With a near-constant parade of pills and jabs, taking medications can be physically and mentally taxing for people with complex illnesses. It can be easy to miss a dose or take it incorrectly, especially while battling side effects, stressors, and all-around exhaustion. On top of all the other pressures of being ill, adhering to doctor’s orders can feel like an impossible task.

It is unsurprising, then, that many people do not stick to medication plans. Researchers estimate that as many as 50 percent of people with chronic illnesses, for example, do not properly consume their medication (1). However, as the former U.S. Surgeon General Everett Koop said, “Drugs don't work in patients who don't take them.” Straying from a prescribed drug can have dire consequences, including hospitalization, increased healthcare costs, and even death.

“With chronic disorders, there has always been this interest in reducing the burden for patients to improve compliance,” said Eric Appel, a materials scientist at Stanford University. “Even something as simple as taking a pill every day is really burdensome for many reasons.”

The solution may not lie in a smaller pill or a less painful needle. Rather, some scientists are turning to a surprisingly squishy and wet material: hydrogels. These Jell-O-like substances can be designed to hold and release a molecular cargo under specific conditions, making them promising vehicles for drug delivery. With the help of hydrogels, researchers hope to make diabetes and cancer treatments as well as vaccines and other biologics more compatible with patients’ needs — but first, they need to address the challenges that come with them.

“If you can use hydrogels to reduce the burden of therapy for people, you're going to make more effective therapeutics,” said Michael Webber, a chemical and biomolecular engineer at the University of Notre Dame.

Water, water everywhere

While not always obvious, hydrogels are everywhere. Think of soft contact lenses, glue, or even the inside of an aloe leaf. These are all examples of hydrogels, but they have starkly different shapes, stickiness, and other properties.

There’s no single definition of a hydrogel, but it typically describes a three-dimensional molecular network with water filling the gaps. Water can make up as much as 90 percent of the material, giving it fluidity and a gelatinous appearance. However, other molecules or cells can also be inserted into these spaces and tethered to the scaffold. When this happens, the hydrogel serves as a cushioned vehicle for this cargo. While the cargo can bounce around within its enclosure, its ability to leave is limited by the size of the spaces between the scaffold, which can be thought of as pores. As the hydrogel degrades, its pores become larger, and the cargo moves out of it more freely.

The hydrogel scaffold is also customizable. It is composed of a repeating molecular building block. Changing the chemical qualities of these blocks — for example, their weight, the way they are linked together, or the sizes of the pores between blocks — can imbue the material with different physical qualities, such as stiffness or degradation speed. 

This allows engineers to design a diverse array of hydrogels for different drug delivery tasks. One way to deliver hydrogels to patients is via a subcutaneous injection under the skin where it can release the molecules it contains. But doing so requires tweaking the physical properties of the gel to make sure that it is fluid enough to be sucked into a needle and pushed back out. Rather than having a stiff scaffold, injectable hydrogels are made with a dynamic scaffold where the bonds between molecules can be broken and reformed. “This way, they can be pushed through a syringe, and then they can self-heal once they're in the body,” Webber said.

Some hydrogel-encapsulated drugs, on the other hand, are meant to be swallowed. They release their drug cargo in the intestines, so the hydrogel needs to remain intact until that point. For example, Nicholas Peppas’ team of researchers at the University of Texas at Austin designed a pH-responsive hydrogel that encased the drug in acidic conditions, like those found in the stomach, and then degraded when it moved to the neutral pH of the intestines (2).

For other drugs, the goal might be more complex. Take vaccines, for example: These injections contain fragments of a disease-causing agent to train the immune system to fight it. Delivering these fragments slowly can actually train the immune system better, so scientists have tried to load them into controlled-release hydrogels that slowly loosen their hold on their cargo. 

However, vaccines also contain adjuvant molecules that spur the immune system into action to help the vaccines work better. Adjuvants tend to be a different size than the pathogen fragments in the vaccine, so a hydrogel that can slowly release the pathogen fragments may not be able to release the adjuvant at the same rate. “Small things wiggle their way out and release really quickly,” Appel said. “So, you might have one drug that releases in a day and one drug that releases slowly over the course of months.”

Appel instead designed a different type of hydrogel that he calls “molecular Velcro.” The scaffold within this gel is made up of two different types of molecules that snap together with bonds that can be broken and reformed — just like two strips of Velcro. Having multiple types of molecules in the scaffold allows it to form more flexibly-sized pores for both large and small cargo. This ensured that the two vaccine molecules were released at the same rate for weeks, boosting the immune response more than a standard vaccine (3).

Delivering diabetes drugs

With the flexibility that hydrogels offer, the possibilities may seem endless, but some diseases pose a challenge even for hydrogels. One of those is diabetes.

