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How is 3D Printing Innovating Medical Research in 2020?

3D printing technologies are pushing the boundaries of what was once considered only possible in science fiction novels. The advances being made by engineers from around the world are contributing to a plethora of innovations that are having a major impact on conventional medical practice. Medical researchers have been able to develop solutions in the form of patient-specific prostheses and pre-operative models, tailored, corrective insoles and orthotics, new medical devices and instruments, and 3D bioprinting and tissue engineering. In this article, we will provide a brief review of some of the latest 3D printing technologies and methods that are inspiring medical research.

Pre-operative
planning, prostheses, and implants

The rapid prototyping capability of 3D printing is offering the medical community a fast and cost-effective way of delivering life-altering medical interventions and solutions to patients. For individuals that require a prosthesis or implants such as a bionic hand or leg bone, 3D printing is providing a functional and affordable way to generate patient-tailored parts. The technology offers complete design freedom and rapid turn-around times. 

Using high-resolution images, 3D printing is able to generate accurate models of human anatomy. Image data can be exported as a common medical file format, DICOM (digital imaging and communication in medicine), which can then be converted into a stereolithography format (STL) file. From this file, a 3D virtual model can be created. For orthopedic surgery, implants can be made from these models to replace fractured bones. Further, virtual or physical models can be used by surgeons in pre-operative planning and for teaching patients, alleviating their stress and anxiety by explaining what a procedure would entail.

Biological tissue
generation

In early June of this year, scientists from the University of Colorado (UC) Denver and the University of Science and Technology in China were the first to use new material to 3D print structures that could mimic cartilage. Cartilage replacement has been a notoriously difficult hurdle to cross for scientists and healthcare professionals until now. UC Denver’s mechanical engineer, professor Chris Yakacki, led the team of researchers in using a 3D printing process called digital light processing (DLP) to create a liquid crystal resin-like substance. When exposed to UV-light the researchers observed that the substance cured and formed new bonds in several thin photopolymer layers. The final cured form constituted a strong, yet soft, and compliant elastomer. when printed as a latticed, honeycomb structure, that’s when Yakacki and his team saw that it began to resemble cartilage. Their research findings were published in the journal Advanced Materials.

In addition to utilizing this breakthrough material for cartilage replacement, Yakacki also believes there is potential for liquid crystal elastomer (LCE) to be used in the creation of a spinal cage prototype. The design of complex structures like LCE’s and the use of bioinks to help produce artificial live tissue will provide the medical research community with unique scaffolds with which to generate different components of the human body.

Bioinks

One particular area gaining interest by researchers and clinicians is
the design of patient-specific bone grafts. Associate professor at the Department of Biomedical
Engineering at Texas A&M University, Dr. Akhilesh Gaharwar, believes that developing
replacement bone tissues may be an exciting prospect in the generation of
treatments to help people with dental infections, arthritis, craniofacial
defects, and bone fractures. This is where bioinks enter the scene. In a recent
publication, Dr.
Gaharwar outlines the creation of a structurally stable, biodegradable, and
highly printable bioink. Garharwar’s nanoengineered ionic covalent entanglement
(NICE) bioinks involve two reinforcement techniques known as nonreinforcement
and ionic-covalent network. The use of these two techniques results in much
more stable tissue structures.

Following bioprinting, the NICE
networks form crosslinks with encapsulated stem cells to create stronger
scaffolds. Within the period of three months, the cells start to produce
cartilage-like extracellular matrix which calcifies to form mineralized bone.
The team used next-generation RNA-sequencing technology to establish the role
of nanosilicates (a component of the bioink) in inducing the formation of bone
tissue. Dr. Gaharwar and his team successfully demonstrated the ability of NICE
bioink to create patient-specific implantable 3D frameworks for the repair of craniofacial defects.

Orthoses

Medical research centered around the custom design of orthotics still
bears the stigma of a high price tag and inaccessibility which can be an
irritable deterrent for healthcare providers trying to do the best for their
patients and a disheartening prospect for patients respectively. The revelatory
story of Matej
and his son Nik, shows how powerful a tool 3D printing can be in advancing
medical and engineering research, efficient medical practice, and optimizing
patient care.

One of the latest uses for 3D printing in the world of orthotics was the design of a cervical collar using a novel workflow for a patient with a neurological disability with no alternative means of therapy. Dr. Luke Hale and Associate Professor Dr. Deepak Kalaskar from UCL’s Institute of Musculoskeletal Sciences (IOMS) led the research which was published in Scientific Reports. The research team scanned the head and neck of the patient with a handheld scanner to generate a 3D scan mesh. This framework was then imported into Houdini software (SideFX software, version 16.5). The geometry projected onto the 3D scan conforms with it completely to create a comfortable orthosis.

Using the scan, the design of the orthosis was optimized to incorporate modifications including a porous pattern to improve ventilation. This also reduces the cost and weight of the final orthosis. Four prototypes of the cervical collar were made to accommodate patient feedback and achieve the most comfortable design. The research validated the use of using 3D printing and scanning alongside a tailored workflow for clinically beneficial outcomes while allowing for iteration, modification, and improvement of the design.

These are only some of the latest medical research advancements coming
to fruition with the revolutionary technology of 3D printing. 4D printing and
the use of novel bioinks for organ tissue generation are some more fascinating
research prospects to look forward to in 2020. 

Are you a veteran of medical 3D printing looking for a bespoke manufacturing service, or, are you new to the scene and would like expert guidance? Find out how Shapeways can help with your medical 3D printing needs.

learn more

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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, nScrypt, regenHu, Inventia, Regemat3D, Poietis, and more. Last year, 3DPrint.com 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 three‐dimensional 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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Inventia Life Science Empowers Researchers to Rapidly Scale 3D Cell Culture

No disease has ever been as overwhelming as cancer, not only does it kill close to 10 million people every year, but even though we still fail to understand how to avoid it, one thing is for sure, researchers are beginning to look at this disease from a different perspective. We have seen lots of research on bioprinting human cells to mimic tumors for testing cancer drugs and now more than ever, new companies are surfacing to create bioprinters for a demand that will surely grow in the future. That is the case with Sydney based start-up Inventia Life Science. Built around digital bioprinting technology for fast, scalable, and reproducible printing of 3D cell constructs, company founders Julio Ribeiro, Aidan O’Mahoney, Cameron Ferris, and Philippe Perzi, expected their creation to remove the need for time-consuming manual labor of medical lab workers.

