Healthcare analytics, AI solutions for biological big data, providing an AI platform for the biotech, life sciences, medical and pharmaceutical industries, as well as for related technological approaches, i.e., curation and text analysis with machine learning and other activities related to AI applications to these industries.
Engineers and scientists at California Institute of Technology (Caltech) and ETH Zurich developed an artificial skin capable of detecting temperature changes using a mechanism similar to the biological mechanism that allow snakes to sense prey through heat. In those organs, ion channels in the cell membrane of sensory nerve fibers expand as temperature increases. This dilation allows calcium ions to flow, triggering electrical impulses.
The material used is a long chain molecule found in plant cells which gives the skin its temperature sensing capabilities. The team chose pectin because the pectin molecules in the film have a weakly bonded double-strand structure that contains calcium ions. As temperature increases, these bonds break down and the double strands “unzip,” releasing the positively charged calcium ions.
This would make pectin sensors useful for industrial applications, such as thermal sensors in consumer electronics or robotic skins to augment human-robot interactions. However, they need to change the fabrication process as that the current process leads to the presence of water which tends to bubble or evaporate at high temperatures.
Implants are gradually being used to treat various bone defects. A key factor for long term success of implants is the proper selection of the implant biomaterial. The biologic environment does not accept completely any material so to optimize biologic performance, implants should be selected to reduce the negative biologic response while maintaining adequate function. The implanted structure must if possible stimulate new bone formation, integrate with existing tissue and lastly be resorbed by the body to enable healthy bone growth.
The EU-funded MGNIM project which tailored biodegradable magnesium implant materials focused on producing aluminum- free Mg-based material suitable for bone applications. MAGNIM produced over 20 different Mg alloys and evaluated their mechanical and structural properties. In addition, they assessed their biological interaction, more specifically their corrosion-behavior. Out of these, two of the new alloys (Mg-2Ag and Mg-10Gd) were nominated for animal trials as pilot results indicated an anti-inflammatory function of degradation products.
The two new alloys, Mg-2Ag and Mg-10Gd as well as Mg alloy WE43 were tested in-vivo for biodegradability and functionality. Screws made of these materials were inserted into the femur of rats and their degradation was monitored. Imaging and histological data from explants revealed new bone formation in the screw implant site.
Even though the project has ended, additional testing in large animal models will be carried out prior to human clinical trials. MAGNIM partners propose to optimize implant material homogeneity and surface properties.
For years, scientists have tried ineffectively to create an artificial molecule that emulates the oxygen-carrying function of human red blood cell but the efforts failed because of oxygen delivery and safety issues. Now, a group of researchers led by Dr. Alan Doctor at Washington University in Saint Louis, are trying to resuscitate blood substitutes with a new nanotechnology-based, artificial red blood cell may overcome the problems that killed products designed by a team of companies such as Biopure, Alliance Pharmaceuticals, Northfield Labs and even Baxter. Dr. Alan Doctor’s new company, Kalocyte is advancing the development of the
The donut-shaped artificial cells, ErythroMer are one-fiftieth the size of human red blood cells. ErythroMer is a novel blood substitute composed of a patented nanobialys nanoparticle. A special lining and control system tied to changes in blood Ph allows Erythromer to grab onto oxygen in the lungs and then dispense the oxygen in tissues where it is needed. The new artificial cells are intended to sidestep problems with vasoconstriction or narrowing of blood vessels.
Erythromer is stored freeze dried and reconstituted with water when needed but it can also be stored at room temperature which makes it for military and civilian trauma.
Trials have been successful in rats, mice, and rabbits, and human trials are planned. However, moving Erythromer into human clinical trials is still 8-10 years away.
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.
Fibrin-coated Electrospun Polylactide Nanofibers Potential Applications in Skin Tissue Engineering
Reported by: Irina Robu, PhD
Fibrin plays an essential role during wound healing and skin regeneration and is often applied for the treatment of skin injuries. Fibrin is formed after thrombin cleavage of fibrinopeptide A from fibrinogen Aalpha-chains, thus initiating fibrin polymerization. Double-stranded fibrils form through end-to-middle domain (D:E) associations, and concomitant lateral fibril associations and branching create a clot network. In addition, its primary role is to provide scaffolding for the intravascular thrombus.
