i.e., subvocalization. Using a commercially available simple electroencephalography (EEG) device data were collected from a study participant. All collected data was formatted for computer interpretation and uploaded to a Python notebook. The data was then augmented and preprocessed to make it easier for the neural network model to make predictions. The convolutional neural network model with the best performance had 63.33% classifying 38/60 samples correctly with a statistically significant p value (p<0.00001). Limitations include the reliability of the EEG headset used and time restrictions for collecting data. For future research, better hyperparameters will be investigated using additional data. Finally, the researcher plans to conduct experiments to make real-time predictions with the model once higher accuracies are achieved.

LITE-1 mediates behavioral responses to X-rays in Caenorhabditis elegans.

Rapid sensory detection of X-ray stimulation has been documented across a wide variety of species, but few studies have explored the underlying molecular mechanisms. Here we report the discovery of an acute behavioral avoidance response in wild type Caenorhabditis elegans to X-ray stimulation. The endogenous C. elegans UV-photoreceptor protein LITE-1 was found to mediate the locomotory avoidance response. Transgenic expression of LITE-1 in C. elegans muscle cells resulted in paralysis and egg ejection responses to X-ray stimulation, demonstrating that ectopic expression of LITE-1 can confer X-ray sensitivity to otherwise X-ray insensitive cells. This work represents the first demonstration of rapid X-ray based genetically targeted (X-genetic) manipulation of cellular electrical activity in intact behaving animals. Our findings suggest that LITE-1 has strong potential for use in this minimally invasive form of neuromodulation to transduce transcranial X-ray signals for precise manipulation of neural activity in mammals, bypassing the need for invasive surgical implants to deliver stimulation.

Abstract 5261: Prostate specific sustained anti androgen delivery to delay early stage prostate cancer progression

Abstract Prostate cancer is the most common cancer in men. Commensurate with risk, current approaches to localized prostate cancer include prostatectomy, prostate radiation with or without radiation therapy or active surveillance. Recent data suggest that systemic anti-androgen therapy with enzalutamide reduced the risk of prostate cancer progression in men on active surveillance but was associated with considerable side effects. We developed a novel polymer-based drug delivery method to provide sustained localized drug administration of anti-androgens selectively to the prostate. In vitro and in vivo mouse and canine studies show that this drug eluting implant delivers sustained high prostate to plasma therapeutic anti-androgen levels for an anticipated range of 2 years while preventing accumulation of anti-androgens in the liver, lungs, heart and brain. We performed a proof of concept study in a canine prostate model implanting an 15mm x 1mm bicalutamide eluting implant into each lobe of the prostate. Bicalutamide levels in the prostate measured near the implant at 6 months were 3250 ± 1622 ng/g, n = 3 compared to 3809 ± 638 ng/g, n = 3 to those achieved at steady-state oral administration. Plasma and other off target levels were over 1000-fold lower in the implant cohort compared to oral administration: Plasma: 5.9 ± 0.2 ng/ml, liver: 11.3 ±4.3 ng/g, and brain: 5.4 ±0.8 ng/g versus plasma: 18170 ± 3820 ng/ml, liver: 35407 ±8510 ng/g, and brain: 8870 ±1797 ng/g. The implants were well tolerated without local toxicity and imaged easily with ultrasound. The design characteristics of the implant facilitates minimally invasive surgical implantation under standard image guidance and withstands the concomitant use of prostate radiation. This novel technology warrants future clinical exploration of prostate specific anti-androgen therapy for (neo)adjuvant therapy or in active surveillance. Tissue Bicalutamide oral (2m)(ng/g) Bicalutamide implant (6m)(ng/g) Plasma 18,170 (3820) 5.9 (0.2) Prostate 3,809 (638) 3,250 (1622) Liver 35,407 (8510) 11.3 (4.3) Cerebrum 8,870 (1797) 5.4 (0.8) Cerebellum 8,737 (1550) 6.2 (1.3) Spleen 7,727 (1288) 4.2 (0.9) Lung 27,013 (2896) 11.3 (4.3) Heart 11,737 (3491) 10.0 (1.9) Kidneys 17,413 (6581) 8.5 (2.0) Citation Format: Pujan Desai, Maithili Rairkar, Nela Pawlowska, Scott Thomas, Pamela N. Munster. Prostate specific sustained anti androgen delivery to delay early stage prostate cancer progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5261.

