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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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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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Marvel Medtech Uses Additive Manufacturing by XJet To Prevent Breast Cancer

Marvel Medtech has developed a revolutionary way to defeat early-stage breast cancer by combining three unlikely counterparts: MRIs, cryotherapy, and the XJet Carmel 1400 Additive Manufacturing system.

Marvel Medtech is a US-based startup that is in business to battle breast cancer. Breast cancer kills more than 500,000 women worldwide each year. In the US alone, one in eight women will be diagnosed with breast cancer in their lifetime. Marvel Medtech’s innovation is a robotic guidance system that will destroy breast cancer cells at the time they are discovered – during breast magnetic resonance imaging (MRI) scans.

Marvel Medtech’s cryotherapy probe, developed using XJet NanoParticle Jetting technology.

Ray Harter, President of Marvel Medtech, said, “Our new approach preempts the need for many biopsies, surgeries, radiation and chemotherapy treatments. Obviously, the expectation is that it’s likely to save many lives, but it will also dramatically improve the quality of life for patients. In addition, we also know that by eradicating those procedures, it will also reduce overall healthcare costs. And these are not insignificant savings – annually, these could be in the many billions of dollars.”

Ray Harter, Founder and President of Marvel Medtech LLC

After identifying early-stage tumors during breast MRI scans, Marvel Medtech’s technology carefully targets the most dangerous cancer cells and applies cryoablation to freeze and destroy the cells before they could grow.

Marvel Medtech’s cryotherapy probe targetting cancer cells.

The technology transforms MRIs from a diagnostic-only tool into an actual treatment device.

The final challenge for Marvel Medtech was to develop the intricate probe that would work in conjunction with the MRI but not interfere with the machine’s magnetic field. The probe also needed to have very small features and possess complex geometry. 3D printing was the answer, but which printer could manufacture the appropriate material?

According to Harter:

“The tools used inside an MRI scanner must be compatible with strict safety guidelines, and crucially, not disrupt image quality. Because they are one of the most electrically insulating materials, ceramics are an ideal material to achieve this. However, we were unable to find a ceramic-based 3D printer able to accurately and cost effectively produce our ceramic probe. This is why we are adopting XJet’s Carmel 1400 solution.”

With XJet’s NanoParticle Jetting™ (NPJ) technology and the ability to 3D print zirconia (ceramic), Marvel Medtech was finally able to complete the last piece of their life-saving puzzle. They 3D printed the highly complex, ceramic cryotherapy probe. Now the company and its invention are poised to save thousands of lives, dramatically improve patient care, and save potentially billions of dollars in healthcare spending.

There are untold applications for 3D printing ceramic. Register for AMS 2020 and hear XJet’s Chief Business Officer, Dror Danai, talk about Marvel Medtech’s lifesaving probe at AMS 2020 in Boston, February 12 at 3:20. You will also hear him talk about other potential solutions NPJ technology can provide to industries around the world.

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Researchers Evaluate Comfort and Stability of 3D Printed Applicators for Oral Cancer Therapy

Oral cancer is on the rise around the world, and it’s especially bad in developing countries, such as Pakistan, Sri Lanka, and India, which don’t have the necessary medical infrastructure for early detection and treatment. A team of researchers from Boston and India explained in their paper, “Platform for ergonomic intraoral photodynamic therapy using low-cost, modular 3D-printed components: Design, comfort and clinical evaluation,” that there is “critical demand for an effective treatment modality that can be transparently adapted to low-resource settings.”

“The high expense and logistical barriers to obtaining treatment with surgery, radiotherapy and chemotherapy often result in progression to unmanageable late stage disease with high morbidity. Even when curative, these approaches can be cosmetically and functionally disfiguring with extensive side effects. An alternate effective therapy for oral cancer is a light based spatially-targeted cytotoxic therapy called photodynamic therapy (PDT),” the researchers wrote.

PDT uses a photosensitizer molecule accumulated in the tumor, and once it interacts with a specific light wavelength, it can cause targeted damage. It has few side effects, doesn’t cause disfigurement or loss of sensation, and has shown some good clinical results in terms of good post-treatment healing and epithelial necrosis. For regions with fewer medical resources, it would be very helpful to translate PDT therapy so it can be completed in an outpatient visit, and 3D printed oral applicators would be a great help on this journey.

