IBBME research journal cover-worthy

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IBBME research journal cover-worthy

Undergraduate-authored biomimetic research from Milica Radisic’s Laboratory for Functional Tissue Engineering featured on June scientific journal covers

June 29, 2011


Influence of Substrate Stiffness on the Phenotype of Heart Cells. Bashir Bhana, Rohin K. Iyer, Wen Li Kelly Chen, Ruogang Zhao, Krista L. Sider, Morakot Likhitpanichkul, Craig A. Simmons, Milica Radisic	Biphasic Electrical Field Stimulation Aids in Tissue Engineering of Multicell-Type Cardiac Organoids. Loraine L.Y. Chiu, Rohin K. Iyer, John-Paul King, and Milica Radisic

The June covers of Tissue Engineering A and Biotechnology and Bioengineering feature images from research out of the Institute of Biomaterials and Biomedical Engineering (IBBME) core faculty Milica Radisic's Laboratory for Functional Tissue Engineering. And although Radisic is lead researcher on both papers, first authors are Loraine Chiu (ChemEng 0T7, BME MASc, BME PhD 1T2) for "Biphasic Electrical Field Stimulation Aids in Tissue Engineering of Multicell-Type Cardiac Organoids" and Bashir Bhana (ChemEng 0T8) for "Influence of Substrate Stiffness on the Phenotype of Heart Cells." The cover-worthy research came out of Chiu and Bhana’s undergraduate research projects. To have research featured on a journal cover is an honour; to have undergraduate research featured on a journal cover is very rare.

It’s not surprising given the culture of academic excellence Radisic cultivates in her lab. Rohin Iyer (EngSci 0T5, BME PhD 1T1), IBBME PhD candidate who supervised Chiu and Bhana’s research and co-authored both papers, noted that where others might be more sceptical of undergraduate research, Dr. Radisic "allows for the possibility that undergraduate research can be meaningful right from the outset. This is why her students are first authors. Her trust inspires her students to work hard and live up to her expectations of excellence." Her mentorship of students has not gone unnoticed elsewhere, either; Radisic is featured this month on Nature's website as a model for mentoring.

Chiu, who has worked with Radisic from her undergraduate studies in Chemical Engineering, through to her MASc and now her PhD, chose Radisic to work with because she is one of the "most competitive researchers in cardiac tissue engineering."

"When I was an undergraduate, I read about how Radisic was using electrical impulses to stimulate cells to beat," Chiu recalled in an interview outside the Radisic lab. "That’s what got me interested in working with her." That interest led to Chiu’s featured research, which involved biphasic electrical stimulation of engineered cardiac tissues. Her work is representative of biomimetic experiments which reproduce natural properties and environments of body tissues in engineered cells and tissues.

But Radisic goes above and beyond the call of duty when it comes to her researchers.
"I stayed with her because her lab is a great environment to conduct research in," stated Chiu. "I’ve been able to work on completely different projects and explore various bioengineering methods while remaining in the same field. And Dr Radisic gives me many opportunities to write research papers, reviews and book chapters, even when I was an undergraduate. And she encourages me to present my work at conferences and to research groups."

It was Radisic’s reputation that initially drew Iyer in, initially. "I came to know of Dr Radisic through her papers published while she was still a PhD and postdoc at MIT. When I was still an undergraduate student at the time and read her papers in one of the courses I was taking. When I found out she had recently been hired at U of T, it was almost too good to be true." But it was the person behind the research made it easy for Iyer to work with Radisic: "She is a talented and brilliant young investigator as well as a fun person to be around." Iyer is not alone in his asssement of Radisic as a "brilliant young investigator": it was announced today that Radisic is the recipient of the 2011 Professional Engineers of Ontario Young Engineer Medal.

Bhana, author of the article featured on the cover of Biotechnology and Bioengineering , has moved from research at IBBME to a position in industry. Iyer, who was co-author of the research paper, noted that Bhana’s research represented another biomimetic inquiry, this time into the optimal substrate stiffness for engineered heart cells.

