Category Archive: 3D Bioprinting

  1. Why is the application of 3D Bioprinting important in Drug Development?

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    Drug development is a time-consuming and expensive process that proceeds through several stages from target identification to lead discovery and optimization, preclinical validation, and clinical trials, ending up in approval for clinical use. It is well known that 90 percent of drugs that reach clinical stage development never make it to FDA approval and commercialization. The cost of a failed drug is between $800m and £1.4bn. With this low success rate in clinical trials, drug discovery remains a slow and costly business. Hence, there is an urgent need for new technologies which can mitigate the risk of failures.

    3D bioprinting is one of the most promising areas expected to improve the success rates in drug development. Whilst most people start to imagine printed human organs for transplanting into the patients when they hear the word bioprinting, in realitywe probably won’t see 3D printed, transplantable human organs for many years yet. Internal organs are more complex than simply printing layers of cells into the shape of a kidney or liver. They need to have nerves and blood vessels to function and survive, and bioprinting technology still has a way to go before reaching the required level of complexity.

    The most realistic application of 3D Bioprinting in this decade will most likely be  in drug discovery and development. In the pharma industry, the companies test drugs on animals before the drugs go to expensive clinical trials. However, the human physiology is very different from that of test animals, so what works in an animal, will not necessarily be effective in a person.

    Bioprinting can be used to print a range of 3D culture systems and human tissue models to produce better in vitro testing by generating models with improved physiological relevance and high reproducibility. By applying bioprinting in drug discovery and development organisations can identify ineffective or harmful drugs earlier in the discovery process and shift their resources to more promising drug candidates. They can also reduce the cost of drug development caused by clinical trial failures.

    Organovo’s bioprinted ExVive liver tissues have already proven useful in preclinical toxicology assessment. According to Organovo, the market for liver and kidney in vivo tissue testing is currently valued at close to $3 billion combined1. 3D bioprinting has also been shown to enable the investigation of cancer progression, including tumour heterogeneity, cancer metastasis, and patient specific anticancer drug testing. As bioprinting proves to be a cost-effective and efficient solution, its value in this field is expected to grow from the current $11 million to several hundred millions of dollars over the next decade1.

     

    1SmartTechMarkets (2017) Use Of 3D Bioprinting In Drug Discovery And Cosmetics Testing Expected To Reach $500 Million By 2027 [link]

     

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  2. The key questions of the 3D printed organ market

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    The technology challanges, regulation, and supply chain.

    Currently, 3D bioprinting research focuses on drug discovery and toxicity applications (in vitro), or tissue and organ modeling (in vivo). There are research projects focussed on bioprinted 3D tumor models, which mimic the actual tumor environment, or projects which aim to create realistic 3D tissue constructs with the potential to implant them in the human body in future clinical applications. However, setting up bioprinters in healthcare organisations and printing transplantable organs is still far from today.

    At present, the bioprinting of fully functional complex internal organs, such as hearts, kidneys, and livers, is still far away. One of the limiting factors in achieving 3D printed organs for transplant is the size. Currently, researchers can create miniaturized tissue resembling natural tissue, but many of these constructs are not capable of achieving a therapeutic impact due to their small size.

    The other key issue is the complex network of cells, tissues, nerves, and structures in a human organ. They need to be positioned with the highest precision so that the organ functions properly. Currently, we do not have the technology to precisely blueprint these complex networks using different materials, cell types and bio-inks in the same final structure.

    The technology challenges being faced by the bioprinted industry

    There are three key challenges of bioprinting: the printer technology, the biomaterials, and the vasculature of the printed construct.

    Bioprinter technologiesneed to increase resolution and speed and should be compatible with a wide spectrum of biocompatible materials. Higher resolution will enable better control in the 3D microenvironment.

    Biomaterials are undoubtedly the primary limitation of this technology. Today, we are limited to several biocompatible natural and synthetic bio-inks. Natural bio-inksprovide an excellent microenvironment capable of mimicking the native ECM, while thesynthetic materials provide good mechanical strength and can be modified to promote cell attachment, proliferation, and differentiation. The ideal would be a biocompatible, synthetic, modifiable and modular system. A base material in which mechanical properties can be easily adapted for the chosen additive method and then formulated for each specific cell type or multiple cell types involved in the end application.

