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UC Berkeley accelerates bio-preservation research as part NSF center
Reporter: Irina Robu, PhD
National Science Foundation funded a new research center which focuses on advancing methods for storing and preserving biological cells and tissues. The new center will be directed by John Bischof at the University of Minnesota and co-directed by Mehmet Toner at Massachusetts General Hospital in collaboration with researchers from UC Berkeley and UC Riverside. It is known that the inability to extend shelf life of biological tissues means that patients in Florida can’t receive a heart or lung from California. And when thawing any cell culture, the survival rate of the cells are about 60 percent, which is considered normal .
NSF Engineering Research Centers were founded to bring together academic and industry partners in interdisciplinary collaborations to tackle complex, long-range engineering challenges. The anticipation is that the centers will brood whole new industries with new systems-level technologies. In 2025, the award for ATP-Bio may be renewed for an additional five years.
Imagine a scenario, where years from now, one of your organs stop working properly. What would you do? The current option is to wait in line for a transplant, hoping that the donor is a match. But what if you can get an organ ready for you with no chance of rejection? Even though it may sound like science fiction at the current moment, organ 3D bioprinting can revolutionize medicine and health care.
I have always found the field of tissue engineering and 3D bioprinting fascinating. What interests me about 3D bioprinting is that it has the capacity to be a game changer, because it would make organs widely available to those who need them and it would eliminate the need for a living or deceased donor. Moreover, it would be beneficial for pediatric patients who suffer specific problems that the current bio-prosthetic options might not address. It would minimize the risk of rejection as well as the components would be customized to size.
There have been advancements in the field of 3D bioprinting and one such advancement is using a 3D printed cranium by neurosurgeons at the University Medical Centre Utrecht. The patient was a young woman who suffered from a chronic bone disorder. The 3D reconstruction of her skull would minimize the brain damage that might have occurred if doctors used a durable plastic cranium.
So, what exactly is bioprinting? 3D bioprinting is an additive manufacturing procedure where biomaterials, such as cells and growth factors, are combined to generate tissue-like structures that duplicate natural tissues. At its core, bioprinting works in a similar way to conventional 3D printing. A digital model becomes a physical 3D object layer-by-layer. However, in the case of bioprinting, a living cell suspension is used instead of a thermoplastic.
The procedure mostly involves preparation, printing, maturation and application and can be summarized in three steps:
Pre-bioprinting step which includes creating a digital model obtained by using computed tomography (CT) and magnetic resonance imaging (MRI) scans which are then fed to the printer.
Bioprinting step where the actual printing process takes place, where the bioink is placed in a printer cartridge and deposition occurs based on the digital model.
Post-bioprinting step is the mechanical and chemical stimulation of printed parts in order to create stable biostructures which can ultimately be implanted.
3D bioprinting allows suitable microarchitectures that provide mechanical stability and promote cell ingrowth to be produced while preventing any homogeneity issues that occur after conventional cell seeding, such as cell placement. Immediate vascularization of implanted scaffolds is critical, because it provides an influx of nutrients and outflow of by-products preventing necrosis. The benefits of homogeneous seeded scaffolds are that it allows them to integrate faster into the host tissue, uniform cell growth in vivo and lower risk of rejection.
However, in order to address the limitations of the commercially available technology for producing tissue implants, researchers are working to develop a 3D bioprinter that can fit into a laminar flow hood, ultra-low cost and customizable for different organs. Bioprinting can be applied in a clinical setting where the ultimate goal is to implant 3D bioprinted structures into the patients, it is necessary to maintain sterile printing solutions and ensure accuracy in complex tissues, needed for cell-to-cell distances and correct output.
The final aim of bioprinting is to promote an alternative to autologous and allogeneic tissue implants, which will replace animal testing for the study of disease and development of treatments. We know that for now a short-term goal for 3D bioprinting is to create alternatives to animal testing and to increase the speed of drug testing. The long-term goal is to change the status quo, to develop a personalized organ made from patient’s own cells. However, some ethical challenges still exist regarding the ownership of the organ.
A powerful starting point is the creation of tissue components for heart, liver, pancreas, and other vital organs. Moreover, each small progress in 3D bioprinting will allow 3D bioprinting to make organs widely available to those who need them, instead of waiting years for a transplant to become available.
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.
FDA Guidance On Source Animal, Product, Preclinical and Clinical Issues Concerning the Use of Xenotranspantation Products in Humans – Implications for 3D BioPrinting of Regenerative Tissue
Reporter: Stephen J. Williams, Ph.D.
