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More Efficient Drug Screening with 3D Bioprinting

Taking a drug to market is a competitive, costly and challenging process involving preclinical laboratory and animal testing before the even more time-consuming and expensive four phases of human clinical trials, which can take as many as 7 to 15 years at price tags as high as $5.5 billion. Even if 10 viable drug compounds are identified for human trials, only 1 out of 9 will actually make it to market. Given this high attrition rate, can bioprinting save valuable time and resources by better identifying viable compounds in order to move only the most promising drugs to clinical trials?

The limitations of animal testing

During the initial stages of drug discovery, often referred to as preclinical trials, new chemical entities (NCEs) are monitored to determine the life cycle of the compounds inside and outside of the targeted system (pharmacokinetics) and their chemical reactions (metabolism). Because of the ethical issues surrounding human trials and their high costs, a significant number of these early tests are performed on animals.

While the transition from preclinical animal testing to clinical human trials has improved thanks to better research tools and the rise of artificial intelligence in target identification, there is still a real need for improved preclinical screening because animal testing often fails to recapitulate the complexity of the human metabolism, leading to false positives and negatives that do not accurately reflect the toxicity of drugs to human systems.

3D cell cultures are more relevant

Given the limitations of animal models, it is no wonder that scientists have turned to human organ models. But although human cells have long been cultured in 2D, in recent years, a paradigm shift has led more and more scientists to recognize the importance of working with human cells in the 3D environments afforded by bioprinting in order to produce more physiologically relevant models. Combining the automation of cell culturing in 3D bioprinting with carefully tailored biomaterials, known as bioinks, has made it possible to grow, feed and maintain human organ models in larger quantities and in a lot less time, reducing time and labor spent on these tasks. Laboratory robotics can also now pick and place cell culture reagents or other NCEs and liquid samples in high numbers, enabling higher throughput screening and running a variety of other laboratory tasks more efficiently.

Bioinks better mimic ECM

Bioinks are another powerful tool that help researchers advance their drug discovery research. Tissue-specific bioinks improve cell adhesion and differentiation, helping with the formation of human organoids. Proteins and other biological factors can also be added to more accurately recreate extracellular matrices (ECM), once again better simulating the in vivo microenvironments. Furthermore, with multiple methods of crosslinking (chemical, light, thermal), the stiffness of constructs can be modulated to better serve specific cell types, like cartilage or bone tissue.

Learn more

Bioprinting’s more relevant human organ models can save the drug industry time and money by more efficiently identifying viable compounds in the initial stages of drug development in order to move only the most promising compounds to costly human clinical trials. The technology’s growing influence means that scientists continue to validate more and more applications. Dive deeper into how the bioprinting industry is changing drug screening and development. Watch our webinar on 3D bioprinting for COVID-19 studies or read our application note, which discusses the effectiveness of testing drug efficacy in 2D and 3D.

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LulzBot Releases It’s First Bioprinter

Bioprinting is revolutionizing the way 3D printed tissues can be used to mimic in vivo conditions. The fields of regenerative medicine, pharmaceutical development, and cosmetic testing are benefiting from this technological disruption, enabling researchers and companies to better predict efficacy and toxicology of potential drugs early on in the drug discovery process. But it’s no wonder this technology is so enticing, since bringing a new drug to market, with current methods, could cost $350 million dollars and can take more than a decade from start to finish. On the North American front, Colorado-based manufacturer Aleph Objects, the developer behind the LulzBot 3D Printers, announced today a new open-source bioprinter: the LulzBot Bio.

After almost ten years of manufacturing 3D printers, LulzBot finally decided to move into the bioprinting market. The new machine, which is now available for pre-order on the site and will begin shipping in November, enables 3D printing with materials such as unmodified collagen, bioinks, and other soft materials, and is the company’s first-ever Fluid Deposition Fabrication (FDF) 3D printer. FDF is a newfangled name for the FRESH process which we wrote about here and here. According to LulzBot, unlike its pneumatic counterparts, the Bio’s syringe pump system allows for precise stopping and retraction, preventing unintentional extrusion and stringing while printing intricate models, like vasculature.

The new LulzBot Bio

The printer has a Free Software design that removes proprietary restrictions, providing, what the company considers, a versatile platform for innovation that grows with everchanging discoveries and advancements. LulzBot reports a commitment to freedom of design in general, developing machines that come with freely licensed designs, and specifications, allowing for modifications and improvements to both software and hardware. In this respect, they have partnered with organizations, such as the Open Source Hardware Association, Free Software, and Libre Innovation. The Bio’s free software and open hardware design give researchers the ability to innovate together, letting the machine be easily adjusted for new materials and processes.