“Despite excellent healing of the oral mucosa in PDT, a lack of robust enabling technology for intraoral light delivery has limited its broader implementation,” the team continued in their paper.

“Leveraging advances in 3D printing, we have developed an intraoral light delivery system consisting of modular 3D printed light applicators with pre-calibrated dosimetry and mouth props that can be utilized to perform PDT in conscious subjects without the need of extensive infrastructure or manual positioning of an optical fiber.”

The team’s goal in this study was to evaluate the clinical utility and ergonomics of their 3D printed oral PDT applicators, which were designed to comfortably, and stably, deliver light to patients’ oral lesions.

“Here, the natural structure of the patients’ oral cavity, teeth and jaw provided the support and stability to hold the fiber in place, avoiding any use of posts, holders, reflectors or light pipes,” the researchers explained.

3D Schematics of the applicators for three different regions in the mouth. The photos showcase the integrated unit with the applicator (1), the bite wing (2) and the endoscope (3) utilized in the ergonomics clinical study.

The 3D printed intraoral applicators, which attach to the optical fiber, have two parts – bite blocks and applicators. The blocks position the angle of the applicator, which then delivers the suitable beam spot, along with pre-calibrated dosimetry, to a certain lesion size. The team used Autodesk Fusion 360 to design the light applicators, and they were printed on a Stratasys Objet Pro system out of VeroBlue and VeroBlack filament.

Photograph of the oral cavity with ink marks in three points tested in the ergonomics study.

In order to determine how stable and comfortable the applicators were, the researchers performed a study, approved by the Massachusetts General Hospital Partners Institution Review Board, on ten subjects.

A physician placed three fiducial ink marks on each subject’s inner cheek, and tested the anterior and posterior buccal cheek and retromolar positions for ten minutes, one after the other. The light delivery fiber was replaced with an endoscope of similar size, with a 5.5 mm diameter camera and 6 LEDs, in order to record motion at these three spots.

The researchers explained, “Subjects were asked to rate comfort and fatigue on a numerical scale of 1 to 5 where 1 was no discomfort due to the applicator and 5 was intolerable discomfort due to the applicator.”

Each subject was asked three questions:

  1. Was there any physical discomfort during the ten minutes?
  2. Rate the fatigue or numbness in your mouth.
  3. Would you be comfortable immediately repeating another ten-minute interval at the same site?

Flow chart of video and image processing method to calculate centroid of the fiducial ink mark mimicking the anterior buccal cheek, posterior buccal cheek or retromolar position imaged with a USB Endoscope fitted to the oral applicators.

Additionally, the endoscope actually recorded the movement of the ink marks during testing in order to evaluate the applicators’ stability. Custom-designed algorithms in MATLAB were used to process the videos. They determined that the applicators were indeed stable, and capable of “delivering light precisely to the target location in ten healthy volunteers.” Additionally, the ten subjects rated the devices overall as comfortable, though one did report “no tolerance” to the applicator in the posterior buccal cheek position.

Five of the subjects had confirmed T1N0M0 oral cancer lesions with no lymph node involvement, and several months after PDT treatment, demonstrated no cancerous lesions, fibrosis, or scarring. This showed that the 3D printed applicators, paired with an inexpensive fiber and LED-based light source, “served as a complete platform for intraoral light delivery achieving complete tumor response with no residual disease at initial histopathology follow up in these patients.”

“While we used a set of applicators with pre-determined sizes that were comfortable for various subjects, mouth and jaw dimensions and genders, it is reasonable to envision extension of this approach to customized patient treatment. Specifically, personalized applicators can be rapidly printed at the time of procedure due to advances in image-based 3D printing and the increasing availability of low-cost, high-quality 3D printers in clinical settings,” the researchers concluded.

“The ergonomic design of 3D printable light applicators has significant practical benefit in enabling longer irradiation duration and improved accuracy of light delivery necessary for curative PDT. With costs of healthcare and cancer incidences increasing worldwide, particularly in developing countries, we report an affordable methodology for delivering light stably and ergonomically in the oral cavity which can be used in conjunction with a low-cost, portable, battery-powered fiber-coupled LED based light source.”

This is just one more good example of 3D printing successfully being used for cancer therapy.