    Finally, there is a fundamental challenge with the vasculature of the printed construct. In vivo, the tissue is continually fed by sufficient oxygen and nutrients.If the tissue is constructed using a bioprinter, then it also needs a vascular system. Diffusion by itself will only work up to 150-micrometer thickness. Beyond this thickness, the tissue will not develop properly. Though researchers have made significant advancements in understanding the processes involved in vascular development and function, we do not yet have sufficient knowledge to recreate vascular structures in vitro. If we hope to understand the complex biology of in vivosystems, we must find ways to recapitulate in vitro the major architectural features found in living organisms, particularly multi‐scale, branched vasculature and the associated convective and diffusive transport.

    The regulations of bioprinted products in clinical applications

    At the moment there are no regulations for bioprinting applied to research applications. However, bioprinted regenerative medicine products used in clinical applications will need to satisfy FDA and or GMC regulatory oversight in the future. The regulators have an active program for assessing and evaluating bioprinting in order to develop future regulations for bioprinting applications in the clinic.

    Building on guidance published by the FDA detailing a list of what is not considered a human organ, there is an assumption that the 3D printed organs will not be regulated as human organs for transplantation. Although regulations cannot reflect a class of product that does not yet exist,  the market players think that 3D printed organs will be more likely to be regulated as a drug, device, and or biological product.

    In the clinical environment, the challenge will be associated with the manufacturing process and costs. Today, there are two FDA regulations that outline the minimum production requirements in clinical products. These are the Good Manufacturing Practices (cGMPs) and Good Tissue Practices (cGTPs). The cGMPs are applicable to the facilities that print the organs. The cGTPs are applicable to the facilities that extract and handle the biopsied human cells. These regulations will need to be applied by the healthcare organisations that wish to print human organs in-house. The set up of these production lines can be costly, which might raise the question of the development of such 3D bioprinting-centers.

    The supply chains in bioprinted organ  market will work differently

    Currently, the major end-users of bioprinting technologies are the universities and research institutes. In addition, we also see cosmetic and pharmaceutical companies establishing internal research groups with a focus on bioprinting applications. Howeves, in the future, it is anticipated that healthcare organisations, clinicians and patients will also play a role.

    Thus, whilst today the supply chains work similar to other life science products, industry players expect to see rapid transformation of the procurement strategies as this bioprinting market develops. Healthcare organisations will restructure their tender specifications with a special focus on service and or performance-based logic. Furthermore, the market might also consider the creation of public hubs for 3D bioprinting at the regional level. Since the application of bioprinting technologies to evolve organ supply chains can offer healthcare organisations strong value and a competitive advantage.

     

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  3. Changing the future of medicine with 3D Bioprinting

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    The creation of artificial human tissues and organs may sound like a futuristic dream, but it is happening right now. Research institutes and hospitals around the globe have been working on bioprinting applications, which are providing new options for treatment and scientific study. Potentially, 3d bioprinting will be the next big thing in health care and personalised medicine.

    The idea of printing human organs, has its origins  in the invention of stereolithography in 1983. This special type of 3D printing relied on a laser to solidify a polymer material extruded from a nozzle. However, the material used in this process was not robust enough to create a long-lasting structure. By the early 1990s, the next generation of materials was introduced. Called nanocomposites, they were blends of plastics and powdered metals. These materials were more durable. They made possible the scientist to produce longer lasting end-products.

    It did not take long for medical researchers to notice the protentional of such materials and 3d printing technology in clinical application. In 1999, scientists at the Wake Forest Institute for Regenerative Medicine used a 3D printer to build a synthetic scaffold of a human bladder. They then coated the scaffold with cells taken from their patients and successfully grew working organs. This set the stage for true bioprinting. In 2002, scientists printed a miniature functional kidney capable of filtering blood and producing urine in an animal model. And in 2010,Organovo printed the first blood vessel. Today, 3d bioprinting companies like Cellink, Allevi , Regemat or SunP are focusing on printer and living inks development to provide future opportunities for complex organ printing.

    Within bioprinting, there are three main technologies, namely inkjet, extrusion, and laser-assisted printing. Inkjet printers possess a print-head that generates a pressure pulse (either thermally or acoustically) that forces droplets from the nozzle. Laser-assisted printers use pressure generated by a laser to propel cell-containing material from an absorbing substrate onto a collect substrate. Finally, and most commonly used, are extrusion printers that use pneumatic or mechanical piston/screw dispensing systems to extrude continuous beads of bio-ink.