Dr. Lucie Bacakova and her colleagues from Department of Biomaterials and Tissue engineering at Czech Academy of Sciences prepared electrospun nanofibrious membranes made from poly(L-lactide) modified with a thin fibrin nanocoating. The cell-free fibrin nanocating remained stable in cell culture medium for 14 days and did not change its morphology. The rate of fibrin degradation is correlated to the degree of cell proliferation on membrane populated with human dermal fibroblasts. It was shown that the cell spreading, mitochondrial activity and cell population density were higher on membranes coated with fibrin than on nonmodified membranes. The cell performance was improved by adding ascorbic acid in the cell culture medium. At the same time, fibrin stimulated the expression and synthesis of collagen I in human dermal fibroblasts. The expression of beta-integrins was improved by fibrin. And it is shown that the combination of nanofibrous membranes with a fibrin nanocoating and ascorbic acids is beneficial to tissue engineering.
Images of the 3D-printed parts of the biomimetic liver tissue: liver cells derived from human induced pluripotent stem cells (left), endothelial and mesenchymal supporing cells (center), and the resulting organized combination of multiple cell types (right). (credit: Chen Laboratory, UC San Diego)
University of California, San Diego researchers have 3D-printed a tissue that closely mimics the human liver’s sophisticated structure and function. The new model could be used for patient-specific drug screening and disease modeling and could help pharmaceutical companies save time and money when developing new drugs, according to the researchers.
The liver plays a critical role in how the body metabolizes drugs and produces key proteins, so liver models are increasingly being developed in the lab as platforms for drug screening. However, so far, the models lack both the complex micro-architecture and diverse cell makeup of a real liver. For example, the liver receives a dual blood supply with different pressures and chemical constituents.
So the team employed a novel bioprinting technology that can rapidly produce complex 3D microstructures that mimic the sophisticated features found in biological tissues.
The liver tissue was printed in two steps.
The team printed a honeycomb pattern of 900-micrometer-sized hexagons, each containing liver cells derived from human induced pluripotent stem cells. An advantage of human induced pluripotent stem cells is that they are patient-specific, which makes them ideal materials for building patient-specific drug screening platforms. And since these cells are derived from a patient’s own skin cells, researchers don’t need to extract any cells from the liver to build liver tissue.
Then, endothelial and mesenchymal supporting cells were printed in the spaces between the stem-cell-containing hexagons.
The entire structure — a 3 × 3 millimeter square, 200 micrometers thick — takes just seconds to print. The researchers say this is a vast improvement over other methods to print liver models, which typically take hours. Their printed model was able to maintain essential functions over a longer time period than other liver models. It also expressed a relatively higher level of a key enzyme that’s considered to be involved in metabolizing many of the drugs administered to patients.
“It typically takes about 12 years and $1.8 billion to produce one FDA-approved drug,” said Shaochen Chen, NanoEngineering professor at the UC San Diego Jacobs School of Engineering. “That’s because over 90 percent of drugs don’t pass animal tests or human clinical trials. We’ve made a tool that pharmaceutical companies could use to do pilot studies on their new drugs, and they won’t have to wait until animal or human trials to test a drug’s safety and efficacy on patients. This would let them focus on the most promising drug candidates earlier on in the process.”
The work was published the week of Feb. 8 in the online early edition of Proceedings of the National Academy of Sciences.
Abstract of Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting
The functional maturation and preservation of hepatic cells derived from human induced pluripotent stem cells (hiPSCs) are essential to personalized in vitro drug screening and disease study. Major liver functions are tightly linked to the 3D assembly of hepatocytes, with the supporting cell types from both endodermal and mesodermal origins in a hexagonal lobule unit. Although there are many reports on functional 2D cell differentiation, few studies have demonstrated the in vitro maturation of hiPSC-derived hepatic progenitor cells (hiPSC-HPCs) in a 3D environment that depicts the physiologically relevant cell combination and microarchitecture. The application of rapid, digital 3D bioprinting to tissue engineering has allowed 3D patterning of multiple cell types in a predefined biomimetic manner. Here we present a 3D hydrogel-based triculture model that embeds hiPSC-HPCs with human umbilical vein endothelial cells and adipose-derived stem cells in a microscale hexagonal architecture. In comparison with 2D monolayer culture and a 3D HPC-only model, our 3D triculture model shows both phenotypic and functional enhancements in the hiPSC-HPCs over weeks of in vitro culture. Specifically, we find improved morphological organization, higher liver-specific gene expression levels, increased metabolic product secretion, and enhanced cytochrome P450 induction. The application of bioprinting technology in tissue engineering enables the development of a 3D biomimetic liver model that recapitulates the native liver module architecture and could be used for various applications such as early drug screening and disease modeling.
