Engineering a New Narrative

11/6 Pratt School of Engineering

Duke biomedical engineers are creating unique tools geared toward women's health to address global health inequality

The Pocket Colposcope
Engineering a New Narrative

In the bustling neighborhoods in Lima, Peru, it’s common to see bright pink trailers parked by the side of the road. Although these vehicles stand out because of their vibrant hues, the white inscription on their side also draws a passerby’s attention: Todas las mujeres tiempo para cuidarse.

All women deserve time to take care of themselves.

These cheery trailers are mobile clinics sponsored by Peru’s La Liga Contra el Cancer, or the League Against Cancer, which uses them to help screen women for diseases like cervical cancer and breast cancer. The healthcare workers who run the clinics park the trailers in one location for a week before moving to another district in the sprawling city.

Although the trailers’ mobility offers greater healthcare access to women around Lima, the clinics are limited in the services that they can provide. If screening flags a potential problem, “More than half of the women are lost to follow-up because it is difficult for them to get to a hospital,” says Dr. Gino Venegas, the former director of La Liga Contra el Cancer.

Nimmi Ramanujam, the Robert W. Carr Jr. Professor of Biomedical Engineering at Duke University and director of Duke’s Global Women’s Health Technologies Center, has devoted herself to fixing this problem. With a network of collaborators from local caregivers to Duke undergraduates, she’s creating low-cost medical tools designed around the comfort and specific needs of women around the globe, making them practical and preferable in settings where resources are limited.

The poster child for Ramanujam’s research is the Pocket Colposcope, a compact tool that allows healthcare workers to both screen for and diagnose cervical cancer without expensive imaging equipment.

“Cervical cancer is a disease of excess mortality, because with screening and follow-ups, that mortality rate should be at zero,” says Ramanujam, noting that the World Health Organization (WHO) estimates consistent screening in Peru and other countries throughout Central and South America could curb cervical cancer deaths by more than 50 percent.

Our goal is to use the Pocket Colposcope to impact women’s lives by improving their ease of access to cancer screening and treatment.

Nimmi Ramanujam Robert W. Carr, Jr., Distinguished Professor of Biomedical Engineering

Traditional colposcopes are bulky magnifying devices with cameras that allow doctors to examine a woman’s vagina and cervix for signs of cancer if a Pap smear shows an abnormal result. During a gynecological exam, doctors first use a speculum to spread the vaginal walls. A colposcope is then used to visually check for tumors and other signs of cancer in the surrounding tissue.

Although these exams are essential for accurate diagnosis and treatment of cervical cancer, Pap smears aren’t as common as they should be. Colposcopes can run anywhere from $5,000 to $20,000, and require specialized training to use. In Peru, they’re generally available only in hospitals in major cities—putting them out of reach for many women without the time or resources to access in-hospital care.

Ramanujam’s Pocket Colposcope embodies her goal to shift the traditional perspectives of medical device design from doctor-centric, first-world settings toward the convenience of women in the real world.

Unlike bulky traditional colposcopes, the Pocket Colposcope is the size of a tampon and is equipped with a light and a channel to apply contrast agents that make diagnosis easier. The device can be connected to a phone or laptop to display images of the cervix, which are then sent to a gynecologist for diagnosis.

As an added benefit, healthcare workers don’t need to use a speculum, an aspect of the exam that many women find to be uncomfortable and sometimes even painful. Instead, clinicians can insert only the slender Pocket Colposcope into the vagina to closely examine the tissue, aiming to accomplish the examination without any major discomfort.

As Ramanujam and her collaborators devise a model to commercialize the Pocket Colposcope, they are also enlisting students in Duke’s collaborative Bass Connections program, which brings students from interdisciplinary backgrounds together to solve global problems. In March of 2017, students working on the Pocket Colposcope Bass Connections team traveled to Lima to speak with doctors, midwives in mobile clinics and biomedical engineers to discuss how the Pocket Colposcope could be implemented in Peru’s healthcare system.

“When we went to Lima, we already had expectations about what the Pocket Colposcope could do to improve and change the healthcare situation there,” says Manish Nair, a recent BME graduate in the Bass Connections: Pocket Colposcope program. “But as we learned more about women’s needs, we really saw how the bottlenecks, like a lack of physicians and on-site diagnostic tools, limit the care that women can access. I think it gave us a more realistic understanding of how this device could help in resource-limited settings around the world.”

The WHO estimates that more than 85 percent of the deaths from cervical cancer occur in low- and middle-income countries. That does not mean, however, that it’s absent from the United States. Although the rates of cervical cancer are declining as more people receive the HPV vaccine, each year more than 12,000 American women are diagnosed with the disease—and more than 4,000 die from it. 