In 2013, the company’s research led to the development of a proprietary platform encompassing bioprinting technology, an expanding library of printable bioink materials, and custom protocols for specific applications. Their 3D bioprinting platform called Rastrum has been used to rapidly print human cells to help with cancer drug testing and recently, the Coronavirus pandemic motivated the company to produce 3D lung microtissues for researching therapies.

Highly recognizable and easily distinguished from its competitors due to its stand-out pink color, the device was designed with cell biologists in mind, instead of tissue engineers. In the last years, the developers emphasized how this as a great advantage of the printer for researchers who seek better 3D cell models. In that sense, Rastrum creators claim that the machine delivers a platform where hydrogels, printable structures, and printing parameters are pre-validated, enabling a simple and efficient workflow for the creation of 3D cell models. And best of all, no prior bioprinting knowledge is required.

Last year, the hot pink machine won one of Australia’s major design awards, the prestigious Good Design Award of the Year. Designed by two leading medical and science academics from Sydney’s Australian Centre for Nanomedicine (ACN), at the University of New South Wales (UNSW), Justin Gooding and Maria Kavallaris, as the result of a strong collaboration between the university, the Children’s Cancer Institute, and Inventia Life Science, Rastrum is being used extensively throughout Australia as well as other countries.

Rastrum bioprinting platform (Credit: Inventia Life Science)

The printer uses ink-jet technology to print human cells at a rapid rate, quickly cultivating realistic tumors for testing cancer drugs. The technology focuses on printing high volumes of human cancer cell spheroids so that cancer researchers can try to find better ways to eradicate the disease. At the University of Technology Sydney, researchers are printing ovarian cancer cells, while the Victorian Centre for Functional Genomics (VCFG) at the Peter MacCallum Cancer Center in the Australian city of Victoria, was the first lab to install the Rastrum system and apply the technology to their ongoing cancer research.

The innovative technology allows scientists to print 3D cell models at unprecedented speed, replacing a time-consuming and manual process, expanding the capacity for research and drug development in cell models. According to scientists at VCFG, the machine is able to produce 1,000 3D cell models in less than six hours, a task that would regularly take more than 50 hours using current manual techniques.

One of the first users of the device, Kaylene Simpson, associate professor and head of the VCFG at Peter Mac said that “this is a novel and exciting platform for cancer research,” with “the ability to create realistic three-dimensional cell models through an automated and scalable process [that] will vastly accelerate our research progress and advance therapeutic target discovery.” She also revealed that “we have a very clear vision of the clinical applications of the technology.”

However, Inventia is also moving beyond its focus on cancer cells and is now claiming that the versatility of the Rastrum platform can also rapidly print 3D lung microtissue for COVID-19 therapy development. This is not the first biotechnology company that has chosen to focus its efforts to aid researchers in accelerating procedures and seeking cures for the newly discovered infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

In fact, Inventia revealed in April that their Rastrum 3D bioprinting platform could become a powerful tool for the
production of 3D lung microtissues and that the team of company researchers could move their expertise and capacity to develop these cell models, which can be tailored for therapy development. Furthermore, the Australian-based team proposed to even adjust the 3D cell models for the specific requirements of individual research laboratories and are already working with sites in Australia to explore the potential to accelerate in vitro research into COVID-19 therapies using advanced 3D lung microtissues.

Considering that to date there are currently no effective vaccines, antiviral treatments, or therapeutic agents against COVID-19, Inventia claimed that there is a very high need for multi-cellular in vitro microtissues to understand and assess treatments against this new virus to fend off the global pandemic. Previous lung alveolar research, they say, has shown that in vitro models that recapitulate the original tissue arrangement can be valuable tools both for lung toxicity studies and important therapeutic drug development.

Just like with scalable cancer models, Inventia claims that their cell model platform is capable of reliably producing several hundred 3D alveolar cell models per day, composed of the essential cell types and their native extracellular environment, to enable and accelerate the discovery and validation of novel treatments.

Rastrum regents ((Credit: Inventia Life Science)

Based on proprietary digital bioprinting technology, Rastrum includes hardware, software, and printable biomaterials that together enable a robust drop-on-demand bioprinting approach, as opposed to the common extrusion-based bioprinter.

The Rastrum platform is basically being used by biomedical researchers to print advanced 3D cell culture models. However, the company has indicated that it is also working with world-leading scientists and clinicians on longer-term regenerative medicine programs.

The fast-growing, venture capital-backed startup also sought to transform the medical research sector by providing Rastrum hydrogels, which are the only validated hydrogels that the machine will work with. Inventia chose to provide their own library of natural and synthetic printable hydrogel bioinks, as well as their own custom software-embedded printing protocols, to help users focus on the biology.

A prominent feature of the Australian bioprinting community is how fast it’s growing. From research institutions to universities, companies, and government-funded projects, the field is amassing a lot of followers, mainly students determined to find the next boom in life science occupations. The field is opening up opportunities for young innovators to create new machines and push the boundaries of the technology. And startups, like Inventia Life Science, are doing just that, upgrading their machines to create versatile and robust instruments that are easy to handle and cost-effective for researchers and labs. As one of the leading firms to supply Australian cancer research labs, we certainly expect to hear more about them in the future.

Rastrum inside view (Credit: Inventia Life Science)

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Polbionica Could Become the Next Success Story in Organ Bioprinting

Last year, a scientific team in Warsaw, Poland, bioprinted the world’s first prototype of a bionic pancreas with a vascular system. Led by clinical transplantation expert and inventor, Michał Wszoła, the specialists seek to introduce 3D bioprinting of the bionic pancreas to clinical practices worldwide in just over three years. The work, conducted at Polbionica, a spin-off company from the Foundation of Research and Science Development, will bring to market the research to 3D bioprint scaffolds using live pancreatic islands or insulin-producing cells to create a bionic pancreas, like the bioinks, bioreactor and the g-code files necessary to print bionic pancreas.

With more than 40 million people suffering from type I diabetes worldwide, this project holds a lot of promise. In Europe alone, seven million people are afflicted with the disease, with 700,000 of them undergoing serious complications.

