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There is an unrelenting interest in the development of a reliable bioartificial pancreas construct since the first description of this technology of encapsulated islets by Lim and Sun in 1980 because it promised to be a curative treatment for Type 1 Diabetes Mellitus (T1DM). Despite the promise of the concept of encapsulated islets, there are still some challenges that impede the full realization of the clinical potential of the technology. In this review, we will first present the justification for continued research and development of this technology. Next, we will review key barriers that impede progress in this field and discuss strategies that can be used to design a reliable construct capable of effective long-term performance after transplantation in diabetic patients. Finally, we will share our perspectives on areas of additional work for future research and development of the technology. [ABSTRACT FROM AUTHOR]

Hydrogel-based technologies have emerged as transformative tools in the management of diabetes, offering novel solutions in both drug delivery and diagnostic techniques. Diabetes, a chronic metabolic disorder characterized by elevated blood glucose levels, necessitates precise and consistent therapeutic interventions to mitigate its complications and improve patient outcomes. This abstract explores recent innovations in hydrogel applications tailored for diabetes care, focusing on advanced drug delivery systems and flexible diagnostic techniques. Hydrogels, three-dimensional networks of hydrophilic polymers capable of absorbing and retaining large amounts of water, exhibit properties that make them ideal candidates for biomedical applications. In drug delivery, hydrogels offer controlled release mechanisms that can mimic physiological conditions, enhancing the efficacy of therapeutics such as insulin and GLP-1 receptor agonists. Innovations in this area include stimuliresponsive hydrogels that release drugs in response to changes in glucose levels or other physiological cues, thereby improving glycemic control and patient compliance. Additionally, the development of injectable hydrogel formulations allows for sustained drug release, reducing the frequency of administrations and providing long-term therapeutic benefits. Furthermore, hydrogelbased diagnostic techniques have revolutionized diabetes management by enabling non-invasive and continuous monitoring of glucose levels. Hydrogel-based biosensors offer real-time monitoring capabilities, detecting glucose and other biomarkers through wearable devices or integrated patches. These sensors leverage the biocompatibility and flexibility of hydrogels to adhere comfortably to the skin, ensuring prolonged and accurate monitoring without the discomfort associated with traditional methods. Moreover, advancements in microneedle technology have facilitated minimally invasive glucose monitoring, with hydrogel-based microneedle patches capable of sampling interstitial fluid for glucose analysis. [ABSTRACT FROM AUTHOR]

Definition: The displacement micropump with passive check valves is an attractive solution for precise insulin infusion in patients with type I diabetes. Unlike most insulin pumps that push insulin from a cartridge using a piston, a displacement micropump will first pull insulin from the reservoir before infusing it into the patient. This dual sequence introduces new challenges in terms of insulin stability, notably if the reservoir is not pressurized. After an introduction to displacement micropumps and a brief review of the insulin degradation mechanism, micropump design rules are discussed in light of microfluidic theory. [ABSTRACT FROM AUTHOR]

Abstract Continuous Glucose Monitoring (CGM) systems are revolutionizing the real‐time tracking of blood glucose levels, a cornerstone in effective diabetes management and optimal glycemic control. Transitioning from the “intermittent readings” offered by traditional Blood Glucose Monitoring (BGM) methods, CGM delivers an “uninterrupted flow” of glucose data, enabling a “more detailed” strategy for meeting treatment goals. Initially, the “uptake of CGM faced hurdles due to doubts about its precision, but continuous advancements in technology have not only resolved these concerns but also confirms CGM as a dependable and impactful instrument in diabetes management”. Concurrently, advancements in insulin pump technology have improved their portability and ease of use, greatly increasing patient adoption. The market reflects a growing demand for such innovative healthcare solutions, driven by an increased awareness of diabetes management and bolstered by supportive healthcare policies. Future prospects for CGM and insulin pump technologies are incredibly promising, offering the potential for highly personalized care and sophisticated treatment strategies. This paper aims to explore how the synergy between ongoing technological developments and evolving market dynamics is set to redefine the diabetes care paradigm, positioning CGM and insulin pumps as essential elements in enhancing the quality of life for individuals with diabetes.

The displacement micropump with passive check valves is an attractive solution for precise insulin infusion in patients with type I diabetes. Unlike most insulin pumps that push insulin from a cartridge using a piston, a displacement micropump will first pull insulin from the reservoir before infusing it into the patient. This dual sequence introduces new challenges in terms of insulin stability, notably if the reservoir is not pressurized. After an introduction to displacement micropumps and a brief review of the insulin degradation mechanism, micropump design rules are discussed in light of microfluidic theory.

AbstractThis study focuses on the innovation of an inhaled sustained release form of insulin and the development of a neuro-fuzzy model specifically tailored to predict insulin release kinetics from polycondensed agar-carbomer hydrogels. These were synthesized by blending agar and carbomer, incorporating propylene glycol and glycerol, and then cross-linking by polycondensation. The structure and morphology of the hydrogel were analyzed via Fourier Transform Infrared Spectroscopy, Scanning Electron Microscopy and Proton Nuclear Magnetic Resonance Spectroscopy. The neuro-fuzzy model, a combination of artificial neural networks and fuzzy logic, employs inputs such as concentrations of crosslinking agents, polycondensation time, and release time, with the output being the rate of insulin release. The model demonstrated a strong correlation with experimental data, highlighting its effectiveness and precision in predicting insulin delivery from hydrogel compositions and temporal parameters. This emphasizes the importance of intelligent modelling for forecasting the kinetic release of therapeutic agents from novel drug delivery systems. [ABSTRACT FROM AUTHOR]

Regular blood glucose monitoring and control is necessary for people with type 1 or advanced type 2 diabetes, yet diagnosing and treating patients with diabetes in an accurate, sustained and patient‐friendly manner remains limited. Here, a glucose‐responsive bifunctional nanosystem (PGOxMns) is constructed via one‐pot biomineralisation of manganese dioxide with glucose oxidase and ε‐poly‐L‐lysine. Under hyperglycaemic conditions, the cascade reactions that occur when glucose interacts with PGOxMns can trigger the production of Mn(II), which enhances the magnetic resonance imaging signal. Simultaneously, manganese dioxide catalyses the decomposition of toxic hydrogen peroxide into oxygen, which also maintains glucose oxidase (GOx) activity. In an in vivo model of diabetes, PGOxMns is used to monitor glucose levels (0–20 mm) and allowed identification of diabetic mice via T1‐weighted MRI. Furthermore, PGOxMns is found to have a high insulin‐loading capacity (83.6%), likely due to its positive charge. A single subcutaneous injection of insulin‐loaded nanosystem (Ins‐PGOxMns) into diabetic mice resulted in a rapid and efficient response to a glucose challenge and prolonged blood glucose level control (< 200 mg dL−1) for up to 50 h. Overall, this proof‐of‐concept study demonstrates the feasibility of using biomineralised nanosystems to develop patient‐friendly strategies for glucose monitoring and control. [ABSTRACT FROM AUTHOR]

