RESUMO
Successful innovation clusters are notoriously difficult to establish, and many attempts fail. How can we go about designing such systems reliably? We describe how ecosystems can be strengthened through grassroots bottom-up efforts that empower user and community innovation, as opposed to economic policies that dictate innovation. Specifically focusing on the healthcare industry, we advocate that community hospitals which constitute 90% of all hospitals in Canada are the ideal setting for such community innovation efforts. We investigated the distribution of innovation output from hospitals over the past 13 years and found a decrease in predominance of major teaching hospitals, supporting the potential role for community hospitals in this space. We categorize different types of innovations and recommend institutional policies that can sustain bottom-up, micro-level efforts. Such policies could improve and enhance the development of micro-innovations and the creation of health innovation clusters.
RESUMO
Direct delivery of fluid to brain parenchyma is critical in both research and clinical settings. This is usually accomplished through acutely inserted cannulas. This technique, however, results in backflow and significant dispersion away from the infusion site, offering little spatial or temporal control in delivering fluid. We present an implantable, MRI-compatible, remotely controlled drug delivery system for minimally invasive interfacing with brain microstructures in freely moving animals. We show that infusions through acutely inserted needles target a region more than twofold larger than that of identical infusions through chronically implanted probes due to reflux and backflow. We characterize the dynamics of in vivo infusions using positron emission tomography techniques. Volumes as small as 167 nL of copper-64 and fludeoxyglucose labeled agents are quantified. We further demonstrate the importance of precise drug volume dosing to neural structures to elicit behavioral effects reliably. Selective modulation of the substantia nigra, a critical node in basal ganglia circuitry, via muscimol infusion induces behavioral changes in a volume-dependent manner, even when the total dose remains constant. Chronic device viability is confirmed up to 1-y implantation in rats. This technology could potentially enable precise investigation of neurological disease pathology in preclinical models, and more efficacious treatment in human patients.
Assuntos
Gânglios da Base/diagnóstico por imagem , Cobre/farmacologia , Sistemas de Liberação de Medicamentos , Fluordesoxiglucose F18/farmacologia , Imageamento por Ressonância Magnética/métodos , Substância Negra/diagnóstico por imagem , Animais , Sistemas de Liberação de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/métodos , RatosRESUMO
Enhanced understanding of neuropathologies has created a need for more advanced tools. Current neural implants result in extensive glial scarring and are not able to highly localize drug delivery due to their size. Smaller implants reduce surgical trauma and improve spatial resolution, but such a reduction requires improvements in device design to enable accurate and chronic implantation in subcortical structures. Flexible needle steering techniques offer improved control over implant placement, but often require complex closed-loop control for accurate implantation. This study reports the development of steerable microinvasive neural implants (S-MINIs) constructed from borosilicate capillaries (OD = 60 µm, ID = 20 µm) that do not require closed-loop guidance or guide tubes. S-MINIs reduce glial scarring 3.5-fold compared to prior implants. Bevel steered needles are utilized for open-loop targeting of deep-brain structures. This study demonstrates a sinusoidal relationship between implant bevel angle and the trajectory radius of curvature both in vitro and ex vivo. This relationship allows for bevel-tipped capillaries to be steered to a target with an average error of 0.23 mm ± 0.19 without closed-loop control. Polished microcapillaries present a new microinvasive tool for chronic, predictable targeting of pathophysiological structures without the need for closed-loop feedback and complex imaging.
