Polymer scaffolds guide stem cells growth into customized sizes and shapes.

It may be hard to remember what it was like to lose a tooth as a child, but many adults get an unpleasant reminder as they age when their teeth begin to fall out (even those who don’t play hockey) and must consider dentures or dental implants. For years, researchers have investigated stem cells in an effort to grow teeth made for a person’s own cells. Toward this end, endodontics professor Dr. Peter Murray and colleagues from the College of Dental Medicine at Nova Southeastern University (NSU) have developed methods to control adult stem cell growth toward generating dental tissue and “real” replacement teeth.

The NSU researchers’ approach is to extract stem cells from oral tissue, such as inside a tooth itself, or from bone marrow. After being harvested, the cells are mounted to a polymer scaffold in the shape of the desired tooth. The polymer is the same material used in bioreabsorable sutures, so the scaffold eventually dissolves away. Teeth can be grown separately then inserted into a patient’s mouth or the stem cells can be grown within the mouth reaching a full-sized tooth within a few months.

So far, teeth have been regenerated in mice and monkeys, and clinical trials with humans are underway, but whether the technology can generate teeth that are nourished by the blood and have full sensations remains to be seen. Teeth present a unique challenge for researchers because the stem cells must be stimulated to grow the right balance of hard tissue, dentin and enamel, while producing the correct size and shape.

As Dr. Murray explains it, humans already have two sets of teeth, baby and adult sets, over the course of their lifetimes, so “All we are trying to do is copy nature and give the person the third option to re-grow their teeth.” Not only could this be important for replacing lost teeth, but it could become a standard treatment when extreme orthodontics is necessitated. And if the tooth is malformed or fails, it can be extracted and a new one put into place.

To date, the NSU researchers have received about $1.7 million in grants for their dental stem cell research.

Dr. Murray believes that if they can demonstrate control over tooth re-growth and prove that the technology is safe, these teeth will be the first to see widespread adoption in the US. He also reports that interest has been high from the public and even fellow dentists, as evidenced by the recent selling out of his “Regenerative Endodontic Procedures” presentation at the American Dental Association conference in Las Vegas.

You can check out a news piece about NSU’s research here.

Just as developments in embryonic stem cell research launched umbilical cord banks, the promise that dental stem cell therapy holds has led to the rise of tooth banks, such as BioEden, StemSave, and Store-A-Tooth (StemSave, for instance, charges $2,430 to store a child’s tooth for 20 years.) Stem cell therapies are being actively used to repair bone damage, facial bones, and even organs like a heart, but skeptics continue to scoff at the potential of stem cells, oft citing nightmare scenarios or runaway tissue growth. Furthermore, research progress is often clouded by the politics surrounding embryonic stem cell research.

But the one therapy that could silence the naysayers is tooth regeneration.

The statistics on tooth loss are a bit staggering: 7 out of 10 adults age 35 to 44 have lost at least one tooth and a quarter of those aged 65 or older (or about 20 million people) have lost all their permanent teeth. Additionally, side effects from medications can effect oral health, such as changing properties of the saliva that helps fight bacterial growth. And increased tooth loss leads to poor dietary habits even among dentists, according to a recent study, which leads to secondary health effects. Add to this high sugar diets contributing to the obesity epidemic and increasing cases of periodontal disease due to neglect and you can see that the market for tooth replacement is enormous and expected to grow.

Having a full set of functional teeth is increasingly important as an aging population seeks to maintain an active lifestyle. And the growth of social media has led to people’s faces being plastered all over Facebook, Twitter, and YouTube. So how your teeth look is more important than ever, especially with more people carrying high quality cameras built into their mobile devices.

Dentists are at the front line of the increased demand for perfect teeth. A 2009 nationwide survey by NSU revealed that 96% of the dentists polled expected stem cell regeneration to dominate the future of dentistry. Additionally, more than half predicted that the technology would be available within the next decade.

In mice, stem cells grew into a tooth (in green) that had similar properties to natural teeth.

