Tag Archives: organs

‘Origami organs’ for tissue engineering

This is a different approach to tissue engineering and its the consequence of a serendipitous accident.  From an Aug. 7, 2017 Northwestern University news release (also on EurekAlert),

Northwestern Medicine scientists and engineers have invented a range of bioactive “tissue papers” made of materials derived from organs that are thin and flexible enough to even fold into an origami bird. The new biomaterials can potentially be used to support natural hormone production in young cancer patients and aid wound healing.

The tissue papers are made from structural proteins excreted by cells that give organs their form and structure. The proteins are combined with a polymer to make the material pliable.

In the study, individual types of tissue papers were made from ovarian, uterine, kidney, liver, muscle or heart proteins obtained by processing pig and cow organs. Each tissue paper had specific cellular properties of the organ from which it was made.

The article describing the tissue paper and its function will be published Aug. 7 in the journal Advanced Functional Materials.

“This new class of biomaterials has potential for tissue engineering and regenerative medicine as well as drug discovery and therapeutics,” corresponding author Ramille Shah said. “It’s versatile and surgically friendly.”

Shah is an assistant professor of surgery at the Feinberg School of Medicine and an assistant professor of materials science and engineering at McCormick School of Engineering. She also is a member of the Simpson Querrey Institute for BioNanotechnology.

For wound healing, Shah thinks the tissue paper could provide support and the cell signaling needed to help regenerate tissue to prevent scarring and accelerate healing.

The tissue papers are made from natural organs or tissues. The cells are removed, leaving the natural structural proteins – known as the extracellular matrix – that then are dried into a powder and processed into the tissue papers. Each type of paper contains residual biochemicals and protein architecture from its original organ that can stimulate cells to behave in a certain way.

In the lab of reproductive scientist Teresa Woodruff, the tissue paper made from a bovine ovary was used to grow ovarian follicles when they were cultured in vitro. The follicles (eggs and hormone-producing cells) grown on the tissue paper produced hormones necessary for proper function and maturation.

“This could provide another option to restore normal hormone function to young cancer patients who often lose their hormone function as a result of chemotherapy and radiation,” Woodruff, a study coauthor, said.

A strip of the ovarian paper with the follicles could be implanted under the arm to restore hormone production for cancer patients or even women in menopause.

Woodruff is the director of the Oncofertility Consortium and the Thomas J. Watkins Memorial Professor of Obstetrics and Gynecology at Feinberg.

In addition, the tissue paper made from various organs separately supported the growth of adult human stem cells. Scientists placed human bone marrow stem cells on the tissue paper, and all the stem cells attached and multiplied over four weeks.

“That’s a good sign that the paper supports human stem cell growth,” said first author Adam Jakus, who developed the tissue papers. “It’s an indicator that once we start using tissue paper in animal models it will be biocompatible.”

The tissue papers feel and behave much like standard office paper when they are dry, Jakus said. Jakus simply stacks them in a refrigerator or a freezer. He even playfully folded them into an origami bird.

“Even when wet, the tissue papers maintain their mechanical properties and can be rolled, folded, cut and sutured to tissue,” he said.

Jakus was a Hartwell postdoctoral fellow in Shah’s lab for the study and is now chief technology officer and cofounder of the startup company Dimension Inx, LLC, which was also cofounded by Shah. The company will develop, produce and sell 3-D printable materials primarily for medical applications. The Intellectual Property is owned by Northwestern University and will be licensed to Dimension Inx.

An Accidental Spill Sparked Invention

An accidental spill of 3-D printing ink in Shah’s lab by Jakus sparked the invention of the tissue paper. Jakus was attempting to make a 3-D printable ovary ink similar to the other 3-D printable materials he previously developed to repair and regenerate bone, muscle and nerve tissue. When he went to wipe up the spill, the ovary ink had already formed a dry sheet.

“When I tried to pick it up, it felt strong,” Jakus said. “I knew right then I could make large amounts of bioactive materials from other organs. The light bulb went on in my head. I could do this with other organs.”

