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Wound healing is a complex physiological process that requires precise control and modulation of many parameters. Therapeutic ion and biomolecule delivery has the capability to regulate the wound healing process beneficially. However, achieving controlled delivery through a compact device with the ability to deliver multiple therapeutic species can be a challenge. Bioelectronic devices have emerged as a promising approach for therapeutic delivery. Here, we present a pro-reparative bioelectronic device designed to deliver ions and biomolecules for wound healing applications. The device incorporates ion pumps for the targeted delivery of H+ and zolmitriptan to the wound site. In vivo studies using a mouse model further validated the device's potential for modulating the wound environment via H+ delivery that decreased M1/M2 macrophage ratios. Overall, this bioelectronic ion pump demonstrates potential for accelerating wound healing via targeted and controlled delivery of therapeutic agents to wounds. Continued optimization and development of this device could not only lead to significant advancements in tissue repair and wound healing strategies but also reveal new physiological information about the dynamic wound environment.

The ability to deliver drugs with precise dosages at specific time points can significantly improve disease treatment while reducing side effects. Drug encapsulation for gradual delivery has opened the doors for a superior treatment regimen. To expand on this ability, programming bioelectronic devices to deliver small molecules enables ad-hoc personalized therapeutic profiles that are more complex than gradual release. Here, a wearable bioelectronic device with an integrated electrophoretic ion pump that affords on-demand drug delivery with precise dose control is introduced. Delivery of fluoxetine to wounds in mice result in a 27.2% decrease in the macrophage ratio (M1/M2) and a 39.9% increase in re-epithelialization, indicating a shorter inflammatory phase and faster overall healing. Programmable drug delivery using wearable bioelectronics in wounds introduces a broadly applicable strategy for the long-term delivery of a prescribed treatment regimen with minimal external intervention.

Precise modulation of brain activity is fundamental for the proper establishment and maturation of the cerebral cortex. To this end, cortical organoids are promising tools to study circuit formation and the underpinnings of neurodevelopmental disease. However, the ability to manipulate neuronal activity with high temporal resolution in brain organoids remains limited. To overcome this challenge, we introduce a bioelectronic approach to control cortical organoid activity with the selective delivery of ions and neurotransmitters. Using this approach, we sequentially increased and decreased neuronal activity in brain organoids with the bioelectronic delivery of potassium ions (K+) and γ-aminobutyric acid (GABA), respectively, while simultaneously monitoring network activity. This works highlights bioelectronic ion pumps as tools for high-resolution temporal control of brain organoid activity toward precise pharmacological studies that can improve our understanding of neuronal function.

The development of wearable bioelectronic systems is a promising approach for optimal delivery of therapeutic treatments. These systems can provide continuous delivery of ions, charged biomolecules, and an electric field for various medical applications. However, rapid prototyping of wearable bioelectronic systems for controlled delivery of specific treatments with a scalable fabrication process is challenging. We present a wearable bioelectronic system comprised of a polydimethylsiloxane (PDMS) device cast in customizable 3D printed molds and a printed circuit board (PCB), which employs commercially available engineering components and tools throughout design and fabrication. The system, featuring solution-filled reservoirs, embedded electrodes, and hydrogel-filled capillary tubing, is assembled modularly. The PDMS and PCB both contain matching through-holes designed to hold metallic contact posts coated with silver epoxy, allowing for mechanical and electrical integration. This assembly scheme allows us to interchange subsystem components, such as various PCB designs and reservoir solutions. We present three PCB designs: a wired version and two battery-powered versions with and without onboard memory. The wired design uses an external voltage controller for device actuation. The battery-powered PCB design uses a microcontroller unit to enable pre-programmed applied voltages and deep sleep mode to prolong battery run time. Finally, the battery-powered PCB with onboard memory is developed to record delivered currents, which enables us to verify treatment dose delivered. To demonstrate the functionality of the platform, the devices are used to deliver H[Formula: see text] in vivo using mouse models and fluoxetine ex vivo using a simulated wound environment. Immunohistochemistry staining shows an improvement of 35.86% in the M1/M2 ratio of H[Formula: see text]-treated wounds compared with control wounds, indicating the potential of the platform to improve wound healing.

