Good science does not equate to workable manufacturing. This has been a longstanding truth in tissue engineering, a field that has been in limbo between academic R&D and commercialization for its entire decades-long existence. Now, the U.S. can thank Tom Bollenbach—a Ph.D. in biochemistry who lived that experience for nearly 10 years—for helping to stand up a new and highly functioning Manufacturing USA institute aimed at establishing a new industry that mass-produces human tissues and organs.
That is according to Dean Kamen, inventor of the insulin pump and the Segway—and now executive director of ARMI (Advanced Regenerative Manufacturing Institute).
Kamen tapped Bollenbach, now ARMI’s chief technology officer, to write the proposal for BioFabUSA, ARMI’s Department of Defense-funded tissue and organ manufacturing program.
But his relationship with Bollenbach is one of many that the über-connected entrepreneur called upon after winning the $80 million in funding that seeded ARMI | BioFabUSA, a consortium of about 170 companies, academic institutions and organizations that works together to enable scalable, consistent and cost-effective manufacturing of tissues and organs.
Kamen also reached for the overflowing Rolodex he amassed from founding FIRST (For Inspiration and Recognition of Science and Technology), a not-for-profit that for 30 years has sought to inspire young people to become science and technology leaders and innovators.
“I have hundreds of universities, thousands of companies and hundreds of thousands of mentors all donating their time to this cooperative organization,” he said of FIRST. And among the participants are companies, such as Johnson & Johnson and Medtronic, that “support FIRST together” despite the fact that they are direct competitors in their respective, highly competitive marketplaces.
When the DoD called Kamen in the last weeks of the Obama administration to let him know ARMI won its $80 million grant, he hurriedly rang Rockwell Automation CEO Blake Moret.
“What does Rockwell Automation have to do with making a liver or a kidney or a lung? You could say nothing,” Kamen said. “But Rockwell makes all the equipment that an automobile factory uses to make high-quality cars consistently and very cost-effectively at high volume. A car is a pretty sophisticated device, and it costs less per pound than hamburger. That’s because they’re not made by hand like they were 100 years ago.”
Moret, who knows how to manufacture in volume—and who has been “a huge supporter of FIRST for years”—was pleased to join ARMI’s board—as were Boston Scientific founder John Abele, Worcester Polytechnic Institute President Laurie Leshin, United Therapeutics CEO Martine Rothblatt and Dr. Jim Weinstein, the former CEO of Dartmouth-Hitchcock who is now the senior VP for Microsoft Healthcare, Kamen said.
ARMI | BioFabUSA is now going about the business of creating “the baseline tools by which all sorts of tissues and organs can be manufactured at scale,” he said.
That prodigious effort involves not only automation but also sensing and closed-loop process control, real-time manufacturing quality assurance, artificial intelligence, machine learning and machine vision systems—part of the stew that makes up smart manufacturing, Kamen said.
One of the first tissues the institute is addressing is a combination of bone and ligament—essentially a manufactured anterior cruciate ligament (ACL) derived from living cells.
“It fills a gap that lots of people need,” he said. “ACL reconstruction is one of the most common surgeries performed in the U.S. If you’ve been athletic most of your life and you’re now older, you’re probably going to want your knees returned to a younger state.”
One member company had been working on it. “And their petri-dish-based work had gone a long way: They had a very good recipe,” Kamen said. “So we said, ‘Let’s make that the first one we demonstrate our new capabilities on’.”
In a project funded by the Juvenile Diabetes Research Foundation (JDRF), the institute is also working to manufacture stem cell-derived pancreatic islets, initially for R&D purposes “so that all of the JDRF-funded researchers get the same cells,” Bollenbach said. “We’re going to mass produce those. But the next logical step is, take those same cells and make them for patients. That’s a huge one: Ending the dependence on insulin through implantation of beta cells into diabetic patients.”
Although the production of several types of tissues is in play, the 170-member institute hasn’t yet decided which organ, such as a heart, a kidney or a liver, will be the first to be manufactured.
“We’ve got to stay agnostic about which organ is going to win. And when this med school or that research lab or that big pharma company says, ‘We know how to do this or that or the other thing,’ we’re going to say, ‘Great, we’ve got the tools, we’ve got the manufacturing stuff here. Let’s put the program and the software into this line we set up here to manufacture that’,” Kamen said.“We’re basically saying, ‘We’ll build an oscilloscope. You can use it to test an analogue circuit or a digital circuit. I don’t care if you’re building video games or amplifiers or computers. We’ll build an oscilloscope that will make your job easier to build whatever electronic box you want’.”
The central goal is to make the experience for “every different organization that wants to produce some kind of tissue or organ better, faster and easier,” he said. “We are building the infrastructure to create an industry that will allow all these creative people to make the organ du jour. They’ll figure out how to bring their recipe to our table, or bring our equipment to their place and start making tissues and organs at scale.”
Of course, ARMI | BioFabUSA will also work closely with NIST and standards-development organizations to ensure that robust measurement science, measurement assurance and standards are incorporated into all of its relevant technologies, which the institute anticipates will make meeting requirements for regulatory approval much more streamlined.
It is perfectly clear to Kamen that he needs people used to managing high-stakes assignments.
