Insulin Reservoir Research Articles

Unexpected evolution of a monster case of insulin-induced skin lipohypertrophy

In this journal, in 2020, we published the case of a 74-year-old female outpatient with type-2 diabetes mellitus who self-injected insulin four times a day according to the basal-bolus regimen, with an high glycemic variability and an high rate of severe hypoglycemic episodes. Three years before, we had found two extraordinarily large skin lipohypertrophies, with large underlying fluid collections with high insulin concentration. A long educational and intensive training completely repaired the skin lesions with the disappearance of the subcutaneous insulin reservoirs. Glycemic variability has been reduced dramatically, severe hypoglycemia has almost completely disappeared and the daily dose of insulin has been reduced by 38%. However, this extraordinary, albeit unexpected, result was achieved in five years.

Characterization of Cyclic Olefin Copolymers for Insulin Reservoir in an Artificial Pancreas

Type-1 diabetes is one of the most prevalent metabolic disorders worldwide. It results in a significant lack of insulin production by the pancreas and the ensuing hyperglycemia, which needs to be regulated through a tailored administration of insulin throughout the day. Recent studies have shown great advancements in developing an implantable artificial pancreas. However, some improvements are still required, including the optimal biomaterials and technologies to produce the implantable insulin reservoir. Here, we discuss the employment of two types of cyclic olefin copolymers (Topas 5013L-10 and Topas 8007S-04) for an insulin reservoir fabrication. After a preliminary thermomechanical analysis, Topas 8007S-04 was selected as the best material to fabricate a 3D-printed insulin reservoir due to its higher strength and lower glass transition temperature (Tg). Fiber deposition modeling was used to manufacture a reservoir-like structure, which was employed to assess the ability of the material to prevent insulin aggregation. Although the surface texture presents a localized roughness, the ultraviolet analysis did not detect any significant insulin aggregation over a timeframe of 14 days. These interesting results make Topas 8007S-04 cyclic olefin copolymer a potential candidate biomaterial for fabricating structural components in an implantable artificial pancreas.

Surface Engineered PLGA Nanoparticle for Threshold Responsive Glucose Monitoring and "Self-Programmed" Insulin Delivery.

We have developed a reversible, biocompatible, "self-programmed" PLGA [poly(lactic-co-glycolic acid)] nanoparticle-based optical biosensor capable of sensing and continuous monitoring of glucose above the physiologically relevant threshold value (100-125 mg/dL) as well as "on-demand" insulin delivery via an "On-Off" technique. We have carefully surface engineered the PLGA nanoparticle using amino dextran-fluorescein (A-DexFl) and amino-phenyl boronic acid (A-PBA) to exploit the binding affinity of boronic acids with that of cis-1,2 diols of dextran/glucose. Initially, the dextran chains wrap the nanoparticle surface due to its high affinity toward A-PBA (Kb = 6.1 × 106 M-1). The close proximity of the fluorophores with that of A-PBA quenches the fluorescence, resulting in an "Off" state. On the addition of glucose, it competes with A-DexFl to bind with A-PBA. Above a certain threshold concentration of glucose, the binding affinity overcomes (Kb = 6.3 × 107 M-1) the dextran-A-PBA binding. This opens-up the wrapped A-DexFl chains from the nanoparticle surface and results in an increased distance between the fluorophore and A-PBA, triggering the "On" state. The activation of the On-Off state can be finely tuned in the desired range of physiologically relevant glucose concentrations by varying the ligand ratios on the PLGA surface. The nanoparticle core has also been used as an insulin reservoir to trigger the drug release in the "On" state. We have obtained ∼53% encapsulation efficiency and ∼20% loading efficiency for insulin loading. Once the glucose concentration falls beyond the detection range, the dextran chains collapse on the nanoparticle surface with a suspension in drug release. The process is solely controlled by the competition and multivalent binding affinity between glucose, A-DexFl, and A-PBA, which allows it to be "self-programmed" and "self-regulated" with continuous monitoring up to 8-10 cycles over a 72 h time period. A sustained drug release has been found with ∼70% of released drug over a period of 72 h, although this release is insignificant in the absence of glucose. Several control experiments have been performed to optimize the sensor design.

