Penn State: Pushing the limits of regenerative engineering research?

Three years ago, one email brought two researchers at Penn State together to explore hybrid biomaterial-microsurgical techniques that could change the trajectory of tissue regeneration. At the time, Amir Sheikhi , founding director of the Bio-Soft Materials Laboratory (B-SMaL), Materials Research Institute affiliate, Huck Institutes of the Life Sciences Early Career Chair in Biomaterials and Regenerative Engineering; assistant professor of Chemical Engineering and Biomedical Engineering (by courtesy), was relatively new to 美国宾夕法尼亚州立大学 . When he reached out to Dino Ravnic , director of the Plastic Surgery Research Laboratory and associate professor within the Department of Surgery at Penn State College of Medicine , Huck Chair in Regenerative Medicine and Surgical Sciences; Associate Professor of Surgery about working together, a dynamic collaboration was born. Together, they have created an innovative hybrid tactic combining granular hydrogel biomaterials, developed at the Sheikhi Lab, to pattern blood vessels and vascular micropuncture, developed at the Ravnic Lab, to make small perforations in the recipient vasculature and speed up the formation of new blood vessels.?

“I don’t see any reason why Penn State shouldn’t be at the forefront of biomedical engineering and medical research, especially regenerative medicine, in the United States, if not the world.”

Revolutionizing regenerative engineering?

Sheikhi joined Penn State in 2019 to develop novel soft materials and direct the study of biomaterials for tissue engineering and regeneration.??

“It's always good for us to be informed by surgeons who are treating patients. I knew that Dino at that time was active in research collaboration with many engineering folks,” said Sheikhi.??

He sent an email to Ravnic asking if he’d be interested in learning about biomaterial platforms. When Ravnic agreed, their collaboration began.?

“Nothing can excite me more than having the possibility of saving lives, preserving ecosystems and improving the quality of modern society.” -- Sheikhi

“Nothing can excite me more than having the possibility of saving lives, preserving ecosystems and improving the quality of modern society,” Sheikhi said. “I strongly believe that micro- and nanoengineering of soft materials, which is my research focus in my lab at Penn State Chemical Engineering, has immense potential for those purposes.”??

Sheikhi said that chemical engineering and bioengineering will be the key. “With these skills, we can develop the next generation of biomaterials that can solve real-life healthcare challenges and potentially save lives,” he said.?

Ravnic’s medically-focused perspective on their studies complemented Sheikhi’s background in chemical engineering. Ravnic’s primary specialty is reconstructive surgery for cancer and trauma patients, but he said that many of the techniques and technology in this field are still suboptimal.??

“There's a whole range of new bioengineering technology that has really materialized over the last 20 years or so, some that are directly applicable to what we do in the clinical world and some that still have more of a research platform,” Ravnic said.?

Eliminating the clinical bottleneck?

Both researchers noted that the path to developing ideal conditions for reconstructive surgery is far from simple. According to Ravnic, one of the immediate limiting factors, whether it's clinical or tissue engineering, is blood vessel growth and vascularization. This challenge has created a clinical bottleneck that, unless addressed, will prohibit other engineering advances.??

“You can develop all types of tissues in the lab, all types of new scaffold materials and stem cell technologies, but unless they vascularize when you place them in the body, it's not going to work,” Ravnic said. “This is what prompted my interest in the field. It's a way to tie in what I see clinically with what I see in the limitations of tissue engineering endeavors, and then see how these can be merged for future biomedical advances.”?

Sheikhi and his lab, B-SMaL, are working to accelerate the formation of blood vessels and pattern their architecture through a combination of bioengineering, scaffolding ? creating a cell structure on which growth and assembly can proceed in an organized fashion ? and a surgical approach.?

B-SMaL uses microfluidic technologies to engineer microscale biomaterial building blocks that can assemble to each other right on the tissue, providing an environment for cells to grow inside and form the structure and hierarchy of blood vessels. This way, they can vascularize almost any construct and overcome the bottleneck. But Sheikhi said that biomaterial by itself is not sufficient. That is where Ravnic’s innovation comes in. He has created a technique of making micro punctures on blood vessels to accelerate the process.??

