Lithoz Ready to “Pull the Trigger” on New 3D-Printed Drug & Vaccine Purification Method

3D printing may potentially have an impact on the way that pharmaceuticals and vaccines are produced, including those for fighting the SARS-CoV-2 virus that causes COVID-19. The E.U.’s NESSIE project is a transnational European initiative that brings together five partners across Austria, Norway, and Portugal to develop a new generation of monolithic columns for separating molecules for biopharmaceutical production. The end result may be a quicker, more efficient and less expensive method for making vaccines. To learn more, we spoke to Martin Schwentenwein, head of materials for ceramics 3D printer manufacturer Lithoz.

A chromatography column 3D printed using Lithoz’s ceramic 3D printing technique. Image courtesy of Lithoz.

The project is dedicated to improving the process of chromatography used to separate and purify molecules for pharmaceutical purification. During chromatographic operations molecules and proteins are separated based on size or selective interactions, such as how well they dissolve in water or fats. This is accomplished by pumping a pressurized liquid solvent with the material being purified through a column filled with a specialized material, which separates impurities or unwanted byproducts. The members of the NESSIE project are working to improve this column component to make the process more efficient.

The group is developing methods for tailor-making these columns to optimize the behavior of the fluid running through them and reduce changes in pressure that occur during the purification process. In particular, the fluid pressure drops as the material interacts with the column, limiting the speed of purification. By reducing this drop in pressure, the entire process can be made more efficient, thus improving speed and reducing cost.

Lithoz was brought into the project due to the fact that existing columns are made using silicon dioxide material. As a specialist in ceramic 3D printing, the company is able to offer its expertise to producing columns with the fine resolution and materials needed for biopharmaceutical purification. Silicon dioxide has the advantage of combining the porosity needed to filter molecules, while maintaining temperature stability. It can also be sterilized, which is often required for processing biopharmaceutical materials.

Depending on the pharmaceutical material that is being researched or manufactured, the purification operation can be made up to 20 percent more efficient. With the processing of easier molecules sped up by up to five minutes per run, this translates into hours or days of work saved in drug R&D or even days or weeks saved in mass production of medications and vaccines. At the moment, the partners have developed a proof-of-concept for improving column designs more generally, but Schwentenwein said that the columns can in principle be tailored for each specific biopharmaceutical product that is studied or produced:

“Of course, improving the speed is the most tangible outcome, but going beyond that, is the vision that the separation mechanics can be improved overall, and you can ideally move significantly beyond this 20 percent times saving. You can move more into the domain where it can really get to half the time that you need. But for that also the whole design has to be optimized, has to be tailored. For now, we’re aiming for this basic proof-of-concept that, by using this 3D printing technique in combination with ceramics, that you can get this improvement for the whole separation process.”

Schwentenwein said that these columns could be used for the purification of basically any molecule, whether it’s during the drug screening and research phase, or for production. This includes the wide array of vaccines and medications being developed to combat the SARS-CoV-2 virus.

Renderings of chromatography columns with different geometries. Images courtesy of SINTEFweb on YouTube.

Currently, there are about 23 companies creating such solutions. This includes more inexpensive drugs for treatment, such as the decades-old antimalarials from the chloroquine family of medications to more potentially costly medicines like remdesivir. As for vaccines, products range from more traditional vaccines derived from the inactivated virus to much newer DNA and RNA vaccines, classes of vaccines that were previously not considered acceptable for human use due to the fact that in some cases they could not provide immunity, may have unpredictable effects and could potentially cause unintended consequences.

Despite the uncertainty about these newer vaccines, several RNA and DNA vaccines, some developed by partners of the U.S. Department of Defense, are undergoing clinical trials. Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said in March that a vaccine won’t be available for the public for another 12 to 18 months.

Regardless of the timeline for the public availability of a SARS-CoV-2 vaccine, the technology developed from Project NESSIE wouldn’t necessarily aid in production immediately. However, it could be used to purify a vaccine or drug used to prevent or treat the COVID-19 illness.

At the moment, the team is fine-tuning its production process and ensuring repeatability for printed columns, determining that they are able to achieve feature resolutions of well beyond 100 microns very homogeneously throughout across entire batches parts. This is something that has not been available before. The project is set to conclude at the end of October this year, but it won’t likely be ready for commercialization quite yet at that time.

The group is looking for a manufacturer who is ready to manufacture columns in mass, which would require a farm of Lithoz ceramic 3D printers. According to Schwentenwein, using a single printer that has not been optimized for production, it would be possible to produce 50 columns daily. If this were scaled up, it would be possible to manufacture in the numbers necessary for the market.

The columns currently being developed are smaller, meaning that they are more suitable for R&D purposes, but the size can be made larger for biopharmaceutical manufacturing, which would mean fewer columns per print job. The biggest bottleneck at the moment, Schwentenwein says, is the lack of having a user/partner who is able to produce these columns in a quality controlled environment. However, he believes that they have the technology in place so that, once they find this partner interested in mass production, all that would be necessary would be to “pull the trigger.”

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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]

The post LulzBot Releases It’s First Bioprinter appeared first on 3DPrint.com | The Voice of 3D Printing / Additive Manufacturing.

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:

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