A May 30, 2013 news item on Nanowerk highlights the Katti Group’s (at North Dakota State University [NDSU], US) research using clay from the Red River Valley as scaffolding for tissue engineering projects involving bone. From the news item (Note: A link has been removed),
Weak bones, broken bones, damaged bones, arthritic bones. Whether damaged by injury, disease or age, your body can’t create new bone, but maybe science can. Researchers at North Dakota State University, Fargo, are making strides in tissue engineering, designing scaffolds that may lead to ways to regenerate bone. Published in the Journal of Biomedical Materials Research Part A (“Nanoclays mediate stem cell differentiation and mineralized ECM formation on biopolymer scaffolds”), the research of Dr. Kalpana Katti, Dr. Dinesh Katti and graduate student Avinash Ambre includes a novel method that uses nanosized clays to make scaffolds to mineralize bone minerals such as hydroxyapatite.
The NDSU research team’s 3-D mesh scaffold is comprised of degradable materials that are compatible to human tissue. Over time, the cells generate bone and the scaffold deteriorates. As indicated in the NDSU team’s published scientific research from 2008 to 2013, the nanoclays enhance the mechanical properties of the scaffold by enabling scaffold to bear load while bone generates. An interesting finding by the Katti group shows that the nanoclays also impart useful biological properties to the scaffold.
“The biomineralized nanoclays also impart osteogenic or bone-forming abilities to the scaffold to enable birth of bone,” said Dr. Kalpana Katti, Distinguished Professor of civil engineering at NDSU. “Although it would have been exciting to say that this finding had a ‘Eureka moment,’ this discovery was a methodical exploration of simulations and modeling, indicating that amino acid modified nanoclays are viable new nanomaterials,” said Katti. The work was initially published in the Journal of Biomacromolecules in 2005. The current research findings in 2013 point toward the potential use of nanoclays for broader applications in medicine.
The NDSU’s group most recent study in the Journal of Biomedical Materials Research Part A reports that nanoclays mediate human cell differentiation into bone cells and grow bone. The Katti research group uses amino acids, the building blocks of life, to modify clay structures and the modified nanoclays coax new bone growth. “Our current research studies underway involve the use of bioreactors that mimic fluid/blood flow in the human body during bone tissue regeneration,” said Dr. Kalpana Katti.
Here’s a citation for and a link to the Katti Group’s latest published paper (from the press release),
It’s now possible to print a bionic ear in 3D that can hear beyond the human range and all you need is off-the-shelf printing equipment—and technical expertise. A May 2, 2013 news item on Azonano provides more detail,
Scientists at Princeton University used off-the-shelf printing tools to create a functional ear that can “hear” radio frequencies far beyond the range of normal human capability.
“In general, there are mechanical and thermal challenges with interfacing electronic materials with biological materials,” said Michael McAlpine, an assistant professor of mechanical and aerospace engineering at Princeton and the lead researcher. “Previously, researchers have suggested some strategies to tailor the electronics so that this merger is less awkward. That typically happens between a 2D sheet of electronics and a surface of the tissue. However, our work suggests a new approach — to build and grow the biology up with the electronics synergistically and in a 3D interwoven format.”
McAlpine’s team has made several advances in recent years involving the use of small-scale medical sensors and antenna. Last year, a research effort led by McAlpine and Naveen Verma, an assistant professor of electrical engineering, and Fio Omenetto of Tufts University, resulted in the development of a “tattoo” made up of a biological sensor and antenna that can be affixed to the surface of a tooth.
The tooth tattoo is mentioned in my Nov. 9, 2012 posting; I focused more on Tufts University than Princeton in that piece. As for the ear (from the news item on Azonano),
The finished ear consists of a coiled antenna inside a cartilage structure. Two wires lead from the base of the ear and wind around a helical “cochlea” – the part of the ear that senses sound – which can connect to electrodes. Although McAlpine cautions that further work and extensive testing would need to be done before the technology could be used on a patient, he said the ear in principle could be used to restore or enhance human hearing. He said electrical signals produced by the ear could be connected to a patient’s nerve endings, similar to a hearing aid. The current system receives radio waves, but he said the research team plans to incorporate other materials, such as pressure-sensitive electronic sensors, to enable the ear to register acoustic sounds.
Here’s the technique the researchers used to create their bionic ear (from the news item),
Standard tissue engineering involves seeding types of cells, such as those that form ear cartilage, onto a scaffold of a polymer material called a hydrogel. However, the researchers said that this technique has problems replicating complicated three dimensional biological structures. Ear reconstruction “remains one of the most difficult problems in the field of plastic and reconstructive surgery,” they wrote.
To solve the problem, the team turned to a manufacturing approach called 3D printing. These printers use computer-assisted design to conceive of objects as arrays of thin slices. The printer then deposits layers of a variety of materials – ranging from plastic to cells – to build up a finished product. Proponents say additive manufacturing promises to revolutionize home industries by allowing small teams or individuals to create work that could previously only be done by factories.
