by George Taniwaki

Your smartphone is more than an addictive toy. With simple modifications, it can become a lifesaving medical device. The phone can already receive and send data to medical sensors and controllers wirelessly. By adding the right software, a smartphone can do a better job than a more expensive standalone hospital-grade machine.

In addition, smartphones are portable and patients can be trained to use them outside a clinical setting. The spread of smartphones has the potential to revolutionize the treatment of chronic conditions like diabetes. This can enhance the quality of life of the patient and significantly increase survival.

Monitoring blood sugar

Type 1 diabetes mellitus is an autoimmune disease in which the body attacks the pancreas and interrupts the production of insulin. Insulin is a hormone that causes the cells in the body to absorb glucose (a type of sugar) from the blood and metabolize it. Blood sugar must be controlled to a very tight range to stay healthy.

A lack of insulin after meals can lead to persistent and repeated episodes of high blood sugar, called hyperglycemia. This in turn can lead to complications such as damage to nerves, blood vessels, and organs, including the kidneys. Too much insulin can deplete glucose from the blood, a situation called hypoglycemia. This can cause dizziness, seizures, unconsciousness, cardiac arrhythmias, and even brain damage or death.

Back when I was growing up (the 1970s), patients with type 1 diabetes had to prick their finger several times a day to get a blood sample and determine if their glucose level was too low or too high. If it was too low, they had to eat a snack or meal. (But not one containing sugar.)

They would also test themselves about an hour after each meal. Often, their glucose level was too high, and they had to calculate the correct does of insulin to self-inject into their abdomen, arm, or leg to reduce it. If they  were noncompliant (forgetful, busy, unable to afford the medication, fearful or distrustful of medical institutions or personnel, etc.), they would eventually undergo diabetic ketoacidosis, which often would require a hospital stay to treat.

BloodGlucoseTestStrip

Figure 1a. Example of blood glucose test strip. Photo from Mistry Medical

InsulinShot

Figure 1b. Boy demonstrating how to inject insulin in his leg. Photo from Science Photo Library

If all these needle pricks and shots sound painful and tedious, they were and still are. There are better test devices available now and better insulin injectors, but they still rely on a patient being diligent and awake.

Yes, being awake is a problem. It is not realistic to ask a patient to wake up several times a night to monitoring her glucose level and inject herself with insulin. So most patients give themselves an injection just before going to bed and hope they don’t give themselves too much and that it will last all night.

Continuous glucose monitoring

Taking a blood sample seven or eight times a day is a hassle. But even then, it doesn’t provide information about how quickly or how much a patient’s glucose level changes after a meal, after exercise, or while sleeping.

More frequent measurements would be needed to estimate the rate at which a patient’s glucose level would likely rise or fall after a meal, exercise, or sleeping. Knowing the rate would allow the patient to inject insulin before the glucose level was outside the safe range or reduce the background dosage if it is too high.

In the 1980s, the first continuous glucose meters were developed to help estimate the correct background dosage of insulin and the correct additional amounts to inject after snacks and meals.

The early devices  were bulky and hard to use. They consisted of a sensor that was inserted under the skin (usually in the abdomen) during a doctor visit and had wires that connected it to a monitoring device that the patient carried around her waist. The sensor reported the glucose level every five to ten seconds and the monitor had enough memory to store the average reading every five to ten minutes over the course of a week.

The devices were not very accurate and had to be calibrated using the blood prick method several times a day. The patient would also have to keep a paper diary of the times of meals, medication, snacks, exercise, and sleep. After a week, the patient would return to the doctor to have the sensor removed.

The doctor would then have to interpret the results and calculate an estimated required background dose of insulin during the day and during the night and the correct amount of additional injections after snacks and meals. The patient would repeat the process every year or so to ensure the insulin dosages were keeping the glucose levels within the desired range.

Today, continuous glucose monitors can measure glucose levels using a disposable sensor patch on the skin that will stay in place for a week. It transmits data to the monitor wirelessly. Using a keypad, the monitor can also record eating, medication, exercise, and sleeping. The monitor can store months of personal data and calculate the amount of insulin needed in real-time. Alerts remind the patient when to inject insulin and how much. They are cheap enough and portable enough that the patient never stops wearing it.

