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The new “Big Three” of the 3D bioprinting industry

This indicates a vibrant and lively community, which however is still very much relying on university research and academic adoption, since commercial applications of bioprinting remain limited to early development and testing. These are currently intended as either cosmetics testing or drug development & testing (DDT). Production applications, much like in most industrial 3D printing, remain a mirage mostly due to challenges in terms manufacturability (for organs and tissue grafts) and scalability (in the case of tissues and for the rapidly  emerging area of cellular agriculture/3D printed lab-grown meat applications).

For more than three decades, 3D Systems created new approaches and processes for product development, parts manufacturing and personalized healthcare through additive manufacturing solutions. The company owns patents for multiple different additive manufacturing technologies, including metal and polymer processes used in the orthodontic and orthopedic implant industries – which share several aspects with bioprinting processes and applications.

Today Allevi can be considered a leading innovator in the bioprinting space with an exclusive focus on the research and development community. Leading laboratories leverage Allevi’s portfolio of hardware, biomaterials and software to design, engineer and build solutions for tissue engineering, organ-on-a-chip research, pharmaceutical validation, biomaterial development, and regenerative medicine.

More existing collaborations, with CollPlant Biotechnologies and Antleron, also expand the capabilities in regenerative medicine research and development solutions, as 3D Systems continues to seek partners with the same mission of transforming healthcare through groundbreaking technologies.

3D Systems officially entered the bioprinting segment by acquiring startup company Allevi, which attempted to do something similar to CELLINK (in fact it was one of the very first to launch a low-cost bioprinter) but with less effective results. Instead of starting from materials to progressively expand into hardware, like CELLINK, Allevi (which at the time was called BioBots), started from the hardware and had a more difficult time in establishing a significant installed base. The company went through some changes in management, including the name change to Allevi, and was finally acquired by 3D Systems in May 2021, making it into one of the foundations to its new bioprinting business.

The next step in 3D Systems’ bioprinting strategy focuses on the company’s wide experience in the medical devices and implant segments. To date the company produced more than 2,000,000 serial component medical devices and 140,000 patient-specific surgical cases: now it’s looking to scale the production of bioprinted clinical applications, leveraging and adapting existing technology (which can almost seamlessly be used for scaffolding) to elevate patient care through various clinical applications, ranging from acellular bioresorbable devices to functionalized solid organs for transplantation.

The new "Big Three" of the 3D bioprinting industry as segment consolidates around main players exploring new materials and opportunities
Bionova, the first digital light processing (DLP) based bioprinter for direct printing in multi-well plates, combines technologies from Allegro 3D, Cellink and Advanced BioMatrix

BICO’s mission is to enable the pharmaceutical and biopharma industries to develop new drugs faster and safer, with more specificity and less need for animal testing. The company’s strategy until recently has been to acquire innovative technology companies once they are de-risked and ready for commercialization and scaling up. After some challenges, the group now seems well-positioned for rapid growth, as a leading provider of drug discovery and drug development tools. This is a similar strategy to the one pursued by Organovo, with failing results. However, BICO is operating at an already much larger level in terms of revenues and available technologies, with more cost-efficient and accessible tools which are already generating important returns. Organovo was a pioneer but it may have entered the bioprinting market too early.

Together with United Therapeutics Corporation and its organ manufacturing and transplantation-focused subsidiary, Lung Biotechnology PBC, 3D Systems achieved significant progress in the development of next-generation bioprinting solutions for lung scaffolds that are capable of full-size, vascularized, rapid, micron-level printing.

When we began to track the 3D bioprinting market nearly a decade ago there were less than a dozen companies operating specifically in this segment as commercial entities, with most development taking place at the academic level. Today, 3dpbm’s 3D Printing Business Directory’s Bioprinting section lists 133 entities, of which 47 are hardware (bioprinter) manufacturers, 41 are material (bioink) suppliers and 59 are considered service providers (a category that includes bioprinting laboratories at universities).

The 3D-Bioplotter bioprinters can process open-source biomaterials using air or mechanical pressure to a syringe, which can fabricate scaffolds to create tissue, with X-Y repeatability down to 1 μm. All models have been designed for use in a sterile biosafety cabinet, meet standards for clinical trials and offer build sizes up to 192.4 cubic inches.

The natural evolution of this aspect of 3D Systems’ strategy is to implement advanced bioprinting technology development to meet the evolving needs of the clinical and R&D communities. Here, the trademarked Print to Perfusion process enables 3D printing of high-resolution scaffolds, which can be perfused with living cells to create tissues.