The FDA has submitted Final Guidance on use xeno-transplanted animal tissue, products, and cells into human and their use in medical procedures. Although the draft guidance was to expand on previous guidelines to prevent the introduction, transmission, and spread of communicable diseases, this updated draft may have implications for use of such tissue in the emerging medical 3D printing field.
This document is to provide guidance on the production, testing and evaluation of products intended for use in xenotransplantation. The guidance includes scientific questions that should be addressed by sponsors during protocol development and during the preparation of submissions to the Food and Drug Administration (FDA), e.g., Investigational New Drug Application (IND) and Biologics License Application (BLA). This guidance document finalizes the draft guidance of the same title dated February 2001.
For the purpose of this document, xenotransplantation refers to any procedure that involves the transplantation, implantation, or infusion into a human recipient of either (a) live cells, tissues, or organs from a nonhuman animal source, or (b) human body fluids, cells, tissues or organs that have had ex vivo contact with live nonhuman animal cells, tissues or organs. For the purpose of this document, xenotransplantation products include live cells, tissues or organs used in xenotransplantation. (See Definitions in section I.C.)
This document presents issues that should be considered in addressing the safety of viable materials obtained from animal sources and intended for clinical use in humans. The potential threat to both human and animal welfare from zoonotic or other infectious agents warrants careful characterization of animal sources of cells, tissues, and organs. This document addresses issues such as the characterization of source animals, source animal husbandry practices, characterization of xenotransplantation products, considerations for the xenotransplantation product manufacturing facility, appropriate preclinical models for xenotransplantation protocols, and monitoring of recipients of xenotransplantation products. This document recommends specific practices intended to prevent the introduction and spread of infectious agents of animal origin into the human population. FDA expects that new methods proposed by sponsors to address specific issues will be scientifically rigorous and that sufficient data will be presented to justify their use.
Examples of procedures involving xenotransplantation products include:
transplantation of xenogeneic hearts, kidneys, or pancreatic tissue to treat organ failure,
implantation of neural cells to ameliorate neurological degenerative diseases,
administration of human cells previously cultured ex vivo with live nonhuman animal antigen-presenting or feeder cells, and
extracorporeal perfusion of a patient’s blood or blood component perfused through an intact animal organ or isolated cells contained in a device to treat liver failure.
Imagine stripping out the failing components of an old car — the engine, transmission, exhaust system and all of those parts — leaving just the old body and other structural elements. Replace those old mechanical parts with a brand new electric, hydrogen powered, biofuel, nuclear or whatever kind of engine you want and now you have a brand new car. It has an old frame, but that’s okay. The frame wasn’t causing the problem, and it can live on for years, undamaged.
When challenged to design internal organs, tissue engineers are taking a similar approach, particularly with the most complex organs, like the heart, liver and kidneys. These organs have three dimensional structures that are elaborate, not just at the gross anatomic level, but in microscopic anatomy too. Some day, their complex connective tissue scaffolding, the stroma, might be synthesized from the needed collagen proteins with advanced 3-D printing. But biomedical engineering is not there yet, so right now the best candidate for organ scaffolding comes from one of humanity’s favorite farm animals: the pig.
Chimera alarmists connecting with anti-biotechnology movements might cringe at the thought of building new human organs starting with pig tissue, but if you’re using only the organ scaffolding and building a working organ from there, pig organs may actually be more desirable than those donated by humans.
How big is the anti-chimerite movement?
Unlike anti-GMO and anti-vaccination activists, there really aren’t too many anti-chemerites around. Nevertheless, there is a presence on the web of people who express concern about mixing of humans and non-human animals. Presently, much of their concern is focussed on the growing of human organs inside non-human animals, pigs included. One anti-chemerite has written that it could be a problem for the following reason:
Once a human organ is grown inside a pig, that pig is no longer fully a pig. And without a doubt, that organ will no longer be a fully human organ after it is grown inside the pig. Those receiving those organs will be allowing human-animal hybrid organs to be implanted into them. Most people would be absolutely shocked to learn some of the things that are currently being done in the name of science.
The blog goes on to express alarm about the use of human genes in rice and from there morphs into an off the shelf garden variety anti-GMO tirade, though with an an anti-chemeric current running through it. The concern about making pigs a little bit human and humans a little bit pig becomes a concern about making rice a little bit human. But the concern about fusing tissues and genes of humans and other species does not fit with the trend in modern medicine.
Utilization of pig tissue enters a new age
A porcine human ear for xenotransplantation. source: The Scientist
For decades, pig, bovine and other non-human tissues have been used in medicine. People are walking around with pig and cow heart valves. Diabetics used to get a lot of insulin from pigs and cows, although today, thanks to genetic engineering, they’re getting human insulin produced by microorganisms modified genetically to make human insulin, which is safer and more effective.