“It is really amazing that meat and animal by-products like a kidney, liver, heart and uterus can be transformed into paper-like biomaterials that can potentially regenerate and restore function to tissues and organs,” Jakus said. “I’ll never look at a steak or pork tenderloin the same way again.”

For those who like their news in a video,

As someone who once made baklava, that does not look like filo pastry, where an individual sheet is quite thin and rips easily. Enough said.

Here’s a link to and a citation for the paper,

“Tissue Papers” from Organ-Specific Decellularized Extracellular Matrices by Adam E. Jakus, Monica M. Laronda, Alexandra S. Rashedi, Christina M. Robinson, Chris Lee, Sumanas W. Jordan, Kyle E. Orwig, Teresa K. Woodruff, and Ramille N. Shah. Advnaced Functional Materials DOI: 10.1002/adfm.201700992 Version of Record online: 7 AUG 2017

© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

Small, soft, and electrically functional: an injectable biomaterial

This development could be looked at as a form of synthetic biology without the genetic engineering. From a July 1, 2016 news item on ScienceDaily,

Ideally, injectable or implantable medical devices should not only be small and electrically functional, they should be soft, like the body tissues with which they interact. Scientists from two UChicago labs set out to see if they could design a material with all three of those properties.

The material they came up with, published online June 27, 2016, in Nature Materials, forms the basis of an ingenious light-activated injectable device that could eventually be used to stimulate nerve cells and manipulate the behavior of muscles and organs.

“Most traditional materials for implants are very rigid and bulky, especially if you want to do electrical stimulation,” said Bozhi Tian, an assistant professor in chemistry whose lab collaborated with that of neuroscientist Francisco Bezanilla on the research.

The new material, in contrast, is soft and tiny — particles just a few micrometers in diameter (far less than the width of a human hair) that disperse easily in a saline solution so they can be injected. The particles also degrade naturally inside the body after a few months, so no surgery would be needed to remove them.

A July 1, 2016 University of Chicago news release (also on EurekAlert) by , which originated the news item, provides more detail,

Each particle is built of two types of silicon that together form a structure full of nano-scale pores, like a tiny sponge. And like a sponge, it is squishy — a hundred to a thousand times less rigid than the familiar crystalline silicon used in transistors and solar cells. “It is comparable to the rigidity of the collagen fibers in our bodies,” said Yuanwen Jiang, Tian’s graduate student. “So we’re creating a material that matches the rigidity of real tissue.”

The material constitutes half of an electrical device that creates itself spontaneously when one of the silicon particles is injected into a cell culture, or, eventually, a human body. The particle attaches to a cell, making an interface with the cell’s plasma membrane. Those two elements together — cell membrane plus particle — form a unit that generates current when light is shined on the silicon particle.

“You don’t need to inject the entire device; you just need to inject one component,” João L. Carvalho-de-Souza , Bezanilla’s postdoc said. “This single particle connection with the cell membrane allows sufficient generation of current that could be used to stimulate the cell and change its activity. After you achieve your therapeutic goal, the material degrades naturally. And if you want to do therapy again, you do another injection.”

The scientists built the particles using a process they call nano-casting. They fabricate a silicon dioxide mold composed of tiny channels — “nano-wires” — about seven nanometers in diameter (less than 10,000 times smaller than the width of a human hair) connected by much smaller “micro-bridges.” Into the mold they inject silane gas, which fills the pores and channels and decomposes into silicon.

And this is where things get particularly cunning. The scientists exploit the fact the smaller an object is, the more the atoms on its surface dominate its reactions to what is around it. The micro-bridges are minute, so most of their atoms are on the surface. These interact with oxygen that is present in the silicon dioxide mold, creating micro-bridges made of oxidized silicon gleaned from materials at hand. The much larger nano-wires have proportionately fewer surface atoms, are much less interactive, and remain mostly pure silicon. [I have a note regarding ‘micro’ and ‘nano’ later in this posting.]