Creating organs using 3D printers is a recent advance; several groups have reported using the technology for this purpose in the past few months. But this is the first time that researchers have demonstrated that 3D printing is a convenient strategy to interweave tissue with electronics.
The technique allowed the researchers to combine the antenna electronics with tissue within the highly complex topology of a human ear. The researchers used an ordinary 3D printer to combine a matrix of hydrogel and calf cells with silver nanoparticles that form an antenna. The calf cells later develop into cartilage.
Here’s an image of the ear,
Scientists used 3-D printing to merge tissue and an antenna capable of receiving radio signals. Credit: Photo by Frank Wojciechowski
For interested parties,a link to and a citation for the published research,
A 3D Printed Bionic Ear by Manu S Mannoor , Ziwen Jiang , Teena James , Yong Lin Kong , Karen A Malatesta , Winston Soboyejo , Naveen Verma , David H Gracias , and Michael C. McAlpine. Nano Lett., Just Accepted Manuscript DOI: 10.1021/nl4007744 Publication Date (Web): May 1, 2013
At this point, the ear is strictly for use in the laboratory they have not run any ‘in vivo’ experiments, which would be one of the next steps and a prerequisite before human clinical trials are considered.
I have written about human enhancement before, notably in my Aug. 30, 2011 posting where I highlighted this excerpt from an article by Paul Hochman,
“I don’t think I would have said this if it had never happened,” says Bailey, referring to the accident that tore off his pinkie, ring, and middle fingers. “But I told Touch Bionics I’d cut the rest of my hand off if I could make all five of my fingers robotic.” [originally excerpted from Paul Hochman's Feb. 1, 2010 article, Bionic Legs, i-Limbs, and Other Super Human Prostheses You'll Envy for Fast Company]
The Bailey quote stimulated this question for me, what would you choose if you could get an ear that hears beyond the human range?
Researchers at Johns Hopkins University School of Medicine’s Translational Tissue Engineering Center (TTEC) have developed a material (a kind of hydrogel) which they use with a new technique they’ve developed for growing new tissue and cartilage in knees. From the Jan. 15, 2013 news release on EurekAlert,
Proof-of-concept clinical trial in 18 patients shows improved tissue growth
In a small study, researchers reported increased healthy tissue growth after surgical repair of damaged cartilage if they put a “hydrogel” scaffolding into the wound to support and nourish the healing process. The squishy hydrogel material was implanted in 15 patients during standard microfracture surgery, in which tiny holes are punched in a bone near the injured cartilage. The holes stimulate patients’ own specialized stem cells to emerge from bone marrow and grow new cartilage atop the bone.
…
“Our pilot study indicates that the new implant works as well in patients as it does in the lab, so we hope it will become a routine part of care and improve healing,” says Jennifer Elisseeff, Ph.D., Jules Stein Professor of Ophthalmology and director of the Johns Hopkins University School of Medicine’s Translational Tissue Engineering Center (TTEC). Damage to cartilage, the tough-yet-flexible material that gives shape to ears and noses and lines the surface of joints so they can move easily, can be caused by injury, disease or faulty genes. Microfracture is a standard of care for cartilage repair, but for holes in cartilage caused by injury, it often either fails to stimulate new cartilage growth or grows cartilage that is less hardy than the original tissue.
Tissue engineering researchers, including Elisseeff, theorized that the specialized stem cells needed a nourishing scaffold on which to grow, but demonstrating the clinical value of hydrogels has “taken a lot of time,” Elisseeff says. By experimenting with various materials, her group eventually developed a promising hydrogel, and then an adhesive that could bind it to the bone.
After testing the combination for several years in the lab and in goats, with promising results, she says, the group and their surgeon collaborators conducted their first clinical study, in which 15 patients with holes in the cartilage of their knees received a hydrogel and adhesive implant along with microfracture. For comparative purposes, another three patients were treated with microfracture alone. After six months, the researchers reported that the implants had caused no major problems, and MRIs showed that patients with implants had new cartilage filling an average 86 percent of the defect in their knees, while patients with only microfracture had an average of 64 percent of the tissue replaced. Patients with the implant also reported a greater decrease in knee pain in the six months following surgery, according to the investigators.
The trial continues, has enrolled more patients and is now being managed by a company called Biomet. The trial is part of efforts to win European regulatory approval for the device.
In the meantime, Elisseeff says her team has begun developing a next-generation implant, one in which the hydrogel and adhesive will be combined in a single material. In addition, they are working on technologies to lubricate joints and reduce inflammation.
