The Future of Diabetes Care: Exploring the Potential of Bioartificial Pancreas and Do-It-Yourself Artificial Pancreas System Innovations

Abstract

Background

Type 1 diabetes mellitus (T1D) is an autoimmune disease marked by the destruction of pancreatic β cells, necessitating lifelong management. Current therapies, such as insulin injections and pancreas transplants, are effective but impose significant burdens, driving the need for innovative solutions. Among these, the bioartificial pancreas (BAP) stands out as a promising approach. By integrating living insulin-producing cells with synthetic matrices, BAP technology aims to replicate natural pancreatic function, offering the potential for more physiologically relevant and patient-friendly treatment.

Summary

This review highlights recent advancements in BAP technology, emphasizing innovations in design, materials, and encapsulation techniques that enhance cell viability and function. Key developments include the use of biocompatible materials for cell encapsulation, continuous glucose monitoring systems, and closed-loop control algorithms, which collectively enable real-time glucose regulation. These breakthroughs address critical challenges such as immune rejection and suboptimal device performance, paving the way for clinical translation.

Key Messages

BAP technology represents a paradigm shift in T1D treatment, with the potential to alleviate the daily burdens of insulin management. However, challenges remain, including improving device longevity, bolstering immune protection, and reducing production costs to ensure broader accessibility. Future advancements may emerge from integrating BAP systems with cell-protective therapies, further enhancing their efficacy. While hurdles persist, the BAP signifies a transformative step toward simplifying diabetes management and improving the quality of life for millions worldwide.

Introduction

Type 1 Diabetes and Its Existing Therapies

Diabetes mellitus is a chronic metabolic disorder that results in a hike in blood glucose levels, either due to insufficient insulin production or an inability to utilize it properly. The pancreas produces insulin, a hormone that aids the body in absorbing glucose from the bloodstream, thereby maintaining blood glucose levels and generating energy. Type 1 diabetes (T1D) or insulin-dependent diabetes, is an autoimmune condition where immune T cells destroy the pancreatic cells, preventing insulin production and effective glucose intake, making it the 8th leading cause of death globally and potentially genetically inherited [1]. The symptoms of the disease are excessive thirst or hunger, frequent urination, delay in healing of wounds, weight loss, etc. The patients with T1D currently have no cure. The only way to prevent complications is to keep the sugar level as low as possible. Hence, there is a need for the administration of insulin throughout the lifetime [2]. The blood glucose level is monitored either by finger pricking or using a blood glucose monitor. The long-term glucose level can be monitored through glycated hemoglobin (A1C) [3], which gives us the average glucose level over the past 3 months. Further, long-term complications can also lead to various neurological and cardiovascular diseases [4]. Pancreatic transplantation, first performed in 1999, is a widely used treatment for diabetes. Clinical islet cell transplantation injects pancreatic cells into veins, which migrate to the liver via the bloodstream [5]. Transplantation restores blood sugar levels, but it also has several downsides as the host immune cells destroy the newly introduced cells, thereby resulting in a reduction in the number of newly grafted cells [6]. Due to this, there is a lifelong requirement for immunosuppressants like anti-TNF and IL-1 antagonists, etc. [7]. Hence, there is a need for alternative methods for diabetic patients to improve the quality of their lives. This review focuses on the bioartificial pancreas (BAP), which is one of the innovative treatments for T1D. This mimics the physiology of the real pancreas and can be synthesized using 3D bioprinting. BAP systems or Automated insulin Dosing (AutoDose) systems can also be an effective alternative.

Emergence and Progress in BAP Systems

Since the dawn of the invention of continuous subcutaneous insulin infusion pumps (CS2), there has been an ideology to discover the artificial pancreas. The first experimental pancreas came into existence in 1964. This was difficult to carry everywhere since it was as large as a backpack. It also contained a glucose monitor and delivered the insulin intravenously. Hence, there was ongoing research to improve the design of the Automated Pancreatic System (AutoPS) which includes features like a continuous glucose monitor (CGM), which measures blood sugar levels, analyses them and infuses insulin through pumps upon requirement. The timeline from the discovery of insulin up to the present-day BAP is shown in Figure 1.

Fig. 1.

Evolution of insulin therapy: from discovery to modern automated dosing devices. The timeline illustrated above traces the historical development from the discovery of insulin to significant breakthroughs in insulin research, culminating in the advent of modern Automated insulin Dosing (AutoDose) devices. It highlights key milestones and advancements that have shaped the evolution of insulin therapy over time.