Use of innovative technologies such as continuous glucose monitoring (CGM) and insulin delivery systems have been shown to be safe and effective in helping patients with diabetes achieve significantly improved glycemic outcomes compared to their previous therapies. However, these technologies are underutilized in many primary care practices. This narrative review discusses some of the clinical and economic benefits of tubeless insulin delivery devices and discusses how this technology can overcome the main obstacles inherent to use of conventional insulin delivery devices. [ABSTRACT FROM AUTHOR]

Insulin therapy is integral to the treatment of diabetes mellitus. Epidemiologic studies have shown its benefits both in terms of improving glycemic control and reducing the risk for long-term diabetic complications for both type 1 and type 2 diabetes. Despite these benefits, barriers to insulin therapy are well documented and include perceived inconvenience, needle anxiety, and portability of device in case of insulin pumps. Therefore, this study aims to design and simulate a low frequency sonophoretic array for transdermal insulin delivery. This study utilizes COMSOL Multiphysics software to simulate the transducer used to increase the skin permeability for delivering drugs. It consists of $8\times 5$ array of a piezoelectric elements operated at 100 kHz and 1 volt. To evaluate the effectiveness of the transducer, an intricate skin model has been developed that includes all anatomical layers extending to the bone. The skin layers, particularly muscle and bone, exhibit reflective properties, leading to the formation of a standing wave. This phenomenon arises from the impedance mismatch between muscle and bone. Standing wave served to promote the transportation of the drug into the dermal layer, rich with capillary networks. We found that applying standing wave with 100 kHz the achieved pressure of 0.3 MPa induced acoustic streaming for the drug flow of $1605~\frac {\mathrm {\mu g}}{{\mathrm {cm}}^{2}}$ per 24 hours. Also, the precise modulation of ultrasound frequency and voltage is key to controlling peak acoustic pressure, thereby regulating the rate of insulin delivery through the skin.

Aims: Bespoke glycaemic control strategies following antenatal corticosteroids for women with diabetes in pregnancy (DIP) may mitigate hyperglycaemia. This study aims to identify predictive factors for the glycaemic response to betamethasone in a large cohort of women with DIP. Methods: Evaluation of a prospective cohort study of 347 consecutive DIP pregnancies receiving two doses of 11.4 mg betamethasone 24 h apart between 2017 and 2021 and treated with the Pregnancy‐IVI intravenous insulin protocol. Regression modelling identified factors associated with maternal glycaemic time‐in‐range (TIR) and maternal insulin requirements following betamethasone. Factors associated with neonatal hypoglycaemia (glucose <2.6 mmol/L) in infants born within 48 h of betamethasone administration (n = 144) were investigated. Results: The mean maternal age was 31.9 ± 5.8 years, with gestational age at betamethasone of 33.5 ± 3.4 weeks. Gestational diabetes was present in 81% (12% type 1; 7% type 2). Pre‐admission subcutaneous insulin was prescribed for 63%. On‐infusion maternal glucose TIR (4.0–7.8 mmol/L) was 83% [IQR 77%–90%] and mean on‐IVI glucose was 6.6 ± 0.5 mmol/L. Maternal hypoglycaemia (<3.8 mmol/L) was uncommon (0.47 h/100 on‐IVI woman hours). Maternal glucose TIR was negatively associated with indicators of insulin resistance (type 2 diabetes, polycystic ovary syndrome), late‐pregnancy complications (pre‐eclampsia, chorioamnionitis) and the 1‐h OGTT result. Intravenous insulin requirements were associated with type of diabetes, pre‐eclampsia and intrauterine infection, the 1‐h OGTT result and the timing of betamethasone administration. Neonatal hypoglycaemia was associated with pre‐existing diabetes but not with measures of glycaemic control. Conclusion: An intravenous infusion protocol effectively controls maternal glucose after betamethasone. A risk‐factor‐based approach may allow individualisation of therapy. [ABSTRACT FROM AUTHOR]

Complications associated with Type 1 diabetes (T1D) have complex origins that revolve around chronic hyperglycemia; these complications involve hemostasis disorders, coagulopathies, and vascular damage. Our study aims to develop innovative approaches to minimize these complications and to compare the outcomes of the new approach with those of traditional methods. To achieve our objective, we designed novel nanoparticles comprising covalent organic frameworks (nCOF) loaded with insulin, termed nCOF/Insulin, and compared it to subcutaneous insulin to elucidate the influence of insulin delivery methods on various parameters, including bleeding time, coagulation factors, platelet counts, cortisol plasma levels, lipid profiles, and oxidative stress parameters. Traditional subcutaneous insulin injections exacerbated hemostasis disorder and vascular injuries in streptozotocin (STZ)-induced diabetic rats through increasing plasma triglycerides and lipid peroxidation. Conversely, oral delivery of nCOF/Insulin ameliorated hemostatic disorders and restored the endothelial oxidant/antioxidant balance by reducing lipid peroxidation and enhancing the lipid profile. Our study pioneers the understanding of how STZ-induced diabetes disrupts bleeding time, induces a hypercoagulable state, and causes vascular damage through lipid peroxidation. Additionally, it provides the first evidence for the involvement of subcutaneous insulin treatment in exacerbating vascular and hemostasis disorders in type 1 diabetes (T1D). Introducing an innovative oral insulin delivery via the nCOF approach represents a potential paradigm shift in diabetes management and patient care and promises to improve treatment strategies for type 1 Diabetes.

With the first commercially available smart insulin pens, the predominant insulin delivery device for millions of people living with diabetes is now coming into the digital age. Smart insulin pens (SIPs) have the potential to reshape a connected diabetes care ecosystem for patients, providers, and health systems. Existing SIPs are enhanced with real-time wireless connectivity, digital dose capture, and integration with personalized dosing decision support. Automatic dose capture can promote effective retrospective review of insulin dose data, particularly when paired with glucose data. Patients, providers, and diabetes care teams will be able to make increasingly data-driven decisions and recommendations, in real time, during scheduled visits, and in a more continuous, asynchronous care model. As SIPs continue to progress along the path of digital transformation, we can expect additional benefits: iteratively improving software, machine learning, and advanced decision support. Both these technological advances, and future care delivery models with asynchronous interactions, will depend on easy, open, and continuous data exchange between the growing number of diabetes devices. SIPs have a key role in modernizing diabetes care for a large population of people living with diabetes.

