Advanced biomaterials for diabetes healthcare and complication therapy: A review

Diabetes remains a challenging clinical condition. Hyperglycemia is the main manifestation of diabetes, affecting millions of people worldwide.¹ Its prevalence is increasing owing to factors such as obesity and an aging population. In recent years, the epidemiology and health effects of hyperglycemia have been widely studied, and the significant impact of hyperglycemia on human health has garnered increasing interest among scholars. Epidemiological studies have shown that hyperglycemia is an important public health concern. According to the International Diabetes Federation, ∼463 × 10⁶ adults worldwide were affected by diabetes in 2019, and this number is expected to increase to 700 × 10⁶ by 2045.² In addition, people who do not have diabetes have elevated blood sugar levels, which also increases their risk of developing diabetes. The two main types of diabetes are type 1 and type 2,³ of which both are associated with complications, such as chronic damage to both large and small blood vessels, potentially leading to heart attacks and strokes, as well as complications affecting the kidneys, eyes, feet, and overall health. Diabetes is a leading cause of blindness, end-stage renal disease, and lower-limb amputations.^4–7 Currently, drug therapy is the primary treatment for diabetes. Current medications used to lower blood sugar levels include insulin and islet cell analogs, non-insulin oral hypoglycemic drugs, and genetic drugs. However, these drugs have inherent flaws, coupled with limitations of traditional administration methods. These limitations encompass adverse reactions from long-term subcutaneous injections and various challenges tied to oral administration, including enzymatic degradation, chemical instability, and poor absorption in the gastrointestinal tract. Consequently, there is an urgent need to develop novel therapeutic agents for diabetes that do not exacerbate complications or compromise safety.⁸ 

With continuous research, an increasing number of biomaterials are being used to treat hyperglycemia and its associated complications. Biomaterials, denoting materials employed in medical devices, often play a crucial role.⁹ Biomaterials that can be used to lower blood sugar levels include hydrogels,^10–12 nanoparticles (NPs),^13,14 microspheres, and microneedles.^15–18 Compared with traditional drug treatments, these biomaterials have many benefits, such as maintaining stability, improving bioavailability, and reducing adverse reactions.¹⁹ Researchers have explored their applications to overcome the limitations of traditional insulin delivery methods, such as poor patient compliance, injection site complications, and the need for continuous monitoring. Among these biomaterials, one prevalent application involves using them as carriers for controlled and sustained insulin release.²⁰ By encapsulating insulin in these materials, it becomes possible to mimic the natural insulin secretion process in the body, ensuring stable and prolonged release. This continuous insulin delivery system reduces the number of injections, is convenient for patients, and improves the stability of blood sugar control.

In addition, biocompatible materials have been designed to stimulate islet cell proliferation and regeneration. These materials provide an ideal microenvironment for the growth and differentiation of islet cells, promoting their proliferation and regeneration. This approach holds promise as an alternative therapeutic strategy for restoring pancreatic function and improving blood glucose control. The development of artificial pancreatic- or islet cell-like organ constructs using biocompatible materials has received considerable attention. By utilizing scaffold structures and cell culture techniques, 3D islet cell structures can be created, providing an alternative source for islet cell transplantation. These artificial pancreatic constructs are designed to provide a suitable environment for islet cells and mimic their biological functions, thereby addressing challenges such as the scarcity of organ donors and immune rejection associated with traditional islet cell transplantation. This Review focuses on biomaterials used for the treatment of diabetes and its complications. First, we describe the dangers of high blood sugar levels and the current diabetes management strategies. The advantages and disadvantages of some biomaterials for lowering blood sugar are briefly introduced, and a classification evaluation of the glucose smart response carrier system is presented. In addition, we focused on reviewing the management strategies for diabetes using biomaterials to explore the use of biomaterials to lower blood sugar and treat corresponding complications. Finally, we discuss the use of islet organoids in drug screening and transplantation.

Hyperglycemia is one of the main symptoms of diabetes. If not effectively managed over an extended period, it can inflict significant harm on the human body. It can lead to various diabetic complications, including nervous system disorders, retinopathy, and kidney diseases. These complications affect the quality of life and even endanger patient safety. Therefore, the early detection and control of high blood sugar levels are crucial. Patients with diabetes should be encouraged to actively take comprehensive measures, such as drug treatment, dietary management, exercise management, blood sugar monitoring, and psychological intervention, to control blood sugar levels and reduce the risk of complications. In addition, for high-risk groups, such as those with a family history of diabetes, obesity, or high blood pressure, attention should be paid to regular blood sugar testing and lifestyle adjustments to prevent hyperglycemia.

High blood sugar levels are characteristic of both type 1 and type 2 diabetes,²¹ with potential long-term consequences in the form of widespread neurological damage, often referred to as diabetic neuropathy.²² These changes are usually gradual and subtle at first but can become progressively more severe if left untreated. The neurological effects of hyperglycemia include central nervous system (CNS) and peripheral nervous system lesions.²³ Peripheral neuropathy is the most common neuropathy caused by hyperglycemia.²⁴ High blood sugar levels can damage peripheral nerves, resulting in pain, numbness, and weakness in the hands and feet.²⁵ One of the major mechanisms of hyperglycemic peripheral neuropathy is the accumulation of advanced glycation end products (AGEs).²⁶ AGEs are formed when glucose molecules react with proteins, lipids, and nucleic acids, resulting in irreversible cross-linking. The accumulation of AGEs in peripheral nerves can lead to impaired nerve function and neuropathy. Oxidative stress is another mechanism underlying hyperglycemic peripheral neuropathy.²⁷ Hyperglycemia leads to an increased production of reactive oxygen species (ROS), which damage cellular components such as proteins, lipids, and DNA. The accumulation of ROS in peripheral nerves can lead to neuropathy. Hyperglycemia also leads to increased production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6).²⁴ Production of these cytokines contributes to the development of peripheral neuroinflammation and neuropathy. In addition to these mechanisms, hyperglycemia can activate several different signaling pathways, including the polyol pathway,²⁸ hexosamine pathway,²⁴ and protein kinase C pathway.²⁴ These pathways can lead to neuropathy by disrupting cellular functions and signaling. Although less common than peripheral neuropathy, high blood sugar levels can also damage the CNS.²⁹ Chronically high blood sugar levels can lead to cerebrovascular diseases, resulting in a higher risk of stroke. In addition, high blood sugar levels are associated with a higher risk of cognitive impairment and dementia. Chronic inflammation and oxidative stress caused by high blood sugar levels may accelerate the degenerative processes in the brain. In addition, the formation of AGEs leads to the accumulation of harmful proteins and beta-amyloid plaques in the brain, which are hallmarks of Alzheimer’s disease.²⁶ 

Hyperglycemic retinopathy is one of the most common complications in patients with diabetes and is caused by retinal vascular damage and structural changes due to prolonged high blood sugar levels. Chronic hyperglycemia induces damage to endothelial cells and retinal vessels,³⁰ resulting in retinal microvascular diseases. The two main types of retinal microvascular diseases are non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR).^31,32 PDR is a late manifestation of diabetic retinopathy, the main feature of which is the formation and proliferation of new retinal blood vessels, which rupture easily, exudate, and lead to complications such as retinal edema and retinal detachment.³² Hyperglycemic retinopathy affects the normal structure and function of the retina, resulting in impaired vision or blindness.³³ The degree of vision impairment varies depending on the extent and type of the lesion. In the early stages of NPDR, patients may have no obvious symptoms; however, as the disease progresses, they may experience blurring, dark vision, and blindness.³¹ In the late stages of PDR, rupture and leakage of neovascularization may cause dramatic vision loss, whereas retinal detachment may cause permanent vision loss.

