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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3D Printing Review in Drug Delivery Systems: Pharmaceutical Particulates and Membranes

Researchers from Egypt, India, and the UK are studying the role of 3D printing in drug delivery systems. Their findings are detailed in the recently released ‘Pharmaceutical Particulates and Membranes for the Delivery of Drugs and Bioactive Moleclules,’ as they review new trends and developments.

In reviewing twelve different papers on the subject of pharmaceutical particulates and membranes, the researchers also collaborated with experts regarding design, materials, and applications; for instance, in a study by Kumar et al. [2], the researchers learned of an extended release drug delivery system for nicotine that shows potential for Parkinson’s disease interventions:

“These have been developed in the form of membranes with minimal rates of matrix degradation and retarding nicotine release. This has led to the zero-order release for 50 days following exposure to simulated cerebrospinal fluid (CSF),” stated the researchers.

Mora-Espíet et al. [3] have explored the targeting of microparticles and culturing breast cancer cell lines. Huang et al. [4] confirmed a new process for accelerating drug dissolution with ibuprofen-loaded hydroxypropyl methylcellulose nanoparticles.

Immunofluorescence analysis by confocal laser scanning microscope (CLSM) of cells cultured in static conditions. Confocal images of D492 and D492HER2 cells cocultured in static conditions and incubated with microparticles biofunctionalized with a non-specific secondary antibody (µP-secAb) or a specific anti-HER2 antibody (µP-antiH). Cells, constitutively expressing green fluorescent protein (GFP, green), were incubated with Alexa Fluor® 546 Phalloidin (red) to label actin microfilaments and Alexa Fluor® 405 conjugate secondary antibody (blue) to label HER2 in the plasma membrane. The arrows point to some examples of µPs located inside the cells. From ‘Cell Internalization in Fluidic Culture Conditions Is Improved When Microparticles Are Specifically Targeted to the Human Epidermal Growth Factor Receptor 2 (HER2).’

“During this process, it was shown that a key parameter, i.e., the spreading angle of atomization could provide a linkage among the working process, the property of generated nanoparticles and their functional performance,” stated the researchers. “They confirmed that the nanoparticle diameter (prepared based on a modified technique) has a profound influence on the drug release performance.”

Shah et al. [5] contributed a study as they moved forward to refine the effectiveness of moxifloxacin, an antibiotic used to treat a variety of bacterial infections. With a new system for optimizing nanoemulsion, they were able to ‘enhance the therapeutic effects of moxifloxacin,’ resulting in safe delivery.

Another development, contributed by Wan et al. [6], allowed for sustained release of loxoprofen sodium (LXP), with the addition of a unique coating:

“Their results identified both the citric acid (CA) and ADEC as the dissolution and diffusion-rate controlling materials significantly decreasing the drug release rate,” stated the researchers. “The optimal formulation for a pH-independent drug release in media has been suggested as at a pH above 4.5 and at slightly slow release in acid medium.”

“The pharmacokinetic studies have revealed that a more stable and prolonged plasma drug concentration profile of the optimal pellets has been achieved, with a relative bioavailability of 87.16% compared with the conventional tablets.”

Studying magnetic nanoparticles, Iglesias et al. [7] stated that BMNPs (biometic) were superior to MNPs (inorganic) for drug loading of molecules ‘positively charged at neutral pH.’ MNPs, however, have the potential for suitable transport abilities while under a magnetic field. Savin et al [8] explored gel formulations for skin melanoma treatment, along with fabricating breast cancer cells in 3D models—following one of the major trends in medicine today using models for treatment, training, and surgical planning too.

“The in vitro results for the tested CD-NHF-loaded gel formulations have revealed that the new composites can affect the number, size, and cellular organization of spheroids and impact individual tumor cell ability to proliferate and aggregate in spheroids,” stated the researchers.

Guadarrama-Acevedo et al. [9] created a new wound dressing made of alginate membrane and polycaprolactone nanoparticles, loaded with curcumin for healing. Integrating nanocarriers allows for drug permeation into multiple layers of skin, thus eliminating solubility issues with curcumin. Rancan et al. [10] performed research showing that after six hours, nanofiber mats offer the best drug concentration upon delivery.

Morphology and porosity of alginate membranes. (a) Micrographs by scanning electronic microscopy of the alginate membrane surface (A, B, D, and E) and membrane thickness (C and F). Magnification of 100× for A, D; 220× in B, C, E and F; the scale bar is 100 μm; (b) pore diameter and membrane thickness of M4 and CNp‒M4 membranes, mean ± SE, n = 3. * indicates that p < 0.05 is statistically significant. From ‘Development and Evaluation of Alginate Membranes with Curcumin-Loaded Nanoparticles for Potential Wound-Healing Applications.’

Further, Lian et al. [11] developed a system for using red blood cell membrane-camouflaged ATO-loaded sodium alginate nanoparticles (RBCM-SA-ATO-NPs, RSANs) to eliminate toxicity of ATO. Their work also showed that RSANS have lower levels of cytotoxicity, upon comparison with normal cells; RSANS also displayed antitumor effects on NB4 cells and 7721 cells.

Adeleke et al. [12] developed an isoniazid suspension as an antitubercular agent against TB, offering extended release:

RDS has been dispersible and stable in the dried and reconstituted states over 4 months and 11 days respectively, under common storage conditions.

Representative graphs displaying: (a) particle size distribution, (b) zeta potential distribution, as well as TEM micrographs showing different surface topographies and characteristics of the reconstitutable dry suspension (RDS) particles at different scales: (c) 1μm and (d) 5 μm, respectively. ‘Development and Evaluation of a Reconstitutable Dry Suspension Containing Isoniazid for Flexible Pediatric Dosing.’

“The published papers are also being compiled as an edited e-book, to be published by MDPI,” stated the researchers.

What do you think of this news? Let us know your thoughts! Join the discussion of this and other 3D printing topics at

[Source / Images: ‘Pharmaceutical Particulates and Membranes for the Delivery of Drugs and Bioactive Moleclules’]


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3DHEALS2020: A Not So Lonely Planet

Only a few weeks away from 3DHEALS2020, and I just got off the phone with one of our speakers, Dr. Ho, from NAMIC Singapore. Our brief interview reminded me just how much I enjoyed Singapore—its start-up like government, incredible universities, and its beautiful modern architecture, chili crabs, and unpredictable rainstorms. Now, I’m on my way to some of the best meals in my life with another 3DHEALS community event in a foreign city. Looking back, there are many stories like that: in Detroit, Vigo, Paris, Shanghai, or Boston, my work with 3DHEALS communities has been a journey of adventures and friendships. 3DHEALS2020 is really a way to summarize my travels from the last two years. It is my version of Lonely Planet—the healthcare 3D printing version.

