Images courtesy of MIT.
Physician Joseph P. Vacanti and engineer Robert Langer first introduced the concept of tissue engineering in the early 1980s. Today, they are among a Boston/Cambridge stronghold of scientific researchers making advances in that seminal work. Also propelling progress is biomedical researcher and SLAS member Ali Khademhosseini, associate professor at Harvard-MIT's Division of Health Sciences and Technology, Brigham and Women's Hospital and Harvard Medical School as well as an associate faculty member at the Wyss Institute for Biologically Inspired Engineering.
Ali Khademhosseini, Ph.D., like many productive researchers, grew into his current career and research passion because he nurtured his initial curiosity during undergraduate study.
"Because I was good at chemistry and math, people thought that chemical engineering would be a good academic path for me and I went to the University of Toronto," Khademhosseini says. "To be honest, at first I didn't really know what this entailed but learned that chemical engineering is a great discipline and it can offer good ways to solve problems using critical and analytical skills, reasoning and basically teach you how to come to the gist of the problem by simplifying it to the important parameters."
In Toronto, Khademhosseini had the opportunity to begin the work that now defines his career – engineering cells to make artificial tissues outside the body. After earning his bachelor's and master's degrees in chemical engineering at Toronto, Khademhosseini pursued his doctorate degree in the laboratory of tissue engineering pioneer Langer at the Massachusetts Institute of Technology.
"MIT is a very good place with lots of opportunities and was the best place to go at the time," Khademhosseini adds. "I learned a lot during my Ph.D. studies about approaches using microfabrication technology to pattern surfaces and explore regions where cells attach and other regions where they potentially don't attach. Basically I used chemistry and combined it with microfabrication approaches to influence cells, particularly cell attachment, spreading and migration on a two-dimensional substrate. All the work during my Ph.D. focused on making things on a surface and controlling cells interacting with these surfaces. I developed lots of different approaches to interface cells inside microfluidic channels, to be able to micropattern surfaces and cell interaction."
But, perhaps more importantly, he says he learned the fundamental and foundational basics of effective laboratory science and technology that are earned by sweating through the hard work and facing head on the occasional tough moments.
"I began to understand perseverance and how to stick in there and not give up, and I discovered how to design experiments so that even if they fail you can learn from them," Khademhosseini explains. "I would have my vision, my story, and then think of all the questions I wanted to answer. That way every experiment I did – whether or not it had positive results – moved me toward answering those questions."
Khademhosseini says he wasn't a "quick starter" as it wasn't until the end of 2003 in the middle of his Ph.D. work that he published his first paper as lead author, "Direct patterning of cell and protein resistant polymeric monolayer and microstructures," in Advanced Materials 15 (23).
That paper concludes: "we present a novel method of patterning cells and proteins with a copolymer comprised of poly-anchoring groups. The technique allows for control over surface topography and surface molecules. The potential use of the technique for the development of improved biosensors and analytical tools is an area of active research."
And active research there has been! Following his Ph.D. work on 2D surfaces, Khademhosseini wanted to elevate his work to the next level.
"When beginning my faculty career, I wanted to do similar work in a controlled environment but wanted to explore what cells are seeing in a 3D aspect," he shares.
They developed gelatin-like materials that allow researchers to control the architecture and encapsulate cells. This engineering marvel solved a persistent problem that previously had been holding work back – that of mimicking human function where cells and blood are separate but yet nearby to allow for the necessary exchange of molecules.
"This work allowed us to start making tissues that have much better behavior, to make 3D tissues that actually function like the tissues of our body," he says. "For example, this technique was used to make pieces of heart muscle. We engineered a piece of tissue in the laboratory that reflected the same type of beating or contractual activity as the human heart."
They first aligned cardiac muscle cells to form small, beating strings. Next, they embedded these strings in their gelatin material to resemble the sheets of muscle that comprise the human heart. With this method, they also were able to add other types of cells to provide support for the muscle, replicating how natural tissues involve cells to form interactions in the body.
"Down the road, this technique can this be used in regenerative medicine for therapy. Or, because we have a functioning piece of heart tissue, we can interface these tissues inside fluidic reactors and engineer these devices for testing drugs," he explains.
His landmark work in this area was acknowledged when he was named one of the TR35, Technology Review's annual list of 35 innovators under 35 in 2007. Khademhosseini dubbed this technique Living Legos, due to its step-by-step, building blocks process.