“This is the beauty of nanoscience,” Jiang said. “It allows you to engineer chemical compositions just by manipulating the size of things.”

Web-like nanostructure

Finally, the mold is dissolved. What remains is a web-like structure of silicon nano-wires connected by micro-bridges of oxidized silicon that can absorb water and help increase the structure’s softness. The pure silicon retains its ability to absorb light.

Transmission electron microscopy image shows an ordered nanowire array. The 100-nanometer scale bar is 1,000 times narrower than a hair. Courtesy of Tian Lab

Transmission electron microscopy image shows an ordered nanowire array. The 100-nanometer scale bar is 1,000 times narrower than a hair. Courtesy of
Tian Lab

The scientists have added the particles onto neurons in culture in the lab, shone light on the particles, and seen current flow into the neurons which activates the cells. The next step is to see what happens in living animals. They are particularly interested in stimulating nerves in the peripheral nervous system that connect to organs. These nerves are relatively close to the surface of the body, so near-infra-red wavelength light can reach them through the skin.

Tian imagines using the light-activated devices to engineer human tissue and create artificial organs to replace damaged ones. Currently, scientists can make engineered organs with the correct form but not the ideal function.

To get a lab-built organ to function properly, they will need to be able to manipulate individual cells in the engineered tissue. The injectable device would allow a scientist to do that, tweaking an individual cell using a tightly focused beam of light like a mechanic reaching into an engine and turning a single bolt. The possibility of doing this kind of synthetic biology without genetic engineering [emphasis mine] is enticing.

“No one wants their genetics to be altered,” Tian said. “It can be risky. There’s a need for a non-genetic system that can still manipulate cell behavior. This could be that kind of system.”

Tian’s graduate student Yuanwen Jiang did the material development and characterization on the project. The biological part of the collaboration was done in the lab of Francisco Bezanilla, the Lillian Eichelberger Cannon Professor of Biochemistry and Molecular Biology, by postdoc João L. Carvalho-de-Souza. They were, said Tian, the “heroes” of the work.

I was a little puzzled about the use of the word ‘micro’ in a context suggesting it was smaller than something measured at the nanoscale. Dr. Tian very kindly cleared up my confusion with this response in a July 4, 2016 email,

In fact, the definition of ‘micro’ and ’nano’ have been quite ambiguous in literature. For example, microporous materials (e.g., zeolite) usually refer to materials with pore sizes of less than 2 nm — this is defined based on IUPAC [International Union of Pure and Applied Chemistry] definition (http://goldbook.iupac.org/M03853.html). We used ‘micro-bridges’ because they come from the ‘micropores’ in the original template.

Thank you Dr. Tian for that very clear reply and Steve Koppes for forwarding my request to Dr. Tian!

Here’s a link to and a citation for the paper,

Heterogeneous silicon mesostructures for lipid-supported bioelectric interfaces by Yuanwen Jiang, João L. Carvalho-de-Souza, Raymond C. S. Wong, Zhiqiang Luo, Dieter Isheim, Xiaobing Zuo, Alan W. Nicholls, Il Woong Jung, Jiping Yue, Di-Jia Liu, Yucai Wang, Vincent De Andrade, Xianghui Xiao, Luizetta Navrazhnykh, Dara E. Weiss, Xiaoyang Wu, David N. Seidman, Francisco Bezanilla, & Bozhi Tian. Nature Materials (2016)  doi:10.1038/nmat4673 Published online 27 June 2016

This paper is behind a paywall.

I gather animal testing will be the next step as they continue to develop this exciting technology. Good luck!

Better blood vessel growth for regenerative medicine?

If the organs and tissues grown in labs are to be successfully transplanted into bodies, then growing the blood vessels needed to maintain them becomes very important. A May 24, 2016 news item on ScienceDaily describes a new technique for the growing the vessels,

Growing tissues and organs in the lab for transplantation into patients could become easier after scientists discovered an effective way to produce three-dimensional networks of blood vessels, vital for tissue survival yet a current stumbling block in regenerative medicine.