The MiniMed 530G was the first-generation BAP, featuring an Enlite sensor. In 2015, the MiniMed 640G was introduced; this was in the vicinity of the APS and offered features like a bolus progress bar and insulin tracking with good battery life. The MiniMed 670G, the first closed-loop system with an improved sensor, was approved by the Food and Drug Administration (FDA). It controls basal insulin levels automatically, providing more specific targeting based on CGM data every 5 min [8]. The new MiniMed 780G, FDA-approved, is a 7-day usable device featuring new meal detection technology. It is also sensitive to glucose as low as 100 mg/dL and it automatically adjusts and delivers insulin based on carb intake. [9, 10]. The real-time data depicting the performance of MiniMed 780 G is shown in Figure 2.

Fig. 2.

Real-world clinical performance and glycemic outcomes of MiniMed 780G advanced hybrid closed-loop system across age groups. a Baseline metrics (n = 12,870) shows >92% time in AHCL across all cohorts. Mean sensor glucose: 145.1 ± 5.1 mg/dL. Split analysis between ≤15 years (n = 3,211) and >15 years (n = 8,874) users, with better glycemic variability in older group (CV: 33.2 ± 4.5% vs. 36.7 ± 4.9%). b Target achievement comparison: using 110 mg/dL target vs. 100 mg/dL shows improved outcomes. For ≤15 years, GMI <7% achievement increased from 77.5% to 92.3%; for >15 years: improvement from 77.0% to 93.8%. Time-in-range goals similarly enhanced with a 110 mg/dL target. c Six-month longitudinal analysis: both age groups maintained stable performance. Users ≤15 years sustained ∼94–96% time in AHCL; >15 years maintained consistent ∼77–78% time in range. Total daily insulin doses remained stable across study period. d Pre-post AHCL initiation outcomes: significant improvements in both groups. ≤15 years (n = 661): mean glucose decreased from 163.1 to 146.4 mg/dL (p < 0.001); >15 years (n = 2,014): improved from 159.6 to 145.4 mg/dL. Time-in-range increased ∼11% in both groups. Adapted with permission from [9].

The Omnipod DASH system by Insulet was the first disposable 3-day tubeless insulin pump designed for children as young as 2 years. It reduces hyperglycemic levels by 2.9%, improves the hypoglycemic range and enhances sleep quality. It features Bluetooth compatibility, a portable insulin pod that holds up to 200 units of U-100 insulin, a touchscreen interface and an integrated digital display for easy insulin dosing. This is the only insulin pump that is certified with DTsec and ISO 27001 for cyber and information security and safety [11]. The new Omnipod 5 (2023) is a fully on-body AID and hybrid closed-loop system integrated with the Dexcom G6 sensor for automated insulin delivery. Its improved UI made it easy to use. The system also enters automated mode when the connection is lost, delivering insulin based on previous safe static data [10]. Recently, the homemade or do-it-yourself (DIY) artificial pancreas system (APS) came into existence. This was initiated by a T1D individual with technical skills due to a delay in the development of devices by the company. This utilizes commercially available insulin pumps and CGMs with other additional components to create a closed loop for automated insulin delivery. However, there was no automation in the earlier stages. In 2013, the hashtag #WeAreNotWaiting was created by members who are using DIY pancreas systems and seeking improvement in the quality of their lives. Hence, in 2014, the open-source Artificial Pancreas System (OpenAPS) came into play, which was an algorithm that used a minicomputer with a radio antenna developed by Dana Lewis and her collaborators [12]. The OpenAPS is not a commercial product since it is not approved by the FDA and is unavailable for sale [13, 14]. This code can be integrated into the individual’s existing hardware to enable automation. Currently, there are three primary DIY looping systems, namely, Android APS, Loop, and OpenAPS. The first released algorithm was oref0 (OpenAPS Reference Design Zero). The AndroidAPS also runs with the same OpenAPS code and uses an Android phone for monitoring. On the other hand, Loop is the algorithm dedicated to the iOS platform that uses RileyLink for communication [15]. Nightscout, an open-source tool developed by the parent of a child with T1D, was a cornerstone of the DIY-APS. This is a cloud-based tool that enables real-time data monitoring and sharing via browsers [16]. The individual just requires a CGM sensor, a mobile phone with internet access and basic computer knowledge [13, 17]. The DIY-APS was found to be cost-effective and quite simple to build at the ease of home. Day by day, the use of this is increasing widely. Parents should also be careful and check for risks and other impacts before using them with their kids. Table 1 provides a comprehensive comparison of commercially available Automated Insulin Delivery (AID) devices, detailing their distinctive features and technical specifications.

