Glucose-responsive Insulin Delivery Research Articles

Perioperative Fully Closed-loop versus Usual Care Glucose Management in Adults Undergoing Major Abdominal Surgery - A Two-centre Randomised Controlled Trial.

To assess the efficacy and safety of fully closed-loop (FCL) compared with usual care (UC) glucose control in patients experiencing major abdominal surgery-related stress hyperglycaemia. Major abdominal surgery-related stress and periprocedural interventions predispose to perioperative hyperglycaemia, both in diabetes and non-diabetes patients. Insulin corrects hyperglycaemia effectively, but its safe use remains challenging. In this two-centre randomised controlled trial, we contrasted subcutaneous FCL with UC glucose management in patients undergoing major abdominal surgery anticipated to experience prolonged hyperglycaemia. FCL (CamAPS HX, Dexcom G6, mylife YpsoPump 1.5x) or UC treatment was used from hospital admission to discharge (max 20d). Glucose control was assessed using continuous glucose monitoring (masked in the UC group). The primary outcome was the proportion of time with sensor glucose values in target range 5.6-10.0mmol/L. Thirty-seven surgical patients (54% pancreas, 22% liver, 19% upper gastrointestinal, 5% lower gastrointestinal), of whom 18 received FCL and 19 UC glucose management, were included in the analysis. Mean±SD percentage time with sensor glucose in target range was 80.1±10.0% in the FCL and 53.7±19.7% in the UC group (P<0.001). Mean±SD glucose was 7.5±0.5mmol/L in the FCL and 9.1±2.4mmol/L in the UC group (P=0.015). Time in hypoglycaemia (<3.0mmol/L) was low in either group. No study-related serious adverse events occurred. The FCL approach resulted in significantly better glycaemic control compared to UC management, without increasing the risk of hypoglycaemia. Automated glucose-responsive insulin delivery is a safe and effective strategy to minimise hyperglycaemia in complex surgical populations.

Glucose-Responsive Microneedle Patch with High Insulin Loading Capacity for Prolonged Glycemic Control in Mice and Minipigs.

Transdermal microneedle-mediated glucose-responsive insulin delivery systems can modulate insulin release based on fluctuations in blood glucose levels, thus maintaining normoglycemia effectively in a continuous, convenient, and minimally invasive manner. However, conventional microneedles are limited by the low drug loading capacity, making it challenging to be applied on human skin at a reasonable size for a lasting glucose-controlling effect, thus hindering their clinical translation. Here, we design a microneedle patch with a solid insulin powder core to achieve a high loading capacity of insulin (>70 wt %) as well as a glucose-sensitive polymeric shell to realize glucose-responsive insulin release. Once exposed to hyperglycemia, the formation of negatively charged glucose-boronate complexes increases the charge density of the shell matrix, leading to swelling of the shell and accelerating insulin release from the core. We have demonstrated that this glucose-responsive microneedle patch could achieve long-term regulation of blood glucose levels in both type 1 diabetic mice and minipigs (up to 48 h with patches of ∼3.5 cm2 for minipigs >25 kg).

Injectable Gelled Multiple Emulsion for Glucose-Responsive Insulin Delivery.

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 (W1/O/W2) 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.

