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Archive for the ‘3D Plotting Scaffolds’ Category

3D printing: Improvising the Next-generation Batteries

Reporter: Vaishnavee Joshi BSc and MSc.

Batteries are the building blocks of 21st-century technology; it has been with us for a long time. The true significance of the batteries can be traced down to the 1800s when the first true battery was invented by the Italian physicist Alessandro Volta. With the pace of time and invention, many great contributions were made in the production and advancement of batteries. The two great leaps that are a first great leap forward:

  • Lithium-ion batteries and second leap forward:
  • Nanotechnology, completely transformed the production.

What began as an experiment, developed as an indispensable item in our world.

Dawn of 3-D printing technology

Astonishingly, the rapid growth in high throughput computer-aided technology and the earliest 3D printing manufacturing equipment which was developed by Hideo Kodama increased the development of three broad types of 3D manufacturing technologies that is :

  • Sintering,
  • Melting
  • Stereolithography.

3-D printing, also known as additive manufacturing is a method of creating a 3D object layer by layer using a computer created design since the last decade 3D printed batteries have been an area of interest for both consumer electronics and electric vehicles. The benefit of 3D printing of batteries are that the production of batteries is flexible, customizable for one particular application and printing can save weight or reduce mass, and even higher energy densities can be achieved by transforming the internal topologies. Production and research in 3D printing technologies are at their highest peaks in Asia and America many American firms considers battery 3D printing to be a publicly traded U.S branch.

Blackstone Resources AG(Swx: BLS) is a Swiss holding company focused on battery technology and metals they are creating processes tagged as Blackstone thick layer technology for 3D printing lithium-ion batteries. The patented process can fabricate both electrolyte and solid-state batteries and also cutting the expenditure by 70  percent the other demonstrated organizations that are located at Canada, Peru, Mongolia. It also claims to have begun exploring several minerals

https://www.blackstoneresources.ch/activities/battery-technology/lack

Sakuu Corporation

A bay area start up that developed a unique Blackstone thick layer technology that process and combines materials such as ceramics and metals for a variety of applications. It also claims that the production of lithium SSBs can be manufactured at scale using its multi-material multi-method (4M) technology. it uses standard cathode materials but in the future, it will also feature higher voltage cathodes with the potential of 25 % more energy the firms also states that “They are focused on finishing the platform that can do it.

We are working in parallel with all of the battery chemistry and everything else

Blackstone and Sakuu are some of many firms that are competing in re-creating and patenting the 3D printing methods. Nevertheless, the 4M technology of Sakuu holds a promising future in the world of lithium batteries with this elixir the applications are immense and beyond the scope.   

SOURCES

First Lithium Solid State Battery Produced by 3D Printing Startup Sakuu

2. Battery 3D printing firm considers publicly traded U.S. branch. June 22,20121, Michael Molitch-Hou, 3D printing. LIVE

3. 3D printed batteries: here comes the future. August 10, 2020, Jeff Butler.

4. The history and development of batteries. April 30, 2015, Jose Alarco and Peter Talbot

https://phys.org/news/2015-04-history-batteries.html

5. Sakuu to Release Multi-Material, Multi-Process Battery 3D Printer

3dprint.com/281555/sakuu-to-release-multi-material-multi-process-3d-printer-for-fabricating-e-mobility-batteries/

Other related articles published in this Open Access Online Scientific Journal include the following:

Series E, Volume Four: Medical 3D BioPrinting – The Revolution in Medicine, Technologies for Patient-centered Medicine: From R&D in Biologics to New Medical Devices

Editors: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Available on Kindle Store @ Amazon.com since 12/30/2017

  • Volume 4: Medical 3D BioPrinting – The Revolution in Medicine, Technologies for Patient-centered Medicine: From R&D in Biologics to New Medical Devices. On Amazon.com since 12/30/2017

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Philly Biotech Scene: Biobots and 3D Bioprinting (Now Called Allevi)

Reporter: Stephen J. Williams, Ph.D.

Biobots now known as Allevi, Inc..  Their new Biobots community has been renamed Allevi Academy.

The goal of BioBots has always been the same: Give laboratories the ability to create living things from scratch. Those things–such as pieces of tissue or bone–could then be studied with the hopes of finding cures and solving diseases.

That vision helped the company’s co-founders, Ricky Solorzano and Danny Cabrera, land on Inc.’s 30 Under 30 list in 2016. And while the original goal has remained, much has changed. In August, Cabrera, the company’s first CEO, left the Philadelphia-based startup. And in November, the company rebranded, changing its name to a more mature but far less memorable name, Allevi.

“People think running a startup is just a straight line, that you go in one direction,” Solorzano, who has since shifted from CTO to CEO, tells Inc. “You really go up, down, sideways, left, right, 45 degrees this way, 90 degrees that way.”

For Solorzano and Cabrera, the split represents the end of an era. The two Miami residents both attended the University of Pennsylvania, where they first discussed the idea of developing an affordable three-dimensional printer that could produce living tissue. They founded the company together in 2014.

The following is based on an interview back in 2016 I did with Biobots founders Danial Cabrera, Ricardo Solorzano, and Sohaib Hashimi.

A year ago (2014), we founded BioBots in a dorm room on top of a noisy college bar with the mission of conquering the largest mystery of our generation – life. Disillusioned with existing tools and technologies for engineering organisms, and inspired by the idea of biology as technology, we launched BioBots with a command: “Build with Life.”

It only took a few weeks for our first apostles to join us. Dr. Dan Huh and his student Yooni at Penn began working with a prototype that would become the first BioBot. With the help and unyielding support of our early clients and partners like Elliot Menschik at DreamIt Health, we began the journey of bringing biofabrication technology to people across the world.

Today hundreds of labs are turning to BioBots for tools that allow them to engineer biology. I am constantly inspired by our partners’ research projects, goals and progress; they consistently remind me that we are accelerating the pace not only of regenerative medicine, but of human evolution.

None of this would be possible without all of our BioBot employees, their families, our friends in the media, investors, and most importantly – our visionary clients, who continue to pour their passion, talents, energy and love into building this company. A year ago we were two guys in a bar. Today, hundreds of supporters have taken up the mantle of biofabricator.

Our vision at BioBots is to make tools that harness life as an engineering discipline and push the human race forward. We look forward to helping you do much more and test the boundary of what we can build with biology.  Thank you for being a part of our journey!

BioBots to Bring Revolutionary 3D Bioprinter to the Masses with $5,000 Beta Program & Eventually Print Whole Organs

“​Life is the oldest and most efficient manufacturing technology that we as people know of. It’s become clear over the past several decades as scientists have engineered life to work for us, that biology is the next frontier for manufacturing. However, there is one thing missing. ​Doing biology today is the equivalent of computer programming 50 years ago – it’s inefficient, it’s slow, and the technology is only available to scientists at well-funded institutions​, out of the hands of the ordinary people that could be leading this new revolution​.” ~ BioBots CEO Danny Cabrera to 3DPrint.com

BioBots is a company launched by Daniel Cabrera, a recent graduate of University of Pennsylvania’s Engineering School, as well as Ricardo Solorzano and Sohaib Hashmi, who are staff research specialists in the Perelman School of Medicine (UPenn). The three got together to create a 3D bioprinter capable of printing in multiple body tissues. While this certainly isn’t the first ever bioprinter created, Cabrera tells us that it is not the same as others on the market today.

