Miniature battery-free epidural cortical stimulators.

Miniaturized neuromodulation systems could improve the safety and reduce the invasiveness of bioelectronic neuromodulation. However, as implantable bioelectronic devices are made smaller, it becomes difficult to store enough power for long-term operation in batteries. Here, we present a battery-free epidural cortical stimulator that is only 9 millimeters in width yet can safely receive enough wireless power using magnetoelectric antennas to deliver 14.5-volt stimulation bursts, which enables it to stimulate cortical activity on-demand through the dura. The device has digitally programmable stimulation output and centimeter-scale alignment tolerances when powered by an external transmitter. We demonstrate that this device has enough power and reliability for real-world operation by showing acute motor cortex activation in human patients and reliable chronic motor cortex activation for 30 days in a porcine model. This platform opens the possibility of simple surgical procedures for precise neuromodulation.

Magnetoelectrics enables large power delivery to mm-sized wireless bioelectronics.

To maximize the capabilities of minimally invasive implantable bioelectronic devices, we must deliver large amounts of power to small implants; however, as devices are made smaller, it becomes more difficult to transfer large amounts of power without a wired connection. Indeed, recent work has explored creative wireless power transfer (WPT) approaches to maximize power density [the amount of power transferred divided by receiver footprint area (length × width)]. Here, we analyzed a model for WPT using magnetoelectric (ME) materials that convert an alternating magnetic field into an alternating voltage. With this model, we identify the parameters that impact WPT efficiency and optimize the power density. We find that improvements in adhesion between the laminated ME layers, clamping, and selection of material thicknesses lead to a power density of 3.1 mW/mm2, which is over four times larger than previously reported for mm-sized wireless bioelectronic implants at a depth of 1 cm or more in tissue. This improved power density allows us to deliver 31 and 56 mW to 10 and 27-mm2 ME receivers, respectively. This total power delivery is over five times larger than similarly sized bioelectronic devices powered by radiofrequency electromagnetic waves, inductive coupling, ultrasound, light, capacitive coupling, or previously reported magnetoelectrics. This increased power density opens the door to more power-intensive bioelectronic applications that have previously been inaccessible using mm-sized battery-free devices.

Magnetoelectrics Enables Large Power Delivery to mm-Sized Wireless Bioelectronics.

To maximize the capabilities of minimally invasive implantable bioelectronic devices, we must deliver large amounts of power to small implants; however, as devices are made smaller, it becomes more difficult to transfer large amounts of power without a wired connection. Indeed, recent work has explored creative wireless power transfer (WPT) approaches to maximize power density (the amount of power transferred divided by receiver footprint area (length × width)). Here, we analyzed a model for WPT using magnetoelectric (ME) materials that convert an alternating magnetic field into an alternating voltage. With this model, we identify the parameters that impact WPT efficiency and optimize the power density. We find that improvements in adhesion between the laminated ME layers, clamping, and selection of material thicknesses lead to a power density of 3.1 mW/mm 2 , which is over 4 times larger than previously reported for mm-sized wireless bioelectronic implants at a depth of 1 cm or more in tissue. This improved power density allows us to deliver 31 mW and 56 mW to 10-mm 2 and 27-mm 2 ME receivers, respectively. This total power delivery is over 5 times larger than similarly sized bioelectronic devices powered by radiofrequency electromagnetic waves, inductive coupling, ultrasound, light, capacitive coupling, or previously reported magnetoelectrics. This increased power density opens the door to more power-intensive bioelectronic applications that have previously been inaccessible using mm-sized battery-free devices.

Magnetoelectric Bio-Implants Powered and Programmed by a Single Transmitter for Coordinated Multisite Stimulation.