Table 1.

Automated insulin Dosing (AutoDose) devices available in the market

AutoDose devices	Approval and other certifications	Targeted audience	Sensors used	Perks of using the devices	References
Medtronic’s MiniMed 670G	FDA approved	7 years and above	Guardian sensor 3	Waterproof, auto-mode, 300 units of insulin capacity	[8]
Medtronic’s MiniMed 780G	FDA approved	7 years and above	Guardian sensor 4	7-days usage, sensitive to glucose as low as 100 mg/dL, waterproof, auto-mode, SmartGuard technology detects meals automatically and delivers insulin upon carb intake	[9, 10]
Insulet’s Omnipod 5	FDA approved, CE mark approved, DT sec, ISO27001 certifications	2 years and above	Abbot FreeStyle Libre 2 plus system, Dexcom G6 sensor	3 days usage, tubeless, waterproof on the body, more TIR can regulate glucose from 110 to 150 mg/dL, first FDA-approved system that can be fully controlled from a smartphone, certified data transmission security, 200 units of insulin capacity, smart adjust technology predicts 60 min of future and adjusts insulin every 5 min	[10, 18]
Beta Bionics iLet Bionic Pancreas	FDA approved	6 years and above	Dexcom G7 sensor	Just 30 min warmup time required, user just have to enter their weight and insulin delivers automatically, claimed to determine 100% of all insulin doses	[19]
DIY artificial pancreas system	Not approved	No restrictions patient’s own risk	Can be integrated and automated with any hardware components	Most runs on OpenAPS also have separate platforms for iOS and android users, user-friendly and can be made at home	[12, 14]
Night scout	Not approved	No restrictions patient’s own risk	Can be integrated and automated with any hardware components	Cloud-based, seamless sharing, real-time monitoring, can be made at home	[13, 17]
T: Slim X2 IQ Artificial Pancreas	FDA approved	6 years and above	Dexcom G6 sensor	A rechargeable insulin pump can predict insulin up to 30 min ahead in future and adjust upon it, auto insulin shutoff and resume, and can regulate from 112 to 160 mg/dL, 300 units capacity	[20]

Components of the BAP

Overview of Different Cell Sources Producing Insulin (e.g., Islets, Stem Cells)

T1D is caused when the insulin-producing β-cell mass, which constitutes about 80% of the islets of Langerhans [21], gets reduced to 20% of its normal count due to its autoimmune destruction, which does not allow it to secrete insulin. Mature β cells are difficult to grow under in vitro conditions, for which cell replacement therapies or organ transplantations can pose as good alternatives. However, due to the lack of organ donors, adult stem cells, including induced pluripotent stem cells and mesenchymal stem cells, as well as embryonic stem cells, have been used to create insulin-producing cells (IPCs) [22]. Cells are also retrieved from the umbilical cord blood, liver, intestine, neuronal tissues, adipose tissues, spleen, and bone marrow due to their potential for multiple differentiation [21].

Sensor Technologies

CGM Systems

Self-monitoring of blood glucose is the conventional method for monitoring blood glucose levels in T1D patients. However, due to their not-so-user-friendly usage and lack of timely feedback, CGM systems were developed [23]. These medical devices monitor blood sugar levels continuously using small implants that are attached to the upper arm or abdomen for up to 2 weeks and can be implanted under the skin for up to 180 days [24]. The CGMs operate electrochemically, with the addition of hydrogen peroxide or hydrogels as redox mediators. Glucose is determined by the glucose oxidase enzyme, which can recognize sugar levels in sweat, tears, urine, and saliva [25].

The CGMs have become more reliable over time with their delivery of organized and standardized data that can be easily conveyed directly to the patient’s mobile phone. CGMs transmit data to the monitor or the patient’s mobile device that continuously updates the status of glucose levels every 5 min. It gives real-time information about glycemic variability-hypoglycemia and hyperglycemia. The three main periods at which glucose levels should be monitored are overnight, the pre-prandial period (before insulin dosage variation), and the post-prandial period (after the insulin dosage variation). Low glucose levels are measured between 12:00 a.m. and 2:00 a.m., while high blood glucose levels are measured from 6:00 p.m. to 11:00 p.m. [23].