I really felt more alive when people have welcomed me into their cities; when they have showed off their latest innovations; when they have bantered enthusiastically with one another in a local pub till midnight after 3DHEALS events. And they felt the same way.

Sadly, however, this pandemic is putting old methods of human connection into question. Perhaps, a virtual summit is a stopgap solution for conferences, but, more likely, it is time for us to explore alternative and better ways to stay connected and informed.

The virtual 3DHEALS2020 summit will be a good start.

While we can’t serve you delicious San Francisco Blue Bottle coffee, there are three things we aim to do right with this conference:

1. Awesome live content

One upside about the virtual summit is that people who could not be available due to logistic barriers are now more available. We added 20+ speakers since the pandemic began and are still adding more parallel workshops to the existing program. Some of highlights include:

A. Biofabrication/Bioprinting Panels and Workshops:

Welcome to the holy grail of healthcare 3D printing applications!

These panels and workshops collect some of the brightest minds in the world of tissue engineering, biofabrication, and bioprinting. It includes the newest generation of startup founders. Names such as Stephanie WillerthAdam FeinbergJordan Miller are already well-established and loved in the scientific communities and just founded their own startups within the last 12 months. More established startup founders whose companies are also critical to the eventual success of biofabrication, tissue engineering, and cell therapy at large will also join us live, including Melanie Mathieu from Prellis Biologics, Jon Rawley from Roosterbio, John O’Reily from Xylyx, Taciana Pereira from Allevi, and Kevin Caldwell from Ossium Health. Qrquidea Garcia (“Orchid”) from JNJ Innovation will also join us on this panel, discussing how an industry leader can work with innovators and startups in this exciting, burgeoning field.

B. Regulatory and Legal Landscape of Healthcare 3D Printing

For those who put their skin in the game, this is probably one of the most must-attend sessions. 3D printing in healthcare is a super new field, and legal experts in this field who have established track records and legitimacy are only a handful. This session will include the most comprehensive list of legal and regulatory concerns specifically for healthcare 3D printing, including intellectual property/patent issues, product liability, FDA pathways, manufacturing standards, and more. Steven Bauer, from FDA CBER, just joined the panel to directly address concerns related to cell therapy from the biofabrication and stem cell communities. The speakers are not just well-versed on how to interpret the law and policies, but also how to interact with scientists, policy makers, organizations, and standards bodies at this early stage of the industry, with practical, real-life examples.

C. Global Perspectives

One lesson from this pandemic is that globalization has consequences. Having a well-rounded worldview of the global healthcare 3D printing ecosystem is a requirement for future success. Our early morning sessions are reserved for international speakers all over the world to meet the audience and share their unique perspectives, needs, and hopes. Both America Makes director John Wilczynski and NAMIC director Dr. Chaw Sing Ho, along with experts from Turkey, India, and Taiwan, will share how healthcare innovations can thrive in both local and global environments. On day two (June 6th), the audience will learn about how different countries are implementing the concept of 3D printing for Point of Care, which cannot be taken out of context of different healthcare systems and cultures. The audience will meet and learn from the leaders at UCSFStanfordGermany (Kumovis), India (Anatomiz3D), and developing countries.

2. Pre- and post-event networking opportunities

The attendees will have the opportunity to meet other attendees, speakers, and conference organizers as soon as they sign up the event using a dedicated conference app. They can send direct messages, post threads, share photos, host their own virtual events days before the conference. The app will be available to registered attendees for six months after the conference ends.

3. Entrepreneurship

One of the most exciting aspects of 3DHEALS2020 is its focus on entrepreneurship. Pitch3D has been a quarterly free and online pitch platform to selected early-stage startups in healthcare 3D printing and bioprinting spaces for the last two years, introducing 30+ startups from all over the world to institutional investors. 3DHEALS2020 also gathered some of the most experienced VCs and entrepreneurs in the space to share their stories, perspectives, and directly engage with the startups and the 3DHEALS2020 attendees directly during both pitch sessions and investor panels. There will be ten startups pitching each day at 5-6 PM PST. Interested startups can apply here.

This is the time of uncertainty and change.

Join us at 3DHEALS2020, connect with the world, and take control of your future. This is a Not So Lonely Planet.

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A Guide to Bioprinting: Understanding a Booming Industry

The success of bioprinting could become the key enabler that personalized medicine, tissue engineering, and regenerative medicine need to become a part of medical arsenals. Breakthroughs in bioprinting will enable faster and more efficient patient care and recovery. Biofabrication could be used to reshape the foundations of drug development, medicine, cosmetics, organ transplantation, and many other fields. It will transform the way doctors repair damaged ligaments, recreate tissues, and even reproduce the layers of the skin.

We are entering an era of bioprinting revolution. But to understand the role that bioprinting will play in the future, it is important to look back at how early discoveries in the field provided a strong basis to push its capability forward:

  • Back in the ’90s, Anthony Atala, pediatric surgeon, urologist, and director of the Wake Forest Institute for Regenerative Medicine (WFIRM) in North Carolina, created by hand bladders, skin, cartilage, urethra, muscle, and vaginal organs. By the end of that decade, the Institute used a 3D printer to build a synthetic scaffold of a human bladder, which they then coated with cells taken from their patients and implanted it, preparing the stage for bioprinting.
  • Then in 2002, scientists from Harvard University printed two-inch-long mini-kidneys capable of filtering blood that was then transplanted back into genetically identical cows, where they started making urine. The novel research raised the prospect of using stem cells taken from human patients with kidney failure to create new organs for transplant.
  • However, it wasn’t until 2003, when bioengineering professor Thomas Boland adapted a Hewlett-Packard inkjet printer in his lab at Clemson University to begin printing a bioink made of living bovine cells suspended in the cell-culture medium, that bioprinting began to materialize. This led to the creation of the world’s first 3D bioprinter, capable of creating living tissue from a solution of cells, nutrients, and other bio-compatible substances.
picture os a man using the bioprinter on a limb

A member of WFIRM team operates with the bioprinter (Image: WFIRM)

Twenty years later, researchers still face challenges as they continue working with bioprinters and bioinks. Even though there has been an increasing adoption of the technology, the extent of its potential has not been fully exploited. From choosing the bioinks to actually bioprinting human tissues and organs, this new field is quickly becoming the go-to technology that bioengineers, researchers, and hospitals need to evolve from lengthy and cumbersome manual work to scalable and replicable results.

