January 1, 2015 (Vol. 35, No. 1)
Laura Hockaday, Ph.D. postdoctoral scholar Tufts University
Fabricate a whole organ from scratch? Yes, some day. But until then, 3D bioprinting companies will stay focused on intermediate goals.
Structural complexity. Functional integration. Completeness. All these qualities are necessary in bioprinted organs. They are also necessary in the bioprinting industry, which is still emerging, little by little, much the way fabricated biomaterials emerge from the bioprinting process layer by layer.
In the bioprinting industry, inventors and entrepreneurs have settled on a piecemeal approach to commercialization. Although bioprinting’s players might like to “swing for the fences” and use 3D bioprinting to fabricate entire complex organs, they are currently playing “small ball.” Essentially, they are pursuing more easily achieved short-term goals, the way a baseball team might advance runners base by base instead of counting on home runs.
3D bioprinting, a frontier technology, is pressing against the limits of biological understanding, materials science, and engineering knowhow. Like any frontier technology, 3D bioprinting consists of a set of not-yet-standarized methods and relies on a high degree of troubleshooting. In addition, it struggles with an incomplete mechanistic understanding of both natural and engineered conditions.
3D bioprinting is not merely a matter of printing with living cells. Challenges that are particular to 3D bioprinting include:
- choosing materials compatible with different cell types.
- inclusion of growth and differentiation factors.
- construction of tissues with complex geometry and heterogeneity.
- fabrication timing and nutrient transport to keep what is printed alive.
While daunting, these challenges have not deterred intrepid companies from attempting to build a 3D bioprinting industry. These companies, however, are also being circumspect, as indicated by a recent shift in their bioprinting business models and product targets.
Less emphasis is being placed on the holy grail of bioprinting—the making of a functional whole organ from cell mixtures and biomaterials. Doing so seems too high a bar for an established company, let alone an insecure startup. After all, startups need to achieve tangible results in a time frame that will draw investment and provide a deliverable product.
In a recent Nature Biotechnology review, Gunjan Sinha observed that companies are instead pursuing the more short-term tangible goals of delivering printers and “inks” to researchers and providing small-scale engineered tissues for research and development and drug testing. To address wound healing and tissue repair, some bioprinting companies are manufacturing scaffold implants or are targeting partial/small graft tissues. These products face major regulatory hurdles and stringent manufacturing guidelines before they can be marketed.
In commercial bioprinting, which is currently focused on research and development, companies offer various kinds of printers. Broadly, there are laser-based printers, nozzle-based printers, inkjet printers, and printers that exploit spheroid manipulation.
Printers that are specifically adapted and customized for bioprinting represents a critical starter product for several companies. With the progression of bioprinting target products—bioprinters, tissues for pharma, small grafts and functional units (such as osteochondral plugs, blood vessels, heart valves, knee meniscus), and eventually whole organs—the level of difficulty, engineering, and regulation that will be required for the target to reach market increases.
The Table lists bioprinting companies and their current or projected products. A few companies founded around the time of the invention of 3D printing (1980s) now have divisions dedicated to developing bioprinting technologies. MicroFab Technologies and Advanced Solutions Life Sciences are two examples.
Several bioprinting companies were founded to commercialize technologies that originated in university laboratories. One of the newest, a University of Oxford spin-out called OxSyBio, was founded in April 2014. Organovo, Cyfuse Biomedical, TeVido BioDevices, Aspect Biosystems, and Seraph Robotics were all founded with technologies developed in university laboratories.
Printers and Tools
One product strategy is to provide printers, software, assessment tools, and ink for bioprinting. In this format, the company provides tools to be used in the development of biological assays or tissues. The researcher assumes the burdens of printing, troubleshooting, and biological exploration.
RegenHU, which has developed products from each of these four categories, is one example of this business model. RegenHU has two printers on the market, the Biofactory® and the 3DDiscovery®. It is marketing printable materials as consumables, a chemically defined hydrogel (Bioink™), and a calcium phosphate paste (Osteoink™). RegenHU sells a modeling software for generating printable geometries that is usable with their printers or stand alone (BioCAD®) and an optical biopsy device that can incorporate into the printing system to assess printed tissue (BioTrack®).
Additional companies targeting the bioprinter market include Seraph Robotics (Fab@Home Model 3); Regenovo Biotechnology (Regenovo); GeSim (BioScaffolder 2.1); Bio 3D Technologies (Life-Printer X); Rainbow Biosciences and Nano3D Biosciences (BiO Assay™); nScrypt (TE Tabletop Series 3D and 300 Series Micro Dispense Pump Machine); EnvisionTEC; DigiLab (CellJet); MicroFab Technologies (Jetlabs®, SphereJet™), and Advanced Solutions Life Sciences (BioAssemblyBot® printer and Tissue Structure Information Modeling® software).
Bioprinting platforms are being sold with different degrees of customization. Accessories can be sold separately; the printer can be sold as a single all in one package kit; or the printer can be built for the researcher’s individual needs.
