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Archive for the ‘BioPrinting in Regenerative Medicine’ Category


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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 A Revolution in Medicine: Medical 3D BioPrinting

Curated by : Irina Robu, PhD

Imagine a scenario, where years from now, one of your organs stop working properly. What would you do?  The current option is to wait in line for a transplant, hoping that the donor is a match. But what if you can get an organ ready for you with no chance of rejection? Even though it may sound like science fiction at the current moment, organ 3D bioprinting can revolutionize medicine and health care.

I have always found the field of tissue engineering and 3D bioprinting fascinating. What interests me about 3D bioprinting is that it has the capacity to be a game changer, because it would make organs widely available to those who need them and it would eliminate the need for a living or deceased donor.  Moreover, it would be beneficial for pediatric patients who suffer specific problems that the current bio-prosthetic options might not address. It would minimize the risk of rejection as well as the components would be customized to size.

There have been advancements in the field of 3D bioprinting and one such advancement is using a 3D printed cranium by neurosurgeons at the University Medical Centre Utrecht. The patient was a young woman who suffered from a chronic bone disorder. The 3D reconstruction of her skull would minimize the brain damage that might have occurred if doctors used a durable plastic cranium.

So, what exactly is bioprinting? 3D bioprinting is an additive manufacturing procedure where biomaterials, such as cells and growth factors, are combined to generate tissue-like structures that duplicate natural tissues. At its core, bioprinting works in a similar way to conventional 3D printing. A digital model becomes a physical 3D object layer-by-layer.  However, in the case of bioprinting, a living cell suspension is used instead of a thermoplastic.

The procedure mostly involves preparation, printing, maturation and application and can be summarized in three steps:

  1. Pre-bioprinting step which includes creating a digital model obtained by using computed tomography (CT) and magnetic resonance imaging (MRI) scans which are then fed to the printer.
  2. Bioprinting step where the actual printing process takes place, where the bioink is placed in a printer cartridge and deposition occurs based on the digital model.
  3. Post-bioprinting step is the mechanical and chemical stimulation of printed parts in order to create stable biostructures which can ultimately be implanted.

3D bioprinting allows suitable microarchitectures that provide mechanical stability and promote cell ingrowth to be produced while preventing any homogeneity issues that occur after conventional cell seeding, such as cell placement. Immediate vascularization of implanted scaffolds is critical, because it provides an influx of nutrients and outflow of by-products preventing necrosis. The benefits of homogeneous seeded scaffolds are that it allows them to integrate faster into the host tissue, uniform cell growth in vivo and lower risk of rejection.

However, in order to address the limitations of the commercially available technology for producing tissue implants, researchers are working to develop a 3D bioprinter that can fit into a laminar flow hood, ultra-low cost and customizable for different organs. Bioprinting can be applied in a clinical setting where the ultimate goal is to implant 3D bioprinted structures into the patients, it is necessary to maintain sterile printing solutions and ensure accuracy in complex tissues, needed for cell-to-cell distances and correct output.

The final aim of bioprinting is to promote an alternative to autologous and allogeneic tissue implants, which will replace animal testing for the study of disease and development of treatments.  We know that for now a short-term goal for 3D bioprinting is to create alternatives to animal testing and to increase the speed of drug testing. The long-term goal is to change the status quo, to develop a personalized organ made from patient’s own cells. However, some ethical challenges still exist regarding the ownership of the organ.

A powerful starting point is the creation of tissue components for heart, liver, pancreas, and other vital organs.  Moreover, each small progress in 3D bioprinting will allow 3D bioprinting to make organs widely available to those who need them, instead of waiting years for a transplant to become available.

I invite you to read a biomedical e-book that I had the pleasure to author along with several other scientists, called Medical 3D BioPrinting – The Revolution in Medicine Technologies for Patient-centered Medicine: From R&D in Biologics to New Medical Devices (Series E: Patient-Centered Medicine Book 4).

 

 

 

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Audio Podcasts

Reporter: Gail S. Thornton, M.A.

UPDATED on 1/11/2020

In May 2019, Aviva Lev-Ari, Ph.D., R.N., Stephen Williams, Ph.D., and Irina Robu, Ph.D., spoke with Partners in Health and Biz, an half-hour audio podcast that reaches 40,000 listeners, about the topic of 3D Medical BioPrinting Technology: A Revolution in Medicine. The topic is also the title of a recently offered e-book by the LPBI Group on 3D BioPrinting, available on Amazon/Kindle Direct [https://www.amazon.com/Medical-BioPrinting-Technologies-Patient-centered-Patient-Centered-ebook/dp/B078QVDV2W]. https://www.spreaker.com/user/pihandbiz/bioprinting-2019-final

The 3D BioPrinting technology is being used to develop advanced medical practices that will help with previously difficult processes, such as delivering drugs via micro-robots, targeting specific cancer cells and even assisting in difficult eye operations. 