But within those statistics, cervical cancer rates vary between states. Research from the Centers for Disease Control shows that a woman in Texas is three times more likely to develop cervical cancer than a woman in Massachusetts. In North Carolina alone, cervical cancer rates in rural areas like Anson County are twice as high as the rates in Durham County, where the metropolitan hospital system is more robust.

“When we discuss global health, my concern is that we focus on countries outside the US, even though we still have issues with cancer mortality in rural communities here at home,” says Ramanujam. “We need to find ways to fix that, and I think we start by investing in tools and education that will help women take control of their own health.”

When Ramanujam is asked how she hopes to achieve these goals, she creates a diagram. In it, her various projects branch out from a central idea that is communicated as clearly as the message on the pink mobile clinics: improving women’s lives.

Beyond developing new technologies, Ramanujam is focusing on what else she can do as a biomedical engineer and educator to empower women—such as launching outreach programs in Kolkata, India and Orange County, California to teach girls basic engineering problem-solving skills, working with Duke students who are passionate about creating a system of advocacy and awareness.

“Ultimately, we’d like to increase our pipeline of researchers and students who can make a difference with their work,” says Ramanujam. “We’re encouraging our students to actively engage with young women to show them how engineering can impact their healthcare.

HIV Prevention with Women’s Needs in Mind

Empowering women is critical to any attempt to improve healthcare on a global scale, agrees Ramanujam’s colleague, David Katz, the Nello L. Teer, Jr. Professor of Biomedical Engineering at Duke. In fact, as Katz often says, “Women’s health is global health.”

“A woman’s own personal and reproductive health often affects the health of her children and partner,” he notes. “Women across the globe are disproportionately affected by issues like sexually transmitted diseases and limited access to screening, and the ramifications from these issues can extend to the entire family.”

Since starting at the university in 1994, Katz has applied biomedical engineering to the science of reproductive biology––designing treatments to that empower women to protect themselves against sexually transmitted diseases such as HIV, the virus that causes AIDS.

Today, more than 36 million people around the world are living with HIV/AIDS. Most of them live in low- and middle-income countries, and most of them are young women: according to the United Nations, females make up 60 percent of the HIV cases in people between the ages of 15 and 24. 

Although men and women can currently take a pill, called pre-exposure prophylaxis, or PrEP, that is 90 percent effective at preventing HIV infection, it can cause digestive issues and stomach pain that cause them to stop taking it. Condoms are also effective, but only if men decide to wear one.  

As an alternative, Katz is designing topical microbicides with the goal of creating a treatment that mirrors the way women take birth control. Ideally, these prophylactics would be in the form of gels, implants or even vaginal rings, giving women the option to choose a method that works best for them.

When a woman has unprotected sex with a man who is HIV-positive, the virus in his sperm comes into contact with the mucous membranes in her reproductive tract. From there, the virus migrates below the top epithelial layer of cells in her vagina, where it can infect its target cells.

Microbicides would create a barrier between the virus and the mucous membranes, making it difficult­­––if not impossible––for the virus to pass through.  But first, the researchers in Katz’s lab need to understand how these microbicides maintain their potency, and how much of the compound is needed to ensure complete protection from HIV and other STDs.

The big question is understanding what women prefer to put in their bodies for protection. For example, some women prefer condoms because they are on-demand pregnancy protection, but others prefer to get a shot of progestin that offers long-lasting protection. Different people want different things, and we’re trying to cater to that.

David Katz Professor of Biomedical Engineering

Trained as a mechanical engineer, Katz draws on his expertise in fluid mechanics to study how these gel-like microbicides act once they are in the body. Through mathematical modeling and in-vivo studies, Katz and his students examine how microbicides move around when women place them in their vagina, how the compounds react to vaginal fluids and semen, and how well they stay in place during sex to ensure constant protection.

“Microbicides are tricky. Not only do we need to understand the pharmaceutical side of these compounds, we also need to understand how they interact with the physiology of women and the behavioral science associated with the willingness to use them,” says Katz. “For example, behavioral studies have shown women are less willing to use a microbicide if it’s really messy and difficult to apply.”

Katz and his collaborators in Duke BME have recently focused their efforts on a specific compound called Griffthsin. Originally a protein that was isolated from a type of red algae, Katz and Mike Lynch, an associate professor in BME, have started producing and refining Griffithsin using E. coli bacteria to study its potential as a microbicide.

Griffithsin is an ideal candidate because previous studies have shown that the protein can efficiently bind to key surface proteins on HIV, preventing it from attaching to human cells. And, says Katz, because Griffithsin is a very ‘sticky’ protein, it can attach itself to tissue in the reproductive tract with relative ease.