“Employing the tool that transformed traditional avenues of manufacturing, we at BioBots are using 3D printers to engineer biology,” Cabrera told 3DPrint.com. “Our 3D bioprinters employ the use of a novel extrusion process that addresses the previous technical hurdles of 3D bioprinting, as well as a biomaterials cartridge system that makes this revolutionary technology accessible to untrained users. Just imagine ​the kind of products that people will build now that they can plug and print living tissues. At BioBots, we are building this future, today.”

The BioBot 3D printer works with both “Blue Light” and UV light. The cell solution, which contains living, growing cells as well as vasculature for nourishment, is extruded from the 3D printer in a similar fashion to how at-home fused filament fabrication (FFF) 3D printers work. However, different from your typical FFF 3D printer, once a biological material has been extruded, an ultraviolet light (or Blue Light) cures and hardens it. This occurs one layer at a time until the desired object is printed.  The objects printed can be living cell tissue or non-living scaffolds, and Cabrera tells us that over a dozen different cell types have been used with these printers so far. The unique cartridge system that BioBots’ bioprinter uses, enable users to easily switch between the printing of different biological materials, almost as easily as a normal desktop printer can switch between colors.

“We have won several innovation competitions and recently received funding from DreamIt Health, a start-up accelerator program based out of Philadelphia,” said Cabrera. “We are opening a Beta program with the goal of placing printers in the hands of the best experts and working with them to generate publishable data. The idea is to generate interest in this area and inform scientists about the tool we’re developing through published research. We currently have Beta tester relationships in place with Dr. Dan Huh’s lab at Penn, Dr. Kara Spiller’s lab in Drexel, and Dr. Kevin Costa’s lab in Mt. Sinai and are definitely looking to expand.”

The company is also open to accepting many new Beta testers into the program. That program costs a mere $5,000 and supplies the following benefits to the testers:

  • A 3D bioprinter (80um resolution) capable of extruding a variety of hydrogels (collagen, alginate, agarose, polyethylene glycol, hyaluronic acid, etc.)
  • 1 Year service agreement & active development for your bioprinter
  • BioBots software package
  • Access to an online community of collaborators who are working together to solve tough tissue engineering, regenerative medicine, and biomaterials problems
  • Having your work showcased at a number of conferences that BioBots has been invited to speak at

For those interested in joining the Beta program, they are asked to email the company for more details.

The team behind BioBots is equally as impressive as the machine itself. Cabrera has recently graduated from UPenn, where he studied computer science and biology, and won first place in the North America International Genetically Engineered Machines competition for his work on automating genetic engineering work flows and making life easier to engineer. The company’s CTO has been working in the field of regenerative medicine for about 4 years, and has authored several papers on building 3D blood vessels. He actually built the first BioBots prototype from his dorm room at UPenn.

While the Beta program is meant as a way in which the company can build up their user base, solidify a community of doctors, engineers, designers, educators and students, and test out their latest version of their BioBots bioprinter, others can pre-order the printer for $25,000. The team isn’t only targeting Ph.D researchers. They want these machines to be used by educators and researchers everywhere. “Our 3D bioprinters enable users to easily print high resolution biological structures – whether you’re a researcher on the frontier of regenerative medicine or a high school biology teacher,” said Cabrera.

While we are still far away from 3D printing working organs, the fact that BioBots offers a 3D printer capable of printing in a vast array of biological materials at a price starting as low as $5,000, means that this technology can reach the hands of virtually any researchers interested in studying the potential that it holds for the future. Other bioprinters from larger companies can cost upwards of $250,000, severely limiting access.  This is wear BioBots may become quite revolutionary.

Cabrera tells us that they are working on curriculum/lesson plans to go along with their printers, so that high school students can learn about bioprinting through the use of these relatively affordable machines.

When I asked Cabrera how long he thinks it will be, before we see fully printed working organs, he told me that it isn’t about the technology not being there, but rather its about researchers being able to come up with ways to use it. His guess is that within the next 10-15 years we may see the first 3D printed working organ.

What do you think? Will the BioBots 3D bioprinter lead the way in allowing researchers to fully investigate and innovate upon this technology? Discuss in theBioBots forum thread on 3DPB.com. Check out the videos below, including the first one, showing a demo of the BioBots printer using photocurable PEG.

 Source: https://www.biobots.io/news-article/biobots-to-bring-revolutionary-3d-bioprinter-to-the-masses-with-5000-beta-program-eventually-print-whole-organs/

Biobots offers, on their site at https://www.biobots.io/build-with-life/

  • Wikis: where one can browse through these pages to learn about established biotechnologies, tissue fabrication methods, foundational advances in biology and in our ability to design and engineer living things.
  • Protocols: where one can find information in a “Use the protocols section” to learn more about how to interact with your BioBot 1, different bioinks, and new emerging biofabrication techniques. This is the place to develop and share new methods.
  • BioReports: a collection of experimental logs with methodology used and results obtained from experiments using the BioBot systems

Advantages of the Biobots system

PRECISION

Our team of engineers has worked hard to ensure precision in every aspect of BioBot 1. We use linear rails over less expensive belt systems that slip and require adjustment, guaranteeing a consistent 10 micron precision on each axis.

 

Other Articles on this Open Access Journal on 3D Bioprinting Include:

A Revolution in Medicine: Medical 3D BioPrinting

Audio Podcasts – 3D Medical BioPrinting Technology

Global Technology Conferences on 3D BioPrinting 2015 – 2016

Volume Four: Medical 3D BioPrinting – The Revolution in Medicine

 

 

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Use of 3D Bioprinting for Development of Toxicity Prediction Models

Curator: Stephen J. Williams, PhD

SOT FDA Colloquium on 3D Bioprinted Tissue Models: Tuesday, April 9, 2019

The Society of Toxicology (SOT) and the U.S. Food and Drug Administration (FDA) will hold a workshop on “Alternative Methods for Predictive Safety Testing: 3D Bioprinted Tissue Models” on Tuesday, April 9, at the FDA Center for Food Safety and Applied Nutrition in College Park, Maryland. This workshop is the latest in the series, “SOT FDA Colloquia on Emerging Toxicological Science: Challenges in Food and Ingredient Safety.”

Human 3D bioprinted tissues represent a valuable in vitro approach for chemical, personal care product, cosmetic, and preclinical toxicity/safety testing. Bioprinting of skin, liver, and kidney is already appearing in toxicity testing applications for chemical exposures and disease modeling. The use of 3D bioprinted tissues and organs may provide future alternative approaches for testing that may more closely resemble and simulate intact human tissues to more accurately predict human responses to chemical and drug exposures.