Since BICO is the only public bioprinting (almost) pure player (after Organovo collapsed and exited the segment), its public financial results and publicly disclosed strategies are a good indicator of bioprinting’s overall health. BICO’s long-term and mid-term goals are to reduce the organ shortage and speed up drug development by providing accessible life science solutions that combine biology and technology. The concept of bioconvergence, which inspired the company’s name, refers to using a combination of robotics, artificial intelligence, advanced genomics, and 3D bioprinting, to create new healthcare solutions.

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The Big Three bioprinting companies are each targeting these areas from different angles that they considered strategic.

Bioconvergence for commercial applications

The system uses modular components, such as sterilized heating and cooling cartridges, standard Luer-Lok syringes with standard needle-tip sizes and an easy-to-use 365 nm UV curing head. “It’s a popular tool because it’s a very flexible, but also user-friendly machine,” Carlos explained. The software also allows for maximum freedom in combining different materials using different temperatures.

BICO’s acquisition phase was very rapid (over a period of just about 2 years), and the result is a highly diversified product offering, which limits technical risks. In several cases, these technologies fundamentally change the way laboratories work, implementing new and efficient workflows to automate operations. Many of these solutions are the results of synergistic work from several of BICO’s companies working cooperatively. Examples include customizable MatTek Dishes combined with the ECHO Revolve hybrid microscope for easy to use, universal compatibility with laboratory equipment, built-in glass coverslip for ultraclear imaging, no messy or fragile slides, and customized options to suit cell culture and/or imaging objectives. Another is the G.STATION NGS, developed in collaboration between Dispendix, Cytena and Qinstruments to provide automated workflows for next-generation sequencing. Finally, Bionova, the first digital light processing (DLP) based bioprinter for direct printing in multi-well plates, combines technologies from Allegro 3D, Cellink and Advanced BioMatrix. It prints functional tissue models in seconds with superior resolution, speed and reproducibility. It also accelerates research by providing biomimetic models for regenerative medicine, precision medicine and disease modeling.

Recently 3D Systems also launched Systemic Bio, a fully owned company based in Houston, Texas, focused on the development of vascularized organ models made out of hydrogels and human cells to be used for drug discovery and development. With a state-of-the-art laboratory and a team of bioengineering experts, Systemic Bio is pushing the boundaries of preclinical drug testing. Its proprietary platform is built with production-level 3D Systems technology, which has a greater build volume and a higher resolution than most commercially available technologies.

Today – at this point in time – we can take this step in regenerative medicine to influence the future of mankind.Chuck Hull, Founder of 3D Systems and inventor of 3D printing (stereolithography).

Given the change in the macroeconomic environment, we [BICO] have a firm focus on profitability and cash flowErik Gatenholm, CEO, BICO

Chuck Hull, Founder and now Chief Technology Officer at 3D Systems.

All these are based on the development and introduction of both bioprinting-specific materials and general healthcare 3D printing materials. The 3D-Bioplotter platform uses Hydrogels & Cells designed to be both biocompatible and cell-friendly, capable of supporting a variety of applications in bone regeneration, cartilage regeneration, soft tissue fabrication, drug release, and organ 3D printing. Other 3D-Bioplotter supported materials include Ceramics, which is bio-active, osteoinductive and osteoconductive materials that are designed to promote bone growth in the implantation area. These are used in critical size defects as bone grafts with complex inner patterns that mimic the surrounding bone’s mechanical properties, and as custom ceramic implants in maxillofacial applications. The overall healthcare strategy also includes Photopolymers (for immediate medical device fabrication), Metals (for surgical tools, prosthetics, splints and implants) and Thermoplastics (for cartilage regeneration applications, such as knee meniscus or trachea defects).

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Erik Gatenholm, Co-Founder and CEO, BICO

In terms of financial outlook, 3D System’s bioprinting-related activities do not yet represent a significant revenue generation segment however they are considered highly strategic. In its latest Q3 financial results, the company stated that “new opportunities for large-scale adoption of additive manufacturing opening before us, and entirely new markets being created in bioprinting, we believe we are very well positioned to deliver on our commitment to become a $1 billion revenue company in five years.”

Embracing the past and future of bioprinting

The final element in 3D Systems’ bioprinting strategy is to develop more complex biological structures and tissue engineering. This is where the acquisition of Volumetric Biotechnologies brought on significant tissue engineering expertise to expand the scope of human organ bioprinting efforts. The companies are now establishing a research facility in Houston, Texas to accelerate the development and commercialization of vascularized human tissues and bioprinted constructs for non-organ applications, and creating clear technological leadership in the rapidly emerging bioprinting field for laboratory applications including drug discovery.

