It’s the kind of surgery that makes headlines whenever a famous athlete is sidelined with a torn rotator cuff. Major League Baseball All-Star pitchers Clayton Kershaw and Justin Verlander, for example, both had rotator cuff surgeries and made successful comebacks.
For those of us who can’t throw baseballs 95 miles an hour, the rotator cuff may tear over time from repeated overhead motions (painters and carpenters, for instance). Or an injury can occur as we age and our body’s tissues naturally degenerate. And although rotator cuff injuries are common, they can be serious, leading to muscle degeneration after surgery.
Now, two professors from the Wallace H. Coulter Department of Biomedical Engineering, a joint department of Georgia Tech and Emory University, have addressed the problem with a novel cell-based dual treatment, which they describe in a study published recently in the journal Tissue Engineering.
“We’re thinking mainly of an aging population with this study — the people most likely to have these injuries,” said Johnna Temenoff, whose research group collaborated with the lab of Ed Botchwey on this work. “The great thing about this system is, it isn’t specific to a particular population. These are cells we all have, and this treatment system might work even better in younger patients.”
The rotator cuff is a group of muscles and tendons surrounding and protecting the shoulder joint, keeping the head of the upper arm bone firmly in the shallow socket of the shoulder. It’s tight jumble of tissues, and not an easy environment for muscle regeneration.
“With a rotator cuff injury, you’re actually tearing the tendon,” said Temenoff, director of the NSF Engineering Research Center for Cell Manufacturing Technologies (CMaT) at Georgia Tech. “And that causes the muscle to atrophy.”
While pro athletes have access to world-class training and rehabilitation to help rebuild the shoulder following surgery, for many patients that rotator cuff muscle doesn’t fully regenerate, even after a successful surgery. Temenoff isn’t sure why.
“That’s a big unknown,” she said. “And it’s a big field of study right now, an active area of research. There is a need for regenerative therapies that can be used in conjunction with rotator cuff restoration surgery, as a long-term treatment option —that is what we are addressing.”
In previous studies using mouse models, Temenoff found that she could change the cellular environment in the muscle with the local injection of microparticles loaded with a protein called stromal cell-derived factor (SDF), which can attract various pre-regenerative cells circulating to the muscle.
The idea is to mobilize the cells that can heal, the cells that rebuild muscle at the source. Getting enough of them to do the work is the trick.
Temenoff’s lab has developed microparticles that use heparin, a natural sugar-based molecule found in the body that has a high negative charge. SDF is positive-charged, so that electrostatic interaction between the two particles allows for controlled release of SDF over time.
SDF interacts almost magnetically with a receptor on pro-regenerative cells in bone marrow or circulation to “call” them to a certain location. However, older people may not have enough of these cells in circulation to make much of a difference in healing. That’s where Botchwey’s lab entered with the major assist.
His team provided experience with a bone marrow mobilizing agent (called VPC01091) that can send healing cells into circulation around the body. In clinical settings, bone marrow mobilizing agents are used to “push” stem cells out of the marrow and into the blood. These cells can regenerate and differentiate into all kinds of cells in multiple tissue environments.
The researchers set out to develop a single therapeutic option by combining the two technologies. Here's what happened when they tested the system in rats: The mobilizing agent was injected systemically while the SDF was injected locally into the shoulder. So, while the mobilizing agent “pushed” pro-healing cells into circulation, SDF’s magnetic effect “pulled” them to the injury site, resulting in the desired regenerative effects.
The researchers found different levels of regeneration spatially—in other words, where they applied the local injection really matters. Further research will aim to fine-tune the process, so clinicians can recruit healing cells to even more specific areas of the damaged muscle. Temenoff and her collaborators believe they are onto something that will result in better muscle regeneration, with potential applications beyond the rotator cuff.
This work was supported by the National Institutes of Health (grant no. R01AR071026).
CITATION: Leah Anderson, Liane Tellier, Keshav Shah, Joseph Pearson, Alexandra Brimeyer, Ed Botchwey, Johnna Temenoff. “Bone Marrow Mobilization and Local Stromal Cell-Derived Factor-1a Delivery Enhances Nascent Supraspinatus Muscle Fiber Growth,” Tissue Engineering.