CGMs can optimize the lifestyle by monitoring nutritional behavior, physical activity, stress level, and athletic performance [24]. Technological advancements have led to optical continuous glucose sensing systems using fluorescence monitoring, which can measure the differences in the modified fluorescence probe on abiotic synthetic compounds such as di-boronic acid derivatives and glucose-binding molecules like hexokinase and concanavalin A. However, because of their complex work, they have not yet been commercialized [25].

Integration of Sensors with the BAP

An artificial pancreas could be a better alternative for T1D due to factors such as the need for multiple doors, ischemic damage, apoptosis and poor islet engraftment. AID systems can measure glucose levels and automatically administer insulin doses, functioning in a closed-loop manner without external intervention. Hybrid closed-loop systems are commercially available, allowing adjustable insulin doses based on a patient’s diet and exercise. Research is ongoing to close these hybrid loops [26]. The hybrid-closed loop mechanisms are sensor glucose-driven, calculate carbohydrate consumption levels and provide room for adjustment through manual insulin injections in times of need. It can send data and has a significant role in AID and BAP systems [23].

Pancreas-on-a-chip is based on the organ-on-a-chip technology, where the endocrine part of the pancreas on a microfluidic chip is used to assess the islet potency, quality, functionality, and in vivo pathophysiological responses for real-time monitoring and drug testing of various cultured tissue types for making APS [27]. The conventional enzymatic glucose sensors pose barriers to closed-loop mechanisms because of their full automation and lack of variability. To overcome this, biosensors have been developed that integrate a microelectrode array that contains a few murine or human islet cells that provide real-time observations like glucose homeostasis through online signal processing and ensure timely measures like lifestyle and dietary changes. These sensors display several action potentials that are recorded using microelectrode arrays. Islets with slow potentials have frequency ranges between 0.2 and 2 Hz. This information is decoded using amplifiers and filters that produce useful data [28].

Control Algorithms

Adaptive Control Strategies

Adaptive control algorithms manage blood glucose concentration fluctuations and complexity [29], adjusting insulin infusion rates based on real-time glucose levels. Various other algorithms have also been tested in silico along with the control algorithms in closed-loop therapies to overcome issues like delays in subcutaneous insulin infusion [30]. The model predictive control model manipulates input data according to output data. It consists of several algorithms and solves problems with the variations caused by diet and exercise and the consequent delay in insulin absorption. It implements mathematical models of glucose-insulin interactions [29]. For example, the Minimal Model of Bergman is used on most T1D models, where the glucose rate and subcutaneously injected insulin flow are the inputs and the plasma glucose level is the output [30].

The concept behind proportional-integral-derivative control is to employ a feedback mechanism to control a single target by summing up the integral, proportional, and derivatives by analyzing the rate of change in recorded glucose (the derivative term). The area under the curve between recorded and intended glucose (integral term) and the deviation from the intended glucose level (proportional term) alter insulin administration. It also develops an efficient control technique for individuals with T1D. The insulin dosages are calculated by fuzzy logic using elements that control the glucose levels [29].

Soylu et al. [31] proposed an adaptive model predictive control algorithm for a dual-hormone artificial pancreas that works mutually with the proportional-integral-derivative and FLC controller models. Nath et al. designed a nonlinear adaptive controller that, in the presence of intra-patient differences and unpredictable meal disturbances, achieves the required glycemic control [32].

Research shows patients’ glucose levels consistently exceed normal, demonstrating hormone responsiveness. An adaptive control technique is developed to manage uncertainties in the patient’s body [33].

Personalized and Closed-Loop Systems

An externally worn medical device called an automatic closed-loop artificial pancreatic device is a medical device that includes an infusion pump that supplies insulin, a CGM to track sugar levels, and a digital controller that acts as a control center [29] (shown in Fig. 3). The dual-hormone closed-loop systems have been proven to decrease hypoglycemia and improve average glucose levels using the insulin-glucagon system with the ingestion of small boluses or intermittent glucagon administration for better insulin delivery [34]. Currently, three existing DIY-APS, which require insulin pumps, a CGM, and a smartphone, have been reported to improve patient outcomes, with 70% of respondents transitioning from conventional insulin delivery systems and 64% showing improvements in TIR, sleep disturbances, hemoglobin A1C, and hyper or hypoglycemia frequencies [35].