How Well Do you Know Bioprinters? (or How Bioprinters Work and Who Makes Them)

Bioprinters work by extruding cells and other biomaterials contained in bioinks, from syringes that deposit the material layer by layer to create different types of tissues or organ-like constructs. The technology behind the bioprinters vary. Nonetheless, to date, the three main and most popular bioprinting technologies are extrusion, inkjet, and laser-based bioprinting. Some mainstream examples are:

  • Some manufacturers, like Cellink or Allevi, use pneumatic-driven extrusion systems that pump high-pressure air in a cartridge to force bioinks to flow through a nozzle. 
  • Other fabrication systems, such as the one designed by Poietis has laser-assisted bioprinting that allows cells to be positioned in three dimensions with micrometric resolution and precision to design living tissue.
  • Another type of bioprinting technology uses a stereolithography-based bioprinting platform. Vendors using this process include Volumetric and Cellink’s jointly produced Lumen X projection stereolithography based bioprinter.
  • Another project that could revolutionize the way surgical procedures are performed is handheld bioprinters; these systems enable surgeons to deploy cells — or material to aid in cellular growth — directly into a defect site in the body, such as severely burnt skin, corneal ulcerations or bone. One of the most talked-about handheld bioprinters has been Australia’s University of Wollongong BioPen, allow surgeons to repair damaged bone and cartilage by “drawing” new cells directly onto bone in the middle of a surgical procedure. Although still in pre-clinical trials, these devices have attracted the attention of healthcare practitioners due to its versatility.

A few of the main manufacturers supplying the market include 3D Bioprinting Solutions, Allevi, Aspect Biosystems, Cellink, nScryptregenHuInventiaRegemat3DPoietis, and more. Last year, counted 111 established bioprinting firms around the world. Mapping the companies that make up this industry is a good starting point to understand the bioprinting ecosystem, determine where most companies have established their headquarters and learn more about potential hubs, like the one in San Francisco.

Types of Bioinks

3D bioprinters use bioinks. Bioinks are substances made of living cells that can be used for 3D printing complex tissue models — they mimic an extracellular matrix environment to support the adhesion, proliferation, and differentiation of living cells. Choosing which bioink to use can be challenging. To date, we have witnessed researchers using bioinks based on several biomaterials, such as alginate, gelatin, collagen, silk, hyaluronic acid, even some synthetic-biomaterials-based-bioinks.

The promise of hydrogels. A macromolecular polymer gel constructed of a network of cross-linked polymer chains, hydrogels are able to meet the stringent requirements of cells and are the basis of almost all bioink formulations. As stated in “Engineering Hydrogels for Biofabrication”, published in Advanced Materials, “hydrogels are particularly attractive for biofabrication as they recapitulate several features of the natural extracellular matrix and allow cell encapsulation in a highly hydrated mechanically supportive threedimensional environment.” This makes hydrogel-based bioinks a very promising choice for many researchers and bioengineers.

Bioinks from patients’ cells. The biomaterials can also use a patient’s own cells, adult stem cells, manipulating them to recreate the required tissue. The source of the cells varies depending on what researchers are bioprinting. For example, in the case of Alzheimer’s disease, experts at the University of Victoria in Canada, have bioprinted neural tissues using stem cells as a tool for screening drug targets for the disease. The ability to program patient-specific cells is the beginning of customized bioprinting since the unlimited potential of these cells can be used to regenerate or repair damaged tissue. 

Polbionica’s bioinks (Image: Polbionica)

What is Bioprinting Good For?

What is most exciting about bioprinting, are the many ways that doctors and researchers are using currently available devices in the market or are creating their own systems to facilitate new processes and applications. The orchestrated interaction between machine and user has led to innovation that could reinvent the world of tissue engineering.

Moving oncology forward:  Bioprinting is being employed in the battle against cancer, whereby scientists create tumor models for research. Modeling cancer using 2D cell cultures fails to accurately replicate the microenvironment of tumors. This is why scientists have turned to biofabrication tools to make three-dimensional models that mimic the intricate in vivo tumors. These models help test anticancer drugs; aid scientists in understanding the underlying causes of metastasis, and can even personalize treatment for individual cancer patients. There have been plenty of initiatives that apply bioprinting to oncology. These range from immersion bioprinting of human organoids to printing cancer tissues in 3D

Microtumors (Image: CTI Biotech)

The market for oncology-oriented bioprinting seems sure to grow. The number of patients suffering from the disease continues to go up. In 2018 alone there were 17 million new cases of cancer worldwide, and projections suggest that there will be 27.5 million new cases of cancer each year by 2040. What that effectively means is that we are witnessing an increase in oncology bioengineering research and whether it is for glioblastoma, bone cancer tumors, or lung models with tumors, the implications can be profound since the ability to use bioinks and bioprinters to create tumors frees researchers of the many ethical concerns associated with testing as well as reduces the costs associated with such research activities. 

Building scaffolds: Probably the most important practical use for bioprinting at the present time is in regenerative medicine. For instance, in 2019, researchers from North Carolina State University (NCSU) and the University of North Carolina at Chapel Hill created a 3D biomedical fiber printer used to create biocompatible scaffolds. Also, Harvard researchers working in Jennifer Lewis’ Lab at Harvard´s Wyss Institute for Biologically Inspired Engineering and John A. Paulson School of Engineering and Applied Sciences (SEAS), came up with a much talked about breakthrough new technique, the SWIFT method, that allows 3D printing to focus on creating the vessels necessary to support a living tissue construct. A team of researchers at Texas A&M University have even developed a 3D printable hydrogel bioink containing mineral nanoparticles that can deliver protein therapeutics to control cell behavior.

Limitations of Bioprinting

Though we heard it many times before, knowing that someday 3D printed artificial organs could eliminate the need for an organ donor waiting list is comforting. Creating personalized replacement organs sounds like the solve-all solution to the organ shortage crisis, yet, a functional organ compatible for human implantation may be decades away. Today, 3D printed organs are still raw to be used for transplantation and lack the vasculature required to function within the human body.

Creation. Last year, mainstream news outlets headlined a story about researchers who had 3D printed a heart. However, the published scientific paper behind that story described how a group of scientists from Tel Aviv, Israel, created bioink out of heart cells and other materials from a patient, and were able to develop cardiac patches and ultimately, 3D print comprehensive tissue structures that include whole hearts. The tissue was shaped in the form of a tiny heart that was kept alive in a nutrient solution. The paper expresses how this development could not function like a real heart since the cells in the construct can contract, but don’t yet have the ability to pump.

This was certainly not the first heart to be 3D printed, yet Tal Dvir, who led the project at Tel Aviv University’s School of Molecular Cell Biology and Biotechnology, indicated that never before had it resulted in an organ “with cells or with blood vessels.” It was an amazing breakthrough for the field, and it proves that biotechnology has made significant advances, but it is still a long way from creating organs that can be transplanted to people, considering that the vasculature — the network of blood vessels that feeds the organ — remains a challenge, but scientists are determined to troubleshoot these issues.

So, no matter how enticing the idea of successfully bioprinted organs sound, stories like this remind us to keep the hype in check, making the work of news outlets fundamental for reporting advancements in research and medical breakthroughs (which usually take much more time).

Where to Next?