“For researchers, you don’t know what materials or processes you’ll be using in six months, let alone one year from now, so you need hardware that can be adjusted quickly and easily, without proprietary restrictions,” said Grant Flaharty, CEO and President of Aleph Objects.

The LulzBot Bio touchscreen for easy control

The LulzBot Bio comes with nearly everything needed to start bioprinting right away, including extensively tested, preconfigured material profiles in Cura LulzBot Edition, the recommended software for the LulzBot printers; Petri dishes; Life Support gel (by FluidForm); alginate, and tools. It also enables printing with unmodified collagen, something that has proven extremely difficult and is considered one of the most promising materials for bioprinting applications, since it is the human body’s major structural protein and is prominent in biological structures.

Actually, printing with unmodified collagen is currently done using the FRESH method, short for Freeform Reversible Embedding of Suspended Hydrogels, which was developed and refined by the Regenerative Biomaterials and Therapeutics Group at Carnegie Mellon University, in Pittsburgh. The LulzBot Bio is actually FRESH-certified, which means it uses thermoreversible support gels to hold soft materials during printing. Then, the temporary support gel is then dissolved, leaving the print intact.

“Other bioprinting techniques often require materials to be chemically altered or mixed with other materials to make them 3D printable,” explained Steven Abadie, CTO of Aleph Objects. “Because of the excellent biocompatibility of collagen, being able to 3D print with it in its original form brings us that much closer to recreating models that mimic human physiology.”

As stated by the company, the LulzBot Bio has already been instrumental in 3D printing some of the first-ever fully functional human heart tissue. This was achieved by a team of researchers at Carnegie Mellon, led by Adam Feinberg, that used the new device to 3D print heart tissue containing collagen and producing parts of the heart at various scales, from capillaries to the full organ.

“What we’ve shown is that we can print pieces of the heart out of cells and collagen into parts that truly function, like a heart valve or a small beating ventricle. By using MRI data of a human heart, we were able to accurately reproduce patient-specific anatomical structure and 3D bioprint collagen and human heart cells,” inidcated Adam Feinberg, principal investigator of the Regenerative Biomaterials and Therapeutics Group at Carnegie Mellon and co-founder of FluidForm.

FluidForm, powered by Carnegie’s research, has been working on the science behind the FRESH technology for quite some time. Now, Aleph Objects has taken the concept straight to the hardware, manufacturing this new machine, which they expect will be the first step to open up bioprinting to the broader market for exponential innovation.

Last June, LulzBot had already announced its collaboration with FluidForm, to combine their expertise and offer new bioprinting solutions. The LulzBot Bio has also been used by Newell Washburn, professor of biomedical engineering and chemistry at Carnegie, and a team of his colleagues to demonstrate how a new machine-learning algorithm could optimize high quality, soft material 3D prints.

According to company execs, the LulzBot Bio will satisfy the needs of many industries, for example, biotechnology, pharmaceuticals, cosmetics, medical devices, and life sciences. It could be ideal for producing bioprinted tissue for pre-clinical testing or used to recreate physiology to study diseases. It certainly seems like a great start to a new printer and perhaps the beginning of the company’s immersion in the bioprinting world.

[Images: LulzBot]

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Interview with Tamer Mohamed of Aspect Biosystems on Advancing Tissue Therapeutics

While attending The University of British Columbia (UBC), Tamer Mohamed, along with fellow graduate student Simon Beyer, began working at the Walus Laboratory on the development of a novel microfluidics-based bioprinting platform that could be used to fabricate human tissue constructs. One of the main reasons for their innovation was to potentially replace animal models in drug testing, which are costly, time-consuming and can have poor predictive accuracy. A few years went by and the two went on to win a MEMSCAP Design Award for their pioneering creation (the Lab-on-a-Printer Bioprinter) which would later become the basis for their startup, Aspect Biosystems. The UBC spinoff company was founded by Mohamed, Beyer, Konrad Walus (associate professor at UBC and head of the Walus Lab), and Sam Wadsworth, to turn their idea into a commercial product. The company quickly began providing pharmaceutical companies with high-efficacy tissue models that better mimic in vivo conditions, looking to improve the predictive accuracy of the front end drug discovery process. 3DPrint.com spoke to Mohamed to learn about his successful transition from graduate student to CEO of Aspect Biosystems.

