Bioartificial Pancreas Research Articles

The Role of the Pancreatic Extracellular Matrix as a Tissue Engineering Support for the Bioartificial Pancreas.

Type 1 diabetes mellitus (T1DM) is a chronic condition primarily managed with insulin replacement, leading to significant treatment costs. Complications include vasculopathy, cardiovascular diseases, nephropathy, neuropathy, and reticulopathy. Pancreatic islet transplantation is an option but its success does not depend solely on adequate vascularization. The main limitations to clinical islet transplantation are the scarcity of human pancreas, the need for immunosuppression, and the inadequacy of the islet isolation process. Despite extensive research, T1DM remains a major global health issue. In 2015, diabetes affected approximately 415 million people, with projected expenditures of USD 1.7 trillion by 2030. Pancreas transplantation faces challenges due to limited organ availability and complex vascularization. T1DM is caused by the autoimmune destruction of insulin-producing pancreatic cells. Advances in biomaterials, particularly the extracellular matrix (ECM), show promise in tissue reconstruction and transplantation, offering structural and regulatory functions critical for cell migration, differentiation, and adhesion. Tissue engineering aims to create bioartificial pancreases integrating insulin-producing cells and suitable frameworks. This involves decellularization and recellularization techniques to develop biological scaffolds. The challenges include replicating the pancreas's intricate architecture and maintaining cell viability and functionality. Emerging technologies, such as 3D printing and advanced biomaterials, have shown potential in constructing bioartificial organs. ECM components, including collagens and glycoproteins, play essential roles in cell adhesion, migration, and differentiation. Clinical applications focus on developing functional scaffolds for transplantation, with ongoing research addressing immunological responses and long-term efficacy. Pancreatic bioengineering represents a promising avenue for T1DM treatment, requiring further research to ensure successful implementation.

Clinical Translation and Implementation of a Bioartificial Pancreas Therapy: A Qualitative Study Exploring the Perspectives of People With Type 1 Diabetes.

The development of a hybrid beta-cell replacement approach, referred to as a personalized, transplantable bioartificial pancreas (BAP), holds promise to treat type 1 diabetes (T1D). This interview study aimed to explore patients' expectations, needs, concerns, and considerations when considering to undergo a BAP transplantation. Semistructured interviews were conducted with 24 participants diagnosed with T1D. Data collection stopped once data saturation was reached. Audio recordings of the interviews were transcribed verbatim. The interviews were independently analyzed by 2 researchers. A qualitative content analysis using an inductive approach was used. Three main themes emerged as follow: (1) hoped-for benefits, (2) concerns and decision-making considerations, and (3) procedural aspects. First, the participants expected benefits across medical, psychological, and social domains. Over these 3 domains, 9 subthemes were identified, including improved clinical outcomes, a cure for diabetes, more headspace, emotional relief, a shift in responsibility, protection of privacy, improved flexibility in daily life, less visible diseases, and improved relationships with others. Second, concerns and considerations about undergoing a BAP transplant comprised adverse events, the functionality of the BAP, the surgery procedure, the biological materials used, the transplant location, and the intrusiveness associated with follow-up care. Finally, procedural considerations included equitable access, patient prioritization, and trust and control. Incorporating insights from this study into the clinical development and implementation of the BAP is crucial to ensure alignment of the product and procedures with the needs and expectations of people with T1D.

An injectable and retrievable bioartificial pancreas fabricated by time-sequentially assembling islets-laden microgels for minimally invasive treatment of type 1 diabetes