Abstract The Periacetabular Osteotomy is a technically demanding procedure that requires precise intraoperative evaluation of pelvic anatomy. Fluoroscopic images pose a radiation risk to operating room staff, scrubbed personnel, and the patient. Most commonly, a Standard Fluoroscope with an Image Intensifier is used. Our institution recently implemented the novel Fluoroscope with a Flat Panel Detector. The purpose of this study was to compare radiation dosage and accuracy between the two fluoroscopes. A retrospective review of a consecutive series of patients who underwent Periacetabular Osteotomy for symptomatic hip dysplasia was completed. The total radiation exposure dose (mGy) was recorded and compared for each case from the standard fluoroscope (n = 27) and the flat panel detector (n = 26) cohorts. Lateral center edge angle was measured and compared intraoperatively and at the six-week postoperative visit. A total of 53 patients (96% female) with a mean age and BMI of 17.84 (± 6.84) years and 22.66 (± 4.49) kg/m2 (standard fluoroscope) and 18.23 (± 4.21) years and 21.99 (± 4.00) kg/m2 (flat panel detector) were included. The standard fluoroscope averaged total radiation exposure to be 410.61(± 193.02) mGy, while the flat panel detector averaged 91.12 (± 49.64) mGy (p

Background Racial and ethnic minority groups are underrepresented among patients undergoing aortic valve replacement in the United States. We evaluated the impact of race and ethnicity on the diagnosis of aortic stenosis (AS). Methods and Results In patients with transthoracic echocardiography (TTE)-confirmed AS, we assessed rates of AS diagnosis as defined by assignment of an International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) code for AS within a large multicenter electronic health record. Multivariable Cox proportional hazard and competing risk regression models were used to evaluate the 1-year rate of AS diagnosis by race and ethnicity. Among 14 800 patients with AS, the 1-year diagnosis rate for AS following TTE was 37.4%. Increasing AS severity was associated with an increased likelihood of receiving an AS diagnosis (moderate: hazard ratio [HR], 3.05 [95% CI, 2.86-3.25]; P

Rad And Gem-Like GTP-Binding Protein 2 (Rem2), a member of the RGK family of Ras-like GTPases, is implicated in Huntington’s disease and Long QT Syndrome and is highly expressed in the brain and endocrine cells. We examine the evolutionary history of Rem2 identified in various mammalian species, focusing on the role of purifying selection and coevolution in shaping its sequence and protein structural constraints. Our analysis of Rem2 sequences across 175 mammalian species found evidence for strong purifying selection in 70% of non-invariant codon sites which is characteristic of essential proteins that play critical roles in biological processes and is consistent with Rem2’s role in the regulation of neuronal development and function. We inferred epistatic effects in 50 pairs of codon sites in Rem2, some of which are predicted to have deleterious effects on human health. Additionally, we reconstructed the ancestral evolutionary history of mammalian Rem2 using protein structure prediction of extinct and extant sequences which revealed the dynamics of how substitutions that change the gene sequence of Rem2 can impact protein structure in variable regions while maintaining core functional mechanisms. By understanding the selective pressures, protein- and gene - interactions that have shaped the sequence and structure of the Rem2 protein, we gain a stronger understanding of its biological and functional constraints.

Background: Uncontrolled asthma (UCA) is different from severe asthma and can be identified in children across all ranges of prescribed treatment. Objective: Our aim was to characterize uncontrolled childhood asthma in pediatric specialist care. Methods: We performed a nationwide cross-sectional study of 5497 children (aged 6-17 years) with asthma who were treated by pediatricians at outpatient clinics during 2019 and registered in the Swedish National Airway Register. UCA was defined as an Asthma Control Test score of 19 or lower and/or 2 or more exacerbations in the past year and/or an FEV1 value less than 80% predicted. Treatment was categorized from step 1 to step 5 according to the Global Initiative for Asthma. Results: UCA was identified in 1690 children (31%), of whom 64% had an Asthma Control Test score of 19 or lower, 20% had recurrent exacerbations, and 31% had an FEV1 value less than 80% predicted. UCA was associated with female sex (odds ratio [OR] = 1.29 [95% CI = 1.15-1.45]), older age (OR = 1.02 [95% CI = 1.00-1.04]), obesity (OR = 1.43 [95% CI = 1.12-1.83]), and more treatment using steps 1 and 2 as a reference (step 3, OR = 1.28 [95% CI = 1.12-1.46]); steps 4-5, OR = 1.32 [95% CI = 1.10-1.57]). UCA in children prescribed treatment steps 1 and 2 (group UCA1-2) occurred in 28% of all children at this treatment step (n = 887). Children in group UCA1-2 had exacerbations more frequently than did those children with UCA who were prescribed steps 4 and 5 treatment (24% vs 15% [P = .001]). Conclusion: UCA was common and associated with female sex, increasing age, obesity, and higher Global Initiative for Asthma treatment step. Surprisingly, UCA was also common in children prescribed less than the maximum treatment, and those children could be considered undertreated patients.