Fig. 3.

Integration of automated insulin delivery systems: real-world implementation and clinical outcomes. a Loop interface showing glucose tracking (5.9 mmol/L), insulin monitoring (active: 1.75 U, total: 23 U), and carbohydrate tracking (10 g). b 90-day comparative outcomes: pre-loop (eA1C: 6.5%, glucose: 7.8 ± 2.8 mmol/L, TIR: 48%) versus post-loop (eA1C: 5.5%, glucose: 6.1 ± 1.9 mmol/L, TIR: 76%), demonstrating significant improvement in glycemic control with automated delivery system. Adapted with permission from [17].

Encapsulation of Islet Cells

The BAP is a semipermeable membrane device that encapsulates insulin-producing cells, protecting them from immune reactions. It uses polymer microcapsules with pores for oxygen, carbon dioxide, insulin, nutrients, and waste passage. The architecture of the artificial pancreas resembles normal pancreatic physiology. This technique is being explored as a new-age therapeutic cell transplantation solution for T1D without the need for immunosuppressive drugs, based on ongoing human and animal studies [36]. Islet cells are encapsulated in semipermeable biocompatible materials for BAP development that provide structural and functional support, whose biocompatibility depends on factors like pH, hydrogel enzymes, temperature, hydrogel preparation methods, and the combinations of materials used [37].

Cell encapsulation techniques, including microspheres, casting/moulding and bioprinting, are being explored as alternatives to traditional islet and pancreatic cell transplantation. Bioprinting uses biomaterials like alginate or fibrinogen hydrogels to create more porosity in the BAP, allowing for easy waste and nutrient exchange. β cells are sensitive to hypoxia; thus, the cells and biomaterials used must be well-oxygenated. The contrasts between traditional insulin treatments and modern BAP systems illustrate how current methods differ from past approaches as shown in Figure 4.

Fig. 4.

Progression of type 1 diabetes (T1D) management: from pathophysiology to conventional insulin therapies and bioartificial pancreas technologies. The schematic representation illustrates the mechanism of T1D, followed by an overview of traditional insulin therapies such as insulin syringes and finger pricking. It also highlights modern treatment approaches, including β-cell synthesis and encapsulation, 3-D bioprinting and bioartificial pancreas (BAP) technologies. Created with BioRender.com.

Cell seeding techniques, such as salt leaching and bioprinting, form micro- and nanopores for better encapsulation of β cells. Encapsulation devices with gas chambers for oxygenation, made of materials like perforated polytetrafluoroethylene membranes, are then implanted subcutaneously, providing a more efficient alternative to islet and pancreatic cell transplantation. This technology is expected to replace traditional cell transplantation with BAP, which will source pancreatic or alternate therapeutic cells like microvascular segments, endothelial cells, pericytes, mesenchymal stromal cells, and bone marrow-derived endothelial progenitors [38]. Cells are encapsulated to create a BAP using three techniques: macroencapsulation, microencapsulation, and nanoencapsulation.

Macro encapsulation encloses an islet in an inner chamber of hollow fibers, flat sheets, or disks, with a 200 µm diffusing gap between the islets and oxygen supply. Microencapsulation uses a micrometer-thick lining of biocompatible permeable substances like hydrogels, while nanoencapsulation uses a nanometer-thick layer of biocompatible material, limiting diffusion distance to the islets. These devices are implanted extravascularly in subcutaneous tissues or intravascularly in the arterial blood and their location is influenced by factors such as retrieval, effortless implantation, and proximity to the source of nutrients [39].

Hydrogels have been widely used for cell encapsulation, using both natural and synthetic materials. Synthetic hydrophilic polymers like acrylic acid and its byproducts, alcohol, polyacrylic acid, polyacrylamide, and polymethacrylic acid are used, while natural hydrophilic polymers like cellulose, starch, hyaluronic acid, and peptides like poly-l-glutamic acid, collagen, and poly-l-lysine are used [37].