Islets transplantation is a promising method to treat type 1 diabetes. Unfortunately, current islet encapsulation and transplantation strategies are difficult to simultaneously achieve the minimally invasive transplantation, rapid mass transportation, accurate positioning, long-term stability and easy retrieval. Herein, we present a novel strategy for islet encapsulation and transplantation that integrates the advantages of microencapsulation and macroencapsulation. Specifically, islets are first encapsulated in methacrylated carboxymethyl chitosan (CMCSMA) microgels by droplet microfluidic technology, and then oxidized sodium alginate-succinimide ester (OSA-NHS) as the assembling agent is added to time-sequentially assemble the islets-laden microgels. The as-formed microgel assembly (MA-CHO/NHS), or namely bioartificial pancreas, is injectable before transplantation due to the quick formation of dynamic Schiff base bonds, and becomes quite stable after transplantation with the slow formation of stable amide bonds. In addition, the interconnected micropores inside the microgel assembly is beneficial for mass transportation, and the abundant aldehyde and succinimide ester groups on assembling agent ensures good tissue adhesion. This injectable, tissue-adhesive, microporous, positionable and retrievable bioartificial pancreas can reverse the blood glucose levels of diabetic mice from hyperglycemia to normoglycemia for at least 90 days, and thus shows a broad application prospect in the field of diabetes treatment.

Bio Artificial Pancreas - Encapsulation of Human Pancreatic Islet Cells Using Calcium Alginate Micro Beads for the Use in the Clinical Therapy

Bio Artificial Pancreas - Encapsulation of Human Pancreatic Islet Cells Using Calcium Alginate Micro Beads for the Use in the Clinical Therapy

Functional efficiency of pancreatic cell-engineered construct in an animal experimental model for type I diabetes

The creation of a cell-engineered pancreatic construct (CEPC) from islets of Langerhans and biocompatible matrix carrier (framework/scaffold), which imitates the native microenvironment of pancreatic tissue, is an approach to the treatment of type I diabetes mellitus (T1D).The objective of this work is to conduct a comparative analysis of the functional efficacy of CEPC and isolated rat islets of Langerhans after intraperitoneal administration into rats with experimental T1D.Materials and method. T1D was induced in rats by injecting low-dose (15 mg/ kg) streptozotocin (STZ) for 5 days. CEPC samples were created using viable and functional allogeneic isolated islets of Langerhans and tissue-specific scaffold obtained by decellularization of human pancreatic fragments. The rats received intraperitoneal injection of allogeneic islets of Langerhans (experimental group 1, n = 4) and CEPC (experimental group 2, n = 4). Control group rats received no treatment (n = 4). Blood glucose levels in the rats were measured, and the pancreas and kidneys of the experimental animals were examined histologically. The follow-up period for all animals continued for 10 weeks. Results. In experimental group 1, on day 7 after injection of Langerhans islets, glycemia decreased significantly from 28.2 ± 4.2 mmol/L to 13.4 ± 2.6 mmol/L. This fall persisted for 7 weeks, following which blood sugar increased to nearly their initial levels (prior to islets administration). In experimental group 2, on day 7 after CEPC administration, there was a more noticeable drop in blood sugar levels from 25.8 ± 5.1 mmol/L to 6.3 ± 2.7 mmol/L compared to experimental group 1. By the 10th week of the experiment, the average glucose level was two times lower than it was at the beginning. Blood glucose levels dropped more sharply in the CEPC group than in the islet group (by 75.6% and 52.5%, respectively).Conclusion. In T1D rats, CEPC has a more potent antidiabetic effect than islets of Langerhans. Thus, it has been shown that a tissue-specific scaffold may be used to create bioartificial pancreas in order to increase the functional efficiency of islets.

Which detergent is most suitable for the generation of an acellular pancreas bioscaffold?

