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New Facility for Bioengineering Research Opens in Los Angeles

In a world eager to solve the problem of rejection in organ transplantation, a young American scientist developed a breakthrough test in 1964 that would help establish the compatibility of tissue types between organ donors and patients in need of transplants. Even though, today, efforts to meet organ transplant demand are shifting toward the field of bioengineering, as researchers search for ways to recreate complex organs with patient-derived cells, the legacy of that scientist, Paul Ichiro Terasaki, continues to inspire discoveries in transplant medicine through his philanthropic ventures.

The Terasaki Institute for Biomedical Innovation (TIBI), a nonprofit research organization established by Terasaki, professor emeritus of surgery at the David Geffen School of Medicine at the University of California Los Angeles (UCLA), will open the doors to a new facility in 2022. The newly-acquired addition will house interdisciplinary research in bioengineering, micro- and nanoscale technologies to enable transformative biomedical innovation as part of continuing research to solve the biggest problems related to organ transplantation and beyond.

Earlier this month, the Terasaki Institute announced the revamping of a building in the Woodland Hills area of the city of Los Angeles. Once home to the Weider Health and Fitness Center, created by bodybuilder and entrepreneur Joe Weider, the two-story building will be custom-designed to house the latest technology in cutting-edge research and will provide 50,000 square feet of floor space for up to 200 employees.

Located just 22 miles north of the original Terasaki Institute facilities in Westwood, the new space devoted to laboratory research will be designed to accommodate multiple teams of scientists, who will be developing bioengineered systems, devices, and other products with several biomedical applications. This new facility will be fully equipped to enable such technologies as tissue engineering and regeneration, biofabrication using 3D printing, nano- and micro-engineering, stem cell engineering, and the creation of human organs on chips.

When the new facility is inaugurated, with the renovation of the building set to begin in fall 2020, it will become the Terasaki Institute’s third research facility. In addition to the ample space and unique design features of the laboratory, the new facility will include in-house technology translation capabilities to be able to build prototypes and scale models of devices engineered by the institute. It will also be able to accommodate meetings, seminars, and conferences to further the education and exchange of ideas among its researchers and collaborators.

“I’m very excited about the addition of the new building to the Terasaki Institute. I believe that this addition will give us needed research space to bring together a number of leading scientists in our efforts to develop the next generation of biomedical innovations,” said Terasaki Institute’s new director and CEO, Ali Khademhosseini. “I’m particularly excited about furthering the great legacy of the Weider family and the building’s history in promoting health and fitness by focusing on individualized cures and diagnostics.”

Previously at Harvard Medical School, the Wyss Institute for Biologically Inspired Engineering, and most recently at UCLA Bioengineering, Khademhosseini has been an influential figure in pushing bioengineering forward. His research in regenerative medicine, tissue engineering, and micro- and nanotechnologies for the treatment of diseases has been related to advancements that allow reprogramming of adult cells to become progenitors, as well as editing genes. The bioengineer has also created a technique that uses a specially adapted 3D printer that could help advance the field of regenerative medicine by making it possible to 3D print complex artificial tissues on demand. He has also established the Khademhosseini Lab, an industry-leading tissue engineering lab that is co-sponsored by both MIT and Harvard and acts as a strategic partner to 3D bioprinting startup BioBots.

Ali Khademhosseini (Image: Ali Khademhosseini)

Stewart Han, president of the Terasaki Institute, has been working hard overseeing the planning and renovation of the new building: “It is exciting to be able to create a brand-new laboratory and research facility from the ground up, and it will greatly enhance our research capabilities when it’s completed. We also know that the new building will facilitate the future growth of our institute.

Founded in 2001, the Terasaki Institute was made possible through an endowment from the late Paul Terasaki, and it is expected to continue leveraging scientific advancements that enable an understanding of personalized medicine, from the macroscale of human tissues down to the microscale of genes, as well as to create technological solutions for some of the most pressing medical problems of our time.

Paul Terasaki in front of the Terasaki Life Sciences Building UCLA. (Image: Leslie Barton/UCLA)

“The board of the Terasaki Institute is very excited about the purchase of the new building in Woodland Hills, and we look forward to developing it into a world-class biomedical research center,” said board chair and diagnostic radiology specialist Keith Terasaki. “My father, the late Paul I. Terasaki, started the Terasaki Institute in hopes that it will make impactful discoveries in medical research. This new research facility will enable us to do so.”