This paper presents a hardware platform including stimulating implants wirelessly powered and controlled by a shared transmitter for coordinated leadless multisite stimulation. The adopted novel single-transmitter, multiple-implant structure can flexibly deploy stimuli, improve system efficiency, easily scale stimulating channel quantity and relieve efforts in device synchronization. In the proposed system, a wireless link leveraging magnetoelectric effects is co-designed with a robust and efficient system-on-chip to enable reliable operation and individual programming of every implant. Each implant integrates a 0.8-mm2 chip, a 6-mm2 magnetoelectric film, and an energy storage capacitor within a 6.2-mm3 size. Magnetoelectric power transfer is capable of safely transmitting milliwatt power to devices placed several centimeters away from the transmitter coil, maintaining good efficiency with size constraints and tolerating 60-degree, 1.5-cm misalignment in angular and lateral movement. The SoC robustly operates with 2-V source amplitude variations that spans a 40-mm transmitter-implant distance change, realizes individual addressability through physical unclonable function IDs, and achieves 90% efficiency for 1.5-to-3.5-V stimulation with fully programmable stimulation parameters.

A wireless millimetric magnetoelectric implant for the endovascular stimulation of peripheral nerves.

Implantable bioelectronic devices for the simulation of peripheral nerves could be used to treat disorders that are resistant to traditional pharmacological therapies. However, for many nerve targets, this requires invasive surgeries and the implantation of bulky devices (about a few centimetres in at least one dimension). Here we report the design and in vivo proof-of-concept testing of an endovascular wireless and battery-free millimetric implant for the stimulation of specific peripheral nerves that are difficult to reach via traditional surgeries. The device can be delivered through a percutaneous catheter and leverages magnetoelectric materials to receive data and power through tissue via a digitally programmable 1 mm × 0.8 mm system-on-a-chip. Implantation of the device directly on top of the sciatic nerve in rats and near a femoral artery in pigs (with a stimulation lead introduced into a blood vessel through a catheter) allowed for wireless stimulation of the animals' sciatic and femoral nerves. Minimally invasive magnetoelectric implants may allow for the stimulation of nerves without the need for open surgery or the implantation of battery-powered pulse generators.

Distributed sensor and actuator networks for closed-loop bioelectronic medicine.

Designing implantable bioelectronic systems that continuously monitor physiological functions and simultaneously provide personalized therapeutic solutions for patients remains a persistent challenge across many applications ranging from neural systems to bioelectronic organs. Closed-loop systems typically consist of three functional blocks, namely, sensors, signal processors and actuators. An effective system, that can provide the necessary therapeutics, tailored to individual physiological factors requires a distributed network of sensors and actuators. While significant progress has been made, closed-loop systems still face many challenges before they can truly be considered as long-term solutions for many diseases. In this review, we consider three important criteria where materials play a critical role to enable implantable closed-loop systems: Specificity, Biocompatibility and Connectivity. We look at the progress made in each of these fields with respect to a specific application and outline the challenges in creating bioelectronic technologies for the future.

An Integrated Primary Care Initiative for Child Health in Northern Togo.

OBJECTIVES: To determine if the Integrated Community-Based Health Systems-Strengthening (ICBHSS) initiative was effective in expanding health coverage, improving care quality, and reducing child mortality in Togo. METHODS: Population-representative cross-sectional household surveys adapted from the Demographic Household Survey and Multiple Indicator Cluster Surveys were conducted at baseline (2015) and then annually (2016-2020) in 4 ICBHSS catchment sites in Kara, Togo. The primary outcome was under-5 mortality, with health service coverage and health-seeking behavior as secondary outcomes. Costing analyses were calculated by using "top-down" methodology with audited financial statements and programmatic data. RESULTS: There were 10 022 household surveys completed from 2015 to 2020. At baseline (2015), under-5 mortality was 51.1 per 1000 live births (95% confidence interval [CI]: 35.5-66.8), and at the study end period (2020), under-5 mortality was 35.8 (95% CI: 23.4-48.2). From 2015 to 2020, home-based treatment by a community health worker increased from 24.1% (95% CI: 21.9%-26.4%) to 45.7% (95% CI: 43.3%-48.2%), and respondents reporting prenatal care in the first trimester likewise increased (37.5% to 50.1%). Among respondents who sought care for a child with fever, presenting for care within 1 day increased from 51.9% (95% CI: 47.1%-56.6%) in 2015 to 80.3% (95% CI: 74.6%-85.0%) in 2020. The estimated annual additional intervention cost was $8.84 per person. CONCLUSIONS: Our findings suggest that the ICBHSS initiative, a bundle of evidence-based interventions implemented with a community-based strategy, improves care access and quality and was associated with reduction in child mortality.

