Encapsulation is the evolution of islet cell transplantation. It is an exciting branch of transplant that could free people with type 1 diabetes from administering insulin for up to years, although it will be some time before the treatment is widely available. In part two of our journey into islet cell transplantatio, we examine the origins of encapsulatio, its research milestones and its prospects for treating diabetes. If you missed part one, catch up here.

Encapsulation offers tremendous potential as a treatment for type 1 diabetes. Benefits include prevention of blood sugar levels climbing too high and falling too low, reduced daily need for daily blood sugar tests and, most saliently, eliminating the need for insulin to be administered.

The procedure has so far only been tested in clinical trials and is therefore currently experimental, but growth has been vast, particularly over the last 20 years.

Encapsulation is particularly exciting because it addresses two major obstacles of islet cell transplantation. Firstly, encapsulation could eliminate or at least significantly decrease the need for immunosuppressant drugs after transplantatio, which carry risks such as increased risk from infection. Secondly, modern encapsulation developments require fewer islet donors, which is important given the limited donor pool.

What is encapsulation?

Encapsulation is pretty much what it says on the tin. Insulin-producing islet cells are held in a protective capsule and transplanted into a patient. The capsule is designed to allow oxygen and nutrients in whilst offering protection from the immune attack of white blood cells, which characterises type 1 diabetes.

These devices are referred to either as encapsulated islets or bio-artificial pancreas, and their aim by design is to enable immune-isolatio, ensuring a steady flow of insulin production.

Trials and errors

It’s unclear just when the concept of encapsulation was theorised, however one of the first reported attempts to transplant encapsulated islet cells occurred in 1977. Gates and Lazarus encapsulated pancreatic rabbit tissue and transplanted it into rodent models of diabetes, with encouraging results. The islets were shown to secrete insulin and glucagon[1].

Three years later, Lim and Sun succeeded in normalising blood sugar levels in diabetic rats for up to three weeks[2]. They micro-encapsulated islets using a gel-like material called alginate, which is found in brown algae and bacterial species. Micro-encapsulation refers to each individual islet cell being coated in the alginate to protect the cell.

Following similar trials, alginate went on to become the quintessential encapsulation material because it is designed to be biologically inert, meaning it doesn’t induce an immune response. Therefore, it theoretically cloaks islet cells invisibly. However, while alginate was well tolerated, studies in the 1990s evidenced that immune cells were breaking through capsules within weeks of transplantatio, killing off islet cells and causing scar tissue[3]. Thus, the mission of scientists was to extend the islets’ longevity, protection and safety.

Patrick Soon-Shiong performed the first encapsulated islet cell transplant on a human.

In 1999, the first encapsulated islet transplantation was performed on a human. The subject, a 38-year-old man with type 1 diabetes, was administered with 10,000 islets. Patrick Soon-Shiong, the researcher who conducted the trial, had developed the islets in an aginate-polylysine material which had improved biocompatibility, mechanical strength and chemical stability. Within 24 hours insulin secretion was detected, and this continued for more than 58 months without any adverse effects[4].

But in spite of its success, alginate has been criticised. Scientists have lamented its inflammatory response and propensity for encouraging abnormal cell growth. Subsequently, several materials have been studied that are similar to alginate, such as polysulphone and sulphate, with mixed success.

Scientists are continually innovating and adapting to utilise gels successfully, but research is now expanding further outside the box (pardon the pun), specifically in reference to the cells and cell lines used in transplantation. And the outcomes have been fascinating.

Bigger and better

In 2014 biotech company ViaCyte introduced us to Encaptra, a macro-encapsulation device. Macro-encapsulation involves applying a protective coating around a collection of numerous cells (rather than individual cells).

Encaptra uses a plastic capsule to contain the islet cells which can be retrieved from the body if needed to assess how well the cells are faring. The technology also takes advantage of the recent availability of human embryonic stem cells, meaning that the treatment does not depend on large numbers of human donor cells because stem cells can be grown in the lab.