When it comes to building new organs from old ones, however, pig organs could actually be superior for a couple of reasons. For one thing, there’s no availability problem with pigs. Their hearts and other organs also have all of the crucial components of the extracellular matrix that makes up an organ’s scaffolding. But unlike human organs, the pig organs don’t tend to carry or transfer human diseases. That is a major advantage that makes them ideal starting material. Plus there is another advantage: typically, the hearts of human cadavers are damaged, either because heart disease is what killed the human owner or because resuscitation efforts aimed at restarting the heart of a dying person using electrical jolts and powerful drugs.
Rebuilding an old organ into a new one
How then does the process work? Whether starting with a donated human or pig organ, there are several possible methods. But what they all have in common is that only the scaffolding of the original organ is retained. Just like the engine and transmission of the old car, the working tissue is removed, usually using detergents. One promising technique that has been applied to engineer new hearts is being tested by researchers at the University of Pittsburgh. Detergents pumped into the aorta attached to a donated heart (donated by a human cadaver, or pig or cow). The pressure keeps the aortic valve closed, so the detergents to into the coronary arteries and through the myocardial (heart muscle) and endocardial (lining over the muscle inside the heart chambers) tissue, which thus gets dissolved over the course of days. What’s left is just the stroma tissue, forming a scaffold. But that scaffold has signaling factors that enable embryonic stem cells, or specially programed adult pleuripotent cells to become all of the needed cells for a new heart.
Eventually, 3-D printing technology may reach the point when no donated scaffolding is needed, but that’s not the case quite yet, plus with a pig scaffolding all of the needed signaling factors are there and they work just as well as those in a human heart scaffold. All of this can lead to a scenario, possibly very soon, in which organs are made using off-the-self scaffolding from pig organs, ready to produce a custom-made heart using stem or other cells donated by new organ’s recipient.
David Warmflash is an astrobiologist, physician, and science writer. Follow @CosmicEvolution to read what he is saying on Twitter.
And a Great Article in The Scientist by Dr. Ed Yong Entitled
To cope with a growing shortage of hearts, livers, and lungs suitable for transplant, some scientists are genetically engineering pigs, while others are growing organs in the lab.
.. where Joseph Vacanti and David Cooper figured that using
“engineered pigs without the a-1,3-galactosyltransferase gene that produces the a-gal residues. In addition, the pigs carry human cell-membrane proteins such as CD55 and CD46 that prevent the host’s complement system from assembling and attacking the foreign cells”
… thereby limiting rejection of the xenotransplated tissue.
In addition to issues related to animal virus transmission the issue of optimal scaffolds for organs as well as the advantages which 3D Printing would have in mass production of organs is discussed:
To Vacanti, artificial scaffolds are the future of organ engineering, and the only way in which organs for transplantation could be mass-produced. “You should be able to make them on demand, with low-cost materials and manufacturing technologies,” he says. That is relatively simple for organs like tracheas or bladders, which are just hollow tubes or sacs. Even though it is far more difficult for the lung or liver, which have complicated structures, Vacanti thinks it will be possible to simulate their architecture with computer models, and fabricate them with modern printing technology. (See “3-D Printing,” The Scientist, July 2012.) “They obey very ordered rules, so you can reduce it down to a series of algorithms, which can help you design them,” he says. But Taylor says that even if the architecture is correct, the scaffold would still need to contain the right surface molecules to guide the growth of any added cells. “It seems a bit of an overkill when nature has already done the work for us,” she says.
Other articles of FDA Guidance and 3D Bio Printing on this Open Access Journal Include:
“When heart failure (HF) progresses to an advanced stage, difficult decisions must be made,” the AHA says on its website. “Do I want to receive aggressive treatment? Is quality of life more important than living as long as possible? How do I feel about resuscitation?”
LVADs can take over the pumping function of a failing heart, but they also present some of the most expensive implantable-device surgeries. An article in the peer-reviewed journal JACC: Heart Failure reported last year that the average total cost to implant an LVAD in Medicare beneficiaries was $175,000, more than double the cost of a heart transplant.
Amador said between 5,000 and 5,500 Americans will have LVAD implants this year. That compares with 2,200 adult heart transplants that happen annually in the U.S., according to the JACC article.
For patients with advanced heart failure, outcomes are good after heart transplantation, but not enough donor hearts are available. Fortunately, mechanical circulatory assist devices have become an excellent option and should be considered either as a bridge to transplantation or as “destination therapy.” Current mechanical circulatory assist devices improve quality of life in patients who are candidates.