The statistics alone offer a troubling overall pan of the disease. Even more so because, as Wszoła suggested in an interview with 3DPrint.com, hypoglycemia unawareness is a life-threatening complication that causes sudden death and is one of the major problems for type I diabetes; and the only method leading to a complete cure is a pancreas or pancreatic islet transplantation. But less than 200 pancreatic transplantations are carried out annually in Europe, which means that hundreds of people die while waiting for a transplant.

Polbionica is working to develop the key building blocks that support the development of the first bionic pancreas suitable for transplantation: bioink A for bioprinting bionic pancreas, bioink B for bioprinting vasculature, a novel bioreactor for growing organs, and a g-code file with specific bioprinting commands.

The company developed its own bioinks for this project and for bioprinting other organs of the body, while another bioink was used in 3D bioprinting of vessels with endothelial cells. Moreover, to carry out their research, they used Cellink‘s BioX bioprinter.

Bioreactor (Image: Polbionica)

According to Wszoła, the organ based on bioprinted 3D cell-laden bioinks, functional vessels, and pancreatic islets would restore the body’s ability to regulate blood sugar levels and revolutionize the treatment of diabetes.

For now, the scientific team has the ability to bioprint a living organ of 3x5x3.5 centimeters, which consists of more than 600,000 islets equivalent that are retrieved from the donor and considered to be the suitable amount to cure a person with diabetes.

“Our next step is to replace the pancreatic islets with stem cell-derived alpha and beta cells. With this approach, the patient would not have to wait for donor cells since the pluripotent stem cells being used are derived from their own tissues,” indicated Wszoła, who is also a transplant and general surgeon. “So far, studies on animals proved that the use of established products was safe.”

Scientists at work at the lab (Image: Polbionica)

“In order to reverse diabetes in humans, we need to have about one billion stem cells because efficacy to transform them into insulin-producing cells varies between 15% and 40%. I don’t believe that we will be able to solve the problem of brittle diabetes with transplantation of stem cell-derived islets (alpha and beta cells mixed into 3D organoids) alone,” he stated. “We should remember the lesson learned from pancreatic islet transplantation, whether we use original islets derived from a donor pancreas or produced from a patients’ stem cells, it will not solve the problem. In my opinion, we have to give those new islets a special nest, which involves an extracellular matrix through our bioinks and vessels with oxygen supply.”
Researchers at Polbionica have recently performed studies on mice proving that the bioprinted pancreatic petals using bioinks were well tolerated by the animals without any extended foreign body reaction to them. In April they will move onto studies with pigs and are planning studies with bigger animals together with Artur Kaminski, head of the Department of Transplantology and Central Tissue Bank at Warsaw Medical University.
“We expect clinical trials will be performed in Warsaw with the cooperation of our partners MediSpace Medical Centre and Warsaw Medical University. However, to begin this stage, we still have to overcome a few hurdles, like product stability, animal trials, approval from authorities as well as funding. If all that happens, just a few patients will be involved in the first stage of the clinical trial, mainly those who cannot receive any other treatment, and we have to remember that for the majority of people with diabetes, intensive insulin intake with CGM control is sufficient,” described Wszoła.
In 2012, diabetes expenses around the world accounted for 11% of the total health care expenditure. The Polish state needs close to one billion euros every year for diabetes. According to Wszoła, their potential competition, working on developing artificial pancreas is only offering a bridge treatment. Polbionica wants to go beyond that: their bionic pancreas could be a living organ that is a breakthrough in the treatment of type 1 diabetes.
He, along with his team hopes that their final product and know-how will solve problems related to the shortage of organs, postoperative complications and immunosuppression after transplantation, and above all, will be a chance to completely cure type 1 diabetes.
Moreover, the positive development of the organ production technology would significantly affect the general health of society, largely eliminating the problem of diseases associated with end-stage organ failure, reducing treatment costs, the need for social care, and professional absenteeism, while improving the quality of life of patients, and speeding up the process of introducing new drugs into the market.
“Bioprinting can have a great impact on the development of medicine, however, like every technology, it also has some limitations. We must remember that we are handling living cells, and the stress and other conditions which cells undergo during the bioprinting process has an influence on its function. Besides, we still have to work on better materials to build organs, materials that will keep cells together and allow them to function properly, materials with special strength, viscosity, and elascity,” claimed Wszoła.
The technology established by Polbionica even could let researchers bioprint vascularized organ models with cancer tumors to conduct research on the efficacy of newly implemented drugs. It may even revolutionize drug implementation routes and help diminish the need to perform animal studies.
“The field of drug testing can highly benefit from bioprinitng, with our technology we are now able to bioprint different pathologic models, such as pancreatic and liver cancers, melanomas, large bowel and breast cancer. We can also mimic microenvironments within tumors, print vessels and observe them in the lab when we add drugs and perform different analysis. In short, we can give a lot of answers and have an insight on drug development like never before.”

Polbionica is implementing the project as part of the Prevention Practises and Treatment of Civilization Diseases (STRATEGMED) program, funded by the Polish National Center for Research and Development. With experts in the fields of biotechnology, chemistry, mechatronics, bioprinting, and medicine, the team is moving forward quite rapidly in an area that to date has no cure, new technology can help patients reduce the burden of managing the condition, especially with regards to measuring their blood sugar levels and administering insulin, however, breakthroughs are not common. And although still in animal trials, the team is looking forward to the day when they will bioprint a bionic pancreas with living cells and tissues using their own bioinks.

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Allevi and Corning Present the First Protocol for Bioprinting With Matrigel

Mouse models of malignant tumors called sarcomas have provided a fundamental tool for researchers to understand the pathology behind human cancers. However, it was not until the 1980s when researchers began looking for ways to grow mouse sarcoma cells and develop genetically manipulable mouse models that they became fully capable of examining the direct causes of many cancers in an in vivo setting. Around that time, material sciences and technology multinational Corning, developed Matrigel matrix, a solubilized basement membrane preparation extracted from the Engelbreth-Holm-Swarm (EHS) mouse sarcoma, a tumor rich in extracellular matrices (ECM) proteins, such as laminin, collagen IV, heparan sulfate proteoglycans, entactin/nidogen, Transforming growth factor-beta (TGF-ß), epidermal growth factor, insulin-like growth factor, fibroblast growth factor, tissue plasminogen activator, and other growth factors.

