Grid-Enabled Non-Invasive Blood Glucose Measurement

Abstract. Earth and life sciences are at the forefront to successfully include computational simulations and modeling. Medical applications are often mentioned as the killer applications for the Grid. The complex methodology and models of Traditional Chinese Medicine offer different approaches to diagnose and treat a persons health condition than typical Western medicine. A possibility to make this often hidden knowledge ex-plicit and available to a broader audience will result in mutual synergies for Western and Chinese medicine as well as improved patient care. This paper proposes the design and implementation of a method to accurately estimate blood glucose values using a novel non-invasive method based on electro-transformation measures in human body meridians. The frame-work used for this scientific computing collaboration, namely the China-Austria Data Grid (CADGrid) framework, provides an Intelligence Base offering commonly used models and algorithms as Web/Grid-Services. The controlled execution of the Non-Invasive Blood Glucose Measure-ment Service and the management of scientific data that arise from model execution can be seen as the first application on top of the CADGrid

Precision medicine and artificial intelligence : a pilot study on deep learning for hypoglycemic events detection based on ECG

Tracking the fluctuations in blood glucose levels is important for healthy subjects and crucial diabetic patients. Tight glucose monitoring reduces the risk of hypoglycemia, which can result in a series of complications, especially in diabetic patients, such as confusion, irritability, seizure and can even be fatal in specific conditions. Hypoglycemia affects the electrophysiology of the heart. However, due to strong inter-subject heterogeneity, previous studies based on a cohort of subjects failed to deploy electrocardiogram (ECG)-based hypoglycemic detection systems reliably. The current study used personalised medicine approach and Artificial Intelligence (AI) to automatically detect nocturnal hypoglycemia using a few heartbeats of raw ECG signal recorded with non-invasive, wearable devices, in healthy individuals, monitored 24 hours for 14 consecutive days. Additionally, we present a visualisation method enabling clinicians to visualise which part of the ECG signal (e.g., T-wave, ST-interval) is significantly associated with the hypoglycemic event in each subject, overcoming the intelligibility problem of deep-learning methods. These results advance the feasibility of a real-time, non-invasive hypoglycemia alarming system using short excerpts of ECG signal

Precision medicine and artificial intelligence : a pilot study on deep learning for hypoglycemic events detection based on ECG

Tracking the fluctuations in blood glucose levels is important for healthy subjects and crucial diabetic patients. Tight glucose monitoring reduces the risk of hypoglycemia, which can result in a series of complications, especially in diabetic patients, such as confusion, irritability, seizure and can even be fatal in specific conditions. Hypoglycemia affects the electrophysiology of the heart. However, due to strong inter-subject heterogeneity, previous studies based on a cohort of subjects failed to deploy electrocardiogram (ECG)-based hypoglycemic detection systems reliably. The current study used personalised medicine approach and Artificial Intelligence (AI) to automatically detect nocturnal hypoglycemia using a few heartbeats of raw ECG signal recorded with non-invasive, wearable devices, in healthy individuals, monitored 24 hours for 14 consecutive days. Additionally, we present a visualisation method enabling clinicians to visualise which part of the ECG signal (e.g., T-wave, ST-interval) is significantly associated with the hypoglycemic event in each subject, overcoming the intelligibility problem of deep-learning methods. These results advance the feasibility of a real-time, non-invasive hypoglycemia alarming system using short excerpts of ECG signal