The study has been published in the AAAS’s (American Association for the Advancement of Science) Science Translational Medicine journal,
Surgical options for cartilage resurfacing may be significantly improved by advances and application of biomaterials that direct tissue repair. A poly(ethylene glycol) diacrylate (PEGDA) hydrogel was designed to support cartilage matrix production, with easy surgical application. A model in vitro system demonstrated deposition of cartilage-specific extracellular matrix in the hydrogel
Sci Transl Med 9 January 2013:
Vol. 5 no. 167 pp. 167ra6DOI:10.1126/scitranslmed.3004838
This article is behind a paywall and for some reason the authors are listed only in the news release,
Jennifer Elisseeff, Blanka Sharma, Sara Fermanian, Matthew Gibson, Shimon Unterman, Daniel A. Herzka, Jeannine Coburn and Alexander Y. Hui of the Johns Hopkins School of Medicine; Brett Cascio of Lake Charles Memorial Hospital; Norman Marcus, a private practice orthopedic surgeon; and Garry E. Gold of Stanford University
I came across the information about Autodesk’s venture into tissue printing in a Dec. 19, 2012 article by Kelsey Campbell-Dollaghan for Fast Company Co.Design.com (Note: Links have been removed),
Bioprinters–or 3-D printing hybrids that can print human tissue–have been around for a few years now. As the technology emerged, a single nagging question stuck out in the mind of this post-architecture school student: what’s the software of choice for a scientist modeling a human organ?
Today, an announcement from biomedical startup Organovo and software giant Autodesk goes a long way towards answering it. …
Organovo Holdings, Inc. (OTCQX: ONVO) (“Organovo”), a creator and manufacturer of functional, three-dimensional human tissues for medical research and therapeutic applications, is working together with researchers at Autodesk, Inc., the leader in cloud-based design and engineering software, to create the first 3D design software for bioprinting.
The software, which will be used to control Organovo’s NovoGen MMX bioprinter, will represent a major step forward in usability and functionality for designing three-dimensional human tissues, and has the potential to open up bioprinting to a broader group of users.
This looks like it’s going to be a proprietary system, i.e., the software is designed for one type of hardware, Organovo’s hardware, reminiscent of the late 1990s where printers in the graphic arts field were, in some cases, were trapped into proprietary computer-to-plate printing systems. There was an open source vs. proprietary systems competition which was eventually won by open source systems.
Organovo’s press release describes the technology they’ve developed,
Organovo’s 3D bioprinting technology is used to create living human tissues that are three-dimensional, architecturally correct, and made entirely of living human cells. The resulting structures can function like native human tissues, and represent an opportunity for advancement in medical research, drug discovery and development, and in the future, surgical therapies and transplantation.
The Dec. 17, 2012 article by Kim-Mai Cutler for TechCrunch adds more technical and business detail (Note: Link removed.),
Organovo, which went public earlier this year through a small cap offering and has a market cap of $98 million, manufactures a bioprinter that can create 1 millimeter-thick tissues. Based on research out of the University of Missouri, the company’s technology creates a bio-ink from cells and deposits new cells in a layer-by-layer matrix according to a computer design.
The Dec. 18, 2012 article by Joseph Flaherty for Wired magazine offers an analysis of the business advantages for both companies (Note: Links removed.),
Autodesk, the industry leader in CAD software, has announced it is partnering with biological printer manufacturer Organovo to create 3-D design software for designing and printing living tissue.
It’s an area of interest to Autodesk, whose software runs the industrial design and architecture worlds, allowing them to expand further into new fields by helping researchers interface with new tools.
…
“Autodesk is an excellent fit for developing new software for 3D bioprinters,” Organovo CEO Keith Murphy says in a press release. “This partnership will lead to advances in bioprinting, including both greater flexibility and throughput internally, and the potential long-term ability for customers to design their own 3D tissues for production by Organovo.”Jeff Kowalski, senior VP/CTO at Autodesk, echoes Murphy’s sentiment. “Bioprinting has the potential to change the world,” he says. “It’s a blend of engineering, biology and 3D printing, which makes it a natural for Autodesk. I think working with Organovo to explore and evolve this emerging field will yield some fascinating and radical advances in medical research.”
While this announcement is certainly big news, we’re multiple revisions away from 3-D printing replacement body parts. Even after the technical difficulties of printing organs or even tissue for live human use are worked through, any resulting process will need to be validated through complex clinical trials and a long review by the FDA and international authorities. Still, it will be exciting to see what medical researchers and DIY biohackers will do with these tools.
Oddly, as of today (Dec. 26, 2012) Autodesk has yet to post a press release about this deal on its own website.
I was reminded of the 1992 Olympics in Barcelona while reading the Nov. 22, 2012 news item on Nanowerk about printing cartilage for knees. Some years ago I knew a Canadian wrestler who’d participated in those games and he had a story about knee cartilage that featured amputation.
Apparently, wrestlers in earlier generations had knee surgeries that involved removal of cartilage for therapeutic purposes. Unfortunately, decades later, these retired wrestlers found that whatever cartilage had remained was now worn through and bones were grinding on bones causing such pain that more than one wrestler agreed to amputation. I never did check out the story but it rang true largely because I’d come across a similar story from a physiotherapist regarding a shoulder joint and the consequences of losing cartilage in there (very, very painful).