The optimal treatment of diabetes (in particular, type 1 diabetes—T1D) remains a challenge. Closed-loop systems (implants/inserts) provide significant advantages for glucose responsivity and providing real-time sustained release of rapid-acting insulin. Concanavalin A (ConA), a glucose affinity agent, has been used to design closed-loop insulin delivery systems but not without significant risk of leakage of ConA from the matrices and poor mechanical strength of the hydrogels impacting longevity and control of insulin release. Therefore, this work focused on employing a thermoresponsive co-forming matrix between Pluronic F-127 (PL) and structurally robust chitosan (CHT) via EDC/NHS coupling (i.e., covalent linkage of -NH2 from CHT and ConA to the -COOH of PL). The system was characterized for its chemical structure stability and integrity (FTIR, XRD and TGA), injectability, rheological parameters and hydrogel morphology (Texture Analysis, Elastosens TM Bio2 and SEM). The prepared hydrogels demonstrated shear-thinning for injectability with a maximum force of 4.9 ± 8.3 N in a 26G needle with sol–gel transitioning from 25 to 38 °C. The apparent yield stress value of the hydrogel was determined to be 67.47 Pa. The insulin loading efficiency within the hydrogel matrix was calculated to be 46.8%. Insulin release studies revealed glucose responsiveness in simulated glycemic media (4 and 10 mg/mL) over 7 days (97%) (305 nm via fluorescence spectrophotometry). The MTT studies were performed over 72 h on RIN-5F pancreatic cells with viability results >80%. Results revealed that the thermoresponsive hydrogel is a promising alternative to current closed-loop insulin delivery systems. [ABSTRACT FROM AUTHOR]

Diabetes has been listed as one of the three major diseases that endanger human health. Accurately injecting insulin (Ins) depending on the level of blood glucose (LBG) is the standard treatment, especially controlling LBG in the long‐term by a single injection. Herein, the pH‐responsive hexa‐histidine metal assembly (HmA) encapsulated with enzymes (GOx and CAT) and Ins (HmA@GCI) is engineered as the vehicle for glucose‐mediated insulin delivery. HmA not only shows high proteins loading efficiency, but also well retained proteins activity and protect proteins from protease damage. Within HmA, the biocatalytic activities of enzymes and the efficiency of the cascade reaction between GOx and CAT are enhanced, leading to a super response to the change of LBG with insulin release and efficient clearance of harmful byproducts of GOx (H2O2). In the treatment of diabetic mice, HmA@GCI reduces LBG to normal in half an hour and maintains for more than 5 days by a single subcutaneous injection, and nearly 24 days with four consecutive injections. During the test period, no symptoms of hypoglycemia and toxicity to tissues and organs are observed. These results indicate that HmA@GCI is a safe and long‐acting hypoglycemic agent with prospective clinical application. [ABSTRACT FROM AUTHOR]

Lipid nanoparticle‐based drug delivery systems have a profound clinical impact on nucleic acid‐based therapy and vaccination. Recombinant human insulin, a negatively‐charged biomolecule like mRNA, may also be delivered by rationally‐designed positively‐charged lipid nanoparticles with glucose‐sensing elements and be released in a glucose‐responsive manner. Herein, we have designed phenylboronic acid‐based quaternary amine‐type cationic lipids that can self‐assemble into spherical lipid nanoparticles in an aqueous solution. Upon mixing insulin and the lipid nanoparticles, a heterostructured insulin complex is formed immediately arising from the electrostatic attraction. In a hyperglycemia‐relevant glucose solution, lipid nanoparticles become less positively charged over time, leading to reduced attraction and subsequent insulin release. Compared with native insulin, this lipid nanoparticle‐based glucose‐responsive insulin shows prolonged blood glucose regulation ability and blood glucose‐triggered insulin release in a type 1 diabetic mouse model. [ABSTRACT FROM AUTHOR]

Aloe vera gel and whole leaf materials, as well as polysaccharides, precipitated from the gel, have previously been shown to enhance macromolecular drug delivery across epithelial tissues. This study investigated the effectiveness of microparticle formulations prepared from A. vera polysaccharides for nasal delivery of insulin across excised sheep olfactory and respiratory nasal epithelial tissues. An emulsion-solvent evaporation technique was used to prepare two insulin microparticle formulations, namely one containing Eudragit® L100 and A. vera polysaccharides and one containing A. vera polysaccharides only. In addition, an ionic gelation technique was used to prepare an insulin microparticle formulation with A. vera polysaccharides, where calcium chloride was used as a cross-linker. The microparticle formulations were evaluated in terms of drug content (assay), particle size, drug release (dissolution), ex vivo drug permeation, and histology. The microparticle formulations exhibited statistically significantly higher insulin delivery across excised sheep olfactory and respiratory nasal epithelial tissues compared to that of the control group (insulin alone). In conclusion, the use of A. vera polysaccharides in microparticle formulations significantly improved nasal insulin delivery. Therefore, A. vera polysaccharide containing microparticles showed high potential to enhance systemic bioavailability and delivery into the brain of macromolecular drugs such as insulin after intranasal administration. [ABSTRACT FROM AUTHOR]

The design of nanoparticle formulations composed of biopolymers, that govern the physicochemical properties of orally delivered insulin, relies on improving insulin stability and absorption through the intestinal mucosa while protecting it from harsh conditions in the gastrointestinal (GI) tract. Chitosan/polyethylene glycol (PEG) and albumin coating of alginate/dextran sulfate hydrogel cores are presented as a multilayer complex protecting insulin within the nanoparticle. This study aims to optimize a nanoparticle formulation by assessing the relationship between design parameters and experimental data using response surface methodology through a 3-factor 3-level optimization Box–Behnken design. While the selected independent variables were the concentrations of PEG, chitosan and albumin, the dependent variables were particle size, polydispersity index (PDI), zeta potential, and insulin release. Experimental results showed a nanoparticle size ranging from 313 to 585 nm, with PDI from 0.17 to 0.39 and zeta potential ranging from −29 to −44 mV. Insulin bioactivity was maintained in simulated GI media with over 45% cumulative release after 180 min in a simulated intestinal medium. Based on the experimental responses and according to the criteria of desirability on the experimental region's constraints, solutions of 0.03% PEG, 0.047% chitosan and 1.20% albumin provide an optimum nanoparticle formulation for insulin oral delivery. [ABSTRACT FROM AUTHOR]

Abstract Diabetes has been listed as one of the three major diseases that endanger human health. Accurately injecting insulin (Ins) depending on the level of blood glucose (LBG) is the standard treatment, especially controlling LBG in the long‐term by a single injection. Herein, the pH‐responsive hexa‐histidine metal assembly (HmA) encapsulated with enzymes (GOx and CAT) and Ins (HmA@GCI) is engineered as the vehicle for glucose‐mediated insulin delivery. HmA not only shows high proteins loading efficiency, but also well retained proteins activity and protect proteins from protease damage. Within HmA, the biocatalytic activities of enzymes and the efficiency of the cascade reaction between GOx and CAT are enhanced, leading to a super response to the change of LBG with insulin release and efficient clearance of harmful byproducts of GOx (H2O2). In the treatment of diabetic mice, HmA@GCI reduces LBG to normal in half an hour and maintains for more than 5 days by a single subcutaneous injection, and nearly 24 days with four consecutive injections. During the test period, no symptoms of hypoglycemia and toxicity to tissues and organs are observed. These results indicate that HmA@GCI is a safe and long‐acting hypoglycemic agent with prospective clinical application.