Hyperglycemic cerebrovascular disease is mainly caused by long-term high blood sugar levels that cause cerebrovascular damage, which may lead to a series of clinical diseases such as cerebrovascular disease, diabetic encephalopathy, and diabetic stroke.³⁴ Hyperglycemic cerebrovascular disease can manifest in many forms because it affects the cerebrovascular system through multiple mechanisms.³⁵ In addition, there are many mechanisms of hyperglycemic cerebrovascular disease³⁶ that can cause endothelial cell dysfunction in the blood vessel walls, leading to hardening and narrowing of blood vessels, which affects the blood supply to the brain.³⁷ Hyperglycemia can also trigger an inflammatory response, leading to inflammation of the vascular endothelium, which may further exacerbate arteriosclerosis.³⁸ High blood sugar levels increase blood viscosity and promote the formation of blood clots, which can lead to clogging of blood vessels in the brain. Long-term high blood sugar levels can also directly damage nerve cells, thereby affecting the function of cerebral blood vessels.³⁴ Individuals with high blood sugar levels are more at risk of experiencing a stroke because of arterial hardening and blood clot formation. Insufficient blood supply to the brain and nerve damage may cause cognitive decline in patients with high blood sugar, including memory loss and inattention, which can lead to stroke, coma, and even death in severe cases.³⁹ In addition, hyperglycemia and cerebrovascular disease increase the risk of cardiovascular diseases such as coronary heart disease and myocardial infarction.³⁴ 

Hyperglycemic peripheral vascular disease is a peripheral vascular disease, particularly of the blood vessels of the lower extremities, caused by persistently high blood sugar levels. This disease often results in the hardening, narrowing, or even blockage of blood vessels, leading to muscle pain, foot infection, gangrene, and amputation in severe cases.⁴⁰ Long-term high blood sugar levels trigger an inflammatory response of the blood vessel wall and dysfunction of endothelial cells, leading to hardening and narrowing of blood vessels and reduced blood flow.⁴¹ High blood glucose levels can increase blood viscosity, trigger thrombosis, and block blood flow. Hyperglycemia can also cause peripheral neuropathy, which prevents blood vessels from being properly regulated by nerves.⁴² Furthermore, hyperglycemic peripheral vascular disease can cause lower extremity pain, numbness, cold sensation, and muscle atrophy.⁴³ Pain may worsen with walking and even be felt at rest. Hyperglycemia can also lead to foot infections, ulcers, and gangrene. Vascular disease reduces blood supply to the feet, making wound healing difficult and susceptible to infection, and gangrene may develop in severe cases, requiring amputation.⁴⁴ Notably, peripheral vascular diseases often co-occur with cardiovascular and cerebrovascular diseases because they are caused by the same atherosclerotic processes.⁴⁵ 

Diabetic nephropathy is a kidney disease caused by diabetes and is a common complication of diabetes.⁴⁶ Patients with diabetes who suffer from high blood sugar levels for a long time, especially those who fail to effectively control their blood sugar levels, are most at risk of developing diabetic nephropathy. This gradually impairs the filtering function of the kidneys, resulting in a decrease in the glomerular filtration rate. As the disease progresses, kidney function may gradually decline, eventually leading to kidney failure, requiring dialysis or kidney transplantation for survival. Moreover, diabetic nephropathy can cause high blood pressure. The kidneys play an important role in regulating blood pressure; however, when glomerular filtration is impaired, the body releases hormones,⁴⁷ such as renin and angiotensin, leading to an increase in blood pressure. High blood levels further aggravate kidney damage, resulting in a vicious circle. This kidney damage leads to issues such as disruptions in the body’s water and salt balance, electrolyte imbalances, and arteriosclerosis, of which all elevate the risk of cardiovascular diseases such as heart attack, myocardial infarction, and stroke. Hyperglycemia can also lead to abnormal renal tubular cell function, further exacerbating kidney damage. In hyperglycemia, a large number of free radicals are produced, and the antioxidant capacity is reduced, leading to the aggravation of oxidative stress.^48,49 Oxidative stress can damage kidney tissue, leading to inflammation and fibrosis. In the early stages of diabetic nephropathy, cell proliferation in the glomerular filtration membrane increases, resulting in an increased filtration membrane thickness. As the disease progresses, cells in the glomeruli and tubules start overproducing collagen and other fibrotic substances, resulting in fibrosis of the kidney tissue.⁵⁰ This, in turn, further damages the kidney structure and function. In addition, patients with diabetic nephropathy often experience inflammatory reactions in their kidneys. Elevated blood sugar levels trigger an increase in the production of inflammatory mediators, triggering an inflammatory response. The inflammatory response activates the immune and inflammatory cells in the kidney, leading to the destruction of kidney tissue and inflammatory damage.⁵¹ 

In summary, the main mechanisms of diabetic nephropathy include hyperglycemic injury, oxidative stress, cell proliferation, fibrosis, inflammatory responses, and renal arterioles. These mechanisms lead to the progressive deterioration of kidney structure and function, eventually leading to renal failure and other serious complications. Early control of blood sugar levels, regular monitoring of kidney function, and appropriate treatment measures, such as medication and lifestyle changes, are essential for preventing and delaying the progression of diabetic nephropathy.

As previously mentioned, long-term high blood sugar levels can lead to various complications, including diabetic feet, ulcers, and other diabetic wounds.^52,53 Diabetic wounds are skin ulcers caused by factors such as tissue ischemia, hypoxia, and nerve dysfunction due to long-term high blood sugar levels.⁵⁴ Diabetic wounds are a common complication in patients with diabetes, significantly impacting their quality of life and overall health. Patients with diabetes often exhibit poor wound healing caused by a variety of factors including microcirculation disorders, nerve disorders, and abnormal cytokines. Patients with diabetes frequently suffer from microcirculation disorders, such as capillary damage and vascular endothelial cell impairment.⁵⁵ These lesions can lead to reduced blood flow and an insufficient oxygen supply, thereby negatively affecting wound healing. In addition, diabetes often coincides with metabolic abnormalities, such as high blood sugar levels and insulin resistance, which also disrupt normal microcirculation function.⁵⁶ Moreover, patients with diabetes commonly experience neurological disorders, including peripheral and autonomic neuropathy. These disorders can lead to sensory and motor nerve dysfunctions, skin dryness, and ulcer formation, of which all hamper wound healing. In addition, neurological disorders can reduce pain perception, making patients less aware of their wounds and more likely to overlook or misdiagnose them. Wound healing in patients with diabetes may also be associated with cytokine abnormalities. Studies have shown that the expression and secretion of cytokines in the wound tissue of patients with diabetes are different from those in healthy individuals. For example, the expression and secretion of growth factors and inflammatory factors in fibroblasts, macrophages, and other cell types in the wound tissue of patients with diabetes are altered, thereby impacting wound healing. Patients with diabetes often have compromised immune functions, making them prone to infections.⁵⁷ Patients with diabetes with poor wound healing are particularly prone to infections. The high-sugar environment in diabetic wounds accelerates microbial growth, further delaying wound healing and potentially leading to severe complications.⁵⁸ In conclusion, poor wound healing is a common complication of diabetes, and its mechanism involves various factors such as microcirculation disturbances, neurological disturbances, abnormal cytokines, and a high glucose environment. To effectively treat and prevent poor wound healing in patients with diabetes, it is necessary to fully understand the mechanism and implement comprehensive treatment measures, including controlling blood sugar levels, improving microcirculation, protecting nerves, and regulating cytokines. Figure 1 shows some biomaterials used in wound healing.

The management of blood sugar levels is critical for preventing complications and reducing the risk of hyperglycemia. Blood sugar management includes regular monitoring of blood sugar levels, taking prescribed medications, following a healthy diet, and engaging in regular physical activity. Blood sugar management aims to maintain blood sugar levels within a healthy range to prevent complications and improve overall health. Liu et al.⁶⁰ investigated the use of new technologies, such as continuous glucose monitoring (CGM), to improve blood sugar management through regular monitoring, medication management, a healthy diet, and regular physical activity, all aimed at controlling blood sugar levels and preventing complications. Brown et al.⁶¹ and Ferris and Nathan⁶² separately highlighted the importance of glycemic control in reducing the risk of cardiovascular disease, diabetic retinopathy, and other complications. New technologies, such as CGM, can also improve blood sugar management and reduce the risk of hyperglycemia. Although current diabetes management strategies have proven effective in controlling blood glucose levels and preventing complications, there are still limitations and challenges that need to be addressed. One of the limitations of current diabetes management strategies is the burden of self-management on patients with diabetes. Diabetes requires constant monitoring of blood sugar levels, medication management, and lifestyle changes, which can be challenging and overwhelming for patients with diabetes. Another limitation of this study is the cost of care. Diabetes management requires the regular monitoring of blood glucose levels, medication management, and healthcare visits, which can be expensive for both individuals and healthcare systems. Challenges in diabetes management include the complexity of the condition and the variability in individual responses to treatment. Diabetes is a complex disease requiring an individualized treatment plan based on factors such as age, health, and lifestyle. Although current diabetes management strategies have proven effective in controlling blood glucose levels and preventing complications, there are still limitations and challenges that need to be addressed. The burden of self-management, cost of care, and complexity of the condition represent the major challenges in diabetes management.

