Category Archive: Regenerative Medicine

  1. 3D bioprinting of cartilage for orthopaedic surgeons

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    Printing techniques and materials which have the potential in this research area

    Chondral and osteochondral lesions represent one of the most challenging scenarios for the orthopaedic surgeon and for the patient, as the current therapeutic strategies are not providing satisfactory results in restoring function or slowing the progression of osteoarthritis. Based on research outcomes in the recent years, tissue engineering seems to have the potential to address the issue of osteoarticular loss and provide a viable alternative to current treatments by applying 3d bioprinting techniques in the clinical environment.

    It is known that cartilage injuries cannot heal spontaneously, and that any type of repair will be characterised by fibrocartilage i.e. scar tissue. This tissue lacks properties such as resistance to shear and compression which make hyaline cartilage so distinctive, and in turn leads to degenerative changes and arthritis.

    Despite its simple appearance, cartilage is a tissue that is characterized by a composition exhibiting differences depending on the depth of the tissue, which makes it much complex than initially was thought.

    Which bioprinting techniques work for osteoarticular tissues?

    With the boom of 3D bioprinting, there has been widespread development of printers and additive manufacturing techniques, which allow the biofabrication of complex structures. These technologies include fused deposition modelling (FDM), stereolithography, extrusion printing, inkjet printing and laser-based techniques. With regards to cartilage regeneration, the hydrogel-based scaffolds are the main materials used due to their inherent compatibility with chondral tissue. Therefore, inkjet and extrusion printers are the most commonly used machines in cartilage tissue engineering. Having said this, it has been extrusion-based methods that have been most widely used in recent years. The popularity of this printing technique is most likely due to its simplicity, diversity, and predictability. Whilst in comparison to inkjet, for the moment extrusion-based bioprinting has lower speed and resolution, it offsets this by being able to offer advantages such as higher cell densities, a wider range of printable biomaterials (viscosity in the range of 30-6 x 107 mPa/s) and relatively inexpensive equipment.

    Featured materials for cartilage bioprinting

    Properties of bio-inks are also crucial for the development of functional living tissues such as cartilage by 3D bioprinting. Bio-inks based on the combination of scaffold and cells should satisfy biological features, biodegradability, and printability. Generally, available scaffold options for bio-inks are hydrogels, decellularized ECM (dECM) and microcarriers.

    Hydrogels are water-swellable, yet water-insoluble, cross-linked networks. Often these are naturally-derived polymers, in which the 3D environment provided is able to maintain a high-water content, which resembles biological tissues and facilitates cell proliferation. The only limitation of such hydrogels for tissue engineering might be their inability to maintain a uniform 3D structure. However, researchers have been able to overcome this problem by applying synthetic hydrogels or natural-synthetic hydrogels hybrids.

    Synthetic biocompatible polymers and peptides have been utilised to develop hydrogels for cartilage tissue engineering. Their properties can be controlled and custom-designed to match the requirements of a given cell type. This is especially true for peptide-based hydrogels., in which the physical and the biomimetic properties can be tailored.

    It has been proven that chondrocytes change their function and morphology based on the ECM. Therefore, being able to provide the appropriate ECM structure is considered paramount in cartilage tissue engineering.

    Peptide-based Hydrogel Inks

    Synthetic ECM mimics are increasingly being used as they can provide solutions to some of the issues that naturally-derived materials pose. The main benefit of synthetic hydrogels is consistency. There should be no batch to batch variations as they are produced using known quantities, optimised procedure, and generally the chemistry of the polymer does not change unless required. As they are synthetic, there are no components from animal-derived sources which is an important factor for cell culture and tissue engineering research with the ultimate aim of clinical applicability.

    BiogelxTMsynthetic 3D cell culture products have demonstrated the ability to improve the phenotype of chondrocytes differentiated from perivascular stem cells in the context of cartilage engineering. Based on these core products, Biogelx has designed a novel bioink family, which is printable at room temperature and do not require exposure to UV light, extreme temperature or pH changes.These new bioinks have been optimised for extrusion-based printing and are ideal for the development of cartilage bioprinting applications. The BiogelxTM-Ink products will be available from April. Watch this space for more info and details on the launch!

     

    Source:

    Roseti et.al. (2018) Three-Dimensional Bioprinting of Cartilage by the Use of Stem Cells: A Strategy to Improve Regeneration, Materials.