Research into using stem cells to regrow new teeth has been around for at least 10 years. In 2002, Professor Paul Sharpe at the Dental Institute of King’s College in London received a $500,000 Wellcome Trust grant to translate tooth regrowth with stem cells in mice into regenerative dentistry for humans. A company was formed, Odontis, and in 2010 seemed ready to launch its BioTooth technology, but has since fallen off the radar and had its website shut down possibly suffering the same fate that led to Geron Corporation abandoning stem cell research last year. Researchers from Tokyo University in 2009 reported success with implantation of stem cell tooth germs in mice which grew into fully functional teeth within a few months. Scaffolds were also successfully used to regrow anatomically correct teeth in nine weeks by researchers at Colombia University Medical Center.

Although the promise of stem cell therapies remains to be realized, there’s little doubt that researchers at NSU and around the world will continue in their efforts to use stem cells for regenerative medicine.

Dr. Murray remains optimistic: “When dental stem cell therapies become routine it will be historic, and the most fantastic time to practice as a dentist.”

[Media: Sun Sentinel]

[Sources: ABC, BBC, DentalAegis, Ivanhoe, PopSci, Sun Sentinel]

ACell is the company behind the powder that regrows fingertips.

I’d be surprised if you hadn’t heard about ACell, or at least about some of their results. Their MatriStem powder has been able to grow back people’s missing fingertips. A cut off finger is sprinkled with the pig-derived material every other day, and in a few weeks the missing tip is regrown. It’s been everywhere on TV in the last few years including the Oprah Winfrey Show with Dr. Oz and 60 Minutes. That’s actually been a bad thing. People have dismissed these results because of the natural healing of fingertips. Well, ACell’s technology can do a lot more than just give you the finger. We’ve got videos and photos below to explain how this form of regenerative medicine is poised to make a big difference in surgery.

ACell isn’t the only name in the pig-derived matrix game. Cook Biotech, who we’ve discussed before has a somewhat similar line of products that have been used to promote rapid healing after surgery. What are they selling? Acellular, or extracellular matrix (ECM), which is like a scaffolding for the cells in your body. Pigs and people systems are close enough that ECM taken from the porkers can be processed and reformed into sheets or powders compatible with humans. When placed on a surface wound, or used to connect a gap in internal tissue, the ECM serves as a medium upon which your body’s cells can grow. As your body grows upon the scaffold, it is slowly absorbed and metabolized into the body. This allows for faster healing and the generation of normal tissue where the wound used to be. It is likely (as experiments in mice have shown) that the ECM is actually attracting stem cells from your marrow to itself and that these stem cells are at least partially responsible for the rapid, more complete healing associated with the technology.

The media has typically focused on a few anecdotal cases of impressive healing associated with the technology. I think Oprah’s a great example of this approach to the topic:

So, yeah. People have regrown fingertips using a powdered form of ACell’s MatriStem ECM product. The first such case was Lee Spievack, brother to Alan who was one of the original scientific minds behind ACell’s founding (he has since passed away). Others include Mike Christensen, from Nebraska, who regrew a 16mm portion of his left thumb. While Spievack received his treatment for free, Christensen paid about $1200 for his powdered MatriStem which was prescribed and applied by a doctor. “$1200 for a new thumb”, you say, “sign me up!” But that’s kind of the problem.

Two different cases of ACell MatriStem being used to regrow fingertips. Left images are taken over two weeks. Right images over ten weeks. Impressive, but this is just the tip of the iceberg of what ACell can do.

ACell has been called quack science and other derivative names in the press because of the sensationalized cases of these fingertip stories. Its critics point out that fingertips sometimes will regrow on their own. Not completely. Not 16mm perhaps, but a good percentage of that, especially among the very young. “This isn’t miracle science”, they say, “it’s a natural healing process.” It doesn’t help that most television programs that discuss the technology get hyperbolic very quickly. We can heal any wound! We’ll be able to regrow your limbs! We’ll turn you into a lizard! No, no, and weird.

Luckily, we can throw away all the anecdotal and controversial evidence for finger regeneration. We don’t need it. ECM technology has many more applications and many more successes to support its claims. It has been shown to be effective in surgeries involving the heart, esophagus, hernia, surface injuries, bladder, orthopedics, and ear drum. It has helped humans heal fissures in skin, ligament, and muscle tissues. Steven Badylak, a researcher in regenerative medicine at the University of Pittsburgh, gave a great overview of acellular/extracellular matrices back in 2008 at Pop Tech. Skip to -14:15 to get to the good stuff, and watch out for the obligatory fingertip mention at -5:10.