Abstract 1660: Comparison between surgical and ultrasound-guided orthotopic implantation of hepatocellular carcinoma models in mice using ultrasound and bioluminescence imaging

Abstract Introduction: Orthotopic tumour mouse models are often preferred to subcutaneous models due to their increased clinical relevance and pathophysiological features, as the tumour microenvironment can influence stromal interaction, immune response, angiogenesis, tumour growth and progression as well as response to treatment. Orthotopic implantation of liver cancer cell lines can be time consuming and inefficient due to the surgical procedures involved to establish the tumour. This study assesses the benefits of replacing traditional invasive surgical orthotopic implantation of two hepatic tumour cell lines with a minimally invasive ultrasound guided approach. Tumour growth of both implantation methods were assessed using ultrasound and bioluminescence, as well as duration of surgery and animal recovery time. In addition, the immune landscape of both implantation methods was assessed using flow cytometry. Methods: Hep3B and Hepa 1-6 cells were transfected with luciferase for bioluminescence imaging. Hep3B-luc or Hepa 1-6-luc cells were orthotopically injected into the left liver lobe of C57BL/6 mice via either conventional surgery or ultrasound guided injection. Tumour growth was measured using both Ultrasound (Fujifilm Vevo 3100 imaging system, Visualsonics) and bioluminescence (IVIS® Spectrum in vivo imaging system, Perkin Elmer). Surgery times were recorded as the duration each animal was under anaesthesia. Recovery times were reported as the time animals were held in recovery before returning to their cage. An in house validated flow cytometry T cell panel was used to assess T cell infiltration in the Hepa1-6 syngeneic model. Results: A comparison of tumour volume versus tumour associated bioluminescence demonstrated good correlation between both methods for each cell line. The duration of surgery and post implantation recovery times were significantly reduced for mice that underwent ultrasound-guided implantation compared to surgery, as well as fewer post-operative clinical observations. No significant difference in body weight was observed throughout the study. T cell infiltration by flow cytometry assessment enabled further evaluation of potential differences in the immune landscape of Hepa 1-6 tumours. Conclusion: Ultrasound guided implantation of orthotopic hepatic tumours is a minimally invasive technique that leads to improved recovery times for animals, which adheres to the principles of the 3R’s. The time taken for ultrasound guided implantation compared to traditional surgical methods was also significantly reduced, enabling a higher throughput of animals on study. Tumour growth kinetics in both Hep3B and Hepa 1-6 models were comparable between the 2 methods. Citation Format: Chris Payne, Yasmin Amer, Ruth Storer, Ganisha Hutchinson, Lucy Harris, Amanda Miles, Yinfei Yin. Comparison between surgical and ultrasound-guided orthotopic implantation of hepatocellular carcinoma models in mice using ultrasound and bioluminescence imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1660.

Degradable smart composite foams for bone regeneration

Degradable scaffolds with high porosity, certain mechanical and shape memory properties and biocompatibility are ideal materials in the field of bone tissue engineering for minimally invasive surgical implantation methods. In this study, we prepared porous scaffolds using hydrophilic polyethylene glycol and degradable polycaprolactone as raw materials and calcium citrate/amorphous calcium phosphate as hybrid particles, via sequential gas foaming, salt leaching and freeze drying methods. The fabricated bone scaffold exhibited adjustable mechanical properties and pore structure, with high shape fixation (>94.5%) and shape recovery (>87%) in thermal cycling and excellent shape memory properties under simulated body fluid immersion near body temperature. Moreover, in cell proliferation and live/dead cell activity assay experiments, the scaffolds promoted the proliferation of mesenchymal stem cells (MSCs). Immunofluorescence staining assay experiments further showed that the scaffolds had strong expressions of human type Ⅰ collagen (Col I) and alkaline phosphatase (ALP) in bone matrix. The material is expected to be a potential alternative material for bone tissue engineering.