To the field of transplant surgery, transplant pioneer Paul Terasaki enabled a broad understanding of organ transplant outcomes around the world. More than 70 years after his original discovery, patients still rely on organ donor transplants and the fundamentals of Terasaki’s laboratory developed tissue typing tests are still used today for the determination of transplant compatibility. Nonetheless, the Terasaki Institute envisions a world where personalized medicine is available to all. So, as the researchers at the institute continue to address the challenges that can finally advance the field of organ transplants from human donors to bioengineered artificial organs, they might bridge the gap between sickness and health. With one of the most productive 3D printing researchers as director, Khademhosseini, and a new facility to further explore biofabrication technology, we can expect to hear much more from the Terasaki Institute in years to come.

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New Method: Immersion Bioprinting of Tumor Organoids Will Increase the Throughput of 3D Drug Screening

Drug testing and screening for cancer drug discovery can take years and the 2D cell cultures and animal models used to estimate their efficacy before reaching human trials are often not representative of the human body, which is why researchers are turning to bioprinting technologies to increase the success rate during human trials by providing human-specific preclinical data. In 2018 there were 17 million new cases of cancer worldwide, and the disease is expected to affect 27.5 million people each year by 2040, this high incidence level makes tackling the disease enough of a reason for researchers to consider new technologies that could accelerate drug discoveries and screenings. Although still in its lab phase, a new development that uses immersion bioprinting of human organoids could change 3D drug screening.

Researchers from Cornell University, Wake Forest School of Medicine, Virginia Polytechnic Institute and State University and The Ohio State University have published an article in Micromachines, demonstrating an immersion printing technique to bioprint tissue organoids in 96-well plates to increase the throughput of 3D drug screening. Using a hydrogel bioink comprised of hyaluronic acid (HA) and collagen they were able to bioprint it into a viscous gelatin bath, which blocks the bioink from interacting with the well walls and provides support to maintain a spherical form.

According to the article, the use of bioengineered human cell-based organoids may not only increase the probability of success during human trials, but they could also be deployed for personalized medicine diagnostics to optimize therapies in diseases such as cancer. However, they suggest that one limitation in employing organoids in drug screening has been the difficulty in creating large numbers of homogeneous organoids in form factors compatible with high throughput screening, so bioprinting can be used to scale up the deposition of such organoids and tissue constructs.

The team of scientists employed two commercially available bioprinters to evaluate the compatibility of the collagen-HA hydrogel and the HyStem-HP hydrogel: Cellink‘s INKREDIBLE bioprinter and Allevi‘s Allevi2 bioprinter. This method was validated using several cancerous cell lines and then applied to patient-derived glioblastoma (GBM) –a fast-growing brain tumor– and sarcoma (or malignant tumor) biospecimens for drug screening.

For the initial analysis of hydrogel biocompatibility, researchers used two common cell lines: human liver cancer and human colorectal cancer.

While carrying out patient-derived tumor biospecimen processing, they obtained two glioblastomas and one sarcoma biospecimen from three surgically treated patients in adherence to the guidelines of the Wake Forest Baptist Medical Center IRB protocols. These biospecimens were processed into cell suspensions, successfully yielding millions of viable cells from each sample. The cells were then combined with the collagen–HA bioink for deployment in immersion bioprinting. After bioprinting, the GBM and sarcoma patient-derived tumor organoids (PTOs) were maintained for seven days in the incubator, after which a chemotherapy screening study was initiated.

Schematic of the printing process using 2 bioinks in two commercially available bioprinters: Cellink Inkredible and Allevi 2 (Image: Cornell University/Wake Forest)

The researchers claim that while their PTOs have been useful for disease modeling, mechanistic study, and drug development, they have also used these models in a diagnostic sense to influence therapy, which might just be the ultimate goal of their work.

This 3D bioprinting approach called immersion bioprinting is an efficient way to surpass the limitations that have plagued tumor organoid systems. The experts, in this case, suggest that there have been few advances in regard to approaches to the printing process itself, or generation of novel, more user-friendly bioinks. Indicating that “unfortunately, many bioprinting studies are somewhat repetitive, falling back on traditional biomaterials and their crosslinking approaches, which were never developed to be bioprinted or to accurately represent the complexities of the native ECM (extracellular matrix).”