It seems that scientists are now working on a solution for those of us unlucky enough to have damaged or worn through cartilage in our joints, from the Nov. 22, 2012 IOP science news release, (Institute of Physics) which originated the news item,
The printing of 3D tissue has taken a major step forward with the creation of a novel hybrid printer that simplifies the process of creating implantable cartilage.
…
The printer is a combination of two low-cost fabrication techniques: a traditional ink jet printer and an electrospinning machine. Combining these systems allowed the scientists to build a structure made from natural and synthetic materials. …
In this study, the hybrid system produced cartilage constructs with increased mechanical stability compared to those created by an ink jet printer using gel material alone. The constructs were also shown to maintain their functional characteristics in the laboratory and a real-life system.
The key to this was the use of the electrospinning machine, which uses an electrical current to generate very fine fibres from a polymer solution. Electrospinning allows the composition of polymers to be easily controlled and therefore produces porous structures that encourage cells to integrate into surrounding tissue.
…
In this study, flexible mats of electrospun synthetic polymer were combined, layer-by-layer, with a solution of cartilage cells from a rabbit ear that were deposited using the traditional ink jet printer. The constructs were square with a 10cm diagonal and a 0.4mm thickness.
The researchers tested their strength by loading them with variable weights and, after one week, tested to see if the cartilage cells were still alive.
The constructs were also inserted into mice for two, four and eight weeks to see how they performed in a real life system. After eight weeks of implantation, the constructs appeared to have developed the structures and properties that are typical of elastic cartilage, demonstrating their potential for insertion into a patient.
The researchers state that in a future scenario, cartilage constructs could be clinically applied by using an MRI scan of a body part, such as the knee, as a blueprint for creating a matching construct. A careful selection of scaffold material for each patient’s construct would allow the implant to withstand mechanical forces while encouraging new cartilage to organise and fill the defect.
The researchers’ article in the IOP science jouBiofrarnal, Biofabrication, is freely available for 30 days after its date of publication, Nov. 21, 2012. You do need to register with IOP science to gain access. Here’s the citation and a link,
Hybrid printing of mechanically and biologically improved constructs for cartilage tissue engineering applications by Tao Xu, Kyle W Binder, Mohammad Z Albanna, Dennis Dice, Weixin Zhao, James J Yoo and Anthony Atala in 2013 Biofabrication5 015001 doi:10.1088/1758-5082/5/1/015001
Sometimes I look at my printer and just shake my head at the thought that one day it might produce living cells if the researchers at University of Wollongong (New South Wales, Australia) have their way. From the Nov. 16, 2012 news item on phys.org,
Researchers have been aware for some time of the potential for using commercially available inkjet printer heads to print living human cells into 3D structures, but design of the actual ink capable of carrying cells through the printer has been a challenge.
The ARC Centre of Excellence for Electromaterials Science at UOW has led a team of scientists including Cameron Ferris, Dr Kerry Gilmore, Dr Stephen Beirne, Dr Donald McCallum, Professor Gordon Wallace and Associate Professor Marc in het Panhuis to develop a new bio-ink that improves the viability of living cells and allows better control of cell positioning through the printing process.
“To date, none of the available inks has been optimised in terms of both printability and cell suspending ability,” according to ACES Associate Researcher Cameron Ferris.
“Our new bio-ink is printable and cell-friendly, preventing cell settling and allowing controlled deposition of cells.”
The 2D structures being printed with the bio-ink enables exquisite control over cell distribution and this already presents exciting opportunities to improve drug screening and toxicology testing processes. Building on this, 3D bio-printing, with which patient-specific tissue replacements could be fabricated, is within the grasp of researchers.
The abstract for the researchers’ paper in Biomaterials helped me to build my understanding of this innovation,
Drop-on-demand bioprinting allows the controlled placement of living cells, and will benefit research in the fields of tissue engineering, drug screening and toxicology. We show that a bio-ink based on a novel microgel suspension in a surfactant-containing tissue culture medium can be used to reproducibly print several different cell types, from two different commercially available drop-on-demand printing systems, over long printing periods. The bio-ink maintains a stable cell suspension, preventing the settling and aggregation of cells that usually impedes cell printing, whilst meeting the stringent fluid property requirements needed to enable printing even from many-nozzle commercial inkjet print heads. This innovation in printing technology may pave the way for the biofabrication of multi-cellular structures and functional tissue.
You can access the paper (free access) but you must be registered (it’s free) with RSC (Royal Society of Chemistry) Publishing. Here’s a link and the citation,
Cameron J. Ferris , Kerry J. Gilmore , Stephen Beirne , Donald McCallum , Gordon G. Wallace and Marc in het Panhuis
Biomater. Sci., 2013, Advance Article
DOI: 10.1039/C2BM00114D
Received 09 Aug 2012, Accepted 11 Oct 2012
First published on the web 05 Nov 2012
Even more helpful than the abstract and assuming you’re not ready to read the paper is Jennifer Newton’s Nov. 7, 2012 article for the RSC’s Chemistry World,
‘The first bio-inks used in drop-on-demand cell printing were simple salt solutions,’ says Marc in het Panhuis, who was part of the research team at the University of Wollongong. ‘The cells in these inks settled and aggregated quickly, which impeded printing. Cell viability can also be compromised if the salt concentration is too high.’