CGM is a technology that can monitor real-time blood sugar levels in patients with diabetes.⁶³ CGM devices offer valuable insights into both diabetic patients and their healthcare providers, enabling them to modify medications and lifestyle effectively.⁶⁴ A CGM system consists of a sensor inserted under the skin to measure glucose levels in the interstitial fluid and a transmitter that sends the data to a receiver or smartphone application. The importance of CGM in diabetes management has been widely recognized in recent years, with multiple studies reporting its benefits. Recent studies have highlighted the importance of CGM and suggested potential solutions to improve diabetes care.

There is growing evidence that insulin pumps combined with CGM and closed-loop algorithm controllers can achieve more accurate basal insulin delivery. This combination therapy, known as the Hybrid Closed-Loop System (HCLS),^65–67 can assist patients with diabetes to better control their blood sugar levels and reduce the occurrence of hypoglycemic events, ultimately improving their quality of life. Similarly, CGM systems may improve the management of gestational diabetes. Gestational diabetes is a condition that develops during pregnancy and can cause complications in both mothers and infants. In addition to improving diabetes management, CGM systems can provide valuable data for future research and clinical practice. CGM systems provide data on blood glucose variability and can be used to develop individualized treatment plans for patients with diabetes. CGM systems can also provide data regarding the effectiveness of new drugs and interventions for diabetes management.

In conclusion, CGM is essential for effective management of diabetes. CGM systems provide real-time blood glucose level measurements that can help patients with diabetes make informed decisions regarding treatment and lifestyle choices. Recent studies have highlighted the effectiveness of CGM systems in improving diabetes management and have encouraged further research in this area. Future research should focus on developing and evaluating the effectiveness of CGM systems in diabetes management and expanding access to these systems for patients with diabetes.⁶⁸ 

Traditional treatments for diabetes include subcutaneous insulin and oral hypoglycemic agents, including sulfonylureas, biguanides, megatinib, thiazolidinediones, and alpha-glucosidase inhibitors.^69–71 However, these traditional treatment methods present various disadvantages. For example, subcutaneous injections of insulin may cause complications in the corresponding organs, such as hard lumps or lipoatrophy at the injection site. In addition, some oral hypoglycemic drugs have low solubility and high permeability, necessitating large doses to maintain normal blood sugar levels, potentially resulting in serious adverse reactions. Moreover, regardless of whether subcutaneous injections or oral hypoglycemic drugs are administered, patients often struggle with compliance, leading to poor blood sugar control. These represent major challenges in current drug management.^70,72

Recently, an increasing number of studies have focused on sustained-release insulin delivery.⁷³ This aims to maintain the concentration of insulin in the body by slowly releasing insulin components to effectively control blood sugar levels in patients with diabetes. These systems sense changes in blood glucose levels and precisely control insulin release as required, improving treatment compliance and quality of life in patients with diabetes.⁷⁴ The advantage of a sustained-release drug delivery system is that it can reduce the number of times a patient with diabetes needs to take the drug, thereby improving patient compliance and reducing the peak blood concentration and risk of adverse reactions. In addition, it can provide more consistent blood sugar control and reduce the risk of hypoglycemia and hyperglycemia. Sustained-release drug delivery systems can be tailored to individual patient conditions, with dosage and administration times adjusted accordingly.^71,72,75

In conclusion, sustained-release medication for diabetes enhance patient compliance, reduce the risk of adverse reactions, offer more stable blood sugar control, and allow for personalized treatment, serving as a crucial tool in diabetes treatment.

Biomaterials are increasingly used in the management of diabetes to improve drug delivery, tissue engineering, and wound healing. Bardill et al.⁷⁶ highlighted the importance of biomaterials in diabetes management and suggested potential solutions to improve diabetes care. Biological materials are synthetic or natural materials that interact with various biological systems. The use of biomaterials in diabetes management involves their incorporation into medical devices, drug delivery systems, and tissue-engineered structures. Biomaterials can improve diabetes care by enhancing the therapeutic efficacy, promoting tissue regeneration, and improving wound healing. Drug delivery is one of the most important applications of biomaterials for diabetes management. Biomaterials can be used to encapsulate therapeutic drugs such as insulin and improve their stability and bioavailability. Moreover, biomaterials can improve drug delivery, tissue engineering, and wound healing in patients with diabetes. Thus, biomaterials are crucial for the management of diabetes, and their widespread use has the potential to improve diabetes care and prevent complications. Therefore, future studies should focus on developing and evaluating the effectiveness of biomaterials for diabetes management.

Hydrogels are polymer materials known for their remarkable water absorption and retention properties. They transform into a gel-like substance when exposed to water, exhibiting excellent plasticity and elasticity. Because hydrogels contain a large amount of water (∼70%–99%), they exhibit excellent biocompatibility and can encapsulate hydrophilic drugs (e.g., insulin), cells, and other materials within their matrix structure.⁷⁷ The cross-linking network can also be tuned to limit the penetration of external proteins and protect bioactive therapeutics from degradation by inwardly diffusing enzymes. To date, significant progress has been made regarding hydrogel-based diabetes treatment.⁷⁸ 

Poor wound healing is one of the mechanisms underlying the severe progression of diabetes. None of the currently available wound dressings guarantee rapid and effective restoration of injured tissue.⁷⁹ No single dressing can offer a comprehensive solution for the multifaceted issues associated with chronic diabetic wounds, stemming from various diabetes-related complications.⁸⁰ Therefore, intensive research and development of new technologies is required to ensure a continuous supply of essential materials, combat invading micro-organisms, and manage wound exudates effectively. Hydrogels can be used as drug delivery systems to slowly release antidiabetic drugs into the body to control the drug release rate and dose.⁸¹ For example, insulin and other antidiabetic drugs can be encapsulated within hydrogels and administered to patients either through the skin or orally. This approach can reduce side effects and improve patient compliance. Jiang et al. reported a temperature-responsive hydrogel patch composed of polymeric gallic acid (PGA) and gelatin methacryloyl (GelMA) for the treatment of diabetic wounds. Owing to the high density of noncovalent bonds, PGA-GelMA hydrogels exhibit temperature-triggered adhesion and detachment properties. Once in contact with the skin surface, GelMA chains disintegrate at body temperature (37 °C), forming a soft hydrogel that easily adheres to the skin surface. The freely moving GelMA within the hydrogel chain possesses numerous reactive motifs, including amino and carboxyl groups, enabling the hydrogel to form multiple interfacial bonds on the skin surface and exhibit strong adhesion.⁸⁰ It can automatically modulate insulin release based on blood sugar concentration, thanks to functional molecules within the sensitive hydrogel capable of binding to glucose. When the blood sugar concentration increases, these molecules bind to glucose, causing a change in the structure of the hydrogel, thereby accelerating the release of insulin. This smart drug delivery system is expected to provide more personalized and precise treatment for patients with diabetes.

Islet cell transplantation is another potential therapeutic approach for diabetes. It can be used to restore insulin secretion by transplanting healthy islet cells into patients with diabetes. However, islet cell transplantation is associated with certain risks, including immune rejection and infection. To address these issues, An et al. encapsulated islet cells in a biocompatible and immunoprotective hydrogel.⁸² This hydrogel provided a suitable environment for the growth of islet cells while preventing the immune system from damaging them. Diabetes is often accompanied by difficulties in wound healing and an increased risk of infection. Hydrogels can be used as biomaterials for wound healing and tissue regeneration in patients with diabetes.⁷⁹ Owing to its high water content and biocompatibility, the hydrogel maintains a moist environment in the wound, expediting the healing process. In addition, active substances such as antibiotics, anti-inflammatory drugs, and growth factors can be added to the hydrogel to further promote wound healing and tissue regeneration. Diabetic foot is a common complication in patients with diabetes, manifesting as infection, ulcer, and necrosis. The hydrogel can be used as a dressing or an insole material for the treatment and prevention of diabetic foot. Hydrogel dressings maintain wound moisture, reduce infection risks, and accelerate healing. Hydrogel insoles relieve foot pressure, reduce wear and tears, and improve patient comfort and quality of life.⁸³ In addition to their role in wound healing, hydrogels are also used to delivery insulin orally. For example, Ren et al.⁷⁷ developed a microalgae-based oral insulin system based on a Chlorella-based insulin delivery system cross-linked with sodium alginate (ALG), which can overcome the gastrointestinal barrier, protect insulin from harsh gastric conditions, and achieve pH-responsive drug release in the intestinal tract.