Electronic Drugs: Spatial and Temporal Medical Treatment of Human Diseases.

Recent advances in diagnostics and medicines emphasize the spatial and temporal aspects of monitoring and treating diseases. However, conventional therapeutics, including oral administration and injection, have difficulties meeting these aspects due to physiological and technological limitations, such as long-term implantation and a narrow therapeutic window. As an innovative approach to overcome these limitations, electronic devices known as electronic drugs (e-drugs) have been developed to monitor real-time body signals and deliver specific treatments to targeted tissues or organs. For example, ingestible and patch-type e-drugs could detect changes in biomarkers at the target sites, including the gastrointestinal (GI) tract and the skin, and deliver therapeutics to enhance healing in a spatiotemporal manner. However, medical treatments often require invasive surgical procedures and implantation of medical equipment for either short or long-term use. Therefore, approaches that could minimize implantation-associated side effects, such as inflammation and scar tissue formation, while maintaining high functionality of e-drugs, are highly needed. Herein, the importance of the spatial and temporal aspects of medical treatment is thoroughly reviewed along with how e-drugs use cutting-edge technological innovations to deal with unresolved medical challenges. Furthermore, diverse uses of e-drugs in clinical applications and the future perspectives of e-drugs are discussed.

A perfusable, multifunctional epicardial device improves cardiac function and tissue repair.

Despite advances in technologies for cardiac repair after myocardial infarction (MI), new integrated therapeutic approaches still need to be developed. In this study, we designed a perfusable, multifunctional epicardial device (PerMed) consisting of a biodegradable elastic patch (BEP), permeable hierarchical microchannel networks (PHMs) and a system to enable delivery of therapeutic agents from a subcutaneously implanted pump. After its implantation into the epicardium, the BEP is designed to provide mechanical cues for ventricular remodeling, and the PHMs are designed to facilitate angiogenesis and allow for infiltration of reparative cells. In a rat model of MI, implantation of the PerMed improved ventricular function. When connected to a pump, the PerMed enabled targeted, sustained and stable release of platelet-derived growth factor-BB, amplifying the efficacy of cardiac repair as compared to the device without a pump. We also demonstrated the feasibility of minimally invasive surgical PerMed implantation in pigs, demonstrating its promise for clinical translation to treat heart disease.

Osteonecrosis of the Femoral Head Safely Healed with Autologous, Expanded, Bone Marrow-Derived Mesenchymal Stromal Cells in a Multicentric Trial with Minimum 5 Years Follow-Up.

Background: Osteonecrosis (ON) of the femoral head represents a potentially severe disease of the hip where the lack of bone regeneration may lead to femoral head collapse and secondary osteoarthritis, with serious pain and disability. The aim of this European, multicentric clinical trial was to prove safety and early efficacy to heal early femoral head ON in patients through minimally invasive surgical implantation of autologous mesenchymal stromal cells (MSC) expanded from bone marrow (BM) under good manufacturing practices (GMP). Methods: Twenty-two patients with femoral head ON (up to ARCO 2C) were recruited and surgically treated in France, Germany, Italy and Spain with BM-derived, expanded autologous MSC (total dose 140 million MSC in 7 mL). The investigational advanced therapy medicinal product (ATMP) was expanded from BM under the same protocol in all four countries and approved by each National Competent Authority. Patients were followed during two years for safety, based on adverse events, and for efficacy, based on clinical assessment (pain and hip score) and imaging (X-rays and MRIs). Patients were also reviewed after 5 to 6 years at latest follow-up for final outcome. Results: No severe adverse event was recalled as related to the ATMP. At 12 months, 16/20 per protocol and 16/22 under intention-to-treat (2 drop-out at 3 and 5 months) maintained head sphericity and showed bone regeneration. Of the 4 hips with ON progression, 3 required total hip replacement (THR). At 5 years, one patient (healed at 2 years visit) was not located, and 16/21 showed no progression or THR, 4/21 had received THR (all in the first year) and 1 had progressed one stage without THR. Conclusions: Expanded MSCs implantation was safe. Early efficacy was confirmed in 80% of cases under protocol at 2 years. At 5 years, the overall results were maintained and 19% converted to THR, all in the first year.

