If the equations scrawled on nearby laboratory hood panes are any indication, Jonah Kaplan is orchestrating some very complex chemistry. But to watch him in action, he appears as relaxed as if he were mixing a batch of Jell-O. The biomedical engineering doctoral candidate tends to a round-bottom flask undergoing a polymerization reaction while planted in a swirling bath of hot oil. Over the next five days, he’ll convert this concoction from a molten liquid to a clear, waxy polymer that holds promise as a postsurgery delivery system for chemotherapy to early-stage lung cancer patients.
“The main thing that you can mess up is introducing moisture from your syringes, reagents, or even the humidity in the air” because it will cause unwanted variation in the polymer’s molecular weight, explains Kaplan (ENG’14), deftly attaching a vacuum tube to the flask to exchange its atmosphere with inert nitrogen. As he works, he refers to chemical equations in a thick red book—the lab’s treasure trove of intellectual property—and walks Julia Wang (ENG’17), another biomedical engineering doctoral student, through the process.
The 2 are members of the Grinstaff Group, a cadre of more than 20 graduate students and postdoctoral fellows with expertise in chemistry, pharmacology, and biomedical and mechanical engineering who tackle some of the most complicated medical challenges under the guidance of Mark Grinstaff, a College of Arts & Sciences professor of chemistry, a College of Engineering professor of biomedical engineering, and a member of the ENG Division of Materials Science and Engineering.
Kaplan, Wang, and a third biomedical engineering doctoral candidate, Eric Falde (ENG’15), are working with a highly water-resistant polymer mesh that can be sewn or stapled along soft tissues where tumors have been surgically removed. The stretchy biodegradable patches contain embedded chemotherapy, such as paclitaxel, that will slowly release from within the mesh fibers and deliver a deathblow to remaining cancer cells.
The idea for this material emerged from a conversation in 2006 between Grinstaff, former group member Jesse Wolinsky (ENG’09), and Yolonda Colson, a thoracic surgeon at Brigham and Women’s Hospital and a Harvard Medical School professor of surgery. Colson was describing the delicate line she walks when she operates on early-stage lung cancer patients: while her goal is to remove all visible tumors, she knows that cutting out too much will damage patients’ quality of life by reducing lung capacity.
Lung cancer is the most deadly form of cancer in the United States, according to the National Cancer Institute. Every year, roughly 200,000 people are diagnosed with the disease, and more than 159,000 die from it. From 1995 to 2001, only about 16 percent of patients survived longer than five years. Those who relapse and undergo a second round of chemotherapy usually live less than six months. Conventional chemotherapy is given as a general infusion to the whole body, which means all cells are exposed to the poison. The amount of a drug that actually reaches tumor cells is often a small percentage of the overall dose.
Hoping to become Wolinskys
After talking with Colson, Grinstaff and Wolinsky returned to the lab and Wolinsky started designing the first generation of drug-loaded pliable polymer films that could be sutured along the surface of lung tissue. He tested the material in animals with encouraging results. Among the animals implanted with his films after lung cancer surgery, more than 80 percent were tumor-free 90 days later. That was more than double the survival time of animals who received a systemic injection of chemotherapy following surgery.
With Grinstaff’s help, Wolinsky founded AcuityBio in 2010 to push his research to clinical trials. The company is working to prevent the recurrence of postsurgical cancer using the drug delivery technology. Now Wolinsky’s name is among those dropped regularly around the fifth floor of the Metcalf Center for Science and Engineering, the Grinstaff Group’s base of operations. Members love pushing the boundaries of basic science, yet what keeps them plugging away—sometimes seven days a week—is the hope that their work could translate into a medical breakthrough, that they might someday be Wolinskys too.
“I don’t think every project in the lab should become a company,” says Grinstaff. “But I think if a project continues to work, you continue asking more and more difficult questions, and if it keeps passing the tests, then you need to keep moving it forward until it fails. If you are fortunate, then you can make a difference at the end of the day.”
In that spirit, Kaplan, Wang, and Falde are working in their Metcalf Center lab to create additional forms for their chemotherapy delivery system, such as one that can be made into a mesh-like material when passed through a device called an electrospinner. The polymer is innately water-resistant and has a fibrous architecture when spun, helping the mesh trap air bubbles and delay the release of embedded chemotherapy drugs—an important factor for the material’s success within the body.
“Just after you take out a tumor, you have to allow the area to heal…before you go after and kill the cells,” Wang explains. If the mesh released chemotherapy immediately, it might exacerbate tissue inflammation or delay healing.
Another reason long-term drug release is important is because many chemotherapeutics “are toxic to cells at only one stage in the cell cycle,” Falde says. “If you give one big dose, as in traditional chemotherapy, you’re going to miss a significant portion of tumor cells.”
Targeted chemotherapy, which spares healthy cells from a toxic blast, also means physicians can administer a smaller dosage of a drug and get a greater impact—a strategy that’s music to the ears of policy makers and hospital administrators interested in cutting health care costs.
The group is also experimenting with a type of sprayed polymer mesh that, at least after initial testing, pushes the material’s water-resistance even further. Kaplan says the material was accidentally created when they “tested the limits” in spinning the fibrous mesh.
In a biomedical engineering lab, Wang tapes a thin strip of the group’s sprayed mesh onto the platform of a goniometer, an instrument used to measure contact angles. Then she grabs a pipette and delicately deposits a row of deionized water droplets on its surface, each standing like a miniature crystal ball on a white tablecloth. She zooms an attached camera to the exact point where the bottom edge of each droplet sits atop the mesh, and the instrument takes a measurement. This sample registers at an impressive 162-degree angle.
Reaching 180 degrees is difficult, Wang says, but “with the sprayed method, I’ve had water actually roll off of my surfaces.”
So far, the team has tested its drug-loaded fibrous meshes in animal models with lung cancer, and Falde describes the results as “very promising.” At this point, he prefers to stay mum on the details. “We hope to have the studies completed by this summer.”