Assuntos
Procedimentos Cirúrgicos Robóticos/métodos , Animais , Encéfalo/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Desenho de Equipamento , Feminino , Humanos , Microscopia de Fluorescência/métodos , Imagens de Fantasmas , Ratos , Ratos Endogâmicos F344 , SuínosRESUMO
Aberrantly high levels of tyrosine-phosphorylated signal transducer and activator of transcription 3 (p-STAT3) are found constitutively in ~50% of human lung and breast cancers, acting as an oncogenic transcription factor. We previously demonstrated that Manuka honey (MH) inhibits p-STAT3 in breast cancer cells, but the exact mechanism remained unknown. Herein, we show that MH-mediated inhibition of p-STAT3 in breast (MDA-MB-231) and lung (A549) cancer cell lines is accompanied by decreased levels of gp130 and p-JAK2, two upstream components of the IL-6 receptor (IL-6R) signaling pathway. Using an ELISA-based assay, we demonstrate that MH binds directly to IL-6Rα, significantly inhibiting (~60%) its binding to the IL-6 ligand. Importantly, no evidence of MH binding to two other cytokine receptors, IL-11Rα and IL-8R, was found. Moreover, MH did not alter the levels of tyrosine-phosphorylated or total Src family kinases, which are also constitutively activated in cancer cells, suggesting that signaling via other growth factor receptors is unaffected by MH. Binding of five major MH flavonoids (luteolin, quercetin, galangin, pinocembrin, and chrysin) was also tested, and all but pinocembrin could demonstrably bind IL-6Rα, partially (30-35%) blocking IL-6 binding at the highest concentration (50 µM) used. In agreement, each flavonoid inhibited p-STAT3 in a dose-dependent manner, with estimated IC50 values in the 3.5-70 µM range. Finally, docking analysis confirmed the capacity of each flavonoid to bind in an energetically favorable configuration to IL-6Rα at a site predicted to interfere with ligand binding. Taken together, our findings identify IL-6Rα as a direct target of MH and its flavonoids, highlighting IL-6R blockade as a mechanism for the anti-tumor activity of MH, as well as a viable therapeutic target in IL-6-dependent cancers.
Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Mel , Receptores de Interleucina-6/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Antineoplásicos/química , Comunicação Autócrina/efeitos dos fármacos , Produtos Biológicos/química , Linhagem Celular Tumoral , Humanos , Janus Quinase 2/metabolismo , Fosforilação/efeitos dos fármacos , Ligação Proteica , Fator de Transcrição STAT3/metabolismo , Células Tumorais CultivadasRESUMO
Constant exposure to blue light emanating from screens, lamps, digital devices, or other artificial sources at night can suppress melatonin secretion, potentially compromising both sleep quality and overall health. Daytime exposure to elevated levels of blue light can also lead to permanent damage to the eyes. Here, we have developed blue light protective plasmonic contact lenses (PCLs) to mitigate blue light exposure. Crafted from poly(hydroxyethyl methacrylate) (pHEMA) and infused with silver nanoparticles, these contact lenses serve as a protective barrier to filter blue light. Leveraging the plasmonic properties of silver nanoparticles, the lenses effectively filtered out the undesirable blue light (400-510 nm), demonstrating substantial protection (22-71%) while maintaining high transparency (80-96%) for the desirable light (511-780 nm). The maximum protection level reaches a peak of 79% at 455 nm, aligned with the emission peak for the blue light sourced from LEDs in consumer displays. The presence of silver nanoparticles was found to have an insignificant impact on the water content of the developed contact lenses. The lenses maintained high water retention levels within the range of 50-70 wt %, comparable to commercial contact lenses. The optical performance of the developed lenses remains unaffected in both artificial tears and contact lens storage solution over a month with no detected leakage of the nanoparticles. Additionally, the MTT assay confirmed that the lenses were biocompatible and noncytotoxic, maintaining cell viability at over 85% after 24 h of incubation. These lenses could be a potential solution to protect against the most intense wavelengths emitted by consumer displays and offer a remedy to counteract the deleterious effects of prolonged blue light exposure.
RESUMO
Ingestible electronics have the capacity to transform our ability to effectively diagnose and potentially treat a broad set of conditions. Current applications could be significantly enhanced by addressing poor electrode-tissue contact, lack of navigation, short dwell time, and limited battery life. Here we report the development of an ingestible, battery-free, and tissue-adhering robotic interface (IngRI) for non-invasive and chronic electrostimulation of the gut, which addresses challenges associated with contact, navigation, retention, and powering (C-N-R-P) faced by existing ingestibles. We show that near-field inductive coupling operating near 13.56 MHz was sufficient to power and modulate the IngRI to deliver therapeutically relevant electrostimulation, which can be further enhanced by a bio-inspired, hydrogel-enabled adhesive interface. In swine models, we demonstrated the electrical interaction of IngRI with the gastric mucosa by recording conductive signaling from the subcutaneous space. We further observed changes in plasma ghrelin levels, the "hunger hormone," while IngRI was activated in vivo, demonstrating its clinical potential in regulating appetite and treating other endocrine conditions. The results of this study suggest that concepts inspired by soft and wireless skin-interfacing electronic devices can be applied to ingestible electronics with potential clinical applications for evaluating and treating gastrointestinal conditions.
