Impact of Bindarit, a CCL2 Chemokine Synthesis Inhibitor, on Macrophage-Based Biofouling and Continuous Glucose Monitoring .

Continuous glucose monitoring (CGM) using implantable glucose sensors is a critical tool in the management of diabetes. Unfortunately, current commercial glucose sensors have limited performance and lifespans , considered to be due to sensor-induced tissue reactions (inflammation, fibrosis, and vessel regression). Previously, our laboratory utilized monocyte/macrophage (Mo/MQ) deficient and depleted mice to establish a causal relationship between Mo/MQ accumulation and inflammation in glucose sensor performance .

The DERMIS Study: Methodologies, Results, and Implications for the Future.

Ongoing innovation in diabetes technologies has led to the development of advanced tools such as automated insulin delivery (AID) systems that adjust insulin delivery in response to current and predicted glucose levels, residual insulin action, and other inputs (eg, meal and exercise announcements). However, infusion sets continue to be the "Achilles heel" of accurate and precise insulin delivery and continued device use. A recent study by Kalus et al (DERMIS Study) revealed higher vessel density and signals of inflammation by optical coherence tomography (OCT), in addition to increased inflammation, fat necrosis, fibrosis, and eosinophilic infiltration by histopathology.

Microglia Mediate Metabolic Dysfunction From Common Air Pollutants Through NF-κB Signaling.

The prevalence of type 2 diabetes (T2D) poses a significant health challenge, yet the contribution of air pollutants to T2D epidemics remains under-studied. Several studies demonstrated a correlation between exposure to volatile organic compounds (VOCs) in indoor/outdoor environments and T2D. Here, we conducted the first meta-analysis, establishing a robust association between exposure to benzene, a prevalent airborne VOC, and insulin resistance in humans across all ages.

Mast Cell Deficiency in Mice Attenuates Insulin Phenolic Preservative-Induced Inflammation.

One major obstacle that limits the lifespan of insulin infusion pumps is surmounting the tissue site reaction at the device implantation site. All commercial insulin formulations contain insulin phenolic preservatives (IPPs) designed to ensure insulin protein stability and prolong shelf-life. However, our laboratory demonstrated that these preservatives are cytotoxic and induce inflammation.

Inflammation at Site of Insulin Infusion Diminishes Glycemic Control.

The approximation of euglycemia is the most effective means of preventing diabetic complications, which is achieved through effective insulin delivery. Recent reports indicate that insulin phenolic preservatives, which are found in all commercial insulin formulations, are cytotoxic, pro-inflammatory and induce secondary fibrosis. Therefore, we hypothesize that these preservatives induce an inflammatory response at the site of insulin infusion leading to diminished glycemic control and adverse pharmacokinetic outcomes.

A pharmacological approach assessing the role of mast cells in insulin infusion site inflammation.

Background Extending the lifespan of subcutaneous insulin administration sets and infusion pumps requires overcoming unreliable insulin delivery induced by dermal reactions. All commercially available insulin formulations contain insulin phenolic preservatives (IPP), which stabilize the insulin molecule but result in unwanted cell and tissue toxicity. Mast cells, which are the first line of defense once the epithelium is breached, are particularly abundant beneath the skin surface.

Insulin Derived Fibrils Induce Cytotoxicity and Trigger Inflammation in Murine Models.

Background: Effective exogenous insulin delivery is the cornerstone of insulin dependent diabetes mellitus management. Recent literature indicates that commercial insulin-induced tissue reaction and cellular cytotoxicity may contribute to variability in blood glucose as well as permanent loss of injection or infusion site architecture and function. It is well accepted that insulin formulations are susceptible to mechanical and chemical stresses that lead to insulin fibril formation.

Phenolic Preservative Removal from Commercial Insulin Formulations Reduces Tissue Inflammation while Maintaining Euglycemia.

: Exogenous insulin therapy requires stabilization of the insulin molecule, which is achieved through the use of excipients (e.g., phenolic preservatives (PP)) that provide protein stability, sterility and prolong insulin shelf life.

Nourin-Dependent miR-137 and miR-106b: Novel Early Inflammatory Diagnostic Biomarkers for Unstable Angina Patients.