Today, 30 years later, this natural ECM-based hydrogel is widely used as a model for 2D and 3D cell culture in vitro, and together with 3D bioprinter manufacturer Allevi, they have created the first-ever protocol for bioprinting using Matrigel matrix called: ‘Allevi bioprinting protocol using Corning Matrigel matrix’.

From the development of several types of tumor cell invasion assays to exploring organoid model environments, from cancer and stem cell research to neurobiology, tissue engineers, biologists, and industry giants are using Matrigel matrix as a foundational biomaterial for diverse applications.

It has been tested for the ability to promote neurite outgrowth of chick dorsal root ganglia cells, in mouse colonies routinely screened for pathogens via Mouse Antibody Production (MAP) testing, in protein concentrations, and is very commonly used in cell growth and differentiation; metabolism and toxicology studies; invasion assays; in vitro and in vivo angiogenesis assays; in vivo angiogenesis studies and augmentation of tumors in immunosuppressed mice.

Corning Matrigel matrix (Image: Corning)

Since 2014, Allevi has turned into one of the companies leading the way in bioprinting thanks to its easy-to-use and cost-efficient bioprinters, software, as well as their broad understanding of cells. Years of experience taught them how to keep the cells alive during the printing process and what materials can help with this, like Corning Matrigel matrix. The company claimed that their 3D bioprinters are capable of printing high-quality bioinks without the need for viscosity agents that can hinder the ECM’s performance. They suggest that they engineered their patented CORE printheads to optimally print pure biomaterials, such as Matrigel matrix.

Moreover, Corning’s Matrigel matrix offers a network of proteins that provide the environment needed for optimal tissue performance, driving cellular responses such as proliferation and attachment. Allevi explained that Matrigel matrix has a unique formulation that, when used with Allevi bioprinters, allows users to create custom 3D tissues. Claiming that this is an optimal platform for cells to differentiate and behave more closely to how they would in the human body.

Matrigel matrix is a hydrogel that is rich in extracellular matrix proteins. The company behind it indicates that it has been successfully used for several 3D culture and tissue engineering applications. Now, it can also be used on the Allevi Platform to 3D bioprint cancer spheroids with a variety of cell lines. Furthermore, combining Matrigel matrix with Allevi 3D bioprinters can enable the automation of spheroid and organoid generation in a standardized and repeatable manner.

3D bioprinted cancer spheroids with a variety of cell lines (Image: Allevi)

Allevi officials stated that “we can’t wait to see what you will do when you bioprint with Allevi and Matrigel matrix in your lab. It’s been 30 years of breakthroughs with Matrigel matrix, and we have a feeling that the pace of discovery is bound to quicken as we add another dimension to this bioink.”

The protocol developed clearly establishes that Matrigel matrix should be stored at -20˚C and that once removed from storage it needs to be thawed in an ice bucket at 4˚C overnight. Other indications include using an Allevi 5 mL Syringe, a syringe cap, a full metal 250 µm nozzle, and Costar Multi-well Plate or Falcon® Petri Dish.

Allevi is a company that understands the importance of teaming up to enhance the power of bioprinting. Last year they partnered with Xylyx Bio to create liver-specific bioinks, and previously with Made In Space for 3D bioprinting in orbit. This new protocol will help researchers and scientists make the best out of a combination of products that have a lot of potential for new trends in in vivo applications, virus testing, 3D cell culture research, and much more.

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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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The Future of Bioprinting Research Has a New Road Map

Improving efficiency, optimizing technology, increasing awareness, even reducing costs and time, these are all traits that result from strategic road maps, and in the case of bioprinting, where the outcomes affect tissue engineering, bespoke outcomes for patients, regenerative therapy, and much more, having a blueprint for the entire industry seems like a bright idea. Especially when this blueprint highlights some of the challenges on the way to achieving meaningful and innovative scientific development.

Published in IOP Science’s Biofabrication Journal, “The Bioprinting Roadmap” features advances in selected applications of bioprinting and highlights the status of current developments and challenges, as well as envisioned advances in science and technology. The roadmap brings together researchers, specialists, and physicians from a myriad of universities, institutions, and hospitals around the world, combining their knowledge to focus on different aspects of bioprinting technology. These include: Jürgen Groll, professor of functional materials in medicine and dentistry at the University of Würzburg in Germany; Binil Starly, professor of mechanical engineering at North Carolina State University; Andrew Daly, an orthopedic surgeon at Emory University Hospital; Jason Burdick, a bioengineer from the University of Pennsylvania; Gregor Skeldon, a life science medical writer at Maverex, in the UK; Wenmiao Shu, professor of biomedical engineering at the University of Strathclyde in Glasgow; Dong-woo Cho, mechanical engineer at Pohang University of Science and Technology; Vladimir A. Mironov, chief scientific officer of 3D Bioprinting Solutions, and many more.

The roadmap focuses on a broad spectrum of topics, in a detailed and readable fashion that showcases broad knowledge of the field by its authors, as well as a great deal of research that went into the making of the guide. The paper is categorized into the following sections:

  1. Charting the progress from cell expansion to 3D cell printing
  2. Examining the developments and challenges in the bioinks used for bioprinting
  3. Looking into bioprinting of stem cells
  4. Presenting a strategy for bioprinting of tissue vascular systems and tissue assembly:
  5. Examining the potential for using 3D printed biohybrid tissues as in vitro biological models for studying disease
  6. Analyzing how 3D bioprinting can be used for the development of organs-on-a-chip
  7. Biomanufacturing of multi-cellular engineered living systems
  8. Exploring how researchers are pushing boundaries with bioprinting in space
  9. Investigating the developments of bioprinting technologies

The introduction of the research work was in charge of Wei Sun, chair professor of the College of Engineering from Drexel University, in Philadelphia, and Tsinghua University in Beijing, China, who said to IOP Publishing that “there are a number of challenges to overcome, including the need for a new generation of novel bioinks with multi-functional properties to better transport, protect and grow cells during and after printing; better printing processes and printers to deliver cells with high survivability and high precision; efficient and effective crosslinking techniques and crosslinkers to maintain the structure integrity and stability after printing; integration with microfluidic devices to provide a long term and a simulated physiological environment to culture printed models.”