DOI: https://doi.org/10.1089/ten.tea.2023.0128
]]>The workshop, which provided a forum for sharing some of the latest developments in cell manufacturing from researchers, clinicians, industry, and regulatory bodies, was hosted and sponsored by the NSF Center for Cell Manufacturing Technologies (CMaT), the Petit Institute for Bioengineering and Bioscience, and the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory, in conjunction with ASTM International (formerly known as American Society for Testing and Materials), a 120-year-old standards organization that develops and provides technical standards in a wide range of processes, materials, products, and services.
ATSM’s Committee E55 on the Manufacture of Pharmaceutical and Biopharmaceutical Products and CMaT organized the workshop, which took place in the Krone Engineered Biosystems Building at Georgia Tech. Then E55 stuck around for a series of open technical meetings the next two days, Oct. 3-4.
“Our main goal was to demonstrate to members of ATSM International the need for, and crucial role of, standards as we move forward with the translation and commercialization of cell and tissue-based therapeutics,” said Johnna Temenoff, deputy director of CMaT, professor and Associate Chair for Translational Research in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory, and a researcher in the Petit Institute for Bioengineering and Bioscience at Tech.
“Equally important, though, was offering a forum for scientists to discuss how their technologies, and even how they report their data, could promote further understanding of what ‘product quality’ means in this field,” Temenoff added.
Of the 120 or so participants in the workshop, about 25 were members and officers of E55, which has 200 members worldwide, technical experts from the public and private sectors who write voluntary consensus standards designed to drive new innovations in pharmaceutical and biopharmaceutical manufacturing and process control. Members of E55 develop standardized language and definitions of terms, recommended practices, guides, test methods, specifications, and performance standards.
“We feel that we were very successful in getting the right people ‘in the room’ for this workshop,” said Temenoff, who managed the event for Georgia Tech-based CMaT, a National Science Foundation engineering research center that also includes the University of Georgia, University of Puerto Rico at Mayaguez, and the University of Wisconsin-Madison. “During the course of the day we saw important connections being made between ASTM and other standards organizations and industry representatives to determine how E55 in particular can play a key role in developing future standards for cell therapy products.”
From the point of view of the standards makers, the workshop provided some helpful insights.
“At a fundamental level, there is a need for standardization in approaches within different labs, and between different institutions in order to minimize variability through harmonization of materials and methods in order to leverage information and further understanding across the field,” noted E55 officer Duncan Low. “The stated purpose of several groups was to enable reproducible, affordable manufacture of cells. Determining what to measure, how to measure it and how to manufacture with high quality and low cost at large scale were recurring themes.”
Industry representatives were front and center at the workshop, as panel participants and as sponsors (which included IFPAC, RoosterBio, and TerumoBCT). RoosterBio also took part in the industry panel discussion, along with representatives from MilliporeSigma, Celgene, and Immulus.
“Our industry panel, many of whom are partners in CMaT, represented diverse viewpoints, from start-ups to large, multi-national companies,” Temenoff declared. And they hammered home the theme of this workshop.
“Each spoke about the need from their company’s perspective for further standards and best practices in shortening the approval process and streamlining commercialization of cell-based therapies,” Temenoff said. “These are inherently very complex products that require long time-lines and tremendous investment to produce.”
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He needed a bone marrow transplant, his doctors said, and even then he’d only have a 30 percent chance of survival. Connor’s father, Don, who looks like he could have been a professional hockey player, had to deliver the hard news to his son, a conversation neither man will ever forget, down in the basement of their home in Cumming, Georgia.
“I told him the truth,” said Don, a New Jersey native and successful entrepreneur who has started and operated a diverse range of businesses. “I told him the prognosis was not good and that there was a good chance he would die from this disease.”
Don was sharing his family's story on Tuesday before a crowd of about 180 people who are attending the second annual CMaT ERC Retreat at the University of Georgia in Athens. He hestitated after telling the audience how he delivered the frightening news to his son. He composed himself.