A synopsis of the schedule and related works from the speakers is given below:

 

8:40 AM–9:20 AM Overview and Challenges of Bioprinting
Sharon Presnell, Amnion Foundation, Winston-Salem, NC
9:20 AM–10:00 AM Putting 3D Bioprinting to the Use of Tissue Model Fabrication
Y. Shrike Zhang, Brigham and Women’s Hospital, Harvard Medical School and Harvard-MIT Division of Health Sciences and Technology, Boston, MA
10:00 AM–10:20 AM Break
10:20 AM–11:00 AM Uses of Bioprinted Liver Tissue in Drug Development
Jean-Louis Klein, GlaxoSmithKline, Collegeville, PA
11:00 AM–11:40 AM Biofabrication of 3D Tissue Models for Disease Modeling and Chemical Screening
Marc Ferrer, National Center for Advancing Translational Sciences, NIH, Rockville, MD

Sharon Presnell, Ph.D. President, Amnion Foundation

Dr. Sharon Presnell was most recently the Chief Scientific Officer at Organovo, Inc., and the President of their wholly-owned subsidiary, Samsara Sciences. She received a Ph.D. in Cell & Molecular Pathology from the Medical College of Virginia and completed her undergraduate degree in biology at NC State. In addition to her most recent roles, Presnell has served as the director of cell biology R&D at Becton Dickinson’s corporate research center in RTP, and as the SVP of R&D at Tengion. Her roles have always involved the commercial and clinical translation of basic research and early development in the cell biology space. She serves on the board of the Coulter Foundation at the University of Virginia and is a member of the College of Life Sciences Foundation Board at NC State. In January 2019, Dr. Presnell will begin a new role as President of the Amnion Foundation, a non-profit organization in Winston-Salem.

A few of her relevant publications:

Bioprinted liver provides early insight into the role of Kupffer cells in TGF-β1 and methotrexate-induced fibrogenesis

Integrating Kupffer cells into a 3D bioprinted model of human liver recapitulates fibrotic responses of certain toxicants in a time and context dependent manner.  This work establishes that the presence of Kupffer cells or macrophages are important mediators in fibrotic responses to certain hepatotoxins and both should be incorporated into bioprinted human liver models for toxicology testing.

Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro

Abstract: Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI). This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM). Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level.

A great interview with Dr. Presnell and the 3D Models 2017 Symposium is located here:

Please click here for Web based and PDF version of interview

Some highlights of the interview include

  • Exciting advances in field showing we can model complex tissue-level disease-state phenotypes that develop in response to chronic long term injury or exposure
  • Sees the field developing a means to converge both the biology and physiology of tissues, namely modeling the connectivity between tissues such as fluid flow
  • Future work will need to be dedicated to develop comprehensive analytics for 3D tissue analysis. As she states “we are very conditioned to get information in a simple way from biochemical readouts in two dimension, monocellular systems”  however how we address the complexity of various cellular responses in a 3D multicellular environment will be pertinent.
  • Additional challenges include the scalability of such systems and making such system accessible in a larger way
  1. Shrike Zhang, Brigham and Women’s Hospital, Harvard Medical School and Harvard-MIT Division of Health Sciences and Technology

Dr. Zhang currently holds an Assistant Professor position at Harvard Medical School and is an Associate Bioengineer at Brigham and Women’s Hospital. His research interests include organ-on-a-chip, 3D bioprinting, biomaterials, regenerative engineering, biomedical imaging, biosensing, nanomedicine, and developmental biology. His scientific contributions have been recognized by >40 international, national, and regional awards. He has been invited to deliver >70 lectures worldwide, and has served as reviewer for >400 manuscripts for >30 journals. He is serving as Editor-in-Chief for Microphysiological Systems, and Associate Editor for Bio-Design and Manufacturing. He is also on Editorial Board of BioprintingHeliyonBMC Materials, and Essays in Biochemistry, and on Advisory Panel of Nanotechnology.

Some relevant references from Dr. Zhang

Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform.

Skardal A, Murphy SV, Devarasetty M, Mead I, Kang HW, Seol YJ, Shrike Zhang Y, Shin SR, Zhao L, Aleman J, Hall AR, Shupe TD, Kleensang A, Dokmeci MR, Jin Lee S, Jackson JD, Yoo JJ, Hartung T, Khademhosseini A, Soker S, Bishop CE, Atala A.

Sci Rep. 2017 Aug 18;7(1):8837. doi: 10.1038/s41598-017-08879-x.

 

Reconstruction of Large-scale Defects with a Novel Hybrid Scaffold Made from Poly(L-lactic acid)/Nanohydroxyapatite/Alendronate-loaded Chitosan Microsphere: in vitro and in vivo Studies.

Wu H, Lei P, Liu G, Shrike Zhang Y, Yang J, Zhang L, Xie J, Niu W, Liu H, Ruan J, Hu Y, Zhang C.

Sci Rep. 2017 Mar 23;7(1):359. doi: 10.1038/s41598-017-00506-z.

 

 

A liver-on-a-chip platform with bioprinted hepatic spheroids.

Bhise NS, Manoharan V, Massa S, Tamayol A, Ghaderi M, Miscuglio M, Lang Q, Shrike Zhang Y, Shin SR, Calzone G, Annabi N, Shupe TD, Bishop CE, Atala A, Dokmeci MR, Khademhosseini A.

Biofabrication. 2016 Jan 12;8(1):014101. doi: 10.1088/1758-5090/8/1/014101.

 

Marc Ferrer, National Center for Advancing Translational Sciences, NIH

Marc Ferrer is a team leader in the NCATS Chemical Genomics Center, which was part of the National Human Genome Research Institute when Ferrer began working there in 2010. He has extensive experience in drug discovery, both in the pharmaceutical industry and academic research. Before joining NIH, he was director of assay development and screening at Merck Research Laboratories. For 10 years at Merck, Ferrer led the development of assays for high-throughput screening of small molecules and small interfering RNA (siRNA) to support programs for lead and target identification across all disease areas.

At NCATS, Ferrer leads the implementation of probe development programs, discovery of drug combinations and development of innovative assay paradigms for more effective drug discovery. He advises collaborators on strategies for discovering small molecule therapeutics, including assays for screening and lead identification and optimization. Ferrer has experience implementing high-throughput screens for a broad range of disease areas with a wide array of assay technologies. He has led and managed highly productive teams by setting clear research strategies and goals and by establishing effective collaborations between scientists from diverse disciplines within industry, academia and technology providers.

Ferrer has a Ph.D. in biological chemistry from the University of Minnesota, Twin Cities, and completed postdoctoral training at Harvard University’s Department of Molecular and Cellular Biology. He received a B.Sc. degree in organic chemistry from the University of Barcelona in Spain.

 

Some relevant references for Dr. Ferrer

Fully 3D Bioprinted Skin Equivalent Constructs with Validated Morphology and Barrier Function.

Derr K, Zou J, Luo K, Song MJ, Sittampalam GS, Zhou C, Michael S, Ferrer M, Derr P.

Tissue Eng Part C Methods. 2019 Apr 22. doi: 10.1089/ten.TEC.2018.0318. [Epub ahead of print]

 

Determination of the Elasticity Modulus of 3D-Printed Octet-Truss Structures for Use in Porous Prosthesis Implants.