Pancreatic bioengineering is a potential therapeutic alternative for type 1 diabetes (T1D) in which the pancreas is decellularized, generating an acellular extracellular matrix (ECM) scaffold, which may be reconstituted by recellularization with several cell types to generate a bioartificial pancreas. No consensus for an ideal pancreatic decellularization protocol exists. Therefore, we aimed to determine the best-suited detergent by comparing sodium dodecyl sulfate (SDS), sodium deoxycholate (SDC), and Triton X-100 at different concentrations. Murine (n=12) and human pancreatic tissue from adult brain-dead donors (n=06) was harvested in accordance with Institutional Ethical Committee of the University of São Paulo Medical School (CEP-FMUSP) and decellularized under different detergent conditions. DNA content, histological analysis, and transmission and scanning electron microscopy were assessed. The most adequate condition for pancreatic decellularization was found to be 4% SDC, displaying: a) effective cell removal; b) maintenance of extracellular matrix architecture; c) proteoglycans, glycosaminoglycans (GAGs), and collagen fibers preservation. This protocol was extrapolated and successfully applied to human pancreas decellularization. The acellular ECM scaffold generated was recelullarized using human pancreatic islets primary clusters. 3D clusters were generated using 0.5×104 cells and then placed on top of acellular pancreatic slices (25 and 50 μm thickness). These clusters tended to connect to the acellular matrix, with visible cells located in the periphery of the clusters interacting with the ECM network of the bioscaffold slices and continued to produce insulin. This study provided evidence on how to improve and accelerate the pancreas decellularization process, while maintaining its architecture and extracellular structure, aiming at pancreatic bioengineering.

Recent advances in the development of bioartificial pancreas using 3D bioprinting for the treatment of type 1 diabetes: a review

Type 1 diabetes is a chronic condition that results from the destruction of insulin-producing β-cells in the pancreas. Current treatments for type 1 diabetes, such as insulin therapy and pancreatic islet transplantation, have several limitations and, hence not quite effective in the long run. As current therapy methods fail to slow disease development, novel strategies such as the development of a bioartificial pancreas are being seriously considered. Over the last decade, research has focused on tissue engineering, which aids in the design of biological alternatives for the repair and replacement of non-functional or damaged organs. Three dimensional (3D) bioprinting technology which employs 3D printing technology to generate 3D tissue-like structures from biomaterials and cells, offers a promising solution for the treatment of type 1 diabetes by providing the ability to generate functional endocrine pancreatic tissue. Bioprinted structures are therefore an important aspect of tissue engineering because they have been found to replicate the native extracellular matrix, promoting cell survival and proliferation. In this review, recent developments in 3D bioprinting of endocrine pancreas for the treatment of type 1 diabetes particularly focussing on the choice of cells, biomaterials, growth factors, and essential considerations have been discussed in detail. Additionally, the key challenges and perspectives towards recapitulation of the pancreatic function of the pancreatic organ engineering technologies have also been discussed.

Regulatory Challenges at the Intersection of Cellular and Medical Device Therapies in Europe: The Case of the Bioartificial Pancreas

Regenerative medicine solutions for type 1 diabetes are a rapidly developing field of medical technology. So far, these solutions have been principally cell-based treatments and, at present, in Europe, are regulated under the European Union regulations for Advanced Therapy Medicinal Products (ATMPs). But now, new, emerging technology combining cellular therapy with medical devices is under development. The potential of this novel hybrid model to create a bioartificial pancreas is tantalising. However, incorporating medical devices creates a further layer of complexity to an already challenging product development process. Moreover, it raises important questions about how bioartificial organs should be regulated. This article seeks to expose the complexity of the legal and regulatory landscape relating to such products, focusing on the laws of the European Union and, where appropriate, bringing in examples from other jurisdictions. We set out the role of the European Medicines Agency (EMA) and review the classification of existing ATMPs and those proposed for type 1 diabetes to highlight the potential consequences and effects of nomenclature and classifications. We argue that emerging hybrid regenerative medicine solutions at the intersection of cellular and medical device therapies, in which medical devices are integral to and facilitate the cell therapy mechanism of action, are not satisfactorily accounted for in the existing legal paradigm regulating regenerative medical therapies. We suggest that these functional hybrid products, currently in their infancy, may yet have far-reaching implications for the interface of law, regulation and technology. For example, they are likely to challenge the conventional discourse related to a market in (bioartificial) organs. We recommend that the EMA, national competent authorities for medical devices, national transplantation authorities and those responsible for overseeing translational clinical research respond to this by developing the existing regulatory framework in such a way that captures the essence of these hybrid products as a single entity. Issuing guidance on updated regulations to researchers engaged in this emerging technology will be key to the success of its translation into human therapies.

A Bioartificial Pancreas with "Immune Stealth" and Continuous Oxygen Supply for Islet Transplantation.