Desktop Health’s bioprinting and general healthcare strategy identified five different levels. The first is Drug Discovery, which includes mimicking pathologic tissue (for efficacy), and healthy tissue (for safety), targeting a high throughput. This is considered a well-established segment of bioprinting. The next two levels represent the company’s current focus and are considered to be within reach. Custom Implants & Grafts (level 2) refer to treatments for spine fusion, non-union fractures, craniomaxillofacial, nerve conduits, tendons, ligaments, and bones. Tissue (level 3) refers to the bioprinting of breast, skin, cornea, bones, cartilage, and heart valves

After some turmoil in mid-2022, due to the tumbling stock price and an internal feud between Co-founders Erik Gatenholm (CEO) and Gusten Danielsson (CFO), which led to the latter leaving the company, BICO is now again trending upwards. The company has consolidated a number of acquisitions conducted over the past couple of years and is now growing by targeting two main areas.

The new "Big Three" of the 3D bioprinting industry as segment consolidates around main players exploring new materials and opportunities
3D Organ-on-a-Chip with Carbohydrate Glass from Volumetric Inc

When considering all the companies that are now part of the BICO group, there are as many as 11,000 instruments in the field, with most of these being bioprinters of various kinds (including 3D printers used for scaffolding in cellular cultures). Under bioconvergence, the lines between biology, engineering, nanotech, and data become increasingly blurred, allowing synergies to approach to biology as highly advanced engineering that’s been refined over billions of years. Within bioconvergence, Biosciences, provide user-friendly instruments to bring efficiency and speed to multiple application areas, such as cell line development, drug screening, and microscopy. Bioautomation accelerates the development and manufacturing of diagnostic and bioanalysis test platforms for patients, consumers, public health and the environment. Finally, Bioprinting enables printing with cells and biomaterials, creating tissues and organ-like structures that mimic physiological conditions.

Desktop Metal was founded in late 2015 with the stated objective of making metal additive manufacturing both more accessible (at first, via a bound metal extrusion process) and more scalable (via a metal binder jetting process). Six years later, these objectives have not yet been achieved but they are a lot closer. More importantly, many more bought into Desktop Metal’s vision including competitors, customers and – most importantly – investors, with the company raising over $2 billion after going public via a SPAC merger in late 2020.

On the one side, the company is targeting the expansion of bioprinting research at the academic level through its cost-effective CELLINK range of bioprinters (and gradually evolving to more advanced systems in its offer), feeding it with a wider range of bioink materials (obtained from the acquisition of Advanced BioMatrix).

The new "Big Three" of the 3D bioprinting industry as segment consolidates around main players exploring new materials and opportunities I personally find it fascinating seeing what researchers will do with it nextCarlos Carvalho, Team Leader Bioprinting Team at EnvisionTEC (now ETEC)

The new "Big Three" of the 3D bioprinting industry as segment consolidates around main players exploring new materials and opportunities
3D Systems Print to Perfusion advanced technology development

The ability to print large, vascularized, highly detailed hydrogel scaffolds at rapid speeds is opening new opportunities for a range of tissue applications. In addition, 3D Systems is developing bioprinting solutions that are both commercially viable and scalable from prototype to production.

Allevi’s newest desktop 3D bioprinters are versatile and easy to use, giving users access to a wide range of biomaterials—bioinks, bioink additives, cells, reagents and consumables—as well as an intuitive software interface.

At the time of the acquisition, Chuck Hull, Co-founder of 3D Systems and inventor of 3D printing (stereolithography), who has taken a keen interest in the company’s move towards bioprinting, commented by saying that “Today – at this point in time – we can take this step in regenerative medicine to influence the future of mankind.”

Just like industrial additive manufacturing, the bioprinting industry lives on extreme ups and downs. The ups bring new enthusiasm and innovation, and the downs bring back the reality of how complex it is for any new industrial segment to emerge into a real commercial opportunity. At the same time, the down periods often hide key trends that silently feed the next growth cycle, with new players emerging as technological and market leaders. That’s more or less what has been happening lately in bioprinting, with three key companies, BICO, 3D Systems and Desktop Metal (yes, Desktop Metal, via the recently formed Desktop Health division) emerging as leaders, even as dozens of smaller companies and startups continue to bring innovation to the table.

The new "Big Three" of the 3D bioprinting industry as segment consolidates around main players exploring new materials and opportunitiesThe final two levels represent the long-term goal of Desktop Health’s strategy and of bioprinting in general. They include Endocrine Glands (level 4), which is the ability to produce a complete ovary, pancreas, thyroid for testing and eventually for implantation, and Organs (level 5), which include the ability to produce functional lungs, kidneys, livers, and hearts.