Bagheri A, Buj-Corral I, Ferrer M, Pastor MM, Roure F.

Materials (Basel). 2018 Nov 29;11(12). pii: E2420. doi: 10.3390/ma11122420.

 

Mutation Profiles in Glioblastoma 3D Oncospheres Modulate Drug Efficacy.

Wilson KM, Mathews-Griner LA, Williamson T, Guha R, Chen L, Shinn P, McKnight C, Michael S, Klumpp-Thomas C, Binder ZA, Ferrer M, Gallia GL, Thomas CJ, Riggins GJ.

SLAS Technol. 2019 Feb;24(1):28-40. doi: 10.1177/2472630318803749. Epub 2018 Oct 5.

 

A high-throughput imaging and nuclear segmentation analysis protocol for cleared 3D culture models.

Boutin ME, Voss TC, Titus SA, Cruz-Gutierrez K, Michael S, Ferrer M.

Sci Rep. 2018 Jul 24;8(1):11135. doi: 10.1038/s41598-018-29169-0.

A High-Throughput Screening Model of the Tumor Microenvironment for Ovarian Cancer Cell Growth.

Lal-Nag M, McGee L, Guha R, Lengyel E, Kenny HA, Ferrer M.

SLAS Discov. 2017 Jun;22(5):494-506. doi: 10.1177/2472555216687082. Epub 2017 Jan 31.

 

Exploring Drug Dosing Regimens In Vitro Using Real-Time 3D Spheroid Tumor Growth Assays.

Lal-Nag M, McGee L, Titus SA, Brimacombe K, Michael S, Sittampalam G, Ferrer M.

SLAS Discov. 2017 Jun;22(5):537-546. doi: 10.1177/2472555217698818. Epub 2017 Mar 15.

 

RNAi High-Throughput Screening of Single- and Multi-Cell-Type Tumor Spheroids: A Comprehensive Analysis in Two and Three Dimensions.

Fu J, Fernandez D, Ferrer M, Titus SA, Buehler E, Lal-Nag MA.

SLAS Discov. 2017 Jun;22(5):525-536. doi: 10.1177/2472555217696796. Epub 2017 Mar 9.

 

Other Articles on 3D Bioprinting on this Open Access Journal include:

Global Technology Conferences on 3D BioPrinting 2015 – 2016

3D Medical BioPrinting Technology Reporting by Irina Robu, PhD – a forthcoming Article in “Medical 3D BioPrinting – The Revolution in Medicine, Technologies for Patient-centered Medicine: From R&D in Biologics to New Medical Devices”

Bio-Inks and 3D BioPrinting

New Scaffold-Free 3D Bioprinting Method Available to Researchers

Gene Editing for Gene Therapies with 3D BioPrinting

 

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A Realistic 3D Model of a Human Heart Ventricle

Reported: Irina Robu, PhD

Scientists from Harvard University designed a working 3D model of a human heart’s left ventricle whose objective is to replace animal models with human models and patient-specific human models. The discovery could improve how diseases are studied, drugs are tested and lead to patient-specific treatments for various heart ailments, including arrhythmia.

The researchers reinvented the tissue’s unique structure, where parallel myocardial fibers act as a scaffold to direct brick-shaped heart cells to align and accumulate end-to-end and form a hollow, cone-shaped structure. When the heart beats, the cells expand and contract. The new tissue is engineered using a nanofiber scaffold that is seeded with human heart cells and acts like a 3D template to guide the cells and their assembly into ventricle chambers that beat in vitro.

In this research, they used a nanofiber production platform called pull spinning, which uses a high-speed rotating bristle that slopes into a polymer reservoir and pulls a droplet from the solution into a jet, to recreate the scaffold. The fiber travels in a spiral trajectory and solidifies before detaching from the bristle and moving toward a collector.

The team made the ventricle using a combination of biodegradable polyester and gelatin fibers collected on a rotating collector in which all of the fibers align in the same direction. The scientists then cultured the ventricle with rat myocytes or human cardiomyocytes from induced stem cells and found that within three to five days, a thin wall of tissue covered the scaffold and the cells were beating in synch. The procedure allowed control and monitor of the calcium and insert a catheter to study the pressure and volume of the beating ventricle.

The tissue is then exposed to a drug similar to adrenaline called isoproterenol and measured as the beat-rate increased.  They also poked holes in the ventricle to mimic a myocardial infarction and studied the effect of the heart attack in a petri dish. The ventricle is then conditioned in a self-contained bioreactor with separate chambers for optional valve inserts, extra access ports for catheters and ventricular assist capabilities. The cultures were run for six months and stable pressure-volume loops were measured.

With this new model, scientists might study the heart’s function by many of the same tools now being used in the clinic, including pressure-volume loops and ultrasound. They hope to use patient-derived, pre-differentiated stem cells to seed the ventricles, letting for more high-throughput production of the tissue.

SOURCE

https://www.rdmag.com/article/2018/07/tissue-engineered-heart-model-gives-researchers-realistic-testing-platform?et_cid=6407213

 

 

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Functioning Human Neural Networks Grown in 3-D from Stem Cells

Reporter: Irina Robu, PhD

 

Researchers at Tuffs University developed three-dimensional human tissue model that mimics structural and functional features of the brain and were able to demonstrate sustained neural activity over several months. The 3D brain tissue models were the result of a collaborative effort between researchers from Tufts University School of Engineering, Tufts University School of Medicine, the Sackler School of Graduate Biomedical Sciences at Tufts, and the Jackson Laboratory.

 

These tissue models have the ability to populate a 3D matrix of silk protein and collagen with cells from patients with Parkinson’s disease, Alzheimer’s disease and the ability to

  • explore cell interactions,
  • disease progression and
  • response to treatment.

The 3D brain tissue models overcome a crucial challenge of previous models which is the availability of human source neurons due to the fact that neurological tissues are rarely removed from

  • healthy patients, and are usually available
  • post-mortem from diseased patients.

The 3D tissue models are populated with human induced pluripotent stem cells (iPSCs) that can be derived from several sources, including patient skin. The iPSCs are generated by turning back the clock on cell development to their embryonic-like precursors. They can then be dialed forward again to any cell type, including neurons. The porous structure of the 3D tissue cultures labeled in the research delivers sufficient oxygenation, access for nutrients and measurement of cellular properties. A clear window in the center of each 3D matrix allows researchers to visualize the

  • growth,
  • organization and
  • behavior of individual cells.

According to David L. Kaplan, “the silk-collagen scaffolds provide the right environment to produce cells with the genetic signatures and electrical signaling found in native neuronal tissues”. Compared to growing and culturing cells in two dimensions, the three-dimensional matrix yields a knowingly extra complete mix of cells found in neural tissue, with the appropriate morphology and expression of receptors and neurotransmitters. Other researchers have used iPSCs to create brain-like organoids, but can still make it difficult figuring out what individual cells are doing in real time. Likewise, cells in the center of the organoids may not obtain enough oxygen or nutrients to function in a native state.