Background: Currently, no blood biomarkers exist that can diagnose unstable angina (UA) patients. Nourin is an early inflammatory mediator rapidly released within 5 min by reversible ischemic myocardium, and if ischemia persists, it is also released by necrosis. Nourin is elevated in acute coronary syndrome (ACS) patients but not in symptomatic noncardiac and healthy subjects.

Noninflammatory Stress-Induced Remodeling of Mandibular Bone: Impact of Age and Pregnancy.

Purpose: The impact of noninflammatory stress, such as aging and pregnancy, on human long bone remodeling is well-established, but little is known about the impact of these stressors on oral bones, including the mandibular bone. To begin to fill this gap in our knowledge, we utilized a mouse mandibular model to evaluate the impact of noninflammatory simple stressors, ie, aging and pregnancy, on bone mandibular architecture and bone density in the mandible using micro-CT.

Materials And Methods: For the present study, mandibles were obtained from both aged and pregnant C57BL/6 mice and analyzed using micro-CT technology.

Advancing continuous subcutaneous insulin infusion in vivo: New insights into tissue challenges.

Continuous Subcutaneous Insulin Infusion (CSII) is superior to conventional insulin therapy as it improves glycemic control thus reducing the probability of diabetic complications. Notwithstanding CSII's benefits, insulin dependent diabetic patients rarely achieve optimal glucose control. Moreover, CSII is only FDA approved for 3 days and often fails prematurely for reasons that have not been fully elucidated.

Continuous Glucose Monitoring Devices: Past, Present, and Future Focus on the History and Evolution of Technological Innovation.

The concept of implantable glucose sensors has been promulgated for more than 40 years. It is now accepted that continuous glucose monitoring (CGM) increases quality of life by allowing informed diabetes management decisions as a result of more optimized glucose control. The focus of this article is to provide a brief overview of the CGM market history, emerging technologies, and the foreseeable challenges for the next CGM generations as well as proposing possible solutions in an effort to advance the next generation of implantable sensor.

Crosslinked basement membrane-based coatings enhance glucose sensor function and continuous glucose monitoring in vivo.

Overcoming sensor-induced tissue reactions is an essential element of achieving successful continuous glucose monitoring (CGM) in the management of diabetes, particularly when used in closed loop technology. Recently, we demonstrated that basement membrane (BM)-based glucose sensor coatings significantly reduced tissue reactions at sites of device implantation. However, the biocompatible BM-based biohydrogel sensor coating rapidly degraded over a less than a 3-week period, which effectively eliminated the protective sensor coating.

Impact of CCL2 and CCR2 chemokine/receptor deficiencies on macrophage recruitment and continuous glucose monitoring in vivo.

The accumulation of macrophages (MΦ) at the sensor-tissue interface is thought to be a major player in controlling tissue reactions and sensor performance in vivo. Nevertheless until recently no direct demonstration of the causal relationship between MΦ aggregation and loss of sensor function existed. Using a Continuous Glucose Monitoring (CGM) murine model we previously demonstrated that genetic deficiencies of MΦ or depletion of MΦ decreased MΦ accumulation at sensor implantation sites, which led to significantly enhanced CGM performance, when compared to normal mice.

Basement Membrane-Based Glucose Sensor Coatings Enhance Continuous Glucose Monitoring in Vivo.

Background: Implantable glucose sensors demonstrate a rapid decline in function that is likely due to biofouling of the sensor. Previous efforts directed at overcoming this issue has generally focused on the use of synthetic polymer coatings, with little apparent effect in vivo, clearly a novel approach is required. We believe that the key to extending sensor life span in vivo is the development of biocompatible basement membrane (BM) based bio-hydrogels as coatings for glucose sensors.

Cell based metabolic barriers to glucose diffusion: macrophages and continuous glucose monitoring.

It is assumed that MQ are central to glucose sensor bio-fouling and therefore have a major negative impact on continuous glucose monitoring (CGM) performance in vivo. However to our knowledge there is no data in the literature to directly support or refute this assumption. Since glucose and oxygen (O2) are key to glucose sensor function in vivo, understanding and controlling glucose and O2 metabolic activity of MQ is likely key to successful glucose sensor performance.

Role of interleukin-1/interleukin-1 receptor antagonist family of cytokines in long-term continuous glucose monitoring in vivo.

Background: Glucose-sensor-induced tissue reactions (e.g., inflammation and wound healing) are known to negatively impact sensor function in vivo.