Co-authors of the paper are Srivalleesha Mallidi, Amjad P. Khan, Hui Liu, Liam Daly, Grant Rudd, Paola Leon, Shakir Khan, Bilal M. A. Hussain, Syed A. Hasan, Shahid A. Siddique, Kafil Akhtar, Meredith August, Maria Troulis, Filip Cuckov, Jonathan P. Celli, and Tayyaba Hasan.

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3D Printing Helps a Five-Year-Old Girl to Dance Again

Five-year-old Daria loves dancing, but that was imperiled when she was diagnosed with Ewing’s Sarcoma, a rare malignant bone tumor, in her right leg. The tumor was large, extending almost to her distal femur, so removing it while still allowing her to walk – and dance – normally was a special challenge. Careful planning was required, but thankfully, Daria’s doctors had the tools to do just that.

“With all the soft tissues and skin in the way, what surgeons experience in surgery can be completely different to what they see on a 2D scan,”  said Mieke Motmans, Clinical Engineer at Materialise. “Using 3D digital and physical models gives an extra level of information and to work out exactly how best to proceed – it’s like the difference between outlining a journey on a paper map, and using a GPS that tells you exactly where you are going and when you will get there.”

Dr. A.H. Krieg and colleagues at the University Children’s Hospital in Basel, Switzerland had to remove the tumor and reconstruct Daria’s femur using a combination of her own live fibula and a donor bone.

“Endoprostheses (artificial bones) are the usual limb-salvage treatment if the tumor is close to the knee joint or extends to the epiphysis, but this is rarely possible for children as young as Daria – there are high complication rates,” said Dr. Krieg. “Making the reconstruction a success meant using 3D printing to its full potential and working with the right experts.”

Materialise has worked with surgeons to plan for more than 2,000 osteotomy cases, or corrective surgery where a bone is cut to allow realignment. The company has also designed and 3D printed more than 700 custom implants or endoprostheses.

“I’d actually worked with Mieke and her team before, so I knew they could help,” said Dr. Krieg. “The first step was uploading our MRI and CT scans of Daria’s leg to Materialise’s online portal for evaluation.”

Motmans specializes in oncology cases. Her team began by aligning meshes from Daria’s CT and MR scans, checking them in the Materialise Mimics medical imaging processing software and verifying the tumor’s position.

“Finding the tumor outline is where we start,”  she said. “Sometimes tumors are only visible in MRI, so Mimics helps us transfer its boundaries to the more accurate CT scans. Then we combine the CT scan ‘slices’ to build the 3D bone geometry model that lets surgeons see the overall picture and zoom in to the detail. Some surgeons have a very clear idea of what they want to do, while others will simply send us the scans and ask us for a solution. Either way, getting to this stage – seeing the 3D model – is often a critical moment. The model’s accuracy lets us verify the planned approach and sometimes it can be very obvious that the initial plan just isn’t going to work.”

Materialise and the hospital team worked together to map out the surgical procedure and position the resection plains that would be used to show exactly where saw cuts would be needed around the tumor. They had to retain as much bone as possible to keep Daria’s knee joint intact to support the screws for the titanium bridge that would hold the remaining bone, the allograft and fibula as they grew together during osteosynthesis. The margins were tight because the tumor was so big and so close to Daria’s knee.

“Where to cut the tumor influenced the size of the hole, which in turn governed the required shape of the donor bone,” said Motmans. “We couldn’t print anything until the whole planning stage – where to resect the tumor and allograft, the plate size, the position of the screws – was complete.”

The surgeons had to trim their normal safety margins and sacrifice the lower epiphyseal plate which contains live growing bone tissue, but they were finally able to set their resection planes. Materialise then 3D printed the models and the three cutting guides. Slots in these templates, two for the femur and one for the allograft, would be used to precisely position the surgeon’s saw blade, with carefully positioned holes directing the drill to ensure correct screw positions and insertion angles. The allograft guide defined the channel where the fibula would be inserted. Motmans used models showing pre- and post-operative bone geometry to check that each cutting guide and plate fitted precisely.

“The operation lasted ten hours, involved seven surgeons and was a great success,” said Dr. Krieg. “Although Daria still has a long way to go in rehabilitation, she now has the chance to make a nearly full recovery and use her leg without major restrictions.”

“The skilled teams that perform these operations are amazing,” said Motmans. “To be able to help them is a privilege. 3D printing means surgeons can plan ahead, allowing them to deal with problems before they even enter the operating room, and so avoid surprises during surgery. That’s an outcome that’s great for everyone.”