Results of the published study suggests that the realization of this technology that can fabricate PTOs in a consistent and high-throughput fashion will provide a valuable ex vivo/ in vitro tool that can be deployed for many subsequent studies, including target discovery, mechanistic investigation of tumor biology, drug development, and personalized drug screens to aid in treatment selection in the clinic.

Clinical oncology is faced with some critical challenges during this decade, from inefficient trial design to integrating new technologies in diagnostics and drug trails. However, advances in new methodologies, from hardware design to improved bioinks developed specifically for bioprinting, are opening up new opportunities for bioprinting-based applications. This new study, in particular, suggests that with advances in bioprinting hardware, software, functional ECM-derived bioinks, and modifications to printing protocols, bioprinting can be harnessed not only to print larger tissue constructs, but also large numbers of micro-scaled tissue and tumor models for applications such as drug development, diagnostics, and personalized medicine.

Employing bioprinted patient-derived tumor organoids in a clinical precision medicine setting (Image: Cornell University/Wake Forest)

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3D Printing Industry Experts Interview With Ricky Solorzano Co-Founder and CEO of Allevi

Ricky Solorzano

Ricky Solorzano is the Co-Founder and CEO of Allevi. Ricky is looking to combining IoT, organ engineering, and 3D Printing to bring bioprinting solutions to the World, Space, and Beyond. Allevi, Inc. believes 3D tissues will have a huge impact on humanity and create an entire new industry. They want to help scientists create more accurate hearts, lungs, and even brains in the lab. Users are automating the creation of tumor models, printing vasculature within 3D gels, and achieving physiological markers unseen before in tissues.

Explain how you got to your current state in life?

Following my passion got me to this point. It was really about pursuing tissue engineering and thinking it had the possibility to change the world. At first I thought about medical school, but then I had a chance to start a company which was really cool.

What is your educational background?

I went to bioengineering school and worked in a tissue lab. I learned about geometry and how tissue engineering is important. I also took an entrepreneurship class in college. It opened my eyes to different ways one can affect the world around me.

Are startups on the cutting edge vs universities?

Our value is giving the scientist the ability to execute the idea. It is important for us to give people value and for them to bring theirs. It’s the combination of this co-creation that really pushes the fields forward.

What is your value proposition?

We are able to have a lot of power go into a bioprinter. We make them very friendly and easy to use still. We are abstracting the complexity of a bioprinter to simplicity.

Allevi

What are future thoughts on this industry?

More and more tissues will be in the drug testing space. There will be more and more adoptions in investigative PIs (private investigators) to have a bioprinter within their labs. More companies will realize that it is important to have one in their labs. It is important to apply geometry to biology.

A lot of people within the industry of bioprinting are focusing on the importance of geometry applied to biology. Could you explain this a bit more?

Hearts need to be aligned. Shapes need to be consistent when created. It causes an organ or body part to be functional or not. Without geometric properties being maintained, parts will not work as efficiently as they could.

What would you do outside of this if you were not running Allevi?

Tissue engineering product development is probably where I would be. Being able to commercialize things is great way to make an impact. I have been able to learn this really well and continue.

Allevi Dual Extruder

What skills should people be looking into to be in this industry?

Be passionate about a specific direction. If you are passionate about using a bioprinter, work as a bioengineer. It is really important to have a skill set within biology and biomaterials. I think every field can contribute, it just matters what makes you personally excited.

What is the toughest obstacle in terms of work?

Discovery and where do we go. It is hard to figure out what the next step is. We do not have a clear guidance on what to do. It is important to understand the industry as a whole and where it is progressing.

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Breakthrough 3D Printed Neural Scaffold Could Help Patients with Spinal Cord Injuries Regain Some Functions

Right now, 285,000 people in the US suffer from spinal cord injuries, with roughly 17,000 new injuries each year. 3D printed spinal implants have been shown to help patients recover more easily, and a team of engineers and medical researchers from the University of Minnesota (UMN) have spent the last two years developing an innovative new 3D printed medical device that could help long-term spinal cord injury patients regain some function in the future.

“This is a very exciting first step in developing a treatment to help people with spinal cord injuries. Currently, there aren’t any good, precise treatments for those with long-term spinal cord injuries,” said Ann Parr, MD, PhD, a UMN Medical School Assistant Professor in the Department of Neurosurgery and Stem Cell Institute.