In summary, as a new type of biomaterial, hydrogels have broad application prospects in the treatment of diabetes. Hydrogels can be used as sustained-release carriers to assist insulin and other drugs achieve sustained release and improve the bioavailability and stability of drugs. Hydrogels find applications in islet cell transplantation, wound healing, infection management, and diabetic foot care. While challenges remain in diabetes treatment, hydrogels boast valuable properties such as biocompatibility, biodegradability, plasticity, and elasticity, forming a solid foundation for their extensive use in diabetes treatment. Future research will further refine hydrogel preparation methods and application techniques, enhancing their therapeutic effectiveness and safety and offering more convenient, effective, and personalized treatment methods for patients with diabetes. Figure 2 introduces the synthetic route of CV@INS@ALG, which reduces blood sugar in streptozotocin (STZ)-induced type 1 diabetic mice and its fluorescence image.

Microneedles are tiny, elongated, needle-like structures usually made of metals, polymers, or biodegradable materials.⁸⁴ They can have various lengths and diameters, typically ranging from a few hundred micrometers to several millimeters. Microneedles are designed to penetrate the skin or other biological tissues for transdermal drug delivery, biological indicator monitoring, or tissue stimulation. The small size of the microneedles allows them to penetrate the skin without causing significant pain or trauma. Moreover, the length and diameter of microneedles can be adjusted to suit different application requirements. Microneedles can penetrate the stratum corneum to access superficial or deep skin tissues for effective transdermal delivery or monitoring. These microneedles can be fabricated using biocompatible materials to ensure compatibility and safety with biological tissues. Handheld devices and patches incorporating microneedles are user-friendly and easy to apply. Microneedles can be categorized into three main types. Solid microneedles are made of hard materials such as metals or polymers, which are used to pierce the skin and achieve transdermal drug delivery or monitoring. Hollow microneedles feature channels within their structure, facilitating drug delivery, biological sample collection, or monitoring of biological markers through these internal channels. Nanomicroneedles are microneedles of nanoscale size, usually made of nanomaterials, for more precise transdermal delivery or monitoring.

Traditional diabetes management relies on painful finger-prick blood tests, oral hypoglycemic drugs, or insulin injections, of which all carry inconvenience, potential infection risks, and an inability to continuously track blood sugar fluctuations and manage diabetes over time. Microneedles offer benefits such as low trauma, precise control, ease of use, and reduced infection risk^85,86 and have been widely used in the fields of medicine and biotechnology. They have gained widespread acceptance in the medical and biotechnology fields. The application of microneedle systems holds immense promise for continuous real-time diabetes monitoring, as they can reach the dermal layer without causing pain and reduce infection risks, thus enhancing safety. Microneedles can simultaneously and continuously monitor various biochemical indicators such as glucose, potassium ions, and sodium ions, contributing to a more profound understanding of diabetes development mechanisms and guiding diabetes treatment and complication prevention.⁸⁷ For instance, in blood sugar monitoring,¹⁶ microneedles typically immobilize glucose oxidase (GOx) on the sensor’s gold working electrode. In the presence of subcutaneous glucose, the enzymatic reaction on the electrode generates H₂O₂, yielding a current signal response and indirectly monitoring blood glucose levels.

Microneedles are one of the most widely researched and applied technologies, offering a means of transdermal delivery for antidiabetic drugs such as insulin.⁸⁸ They effectively manage glucose levels by providing sustained drug release, surpassing the limitations of subcutaneous injections that often result in hypoglycemia. Various nonimplantable or soluble microneedle diagnosis and treatment integration platforms have been successfully developed and applied to build a closed-loop system for the minimally invasive tracking of blood sugar and effective treatment of diabetes.¹⁵ In these all-in-one systems that combine sensors and drug delivery microneedles for monitoring blood glucose levels, ensuring stability and tolerability is paramount. Researchers can address these concerns by optimizing sensor designs through techniques such as 3D printing, microfabrication, electroplating, and enzyme immobilization. These approaches enhance sensor surface area, specificity, sensitivity, and selectivity by adjusting materials and structures at the micro-/nanoscale, enabling continuous and stable diabetes treatment. In summary, the integrated microneedle diagnosis and treatment system has significant development prospects and will likely play an increasingly important role in the future medical technologies. Figure 3 illustrates how microneedling lowers blood sugar.

NPs are particles with diameters ranging from 1 to 100 nm.⁹⁰ At this scale, the surface area of NPs is large relative to their volume; therefore, their properties differ significantly from those of macroscopic materials. NPs possess a larger specific surface area and can encapsulate drugs for quicker absorption, thus enhancing drug bioavailability.⁹¹ An increasing number of NPs and nanocarriers are being used in drug delivery systems. NPs encapsulate drugs, prevent drug degradation, and enhance drug stability. Furthermore, their small size allows increased tissue penetration and accumulation at the target site. This targeted drug delivery approach minimizes systemic side effects and improves therapeutic efficacy. Nanotechnology facilitates the repair of diabetic foot-damaged skin by providing scaffolds, nanofibers, and nanomaterials that mimic the natural extracellular matrix (ECM), which can support cell growth, differentiation, and tissue regeneration. Thus, they find utility in creating artificial islets, skin substitutes, and regeneration techniques. Nanotechnology has enabled the development of highly sensitive biosensors for the rapid and accurate detection of diseases. Nanoscale sensors can detect specific biomarkers or analytes in bodily fluids, aiding in the early diagnosis and monitoring of diabetes. These biosensors can be integrated into portable point-of-care devices for real-time onsite testing. Targeted NPs direct drugs to specific tissues or cells, improving drug efficacy and reducing side effects. Based on these advantages, the loading of insulin into NPs for oral administration has been proposed. For instance, Yu et al.⁹² developed a glucose-responsive oral insulin liposome with hyaluronic acid-poly(butyl acrylate) (HA-PBA) shells and insulin-loaded targeting Fc receptors. In mouse studies with chemically induced type 1 diabetes, this approach effectively reduced postprandial blood glucose fluctuations. In general, NPs, as a new type of diabetes treatment, have many advantages and broad application prospects. However, further research and development are needed to achieve improved therapeutic effects. In addition, in-depth studies on the safety and toxicity of NPs are required to ensure their safety and reliability in clinical applications. Figure 4 illustrates the effectiveness of nanoparticles in treating diabetes in mice.

Microspheres are tiny particles with a spherical structure.⁹⁴ They are made of materials such as polymers, ceramics, glass, or metals, exhibiting specific physical and chemical properties. The properties of microspheres depend primarily on their constituent materials and preparation methods. Their size, ranging from micrometers to hundreds of micrometers, closely matches cell and tissue scales, facilitating distribution and interaction in living organisms. Because of their small size and spherical structure, microspheres have a large specific surface area, providing more surface area for interacting with other substances. Moreover, microspheres can encapsulate or adsorb drugs in their structure to achieve drug-loading and controlled drug release. As an effective drug delivery system, microspheres regulate drug release rates and pathways, enhancing stability and bioavailability.^17,18,94,95 In addition, the physical and chemical properties of microspheres can be tuned by selecting appropriate materials and adjusting preparation conditions. The customizability of microspheres allows for design optimization tailored to specific applications. Microspheres can be classified into several categories depending on their composition and preparation method. For example, polymer microspheres are made of polymer materials and include polyvinyl alcohol and polylactic acid–glycolic acid copolymers.¹⁸ Ceramic microspheres are made of ceramic materials, such as alumina and silica.¹⁷ Finally, metal microspheres refer to microspheres made of metals such as gold, silver, and copper.⁹⁶ 

Microspheres are widely used across several fields. In diabetes treatment,⁹⁷ microspheres serve as carriers and insulin delivery systems. By encapsulating insulin, they improve insulin stability and achieve controlled release, aiding in blood sugar level management.^97,98 Moreover, microspheres can simulate the insulin injection process,⁹⁹ aiding patients with diabetes in mastering correct injection techniques and insulin syringe usage, which is crucial for diabetes management.¹⁸ Microspheres can also be used to encapsulate and protect islet cells and act as carriers in islet cell transplantation.⁹⁵ 

To summarize, microspheres are tiny particles with diverse properties that have the potential for a wide range of applications. They can be used for insulin delivery, insulin injection simulation, and islet cell transplantation, thereby providing new possibilities for the treatment and management of diabetes.