Organ bioprinting. The application of 3D bioprinting will be a game-changer in medicine, as the machines successfully replicate tissues and organs, build muscles and cartilage, and enable the adoption of customized medicine. The long-term dream for bioprinting has always been the routine printing of body organs. Current ongoing projects include Michal Wszola’s 3D bioprinted bionic pancreas or Organovo’s 3D bioprinted liver.

The space frontier. Bioprinting in space could hold the key to developing fully functional organs. This is because bioprinting without gravity allows organs to grow without the need for scaffolds. The National Aeronautics and Space Administration (NASA) considers that terrestrial gravitation represents a significant limitation, while a gravity-free environment, magnetic and diamagnetic levitation will allow for biofabrication of 3D tissue constructs with a scaffold-free and even nozzle-free approach. Some bioprinters have already been launched and used in space.  This includes nScrypt and Techshot’s BioFabrication Facility (BFF), or the Organaut 3D bioprinter created by Russian biotech firm 3D Bioprinting Solutions and Roscosmos, the Russian state corporation responsible for space flights.

Healthcare at its best. More prosaically, biomaterials specialist and a professor of biofabrication at Queensland University of Technology, Australia, Mia Woodruff, has been advocating the hospitals of the future for years. She has an exciting vision of a future where the fabrication of patient-specific replacement tissue and organs is safe, cost-effective, and routine. Though perhaps years from happening, her vision is in tune with what many think bioprinting could become, that is, with enough researchers, companies, and funding.

An astronaut aboard the ISS using Techshot’s BioFabrication Facility or BFF (Image: Techshot/NASA)

Coming regulation. Back here on Earth, there will be a growing need for common guidelines for bioprinting to make the process more standardized. In the EU, for example, there currently no particular regulatory regime governing the whole bioprinting process, but piecemeal legislation is relevant in relation to tissue engineering and regenerative medicine. While the Food and Drug Administration (FDA) of the United States plans to review the regulatory issues related to the bioprinting of biological, cellular and tissue-based products in order to determine whether additional guidance is needed beyond the recently released regulatory framework on regenerative medicine medical products.

As the development of the technology strongly advances and proves successful for researchers, we will surely continue to observe brilliant minds perfecting devices and biomaterials, envisioning new systems for future needs, especially as startups emerge out of universities and research institutes, and established companies upgrade their machines to face the limitations we previously addressed in this article.

Still, there is a long way to go, what was largely built so far is a very promising technology. For instance, fully functional organ fabrication for transplantation might take decades. Nonetheless, the unquestionable contribution of bioprinting to so many fields remains an incentive to invest in this area to overcome medical challenges and to move the healthcare industry in a different path, where technology will not only aid in curing diseases but also guiding people by helping them stay healthy, recognizing symptoms early and personalizing solutions in real-time. 

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Cell Culture Bioreactor for Tissue Engineering

Researchers from the US and Portugal are refining tissue engineering applications further, releasing the findings of their study in the recently published ‘A Multimodal Stimulation Cell Culture Bioreactor for Tissue Engineering: A Numerical Modelling Approach.’ In creating a new bioreactor for 3D printing, the authors worked to promote reproducibility and optimization, fabricating a design not possible using conventional techniques.

In most bioprinting, cells are seeded onto scaffolds—also the source of much study, whether in regard to new techniques, enhancements, or interface engineering—and then researchers must hope for viability. Promoting cell growth and sustainability is one of the greatest challenges in any type of bioprinting, and often devices like perfusion flow bioreactors are used in replacing culture mediums to remove toxins. In some cases, they are also used for mechanical stimulation through fluid flow shear stress (FFSS). Electric field stimulation devices can also be easily used to encourage cells to grow, mature, and differentiate.

The bioreactor used here was part of a previous study conducted by the authors, but now updated (using SOLIDWORKS 2018 Student Edition ) to include capabilities in E-Field stimulation and fluid flow mechanical stimulation. 3D design was performed in SOLIDWORKS 2018 Student Edition. Assessment of the new design was part of this study, leaving the team to create a numerical finite element analysis (FEA) of the model.

With FEA, the researchers could project input conditions for the bioreactor, further enhancing effectiveness of cell stimulation, determined from in vitro data. Overall, in vitro tests can offer ‘essential’ information for confirming ranges of multimodal stimulation—projected via numerical studies.

Numerical finite element analysis (FEA) analysis of the proposed bioreactor design with a DC electric stimulation parallel plate capacitor set-up with lateral and top slice views. The three top views represent the ROI upper slice (T1), the ROI middle plane slice (T2) and the ROI bottom slice (T3). (a) Electric potential distribution predicted in the bioreactor due to DC stimulation. (b) E-Field magnitude distribution predicted for the same electric DC stimulation conditions.

Numerical FEA analysis of the proposed bioreactor design for a laminar perfusion flow with lateral and top slice views. The three top views represent the ROI upper slice (T1), the ROI middle plane slice (T2) and the ROI bottom slice (T3). (a) Pressure distribution predicted considering applied inlets velocity of 0.003 m/s and a outlet pressure of 0 Pa. (b) Fluid velocity distribution predicted for the same inlet/outlet conditions. The velocity distribution at the ROI middle plane slice is presented in more detail in a top view inset at the right of the slice plane.

“Electrical and mechanical stimulation conditions in the region-of-interest (ROI) were considered for bone cell stimulation optimization, according with reference values obtained from two previous in vitro studies on bone cell stimulation, one applying mechanical stimulation, and the other using E-Field stimulation,” explained the authors.

Novel bioreactor design: (a) Vertical cut view of the bioreactor design, where the parallel electrodes set up, the upper and bottom inlets and the inlet flow splitters can be observed. (b) Horizontal cut view of the bioreactor design, where the radial outlet system can be observed. The green regions represent the region-of-interest (ROI) where the scaffold will be placed, represented by a cylinder with 4 mm of height and a diameter of 10 mm. (c) CAD bioreactor design assembled in frontal view, the main outlet hole is visible in the middle. (d) CAD bioreactor design assembled in lateral view, showing both electrode connector wires (in brown).

Flow splitters were added between the inlet and the scaffold, resulting in ‘indirect flow prevalence.’ Inlets and outlets were fitted with hose joiners, connecting them to the perfusion pump. The cell culture chamber was separated into two different areas for cell cultures and cell seeding exercises. Materials for use in the platform were required to be non-toxic and suitable according to ISO 10993-5 standards.

Bioreactor geometry volume mesh created using COMSOL Multiphysics, with 1.9 × 106 elements, and an average element quality of 0.65.