On-demand transdermal insulin delivery system for type 1 diabetes therapy with no hypoglycemia risks

Diabetes is a metabolic disease that is affecting an ever-increasing number of people worldwide, resulting in increased burdens on healthcare systems and societies. Constant monitoring of blood glucose levels is required to prevent serious or even deadly complications. One major challenge of diabetes management is the simple and timely administration of insulin to facilitate consistent blood glucose regulation and reduce the incidence of hypoglycemia. With this research, we construct an insulin delivery system, the delivery system is comprised of phenylboronic acid based fluorescent probes, which is used as glucose responsive linkers, mesoporous silica nanoparticles providing an insulin reservoir, and zinc oxide nanoparticles used as gate keepers. The system with glucose sensitive responsive linker exhibits controlled release of insulin under high glucose concentrations, providing prolonged blood glucose regulation and no risks of hypoglycemia. Furthermore, the system is combined with a hyaluronic-acid based microneedle patch, which exhibit efficient skin penetration for transdermal delivery. With our system, the nanoparticles provide outstanding in vivo glucose regulation when administrated by subcutaneous injection or via transdermal microneedle patch. We anticipate that our biocompatible smart glucose responsive microneedle patch (SGRM patch) will facilitate the development of clinically useful systems.

Insulin Solution Stability and Biocompatibility with Materials Used for an Implantable Insulin Delivery Device Using Reverse Phase HPLC Methods

Insulin (Humulin® R IU500) has been delivered from an implantable artificial pancreas in diabetic rats and pigs. The artificial pancreas which was implanted in the peritoneum was fabricated from several biocompatible materials such as polycarbonate, stainless steel, polyurethane, titanium and a polyurethane resin. The device also contains a glucose responsive smart gel which controls the diffusion of insulin dependent on the surrounding glucose environment. As the insulin reservoir is refillable and in contact with the device materials, assessing its biocompatibility with these various device component materials was conducted. Insulin can undergo chemical degradation mainly via a deamidation reaction on glutamine and asparagine residues rendering its biological hormone functionality. Two Reverse Phase High Performance Liquid Chromatography (RP-HPLC) methods were developed and validated for detection of insulin and degradant Asn A21 desamido insulin (method A) and insulin and degradant Asn B3 desamido insulin (method B). Material biocompatibility studies show that stainless steel and titanium are suitable for an implantable insulin delivery device design over a 31-day period. The use of polycarbonate and polyurethane could be considered if the insulin reservoir in the device was only to remain in the device for less than 11 days after which time there is a loss in cresol which acts in a protective capacity for insulin stability.

Children with type 1 diabetes of early age at onset - immune and metabolic phenotypes.

Objectives We aimed to evaluate children with type 1 diabetes (T1D) with early age at onset (EAO) for clinical, immune and metabolic features in order to identify age-related disease phenotypes. Methods Comparative study of two groups of T1D children: EAO (≤5 years) and later age at onset (LAO; >5 years), regarding the presence of other autoimmune (AI) diseases, diabetes ketoacidosis and immunologic profile at onset and metabolic data 1 year after diagnosis. Statistical analysis was performed with significance set for p < 0.05. Results The study included 137 children (EAO = 52, mean age 3.6 ± 1.5 [mean ± standard deviation (SD)] and LAO = 85, mean age 10.4 ± 2.9). EAO was more associated with concomitant AI diseases (p = 0.032). Despite no differences in disease onset, EAO presented with lower C-peptide levels (p = 0.01) and higher absolute lymphocyte number (p < 0.0001), with an inverse correlation between these two variables (p = 0.028). Additionally, the EAO group had a higher frequency of serum detection of three antibodies (Abs) (p = 0.0008), specifically insulin Abs (p = 0.0001). One year after diagnosis, EAO had higher total daily insulin (TDI) dose (p = 0.008), despite similar hemoglobin A1c (HbA1c). Conclusions Our data show an association of EAO T1D with more AI diseases, higher number of Abs, lower initial insulin reservoir and higher insulin requirements 1 year after diagnosis. In this group, immune imbalance seems more evident and disease progression faster, probably reflecting distinct "immune environment" with different ages at disease onset. Further studies in the field of immunogenetics and immune tolerance are required, to improve patient stratification and find novel targets for therapeutic intervention.