당뇨병 의 최소침습 진단 및 약물 치료를 위한 방법론

학위논문 (박사) -- 서울대학교 대학원 : 공과대학 협동과정 바이오엔지니어링전공, 2021. 2. 최영빈.This dissertation is focused on design, fabrication and evaluation of a strip-type tear glucose sensor and an implantable magnetic pump for minimally-invasive diagnosis and drug therapy, respectively. Management of diabetes mellitus have been painful procedures to many patients, because the diagnosis included needled finger pricking with a lancet, and the drug therapy were conducted with needled injections. There have been research efforts to minimize the pain associated with the diabetes mellitus management, but still there are unmet drawbacks. Therefore, methodologies of minimally-invasive diagnosis and drug therapy are proposed in this study. First, a strip-type tear glucose sensor was developed for concurrent tear collection and measurement with a small tear volume. Current tear glucose measurement has drawbacks such as large tear sample volume, long tear collection time, discomfort to patients, and two-step procedure that require sample transfer from tear collector to measuring instruments. To resolve these issues, a highly-accurate strip-type electrochemical sensor was modified by reducing the volume of reaction chamber to 0.4 μl. Then the modified sensor and a 3D printed lid to ensure safety to the eye were assembled. The assembled sensor, or the tear-glucose device, could collect tear fluid sample within 2 seconds, and simultaneously measure tear glucose concentration accurately without sample transfer. Through animal experiments, a high correlation between tear glucose concentration and the blood glucose concentration were determined with the tear-glucose device. The Clarke error grid analysis suggested that the blood glucose concentration estimated from the tear glucose sensor showed acceptable accuracy compared to that measured with commercially available blood glucometer. In addition, an implantable magnetic pump enabled with on-demand bolus delivery of exenatide was developed. The magnetic pump could deliver a bolus of 11.4 ± 0.3 μg of exenatide for optimal exenatide delivery regimen. This magnetic pump was designed to be actuated with a patterned magnetic field, thus could prevent unintended actuations by a single household magnet. In addition, a flexible polyurethane drug container in the magnetic pump could resolve negative pressure issues that could occur in solid drug container. The magnetic pump could deliver up to 300 times without a drug replenishment. The absence of battery and the presence of refillable drug container enabled a semi-permanent usage of the magnetic pump. The magnetic pump showed a similar pharmacokinetic profile compared to the injection therapy. When implanted in type 2 diabetic animal models, the magnetic pump showed comparable efficacy to injection therapy, in terms of body weight change, food intake, glycemic control, insulin secretion, insulin sensitivity, gastric emptying rate, beta cell proliferation and adipocyte size reduction. Through these studies, it is concluded that the strip-type tear glucose sensor and the magnetically actuated pump developed herein could be suggested as methodologies to replace invasive finger pricking and injection therapy.많은 당뇨 병 환자들이 현재 채혈을 통한 진단 방법과 주사를 통한 약물 치료를 통해 혈당을 관리하고 있다. 이런 침습적인 진단 및 투약 방식은 환자들에게 많은 고통과 트라우마 굳은 살, 가려움증 및 염증 등의 부작용을 초래하는 문제점이 있다. 이를 해결하기 위해 본 논문에서는 당뇨 병 진단 및 약물치료를 위한 최소침습 방법론 을 제안하고자 한다. 먼저 채혈 진단 방식의 대안으로 눈물 내 당 농도, 즉 누당을 측정 하는 센서를 개발하였 다 누당은 혈당과 높은 상관관계를 보이는 까닭에 많은 진단 연구가 진행되었다. 그러나 많은 양의 눈물 샘플을 필요로 하며 이를 채취하는 시간이 길어져 환자에게 불편함과 고통을 야기하는 문제점이 있었다. 또한 눈물 샘플을 채취 장치에서 측정 장치로 옮기는 과정에서 발생하는 정확도의 하락과 불편함이 문제가 되었다. 이런 문제를 해결하기 위해 높은 정확도를 가지는 전기화학 센서를 개조하여 필요 눈물 양을 0.4 μl로 줄였으며, 3D 프린트 된 lid의 장착을 통하여 전안부 접촉 시에도 손상을 야기하지 않도록 하였다. 개조된 센서와 lid의 결합으로 구성된 tear-glucose device는 전안부에 접촉한 지 2 초 이내에 필요한 양의 샘플을 채취할 수 있었으며 채취와 동시에 누당 농도를 측정하였다. 동물 모델에 적용한 결과, tear-glucose device를 통해 혈당과 누당 간의 높은 상관관계를 확인할 수 있었다. 또한 Clarke error grid analysis결과, 개발된 tear-glucose device를 통해 계산된 혈당값이 이미 상용화된 혈당 측정기 대비 준수한 정확도를 보였음을 확인할 수 있었다. 다음으로 주사 약물 치료의 대안으로 이식형 약물전달 디바이스를 개발하였다. 현재 개발된 당뇨 병 관리용 이식형 약물전달 디바이스의 경우, 약물치료 regimen을 최적화하지 못하여 tachyphylaxis를 야기하거나 디바이스의 크기, 수명, 안전성에 문제가 있는 경우가 있었다. 이러한 문제를 해결하기 위해 패턴화된 자기력 구동 이식형 약물전달 펌프를 개발하였다. 본 펌프는 on-demand bolus 전달 방식을 통해 최적화된 약물치료 regimen을 구현하고, 배터리 대신 자기력 구동 방식을 사용해 디바이스의 크기, 수명 문제를 해결하고, 패턴화된 자기력을 사용함으로 안전성 문제를 해결하였다. 또한 폴리우레탄 약물저장소를 사용하여 고체 약물저장소에서 나타나는 음압으로 인한 방출 문제를 해결하였다. 본 펌프를 평가한 결과, 11.4 ± 0.3 μg의 exenatide를 약물 충전 없이 300 회 방출시킬 수 있었다. 동물 모델에서 평가한 결과 약력학 및 약동학에서 기존 주사 약물치료와 유사한 효과를 보였다. 본 연구를 통해 개발된 누당 측정 센서와, 자기력 구동 이식형 약물전달 펌프는 기존 사용되는 혈당측정기와 주사 약물치료 방법론과 유사한 효용성을 보이는 것을 확인하였다. 따라서 이는 침습적인 당뇨 병 의 진단 및 약물치료 방식의 대안으로 제시될 수 있을 것이라 기대 한다.Abstract ……………………………………………………………………… i Contents …………………………………………………………………… iv List of Tables ……………………………………………………………… vii List of Figures …………………………………………………………… viii Chapter 1. Introduction …………………………………………………… 1 1.1. Current management methodologies for diabetes mellitus……………. 1 1.2. Tear-based methodologies of minimally-invasive diagnosis for diabetes mellitus ……………………………………………………………………… 3 1.3. Implantable drug delivery device for minimally-invasive drug therapy for diabetes mellitus………………………………………………………………5 1.4. Current limitations and research aims ………………………………… 7 Chapter 2. Strip-type tear glucose sensor for concurrent tear collection and glucose measurement ………………………………………………… 9 2.1. Device design …………………………………………………………… 9 2.2. Methods ……………………………………………………………… 11 2.2.1. Lid ……………………………………………………………… 11 2.2.2. Strip-type glucose sensor ………………………………………… 14 2.2.3. In vitro evaluation ……………………………………………… 15 2.2.4. In vivo evaluation ……………………………………………… 17 2.2.5. Statistical analysis ……………………………………………… 18 2.3. Results ……………………………………………………………… 18 2.3.1. Tear-glucose device ……………………………………………… 18 2.3.2. In vitro performance evaluation ………………………………… 20 2.3.3. In vivo performance evaluation ………………………………… 20 2.3.4. In vivo safety evaluation ………………………………………… 26 2.4. Discussions …………………………………………………………… 28 Chapter 3. Implantable magnetic pump for bolus delivery of exenatide 33 3.1. Device design ………………………………………………………… 33 3.2. Methods ……………………………………………………………… 35 3.2.1. Materials ………………………………………………………… 35 3.2.2. Magnetic pump fabrication ……………………………………… 35 3.2.3. Magnetic design principles ……………………………………… 38 3.2.4. High-performance liquid chromatography measurements ……… 38 3.2.5. In vitro performance test ………………………………………… 38 3.2.6. Accelerated depletion test ……………………………………… 39 3.2.7. Stability evaluation of exenatide ………………………………… 39 3.2.8. Animal study …………………………………………………… 40 3.2.9. Glucose tolerance test …………………………………………… 43 3.2.10. Paracetamol absorption test …………………………………… 43 3.2.11. Histology and immunohistochemistry ………………………… 43 3.2.12. Statistical analysis ……………………………………………… 44 3.3. Results ………………………………………………………………… 45 3.3.1. Pump design and working principles …………………………… 45 3.3.2. In vitro performance test ………………………………………… 52 3.3.3. In vivo pharmacokinetic tests …………………………………… 57 3.3.4. In vivo pharmacodynamic tests ………………………………… 62 3.3.5. Effects on the pancreatic islets and adipose tissues ……………… 70 3.3.6. Biocompatibility assessment …………………………………… 77 3.4. Discussions …………………………………………………………… 82 Chapter 4. Conclusion and perspective ………………………………… 86 References ………………………………………………………………… 89 Abstracts in Korean ……………………………………………………… 97 Acknowledgment……………………………………………………… 100Docto