I wonder how equivalent are these hepatic cells derived from human induced pluripotent stem cells (hiPSCs) compared with the real hepatic cell populations.
All cells in our organism share the same DNA info, but every tissue is special for what genes are expressed and also because of the specific localization in our body (which would mean different surrounding environment for each tissue). I am not sure about how much of a step forward this is. Induced hepatic cells are known, but this 3-D print does not have liver shape or the different cell sub-types you would find in the liver.
I agree with your observation that having the same DNA information doesn’t account for variability of cell function within an organ. The regulation of expression is in RNA translation, and that is subject to regulatory factors related to noncoding RNAs and to structural factors in protein folding. The result is that chronic diseases that are affected by the synthetic capabilities of the liver are still problematic – toxicology, diabetes, and the inflammatory response, and amino acid metabolism as well. Nevertheless, this is a very significant step for the testing of pharmaceuticals. When we look at the double circulation of the liver, hypoxia is less of an issue than for heart or skeletal muscle, or mesothelial tissues. I call your attention to the outstanding work by Nathan O. Kaplan on the transhydrogenases, and his stipulation that there are significant differences between organs that are anabolic and those that are catabolic in TPNH/DPNH, that has been ignored for over 40 years. Nothing is quite as simple as we would like.
3-D printed liver Larry H. Bernstein, MD, FCAP, Curator LPBI 3D-printing a new lifelike liver tissue for drug …
I wonder how equivalent are these hepatic cells derived from human induced pluripotent stem cells (hiPSCs) compared with the real hepatic cell populations.
All cells in our organism share the same DNA info, but every tissue is special for what genes are expressed and also because of the specific localization in our body (which would mean different surrounding environment for each tissue). I am not sure about how much of a step forward this is. Induced hepatic cells are known, but this 3-D print does not have liver shape or the different cell sub-types you would find in the liver.
New scaffold-free 3-D bioprinting method available for first time in North America
Cell Applications primary cells and Regenova 3D Bio Printer from Cyfuse Biomedical combine to print robust 3-D tissue without introduction of extraneous scaffolding material
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Regenova, Bio 3D Printer by Cyfuse
Cyfuse Biomedical K.K. and Cell Applications.Inc. publicized on February 3, 2016 that advanced tissue engineering services using 3D bioprinting approach will be available in North America. The services involved using Cyfuse Biomedica’s Regenova 3D Bio Printer, a state of the art robotic system that produces 3D tissues from cell and Cell Applications has created a pay by service bio-printing model that produces scaffold-free tissue available immediately to scientists in the U.S. and Canada for research use.
According to James Yu, Founder and CEO of Cell Applications having the Regenova 3D Bio Printer at our San Diego headquarters offers researchers an end-to-end, customized solution for creating scaffold-free, 3D-engineered tissues that diminish costs by reducing the lengthy processes typical in pharmaceutical drug discovery. In addition , Koji Kuchiishi, CEO of Cyfuse Biomedical having the Regenova 3D Bio Printer, combined with Cell Applications’ comprehensive, high-quality primary cell bank, offers researchers streamlined access to a nearly limitless selection of three dimensional tissues including those mimicking blood vessels, human neural tissue and liver constructs.
Unlike the other bioprinters on the market the bio-printer made by Regenova does not depend on scaffolding made of biomaterials such as collage or hydrogel to construct 3D tissue, the instrument assembles three dimensional microscopic tissue by forming spheroids, one at the time and lancing them on a fine needle array. The spheroids are guided by pre-programmed software which can be design and constructed into rods, spheres, tubes, sheets and other tissue configurations. In order for the engineered tissue to mature a bioreactor chamber is used. As the cells mature, they self-organize promoting strong, reliable tissue that can be further optimized by design of bio printer’s needle array that allows for optimum circulation of culture medium.
Scientists based at Ecole Polytechnique Fédérale de Lausanne led by Matthias Lutolf have been engineering 3D extracellular matrices—gels. These scientists report that they have developed a gel that boosts the ability of normal cells to revert into stem cells by simply “squeezing” them.