Nocturnal blood glucose regulation was one of the key challenges in diabetic treatments. However, development of the smart insulin complexes with mild and glucose-responsive delivering performances was mostly relied on experience of the senior researchers and numerous confirmation experiments. In this work, a series of bioinspired fatty-acid-modified glucose-responsive insulin-delivering polymeric nanoparticles were designed. The molecular docking technique was utilized to efficiently screen the fatty-acid-derived functional groups. The results provided the basis for polymer functionalization and simplified the optimization experiments. For the optimized formulation (C10MS), insulin-loaded C10MS successfully fulfilled the nocturnal-glycemic-controlling requirement of the diabetic rats with lower occurrence of hypoglycemia than the conventional insulin injection schemes. Such formulation also possessed good biocompatibility with the moderate elimination kinetics in vivo , which matched the demand of bio-safety in the daily treatments. Overall, this work opened up a new path for efficient design of functional polymeric materials. [Display omitted] [ABSTRACT FROM AUTHOR]

Featured Application: This work describes the design for testability and the industrialized functional test methods of an insulin micropump for type 1 diabetes care. The test in the production of microfluidic devices dedicated to medical applications poses several challenges in terms of contamination, reliability, and cost. The present article describes the Design-for-Testability approach used to make an insulin MEMS micropump that can be fully tested in production in a few seconds. Each key functional parameter of a positive displacement micropump with check valves is described together with detailed pneumatic test methods. The typical failure modes of the device are considered and tested experimentally to show that these methods can also be used for failure analysis and process control. A simplified Built-In-Self-Test is also presented. Finally, advanced methods to characterize the piezoelectric actuator are also described and tested. [ABSTRACT FROM AUTHOR]

The optimal treatment of diabetes (in particular, type 1 diabetes—T1D) remains a challenge. Closed-loop systems (implants/inserts) provide significant advantages for glucose responsivity and providing real-time sustained release of rapid-acting insulin. Concanavalin A (ConA), a glucose affinity agent, has been used to design closed-loop insulin delivery systems but not without significant risk of leakage of ConA from the matrices and poor mechanical strength of the hydrogels impacting longevity and control of insulin release. Therefore, this work focused on employing a thermoresponsive co-forming matrix between Pluronic F-127 (PL) and structurally robust chitosan (CHT) via EDC/NHS coupling (i.e., covalent linkage of -NH2 from CHT and ConA to the -COOH of PL). The system was characterized for its chemical structure stability and integrity (FTIR, XRD and TGA), injectability, rheological parameters and hydrogel morphology (Texture Analysis, Elastosens TM Bio2 and SEM). The prepared hydrogels demonstrated shear-thinning for injectability with a maximum force of 4.9 ± 8.3 N in a 26G needle with sol–gel transitioning from 25 to 38 °C. The apparent yield stress value of the hydrogel was determined to be 67.47 Pa. The insulin loading efficiency within the hydrogel matrix was calculated to be 46.8%. Insulin release studies revealed glucose responsiveness in simulated glycemic media (4 and 10 mg/mL) over 7 days (97%) (305 nm via fluorescence spectrophotometry). The MTT studies were performed over 72 h on RIN-5F pancreatic cells with viability results >80%. Results revealed that the thermoresponsive hydrogel is a promising alternative to current closed-loop insulin delivery systems.

Diabetes mellitus is one of the fastest-growing lifestyle disorders in the world. While numerous regimes have been developed to manage diabetes, there continue to be high numbers of diabetes-related deaths worldwide. The review gives a brief introduction to the pathology and aetiology of the disorder, different solutions developed over time with their advantages and disadvantages, and highlights the technological components and challenges of the latest technologies: artificial pancreas and regenerative medicine. The study is restricted to a set of high-quality publications from the last decade. [ABSTRACT FROM AUTHOR]

The present study develops on insulin-release studies from the chitosan-amide-modified stimuli-responsive polymers formed from various fatty acids including stearic acid, oleic acid, linoleic acid, and linolenic acid. This is the continuation of an earlier reported study that investigates the insulin-release profiles of chitosan-modified fatty acid amides (without stimuli responsive polymers). Following the synthesis and characterization of many different fatty acid amides with a varying amount of unsaturation, the insulin drug loading and release effects were compared among N-isopropylacrylamide (NIPAm), a thermo-responsive polymer, and 2-acrylamide-2-methylpropane sulfonic acid (AMPS), a pH-responsive polymer-modified hydrogel that is expected to enhance environmental response and the controllability of release. Finally, drug release effects were studied to investigate the drug release mechanisms with the help of five different pharmacokinetic models including the zero-order, first-order, Higuchi, Korsmeyers–Peppas, and Hixson models. The results indicate that the Higuchi and Hixson models are valid in terms of the operation of the NIPAm and AMPS matrices during the delivery of insulin. [ABSTRACT FROM AUTHOR]

Background: This study assessed changes in actigraphy-estimated sleep and glycemic outcomes after initiating automated insulin delivery (AID)., Methods: Ten adults with long-standing type 1 diabetes and impaired awareness of hypoglycemia (IAH) participated in an 18-month clinical trial assessing an AID intervention on hypoglycemia and counter-regulatory mechanisms. Data from eight participants (median age = 58 years) with concurrent wrist actigraph and continuous glucose monitoring (CGM) data were used in the present analyses. Actigraphs and CGM measured sleep and glycemic control at baseline (one week) and months 3, 6, 9, 12, 15, and 18 (three weeks) following AID initiation. HypoCount software integrated actigraphy with CGM data to separate wake and sleep-associated glycemic measures. Paired sample t -tests and Cohen's d effect sizes modeled changes and their magnitude in sleep, glycemic control, IAH (Clarke score), hypoglycemia severity (HYPO score), hypoglycemia exposure (CGM), and glycemic variability (lability index [LI]; CGM coefficient-of-variation [CV]) from baseline to 18 months., Results: Sleep improved from baseline to 18 months (shorter sleep latency [ P < .05, d = 1.74], later sleep offset [ P < .05, d = 0.90], less wake after sleep onset [ P < .01, d = 1.43]). Later sleep onset ( d = 0.74) and sleep midpoint ( d = 0.77) showed medium effect sizes. Sleep improvements were evident from 12 to 15 months after AID initiation and were preceded by improved hypoglycemia awareness (Clarke score [ d = 1.18]), reduced hypoglycemia severity (HYPO score [ d = 2.13]), reduced sleep-associated hypoglycemia (percent time glucose was < 54 mg/dL, < 60 mg/dL,< 70 mg/dL; d = 0.66-0.81), and reduced glucose variability (LI, d = 0.86; CV, d = 0.62)., Conclusion: AID improved sleep initiation and maintenance. Improved awareness of hypoglycemia, reduced hypoglycemia severity, hypoglycemia exposure, and glucose variability preceded sleep improvements.This trial is registered with ClinicalTrials.gov NCT03215914 https://clinicaltrials.gov/ct2/show/NCT03215914., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Nanoceria (NC) is gaining scientific attention due to its widespread drug delivery efficacy and modulation of oxidative stress. Herein, we developed dextran (Dex) capped insulin (INS)-loaded phenylboronic acid (PBA)-functionalized nanoceria (NC-PBA-INS-Dex) for glucose-responsive insulin delivery and mitigating excessive ROS production to regulate both hyperglycemia and oxidative stress in diabetes mellitus (DM). The prepared nanoparticle showed favorable loading capacity and excellent encapsulation efficiency of insulin. Glucose-responsive insulin release from NC-PBA-INS-Dex was observed initially in the cell-free mode when subjected to varying glucose concentrations (5.5, 11, and 25 mM). Interestingly, under in vitro setting, promising insulin release from NC-PBA-INS-Dex was found in muscle cells (major glucose storage cells) compared to lung cells against exposure to different glucose concentration suggesting a glucose-sensitive intracellular insulin delivery. NC-PBA-INS-Dex treatment further upregulated GLUT4 translocation and glucose uptake/utilization in sodium palmitate-exposed muscle cells, and results were significantly higher compared to NC or INS alone treated cells. Studies in diabetic animals demonstrated the maintenance of normoglycemia for up to 12 h upon gavaging a single dose of NC-PBA-INS-Dex compared to INS alone treatment (subcutaneous/oral). Oral administration of NC-PBA-INS-Dex also increased insulin bioavailability (in both serum and muscle tissue) compared with either subcutaneous or oral insulin administration. NC-PBA-INS-Dex further exhibited ROS scavenging (superoxide radical) potential in cell-free, in vitro, and in vivo systems, and results were comparable to treatment with NC alone. NC-PBA-INS-Dex could effectively regulate the expression of occludin and induce the reversible opening of a tight junction in intestinal epithelial cells, allowing the particle transport through the intestinal mucosa. Treatment with NC-PBA-INS-Dex did not exhibit any toxicity to in vitro and in vivo models. The NC-based drug delivery system will mimic the physiological regulation of insulin secretion in a noninvasive manner, offering improved patient compliance, reduced risk of hyperglycemia, and enhanced overall management of DM.

