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  1. 3D BIOPRINTING: PRINCIPLE, TECHNIQUES AND IT’S APPLICATION IN HUMAN THERAPY Presented By: Akshita Dholakiya B.Pharm SMT R.D. Gardi B.Pharmacy College Nyara, Rajkot
  2. Content Dr. R.D Gardi B.Pharmacy college nyara, Rajkot 2 Application of 3D Bioprinting Types of Bioink Used In 3D Bioprinting 3D Bioprinting Techniques Basic Principal of 3D Bioprinting History of 3D Bioprinting Introduction Challenges And Future Perspective
  3. • 3D bioprinting is an additive manufacturing process where organic and biological materials such as living cells and nutrients are combined to create artificial structures that imitate natural human tissues. • In other words, bioprinting is a type of 3D printing that can potentially produce anything from bone tissue and blood vessels to living tissues for various medical applications, including tissue engineering and drug testing and development. • THE FIRST INTERNATIONAL WORKSHOP on Bioprinting and Biopatterning was held at the University of Manchester (United Kingdom) in September 2004 and was organized by Dr. Douglas B. Chrisey , Dr. Richard K. Everett and Dr.Nuno Reis. 1 Dr. R.D Gardi B.Pharmacy college nyara, Rajkot Introduction
  4. Dr. R.D Gardi B.Pharmacy college nyara, Rajkot 4 • In the early 1980s, Charles Hull created 3D printing, often known as "stereolithography."Hull, who has a bachelor's degree in engineering physics, was employed by the California company Ultra Violet Products to create plastic items out of photopolymers. • Stereolithography interprets the information in a CAD file using the STL file format, enabling these instructions to be sent electronically to the 3D printer. The file's instructions could additionally specify the colour, texture, shape and thickness of the printed object. History of 3D Bioprinting
  5. Dr. R.D Gardi B.Pharmacy college nyara, Rajkot 5 2.Autonomous self assembly, 1.Biomimicry or biomimetics 3.Mini-tissue building blocks • The base of 3D bioprinting is the layer-by-layer exact positioning of biological constituents, biochemicals, and living cells. • The process of 3D bioprinting is based on three distinct approaches: Basic Principal of 3D Bioprinting
  6. Dr. R.D Gardi B.Pharmacy college nyara, Rajkot 6 3D Bioprinting Techniques • Highly functional 3D structures have been constructed using a range of 3D bioprinting processes, including extrusion- based, light-assisted, and inkjet-based printing systems. These systems frequently use computer-aided design and computer-aided manufacturing to create 3D structures with great accuracy. 1. Extrusion-based bioprinting The most popular 3D bioprinting technique is extrusion. Extrusion-based bioprinting uses pressures that are driven by air, screws, and pistons to dispense the cells that contain the bioink through a nozzle. 1. .
  7. 2. Light-assisted Bioprinting • Light-assisted printing also called as laser-assisted bioprinting is a bioprinting technique that uses light to solidify a photocurable bioink. Dr. R.D Gardi B.Pharmacy college nyara, Rajkot 5
  8. 3. Inkjet-based Bioprinting  The first bioprinting study, known as inkjet-based printing, disperses cells and biomaterials to create 2D live cell patterns using a modified office inkjet printer. This bioprinting technique can produce and precisely apply picoliter amounts of bioink (1–100 pL) to a substrate. Dr. R.D Gardi B.Pharmacy college nyara, Rajkot 8
  9. 7 Dr. R.D Gardi B.Pharmacy college nyara, Rajkot 1. Cell-Laden Hydrogel Bioink As they are simple to create for extrusion-based, droplet-based (inkjet), and laser-based bioprinting methods, cell-laden hydrogels are the most widely used bioinks. Formulations for cell-laden hydrogel bioinks use a combination of natural and synthetic hydrogels, including agarose, alginate, chitosan, collagen, gelatin, fibrin, and hyaluronic acid, PGA. Types of Bioinks Used In Bioprinting • The ideal bioink formulation should satisfy certain material and biological requirements. Material properties are printability, mechanics.