Assuntos
Grelina , Animais , Suínos , Grelina/metabolismo , Grelina/sangue , Robótica/instrumentação , Mucosa Gástrica/metabolismo , Estimulação Elétrica/instrumentação , Terapia por Estimulação Elétrica/instrumentação , Terapia por Estimulação Elétrica/métodos , Feminino , Humanos , Fontes de Energia Elétrica , Trato Gastrointestinal , EletrodosRESUMO
Localization and tracking of ingestible microdevices in the gastrointestinal (GI) tract is valuable for the diagnosis and treatment of GI disorders. Such systems require a large field-of-view of tracking, high spatiotemporal resolution, wirelessly operated microdevices and a non-obstructive field generator that is safe to use in practical settings. However, the capabilities of current systems remain limited. Here, we report three dimensional (3D) localization and tracking of wireless ingestible microdevices in the GI tract of large animals in real time and with millimetre-scale resolution. This is achieved by generating 3D magnetic field gradients in the GI field-of-view using high-efficiency planar electromagnetic coils that encode each spatial point with a distinct magnetic field magnitude. The field magnitude is measured and transmitted by the miniaturized, low-power and wireless microdevices to decode their location as they travel through the GI tract. This system could be useful for quantitative assessment of the GI transit-time, precision targeting of therapeutic interventions and minimally invasive procedures.
RESUMO
The gut-brain axis, which is mediated via enteric and central neurohormonal signaling, is known to regulate a broad set of physiological functions from feeding to emotional behavior. Various pharmaceuticals and surgical interventions, such as motility agents and bariatric surgery, are used to modulate this axis. Such approaches, however, are associated with off-target effects or post-procedure recovery time and expose patients to substantial risks. Electrical stimulation has also been used to attempt to modulate the gut-brain axis with greater spatial and temporal resolution. Electrical stimulation of the gastrointestinal (GI) tract, however, has generally required invasive intervention for electrode placement on serosal tissue. Stimulating mucosal tissue remains challenging because of the presence of gastric and intestinal fluid, which can influence the effectiveness of local luminal stimulation. Here, we report the development of a bioinspired ingestible fluid-wicking capsule for active stimulation and hormone modulation (FLASH) capable of rapidly wicking fluid and locally stimulating mucosal tissue, resulting in systemic modulation of an orexigenic GI hormone. Drawing inspiration from Moloch horridus, the "thorny devil" lizard with water-wicking skin, we developed a capsule surface capable of displacing fluid. We characterized the stimulation parameters for modulation of various GI hormones in a porcine model and applied these parameters to an ingestible capsule system. FLASH can be orally administered to modulate GI hormones and is safely excreted with no adverse effects in porcine models. We anticipate that this device could be used to treat metabolic, GI, and neuropsychiatric disorders noninvasively with minimal off-target effects.
Assuntos
Fome , Robótica , Animais , Suínos , HormôniosRESUMO
The majority of biomedical research is funded by public, governmental, and philanthropic grants. These initiatives often shape the avenues and scope of research across disease areas. However, the prioritization of disease-specific funding is not always reflective of the health and social burden of each disease. We identify a prioritization disparity between lung and breast cancers, whereby lung cancer contributes to a substantially higher socioeconomic cost on society yet receives significantly less funding than breast cancer. Using search engine results and natural language processing (NLP) of Twitter tweets, we show that this disparity correlates with enhanced public awareness and positive sentiment for breast cancer. Interestingly, disease-specific venture activity does not correlate with funding or public opinion. We use outcomes from recent early-stage innovation events focused on lung cancer to highlight the complementary mechanism by which bottom-up "grass-roots" initiatives can identify and tackle under-prioritized conditions.