Transplantation of microencapsulated islet cells remains a promising strategy for the normalization of glucose metabolism control in type 1 diabetes mellitus. However, vigorous host immunologic rejection, fibrotic overgrowth around the microcapsules, and poor oxygen supply often lead to graft failure. Herein, a bioartificial pancreas is constructed, which incorporates the "stealth effect" based on polyethylene glycol copolymers and the high oxygen-carrying performance of fluorinated nanoparticles. Polycationic poly(l-lysine)-grafted-poly(ethylene glycol) is successfully coated on the surface of alginate microcapsules through electrostatic interaction, which can not only resist fibrinogen adhesion and avoid excessive fibrosis around the microcapsules but also isolate the host immune system from attacking, achieving a "stealth effect" of microencapsulated islet cells. Furthermore, the coloading of fluoride-based O2 nanocarriers gives them enhanced oxygen-carrying and continuous oxygen supply capabilities, thereby effectively prolonging the survival of islet cells. The intracapsular islet cells still display similar cell viability and almost normal insulin secretion function even in long-term culture under hypoxic conditions. Collectively, here a new approach is opened for microencapsulated islets to efficiently evade host immune attack and improve oxygen supply and a promising strategy is provided for islet transplantation in type 1 diabetes mellitus.

105.6: Engineering a vascularized bioartificial pancreas for stem cell derived islet maturation

105.6: Engineering a vascularized bioartificial pancreas for stem cell derived islet maturation

228.6: Vascularizing a human-scale bioartificial pancreas using sacrificial embedded 3D printing into self-healing alginate

228.6: Vascularizing a human-scale bioartificial pancreas using sacrificial embedded 3D printing into self-healing alginate

328.8: A novel endovascular bioartificial pancreas device to treat type 1 diabetes

328.8: A novel endovascular bioartificial pancreas device to treat type 1 diabetes

328.9: Development, optimization, and preclinical evaluation of a bio-artificial pancreas for the treatment of type 1 diabetes (T1D)

328.9: Development, optimization, and preclinical evaluation of a bio-artificial pancreas for the treatment of type 1 diabetes (T1D)

Legal and Regulatory Challenges for Emerging Regenerative Medicine Solutions for Diabetes.

Regenerative medicine solutions for type 1 diabetes are a rapidly developing field of medical technology. To date, these solutions have been principally cell-based treatments and at present, in Europe, these therapies are regulated under European Union regulations for advanced therapy medicinal products. But now, new emerging technology combining cellular therapy with medical devices is under development. The potential of this novel hybrid model to create a bioartificial pancreas to treat type 1 diabetes is tantalizing. However, incorporating medical devices creates a further layer of regulatory complexity. This article seeks to expose the complexity of this legal and regulatory landscape and demonstrate how evolving technology could challenge the entire existing legal paradigm. We start by summarizing the status of the only established cell-based therapy-transplantation. We set out the regulation of cellular therapies, their classification, and the role of statutory bodies. We examine the bottleneck of therapies moving from bench to bedside, and we consider the additional challenges of products, which use a combination of cells and medical devices. Finally, we argue that for the potential of this rapidly growing area of technology to be realized a seismic shift in how we regulate frontier cellular therapies will be required.

Transplantable cell-encapsulation device using a semipermeable ethylene-vinyl alcohol copolymer membrane in a mouse diabetic model

Cell-based therapy is an attractive approach, and encapsulation of therapeutic cells is a promising strategy because it prevents immune responses and allows transplanted cells to be retrieved in case of dysfunction. Bioartificial pancreas, in which insulin-secreting cells are encapsulated in a semipermeable membrane bag, is a new class of medical device for treating type-I diabetes. In this study, we developed a macroencapsulation device in which the pancreatic beta cell line MIN6 was encapsulated in a semipermeable bag made of an ethylene-vinyl alcohol copolymer membrane. Invitro evaluation of ATP and insulin levels revealed that MIN6 cells grown in Matrigelwithin the device secreted insulin in response to glucose levels. Transplantation of the device lowered blood glucose levels for 30 days in diabetic mice. Histological observation revealed that MIN6 cells formed spheroids in Matrigel, and no host cells were detected within the device. Blood levels of inflammatory cytokines in the transplanted mice were similar to those in non-transplanted mice, and antibody levels in the device were lower than those in the intraperitoneal fluid. These results suggest that the semipermeable ethylene-vinyl alcohol copolymer membrane developed in this study is useful for cell encapsulation in cell-based therapies, including beta-cell macroencapsulation for type-1 diabetes.

