Advancing the Field of 3D Bioprinting: An Interview with Ibrahim T Ozbolat

Keywords::

• 3D bioprinting
• 3D models
• biofabrication
• clinical translation
• immunotherapy

Biography

Ibrahim T Ozbolat is a Professor of Engineering and Mechanics at The Pennsylvania State University. With significant contributions to the field of 3D bioprinting, Ibrahim’s research focuses on the generation of 3D-printed tissues and organs and the development of 3D bioprinting processes and related technologies for a range of purposes including regenerative medicine, drug testing and understanding of diseases. He serves as the principal investigator of the Ozbolat lab, an interdisciplinary lab drawing on experts from various backgrounds including medicine, chemistry, biomedical engineering, industrial engineering and mechanical engineering. This collaborative approach fosters innovation and seeks to address complex challenges in 3D bioprinting.

What inspired your interest in bioprinting?

I hold dual Bachelor of Science degrees from the Middle East Technical University (Ankara, Turkey), where my primary interest during my degree was manufacturing. During a visit to a center in the university, I came across a 3D printer that was printing inert materials for fabrication of 3D objects, specifically plaster. It was fascinating because it was my first time seeing complex structures being manufactured. So, this sparked my interest to move into 3D printing research, and so I applied for PhD at the University at Buffalo, New York.

At the time, the lab that I joined just started tissue engineering work. Combining 3D printing with tissue engineering, we then started bioprinting research there. After completing my PhD, I joined The University of Iowa as an assistant professor, where I established my independent lab and started my career as an independent researcher. We began working on various aspects of bioprinting, developing innovations there including co-axial bioprinting technology which has been translated into the market now. Then in 2015, I joined The Pennsylvania State University.

You recently created a 3D-printed breast cancer tumor model. Could you tell us a bit more about this?

One of the application areas of bioprinting technologies in our lab is building 3D tissue models, such as cancer. Our primary area of interest lies in breast cancer and understanding how the cancer grows, metastasizes and how it interacts with the immune cells. We have published two articles on the use of 3D-printed cancer models. The first explores perfusion systems through the incorporation of vascularization into 3D models [1] and the second one is without vascularization and a non-perfused model of cancer [2]. We then explore the interactions of the immune cells with the cancer models that we developed, and then we could be able to control several factors with the use of bioprinting technologies.

For example, we can control the tumor size and the vascular environments including the proximity of tumor to the blood vessels that we perfuse the immune cells through. We are particularly interested in cancer immunotherapy and the development and translation of these immunotherapies into the clinic, particularly for solid tumors like breast cancer. It is important to understand how the immune cells infiltrate into the cancer microenvironment. We cannot really do this in animal models because they do not really recapitulate the physiology of humans which is why we built these 3D models. Nowadays, we are working with primary tumors from patients, so we make these models with the cells that are obtained from various patients. We are also interested in the role of ageing in cancer development and the response of immunotherapy processes.

How do these 3D models provide insights into the tumor in ways that traditional 2D models might not capture in the same way?

The traditional 2D models are simple models where you culture the cells on Petri dishes, resulting in a very thin layer of cells. When you consider the cancer microenvironment, it is a complex 3D structure with vascular and immune components. In addition, the tumor itself is heterogenous, composed of multiple different cell types, and recapitulating that complex 3D dynamic microenvironment in 2D models is almost impossible. There are significant differences, which is why we have been developing these 3D models.

The National Institutes of Health recently awarded you with a grant to develop technology to expedite the bioprinting process of bones, trachea & organs. Could you tell us a bit more about this?

This has been something that we have been working on since 2017/18. We spent time understanding the fundamentals of the technology, which focuses on the 3D bioprintability of tissue spheroids [3,4]. Currently, most of the researchers in the bioprinting community use bioinks where the cells are primarily loaded in hydrogels, which has several limitations. One being that native tissues have a high cell density, which is tough to mimic if you use cell-laden hydrogels.

That’s why we sometimes use scaffold-free, hydrogel-free systems where we compact the cells into three-dimensional aggregates known as spheroids, utilizing them as building blocks. We then print them next to each other, allowing them to self-assemble to make a larger tissue structure. Currently with all the available technologies in the field, the major problem with this process is that these spheroids are printed individually. So, the process is very slow, and it takes a very long time to create something scalable. To address this issue, we developed a technology that can expedite the process considerably. So, instead of waiting days, you can make structures in an hour. We can use this technology for making trachea and bone.