The table of contents in this book includes: Chapter 1: 3D Bioprinting: Latest Innovations in a Forty year-old Technology. Chapter 2: LPBI Initiative on 3D BioPrinting, Chapter 3: Cardiovascular BioPrinting, Chapter 4: Medical and Surgical Repairs – Advances in R&D Research, Chapter 5: Organ on a Chip, Chapter 6: FDA Regulatory Technology Issues, Chapter 7: DNA Origami, Chapter 8: Aptamers and 3D Scaffold Binding, Chapter 9: Advances and Future Prospects, Chapter 10: BioInks and MEMS, Chapter 11: BioMedical MEMS, Chapter 12: 3D Solid Organ Printing and Chapter 13: Medical 3D Printing: Sources and Trade Groups – List of Secondary Material. 

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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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Immunoediting can be a constant defense in the cancer landscape


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

There are many considerations in the cancer immunoediting landscape of defense and regulation in the cancer hallmark biology. The cancer hallmark biology in concert with key controls of the HLA compatibility affinity mechanisms are pivotal in architecting a unique patient-centric therapeutic application. Selection of random immune products including neoantigens, antigens, antibodies and other vital immune elements creates a high level of uncertainty and risk of undesirable immune reactions. Immunoediting is a constant process. The human innate and adaptive forces can either trigger favorable or unfavorable immunoediting features. Cancer is a multi-disease entity. There are multi-factorial initiators in a certain disease process. Namely, environmental exposures, viral and / or microbiome exposure disequilibrium, direct harm to DNA, poor immune adaptability, inherent risk and an individual’s own vibration rhythm in life.

 

When a human single cell is crippled (Deranged DNA) with mixed up molecular behavior that is the initiator of the problem. A once normal cell now transitioned into full threatening molecular time bomb. In the modeling and creation of a tumor it all begins with the singular molecular crisis and crippling of a normal human cell. At this point it is either chop suey (mixed bit responses) or a productive defensive and regulation response and posture of the immune system. Mixed bits of normal DNA, cancer-laden DNA, circulating tumor DNA, circulating normal cells, circulating tumor cells, circulating immune defense cells, circulating immune inflammatory cells forming a moiety of normal and a moiety of mess. The challenge is to scavenge the mess and amplify the normal.

 

Immunoediting is a primary push-button feature that is definitely required to be hit when it comes to initiating immune defenses against cancer and an adaptation in favor of regression. As mentioned before that the tumor microenvironment is a “mixed bit” moiety, which includes elements of the immune system that can defend against circulating cancer cells and tumor growth. Personalized (Precision-Based) cancer vaccines must become the primary form of treatment in this case. Current treatment regimens in conventional therapy destroy immune defenses and regulation and create more serious complications observed in tumor progression, metastasis and survival. Commonly resistance to chemotherapeutic agents is observed. These personalized treatments will be developed in concert with cancer hallmark analytics and immunocentrics affinity and selection mapping. This mapping will demonstrate molecular pathway interface and HLA compatibility and adaptation with patientcentricity.

References:

 

https://www.linkedin.com/pulse/immunoediting-cancer-landscape-john-catanzaro/

 

https://www.cell.com/cell/fulltext/S0092-8674(16)31609-9

 

https://www.researchgate.net/publication/309432057_Circulating_tumor_cell_clusters_What_we_know_and_what_we_expect_Review

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840207/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00414/full

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388310/

 

https://www.linkedin.com/pulse/cancer-hallmark-analytics-omics-data-pathway-studio-review-catanzaro/

 

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3D Print Shape-Shifting Smart Gel

Reporter: Irina Robu, PhD

Hydrogel scaffolds that mimic the native extracellular matrix (ECM) environment play a crucial role in tissue engineering and they are ubiquitously in our lives, including in contact lenses, diapers and the human body.

Researchers at Rutgers have invented a printing method for a smart gel that can be used to create materials for transporting small molecules like drugs to human organs. The approach includes printing a 3D object with a hydrogel that changes shape over time when temperature changes. The potential of the smart hydrogels could be to create a new are of soft robotics and enable new applications in flexible sensors and actuators, biomedical devices and platforms or scaffolds for cells to grow.