Abstract The development of wearable bioelectronic systems is a promising approach for optimal delivery of therapeutic treatments. These systems can provide continuous delivery of ions, charged biomolecules, and an electric field for various medical applications. However, rapid prototyping of wearable bioelectronic systems for controlled delivery of specific treatments with a scalable fabrication process is challenging. We present a wearable bioelectronic system comprised of a polydimethylsiloxane (PDMS) device cast in customizable 3D printed molds and a printed circuit board (PCB), which employs commercially available engineering components and tools throughout design and fabrication. The system, featuring solution-filled reservoirs, embedded electrodes, and hydrogel-filled capillary tubing, is assembled modularly. The PDMS and PCB both contain matching through-holes designed to hold metallic contact posts coated with silver epoxy, allowing for mechanical and electrical integration. This assembly scheme allows us to interchange subsystem components, such as various PCB designs and reservoir solutions. We present three PCB designs: a wired version and two battery-powered versions with and without onboard memory. The wired design uses an external voltage controller for device actuation. The battery-powered PCB design uses a microcontroller unit to enable pre-programmed applied voltages and deep sleep mode to prolong battery run time. Finally, the battery-powered PCB with onboard memory is developed to record delivered currents, which enables us to verify treatment dose delivered. To demonstrate the functionality of the platform, the devices are used to deliver H $$^+$$ + in vivo using mouse models and fluoxetine ex vivo using a simulated wound environment. Immunohistochemistry staining shows an improvement of 35.86% in the M1/M2 ratio of H $$^+$$ + —treated wounds compared with control wounds, indicating the potential of the platform to improve wound healing.

BACKGROUND: Clinical guidelines recommend patients with aortic stenosis (AS) being considered for transcatheter aortic valve implantation or surgical aortic valve replacement to participate in shared decision-making (SDM) with a heart valve team (HVT). Data supporting these recommendations are limited. This project gathered data on feasibility and preliminary efficacy of a decision aid (DA) in decision-making for patients with severe AS deciding between transcatheter aortic valve implantation and surgical aortic valve replacement. METHODS: This institutional review board-approved randomized pilot trial assigned eligible patients to receive either the American College of Cardiologys DA for patients with AS or usual care. Patients were surveyed after their visit regarding knowledge, treatment-preference concordance, SDM (SDM process and CollaboRATE Scales), and decisional conflict. Patients were followed for 3 months to collect data on treatment received. RESULTS: Of 62 patients approached, 59 (95%) consented and participated. The average age of participants was 72 years, they were 100% white, and 32% of them were female. Intervention patients had higher knowledge scores (75.6 vs 65.5) and more frequently reported CollaboRATE top scores (67% vs 33%) than usual care patients. No other group comparisons reached significance. Patients who saw both members of the HVT before survey completion reported higher SDM process scores than those who saw only 1 specialist (3.1 vs 2.4). CONCLUSIONS: The study exceeded enrollment targets, indicating feasibility. Results suggest the American College of Cardiologys DA improved patient knowledge and communication scores. Patients who met with both members of the HVT reported higher SDM. These observations highlight the importance of SDM and multidisciplinary HVT assessment in the management of severe AS.

Organ-on-a-chip systems combine microfluidics, cell biology, and tissue engineering to culture 3D organ-specific in vitro models that recapitulate the biology and physiology of their in vivo counterparts. Here, we have developed a multiplex platform that automates the culture of individual organoids in isolated microenvironments at user-defined media flow rates. Programmable workflows allow the use of multiple reagent reservoirs that may be applied to direct differentiation, study temporal variables, and grow cultures long term. Novel techniques in polydimethylsiloxane (PDMS) chip fabrication are described here that enable features on the upper and lower planes of a single PDMS substrate. RNA sequencing (RNA-seq) analysis of automated cerebral cortex organoid cultures shows benefits in reducing glycolytic and endoplasmic reticulum stress compared to conventional in vitro cell cultures.

