Archive for the ‘Tissue Engineering’ Category

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.



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New Liver Tissue Implants Showing Potential

Reporter: Irina Robu, MSc, PhD

To develop new tissues, researchers at the Medical Research Council Centre 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 reprograming technologies to provide renewable supplies of liver tissue products for transplantation.


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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.



Printed human body parts could soon be available for transplant


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


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


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


Our Grandkids May Be Born From 3D-Printed Ovaries


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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.





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3-D Printed Liver

Curator: Larry H. Bernstein, MD, FCAP



3D-printing a new lifelike liver tissue for drug screening

Could let pharmaceutical companies quickly do pilot studies on new drugs
February 15, 2016

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.

Fernando commented on 3-D printed liver

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.


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New Scaffold-Free 3D Bioprinting Method Available to Researchers

Reporter: Irina Robu, PhD


UPDATED ON 2/6/2016



Bio 3D Printer Regenova with Kenzan method



Cyfuse and Cyberdyne Are Pushing the Boundaries of 3D Printed Human Engineering With Regenova

by TE Halterman | Mar 3, 2015 | 3D Printers3D PrintingHealth 3D Printing |





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



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.


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Platform Technologies for Directly Reconstructing 3D Living Biomaterials

Reported by: 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.


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