ContinuousGlucoseMonitor

Figure 2. Wireless continuous blood glucose monitor and display device. Image from Diabetes Healthy Solutions

Continuous insulin pump

Also in the 1980s, the first generation of subcutaneous insulin pumps were commercialized. These pumps could supply a low background dose of insulin rather than big spikes provided by manual injections. The first pumps were expensive, bulky, hard to use. By the early 2000s though, insulin pumps became widely available and were shown to reliably reduce the fluctuations in glucose levels seen in patients who relied on manual injections. By providing a low dose of insulin continuously during the day and at night with the ability of the patient to manually apply larger doses after meals, it lowered the average level of glucose while also reducing the incidence of hypoglycemia. Over longer periods it also reduced the incidence of complications commonly seen with diabetes.

InsulinPumpEarlyinsulinpump

Figure 3a and 3b. Early insulin pump (left) and modern version (right). Images from Medtronic

There is one drawback to the continuous insulin pump. It can provide too much insulin at night while the patient is asleep. While sleeping, the patient’s glucose level falls. Since she is not performing blood tests, she will not notice that the insulin pump is set too high. Further, since she is asleep she may not realize that she is in danger, a condition called nocturnal hypoglycemia.

Software to control the pump

Imagine combining the continuous glucose meter with the continuous insulin pump. Now you have a system the mimics the behavior of the human pancreas. Sensors constantly monitor the patient’s glucose level, and anticipate changes caused by activities like eating, sleeping, and exercise.

The key is to use a well-written algorithm to predict the amount of insulin needed to be injected by the pump to keep sugar levels within the acceptable range. Instead of a human, software controls the insulin pump. If the glucose level does not stay within the desired levels, the algorithm learns its mistake and corrects it.

The initial goal of the combined monitor and pump was to predict low glucose levels while a patient was sleeping and suspend the pumping of insulin to prevent nocturnal hypoglycemia. Ironically, the US FDA panel rejected the first application submitted for the device saying that the traditional uncontrolled continuous insulin pump was actually safer than a new device because of the new device’s lack of field experience.

After years of additional studies the combined device, manufactured by Medtronic, was approved for use in the US in 2013. Results of a study involving 25 patients in the UK was published in Lancet Jun 2014. Another trial, involving 95 patients in Australia was published in J. Amer. Med. Assoc. Sept 2013.

CombinedGlucoseMonitorInsulinPump

Figure 4. Combined glucose meter and insulin pump form a bionic pancreas. Image from Medtronic

Better software and smartphones

The Medtronic combined device is proprietary. But several groups are hacking it to make improvements. For instance, researchers led by Z. Mahmoudi and M. Jensen at Aalborg University in Denmark have published several papers (Diabetes Techn Ther Jun 2014Diabetes Sci Techn Apr 2014, Diabetes Techn Ther Oct 2013) on control algorithms that may be superior to the one currently used in the Medtronic device.

Another interesting paper appeared in the New Engl J Med Jun 2014. It reports a study by Dr. Steven Russell of Massachusetts General Hospital and his colleagues. They wrote an app for a smartphone (Apple’s iPhone 4S) that could receive the wireless data from the Medtronic glucose meter and wirelessly control the Medtronic insulin pump.

Smartphones are ideal platforms for use in developing medical devices because they can communicate wirelessly with other devices, have sufficient computing power and memory for even the most complex control tasks, are designed to be easy to program and easy to use, and many people already own one.

Dr. Russell and his colleagues used a machine learning algorithm they had previously developed (J Clin Endocrinol Metab May 2014) to couple the two.

Even though this is a research project, not a commercial product, the results are pretty impressive. The study lasted 5 days, with the first day used to calibrate the algorithm and days 2-5 as the test.

As can be seen in Figure 5, after a day of “training” patients using the bionic pancreas (solid black line) had lower average glucose levels than patients on the standard protocol (solid red line). Further, the variance of their glucose level (black shaded area) was smaller than for patients on the standard protocol (red shaded area). Notice how much better the control is using the bionic pancreas, especially at night.

InsulinNEJM1

Figure 5. Variation in mean glucose level among adults during 5-day study. Image from New Engl J Med

Another measure of quality is the amount of time the patients’ glucose levels were within the desired level of 70 to 120 mg/dl (the green shaded region in Figure 6). Patients with the bionic pancreas (solid black line) spent about 55% of the time within the desired level. They also had fewer incidents of hypoglycemia (pink shaded region) or hyperglycemia (white region on right) than patients using the standard protocol (red line).

Note that even with the bionic pancreas, 15% of the time patients had a glucose level above 180, so there is still plenty of room to improve control.