Evaluation of a Non-Invasive Optical Glucose Monitoring Device

Tesina final de màster realitzada en col.laboració amb ICFOA non invasive optical glucose monitoring device based on a commercial pulse oximeter has been the object of this study. The fundamental principles of the technology and the proprietary algorithm were studied. The results of a prior clinical trial were analyzed with advanced biostatistical tools. Finally, a preliminary optical setup was designed and utilized to study the potential of additional wavelengths to improve the device/algorithm performance

Pilot study in human healthy volunteers on the use of magnetohydrodynamics in needle-free continuous glucose monitoring

The benefits of continuous glucose monitoring (CGM) in diabetes management are extensively documented. Yet, the broader adoption of CGM systems is limited by their cost and invasiveness. Current CGM devices, requiring implantation or the use of hypodermic needles, fail to offer a convenient solution. We have demonstrated that magnetohydrodynamics (MHD) is effective at extracting dermal interstitial fluid (ISF) containing glucose, without the use of needles. Here we present the first study of ISF sampling with MHD for glucose monitoring in humans. We conducted 10 glucose tolerance tests on 5 healthy volunteers and obtained a significant correlation between the concentration of glucose in ISF samples extracted with MHD and capillary blood glucose samples. Upon calibration and time lag removal, the data indicate a Mean Absolute Relative Difference (MARD) of 12.9% and Precision Absolute Relative Difference of 13.1%. In view of these results, we discuss the potential value and limitations of MHD in needle-free glucose monitoring.Peer reviewe