User Satisfaction and Insulin Pump Handling With a Prefilled Insulin Cartridge in Adults and Adolescents With Type 1 Diabetes.

Background:This comparative handling study investigated user satisfaction and insulin pump handling with a prefilled insulin cartridge versus a self-filled insulin reservoir in insulin pump users with type 1 diabetes (T1D).Methods:Adult (n = 105) and adolescent (n = 25) participants performed insulin pump preparations using a prefilled insulin cartridge and self-filled insulin reservoir. User satisfaction, insulin pump preparation time, and residual air in infusion set tubing were assessed for each insulin filling method. Post hoc analysis evaluated training time.Results:User satisfaction scores were statistically significantly different in favor of the prefilled insulin cartridge versus the self-filled insulin reservoir (mean [SD]: overall, 4.0 [0.5] vs 3.3 [0.9]; burden on the user, 1.8 [0.6] vs 2.9 [1.0]; user inconvenience, 2.0 [0.7] vs 2.8 [1.1]; device effectiveness, 3.9 [0.7] vs 3.6 [0.9]; all P < .001). Insulin pump preparation time and residual air measurements were significantly different and numerically lower for the prefilled insulin cartridge versus the self-filled insulin reservoir (mean [SD]: preparation time, 124.4 [30.3] vs 237.8 [64.2] seconds, P < .001; residual air, 2.3 [26.3] vs 10.0 [63.3] mm, P = .007). Training time was shorter with the prefilled insulin cartridge versus the self-filled insulin reservoir (mean [min; max]: 193.1 [36; 453] vs 535.8 [124; 992] seconds).Conclusions:Adult and adolescent insulin pump users were more satisfied with the prefilled insulin cartridge versus the self-filled insulin reservoir when preparing an insulin pump. The prefilled insulin cartridge was associated with reduced insulin pump preparation time and reduced training time versus the self-filled insulin reservoir.

Toward Dosing Precision and Insulin Stability in an Artificial Pancreas System

A fully implantable artificial pancreas (AP) still represents the holy grail for diabetes treatment. The quest for efficient miniaturized implantable insulin pumps, able to accurately regulate the blood glucose profile and to keep insulin stability, is still persistent. This work describes the design and testing of a microinjection system connected to a variable volume insulin reservoir devised to favor insulin stability during storage. The design, the constitutive materials, and the related fabrication techniques were selected to favor insulin stability by avoiding—or at least limiting—hormone aggregation. We compared substrates made of nylon 6 and Teflon, provided with different surface roughness values due to the employed fabrication procedures (i.e., standard machining and spray deposition). Insulin stability was tested in a worst case condition for 14 days, and pumping system reliability and repeatability in dosing were tested over an entire reservoir emptying cycle. We found that nylon 6 guarantees a higher insulin stability than Teflon and that independent of the material used, larger roughness determines a higher amount of insulin aggregates. A dedicated rotary pump featured by a 1-μL delivery resolution was developed and connected through a proper gear mechanism to a variable volume air-tight insulin reservoir. The microinjection system was also able to operate in a reverse mode to enable the refilling of the implanted reservoir. The developed system represents a fundamental building block toward the development of a fully implantable AP and could be advantageously integrated even in different implantable drug delivery apparatus (e.g., for pain management).