InsulinNEJM

Figure 6. Cumulative glucose level in adults during day 1 where the bionic pancreas adapted to the patient (dashed line) and days 2-5 (solid black). Image from New Engl J Med

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by George Taniwaki

Two weeks ago, I posted a blog entry with an update on advances in artificial organs. I try not to cover a topic in my blog too frequently, so as to not overemphasize any one area of research. Thus, I  wasn’t planning to write about regenerative medicine again for several months. However, last week an exciting paper was published and I’ve decided not to put it in my pile for discussion later.

Scientists at the Massachusetts General Hospital (MGH) in Boston have created a functioning  kidney and transplanted it into a rat, where it began making urine. The process is described in detail in Nature Medicine May 2013 (subscription required) and summarized in The New York Times Apr 2013.

The bioengineered kidney starts with a kidney from a rat cadaver. The kidney is perfused with detergent to remove the kidney cells to leave behind a scaffold called an extracellular matrix. One of the authors of the current study is Dr. Harald Ott, who was one of the developers of this decellularization process while at the University of Minnesota. (His decellularization process is described in an Aug 2010 blog post).

In previous research into constructing an artificial kidney, the decellularization process caused severe damage to the vascular, glomerular, and tubular structures. In the MGH process, much lower pressures were used to better preserve these important structures.

Further, previous research made no attempt to repair these structures after decellularization. The group at MGH seeded the kidney scaffold with a small number of human epithelial stem cells. These cells can grow to repair the blood vessels, glomeruli, and tubules. (See the Apr 2013 blog post for a more controlled way to form blood vessels and tubules using a 3D printer.)

The MGH group then seeded the kidney scaffold with newborn rat kidney cells by perfusing it with a whole-organ culture (see image below). After several days, the kidney was able to produce urine at about 10% of the efficiency of a biological rat kidney.

As a final test, the kidney was transplanted into a live rat where it continued to work.

NatureMedicine2013_3154

Bioengineered rat kidney incubating in whole-organ culture. Photo courtesy of MGH

This is a first successful attempt to create a working artificial kidney. It is a logical next step based on knowledge gained from earlier experiments, but it is still a remarkable achievement. Several hurdles must be overcome to turn it into a possible therapy.

First, the incubation process must be perfected to allow the bioengineered kidneys to perform for extended periods of time (hopefully for the normal lifespan of the animal) after transplant. Often, transplanted organs can suffer damage called reperfusion injury once they are connected to the living blood supply.

Second, the efficiency of the kidney needs to be significantly increased above the current 10%. The goal would be to have one or two artificial kidneys able to supply the capacity needed for normal function. This may require applying the correct cell type to each area of the kidney rather than bathing the entire kidney in a mixed culture.

Third, the kidneys need to be scaled up to human size. Larger mammals have about the same size cells as smaller ones. So large mammals, such as humans, have several thousand-fold more cells than smaller ones. Each cell needs to have access to blood from capillaries. Thus, large mammals have much more complex branching in their circulatory network than smaller mammals. Similarly, large mammal kidneys have many more tubules than those in smaller mammals.

Finally, another issue in creating human-sized artificial kidneys is the limited availability of human-sized kidneys for creating the extracellular matrix. As readers of this blog know, there is a severe shortage of deceased donor human kidneys available for transplant. However, this may be overcome by the fact that the kidneys used as scaffolds do not need to be of transplant quality. The supply of scaffolds may be increased further by using pig kidneys, which are a similar size to human ones and readily available.

If these problems can be solved, and I believe they can, then the first clinical trials of artificial kidneys may begin within the next few years.

An interview with Dr. Ott is available on YouTube.

HaraldOtt

Harald Ott discusses artificial organs. Video still from Nature Medicine

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In addition to not wanting to run a story on regenerative medicine so soon because of topic fatigue, I was also worried about the impact the story may have on kidney patients and potential donors.

If you are a kidney patient, do not let the rapid progress in the development of artificial kidneys deter you from seeking a live donor. You want to take control of your medical outcome and improve your quality of life now, not wait for a scientific breakthrough some day in the future.

Similarly, if you are considering becoming an organ donor, don’t turn down the opportunity to give the gift of life. People need transplants now.

There will be many clinical trials before the enough data is submitted to the FDA for it to approve implanting artificial kidneys in humans. It may be over a decade before the first products come to market.

By George Taniwaki

As often mentioned in this blog, there is a severe shortage of transplantable organs available for patients who need them. In the short-term, the only solution is to increase the number of donors, both living and deceased. But a possible long-term solution is to create artificial organs, also called regenerative medicine.