A glucose-responsive insulin delivery system that sustains blood glucose equilibrium for an extended duration can address the low therapeutic window of insulin in diabetes treatment. Herein, insulin is loaded in a water-in-oil-in-water (W 1 /O/W 2 ) gelled multiple emulsion using poly (4-vinylphenylboronic acid) (PVPBA) homopolymer as an effective emulsifier. The gelled multiple emulsion exhibits a high encapsulation efficiency (99%), enhanced stability and remarkable shear-thinning behavior, making it easy to inject. Under hyperglycemic conditions, the gelled emulsion system instantly binds to glucose molecules and reduces the hydrogen bonds of the PVPBA homopolymer, resulting in insulin release. In a streptozotocin-induced type 1 diabetic mouse model, a single subcutaneous injection of the gelled emulsion rapidly responds to high blood glucose concentration (BGC) and release insulin in a glucose dependent manner, thus prolonging the antihyperglycemic effect compared with free insulin., (© 2024 Wiley‐VCH GmbH.)

Glucose tolerance improves significantly upon consuming a second, identical meal later in the day (second meal phenomenon). We previously established that morning hyperinsulinemia primes the liver for increased afternoon hepatic glucose uptake (HGU). Although the route of insulin delivery is an important determinant of the mechanisms by which insulin regulates liver glucose metabolism (direct hepatic vs indirect insulin action), it is not known if insulin's delivery route affects the second meal response. To determine whether morning peripheral insulin delivery (as occurs clinically (subcutaneous)) can enhance afternoon HGU, conscious dogs were treated in the morning with insulin delivered via the portal vein, or peripherally (leg vein), while glucose was infused to maintain euglycemia. Consequently, arterial insulin levels increased similarly in both groups, but relative hepatic insulin deficiency occurred when insulin was delivered peripherally. In the afternoon, all animals were challenged with the same hyperinsulinemic-hyperglycemic clamp to simulate identical postprandial-like conditions. The substantial enhancement of HGU in the afternoon caused by morning portal vein insulin delivery was lost when insulin was delivered peripherally. This indicates that morning insulin does not cause the second meal phenomenon via its indirect actions on the liver, but rather through direct activation of hepatic insulin signaling., Competing Interests: Conflict of Interest. A.D.C. has research contracts with Fractyl, Abvance, Fluidics, and Novo Nordisk, as well as grants from the NIH and the Helmsley Charitable Trust. A.D.C. is a consultant to Novo Nordisk, Paratus, Portal Insulin, Fractyl, and Thetis. No other individuals have conflicts of interest relevant to this article.

Needle reuse is a common practice and primary cause of customer compliance issues such as pain, bruising, clogging, injection site reactions (ISR), and associated lipodystrophy. This study aimed to characterize skin microflora at injection sites and establish microbial contamination of used pen injectors and needles. The second objective was to evaluate the risk of infections during typical and repeated subcutaneous injections. 50 participants with diabetes and 50 controls (n = 100) were sampled through tape strips and skin swabs on the abdomen and thigh for skin microflora. Used pen injectors and needles were collected after in‐home use and from the hospital after drug administration by health care professionals (HCPs). Samples were analyzed by conventional culture, matrix‐assisted laser desorption/ionization‐time of flight (MALDI‐TOF), mass spectrometry (MS), confocal laser scanning microscopy (CLSM), and 16S/ITS high throughput sequencing (HTS). A mathematical model simulated the risk of needle contamination during injections. Injection site populations were in 102 cells/cm2 order, with increased viable bacteria and anaerobic bacteria on the skin in persons with diabetes (p = 0.05). Interpersonal variation dominated other factors such as sex or location. A higher prevalence of Staphylococcus aureus on abdominal skin was found in persons with diabetes than control skin (p ≤ 0.05). Most needles and cartridges (95% and 86%) contained no biological signal. The location of the device collection (hospital vs home‐use) and use regimen did not affect contamination. CLSM revealed scarcely populated skin microflora scattered in aggregates, diplo, or single cells. Our mathematical model demonstrated that penetrating bacteria colonies during subcutaneous injection is unlikely. These findings clarify the lack of documented skin infections from subcutaneous insulin injections in research. Furthermore, these results can motivate the innovation and development of durable, reusable injection systems with pharmacoeconomic value and a simplified and enhanced user experience for patients. [ABSTRACT FROM AUTHOR]

Background: Although insulin pump infusion set failures are common, studies assessing the failure rate are limited. Methods: Data were analyzed from two clinical trials, in which 263 participants aged 6-72 years used 22,741 infusion sets. The frequency of removal due to prolonged hyperglycemia (continuous glucose monitor measuring >300 mg/dL immediately before removal and >250 mg/dL continuously for at least 2 h before removal with at least 90 min >300 mg/dL out of the prior 120 min) was determined. Differences in failure rates among age groups and infusion set types were evaluated. Results: Among 22,741 infusion sets, 748 (3.3%) were removed before 72 h in association with prolonged hyperglycemia. The percentage replaced within 48 h and within 24 h with prolonged hyperglycemia were 1.8% and 1.0%, respectively. Mean duration of continuous time >250 mg/dL before removal was 5.1 ± 3.7 h. Using a less restrictive definition of failure related to hyperglycemia, 1688 (7.4%) sets were removed before 72 h with a glucose level >300 mg/dL at the time of removal. The frequency of insulin set failure with prolonged hyperglycemia was lower in adults ≥18 years old (1.9%) than in those 14-17 years old (5.8%, P < 0.001) or 6-13 years old (4.4%, P = 0.002). The 90° Teflon sets had the highest frequency of prolonged hyperglycemia failure within 72 h (4.0%) compared with the angled Teflon set frequency (1.3%, P = 0.01) or the steel set frequency (1.9%, P = 0.006). Conclusions: Based on the data from these 22,741 infusion sets, infusion set changes associated with prolonged hyperglycemia occur on average about four times a year, with the frequency being higher in youth than adults. The frequency also appears to be higher with straight Teflon sets compared with angled Teflon sets and steel sets. Clinical Trials Registration Number: NCT03563313. [ABSTRACT FROM AUTHOR]