People with diabetes are unable to maintain healthy blood glucose levels either because their pancreas does not produce insulin, the hormone that triggers glucose removal from the blood (type 1 diabetes), or because their cells have become insensitive to insulin for other reasons (type 2 diabetes). Treatment often involves checking blood sugar levels and, if they become too high, injecting insulin. This means that many people with diabetes are regularly forced to stick themselves with needles to either monitor or correct their blood sugar levels, an unpleasant process that as many as 50 percent of type 2 diabetes patients may forgo to the detriment of their health (4).

We actually generated a material that responds to the absence of a stimulus, which is reverse engineering the typical design framework. 
- Michael Webber, University of Notre Dame

A hydrogel alternative would have to be very carefully calibrated. “There has to be a lot of temporal precision in delivery,” Webber said. The gel could be loaded with insulin, but it would have to release the drug when blood sugar levels became high and stop when levels become normal again — which could happen in just a few hours, he added.

“[Blood glucose control] is a more challenging problem than traditional hydrogel-based drug delivery,” Webber said.

Luckily, certain molecules bind to glucose, so multiple teams of researchers repurposed these molecules to build glucose-responsive hydrogels (5). When glucose levels were high, water would leave the gel, which loosened the gel’s structure and released the insulin (6). In animal models, this gel reduced elevated blood sugar levels. Moreover, hydrogel injections could reduce the four or more insulin injections that some people with diabetes require each day, making it more likely that people would adhere to the treatment, Webber said.

Webber wanted to go one step further. Diabetes patients also sometimes suffer from too low blood sugar, which can also be dangerous. When this happens, people can be treated with an injection of glucagon, a hormone that counteracts insulin. 

Building a hydrogel to release glucagon in the presence of low blood sugar levels posed a new challenge: Now, the gel had to respond to the absence of a molecule, rather than its presence. In a 2021 study, Webber and his team devised a strategy to load glucagon into a hydrogel containing an enzyme that converts glucose into an acidic molecule (7). This reduced the pH of the surroundings and, by using pH-sensitive chemistry, kept the hydrogel intact. However, in the presence of low glucose levels, the enzyme couldn’t operate, and the pH increased again, triggering the hydrogel to release its cargo.

“We actually generated a material that responds to the absence of a stimulus, which is reverse engineering the typical design framework,” Webber said. His team suspected the material could be even better. For example, although the glucose-sensing enzyme was effective, it can make toxic byproducts. In an update published in 2024, Webber’s team presented a revamped way to make insulin-responsive hydrogels without this enzyme (8). Instead, they used a glucose-responsive molecule called phenylboronic acid (PBA) that forms a gel in high-glucose settings, allowing it to hold molecules such as glucagon. When glucose levels are low, the gel breaks down and releases glucagon.

The advent of new diabetes drugs has also sparked interest in new hydrogel delivery mechanisms. For example, GLP-1 receptor agonists are a class of drugs for weight loss and blood sugar control that have recently undergone a meteoric rise in popularity. These molecules trigger insulin production — and thus reduce blood sugar — and typically require either daily or weekly injections. With the help of a controlled-release hydrogel recently published in Cell Reports Medicine, Appel hopes to make it even easier for people to take GLP-1 receptor agonists (9).

Webber noted that administering GLP-1 receptor agonists is simpler than administering insulin or glucagon because it doesn’t have to respond to blood glucose levels. His team is continuing to work on improving their insulin- and glucagon-releasing hydrogels, but he’s still unsure whether they will ultimately pass muster for clinical use. “We always have to be mindful of the unique features of treating diabetes,” he said. “It's a lifetime of treatment, and with that comes a lot of considerations for the material you use.”

For example, Appel wants to make sure that his hydrogels are as easy for people to inject as their current medications. “We have a very promising material candidate,” he said. “You can inject it with the forces of a standard autoinjector. You just click, and then it administers.”

When technology meets the real world

Hydrogels seem to offer patients an alternative to the painful, inconvenient, and frequent medication dosing methods of the past. A hydrogel to deliver a long-acting injectable HIV medication promises to reduce the “pill fatigue” faced by people taking antiretroviral therapies (10). But a hydrogel-powered future may not be as close — or as idyllic — as it seems.

Mark Tibbitt, a molecular engineer at ETH Zurich, has developed hydrogels for 15 years. (In fact, he, Appel, and Webber all did their postdoctoral research on hydrogels under the mentorship of Robert Langer, a chemical engineer at the Massachusetts Institute of Technology.) Tibbitt’s work has spanned many different applications of hydrogels. In 2022, he led a study designing a hydrogel to stabilize biologic therapeutics for storage and transport — a “molecular shrink wrap,” as he described it (11). Encapsulating biologics such as vaccines or diagnostic tests in a flexible hydrogel increased their shelf-life.