    There are also different biomaterials which are reported as bioinks for 3D bioprinting. They are the Agarose-based, Alginate-based, Collagen-based, Hyaluonic acid-based, Fibrin-based, Cellulose-based, Silk-based and Synthetic biomaterials. Each class of bioink has pros and cons, however, they have a common requirement for control of mechanical and biological properties of the printable material.In terms of mechanical control, it is imperative that the bioink forms a microstructure which mimics that of the cell’s native environment. As well as a familiar architecture, the gel stiffness and porosity should be matched to that found in vivo so as to support cell growth, signalling, and proliferation. Ideally, the bioink will exhibit shear-thinning behaviour, as this will reduce the stress exerted on the cells during the printing process, which most commonly involves extrusion of the bioink through a narrow print-head. In order to assure biocompatibility, the raw materials used for the production of the bioink should not be cytotoxic to the cells in question, nor elicit an immune or inflammatory response.

    Using a combination of the right printing process and bioink, researchers have already been printing bone and skin tissues in the labs. Whilst work towards the bioprinting of more complex internal organs, such as the liver, is happening today in research labs all across the world,  it is anticipated that  fully functioning lab grown versions of these are still at least 10 years away, possibly more.

     

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  4. Next Stop Mars: Applying bioprinting and regenerative medicine in Space

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    3D bioprinting is a highly promising technique in the field of medicine. The technology is being used to in a range of 3D cell culture applications, from research projects developing bioprinted 3D tumor models, which better mimic the actual tumor environment, to projects which aim to create realistic 3D tissue constructs with the potential to implant them to the human body in future clinical applications. Whilst the concept of printing body parts here on Earth may seem far-fetched enough to some, and in reality is still a while away, there are some researchers taking this concept to the next level, and considering the clinical applications of bioprinting in space.

    A Study on the Survivability and Adaptation of Humans to Long-Duration Exploratory Missions (HUMEX) discusses the potential health-related issues including survivability and adaptation of astronauts undertaking long-duration missions. The study highlights the effects of cosmic radiation, reduced gravity on Moon and Mars, gravity changes during launch, and related psychological health issues. Let’s imagine a one hundred and eighty days stay on the Moon with a crew size of four. Getting medical attention to the traveling crew is nearly impossible. Communication of medical instructions via IT and telecommunications technology (telemedicine), will be difficult due to the communication delay on deep space missions. In the event of a medical emergency, a rapid return home will not be feasible. Therefore, the patients will have to be treated on the spot. To find a solution for this issue, scientists are evaluating the feasibility of technologies such as 3D bioprinting in future exploration missions.

    Doing 3D bioprinting in space, like on Earth, requires careful control of the extrusion process and control of the machine’s operating temperatures. However, the microgravity environment lacks the convection we are accustomed to here on Earth. Hence, we have to develop specific printing systems and bioinks which are able to perform in a microgravity environment.

    To alleviate the issues caused by the specific space environment, a strategic partnership has been developed between the bioprinter company Allevi and Made in Space. The strategic alliance has designed a printer, which is capable of printing biomaterials in microgravity. The project aims to place this machine aboard the International Space Station (ISS), and could be considered the first step toward those scenes of sci-fi medicine.

    There is also a project lead by the European Space Agency (ESA), which intends to advance 3D bioprinting to the level where it becomes possible to 3D print skin, bones and organs.

    The human organ has a complex network of cells, tissues, nerves, and structures. They need to be positioned with the highest precision so that the organ functions properly. Currently, we do not have the technology to precisely blueprint these complex networks using different materials, cell types and bio-inks in the same final structure. Companies like Organovo are working hard to meet this challenge.

    Although the printer technology and printing processes will be key to bioprinting in space, the biggest hurdle may still be the materials. Although the printer technology and printing processes will be key in developing bioprinting technology for space travel, another hurdle will still be the materials. In the future, if a medical emergency arises on a space mission where bioprinting could provide an immediate solution, access to reproducible bioinks with high biocompatibility and consistent printability could be vital.

     

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  5. Application of Biogelx synthetic hydrogels for osteogenic stimulation | Interview with Álvaro Sánchez Rubio

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    Álvaro Sánchez Rubio is one of our new Biogelx sponsored PhD students! His MRS funded project aims to apply novel synthetic hydrogels for osteogenic stimulation and to demonstrate their value for tissue engineering and bone repair. In this interview, he speaks about his research and shares his hands-on experiences working with our new BiogelxTM-Ink.