Wearable wireless power systems for 'ME-BIT' magnetoelectric-powered bio implants.

Objective.Compared to biomedical devices with implanted batteries, wirelessly powered technologies can be longer-lasting, less invasive, safer, and can be miniaturized to access difficult-to-reach areas of the body. Magnetic fields are an attractive wireless power transfer modality for such bioelectronic applications because they suffer negligible absorption and reflection in biological tissues. However, current solutions using magnetic fields for mm sized implants either operate at high frequencies (>500 kHz) or require high magnetic field strengths (>10 mT), which restricts the amount of power that can be transferred safely through tissue and limits the development of wearable power transmitter systems. Magnetoelectric (ME) materials have recently been shown to provide a wireless power solution for mm-sized neural stimulators. These ME transducers convert low magnitude (<1 mT) and low-frequency (∼300 kHz) magnetic fields into electric fields that can power custom integrated circuits or stimulate nearby tissue.Approach.Here we demonstrate a battery-powered wearable magnetic field generator that can power a miniaturized MagnetoElectric-powered Bio ImplanT 'ME-BIT' that functions as a neural stimulator. The wearable transmitter weighs less than 0.5 lbs and has an approximate battery life of 37 h.Main results.We demonstrate the ability to power a millimeter-sized prototype 'ME-BIT' at a distance of 4 cm with enough energy to electrically stimulate a rat sciatic nerve. We also find that the system performs well under translational misalignment and identify safe operating ranges according to the specific absorption rate limits set by the IEEE Std 95.1-2019.Significance.These results validate the feasibility of a wearable system that can power miniaturized ME implants that can be used for different neuromodulation applications.

Wireless Power Delivery Techniques for Miniature Implantable Bioelectronics.

Progress in implanted bioelectronic technology offers the opportunity to develop more effective tools for personalized electronic medicine. While there are numerous clinical and pre-clinical applications for these devices, power delivery to these systems can be challenging. Wireless battery-free devices offer advantages such as a smaller and lighter device footprint and reduced failures and infections by eliminating lead wires. However, with the development of wireless technologies, there are fundamental tradeoffs between five essential factors: power, miniaturization, depth, alignment tolerance, and transmitter distance, while still allowing devices to work within safety limits. These tradeoffs mean that multiple forms of wireless power transfer are necessary for different devices to best meet the needs for a given biological target. Here six different types of wireless power transfer technologies used in bioelectronic implants-inductive coupling, radio frequency, mid-field, ultrasound, magnetoelectrics, and light-are reviewed in context of the five tradeoffs listed above. This core group of wireless power modalities is then used to suggest possible future bioelectronic technologies and their biological applications.

MagNI: A Magnetoelectrically Powered and Controlled Wireless Neurostimulating Implant.

This paper presents the first wireless and programmable neural stimulator leveraging magnetoelectric (ME) effects for power and data transfer. Thanks to low tissue absorption, low misalignment sensitivity and high power transfer efficiency, the ME effect enables safe delivery of high power levels (a few milliwatts) at low resonant frequencies (  âˆ¼ 250 kHz) to mm-sized implants deep inside the body (30-mm depth). The presented MagNI (Magnetoelectric Neural Implant) consists of a 1.5-mm 2 180-nm CMOS chip, an in-house built 4 × 2 mm ME film, an energy storage capacitor, and on-board electrodes on a flexible polyimide substrate with a total volume of 8.2 mm 3. The chip with a power consumption of 23.7  µW includes robust system control and data recovery mechanisms under source amplitude variations (1-V variation tolerance). The system delivers fully-programmable bi-phasic current-controlled stimulation with patterns covering 0.05-to-1.5-mA amplitude, 64-to-512- µs pulse width, and 0-to-200-Hz repetition frequency for neurostimulation.

Recent Advances in Electrical Neural Interface Engineering: Minimal Invasiveness, Longevity, and Scalability.