"It doesn't matter if I give this speech a million times," he said. "It affects me every time, because it's personal."
Ultimately, it was a personal story of triumph that the McMahons shared at this meeting of the NSF Cell Manufacturing Technologies Engineering Research Center, launched in 2017 and based at the Georgia Institute of Technology. The reason the 18-year-old rising freshman at Mississippi State University is alive, said his father, “is because of CAR T-cell therapy. This is the future of medicine. The manufacturing of cells is the direction the world needs to go. This should be first line defense.”
Don was preaching to the choir as he delivered the retreat’s keynote address, with his son and Bruce Levine, the physician-researcher from the University of Pennsylvania, and the lead innovator in the cell and gene therapy world, who developed the therapeutic use of synthetic immune cells, or CAR T-cells, to attack cancer calls – a treatment unanimously approved by the FDA in 2017.
Their keynote presentation, which also featured an emotional slide show, set the tone for the second annual retreat, following opening remarks from CMaT Director Krish Roy, a researcher in the Petit Institute for Bioengineering and Bioscience at Georgia Tech, where he is based as a professor in the Wallace H. Coulter Department of Biomedical Engineering (a joint department of Emory University and Georgia Tech).
“This is a good time for us to take stock on how we are doing and what we really need to do to take our next steps,” said Roy, who also is director of the Marcus Center for Cell Therapy Characterization and Manufacturing (MC3M) and technical lead of the National Cell Manufacturing Consortium. “No matter where we are from – academia, industry, government, patient advocacy – our goal, the reason we are all here, is to help patients.”
The McMahons played the most critical role in the message that Roy and CMaT leadership want to convey – they put a human face on the center’s primary ambition, and emphasized the importance of the goals to support the notion of helping patients: to achieve quality, lower-cost cell-based drugs to cure devastating diseases, like the leukemia that Connor, a talented goalie for his championship-level travel hockey team, has now defeated three times.
Connor’s treatments in the Children’s Healthcare of Atlanta system was the old standard, and it worked twice. The third time required the groundbreaking therapy (Kymriah, licensed to Novartis) that Levine and his collaborator Carl June developed. Now cancer free, Connor is about to begin the next phase of his life as a college freshman. So his father had a message he wanted to deliver specifically to the CMaT trainees – students and postdocs – who are just a little bit older than Connor.
“You guys are part of the solution,” Don said. “If you’re looking at a test tube or through a microscope or sitting in a cubicle wondering, ‘what the hell am I doing,’ well, you are changing lives. Some of us go through our entire lives wondering if we made a difference in the world. None of you will have that problem.”
With that, Connor and Don and Dr. Levine received a deafening applause, and the retreat progressed along usual means – discussions of research and policy and, coming up on Thursday, the last day of the gathering, an update on the CMaT roadmap – the industry-driven, 10-year national guide for cell manufacturing that provides a prioritized pathway for critical technology development.
For one Petit Institute researcher, the first day of the retreat – specifically, the keynote presentation by the McMahons – provided a burst of inspiration and energy.
“Listening to Don and Connor made me want to rush back to the lab and work like a maniac,” Facundo Fernandez, professor in the School of Chemistry and Biochemistry, shared on his Twitter page. “Although some days in science can be difficult, even being able to make the tiniest contribution to improve patients’ outcomes makes it all worth it.”
]]>Georgia BioEd teacher initiative (a program from statewide trade association, Georgia Bio) was developed in collaboration with CMaT and will provide hands-on STEM learning to solidify what students are learning in their other classes while providing skills required for the workforce of the future.
“The life sciences industry is a leading driver of employment nationally, but leaders express concern about the availability of a strong workforce,” says Georgia Bio President and CEO Maria Thacker-Goethe. “We need educators to be aware of the vast, high-paying jobs available in the life sciences industry here in Georgia. By expanding our proven teacher trainings statewide, we will equip educators with the academic, technical, and leadership skills to meet the students’ interests and industry’s needs.”