RESUMO
Long-term treatment outcomes for patients with high grade ovarian cancers have not changed despite innovations in therapies. There is no recommended assay for predicting patient response to second-line therapy, thus clinicians must make treatment decisions based on each individual patient. Patient-derived xenograft (PDX) tumors have been shown to predict drug sensitivity in ovarian cancer patients, but the time frame for intraperitoneal (IP) tumor generation, expansion, and drug screening is beyond that for tumor recurrence and platinum resistance to occur, thus results do not have clinical utility. We describe a drug sensitivity screening assay using a drug delivery microdevice implanted for 24 h in subcutaneous (SQ) ovarian PDX tumors to predict treatment outcomes in matched IP PDX tumors in a clinically relevant time frame. The SQ tumor response to local microdose drug exposure was found to be predictive of the growth of matched IP tumors after multi-week systemic therapy using significantly fewer animals (10 SQ vs 206 IP). Multiplexed immunofluorescence image analysis of phenotypic tumor response combined with a machine learning classifier could predict IP treatment outcomes against three second-line cytotoxic therapies with an average AUC of 0.91.
RESUMO
Healthcare innovation is impeded by high costs, the need for diverse skillsets, and complex regulatory processes. The COVID-19 pandemic exposed critical gaps in the current framework, especially those lying at the boundary between cutting-edge academic research and industry-scale manufacturing and production. While many resource-rich geographies were equipped with the required expertise to solve challenges posed by the pandemic, mechanisms to unite the appropriate institutions and scale up, fund, and mobilize solutions at a time-scale relevant to the emergency were lacking. We characterize the orthogonal spatial and temporal axes that dictate innovation. Improving on their limitations, we propose a "pre-emptive innovation infrastructure" incorporating in-house hospital innovation teams, consortia-based assembly of expertise, and novel funding mechanisms to combat future emergencies. By leveraging the strengths of academic, medical, government, and industrial institutions, this framework could improve ongoing innovation and supercharge the infrastructure for healthcare emergencies.
RESUMO
The field of electroceuticals has attracted considerable attention over the past few decades as a novel therapeutic modality. The gastrointestinal (GI) tract (GIT) holds significant potential as a target for electroceuticals as the intersection of neural, endocrine, and immune systems. We review recent developments in electrical stimulation of various portions of the GIT (including esophagus, stomach, and small and large intestine) and nerves projecting to the GIT and supportive organs. This has been tested with varying degrees of success for several dysmotility, inflammatory, hormonal, and neurologic disorders. We outline a vision for the future of GI electroceuticals, building on advances in mechanistic understanding of GI physiology coupled with novel ingestible technologies. The next wave of electroceutical therapies will be minimally invasive and more targeted than current approaches, making them an indispensable tool in the clinical armamentarium.
Assuntos
Estimulação Elétrica , Gastroenteropatias , Humanos , Preparações FarmacêuticasRESUMO
The vast majority of techniques to study the physiology of the nervous system involve inserting probes into the brain for stimulation, recording, or sampling. Research is increasingly uncovering the fine microstructure of the brain, each of its regions with dedicated functions. Accurate knowledge of the placement of probes interrogating these regions is critical. We have developed a customizable concentric marking electrode (CME) consisting of an iron core within a 125 µm-stainless steel (SS) sheath for co-localization of targeted regions in the brain. We used a dielectric layer stack of SiO2, Al2O3, SiO2 to electrically encapsulate the iron core and minimize exposure area to avoid significant increases in inflammatory response triggered by the probes. The CME can record multi-neuronal extracellular firing patterns. Appropriate electrical polarity of the iron and SS components controls the deposition of iron microdeposits on brain tissue. We show that in vivo labels by this method can be as small as 100 µm, visible via noninvasive magnetic resonance imaging (MRI) as well as post-mortem histology, and illustrate how deposit size can be tuned by varying stimulus parameters. We targeted the CA3 area of the hippocampus in adult rats and demonstrate that iron microdeposits are remarkably stable and persist up to 10 months post-deposition. Using a single probe for recording and marking avoids inaccuracies with re-insertion of separate probes and utilizes iron microdeposits as valuable fiducial markers in vivo and ex vivo.