Electrical neural interfaces serve as direct communication pathways that connect the nervous system with the external world. Technological advances in this domain are providing increasingly more powerful tools to study, restore, and augment neural functions. Yet, the complexities of the nervous system give rise to substantial challenges in the design, fabrication, and system-level integration of these functional devices. In this review, we present snapshots of the latest progresses in electrical neural interfaces, with an emphasis on advances that expand the spatiotemporal resolution and extent of mapping and manipulating brain circuits. We include discussions of large-scale, long-lasting neural recording; wireless, miniaturized implants; signal transmission, amplification, and processing; as well as the integration of interfaces with optical modalities. We outline the background and rationale of these developments and share insights into the future directions and new opportunities they enable.

Magnetoelectric Materials for Miniature, Wireless Neural Stimulation at Therapeutic Frequencies.

A major challenge for miniature bioelectronics is wireless power delivery deep inside the body. Electromagnetic or ultrasound waves suffer from absorption and impedance mismatches at biological interfaces. On the other hand, magnetic fields do not suffer these losses, which has led to magnetically powered bioelectronic implants based on induction or magnetothermal effects. However, these approaches have yet to produce a miniature stimulator that operates at clinically relevant high frequencies. Here, we show that an alternative wireless power method based on magnetoelectric (ME) materials enables miniature magnetically powered neural stimulators that operate up to clinically relevant frequencies in excess of 100 Hz. We demonstrate that wireless ME stimulators provide therapeutic deep brain stimulation in a freely moving rodent model for Parkinson's disease and that these devices can be miniaturized to millimeter-scale and fully implanted. These results suggest that ME materials are an excellent candidate to enable miniature bioelectronics for clinical and research applications.

Childhood Leukemia and Primary Prevention.

Leukemia is the most common pediatric cancer, affecting 3800 children per year in the United States. Its annual incidence has increased over the last decades, especially among Latinos. Although most children diagnosed with leukemia are now cured, many suffer long-term complications, and primary prevention efforts are urgently needed. The early onset of leukemia-usually before 5 years of age-and the presence at birth of "pre-leukemic" genetic signatures indicate that pre- and postnatal events are critical to the development of the disease. In contrast to most pediatric cancers, there is a growing body of literature-in the United States and internationally-that has implicated several environmental, infectious, and dietary risk factors in the etiology of childhood leukemia, mainly for acute lymphoblastic leukemia, the most common subtype. For example, exposures to pesticides, tobacco smoke, solvents, and traffic emissions have consistently demonstrated positive associations with the risk of developing childhood leukemia. In contrast, intake of vitamins and folate supplementation during the preconception period or pregnancy, breastfeeding, and exposure to routine childhood infections have been shown to reduce the risk of childhood leukemia. Some children may be especially vulnerable to these risk factors, as demonstrated by a disproportionate burden of childhood leukemia in the Latino population of California. The evidence supporting the associations between childhood leukemia and its risk factors-including pooled analyses from around the world and systematic reviews-is strong; however, the dissemination of this knowledge to clinicians has been limited. To protect children's health, it is prudent to initiate programs designed to alter exposure to well-established leukemia risk factors rather than to suspend judgment until no uncertainty remains. Primary prevention programs for childhood leukemia would also result in the significant co-benefits of reductions in other adverse health outcomes that are common in children, such as detriments to neurocognitive development.

Maternal diet quality before pregnancy and risk of childhood leukaemia.

Previous studies on maternal nutrition and childhood leukaemia risk have focused on the role of specific nutrients such as folate and have not considered broader measures of diet quality, which may better capture intake of diverse nutrients known to impact fetal development. We examined the relationship between maternal diet quality before pregnancy, as summarised by a diet quality index, and risk of childhood acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) in a case-control study in California. Dietary intake in the year before pregnancy was assessed using FFQ in 681 ALL cases, 103 AML cases and 1076 matched controls. Conditional logistic regression was used to estimate OR and 95 % CI for diet quality continuous score and quartiles (Q1-Q4). Higher maternal diet quality score was associated with reduced risk of ALL (OR 0·66; 95 % CI 0·47, 0·93 for Q4 v. Q1) and possibly AML (OR 0·42; 95 % CI 0·15, 1·15 for Q4 v. Q1). No single index component appeared to account for the association. The association of maternal diet quality with risk of ALL was stronger in children diagnosed under the age of 5 years and in children of women who did not report using vitamin supplements before pregnancy. These findings suggest that the joint effects of many dietary components may be important in influencing childhood leukaemia risk.