I must admit that I have been very cautious about believing in ACell’s technology. In fact, I may have yelled disparaging words at my TV when I first saw it appear on daytime television. The idea of a powder regrowing limbs seemed like pure science fiction.

Now, my opinion about the technology is much closer to ‘begrudgingly optimistic’. Anthony Atala, a name in regenerative medicine I have come to respect, is one of the members of ACell’s scientific board. The MatriStem product (in both sheets and powders) is FDA approved for surgical and topical uses. The list of ACell publications continues to grow, with many peer-reviewed-journal articles. Their veterinary applications (horses especially) are also well researched and reviewed. Yes there’s a lot of idiotic hype on the web about this technology, and I don’t want to be associated with it, but I can’t ignore that ECM has been shown to be ‘good science’.

MatriStem, or competiting ECM technology, is likely to become increasingly prevalent in the years ahead.

It seems that MatriStem, or some other ECM product from ACell or Cook Biotech or their competitors, is going to start becoming a more widely used tool in surgery. But it will be just one of many. We’ve seen different regenerative medicine technologies lately that are likely to fit together or work in different tiers. Skin printing and ECMs may help with surface injuries. ECMs will assist with surgeries for injured internal organs. Organ printing or stem cells on collagen scaffolds will allow us to replace organs that cannot be healed. Some form of advanced transplants may be able to replace large portions of our missing bodies (including faces and hands). Minor regeneration of missing parts could be accomplished via ECM, protein treatments to affect stem cell activation, and other techniques. When regenerative medicine as a field finally breaks through into standard medical practice, we’ll have all these options and more. The next generation in healing is near.

[image credits: Alyssa Schukar/The World Herald, ACell]
[video credits: The Oprah Winfrey Show, PopTech]
[sources: ACell, Omaha World Herald]

MRL mice can regrow tissue.

More than twelve years ago, Dr. Ellen Heber-Katz at the Wistar Institute did what so many great scientific minds have done throughout time – she discovered something by accident. In particular, she found that a particular breed of mouse used in lab experiments (the Murphy Roth Large or MRL) could regenerate and heal a hole punched in its ear. Normally reserved for salamanders, newts, and other lower order animals, regeneration in mammals is one of the Holy Grails of medicine. Naturally people were excited by the news. Over the last decade, Heber-Katz and others have shown that the MRL could not only repair a hole punched in an ear, it could repair heart damage as well. Every few years, there’s a new break through in this research. 2010 saw the Wistar Institute team demonstrating that the MRL’s regenerative traits can be induced in other mice by manipulating the p21 protein. This is some really cool news – regenerative properties in mice by changing just one gene and protein pathway! …But don’t buy into the hype that human regeneration is just around the corner.

Medicine has been taking promising steps forward with healing major wounds. Results with stem cells, transplants, nanotechnology, and tissue printing have all shown the potential for repairing or replacing large sections of our bodies. Actual regeneration, however, is still a very enticing prospect. We’d all like to regrow a missing limb like a lizard. The MRL mice heal tissue damage without need for treatment or special equipment. Furthermore, this ability has been induced in other mice (in a limited fashion) through manipulation of a single gene. That raises some hope that humans could be given a similar ability through a relatively direct treatment (protein regulation or gene therapy).

Part of the recent news really fuels that hope. Heber-Katz and her colleagues are well on their way in discovering exactly how MRL mice are able to regenerate. As described in PNAS, the Wistar team had previously seen that the p21 proteins (related to cell reproduction) was not expressed in MRL ear wounds, so they decided to manipulate that protein pathway in a non-MRL mouse. This non-regenerative mouse had it’s p21 protein suppressed (down-regulated) and then demonstrated the characteristic ear-healing of the MRL. Turn off one protein and presto – a new healing mouse.

The MRL breed of mouse seems almost the size of a rat. It is used extensively in testing because it has a genetic bias for an autoimmune disease. It's ability to regenerate some tissue damage seems unrelated.

