Making the (right) Cut

the term “Surgical Precision” is used to describe the finesse and the highly accurate nature in which a surgeon can cut diseased tissue from healthy tissue. This precision depends as much on the skill of the surgeon, as it does on the information they have about the tissue, to inform their surgical decision-making process. As is the case for most medical conditions, it is critical to remove and/or treat diseased tissue to prevent its spread into surrounding healthy tissue. In a disease like cancer, the complete removal of the tumour in some cases is the critical step in ensuring that relapse does not occur. But how do you know for certain that all the diseased tissue has been removed?

Co-founded in 2013 by Liz Munro (IBBME0T9), Perimeter Medical Imaging’s mission is to provide better tools for cancer surgeons. They specialize in building real-time, high resolution imaging devices which provide sub-surface images of tissue that can be used by surgeons for intra-operative tissue assessment.

“Surgeons are usually working with images collected preoperatively – that is, before the surgery, as well as their own visual inspection and palpation of a piece of tissue once it has been excised. They have limited real-time tissue assessment tools to make more informed decisions during the operation.” says Liz.

The gold standard for tissue assessment is post-operative pathology. In this process, an excised tissue specimen is fixed in formalin, embedded in paraffin, and sliced thinly to produce histology slides which can be viewed with a microscope, often leveraging dyes to highlight different cellular structures. A pathologist examines the slides and writes a pathology report outlining their findings. In the case of cancer removal surgeries, if cancer cells are reported as being close to or at the surface of the excised tissue specimen, additional intervention such as a second surgery may be recommended to the patient.

“Postoperative pathology will always be the diagnostic step for excised tissue,” explains Liz, “the challenge is that it takes a significant amount of time – from half-a-day to a full week, to receive the results of this detailed analysis. With a limited number of intraoperative, tissue assessment techniques available to surgeons, a reduction in second surgeries has been a challenge. We aim to give surgeons additional information at the time of surgery, which we hope will inform their real-time decision making, allowing them to achieve better results and reduce the need for patients to come back for second surgeries.”

Perimeter’s first product – the OTIS™ tissue imaging system – has received United States Food and Drug Administration (FDA) clearance and the company is preparing for a sales launch in 2020. The OTIS™, is an imaging tool which provides high-resolution, real-time imaging of the margin of an excised tissue specimen, enabling clinicians to visualize sub-surface structures up to 2 mm below the surface, while maintaining the integrity of the specimen for post-operative pathology. This is a crucial data set that is currently unavailable to surgeons in real-time.

Researchers from the Institute of Biomedical Engineering (BME) at the University of Toronto have developed a new method to precisely control the structure and function of immune complexes (ICs) using DNA origami. The findings, published in a recent issue of ACS Nano, could advance our understanding of immune system responses and pave the way for improved vaccines and immunotherapies.

Immune complex formation is a critical process in the body’s defense, occurring when antibodies bind foreign antigens, marking them for destruction by the immune system. The immune responses triggered by immune complexes depend on their physical properties, such as size and composition. However, traditional methods for synthesizing ICs produce heterogeneous assemblies, limiting the ability to predict or control these responses.

A cornerstone in Professor Leo Chou’s research is DNA origami, which uses DNA––the same biological building block that makes up the genome–– to create nano-sized structures onto which molecules can be positioned with nanometer precision.

The research team designed DNA nanostructures decorated with antigens and studied their interactions with antibodies. By tuning factors such as antigen spacing and valency on the nanoparticle, the researchers discovered that the spatial pattern of antigens controlled the formation of immune complexes as either single monomers or large aggregates. This could significantly change how these structures interact with immune cells and elicit downstream immune responses.

“We were surprised that a difference of just a few nanometers in antigen spacing had such a drastic effect on immune complex structure. This could have implications for vaccine and immunotherapy design,” explains Professor Leo Chou, the corresponding author of the study. ” DNA origami provided us with the perfect tool to tackle this question.”

Using DNA origami, the researchers were able to design a library of synthetic immune complexes or various configurations, and test their uptake by immune cells, such as macrophages and dendritic cells. The experiments demonstrated that IC structure directly influenced how these cells engaged and internalized the complexes.

“By engineering the structure of immune complexes using DNA origami, we were able to systematically explore how IC design impacts their interactions with immune cells,” says Travis Douglas, a PhD student and the study’s lead author. “These synthetic immune complexes are quite versatile and can be programmed with different functionalities. We are excited to explore their utility such as delivery systems for immunotherapies and vaccines.”

Looking ahead, the team plans to expand their research by studying how these synthetic ICs can be formed from different types of antibodies as well as how they behave in vivo. ” This is only the beginning of this project. We’ve created immune complexes that do not exist in Nature. We need to better characterize their immune responses both in vitro and in vivo,” says Chou. “We believe DNA nanotechnology offers an exciting opportunity to create programmable immune interventions.”

“You can think of OTIS™ like a photocopier for excised tissue,” says Liz, “but it allows the user to see just inside the specimen. The imaging technique we use is called Optical Coherence Tomography, which is analogous to ultrasound, but uses light instead of sound to produce much higher resolution subsurface images. The product has come a long way since we started the company. We received FDA clearance on an earlier generation of the device in 2016, and just recently (at the start of 2019) received another FDA clearance for an updated model that is 10x faster than the original and includes a novel specimen positioning system. I’m very lucky to work with a team of talented and highly motivated individuals in making this happen.”

After finishing her undergraduate studies at McGill in physics, Liz Munro pursued her Masters of Applied Sciences (MASc) degree in biomedical engineering with Dr. Ofer Levi, graduating in 2009. After an initial stint working with Ontario Centre of Excellence (OCE) on technology innovation projects, Liz started working with a local Toronto startup, Tornado Medical Systems. A project which had been incubated and researched by Tornado was spun out into a new company- Perimeter Medical Imaging, in 2013, and Liz was part of the founding team.

Since then, the company has grown from the original four founders to over 20 people, and has raised more than $21 million from private investors and government agencies.

“I remember when I started at Tornado, I was surprised by how complex their medical device quality management system was.” says Liz. “There were an incredible number of standard operating procedures to learn as part of onboarding, and it was not something that I had been exposed to in the past.”

Adherence to quality standards is a critical aspect of working at a medical device company. Every job function, from administration to engineering to sales must comply with applicable regulatory requirements to ensure that the medical device they design, develop and eventually manufacture, is safe, effective and can be legally sold.

“This has been a huge advantage of hiring staff out of the IBBME MEng (Masters of Engineering) program, as the curriculum includes an introduction to regulatory requirements and quality management systems. We’ve found that individuals coming out of this program tend to “get it” and are quick to learn the ropes of working in a medical device development environment.”