Assuntos
Encéfalo , Dióxido de Silício , Animais , Encéfalo/diagnóstico por imagem , Eletrodos , Hipocampo , Imageamento por Ressonância Magnética , RatosRESUMO
Treatments for neurologic diseases are often limited in efficacy due to poor spatial and temporal control over their delivery. Intracerebral delivery partially overcomes this by directly infusing therapeutics to the brain. Brain structures, however, are nonuniform and irregularly shaped, precluding complete target coverage by a single bolus without significant off-target effects and possible toxicity. Nearly complete coverage is crucial for effective modulation of these structures. We present a framework with computational mapping algorithms for neural drug delivery (COMMAND) to guide multi-bolus targeting of brain structures that maximizes coverage and minimizes off-target leakage. Custom-fabricated chronic neural implants leverage rational fluidic design to achieve multi-bolus delivery in rodents through a single infusion of radioactive tracer (Cu-64). The resulting spatial distributions replicate computed spatial coverage with 5% error in vivo, as detected by positron emission tomography. COMMAND potentially enables accurate, efficacious targeting of discrete brain regions.
Assuntos
Biologia Computacional/métodos , Sistemas de Liberação de Medicamentos/métodos , Implantes de Medicamento/metabolismo , Preparações Farmacêuticas/metabolismo , Algoritmos , Animais , Humanos , CamundongosRESUMO
Strategies to split ventilators to support multiple patients requiring ventilatory support have been proposed and used in emergency cases in which shortages of ventilators cannot otherwise be remedied by production or procurement strategies. However, the current approaches to ventilator sharing lack the ability to individualize ventilation to each patient, measure pulmonary mechanics, and accommodate rebalancing of the airflow when one patient improves or deteriorates, posing safety concerns to patients. Potential cross-contamination, lack of alarms, insufficient monitoring, and inability to adapt to sudden changes in patient status have prevented widespread acceptance of ventilator sharing. We have developed an individualized system for augmenting ventilator efficacy (iSAVE) as a rapidly deployable platform that uses a single ventilator to simultaneously and more safely support two individuals. The iSAVE enables individual-specific volume and pressure control and the rebalancing of ventilation in response to improvement or deterioration in an individual's respiratory status. The iSAVE incorporates mechanisms to measure pulmonary mechanics, mitigate cross-contamination and backflow, and accommodate sudden flow changes due to individual interdependencies within the respiratory circuit. We demonstrate these capacities through validation using closed- and open-circuit ventilators on linear test lungs. We show that the iSAVE can temporarily ventilate two pigs on one ventilator as efficaciously as each pig on its own ventilator. By leveraging off-the-shelf medical components, the iSAVE could rapidly expand the ventilation capacity of health care facilities during emergency situations such as pandemics.
Assuntos
Pandemias , Ventiladores Mecânicos , Animais , Humanos , Pulmão , SuínosRESUMO
The nationwide opioid epidemic has substantially impacted economically-depressed regions in the USA. Eastern Appalachia has some of the lowest socioeconomic indicators in the USA and has suffered the highest rate of opioid-related fatality in 2016. Despite devoting considerable federal and state resources towards public health initiatives, the region continued to experience one of the highest death rates and sought alternative approaches to address the opioid crisis. Here, we describe a community-based co-creation initiative that convened diverse sectors and utilised design thinking principles to generate sustainable public health ventures towards addressing the opioid crisis. Participants of diverse backgrounds came together to attack key challenges and developed and implemented solutions, including a mobile application for naloxone delivery and exercise programs for high schools to promote healthy habits. Grassroots innovation efforts catalysed by the event strengthened community engagement and facilitated a sense of agency among participants. Through specific examples of initiatives that were launched, we provide evidence to encourage and highlight the value of healthcare innovation efforts in low-resource settings.
RESUMO
Liquid medication overdose in pediatric patients results in over 70000 visits to the emergency room yearly in the USA. Various studies have demonstrated that the root cause of this high incidence is due to user and device error in dose measurement. The standard measuring cup and syringe suffer from the challenge of accurately measuring and dispensing viscous liquids, which comprise the majority of children's medication formulations. Here, we describe the development of a precision medication dispenser that overcomes challenges associated with viscous fluid flow at low volumes and flow rates, while incorporating various ergonomic and user-friendly features. The device performs with >95% accuracy and 94% precision across the 1-5-mL range of volume, a significant improvement when compared to current commercially available dispensers.