Cofounders of Aspect Biosystems Tamer Mohamed and Simon Beyer at the Walus Lab when they were grad students

What was the inspiration behind Aspect Biosystems?

Aspect Biosystems was established with the vision of leveraging advancements in biology, microfluidics, and 3D printing to create technology-enabled therapeutics that will ultimately have a meaningful impact on patients. We are marrying our deep knowledge of human biology with cutting-edge 3D printing technology to create. Our story started almost a decade ago so we’ve spent years developing our foundational microfluidic bioprinting technology and are now applying our platform technology to create functional tissues, both internally through our proprietary programs, and with our partners around the world.

Can you tell me about the company’s growth model?

Platform technologies often have the advantage of flexibility, as they could allow you to pursue multiple applications. This also presents a challenge though, in that it is easy to become unfocused. At Aspect, we’ve built a strategy that allows us to both focus and diversify. Internally, we are advancing proprietary tissue programs in regenerative medicine. But we also recognize that to achieve our vision of enabling human tissues on demand, we can’t work alone. By providing access to our technology to partners around the world, we are able to create a network effect and tap into specific domain expertise. This allows our technology to be applied to a wide range of research purposes externally, without detracting resources or focus from our specific tissue programs internally. We collaborate with academia and industry on specific applications that allow us to fuel our growth and help generate revenue and a robust innovation pipeline.

How much has Aspect grown?

Aspect is the first and only company to leverage microfluidics to create functional tissue, and we are proud to pioneer this approach. Academically, we were one of the first groups in the world to print cells while at the UBC, so we see ourselves as pioneers in both bioprinting and platforms for creating tissue therapeutics. Five years ago, we had four full-time employees. Today we have a team of over 40 people focused on our mission and over 20 collaborations globally. We have attracted smart venture capital, partnered with some of the biggest names in our industry, and made major breakthroughs in applying our technology to create functional tissues. It is a great sign that, year-after-year, we continue to raise the bar. It is an even better sign that I believe the best is yet to come.

The Aspect Biosystem team celebrating Canada Day

What will the applications of this technology be in pharmaceutical research and drug trials?

I believe the opportunity with the highest value and best poised to make a significant impact on the pharmaceutical space is disease modeling. Using 3D bioprinting technology allows us to model diseases in a human-relevant system that would otherwise be difficult to study in animals or less sophisticated in vitro models. For example, working with GSK and Merck, we are leveraging our microfluidic 3D bioprinting platform to create physiologically-relevant 3D tissues containing patient-derived cells to assess the efficacy of anti-cancer drugs and to predict a patient’s response to treatment. This partnered program could unlock the discovery of novel therapeutic targets and the development of immuno-oncology therapeutics.

Would you tell us more about Aspect’s current and future work?

Our current internal programs are focused on orthopedic and metabolic diseases. On the orthopedic side, we are leveraging our deep knowledge of musculoskeletal biology and biomaterials to create knee meniscal replacements. On the metabolic side, we are focused on liver tissue and creating a therapeutic tissue for Type 1 diabetes. Externally, our partners around the world are using our 3D bioprinting technology to advance research in the brain, lungs, heart, pancreas, and kidneys, just to name a few. By being both focused internally and diversified externally, we are building a robust pipeline for the future. Our end goal is to enable the creation of human tissues on demand, and we know that we can’t do it alone. Our network of academic researchers and industry partners are key to making our vision a reality.

How fast is the technology moving towards a future with lab-made functional organs?

Tamer Mohamed

We are focused on identifying specific diseases or biological malfunction inside the body and rationally designing advanced tissue therapeutics that address these areas of unmet medical need. So, while we may not actually be making something that looks exactly like an organ, we are recreating the biological function that has been lost or damaged to address the problem. For example, someone with Type 1 diabetes has a pancreas that is unable to perform the vital function of creating insulin. We don’t necessarily need to engineer something for them that looks exactly like a pancreas – instead, we are creating an implantable therapeutic tissue that replaces function that has been lost. In this case, that function is sensing glucose levels in the blood and biologically releasing insulin in response. This is an example of one of our internal programs – a bioengineered pancreatic tissue therapeutic that restores a critical function that been lost due to an autoimmune disease.

Is Canada a great place to develop a bioprinting company?

Canada has a long and rich history in the field of regenerative medicine, going back to the discovery of stem cells in the 1960s. As a country, we have an opportunity to be a global leader in the field. At Aspect, we are proud to be part of these efforts. We are in ongoing discussions with different government groups as to how we can play a role in helping to lead the charge and the government has been embracing that. We have seen significant federal and provincial support for innovation and public/private partnerships, which definitely help stimulate growth in the field.