But we have to avoid the hype. This is certainly very incredible news, but implying that we’re actually close to human regeneration ignores many potential problems and limitations. The biggest problem is cancer. p21 (and it’s related protein p53) play crucial roles in making sure cells don’t reproduce erratically or too often. If we begin to tinker with these protein pathways, we run the risk of defeating your body’s failsafe mechanisms that keep cancer in check.

There’s also some clear limitations to the MRL regeneration Heber-Katz and others have observed. Heart damage and ear damage are healed very consistently. Lost limbs are not. The tip of a digit (finger) on the mouse will regrow. Cut off the joint, and the wound has some promising characteristics (like the presence of the right kind of regenerative cells) but it doesn’t actually grow back. Not exactly as lizard-like as we would hope.

Finally, there’s the biggest reason to not over-hype this latest discovery -it’s in mice! Rodent tests are very important, and they are a promising step towards work in humans. We should always keep in mind, however, that even when scientists clearly understand a phenomenon in mice, that there is only promise, not guarantee, that the phenomenon can be brought to people. And it usually takes years for such translations to occur when they do happen.

What then, are we to make of the continued MRL saga? To me, it’s all about the genes. Heber-Katz and her crew have understood the importance of the genetic angle from the beginning, seeking from the onset to hunt down the DNA responsible for the ability in MRL mice. At the hub, we’ve consistently seen that while most important physical traits are a result of a complex interplay between genes, there are the occasional cheats and short cuts. A single gene in rodents helps boost intelligence. Another gene may help increase lifespan in mice by 20%. There are single genes in humans which may be crucial to longevity as well. We also see small gene groups determining a large portion of risk for diseases. Understanding these genetic connections is going to be crucial in the years ahead. Thankfully, our technology for collecting genetic data is poised for impressive gains. Complete Genomics and Illumina are in an arms race to bring us cheap whole genome sequencing. We’re going to learn more about the way genes effect our health, whether through regeneration, longevity, or whatever. So, the latest p21 protein discovery about MRL mice regeneration may be just a single step on a long road to human regeneration. Developments in genetics, however, may help us start to run down that path very soon.

[image credits:Wistar Institute]
[source: PNAS, Wistar Institute]

A homegrown bladder (Photo courtesy of BBC)

This research isn’t something that might happen in the distant future.  It’s being used today to grow fresh organs, open up new ways to study disease and the immune system, and reduce the need for organ transplants. Organ-farming laboratories are popping up across the planet, and showing impressive results. Here we look at the state of the union of a rapidly advancing field called tissue engineering: what’s been accomplished so far, and what’s right around the corner.

Patients who undergo organ transplants require loads of toxic drugs to suppress their immune systems; otherwise their body might reject the organ. But tissue engineering could make organ transplants a thing of the past. By using a patient’s cells to grow new types of tissue in the lab, researchers are finding new ways to custom-engineer you new body parts by using your own cells.

At the cutting edge of organ engineering is Tengion, a clinical-stage biotech company based outside of Philadelphia. Their most successful research to date led to the creation of the Neo-Bladder. Tengion takes some of your cells and grows them in culture for five to seven weeks around a biodegradable scaffold. When the organ is ready, it can be transplanted without the need to suppress the patient’s immune system (because the organ was grown from the patient’s own cells, it carries no risk of rejection). Once the organ is in, the scaffold degrades and the bladder adapts to its new (old) home.

The Tengion Neo-Bladder is in Phase II testing, meaning that they have already implanted the organ into individuals and studied how the body adapts to it.  After 5 years, the company was able to show that the homegrown organs are safe and effective, capable of treating the bladder effects of spina bifida (a neural tube defect that effects bladder function, among other things). After another round of Phase II trials, Tengion will move on to Phase III testing; after that, the Neo-Bladder should be approved and be made commercially available.

Atala wants to grow you an organ

Tengion’s Neo-bladder is nearing the completion of its clinical trials, but they weren’t the first to grow one. If anyone on Earth deserves the job title “Organ Farmer,” it’s Dr. Anthony Atala. He and his research team at Wake Forest University Medical Center pioneered the world’s first lab-grown bladder, and they remain at the forefront of the organ-growing field (Atala is also the chairman of Tengion’s scientific advisory board). Wake Forest is the world’s largest regenerative medicine research center, and their current research is growing 22 different types of tissue: heart valves, muscle cells, arteries, and even fingers.