“We’re never going to turn any of these biological miracles in petri dishes into full-scale, manufactured organs with billions of cells in them unless the FDA is convinced we have a highly reproducible, highly measurable, quality-controlled system,” he said. “Because if something goes wrong here, you can’t send the patient a replacement with a gift certificate and an apology for $99 and say, ‘Here’s a new one.’ If we make a product, and even if 99 percent work, I’m sorry, you can’t let one out of a 100 people find out that that organ is a failure after it’s been sewn into their body.”
It is no surprise that Kamen also brought in some senior folks from the FDA, and that the institute has a partnership agreement with the agency.
Kamen has brought to ARMI | BioFabUSA his experience running DEKA, which has hundreds of engineers doing “hardcore engineering” in their work on everything from dialysis equipment and stents to artificial organs and limbs. And as ARMI started showing success in building engineering tools within the BioFabUSA program, it was awarded up to $51 million from the U.S. Department of Health and Human Services. Together with matching contributions from corporate sponsors, ARMI now has hundreds of millions of dollars at its disposal to make advanced bio-manufacturing a reality.
The money is going toward delivering a big dose of modern manufacturing reality—automated assembly equipment and process control, for starters—to docs and academic institutions and companies large and small, looking to turn their discoveries into products, who have been laboring with only manual tool sets: the petri dish, the roller bottle and the pipette.
Scientists today at top medical schools who are working on replacement pancreases and kidneys are largely still mired in siloed thinking. After visiting them, Kamen is repeatedly reminded of the fact that they have done incredible work in harnessing the power of biology to fabricate tissues and organs—but understandably lack the background to bring those technologies out of the lab and onto the manufacturing floor.
“In each one of these places, it was like going to watch grandma put in a pinch of this and a dash of that to make her homemade special chicken soup—one cup at a time,” he said. “We want to help them turn grandma’s kitchen into a Campbell’s factory.”
The tissue-engineering companies Bollenbach worked at “were trying to develop the means to manufacture through the eyes of the scientist and using the scientist’s tool set,” Kamen said. “They discovered that trying to bring scale and consistency to a regulated manufacturing environment wasn’t as easy as adding more technicians doing manual fabrication.”
From its start, ARMI | BioFabUSA has “meticulously avoided any effort to do basic research or basic science or basic biology to advance the process of understanding what the organ is or how the cell works,” he said. “We focus on building the tools to take whatever it is that the scientists have and bring it to scale.”
In addition to developing “the baseline manufacturing tool set” for tissue and organ manufacturing, the Manchester, N.H.-based institute is also creating programs to teach manufacturing skill sets for the manufacture of human organs in the new industry.
“We’re working with our member organizations across the United States to build a whole curriculum to train people to work in what we hope will be a fast-growing industry to manufacture all of these things,” Kamen said.
Within a few years, “I think we will have a number of production lines up and operating, all sharing the same core technologies but making a pretty wide array of different cells, tissues and organs,” he said. “The next phase after that will be to start figuring out how to get them out of the manufacturing process and find delivery structures that can get them into an operating room.
“To achieve that next milestone will require even closer collaboration with academia and product developers, tool developers, NIST and FDA—to test these new replacement tissues and organs in animals to determine their safety and then eventually start the process of making ones that are going into people.”
Vascularization—the development of blood vessels in tissues and organs—is a major impediment to manufacturing substitute tissue and organs. Advanced Solutions, one of the first members of ARMI, believes it has the answer: a product line called Angiomics.
“We’ve invented the process of extracting blood vessels from human fat, adipose tissue,” CEO Michael Golway said. “From some belly fat, we have all the ingredients we need to harvest blood vessels and then 3D print them in vitro, or outside the body, and get them to reestablish blood vessels and perfusion outside the human body. When you’re talking about building human tissues and human organs, getting blood to those is pretty important.”
In the process Angiomics uses to harvest blood vessels from fat, “the blood vessels break up,” he added. “But, in the right conditions, you can get those blood vessels to undergo angiogenesis (grow new blood vessels). That’s where Angiomics stems from. We’ve been able to figure out the right conditions under which those fragments undergo angiogenesis and recreate a microcirculation—a brand new blood vessel path based on the tissue environment they’re in.”
For example, Advanced Solutions has found that if it combines the blood vessels harvested from belly fat with hepatocytes, which are liver cells, “in about two weeks we get a vasculature that looks very liver-like,” Golway said. “If we combine our blood vessels with astrocytes, which are brain cells, in a couple weeks we get a vasculature that’s got blood-brain-barrier-type characteristics.
“If you get the cells in the right environment where they’re happy, they know exactly what to do. And they talk to each other and figure out how to work together and do what their functions are,” he said.
Advanced Solutions also developed BioAssemblyBot, “the only six-axis robot in the world that is used for 3D bioprinting,” Golway said.
BioAssemblyBot is “a workstation where we’ve got a six-axis [Epson] robot that can learn how to build tissue structures,” he added. “It’s more than just a 3D printer. With a six-axis arm, it moves more like a human arm: It can move and work in tight spaces like those your human arm can reach.”
BioAssemblyBot “makes” the biology and a confocal scanner “takes pictures” of the biology. (In the 2019 photo right above, the system is connected to a Cytiva InCell 6500 confocal scanner.) For quality control, the BioAssemblyBot then uses AI to determine the health of the biology and performs the appropriate workflow to continue to “make” the biology, such as human tissue or organs.
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