In vitro oxygen imaging of acellular and cell-loaded beta cell replacement devices

Type 1 diabetes (T1D) is an autoimmune disease that leads to the loss of insulin-producing beta cells. Bioartificial pancreas (BAP) or beta cell replacement strategies have shown promise in curing T1D and providing long-term insulin independence. Hypoxia (low oxygen concentration) that may occur in the BAP devices due to cell oxygen consumption at the early stages after implantation damages the cells, in addition to imposing limitations to device dimensions when translating promising results from rodents to humans. Finding ways to provide cells with sufficient oxygenation remains the major challenge in realizing BAP devices’ full potential. Therefore, in vitro oxygen imaging assessment of BAP devices is crucial for predicting the devices’ in vivo efficiency. Electron paramagnetic resonance oxygen imaging (EPROI, also known as electron MRI or eMRI) is a unique imaging technique that delivers absolute partial pressure of oxygen (pO2) maps and has been used for cancer hypoxia research for decades. However, its applicability for assessing BAP devices has not been explored. EPROI utilizes low magnetic fields in the mT range, static gradients, and the linear relationship between the spin–lattice relaxation rate (R1) of oxygen-sensitive spin probes such as trityl OX071 and pO2 to generate oxygen maps in tissues. With the support of the Juvenile Diabetes Research Foundation (JDRF), an academic-industry partnership consortium, the “Oxygen Measurement Core” was established at O2M to perform oxygen imaging assessment of BAP devices originated from core members’ laboratories. This article aims to establish the protocols and demonstrate a few examples of in vitro oxygen imaging of BAP devices using EPROI. All pO2 measurements were performed using a recently introduced 720 MHz/25 mT preclinical oxygen imager instrument, JIVA-25™. We began by performing pO2 calibration of the biomaterials used in BAPs at 25 mT magnetic field since no such data exist. We compared the EPROI pO2 measurement with a single-point probe for a few selected materials. We also performed trityl OX071 toxicity studies with fibroblasts, as well as insulin-producing cells (beta TC6, MIN6, and human islet cells). Finally, we performed proof-of-concept in vitro pO2 imaging of five BAP devices that varied in size, shape, and biomaterials. We demonstrated that EPROI is compatible with commonly used biomaterials and that trityl OX071 is nontoxic to cells. A comparison of the EPROI with a fluorescent-based point oxygen probe in selected biomaterials showed higher accuracy of EPROI. The imaging of typically heterogenous BAP devices demonstrated the utility of obtaining oxygen maps over single-point measurements. In summary, we present EPROI as a quality control tool for developing efficient cell transplantation devices and artificial tissue grafts. Although the focus of this work is encapsulation systems for diabetes, the techniques developed in this project are easily transferable to other biomaterials, tissue grafts, and cell therapy devices used in the field of tissue engineering and regenerative medicine (TERM). In summary, EPROI is a unique noninvasive tool to experimentally study oxygen distribution in cell transplantation devices and artificial tissues, which can revolutionize the treatment of degenerative diseases like T1D.

Clinical Translation of Bio-Artificial Pancreas Therapies: Ethical, Legal and Psychosocial Interdisciplinary Considerations and Key Recommendations.

