Hydrogels and Their Life-Saving Capabilities

Welcome to the world of hydrogels — nano-sized materials that can impact billions worldwide!

Since we were kids, we have been taught that matters exist in three states: solid, liquid and gas. But nature is in fact more intricate than that, where some materials exist between the states. For example, think gelatin, the ingredient that makes desserts jiggle. It is neither solid nor liquid nor gas; it’s a hydrogel!

Injection of fluorescein encapsulated calcium cross-linked alginate hydrogels into saline solution. Credit: Wyss Institute at Harvard University

Hydrogels are water insoluble, crosslinked, three-dimensional networks of polymer chains, coupled with the water that fills the voids between polymer chains. The cross-linking between polymer chains give rise to the mechanical strength and physical integrity of the structure. Hydrogels are highly absorbent, containing at least 90% of water. That is even a higher percentage of water that the human body can retain!

Furthermore, hydrogel is an easily programmable material, meaning that we can design chemical reactions to combine hydrogel with other molecules for a specific purpose.

Since the 1960s, scientists have envisioned hydrogel as a promising candidate for permanent contact applications, ones that are implanted in the body permanently without rejection from the body immune system.

Here’s the coolest part: Hydrogels are smart materials! They change some properties, such as shape, in response to different changes in the environment. Some common stimuli for smart hydrogels in biological applications are pH, temperature and ionic strength. This enables hydrogels to be perfect candidates when entering the body’s localized environments. We can also change the external environment from the outside to manipulate the activity of the hydrogel inside the body.

What makes hydrogels so “smart”?

There are many functional groups that are attached to the polymer backbone, one prominent example being carboxylic acid groups, or RCOOH. When a carboxylic acid group is added to water, the hydrogen of the acid group may dissociate. The result is a carboxylate ion (RCOO- ) with a negative charge and hydrogen ion (H+). If the environment favors dissociation of the hydrogen, then the polymer chain has lots of negative charges along its backbone. The negative charges of the polymer chains repel each other, causing the hydrogel to uncoil (open up). The negative charges also increase the attraction of polymer to water by attracting the positive hydrogen dipole of water.

Also, the reaction of RCOOH to RCOO- is reversible, and the chemical environment will determine whether the forward reaction occurs. Since the polymer backbone needs to be more negative relative to chemical molecules in its environment, a H+ rich/ acidic (low pH) environment will favor a ROOH — or neutral — backbone. On the other hand, more alkali (higher pH) favors a negative charge. Boom, this is an example of how a small change in pH level can markedly influence the degree of swelling of hydrogels!

Drug Delivery

One of the most exciting clinical applications being tested is in drug delivery. People with type 1 diabetes need to constantly inject themselves with insulin in order to control their blood sugar levels.

Hydrogels could help patients dispense with that need. In fact, researchers are using poly(β-amino ester) (PAE) to synthesize hydrogels that can be injected under the skin, which creates a deposit of insulin in the body. Insulin naturally diffuse from the environment with higher insulin concentration to lower insulin concentration, leading to the slow release of hormone from the interior of the hydrogel into the bloodstream.

In this way, multiple insulin injections can be replaced with a single hydrogel injection!

Fresh Blood for Damaged Tissues

Not only can hydrogels potentially replace insulin shots, it is a promising alternative to blood-thinning medications and angioplasty and bypass surgery — current treatment methods for ischemia.

A demonstration of cerebral ischemia — a type of stroke that occurs when blood flow to the brain is interrupted

Ischemia is a serious medical condition in which the flow of blood and delivery of oxygen to tissues is restricted, thus resulting in pain, weakness, and more seriously, tissue and organ damage. When occurs in the muscle tissue, especially in the form of atherosclerosis, ischemia can result in fatal diseases such as coronary artery disease and stroke — which are currently the leading cause of death according to the World Health Organization.

Scientists have found a very interesting approach to treating ischemia: Growing new blood vessels in order to increase blood flow at the ischemic site via delivery of angiogenic growth factors like Vascular Endothelial Growth Factor (VEGF) and Insulin-like Growth Factor-1 (IGF)!

This video describes how an alginate hydrogel can be used to trigger the formation of new blood vessels at an ischemic site in the body. Credit: Wyss Institute at Harvard University

After being infused with VEGF and IGF, the alginate hydrogels can be delivered to the body using microneedles.

Peptide-modified chitosan hydrogel leading to the formation of new blood vessels. (Chen et. al (2015). Laminin mimetic peptide SIKVAV- chitosan hydrogel promoting wound healing by enhancing angiogenesis, re-epithelialization and collagen deposition. J. Mater. Chem. B. 3. 10.1039/C5TB00842E)

Typically grouped together in a large number, microneedles are designed to be applied to the skin like a patch. When pressed onto the skin surface, the needles are able to cross the very outermost layer of the skin (“stratum corneum”) which then creates microscopic pores, allowing the growth factors to enter the body and stimulate the growth of new blood vessels without causing any damage to the existing ones.

A demonstration of microneedles releasing chemicals

Killing Superbugs

Researchers from the Institute of Bioengineering and Nanotechnology (IBN) and IBM Research developed the first-ever antimicrobial hydrogel that can break apart biofilms and destroy multidrug-resistant superbugs upon contact using hydrogels in 2013. And it is truly amazing!

Normal cells of the Acinetobacter baumannii bacteria before (left) and after (right) treatment with the polymers [Credit: Institute of Bioengineering and Nanotechnology]

There is an underlying fundamental problem with the way we treat bacteria today: antibiotics is they are a sledgehammer that depletes and destroys the gut microbial community.

What’s really important to understand is that if we continue using antibiotics till 2050, 10 million people will die per year due to bacterial infections. That is even more deaths than all types of cancers combined.

Hydrogels can be loaded with metal nanoparticles as a new way to fight against microbes. For example, Ag+ released from Ag nanoparticles interact with cysteine in certain regions of proteins on bacterial membranes, causing K+ loss from inside and the disruption of cellular transport systems, which finally leads to bacterial cell death.

A diagram of the four-step killing mechanism of the polymer against drug-resistant superbugs (Step 1) Binding of the positively charged polymer to the bacteria cell surface, (Step 2) Neutralizing the positive charges of the polymer to enter the bacterial cell membrane, (Step 3) Penetrating into the bacterial cyotoplasm, a fluid that fills the cell, and (Step 4) Precipitating the cytoplasmic substances to kill the bacterium. (Credit: Institute of Bioengineering and Nanotechnology)

Other studies have also shown that Ag+ interact with proteins of the cell wall and plasma membrane of bacteria. Combination of Ag+ with negatively charged membrane perforates the membrane, thus allowing cytoplasmic contents to flow out of the cell, dissipating the H+gradient across the membrane and sometimes causing cell death.

With its versatile and programmable nature, hydrogels are one of the simplest yet most intriguing and powerful materials in our world today!


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