Other bio-inks include low viscosity biopolymer solutions, which are known to slow cell settling. The team’s bio-ink consists of a biopolymer – gellan gum – and two surfactants in a standard tissue culture medium. The surfactants – Novec FC4430 and Poloxamer 188 – reduce surface tension, allowing optimal inkjet printing, and protect the cells from fluid-mechanical damage.
The cells do not settle and aggregate because the biopolymer creates a structured network of micro-gel particles that keep the cells suspended in the gel. However, the bio-ink remains printable as the network is not rigid and is easily broken down during printing. ‘Our bio-ink allowed us to print multiple cell types over long printing periods without changing print heads or replenishing ink solutions,’ says in het Panhuis.
There are more details in Newton’s article and the image that accompanies it is quite striking.
A team from Harvard University have developed a technique for creating hydrogels that could be used effective in tissue engineering projects. From the Sept. 5, 2012 news release on EurekAlert,
A team of experts in mechanics, materials science, and tissue engineering at Harvard have created an extremely stretchy and tough gel that may pave the way to replacing damaged cartilage in human joints.
Called a hydrogel, because its main ingredient is water, the new material is a hybrid of two weak gels that combine to create something much stronger. Not only can this new gel stretch to 21 times its original length, but it is also exceptionally tough, self-healing, and biocompatible—a valuable collection of attributes that opens up new opportunities in medicine and tissue engineering.
Here’s an image of the hydrogel provided by the researchers,
The researchers pinned both ends of the new gel in clamps and stretched it to 21 times its initial length before it broke. Credit: Photo courtesy of Jeong-Yun Sun
“Conventional hydrogels are very weak and brittle — imagine a spoon breaking through jelly,” explains lead author Jeong-Yun Sun, a postdoctoral fellow at the Harvard School of Engineering and Applied Sciences (SEAS). “But because they are water-based and biocompatible, people would like to use them for some very challenging applications like artificial cartilage or spinal disks. For a gel to work in those settings, it has to be able to stretch and expand under compression and tension without breaking.”
To create the tough new hydrogel, they combined two common polymers. The primary component is polyacrylamide, known for its use in soft contact lenses and as the electrophoresis gel that separates DNA fragments in biology labs; the second component is alginate, a seaweed extract that is frequently used to thicken food.
Separately, these gels are both quite weak — alginate, for instance, can stretch to only 1.2 times its length before it breaks. Combined in an 8:1 ratio, however, the two polymers form a complex network of crosslinked chains that reinforce one another. The chemical structure of this network allows the molecules to pull apart very slightly over a large area instead of allowing the gel to crack.
The alginate portion of the gel consists of polymer chains that form weak ionic bonds with one another, capturing calcium ions (added to the water) in the process. When the gel is stretched, some of these bonds between chains break — or “unzip,” as the researchers put it — releasing the calcium. As a result, the gel expands slightly, but the polymer chains themselves remain intact. Meanwhile, the polyacrylamide chains form a grid-like structure that bonds covalently (very tightly) with the alginate chains.
Therefore, if the gel acquires a tiny crack as it stretches, the polyacrylamide grid helps to spread the pulling force over a large area, tugging on the alginate’s ionic bonds and unzipping them here and there. The research team showed that even with a huge crack, a critically large hole, the hybrid gel can still stretch to 17 times its initial length.
Importantly, the new hydrogel is capable of maintaining its elasticity and toughness over multiple stretches.
Anyone can see that the ability to stretch, self-heal and stretch mimics the body’s own processes and that materials which can mimic those processes are very promising. From the news item on ScienceDaily,
Beyond artificial cartilage, the researchers suggest that the new hydrogel could be used in soft robotics, optics, artificial muscle, as a tough protective covering for wounds, or “any other place where we need hydrogels of high stretchability and high toughness.”
If you’re interested, there are still more details in the news release on EurekAlert or in the news item on ScienceDaily.
A multi-institutional research team has developed a method for embedding networks of biocompatible nanoscale wires within engineered tissues. These networks—which mark the first time that electronics and tissue have been truly merged in 3D—allow direct tissue sensing and potentially stimulation, a potential boon for development of engineered tissues that incorporate capabilities for monitoring and stimulation, and of devices for screening new drugs.
The Aug. 27, 2012 news item on Nanowerk provides more detail about integration of the cells and electronics,
Until now, the only cellular platforms that incorporated electronic sensors consisted of flat layers of cells grown on planar metal electrodes or transistors. Those two-dimensional systems do not accurately replicate natural tissue, so the research team set out to design a 3-D scaffold that could monitor electrical activity, allowing them to see how cells inside the structure would respond to specific drugs.
