Experts comment on STM Ma Minglin's team to develop a new artificial pancreas for the delivery of islet cells and the treatment of type 1 diabetes

Expert comment | Deng Hongkui (Peking University) Editor | Enzymic Type I Diabetes is an autoimmune disease.
The patient's own immune cells attack the insulin-secreting β cells in the pancreatic islets, resulting in insufficient insulin secretion and uncontrollable blood sugar.

Clinically, tens of thousands of islets are separated from 2-3 donors and injected into the body through the hepatic portal vein.
The patient can maintain blood glucose steady state for 3-5 years and get rid of exogenous insulin injection.

However, immediate blood-mediated inflammation, side effects of immunosuppressive agents, and shortage of donor pancreatic islet cells have prevented this treatment from being widely used in clinical practice.

In recent years, a steady stream of islet cells can be obtained through stem cell differentiation technology, which fundamentally solves the problem of insufficient donors, which has great potential for application.

However, how to get rid of the use of immunosuppressive agents and the tumorigenesis of undifferentiated stem cells still need to be resolved.

Cell encapsulation technology is to load exogenous cells in devices and materials with immune isolation barriers, usually semipermeable membranes with a certain pore size, allowing small molecules such as oxygen and glucose to enter and exit freely, while preventing exogenous cells from being Host immune cells attack, eliminating the need for immunosuppressive agents.

Immune isolation devices are mainly divided into micro-encapsulated and large-encapsulated devices.

The most researched microencapsulation devices are hydrogels.
However, hydrogels are usually weak in mechanical properties, and the transplant body is easily destroyed by external forces, and the immune protection effect will be invalid.

Large cysts generally have better mechanical properties than micro encapsulations.
However, large cysts have a larger unit volume and a smaller specific surface area than micro encapsulations, resulting in the exchange of nutrients and metabolic waste in the device compared to micro encapsulations.
The capsule is poor, so the large-encapsulated device has higher requirements for the biocompatibility of the material, otherwise the fibrous layer caused by the foreign body reaction will affect the survival state and physiological function of the cells or tissues in the device.

At present, a number of immune isolation devices have made some progress in clinical trials, but none of them can balance safety and functionality at the same time.

On June 2, the team of Professor Minglin Ma from Cornell University published a research paper titled A nanofibrous encapsulation device for safe delivery of insulin-producing cells to treat type 1 diabetes in Science Translational Medicine.

The research designed and developed a safe and functional immune isolation device for the delivery of pancreatic islet cells (including pancreatic islet cells derived from human stem cells), achieving long-term protection of pancreatic islet cells and maintaining pancreatic islets in experimental mice.
Cell function and survival, and control the homeostasis of blood sugar.

Specifically, the design of the device considers the following aspects: 1) Strong mechanical properties to ensure long-term stability and safety of the device in the body; 2) Tubular structure to achieve high specific surface area and facilitate minimally invasive surgery transplantation and retrieval 3) Good biocompatibility to avoid fibrosis; 4) Precisely controlled pore size ensures that immune cells are isolated without affecting material transmission; 5) Simple design is convenient for possible mass production and clinical applications in the future.

The surface of the device is a nanofiber membrane, and the core is sodium alginate hydrogel (as shown in Figure 1).
The pore size of the nanofiber membrane is about 1 micron, which can effectively prevent host immune cells from entering the device, and at the same time prevent the delivered foreign cells from escaping to In the host body, safety is guaranteed; and the porous structure of the nanofiber membrane can ensure the exchange of substances (such as oxygen, glucose, insulin, etc.
), which is conducive to cell survival and the perception and regulation of blood sugar changes.

The advantage of sodium alginate hydrogel is that it is easy to gel, and it can disperse the islets so that it is not easy to agglomerate and cause hypoxic necrosis.
At the same time, it can isolate larger proteins such as antibodies, which has a certain immune protection effect.
.

Figure 1.
Schematic diagram and device diagram of the nanofiber membrane immune isolation device.
The researchers first tested the biocompatibility of the device in mice.

In the three clinical transplantation sites (subcutaneous, abdominal omentum, and abdominal cavity), they found that the abdominal cavity caused the smallest immune response, and there was no tissue stickiness, which was convenient for the removal of the device.

Therefore, in subsequent experiments, the researchers transplanted the device into the abdominal cavity of mice for research.

Furthermore, they used luciferase to bioluminescence in mice to track the survival of cells.
They found that the device could protect pancreatic islets and the cancer cell line 4T1 to survive in the allogeneic environment for up to 150 days, but the cells that were not protected by the device were in the allogeneic environment.
It will be rejected by the host in just 14 days.

