One day in 2005, polymer chemist and undergraduate student Xian Jun Loh was sprinkling organic compounds into a container of water to see whether they would dissolve. The polymer proved to be soluble, but something unexpected happened when Xian Jun heated the mixture in an oven set to body temperature — the clear, odorless liquid formed into a gel. “It looked and felt like hair gel,” recalls Xian Jun, who was used to seeing water-based solutions solidify and freeze when cooled, but not when heated. He immediately proceeded to repeat the experiment. “I had to make sure it wasn’t just a one-off accident.”
Much to his relief, the result wasn’t a fluke. Xian Jun had discovered a polymer that not only formed a gel when heated but was also biodegradable, due to the hydrolysable linkages connecting individual monomers. Further study has shown that the polymer and its variants are ideal for biomedical and cosmetic applications, with the potential to restrain the growth of cancerous tumors, temper the effects of aging on skin and slash insulin injections for diabetics1.
Xian Jun now heads Research Planning and co-manages the Consumer Care Technology Programme at the A*STAR Institute of Materials Research and Engineering (IMRE), but is still based in the same lab where he made his initial discovery. At IMRE, Xian Jun has access to state-of-the-art facilities for developing and testing new gels as well as the expertise of like-minded polymer chemists. The institute has given him the space to really test the versatility of his polymers.
Making it biodegradable
Researchers have been studying and clinically testing thermogels for controlled drug delivery for over 30 years now. Earlier gels typically consisted of linked blocks of homogenous polymer chains, such as a polymeric string of ethylene oxide monomers connected to another polymeric string of propylene oxide monomers.
But these substances were not biodegradable and required much higher polymer quantities — about a fifth of the formulation — to be mixed with water. This meant introducing more foreign substances to the body, which raised concerns over unknown side effects. Some studies found that rats and rabbits had higher lipid and cholesterol concentrations following these therapies. Furthermore, the gels dissolved back to liquid within hours, making them unsuitable for long-term delivery.
Xian Jun resolved many of these problems by introducing biodegradable linkages into the thermogelling polymer chain. “The idea was somewhat bio-inspired,” he explains. All the proteins in our bodies are made of amino acids. Each amino acid unit is connected to its neighbors by stable amide bonds and further packed into a compact three-dimensional structure via reversible hydrogen bonds. Xian Jun identified that urethane bonds had a similar structure to these naturally occurring polyamide linkages with a comparably high presence of hydrogen bonding. He decided to use urethane linkages to assemble the synthetic monomers in a way that mimicked naturally occurring systems.
This resulted in polymers that broke down into smaller units and could be flushed out of circulation weeks or even six months after being introduced to the body. The tighter packing meant that less polymer is needed to turn water into gel — from 20 per cent of the mixture down to 2 per cent. Once solidified, the coherent structure released trapped proteins at a sustained rate for an unprecedented three months. “No other thermogel can release proteins for such a long time,” says Xian Jun.
Xian Jun is now conducting research to test the polymer’s efficacy for cancer drug delivery. His team first examined the polymer in environments designed to simulate the dynamic conditions in the human body. They infused a known anticancer drug into a polymer formulation and then affixed the gel onto a semipermeable membrane in a constantly replenishing solution. The gel lay just above a persistent colony of cells derived from cervical cancer, known as HeLa cells. For two weeks straight, the drug permeated into the solution through tiny pores in the gel, like the slow and steady trickle in a drip chamber. During this time, the researchers observed reduced proliferation of the HeLa cells. Further studies on tumors in a mouse model showed similar impedance to growth.
Localized injection of the gel offers a more direct route for delivering drugs to a tumor than ingesting medication, which involves circulating drugs throughout the body. The gel-based treatment could eventually lead to reduced drug doses and limit the side effects of chemotherapy for cancer patients.
Since this novel carrier can deliver small-molecule drugs, proteins, lysosomes and even insulin, it has the potential to improve the lives of many patients. Its long active lifetime may allow diabetics to forgo daily insulin injections and instead just have them four times a year. Furthermore, sustained and localized delivery of pain medication could provide constant relief to patients. Xian Jun foresees working closely with drug companies to introduce their tried and tested drugs in more effective ways.
In addition to administering drugs, the thermogel could also be used for tissue repair and engineering. One approach would be to use the gel as a fibrous mat or scaffold for growing thin sheets of cells. Once matured, the cells could then be implanted onto various parts of the body with the polymer eventually degrading into nonexistence. But since the field of scaffold engineering is crowded with other promising alternatives (such as hydrogels, carbon nanotubes and fibrin mesh), Xian Jun sees greater potential for biodegradable thermogels as cell encapsulation materials. In this scenario, researchers would grow and maintain living cells in the polymer matrix itself, which could then be used to seal injured tissue and caulk perforations through direct injection. So far, Xian Jun has proved that cells can survive in the gel, but he has yet to find a way of squeezing the encapsulated cells through a tiny needle without rupturing their membranes.
While these thermogels are extremely promising, it may be some time before they find their way into actual patient treatments. In the meantime, Xian Jun is collaborating with a cosmetics manufacturer to develop gels with even lower polymer concentrations that can trap and slowly release active anti-aging ingredients. The company is keen on moving away from the traditional tinted and turbid creams toward a product that is transparent and slightly viscous. “Our material fits the bill, and it is aesthetically pleasing,” says Xian Jun, who expects the gels to make a public appearance within a year. “These thermogels are proving to be really special materials.”
About the Institute of Materials Research and Engineering
The A*STAR Institute of Materials Research and Engineering (IMRE) was established in 1997 with the aim of becoming a leading research institute for materials science and engineering. The IMRE has developed strong capabilities in materials analysis, characterization, materials growth, patterning, fabrication, synthesis and integration, and has established research and development programs in collaboration with industry partners.