For some patients, conventional treatments are inadequate to relieve the effects of heart failure. Under these circumstances, mechanical circulatory support is considered. There are now a variety of devices capable of pumping blood to restore circulation of vital organs, even temporarily replacing the function of the native heart.
The ABIOMED AB5000™ Circulatory Support System is a short-term mechanical system that can provide left, right, or biventricular support for patients whose hearts have failed but have the potential for recovery. The AB5000™ can be used to support the heart, giving it time to rest – and potentially recover native heart function. The device can also be used as a bridge to definitive therapy.
What is Acute Heart Failure? (Photo credit: Novartis AG)
English: The CardioWest™ temporary Total Artificial Heart (Photo credit: Wikipedia)
English: Graph showing the correlation between BNP serum level and mortality. Source: Inder S. Anand, Lloyd D. Fisher, Yann-Tong Chiang, Roberto Latini, Serge Masson,Aldo P. Maggioni, Robert D. Glazer, Gianni Tognoni, Jay N. Cohn (24th Feb 2003). Changes in Brain Natriuretic Peptide and Norepinephrine Over Time and Mortality and Morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation 107: 1278-83. DOI: 10.1161/01.CIR.0000054164.99881.00 (Photo credit: Wikipedia)
The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group (WG) on August 5 to 6, 2010 in Bethesda, Maryland to discuss future directions of research in heart transplantation (HT). The WG was composed of researchers with expertise in the basic science, clinical science, and epidemiological aspects of advanced heart failure and HT.
These experts were asked to
identify the highest priority research gaps in the field and
make recommendations for future research strategies.
The WG was also asked to include approaches that capitalize on current scientific opportunities and focus on areas that requiredunique NHLBI leadership. Finally, the WG was charged with developing recommendations that would have short- and long-term impact on the field of HT. The WG participants reviewed key areas in HT and identified the most urgent knowledge gaps.
These gaps were then organized into the following 4 specific research directions:
1) enhanced phenotypic characterization of the pre-transplant population;
2) donor-recipient optimization strategies;
3) individualized immunosuppression therapy; and,
4) investigations of immune and non-immune factors affecting late cardiac allograft outcomes.
Finally, because the HT population is relatively small compared with other patient groups, the WG strongly urged concerted efforts to enroll every transplant recipient into a clinical study and to increase collaborative networks to optimize research in this field.
Forrester-classification for classification of Congestive heart failure ; Forrester-Klassifikation zur Einteilung einer akuten Herzinsuffizienz (Photo credit: Wikipedia)
Artificial heart: JARVIK-7 Heart, provided to the National Heart, Lung and Blood Institute (NHLBI) by the University of Utah. (Photo credit: Wikipedia)
Schematic of a transplanted heart with native lungs and the great vessels. (Photo credit: Wikipedia)
BACKGROUND: We retrospectively analyzed the potential of sirolimus as a primary immunosuppressant
in the long-term attenuation of cardiac allograft vasculopathy progression and
the effects on cardiac-related morbidity and mortality.
METHODS: Forty-five cardiac transplant recipients were converted to sirolimus 1.2 years (0.2, 4.0) after transplantation with complete calcineurin inhibitor withdrawal. Fifty-eight control subjects 2.0 years (0.2, 6.5 years) from transplantation were maintained on calcineurin inhibitors.
Age,
sex,
ejection fraction, and
time from transplantation to baseline intravascular ultrasound study were not different (P>0.2 for all) between the groups;
neither were secondary immunosuppressants and
use of steroids.
Three-dimensional intravascular ultrasound studies were performed at baseline and 3.1 years (1.3, 4.6 years) later.
RESULTS: Plaque index progression (plaque volume/vessel volume) was attenuated in the sirolimus group (0.7±10.5% versus 9.3±10.8%; P=0.0003) owing to
reduced plaque volume in patients converted to sirolimus early (<2 years) after transplantation (P=0.05) and
improved positive vascular remodeling (P=0.01) in patients analyzed late (>2 years) after transplantation.
Outcome analysis in 160 consecutive patients maintained on 1 therapy was performed regardless of performance of intravascular ultrasound examinations.
Five-year survival was improved with sirolimus (97.4±1.8% versus 81.8±4.9%; P=0.006),
There was freedom from cardiac-related events (93.6±3.2% versus 76.9±5.5%; P=0.002).
CONCLUSIONS: Substituting calcineurin inhibitor with sirolimus as primary immunosuppressant
attenuates long-term cardiac allograft vasculopathy progression and
may improve long-term allograft survival owing to favorable coronary remodeling.
Because of the lack of randomization and retrospective nature of our analysis, the differences in outcome should be interpreted cautiously, and prospective clinical trials are required.
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