  10. • Synthetic hydrogels often have good mechanical qualities in comparison to natural hydrogels. In order to generate cross-linking (chemical- and/or photo-cross-linking) or extra bioactivity 8 Dr. R.D Gardi B.Pharmacy college nyara, Rajkot
  11. 9 Dr. R.D Gardi B.Pharmacy college nyara, Rajkot 2. Cell Suspension Bioink • Modified inkjet printers have long been used to print cells into cellular assemblies. For instance, endothelial cells were printed from cell suspension in growth media. • The bioink formulation undergoes a fully biological self-assembly without or in the presence of a temporary support layer. This technique relies on tissue liquidity and fusion, which allow cells to self-assemble and fuse due to cell–cell interactions
  12. 3. dECM-Based Bioink • Decellularized extracellular matrix-based bioinks include eliminating the cells from a tissue of interest while leaving the ECM in place. To create the bioink, the ECM is then ground into a powder and soaked in a buffer solution that is favourable to cells. 10 Dr. R.D Gardi B.Pharmacy college nyara, Rajkot
  13. • Today, 3D bioprinting is successfully used in a variety of tissue engineering and regenerative medicine applications, including the creation of disease models from hard tissue and soft tissue. 1. Biofabricated in vitro models for studying infectious diseases  Organoids Organoids, made up of many cell types, have been designed to morphologically and functionally reproduce human organs. Human organoids have been effectively used in recent years to identify the pathophysiology following either bacterial or viral infection due to this advantage Human proximal airway organoids have shown their capacity to distinguish between the poorly human-infecting viruses, such as the avian- infecting influenza virus and the swine- infecting influenza virus, and the human infecting influenza virus. 13 Dr. R.D Gardi B.Pharmacy college nyara, Rajkot Application of 3D Bioprinting
  14. 14 Dr. R.D Gardi B.Pharmacy college nyara, Rajkot  Microfluidic organs-on-chip • Numerous organ types have been studied for infectious disorders using microfluidic organs-on-chips. • Hepatitis B virus infection was studied using a human liver-on-a-chip to replicate hepatocyte organization on liver sinusoids using a microfluidic recirculation system.
  15. 2. 3D Bioprinted cell and drug delivery system • Due to the limited solubility of the majority of chemotherapy medicines, such as 5-fluorouracil, paclitaxel, and cisplatin, the necessary drug concentration cannot be delivered to the infected site using traditional medication approaches (such as intravenous injection and oral medication). Even worse, the systemic toxicity and post-infusion cytokine release syndrome of such medications harm the entire organism.  Cell delivery system In addition to the development of cell encapsulated scaffolds in tissue engineering studies, there are some macrophage- and antibiotic-laden delivery systems that reduce infection after surgery. Aldrich et al. presented a 3D printed composite scaffold with antibacterial efficacy for treating bone infections after craniotomy 15 Dr. R.D Gardi B.Pharmacy college nyara, Rajkot
  16. 16 Dr. R.D Gardi B.Pharmacy college nyara, Rajkot  Sustained drug release system Systems loaded with antibiotic medications are also necessary following internal organ surgeries. Various geometries of the administration site were used to produce the polymeric patch.
  17.  Aerosolized delivery system • Non-invasive mucosal administration of biologics has been developed along with local direct delivery at the surgical site. A 3D-printed MucoJet device was created by Aranet et al. for oral vaccination. 17 Dr. R.D Gardi B.Pharmacy college nyara, Rajkot
  18. 3. Bioprinting in engineering vaccines and therapeutics • Vaccines are biological agents that stimulate the immune system to defend against contagious germs and viruses. The best medical strategy for preventing and managing infectious diseases at the moment is vaccination. There are typically three types of vaccines: nucleic acid vaccines, subunit/conjugate vaccines, and whole-pathogen vaccines.  RNA printer (CureVac) • A proof-of-concept for the mRNA printing facility has been created for pandemic responses, allowing for the quick formulation and delivery of vaccines. The idea is that the RNA printer would create a vaccine that is ready for use in a clinic after the creation and validation of several RNA vaccines CureVac, a pioneer in mRNA printing technologies, creates mRNA vaccines for a variety of viral illnesses, such as yellow fever, Lassa fever, MERS, and COVID-19 using traditional production techniques. 18 Dr. R.D Gardi B.Pharmacy college nyara, Rajkot
  19. 19 Dr. R.D Gardi B.Pharmacy college nyara, Rajkot  Drug printer • The pharmaceutical industry adopted 3D printing in the hopes of creating patient-centered dosages based on structural designs. The controlled release characteristics of the 3D printed tablets allowed patients to take less amounts more frequently as part of their regular routine. • Aprecia Pharmaceuticals reformulated the anti-epileptic medication levetiracetam, named Spritam.The first 3D printed tablets that disintegrate within seconds in an aqueous solution were developed through a proprietary powder bed and inkjet 3D printing technology known as Zip Dose.
