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 sides also draws a passerby’s attention: Todas las mujeres merecer 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, 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, a joint center between the Pratt School of Engineering and the Duke Global Health Institute, has devoted herself to fixing this problem. With a network of collaborators, from local caregivers to Duke faculty and students, she’s creating low-cost medical tools designed for women in settings with limited resources.

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

“Cervical cancer is a disease of excess mortality. This is the one cancer that can be prevented through well-established interventions, and if these interventions were available to all women I believe the cervical cancer mortality rate would be zero,” says Ramanujam. “The Pocket Colposcope is our first step towards bringing complex services traditionally offered at hard-to-reach referral settings to primary care.”

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 abnormalities.

Shaped like a tampon and packing the performance of a high-end clinical colposcope, the Pocket Colposcope re-imagines the way a gynecological exam is performed compared to both traditional and other redesigned, low-cost colposcopes on the market. Rather than visualizing the cervix from the outside, the tool is slender enough to be used inside the speculum. Due to the camera’s proximity to the cervix, the Pocket Colposcope works effectively with consumer-grade LEDs and a five-megapixel camera in lieu of high-end components, making it both cheaper and lighter than traditional colposcopes. Working with Robert Miros at 3^rd Stone Design to finalize the design, the team has the cost down to about $500 and weight under half a pound, making it ideal for use in mobile screening vans.

So far, Ramanujam, Dr. John Schmitt, a professor of obstetrics and gynecology in the Duke University School of Medicine, and their collaborators have implemented the Pocket Colposcope with over 500 women in seven sites on four continents.  Ramanujam and her team are working with Duke electrical and computer engineering professor Guillermo Sapiro to develop smart algorithms that bring clinical expertise in image interpretation to the community level.  And, in another effort to ensure women receive effective treatment in the community setting, she is collaborating with Duke BME’s David Katz to develop a novel “liquid scalpel” as a low-cost therapeutic that promises to be as effective yet significantly more accessible than standard-of-care ablative techniques for treating lesions in low-resource settings.

As Ramanujam and her team devise a model to commercialize the Pocket Colposcope, they are enlisting help from students from interdisciplinary backgrounds through Duke’s collaborative Bass Connections program. In March 2017, students working on the Pocket Colposcope Bass Connections team traveled with team leaders to Lima to speak with doctors, midwives in mobile clinics and biomedical engineers to discuss how the tool should be implemented into Peru’s healthcare system.

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. Each year more than 12,000 American women are diagnosed with the disease—and more than 4,000 die from it. 

“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 medically underserved communities here at home,” says Ramanujam. “We need to find ways to fix that. We need to invest in low-cost, high-quality interventions that can not only empower primary caregivers, but also improve a woman's experience during her gynecological exam.”

Toward that end, Ramanujam’s team has more recently developed a tampon-like introducer called the Calla for the Pocket Colposcope that can make the entire exam speculum-free, particularly for women who have never had a gynecological exam or are afraid of the speculum. A slimmer version of the Pocket Colposcope can be positioned through the Calla, which is then inserted either by a care provider or the woman herself into the vagina to provide reliable views of the cervix. 

Ramanujam is using the Calla in an advocacy project to raise women’s awareness of their reproductive anatomy and cervical cancer through a collaboration with Duke Center for Documentary Studies director Wesley Hogan, Franklin Humanities Institute director Deborah Jenson and School of Medicine faculty Megan Huchko and Gita Suneja. The idea is for a woman to be able to explore her anatomy in the comfort of her home in order to understand both what her cervix looks like and the importance of cervical health and cervical cancer prevention.

Beyond developing new technologies, Ramanujam is focusing on what she can do as a biomedical engineer and educator to encourage women to be the next generation of technology leaders for women’s health. “Ultimately, we’d like to increase our pipeline of researchers and students who can design technologies that improve women’s lives,” says Ramanujam. “We’re encouraging our students to actively engage with young women to show them how engineering can impact women’s health.”

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 and Professor of Obstetrics and Gynecology 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 of her partner,” he notes. “Women across the globe are disproportionately affected by the challenges of 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 and medicine – focusing on diagnostics and treatments that empower women to protect themselves against sexually transmitted infections such as HIV, the virus that causes AIDS, as well as on contraception.  Prior to his arrival at Duke, Katz had become an authority on advancing methods of contraception and understanding, diagnosing and treating fertility and infertility.

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. 