Ideally, the extravascular microencapsulation device consists of a diffusion chamber, layered alginate sheets with islets and a coiled hollow fiber tube. Alginate is widely used due to its biocompatibility and easy gelling ability [40]. Now, synthetic polymers are used in hydrogels that integrate with inorganic membranes of aluminum, aluminum oxide, silicon, titanium, and titanium oxides with adhesives like epoxy polymer. The microencapsulation technique uses alginate, agarose, polyethylene glycol, and peptide amphiphile [41]. Microwell membranes made up of polyether sulfone or polyvinyl pyrrolidone polymers are used to encapsulate islet cells, requiring high insulin, and glucose permeability for successful encapsulation [42]. Although these encapsulation techniques have proved to be an advanced and better alternative for treating T1D, they still must overcome certain obstacles that do not allow this to be a fool-proof solution.

3-Dimensional Bioprinting of Artificial Pancreas

3-dimensional bioprinting is an automatic additive manufacturing tissue engineering process that involves creating layers of matrices using various materials to create cells or organs. The process involves three stages. Pre-bioprinting is a preparatory step where minimally invasive cells are selected. Generally, embryonic stem cells are preferred since they can be transformed into any cell type. CT or MRI scans are used to analyze the internal structure of the cells or organs. 3D modeling is then done using software like MIMICS, TSIM, OsiriX, etc., and the design will be converted into the single triangle language format for bioprinting [43]. Common 3D printing technologies include extrusion-based, UV curing, inkjet and fused deposition modeling [44]. Second, the bioprinting stage is where bio-ink is chosen based on bio-printability, cytotoxicity, cell density, affordability, and other physical and chemical properties [43]. The natural polymers used to synthesize the bio-ink are gelatin, alginate, and hyaluronic acid, and the synthetic polymers are polylactic acid, polycaprolactone, polyurethane, etc. The loaded bio-ink then starts printing the model using the proposed design, and cross-linking of polymers takes place [45]. The ultimate step is the post-bioprinting stage, which involves maintaining printed cells in a controlled environment, preferably a bioreactor with desired physical and chemical stimuli. Nutrients, oxygen, CO₂, temperature, pH, and other growth factors should be properly maintained to test and maintain cell growth and proliferation [43].

In 2009, Professor Wang used adipose stem cells embedded in gelatin, alginate, or fibrin hydrogels to print the first pancreas using 3D printing [46]. In 2019, Duin et al. [47] used alginate/methylcellulose for the islet encapsulation and the resulting hydrogel was shown to have higher viability and work efficiently by constantly producing insulin under observation. In 2021, a novel bio-ink was developed by adding Pluronic F127 to alginate, enhancing printability and hypomethylated pectin was added to reduce inflammation by TLR2/1 inhibition. The combination of these three compounds lowered immune rejection and extended the survival of islet cells [48]. In recent studies, it has been found that most synthetic polymers have supermechanical properties and cells are found to be more viable compared to natural polymers [44].

In 2019, the pancreatic-derived ECM model, which utilizes ECM and decellularized ECM, is highly efficient and enhances the maturity of 3D islet cells [49]. In 2022, Wang et al. [50] synthesized a new bio-ink with hyaluronic acid methacrylate and pECM and the pancreas was printed using UV-curable printing. Later, this was implanted into the diabetic mouse model, resulting in a normal glucose level for 90 days with a significant increase in insulin activity [44]. Recently, EPFL’s Laboratory of Applied Photonics Devices and Readily3D developed a 30-s technique for printing mini pancreas and blood vessels from the patient’s stem cells. The strength of the laser beam can be modified, and the whole organ can be printed in a single mold. This allows in vitro drug testing and eliminates the need for animal testing, allowing personalized and efficient treatment [51].

Clinical Trials

Overview of Ongoing and Completed Clinical Trials

Numerous BAP devices have undergone extensive preclinical and clinical testing, including Viacyte’s Encaptra device, Nestle Research’s planar macro-sheets, βO2 Technologies’ βAir and Theracyte’s BAP device to reduce insulin dependence in animal models [39]. The Encaptra device uses a macro-encapsulation method to implant pancreatic progenitor cells under the skin, allowing them to mature into functional islets that can secrete insulin. Another promising BAP device is the Sernova Cell Pouch System, which utilizes a biomaterial carrier to house insulin-producing cells and is implanted under the skin. The Cell Pouch System has shown promising results in preclinical studies and is currently in clinical trials [41]. BAP devices that are in development and preclinical testing include intravascular macrocapsules, microcapsules, and whole-organ bioengineering [52–54]. The advancements in BAP will benefit from the comparison of device functionality measures like glucose-insulin kinetics, islet load and basal and stimulated C-peptide levels.

