Objective
Our specific aim using the scaffold seeded with encapsulated islets and nutrients derived from donor human
pancreas is to examine its ability to normalise blood glucose levels of diabetic immunodeficient rats comparing this with the effect of implanting:
a. encapsulated islets alone (no nutrients); and
b. the seeded device without nutrients
Background Rationale
Previously we have demonstrated the benefit of using pancreatic nutrients to promote the function of encapsulated
non-enriched stem cell derived human islets implanted in diabetic mice. To make this more relevant to possible
human use, we now need to confirm the same is true in a larger animal model, namely the rat.
Description of Project
The holy grail of treating patients with type 1 diabetes (T1D) is to replace the pancreatic ß cells that have been
destroyed as part of an autoimmune process, and without administering anti-rejection drugs to the recipients. The
need to administer such toxic drugs limits potential recipients to those with unrecognized hypoglycaemic events
and in whom an insulin delivery system placed beneath the skin combined with continuous glucose monitoring
does not provide a practical outcome. One means of delivering replacement ß cells without anti-rejection drugs is to
place the insulin-producing cells in microcapsules inside a scaffold and implant these.
The microcapsules provide some degree of protection from the immune system of the host. They have pores which
are large enough to allow entry of oxygen and removal of waste products, but small enough to block entry of
immune cells.
Scaffolds are being used to deliver the microcapsules so that the implant is a device that can readily be removed
from human recipients if necessary. Moreover, scaffolds promote ingrowth of blood vessels to the grafted cells,
thereby providing oxygen to the cells and allowing insulin to egress from them.
A difficulty in using scaffolds is that the encapsulated insulin-producing cells in them do not function as efficiently
as when there is no supportive scaffold. This is a stumbling block that needs to be overcome. A means of achieving
this is to add appropriate nutrients to the scaffold which will make the cells in it comfortable so that they function
efficiently. Preliminary experiments we have carried out recently with human stem cell differentiated insulin producing
cells have shown the nutrients needed to achieve this are found in the human pancreas.
When these nutrients are isolated from donor human pancreases and added to encapsulated insulin-producing cells
seeded into a scaffold, the cells produce insulin as efficiently as from encapsulated insulin-producing cells alone.
We have confirmed this outcome in two separate experiments with diabetic mice in which the cells/scaffold are
implanted. And this was regardless of whether the scaffold was implanted in the abdomen or more superficially
under the skin.
If these nutrients are not added to the encapsulated cells in the scaffold, the cells produce less insulin and have
less effect in lowering the blood glucose levels of the recipient diabetic mice.
We are now moving on and testing out this new strategy in a larger animal model, namely the diabetic nude rat.
Success with our experiments in diabetic rats using nutrients derived from human pancreases will allow progress
to be made towards a clinical trial in patients with T1D using human stem cells in a scaffold.
Anticipated Outcome
We anticipate that:
1. Blood glucose levels will be normalised in diabetic rats implanted with our complete bioengineered device containing stem cell differentiated islets and pancreatic nutrients, as efficiently as in the absence of the device.
2. The outcome described in item 1 will be achieved regardless of whether the device is implanted in the abdomen or beneath the skin.
3. Production of human insulin will be higher in the rats receiving the device containing pancreatic nutrients than those implanted with the device receiving the device without the pancreatic nutrients.
4. At the end of the experiment, the host reaction to the device will be less in the group containing pancreatic nutrients than that in the group without pancreatic nutrients.
These data together with our previous data obtained in diabetic mice will form the basis for initiating a First In Human study in diabetic humans using stem cell differentiated islets.
Relevance to T1D
The proposed experiments provide the necessary details to improve the chance of success of implanting stem cell
derived islets into patients with T1D, thereby overcoming the need for patients to administer insulin. The model we
are using is one that will not require recipients to take toxic anti-rejection drugs. It consists of human islets placed
in microcapsules which are seeded into a scaffold containing pancreatic nutrients before being implanted into
patients with T1D.
Our goal is to allow all 8 million people with T1D around the world to cease administering insulin daily, but having
normal blood sugar levels.