Radisic is an Associate Professor with appointments at both IBBME and in the Department of Chemical Engineering. Her research program focuses on cardiac tissue engineering and regenerative medicine, including work in tissue engineering of cardiac patches, injectable biomaterials, microfluidic cell separation, and microfabricated systems for cell culture. Her work falls under the IBBME research theme of Biomaterials, Tissue Engineering and Regenerative Medicine.

Paper Abstracts

Influence of Substrate Stiffness on the Phenotype of Heart Cells.
Bashir Bhana, Rohin K. Iyer, Wen Li Kelly Chen, Ruogang Zhao, Krista L. Sider,
Morakot Likhitpanichkul, Craig A. Simmons, Milica Radisic

Adult cardiomyocytes (CM) retain little capacity to regenerate, which motivates efforts to engineer heart tissues that can emulate the functional and mechanical properties of native myocardium. Although the effects of matrix stiffness on individual CM have been explored, less attention was devoted to studies at the monolayer and the tissue level. The purpose of this study was to characterize the influence of substrate mechanical stiffness on the heart cell phenotype and functional properties. Neonatal rat heart cells were seeded onto collagen-coated polyacrylamide (PA) substrates with Young’s moduli of 3, 22, 50, and 144 kPa. Collagen-coated glass coverslips without PA represented surfaces with effectively ‘‘infinite’’ stiffness. The local elastic modulus of native neonatal rat heart tissue was measured to range from 4.0 to 11.4 kPa (mean value of 6.8 kPa) and for native adult rat heart tissue from 11.9 to 46.2 kPa (mean value of 25.6 kPa), motivating our choice of the above PA gel stiffness. Overall, by 120 h of cultivation, the lowest stiffness PA substrates (3 kPa) exhibited the lowest excitation threshold (ET; 3.5_0.3 V/cm), increased troponin I staining (52% positively stained area) but reduced cell density, force of contraction (0.18_0.1 mN/mm2), and cell elongation (aspect ratio¼1.3–1.4). Higher stiffness (144 kPa) PA substrates exhibited reduced troponin I staining (30% positively stained area), increased fibroblast density (70% positively stained area), and poor electrical excitability. Intermediate stiffness PA substrates of stiffness comparable to the native adult rat myocardium (22–50 kPa) were found to be optimal for heart cell morphology and function, with superior elongation (aspect ratio>4.3), reasonable ET (ranging from 3.95_0.8 to 4.4_0.7 V/cm), high contractile force development (ranging from 0.52_0. to 1.60_0.6mN/mm2), and well-developed striations, all consistent with a differentiated phenotype.

Biphasic Electrical Field Stimulation Aids in Tissue Engineering of Multicell-Type Cardiac Organoids.
Loraine L.Y. Chiu, Rohin K. Iyer, John-Paul King, and Milica Radisic

The main objectives of current work were (1) to compare the effects of monophasic or biphasic electrical field stimulation on structure and function of engineered cardiac organoids based on enriched cardiomyocytes (CM) and (2) to determine if electrical field stimulation will enhance electrical excitability of cardiac organoids based on multiple cell types. Organoids resembling cardiac myofibers were cultivated in Matrigel-coated microchannels fabricated of poly(ethylene glycol)-diacrylate. We found that field stimulation using symmetric biphasic square pulses at 2.5 V/cm, 1 Hz, 1 ms (per pulse phase) was an improved stimulation protocol, as compared to no stimulation and stimulation using monophasic square pulses of identical total amplitude and duration (5 V/cm, 1 Hz, 2 ms). This was supported by the highest success rate for synchronous contractions, low excitation threshold, the highest cell density, and the highest expression of Connexin-43 in the biphasic group. Subsequently, enriched CM were seeded on the networks of (1) cardiac fibroblasts (FB), (2) D4T endothelial cells (EC), or (3) a mixture of FB and EC that were precultured for 2 days prior to the addition of enriched CM. Biphasic field stimulation was also effective at improving electrical excitability of these cardiac organoids by improving the three-dimensional organization of the cells, increasing cellular elongation and enhancing Connexin-43 presence.

University of Toronto Institute of Biomaterials and Biomedical Engineering

IBBME research journal cover-worthy