Maternal prenatal intake of one-carbon metabolism nutrients and risk of childhood leukemia.

PURPOSE: Folate, vitamins B12 and B6, riboflavin, and methionine are critical nutrients for the one-carbon metabolism cycle involved in DNA synthesis and epigenetic processes. We examined the association between maternal intake of these nutrients before pregnancy and risk of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in a matched case-control study. METHODS: Maternal dietary intake and vitamin supplement use in the year before pregnancy was assessed by food frequency questionnaire for 681 ALL cases, 103 AML cases, and 1076 controls. Principal component analysis was used to construct a variable representing combined nutrient intake, and conditional logistic regression estimated the odds ratio (OR) and 95% confidence interval (CI) for the association of ALL and AML with the principal component and each nutrient. RESULTS: Higher maternal intake of one-carbon metabolism nutrients from food and supplements combined was associated with reduced risk of ALL (OR for one-unit change in the principal component = 0.91, CI 0.84-0.99) and possibly AML (OR for the principal component = 0.83, CI 0.66-1.04). When analyzed separately, intake of supplements high in these nutrients was associated with a reduced risk of ALL in children of Hispanic women only. CONCLUSIONS: In conclusion, these data suggest that higher maternal intake of one-carbon metabolism nutrients may reduce risk of childhood leukemia.

Periconceptional folate consumption is associated with neonatal DNA methylation modifications in neural crest regulatory and cancer development genes.

Folate deficiency during early embryonic development constitutes a risk factor for neural tube defects and potentially for childhood leukemia via unknown mechanisms. We tested whether folate consumption during the 12 months prior to conception induced DNA methylation modifications at birth in healthy neonates with a genome-wide and agnostic approach. We hypothesized that DNA methylation in genes involved in neural tube development and/or cancer susceptibility would be affected by folate exposure. We retrospectively assessed folate exposure at the time of conception by food-frequency questionnaires administered to the mothers of 343 healthy newborns. We measured genome-wide DNA methylation from neonatal blood spots. We implemented a method based on bootstrap resampling to decrease false-positive findings. Folate was inversely associated with DNA methylation throughout the genome. Among the top folate-associated genes that were replicated in an independent Gambian study were TFAP2A, a gene critical for neural crest development, STX11, a gene implicated in acute myeloid leukemia, and CYS1, a candidate gene for cystic kidney disease. Reduced periconceptional folate intake was associated with increased methylation and, in turn, decreased gene expression at these 3 loci. The top folate-sensitive genes defined by their associated CpG sites were enriched for numerous transcription factors by Gene Set Enrichment Analysis, including those implicated in cancer development (e.g., MYC-associated zinc finger protein). The influence of estimated periconceptional folate intake on neonatal DNA methylation levels provides potential mechanistic insights into the role of this vitamin in the development of neural tube defects and childhood cancers.

Does Food Insecurity Undermine Adherence to Antiretroviral Therapy? A Systematic Review.

A growing body of research has identified food insecurity as a barrier to antiretroviral therapy (ART) adherence. We systematically reviewed and summarized the quantitative literature on food insecurity or food assistance and ART adherence. We identified nineteen analyses from eighteen distinct studies examining food insecurity and ART adherence. Of the thirteen studies that presented an adjusted effect estimate for the relationship between food insecurity and ART adherence, nine found a statistically significant association between food insecurity and sub-optimal ART adherence. Four studies examined the association between food assistance and ART adherence, and three found that ART adherence was significantly better among food assistance recipients than non-recipients. Across diverse populations, food insecurity is an important barrier to ART adherence, and food assistance appears to be a promising intervention strategy to improve ART adherence among persons living with HIV. Additional research is needed to determine the effectiveness and cost-effectiveness of food assistance in improving ART adherence and other clinical outcomes among people living with HIV in the era of widespread and long-term treatment.