3D printing of Pickering emulsion inks to construct poly(D,L-lactide-co-trimethylene carbonate)-based porous bioactive scaffolds with shape memory effect

Biocompatible and bioactive scaffolds with multiscale porosity, shape memory effect and drug delivery performance are highly promising in bone tissue engineering applications within the approach of minimally invasive surgical implantation. In this study, we report an effective method to fabricate multiscale porous bioactive (MPB) scaffolds with shape memory effect by freeze drying of 3D printed high internal phase Pickering emulsion (Pickering HIPE) templates stabilized by hydrophobically modified hydroxyapatite and silica nanoparticles. MPB scaffolds containing a shape memory polymer matrix of poly(D,L-lactide-co-trimethylene carbonate) display high porosity and fully interconnected filament networks with multiscale pore structures. The in vitro biomineralization study verifies that MPB scaffolds are bioactive with the apatite formation ability. The thermal property testing shows that the glass transition temperature of MPB scaffolds is easily tuned to fall between 45.9 and 49.1 °C by varying the HIPE composition. Moreover, MPB scaffolds exhibit observable shape memory properties with fast shape recovery. The antibacterial drug enrofloxacin can be efficiently loaded into MPB scaffolds and then released in a sustained manner displaying effective antimicrobial effect. Furthermore, cell culture assays confirm that MPB scaffolds could sustain the cell growth, proliferation and osteogenic differentiation, indicating the cytocompatibility and osteoinduction activity of MPB scaffolds. Therefore, combining freeze drying with 3D printing of Pickering HIPE templates paves the way towards MPB scaffolds with shape memory effect, which are promising as minimally invasive implantation scaffolds in bone tissue engineering applications.

Feasibility of Non-Invasive Vagus Nerve Stimulation (gammaCore VET™) for the Treatment of Refractory Seizure Activity in Dogs.

Idiopathic epilepsy is the most common chronic neurologic condition in dogs. Approximately 20–30% of those dogs are refractory to standard medical therapy and commonly experience side effects from antiepileptic drugs. Non-invasive vagus nerve stimulation (nVNS) has been frequently used in human medicine as an adjunct seizure therapy with low incidence of adverse events. Canine studies are limited to invasive surgical implants with no non-invasive evaluations currently published. We investigated the feasibility and efficacy of nVNS (gammaCore VET) as an adjunct treatment for refractory epilepsy in dogs. In total, 14 client-owned dogs completed the trial of either 8- or 16-week treatment periods during which they received 90–120 s stimulation three times per day in the region of the left cervical vagus nerve. Owners recorded seizure type (focal or generalized) and frequency as well as any adverse effects. Out of 14 dogs, nine achieved a reduction in seizure frequency and four were considered responders with a 50% or greater reduction in seizures from baseline to the final treatment period. However, there was no statistically significant difference in overall seizure frequency (p = 0.53) or percent change in seizure frequency between groups (p = 0.75). Adverse effects occurred in 25% of dogs originally enrolled, with reports of a hoarse bark and limb trembling, lethargy, behavioral changes, and an increase in seizure frequency. Non-invasive VNS was found to be safe and easy to administer with mild adverse events. It is considered a feasible treatment option as an adjunct therapy in refractory seizures and should be further investigated.

Minimally Invasive Gastric Electrical Stimulation Using a Newly Developed Wireless Gastrostimulator: A Pilot Animal Study.