Wei Sun (Credit: Drexel University)

“Due to the rapid advancements in bioprinting techniques and their wide-ranging applications, the direction in which the field should advance is still evolving,” went on Sun. “The roadmap aims to address this unmet need by providing a comprehensive summary and recommendations, useful to experienced researchers and newcomers to the field alike.”

The research sheds light on the main roadblocks to overcome in the future. The specialists consider that the next technologies will use “multiple modalities” in one single platform and “novel processes, such as cell aggregate bioprinting techniques” to create scalable, structurally‐stable, and perfusable tissue constructs. But in the meantime the challenges that remain are many. In his introduction, Sun talks about the need for a new generation of novel bioninks with multifunctional properties to better transport, protect, and grow cells during and after printing; better printing processes and printers to deliver cells with high survivability and high precision; efficient and effective crosslinking techniques and crosslinkers to maintain bioink structural integrity and stability after printing, and integration with microfluidic devices to provide a long-term and a simulated physiological environment in which to culture printed models.

Other researchers highlighted the importance of further improving bioreactor-based cell-expansion systems to lower barriers to the adoption of bioprinting in regenerative medicine and tissue engineering product markets. While Skeldon and Shu suggest that stem cell bioprinting can be realized if scientists find a way to reduce the shear stress of bioprinting stem cells.

Another obstruction is the high production costs and the difficulty of having large-scale production of organoids. Jinah Jang and Dong-Woo Cho from the Pohang University of Science and Technology suggest that there have been remarkable advances to the recreation of vasculatures and large organs even though challenges remain immense.

Whereas some of the highlights of the research include novel benefits from bioprinting in space, considering that microgravity conditions enable 3D bioprinting of tissue and organ constructs of more complex geometries with voids, cavities, and tunnels; cell expansion as a critical upstream process step for cell and tissue manufacturing; the great promise of stem cells in biomedical research and applications, which through bioprinting, can be particularly positioned in 3D in relation to other cell types and/or biomaterials, as well as progress in stem cell biology and in vitro culture which is opening up new doors to regenerative medicine and better physiological cell-based assays for disease models.

With so many advances in bioprinting around the world and remaining challenges to overcome, both seasoned researchers and newcomers will find an interesting and complete summary of the bioprinting industry. This game plan can help researchers come together to create new novel processes and fill in current technological gaps, as the researchers suggest.

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3D Printing News Briefs: February 4, 2020

In today’s 3D Printing News Briefs, we’re covering a range of topics. First, Digital Alloys is sharing a guide on the cold spray metal 3D printing process. UPM just launched its new GrowInk Bioinks product range. STPL3D offered its 3D printing expertise to help with a complex orthopaedic surgery, and the Smithsonian Institution is using Mimaki’s full-color 3D printer to make virus models for an exhibit. Finally, 3D printing was used to give an ancient mummy a voice…sort of.

Digital Alloys’ Cold Spray Guide

Massachusetts-based Digital Alloys has been publishing a Guide to Metal Additive Manufacturing, and the 16th part is all about Cold Spray technology, which was used as a coating process for many years before it was adapted into a metal 3D printing technology for rapid fabrication of near-net-shape parts. The technology uses pressurized gas to rapidly fire metal powders through a nozzle, aimed at the deposition point, with high enough velocity to create a metallurgical bond on impact but without melting the material. High-pressure Cold Spray systems allow for the processing of heavier materials, like steel and titanium alloys, while low-pressure systems use ambient air as a propellant, making them better for more ductile metals, like copper and aluminum.

“Cold Spray’s advantages include compatibility with heat-sensitive materials, low thermal stresses, and the ability to operate in an open (non-inert) environment. Disadvantages include restrictive part geometry, low density and accuracy, and material embrittlement,” the blog post states. “This post provides an overview of Cold Spray metal AM technology: how it works, geometry capability, material compatibility, economics, applications, and current state of commercialization.”

UPM Launched GrowInk Product Range 

Biomaterials company UPM, which introduced the biocomposite 3D printing material Formi 3D two years ago, is now launching a new line of hydrogels. The GrowInk 3D printing product range, which consists of non-animal derived, ready-to-use hydrogels, was introduced at the recent SLAS2020 conference. These bioinks, made up of water and nanofibrillar cellulose, support cell growth and differentiation by mimicking the in vivo environment, and are compatible with a wide range of 3D printers.

GrowInk Bioinks provide excellent imaging quality, and are perfect for many different 3D bioprinting applications, such as scaffold preparation and cell encapsulation for drug discovery, regenerative medicine, and tissue engineering. Additionally, UPM is also expanding its GrowDex product range with the sterile hydrogel GrowDex-A, which was created to debind biotinylated molecules, like antibiotics and peptides.

STPL3D Provides 3D Printing Help in Orthopedic Surgery

In December, 14-year-old Aaska Shah from India sustained multiple fractures to her left elbow while playing, and at her young age, a prosthetic implant would only compromise her natural movements. So doctors were left with no choice but to operate, using clamps to keep the bone pieces in place. Aaska’s surgery was denied because of how complex it would be, but Dr. Jignesh Pandya took on the task, and partnered up with Agam Shah from 3D printing service STPL3D to create a 3D printed resin model of the patient’s fractured elbow bone for surgical planning.

“Dr Pandya and his team first reviewed x-rays and 2D scans of the patient and reviewed their surgical plan. The doctors were a little concerned because there are a frightening amount of things that can go wrong during the operation but refused to give up hope,” an STPL3D blog post states. “The doctors have faced many challenges during the operation like deciding the clamp length and attaching points in the bone but the surgeries were successful largely thanks to the skilled surgeons.”

The doctors said the 3D model gave them “greater confidence,” and the patient was also on the operation table for roughly 25% less time.

Smithsonian Institution 3D Printing Full-Color Virus Models

This image shows the Influenza virus model, created using the Mimaki 3DUJ-553 3D printer, in an opened position. The clear disk that contains the eight purple capsids and the eight yellow RNA strands has been removed from the green envelope. Image credit: Carolyn Thome/SIE

The world’s largest museum, education, and research complex, the Smithsonian Institution, is working with Mimaki USA to help with art, cultural, educational, and science exhibits and experiences. The Maryland-based Smithsonian Exhibits’ (SIE) studios works with the Institution’s offices and museums, and the federal government, to help plan engaging exhibits, as well as create models for research and public programs. The SIE team is using the full-color Mimaki 3DUJ-553 3D printer to create detailed, 3D printed models of enlarged viruses for the Smithsonian National Museum of Natural History’s Outbreak: Epidemics in a Connected World exhibition.