The field of regenerative medicine offers potential therapies for Type 1 Diabetes, whereby metabolically active cellular components are combined with synthetic medical devices. These therapies are sometimes referred to as "bioartificial pancreases." For these emerging and rapidly developing therapies to be clinically translated to patients, researchers must overcome not just scientific hurdles, but also navigate complex legal, ethical and psychosocial issues. In this article, we first provide an introductory overview of the key legal, ethical and psychosocial considerations identified in the existing literature and identify areas where research is currently lacking. We then highlight two principal areas of concern in which these discrete disciplines significantly overlap: 1) individual autonomy and 2) access and equality. Using the example of beta-cell provenance, we demonstrate how, by harnessing an interdisciplinary approach we can address these key areas of concern. Moreover, we provide practical recommendations to researchers, clinicians, and policymakers which will help to facilitate the clinical translation of this cutting-edge technology for Type 1 Diabetes patients. Finally, we emphasize the importance of exploring patient perspectives to ensure their responsible and acceptable translation from bench to body.

A novel bioartificial pancreas fabricated via islets microencapsulation in anti-adhesive core-shell microgels and macroencapsulation in a hydrogel scaffold prevascularized in vivo.

Islets transplantation is a promising treatment for type 1 diabetes mellitus. However, severe host immune rejection and poor oxygen/nutrients supply due to the lack of surrounding capillary network often lead to transplantation failure. Herein, a novel bioartificial pancreas is constructed via islets microencapsulation in core-shell microgels and macroencapsulation in a hydrogel scaffold prevascularized in vivo. Specifically, a hydrogel scaffold containing methacrylated gelatin (GelMA), methacrylated heparin (HepMA) and vascular endothelial growth factor (VEGF) is fabricated, which can delivery VEGF in a sustained style and thus induce subcutaneous angiogenesis. In addition, islets-laden core-shell microgels using methacrylated hyaluronic acid (HAMA) as microgel core and poly(ethylene glycol) diacrylate (PEGDA)/carboxybetaine methacrylate (CBMA) as shell layer are prepared, which provide a favorable microenvironment for islets and simultaneously the inhibition of host immune rejection via anti-adhesion of proteins and immunocytes. As a result of the synergistic effect between anti-adhesive core-shell microgels and prevascularized hydrogel scaffold, the bioartificial pancreas can reverse the blood glucose levels of diabetic mice from hyperglycemia to normoglycemia for at least 90 days. We believe this bioartificial pancreas and relevant fabrication method provide a new strategy to treat type 1 diabetes, and also has broad potential applications in other cell therapies.

Intraperitoneal injection of cell-engineered pancreas in rats with experimental type i diabetes (preliminary results)

Creation of a bioartificial pancreas, including a cell-engineered construct (CEC) formed from pancreatic islets (islets of Langerhans) and a biocompatible matrix mimicking the native microenvironment of pancreatic tissue, is one of the approaches to the treatment of type 1 diabetes mellitus (T1D).Objective: to conduct preliminary in vivo studies of the functional efficacy of intraperitoneal injection of a cell-engineered pancreatic endocrine construct and a suspension of rat pancreatic islets in an experimental T1D model.Materials and methods. Tissue-specific scaffold was obtained by decellularization of human pancreatic fragments. The viability and functional activity of rat islets isolated with collagenase were determined. Experimental T1D was modeled by intraperitoneal injection of low-dose streptozotocin and incomplete Freund’s adjuvant into rats. The rats were intraperitoneally injected twice with pancreatic CEC (n = 2) or islet suspension (n = 1). Glucose levels in the blood and urine of the rats were assessed. Histological examination of organs (pancreas and kidneys) of the experimental animals was carried out.Results. After the first injection, blood glucose levels gradually decreased in all animals by more than 47% of the initial values; by follow-up day 24, the glucose level rose to the initial hyperglycemic values. After repeated administration, a 63.4% decrease in glycemic level was observed in the rats with pancreatic CEC and a 47.5% decrease in the one with islet suspension. At week 5 of the experiment, blood glucose levels gradually increased in all animals. At the same time, the glycemic index of the rat with injected pancreatic CEC was 62% lower than the glycemic index of the rat with injected islets.Conclusion. Allogeneic pancreatic islets in pancreatic CEC increase the duration of stable glycemic level in T1D rats.

Challenges and Perspectives for Future Considerations in the Bioengineering of a Bioartificial Pancreas.

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