Background/AimsGastric electrical stimulation (GES) is a feasible modality for the treatment of gastroparesis; however, the presently available device requires invasive surgical implantation for long-term stimulation and repeated surgical procedure after a period of time. This study is aimed at developing a wireless miniature GES device and testing its endoscopic insertion in animal models.MethodsEndoscopic gastric implantation of the GES device was performed on 5 healthy weaner pigs under general anesthesia. We created an endoscopic submucosal pocket and inserted the gastro-electrical stimulator. In vivo gastric slow waves were recorded and measured during electrical stimulation. A multi-channel recorder, called an electrogastrogram, was used to record the gastric myoelectrical activity in the study.ResultsThe gastric slow waves on the electrogastrogram were more consistent with GES on the gastric tissues compared to no stimulation. The frequency-to-amplitude ratio was also significantly altered after the electrical stimulation.ConclusionsGES is feasible with our minimally invasive wireless device. This technique has the potential to increase utilization of GES as a treatment alternative.

Novel percutaneous dual-lumen cannula-based right ventricular assist device provides effective support for refractory right ventricular failure after left ventricular assist device implantation.

Right heart failure after left ventricular assist device (LVAD) implantation is associated with significant morbidity and mortality. A new generation of percutaneous right ventricular assist devices (RVADs) may mitigate the need for invasive surgical RVAD implantation. The purpose of this study was to evaluate the safety and efficacy of the Protek Duo (TandemLife, Pittsburgh, PA, USA) RVAD in patients who developed severe acute right heart failure in the intensive care unit after LVAD implantation. This was a retrospective cohort study of 27 patients who received a Protek Duo after LVAD implantation from January 2016 to March 2019 at our centre. The primary outcome of interest was survival to hospital discharge. Secondary outcomes included procedural success, device-related complications and conversion to a surgical RVAD. The median age of patients was 63 years (interquartile range 58-71), 78% were men and 78% were Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1 or 2. Patients were on a median of 2 inotropes and 2 pressors prior to Protek Duo insertion. The device successfully implanted on the first attempt in all patients a median of 1 day (interquartile range 1-2) after LVAD implantation and the median duration of support was 11 days (interquartile range 7-16). Device weaning occurred in 86% of patients, with 15% in-hospital mortality. Major complications related to the device included new moderate-to-severe tricuspid regurgitation (36%), haemolysis (14%) and cannula migration (7%). Three patients (11%) required conversion to surgical RVAD. Overall survival to 1 year was 81%. The use of the Protek Duo as a percutaneous RVAD is a safe and feasible treatment for patients who develop acute right heart failure after LVAD implantation.

Subject-Specific, Non-Invasive Helmet-Restraint RF Coil for Awake, Non-Human Primate MR Imaging

The purpose of this study was to develop a non-invasive restraint helmet integrated with an radio frequency (RF) coil for awake-behaving non-human primate MR imaging. To prevent image-corrupting motion, the head needs to be immobilized, which is currently achieved via invasive surgical headpost implants. In this work, an RF coil holder was integrated into the design of a subject-specific helmet to place the coil in closest distance to the head for improved signal-to-noise ratio (SNR). Additive manufacturing was used to print the helmet based upon computed tomography images of the subject. A single channel transmit/receive loop coil was designed using electromagnetic simulations loaded with a voxel-based monkey head model. The Rhesus macaque used in this study underwent behavioral training based on positive reinforcement before engaging in MR imaging. Imaging was performed using the helmet coil, which was successful in immobilizing the macaque head in an awake, unanesthetized subject. Results showed improved SNR by approximately 30% compared to a loop coil used with an implanted head post, and minimal motion artifact in structural imaging. The non-invasive helmet coil eliminates the need for permanently implanting monkeys with a headpost, provides the necessary head immobilization, and allows the use of more subjects for neuroimaging studies.

Simple minimally-invasive automatic antidote delivery device (A2D2) towards closed-loop reversal of opioid overdose