The first human transplantation of the device occurred in 2014. ViaCyte’s intention was for the stem cells to mature into insulin-producing cells once implanted into the abdomen, however study author Dr. Melena Bellin revealed the protection afford to the islets seemed to cut off their access to oxygen, limiting their ability to proliferate. Since then a second attempt has been launched in 2017 by the University of Minnesota in which the Encaptra pouches encourage blood flow into the pouch (revascularisation) to improve the survival rate of the cells.

This is a compromise however, as Encaptra currently allows the immune system access to attack the islet cells. As a result, immunosuppressive drugs are required, just as they are in regular islet cell transplants.

A young boy testing the Encaptra device (photo: ViaCyte)

The use of stem cells is an exciting problem-solving method, not just as a source replacement for islet donors, but because researchers hope stem cells could reduce the immune response in patients following implantation[5]. At this stage, though, findings remain preliminary and short-term.

Concurrently, another genetically modified cell line is being studied. Melligen cells, which are derived from human liver cells, can be altered to develop into islets and produce insulin on demand. In 2015 Melligen cells were shown to reverse type 1 diabetes in mice, but because these cells would have been destroyed in humans, additional trials have investigated their efficacy when encapsulated.

The result was Cell-in-a-Box. A collaboration by Austrianova and Nuvilex, Cell-in-a-Box is similar to Encaptra in that it encapsulates the Melligen cells in a protective, semi-permeable device, while small pores allow for nutrients to enter. In 2016, Cell-in-a-Box received a US patent for the combination, with University of Technology Sydney (UTS) scientists optimistic that because the device could remain in the body for up to two years without damage, it could produce a “long-term solution” for type 1 diabetes.

Who are the other key players?

Worldwide, research teams are striving to make available encapsulation safe and effective enough to be available to everyone with type 1 diabetes. Tackling obstacles is as important as driving innovatio, and a range of recent studies have yielded enthralling progress.

By way of widening donor access, British company Islexa was formed in 2016, a company which manufactures lab-grown islets using technology which reprograms donated pancreatic tissue into fully functional islets.

Concerning cell longevity, Betalin Therapeutics’s engineered micro-pancreas (EMP) was shown in 2015 to help prevent transplanted islet cells from failing. A biological scaffold, EMP encourages transplanted islet cells to connect to the body, enabling long-term insulin production, although immunosuppressant drugs are still required.

Taking a different approach, US facility City of Hope has developed a technique for predicting how cells will fare in patients, therefore gauging success rates.

Cornell University has created a doughnut-shaped vortex ring which reduces the distance nutrients need to travel to reach islet cells, improving their long-term health. The research team went on to attach encapsulated islets along a polymer thread allowing the islets to be inserted and removed much more easily compared with larger pouches. This development could reduce the need to have immunosuppressant drugs.

In a bid to omit immunosuppressant drugs, American biotechnology firm SymbioCellTech (SCT) has combined mesenchymal stem cells with pancreatic islet cells to create neo-islets. These neo-islets reportedly provide “durable blood sugar control” without the need for drugs, but long-term results from human clinical trials are currently absent.

As demonstrated by this two-part journey, islet cell transplantation is a complex but ultimately exciting method of treating type 1 diabetes. Developments are ubiquitous, and scientists’ ambitions are lofty. But progress, for now, remains distant in terms of permanently replacing insulin injections. Clinical trials are underway on a plenitude of fronts, and each set of results will be pivotal in writing islet cell transplantation’s history within diabetes. It promises to be a fascinating ride.

[1] https://www.ncbi.nlm.nih.gov/pubmed/73954

[2] https://www.ncbi.nlm.nih.gov/pubmed/6776628

[3] https://www.nature.com/articles/540S60a

[4] https://www.ncbi.nlm.nih.gov/pubmed/10837701

[5] https://www.fasebj.org/doi/10.1096/fj.09-131888

[6] https://www.ncbi.nlm.nih.gov/pubmed/17426276


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