The glucose-responsive carrier system represents an intelligent drug delivery mechanism finely attuned to plasma glucose levels. Encased medications are swiftly released when high glucose levels are detected. Glucose oxidase (GOx) plays a pivotal role in this process, catalyzing glucose to produce gluconic acid, which lowers pH levels, leading to the generation of antibacterial H₂O₂ and angiogenesis-promoting NO. Notably, NO does not play a role in hypoglycemia. This system shows great potential in the medical field, particularly for the treatment of diabetes. Its ability to respond to blood sugar fluctuations ensures precise drug release, maintaining stable glucose levels and offering patients a dependable and continuous treatment approach. This feature minimizes potential side effects linked to overdosing, such as hypoglycemia. In addition, for patients with diabetes, blood sugar management may be challenging. This intelligent system simplifies this complexity, thereby enhancing patients’ quality of life and compliance with treatment. Moreover, the glucose-responsive system shines in glucose therapy, primarily focusing on diabetes management and treatment. Given that diabetes revolves around blood sugar regulation, close monitoring and control are imperative. This innovation automates and personalizes the adjustment process. For example, an intelligent insulin delivery system can automatically adjust the amount of insulin released according to the concentration of glucose in the body, thereby mimicking the function of a healthy pancreas. When blood sugar levels increase, more insulin is released, and vice versa. In addition to the release of insulin, this system can also be loaded with other drugs, such as exosomes, Chinese herbal medicines, and nano-preparations, for the treatment of diabetic wounds.

In summary, the glucose response system has great application value in glucose therapy and may provide safer and more effective treatments for patients with diabetes. Nonetheless, its development and application must overcome challenges related to system stability, accuracy, and long-term effectiveness.

GOX-based glucose-responsive carrier systems operate by releasing insulin in response to a signal generated by the GOX-catalyzed oxidation of glucose. GOX, an enzyme containing flavin, facilitates the production of H₂O₂ and gluconic acid, exhibiting remarkable selectivity for glucose. This catalytic enzyme finds primary utility in glucose-responsive systems that react to alterations in local pH, H₂O₂ concentration, and O₂ levels induced by GOX-catalyzed glucose oxidation. The gluconic acid produced by GOX in the process of oxidizing glucose lowers the surrounding pH value, thereby controlling the release of the loaded hypoglycemic drug from the pH-responsive component. For example, Ishihara et al. developed a pH-sensitive membrane for glucose-responsive delivery.¹⁰⁰ The enzymatic reaction between glucose and GOX generates gluconic acid,¹⁰¹ lowering the pH of the medium. This leads to the protonation of the tertiary amino groups in the membrane, increasing the water content of the poly(amine) membrane. Thus, the permeability of insulin through this composite membrane increases with increasing glucose concentration. Brown et al.¹⁰² designed a GOX-immobilized polymer that accelerates insulin release as pH decreases, achieving blood sugar control. However, rapid pH drops may result in excessive insulin release and hypoglycemia. Yao et al. developed an insulin microneedle patch,¹⁰³ serving as a prototype for the “smart insulin patch.” It carries hypoxia-sensitive vesicles that release insulin swiftly in a hypoxic, high blood sugar environment while inhibiting insulin release when blood sugar levels are normal. This innovative patch minimizes the risk of hypoglycemia, ensuring safety.

Glucagon-like peptide-1 (GLP-1) is an effective drug for the treatment of diabetes; however, its short half-life in vivo greatly limits its clinical application. Ruan et al. prepared a new type of GLP-1 analog (PGLP-1)¹⁰⁴ loaded into poly(d, l-lactide-co-glycolide) microspheres to achieve long-term blood sugar control. These PGLP-1 microspheres exhibited extended half-lives and enhanced safety. Peppas et al. reported the delivery of glucose-responsive insulin using pH-sensitive hydrogels.^105,106 With advancements in acid-sensitive materials and nanotechnology, novel formulations and designs have emerged, such as glucose-responsive bioinorganic nanohybrid membranes for closed-loop insulin delivery. These devices effectively maintained blood glucose levels within the normal range for up to 4 days in diabetic rats. In addition, pH-sensitive spongy matrices have been explored as insulin reservoirs that can be encapsulated within non-covalently cross-linked polymer matrices.

Acid hydrolysis has also been utilized in glucose-responsive systems mediated by GOX, in addition to pH-induced volume changes. Gu et al.¹⁰⁷ developed an injectable, acid-degradable polymer network for self-regulated insulin delivery. In this system, insulin, GOx, and CAT were encapsulated in acid-sensitive NPs composed of acetal-modified dextran (m-glucan). The particles were prepared using a double-emulsion-based solvent evaporation/extraction method. In this system, m-glucan is hydrolyzed into water-soluble dextran in the presence of gluconic acid, resulting in the dissociation of NPs and sustained release of insulin. To ensure injectability and mitigate burst release, oppositely charged polymers, chitosan, and alginate coated the NPs, forming a nanocomposite-based porous network. At blood sugar levels of 400 mg/dl, this gel-like nanonetwork effectively dissociates and releases insulin. However, under normal blood glucose levels (100 mg/dl), insulin release remains minimal. In a single subcutaneous injection test in mice with type 1 diabetes, this nanonetwork demonstrated improved blood sugar regulation for up to 10 days. Moreover, glucose can easily traverse the double membrane of polymersomes¹⁰⁸ and, when acted upon by GOX, transform into gluconic acid. This enzymatic reaction triggers hydrolysis of gluconic acid, causing amphiphilic polyethylene glycol (PEG)-poly(silicone ketal) to shift from hydrophobic to hydrophilic. This change in solubility leads to the collapse of nanovesicles, releasing insulin in response to glucose levels. Injected subcutaneously with a thermoresponsive and biodegradable polymer (PF127), the nanovesicle-containing suspension forms a stable hydrogel in mice. The hydrogel exhibited an excellent in vivo performance, with glucose-responsive nanobubbles maintaining normoglycemic levels for up to 5 days. Figure 5 introduces two GOX-reactive delivery systems.

The controlled release of insulin and other drugs relies on phenyl borate-based glucose sensing materials, which respond through phenyl borate contraction or expansion, or competition reactions. In aqueous solutions, PBA exists in a hydrophobic form with planar triangles and a hydrophilic ionized tetrahedral form, with a dynamic equilibrium between these two forms. Both forms specifically bind to vicinal diol-containing substances, such as glucose, to form five- or six-membered-ring phenyl borate complexes. The ionized PBA form covalently bonds with glucose to form a stable phenyl borate structure.¹¹⁰ Therefore, by leveraging the reversible effect of benzene, boric acid forms a copolymer hydrogel as an insulin network carrier. It introduces PBA groups into the copolymer network to react with glucose and is responsible for the PBA complex reaction, thereby causing a dissociation deviation of the equilibrium between PBA and water and increasing the water charge density in the gel network.¹⁰³ The combination of electrostatic repulsion and Donnan equilibrium drives PBA loading and insulin release, with rapid hydrogel swelling.¹¹¹ This PBA characteristic enables the drug carrier to release its payload in response to glucose concentration changes. Higher glucose concentrations lead to faster drug release rates and greater release amounts. PBA smart materials can also achieve controlled drug release through competitive reactions. Placing the PBA complex alongside glycosylated drugs in a glucose environment results in glucose displacing drugs such as insulin, releasing them into the surroundings. pH-sensitive polymers consist of acidic or basic groups that can accept or release protons in response to changes in environmental pH. Weak acids accept protons at a low pH and release them in neutral and high pH environments. Common pH-sensitive polymers include polyacrylic acid (PAAc), polymethacrylic acid (PMAAc), and chitosan.^112,113 PAAc and PMAAc can undergo electrolysis at specific pH levels, altering the polymer chain’s molecular structure with rapid changes in net charge. Chitosan, a polycation, dissolves in acidic solutions and deprotonates its primary amino groups when exposed to inorganic ions. This process occurs at pH values close to those of neutral biopolymers. In addition, the abundant hydroxyl and amino groups in chitosan chains serve as reaction sites, showing a strong affinity for phenylboronic acid.^114,115 Modifying PBA as a pH-responsive carrier involves synthesizing new polymers or cross-linkers that lower PBA’s pKa value, enabling glucose sensitivity under human physiological pH conditions. This approach holds broad application potential. The introduction of PBA as side groups in polyethylene glycol-b-polyacrylic acid (PEG-b-PAA) in the formation of an amphiphilic block copolymer is known as PEG-b-(PAA). In the PAA-co-PAAPBA segment, the carboxylate has a stabilizing effect on borate, reducing the apparent pKa of the PBA group. These results suggest that micelles have ideal glucose responsiveness (stable and fast response in normoglycemia under high blood glucose concentrations) and are suitable for constructing insulin delivery systems. Mandal et al.¹¹¹ synthesized a poly(acrylamide-co-3-acrylamide-phenylboronic acid-chitosan-grafted maleic acid) [p(AM-co-AAPBA-co-CSMA)s] hydrogel for glucose sensing and insulin release. The findings showed that at physiological pH, the hydrogel’s response to glucose concentration underwent two steps: shrinking at low concentrations and swelling at high concentrations. In addition, it boasted high insulin loading and encapsulation rates, making it suitable as an implantable glucose sensor and insulin release system. Compared to single micelles, complex micelles have better stability and biocompatibility, providing a new approach for the construction of glucose-sensitive polymers. Gabala and Theato¹¹⁶ successfully synthesized them in just two reaction steps with post-polymerization modification of PBA and diol-based block copolymers. These polymers exhibited excellent glucose reactivity at neutral pH, and composite micelles exhibited enhanced glucose reactivity under physiological conditions compared with pure PBA micelles. Insulin release from the polymeric micelles occurred in a glucose solution. These studies confirmed that pH-based PBA-sensitive polymers exhibit superior glucose responsiveness and self-regulated insulin release under physiological pH conditions in humans, highlighting their application in controlling blood glucose changes for diabetes treatment.