Anti-inflammatory PEGylated bilirubin microneedle patch for diabetes treatment

The long-term hyperglycemic environment could easily cause chronic metabolic inflammation with physiological disorders, exacerbate inflammatory cytokine storms, increase the risk of patients contracting other complications. Thus, to develop glucose-responsive insulin delivery microneedles with anti-inflammatory is of much importance. Herein, a novel in-situ H2O2-sensitive insulin delivery microneedle array patch was constructed for the intelligent management of blood glucose in diabetics, which was integrated with nanoparticles (NPs) to achieve synergistic enhancement of anti-inflammatory and antioxidant functions. Specifically, PEGylated bilirubin (BR) nanoparticles were loaded with insulin and glucose-sensing element glucose oxidase (GOD), named as I@PEG-BR/GOD NPs, which could release drugs in response to high concentrations of glucose. Moreover, bilirubin with potent antioxidant and anti-inflammatory functions could induce reprogramming macrophages to M2 type polarization, which was much beneficial to inhibit inflammation caused by hyperglycemia. In vivo results demonstrated such in situ H2O2-sensitive insulin delivery microneedle array patch had good anti-inflammatory and antioxidant therapeutic efficacy in a mice model of diabetes. This novel glucose-responsive insulin delivery combined with the anti-inflammatory functions of microneedle patches show great promising for the treatment of diabetes with safe controlled release of insulin.

Electrostatic-Interaction-Aided Microneedle Patch for Enhanced Glucose-Responsive Insulin Delivery and Three-Meal-Per-Day Blood-Glucose Regulation.

The phenylborate-ester-cross-linked hydrogel microneedle patch (MNP) was promising in the diabetic field for the glucose-responsive insulin-delivering property and simple fabrication process. However, the unfit design of the charging microneedle network limited the improvement of blood-glucose regulating performances. In this work, insulin-loaded phenylborate-ester-cross-linked MNPs, with the polyzwitterion property, were constructed based on the modified ε-polylysine and poly(vinyl alcohol). The relationship between the charging nature of the MNP network and insulin release was verified by regulating the content of postprotonated positively charged amino groups. The elaborately designed MNP possessed improved glucose-responsive insulin-delivering performance. The in vivo study revealed the satisfactory results on blood-glucose regulation by the optimized MNP under the mimic three-meal-per-day mode. Moreover, the insulin bioactivity in the MNP could be maintained for 2 weeks under 25 °C. In summary, this work developed an effective strategy to improve the glucose-responsive phenylborate-ester-cross-linked MNP and enhance its potential for clinical transformation.

Glucose-Responsive Self-Regulated Injectable Silk Fibroin Hydrogel for Controlled Insulin Delivery.

Stimuli-responsive drug delivery systems are gaining importance in personalized medicine to deliver therapeutic doses in response to disease-specific stimulation. Pancreas-mimicking glucose-responsive insulin delivery systems offer improved therapeutic outcomes in the treatment of type 1 and advanced stage of type 2 diabetic conditions. Herein, we present a glucose-responsive smart hydrogel platform based on phenylboronic acid-functionalized natural silk fibroin protein for regulated insulin delivery. The modified protein was synergistically self-assembled and cross-linked through β-sheet and phenylboronate ester formation. The dynamic nature of the bonding confers smooth injectability through the needle. The cross-linked hydrogel structures firmly hold the glucose-sensing element and insulin in its pores and contribute to long-term sensing and drug storage. Under hyperglycemic conditions, the hydrogen peroxide generated from the sensing element induces hydrogel matrix degradation by oxidative cleavage, enabling insulin release. In vivo studies in a type 1 diabetic Wistar rat model revealed that the controlled insulin release from the hydrogel restored diabetic glucose level to physiological conditions for 36 h. This work establishes the functional modification of silk fibroin into a glucose-responsive hydrogel platform for regulated and functional insulin delivery application.

Injectable nanosized formulation for glucose-responsive insulin delivery

Glucose-responsive insulin (GRI) can tremendously facilitate insulin administration via expanding the safe dosage window and reducing injection frequency, as well as enhancing blood glucose control via actively adjusting the insulin release rate. We have previously prepared a robust ion complex-based GRI for type 1 diabetes treatment; however, this complex precipitates easily, which could cause difficulty of injection and inaccuracy of dosage. It remains elusive whether nanoparticulation of this complex could increase suspension stability and retain glucose responsiveness. Herein, we have linked poly (ethylene glycol) (PEG) to 4-carboxy-3-fluorophenylboronic acid (FPBA)-modified poly-ʟ-lysine to obtain PEG-PLL-FPBA. PEG-PLL-FPBA and insulin can form nanosized insulin complex (NIC) with a high insulin loading content and encapsulation efficiency. Of note, the size of the prepared NIC can keep stable for more than 7 days. The NIC showed glucose-stimulated insulin release in vitro with a maximal glucose-responsive index of 400 %. In a streptozotocin (STZ)-induced type 1 diabetic mouse model, the subcutaneously injected NIC could normalize hyperglycemia in 30 min and maintain it normally for 20 h, while minimal toxicity has been identified.