In a Mar 2011 blog post and an Aug 2010 blog post, I discussed various processes for making the substrates for artificial organs. These include using existing scaffolds from human or animal organs, printing the scaffold using 3D printers, or building the scaffolds from microbeads.

However, a kidney (and any other organ) is more than just a scaffold. The scaffold has to be filled with cells. The cells have to be the right kinds and have to be arranged in the correct order. And the cells have to be connected to a network of blood vessels that transports blood, tubules that carry away the urine, nerves that monitor and control the organ, and other systems that connect the organ to the rest of the body.

Blood vessels and tubules

One advance described in Los Angeles Times Jul 2012 is a novel technique for creating the blood vessels and tubules. The work was led by Jordan Miller and Christopher Chen, both of University of Pennsylvania’s Tissue Microfabrication Lab. A network of filaments is printed using a 3D printer. Instead of plastic that is commonly used in these printers use, the filaments are made from a special combination of glass-like sugars. The filaments are then coated with a polymer that acts as the scaffold for the endothelial cells that will become the blood vessels and tubules. After the cells are added, the sugar is washed away with water leaving a hollow tube. A great video explaining the process is available on YouTube.

3DPrinter

Still image of Rep Rap 3D printer producing sugar filaments. Courtesy of Univ. of Pennsylvania

Creating organs without stem cells

So far, in these discussions of the use of 3D printers, the structures created have been in the order of 100 micron to 1 millimeter in scale. A recent advance in 3D printing of organic materials appears in Science Apr 2013 (subscription required). Gabriel Villar and Hagan Bayley of University of Oxford have created self-organizing shapes using droplets of aqueous material surrounded in a lipid film. Currently, each droplet is 50 microns in diameter. This is about 5 times larger than living cells, but the researchers believe there is no reason why future printers could not make smaller drops. Thus, entire “organs” could be made from these drops. A press release describes the process. Additional pictures showing layered droplets are available in the Los Angeles Times Apr 2013.

Two videos in the press release show how a network of drops with different electrical properties could be self-organizing. One is a computer animation, the other is an actual stop motion of a flat sheet of droplets curling into a sphere over a span of 348 minutes (just under 6 hours).

3DPrinter2

Still image of  droplet network forming a sphere. Courtesy of University of Oxford

by George Taniwaki

Patients with end-stage renal disease (ESRD) often wait many years for a transplant. There are currently over 85,000 people in the U.S. waiting for a kidney transplant and the number grows each year. The average wait time is over three years. The mortality rate for those with ESRD on dialysis is over 15% per year, meaning that almost half of the patients die and never get a transplant.

Eliminating the waiting list for kidney transplants is a complex problem. But I see four separate solutions. They are reduce the incidence rate of ESRD, increase the supply of deceased donor organs, increase the supply of live donor organs, and apply new technologies to enhance or replace human organs. These solutions are not mutually exclusive and should each be investigated and instituted by the appropriate organizations. In fact, I don’t believe any one of these solutions will eliminate the list on its own, and so possibly all of them will need to be pursued.

I will illustrate the various pieces of this problem with the four flow charts shown below and then discuss each of the four solution areas in future blog posts. The text in orange boxes represent actions that can be taken. The text in green boxes indicate the intended results of those actions.

Access to healthcare

For blog posts related to patient access to preventative care, patient education on treatment modalities, or dialysis treatment, see entries tagged with Access To Healthcare or Dialysis.

Note that in the right side of Figure 1, educating patients about the advantages of transplant therapy will increase the demand for transplants, which will make the waiting list longer if other steps are not taken to reduce the incidence of ESRD or increase the supply of organs.

KidneyFlowESRD

Figure 1. Actions that may reduce the incidence of ESRD (left) and increase demand for transplant therapy (right)

Deceased donor transplants

For blog posts related to deceased donor transplants, including patient evaluation and experience, see entries tagged with Deceased Donor.

KidneyFlowDeceasedTX

Figure 2. Actions that may increase supply of deceased donor kidneys

Live donor transplants

For blog posts related to live donor transplants, see entries tagged with Live Donor or Kidney Exchange. (For more on the live donor evaluation process, see entries tagged with Donor Story.)

KidneyFlowLiveTx

Figure 3. Actions that may increase supply of live donor kidneys

New technologies

For blog posts related to alternatives to current transplant therapy, see entries tagged with Artificial Organs, Stem Cells, and New Therapies.