So how many different types of human organs have been grown and transplanted? The lab-grown bladders are among the only transplants of an entire organ, but a wide variety of partial organ transplants have taken place. Skin cells are regularly grown in culture and grafted onto patients’ bodies. A graft was grown from a patient’s trachea cells and transplanted to replace part of her airway that had degraded due to disease. Cartilage has been grown and transplanted into a patient’s knee.

A number of technologies are under development but have yet to be transplanted into human bodies. Recently, Dr. Nicholas Kotov and his lab at the University of Michigan have engineered artificial bone marrow, a task that was previously doomed to failure. Kotov and his colleagues realized that in the body, stem cell differentiation relies on chemical signals in three dimensions (whereas in a petri dish, it takes place in two dimensions). This insight led to a new methodology that more closely replicated the natural environment of stem cell differentiation in bone marrow tissue. The resultant homegrown marrow grew and divided normally, even releasing antibodies in fight off an introduced influenza strain. It can be used to study the role of bone marrow in fighting disease within the body, as well as creating a “bioreactor”: harnessing the artificial marrow within a device to grow cells and tissues.

Tengion is pretty busy these days as well. Their new website lists a variety of new applications on the horizon, including a Neo-Kidney augment, artery replacements (including in the heart), and variations on their bladder technique to replace cancerous organs. Their company pipeline gives a general idea of the relative stages of each project.

A number of initiatives are under way to create an artificial pancreas, which would revolutionize the way we treat diabetes. By providing diabetics with a healthy pancreas, doctors could restore their natural control of blood glucose by giving them an endogenous source of insulin. Anyone with experience of diabetes knows the difficulty of manually monitoring and controlling your sugar levels, not to mention regularly injecting insulin. A lab-grown pancreas replacement would be an incredible benefit to the 23.6 million individuals in America alone who suffer from diabetes.

The Minnesota rat heart

As we previously reported, researchers at the University of Minnesota grew an entire rat heart in a laboratory last year. Their next goal is to grow a pig heart, a significant milestone towards growing a human heart due to their similar structure. Researchers hope to combine the scaffold of a pig heart with human cardiac tissue to grow a hybrid heart suitable for transplant.

Another exciting frontier is the field of printable tissue and organs, which is just what it sounds like. Inkjet cartidges are cleaned out and loaded with a mixture of live human cells and “smart gel.” Then, layer by layer, the cells are printed atop one another until a 3D organ is constructed. Just as a normal printer can deposit different colored ink, organ printing allows scientists to specify where to place different cell types. Organ printing has already created beating cardiac cells, and could soon produce organs that are viable for transplant. But unlike other 3D printers, I wouldn’t want this one in my living room.

The hottest areas in tissue growth are the types hardest to make: nerve, liver, kidney, heart and pancreas cells.  But these are precisely where Alata and Tengion are heading, pushing the industry into fresh territory. Coupled with new regenerative treatments like Cook biotech’s foams and stem-cell organ patching, tissue engineering will be keeping our organs young and healthy in the years to come.

Merely a decade ago, tissue engineering was still a new field that struggled to find funding and support. Today, thousands of scientists worldwide are coordinating efforts to reach new breakthroughs, and the demonstrated potential of these methods has helped bring in investors. That should keep the organ growing field moving forward in the future months and years, and we’ll be covering new advances as they emerge.

Check out this Wired Science video that tours around Atala’s lab:

Readers may recall our story from a few months ago covering Cook Biotech’s awesome family of tissue regeneration products marketed under the Biodesign name.  These sheets of pig derived bio-material, known as acellular matrix, can greatly enhance the body’s ability to regenerate healthy, lasting tissue when inserted into wounds from burns, gashes, or surgery.

Today Cook has announced that a 5 year study has verified the long term strength and durability of Biodesign treated hernias.  The study, administered by Morris E. Franklin, Jr., MD, et. al, of the Texas Endosurgery Institute, San Antonio, Texas, followed the progress of 116 patients, and was published in Surgical Endoscopy in September 2008.

Although the announcement from Cook further validates the effectiveness of sheets of biomaterial as tissue regeneration substrates, foams and gels may offer increased flexibility and control with their ability to take on any shape and squeeze into any opening.  No word on when these foams and gels will come to market, but we can confirm that they are in development and we will be watching closely for updates.