However, the researchers can see a great advantage of the 3D tissue models with advanced imaging techniques, and the addition of cell types such as microglia and endothelial cells,to create a more complete model of the brain environment and the complex interactions that are involved in

  • signaling,
  • learning and plasticity, and
  • degeneration.

 

SOURCE

https://www.rdmag.com/news/2018/10/scientists-grow-functioning-human-neural-networks-3d-stem-cells

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First 3D Printed Tibia Replacement

Reporter: Irina Robu, PhD

Current advances have allowed 3D printing of biocompatible materials, cells and supporting components into complex 3D functional living tissues. 3D bioprinting has already been used for the generation and transplantation of several tissues, including multilayered skin, bone, vascular grafts, tracheal splints, heart tissue and cartilaginous structures. Thanks to 3D printing, an Australian man got to keep his leg. The man, Reuben Lichter nearly lost his leg above the knee due to a bacterial infection. Doctors told him that he had osteomyelitis which infected his entire bone. Lichter’s bacterial disease of osteomyelitis affects 2 in every 10,000 people in the United States. He had two choices: an experimental procedure using the 3D printed bone or lose his leg. For Lichter, the choice was easy.

Michael Wagels who served as the lead surgeon performed the world’s first-ever transplant surgery using a 3D printed bone. The scaffold was initially modeled at Queensland University of Technology. Biomedical engineers designed the scaffold to promote bone growth around it and then slowly dissolve over time. To have the body successfully grow around the scaffold, the team introduced tissue and blood vessels from both of Lichter’s legs to the scaffold. The surgery itself happened over five operations at Brisbane’s Princess Alexandra Hospital.

However, the next major challenge for biomedical engineers is how to successfully 3D print organs.

SOURCE

https://interestingengineering.com/australian-man-gets-worlds-first-3d-printed-tibia-replacement

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3-D Printing in Water using Novel Hybrid Nanoparticles

Reporter: Irina Robu, PhD

3D printing has become an essential tool for fabricating different organic based materials, but printing structures in water has been thought-provoking due to lack of water soluble molecules known as photo initiators. The photo initiator can induce chemical reactions needed to form solid printed material by light.  However, researchers at the Hebrew University of Jerusalem’s Center for Nanoscience and Nanotechnology have developed a new type of photo initiator for three-dimensional printing in water. This innovative nanoparticle allows the creating of bio-friendly 3D structures.

By 3D printing in water, it also opens up the digital light processing method to medical applications, leading toward a competitive response for patient specific implants and tissues because the photo initiators cause rapid solidification of a liquid material that can create faster reactions when exposed to light. 3D printing in water opens up innovative ways for tailored fabrication of medical devices and for printing hydrogels or bio-scaffolds that are typical used in tissue engineering.

The challenge of 3D printing in water is finding an initiator that is not consumed by irradiation. However, unlike regular photo initiators, the novel hybrid nanoparticles developed by Prof. Magdassi present tunable properties, wide excitation window in the UV and visible range, high light sensitivity, and their ability to split water, and absorb oxygen molecules that typically inhibit the performance of the process. The particles added as photo initiator are semi conductive hybrid nanoparticles and are used to create high resolution 3D objects at sub-microscopic scale.

Therefore, 3-D printing in water could allow personalized fabrication of joint replacements, heart valves, artificial tendons and ligaments etc.

SOURCE

  1. https://phys-org.cdn.ampproject.org/c/s/phys.org/news/2017-08-rapid-d-hybrid-nanoparticles.amp
  2. Amol Ashok Pawar et al. Rapid Three-Dimensional Printing in Water Using Semiconductor–Metal Hybrid Nanoparticles as Photoinitiators, Nano Letters (2017)

 

 

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3-D Printed Ovaries Produce Healthy Offspring

Reporter: Irina Robu, PhD

Each year about 120,000 organs are transplanted from one human being to another and most of the time is a living volunteer. But lack of suitable donors, predominantly means the supply of such organs is inadequate. Countless people consequently die waiting for a transplant which has led researchers to study the question of how to build organs from scratch.

One promising approach is to print them, but “bioprinting” remains largely experimental. Nevertheless, bioprinted tissue is before now being sold for drug testing, and the first transplantable tissues are anticipated to be ready for use in a few years’ time. The first 3D printed organ includes bioprosthetic ovaries which are constructed of 3D printed scaffolds that have immature eggs and have been successful in boosting hormone production and restoring fertility was developed by Teresa K. Woodruff, a reproductive scientist and director of the Women’s Health Research Institute at Feinberg School of Medicine, at Northwestern University, in Illinois.

What sets apart these bioprosthetic ovaries is the architecture of the scaffold. The material is made of gelatin made from broken-down collagen that is safe to humans which is self-supporting and can lead to building multiple layers.

The 3-D printed “scaffold” or “skeleton” is implanted into a female and its pores can be used to optimize how follicles, or immature eggs, get wedged within the scaffold. The scaffold supports the survival of the mouse’s immature egg cells and the cells that produce hormones to boost production. The open construction permits room for the egg cells to mature and ovulate, blood vessels to form within the implant enabling the hormones to circulate and trigger lactation after giving birth. The purpose of this scaffold is to recapitulate how an ovary would function.
The scientists’ only objective for developing the bioprosthetic ovaries was to help reestablish fertility and hormone production in women who have suffered adult cancer treatments and now have bigger risks of infertility and hormone-based developmental issues.

 

SOURCES

Printed human body parts could soon be available for transplant
https://www.economist.com/news/science-and-technology/21715638-how-build-organs-scratch

 

3D printed ovaries produce healthy offspring giving hope to infertile women

http://www.telegraph.co.uk/science/2017/05/16/3d-printed-ovaries-produce-healthy-offspring-giving-hope-infertile/

 

Brave new world: 3D-printed ovaries produce healthy offspring

http://www.naturalnews.com/2017-05-27-brave-new-world-3-d-printed-ovaries-produce-healthy-offspring.html

 

3-D-printed scaffolds restore ovary function in infertile mice

http://www.medicalnewstoday.com/articles/317485.php

 

Our Grandkids May Be Born From 3D-Printed Ovaries

http://gizmodo.com/these-mice-gave-birth-using-3d-printed-ovaries-1795237820

 

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Topical Solution for Combination Oncology Drug Therapy: Patch that delivers Drug, Gene, and Light-based Therapy to Tumor, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)

Topical Solution for Combination Oncology Drug Therapy: Patch that delivers Drug, Gene, and Light-based Therapy to Tumor

Reporter: Aviva Lev-Ari, PhD, RN

 

Self-assembled RNA-triple-helix hydrogel scaffold for microRNA modulation in the tumour microenvironment

Affiliations

  1. Massachusetts Institute of Technology, Institute for Medical Engineering and Science, Harvard-MIT Division for Health Sciences and Technology, Cambridge, Massachusetts 02139, USA
    • João Conde,
    • Nuria Oliva,
    • Mariana Atilano,
    • Hyun Seok Song &
    • Natalie Artzi
  2. School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, UK
    • João Conde
  3. Grup dEnginyeria de Materials, Institut Químic de Sarrià-Universitat Ramon Llull, Barcelona 08017, Spain
    • Mariana Atilano
  4. Division of Bioconvergence Analysis, Korea Basic Science Institute, Yuseong, Daejeon 169-148, Republic of Korea
    • Hyun Seok Song
  5. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
    • Natalie Artzi
  6. Department of Medicine, Biomedical Engineering Division, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    • Natalie Artzi

Contributions

J.C. and N.A. conceived the project and designed the experiments. J.C., N.O., H.S.S. and M.A. performed the experiments, collected and analysed the data. J.C. and N.A. co-wrote the manuscript. All authors discussed the results and reviewed the manuscript.