(Invited) Artificial on-Skin Pancreas Fabricated with Smart Hybrid Hydrogel for Self-Regulated Insulin Delivery

Diabetes mellitus is the sixth leading cause of death. Traditional insulin injection not only involves pain, inconvenience, infection and nerve damage, but also is difficult to achieve persistent glycemic control. Current “closed-loop” delivery systems are either electronics-derived or protein-based, leading to the concerns of electrical failure or immunetoxicity. Phenylboronic acid (PBA), which can reversibly bind with glucose, is an attractive candidate for glucose sensing and self-regulated insulin delivery as it does not have the denaturing and immunetoxicity concerns. A totally synthetic smart PBA gel exhibiting supreme glucose-sensitivity at physiological pH and temperature was developed. [1] The release of insulin can be self-regulated by the skin layer formed on the gel surface and the insulin release rate was well corresponding to the external glucose concentration. [2] Recently, a catheter-combined device incorporating this smart gel has been successfully validated for mouse diabetes. [3] In order to deliver insulin in a glucose-responsive, painless, convenient and safe way, we developed an electronics-free, enzyme-free smart artificial on-skin pancreas, which is a microneedles (MNs) patch fabricated with smart hybrid hydrogel and silk fibroin. [4] The semi-interpenetrating network hydrogel was fabricated using PBA derivative for glucose sensing, N-isopropylacrylamide and silk fibroin for mechanical robustness. After skin insertion, the hybrid hydrogel in the tip region of MNs patch will continuously monitor the glucose level. At normoglycemic condition, the skin layer formed on the MNs surface will effectively block the release of insulin. However, with the increase of glucose concentration, the binding of PBA with glucose leads to the hydration of the hybrid MNs, and thus allows the release of insulin at hyperglycemia condition (Fig.1A). The hybrid hydrogel formulation was optimized by systematically investigating key parameters that may affect the gel properties, e.g. monomer concentration, silk fibroin proportion, crosslinking percentage, etc. The optimized hybrid hydrogel formed micro-porous and inter-connected structure, which enabled smooth and sustained release of loaded insulin (Fig. 1B). The physicochemical properties including swelling, stability, and glucose-responsive insulin release were explored. Furthermore, two-layer MNs were fabricated using micro-molding technology with hybrid hydrogel in the tip region and silk fibroin as the base layer. An insulin reservoir was attached to enhance the amount of loaded insulin. The morphology, gel & insulin distribution, mechanical strength of the MNs patch were characterized. The MNs patch penetrated the skin effectively, and could release insulin corresponding to the external glucose concentration (Fig. 1C). This novel on-skin pancreas is patient-friendly, possible to achieve persistent glycemic control, durable and disposable, which is promising to be the next-generation therapy for diabetes. R e ferences: [1]. A. Matsumoto et al., Chem. Commun., 2010, 46, 2203-2205. [2]. A. Matsumoto et al., Angew. Chem. Int. Ed., 2012, 51(9), 2124-2128 [3]. A. Matsumoto et al., Sci. Adv., 2017, 3(11), eaaq0723. [4]. A. Matsumoto and S. Chen, Japanese patent, No. 2018-053817, patent pending. Figure 1

Documentation of Continuous Subcutaneous Insulin Infusion (CSII) Use in the Emergency Department (ED)

The Institute for Safe Medication Practices recommends patients on CSII who present to the hospital (inpatient or the ED), should have CSII use and settings verified within 12 hours. Without CSII orders or scheduled glucose checks in the ED, adverse glycemic excursions from insulin pump misadventures can occur, increasing risk of DKA or severe hypoglycemia. At University of California, San Francisco, (UCSF) 25% of admitted patients enter via the ED with an average door-to-admission of &amp;gt; 12 hours. We have mandatory insulin pump orders for inpatients. To determine the timing of CSII orders, documentation and glucose levels, we performed a retrospective review of patients admitted from the ED who remained on CSII, from June 2012 to August 2016. 32 patients (age 54.3 ± 14.6 years) were admitted to the hospital from the ED who were continued on CSII. We were unable to capture data on ED patients not admitted or who had their CSII discontinued. 37.5% did not have CSII orders written within 12 hours of presentation to the ED. The average time to insulin pump order was 13.3 hours. 43% presented to the ED between1900-0700. The mean time to first glucose was 1.27 hours ± 1.47, and 15.6% had no glucose check within the first 2 hours. &amp;lt;50% had CSII integrity documented (insulin reservoir, site intact, battery capacity) in the first 24 hours. Glycemic control was assessed by 6-hour periods. For these 4 periods: Glucose 80-180 mg/dl (13/32; 12/32; 15/32; 9/32); &amp;gt;180 mg/dl (18/32; 11/32; 12/32; 12/32); &amp;lt;80 mg/dl (0/32; 2/32; 2/32; 2/32); no glucose (0/32; 7/32; 3/32; 9/32). Continuous glucose monitor readings are not part of the patient’s medical record as not approved for clinical decision making. We found few patients had CSII orders or documentation nor appropriate glucose monitoring in the initial 12 hours after presentation to the ED. We anticipate new ED policies, procedures, and RN protocols, with use of new ED pump order sets and early patient involvement, will improve guideline compliance and patient care. Disclosure R.J. Rushakoff: None. J. Zook: None. H.W. Macmaster: None.