X-ray 6 weeks and 3 months after the surgery

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[Source/Images: Materialise]

 

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3D Printed Microfluidic Device Designed to Customize Cancer Treatment

Testing cancer treatments is a lot of trial and error currently, and patients are often subject to multiple uncomfortable and time-consuming therapies before finding one that works. Developments have been made, including growing artificial tumors to test drugs on specific cancer types, but these tumors can take weeks to grow and they don’t account for patients’ individual biological makeup. Now, however, researchers from MIT and Draper University have come up with a new option: a 3D printed microfluidic device that simulates cancer treatments on biopsied cancerous tissue.

The device is a chip slightly larger than a quarter that can be 3D printed in about an hour. It has three cylindrical chimneys protruding from the surface, which are ports that input and drain fluids as well as remove unwanted air bubbles. The biopsied tumor fragments are placed in a chamber connected to a network of deliver fluids to the tissue. These fluids could contain things like immunotherapy agents or immune cells. Clinicians can then use imaging techniques to see how the tissue responds to the treatments.

The researchers used a new type of biocompatible resin, traditionally used for dental applications, that can support the long-term survival of biopsied tissue. This contrasts with other 3D printed microfluidic drug testing devices, which have chemicals in the resin that quickly kills the cells. Fluorescence microscopy images showed that the new device, called a tumor analysis platform or TAP, kept more than 90 percent of the tissue alive for at least 72 hours and potentially much longer.

The TAP is cheap and easy to fabricate, so it could quickly be implemented into clinical settings, according to the researchers. The devices is adaptable as well – doctors could 3D print a multiplexed device that could support multiple tumor samples in parallel, so that the interactions between tumor fragments and several different drugs could be modeled simultaneously for a single patient.

“People anywhere in the world could print our design. You can envision a future where your doctor will have a 3-D printer and can print out the devices as needed,” said Luis Fernando Velásquez-García, a researcher in the Microsystems Technology Laboratories. “If someone has cancer, you can take a bit of tissue in our device, and keep the tumor alive, to run multiple tests in parallel and figure out what would work best with the patient’s biological makeup. And then implement that treatment in the patient.”

One potential application is testing immunotherapy, a new treatment method that uses drugs to “rev up” a patient’s immune system to help it fight cancer.

“Immunotherapy treatments have been specifically developed to target molecular markers found on the surface of cancer cells,” said graduate researcher Ashley Beckwith. “This helps to ensure that the treatment elicits an attack on the cancer directly while limiting negative impacts on healthy tissue. However, every individual’s cancer expresses a unique array of surface molecules — as such, it can be difficult to predict who will respond to which treatment. Our device uses the actual tissue of the person, so is a perfect fit for immunotherapy.”

The research was published in a paper entitled “Monolithic, 3D-Printed Microfluidic Platform for Recapitulation of Dynamic Tumor Microenvironments.“

“A key challenge in cancer research has been the development of tumor microenvironments that simulate mechanisms of cancer progression and the tumor-killing effects of novel therapeutics,” said Jeffrey T. Borenstein, who leads the immuno-oncology program at Draper. “Through this collaboration with Luis and the MTL, we are able to benefit from their great expertise in additive manufacturing technologies and materials science for extremely rapid design cycles in building and testing these systems.”

Microfluidic devices are typically produced via micromolding with PDMS. The technique was not suitable, however, for producing a device with fine 3D features such as the fluid channels, so the researchers turned to 3D printing, which allowed them to create the device in one piece. They experimented with several resins, but finally settled on Pro3dure GR-10, which is often used to make mouth guards. The resin is nearly as transparent as glass, can be printed in very high resolution, and has hardly any surface defects – and it doesn’t harm the cells.

“When you print some of these other resin materials, they emit chemicals that mess with cells and kill them. But this doesn’t do that,” Velasquez-Garcia said. “To the best of my knowledge, there’s no other printable material that comes close to this degree of inertness. It’s as if the material isn’t there.”