Nature Materials
15,
353–363
(2016)
doi:10.1038/nmat4497
Received
22 April 2015
Accepted
26 October 2015
Published online
07 December 2015

The therapeutic potential of miRNA (miR) in cancer is limited by the lack of efficient delivery vehicles. Here, we show that a self-assembled dual-colour RNA-triple-helix structure comprising two miRNAs—a miR mimic (tumour suppressor miRNA) and an antagomiR (oncomiR inhibitor)—provides outstanding capability to synergistically abrogate tumours. Conjugation of RNA triple helices to dendrimers allows the formation of stable triplex nanoparticles, which form an RNA-triple-helix adhesive scaffold upon interaction with dextran aldehyde, the latter able to chemically interact and adhere to natural tissue amines in the tumour. We also show that the self-assembled RNA-triple-helix conjugates remain functional in vitro and in vivo, and that they lead to nearly 90% levels of tumour shrinkage two weeks post-gel implantation in a triple-negative breast cancer mouse model. Our findings suggest that the RNA-triple-helix hydrogels can be used as an efficient anticancer platform to locally modulate the expression of endogenous miRs in cancer.

SOURCE

http://www.nature.com/nmat/journal/v15/n3/abs/nmat4497.html#author-information

 

 

Patch that delivers drug, gene, and light-based therapy to tumor sites shows promising results

In mice, device destroyed colorectal tumors and prevented remission after surgery.

Helen Knight | MIT News Office
July 25, 2016

Approximately one in 20 people will develop colorectal cancer in their lifetime, making it the third-most prevalent form of the disease in the U.S. In Europe, it is the second-most common form of cancer.

The most widely used first line of treatment is surgery, but this can result in incomplete removal of the tumor. Cancer cells can be left behind, potentially leading to recurrence and increased risk of metastasis. Indeed, while many patients remain cancer-free for months or even years after surgery, tumors are known to recur in up to 50 percent of cases.

Conventional therapies used to prevent tumors recurring after surgery do not sufficiently differentiate between healthy and cancerous cells, leading to serious side effects.

In a paper published today in the journal Nature Materials, researchers at MIT describe an adhesive patch that can stick to the tumor site, either before or after surgery, to deliver a triple-combination of drug, gene, and photo (light-based) therapy.

Releasing this triple combination therapy locally, at the tumor site, may increase the efficacy of the treatment, according to Natalie Artzi, a principal research scientist at MIT’s Institute for Medical Engineering and Science (IMES) and an assistant professor of medicine at Brigham and Women’s Hospital, who led the research.

The general approach to cancer treatment today is the use of systemic, or whole-body, therapies such as chemotherapy drugs. But the lack of specificity of anticancer drugs means they produce undesired side effects when systemically administered.

What’s more, only a small portion of the drug reaches the tumor site itself, meaning the primary tumor is not treated as effectively as it should be.

Indeed, recent research in mice has found that only 0.7 percent of nanoparticles administered systemically actually found their way to the target tumor.

“This means that we are treating both the source of the cancer — the tumor — and the metastases resulting from that source, in a suboptimal manner,” Artzi says. “That is what prompted us to think a little bit differently, to look at how we can leverage advancements in materials science, and in particular nanotechnology, to treat the primary tumor in a local and sustained manner.”

The researchers have developed a triple-therapy hydrogel patch, which can be used to treat tumors locally. This is particularly effective as it can treat not only the tumor itself but any cells left at the site after surgery, preventing the cancer from recurring or metastasizing in the future.

Firstly, the patch contains gold nanorods, which heat up when near-infrared radiation is applied to the local area. This is used to thermally ablate, or destroy, the tumor.

These nanorods are also equipped with a chemotherapy drug, which is released when they are heated, to target the tumor and its surrounding cells.

Finally, gold nanospheres that do not heat up in response to the near-infrared radiation are used to deliver RNA, or gene therapy to the site, in order to silence an important oncogene in colorectal cancer. Oncogenes are genes that can cause healthy cells to transform into tumor cells.

The researchers envision that a clinician could remove the tumor, and then apply the patch to the inner surface of the colon, to ensure that no cells that are likely to cause cancer recurrence remain at the site. As the patch degrades, it will gradually release the various therapies.

The patch can also serve as a neoadjuvant, a therapy designed to shrink tumors prior to their resection, Artzi says.

When the researchers tested the treatment in mice, they found that in 40 percent of cases where the patch was not applied after tumor removal, the cancer returned.

But when the patch was applied after surgery, the treatment resulted in complete remission.

Indeed, even when the tumor was not removed, the triple-combination therapy alone was enough to destroy it.

The technology is an extraordinary and unprecedented synergy of three concurrent modalities of treatment, according to Mauro Ferrari, president and CEO of the Houston Methodist Research Institute, who was not involved in the research.

“What is particularly intriguing is that by delivering the treatment locally, multimodal therapy may be better than systemic therapy, at least in certain clinical situations,” Ferrari says.

Unlike existing colorectal cancer surgery, this treatment can also be applied in a minimally invasive manner. In the next phase of their work, the researchers hope to move to experiments in larger models, in order to use colonoscopy equipment not only for cancer diagnosis but also to inject the patch to the site of a tumor, when detected.

“This administration modality would enable, at least in early-stage cancer patients, the avoidance of open field surgery and colon resection,” Artzi says. “Local application of the triple therapy could thus improve patients’ quality of life and therapeutic outcome.”

Artzi is joined on the paper by João Conde, Nuria Oliva, and Yi Zhang, of IMES. Conde is also at Queen Mary University in London.

