When Nivan Sharma imagines his future, it always includes children. But the third-year medical student knows his pathway to parenthood will be tougher than most.

Ten years ago, at the age of 16, Nivan was diagnosed with osteosarcoma. The bone-cancer diagnosis upended his life; he and his parents temporarily moved from Prince Rupert to Vancouver for care at BC Children’s Hospital, where he underwent surgery followed by nine months of chemotherapy. Today Nivan thankfully remains cancer-free, but the treatments he endured carried the risk of long-term side effects — including infertility.

“Post-treatment, I ended up out of curiosity getting checked for infertility, as I was starting to get into relationships,” he shares. Although he had stored sperm prior to beginning treatment, the result was difficult to hear. “I got a call from the lab, and they said, ‘We don’t see anything.’ The news shook me more than I was expecting.”

Nivan is not alone. Up to two-thirds of male pediatric cancer survivors will face infertility in adulthood, as radiation and chemotherapy treatments carry the risk of a severe form of male infertility called non-obstructive azoospermia, or NOA, in which the body produces very few, if any, sperm. Although rarely discussed openly, NOA is not uncommon, affecting one in 100 men, as well as people of diverse gender identities assigned male at birth. The impact can be devastating.

“Infertility can be really, really difficult for a lot of men and couples that I see. It takes an emotional toll,” says Dr. Flannigan, associate professor and director of the Reproduction and Sexual Medicine Centre in the UBC Department of Urological Sciences.

Globally, about one in six couples experience difficulty conceiving a child. About half of those cases involve male infertility, with NOA affecting about 15 percent of infertile men. The condition can be the result of cancer treatments or certain genetic conditions, but in the vast majority of cases, its underlying cause is a mystery — one that Dr. Flannigan and his colleagues are determined to solve with the help of next-generation bioengineering, genomics and machine-learning technologies.

Currently, the only available treatment for patients with NOA is an invasive and time-consuming procedure to surgically extract testicular tissue and search it for ‘rare sperm.’

“If we find enough viable sperm, we can do IVF,” Dr. Flannigan explains. “Right now, we’re able to find sperm about 50 per cent of the time, but that doesn’t guarantee success. We ideally need to find at least one sperm per each egg, among millions of other cells, which takes hours. It’s the literal definition of looking for a needle in a haystack.”

Determined to make the procedure more effective and accessible, Dr. Flannigan teamed up with UBC’s Dr. Hongshen Ma, professor in the Department of Mechanical Engineering and School of Biomedical Engineering (SBME). Together, they built an AI model that can automate and accelerate the search process, enabling the collection of rare sperm that might otherwise be missed.

“We think there’s a lot of room to improve the IVF process by leveraging machine-learning technology,” he says.

The results have been promising — so much so that Dr. Flannigan expects to start clinical trials of the AI tool within three to five years. But while the tool has the potential to improve clinical outcomes for many people, it isn’t a complete solution.

“Ultimately, there are still going to be a lot of patients that simply don’t have sperm,” he says.

For these people — including young cancer patients who have not yet gone through puberty and therefore don’t have the option to store sperm prior to treatment — there are no other currently viable options.

But Dr. Flannigan and his UBC colleagues are working to change that, using techniques that would have been scarcely imaginable even five years ago.

Lab-grown sperm on the horizon

In Dr. Flannigan’s lab at the UBC-VGH M.H. Mohseni Institute of Urologic Sciences (MIUS), a hum fills the air as a 3D-bioprinter begins extruding a gel-like substance onto a glass plate in a complex sequence of movements, under the watchful eye of senior research assistant Meghan Robinson. The sight would be familiar to anyone who’s seen a conventional 3D printer build objects out of polymer plastic filament — only this printer is stitching together the building blocks of life: human cells.

In a world-first, Dr. Flannigan and research colleagues at the MIUS have bio-printed a model of human testicular tissues using human-induced pluripotent stem cells — a special type of stem cell that can differentiate into any type of cell.

Building on an earlier UBC breakthrough, the team generated four types of testicular cells from the stem cells and, using special bio-ink engineered in collaboration with biomedical engineering professor Dr. Stephanie Willerth from the University of Victoria, printed them into a structure resembling the tiny tubes in the testes where sperm are produced.

These bioprinted ‘mini testicles’ were encased in a special gel filled with specific nutrients and vitamins to help them mature. Within a week, some of the cells showed signs that mimicked the onset of puberty — a time when sperm production starts occurring in the human body.

“What we’re trying to do with 3D bioprinting is recreate what’s happening in a healthy testicle as accurately as we can. If we can determine what the cells need to progress through all the phases of sperm production, we can use that knowledge to figure out how to create sperm for a patient with NOA,” says Dr. Flannigan.

Of course, this is easier said than done. Sperm production is a highly complicated process involving an interplay of different types of cells, anatomical structures and an array of chemical signals. It requires team-based, multidisciplinary research.

Precision pathways to parenthood

Serendipitously for Dr. Flannigan, his lab neighbour at the MIUS is Dr. Govind Kaigala, a UBC associate professor of biomedical engineering and expert in microfluidics — an emerging technology that is helping unlock new discoveries across a realm of health science disciplines spanning diagnostics, drug discovery, disease modelling and more.

At the Conconi Family Biodevice Foundry in UBC’s new Gordon B. Shrum Building, home of the School of Biomedical Engineering, Dr. Kaigala is designing special microfluidic chips that will yield precision insights into what happens when sperm production goes right — and what might stop it from going wrong.  

“Some of the techniques we’ve developed in bio-devices for cancer can be repurposed for urological diseases, including, in this case, male infertility,” says Dr. Kaigala, whose research focus has mainly been on cancer and tumour profiling.

Dr. Flannigan and his research partners will use the microfluidic chips to perform rapid, precise testing of all the complex interactions that occur in sperm production at the molecular level. Once the interactions between healthy testes cells are well understood, the team will be able to zero in on what’s happening when those interactions go awry and, hopefully, pinpoint molecules that could help overcome the problem.  

“In a perfect world, we could take a tissue sample and use machine learning to look for sperm. And if we can’t find a sperm, we could build a pipeline to 3D bioprint cells into a microfluidic chip, identify what’s going wrong, and then identify molecules to help correct that,” says Dr. Flannigan.

It’s a bold vision, but one he’s committed to achieving. “I just see there being so much opportunity to have a positive impact in terms of advancing the science in an area that’s understudied, and for couples struggling with infertility. There’s a significant need,” he says.

Nivan Sharma, meanwhile, can’t help but think of the many childhood cancer patients who might one day benefit from Dr. Flannigan’s research.

“I was lucky, in that I was old enough to store a sperm sample before beginning my cancer treatment,” he says. “But most of the kids that I was in treatment with were too young to go through that process, even if they were given a warning by their team about the risk of infertility. If this research comes to fruition, it will be life-changing for so many people.”