KidneyFlowNewTech

Figure 4. New technologies that may someday replace standard transplant therapy

Disclosure note: I am a community member of the Organ Donation Legislative Workgroup in Washington state. I am also a volunteer for several organizations that provide healthcare services to patients with ESRD. However, the opinions in this blog post are my own and do not represent those of any group.

All images by George Taniwaki

[Update1: I modified Figure 3]

[Update2: I added links to tagged blog posts]

I recently watched two videos featuring Anthony Atala, a surgeon and researcher at Wake Forest University who works in the Institute for Regenerative Medicine. The first video is from his talk at TEDMed Oct 2009. In it, he talks about creating artificial tissue and organs. His talk also includes video clips showing working urethras and blood vessels made with biopolymers. He also shows a standard ink jet printer modified to print live endothelial cells to form 3D objects such as heart valves. Finally, he shows a functional liver created using a scaffold made from a decellularized cadaver liver.

TEDMed

Artificial organs. Video from TED Med

The second video is from Dr. Atala’s talk at TED Mar 2011. In this newer video he describes the process of creating a scaffold for a kidney. Much of the content in the first eight minutes is a repeat of the previous talk. The exciting part starts at 10:04 into the video where he describes the process of using a 3D ink jet printer to create the kidney scaffold.

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Printing kidneys. Video from TED Med

The work of researchers at Wake Forest developing artificial organs was mentioned in an Aug 2010 blog post.

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Also in March, I attended the Annual Faculty Lecture at Univ Washington. The speaker was Buddy Ratner, a professor in the Department of Bioengineering . Mr. Ratner is the Michael L. & Myrna Darland Endowed Chair in Technology Commercialization, the founder of Ratner BioMedical, and a member of the scientific advisory board for Tengion, a firm that has licensed the Wake Forest technology.

His talk, entitled “Regenerate, Rebuild, Restore — Bioengineering Contributions to the Changing Paradigm in Medicine”, described the work he and his graduate students have done in creating biodegradable scaffolds made from biopolymers such as polyHEMA, a common material used commercially for soft contact lenses, using a novel process called 6S.

The 6S process gets its name from the six steps used to make the material. First, polystyrene pellets are sieved to isolate pellets of 35 to 40 microns in diameter. These pellets are shaken to create a close-packed arrangement. The packed material is sintered to create a porous solid. This solid acts as a mold. The desired biomaterial, such as polyHEMA, is poured into the mold and surrounds the sintered pellets. The biomaterial is allowed to solidify. Finally, a solvent is added to dissolve the polystyrene mold, leaving only the biomaterial which contains many pores of 35 to 40 micron diameter. (Pores of this size have been shown to reduce the immune reaction that leads to scarring and infection. The explanation of why is beyond the scope of this blog.)

A company named Healionics was formed to commercialize the 6S process. Mr. Ratner is the chairman of the firm’s scientific advisory board.

6S

Schematic of 6S process. Image from U.S. FDA

After the talk I spoke to Mr. Ratner about artificial kidneys. Unfortunately, he indicated that there are no researchers at Univ Washington working on producing artificial kidneys. I also asked him about the pros and cons of natural and synthetic substrates. He believes that using decellularized organs as the substrate for new artificial organs will prove too difficult except for certain uses and that he expects synthetic substrates, like those created using the ink jet process or the 6S process, to be more likely to lead to successful functional organs.

[Update: Corrected the affiliation of Mr. Ratner with Tengion. He is a member of its scientific advisory board.]

In an Aug 2010 blog post, I discussed the prospects for regenerative medicine to alleviate the shortage of transplantable organs. Regenerative medicine usually starts with an organ obtained from deceased donors. But the organ itself isn’t used. Instead the cells are removed and the remaining scaffold is seeded with stem cells to create a new organ. Near the end of that blog post I mentioned that there was work being performed by David Hume and others at the Univ. of Michigan to produce an external device that could perform some of the endocrine functions of a kidney. It would supplement an external dialyzer to provide complete kidney function for a patient with end-stage renal disease.

Recently, Univ. California, San Francisco issued a press release stating that Shuvo Roy and other researchers in the Department of Bioengineering and Therapeutic Sciences have reduced the size of both devices by using a combination of micro-electromechanical systems (MEMS) and human kidney cells. Their prototype is about the size of a coffee cup, or similar in size to a kidney. They hope the device will be implantable, leading to a portable, artificial kidney. Much work remains and they don’t expect clinical trials to begin for another five to seven years. Yet, the promise is great. Such a device could help improve the medical outcomes and quality of life of all patients with ESRD, meaning both those waiting for a transplant and those who would otherwise receive dialysis therapy.

