June 1, 2017 (Vol. 37, No. 11)

Gail Dutton

StemoniX Finds Billion-Cell Lots Enhance the Consistency of Toxicity Testing Operations

The microHeart® and microBrain® microtissues developed by StemoniX overcome many of the challenges associated with tissues developed from human induced pluripotent stem cells (hiPSCs) to provide greater consistency and high degrees of functionality for high-throughput drug screening and toxicity testing, according to company officials.

“When we founded the company in 2014,” recalls Ping Yeh, StemoniX’ CEO and cofounder, “everyone said that they wanted 3D tissue.” But when the prospective customers were invited to describe their drug development work, they revealed that what they really wanted were mature cells that were structured properly.

“Function follows structure in biology,” notes Mr. Yeh. “The stem cell-derived organ cells that were available were created from traditional flat cultureware and were very immature,” and so lacked the structure and function of native human tissue.

Mr. Yeh and StemoniX’ other cofounder, Bob Petcavich, Ph.D., are delivering this structure and cellular maturity in a 2D+ model. The result is organ microtissue that combines the best features of both 2D and 3D tissues in a form than can be analyzed easily.

Traditionally, heart or brain cells developed from hiPSCs were grown on flat surfaces. Making things 3D was thought to be the only way to drive maturity.

“Although traditional cultureware is flat and easy to control, the cells grown there lack the structure and function of cells grown in the body,” says Mr. Yeh. “Our 2D+ approach is the best of both worlds, delivering tissue structure and function similar to that of native tissue.

“To visualize the microHeart tissue structure, think of a corrugated metal roof or corduroy fabric. They’re flat, but they have structure. We’re producing microtissues that are one to two layers thick, but are organized.”

Role of the Microenvironment

In biology, the microenvironment influences the cells, insists Mr. Yeh. This study of mechanobiology has driven the development of the microHeart and microBrain. Mr. Yeh explains that changing the environment in which cardiomyocytes grow, for instance, affects the cells’ shape, which affects their structure and, therefore, their function.

“As the cellular structure changes from flat and disorganized (2D) to stratified and oriented in StemoniX’ 2D+ model,” asserts Mr. Yeh, “the structures within and between the cells are formed accurately.” These structures closely resemble the correct cardiac muscle fiber organization seen in the body, and they lead to accelerated cell maturity. Proving the point, microHeart shows improved sarcomeric assembly and other structures and features indicative of more mature cardiomyocytes.


Cardiomyocytes derived from human induced pluripotent stem cells and aligned with StemoniX’ microHeart, a technology that may be used to create microtissues that integrate mature, structured cells.

“What is also interesting,” continues Mr. Yeh, “is that our cardiomyocytes express genes related to the electrochemical processes of the cell at a rate that is 100–200% greater than those of unstructured cardiomyocytes.”

The microHeart closely mimics native tissue, beating spontaneously and responding to adreniergic stimulation and ion channel inhibition, and so is a highly physiologically relevant model for researchers.

A high correlation with native tissue is also achieved for hiPSC-derived neuronal cells. “Our microBrain,” declares Mr. Yeh, “is unique because the tissue has a high percentage of astrocytes,” cells that play a role in supporting neural processing. The microBrain’s cellular mix also includes glutamatergic and GABAergic neurons.


Cortical cells, glutamatergic and GABAergic neurons and astrocytes, derived from human induced pluripotent stem cells in a culture prepared with StemoniX’ microBrain technology.

Scalability

The microHeart and microBrain tissues are made in very large batches. “Millions of hiPSCs are transformed into billions of cells,” informs Mr. Yeh. The large batch sizes deliver the high degree of consistency needed by drug studies.

Importantly, the tissues are delivered in a format consistent with current laboratory practices. The microHeart microtissue, for example, is available in 96- and 384-well plates. In the future, StemoniX plans to also make them available in 1,536-well plates. That scale and easy deliverability sets StemoniX apart from its competition. It also reduces the need for animal tissue and the accompanying ethical issues and imperfect correlation to human tissue.

The idea behind the microHeart stems from Mr. Yeh’s bout with cancer. “Four years ago, I was diagnosed with Hodgkin’s lymphoma,” relates Mr. Yeh. “Four mouths into treatment, doctors determined that I was resistant to chemotherapy and started me on a more toxic version.”

Mr. Yeh was stunned to learn there was no pretest to determine the likely toxicity to his body, only a postchemotherapy assessment. “I promised myself,” remembers Mr. Yeh, “that if I recovered, I would redirect my skills in nanotechnology, business, and execution from the semiconductor industry to biotechnology.”

The commonality between the two industries is consistency. “The semiconductor industry,” comments Mr. Yeh, “has a lot of know-how surrounding manufacturing and development processes that is light-years ahead of other industries.”

Mr. Yeh and Dr. Petcavich, a serial inventor-entrepreneur, applied the Lean Startup approach to build StemoniX. Rather than developing something interesting, scaling it up, and redesigning it for commercialization—and only then start thinking about markets and reimbursement—the team incorporated scaleup, quality assurance, and commercialization concerns into the early product designs. When applied to living cells, that expertise means controlling the environment very carefully.

StemoniX’ microHeart and microBrain earned the company space at JLABS, a Johnson & Johnson incubator, and the grand prize in the 2016 Minnesota Cup business competition. Mr. Yeh says that StemoniX’ new microtissues are gaining traction with customers, too, and that interest in the company’s 2D+ approach is growing.

“People are understanding that ‘3D’ is just a catchphrase for ‘mature cells,’” states Mr. Yeh. “We provide these cells in an easy format.”

StemoniX

Location: 1635 Hennepin Avenue, Suite 200, Minneapolis, MN 55403

Phone: (855) 783-6669

Website: www.stemonix.com

Principal: Ping Yeh, CEO and Cofounder

Number of Employees: 20+

Focus: StemoniX develops ready-to-use high-throughput screen plates of heart and brain microtissues developed from human induced pluripotent stem cells for use in drug discovery and development.