“There's a lot of impact in being able to provide a kind of safety blanket on your biologic,” he said. While the drug would likely still need to be on ice, “if it gets stuck in customs somewhere, then you don't have to lose the whole batch of material,” he said. Tibbitt also noted that this could be helpful when shipping medications to regions that lack freezers to keep medicines cold.

Even if you get a vaccine or a therapeutic to a part of the world — and it's stable and it works — it's still challenging to get people to take it. This social challenge turns out to be bigger than the technical challenge. 
- Mark Tibbitt, ETH Zurich

But Nanoly Bioscience, the company he had partnered with on this study, recently ceased its operations, he said. The reason? Building new storage technology only addressed part of the problem.

“Even if you get a vaccine or a therapeutic to a part of the world — and it's stable and it works — it's still challenging to get people to take it,” Tibbitt said. “This social challenge turns out to be bigger than the technical challenge.”

He isn’t the only person who raised this concern. New materials that are intended to make it easier to administer, store, and ship medications are only as effective as the social context in which healthcare is delivered. Webber has seen a similar limitation in developing hydrogels for diabetes.

“Type 1 diabetics need insulin — that's non-negotiable,” Webber said. “But it’s one of the drugs that is really in the spotlight now for control of drug pricing.” Hydrogel approaches to deliver insulin might end up being more expensive solutions for delivering a drug that already has a volatile price. Given that some hydrogels can sometimes “leak” their cargo, his team is concurrently exploring other types of glucose-responsive polymers.

Webber pointed instead to other applications of hydrogels that may be better positioned for success such as some of Appel’s recent work in cancer immunotherapy. In 2022, Appel’s team published a new way of delivering chimeric antigen receptor (CAR) T cells to a patient alongside cytokines that stimulated the cells to multiply into an army of tumor-targeting cells (12). “The gel really acts as a little CAR T factory, constantly expanding them and activating them,” Appel said. The result was a stronger anti-tumor response in animal models, which has prompted Appel to think about licensing the material for further development and clinical trials.

This process of producing more cancer-fighting cells is typically an expensive process that happens in a laboratory, and Webber noticed that the hydrogel may provide a way to make this treatment cheaper and more accessible. “If you're going to have the extra cost and manufacturing to make a gel-based delivery technology, it needs to work better than whatever the standard of care is and do so at a price point that is accessible,” he said. “If you take a treatment that is prohibitively expensive and make it accessible to people, I think this would be a really powerful use case.”

References:

1. Baryakova, T.H. et al. Overcoming barriers to patient adherence: the case for developing innovative drug delivery systems. Nat Rev Drug Discov  22, 387-409 (2023).
2. Schoener, C.A. et al. pH-responsive hydrogels with dispersed hydrophobic nanoparticles for the delivery of hydrophobic therapeutic agents. Polym Int  61, 874-879 (2012).
3. Roth, G.A. et al. Injectable Hydrogels for Sustained Codelivery of Subunit Vaccines Enhance Humoral Immunity. ACS Cent Sci  6, 1800-1812 (2020).
4. Aroda, V.R. et al. Greater persistence and adherence to basal insulin therapy is associated with lower healthcare utilization and medical costs in patients with type 2 diabetes: a retrospective database analysis. BMJ Open Diabetes Res Care  12, e003825 (2024).
5. Yesilyurt, V. et al. Injectable Self-Healing Glucose-Responsive Hydrogels with pH-Regulated Mechanical Properties. Adv Mater  28, 86-91 (2016).
6. Matsumoto, A. et al. Synthetic "smart gel" provides glucose-responsive insulin delivery in diabetic mice. Sci Adv  3, eaaq0723 (2017).
7. Yu, S. et al. Glucose-Fueled Peptide Assembly: Glucagon Delivery via Enzymatic Actuation. J Am Chem Soc  143, 12578-12589 (2021).
8. Yu, S. et al. Glucose-Triggered Gelation of Supramolecular Peptide Nanocoils with Glucose-Binding Motifs. Adv Mater  36, e2311498 (2024).
9. d’Aquino, A.I. et al. Use of a biomimetic hydrogel depot technology for sustained delivery of GLP-1 receptor agonists reduces burden of diabetes management. Cell Rep Med  4, 101292 (2023).
10. Coulter, S.M. et al. Enzyme-Triggered l-α/d-Peptide Hydrogels as a Long-Acting Injectable Platform for Systemic Delivery of HIV/AIDS Drugs. Adv Healthc Mater  12, e2203198 (2023).
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12. Grosskopf, A.K. et al. Delivery of CAR-T cells in a transient injectable stimulatory hydrogel niche improves treatment of solid tumors. Sci Adv 8, eabn8264 (2022).