  20. 4. In tissue engineering and regenerative medicine • Patients with valvular heart disease frequently need to have their valves replaced, either mechanically or biologically. However, problems like mechanical failure and calcification are usually connected to these prosthetic valves. As a result, a variety of strategies, including the application of bioprinting technology, have been suggested to enhance the results. Dr. R.D Gardi B.Pharmacy college nyara, Rajkot 20 Blood vessel construct fabricated by extrusion-based bioprinting
  21. • The skin is another area where bioprinting technology has been found to use. In one work, a jetting-based bioprinter was used to produce biomimetic multilayered skin tissue made of keratinocytes and fibroblasts. • In a similar, we have created an in situ skin printer that can print skin cells directly onto the body to treat severe burn wounds. We were able to repair pigs' full-thickness wounds using this skin printer by supplying keratinocytes and fibroblasts, and the wounds quickly reepithelialized and healed more quickly. Dr. R.D Gardi B.Pharmacy college nyara, Rajkot 21 Confocal microscopic image of multilayered skin structure fabricated by jetting-.based bioprinting
  22. • The most difficult aspects of 3D bioprinting are finding the right materials and providing the cells with enough nutrients, which has slowed down the development of this technology for years.  Material selection • Based on the method of manufacturing, the various biomaterials used in 3D bioprinting can be broadly divided into two categories natural polymers like collagen, chitosan, and hyaluronic acid, and synthetic polymers like polylactic acid (PLA), polyglycolic acid (PGA), and poly(lactic-co-glycolic acid) (PLGA). Dr. R.D Gardi B.Pharmacy college nyara, Rajkot 22 Challenges
  23. • Natural biopolymers typically perform poorly in terms of mechanical properties despite having strong biocompatibility, which allows them to attain the needed formability as a single printed material Synthetic biopolymers, in contrast, typically have poor biocompatibility and good formability.  Nutrient supply • The inability to create an effective microvasculature is now a challenging issue in the creation of in vitro large-size organs, making it challenging to provide nutrition to the cells in the interior region of the constructed organ. • One modern technique involves creating some channels inside the bio-fabricated organs, provided adequate nutrients across them to simulate vasculature, and then injecting endothelial cells, smooth muscle cells, or fibroblast cells to create vascular structures However, there is still a ways to go before we have fully vascularized structures. Dr. R.D Gardi B.Pharmacy college nyara, Rajkot 23
  24. • There have been great advances on bioprinting technologies. Future work would be the development of facile and portable bioprinting devices that can be used in clinical settings. For example, a handheld printer was recently developed for the fabrication of skin tissues. • The device was easy to operate and capable of printing multimaterial bioinks. Bioprinting technologies can also be adapted to do in situ bioprinting. A recent example showed a laser-assisted bioprinting for in situ bioprinting of mesenchymal stromal cells in collagen and hydroxyapatite for bone tissue regeneration. Dr. R.D Gardi B.Pharmacy college nyara, Rajkot 24 Future perspective handheld printer
  25. • The most advanced 3D printing application that is anticipated is the bioprinting of complex organs. It has been estimated that we are less than 20 years from a fully functioning printable heart. • Although, due to challenges in printing vascular networks, the reality of printed organs is still some way off, the progress that has been made is promising. As the technology advances, it is expected that complex heterogeneous tissues, such as liver and kidney tissues, will be fabricated successfully Dr. R.D Gardi B.Pharmacy college nyara, Rajkot 25
  26. 1. Guillemot F, Mironov V and Nakamura M, Bioprinting is coming of age: report from the International Conference on Bioprinting and Biofabrication in Bordeaux (3B'09). Biofabrication, vol.2(1): 010201 (2010). 2. Saunders, R. E. & Derby, B. Inkjet printing biomaterials for tissue engineering: bioprinting. Int. Mater. Rev. 59, 430–448 (2014). 3. Norotte, C., Marga, F. S., Niklason, L. E., and Forgacs, G. Scaffold-free vascular tissue engineering using bioprinting. Biomaterials 30, 5910–5917 (2009). 4. Karve, S. S., Pradhan, S., Ward, D. V. & Weiss, A. A. Intestinal organoids model human responses to infection by commensal and Shiga toxin producing Escherichia coli. PLoS ONE 12, e0178966 (2017). 5. Burdick, J. A., and Prestwich, G. D. Hyaluronic acid hydrogels for biomedical applications. Adv. Mater. Weinheim 23, H41–H56. doi:10.1002/ adma.201003963 (2011). 6. Ortega-Prieto, A. M. et al. 3D microfluidic liver cultures as a physiological preclinical tool for hepatitis B virus infection. Nat. Commun. 9, 682 (2018). Dr. R.D Gardi B.Pharmacy college nyara, Rajkot 26 Reference
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