The training program, which was included in Georgia’s 2020 budget and signed into law by Gov. Brian Kemp, will leverage public and private funds and be operated through the Georgia Department of Education and the Georgia Youth Science and Technology Centers.
Georgia BioEd will establish eight cohorts of eight teachers each, and they will attend a two-day training symposium to learn about life science career opportunities and hands-on laboratory activities to deliver in their schools in support of these careers. The teachers will receive the equipment they need to support the lab activities in their classrooms, and the cohorts will take part in an online learning community, giving structured reports on their experiences delivering the hands-on activities.
Meanwhile, Georgia BioEd will hire two people to coordinate and orchestrate the program – a project director and an equipment depot manager.
This is the kind of educational initiative that Georgia Bio’s membership has been supporting for years. The addition of state support, the organization says, will help fuel a high growth, high income industry through educators and students in rural Georgia. Georgia Bio recently reported that employment in the life sciences industry grew by 14.9 percent between 2007 and 2017, a rate nearly twice the national average.
]]>Healthcare spending is projected to accelerate over the next decade, and 60 percent of American adults are now living with at least one chronic condition. Chronic diseases like asthma, cancer, diabetes, and heart disease cost Georgia about $40 billion a year.
Steven Stice, GRA Eminent Scholar of Regenerative Medicine at the University of Georgia and a researcher with the Petit Institute for Bioengineering and Bioscience at Georgia Tech, believes one solution to combat the cost of chronic disease is to produce cell-based therapies in much larger quantities and more consistent quality.
And he isn’t alone.
]]>“It was interesting to see how much money goes into scaling up a product for large-scale use, and how important it is to be able to scale up a product prior to attempting to commercialize it,” noted Kalina Paunovska, a bioengineering Ph.D. student who works in the lab of James Dahlman, Petit Institute researcher and assistant professor in the Wallace H. Coulter Department of Biomedical Engineering (BME).
“The company made a great point that it does not matter how good the product is if it can’t be manufactured at a scale where it can be distributed to a large number of people,” she added.
For most of the trainees, like Ph.D. student Juan Medina from the lab of Petit Institute Executive Director Andrés García, this was a first-time opportunity to visit a cell manufacturing facility.
“I was impressed by Celgene’s foresight, as it has enabled them to scale up their cell therapies while still working on their trials,” Medina said. “Prior to the visit I did not know that individual roles were so specific throughout the pipeline process. I quickly realized that this is set up in such a way to optimize efficiency. The visit was helpful in providing me with an idea of what work is like in a large industrial setting. Coupled with a tour I took of a much smaller company earlier this semester, our visit to Celgene made me realize how broadly applicable and valuable the skills developed during a Ph.D. can be.”
For Ph.D. students in the realm of cell therapy, it was a valuable experience. But it also paid off for trainees outside of the discipline.
“I don’t work in the cell therapy space, but I do appreciate the novelty and impact that these new techniques have,” said Andrew Raddatz, a BME Ph.D. student in the lab of Melissa Kemp, Petit Institute researcher and BME associate professor. “Being able to tour both the research and commercial space of Celgene was incredibly informative. Seeing that the research and development space was like a typical cell culture lab you might see on Georgia Tech’s campus made these employee positions more relatable.”
The trainees spent most of their visit touring Celgene’s analytics development section and process development section, noted Raddatz, who also added, “Being able to see people working in the commercial facility with more routine jobs of developing the CAR T cells, patient by patient, was also helpful. These people are saving lives in a heavily regulated area which carries a lot of stress along with it, so their diligence is not only impressive but necessary. The fact that CAR T manufacture cannot be scaled up, only scaled out, makes each dose a very finely monitored product. Overall, this trip highlighted the importance of the industry and how, in an ideal world, companies can find ways to maximize production, reduce costs, and help the most people possible.”
In addition to Paunovska, Medina, and Raddatz (all based at Georgia Tech), the other participating trainees were, from Georgia Tech, Meghan O’Melia, Shannon Anderson, Alex Beach, Brian Liu, Nico Villa-Roel, and Thomas Turners. From the University of Georgia it was Emily Pendleton. Rocio Arroyo from the University of Puerto Rico and Aaron Simmons from the University of Wisconsin rounded out the group.