The detail of the scientists’ work appeared in Nature Materials, January 11, 2015 in an article entitled, “Defined three-dimensional microenvironments boost induction of pluripotency.” According to the authors they find that the physical cell confinement imposed by the 3D microenvironment boosts reprogramming through an accelerated mesenchymal-to-epithelial transition and increased epigenetic remodeling. They concluded that 3D microenvironmental signals act synergistically with reprogramming transcription factors to increase somatic plasticity.
The researchers discovered that they could reprogram the cells faster and more efficiently by simply adjusting the composition, hence the stiffness and density of the surrounding gel. As a result, the gel exerts different forces on the cells, “squeezing” them.
The scientists propose that the 3D environment is key to this process, generating mechanical signals that work together with genetic factors to make the cell easier to transform into a stem cell. The technique can be applied to a large number of cells to produce stem cells on an industrial scale.
Platform Technologies for Directly Reconstructing 3D Living Biomaterials
Reporter: Irina Robu, PhD
The techniques of electrospraying and electrospinning have existed for at least a century. These techniques employs a high voltage applied to a needle accommodating the flow of media, placed above a counter electrode which could either be grounded or have an opposite charge to the needle—thus introducing the charged media to an electric field.
These endeavors have demonstrated the wider applicability of these technologies and hence in the last 20 years or so have been used for the direct handling of a wide range of materials, including bio-inspired materials. These investigations have generated interest in areas such as the development of fine monolayered surfaces, fabrication of scaffolds which could be used for many laboratory-based fundamental biological studies.
In 2005, Jayasinghe et al. began investigations into both electrospraying and electrospinning of immortalized cell lines. Even though the high voltages involved, these cells were found to be viable post-electrospraying/electrospinning. Additional work has extended these studies to different cell types, both murine and human, immortalized or primary, stem cells, and even whole fertilized embryos from model organisms. Established protocols (such as flow cytometry, genetic/genomic interrogation, and microarray analysis) proved that cells processed using either electrospraying or electrospinning were indistinguishable from controls. Hence bio-electrospraying (BES) and cell electrospinning (CE) have become platform technologies for the biological and life science and are the leading technologies for the direct handling of cells—both for distribution of cells with pinpoint precision as cell-bearing droplets, and for the formation of truly 3D living scaffolds.
Previous studies have been carried out with processed cells suspended in matrices generated from animal/tumor-derived materials which contain largely uncharacterized growth factors and bioactive signals. This makes them very undesirable for clinical assays. While not applicable to humans, they can be used with advanced biopolymers, which could be directly translated to humans, and have the potential for creating artificial constructs which could be used for a variety of applications in the regenerative medicine field. The present study describes the in vivo application of such biopolymers, using murine macrophages to interrogate biocompatibility and cellular behavior post-transfer.
Research on Scaffolds to support Stem Cells prior to Implantation
Reporter: Aviva Lev-Ari, PhD, RN
Fibrous Scaffolds with Varied Fiber Chemistry and Growth Factor Delivery Promote Repair in a Porcine Cartilage Defect Model
Iris L. Kim, Christian G. Pfeifer, Matthew B. Fisher, Vishal Saxena, Gregory R. Meloni, Mi Y. Kwon, Minwook Kim, David R. Steinberg, Robert L. Mauck, Jason A. Burdick
Tissue Engineering Part A. November 2015: 2680-2690.
Hydrogel Microencapsulated Insulin-Secreting Cells Increase Keratinocyte Migration, Epidermal Thickness, Collagen Fiber Density, and Wound Closure in a Diabetic Mouse Model of Wound Healing
Ayesha Aijaz, Renea Faulknor, François Berthiaume, Ronke M. Olabisi
Tissue Engineering Part A. November 2015: 2723-2732.
Ligament Tissue Engineering Using a Novel Porous Polycaprolactone Fumarate Scaffold and Adipose Tissue-Derived Mesenchymal Stem Cells Grown in Platelet Lysate
Eric R. Wagner, Dalibel Bravo, Mahrokh Dadsetan, Scott M. Riester, Steven Chase, Jennifer J. Westendorf,Allan B. Dietz, Andre J. van Wijnen, Michael J. Yaszemski, Sanjeev Kakar
Tissue Engineering Part A. November 2015: 2703-2713.
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