BAP has shown potential for treating T1D. Two devices, Viacyte’s Encaptra and DRC planar sheets, attained physiological ranges for each baseline and inspired C-peptide levels. In a pig model, the βAir tool demonstrates normal baseline C-peptide degrees, but stimulated values have not been recorded. To realize the possible harmful outcomes of supratherapeutic C-peptide levels, additional research is necessary. Although subtherapeutic C-peptide stages are undesirable, additional studies are needed to determine whether supratherapeutic degrees might have dangerous effects. The PEC-01 cell line, which is well known for having an overactive endocrine system, displayed supratherapeutic ranges beneath each stimulated and baseline setting. High baseline and stimulated C-peptide ranges were additionally seen with DRC planar sheets implanted in a prefabricated pouch; this is probably because of improved neovascularization and device engraftment. Utilizing swine islets, βAir's equipment confirmed more suitable basal and enhanced C-peptide levels.

The European Commission-funded VANGUARD project intends to develop a BAP that is vascularized and immune-protected for transplantation to cure T1D. This would enable insulin production and disease management without forcing the patient to take immunosuppressive medicine for the rest of their lives [55].

Efficacy and Safety Outcomes

The scientific results of BAP devices are still unclear, and there is still scope for improvement; further studies need to be done to overcome the constraints [41]. There are very few studies that have been done on human participants and the results, while encouraging, do not demonstrate that diabetes can be treated successfully [56]. However, preclinical studies have shown promising results, with some studies reporting long-term normal fasting blood glucose levels in diabetic canine recipients of multiple hollow fiber tube devices with endogenous islets [41]. It is believed that BAP device safeguards extend the life of the islets and in with long-term endocrine cell activity [39]. A novel pre-vascularized BAP has been evaluated in vitro for safety and functionality based on the susceptibility of its membranes to human IgG, insulin, and glucose that is measured [57].

The safety of BAP devices, which are currently in clinical trials, is a subject of ongoing research. Various approaches, such as macro-encapsulation devices and pre-vascularized BAPs, are being tested for safety and efficacy in preclinical and clinical studies. These devices aim to provide sustained immune protection and optimal function and survival for the encapsulated cells. Safety assessments include histological analyses, evaluation of membrane permeability, and the development of design features to address safety concerns related to surgical procedures and device implantation. However, as of now, there is no comprehensive comparative analysis of the safety of these devices in clinical trials. Therefore, the safety of each device is being evaluated independently as part of their respective clinical studies [57].

Therapeutic Potential and Clinical Impact on the Treatment of T1D

Glycemic Control and HbA1c Reduction

Diabetes patients can achieve significant improvements in their blood glucose levels through lifestyle modifications, such as a strict diet and exercise [58]. This can reduce the risk of cardiovascular complications and improve overall health. However, the relationship between glycemic control and clinical outcomes is complex, and further research is needed to fully understand the factors contributing to the clinical impact of glycemic control in diabetic patients. Hence, glycemic control and HbA1c reduction are crucial in understanding the outcomes of diabetic individuals [59, 60].

Comparisons with Traditional Insulin Therapy

BAP devices are being researched as an alternative to traditional insulin therapy for T1D. Traditional insulin therapy involves injections or pump therapy, which is divided into groups based on their effectiveness, duration and delivery methods [61]. Studies have compared intensive insulin therapy and conventional insulin therapy in various patient populations, including those with traumatic brain injuries and pregnant women [62–64]. However, disappointing clinical trial results have hindered interest in bioartificial pancreatic devices. Figure 4 contrasts traditional insulin treatments with modern BAP systems, illustrating how current methods differ from past approaches. Further investigation is needed to fully understand their effectiveness and reliability [39]. Figure 4 compares these modern treatment methods for the treatment of T1D in comparison with the traditional techniques.