Hybrid point-of-care devices for visual detection of biomarkers and drugs

Early diagnostics is a crucial part of clinical practice offering a rapid and convenient way to investigate and quantify the presence of key biomarkers related to specific pathologies and increasing the chance of successful treatments. In this regard, point-of-care testing (POCT) shows several advantages enabling simple and rapid analyses, allowing for real-time results, and permitting home testing. Metallic nanoparticles (NPs), like gold NPs (AuNPs), can be beneficially integrated into POC devices thanks to their tunable plasmonic properties which provide a naked-eye read-out. Moreover, the high sensitivity of NPs enables the detection of biomarkers in non-invasive fluids where the concentrations are typically low. These biofluids, like saliva and urine, are functionally equivalent to serum in reflecting the physiological state of the body, whilst they are easier to handle, collect, and store. In this thesis, I first reported the design and development of a colorimetric strategy based on the morphological change of multibranched plasmonic AuNPs, aimed at detecting glucose in saliva. The sensing approach relied on a target-induced reshaping process which involves the oxidation of the NP tips and the transformation into a spherical shape, characterized by a naked-eye detectable blue-to-pink color change. The platform proved to be beneficial in the early and non-invasive diagnosis of hyperglycemia. The successful technological transfer on a solid substrate paved the way for the realization of a dipstick prototype for home testing. Then, the strategy was adapted to other biomarkers, leading to the development of a multiplexing test for the simultaneous detection of three salivary analytes (cholesterol, glucose, and lactate). This multiplexing assay enabled to save reagents, costs, and time, whilst increasing the overall clinical value of the test. Exploiting the microfluidics applied on a paper sheet, I realized a monolithic and fully integrated POC device, through a low-cost and fast CO2 laser cutter. The platform showed excellent selectivity and multiplexing ability, with negligible interferences. The second part of my thesis was focused on the development of POC devices for the detection of anticancer drug contaminations in water solutions and urine samples. Antiblastic agents have revealed high toxicity for the exposed healthcare workers who prepare and administer these drugs in occupational environments. Hence, continuous monitoring is highly required, and POCT shows tremendous potential in this context. With this aim, I realized a lateral-flow (LF) device for the assessment of doxorubicin contamination, using the fluorescent properties of the drug for naked-eye detection. The pharmacological recognition of the DNA probe was exploited to overcome the lack of anti-doxorubicin antibodies. The highly sensitive strategy was successfully adapted to a real urine sample, without resorting to complex pretreatment procedures. Then, I developed a competitive LF device for the detection of methotrexate (MTX). AuNPs were employed as the label molecules and the pharmacological competition of folic acid and MTX for the capture enzyme was exploited as the recognition mechanism, instead of costly antibodies. Despite the sensitivity requires further improvements, the strategy showed fast and reliable results, demonstrating a high potential for workers’ safety control

Use of Sensors in the Treatment and Follow-up of Patients with Diabetes Mellitus

Glucose control is the cornerstone of Diabetes Mellitus (DM) treatment. Although self-regulation using capillary glycemia (SRCG) still remains the best procedure in clinical practice, continuous glucose monitoring systems (CGM) offer the possibility of continuous and dynamic assessment of interstitial glucose concentration. CGM systems have the potential to improve glycemic control while decreasing the incidence of hypoglycemia but the efficiency, compared with SRCG, is still debated. CGM systems have the greatest potential value in patients with hypoglycemic unawareness and in controlling daily fluctuations in blood glucose. The implementation of continuous monitoring in the standard clinical setting has not yet been established but a new generation of open and close loop subcutaneous insulin infusion devices are emerging making insulin treatment and glycemic control more reliable

Emerging Translational Opportunities in Comparative Oncology With Companion Canine Cancers: Radiation Oncology.

It is estimated that more than 6 million pet dogs are diagnosed with cancer annually in the USA. Both primary care and specialist veterinarians are frequently called upon to provide clinical care that improves the quality and/or quantity of life for affected animals. Because these cancers develop spontaneously in animals that often share the same environment as their owners, have intact immune systems and are of similar size to humans, and because the diagnostic tests and treatments for these cancers are similar to those used for management of human cancers, canine cancer provides an opportunity for research that simultaneously helps improve both canine and human health care. This is especially true in the field of radiation oncology, for which there is a rich and continually evolving history of learning from the careful study of pet dogs undergoing various forms of radiotherapy. The purpose of this review article is to inform readers of the potential utility and limitations of using dogs in that manner; the peer-reviewed literature will be critically reviewed, and current research efforts will be discussed. The article concludes with a look toward promising future directions and applications of this pet dog "model.