With approximately 48,000 attributed deaths in 2017, the opioid overdose is now the leading cause of death amongst Americans under the age of 50. The overdose process can be interrupted by the administration of naloxone, a safe and effective opiate antagonist that can reverse the effects of overdose and minimizing the delay in administering the antidote is critical in preventing permanent damage to patients. A closed-loop implantable drug delivery system is an ideal solution to minimize the response time, however, they often feature complex designs that are expensive to fabricate and require a more invasive surgical implantation. Here we propose a simple, low-cost, minimally-invasive automatic antidote delivery device (A2D2) that can administer a large dose of naloxone upon detection of overdose-induced respiratory failure. The subcutaneously placed device can be activated using an externally applied time varying magnetic field from a wearable device. Using a custom magnetic field generator, we were able to release the drug within 10 s. Our bench-top evaluation showed that A2D2 can release 1.9 mg of powdered drug within 60 s and up to 8.8 mg in 600 s. We also performed in vivo evaluation to demonstrate rapid drug releasing capability in the subcutaneous space of mice. However, we saw a small amount of leakage (1.75% of payload) over the course of 1000 h of simulated implantation. Thus, additional research is needed to verify the long term stability of our device and to demonstrate the closed-loop release mechanism to revive overdosed animals. Nevertheless, our preliminary results show the potential of using a simple, low-cost, subcutaneous device for emergency drug delivery application.

Mutant KCNJ3 and KCNJ5 Potassium Channels as Novel Molecular Targets in Bradyarrhythmias and Atrial Fibrillation.

Bradyarrhythmia is a common clinical manifestation. Although the majority of cases are acquired, genetic analysis of families with bradyarrhythmia has identified a growing number of causative gene mutations. Because the only ultimate treatment for symptomatic bradyarrhythmia has been invasive surgical implantation of a pacemaker, the discovery of novel therapeutic molecular targets is necessary to improve prognosis and quality of life. We investigated a family containing 7 individuals with autosomal dominant bradyarrhythmias of sinus node dysfunction, atrial fibrillation with slow ventricular response, and atrioventricular block. To identify the causative mutation, we conducted the family-based whole exome sequencing and genome-wide linkage analysis. We characterized the mutation-related mechanisms based on the pathophysiology in vitro. After generating a transgenic animal model to confirm the human phenotypes of bradyarrhythmia, we also evaluated the efficacy of a newly identified molecular-targeted compound to upregulate heart rate in bradyarrhythmias by using the animal model. We identified one heterozygous mutation, KCNJ3 c.247A>C, p.N83H, as a novel cause of hereditary bradyarrhythmias in this family. KCNJ3 encodes the inwardly rectifying potassium channel Kir3.1, which combines with Kir3.4 (encoded by KCNJ5) to form the acetylcholine-activated potassium channel ( IKACh channel) with specific expression in the atrium. An additional study using a genome cohort of 2185 patients with sporadic atrial fibrillation revealed another 5 rare mutations in KCNJ3 and KCNJ5, suggesting the relevance of both genes to these arrhythmias. Cellular electrophysiological studies revealed that the KCNJ3 p.N83H mutation caused a gain of IKACh channel function by increasing the basal current, even in the absence of m2 muscarinic receptor stimulation. We generated transgenic zebrafish expressing mutant human KCNJ3 in the atrium specifically. It is interesting to note that the selective IKACh channel blocker NIP-151 repressed the increased current and improved bradyarrhythmia phenotypes in the mutant zebrafish. The IKACh channel is associated with the pathophysiology of bradyarrhythmia and atrial fibrillation, and the mutant IKACh channel ( KCNJ3 p.N83H) can be effectively inhibited by NIP-151, a selective IKACh channel blocker. Thus, the IKACh channel might be considered to be a suitable pharmacological target for patients who have bradyarrhythmia with a gain-of-function mutation in the IKACh channel.

Shape Recovery with Concomitant Mechanical Strengthening of Amphiphilic Shape Memory Polymers in Warm Water.

Maintaining adequate or enhancing mechanical properties of shape memory polymers (SMPs) after shape recovery in an aqueous environment are greatly desired for biomedical applications of SMPs as self-fitting tissue scaffolds or minimally invasive surgical implants. Here we report stable temporary shape fixing and facile shape recovery of biodegradable triblock amphiphilic SMPs containing a poly(ethylene glycol) (PEG) center block and flanking poly(lactic acid) or poly(lactic-co-glycolic acid) blocks in warm water, accompanied by concomitant enhanced mechanical strengths. Differential scanning calorimetry (DSC), wide-angle X-ray diffraction (WXRD), and small-angle X-ray scattering (SAXS) analyses revealed that the unique stiffening of the amphiphilic SMPs upon hydration was due to hydration-driven microphase separation and PEG crystallization. We further demonstrated that the chemical composition of degradable blocks in these SMPs could be tailored to affect the persistence of hydration-induced stiffening upon subsequent dehydration. These properties combined open new horizons for these amphiphilic SMPs for smart weight-bearing in vivo applications (e.g., as self-fitting intervertebral discs). This study also provides a new material design strategy to strengthen polymers in aqueous environment in general.