“We are pleased to be a part of the Smithsonian Institution’s efforts to engage and inspire audiences through the increase and diffusion of knowledge. This printer will enable the Smithsonian to use new technologies to produce exhibits in new ways, particularly for creating models and tactile elements that help bring exhibits to life for all visitors,” stated Josh Hope, Sr. Manager, 3D Printing & Engineering Projects at Mimaki USA.

3D Printed Vocal Tract for Mummy

The 3D printed trachea and mouth of Nesyamun. (Credit: David Howard/Royal Holloway, University of London)

We’ve seen 3D printing used multiple times to help bring the mysteries of mummies into the modern world, but here’s a new one: a team of researchers from the UK used 3D printing to help an ancient mummy speak. Together, they published a paper, titled “Synthesis of a Vocal Sound from the 3,000 year old Mummy, Nesyamun ‘True of Voice,’ about their work creating a 3D printed vocal box for the mummy. Nesyamun was an Egyptian priest who lived and died over 3,000 years ago, during the reign of Ramses XI. A scribe and incense-bearer who likely sang and chanted prayers at the temple in Thebes, his sarcophagus features an epithet that translates to “true of voice,” because as a priest, he would have said that he lived a virtuous life; this is the reason the researchers gave for their work being ethical. In 2016, the mummy was sent to a facility for CT scanning, which discovered that, while his soft palate was gone and his tongue was shapeless, his larynx and throat were still in good condition – perfect for an experiment to replicate his vocal tract and help him “speak.”

Egyptologist Joann Fletcher said, “The actual mummification process was key here. The superb quality of preservation achieved by the ancient embalmers meant that Nesyamun’s vocal tract is still in excellent shape.”

The team 3D printed a copy of Nesyamun’s vocal tract between the larynx and lips on a Stratysys Connex 260 system. The horn portion of a loudspeaker was removed and replaced with the artificial vocal box, and then connected to a computer to create an electronic waveform similar to what is used in common speech synthesizers. This setup was able to help produce a single vowel sound, which you can hear for yourself here.

Discuss these stories and other 3D printing topics at 3DPrintBoard.com or share your thoughts below.

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An Inside Look into the ACES Lab (Part II: TRICEP)

After peeking into some of the research labs at the ARC Centre of Excellence for Electromaterials Science (ACES), located at the Intelligent Polymer Research Institute (IPRI) in Australia’s University of Wollongong (UOW) Innovation Campus, thanks to a virtual tour by Gordon Wallace, Executive Director of ACES, audiences were able to get a first-hand look into another building at UOW. In the second part of the tour, Wallace showed the recently inaugurated Translational Research Initiative for Cell Engineering and Printing (TRICEP) and how it is leading the initiative for 3D bioprinting, encompassing bioinks, bioprinters, and bioprinting process developments, including the manufacturing of medical devices and the integration of living cells delivered using customized bioprinters to address specific medical challenges, and ultimately how they will scale up production of each of this innovations.

At TRICEP, scientists are using fundamental advances in materials science and engineering to solve real applications. The new facility was created last year to translate the advances into a manufacturable prototype or commercial product.

During this second part of the tour, Wallace explored the development of bioinks and bioprinters that will be commercially manufactured in the future, which is why the focus is more on material applications and protocol development for the manufacture of the bioinks and customized printers. A big part of what the researchers do involves exciting new developments to address very critical medical challenges, which in turn, create a commercial opportunity, according to Wallace.

“This is a great facility that incorporates the development of bioprinters, something you won’t find in a conventional university research environment, and we are taking all those 3D printing processes and making them ready for manufacture by implementing a quality management system that alows us to reallize real commercial opportunities,” suggested Wallace.

BIOINKS

The fundamental formulation for the bioinks developed come from the IPRI lab (as seen in the first part of the virtual tour), and TRICEP researchers need to use the new facility to scale it up and make it into a reliable product, but now without some challenges. Alexander Martyn, a Synthesis and Fabrication Chemist at TRICEP, is leading the bioink revolution and said: “Everything related to upscaling is a lot different here because we have to explore every single parameter of the experiments so that when we make the larger batches of bioink, they are reliable.” 

“We usually need to go back to the source of the material. For some of the research work, small scale is easy to achieve, but here you need to know the primary source of the material to ensure quality control. Before we start making a large scale production of the bioink we have to undergo a suite of characterization to determine a high purity, which basically means determining if it is a very good product for us to work with. So first we would characterize the material to ensure the qualities and then we turn it into the bioink,” said Martyn.

Alexander Martyn showing how the 10-liter reactor works

“We start with small scale reactions, that give us between 20 and 50 grams in scale, much more than the one gram that is used for research. And then we turn to our bioreactors, one of them is a 10-liter reactor, capable of generating quantities of upto 500 grams. It is controlled by a thermoregulation unit plummerd throug the external wallls, so that we can control the temperature and collect the material. We also have a 20 litre reactor, capable of producing kilogram batches, which is the big leap into an industrial process,” he went on.

PRINTING PRINTERS

At TRICEP, researchers are using conventional 3D printers to create a range of customized 3D printers which help them address important research challenges in the medical spheres and built new tools to train the next generation of biofabricators.

Stephen Beirne, Additive Fabrication Capabilities Head at TRICEP, explained that “one of our capabilities includes printing printers. We have a range of additive fabrication tools and have recently been able to expand, even more, acquiring a Mimaki 3D printer that allows us attain components in full-colour representations, that gives more detail so that our collaborators and commercial partners get real realizations on the parts they want to produce. Overall, these systems enable us to print new components for new printing systems.”

TRICEP is a 100 percent owned University of Wollongong initiative that draws on expertise and facilities available within ACES and the Australian National Fabrication Facility (ANFF) Materials Node, both based at the UOW Innovation Campus. It houses a range of additive manufacturing technologies, including the highest resolution metal printer in Australia and the country’s leading biofabrication capability to develop biomaterials, with teams producing specialized 3D printing devices and customized bioinks to treat specific medical conditions, such as wound healing and artificial skin for burn victims.