The use of reversible interactions between glucose and glucose-binding moieties to trigger insulin delivery is a promising nonenzymatic strategy. GBPs encompass a group of natural carbohydrate-binding proteins, such as lectins.^117,118 One of the most commonly used glucose-responsive insulin delivery lectins is concanavalin A (ConA),¹¹⁹ which contains multiple binding sites and can be released through competitive binding when exposed to glucose solution. Kim et al. used gluconate-modified insulin (G-Ins) to complement ConA in glucose-induced insulin release.^120–122 Another glucose-regulated insulin delivery matrix is based on the affinity between ConA and natural polysaccharide polymers, which can form dextran-based NPs.^123–125 Miyata et al.¹²⁶ developed a glucose-responsive hydrogel composed of ConA and poly(2-glucosyloxyethyl methacrylate) [poly(GEMA)], which swells in the presence of glucose, with the swelling rate dependent on glucose concentration. Ji et al.¹²⁷ designed a novel oral glucose complex that delivers insulin efficiently and safely in mice and pigs. Ye et al.¹²⁸ reported a ConA-based nanogel that modulated insulin release in response to glucose concentration in vitro after glucose addition. Moreover, Wu et al.¹²⁹ created a ConA-gated MSN nanocontainer, with pore opening and closing controlled by competitive binding, enabling glucose-responsive insulin release.

Biomaterial-based diabetes management strategies are an emerging therapeutic approach aimed at improving the quality of life and disease management outcomes of patients with diabetes. This strategy leverages the properties of biomaterials, combined with advanced technology, to provide continuous glucose monitoring and drug release as the core, bringing more precise and personalized treatment options to patients. Biomaterials play an important role in diabetes management. Biomaterials can provide an environment suitable for blood glucose monitoring and drug release to ensure their stability and safety. Some biomaterials are biocompatible and biodegradable, can interact well with human tissues, and can be broken down and metabolized away after completing their tasks, thus reducing the impact on patients. At the same time, the biomaterial-based diabetes management strategy realizes real-time monitoring of the disease through continuous glucose monitoring. In traditional diabetes management, patients need to take frequent blood samples for blood glucose monitoring, which is not only inconvenient, but can also cause patients to miss important information. Biomaterial-based strategies can achieve continuous monitoring and recording of blood glucose levels by implanting sensors or using wearable devices, effectively improving the accuracy and convenience of monitoring.

Biomaterial-based diabetes management strategies also include drug delivery systems that can precisely control drug release rates and dosages based on individual patient differences and needs. This strategy can achieve continuous and stable drug delivery, avoid the inconvenience of frequent injection of drugs in traditional treatment, and improve the controllability and stability of drug efficacy.

In conclusion, biomaterial-based diabetes management strategies, with their precision, personalization, and convenience, bring new treatment options to patients with diabetes. With the continuous advancement of technology and the innovative application of biomaterials, it is believed that this strategy will provide better health management and quality of life for people with diabetes.

Biomaterial sensors can measure the concentration of biomolecules and can be used to monitor blood glucose levels.¹³⁰ Maintaining appropriate blood sugar levels is crucial for diabetes management as elevated levels can lead to serious complications. Traditional monitoring methods include blood sampling and glucometer measurements, which involve repeated skin pricking, causing discomfort and infection risks. Therefore, researchers have been exploring biomaterial sensors for glucose monitoring. Typically, biomaterial sensors typically consist of two parts: biomaterials (such as enzymes, antibodies, or cells) and sensors that detect interactions between these materials and target molecules, converting them into electrical or optical signals.¹³⁰ In glucose monitoring biomaterial sensors, glucose itself often serves as the biomaterial. Glucose enzymes transform glucose into gluconic acid, generating electrical signals detected by sensors to provide blood sugar level readings. Biological sensors offer several advantages, including noninvasive monitoring that is more comfortable and convenient for patients, high sensitivity and specificity, and real-time monitoring for timely blood sugar level control.

Nevertheless, enzyme-based glucose sensors face challenges because of their instability, complex immobilization processes, and sensitivity to pH and temperature.¹³⁰ To address these shortcomings, a second-generation sensor has been developed, employing environmentally friendly, multifunctional metal oxide materials known for their cost-effectiveness, reproducibility, ease of fabrication, user-friendliness, and high stability. These sensors also exhibit resistance to harsh conditions such as high temperatures and high pH levels. Among these materials, ZnO is a commonly used metal oxide material that shows high sensitivity and selectivity for blood glucose monitoring. The detection principle of the ZnO sensor is based on the electron transfer process on the ZnO surface. When glucose is present in blood, it chemically reacts with the ZnO surface, thereby affecting the electron transfer process and changing potential signals. Detecting these potential signal changes allows for the determination of blood sugar levels. Hwa and Subramani¹³¹ developed a glucose sensor by immobilizing GOx on carbon nanotubes (CNTs), graphene (GR), and ZnO. GOx–CNT composites were first prepared, followed by the creation of GR–CNT–ZnO composites, enabling immobilization of GOx on the GR–CNT–ZnO composite to fabricate a glucose sensor. To enhance low-level glucose monitoring, Atchudan et al.¹³² functionalized GOX on the surface of NDC-TiO to develop a PECGlu biosensor 2NPs-coated indium tin oxide (ITO) electrode (designated as the GOX/NDC-TiO2NPs/ITO biosensor). This sensor operates based on electron transfer processes on the titanium dioxide surface, where the presence of glucose in blood leads to chemical reactions with the titanium dioxide surface, affecting electron transfer processes and causing changes in current signals. Blood sugar levels can be determined by detecting these current signal changes. Metal oxide sensors, including materials such as zinc oxide, titanium dioxide, indium oxide, aluminum oxide, and gallium oxide, exhibit high sensitivity and selectivity in blood glucose monitoring, offering speed, accuracy, and reliability. These sensors are widely employed for blood glucose monitoring because of their effectiveness.

Microneedle devices have emerged as promising candidates for monitoring glucose levels in the body because of their user-friendly nature, easy accessibility, lightweight design, and minimal invasiveness.¹³³ These microneedles can be manufactured using metal oxides, allowing for adjustments in their length, shape, and density. Importantly, they penetrate the skin at a shallower depth than subcutaneous injection sites, ensuring a painless, comfortable, and non-damaging experience. Consequently, microneedles are considered the sensor platform for third-generation CGM systems and offer an attractive alternative to traditional lancet diagnostic methods. However, their manufacturing processes are complicated and, as the holes are small, they are prone to clogging. To address these challenges, a study improved traditional microneedle sensors, resulting in a high sensitivity, biodegradable microneedle CGM system based on glucose-responsive fluorescence.¹³⁰ These ultra-thin, ultra-light needle sensor arrays provide continuous and accurate glucose concentration monitoring in the interstitial fluid. They offer minimal invasiveness, painlessness, wound-free application, and reduced risk of skin inflammation at various skin thicknesses and locations, overcoming previous system limitations. Microneedle sensors offer promising applications in blood glucose monitoring. Traditional microneedle sensors employ optical, electrochemical, biosensing, and other technologies for blood sugar monitoring, while optical microneedle and nanomicroneedle sensors utilize optical and nanotechnology to detect biomolecules. Microneedle sensors are noted for their high sensitivity, excellent repeatability, non-invasiveness, and portability, making them a highly prospective technology for blood glucose monitoring. As scientific and technological advancements continue, research in the realm of microneedle sensors for blood glucose monitoring is expanding, with more research findings and practical applications expected in the future.