]]>Jerry Grillo
Communications Officer II
Parker H. Petit Institute for
Bioengineering and Bioscience
“The goal is to ultimately translate cell-based therapies through new engineering tools and better manufacturing practices,” said principal investigator Krishnendu Roy, director of the Marcus Center for Therapeutic Cell Characterization and Manufacturing (MC3M) at Georgia Tech, which will lead the three-year effort. “This will be a multi-faceted project requiring the expertise of some great collaborators.”
Working with clinicians at Duke University, Roy and his Marcus Center team are partnering with robotics experts at the Georgia Tech Research Institute (GTRI), and researchers in Tech’s H. Milton Stewart School of Industrial and Systems Engineering (ISyE) on the three-year effort.
Duke is home to one of the nation’s oldest cord blood banks as well as a Marcus Center (the Marcus Center for Cellular Cures, or MC3), both directed by Roy’s co-principal investigator on the FDA grant, Joanne Kurtzberg, whose team already is engaged in several clinical trials utilizing cord blood and cord-tissue derived therapeutic cells.
But rather than therapeutic development, the FDA grant is focused mainly on advanced manufacturing, with emphasis on “identifying critical attributes of cells relevant to their function, then figuring out ways to use bioreactors for larger scale production, then automating some of the processes and developing sensors to monitor cell quality and culture over time,” said Roy, the Robert A. Milton Chaired Professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, and a researcher with the Petit Institute for Bioengineering and Bioscience at Tech.
Researchers at GTRI will work on developing automation platforms while ISyE personnel are developing flexible electronics sensors to interface with bioreactors, he added, “and the Marcus Center at Georgia Tech, is combining everything into an integrated scalable production platform with functionally-relevant cell quality control.”
The FDA grant bolsters Georgia Tech’s existing cell manufacturing ecosystem, which includes the NSF Cell Manufacturing Technologies (CMaT) Center as well as the Marcus Center, both under Roy’s direction, both trying to meet a critical need to develop new engineering tools for effectively scaling up production of innovative cell therapies while ensuring reproducibility and high quality.
That led to a logical partnership with MC3M and Georgia Tech’s engineering expertise.
“Advanced manufacturing technologies hold great promise for improvements in the reliability, flexibility, and cost effectiveness of manufacturing for biological products,” said FDA Commissioner Scott Gottlieb. “These platforms may be critical to unlocking the full potential of novel technologies like cell and gene therapies, and new vaccines.”
The FDA awarded five grants to foster innovations in advanced manufacturing technology. The recipients were Harvard University, Carnegie-Mellon University, Rutgers University, the Massachusetts Institute of Technology, and the Georgia Tech-Duke partnership.
“This is an exciting opportunity,” said Carolyn Yeago, associate director of research for Georgia Tech’s Marcus Center, who will be directing the different moving parts of the FDA-supported project. “We’re exposing our engineers at Tech directly to the clinical side. The whole impetus for this grant came from Dr. Kurtzberg’s need to generate a lot of cells, reliably and efficiently.”
For the Marcus Center, it’s an opportunity to have an impact on the cell therapy industry, and cell therapies used in clinical practice and trials, said Roy.
“The aim is to make these therapies available not just to a few patients, but thousands of patients,” he added. “We really need new, scalable manufacturing tools and platform technologies to make that happen, and this support from the FDA will help us figure some of that out. This is a way for us to leverage the resources that we have been developing at the Marcus Center and at CMaT as well through investment from the State of Georgia.”
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Guldberg, along with James Wehenmeyer, vice president of research and economic development at Georgia State University, received the Industry Growth Awards, the highest honors bestowed each year by Georgia Bio, the state’s life science advocacy and business association, now in its 20th year. The award recognizes individuals in the public and private sectors who have made extraordinary contributions to the growth of Georgia’s life sciences industry.