How do you envision an increased utilization of 3D printing in clinical settings?

Across the world, there are various ongoing clinical trials exploring the use of bio-printed tissues in clinical settings. A New York-based company called 3DBio Therapeutics conducted a clinical trial exploring the development and implantation of 3D-bioprinted ear tissue for microtia, a condition where the ear grows abnormally [5]. This is a great example of the clinical transition of bioprinted tissues. Hopefully, these clinical trials will open new avenues for other tissues such as skin, cartilage, and bone tissue. Creating these tissues will be relatively straightforward and easy compared with solid organs like the pancreas, lungs and liver, that might prove to be more challenging. The good thing is there are many ongoing projects, and I hope that we will see more clinical translation in the next few years.

What are some of the challenges faced in the medical bioprinting field & how do you think they can be overcome?

We still have some technical problems that have not been solved yet, like the integration of vascularization. There are tons of efforts going on with vascularization but creating a blood vessel network from arteries and veins, all the way down to capillaries in a 3D complex organ structure is still a challenge. Without proper integration of this complex vascular network system in large scale tissues or organs, we cannot really make scalable solid organs.

In the meantime, to make these organs, we need organ-specific cell types. While we have stem cells and primary cells, identifying all the cell types that reside in an organ remains a challenge. For example, if we are making a pancreas, we require beta cells, that we can differentiate from induced pluripotent stem cells. With alpha cells and other pancreatic cells, it is more challenging to obtain all these cells and incorporate them into a system. The lack of all the cell types in a particular organ, and the creation of a 3D-bioprinted perfusable complex multi-scale vascular network remain technical challenges that need to be overcome in the next 5–10 years.

Aside from the technical challenges, we have regulatory challenges associated with clinical translation. Sometimes, the regulatory process can take years, but the good thing is we have examples now of bioprinted structures being utilized in clinical trials. They are going to be a great example for regulatory institutions and then that will hopefully make the process certainly easier compared with what it was in the past.

What do you think are some of the most promising recent innovations in the field?

There are several ongoing developments, and I can say in the last 10 years the field has grown significantly. We have seen groundbreaking developments from various research labs, as well as companies. For example, contributed by multiple research labs including my team, intraoperative bioprinting technology, means that we can use 3D bioprinting directly in surgical settings, has advanced significantly [6]. It is also known as in situ or in vivo bioprinting.

We have shown the intraoperative bioprinting of various tissues, organs such as bone, cartilage, muscle, and skin as well as composite versions of bone and skin. This is something that that we [my lab] have contributed significantly to the field [7–9].

This holds a lot of potential in translating 3D bioprinting into clinics, where we will see that operating rooms have bioprinters that the surgeons can fix or repair the body parts via the intraoperative bioprinting technology.

In addition, we have also seen various tissue types printed using the embedded bioprinting processes [10]. Previously, bioprinting was performed without the use of embedded bioprinting where we used to print the structures in air. Researchers can now create very complex shapes, which was not possible in the past. It also brings us a lot of capabilities in recapitulating the complex shape and geometry of these organs.

Where do you think the field of bioprinting will be in the next 10–15 years?

This is a question that commonly comes up. I want to give some idea about how the field has evolved so far. From 2000 to 2010, we could mainly print cells. The goal at that time was not primarily to generate tissue immediately, but rather the focus was on printing cells to show that bioprinting was feasible. From 2010 to 2020, significant progress was made where tissues could be printed. So, we have gone from printing cells to printing tissues that are not too complex without multi-scale blood vessels.

In the next 10 years, we are going to see more progress, particularly with solid organs such as the pancreas, lungs, heart, and kidney. We are also going to see more efforts in the vascularization and integration of vascularization in 3D-bioprinted solid organs. I do not know if it is going to be done in 10 years, but I can say we are going to make significant progress over the next 10 years in the field. In the meantime, we will see more clinical trials and the translation of 3D-bioprinted tissues, particularly musculoskeletal tissue, in the next 10 years.

Competing interests disclosure

IT Ozbolat has an equity stake in Biolife4D and is a member of the scientific advisory board for Biolife4D and Healshape. The author has no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Interview disclosure

The opinions expressed in this interview are those of Ibrahim T Ozbolat and do not necessarily reflect the views of Future Medicine Ltd.

Financial disclosure

IT Ozbolat acknowledges funding from the National Institutes of Health (National Institute of Biomedical Imaging and Bioengineering). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.