Bioprinting Tissue for in Vitro Testing
A critical area of commercialization for bioprinting is providing living tissue for in vitro testing and drug screening. Testing drug toxicity and efficacy on animal subjects is expensive, ethically problematic, and does not always duplicate the effects seen in humans. Reducing or eliminating animal models from the process and better predicting efficacy and toxicity of drugs in humans would expedite progress. It would also lower the costs associated with drug discovery and development.
In January 2014, Organovo delivered samples of 3D-printed liver tissue product for outside testing. Then, in November 2014, the company announced the commercial release of liver tissues for preclinical drug discovery testing. The liver tissues are small and thin, and contain three different cell types.
Aspect Biosystems and Cyfuse Biomedical, appear to be pursuing a similar business strategy. Aspect Biosystems has defined a product goal to manufacture physiologically relevant 3D human tissue as a tool for preclinical drug discovery. Potential users include pharmaceutical companies and contract research organizations.
Cyfuse Biomedical makes a “bioprinter-like” technology (Reganova) that places spheroid cell aggregates onto an array of needle-like projections to secure them in place. The assembled spheroids are allowed to partially mature on the needle-like projections, before the assembled tissue is removed and further cultured. Like Organovo, Cyfuse Biomedical is developing a preclinical hepatocyte/liver tissues for toxicity testing. Cyfuse Biomedical’s website, however, indicates that this product is at a basic research stage of development.
3D Tissue Grafts and Scaffolds
A third 3D bioprinting commercialization area comprises medical implants and grafts. Implant products are subject to considerably more regulation than in vitro tissue models (some) or printing hardware (practically none).
Bone implant scaffolds are a major investigative target for researchers and commercial target for bioprinting companies. For example, Oxford Performance Materials recently obtained 510(k) clearance from the FDA for its selective laser-sintered 3D-printed OsteoFab™ Patient-Specific Cranial Device (OPSCD) (2013) and custom cheek and jaw bone reconstructive implants (2014).
To secure this clearance, the company had to validate its process, establish that its product is biocompatible and can be effectively sterilized, and demonstrate that its facility has sufficient cleanliness and design controls. In addition, the company had to show that it follows current Good Manufacturing Processes.
The company’s implants did not incorporate cells, and so the company was able to make the case that the polymer scaffold devices were substantially equivalent to an already legally marketed device. Following a similar regulatory path, Osteopore International (Osteoplug™ and Osteomesh™), a Singapore-based company, has advanced to the clinical stage with its 3D-printed biomaterial bone scaffolds implants. Such a path may also be followed by Tissue Regeneration Systems, Next 21 K.K., and RegenHU/Vivos Dental (OsteoFlux®). All offer 3D-printed bone scaffolds that lack cells.
Companies engaged in developing 3D-printed living tissue that are ultimately intended for implantation include Telvido, Cyfuse Biomedical, and OxSyBio. In TelVido’s target product, preadipocytes are printed into a custom graft for breast cancer reconstruction. Cyfuse Biomedical is focused on the development of two graft tissue products: one uses autologous mesenchymal stem cells to create a stem cell tissue plug that upon implantation can regenerate joint cartilage and subchondral bone, and the other is a blood vessel graft.
These products will likely fall into the category of an investigational new drug. As a result, they will probably follow a regulatory approval path similar to that of Tengion, which has two living tissue engineered products in clinical trials.
Recent Advances, Future Challenges
Critical research and development using 3D printers and improving the technology associated with bioprinting is ongoing at academic institutions. A report published about worldwide patenting activity for 3D printing technology by the UK Intellectual Property Office highlights the almost unexpected concentration of activity in academia.
In terms of patent assignee statistics, the traditional pattern following the birth of a given technological area is a shift from academic to corporate. In contrast, the applicant type for 3D printing patents is increasingly academic in recent years (from 2000 to 2012). Additionally, when the nonpatent literature (journal articles and conference proceedings) and the patent literature is analyzed, both show a high degree of interest in the biotechnological aspects of the field. The patents associated with the few example companies listed in the Table are effectively the very tip of the iceberg.
In a recent review, Sean Murphy and Anthony Atala highlighted six key areas where advances in biological and biophysical understanding are needed for 3D bioprinting to fully realize its potential in regenerative medicine. Research is needed to:
- enable bioprinter technology scale up and compatibility with physiologically relevant materials.
- characterize additional printable biomaterials and combinations.
- characterize cell source and tissue heterogeneity and control cell proliferation.
- enable vascularization and microvasculature throughout large tissues.
- enable innervation within engineered tissue.
- control maturation and mechanics and establish functionality prior to implantation.
Researchers are working to address these challenges. In 2014, researchers published numerous bioprinting investigations into vascularization; exploration of printable materials and subsequent cellular response; strategies to control cells expansion and loading into printable materials; and controlling and understanding tissue heterogeneity. Ultimately, there is more to come from both academic and industrial researchers on the bioprinting front, and these advances may enable broader commercialization and application of bioprinting.
Laura Hockaday, Ph.D. ([email protected]), is a postdoctoral scholar at Tufts University, Biomedical Engineering Department, Catherine Kuo Laboratory.