Despite significant advances in insulin therapy over the past few decades, subcutaneous insulin injections remain the standard for insulin-requiring diabetes because of their ease of use. However, these injections often lead to skin trauma, pain, inconvenience, and poor patient compliance. Oral insulin administration could resolve these issues but faces challenges such as drug decomposition and absorption barriers in the gastrointestinal tract. In particular, chemical barriers such as the action of enzymes and pH can affect drug absorption.

Microneedle-based insulin delivery systems and transdermal drug delivery systems represent innovative advancements in insulin delivery. They aim to overcome the limitations of traditional insulin injections and pumps, improving patient compliance and reducing complications. By orally administering hyaluronic acid-coated insulin, this technology enhances convenience and bioavailability. While traditional insulin delivery methods rely on subcutaneous injections, microneedle-based systems enable oral insulin administration, bypassing the need for injections. This significantly enhances patient compliance, reduces psychological and physical burdens, and improves blood sugar control. For example, Ren et al. developed a microalgae-based oral insulin delivery strategy (CV@INS@ALG) using a Chlorella-based insulin delivery system cross-linked with ALG. CV@INS@ALG successfully traverses the gastrointestinal barrier, protecting insulin from gastric conditions and achieving a pH-responsive drug release in the gut. It promotes insulin absorption through the direct release of insulin from the delivery system and endocytosis by M cells/macrophages. Moreover, in a streptozotocin (STZ)-induced type 1 diabetes mouse model, CV@INS@ALG showed a more effective and longer-lasting hypoglycemic effect than the direct injection of insulin without causing any damage to the gut. In addition, long-term oral administration of CV@ALG effectively improved the gut microbiota disturbance in db/db type 2 diabetic mice and significantly increased the abundance of probiotic Akkermansia, thereby enhancing insulin sensitivity. Microalgal insulin delivery systems are also biodegradable and safe for intestinal metabolism. This biomaterial-based insulin delivery offers a natural, efficient, and versatile solution for oral insulin delivery.

In addition, hyaluronic acid, a biodegradable material, has been employed to envelop insulin, enhancing its bioavailability. Hyaluronic acid boasts excellent biocompatibility and biodegradability and plays a role in the protection and release of insulin during delivery. Yu et al. developed a novel glucose-responsive insulin delivery device,¹³⁴ using a painless microneedle array patch containing hypoxia-sensitive hyaluronic acid-based vesicles. In a localized hypoxic environment, these vesicles rapidly disintegrate, releasing the encapsulated insulin. This “smart insulin patch” relies on a novel enzyme-based glucose response mechanism, effectively regulating blood sugar levels in type 1 diabetic mice, bringing them within the normal range. Compared to commonly used pH-sensitive formulations, it demonstrates faster response times while mitigating the risk of hypoglycemia. Hyaluronic acid-coated insulin can be delivered orally or transdermally through the digestive tract or the skin barrier, thereby releasing insulin and achieving sustained blood sugar control. Microneedle-based insulin delivery systems and transdermal drug delivery systems present several potential advantages. They not only improve the convenience of insulin delivery and patient compliance but also reduce the discomfort and tissue damage associated with subcutaneous injections. In addition, HA-coated insulin can improve the stability, bioavailability, and therapeutic effect of insulin. Although this technology remains in the research and development phase, it represents an important advancement in the field of insulin delivery. Ongoing research will refine microneedle and transdermal drug delivery system designs, with clinical trials validating their safety and efficacy. These innovations are poised to offer new options for enhancing insulin delivery and providing a more convenient and effective treatment for patients with diabetes.

While various drug delivery systems offer advantages, the fundamental treatment of diabetes relies on tissue-engineered organoids to replace diseased islets. Organoids, a novel technological advancement, offer fresh avenues for disease research. These 3D structures, derived from pluripotent stem cells (PSCs) or adult stem/progenitor cells, faithfully replicate specific organ functions.¹³⁵ The construction of islet organoids represents an emerging field in biomaterial research and application, offering a means to enhance the quality of life for patients by treating conditions such as diabetes. Biomaterials play an important role in islet organoid construction, providing the essential scaffold structure and growth environment for islet cells to thrive and differentiate. Moreover, they regulate cell growth and differentiation, promote cell aggregation, and protect and support islet cells.

In conclusion, islet organoid construction holds significant promise as a technology that can revolutionize disease treatment, particularly diabetes. Biomaterials play an important role in the construction of islet organoids by providing an environment for the growth and differentiation of islet cells, thereby promoting the establishment and repair of islet organoids. As research deepens and technology advances, it is expected that islet organoid construction will mature and gain wider acceptance in the medical field.

Pancreatic islets play a pivotal role in regulating blood sugar levels within the body, primarily through the secretion of insulin and glucagon.¹³⁶ Unlike animal models, organoids can originate from human sources, eliminating the need for translating findings from animals to humans. Organoids are more readily accessible and versatile. In clinical applications, they serve as diverse high-throughput platforms for drug screening, assessing potential therapeutic effects, and as a promising source for organ transplantation because of their functional attributes. Islet organoids mirror the functional structure of human islets, achieved through the targeted cultivation of stem cells.^137–139 

Islet organoids can also be used for drug screening and evaluations. By introducing disease-specific cell types into islet organoids, researchers can model the disease states and assess the efficacy and toxicity of potential drugs. This artificial model provides a more controlled and reproducible environment that can accelerate the drug discovery and development processes. Leveraging islet organoids for drug screening for drug screening enables more accurate predictions of drug responses and effects on the human body, ultimately enhancing the efficiency and success rate of drug development. Furthermore, islet organoids can be used as pivotal models for disease research. For example, single cell types respond poorly to glucose stimulation and cannot mimic the interactions between beta cells and other cell types, which may play a role in islet function and diabetes onset. Thus, islet organoids offer a novel approach to diabetes research. In type 1 diabetes disease progression, beta cells within the pancreatic islets are destroyed, rendering their study challenging.¹⁴⁰ With the advent of induced PSCs (iPSCs) derived from patients with type 1 diabetes, researchers can construct pancreatic islet organoids to investigate cellular responses to various forms of beta cell stress in vitro. Through gene editing of islet organoids or the introduction of disease-associated gene mutations, researchers can simulate the occurrence and development of diseases and gain insights into their molecular mechanisms. This research provides a platform for exploring new therapeutic strategies and disease interventions. In addition, islet organoids contribute significantly to research on islet cell transplantation and regenerative medicine. Islet organoids can serve as precursors and sources for islet cell transplantation, facilitating the expansion and cultivation of islet cells to enhance transplantation outcomes. In addition, islet organoids can be used to study the mechanisms and methods of islet regeneration and to find new therapeutic strategies to stimulate islet cell regeneration.

In summary, islet organoids function as essential tools for diabetes and related islet disease research. By utilizing these synthetic islet organoids, researchers gain deeper insights into disease mechanisms, accelerate drug discovery and development, and advance islet cell transplantation and regenerative medicine. As technology continues to progress, islet organoids are expected to play an important role in diabetes research and treatment. Figure 6 introduces several different ways to obtain pancreatic islet organoids.