The researchers built their new scaffold out of epoxy, a nontoxic material that can take on a porous, 3-D structure. Silicon nanowires embedded in the scaffold carry electrical signals to and from cells grown within the structure.
“The scaffold is not just a mechanical support for cells, it contains multiple sensors. We seed cells into the scaffold and eventually it becomes a 3-D engineered tissue,” Tian says [Bozhi Tian, a former postdoc at MIT {Massachusetts Institute of Technology} and Children’s Hospital and a lead author of the paper ].
The team chose silicon nanowires for electronic sensors because they are small, stable, can be safely implanted into living tissue and are more electrically sensitive than metal electrodes. The nanowires, which range in diameter from 30 to 80 nanometers (about 1,000 times smaller than a human hair), can detect voltages less than one-thousandth of a watt, which is the level of electricity that might be seen in a cell.
“The current methods we have for monitoring or interacting with living systems are limited,” said Lieber [Charles M. Lieber, the Mark Hyman, Jr. Professor of Chemistry at Harvard and one of the study's team leaders]. “We can use electrodes to measure activity in cells or tissue, but that damages them. With this technology, for the first time, we can work at the same scale as the unit of biological system without interrupting it. Ultimately, this is about merging tissue with electronics in a way that it becomes difficult to determine where the tissue ends and the electronics begin.”
The research addresses a concern that has long been associated with work on bioengineered tissue – how to create systems capable of sensing chemical or electrical changes in the tissue after it has been grown and implanted. The system might also represent a solution to researchers’ struggles in developing methods to directly stimulate engineered tissues and measure cellular reactions.
“In the body, the autonomic nervous system keeps track of pH, chemistry, oxygen and other factors, and triggers responses as needed,” Kohane [Daniel Kohane, a Harvard Medical School professor in the Department of Anesthesia at Children's Hospital Boston and a team leader] explained. “We need to be able to mimic the kind of intrinsic feedback loops the body has evolved in order to maintain fine control at the cellular and tissue level.”
Here’s a citation and a link to the paper (which is behind a paywall),
Macroporous nanowire nanoelectronic scaffolds for synthetic tissues by Bozhi Tian, Jia Lin, Tal Dvir, Lihua Jin, Jonathan H. Tsui, Quan Qing, Zhigang Suo, Robert Langer, Daniel S. Kohane, and Charles M. Lieber in Nature Materials (2012) doi:10.1038/nmat3404 Published onlin26 August 2012.
This is the image MIT included with its Aug 27, 2012 news release (which originated the news item on Nanowerk),
A 3-D reconstructed confocal fluorescence micrograph of a tissue scaffold. Image: Charles M. Lieber and Daniel S. Kohane.
At this point they’re discussing therapeutic possibilities but I expect that ‘enhancement’ is also being considered although not mentioned for public consumption.
Modern Meadow Inc. promises to print meat on a 3-D printer at some time in the future but first expects to be printing leather (calfskin) by the end of this year (2012). Anna Kamenetz in her Aug. 15, 2012 (?) article for Fast Company’s Co.Exist website notes,
… Modern Meadow [MM] co-founder and CEO Andras Forgacs, explains, this new venture is, ahem, a natural outgrowth of that one [a company called Organovo, a startup specializing in 3-D printed, bioengineered organs founded by Andras’ father, Gabor Forgacs who’s co-founded MM with Andras]. “The idea struck us that if we can make medical-grade tissues that are good enough for drug companies, good enough for patients, then certainly we can find other applications for tissue engineering.” Forgacs does seem to understand how terrifying that sounds, which is why his startup has been relatively press-shy until the announcement this morning, and also why they’re starting with wearable, not edible, products. Still, he argues that cell culturing for food is as old as, well, culture itself:
…
“Whether you’re brewing beer or making yogurt, you’re really doing cell culture,” he [Andras Forgacs] says. In this case, though, the process involves biopsying a living animal (a relatively harmless procedure), isolating the desired cells, growing large numbers of them, and preparing them into cell aggregates–spheres of tens of thousands of cells. These aggregates can then become the raw material for more industrial processes. In the case of complete organs, that process is something like 3-D printing. For calfskin–the product that Modern Meadow intends to turn out by the end of the year–it would resemble something more like regular printing or weaving. The end result will be a hairless, pre-tanned, soft, smooth, chemical- and waste-free material in any color or pattern imaginable …
It’s not easy to find information about this company (they don’t seem to have a website) and, I gather from elsewhere in Kamenetz’s article, they’ve been media shy until now.