Ravnic explained that the micropuncture procedure is a platform technology for all types of tissue engineering, from skin and adipose replacement to even more advanced procedures like heart tissue replacement. He and Sheikhi hope to target two main issues to bring it from the lab to the bedside: stimulating blood vessel growth out of an area that's not prone to rapidly vascularizing something on its own and creating a material that provides a suitable environment for the blood vessels to grow into.?

“When we think about replacement, we really want to create tissues where the form will allow a specific function to develop." -- Ravnic

“When we think about replacement, we really want to create tissues where the form will allow a specific function to develop. If you don't have the correct blood vessel form at this onset, you will not have the correct tissue function at a later stage. This is what we're hoping to achieve,” Ravnic said.??

While thinner tissue replacements will be attainable earlier on, he believes that whole organ replacements like the cornea, the colon and the liver could be a reality in the future.?

“The sky is the limit” for bioengineering breakthroughs?

“Since I joined Penn State, I have had the pleasure of mentoring graduate students, undergraduate students, postdocs and visiting scientists who have contributed to numerous research projects,” Sheikhi said. “One of the main discoveries was when we realized that our microengineered granular hydrogel biomaterials can guide the formation of tissues, such as blood vessels in animals. When Dino did the surgery and we implanted them, the blood vessels that were formed in the material were very, very interesting. We could shape the architecture of blood vessels by tuning the microarchitecture of the material.”?

“I remember sending Amir the text of the images of the blood vessels. There was stuff that reminded me, much like when I did my post-doc fifteen years ago, of what normal blood vessel development looks like in specific organs, and here we had a pattern-induced microvasculature,” Ravnic added.?

Their breakthrough in microengineered biotechnology is only the first step of the journey for Sheikhi and Ravnic.??

“I think the sky is the limit, so we do not have any clear end. We want to tackle lots of problems to get there, so it's just the beginning,” Sheikhi said.?

?Penn State: A catalyst for collaborative research?

Ravnic said that he is “mesmerized” by the collaborative culture at Penn State.??

“People will say, ‘I have a material solution for this’ or ‘an approach for this’ that I would never be able to see. And even though we're somewhat separated by distance, I find the environment very, very welcoming,” Ravnic said.?

“[The University] has enabled me to set up my lab, recruit and train the first cohorts of my graduate students and acquire data in collaboration with people like Dino to start writing grants and bring in more extramural funds to the lab. And now the lab has grown. I have 13 graduate students, 15 undergraduate researchers and two post-doctoral mentees, and we are expanding even beyond that. I think these are all because of the support that I have had from the University — both administrative support and collaboration and mentorship support,” Sheikhi added.?

“I don’t see any reason why Penn State shouldn’t be at the forefront of biomedical engineering and medical research, especially regenerative medicine, in the United States, if not the world,” Ravnic said.?

Their work was also supported by the Huck HITS Fund program.

Additional relevant links:

• Novel microneedle bandage could save lives by stopping blood loss from wounds
• Soft tissue restoration, blood vessel formation focus of $3M grant
• NIH diversity grant to fund student’s 3D bioprinting research
• Materials Research Institute announces 2022 seed grant recipients

About Penn State Research

The Office of the Senior Vice President for Research is responsible for facilitating the $1B+ research enterprise at Penn State by working with a broad range of units across the University. The mission of the Office of the Senior Vice President for Research is to support a rigorous program of faculty and student research and creative accomplishment by enhancing the environment for scholarly and artistic endeavors, encouraging the highest standards of quality, and fostering ethical conduct in research.??

About Penn State

Penn State is a multi-campus, land-grant, public research University that educates students from around the world, and supports individuals and communities through integrated programs of teaching, research and service. Penn State is an R1 university, a classification given by the Carnegie Foundation for the Advancement of Higher Education to the very best research universities in America, reaching a record $1.034 billion in research expenditures during fiscal year 2021-22.

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