NIH animal study shows dissolvable microneedles trigger body’s own insulin response
For millions of people with type 2 diabetes, ongoing vigilance over the amount of sugar, or glucose, in their blood is the key to health. A finger prick before mealtimes and maybe an insulin injection is an uncomfortable but necessary routine.
“This experimental approach could be a way to take advantage of the fact that persons with type 2 diabetes can still produce some insulin,” said Richard Leapman, Ph.D., NIBIB scientific director. “A weekly microneedle patch application would also be less complicated and painful than routines that require frequent blood testing.”
Global incidence of all types of diabetes is about 285 million people, of which 90 percent have type 2 diabetes. Many require insulin therapy that is usually given by injection just under the skin in amounts that are calculated according to the deficit in naturally generated insulin in the blood. Insulin therapy is not managed well in half of all cases.
NIBIB researchers led by Xiaoyuan (Shawn) Chen, senior investigator in the Laboratory of Molecular Imaging and Nanomedicine, are working on an alternate therapy approach to regulate blood sugar levels in type 2 diabetes using a painless skin patch. In a Nov. 24, 2017, study published online in Nature Communications, the team applied the treatment to mice to demonstrate its potential effectiveness.
The base of the experimental patch is material called alginate, a gum-like natural substance extracted from brown algae. It is mixed with therapeutic agents and poured into a microneedle form to make the patch. “Alginate is a pliable material—it is soft, but not too soft,” Chen said. “It has to be able to poke the dermis, and while not a commonly used material for needles, it seems to work pretty well in this case.”
Chen’s team infused the alginate with a formula of biochemical particles that stimulates the body’s own insulin production when needed and curtails that stimulation when normal blood sugar concentration is reached. The responsive delivery system of the patch can meet the body’s need for days instead of being used up all at once.
“Diabetes is a very serious disease and affects a lot of people,” Chen said, explaining that his group is part of a crowded field of drug research and developers with competing ideas. “Everybody is looking for a long-acting formula.”
Chen’s formula puts two drug compounds—exendin-4 and glucose oxidase—into one patch. The two compounds react with the blood chemistry to trigger insulin secretion. Each is matched with a phosphate mineral particle, which stabilizes the compound until it is needed. Acidity that occurs when sugar concentrations rise weakens the bond with the drug being held by one, but not the other mineral.
Exendin-4 is similar in genetic makeup to a molecule the body produces and secretes in the intestine in response to food intake. Though it is somewhat weaker than the naturally occurring molecule, the team chose exendin-4 for its application because exendin-4 does not degrade in the bloodstream for an hour or more, so can have long-lasting effect after being released. However, it can induce nausea when too much is absorbed. To control how quickly it is absorbed, the researchers combined exendin-4 with mineral particles of calcium phosphate, which stabilize it until another chemical reaction occurs. That chemical reaction is caused by the second drug compound in the patch—glucose oxidase— that is held in its mineral buffer of copper phosphate.
Chen explained that when blood sugar is elevated beyond a precise point, it triggers a reaction with copper phosphate and glucose oxidase to produce slight acidity, which causes calcium phosphate to release some exendin-4. Rising glucose levels trigger the release of exendin-4; but exendin-4 then gets insulin flowing to reduce the glucose level, which slows down and stops release of exendin-4. “That’s why we call it responsive, or smart, release,” said Chen. “Most current approaches involve constant release. Our approach creates a wave of fast release when needed and then slows or even stops the release when the glucose level is stable.”
The researchers demonstrated that a patch about half an inch square contained sufficient drug to control blood sugar levels in mice for a week. For the approach to advance as an application that people with type-2 diabetes can use, the team will need to perform tests to treat larger animals with a patch that contains proportionately more therapeutic compound. In addition to its size, the patch would need to be altered for application on human skin, likely requiring longer needles.
“We would need to scale up the size of the patch and optimize the length, shape, and morphology of the needles,” Chen said. “Also, the patch needs to be compatible with daily life, for instance allowing for showering or sweating.”
Chen is encouraged by the success of his experiments, and by research reports of steady progress by other experimental microneedle patch developers. For instance, others have completed early human studies with microneedle patch devices that contain insulin and that would benefit people with type 1 as well as type 2 diabetes. He hopes there will be lessons from development of those devices that can be applied to the microneedle patch that his team tested in this study.
Microneedle-array patches loaded with dual mineralized protein/peptide particles for type 2diabetes therapy. Chen W, Tian R, Xu C, Yung BC, Wang G, Liu Y, Ni Q, Zhang F, Zhou Z, Wang J, Niu G, Ma Y, Fu L, Chen X. Nat Commun. 2017 Nov 24.