“Accordingly, in the direct contact test, cells cultured in contact with all the materials presented normal fibroblast morphology with no evidence of any inhibition halo effect or cell death. According to the cytotoxicity tests results, all candidate materials are suitable for our bioreactor AM fabrication,” concluded the researchers. “We will consider C8 and PETG as materials of interest for future design fabrication. C8 is a new material with good layer adhesion and surface quality, which are key features for the perfusion flow. The C8 supplier datasheet reveals that this material has a higher tensile strength than ABS, resulting in improved mechanical characteristics, which are important for the overall robustness of the bioreactor to withstand the tightness of pressure chambers.”

Cytotoxicity assay with L929 mouse fibroblast according to ISO 10993-5 standards: (a) indirect contact (MTT protocol); (b) direct contact (digital images of the material samples and the negative and positive controls, fresh culture medium and Latex, respectively). A one-way ANOVA with no corrections for multiple comparisons (Fisher’s test) statistical analysis was performed using GraphPad Prism6.

“A design–numerical modelling approach will be essential to understand the underlying biophysical effects of electric and mechanical stimuli in cell cultures and can be a powerful tool for standardization of stimulation protocols considering different bioreactor designs and specific TE outcomes.”

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[Source / Images: ‘A Multimodal Stimulation Cell Culture Bioreactor for Tissue Engineering: A Numerical Modelling Approach’]

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Aalto University Develops a Novel Bioink for Cardiac Tissue Applications

Finland is one of Europe’s most forested nations. Over 70 percent of the country’s boreal forest is covered with spruce, pine, downy birch, and silver birch. But beyond the splendor of the Finnish woodlands, all these trees have one thing in common, and that is nanocellulose. A light solid substance obtained from plant matter which comprises cellulose nanofibrils (CNF) and is considered a pseudo-plastic that possesses the property of specific kinds of gels that are generally thick in normal conditions. Overall, it is a very environmentally friendly and non-toxic substance that is compatible with the human body and has the potential to be used for a range of medical applications.

In 2018, the Department of Bioproducts and Biosystems at Aalto University, located just outside Helsinki, began searching for new ideas to revitalize one of the country’s traditional economic engines, forests (which are handled sustainably thanks to renewable forest resources). At the time, they noticed that one of the possible applications could be working with nanocellulose. Forward two years and the researchers have come up with a new bioink formulation praising nanocellulose at its basis.

Thanks to the structural similarity to extracellular matrices and excellent biocompatibility of supporting crucial cellular activities, nanocellulose-based bioprinting has clearly emerged for its potential in tissue engineering and regenerative medicine. The qualities of the generally thick and fluid light substance make it an excellent match to develop bioinks that are both suitable and scalable in their production, but also have consistent properties. However, there have been major challenges in processing nanocellulose.

As described by Aalto University researchers in a recently published paper in the science journal ACS Publication, the unresolved challenges of bioink formulations based on nanocelluloses are what stops the substance from becoming one of the preferred components for 3D bioprinting structures. This is why Finnish researchers focused on developing a single-component bioink that could be used to create scaffolds with potential applications in cardiac biomedical devices, while fundamentally dealing with some of the limitations of using nanocellulose-based bioinks.

A co-author of the paper and a doctoral candidate at Aalto’s Department of Bioproducts and Biosystems, Rubina Ajdary, told that “other than natural abundance and as a renewable resource, nanocellulose has demonstrated to have an outstanding performance in tissue engineering.” She also suggested that “recent efforts usually consider the use of nanocellulose in combination with other biopolymers, for example, in multicomponent ink formulations or to encapsulate nanoparticles. But we were interested in investigating the potential of monocomponent nanocellulose 3D printed scaffolds that did not require crosslinking to develop the strength or solidity.”

In fact, the Biobased Colloids and Materials (BiCMat) research group at Aalto University, led by Orlando Rojas, proposed heterogeneous acetylation of wood fibers to ease their deconstruction into acetylated nanocellulose (AceCNF). As a unique biomaterial opportunity in 3D scaffold applications, the team considered using nanocelluloses due to the natural, easy to sterilize, and high stability porosity of the substance, and chose to introduce AceCNF for the generation of 3D printed scaffolds for implantation in the human body. The team then went on to evaluate the interactions of the scaffolds with cardiac myoblast cells.
“Most modifications make the hydrogels susceptible to dimensional instability after 3D printing, for instance, upon drying or wetting. This is exacerbated if the inks are highly diluted, which is typical of nanocellulose suspensions, forming gels at low concentrations,” went on Ajdary. “This instability is one of the main reasons why nanocellulose is mainly combined with other compounds. Instead, in this research, we propose heterogeneous acetylation of wood fibers to ease their deconstruction into acetylated nanocellulose for direct ink writing. A higher surface charge of acetylated nanocellulose, compared to native nanocellulose, reduces aggregation and favors the retention of the structure after extrusion even in significantly less concentration.”
This is exactly why it was important for the researches to develop a single component bioink. Nanocellulose has shown promises when combined with other biopolymers and particles. However, Ajdary insists that benefits including similarity to the extracellular matrix, high porosity, high swelling capacity, ease of surface modification, and shear thinning behavior of cellulose, encouraged them to study the potential of monocomponent surface-modified nanocelluloses.

Acetylated nanocellulose (Credit: Aalto University School of Chemical Engineering)

The team at Aalto University used the sustainable and widely available nanocelluloses to make several formulations of bioinks and evaluate them, including unmodified nanocellulose CNF, Acetylated CNF (AceCNF), and TEMPO-oxidized CNF.
To 3D bioprint the hydrogels, researchers used Cellink bioprinters, something Ajdary attributed to the user-friendliness of the device and because it provided a lot of flexibility to test different types of hydrogels and emulsions produced in the research group.
In this new process, the single-component nanocellulose inks were first 3D printed into scaffolds using Cellink’s BIO X bioprinter, which is equipped with a pneumatic print head was used to extrude single filaments and form the 3D structures. Then freeze-dried to avoid extensive shrinkage, and sterilized under UV light. After sterilization the scaffold was ready and cells seeded on the samples.
“3D structures of acetylated nanocellulose are highly stable after extrusion in far less concentrations. The lower concentration in wet condition facilitates the scaffold with higher porosity after dehydration which can improve the cell penetration in the structure and assist in nutrient transport to the cells as well as in the transport of metabolic waste,” specified Ajdary.
The researchers claim that the method was successful as the 3D printed scaffolds were compatible with the cardiomyoblast cells, enabling their proliferation and attachment, and revealing that the constructs are not toxic. Although still in research stages, these bioinks and technique can be used for the inexpensive, consistent fabrication and storage of constructs that can be applied as base materials for cardiac regeneration.
What is novel in this study is the particular focus on single-component nanocellulose-based bioinks that open up a possibility for the reliable and scale-up fabrication of scaffolds appropriate for studies on cellular processes and for tissue engineering. Since this is an ongoing research, we can expect to read more published material from Aalto University researchers as they continue testing their unique technique even further.