Challenges and Future Directions

Immune Response to Implanted Cells

The immune response to implanted materials and devices is a complex process that can have both beneficial and detrimental effects [65]. Factors such as chemical composition, surface topography, wettability, surface charge, and release of bioactive molecules can influence the local immune response and implant success [66, 67]. The tissue surrounding the implant determines how the material and immune reactions occur, triggering innate defenses and adaptive immune responses. Degradable and non-degradable alloy implants have different immune responses, with degradable implants potentially developing substantial responses [68]. Further investigation is needed to understand the function of innate and adaptive immune responses to different types of implants [69].

Strategies for Immune Evasion

Immune evasion strategies can be passive or active. Passive evasion involves parasites predicting immune-privileged tissues or placing eggs in unpatrolled tissues [70]. Active evasion involves altering surfaces, releasing proteins, or imitating host molecules [71, 72]. In implanted cells, evasion strategies involve modifying cell surfaces, releasing proteins, or mimicking host molecules to prevent detection by the host immune system [72, 73].

Long-Term Viability and Durability

Maintenance of Cell Function over Time

Maintaining cell function in T1D is crucial for disease management and therapeutic interventions. Studies have explored strategies to preserve and enhance β-cell activity in patients [74]. Verapamil partially maintained enhanced C-peptide secretion in children with T1D, suggesting potential advantages in β-cell maintenance. Combining saxagliptin and vitamin D may be a novel supplement to insulin and metformin [75]. In T1D, several immunological strategies have been investigated to restore immune tolerance to β cells, preserving remaining cells during identification or regaining function [76]. Research has focused on β-cell physiology, developing treatments and insulin production. Improving the potential of individual β cells can restore their function, which is essential for effective therapy for the treatment of diabetes [77].

Cost-Effectiveness and Accessibility

The adoption of BAP devices by a large population is crucial for assessing their feasibility and impact. However, the currently available sources only provide limited information on the economic aspects of these devices. To enhance accessibility for T1D patients, further research is needed on cost-effectiveness, market insights and early health economic evaluations. This would include insights from health economists, market analysts and researchers involved in the development and implementation of these innovative technologies [52–54].

Limitations of Current BAP Devices

The limitations of current BAP devices also play a significant role in the advancement and successful implementation of BAP devices as a viable cure for individuals with T1D. The necessity for immunosuppression in transplant recipients is a significant limitation as it poses inconveniences and potential health risks associated with lifelong adherence to immunosuppressive drug regimens [78]. Disappointing clinical trial results have impacted the enthusiasm for BAP devices, indicating challenges and potential setbacks in their development and adoption [39]. Despite good functional results, the use of islet transplantation remains restricted because of things like scarcity of donors, the loss of cells due to hypoxia and irritation, inadequate revascularisation and the necessity of immune suppression [79] (shown in the Fig. 5).

Fig. 5.

Challenges, opportunities, and strategies for advancing bioartificial pancreas (BAP) research and clinical application. The illustration above highlights the current challenges and opportunities in BAP research. It also outlines strategies for improvement and emphasizes the need for clinical application and validation to enhance the efficiency of BAP developments. Created with BioRender.com.

Conclusion

BAP devices are being explored as a potential treatment for T1D. These devices aim to mimic the function of the pancreas and improve glycemic control [30]. However, challenges such as immunosuppression, achieving euglycemia and economic considerations remain significant barriers to their widespread adoption [80]. The design of BAP devices is critical, focusing on enhancing oxygen supply and immune protection [78]. BAP technology has enhanced glucose and patient-centered outcomes for individuals with T1D [81]. Immunological treatments are also being explored to maintain β-cell activity in T1D patients [76]. Teplizumab, a drug designed to modify the disease’s progression, has shown promising results in clinical trials. However, long-term safety studies are needed for newer, more effective drugs and their applications in other diseases. Recent advancements in T1D therapeutics, such as immunotherapy, offer potential treatment options for T1D patients [52, 82]. BAP devices are being explored as promising therapies for T1D, with a focus on improving blood glucose control and reducing the reliance on exogenous insulin delivery. However, issues such as excessive equipment costs for purchase, early sensor malfunction, and the development of scars due to repetitive microneedle insertion still need to be addressed.

Conflict of Interest Statement

The author declares that they have no conflicts of interest.

Funding Sources

This write-up was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2022R1I1A1A01068652).

Author Contributions

A.N.: conceptualization, writing – original draft, and editing. A.R. and R.L.R.: writing – original draft. P.G. and R.N.S.: supervision and writing – review and editing.

Funding Statement

This write-up was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2022R1I1A1A01068652).