In addition the technique to grow the blood vessels in a 3D scaffold cuts down on the risk of transplant rejection because it uses cells from the patient. It was developed by researchers from the University of Bath’s Department of Pharmacy and Pharmacology, working with colleagues at Bristol Heart Institute.

A May 24 (?), 2016 University of Bath (UK) press release, which originated the news item, expands on the theme (Note: Links have been removed),

So far the shortage of adequate patient-derived scaffolds that can support blood vessel growth has been a major limitation for regenerative medicine and tissue engineering.

Other methods only allow limited formation of small blood vessels such as capillaries, which makes tissue less likely to successfully transplant into a patient. In addition other methods of tissue growth require the use of animal products, unnecessary in this technique which uses human platelet lysate gel (hPLG) and endothelial progenitor cells (EPCs) – a type of cell which helps maintain blood vessel walls.

Dr Giordano Pula, Lecturer in Pharmacology at the University of Bath and head of the research team making the discovery, said: “A major challenge in tissue engineering and regenerative medicine is providing the new tissue with a network of blood vessels, and linking this to the patient’s existing blood supply; this is vital for the tissue’s survival and integration with adjacent tissues.

Dr Paul De Bank, Senior Lecturer in Pharmaceutics at the University of Bath and co-author of the paper, said: “By embedding EPCs in a gel derived from platelets, both of which can be isolated from the patient’s blood, we have demonstrated the formation of a network of small vessels. What is more, the gel contains a number of different growth factors which can induce existing blood vessels to infiltrate the gel and form connections with the new structures. Combining tissue-specific cells with this EPC-containing gel offers the potential for the formation of fully vascularised, functional tissues or organs, which integrate seamlessly with the patient.

“This discovery has the potential to accelerate the development of regenerative medicine applications.”

Professor Peter Weissberg, Medical Director of the British Heart Foundation, said: “Over a half a million people in the UK are living with heart failure, a disabling condition which can leave people unable to carry out everyday activities such as climbing the stairs or even walking to the shops. This regenerative research brings the British Heart Foundation’s goal to mend a broken heart and beat heart failure one step closer.

“All living tissues, including new heart muscle, need a blood supply. One of the fundamental goals of regenerative medicine is to find ways to grow a new blood supply from scratch. Previous attempts at this using human cells and synthetic scaffolds have met with only limited success.

“The beauty of this new approach is that components of a person’s own blood could be manipulated to create a scaffold on which new blood vessels could grow. This increases the likelihood that the new tissue will be integrated into the patient’s body which, if proven successful with more research, could improve the lives of people affected by heart failure.”

Here’s a link to and a citation for the paper,

Platelet lysate gel and endothelial progenitors stimulate microvascular network formation in vitro: tissue engineering implications by Tiago M. Fortunato, Cristina Beltrami, Costanza Emanueli, Paul A. De Bank & Giordano Pula. Scientific Reports 6, Article number: 25326 (2016)  doi:10.1038/srep25326 Published online: 04 May 2016

This is an open access paper.

One of the criticisms of Paolo Macchiarini’s work with synthetic tracheas centered around blood supply to the cells (from my April 19, 2016 posting; it was part 1 of a 2-part series),

This ground-breaking achievement consisted of bringing to life a dead windpipe from a donor, by putting it in a plastic box, a so-called ‘bioreactor’ together with bone marrow fluid (stem cells). A few weeks later, I [Pierre Delaere*]  wrote a letter to The Lancet, pointing out:

“The main drawback of the proposed reconstruction is the lack of an intrinsic blood supply to the trachea. We know that a good blood supply is the first requirement in all other tissue and organ transplantations. Therefore, the reported success of this technique is questionable” (correspondence by Delaere and Hermans, Lancet 2009).

The excerpt you’ve just seen features part of an open letter Pierre Delaere (a long time Macchiarini critic), published in Leonid Schneider’s blog ‘For Better Science’ in an April 2, 2016 posting.

Getting back to Bath, this is exciting stuff and I hope the research is reproducible.