Effect of reinforcement volume fraction and orientation on a hybrid tissue engineered aortic heart valve with a tubular leaflet design

Transcatheter aortic valve implantation of fibrin-based tissue engineered heart valves with a tubular leaflet construct have been developed as an alternative to invasive traditional surgical heart valve implantation. In general, they are well suited for the pulmonary position, but display insufficient mechanical properties for the aortic position. To enable the application of tissue-engineered valves in the systemic circulation, the tissue is reinforced with a textile scaffold. The current study seeks to compare the effect of varying the fiber volume fraction and orientation of bidirectional textile reinforcement on the closed-valve configuration. An anisotropic large deformation material model based on structural tensors was chosen and the materials were characterized. A finite element model was constructed of the heart valve, and the pinching and suturing of the corners along with application of pressure was simulated. Virtual experiments were conducted with fiber volume fractions of 0.1, 0.01, 0.001, and 0.0001 for ±45° fiber orientations. Furthermore, volume fraction was held at 0.01 and fiber orientations of 0°, ±15°, ±30°, ±45°, ±60°, ±75° and 90° from the tube’s axial direction were simulated and compared. It was shown that increasing the fiber volume fraction decreased the maximum principle strain in the valve, but lead to less closure. Additionally, the effect of fiber orientation affected the strains differently at different locations, depending on the local deformed geometry. This indicates that a non-uniform fiber distribution using tailored fiber placement could be used to optimize reinforcement design.

Novel mitral repair device for the treatment of severe mitral regurgitation: preclinical ovine acute and chronic implantation model.

A project is now underway to implement a novel percutaneous mitral repair system for severe mitral regurgitation (MR). The initial phase of the project consists of proof-of-concept by testing device characteristics using open surgical implantation. When surgical proof-of-concept of the intended percutaneous design is completed, a second phase of the project will consist of in vivo testing of the percutaneous transseptal system. The device is currently being designed to fold into a 17F catheter system and to unfold within the left atrium where attachment is accomplished using a reversible anchoring system. The purpose of this study was to show functionality of the device in elimination of MR using the open surgical method. We have performed surgical prototype device implantation in 5 acute and 7 chronic sheep preparations. We created a P2-flail model of severe (4+) MR in the 12 sheep. Via a minimally invasive left thoracotomy incision and open repair on cardiopulmonary bypass, the device was implanted to determine efficacy of elimination of severe MR. Implantation was considered successful if 4+ regurgitation was converted to 1+ MR or lower. Left ventriculography and epicardial 2-dimensional/3-dimensional echocardiography were used to assess repair; serial 2-dimensional/3-dimensional transthoracic echocardiography was used to assess long-term mitral repair status. Twelve sheep had surgical creation of severe (4+) MR by cutting all chordae to the P2 scallop of the mitral valve; this preparation was tested and was found to produce 100% acute fatality without repair of the mitral valve. Five sheep had acute implantation of the device with elimination of regurgitation in 5/5 sheep. Seven sheep had chronic (1-7 month) implantation of the device. The device was tested in the chronic model for clinical status, residual regurgitation, thrombosis, and histopathology. All sheep had mitigation of MR and survived to the intended date of death. Proof-of-concept of a novel percutaneous mitral repair device has been completed using an ovine P2-flail severe MR model. The device has characteristics that will allow its use in posterior leaflet degenerative disease and functional/secondary MR. Open, minimally invasive, and robotic surgical implantation of the device can also be developed as an alternative to the percutaneous approach.