An Engineered Nanosugar Enables Rapid and Sustained Glucose-Responsive Insulin Delivery in Diabetic Mice.

Glucose-responsive insulin-delivery platforms that are sensitive to dynamic glucose concentration fluctuations and provide both rapid and prolonged insulin release have great potential to control hyperglycemia and avoid hypoglycemia diabetes. Here, biodegradable and charge-switchable phytoglycogen nanoparticles capable of glucose-stimulated insulin release are engineered. The nanoparticles are "nanosugars" bearing glucose-sensitive phenylboronic acid groups and amine moieties that allow effective complexation with insulin (≈95% loading capacity) to form nanocomplexes. A single subcutaneous injection of nanocomplexes shows a rapid and efficient response to a glucose challenge in two distinct diabetic mouse models, resulting in optimal blood glucose levels (below 200mg dL-1 ) for up to 13h. The morphology of the nanocomplexes is found to be key to controlling rapid and extended glucose-regulated insulin delivery in vivo. These studies reveal that the injected nanocomplexes enabled efficient insulin release in the mouse, with optimal bioavailability, pharmacokinetics, and safety profiles. These results highlight a promising strategy for the development of a glucose-responsive insulin delivery system based on a natural and biodegradable nanosugar.

Glucose-responsive microneedle patch for closed-loop dual-hormone delivery in mice and pigs

Insulin and glucagon secreted from the pancreas with dynamic balance play a vital role in regulating blood glucose levels. Although distinct glucose-responsive insulin delivery systems have been developed, the lack of a self-regulated glucagon release module limits their clinical applications due to the potential risk of hypoglycemia. Here, we describe a transdermal polymeric microneedle patch for glucose-responsive closed-loop insulin and glucagon delivery to achieve glycemic regulation with minimized risk of hypoglycemia. The glucose-responsive phenylboronic acid units can bind to glucose to reversibly shift the net charge (from positive to negative) of the entire polymeric matrix within microneedles. Therefore, the release ratio of the negatively charged insulin and the positively charged glucagon analog from the patch can be dynamically tuned upon the fluctuation of blood glucose levels to realize glycemic homeostasis. In both chemically induced type 1 diabetic mouse and minipig models, this glucose-responsive dual-hormone microneedle patch demonstrated tight long-term regulation in blood glucose levels (>24 hours in minipigs).

Partially Oxidized Alginate as a Biodegradable Carrier for Glucose-Responsive Insulin Delivery and Islet Cell Replacement Therapy.

Self-regulated insulin delivery that mimics native pancreas function has been a long-term goal for diabetes therapies. Two approaches towards this goal are glucose-responsive insulin delivery and islet cell transplantation therapy. Here, biodegradable, partially oxidized alginate carriers for glucose-responsive nanoparticles or islet cells are developed. Material composition and formulation are tuned in each of these contexts to enable glycemic control in diabetic mice. For injectable, glucose-responsive insulin delivery, 0.5mm 2.5% oxidized alginate microgels facilitate repeat dosing and consistently provide 10 days of glycemic control. For islet cell transplantation, 1.5mm capsules comprised of a blend of unoxidized and 2.5% oxidized alginate maintain cell viability and glycemic control over a period of more than 2 months while reducing the volume of nondegradable material implanted. These data show the potential of these biodegradable carriers for controlled drug and cell delivery for the treatment of diabetes with limited material accumulation in the event of multiple doses.

