Biomaterials are crucial to the development of many modern medical devices and products including biodegradable sutures, bone screws, pins, rods and plates, and scaffolds for regenerating bone, cartilage and blood vessels. With each new discovery comes a chance to solve yet-unmet clinical challenges.

As new research drives the evolution of biomaterials toward increasingly sophisticated applications, the functional requirements of those materials have expanded to include both therapeutic and diagnostic elements, with particular focus on optical imaging capabilities, where Huck Institutes faculty researcher Jian Yang and his Transformative Biomaterials and Biotechnology Lab have recently made several revolutionary innovations.

Polylactone materials

“My lab focuses on developing materials that can be used for 3-D printing and regenerative engineering,” says Yang. “Polylactones, such as polylactic acid (PLA), are one of the few types of biodegradable polymers that have been widely used in FDA-approved medical devices such as orthopedic fixation devices, tissue engineering scaffolds and drug-delivering micro- or nano-particles. We are innovating this material by making it intrinsically photoluminescent without adding traditional photobleaching organic dyes or cytotoxic quantum dots. That was a challenge previously, but we've managed to do it now.”

By modifying the PLA polymer to be intrinsically fluorescent, the Yang lab has made a biodegradable material that can also be useful in bioimaging, diagnosis, sensing and other related applications.

Cancer management

In one of their research projects, the Yang lab makes the PLA polymer into nanoparticles that can carry chemotherapeutic drugs to target cancerous tumors.

“Because the cell membranes of cancer cells overexpress folate receptors,” Yang explains, “we can target those cells and tumors with our nanoparticle by conjugating folic acid on its surface; and now that our nanoparticle is fluorescent, we can also use it to image the tumors via fluorescence imaging.”

Yang said that during surgery, a doctor can only see down to roughly millimeter-sized tumors. Other cancerous cells near a tumor cannot be seen with the naked eye, and if those cells aren’t removed, the cancer will return.

"Our nanoparticles can target the tumor cells, and then we can use fluorescence imaging to illuminate those cells for surgical removal." -- Jian Yang, faculty researcher

"We needed a better way to detect smaller-sized tumor cells and cell clusters," Yang says, "and since fluorescence imaging is a very sensitive tool, it can be used to detect those cells that cannot be seen with the naked eye. Our nanoparticles can target the tumor cells, and then we can use fluorescence imaging to illuminate those cells for surgical removal."

His lab has also used the fluorescent PLA polymer to create "dual-imaging" nanoparticles that incorporate both cancer drugs and magnetic nanoparticles so they can be used for both magnetic resonance imaging (MRI) and fluorescence imaging.

"MRI has become a very popular tool in cancer treatment since it can be used to look deep into the body and rapidly locate solid tumors," he says. "Then the fluorescence imaging enables doctors to identify small cancer cell clusters around the tumor areas.”

Image Jian Yang and Zhiwei Xie discuss the fluorescent polymers they are developing in the Yang lab. IMAGE: Seth Palmer

Regenerative engineering

Because these nanoparticles have two functions, therapeutic drug delivery and diagnostic imaging, they are known as theranostics -- a portmanteau word combining therapeutic and diagnostic -- but Yang's fluorescent PLA polymer isn't just limited to those two roles. The same fluorescent PLA material can also be used for regenerative engineering.

Yang says that biodegradable polymers are often used to make temporary scaffolds for tissue generation where the scaffolds, sometimes seeded with cells before implantation, are placed in a wound area to recruit the body's own cells. Such scaffolds eventually degrade and are absorbed by the body. Yang hopes to design materials with different degradation rates for different medical applications.

“In bone regeneration, we may want the material to degrade over six months or a year," he says, "but in wound healing, we may want the material to degrade over a couple of months.”

He says the question is first how to determine materials’ degradation rates, and then how to design materials that can match the need for specific degradation rates in vivo.

"When we design a material to degrade over a specific period of time, we test it in the lab with an incubator and buffer solution set at 37 degrees Celsius and 7.4 pH to simulate normal conditions inside the body," he says. "This allows us to rapidly assess the rate of degradation in vitro, but in vivo situations are very different. Our in vitro understanding cannot be translated directly in vivo; we need to do in situ monitoring to assess how materials actually degrade in vivo.”

Now that they have made a material that is intrinsically fluorescent, the Yang lab can do non-invasive imaging to monitor a material’s degradation in the body. As the fluorescent signal becomes weaker over time and eventually disappears, its decay can be translated into the rate of the material’s degradation without ever needing to re-open the body.

Elastomeric scaffolds

Scaffold materials are also needed that mimic the elastic nature of soft tissues such as those found in the bladder, lungs, skin, and blood vessels, and this need has led the Yang lab to work on developing biodegradable elastomeric polymers based on citric acid.

Unfortunately, Yang says, many elastomeric materials are mechanically weak, and they become even weaker when fabricated into medical devices, which severely limits their use.

“Current methods used to strengthen these biomaterials sacrifice the limited functional groups available for future bioconjugation/functionalization,” he says, “and also slow down the materials' degradation rate. So my lab is focused on creating citric-acid-based materials that are elastic in nature and effectively balance the desired mechanical properties, functionality and degradation through innovative chemistry known as 'click' chemistry.”

Click chemistry involves the use of two chemical groups that “click” together like a lock and key to strengthen materials without sacrificing their degradability or functionality.

Bone-inductive orthopedics

Yang's rationale behind developing citric-acid-based materials is based on evidence suggesting that citric acid plays an important role in bone development, physiology, and structure.

"Recent research has found that citric acid plays important roles in controlling the formation of the mineral structures that give our bones their high strength," he says. "My lab's previous research has shown that citric acid -- whether located in biomaterials or released during the course of those materials' degradation -- can be used by the body for enhanced bone development and regeneration."

In addition, the chemistry of citric acid also allows him to incorporate bioceramics into the material so it better matches the strength and mineral content of native bone.

Image Jian Yang demonstrates the pliability of his bone biomaterial. IMAGE: Seth Palmer

"We started to realize that this might be a niche in bone biomaterials design." -- Jian Yang, faculty researcher

"The whole idea of our click chemistry work is to make a mechanically strong, biodegradable polymer that also has intrinsic bone-inductive properties, since most other biodegradable polymers don’t have the intrinsic ability to induce bone regeneration," says Yang. "In the past 30 years, even though people knew that citrate was present in natural bone, very few biomaterials researchers considered citrate as a catalyst for bone regeneration. We started to realize that this might be a niche in bone biomaterials design."

Tailored degradation

The Yang lab is also developing citrate-based polymers with unique degradation profiles such as a material that will degrade slowly at first and then faster in later stages.

“Materials provide mechanical support for tissue regeneration,” he explains, “so they should be strong in the beginning, but when the tissues start growing, then the materials should begin to degrade.”

In addition to their unique degradation profiles, his lab's bone composite materials can be made to exceed the strength of cortical bone (the exceptionally dense, hard outer layer) by forming composites with calcium-containing apatite crystals in the body. As a result, these materials are suitable for extreme load-bearing functions – for example, replacing or reinforcing sections of long bones such as the femur.

Success by multifunctional design

By designing multifunctional materials, the Yang lab is improving the potential for complex medical procedures to be performed concurrently through a single product or device and without the need to re-open the body in order to monitor progress.

"We hope that these innovations will help to overcome some of the major hurdles in biomaterials development," Yang says. "As a result, we should begin to see medical products and procedures that work and integrate better to produce superior outcomes for doctors and patients alike."

Read the unabridged article by Seth Palmer on the website of the Huck Institutes of the Life Sciences.