    Bella et.al. (2015) 3D Bioprinting of Cartilage for Orthopedic Surgeons: Reading between the Lines, PubMed. DOI: 10.3389/fsurg.2015.00039

    Derakhshanfar et.al. (2018) 3D bioprinting for biomedical devices and tissue engineering: A review of recent trends and advances, Bioactive Materials. volume 3, issue 2, page 144-156p, DOI: 10.1016/j.bioactmat.2017.11.008

     

     

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  2. Application of Biogelx hydrogels in 3d osteoarthritis in-vitro model

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    Interview with David Hughes

    David Hughes is one of our new Biogelx sponsored PhD students.His MRS funded project aims to develop a reproducible and easily manipulated 3D osteoarthritis in vitro model by using BiogelxTM peptide hydrogelsto examine bone and cartilage crosstalk in healthy and pathological ageing. In this interview, he speaks about his research and shares his hands-on experiences working with our products.

    1. Please tell us a little bit about yourself.

    I’m a PhD student from central Scotland with a keen interest in biomedical science; I originally undertook an undergraduate degree in Biology and Psychology. Due to my interest particularly in the biological side of my studies I then went on to pursue an MSc in Biomedical Science and Drug Design. This masters gave me an insight into tissue culture and its potential research value which lead me to where I am today. Outside of my studies I am a keen guitarist and play as part of a band.

    1. What research do you focus on?

    My research is focused on the development of a novel 3D model to investigate the crosstalk between bone and cartilage in osteoarthritis (OA). Currently there is no validated in vitromodel of the whole joint for OA research and the limitations posed by current 2D techniques necessitates the development of an appropriate 3D model that is more like the in vivoconditions. My PhD is funded by Medical Research Scotland in the lab of Dr Katherine Staines at Edinburgh Napier University.

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

     Synthetic 3D culture materials such as those produced by Biogelx, provide a reliable and reproducible platform that allows me to conduct a variety of techniques on my cells of interest. Importantly synthetic 3D culture systems help eliminate further factors introduced through the variability associated with the use of a biologic system.

    1. Have you tried any alternative materials? What are the key features of a good 3D cell culture?

    I have not tried any additional 3D culture materials; however, I believe that the key features of a good 3D cell culture system are biocompatibility, modifiability and ease of handling. These features can allow for the investigation of a broad spectrum of variables across a variety of cell types whilst allowing the researcher additional optimization options which can save time and provide financial benefits.

    1. How easy is to use Biogelx products?

    Biogelx products are very easy to use, it’s as simple as weighing a powder out, rehydrating it and then adding the cell culture media that contains divalent cations to promote cross-linkage. The resources required to do this are commonplace in biomedical laboratories, keeping the gel preparation process simple and accessible.

    1. What cell types do you use in your research? Please share your experience in growing cells in our gel(s). If you have any pictures that you can share, please do.

    My research is still in early stages – I’ve been working with chondrocytes in the gels and have had no issues so far. Chondrocytes are the cells found in the cartilage, which covers the ends of the bones in the joint. Preliminary imaging shows that the cells seeded on the gels take on the characteristic rounded chondrocyte shape associated with their in vivomorphology; chondrocytes plated in a monolayer do not display this and take on a fibroblast-like shape, which is not ideal for investigating these cells and their functions in vitro.

    1. What are the next steps in your research?

    The next steps in my research will involve characterising the morphology and molecular phenotype of the chondrocytes and comparing it between cells cultured in monolayers (2D) and in Biogelx hydrogels (3D). Following on from this I intend to conduct similar optimisation on cells from the other joint tissues, before looking to develop my 3D model which I will use to investigate the crosstalk between bone and cartilage in OA.

     

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    Would you like to collaborate with Biogelx?

     

  3. Biogelx are proud to continue working with ReMDO to apply advanced manufacturing to regenerative medicine.

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    The RegenMed Development Organization (ReMDO) is a non-profit organization that manages a consortium of more than 60 industry and academic members to advance regenerative medicine manufacturing technologies.

    In partnership with the US Army Medical Research & Materiel Command (USAMRMC), the Medical Technology Enterprise Consortium (MTEC) awarded ReMDO a five million, five-year programme to develop universal bioink with tunable mechanical properties for regenerative manufacturing of clinical products.

    Biogelx joined the ReMDO Advanced Biomanufacturing Initiative in 2017 and have been collaborating with other consortium members, such as Wake Forest Institute for Regenerative Medicine (WFIRM), to achieve the overall objective of this program. The aim is to formulate a base bioink with a modular cocktail of cross-linkers that can be used to tune the mechanical properties of the hydrogel, both for bioprinting, and for adjusting the final stiffness of the bioprinted construct to match the stiffness of native tissues, ensuring optimal cell survival and tissue construct function.

    Biogelx specializes in tunable peptide hydrogels and bioinks that can be configured to mimic specific tissue types, and are compatible with a range of 3D printing technology.

    For further information please see https://lnkd.in/gsWspS9

     

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  4. 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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  5. 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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