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; and with each new discovery comes a chance to solve yet-unmet clinical challenges. As new, innovative 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 Penn State University's Huck Institutes faculty researcher Jian Yang and his Transformative Biomaterials and Biotechnology Lab have recently made several revolutionary innovations.
"My lab focuses on developing materials that can be used for 3-D printing and regenerative engineering" said 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.
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 explained, "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 adds that during surgery, however, a doctor can only see down to roughly millimeter-sized tumors with the naked eye, and so another problem arises: there are other cancerous cells surrounding the tumors that the doctor cannot see, and if those cells aren't also removed, then the cancer will return. We needed a better way to detect smaller-sized tumor cells and cell clusters, 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. We've also used the fluorescent PLA polymer to create what we call 'dual-imaging' nanoparticles for cancer treatment" he continued, "meaning that we can encapsulate both cancer drugs and magnetic nanoparticles in our fluorescent PLA nanoparticles in order to use them 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; then the fluorescence imaging enables doctors to identify small cancer cell clusters around the tumor areas."
Because these nanoparticles have two functions, for both 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 these roles, either.
This fluorescent PLA material can also be used for regenerative engineering. Yang notes that biodegradable polymers are often used to make temporary scaffolds for tissue regeneration, where the scaffolds are placed in the body to recruit cells – sometimes pre-seeded with cells before implantation – and will then degrade and eventually be absorbed by the body; so for different applications, Yang explains, he wants to design materials with different specific degradation rates. “For example" he said, "in bone regeneration, we may want the material to degrade over six months or a year; but in wound healing, we may want the material to degrade over a couple of months. So the question, according to Yang, 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," he explained, " We test it in the lab with an incubator and buffer solution set at 37ºC and 7.4 pH to simulate normal conditions inside the body; this allows us to rapidly assess the rate of degradation in vitro, but in vivo situations are very different and so this poses a challenge."
Many factors in the body, such as enzymes and other biomolecules, influence materials' degradation rates, and so, Yang stated, 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 for real-time in situ monitoring of the material's degradation: 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. Still – in many cases, even when the body is re-opened, it can be difficult to measure a material's degradation. If we are making a material to be porous, Yang explained, then the body's tissues grow through the material and it becomes impossible to differentiate the native tissues from the material.
But, Yang said, when those tissues grow into the fluorescent biomaterial, their interaction may change the fluorescent signal, and so it may be possible to correlate that signal change with the tissues' growth into the material."In other words, he concludes, we may also have a way to measure tissue regeneration in addition to measuring material degradation, and therefore we can better design our materials to meet specific medical needs."
This work is published in Advanced Materials.