Scaling manufacture of 3D bioprinters (Image credit: TRICEP)

TRICEP can commercialize opportunities in 3D bioprinting including printer manufacturing, biomaterials, bioinks, and material-cellular combinations to address significant industry challenges that require an exclusive, tailored solution, bringing to life novel technology from concept stage through to prototyping and manufacture of hardware and the formulation of customized bioinks to accelerate product development and rapidly decrease time to market.

Professionals at the TRICEP facility are creating and developing prototypes, making sure that these are ready to be manufactured at scale. Instead of making devices and integrating those into commercial type platforms, they are developing their own customized platforms for clinical challenges at hand, that allow for additional functionalities, such as to incorporate additional extruder or deposition techniques simultaneously as well as cross-linking methods. 

For example, they are developing a series of handheld devices that are ideal for practical use in a clinical environment. Beirne described that “to characterize the device as we are going into our experimental protocols it is ideal to be able to transfer our mounting system into a tri-axis stage or even a five-axis stage, to have fine control over the scaffold and structures that we produce, to then be able to determine the repeatability and the consistency of the printing system we have developed.”

And the best part is, they have a whole suite of these, like the iFix pen, a cornea-correcting device created in collaboration with ACES at UOW. Beirne uses metal additive fabrication, basically, two selective laser melting systems, the first has a cylindrical build volume with a maximum built height of 74 mm (probably Trumpf or Sisma), while the newest and most recent system they added to the facility is a Concept Laser that allows printing volumes of 100mm x 100mm x 100 mm. They can also print in a range of different metals, like stainless steel and titanium, allowing for high resolution, low surface roughness components that are ideal for customized prototypes. He said that some of these structures are difficult to make with conventional manufacture devices.

“Some of the printers we created have also become educational printers and are an important part of our online teaching program. We have a graduate certificate on biofabrication which is available now, and that is the course work necessary to move to to the masters of biofabrication and it is exposure to this type of printers that give high level and state-of-the-art training in 3D printing. So that our prospective engineers and bioengineers have a range of tools and capabilities for them to learn, from the fundamentals of the 3D positioning systems all the way to the development of the mechanical extrusion mechanism and temperature management to allow them to see what happens to different materials and temperature conditions, printing conditions or extrusion parameters,” said Wallace.

Researcher working at the lab (Image credit: TRICEP)

One last customized printer to look at during the tour is 3D Alek, the bioprinter that replicates human ears for patients with microtia, built in collaboration with Payal Mukherjee, a nose and throat surgeon and Associate Professor at the University of Sydney School of Medicine. All of the components were built at the facility and it is able to print three different materials, each having their individual printing speed and condition. 

The in-house ability of TRICEP researchers to develop both customized hardware and bioinks, as well as the growing clinical network, makes them uniquely placed to help companies create a complete end product that is tailor-made to combat a specific medical challenge. In addition, their extensive medical network throughout Australia helps them develop clinically relevant systems and protocols.

“All the projects are driven by real clinical needs, we are very fond of working with clinicians around the country who are really defining the challenges with us, and implementing a plan with us, and then helping us in terms of translation,” said Wallace.

You can tune in to see the second part of the virtual lab tour here.

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FRESH News: SLAM Used to Fabricate Complex Hydrogel Structures With Gradients

There has been plenty of research on creating 3D printed hydrogels and using them to fabricate functional tissues. Biopolymer hydrogels, with properties that can be tailored and controlled, can be crosslinked to replicate tissue structures, and extrusion-based 3D printing is often used. But, the use of biopolymer hydrogels as 3D printing bioinks is tough, due to issues like low viscosity and trouble controlling microstructure variations. Some researchers have turned to embedded 3D printing methods, but this comes with its own laundry list of problems, such as having difficulty extracting the final product.

UK researchers Jessica J. Senior, Megan E. Cooke, Liam M. Grover, and Alan M. Smith from the University of Huddersfield and University of Birmingham created a method called suspended layer additive manufacturing, or SLAM, that can extrude low viscosity biopolymers into a self‐healing fluid‐gel matrix. The team recently published a paper on their work, titled “Fabrication of Complex Hydrogel Structures Using Suspended Layer Additive Manufacturing (SLAM).” It is worthwhile to note here that FRESH (Freeform Reversible Embedding of Suspended Hydrogels) is a super remarkably similar if not identical technology. So far we’re not getting involved with calling out which term should win here but we are leaning towards using FRESH because it will make it simpler for everyone going forward.

A schematic showing the production of a 3D bioprinted scaffold by use of SLAM.

The abstract states, “There have been a number of recently reported approaches for the manufacture of complex 3D printed cell‐containing hydrogels. Given the fragility of the parts during manufacturing, the most successful approaches use a supportive particulate gel bed and have enabled the production of complex gel structures previously unattainable using other 3D printing methods. The supporting gel bed provides protection to the fragile printed part during the printing process, preventing the structure from collapsing under its own weight prior to crosslinking. Despite the apparent similarity of the particulate beds, the way the particles are manufactured strongly influences how they interact with one another and the part during fabrication, with implications to the quality of the final product. Recently, the process of suspended layer additive manufacture (SLAM) is demonstrated to create a structure that recapitulated the osteochondral region by printing into an agarose particulate gel. The manufacturing process for this gel (the application of shear during gelation) produced a self‐healing gel with rapid recovery of its elastic properties following disruption.”

SLAM works like this: shear cooling a hot agarose solution throughout the sol–gel transition creates the fluid-gel print bed, as fluid gels behave like liquids once stress is applied. Then, the solution is put into a container in order to support the scaffold. Hydrogel and cells are mixed to produce a bioink, which is added to a bioprinter cartridge and extruded into the self-healing, fluid-gel matrix. The bioink is then suspended in its liquid state, and solidification is induced through crosslinking and cell media, which also provides the cell scaffold with metabolites. The construct is released from the supporting gel through low shear washing with deionized water.

The method prevents the initiation of gelation during 3D printing, which allows for great layer integration and “the production of constructs from two or more different materials that have dissimilar physicochemical and mechanical properties,” which creates a part with anisotropic behavior.