Abstract Background Diabetes complications are the leading cause of mortality in diabetic patients. The common complications are decline in antioxidant capacity and the onset of micro-inflammation syndrome. At present, glucose-responsive nanoparticles are widely used, as they can release insulin-loaded ultrafine particles intelligently and effectively reduce blood sugar. However, the toxicology of this method has not been fully elucidated. The plant extracts of pterostilbene (PTE) have a wide range of biological applications, such as antioxidation and inflammatory response improvement. Therefore, we have proposed new ideas for the cross application of plant extracts and biomaterials, especially as part of a hypoglycaemic nano-drug delivery system. Results Based on the PTE, we successfully synthesised poly(3-acrylamidophenyl boric acid-b-pterostilbene) (p[AAPBA-b-PTE]) nanoparticles (NPs). The NPs were round in shape and ranged between 150 and 250 nm in size. The NPs possessed good pH and glucose sensitivity. The entrapment efficiency (EE) of insulin-loaded NPs was approximately 56%, and the drug loading (LC) capacity was approximately 13%. The highest release of insulin was 70%, and the highest release of PTE was 85%. Meanwhile, the insulin could undergo self-regulation according to changes in the glucose concentration, thus achieving an effective, sustained release. Both in vivo and in vitro experiments showed that the NPs were safe and nontoxic. Under normal physiological conditions, NPs were completely degraded within 40 days. Fourteen days after mice were injected with p(AAPBA-b-PTE) NPs, there were no obvious abnormalities in the heart, liver, spleen, lung, or kidney. Moreover, NPs effectively reduced blood glucose, improved antioxidant capacity and reversed micro-inflammation in mice. Conclusions p(AAPBA-b-PTE) NPs were successfully prepared using PTE as raw material and effectively reduced blood glucose, improved antioxidant capacity and reduced the inflammatory response. This novel preparation can enable new combinations of plant extracts and biomaterials to adiministered through NPs or other dosage forms in order to regulate and treat diseases. Graphic abstract

Aloe vera gel and whole leaf materials, as well as polysaccharides, precipitated from the gel, have previously been shown to enhance macromolecular drug delivery across epithelial tissues. This study investigated the effectiveness of microparticle formulations prepared from A. vera polysaccharides for nasal delivery of insulin across excised sheep olfactory and respiratory nasal epithelial tissues. An emulsion-solvent evaporation technique was used to prepare two insulin microparticle formulations, namely one containing Eudragit® L100 and A. vera polysaccharides and one containing A. vera polysaccharides only. In addition, an ionic gelation technique was used to prepare an insulin microparticle formulation with A. vera polysaccharides, where calcium chloride was used as a cross-linker. The microparticle formulations were evaluated in terms of drug content (assay), particle size, drug release (dissolution), ex vivo drug permeation, and histology. The microparticle formulations exhibited statistically significantly higher insulin delivery across excised sheep olfactory and respiratory nasal epithelial tissues compared to that of the control group (insulin alone). In conclusion, the use of A. vera polysaccharides in microparticle formulations significantly improved nasal insulin delivery. Therefore, A. vera polysaccharide containing microparticles showed high potential to enhance systemic bioavailability and delivery into the brain of macromolecular drugs such as insulin after intranasal administration.

The design of nanoparticle formulations composed of biopolymers, that govern the physicochemical properties of orally delivered insulin, relies on improving insulin stability and absorption through the intestinal mucosa while protecting it from harsh conditions in the gastrointestinal (GI) tract. Chitosan/polyethylene glycol (PEG) and albumin coating of alginate/dextran sulfate hydrogel cores are presented as a multilayer complex protecting insulin within the nanoparticle. This study aims to optimize a nanoparticle formulation by assessing the relationship between design parameters and experimental data using response surface methodology through a 3-factor 3-level optimization Box–Behnken design. While the selected independent variables were the concentrations of PEG, chitosan and albumin, the dependent variables were particle size, polydispersity index (PDI), zeta potential, and insulin release. Experimental results showed a nanoparticle size ranging from 313 to 585 nm, with PDI from 0.17 to 0.39 and zeta potential ranging from −29 to −44 mV. Insulin bioactivity was maintained in simulated GI media with over 45% cumulative release after 180 min in a simulated intestinal medium. Based on the experimental responses and according to the criteria of desirability on the experimental region’s constraints, solutions of 0.03% PEG, 0.047% chitosan and 1.20% albumin provide an optimum nanoparticle formulation for insulin oral delivery.

Delivery of therapeutic peptides via sublingual administration is extremely desired and 3D printed scaffolds are potential candidates as carriers to enhance insulin delivery. 3D printed sublingual sodium alginate (SA)/polyethylene glycol (PEG) composite scaffolds were produced for enhancing insulin delivery by examining the chemical, morphological, mechanical, thermal, cytotoxic, and pharmacokinetic features. The tensile strength and flexibility of scaffolds increased after loading insulin due to the crystalline structure of insulin. Furthermore, insulin-loaded 9SA/3PEG scaffolds showed ultrafast wetting (<1 s), disintegration (<6 s), and also dissolution (<30 s) according to Hixson-Crowell kinetic model. The cell viability of L929 cells on 3D printed scaffolds was examined and these scaffolds could be safely applied on animals. Pharmacokinetic parameters and blood glucose level were evaluated following sublingual administration of scaffolds to type-1 diabetic rats. A single dose of scaffold presented a longer hypoglycemic effect, reducing ~60% of glycemia after 30 min and it lasted for 12 h by increasing the bioavailability of insulin. Scaffolds indicated a sustained profile for serum insulin levels, which continued to increase slightly after 3 h during the study. The polymeric scaffold with a high safety and efficacy holds a new promising delivery strategy for administering injectable insulin through the sublingual route. [Display omitted] • Sodium alginate/polyethylene glycol scaffolds were produced by 3D printing. • Scaffolds were used as carriers to enhance insulin delivery via sublingual route. • Ultrafast wetting, disintegration (<6 s), and dissolution (<30s) were presented. • Scaffolds show a longer hypoglycemic effect, reducing ~60% of glycemia after 30 min. • Scaffolds indicated a sustained profile for serum insulin levels lasted for 12 h. [ABSTRACT FROM AUTHOR]