Scaffolds corresponding to 3D printed AceCNF (Credit: Aalto University)

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Texas A&M Researchers Make “NICE” Bioinks to Create Functional Bone Tissues

Managing bone defects and injuries using traditional treatments can be slow and expensive. When bones break, bone cells can usually repair them, unless the break is too large. In that case, clinicians have historically turned to bone grafts using non-essential segments of bone taken from other parts of the same patient; bone from the hips, pelvis, chin, or ribs can do the job. Unfortunately, this requires additional surgeries, which translates into more pain for patients, and basically, there is a limit to how much non-essential bone surgeons can take from a patient.

As in many fields, bioprinting is disrupting the way healthcare specialists think about solving problems. So with an estimated 500,000 annual bone grafting procedures in the United States and more than 2 million around the world, an efficient bone substitute could change millions of lives. In a search to fabricate patient-specific, implantable 3D constructs for regenerative medicine, scientists in the Department of Biomedical Engineering at Texas A&M University have developed a new bioink formulation for 3D bone bioprinting called NICE, which is short for Nanoengineered Ionic–Covalent Entanglement, and have gone on to demonstrate that this bioink can precisely reconstruct large bone structures based upon CT scans that were obtained from actual patients.

Led by Akhilesh K. Gaharwar, an associate professor in the Department of Biomedical Engineering, the research group developed a highly printable bioink as a platform to generate anatomical-scale functional tissues. Their study was recently published in the American Chemical Society’s Applied Materials and Interfaces scientific journal, whereby they state that the NICE bioinks allow precise control over printability, mechanical properties, and degradation characteristics, enabling custom 3D fabrication of mechanically resilient, cellularized structures.

Bioprinting requires cell-laden biomaterials that can flow through a nozzle like a liquid, but solidify almost as soon as they’re deposited. This is why bioinks need to act as both cell carriers and structural components, requiring them to be highly printable while providing a robust and cell‐friendly microenvironment. However, the research group realized that many current bioinks lack sufficient biocompatibility, printability, structural stability, and tissue‐specific functions needed to translate this technology to preclinical and clinal applications.

To address this issue, Gaharwar and his team are leading efforts in developing the more advanced NICE bioinks, essentially a combination of two reinforcement approaches, ionic-covalent entanglement, and nanoreinforcement. In fact, the researchers claim that to design the NICE reinforced bioinks for osteogenic tissue bioprinting, the bioink must be highly printable, mechanically strong, induce osteogenic differentiation, and be biodegradable. However, the difficulty of combining these requirements into a single bioink has been a major obstacle in bioprinting since its inception. So by combining these two distinct reinforcement methods, NICE becomes a robust and superior bioink while providing a highly hydrated and cell-friendly microenvironment for bone bioprinting.

NICE printed structures are highly flexible and resilient, as seen in these 3D printed tube structures that can be completely collapsed and quickly regain their shape (Credit: Texas A&M Engineering)

According to Texas A&M Today, Gaharwar said that developing replacement bone tissues could create exciting new treatments for patients suffering from arthritis, bone fractures, dental infections, and craniofacial defects.

“The next milestone in 3D bioprinting is the maturation of bioprinted constructs toward the generation of functional tissues,” Gaharwar said. “Our study demonstrates that NICE bioink developed in our lab can be used to engineer 3D-functional bone tissues.”

NICE bioinks have three major components: covalently crosslinkable gelatin methacryloyl (GelMA), ionically crosslinkable kappa-carrageenan (kCA), and electrostatically charged nanosilicates (Laponite XLG, obtained from BYK Additives & Instruments).
To bioprint scaffolds that can demonstrate potential clinical uses, the team used their osteoinductive NICE bioinks. Then human mesenchymal stem cells (hMSCs) were encapsulated in the NICE bioink and bioprinted into 3D scaffolds. Once bioprinting was complete, this cell-laden 3D printed NICE structures were crosslinked to form stronger scaffolds. This technique has allowed the lab to produce full-scale, cell-friendly reconstructions of human body parts, including ears, blood vessels, cartilage and even bone segments.

hMSCs are encapsulated in the NICE bioink and cell-laden scaffolds are printed (Credit: Texas A&M Engineering)

Soon after bioprinting, the enclosed cells start depositing new proteins rich in a cartilage-like extracellular matrix that subsequently calcifies to form a mineralized bone over a three-month period. Texas A&M stated that almost five percent of these printed scaffolds consisted of calcium, which is similar to cancellous bone, the network of spongy tissue typically found in vertebral bones.

The scaffolds are initially transparent but turn translucent due to remodeling and deposition of nascent proteins after 60 days (Credit: Texas A&M Engineering)

To understand how these bioprinted structures induce stem cell differentiation, the team worked with Irtisha Singh from the Texas A&M Health Science Center, who served as a co-investigator, to use a next-generation genomics technique called whole transcriptome sequencing (RNA-seq) technology, which takes a snapshot of all genetic communication inside the cell at a given moment.
As for the bioprinting, the researchers modified a commercial ANET A8 3D printer kit to utilize screw extrusion. They replaced the thermoplastic extruder assembly with a 3D printed screw extruder assembly, which holds a stepper motor, guide rail, and a modified clay extruder.

To illustrate the practical utility of NICE bioinks for bone tissue reconstruction, the team demonstrated how to create full-scale bioprinted implants customized for craniofacial defects on real patient CT scans. Relying entirely on open-source software, they used the free 3D modeling software Meshmixer to process the models and create bone defects, and the 3D printing applications PrusaSlicer and Repetier Host to bioprint the scaffolds. After bioprinting, the scaffold was crosslinked and implanted in a thermoplastic model of the lower jaw to demonstrate the closeness of fit. Strength of fit was also demonstrated by injecting and crosslinking NICE bioink between two sections of a full-thickness fracture to prove that NICE is able to quickly adhere surfaces together and resist shearing and delamination forces.

Funded by the National Institutes of Health (NIH)’s Director’s New Innovator Award, a National Science Foundation (NSF)’s Award and an X-Grant from Texas A&M University, the researchers suggest they have discovered a new way to design and produce 3D bioprinted bone tissue to benefit bone regeneration.

Moreover, Gaharwar claims to have demonstrated that the highly printable NICE bioinks can precisely reconstruct large bone structures from CT scans obtained from actual patients. The aim of the research is to enable patient-specific bioprinting of bone scaffolds to precisely match their injuries. The researchers stated their desire to have this technique act as a customizable and easy to work with an alternative to autografts that will provide surgeons with greater options for bone surgery. And with the ultimate goal of getting NICE bioink technology from bench to bedside, Gaharwar’s team plans to establish the in vivo functionality of the 3D bioprinted bone tissue.

