<p>Multifunctional Islet Transplantation Hydrogel Encapsulating A20 High-Expressing Islets</p>

Abstract

Islet transplantation is regarded as the most promising treatment for type 1 diabetes (T1D). However, the function of grafted islet could be damaged on account of transplant rejection and/or hypoxia several years later after transplantation. We proposed a hypothetical functionalized hydrogel model, which encapsulates sufficient A20 highexpressing islets and supporting cells, and performs as a drug release system releasing immunosuppressants and growth factors, to improve the outcome of pancreatic islet transplantation. Once injected in vivo, the hydrogel can gel and offer a robust mechanical structure for the A20 high-expressing islets and supporting cells. The natural biomaterials (eg, heparin) added into the hydrogel provide adhesive sites for islets to promote islets' survival. Furthermore, the hydrogel encapsulates various supporting cells, which can facilitate the vascularization and/or prevent the immune system attacking the islet graft. Based on the previous studies that generally applied one or two combined strategies to protect the function of islet graft, we designed this hypothetical multifunctional encapsulation hydrogel model with various functions. We hypothesized that the islet graft could survive and maintain its function for a longer time in vivo compared with naked islets. This hypothetical model has a limitation in terms of clinical application. Future development work will focus on verifying the function and safety of this hypothetical islet transplantation hydrogel model in vitro and in vivo.

Immune-Protective Formulations and Process Strategies for Improved Survival and Function of Transplanted Islets

“…In healthy tissues in the physiological state, ROS could be neutralized by effective intracellular antioxidant systems. However, islets usually possess a weak antioxidant defense system and hold poor capacity to scavenge ROS and other free radicals, making them particularly susceptible to hypoxia and following oxidative stress ( 25 ). During the isolation procedure, enzymatic and mechanical digestion could both harm the delicate pancreatic islets.…”

“…Ubiquitin-editing protein A20 functions as a negative regulator of immunostimulatory factors (38). It is essential for controlling signals, including the activation of nuclear factor-kB transcription factors, which might be an ideal gene therapy candidate for islet transplantation (25). Chu et al demonstrate that loss of A20 in B cells can cause an inflammatory syndrome with autoimmune manifestations in old mice (39).…”

Overcoming the Limitations of Stem Cell-Derived Beta Cells

“…The function of such capsules is not only to protect cells from immune system response, but also to allow nutrients and oxygen to be transferred inside as well as insulin and other by-products to be released [ 108 ]. It is possible to develop hydrogel models that could encapsulate islets and supporting cells such as endothelial cells or MCSs, as well as ECM and growth factors [ 109 ]. Hydrogels are permeable for blood vessels, so cells will be able to access blood oxygen.…”

“…Hydrogels are permeable for blood vessels, so cells will be able to access blood oxygen. A major drawback is the high probability of a blood-mediated inflammatory reaction, which will ultimately result in graft cell death [ 109 ]. There are some ways to avoid that: for example, by incorporating anti-inflammatory peptides in hydrogel capsules [ 110 ].…”

An Overview of Engineered Hydrogel-Based Biomaterials for Improved β-Cell Survival and Insulin Secretion

“…PEG-based synthetic hydrogels are regarded as one of the most promising carriers in cell delivery applications. This is due to their intrinsic low protein adsorption, immunoprotective properties, minimal inflammatory invasion, and exceptional biocompatibility ( Bai et al, 2020 ). In a study, Knobeloch et al have developed an injectable PEG hydrogel that supports the survival of islet cells in vitro and in vivo ( Knobeloch et al, 2017 ).…”