Glucose Oxidase-Based Glucose-Sensitive Drug Delivery for Diabetes Treatment.

The glucose-sensitive drug delivery systems based on glucose oxidase (GOD), which exhibit highly promising applications in diabetes therapy, have attracted much more interest in recent years. The self-regulated drug delivery systems regulate drug release by glucose concentration automatically and continuously to control the blood glucose level (BGL) in normoglycemic state. This review covers the recent advances at the developments of GOD-based glucose-sensitive drug delivery systems and their in vivo applications for diabetes treatment. The applications of GOD-immobilized platforms, such as self-assembly layer-by-layer (LbL) films and polymer vesicles, cross-linking hydrogels and microgels, hybrid mesoporous silica nanoparticles, and microdevices fabricated with insulin reservoirs have been surveyed. The glucose-sensitive drug delivery systems based on GOD are expected to be a typical candidate for smart platforms for potential applications in diabetes therapy.

Closed-loop glycaemic control using an implantable artificial pancreas in diabetic domestic pig (Sus scrofa domesticus)

The performance of a completely implantable peritoneal artificial pancreas (AP) has been demonstrated in principle in a live diabetic domestic pig. The device consists of a smart glucose-sensitive gel that forms a gateway to an insulin reservoir and is designed to both sense glucose and deliver insulin in the peritoneal cavity. It can be refilled with insulin via subcutaneous ports and surgery was developed to insert the AP. Diabetes was induced with streptozotocin (STZ), the device filled with insulin (Humulin® R U-500) in situ and the animal observed for several weeks, during which time there was normal access to food and water and several oral glucose challenges. Blood glucose (BG) levels were brought down from >30mmol/L (540mg/dL) to non-fasted values between 7 and 13mmol/L (126–234mg/dL) about five days after filling the device. Glucose challenge responses improved ultimately so that, starting at 10mmol/L (180mg/dL), the BG peak was 18mmol/L (324mg/dL) and fell to 7mmol/L (126mg/dL) after 30min, contrasting with intravenous attempts. The reservoir solution was removed after 8days of blood glucose levels during which they had been increasingly better controlled. A rapid return to diabetic BG levels (30mmol/L) occurred only after a further 24days implying some insulin had remained in the device after removal of the reservoir solution. Thus, the closed loop system appeared to have particular influence on the basal and bolus needs for the 8days in which the reservoir solution was in place and substantial impact for a further 3 weeks. No additional insulin manual adjustment was given during this period.

Nuevo tratamiento de la diabetes por las sulfamidacarbamidas

Hace treinta y seis años, los investigadores Frederick Grant Banting y Best, de Toronto, logran aislar la insulina del páncreas y aplicarlo al tratamiento de la diabetes, se trata de la insulina corríente, natural, de acción rápida; pero por esta propiedad de ser de acción rápida es que se hace laborioso su manejo, requiere muchas inyecciones al día y se gasta mucha insulina, sembrando cierta desconfianza en los pacientes por los accidentes a que da lugar. Entonces hay que resolver el primer problema de la insulinización : Retardar la acción de la insulina, para cuyo efecto se le asocia a los vasoconstríctores, como las hormonas hipofisarias y la adrenalina, con lo que se prolonga su acción a las ocho horas, pero, endocrinólogos de ese tiempo como Umber, no la admiten como insulina de depósito, y es retirada del uso terapéutico.