SOURCE

http://news.mit.edu/2016/patch-delivers-drug-gene-light-based-therapy-tumor-0725

Other related articles published in thie Open Access Online Scientific Journal include the following:

The Development of siRNA-Based Therapies for Cancer

Author: Ziv Raviv, PhD

https://pharmaceuticalintelligence.com/2013/05/09/the-development-of-sirna-based-therapies-for-cancer/

 

Targeted Liposome Based Delivery System to Present HLA Class I Antigens to Tumor Cells: Two papers

Reporter: Stephen J. Williams, Ph.D.

https://pharmaceuticalintelligence.com/2016/07/20/targeted-liposome-based-delivery-system-to-present-hla-class-i-antigens-to-tumor-cells-two-papers/

 

Blast Crisis in Myeloid Leukemia and the Activation of a microRNA-editing Enzyme called ADAR1

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/06/10/blast-crisis-in-myeloid-leukemia-and-the-activation-of-a-microrna-editing-enzyme-called-adar1/

 

First challenge to make use of the new NCI Cloud Pilots – Somatic Mutation Challenge – RNA: Best algorithms for detecting all of the abnormal RNA molecules in a cancer cell

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/07/17/first-challenge-to-make-use-of-the-new-nci-cloud-pilots-somatic-mutation-challenge-rna-best-algorithms-for-detecting-all-of-the-abnormal-rna-molecules-in-a-cancer-cell/

 

miRNA Therapeutic Promise

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/05/01/mirna-therapeutic-promise/

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3-D Printed Organs

Curator: Larry H. Bernstein, MD, FCAP

 

 

 

The Future of 3-D Printing in Medicine

Today’s 3-D printed plastic models of hearts may one day translate into on-demand printed, functional replacement organs
http://www.dicardiology.com/article/future-3-d-printing-medicine?eid=333021707&bid=1408765#sthash.M7AYV16i.dpuf

http://www.dicardiology.com/sites/daic/files/styles/content_feed_large_new/public/field/image/3-D%20printed%20blood%20vessel%20like%20tube%20made%20of%20living%20cells.jpg

A 3-D printed vessel-like lumen made from living cells as part of the research at The South Carolina Project for Organ Biofabrication.

Science fiction offers a lot of ideas for creating new body parts on demand, and the advancement of 3-D printing (also called additive manufacturing) is slowly translating this idea into science fact. Today, the 3-D printed anatomic models created from patient computed tomography (CT), magnetic resonance imaging (MRI) or 3-D ultrasound imaging datasets are used for education and to plan and navigate complex procedures. These models are used to teach about complex or rare cardiac or congenital conditions that up until recently could only be seen using examples extracted from cadavers. Today, anatomical models of rare cardiac anatomy can be printed on demand from CT scans of surviving patients.  That concept can now be translated into 3-D printing of implantable devices customized to a specific patient using their imaging. Experts at several medical conferences are also saying printing functional biological replacement tissues is already in development.

Video interview with Dee Dee Wang, M.D., FACC, FASE, Henry Ford Hospital, explaining the use of 3-D printing to aid procedural planning and guidance in complex structural heart cases.

See video examples of 3-D printed hearts as part of the editor’s choice of the most innovative new teachnology at ACC.16. – See more at: http://www.dicardiology.com/article/future-3-d-printing-medicine?eid=333021707&bid=1408765#sthash.M7AYV16i.dpuf

Early Experience Printing Implantable Devices Printed 3-D models are currently used for surgical planning in complex cases, especially in pediatric congenital heart procedures, said Richard G. Ohye, M.D., professor of cardiac surgery, head, section of pediatric cardiovascular surgery, surgical director, pediatric cardiovascular transplant program, co-director, Michigan Congenital Heart Center, C.S. Mott Children’s Hospital, Ann Arbor, Mich. However, he explained 3-D printing will soon allow the creation of customized implantable medical devices, including actual tissue or vessel replacements.  In fact, 3-D printed devices are already being used on a small scale.

He presented a case of a three-month-old patient whose airway was underdeveloped and required a splint to hold it open. The patient underwent a CT scan and a 3-D reconstruction of the airway allowed doctors to create a virtual airway splint implant customized to fit into the small anatomy. The design included a “C”-shaped tube that had numerous holes to use as suture anchor points. The shape was designed to allow it to expand outward as the patient grew. They then 3-D printed the splint from bioresorbable plastic and implanted it in the patient. He said the material it was made from is expected to dissolve within three to four years.

The Finnish dental equipment maker Planmeca recently introduced a 3-D printer that allows dental laboratories and large clinics to create dental splints, models and surgical guides. In the near future, the Planmeca Creo printer will also support the creation of intricate, customized temporary fillings. The jump to printing full organs to transplant is much more complex, but the groundwork is being laid today. Ohye said engineered heart tissue created using cardiac stem cells has already been created, but it is limited to a size of about 200 microns. Anything larger requires blood vessels to keep the cells alive, he explained.

3-D Printing of Biological Tissue Implants Research is being conducted to enable 3-D printing of blood vessels, where cells are deposited by the robotically driven printer in patterns that build up layer-by-layer to create a lumen. That same concept is being tested at a few centers to create 3-D print heart valves. Ohye said the process currently being investigated used a printed matrix of biocompatible material, in which stem cells can then be deposited. If the process can be worked out to create engineered, printed organs, these might be used to create benchtop model organs for new drug testing in the next few years. Implantable 3-D printed living organs for transplant into human patients are also a very real possibility.

“Bioprinting is likely to be a huge field for the future of medicine,” said Roger Markwald, Ph.D., director, Cardiovascular Developmental Biology Center, Medical University of South Carolina. He is involved with The South Carolina Project for Organ Biofabrication, one of the groups at the forefront of 3-D bioprinting research. He explained there are too few organ donors to meet demand and there is an even greater need for soft tissues for reconstructive surgeries for things such as injuries, burns, infections, tumor resections and congenital malformations.  “There are too few organ donors to meet the needs,” Markwald said. “At least 21 people die each day because of the lack of implants.”  This organ shortage might be solved in the future by bioprinting organs on demand.

Biomaterials can be printed using current technology, but there is a fatal flaw. “The Achilles heel of tissue engineering today is the need to create vascularity in the structure, and that has been the focus of what we have been trying to do,” Markwald said.   The key to printing vascularizable micro-organs may involve chemical modifications of alginate hydrogels. Markwald’s lab created an oxidized alginate, which is biodegradable and provides stability for 3-D bioprinting. It also is bioactive, allowing cells to migrate and remodel. They created “plug and play” molds to prepare micro-organ constructs for surgical implantation. These are made with the biodegradable alginate, which contain small molecules to promote host vascular in-growth and suppress inflammatory responses.

Bioprinting is enabled using a “biopaper” made of bioresorbable hydrogels. These allow printing of the cells against gravity and allow the cells to grow, interact and function physiologically. Markwald said research is leading to the development of hydrogels specific to each type of organ tissue.  The “bioink” is made from 300 micron diameter spheroids that contain between 8,000-12,000 autologous adipose-derived stem cells. He said it takes about 7 million cells to make 840 spheroids, and it takes thousands of these spheroids to print a 1 mm cube.

Just as 3-D printing allows simultaneous printing of several different colors of materials to build a color 3-D model, bioprinting is being developed to allow use of several different cell types to create complex tissue units.  “Eventually we will be able to make functional hearts or livers,” Markwald said. “What we can print right now are cardiac patches and small- to medium-sized blood vessels, skin tissue, soft tissue (adipose, muscle) for reconstructive surgery, and vascularized micro-organs that can be grown in a bioreactor and used to supplement the function of a diseased organ like the liver.”