Then the researchers used a series of pancreatic islet cells from different sources, including allogeneic mouse pancreatic islets, allogeneic mouse pancreatic islets, xenogeneic rat pancreatic islets, and human pancreatic islets to achieve long-term islet cells in the mouse diabetes model.
The protection and effective control of blood glucose homeostasis (up to 200 days) proves the safety and functionality of the device.

However, the most valuable clinical application is the islet cells derived from human stem cells (stem cell-derived β cells, SC-β cells).

In immunodeficient diabetic mice, using the device to deliver human stem cell-derived islet cells can reverse diabetes in mice and control blood sugar for up to 120 days.
These wrapped islet cells can respond to changes in blood sugar in the body and secrete insulin.
Take the device out Later, tissue sections showed that pancreatic islet cells survived well in the device, expressing β-cell markers such as insulin, C-peptide and transcription factor NKX6.
1 (Figure 2).

Furthermore, the researchers used the device to deliver human stem cell-derived pancreatic islet cells in a diabetic mouse model with sound immune function to restore normal blood sugar, further proving the device's immune isolation effect and function.

Figure 2.
Pancreatic islet cells derived from human stem cells survive for 120 days in the device and express pancreatic islet cell-specific markers.

In order to prove the feasibility of the clinical application of the device, the team expanded the size of the device and used laparoscopic minimally invasive technology to deliver the device loaded with human stem cell-derived islet cells into the abdominal cavity of the experimental dog.
Two weeks later, the laparoscopic energy was used again.
The device was successfully taken out completely, and there was almost no tissue stickiness.

At the same time, it can be observed that there are still insulin-expressing pancreatic islet cells in the device, which proves the clinical application potential of this technology.

Figure 3.
The application of a device containing human stem cell-derived islet cells in a large animal model.

(A) Laparoscopy is used to transplant the device into a large animal, (B) Laparoscopy is used to retrieve the device from a large animal.

Professor Ma Minglin of Cornell University and Professor Jeffrey Millman of Washington University are the co-corresponding authors of the paper.
Ma Minglin’s team has long-term research and development of immune isolation devices with safe, functional, and biocompatible interfaces.
Jeffrey Millman’s team differentiated and provided them.
Pancreatic islet cells derived from stem cells, the first author is Cornell University doctoral student Wang Qian, and based on this research applied for two US and world patent protection.

Original link: https://stm.
sciencemag.
org/lookup/doi/10.
1126/scitranslmed.
abb4601 Expert comment Prof.
Hongkui Deng (Boya Chair Professor of Peking University, Director of Peking University Stem Cell Research Center) Cell therapy as a strategy for the treatment of diabetes The transplantation of islet cells, especially the islet cells derived from stem cells (SC-β), is expected to allow patients to get rid of the injection of exogenous insulin.

Although SC-β can be obtained in large quantities in theory, it is often incompletely mature cells.
At the same time, SC-β without purification may be at risk of developing teratomas after transplantation into the body.

How to efficiently deliver and transplant these cells in the body, maintain cell viability and function, overcome the body's rejection and autoimmune response, and be able to smoothly remove cells to ensure safety in an emergency is still a challenge.

In a recent work published in Science Translational Medicine, Wang Qian and her colleagues reported a nanofiber device (NICE) with a diameter of millimeters: NICE is soft but has good mechanical properties and can be used in animals.
It maintains the stability and integrity of the device, prevents cell leakage while also preventing the invasion of recipient immune cells.

The NICE device has good biocompatibility in the body, especially in the abdominal cavity, which causes a small foreign body reaction and fibrosis reaction, and ensures the smooth material exchange, which is the maturation and long-term maintenance of SC-β in the body.
The function provides protection, and less tissue adhesion also creates conditions for later removal.

In addition to a layer of nanofiber coat, the inner core based on sodium alginate hydrogel can also disperse SC-β evenly, reduce hypoxic necrosis caused by accumulation and provide a certain degree of immune isolation.

In short, the work of Wang Qian and others has promoted the encapsulation and transplantation of SC-β to a new level.

We still have to see that the existing SC-β and NICE devices are not perfect.
Facing the future, there are still many areas that need to be improved: (1) How to develop mature and functional in vitro closer to adult human islet cells (adult human islet) The SC-β.

(2) SC-β only occupies a part of the current final products of islet differentiation, and it is necessary to increase the proportion of SC-β or develop a plan to separate and purify SC-β.

(3) The immunogenicity of SC-β restricts the direct transplantation of cells, and also affects the design and manufacture of packaging devices.
How to reduce the immunogenicity of SC-β through gene editing and other methods to produce "universal" SC-β , Is of great significance for reducing the cost of treatment.

(4) There is a huge gap between the success of mouse models and the success of human clinical experiments.
The difference in cell equivalents also poses more challenges to the processing and manufacturing of the device.

Although it is theoretically possible to increase the cell load by extending the length of the NICE device, in fact, more optimization and research are needed.

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