Impact of macrophage deficiency and depletion on continuous glucose monitoring in vivo.

Although it is assumed that macrophages (MQ) have a major negative impact on continuous glucose monitoring (CGM), surprisingly there is no data in the literature to directly support or refute the role of MQ or related foreign body giant cells in the bio-fouling of glucose sensors in vivo. As such, we developed the hypothesis that MQ are key in controlling glucose sensor performance and CGM in vivo and MQ deficiencies or depletion would enhance CGM. To test this hypothesis we determined the presence/distribution of MQ at the sensor tissue interface over a 28-day time period using F4/80 antibody and immunohistochemical analysis.

Role of vascular networks in extending glucose sensor function: Impact of angiogenesis and lymphangiogenesis on continuous glucose monitoring in vivo.

The concept of increased blood vessel (BV) density proximal to glucose sensors implanted in the interstitial tissue increases the accuracy and lifespan of sensors is accepted, despite limited existing experimental data. Interestingly, there is no previous data or even conjecture in the literature on the role of lymphatic vessels (LV) alone, or in combination with BV, in enhancing continuous glucose monitoring (CGM) in vivo. To investigate the impact of inducing vascular networks (BV and LV) at sites of glucose sensor implantation, we utilized adenovirus based local gene therapy of vascular endothelial cell growth factor-A (VEGF-A) to induce vessels at sensor implantation sites.

Analysis: on the path to overcoming glucose-sensor-induced foreign body reactions.

It is generally accepted that unreliable in vivo performance of implantable glucose sensors originates, in large part, from tissue reactions to the implanted sensor, including foreign body reactions (i.e., inflammation, fibrosis, and vessel regression).

Metabolic biofouling of glucose sensors in vivo: role of tissue microhemorrhages.

Objective: Based on our in vitro study that demonstrated the adverse effects of blood clots on glucose sensor function, we hypothesized that in vivo local tissue hemorrhages, induced as a consequence of sensor implantation or sensor movement post-implantation, are responsible for unreliable readings or an unexplained loss of functionality shortly after implantation.

Research Design And Methods: To investigate this issue, we utilized real-time continuous monitoring of blood glucose levels in a mouse model. Direct injection of blood at the tissue site of sensor implantation was utilized to mimic sensor-induced local tissue hemorrhages.

Importance of interleukin-1 and interleukin-1 receptor antagonist in short-term glucose sensor function in vivo.

Background: The importance of the interleukin (IL)-1 cytokine family in inflammation and immunity is well established as a result of extensive in vitro and in vivo studies. In fact, much of our understanding of the in vivo importance of interleukin-1beta (IL-1B) is the result of research utilizing transgenic mice, such as overexpression or deficiencies of the naturally occurring inhibitor of IL-1 known as interleukin-1 receptor antagonist (IL-1RA). For the present studies, we utilized these transgenic mice to determine the role of IL-1B in glucose sensor function in vivo.

Critical role of tissue mast cells in controlling long-term glucose sensor function in vivo.

Little is known about the specific cells, mediators and mechanisms involved in the loss of glucose sensor function (GSF) in vivo. Since mast cells (MC) are known to be key effector cells in inflammation and wound healing, we hypothesized that MC and their products are major contributors to the skin inflammation and wound healing that controls GSF at sites of sensor implantation. To test this hypothesis we utilized a murine model of continuous glucose monitoring (CGM) in vivo in both normal C57BL/6 mice (mast cell sufficient), as well as mast cell deficient B6.

In vitro activation of human peripheral blood mononuclear cells induced by human biologic meshes.

Background: Inflammation and wound healing play critical roles in the integration of biologic meshes (BMs) at sites of hernia repair. Monocytes/macrophages (M/MQs) are key cells involved in mesh integration. Interleukin-1beta (IL-1beta) is one of the major M/MQ-derived cytokines, and its expression is a reflection of the degree of M/MQ activation.

Human monocyte activation by biologic and biodegradable meshes in vitro.

Background: Inflammation and wound healing play critical roles in the integration of biologic and biodegradable meshes (BMs) at hernia repair sites. Monocytes/macrophages (M/MØs) are key cells controlling inflammation and wound healing. These cells release inflammatory cytokines and growth factors such as interleukin (IL)-1beta, IL-6, IL-8, and vascular endothelial growth factor (VEGF) upon activation.