Sharing Insulin Pens: Are You Putting Patients at Risk?

Ease of administration, accuracy, and convenience are among the hallmark characteristics of insulin pens. These devices, which have gained popularity over the past 10 years, are designed to be used multiple times for a single person, using a new needle for each injection. Unfortunately, reports of the misuse of insulin pens also have been growing. Backflow of blood and other biologic material into the insulin cartridge or reservoir can occur after injection (1). For this reason, insulin pens, like other injection devices, must never be used by more than one person. Reports of insulin pen sharing have come from a variety of U.S. health care settings. Since 2011, there have been at least six separate incidents in which patients were contacted and given advice to test for bloodborne pathogens because individual insulin pen devices were …

Type 1 Diabetes Mellitus

1. Justin M. Gregory, MD* 2. Daniel J. Moore, MD, PhD† 3. Jill H. Simmons, MD‡ 1. *Pediatric Endocrinology Clinical Fellow, Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN. 2. †Assistant Professor of Pediatrics, Assistant Professor of Pathology, Microbiology, and Immunology, Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN. 3. ‡Assistant Professor of Pediatrics, Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN. * ADA: : American Diabetes Association DKA: : diabetic ketoacidosis HbA1c: : glycosylated hemoglobin I:C ratio: : insulin-to-carbohydrate ratio IV: : intravenous TDD: : total daily dose T1DM: : type 1 diabetes mellitus T2DM: : type 2 diabetes mellitus 1. All children with type 1 diabetes mellitus (T1DM) should have their blood sugar managed with basal-bolus insulin treatment by either multiple daily injections or an insulin pump. 2. All children with T1DM should have access to a pediatric endocrinologist with a diabetes management team with resources to support patients and families. 3. All children with T1DM should be monitored for symptoms and/or screened for commonly associated conditions such as thyroid and celiac disease. After completing this article, readers should be able to: 1. Recognize the presenting signs and symptoms of type 1 diabetes mellitus (T1DM). 2. Know the key principles of effective diabetes self-management and the diabetes care team’s role in facilitating effective self-management. 3. Know the acute and chronic complications of (T1DM). 4. Identify how different categories of insulin analogues are used in daily insulin regimens. True, it is a fight, but there is pleasure in the struggle. Victory comes to the courageous; and without courage and common sense, success awaits no one. I look upon the diabetic as charioteer and his chariot as drawn by three steeds named Diet, Insulin, and Exercise. It takes skill to drive one horse, intelligence to manage a team of two, but a man must be a very good teamster who can get all three to pull together.EP Joslin, 1933 Type 1 diabetes mellitus (T1DM) is a disorder of glucose homeostasis characterized by autoimmune destruction of the insulin-producing pancreatic β-cell that progressively leads to insulin deficiency and resultant hyperglycemia. If left untreated, insulin deficiency leads to progressive metabolic derangement, with worsening hyperglycemia, ketoacidosis, starvation, and death. In …

Type 1 Diabetes Mellitus

Type 1 Diabetes Mellitus

Wearable and implantable pancreas substitutes

A lifelong-implanted and completely automated artificial or bioartificial pancreas (BAP) is the holy grail for type 1 diabetes treatment, and could be a definitive solution even for other severe pathologies, such as pancreatitis and pancreas cancer. Technology has made several important steps forward in the last years, providing new hope for the realization of such devices, whose feasibility is strictly connected to advances in glucose sensor technology, subcutaneous and intraperitoneal insulin pump development, the design of closed-loop control algorithms for mechatronic pancreases, as well as cell and tissue engineering and cell encapsulation for biohybrid pancreases. Furthermore, smart integration of the mentioned components and biocompatibility issues must be addressed, bearing in mind that, for mechatronic pancreases, it is most important to consider how to recharge implanted batteries and refill implanted insulin reservoirs without requiring periodic surgical interventions. This review describes recent advancements in technologies and concepts related to artificial and bioartificial pancreases, and assesses how far we are from a lifelong-implanted and self-working pancreas substitute that can fully restore the quality of life of a diabetic (or other type of) patient.