Rutgers engineers operated with a hydrogel that has been in use for decades in devices that generate motion and biomedical applications such as scaffolds for cells to grow on. The engineers learned how to precisely control hydrogel growth and shrinkage. In temperatures below 32 degrees Celsius, the hydrogel absorbs more water and swells in size. When temperatures exceed 32 degrees Celsius, the hydrogel begins to expel water and shrinks, the study showed.

According to the Rutgers engineers, the objects they can produce with the hydrogel range from the width of a human hair to several millimeters long. The engineers also showed that they can grow one area of a 3D-printed object by changing temperatures.

Source

https://news.rutgers.edu/rutgers-engineers-3d-print-shape-shifting-smart-gel/20180131

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New Liver Tissue Implants Showing Potential

Reporter: Irina Robu,PhD

To develop new tissues, researchers at the Medical Research Council Center for Regenerative Medicine at the University of Edinburgh have found that stem cells transformed into 3-D liver tissue can support liver function when implanted into the mice suffering with a liver disease.

The scientists stimulated human embryonic stem cells and induced pluripotent stem cells to mature pluripotent stem cells into liver cells, hepatocytes. Hepatocytes are the chief functional cells of the liver and perform an astonishing number of metabolic, endocrine and secretory functions. Hepatocytes are exceptionally active in synthesis of protein and lipids for export. The cells are grown in 3-D conditions as small spheres for over a year. However, keeping the stem cells as liver cells for a long time is very difficult, because the viability of hepatocytes decreases in-vitro conditions.

Succeeding the discovery, the team up with materials chemists and engineers to detect appropriate polymers that have already been approved for human use that can be developed into 3-D scaffolds. The best material to use a biodegradable polyester, called polycaprolactone (PCL).PCL is degraded by hydrolysis of its ester linkages in physiological conditions (such as in the human body) and it is especially interesting for the preparation of long term implantable devices, owing to its degradation which is even slower than that of polylactide. They spun the PCL into microscopic fibers that formed a scaffold one centimeter square and a few millimeters thick.

At the same time, hepatocytes derived from embryonic cells had been grown in culture for 20 days and were then loaded onto the scaffolds and implanted under the skin of mice.Blood vessels successfully grew on the scaffolds with the mice having human liver proteins in their blood, demonstrating that the tissue had successfully integrated with the circulatory system. The scaffolds were not rejected by the animals’ immune systems.

The scientists tested the liver tissue scaffolds in mice with tyrosinaemia,a potentially fatal genetic disorder where the enzymes in the liver that break down the amino acid tyrosine are defective, resulting in the accumulation of toxic metabolic products. The implanted liver tissue aided the mice with tyrosinaemia to break down tyrosine and the mice finally lost less weight, had less buildup of toxins in the blood and exhibited fewer signs of liver damage than the control group that received empty scaffolds.

According to Rob Buckle, PhD, Chief Science Officer at the MRC, “Showing that such stem cell-derived tissue is able to reproduce aspects of liver function in the lab also offers real potential to improve the testing of new drugs where more accurate models of human tissue are needed”. It is believed that the discovery could be the next step towards harnessing stem cell reprogramming technologies to provide renewable supplies of liver tissue products for transplantation.

SOURCE

https://www.rdmag.com/article/2018/08/new-liver-tissue-implants-showing-promise?et_cid=6438323

 

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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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Nanostraws Developed at Stanford Sample a Cell’s Contents without Damage

Reporter: Irina Robu, PhD

Cells within our bodies change over time and divide, with thousands of chemical reactions happening within cell daily. Nicholas Melosh, Associate Professor of Materials Science and Engineering, developed a new, non-destructive system for sampling cells with nanoscale straws which could help uncover mysteries about how cells function.

Currently, cells are sampled via lysing which ruptures the cell membrane which means that it can’t ever be sampled again. The sample system that Dr. Melosh invented banks on, on tiny tubes 600 times smaller than a strand of hair that allow researchers to sample a single cell at a time. The nanostraws penetrate a cell’s outer membrane, without damaging it, and draw out proteins and genetic material from the cell’s salty interior.

The Nanostraw sampling technique, according to Melosh, will knowingly impact our understanding of cell development and could result to much safer and operational medical therapies because the technique allows for long term, non-destructive monitoring. The sampling technique could also inform cancer treatments and answer questions about why some cancer cells are resistant to chemotherapy while others are not. The sampling platform on which the nanostraws are grown is tiny, similar to the size of a gumball. It’s called the Nanostraw Extraction (NEX) sampling system, and it was designed to mimic biology itself.

The goal of developing this technology was to make an impact in medical biology by providing a platform that any lab could build.

SOURCE

http://news.stanford.edu/2017/02/20/minuscule-nanostraws-sample-cells-contents-without-damage

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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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