How disruptive is the technology you created?

By combining microfluidics with 3D printing, we are disrupting tissue engineering. We are able to programmatically process multiple cells and biologically-relevant materials in high-throughput to rationally design and produce functional tissues. We are constantly integrating new microfluidic processing units within our printhead technology and leveraging continuous advancements in the “lab-on-a-chip” space. With our microfluidic technology, we are generating a large amount of data. By using this data and machine learning, we are improving the quality and automation of the biomanufacturing process.

Ultimately, bioprinting is only as good as our understanding of biology – and our understanding of biology is growing wider and deeper. We are combining state-of-the-art stem cell science with our microfluidic 3D printing technology to create tissue therapeutics. For example, we are combining insulin-secreting cells derived from human embryonic stem cells (hESCs) with our printing technology to create therapeutic tissues for patients with Type 1 diabetes.

[Images: Aspect Biosystems and Tamer Mohamed]

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Bioprinting 101 Part 18 – Pharmaceutical Testing

A pharmaceutical test can be referred to as a clinical trial or a rigorously controlled test of a new drug or a new invasive medical device on human subjects. In the United States, it is conducted under the direction of the FDA before being made available for general clinical use. With the testing of various drugs it is important to understand their efficacy. The FDA approves drugs for the public use after said tests have gained FDA clearance. It is such a pivotal moment within the development of any drug and it costs a good amount of money to go through FDA clinical trials. Most of these trials typically involved the testing of a drug on an animal as well. Today we will analyze bioprinting and this particular sector of the healthcare industry and how it may change what is possible in years to come.

The field of pharmaceuticals focuses on the following: drug discovery as well as drug development. When one discovers a novel usage of a chemical in terms of a drug, it must then be tested thoroughly a number of times in order to have validity as a commonplace treatment to a specific pathology or ailment. This also allows for one to see how a drug may be developed in lieu of complications that arise when testing a drug. A lot of these tests can be very expensive when done. A way to reduce cost of said tests could be bioprinting. Currently, the technology is not at a scale where one can mass produce tissues or organs for the use of clinical trials on a large scale quantity. With time though, this could be a reality and it can help save time and materials for pharmaceutical companies. Bioprinting also allows pharmaceutical companies to have models of human organs that may provide more accurate test results than lets say a pig organ genetically.

High Throughput Screening and Pharmaceuticals

We briefly have talked about animal trials already, but let us take a closer look at animal trials. Some animal tests take months or years to conduct and analyze (e.g., 4-5 years, in the case of rodent cancer studies), at a cost of a lot of dollars per substance examined (typically $2 to $4 million per two-species lifetime of a cancer study). The inefficiency and exorbitant costs associated with animal testing makes it impossible for regulators to adequately evaluate the potential effects of the more than 100,000 chemicals currently in commerce worldwide, let alone study the effects of a myriad combinations of chemicals to which humans and wildlife are exposed, at low doses, every day throughout life. One may even look into the ethics behind an animal test overall, and they could argue that bioprinting methods can be a solution to solve ethical problems of using animals detrimentally, but in a manner to serve humans. With bioprinted organs and tissue used for pharmaceutical testing animal ethics may be detracted from pharmaceutical testing (even though ethics is still very apparent if we want to analyze stem cell use within bioprinting, but that is not the topic of discussion).

Bioprinting can truly be beneficial to pharmaceutical testing if high throughput screening is also integrated. High throughput screening is a method to automate and reduce the costs of drug testing. As mentioned previously in our bioprinting series, high-throughput screening (HTS) is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry. Using robotics, data processing/control software, liquid handling devices, and sensitive detectors, high-throughput screening allows a researcher to quickly conduct millions of chemical, genetic, or pharmacological tests. With the combination of high-throughput screening and bioprinting, automation of pharmaceutical testing will cut down the time needed to conduct these type of tests, which also leads itself to better use of time and more money to be made for pharmaceutical companies large and small.

Animal Testing

Overall there lies large potential with bioprinting and pharmaceutical testing. It still is far from a strong reality due to the following factors:

The healthcare industry does not innovate or change methods quickly due to the standards being used.
A lack of FDA clearance for bioprinting as a whole holds back development
Not a lot of work done in terms of perfecting these technologies when applied to a large scale pharmaceutical test being done