Sci Adv | Ma Minglin's team develops a reverse breathing bioartificial pancreas device for the treatment of type 1 diabetes

Responsible Editor | Enzyme Beauty Cell Therapy can achieve regeneration, repair or replacement of damaged cells by injecting or transplanting cells with specific functions into the patient's body.
It presents a good therapeutic prospect in blood diseases, liver diseases, and type 1 diabetes.

Taking type 1 diabetes as an example, clinically, after injecting exogenous pancreatic islet cells into the body through the hepatic portal vein, the patient can get rid of the dependence on exogenous insulin and maintain blood glucose homeostasis, but it is necessary to take anti-immune rejection drugs for a long time after the operation.

Cell encapsulation technology can first place exogenous islet cells or stem cell-differentiated islet cells into an encapsulation device with an immune isolation barrier and then implant them in the body.
It is expected to achieve a once-and-for-all therapeutic effect without the use of later immunosuppressive agents.

At present, a number of cell encapsulation devices have made certain progress in clinical trials, but none of them can achieve the long-term survival rate of the encapsulated cells and the high-efficiency secretion and release of insulin, thus failing to achieve the therapeutic effect.

The reason is that insufficient oxygen supply in cell packaging devices is one of the biggest bottlenecks.

When pancreatic islet cells are in hypoxic environment, their insulin secretion capacity will be greatly reduced, and even cell necrosis will occur.

In order to improve this problem, part of the research is based on peroxide decomposition reaction for oxygen supply in cell encapsulation devices.
However, in the above methods, there are poor control of oxygen release rate, short continuous oxygen supply time, and partial reaction that may be caused by reaction byproducts.
Problems such as pH changes.

In addition, Beta-O2, as one of the most representative companies in the field of cell packaging in clinical trials, can achieve sufficient oxygen by directly injecting oxygen directly into the device on a regular basis (once a day or several days).
Supply, but if the oxygen supplement is not completed on time, the cells in the device will cause irreversible damage and even necrosis due to lack of oxygen.

Recently, the team of Professor Minglin Ma from Cornell University in the United States published an online research paper entitled An inverse-breathing encapsulation system for cell delivery on Science Advances (first author Dr.
Longhai Wang).

The research puts forward a new strategy of self-regulated "reverse breathing", constructs a self-supplying system, and realizes long-term autonomous oxygen supply in cell encapsulation devices to maintain the long-term survival rate and functionality of pancreatic islet cells.

As we all know, plants, algae and certain bacteria can convert carbon dioxide (CO2) and water into organic matter through photosynthesis, and release oxygen (O2); conversely, most living organisms and their cells metabolize organic matter through aerobic respiration , Produce the energy it needs, and release carbon dioxide.

Based on the CO2 response characteristics of alkali metal peroxides (lithium peroxide, Li2O2), this research designed a "photosynthesis"-like "reverse breathing" cell packaging device, which can convert the CO2 waste products produced by cell metabolism into its essential O2 (Figure 1).

In order to verify the feasibility and efficacy of the "reverse breathing" oxygen supply method.

They first prepared a simple cylindrical cell packaging device: the mixture of Li2O2 and fluorocarbon (PFC) was encapsulated in a silicone tube with good gas permeability (no need to worry about the leakage of by-products), in order to ensure normal gas exchange At the same time, it can also isolate liquid water; in addition, due to the hydrophobic nature of PFC, it can also prevent the intrusion of water vapor to avoid the explosion of oxygen caused by the side reaction between Li2O2 and water.

The pancreatic islet cells are dispersed in the sodium alginate hydrogel and covered around the silica gel tube filled with Li2O2.
The hydrogel is ensuring normal material exchange (the input of oxygen and nutrients required by the islets, and the output of secreted insulin).
At the same time, good immune isolation can be achieved.

The effectiveness of the simple device has been confirmed in a mouse model.
The islet cells in the device can survive for about 1 month after being transplanted into the subcutaneous tissue with low oxygen partial pressure.

Figure 1.
Schematic diagram of "reverse breathing" cell packaging device.

In order to further improve the continuous oxygen supply time of the "reverse breathing" device, they combined the results of in vivo experiments and used computer simulation (COMSOL) and electronic paramagnetic resonance (EPR) imaging technology to gradually optimize the cell packaging device design (Figure 2).

Finally, the resulting device cleverly combines (1) Li2O2 oxygen generator with high oxygen generation capacity, (2) PFC dispersion matrix with high oxygen dissolving capacity, (3) Polydimethylsiloxane isolation membrane with high oxygen permeability, (4) Oxygen-rich components such as gas-phase oxygen delivery with high diffusion rate.

Its therapeutic effect has been verified in diabetic mice, achieving stable blood glucose control for more than 3 months.

In addition, the amplified cell encapsulation device was implanted under the skin of a large animal (mouse pancreatic islets to pig recipient, xenotransplantation).
After 2 months, most of the pancreatic islets removed from the device still had good cell viability and function.

Finally, this work also provides a variety of structural designs of the device cell packaging module to expand its cell loading capacity, and the reperfusion or alternative design of the device oxygen generating module to extend its oxygen supply time.

Figure 2.
(a) Schematic diagram of the preparation of the first-generation "reverse breathing" device (iBEDv1), (b) computer simulation of oxygen distribution in different devices for design optimization of cell packaging devices, (c) a glimpse of the results of animal experiments.

In summary, the research work proposed a new type of "reverse breathing" oxygen supply method, and constructed a series of oxygen supply systems with a controllable rate of oxygen generation, self-sufficiency, safe and long-lasting oxygen supply, which can encapsulate cells and deliver cells.
Provide a good oxygen-rich environment and guarantee its cell therapy effect.

Original link: https://advances.
sciencemag.
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