On the other, BICO is working with advanced technologies such as those obtained through the acquisitions of Nanoscribe and, more recently, Allegro 3D, towards the development and implementation of commercial and scalable bioprinting applications, starting with tissue for cosmetics testing and evolving into organ research.

Although it was never supported by aggressive marketing (that is now likely to change, as powerful marketing is at the heart of Desktop Metal’s strategy), the 3D-Bioplotter has been the reference for high-end bioprinting research for over two decades, since the platform was launched in the year 2000. Today there are three 3D-Bioplotter models on the market: Starter, Developer and Manufacturer. Many machine features vary between models. For example, the Manufacturer model allows for 5 print heads and also includes a heated platform and sterile filter, which is recommended for cell printing.

The company is now looking to implement a holistic approach, leveraging this experience to innovate bioprinting technologies and transform patient care. By enabling the fabrication of living tissues, 3D Systems looks at bioprinting as a means to push the limits of regenerative medicine, disrupting healthcare as we know it.

Understanding how and why Desktop Metal is not only directly involved but also one of the leaders of the bioprinting market is a bit more complicated, without first reviewing the company’s recent overall growth strategy. Desktop Metal’s recent acquisitions make its bioprinting approach a hybrid between BICO’s and 3D Systems’, with the Boston-based company qualifying as both a new entry and a traditional additive manufacturing market leader.

BICO management is now bullish about medium and long-term prospects highlighting opportunities across all three business areas. The main driver is identified in big pharma’s move towards laboratory automation processes. Here Biosero’s Green Button Go platform is becoming a standard in lab automation. It offers user-friendly accessible approaches to automating manual processes with accuracy and cost-efficiency. The FDA Modernization Act 2.0 in the US, if it is finally enacted, would allow pharma companies applying for market approval for a new drug to use methods other than animal testing to establish the drug’s safety and effectiveness. Significantly for BICO, these alternative methods may include cell-based assays, organ chips and microphysiological systems, computer modeling, and other human biology-based test methods. What this means for the pharma and cosmetic industries is that animal models will be phased out over time, and the industry will get better results with human models. BICO’s range of products and services in the tissue engineering arena is meant as a one-stop shop that can fit customers in different stages of development.

Putting the AM into bioprinting

3D Systems’ capabilities as a technology innovator, spanning hardware, software, and materials science, combined with United Therapeutics’ renowned expertise in regenerative medicine has enabled advances in lung modeling, 3D printing, as well as material formulation and material handling to yield significant capabilities in bioprinters and biomaterials for the eventual production of transplantable organs.

The new "Big Three" of the 3D bioprinting industry as segment consolidates around main players exploring new materials and opportunities
3D bioprinted trachea model (Image courtesy of United Therapeutics)

These funds were used by the company’s founders to both develop its own proprietary technologies and acquire two traditional additive manufacturing market leaders and pioneers: ExOne, a specialist in ceramic, sand and metal additive manufacturing via binder jetting, and ETEC (formerly EnvisionTEC), the pioneer and leader in digital light projection (DLP) stereolithography technology, which is heavily used in the dental industry. ETEC also included another key technology, which it refers to as its 3D-Bioplotter business. All of ETEC’s dental business and the 3D-Bioplotter business have now been integrated into a division called Desktop Health.

“I personally find it fascinating seeing what researchers will do with it next,” said Carlos Carvalho, Team Leader Bioprinting Team at EnvisionTEC (now ETEC). He led the development of the fourth generation of the 3D-Bioplotter and has worked on the bioprinter since its infancy at the University of Freiburg in Germany. The EnvisionTEC bioprinter has also been used to fabricate parts using graphene, hyperelastic bone inks, ovary implants, a placenta model and is being used in bone regeneration research.

For the first 9 months of 2022, this resulted in net sales of MSEK 1,565.4, about $ 150 million USD, which corresponds to an increase of 112 % compared to the corresponding period during the previous year. In Q3 alone, BICO generated net sales of MSEK 550.6, about $30 million USD, which corresponds to an increase of 74 %, compared to the corresponding quarter previous year. CEO Erik Gatenholm said that “Given the change in the macroeconomic environment, we [BICO] have a firm focus on profitability and cash flow.” The company also reported that organic growth amounted to 28%, (12% in constant currency) and that “all business areas reported double-digit organic growth in constant currency”.

Recognizing that the research community is critical to developing breakthrough innovations in regenerative medicine, 3D Systems began by focusing on Research and Development, with the addition of Allevi in May 2021, providing a set of bioprinting solutions to both researchers and pharmaceutical industry giants in hundreds of labs globally.

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