The device also features a “bubble trap” and a “tumor trap.” Fluids flowing into a device like this one creates bubbles that can disrupt the experiment or burst and release air that destroys tumor tissue. So the researchers created a bubble trap, a chimney that rises from the fluid channel into a threaded port through which air escapes. Fluid gets injected into an inlet port adjacent to the trap, then flows past the trap, where any bubbles in the fluid rise up through the threaded port and out of the device. Fluid is then routed around a small U-turn into the tumor’s chamber, where it flows through and around the tumor fragment.

The tumor trap sits at the intersection of the larger inlet channel and four smaller inlet channels. Tumor fragments, less than one millimeter across, are injected into the inlet channel via the bubble trap. As the fluid flows through the device, the tumor is guided downstream to the tumor trap, where it gets caught. The fluid continues traveling along the outlet channels, which are too small for the tumor to fit into, and drains out of the device. A continuous flow of fluids keeps the tumor fragment in place and constantly replenishes nutrients for the cells.

“Because our device is 3-D printed, we were able to make the geometries we wanted, in the materials we wanted, to achieve the performance we wanted, instead of compromising between what was designed and what could be implemented — which typically happens when using standard microfabrication,” Velásquez-García said.

The next step is to test how the tumor fragments respond to therapeutics.

“The traditional PDMS can’t make the structures you need for this in vitro environment that can keep tumor fragments alive for a considerable period of time,” said Roger Howe, a professor of electrical engineering at Stanford University, who was not involved in the research. “That you can now make very complex fluidic chambers that will allow more realistic environments for testing out various drugs on tumors quickly, and potentially in clinical settings, is a major contribution.”

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[Source/Images: MIT]

 

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Researchers Use 3D Printing to Isolate Aggressive Breast Cancer Cells

Researchers at the University of Girona have successfully isolated stem cells from one of the most aggressive forms of breast cancer – using 3D printing. The goal of isolating the cells is to find a drug that attacks them exclusively, without damaging healthy parts of the body.

According to Dr. Teresa Puig, Director of the Oncology Unit of the Group for the Investigation of New Therapeutic Targets, these breast cancer cells still remain in the body after treatment via chemotherapy or radiotherapy and often cause relapse. This particular type of cancer is the triple negative subtype, which occurs in young women and leads to relapses in 20 to 30 percent of patients within three or four years.

“A tumor is made up of many types of cells, and these are the cells we have in low proportions,” said Dr. Puig. “Therefore, it is complicated to locate these cells within the tumor. This new system is cleaner, allowing us to work more directly with these types of cells later.”

The research is documented in a paper entitled “Screening of Additive Manufactured Scaffolds Designs for Triple Negative Breast Cancer 3D Cell
Culture and Stem-Like Expansion.” The main goal of the study was to develop a scaffold architecture that afforded a high breast cancer cell proliferation rate. Several values of the selected parameters, which included layer height, infill density, infill pattern, infill direction, and flow, were tested on the slicing software BCN3D Cura and the scaffolds were 3D printed on the BCN3D Sigma 3D printer.

Using the Taguchi experimental design method, 27 scaffold configurations were manufactured and analyzed. At least 10 copies of each configuration were 3D printed to perform the characterization and cell proliferation assays, with the objective being to see which geometric form was most effective in separating the stem cells.

“This structure is a mesh that, on the basis of a series of parameters such as porosities, spaces, and the distance between one element and another, is ultimately able to allow cells to stick to the matrix or not, to grow, and to be able to ‘enrich themselves’, as our colleagues say,” said Joaquim de Ciurana, Director of the Research Group on the Engineering of Products, Processes, and Production.

Before this research, these cell cultures were produced two-dimensionally, which did not allow the cells to be effectively separated, so specific drugs could not be produced to attack the cells. But the 3D method in which the researchers isolated the stem cells for this study allows them to better study the cells in order to find the bio-indicators responsible for the tumors. They will then be able to attack them with pharmaceuticals, although the research is not yet at that point.

“We still do not know how to treat them, but we have found a way to isolate them,” said Dr. Puig.

Optical microscope images of cells attached to different scaffolds configurations. White arrows indicate cells adhered to PLA filament.

This method is also more cost-effective than traditional analysis methods, allowing for more frequent experiments in the future.

Authors of the paper include Emma Polonio-Alcalá, Marc Rabionet, Antonio J. Guerra, Marc Yeste, Joaquim de Ciurana and Teresa Puig. Several of these scientists were also involved in a recent study about 3D printed composite stents.

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[Source/Images: BCN3D Technologies]