“This is a very intriguing molecule because of its stickiness,” says Katz. “If the virus can somehow escape the microbicide in the vaginal canal, it still needs to migrate through the tissue to infect cells. But if you have lots of Griffithsin molecules that are also stuck to the tissue, it acts as an effective backup because it’s another opportunity to grab the virus.”

Because they need to make enormous quantities of the molecule, Griffithsin isn’t ready to immediately study as a microbicide, but Lynch is enlisting students in his biochemical design course (BME 490) to refine and efficiently synthesize the protein with E. coli bacteria. That ability would eventually make producing Griffithsin cheaper, making it a viable option for places where resources are limited.

“I like Griffithsin because it is intended for the on-demand user,” says Katz. “The current topical products and microbicides that people use typically have a bit of a lag between when you apply them and when they become effective. But with Griffithsin, you don’t have that problem. The virus just collides with the molecule in the vagina, and because it’s an entry inhibitor, it gets to the virus before the virus can get to the tissue.”

Although more work needs to be done before Griffithsin becomes a viable prophylactic against HIV, Katz is determined to develop an effective vaginal microbicide given the end goal–allowing women to gain better control of how they protect themselves against disease.

“Some problems in medicine require engineering,” he says. “Women’s reproductive health is certainly one of them.”

Combining Expertise to Fight Cancer

Nimmi Ramanujam and David Katz’s labs may be separated by a quarter-mile of dense Duke forest, but their mutual goal of improving women’s lives has brought them together for a new project––one that combines their expertise––to help treat cervical cancer.

“Nimmi and I joke about why it took us so long to work together when we both study how engineering can affect reproductive biology,” says Katz. “With this project, we’re able to use my work with fluid mechanics to continue the line of work she’s doing with the Pocket Colposcope to help treat cervical cancer once it’s diagnosed.”

The project came about after Rob Morhard, a PhD student in Ramanujam’s lab, took Katz’s biofluid mechanics course in 2016. Morhard was interested in a problem pertaining to cervical cancer––specifically how to create a therapeutic that will treat the tumors on the surface of the cervix.

Center for Global Women’s Health Technologies (GWHT) Pocket Colposcope Victoria D’agostino

“This is the wonderful thing about academia, where you just have these conversations about ideas you’re interested in, and the next thing you know you’re working together,” says Katz.

Katz, Ramanujam, Morehead and other students in Ramanujam’s lab got to work studying how they could remove the cancerous tumors from the cervix using an ethanol-based formulation. While previous studies have shown that ethanol can kill tumor cells, the researchers also needed a way to keep the formula in place: “It needs to be localized on the tumor so it can do its job,” says Katz, “and to avoid damaging healthy tissue nearby.”

The team decided to use ethyl cellulose, which dissolves in ethanol and increases the liquid’s viscosity, making it thicker and more effective at ablating the tumors. But one day, as Morhard was cleaning out the storage containers for the liquid, he made a strange discovery.

“After doing a few experiments I was cleaning out the containers and I noticed that when I added water a white gel formed,” he says. “We hadn’t realized until that point that since ethyl cellulose was not water-soluble that it formed a white gel when it was mixed with water.”

This accidental discovery proved to be an advantageous development for the treatment.

“Our man issue with this treatment is ensuring that the injected ethanol stays localized around the injection site and that it stays in the tumor for a long time to increase efficacy,” says Morhard. “The longer the ethanol concentration within the tumor is elevated, the more likely the tumor cells are to die. The fact that this ethyl cellulose-ethanol solution is consistently effective in the treatment of tumors is likely due primarily to this gel formation.”   

Center for Global Women’s Health Technologies (GWHT) Nimmi Ramanujam, Rob Morhard

Along with these positive developments, the team is optimistic about how this new approach could be deployed in resource-limited settings worldwide. The method could cost less than one dollar per treatment, and because it doesn’t require electricity, specialized equipment or hard-to-supply consumables, it would be useful in a multitude of healthcare settings––especially mobile clinics that use Pocket Colposcopes to see how well the treatment is working.

Although the research still has a long road to reach the clinic, the team has established a proof-of-concept and published their first findings in Scientific Reports, a Nature research journal. They next plan to conduct safety trials in animal models.

For Ramanujam, these collaborative projects help to cement her belief in the work biomedical engineers are conducting at Duke­­—and far beyond campus.

“I think Duke is special because we recognize that engineering is part of a larger narrative in making the world a more equal place regarding healthcare for women and girls,” says Ramanujam. “The culture here is one of service, and the researchers and students embody that desire to use our work to help others.”