Microneedle Patches Loaded with Nanovesicles for Glucose Transporter-Mediated Insulin Delivery.

Glucose-responsive insulin delivery systems that mimic insulin secretion activity in the pancreas show great potential to improve clinical therapeutic outcomes for people with type 1 and advanced type 2 diabetes. Here, we report a glucose-responsive insulin delivery microneedle (MN) array patch that is loaded with red blood cell (RBC) vesicles or liposome nanoparticles containing glucose transporters (GLUTs) bound with glucosamine-modified insulin (Glu-Insulin). In hyperglycemic conditions, high concentrations of glucose in interstitial fluid can replace Glu-Insulin via a competitive interaction with GLUT, leading to a quick release of Glu-Insulin and subsequent regulation of blood glucose (BG) levels in vivo. To prolong the effective glucose-responsive insulin release from MNs, additional free Glu-Insulin, which serves as "stored insulin", is loaded after RBC vesicles or liposome nanoparticles bound with Glu-Insulin. In the streptozotocin (STZ)-induced type 1 diabetic mouse model, this smart GLUT-based insulin patch can effectively control BG levels without causing hypoglycemia.

Glucose-Responsive Injectable Thermogels via Dynamic-Covalent Cross-Linking of Pluronic Micelles.

Stimuli-responsive hydrogels are an area of active discovery for approaches to deliver therapeutics in response to disease-specific indicators. Glucose-responsive delivery of insulin is of particular interest in better managing diabetes. Accordingly, hydrogels have been explored as platforms that enable both a rate and dose of insulin release aligning with the real-time physiological disease state; materials often include glucose sensing by dynamic-covalent cross-linking between phenylboronic acids (PBAs) and diols, with competition from ambient glucose reducing cross-link density of the material and accelerating release of encapsulated insulin. Yet, these materials historically have challenges with insulin leakage, offer limited glucose-responsive release of the insulin payload, and require unreasonably high injection pressures for syringe administration. Here, a thermogel platform prepared from temperature-induced micelles formed into a network by PBA-Diol cross-linking is optimized using a formulation-centered approach to maximize glucose-responsive insulin delivery. Importantly, the dual-responsive nature of this platform enables a low-viscosity sol at ambient temperature for facile injection, solidifying into a stable viscoelastic hydrogel network once in the body. The final optimized formulation affords acceleration in insulin release in response to glucose and enables single dose blood glucose control in diabetic rodents when subjected to multiple glucose challenges.

Materials and Carriers Development for Glucose-Responsive Insulin

ConspectusInsulin replacement therapy is an essential and effective treatment strategy for controlling the blood glucose level (BGL) of people without sufficient endogenous insulin production. However, insulin therapy faces challenges such as daily multiple injections and hypoglycemia risk arising from its narrow therapeutic index, which together leads to poor BGL control. Thus, glucose-responsive insulin delivery systems that can mimic β-cell function are developed to improve BGL control and reduce injection frequency. Glucose-responsive materials-based insulin delivery systems are competent in tightly controlling the BGL with an additional benefit of reducing the hypoglycemia risk. Glucose-responsive materials generally work together with three major glucose-sensing elements: glucose oxidase (GOx), phenylboronic acid (PBA), and glucose-binding molecules. Based on glucose-sensing elements, glucose-responsive materials are rationally designed to sense the change in glucose concentration or indirect signals associated with glucose fluctuation, such as pH, H2O2 concentration, and O2 level, and adjust their physical or chemical characteristics accordingly. Many advanced glucose-responsive materials have been developed along this line, aiming to achieve robust glucose-responsive insulin release performance and elevate their therapeutic outcome. These advanced materials mainly include organic materials such as biomacromolecules, synthetic polymers, polypeptides, liposomes, and inorganic materials such as calcium phosphate (Ca3(PO4)2) and metal organic frameworks (MOFs). Built on these glucose-responsive materials, other groups and we have developed various carriers such as hydrogels, micro/nanoparticles, liposomes, complexes, cell–drug conjugates, and microneedle (MN) array patches. These delivery systems can release insulin via glucose-stimulated swelling/contraction, dissolution, pore size change, charge reversal, and polymer deterioration. Also, these carriers are continuously under development to accelerate responsive rate, increase response index, and improve biocompatibility. Our group focuses on the synthesis of glucose-responsive materials and the design of glucose-responsive MN array patches, hydrogels, insulin complexes, and cell–drug conjugates for the treatment of diabetes in a dose-, spatial-, and temporal-controlled fashion. These closed-loop insulin delivery systems can respond to BGL alternation and secrete the correct amount of insulin accordingly. Also, MN array patches have the additional merits of reducing pain and easy administration.In this Account, we briefly introduce the glucose-responsive mechanisms and the relevant requirements of materials that can work cooperatively with these mechanisms. Then, we highlight our group’s work in preparing various materials for constructing glucose-responsive carriers. We are mainly aiming to improve glucose-responsive properties, administration feasibility, and in vivo biocompatibility. The challenges and perspectives associated with glucose-responsive materials for clinical translation are also discussed. We envision that our glucose-responsive MN array patch for insulin release will facilitate the clinical use of glucose-responsive materials.