The method involves a 3D printed silicone guide, which acts as a scaffold for special stem cells that are bioprinted directly on top of it. The aim is to surgically implant the guide into the injured part of the spinal cord, and it should act as a bridge between living nerve cells both above and below the area, which could help alleviate pain for patients, in addition to helping them gain control over functions like bladder, bowel, and muscle control again.

“We’ve found that relaying any signals across the injury could improve functions for the patients. There’s a perception that people with spinal cord injuries will only be happy if they can walk again. In reality, most want simple things like bladder control or to be able to stop uncontrollable movements of their legs,” Parr explained. “These simple improvements in function could greatly improve their lives.”

Spinal cord scaffold assembly process: 3D bioprinting cells on silicone scaffolds
allows for in vitro culture of sNPCs and OPCs. (a) Silicone scaffolds are printed with
channels, and (b) cells are dispensed inside the channels. (c) A layer of silicone covers the channels, and (d) scaffolds are placed inside a dish and cultured for 7 days.

The team recently published a paper on their potentially life-changing work, titled “3D Printed Stem-Cell Derived Neural Progenitors Generate Spinal Cord Scaffolds,” in the peer-reviewed scientific journal Advanced Functional Materials.

Fluorescence images of 3D printed cell-laden Matrigel (50%) matrices cultured for 0 (3 hours), 1, and 4 days. Timescale images show (a) sNPCs extending axons, and (b) OPCs exhibiting bi-polar processes.

The abstract reads, “A bioengineered spinal cord is fabricated via extrusion‐based multimaterial 3D bioprinting, in which clusters of induced pluripotent stem cell (iPSC)‐derived spinal neuronal progenitor cells (sNPCs) and oligodendrocyte progenitor cells (OPCs) are placed in precise positions within 3D printed biocompatible scaffolds during assembly. The location of a cluster of cells, of a single type or multiple types, is controlled using a point‐dispensing printing method with a 200 µm center‐to‐center spacing within 150 µm wide channels. The bioprinted sNPCs differentiate and extend axons throughout microscale scaffold channels, and the activity of these neuronal networks is confirmed by physiological spontaneous calcium flux studies. Successful bioprinting of OPCs in combination with sNPCs demonstrates a multicellular neural tissue engineering approach, where the ability to direct the patterning and combination of transplanted neuronal and glial cells can be beneficial in rebuilding functional axonal connections across areas of central nervous system (CNS) tissue damage. This platform can be used to prepare novel biomimetic, hydrogel‐based scaffolds modeling complex CNS tissue architecture in vitro and harnessed to develop new clinical approaches to treat neurological diseases, including spinal cord injury.”

The process begins with any type of adult stem cell, be it blood or skin, and medical researchers use the latest bioengineering techniques to reprogram these into neuronal stem cells. These cells are then 3D printed onto a silicone guide with a unique extrusion-based technology, which can print both the cells and the guide from the same 3D printer.

Michael McAlpine, PhD, UMN Benjamin Mayhugh Associate Professor of Mechanical Engineering in the University’s College of Science and Engineering, said, “This is the first time anyone has been able to directly 3D print neuronal stem cells derived from adult human cells on a 3D-printed guide and have the cells differentiate into active nerve cells in the lab.”

Photograph of customized 3D bioprinting setup.

The 3D printed silicone guide keeps the stem cells alive, so they can change into neurons.

“Everything came together at the right time. We were able to use the latest cell bioengineering techniques developed in just the last few years and combine that with cutting-edge 3D-printing techniques,” said Parr.

The researchers created a prototype implantable guide to help connect the living cells on each side of a damaged spinal cord area, though this task was not without its difficulties.

“3D printing such delicate cells was very difficult. The hard part is keeping the cells happy and alive,” explained McAlpine. “We tested several different recipes in the printing process. The fact that we were able to keep about 75 percent of the cells alive during the 3D-printing process and then have them turn into healthy neurons is pretty amazing.”

With any luck, the team’s next steps in the process will be successful, which should provide some hope for the future to patients with long-term spinal cord injuries.

Co-authors of the paper are Daeha Joung, Vincent Truong, Colin C. Neitzke, Shuang-Zhuang Guo, Patrick J. Walsh, Joseph R. Monat, Fanben Meng, Sung Hyun Park, James R. Dutton, Parr, and McAlpine.

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