In the HIV/AIDS research and development community, there is emphasis upon prevention (termed pre-exposure prophylaxis – “PrEP”) as well as cure.  Condoms are effective if they are used, but their use is not widespread typically not controlled by the woman.  Vaccine development continues, but an effective one is not on the near-term horizon.

“Women’s health is global health. A woman’s own personal and reproductive health often affects the health of her children and of her partner.”

There is currently a pill containing anti-HIV drugs which, if taken diligently, can reduce the likelihood of HIV infection. This is a major advance, but missed pills reduce effectiveness more for women than men, and there are other drawbacks, including digestive issues and pain.

Globally, there is a need for multiple options for HIV/AIDS prevention, and success will not be a one-size-fits all result.  Katz’s work has a large focus upon topically acting anti-HIV drugs, called microbicides, and emphasizing those that women can apply very soon before sex––“on-demand” products. Microbicide products could take several forms, including gels, dissolving tablets, films and intravaginal rings, as well as injections and implants, to provide women the choice of a method that works best for them.

When a woman has unprotected sex with a man who is HIV-positive, the virus in his semen comes into contact with the mucosal surface 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.

Microbicide products could create both a chemical and physical barrier between the virus and mucosal surface, making it difficult­­––if not impossible––for infectious virus to pass through and reach the infectable cells.  Creating such products is, in part, an engineering design problem, says Katz. And part of the design process is behavioral as well as biological.

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

Originally trained as a mechanical engineer, Katz draws on his expertise in fluid mechanics to study how microbicides migrate once they are in the body. Through mathematical modeling and in vitro and in-vivo experimental studies, Katz and his students examine how microbicides distribute after women place them in their vagina, how the anti-viral compounds react to vaginal fluids and semen, and how well they stay in place during sex to ensure constant protection. 

Some of this work involves developing and applying new imaging instruments, in collaboration with Adam Wax, a BME professor at Duke.  Those instruments are being used both on the bench in laboratory studies and in clinical imaging studies in women.  They measure details of the distributions of products such as gels, the molecules which are delivered, and structural details of the tissue into which the molecules migrate. Wax’s expertise in conceiving, creating and applying new optical imaging devices is combined with Katz’s expertise in mechanical design to tailor the instruments to particular demands of the imaging, for example detailed in vivo imaging within the reproductive tract in women.

“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.”

To study these microbicides, Katz is collaborating with Michael Lynch, an associate professor in BME. The team has recently focused their attention on Griffithsin, a protein isolated from a type of red algae. Lynch began working on the compound in his biochemical design course (BME 490), where students learned how to refine and efficiently synthesize the protein with E. coli bacteria.

Previous studies have shown that Griffithsin can efficiently bind to key surface proteins on HIV, preventing the virus from attaching to and infecting cells. Griffithsin is also a ‘sticky’ molecule, as it can bind to the sugar-coated envelopes of viruses and onto the surface of the reproductive tract with relative ease, with Katz comparing it to ‘molecular flypaper’. 

“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 time 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 it gets to the virus and neutralizes it before the virus can get into the tissue.”

Currently, Lynch is working with students to refine Griffithsin to make it more functional for a global health setting, including increasing its shelf-life as a topical treatment and engineering variants of the molecule to be temperature-resistant. While HIV is the current target, Lynch and his team are also exploring how to expand the molecule’s use to potentially protect against other viruses, including the Herpes simplex virus and human papilloma virus––the virus that causes cervical cancer.

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.

“Many problems in medicine require engineering to solve them, as we in BME know,” he says. “Women’s reproductive health is certainly one of them.”

Combining Expertise to Fight Cancer

Nimmi Ramanujam’s 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 are committed to applying engineering to improve women’s health,” says Katz. “With this project, we’re able to use my work with fluid mechanics, biomechanics and mechanical design to extend the line of work she’s pioneered with the Pocket Colposcope, to help treat cervical cancer once it’s diagnosed.”

“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.”

The idea for 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.

“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, Morhard 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 liquid 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 main 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.”

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 could be implemented without electricity, specialized equipment or hard-to-supply consumables. Thus, it would be useful in a multitude of healthcare settings –– including mobile clinics that use the Pocket Colposcopes to help identify women at risk of cervical cancer.

Although the research still has a long road to reach the clinic, the team has established a proof-of-concept and recently published their first findings in Scientific Reports, a Nature research journal. They next plan to conduct safety trials in other scientific models, while they refine details of the injection process and then design an injection device suitable for the same global settings in which the Pocket Colposcope is applied.

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.”