The use of nanoparticles (NPs) has surely grown in recent years due to their versatility, with a spectrum of applications that range from nanomedicine to the food industry. Recent research focuses on the development of NPs for the oral administration route rather than the intravenous one, placing the interactions between NPs and the intestine at the centre of the attention. This allows the NPs functionalization to exploit the different characteristics of the digestive tract, such as the different pH, the intestinal mucus layer, or the intestinal absorption capacity. On the other hand, these same characteristics can represent a problem for their complexity, also considering the potential interactions with the food matrix or the microbiota. This review intends to give a comprehensive look into three main branches of NPs delivery through the oral route: the functionalization of NPs drug carriers for systemic targets, with the case of insulin carriers as an example; NPs for the delivery of drugs locally active in the intestine, for the treatment of inflammatory bowel diseases and colon cancer; finally, the potential concerns and side effects of the accidental and uncontrolled exposure to NPs employed as food additives, with focus on E171 (titanium dioxide) and E174 (silver NPs). [ABSTRACT FROM AUTHOR]

The design of carriers for insulin delivery has recently attracted major research attentions in the biomedical field. In general, the release of drug from polymers is driven via a variety of polymers. Several mechanisms such as matrix release, leaching of drug, swelling, and diffusion are usually adopted for the release of drug through polymers. Insulin is one of the most predominant therapeutic drugs for the treatment of both diabetes mellitus; type-I (insulin-dependent) and type II (insulin-independent). Currently, insulin is administered subcutaneously, which makes the patient feel discomfort, pain, hyperinsulinemia, allergic responses, lipodystrophy surrounding the injection area, and occurrence of miscarried glycemic control. Therefore, significant research interest has been focused on designing and developing new insulin delivery technologies to control blood glucose levels and time, which can enhance the patient compliance simultaneously through alternative routes as non-invasive insulin delivery. The aim of this review is to emphasize various non-invasive insulin delivery mechanisms including oral, transdermal, rectal, vaginal, ocular, and nasal. In addition, this review highlights different smart stimuli-responsive insulin delivery systems including glucose, pH, enzymes, near-infrared, ultrasound, magnetic and electric fields, and the application of various polymers as insulin carriers. Finally, the advantages, limitations, and the effect of each non-invasive route on insulin delivery are discussed in detail. • Polymeric non-invasive insulin delivery methods have been reviewed. • Common methods of insulin delivery are oral, transdermal, rectal, vaginal, ocular, and nasal. • Hydrogels are considered good insulin delivery systems due to their permeability. • The highest % insulin release was 100% using transdermal delivery. • Future studies should focus on longer release times and fewer side effects. [ABSTRACT FROM AUTHOR]

The present study deals with the comparative analysis of insulin drug release from pure chitosan (CS) and its crosslinked amide derivatives. The objective of this study was to investigate the influence of fatty acid derivatives on the release profiles of insulin drug from CS-based matrices. In order to form cross-linked CS-based amide derivatives, the CS biopolymer was reacted with four different fatty acids with varying amount of unsaturation, including stearic acid (SA), oleic acid (OA), linoleic acid (LA), and linolenic acid (LLA), and then subjected to cross-linking. Following this, the pure CS and cross-linked CS amide derivatives were loaded with insulin drug and were characterized thoroughly by making use of various instrumental techniques such as FTIR, UV–Vis, TGA, HRTEM, DLS, PDI, and zeta potential studies. In addition, the insulin release profiles were studied and compared between pure CS and CS amides at two different pHs, 7.4 and 1.2. Finally, the insulin drug release data was investigated with five different pharmacokinetic models (zero, first, Higuchi, Kersmeyer–Peppas, and Hixson models). From the analysis, the cross-linked CS amides was found to be superior to pure CS, and within the amide derivatives, the one with a high amount of unsaturation, LLA-derived CS biopolymer, was shown to be better for the release of insulin drug by means of the diffusion and dissolution pathways. [ABSTRACT FROM AUTHOR]

Epithelial barriers that seal cell gaps by forming tight junctions to prevent the free permeation of nutrients, electrolytes, and drugs, are essential for maintaining homeostasis in multicellular organisms. The development of nanocarriers that can permeate epithelial tissues without compromising barrier function is key for establishing a safe and efficient drug delivery system (DDS). Previously, we have demonstrated that a water-soluble phospholipid-mimicking random copolymer, poly(2-methacryloyloxyethyl phosphorylcholine 30 - random - n ‑butyl methacrylate 70) (PMB30W), enters the cytoplasm of live cells by passive diffusion manners, without damaging the cell membranes. The internalization mechanism was confirmed to be amphiphilicity-induced membrane fusion. In the present study, we demonstrated energy-independent permeation of PMB30W through the model epithelial barriers of Madin-Darby canine kidney (MDCK) cell monolayers in vitro. The polymer penetrated epithelial MDCK monolayers via transcellular pathways without breaching the barrier functions. This was confirmed by our unique assay that can monitor the leakage of the proton as the smallest indicator across the epithelial barriers. Moreover, energy-independent transepithelial permeation was achieved when insulin was chemically conjugated with the phospholipid-mimicking nanocarrier. The bioactivity of insulin as a growth factor was found to be maintained even after translocation. These fundamental findings may aid the establishment of transepithelial DDS with advanced drug efficiency and safety. A nanocarrier that can freely permeate epithelial tissues without compromising barrier function is key for successful DDS. Existing strategies mainly rely on paracellular transport associated with tight junction breakdown or transcellular transport via transporter recognition-mediated active uptake. These approaches raise concerns about efficiency and safety. In this study, we performed non-endocytic permeation of phospholipid-mimicking polymers through the model epithelial barriers in vitro. The polymer penetrated via transcytotic pathways without breaching the barriers of biomembrane and tight junction. Moreover, transepithelial permeation occurred when insulin was covalently attached to the nanocarrier. The bioactivity of insulin was maintained even after translocation. The biomimetic design of nanocarrier may realize safe and efficient transepithelial DDS. [Display omitted] [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The aim of this work was to assess the relationship between meal nutrients and postprandial blood glucose response (PGR) in individuals with type 1 diabetes on a hybrid closed-loop system (HCLS). Methods: The dietary composition of 1264 meals (398 breakfasts, 441 lunches and 425 dinners) was assessed by 7-day food records completed by 25 individuals with type 1 diabetes on HCLSs (12 men/13 women, mean ± SD age 40 ± 12 years, mean ± SD HbA1c 51 ± 10 mmol/mol [6.9 ± 0.2%]). For each meal, PGR (continuous glucose monitoring metrics, glucose incremental AUCs) and insulin doses (pre-meal boluses, post-meal microboluses automatically delivered by the pump and adjustment boluses) over 6 h were evaluated. Results: Breakfast, lunch and dinner significantly differed with respect to energy and nutrient intake and insulin doses. The blood glucose postprandial profile showed an earlier peak after breakfast and a slow increase until 4 h after lunch and dinner (p < 0.001). Mean ± SD postprandial time in range (TIR) was better at breakfast (79.3 ± 22.2%) than at lunch (71.3 ± 23.9%) or dinner (70.0 ± 25.9%) (p < 0.001). Significant negative predictors of TIR at breakfast were total energy intake, per cent intake of total protein and monounsaturated fatty acids, glycaemic load and absolute amounts of cholesterol, carbohydrates and simple sugars consumed (p < 0.05 for all). No significant predictors were detected for TIR at lunch. For TIR at dinner, a significant positive predictor was the per cent intake of plant proteins, while negative predictors were glycaemic load and intake amounts of simple sugars and carbohydrate (p < 0.05 for all). Conclusions/interpretation: This study shows that nutritional factors other than the amount of carbohydrate significantly influence postprandial blood glucose control. These nutritional determinants vary between breakfast, lunch and dinner, with differing effects on postprandial blood glucose profile and insulin requirements, thus remaining a challenge to HCLSs. [ABSTRACT FROM AUTHOR]