    1. Please tell us a little bit about yourself.

    My name is Álvaro. I was born and raised in Valencia, Spain which is still very close to my heart. Later I moved to Barcelona to study Biomedical Engineering. The opportunity to be educated in different cities allowed me to be involved with hospitals and laboratories in numerous geographical locations. I have found particularly interesting how technology and biology can intersect and provide opportunities for future developments in the healthcare field.

    I have a research interest in 3d bioprinting. I have been using 3D printing technology for 5-years. Currently, I am conducting Ph.D. research which focuses on the application of 3d bioprinting in bone regeneration.

    1. What research does you/your lab focus on? 

    Our lab is a highly interdisciplinary lab that focuses on understanding the interaction between materials, proteins, and cells to engineer and control cell behaviour and stem cell differentiation. Recently the institute’s bone tissue regeneration project has been shortlisted in the “Research Project of the Year: STEM” awarded by Research Impact and Times Higher Education.

    My research aims to investigate a system that can be used to obtain 3D printed cell-laden microarchitectures that mimic complex structures found in native bone. It includes investigating the effects of different materials, cell types and printing approaches.

    1. Why is it so important to use synthetic 3D hydrogels in your research? 

    Using synthetic hydrogels allows me to mitigate the risk of cross-contamination in my research, which is a possibility with animal-derived material. It is also an advantage of these materials that their physicochemical properties can be tuned, and their production is scalable.

    Speaking specifically about BiogelxTM peptide hydrogels, I would highlight their tunable stiffness by just changing the concentration. This key differentiator of these products is of paramount importance to me because the different stiffness matrices can control stem cells fate. Another important feature of BiogelxTM gels is that they are printable.

    One of the main benefits of 3D bioprinting technology is that the scientists can print computer-generated predesigned architectures allowing us to tailor specific scaffolds to patients or applications. Today, we have many different materials used in 3D bioprinting. However often they only provide a structural support which needs further processing to include the cells. By utilizing novel bio-ink materials like BiogelxTM, we can print cell-laden scaffolds that include homogeneous cell distribution within the printed architecture. This technology also allows us to create multi-material structures included the distribution of different cell types and different bio-inks.

    1. Have you tried any alternative bio-inks? What are the key features of a good bio-ink? 

    Yes, as I mentioned I have been working with 3d bioprinting technology for 5-years. Therefore, I have experience working with different bio-ink products available on the market. For my early work in 3D bioprinting, I used alginate bio-inks. I could print simple architectures, and the cellular behaviour was also sufficient. However, I found it to be insufficient to create complex microarchitectures.

    My opinion is that a good bio-ink have to provide a balance between biocompatibility, printer compatibility, convenient crosslinking method, appropriate degradation dynamics, and non-toxicity. Cost and availability also need to be considered. Nevertheless, different cell type may prefer different bio-inks, therefore the features of a good bio-ink may vary amongst different cell types.

    1. How easy is to use BiogelxTM-Ink?

    It is very easy to use BiogelxTM products. It might be one of the main advantages of BiogelxTM peptide hydrogels. The product preparation protocol is easy to follow. The hydrated pre-gel solution is obtained by adding water to the lyophilized powder. The BiogelxTM-Ink formulations are also very similar. When you print with Inks, you notice good shear-thinning behaviour. The viscosity of these materials allows you to see a nice 3D printed thread that does not have excessive lateral diffusion. The format the products are supplied in is also helpful. It ensures a higher control over the stock and contamination issues which can occur by using big pots or leaving them open for longer times.

    1. What cell types do you use in your research? Please share your experience in growing cells in our gel(s)/bioink.

    I am currently working with C2C12, an immortalized mouse myoblast line. They have been extensively used for research in muscle regeneration and are less expensive cells when compared with stem cells. However, I also plant to move onto to working with stem cells as well as some other cell types during my PhD project.

    When adding cells in 3D cultures using BiogelxTM products, you can obtain a homogeneous distribution of cells, which is crucial as having different cell densities will affect the result and make the process unreproducible.

    1. What are the next steps in your research?

    I just started my research; thus, I have a long way ahead. My aim in the first year is to develop a 3D bioprinting protocol that can be used, repeated and reproduced with robustness. I am also focusing on the exploration of how different cell types can be combined with the printing processes. I will use C2C12 or other fibroblast line and start some work along with Mesenchymal Stem Cells and HUVEC cells.

     

    The new BiogelxTM-Ink will be commercially available from next year. Watch this space for more info and details on the launch!

     

     

     

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