“This award from Georgia Bio is a great honor and really a recognition of the efforts of the entire Petit Institute team,” Guldberg said. “It’s remarkable how many more start-ups are being launched now compared to 10 or 20 years ago. I am so proud of the collaborative entrepreneurial culture that we have built, where our students and faculty increasingly expect to successfully translate their lab work into commercial products and new clinical therapies.”
Georgia Tech and the Petit Institute were well represented at the awards podium as nearly 300 of the state’s life science industry leaders gathered to celebrate the contribution and achievements of people and organizations.
In addition to Guldberg, other award winners with Tech connections included Sherry Farrugia (chief operating and strategy officer of the Pediatric Technology Center, a partnership of Georgia Tech and Children’s Healthcare of Atlanta), who won a Community Award, and the NSF Engineering Center for Cell Manufacturing Technologies (CMaT) at Georgia Tech, which won a Deal of the Year Award.
“We are excited to recognize the individuals and organizations improving and saving lives worldwide through their healthcare innovations and leadership here in Georgia.” said Russell Allen, president and CEO of Georgia Bio.
Here’s a list of the 2018 Georgia Bio Life Sciences Health Impact Award winners:
GEORGIA BIO INDUSTRY GROWTH AWARDS: Presented to two people who have made an extraordinary contribution to the growth of the life sciences industry in Georgia.
• Robert E. Guldberg, Ph.D., The Petit Director's Chair in Bioengineering and Bioscience; Executive Director, Parker H. Petit Institute for Bioengineering and Bioscience; and Professor, George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology
• James Weyhenmeyer, Ph.D., VP Research & Economic Development, Georgia State University and Chairman, GSU Research Foundation Inc.
PHOENIX AWARD: Presented to two Georgia honorees who have forged academic and industry relationships that will drive translation and lead to new treatments and cures. This award is sponsored by the Metro Atlanta Chamber.
• UGA Center for Vaccines and Immunology / Sanofi Pasteur
DEALS OF THE YEAR AWARDS: Presented to one or more companies or institutions for the most significant financial or commercial transactions closed from November 1, 2016-October 31, 2017, based on the importance of the transaction to Georgia’s life sciences industry.
• Center for Biotechnology and Genomic Medicine at Augusta University
• CryoLife
• Femasys
• Georgia Clinical & Translational Science Alliance
• NSF Engineering Research Center for Cell Manufacturing Technologies (CMaT) at Georgia Tech
• Vertera Spine
COMMUNITY AWARDS: Presented to a small number of individuals, companies or institutions whose contributions to Georgia’s life sciences community are worthy of special recognition.
• Sherry N. Farrugia, Chief Operating and Strategy Officer, Pediatric Technology Center, Georgia Institute of Technology; Director, Children’s Healthcare of Atlanta Partnership
• Christopher D. McKinney, DA, MBA, Associate Vice President, Innovation Commercialization; Adjunct Professor of Political Science, Augusta University
• Center for Tropical and Emerging Global Diseases
• Suzanne Prichett, Field Sales Manager - Education & Medical Research Division, VWR International LLC
• Atlanta Center for Medical Research
INNOVATION AWARDS: Presented to the department, institution, company or individuals who are forging new ground by thinking outside traditional paradigms to create some unique technology.
• Aruna Biomedical
• George Hsu, M.D., Chief Medical Officer / Interim CEO, Cathaid Inc.
• James Ross, Ph.D., Chief Technology Officer, Axion BioSystems
• PanXome
EMERGING LEADER OF THE YEAR AWARDS: Presented to young individuals who have made a significant impact on the life sciences industry through their studies or employment.
• Ashley Bohn, Ph.D, M.S., R.V.T., Georgia State University
• Tami Hutto, MSPP, Program Manager – Emory University and Georgia Institute of Technology, Atlanta BEST Program
TEACHER OF THE YEAR AWARD: Presented to a Georgia biotechnology high school teacher who exhibits excellence in STEM teaching and support for the biotechnology pathway.
• William E. Schuyler, Forsyth Central High School
For a list of past Georgia Bio Industry Growth Award recipients, click here.
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