Bioelectronic devices can provide an interface for feedback control of biological processes in real-time based on sensor information tracking biological response. The main control challenges are guaranteeing system convergence in the presence of saturating inputs into the bioelectronic device and complexities from indirect control of biological systems. In this paper, we first derive a saturated-based robust sliding mode control design for a partially unknown nonlinear system with disturbance. Next, we develop a data informed model of a bioelectronic device for in silico simulations. Our controller is then applied to the model to demonstrate controlled pH of a target area. A modular control architecture is chosen to interface the bioelectronic device and controller with a bistable phenomenological model of wound healing to demonstrate closed-loop biological treatment. External pH is regulated by the bioelectronic device to accelerate wound healing, while avoiding chronic inflammation. Our novel control algorithm for bioelectronic devices is robust and requires minimum information about the device for broad applicability. The control architecture makes it adaptable to any biological system and can be used to enhance automation in bioengineering to improve treatments and patient outcomes.

Background: This study evaluates the change in an MRI of the proximal metacarpal region in a group of sport horses that returned to work. This retrospective analysis evaluated 18 limbs represented by 17 horses. Results: The hyperintense signal within the dorsal collagenous part of the proximal suspensory ligament (PSL) on T1W/T2*W GRE sequences decreased or stayed the same in the majority of cases. The hyperintense STIR signal within the dorsal collagenous part of the PSL resolved in the majority of the patients, and the third metacarpal bone (McIII) hyperintense STIR signal resolved in all patients. The dorsal margin irregularity of the PSL stayed the same, and McIII sclerosis and resorption of the palmar margin of McIII stayed the same in the majority of cases. McIII hyperintense STIR signal resolution carries a broad time range, with a mean of 94 days and a range of 47–202 days. Conclusions: Complete normalization of the dorsal collagenous part of the PSL does not appear necessary for a return to soundness, but a resolution of the McIII hyperintense STIR signal is expected for horses returning to soundness. A rescan period of 120 days for the proximal metacarpal region is suggested. In addition, there was no significant change in the size of the PSL between the initial and final MRI.

Background Concerns about discordance between echocardiographic and invasive mean gradients after transcatheter aortic valve replacement (TAVR) with balloon-expandable valves (BEVs) versus self-expanding valves (SEVs) exist. Methods and Results In a multicenter study, direct-invasive and echocardiography-derived transvalvular mean gradients obtained before and after TAVR were compared as well as post-TAVR and discharge echocardiographic mean gradients in BEVs versus SEVs in 808 patients. Pre-TAVR, there was good correlation (R=0.614; P

AimsImpaired physical function is common in patients undergoing transcatheter aortic valve replacement (TAVR) and associated with worse outcomes. Participation in centre-based cardiac rehabilitation (CR) after cardiovascular procedures is sub-optimal. We aimed to test a home-based mobile health exercise intervention as an alternative or complementary approach.Methods and resultsAt five centres, after a run-in period, eligible individuals treated with TAVR were randomized 1:1 at their 1-month post-TAVR visit to an intervention group [activity monitor (AM) with personalized daily step goal and resistance exercises] or a control group for 6 weeks. Among 50 participants, average age was 76 years, 34% were female, average STS score was 2.91.8, and 40% had Short Physical Performance Battery (SPPB) 9. Daily compliance with wearing the AM and performing exercises averaged 8590%. In the intention to treat population, there was no evidence that the intervention improved the co-primary endpoints: daily steps +769 (95% CI 244 to +1783); SPPB +0.68 (0.27 to 1.53); and Kansas City Cardiomyopathy Questionnaire 1.7 (9.1 to 7.1). The intervention did improve secondary physical activity parameters, including moderate-to-intense daily active minutes (P

Simultaneous longitudinal imaging across multiple conditions and replicates has been crucial for scientific studies aiming to understand biological processes and disease. Yet, imaging systems capable of accomplishing these tasks are economically unattainable for most academic and teaching laboratories around the world. Here, we propose the Picroscope, which is the first low-cost system for simultaneous longitudinal biological imaging made primarily using off-the-shelf and 3D-printed materials. The Picroscope is compatible with standard 24-well cell culture plates and captures 3D z-stack image data. The Picroscope can be controlled remotely, allowing for automatic imaging with minimal intervention from the investigator. Here, we use this system in a range of applications. We gathered longitudinal whole organism image data for frogs, zebrafish, and planaria worms. We also gathered image data inside an incubator to observe 2D monolayers and 3D mammalian tissue culture models. Using this tool, we can measure the behavior of entire organisms or individual cells over long-time periods.