Embedded Control Design for Insulin Pump

This paper presents the design of an embedded control system for insulin pump. The insulin pump is an integrated component in any closed loop insulin delivery system for type 1 diabetes. The pump consists of three main components: micro-needles, insulin reservoir(syringe), and piezoelectric (PZT) linear servo motor. The actuated syringe has an injection back pressure that resists the linear motion of the driving PZT motor. This back pressure acts as a disturbance and leads to in accurate position and consequently an imprecise insulin dosage. Therefore, a highly precise positioning control on the pump is required to control the insulin dosage and to maintain the blood glucose level in its safe range. The proposed controller is designed using fuzzy logic as a nonlinear controller to compensate any non-modeled nonlinear ities in the system.The embedded controller for the PZT motor can be implemented using FPGA or microcontroller chip. This controller acts as a slave and responds to its master controller which controls the complete closed loop insulin delivery system.

Nanotechnology‐Enabled Closed Loop Insulin Delivery Device: In Vitro and In Vivo Evaluation of Glucose‐Regulated Insulin Release for Diabetes Control

AbstractRecently, a new multifunctional, bio‐inorganic nanocomposite membrane with the ability to self‐regulate the release of insulin in response to blood glucose (BG) levels was reported. Herein, the application of this material as part of a small, implantable, closed‐loop insulin delivery device designed to continuously monitor BG concentrations and regulate insulin release is proposed. The insulin delivery device consists of a nanocomposite glucose‐responsive plug covalently bound to an insulin reservoir made of surface‐modified silicone. The plug is prepared with crosslinked bovine serum albumin (BSA) and enzymes (glucose oxidase (GOx) and catalase (CAT)), pH‐responsive hydrogel nanoparticles, and multifunctional MnO2 nanoparticles. The plug functions both as a glucose sensor and controlled delivery unit to release higher rates of insulin from the reservoir in response to hyperglycemic BG levels and basal insulin rates at normal BG concentration. The surfaces of the device are modified by silanization followed by PEGylation to ensure its safety and biocompatibility and the stability of encased insulin. Our results show that insulin release can be modulated in vitro in response to glucose concentrations. In vivo experiments show that the glycemia of diabetic rats can be controlled with implantation of the prototype device. The glucose‐responsiveness of the device is also demonstrated by rapid drop in BG level after challenging diabetic rats with bolus injection of glucose solution. In addition, it is demonstrated that surface PEGylation of the device is necessary for reducing the immune response of the host to the implanted foreign object and maintaining insulin stability and bioactivity. With this molecular architecture and the bio‐inorganic nanocomposite plug, the device has the ability to maintain normal BG levels in diabetic rats.

In Vivo Study of a Polymeric Glucose-Sensitive Insulin Delivery System Using a Rat Model

This study assesses the feasibility of an intraperitoneal (IP) implantable closed-loop insulin delivery device in rats, that delivers insulin via a glucose-sensitive material such that blood glucose (BG) levels are adjusted automatically to within normal tolerances. A gateway layer of this gel governs the output of insulin from an insulin reservoir device for IP implant. The performance of the system was compared over time in diabetic rats with a control system using oral glucose challenges and daily assessments of BG and body weight. The automated response of the active system was quantified using IP multiple dose injection (MDI) results in the same rat model. Successful control was found for the device containing active gel when assessed daily and when challenged with large glucose doses. This was not found when comparing an inactive gel analog as a control. The regimen was quantified by comparison with the informative MDI study. The device was well tolerated and might operate to further advantage when vascular omentum grows into the perforated front of the device. The successful device must have been outputting approximately 0.5 U/kg/h basal with 2 U/kg boosts in order to match the demand of the challenges. However, the device eventually exhausts and a refill mechanism needs to be devised in future models.