3D-bioprinted NICE scaffolds can be used for bone regeneration (Credit: Texas A&M Engineering)

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3D Printing: Successful Scaffolds in Bone Regeneration

In ‘Comprehensive Review on Full Bone Regeneration through 3D Printing Approaches,’ the authors review new developments and solutions in tissue engineering for the formation of cells, as well as proposing an optimized temporary support geometry for treatment.

Fused Filament Fabrication (FFF) process.

Bone regeneration continues to challenge researchers in their work as well as medical professionals attempting to improve patient treatment:

“Many research groups have been working on bone regeneration for over 10 years, but this has not led to effective therapy in a clinical setting. If it was successful, it would enhance the quality of life for millions of people and significantly reduce the absence to work due to fractures which are considered the second higher cause of working day lost,” state the authors.

“When there are fractures with a bone defect exceeding a critical size, the bone is not able to self-regenerate and, therefore, requires the use of a temporary implant (natural and/or synthetic) to serve as support and cells to help bone regeneration. In this way, tissue engineering (TE) has emerged.”

While scaffolds are used in tissue engineering for transporting nutrients and secretion of waste, the cells must be able to imitate true tissue biology, morphology, and functionality.

Exploring the usefulness of temporary implants, the authors state that in tissue engineering for patients, it is first critical to examine native bone tissue and mechanical properties.

Human long bone properties.

3D printed implants must be able to sustain cell viability in a secure environment, and scaffolds must possess suitable elasticity for matching regular bone. High porosity is desired in most tissue engineering, along with the use of materials that are not only biocompatible but also biologically active. During trials, animal models of fractures are often used in vivo before procedures are attempted on humans.

“Animal studies are needed to understand bone regeneration. Variables such as the amount of bone formation and its kinetics, mechanical properties and safety obtained by the scaffold, including the presence of toxic degradation in different organs and in terms of inflammatory response need to be understood in detail,” explained the researchers.

“However, bone fractures performed in animals do not represent the complexity of healing human fractures. The potential of each different type of cells both in vitro and in vivo plays here a key role.”

Even more interesting though, the authors point out that growth factors are unnecessary, with cells showing the potential to secrete optimal extracellular matrix (ECM) components.

“In vitro studies are advantageous because they offer a controlled environment to experimental test molecular and cellular hypotheses,” stated the researchers. “However, cells cultured in vitro are not replicates of their in vivo counterparts.”

While tissue engineering can be a delicate process overall in terms of working to keep cells alive, bone generation is particularly challenging—and scaffolds must be relied on to maintain the same role as tissue. Biomaterials must be able to mimic the natural environment, along with possessing identical mechanical properties of the initial bone. Appropriate levels of degradation are critical for bone regeneration, and are also dependent on corrosion resistance and materials.

Characteristics of the different materials used to produce a scaffold.

Suitable materials include poly(ε-caprolactone) (PCL) or polylactic acid (PLA), both approved by the FDA and offering stability, biocompatibility, and biodegradability. Scaffolds must be osteoinductive for sustaining cells as well as being osteoconductive, providing growth. They must also serve to:

  • Fill bone defect
  • Ensure pore connectivity
  • Encourage bone formation
  • Promote bone growth

Natural organization of long bones.

Designed in SolidWorks, the structures exhibited ‘superior advantages’ over what could be produced conventionally.

“Considering all types of materials available, associated with the desired bone regeneration and the use of synthetic polymers, as PCL or PLA, combined with collagen type I for the trabecular region and Hap for cortical region, seems to be the best strategy to follow,” concluded the researchers.

“Among the most commonly used bioreactors for bone regeneration, perfusion bioreactors appear as the most suitable, because it improves osteogenic proliferation and differentiation due to improved mass transfer and adequate shear stress. When making a design proposal for bone regeneration, it is necessary to study the mechanical effects, such as stress and tension, and link them.”

Cylindrical scaffold

DNA chain-inspired cylindrical scaffold.

Tissue engineering continues to be an enormous area of study, from seeding human dermal fibroblasts, promoting hydrogel microenvironments, to bioprinting structures for soft tissue engineering applications.

Scaffold requirements in terms of response (left) and what should be taken into account (right) (adapted from [106]).

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[Source / Images: ‘Comprehensive Review on Full Bone Regeneration through 3D Printing Approaches’]

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China: Bioprinting Polycaprolactone/Silk Fibroin Scaffolds to Improve Meniscus Regeneration

Researchers from China are hoping to improve medical outcomes for patients dealing with knee joint issues. Their recent study, ‘Biomechanically, structurally and functionally meticulously tailored polycaprolactone/silk fibroin scaffold for meniscus regeneration,’ outlines their recent study.

Meniscus deficiency is a disease of the knee joints, which can also develop further into osteoarthritis—a degenerative disease that may continue to worsen and cause pain. The authors note that fixing the meniscus can be fraught with difficulties, with today’s most common techniques being meniscus suture, partial or total meniscectomy, and allograft transplantation.

In the hopes that bioprinting could make sweeping changes in the area of regeneration, they have developed a new meniscus scaffold made out of polycaprolactone (PCL)/silk fibroin (SF). Such techniques may be effective, but unfortunately do not ward off osteoarthritis. Allograft transplantation may work also, but research shows that over time results are still shown to be ‘dissatisfactory and uncertain.’

“Also, none of the commercial implants can perfectly restore or permanently replace the natural meniscus tissue, effectively solve the symptoms after meniscectomy, and prevent degenerative cartilage diseases,” state the researchers. “In complex meniscus injuries, the inability of surgical intervention to recover the structural, biomechanical, and functional properties of meniscus remains a great challenge.”

While PCL has been used previously in 3D printing, most studies or experimentation have not been related to strengthening mechanical properties; however, the researchers theorized that PCL could offer the potential for ‘robust’ mechanical properties as well as biomimetic structures. The downside could be ‘risk of attrition of articular cartilage and lack of biological functional bionics.’

Biomimetic meniscus scaffolds were created on a 3D Bioplotter.

Schematic illustration. (A) Fabrication and crosslinking of the scaffolds. (B) Functional optimization of the scaffolds. (C) Biocompatibility assessment in vitro. (D) Implantation in vivo.

Crosslinking procedures of the scaffolds. (A) Proposed cross-linking mechanism of SF under γ-irradiation. (B) Conjugation of L7 peptide onto the scaffolds. (C) Secondary structure changes of SF after ethanol treatment. (D) FTIR spectra of the samples: (1) Pure silk solution, (2) SF after γ-crosslinking and ethanol processing, (3) SF-PCL after γ-crosslinking and ethanol processing, (4) Untreated PCL.

“The pre-created γ-crosslinking network not only provided a preliminary supporting structure for the material system, but also affected the distribution and size of the new physical cross-linker β sheet domains, which contributed to the strength, elasticity, and stability of the SF sponge,” stated the researchers.