Over the past several decades, there have been major advancements in the field of glucose sensing and insulin delivery for the treatment of type I diabetes mellitus. The introduction of closed-loop insulin delivery systems that deliver insulin in response to specific levels of glucose in the blood has shifted significantly the research in this field. These systems consist of encapsulated glucose-sensitive components such as glucose oxidase or phenylboronic acid in hydrogels, microgels or nanoparticles. Since our previous evaluation of these systems in a contribution in 2004, new systems have been developed. Important improvements in key issues, such as consistent insulin delivery over an extended period of time have been addressed. In this contribution, we discuss recent advancements over the last 5 years and present persisting issues in these technologies that must be overcome in order for these systems to be applicable in patients. [ABSTRACT FROM AUTHOR]

Automated delivery of insulin based on continuous glucose monitoring is revolutionizing the way insulin-dependent diabetes is treated. However, challenges remain for the widespread adoption of these systems, including the requirement of a separate glucose sensor, sophisticated electronics and algorithms, and the need for significant user input to operate these costly therapies. Herein, a user-centric glucose-responsive cannula is reported for electronics-free insulin delivery. The cannula-made from a tough, elastomer-hydrogel hybrid membrane formed through a one-pot solvent exchange method-changes permeability to release insulin rapidly upon physiologically relevant varying glucose levels, providing simple and automated insulin delivery with no additional hardware or software. Two prototypes of the cannula are evaluated in insulin-deficient diabetic mice. The first cannula-an ends-sealed, subcutaneously inserted prototype-normalizes blood glucose levels for 3 d and controls postprandial glucose levels. The second, more translational version-a cannula with the distal end sealed and the proximal end connected to a transcutaneous injection port-likewise demonstrates tight, 3-d regulation of blood glucose levels when refilled twice daily. This proof-of-concept study may aid in the development of "smart" cannulas and next-generation insulin therapies at a reduced burden-of-care toll and cost to end-users., (© 2024 Wiley‐VCH GmbH.)

Insulin is a peptide hormone that is essential for regulating body homeostasis. Furthermore, it is involved in various neurological functions such as memory, behaviors, and cognition. The ubiquitous distribution of insulin receptors on various brain cells, such as neurons, microglia, astrocytes, and oligodendrocytes, and their differential localization across various brain regions, including the hippocampus, hypothalamus, and olfactory bulb, collectively underscore the crucial involvement of insulin in the modulation of cerebral functions. Along with ageing, in some pathological conditions such as diabetes and brain insulin resistance, the need for exogenous insulin is felt to compensate for insulin deficiency. In these cases, the biggest obstacle to the delivery of insulin to the brain is the blood-brain barrier (a physical barrier consisting of endothelial cells with tight junctions), which prevents the direct entry of most substances possessing high molecular weight, like insulin, into the brain. Therefore, different delivery methods have been proposed by researchers for insulin delivery that directly or indirectly cause the transfer of insulin to the brain. Some of these methods lack high efficiency and cause many side effects for the patient. In this regard, many new technologies have come to the aid of researchers and have introduced more effective delivery strategies, including the use of nanocarriers. Despite the promising outcomes demonstrated in the experimental models, the utilization of these techniques in human studies remains at a nascent stage and necessitates further comprehensive investigation. This review article aims to examine the diverse methods of insulin administration to the brain by gathering extensive information on insulin and its obstacles to brain delivery., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Subcutaneous injection is crucial for the treatment of many diseases. Especially for regular or continuous injections, automated dosing is beneficial. However, existing devices are large, uncomfortable, visible under clothing, or interfere with physical activity. Thus, the development of small, energy efficient and reliable patch pumps or implantable systems is necessary and research on microelectromechanical system (MEMS) based drug delivery devices has gained increasing interest. However, the requirements of medical applications are challenging and especially the dosing precision and reliability of MEMS pumps are not yet sufficiently evaluated. To enable further miniaturization, we propose a precise 5 × 5 mm2 silicon micropump. Detailed experimental evaluation of ten pumps proves a backpressure capability with air of 12.5 ± 0.8 kPa, which indicates the ability to transport bubbles. The maximal water flow rate is 74 ± 6 µL/min and the pumps' average blocking pressure is 51 kPa. The evaluation of the dosing precision for bolus deliveries with water and insulin shows a high repeatability of dosed package volumes. The pumps show a mean standard deviation of only 0.02 mg for 0.5 mg packages, and therefore, stay below the generally accepted 5% deviation, even for this extremely small amount. The high precision enables the combination with higher concentrated medication and is the foundation for the development of an extremely miniaturized patch pump. [ABSTRACT FROM AUTHOR]

The test in the production of microfluidic devices dedicated to medical applications poses several challenges in terms of contamination, reliability, and cost. The present article describes the Design-for-Testability approach used to make an insulin MEMS micropump that can be fully tested in production in a few seconds. Each key functional parameter of a positive displacement micropump with check valves is described together with detailed pneumatic test methods. The typical failure modes of the device are considered and tested experimentally to show that these methods can also be used for failure analysis and process control. A simplified Built-In-Self-Test is also presented. Finally, advanced methods to characterize the piezoelectric actuator are also described and tested.

The present study develops on insulin-release studies from the chitosan-amide-modified stimuli-responsive polymers formed from various fatty acids including stearic acid, oleic acid, linoleic acid, and linolenic acid. This is the continuation of an earlier reported study that investigates the insulin-release profiles of chitosan-modified fatty acid amides (without stimuli responsive polymers). Following the synthesis and characterization of many different fatty acid amides with a varying amount of unsaturation, the insulin drug loading and release effects were compared among N-isopropylacrylamide (NIPAm), a thermo-responsive polymer, and 2-acrylamide-2-methylpropane sulfonic acid (AMPS), a pH-responsive polymer-modified hydrogel that is expected to enhance environmental response and the controllability of release. Finally, drug release effects were studied to investigate the drug release mechanisms with the help of five different pharmacokinetic models including the zero-order, first-order, Higuchi, Korsmeyers–Peppas, and Hixson models. The results indicate that the Higuchi and Hixson models are valid in terms of the operation of the NIPAm and AMPS matrices during the delivery of insulin.