The US Dept. of Agriculture (USDA) provides some information about a small business grant they gave to Modern Meadow for the 2012 fiscal year. From the Modern Meadow page on the USDA Research, Education & Economics Information System website, here are the project goals,
The objective of this proposal is to construct muscle tissues by a novel and versatile tissue engineering technology and to assess their texture and composition for use as minced meat. The patented “print-based” technology has several distinguishing features. It is scaffold-free – it does not rely on any artificial material to form the desired structure. The process to build a tissue construct utilizes the automated deposition of convenient multicellular units, suitable for rapid prototyping and high-throughput production. The method has solid scientific underpinning based on tissue self-assembly processes akin to those evident in early morphogenesis (i.e. tissue fusion, engulfment and cell sorting). The ultimate product that will be developed based on the proposed studies is an animal muscle strip that can be used as minced meat for the preparation of sausages, patties and nuggets. The two aims that will be pursued in this Phase I application are 1) to fabricate 3D cellular sheets composed of porcine cells and 2) to mature the cellular sheets into muscle tissue and measure its meat characteristics. The related technical objectives are 1) to determine the optimal cellular composition (type and ratio of muscle cells, fibroblasts and adipocytes) to produce “easy-to-handle” cellular sheets and 2) to find the most efficient stimulation method (mechanical, electrical or a combination of both) to achieve muscle formation with similar mechanical and biochemical properties to meat. The successful completion of the proposed project will provide the optimal parameters and conditions for engineering strips of mammalian muscle tissue ((2 x 1 x 0.5) cm3) with appropriate mechanical and biochemical properties to be used as minced lean meat. The building of larger pieces, that may need to be perfused and engineered around bio-printed blood vessels, would be carried out in Phase II.
If you’d told me about ‘vat’ or ‘printed’ meat five years ago I would have been horrified and suspicious. I’m somewhat less horrified today but still suspicious or perhaps I should call it, cautious.
The ‘Medusoid’ is a reverse- tissue-engineered jellyfish designed by a collaborative team of researchers based, respectively, at the California Institute of Technology (Caltech) and Harvard University. From the July 22, 2012 news item on ScienceDaily,
When one observes a colorful jellyfish pulsating through the ocean, Greek mythology probably doesn’t immediately come to mind. But the animal once was known as the medusa, after the snake-haired mythological creature its tentacles resemble. The mythological Medusa’s gaze turned people into stone, and now, thanks to recent advances in bio-inspired engineering, a team led by researchers at the California Institute of Technology (Caltech) and Harvard University have flipped that fable on its head: turning a solid element—silicon—and muscle cells into a freely swimming “jellyfish.”
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“A big goal of our study was to advance tissue engineering,” says Janna Nawroth, a doctoral student in biology at Caltech and lead author of the study. “In many ways, it is still a very qualitative art [emphasis mine], with people trying to copy a tissue or organ just based on what they think is important or what they see as the major components—without necessarily understanding if those components are relevant to the desired function or without analyzing first how different materials could be used.” Because a particular function—swimming, say—doesn’t necessarily emerge just from copying every single element of a swimming organism into a design, “our idea,” she says, “was that we would make jellyfish functions—swimming and creating feeding currents—as our target and then build a structure based on that information.”
Oops! I’m not sure why Nawroth uses the word ‘qualitative’ here. It’s certainly inappropriate given my understanding of the word. Here’s my rough definition, if anyone has anything better or can explain why Nawroth used ‘qualitative’ in that context, please do comment. I’m going to start by contrasting qualitative with quantitative, both of which I’m going to hugely oversimplify. Quantitative data offers numbers, e.g. 50,000 people committed suicide last year. Qualitative data helps offer insight into why. Researchers can obtain the quantitative data from police records, vital statistics, surveys, etc. where qualitative data is gathered from ‘story-oriented’ or highly detailed personal interviews. ( I would have used ‘hit or miss,’ ‘guesswork,’ or simply used the word art without qualifying it in this context.)
The originating July 22, 2012 news release from Caltech goes on to describe why jellyfish were selected and how the collaboration between Harvard and Caltech came about,
Jellyfish are believed to be the oldest multi-organ animals in the world, possibly existing on Earth for the past 500 million years. Because they use a muscle to pump their way through the water, their function—on a very basic level—is similar to that of a human heart, which makes the animal a good biological system to analyze for use in tissue engineering.
“It occurred to me in 2007 that we might have failed to understand the fundamental laws of muscular pumps,” says Kevin Kit Parker, Tarr Family Professor of Bioengineering and Applied Physics at Harvard and a coauthor of the study. “I started looking at marine organisms that pump to survive. Then I saw a jellyfish at the New England Aquarium, and I immediately noted both similarities and differences between how the jellyfish pumps and the human heart. The similarities help reveal what you need to do to design a bio-inspired pump.”
Parker contacted John Dabiri, professor of aeronautics and bioengineering at Caltech—and Nawroth’s advisor—and a partnership was born. Together, the two groups worked for years to understand the key factors that contribute to jellyfish propulsion, including the arrangement of their muscles, how their bodies contract and recoil, and how fluid-dynamic effects help or hinder their movements. Once these functions were well understood, the researchers began to design the artificial jellyfish.