As the PS scaffolds begin to show signs of degradation, the researchers noted both slow degradation of PCL as well as more rapid degradation of SF scaffolds. The ratio between samples demonstrated a balance between biomechanical properties, matching the new meniscus.

Biocompatibility, recruitment, and chondrogenic differentiation of SMSCs in the scaffolds in vitro and in vivo. (A) i) SMSC recruitment was verified using immunofluorescence assay after 1-week of implantation with different scaffolds in vivo. ii) Viability of SMSCs was analyzed by Live/Dead staining 3 days after seeding on different scaffolds without chondrogenic incubation. iii) Morphology of SMSCs was observed via Phalloidin/Hoechst assay after 3 days of culturing with different scaffolds without chondrogenic induction. (B) Number of CD29+/CD90+ double-positive cells on different scaffolds in vivo at 1-week post-surgery. (C) Number of effluent cells at 12 and 24 hours after SMSCs were seeded on different scaffolds in vitro. (D) Viability of SMSCs in different groups was observed by alamarBlue assay, and the OD value at each point was normalized against the average of the first day in each group. No significant difference among different groups was observed at the same time point. (E-G) Cartilaginous matrix production in different scaffolds: (E-F) Col I and Col II production quantified by ELISA; (G) GAG assay. (H-K) cartilage-specific gene expression of Col I, Col II, Sox 9, and ACAN (n = 6, *p < 0.05).

Macroscopic observation, biomechanical and inflammation assessment of regenerated meniscus in vivo. (A-B) Macroscopic observation of joints at 12 weeks and 24 weeks after implantation. (scale bar = 10 mm) Medial meniscal excised from the tibial plateau is shown on the right. The Blank group received no implantation after total medial meniscectomy. (C-D) Biomechanical assay of implants at each time point (12 weeks and 24 weeks) (n = 4, *p < 0.05). (E) Histological evidence of the synovium at 1, 3, 6 weeks after surgery (scale bar = 200 µm). (F) Quantitative assay of Interleukin-1 in the synovial fluid at 1, 3, 6, 12, and 24 weeks after surgery. (G) Quantitative assay of tumor necrosis factor-α in the synovial fluid at 1, 3, 6, 12, and 24 weeks after surgery. (n = 6, **p < 0.01 vs 1 week)

“With the advantages of biomimetic architecture, SMSC recruitment ability, and excellent biomechanical characteristics, the scaffold provided an excellent microenvironment for SMSC recruitment, retention, proliferation, differentiation, and ECM production,” concluded the researchers. “Furthermore, the scaffold displayed superior biomechanical properties and excellent anisotropic meniscus regeneration and chondroprotection.”

“Compared with traditional cell-based therapies, the current study provides a novel approach for one-step meniscus repair and regeneration with the advantages of reduced cost and avoiding secondary operation. Thus, the PS-L7 scaffold developed in the current study exhibits tremendous potential for clinical translation in meniscus tissue engineering.”

The meniscus has been the center of other studies related to 3D printing, from 3D printed implants to help with recovery from sports injuries to fabrication of menisci in outer space. What do you think of this news? Let us know your thoughts! Join the discussion of this and other 3D printing topics at

[Source / Images: ‘Biomechanically, structurally and functionally meticulously tailored polycaprolactone/silk fibroin scaffold for meniscus regeneration’]

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Prellis Biologics Pursues Bioprinted Lymph Nodes for Production of COVID-19 Antibodies

Bay Area bioprinting firm Prellis Biologics is researching the use of bioprinted lymph nodes for the production of SARS-CoV-2 antibodies. The idea of using antibodies as a form of preventing an illness is an increasingly popular one, with the idea of injecting a person with pre-existing, artificially manufactured antibodies to an illness before their body has a chance to develop their own either through recovering from a virus or through a vaccine.

Prellis is working to procure a heat-killed virus with a goal of having the sample within 14 days of the project’s start, at which point the company will spend about four weeks printing human lymph nodes and inoculate it, screening for antibodies and sequencing them. After that, the firm suggests that it will be able to find a research center that can gest for viral neutralization and binding affinity of a given antibody before the antibodies will be mass manufactured by a partner company.

Image courtesy of Prellis Biologics.

Prellis isn’t the only one working to make synthetic antibodies to the SARS-CoV-2 virus. In particular, Dr. Jacob Glanville, of Distributed Bio, has received a great deal of attention for promoting the idea. Manufactured antibodies would be injected into frontline workers, who would theoretically be able to fight off the virus with those antibodies for a shorter period of time, maybe eight to 10 weeks.

Synthetic antibodies have been approved by the U.S. Food and Drug Administration (FDA) since 1986, with 570 therapeutic synthetic antibodies studied in clinical trials by commercial companies and 79 FDA approved for the market. About 30 of these are for cancer, with the rest covering asthma, arthritis, psoriasis, Crohn’s disease, transplant rejection, migraine headaches and infectious diseases. Synthetic antibodies to treat viral illnesses, however, is still in the exploratory phase.

The first clinical trials for an antibody therapy for COVID-19 are now underway with an antibody called gimsilumab, which inhibits the growth of a protein that appears in high concentrations in the blood serum of COVID-19 patients and is thought to contribute to the hyper-inflammation in their lungs.

Though we are not experts in antibody production, we should of course be skeptical about the Prellis COVID-19 project because the stakes are so high. From what we know of bioprinting, it has come a long way since its inception in the early 2000s, including a number of recent achievements in the creation of bioprinted organoids, from hearts to kidneys to tumors.

However, the applications of this technology are yet to be fully realized, with even drug testing, one of the more immediately viable uses of bioprinting tissues, still in the exploratory phases. Some animal studies are currently in the works and have great promise, such as the successful transplantation of 3D-printed knee cartilage into sheep. With that said, even if Prellis were able to print lymph nodes and see them develop antibodies, there are numerous other variables and obstacles to account for when considering the possibility of successfully mass producing and then deploying these antibodies as a form of therapy.

There is some good reason for hope for the Prellis project to keep in mind. According to Prellis, founder Melanie Matheau was able to create a fully functional human lymph node that produced 11 active antibodies to the Zika virus in 2017, receiving a U.S. patent for the technique in December 2019. The process was repeated with different blood donors, with each sample producing antibodies. The company claims that it can perform the same process to develop antibodies to at least one of the strains of coronavirus currently involved in the global pandemic.

Due to the emergency approval fast-tracking that the FDA is currently implementing, a number of initiatives are being given emergency authorization. This includes potentially problematic ones, such as clinical trials for DNA and RNA vaccines developed by companies partnered with the Defense Advanced Research Projects Agency that were previously unable to get their products licensed for human use, as their vaccines were unable to offer sufficient immunity in human trials. It is possible that, if Prellis is able to achieve its goals, it could be given emergency authorization to perform Clinical I trials.

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