Many people don’t realize it, but sheets of pig derived acellular matrix like Cook’s Biodesign, as well as competitor Lifecell’s  cadaver derived Alloderm, are making major inroads in the field of tissue repair.  These tissue regeneration products have been used to treat at least 2 million patients worldwide, aiding in the regeneration of tissue for hernias, large wounds, plastic surgery, colon and rectal surgery, and a slew of other applications.

As is often the case with new technologies, adoption can be slow and doctors may be hesitant to consider these amazing tissue generating materials for treatment.  Readers should keep this in mind in the unfortunate event that they need to heal from a serious wound.

It still seems like science fiction to many, but for more than a decade now mankind has had the technology to regenerate human tissue to repair large or complex wounds resulting from burns, gashes, and surgery.

Earlier we reported on a product from Lifecell called Alloderm that is one of the leaders in this space. Today we would like to introduce you to Cook Biotech, another player in the fascinating field of tissue regeneration medicine. Cook Biotech offers a family of tissue regeneration products that it markets under the name of Surgisis Biodesign.

Cook’s Biodesign family of products have been used to treat nearly one million patients worldwide, aiding in the regeneration of tissue for hernias, large wounds, plastic surgery, colon and rectal surgery, and a slew of other applications.

I found an excellent article here that clearly explains the Biodesign product for those of us that are not tissue experts. Also, here is a clean, short description of Biodesign from the Purdue Research Park. A few cool quotes follow:

“Once in place, Surgisis Biodesign provides a scaffold-like structure and communicates with the body, signaling surrounding tissue to grow across the scaffold. Over time, Surgisis Biodesign is remodeled into fully vascularized tissue, and becomes as strong as the patient’s own tissue. As part of the complete healing process the scaffold is slowly replaced by human tissue and becomes undetectable — providing a permanent repair without a permanent material.”

“According to the American Association of Tissue Banks, one of 20 people will need some sort of soft tissue transplant in their lifetime.”

The Long:

The human body is great at healing itself in the case of small wounds or incisions, but in the case of a severe burn or surgery, the wound is simply too large or complex for the body to regenerate the required tissue properly. For these situations you need a product like Biodesign, which is a thin sheet (called matrix) that serves as a scaffold for new skin to grow and regenerate upon. In the past, synthetic materials such as nylon have been used as a scaffold. These materials are quite limited in their ability to help new tissue grow, are highly susceptible to infection, and stay in the body forever which can cause future complications for the patient. Cook Biotech’s Biodesign product represents a new generation of products based on biological materials that are more capable and more versatile than the synthetic products of the past.

Surgisis Biodesign is a porcine (pig) derived acellullar matrix that can be purchased in different sizes and with different properties based on the desired application. The Biodesign acellular matrix is tissue taken from a very special part of a pig’s intestine that has had its cells removed, leaving behind a valuable collection of proteins, chemical signals, and structural material that human skin cells can populate and vascularize.

Inserting matrix derived from pigs into your body might seem a bit creepy, but keep in mind that the other major competitor in this market, Alloderm, comes from human cadavers! Whether from pigs or cadavers, these matrix products have an amazing ability to help the body regenerate tissue and they have saved or greatly benefited the lives of millions of people. Acellular matrix is a very safe product: it is sterilized through a vigorous process and devoid of any potentially harmful cells, dna, or microbes that may have resided in the originating host.

An advantage of the porcine based matrix from Biodesign is that it is cheaper and the supply is virtually unlimited as compared to human cadaver based solutions such as Alloderm. In order to be more competitive on price and quantity of supply Lifecell has recently launched a porcine based product called Strattice to compete with Cook Biotech’s Biodesign, yet Biodesign appears to be leaps and bounds ahead of Strattice. The secret behind the success of Biodesign is that it comes from a very special part of the pig’s intestine (submucosa) that has just the right chemical makeup to serve as an incredible tissue regeneration matrix in humans. Strattice, on the other hand, is obtained from pig dermis (skin) and although logically it seems as though this should be a superior strategy, it turns out that pig dermis is not nearly as versatile or as effective as intestinal submucosa when it comes to creating the ideal matrix.