“To demonstrate clinical application, we recently created a structure that recapitulated the osteochondral region (the microstructure of which changes across a hard/soft tissue interface) as directed by microcomputed tomography (micro‐CT) imaging to provide accurate dimensions and was tailored to support specific cell phenotypes by controlling the microenvironment,” the researchers explained. “These complex scaffolds feature mechanical gradients that were similar to those found within the ECM and play a crucial role in preventing mechanical failure between interconnecting tissues as well as maintaining cell phenotype.”

The researchers needed to consider the mechanical properties of the fluid-gel print bed during SLAM 3D printing, as “they can impact on construct resolution and complexity.”

“Another embedded printing technique, freeform reversible embedding of suspended hydrogels (FRESH), developed by Hinton et al., uses a gelatin slurry support bath, however the rheological behavior of such material as a suspending agent for 3D bioprinting has not been investigated in depth,” the researchers wrote.

Additionally, they prepared fluid gels at different concentrations of agarose in order to find the best formulation for 3D printing uniform particle sizes, and investigated using needles with differing inner diameters, and a low viscosity dye solution, to find the optimal print resolution.

Optimizing print parameters within agarose fluid gel. A–G) Resolution of bioink printed within fluid bed support using multiple needle diameters and H–J) diffusion of dye through the gel at given time points.

“As the needle inner diameter was increased, the potential resolution decreased. Further, with larger needles, the printable filament thickness was more variable. This is likely due to both more material being extruded and also greater deformation of the fluid‐gel print bed. In very low viscosity solutions of low Mw (molecular weight), diffusion is also a limiting factor for resolution,” the researchers explained.

A) Intricate lattice prior to (left) and following extraction (right) from the bed. B) T7 intervertebral disc as CAD file (left) and lateral (middle) and apical (right) views. C) Intricate bulk structure in the form of a gellan spider. D) Carotid artery as CAD file (left) and during printing (right). D) Tubular structure (left) demonstrating material durability (middle) and perfusibility.

Alginate, collagen, gellan gum, and i‐carrageenan bioinks were used to demonstrate how many complex structures could be made. An intricate lattice structure showed off the scale and complexity that SLAM can achieve, while a T7 intervertebral disc was manufactured to show how the system can print large bulk structures and a spider was an example of 3D printing smaller, more intricate parts.

Several hollow and bifurcating structures, like a carotid artery model and a thick-walled tubular structure, were printed to show how the system can create geometries which are impossible without a 2D collector.

“These structures highlight the capability of this technique for freeform fabrication as large overhanging structures can be printed without the need for additional support structures,” the researchers explained.

The SLAM method can also deposit multiple layers laterally, horizontally, and within “a previously deposited extrude,” which allows constructs to be fabricated with the same biochemical and mechanical gradients that can be found in native tissues. The technique also uses microextrusion to continuously dispense bioinks, which caused better dispensing precision than the use of inkjet printing, and allows for more freedom with cell densities inside the bioink.

“Previous studies have indicated that the use of inkjet printers enables a reduction in print‐induced shear stresses applied to suspended cell populations compared with microextrusion methods, however, there are key features of the supporting bed utilized for SLAM that enable shear minimization utilizing microextrusion,” the researchers wrote.

Due to SLAM’s supporting fluid‐gel bed, low viscosity bioinks can be used – material viscosity can cause shear induction in bioinks, so it’s optimal for fabricating hydrogels.

“Using our system, it has therefore been demonstrated that the issues associated with cell shearing during microextrusion can be easily reduced, achieving admirably low shear stresses on cells that rival those seen during other forms of biofabrication including drop‐on‐demand techniques such as inkjet printing,” the team wrote.

A,B) Bilayer scaffolds using combinations of collagen‐alginate and collagen‐gellan. C) Large collagen‐core gellan‐shell scaffold and D) small collagen‐core alginate‐shell scaffold. E) Schematic of diagram showing control of cell behavior with attachment motif bearing complexes in the upper collagen gel and no attachment motifs for cell suspension within an alginate gel. F) Micro‐CT showing gradient porosity within a lyophilized collagen‐alginate scaffold. G) Confocal micrographs of Hoechst/actin cell staining of HDFs attached in the collagen layer and suspended in the alginate regions of a dual layer scaffold. H) Stress versus Gʹ showing variations in gel strength and elasticity across a collagen‐alginate scaffold.

The SLAM method can also incorporate multiple biopolymer hydrogels into a single structure, which is important to “satisfy the mechanical, chemical, and biological variations that occur throughout native tissue.” The researchers demonstrated this capability by 3D printing an osteochondral construct, with ex vivo chondrocytes deposited into a gellan gum layer and osteoblasts into one of gellan‐hydroxyapatite. But they went even further, and used SLAM to 3D print integrated structures with different chemistries and gelatin mechanisms.

“Ionotropically gelled (alginate, gellan, and ι‐carrageenan) and thermally gelled (collagen) biopolymers were successfully integrated to form interfacing, dual‐phase scaffolds,” the researchers wrote.

The materials blended enough that mechanical failure did not occur – an environment that closely mimics the native tissue environment.

“Furthermore, this technique of printing integrated layered structures is not only compliant to printing different materials layer upon layer, but also deposition of a second material into the center of another. For example, in addition to producing layered constructs, it was possible to create 3D printed core–shell structures comprising a cylindrical core of collagen encapsulated within a gellan or alginate cylinder with various dimensions,” they continued.

“Another advantage of being able to deposit scaffold material precisely is that cell behavior can be spatially manipulated. Polymers such as collagens that are saturated with integrin binding domains allow cell attachment to the scaffold, whereas alginate and gellan do not naturally possess cell attachment motifs and instead, encapsulate cells with minimum attachment to the surrounding material.”

To learn more about the team’s use of SLAM to 3D print multilayer gradient scaffolds, I suggest you read the paper – they can explain it far better.

“In summary, we have demonstrated that the SLAM technique can be used to overcome the problems associated with using low viscosity bioinks in extrusion‐based bioprinting,” the researchers concluded. “The method enabled the successful fabrication of bulk, intricate, dual phase, and phase‐encapsulated hydrogels from a variety of biopolymer materials that are currently widely investigated in regenerative medicine. Furthermore, it was shown that controlled spatial gradients in mechanical and chemical properties can be produced throughout a single part with interface integrity between different materials. This allows for physicochemical properties of the structure to be designed accordingly with the ability to control porosity, mechanical gradients, cell distribution, and morphology.”

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