Biomaterials play a crucial role in the construction of islet organoids by providing scaffolds for cell growth, promoting cell differentiation, and providing mechanical support.¹⁴¹ Among these biomaterials, hydrogels are commonly used for islet organoid construction. Hydrogels represent 3D networks of water-soluble polymers designed to mimic the extracellular matrix (ECM),^142–144 a complex network of proteins and sugars that supports cell growth and differentiation. Hydrogels can be engineered to have specific mechanical properties such as stiffness and porosity, which can affect cell behavior and function. Another valuable biomaterial in islet organoid construction is the decellularized extracellular matrix (dECM).¹⁴⁵ Derived from natural tissues such as the pancreas, dECM undergoes processing to remove all cellular components, leaving behind a scaffold made of proteins and sugars. The use of dECM in islet organoid construction has demonstrated improvements in cell viability and functionality, as well as the promotion of vascularization. In addition to hydrogels and dECM, other biomaterials such as polyethylene glycol (PEG) and alginate have also been used in the construction of islet organoids. PEG is a synthetic polymer that can be engineered with specific mechanical properties. The use of biomaterials in islet organoid construction offers several advantages over conventional islet cell transplantation.¹⁴⁶ Islet organoids can be produced in large quantities, reducing dependence on donor pancreases, and can be engineered to have specific properties, such as size, shape, and mechanical properties, which can affect their function and survival after transplantation. In addition, islet organoids can be stored for extended periods, enabling off-the-shelf transplantation.¹⁴⁷ Alginate, a natural polysaccharide derived from seaweeds, forms a gel-like structure upon exposure to calcium ions. Islet organoids can overcome the shortage of human islet donors and provide an unlimited number of functional islets for regenerative therapy.¹⁴⁸ The combination of iPSC and CRISPR gene editing technology enables the development of patient-customized islet organoids without the need for gene correction.

In conclusion, the use of biomaterials in islet organoid construction is a promising approach for the treatment of type 1 diabetes. Hydrogels, dECM, PEG, and alginate are among the biomaterials used to construct islet organoids, offering scaffolding for cell growth, facilitating cell differentiation, and providing mechanical support. The use of biomaterials in islet organoid construction presents several advantages over traditional islet cell transplantation and has the potential to revolutionize the treatment of type 1 diabetes in the future.

Significant advancements have been achieved in leveraging biomaterials in the treatment of diabetes and its associated complications. Biomaterials play an important role in the development of smart insulin delivery systems. These systems use biological materials as carriers to stabilize and control insulin release. Some biomaterials regulate insulin release in response to changes in blood glucose levels. Such smart delivery systems hold the potential to offer precise insulin administration, thereby aiding individuals with diabetes in better managing their blood sugar levels. Progress has also been made in the realm of CGM. Biosensors employ biological materials as sensing elements to monitor blood glucose levels in real-time. These biosensors can be affixed to the patient’s body to provide continuous blood glucose monitoring data, real-time feedback, and decision support for diabetes management. Biomaterials have the potential to treat complications of diabetes. For example, in the treatment of diabetic foot disease, biomaterials can be used to cover wounds and promote healing, thereby reducing the risk of infection and complications. Biomaterial applications extend to the construction of islet organoids, serving as a platform for drug screening and toxicity testing. These islet organoids can enhance islet cell growth and function using biomaterials as scaffolds and support structures. This model proves invaluable in evaluating the effects of new drugs on islet function and accelerating drug development. In addition, biomaterials can enhance the survival rate of transplanted islets by serving as protective barriers that shield islet cells from immune responses. These biomaterials can also be used as scaffolds and support structures for islet cell transplantation to promote the growth and vascularization of islet cells, thereby improving the transplantation effect.

Despite notable progress in employing biomaterials for diabetes management, several challenges remain. Ensuring the long-term stability and functional permanence of biomaterials in diabetes treatment remain a challenge. Issues such as degradation, inactivation, or functional decline of the material may affect the durability of the therapeutic effect, necessitating further improvements in material stability and durability. The immunocompatibility and safety of biomaterials represent other critical concerns, as adverse immune responses could lead to rejection or chronic inflammation. Therefore, comprehensive immunological evaluations and improved material immunocompatibility are crucial for mitigating the risk of adverse reactions. Despite encouraging laboratory results, there are still many challenges in using biomaterials for the clinical treatment of diabetes. From a clinical perspective, the production cost, scale, feasibility, and long-term effects of biomaterials must be considered. Simultaneously, achieving individualized treatment remains challenging. The condition and needs of each patient with diabetes differ; therefore, more precise control and customized treatment strategies are required. Individualized treatment needs to consider factors such as the patient’s genetic characteristics, lifestyle, and metabolic state, intensifying the demands on biomaterial design and application.

The application of biomaterials holds substantial promise and will continue to foster innovation while enhancing diabetes management methods. The future trend in diabetes treatment revolves around the development of personalized interventions and tailored treatment plans based on genetic characteristics, condition, and lifestyle factors. The incorporation of biomaterials can be combined with disciplines such as gene sequencing, bioinformatics, and precision medicine to provide customized treatment strategies for each patient. Future research should focus on the development of more efficient insulin delivery systems for precise, continuous, and individualized insulin therapy. This may involve the application of novel carrier materials, smart delivery systems, and remote-monitoring technologies to meet the needs of different patients.

We acknowledge all the journals cited in this article for making it easy for us to obtain the valuable data and content.

This study was supported by the Jiangxi Province Traditional Chinese Medicine Science and Technology Plan (Grant No. 2023B0339).

The authors have no conflicts to disclose.

Guoliang Wang: Writing – original draft (equal). Weifang Liao: Investigation (equal). Feng Han: Software (equal). Yuying Shi: Writing – review & editing (equal). Zhijian Hu: Supervision (equal); Writing – review & editing (equal).

The data that support the findings of this study are available from the corresponding author upon reasonable request.

AGEs

advanced glycation end products

ALG

alginate

ASI

antigen-specific immunotherapy

CAT

chloramphenicol acetyltransferase

cDNF

cell-derived neurotrophic factor

CGM

continuous glucose monitoring

CNS

central nervous system

CNTs

carbon nanotubes

ConA

concanavalin A

dECM

decellularized extracellular matrix

DN

diabetic neuropathy

ECM

extracellular matrix

FRAP

ferric iron reducing antioxidant capacity

GelMA

gelatin methacryloyl

G-Ins

gluconate-modified insulin

GLP-1

glucagon-like peptide-1

GLUT4

glucose transporter 4

GOX

glucose oxidase

GR

graphene

HA

hyaluronic acid

HCLS

hybrid closed-loop system

hMSCs

human mesenchymal stem cells

IL-6

interleukin-6

iPSCs

induced pluripotent stem cells

ITO

indium tin oxide

MNTP

microneedle therapy platform

MPs

microparticles

NGF

nerve growth factor

NPDR

non-proliferative diabetic retinopathy

NPs

nanoparticles

Odex

oxidized dextran

PAAc

polyacrylic acid

PBA

poly(butyl acrylate)

PCL

polycaprolactone

PDR

proliferative diabetic retinopathy

PEG

polyethylene glycol

PEG-b-PAA

polyethylene glycol-b-polyacrylic acid

PGA

polymeric gallic acid

PGLP-1

prepared a new type of glucagon-like peptide-1

PI

proinsulin

PLGA

polylactic acid copolymer

PMAAc

polymethacrylic acid

PSCs

pluripotent stem cells

ROS

reactive oxygen species

STZ

streptozotocin

TNF-alpha

tumor necrosis factor-alpha

VEGF

vascular endothelial growth factor

AGEs

advanced glycation end products

ALG

alginate

ASI

antigen-specific immunotherapy

CAT

chloramphenicol acetyltransferase

cDNF

cell-derived neurotrophic factor

CGM

continuous glucose monitoring

CNS

central nervous system

CNTs

carbon nanotubes

ConA

concanavalin A

dECM

decellularized extracellular matrix

DN

diabetic neuropathy

ECM

extracellular matrix

FRAP

ferric iron reducing antioxidant capacity

GelMA

gelatin methacryloyl

G-Ins

gluconate-modified insulin

GLP-1

glucagon-like peptide-1

GLUT4

glucose transporter 4

GOX

glucose oxidase

GR

graphene

HA

hyaluronic acid

HCLS

hybrid closed-loop system

hMSCs

human mesenchymal stem cells

IL-6

interleukin-6

iPSCs

induced pluripotent stem cells

ITO

indium tin oxide

MNTP

microneedle therapy platform

MPs

microparticles

NGF

nerve growth factor

NPDR

non-proliferative diabetic retinopathy

NPs

nanoparticles

Odex

oxidized dextran

PAAc

polyacrylic acid

PBA

poly(butyl acrylate)

PCL

polycaprolactone

PDR

proliferative diabetic retinopathy

PEG

polyethylene glycol

PEG-b-PAA

polyethylene glycol-b-polyacrylic acid

PGA

polymeric gallic acid

PGLP-1

prepared a new type of glucagon-like peptide-1

PI

proinsulin

PLGA

polylactic acid copolymer

PMAAc

polymethacrylic acid

PSCs

pluripotent stem cells

ROS

reactive oxygen species

STZ

streptozotocin

TNF-alpha

tumor necrosis factor-alpha

VEGF

vascular endothelial growth factor