The emergence of biology and material science has brought about new composites that can be used to deliver drugs and repair damaged tissues such as the anterior cruciate ligament (ACL), an injury to which can ruin athletic careers. Developing a balance between mechanical strength and elasticity for artificial tissue scaffolding has been problematic as it requires biocompatibility and and controlled biodegradability. Yang and colleagues in Penn State’s Department of Biomedical Engineering and the Academy of Orthopedics of Guangdong Province in China are using thermal click chemistry to make cross-linked citrate-based biodegradable elastomers with a high mechanical strength with an easy surface biofunctionalization. This elastomer has up to 40 MPa of tensile strength, making it suitable for tissue engineering.
Yang’s click polymers have superior mechanical strength and provide user-friendly and site-specific functionalization with bioactive molecules, for example, promoting cell growth. Furthermore, the click polymers demonstrate a type of biodegradability that Yang refers to as “first slow then fast.” For biological applications, preservation of mechanical strength of artificial scaffoldings during the early period are critical. To date many elastomers begin to degrade at a steady rate after implantation. However, the click polymer known as POC-click-3, has been demonstrated to degrade slowly for a period of time as compared to other polymers, but it rapidly degrades thereafter.
Yang and his team believe that their new elastomer will expand the application of biodegradable polymers to areas like drug delivery, orthopedic fixation devices, tissue engineering and other types of medical implants.
Yang is moving forward to develop nanoparticles that promote healing of damaged endothelium. Endothelium is a lining of blood vessels which can easily be damaged in surgical procedures that unblock clogged arteries (angioplasty and stenting). Yang notes that these procedures often damage arterial walls with a risk of future complications, for example, re-narrowing of the artery or blood clot. Platelets can accumulate on the damaged artery and this in turn can initiate clot formation. Additionally, other cells can deposit building up a blockage which can result in more surgery and multiple stent replacements.
Yang and his co-PI Kytai Truong Nguyen at University of Texas Arlington plan on developing and testing a polymer nanoparticle that mimics platelets to cover the damaged area. The nanoparticle will be covered with a ligand known as GP1b peptide that will link to endothelial progenitor cells that are circulating in blood. The endothelial cells will develop into mature cells and in time the nanoparticles will degrade as the new blood vessel lining repairs damage. This will avoid the need for a stent. Yang notes, “The surgeon will still do angioplasty first, but not put in a stent. Instead they will inject the nanoparticle solution, if necessary more than once”.
The nanoparticles will serve two functions. Firstly, they will act as a temporary scaffolding that will cover the damaged vascular wall to prevent underlying smooth muscle cell over growth and inward block of the artery. Nanoparticle attachment prevents platelet attachment. Secondly, nanoparticles will catch circulating endothelial progenitor cells to form a healthy endothelium on the damaged vascular wall. Once this is accomplished, nanoparticles will disappear. To date, injectable nanoparticles have been demonstrated to work well in animal models with researchers at UT Arlington.
Next on the agenda, Yang and co-principal investigator Jer-Tsong Hsieh, the Dr. John McConnell Distinguished Chair in Prostate Cancer Research at the University of Texas Southwestern Medical Center, will develop biodegradable nanoparticles to image and treat prostate cancer. Prostate cancer is the second leading cause of cancer death in American men. If these patients develop treatment resistance, tumors will continue to grow and and become systemic. To prevent this, Yang and Hsieh plan on identifying a prostate cancer specific drug (genotoxin) that will attack cancer cells and develop a fluorescent nanoparticles to target the cancer cells. Yang and colleagues plan on adding MRI imaging particles to the fluorescent nanoparticles so they can observe the exact location of a given tumor. If the tumor needs to be removed, fluorescent nanoparticles will attach to cancer cells and help the surgeon identify small groups of cancer cells that are generally invisible to the unaided eye.
Yang adds, “We will need to optimize the genotoxin, and make sure we can put it into the nanoparticle. Then we will have to tune the nanoparticle to emit strong fluorescence, and also control the release of the drug into the tumor and not the bloodstream. But we are confident we can do all that”.