To reverse engineer a medusa jellyfish, the investigators used analysis tools borrowed from the fields of law enforcement biometrics and crystallography to make maps of the alignment of subcellular protein networks within all of the muscle cells within the animal. They then conducted studies to understand the electrophysiological triggering of jellyfish propulsion and the biomechanics of the propulsive stroke itself.
Based on such understanding, it turned out that a sheet of cultured rat heart muscle tissue that would contract when electrically stimulated in a liquid environment was the perfect raw material to create an ersatz jellyfish. The team then incorporated a silicone polymer that fashions the body of the artificial creature into a thin membrane that resembles a small jellyfish, with eight arm-like appendages.
Using the same analysis tools, the investigators were able to quantitatively match the subcellular, cellular, and supracellular architecture of the jellyfish musculature with the rat heart muscle cells.
The artificial construct was placed in container of ocean-like salt water and shocked into swimming with synchronized muscle contractions that mimic those of real jellyfish. (In fact, the muscle cells started to contract a bit on their own even before the electrical current was applied.)
“I was surprised that with relatively few components—a silicone base and cells that we arranged—we were able to reproduce some pretty complex swimming and feeding behaviors that you see in biological jellyfish,” says Dabiri.
Their design strategy, they say, will be broadly applicable to the reverse engineering of muscular organs in humans.
For future research direction I’ve excerpted this from the Caltech news release,
The team’s next goal is to design a completely self-contained system that is able to sense and actuate on its own using internal signals, as human hearts do. Nawroth and Dabiri would also like for the Medusoid to be able to go out and gather food on its own. Then, researchers could think about systems that could live in the human body for years at a time without having to worry about batteries because the system would be able to fend for itself. For example, these systems could be the basis for a pacemaker made with biological elements.
“We’re reimagining how much we can do in terms of synthetic biology,” says Dabiri. “A lot of work these days is done to engineer molecules, but there is much less effort to engineer organisms. I think this is a good glimpse into the future of re-engineering entire organisms for the purposes of advancing biomedical technology. We may also be able to engineer applications where these biological systems give us the opportunity to do things more efficiently, with less energy usage.”
I think this excerpt from the Harvard news release provides some insight into at least some of the motivations behind this work,
In addition to advancing the field of tissue engineering, Parker adds that he took on the challenge of building a creature to challenge the traditional view of synthetic biology which is “focused on genetic manipulations of cells.” Instead of building just a cell, he sought to “build a beast.”
A little competitive, eh?
For anyone who’s interested in reading the research (which is behind a paywall), from the ScienceDaily news item,
Janna C Nawroth, Hyungsuk Lee, Adam W Feinberg, Crystal M Ripplinger, Megan L McCain, Anna Grosberg, John O Dabiri & Kevin Kit Parker. A tissue-engineered jellyfish with biomimetic propulsion. Nature Biotechnology, 22 July 2012 DOI: 10.1038/nbt.2269
Andrew Maynard weighs in on the matter with his July 22, 2012 posting titled, We took a rat apart and rebuilt it as a jellyfish, on the 2020Science blog (Note: I have removed links),
Sometimes you read a science article and it sends a tingle down your spine. That was my reaction this afternoon reading Ed Yong’s piece on a paper just published in Nature Biotechnology by Janna Nawroth, Kevin Kit Parker and colleagues.
The gist of the work is that Parker’s team have created a hybrid biological machine that “swims” like a jellyfish by growing rat heart muscle cells on a patterned sheet of polydimethylsiloxane. The researchers are using the technique to explore muscular pumps, but the result opens the door to new technologies built around biological-non biological hybrids.
Ed Yong’s July 22, 2012 article for Nature (as mentioned by Andrew) offers a wider perspective on the work than is immediately evident in either of the news releases (Note: I have removed a footnote),
Bioengineers have made an artificial jellyfish using silicone and muscle cells from a rat’s heart. The synthetic creature, dubbed a medusoid, looks like a flower with eight petals. When placed in an electric field, it pulses and swims exactly like its living counterpart.
“Morphologically, we’ve built a jellyfish. Functionally, we’ve built a jellyfish. Genetically, this thing is a rat,” says Kit Parker, a biophysicist at Harvard University in Cambridge, Massachusetts, who led the work. The project is described today in Nature Biotechnology.
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“I think that this is terrific,” says Joseph Vacanti, a tissue engineer at Massachusetts General Hospital in Boston. “It is a powerful demonstration of engineering chimaeric systems of living and non-living components.”
Here’s a video from the researchers demonstrating the artificial jellyfish in action,
There’s a lot of material for contemplation but what I’m going to note here is the difference in the messaging. The news releases from the ‘universities’ are very focused on the medical application where the discussion in the science community revolves primarily around the synthetic biology/bioengineering elements. It seems to me that this strategy can lead to future problems with a population that is largely unprepared to deal with the notion of mixing and recombining genetic material or demonstrations of “of engineering chimaeric systems of living and non-living components.”