Creating 3-D Printable Files Creating files for 3-D printing from medical imaging datasets starts with good imaging, said Shuai Leng, Ph.D., associate professor of medical physics, Mayo Clinic, Rochester, Minn. “If you start with garbage in, you get garbage out, so you need good image quality,” he stressed.   To create a usable 3-D file, he suggests using 0.6 mm thin imaging slices. This allows for very smooth surfaces. By comparison, he said use of 6 mm slices will make the printed object very rough and textured, appearing pixelated, when it is printed in 3-D.  He said dual-energy CT is great for 3-D printing because it can easily exclude bone so only blood vessels or soft tissue remain in the image area.

Metal implants commonly cause problems when creating 3-D printing files, but dual-energy systems have metal artifact reduction software to separate the metal and artifacts from the anatomy to allow creation of better models.  When using 3-D models for procedural planning and navigation, you need to ensure the precision of the model by using U.S. Food and Drug Administration (FDA)-cleared 3-D printing software, such as programs offered by Stratasys or Materialise. The resulting printed models also should be compared to the original images to ensure quality control. Before printing, images should be checked in three planes and approved by a radiologist or the ordering physician.  The final imaging files are converted into STL/CAD files that can be read by the 3-D printers and translated into the final 3-D object.

Legal Considerations Regarding 3-D printing The field of 3-D printing comes with a new set of legal questions hospitals using the technology will need to consider, said Bruce Kline, a technology licensing manager who oversees patents for new technology developed at Mayo Clinic. For starters, he said the STL files printers use are a lot like MP3 music files, in that they can be protected under copyright and require licensing to use. Copyright violations can occur if a purchased STL anatomical model file for rare disease is illegally shared with another institution that did not purchase the file from the vendor that created the file. Under the law, if a device has a functional use it falls under patent law. If it is not functional, it falls under copyright law. Kline said most medical 3-D printing for educational models and complex anatomy evaluation currently falls under copyright. But, he said that will rapidly change in the coming years as customizable 3-D printable medical devices see wider use. Additive manufacturing allows the creation of patient-specific devices at the point of care. Kline said an interesting fact is that these devices are FDA 510(k)-exempt if produced by a hospital instead of a medical device vendor. He said this blurs the lines between traditional vendor relationships, since the hospital can now become the manufacturer. However, if a hospital makes a device, it also becomes liable for it.

He advised that it might be better for a commercial vendor to make the device for the hospital so the vendor assumes the liability of the device.   Custom-made medical devices are also exempt under FDA regulations, Kline said. So, if a physician creates or modifies a device to meet the clinical needs of a specific patient’s anatomy, he said it is acceptable to use under current FDA rules. This may leave the door wide open for use of 3-D printed devices that are customized for each patient using their own 3-D imaging datasets.  It is possible printable device files may become available in the next few years to customize and print on demand. However, Kline said it will be much more difficult to enforce patents on these types of devices. He explained if someone makes one or two devices, there is no economical way for the creator of those device files to go after the user/maker of unlicensed copies of the device to claim lost profits. Currently, Kline said surgical planning models created with 3-D printing are not reimbursable. No CPT code exists for their use, because he said CPT codes are based on clinical trial data showing clinical efficacy to justify reimbursement.

Proposed FDA Guidance for 3-D Printing   In May, the FDA released the draft guidance “Technical Considerations for Additive Manufactured Devices,” for public comment. It is a leapfrog guidance document to provide FDA’s initial thoughts on technical considerations specific to 3-D printed devices. Specifically, this draft guidance outlines technical considerations associated with additive manufacturing processes, and the testing and characterization for final finished devices fabricated using 3-D printing. It is intended to serve as a mechanism by which the agency can share initial thoughts regarding the content of premarket submissions for emerging technologies and new clinical applications that are likely to be of public health importance very early in product development. The draft document was created following a fall 2014 workshop where 3-D printing experts discussed all the facets of 3-D printing and attempted to anticipate the issues and questions that will be raised as 3-D printable devices begin to come before the FDA for review in the coming years. 

The FDA notes that in medical device applications, 3-D printing has the advantage of facilitating the creation of anatomically matched devices and surgical instrumentation by using a patient’s own medical imaging. The FDA said another advantage is the ease in fabricating complex geometric structures, allowing the creation of engineered open lattice structures, tortuous internal channels and internal support structures that would not be easily made or possible using traditional manufacturing approaches.  However, the FDA stated the unique aspects of the printing process, such as the layer-wise fabrication and the relative lack of history of medical devices manufactured using 3-D printing techniques, pose challenges in determining optimal characterization and assessment methods for the final finished device. There are also questions as to the optimal process validation and verification methods for these devices. The FDA is gathering public feedback on the draft document through August, 2016. The draft document can be found online at www.fda.gov/ucm/groups/fdagov-public/@fdagov-meddev-gen/documents/document/ucm499809.pdf

Partnerships Make 3-D More Accessible The setup and maintenance costs for 3-D printing are more involved than many hospitals want to get involved with. This is especially true at centers where there is very limited application. This has led to partnerships between advanced imaging vendors and 3-D printer vendors to create contract services for one-off printing projects.  Advanced visualization software company Vital Images announced a partnership with 3-D printer company Stratasys at the Radiological Society of North America (RSNA) 2015 annual meeting. They created the industry’s first print-on-demand service using Vital’s Vitrea advanced visualization software and Stratasys’ 3-D printing services. Vital Images’ software takes patient scans and converts them into STL files that can be sent directly to a 3-D printer, improving workflow efficiency and 3-D printing accessibility.

GE Healthcare is working with 3-D printer vendor Materialise to develop a software package that will allow the easy creation of 3-D printable files from GE 3-D ultrasound sound systems. GE hopes to have commercial product launch for this technology later in 2016.  Materialise already offers its Mimics Innovation Suite software to create 3-D printer files from medical imaging. Its latest version includes the ability to create images not only from MRI and CT datasets, but also from fluoroscopic imaging from C-arms. It also includes a virtual X-ray tool to allow engineers to create projects to find the optimal angle for 2-D/3-D registration. This allows for an evaluation of the 3-D position of bones and implants without a post-operative CT or MRI scan. It has an automated heart segmentation tool to easily separate the cardiovascular anatomy for advanced research and analyses. The vendor said on a good quality dataset, segmentation now requires only a few mouse clicks rather than several hours of tedious work.

Editor’s Choice of the Most Innovative Trends and Technologies ACC.16 – See more at: http://www.dicardiology.com/article/future-3-d-printing-medicine?eid=333021707&bid=1408765#sthash.M7AYV16i.dpuf

Stratasys to Present Power of 3-D Printing at HIMSS 2016 – See more at: http://www.dicardiology.com/article/future-3-d-printing-medicine?eid=333021707&bid=1408765#sthash.M7AYV16i.dpuf

 

Selecting the Right Material for 3D Printing

This industrial 3D printing white paper explores the properties of thermoplastic and metal materials available with direct metal laser sintering, selective laser sintering and stereolithography technologies. It also includes a quick-reference guide of material attributes that can steer you toward the proper grade.

http://whitepapers.ecnmag.com/20160517_proto_3d

Click to access 3D-Printing-Materials-WP-US-Final.pdf

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