Closed-Loop Insulin Delivery Systems: Past, Present, and Future Directions.

Closed-loop (artificial pancreas) systems for automated insulin delivery have been likened to the holy grail of diabetes management. The first iterations of glucose-responsive insulin delivery were pioneered in the 1960s and 1970s, with the development of systems that used venous glucose measurements to dictate intravenous infusions of insulin and dextrose in order to maintain normoglycemia. Only recently have these bulky, bedside technologies progressed to miniaturized, wearable devices. These modern closed-loop systems use interstitial glucose sensing, subcutaneous insulin pumps, and increasingly sophisticated algorithms. As the number of commercially available hybrid closed-loop systems has grown, so too has the evidence supporting their efficacy. Future challenges in closed-loop technology include the development of fully closed-loop systems that do not require user input for meal announcements or carbohydrate counting. Another evolving avenue in research is the addition of glucagon to mitigate the risk of hypoglycemia and allow more aggressive insulin dosing.

Recent advances in glucose-responsive insulin delivery systems: novel hydrogels and future applications.

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.

Microfluidic Synthesis of a Bioactive Metal-Organic Framework for Glucose-Responsive Insulin Delivery.

In the current study, we report the microfluidic synthesis of a metal-organic framework (MOF) for insulin delivery based on the stimulus response of glucose. Insulin- and gold nanoparticle (AuNP)-encapsulated zeolitic imidazolate framework-8 (ZIF-8) was synthesized using a continuous-flow, microfluidic mixing system via a single-step process. Glucose oxidase mimicking the activity of AuNPs was utilized for oxidizing glucose molecules that entered the porous ZIF-8. The AuNPs oxidized glucose into gluconic acid and hydrogen peroxide inside the MOF (Ins-AuNP-ZIF-8). The resulting acidic pH led to the disruption of ZIF-8 and released insulin. Thus, the presence of glucose molecules provided a stimulus for insulin release. The bioactive MOFs were characterized for the presence of functional groups, morphology, crystallinity, size, and elemental confirmation. The presence of fluorescein-5-isothiocyanate-labeled insulin in the composite was confirmed using confocal laser scanning microscopy. The loading of insulin per unit weight of the MOF, determined by size-exclusion-high-performance liquid chromatography, was 77 and 88% in the batch and microfluidic processes, respectively. Drug release studies confirmed the response of the MOFs to glucose, which triggered insulin release. The synthesis process did not affect the characteristics and application of ZIF-8 and Ins-AuNP-ZIF-8. This study involving the facile synthesis of bioactive MOFs offers a sustainable strategy to design stimulus-responsive drug delivery systems and could be exploited for biosensing applications.