The Living Legos technique improved upon early tissue engineering efforts for repairing organs, where the process involved creating a temporary, biodegradable scaffold that was implanted into a person's body. The cells within the scaffold formed tissue and then the scaffold dissolved. It was effective for repairing small pieces of tissue. But, the Living Legos approach still wasn't enough for Khademhosseini and his colleagues. Researchers today have better knowledge of the detailed signaling exchanges between cells and their surroundings that necessitate better techniques to achieve higher success, Khademhosseini says.
In work released just last year in the Journal of the American Chemical Society, the Khademhosseini Laboratory told of their efforts to make microparticles of nearly any shape, using a micromold that changes shape in response to temperature. According to an MIT news release, "the mold is first filled with a liquid gel that contains one kind of cell or drug. After the gel has solidified, the mold is heated so the walls surrounding the solid gel shrink, pulling away from the gel and creating extra space for a second layer to be added. The system could also be modified to incorporate additional layers. They can also precisely place drugs into different compartments of the particles, making it easier to control the timing of drug release, or arrange different cells into layers to create tissue that closely mimics the structure of natural tissues."
"We've really utilized the best work from researchers in different disciplines and combined them to address problems," Khademhosseini says. "The best electrical engineers, chemical engineers, mechanical engineers and biologists are integrating their efforts. Our collaborators are here in Boston but also in other areas of the United States, Europe and Asia. Distances are meaningless today, as advances in communications allow us to work together as if our laboratories are in the same building."
Khademhosseini adds that it is critical to keep moving forward, and he has plenty of questions brewing as he continues to design experiments. How does the architecture of the materials that we're making and their chemistry affect the cells that we are attaching? What impact do these have on the control of the cell environment and cell behavior? How can we use these engineered blood vessels or heart muscles or whatever to test drugs? If we create engineered tissue outside the body using a person's own cells, how does this affect toxicity of chemicals on the cells? Will it be more predictive?
"We really are still learning a lot about biology; it's very complex," he states. "We don't have the minimum number of essential elements that is required surrounding the cells to control them in a very predictable way, but more and more knowledge is being discovered each day."
As Khademhosseini has grown in his career, he finds that most lessons learned today are similar to those of his early days – one must work hard with passion and dedication and never give up. He continues to develop new skills to face any new challenges that arise.
"I have had to learn how to work and interact with many different people due to our collaborative efforts," he says. "One skill I'm still working on is learning how to motivate others."
His travel schedule is intense, involving up to 200 days a year out of his laboratory to attend or speak at conferences. He also directs efforts at a satellite laboratory at Japan's World Premier International Advanced Institute for Materials Research (WPI-AIMR) at Tohoku University where post-docs are working on applying his tissue techniques in artificial architectures.
A typical day for Khademhosseini when his feet are on the ground in Cambridge involves handling the day-to-day tasks of a very busy laboratory. This includes meetings with students who are preparing scholarly manuscripts for publication and working with colleagues to write proposals. His laboratory has published upwards of 225 papers in scientific journals.
"It's a tough climate for research in the United States right now with the uncertainty regarding ongoing government support of research," he says.
But he refuses to dwell on that when there is so much left to do. To help with frustration that is sure to arise, he tries to exercise as much as possible. He often doubles up an elliptical workout with reading the latest research or editing a paper in progress. Khademhosseini says even the short walks he takes from one meeting to the next can serve as an opportunity to relax a moment.
"Although I wish I had better techniques for handling when I get frustrated, I often find that if I'm able to put it aside overnight and sleep on it, it seems better in the morning when I wake up," he notes.
Khademhosseini was named the 2010 SLAS Innovation Award winner for his paper, "Microengineered Hydrogels for Tissue Engineering and Stem Cell Bioengineering."
"That was a very humbling experience for me," he shares. "The SLAS Innovation Award is very high profile and it contributed significantly to my being introduced to many colleagues that I interact with today on a daily basis. It definitely got me noticed early on as it recognized my work in microengineering our gelatin-like material."
It also fueled his future and his continued involvement as a member of the JALA Editorial Board and as an annual conference participant. He has published two articles in JALA, including one based on his SLAS Innovation Award-winning presentation that made The 2010 JALA 10 list.
Khademhosseini's list of awards, however, extends far beyond the SLAS umbrella as can be seen on his laboratory website. While honored by each award, he is especially happy about receiving a Presidential Early Career Award for Scientists and Engineers (PECASE), the highest honor given by the U.S. government for early career investigators and the awards he has won from different engineering disciplines.
"To receive an award from a discipline outside my field of chemical engineering means that these organizations realize how important and promising our work is," he states. "To receive an award outside your traditional field is to be treated as one of them and this allows us to integrate our efforts."
August 2, 2012