Glycopolymer Nanoparticles with On-Demand Glucose-Responsive Insulin Delivery and Low-Hypoglycemia Risks for Type 1 Diabetic Treatment

Diabetic patients with type 1 or advanced type 2 stages need timely and precise insulin injection to regulate the daily blood glucose levels (BGLs). Otherwise, risks of serious or even deadly diabetes-associated complications occur. To achieve prolonged glucose regulation and low hypoglycemia risks, a novel on-demand glucose-responsive glycopolymer system was constructed for insulin delivery, which was self-assembled into nanoparticles by dynamic covalent bonds between two polymers: fluorophenylboronic acid-grafted polymer (poly-F) and polyol polymer (poly-G). Insulin was loaded during the assembly process. The nanoparticles showed excellent glucose responsiveness in vitro, with controlled insulin release at different glucose concentrations. In vivo treatment on type 1 diabetic mice showed prolonged BGL regulation and lower hypoglycemia risks. The mild preparation of the nanoparticles and outstanding glucose control shed light on the optional diabetic treatment for further clinical use.

A Porous Reservoir-Backed Boronate Gel Microneedle for Efficient Skin Penetration and Sustained Glucose-Responsive Insulin Delivery.

Recently, phenylboronic acid (PBA) gel containing microneedle (MN) technology with acute and sustained glucose-sensitive functionality has attracted significant research attention. Herein, we report a polyvinyl alcohol(PVA)-coated MNs patch with an interconnected porous gel drug reservoir for enhanced skin penetration efficiency and mechanical strength. The hybrid MNs patch fabricated with a novel, efficient method displayed a “cake-like” two-layer structure, with the tip part being composed of boronate-containing smart gel attached to a porous gel layer as a drug reservoir. The porous structure provides the necessary structural support for skin insertion and space for insulin loading. The mechanical strength of the hybrid MNs patch was further enhanced by surface coating with crystallized PVA. Compared with MNs patches attached to hollow drug reservoirs, this hybrid MNs patch with a porous gel reservoir was shown to be able to penetrate the skin more effectively, and is promising for on-demand, long-acting transdermal insulin delivery with increased patient compliance.

Development, Statistical Optimization and in Vitro/ in Vivo Characterization of an Intelligent Hydrogel Containing Methylated N-(4-N, N-Dimethylaminobenzyl) Chitosan for Glucose-Responsive Insulin Delivery

Development, Statistical Optimization and in Vitro/ in Vivo Characterization of an Intelligent Hydrogel Containing Methylated N-(4-N, N-Dimethylaminobenzyl) Chitosan for Glucose-Responsive Insulin Delivery

Novel glucose-responsive nanoparticles based on p-hydroxyphenethyl anisate and 3-acrylamidophenylboronic acid reduce blood glucose and ameliorate diabetic nephropathy.

An insulin delivery system that self-regulates blood sugar levels, mimicking the human pancreas, can improve hyperglycaemia. At present, a glucose-responsive insulin delivery system combining AAPBA with long-acting slow release biomaterials has been developed. However, the safety of sustained-release materials and the challenges of preventing diabetic complications remain. In this study, we developed a novel polymer slow release material using a plant extract—p-hydroxyphenylethyl anisate (HPA). After block copolymerisation with AAPBA, the prepared nanoparticles had good pH sensitivity, glucose sensitivity, insulin loading rate and stability under physiological conditions and had high biocompatibility. The analysis of streptozotocin-induced diabetic nephropathy (DN) mouse model showed that the insulin-loaded injection of nanoparticles stably regulated the blood glucose levels of DN mice within 48 ​h. Importantly, with the degradation of the slow release material HPA in vivo, the renal function improved, the inflammatory response reduced, and antioxidation levels in DN mice improved. This new type of nanoparticles provides a new idea for hypoglycaemic nano-drug delivery system and may have potential in the prevention and treatment of diabetic complications.