UCSFdialyzer

Artificial kidney. Video from UCSF

[Update: Replaced the cutaway view with a video.]

by George Taniwaki

There is an extreme shortage of kidneys available for transplantation with over 85,000 people on the UNOS transplant waiting list and an additional 300,000 on dialysis who are not on the waiting list but who could still benefit from improvements in renal replacement therapy. Although it is possible for a patient with end-stage renal disease (ESRD) to live several years on dialysis, it is not ideal.

A May 2010 blog post discussed ways to extend the shelf life of organs donated for transplant. Today’s blog post describes technologies in an exciting area of research called regenerative medicine that may provide significantly better outcomes than dialysis and alleviate the shortage in transplantable organs. Regenerative medicine consists of therapies that use live cells, mostly grown from stem cells, to replace a patient’s nonfunctional organ.

Preparing a scaffold for solid organs

Every organ in the body consists of three primary parts. First is a protein scaffold, a framework that defines the shape, mechanical properties, and organization of the cells in the organ. Second, is the network of blood vessels that feed the organ. Finally, there are the various cells within the organ that interact with the blood.

In solid organs, like the heart, the cells do not interact very much with the blood. Thus the requirements for an artificial heart are more clearly defined, and are more mechanical rather than biochemical. In a paper published in Nature Medicine Jan 2008 and summarized in Tech. Rev. Jan 2008, Doris Taylor, a researcher at the Stem Cell Institute at the Univ Minnesota, and her colleagues describe a process to create a scaffold for a heart. In experiments with rats, they start with a cadaver heart and decellularize it using detergents. Then they seeded the acellular matrix with either neonatal cardiac cells or rat aortic endothelial cells (the cells that line the blood vessels). Afterwards, the muscles in these bioengineered hearts would beat when stimulated.

RatHearts

Decellularizing a heart. Image from Nature Medicine

Other organs have been created using a similar process. Working with rat livers, several researchers at Massachusetts General Hospital published a paper in Nature Medicine Jun 2010 (subscription required). They started with a matrix created by removing the cells from an adult cadaver liver and then seeded it with fetal liver cells and endothelial cells. The resulting organ survived and functioned in culture for 10 days. A good description of the work is provided in Tech. Rev. Jun 2010 and includes a video.

Liver

Decellularizing a liver. Image from Tech. Rev.

In another experiment using rats, researchers created a lung by adding fetal lung cells and blood vessel cells to a matrix created from a decellularized cadaver lung. The work was conducted by Laura Niklason and other researchers at Yale. It was reported in the Science Jul 2010 and publicized in the Wall St. J. Jun 2010 (subscription required) and Tech. Rev. Jun 2010, which also has a video. Dr. Niklason has formed a company called Humacyte to commercialize human derived acellular matrices.

Artificial scaffolds

All of the artificial organs described above start with a scaffold made from an existing organ from a cadaver. There is also work underway to develop a man-made scaffold using polymers that mimic the behavior of natural proteins. One advance is reported in Nature Materials Nov 2008 (subscription required) for a honeycomb shaped scaffold that combines flexibility with strength. The polymer is made from poly(glycerol sebacate), a biodegradable elastomer. The work is described in Tech. Rev. Nov 2008.

Another scaffold material, this one made from the same fibronectin protein that serves as the framework for natural organs, is described in Nano Letters Jun 2010 (subscription required) and summarized in Tech. Rev. Aug 2010. The process, developed by Kevin Kit Parker of Harvard, starts by depositing fibronectin molecules on a chilled surface made of a hydrophobic polymer. This causes the protein to relax. Then the fibronectin is transferred to a sheet of glass coated with a water-soluble, hydrophilic polymer. Adding room temperature water causes to fibronectin to crosslink and also dissolves the hydrophilic polymer. This leaves the fabric which is ready to use.

Nanofabric

Protein nanofabric. Image from Nano Letters

Organs without scaffolding

It may be possible to eliminate the need for an existing scaffolding by suspending cells in a hydrogel containing iron oxide particles and held in a magnetic field to create 3D shapes. The technique is described in Nature Nanotech. Apr 2010 and summarized in Tech. Rev. Mar 2010.

Finally, it may be possible to build up an organ without a scaffold by using a 3D printer. Tom Boland and other researchers at Clemson University reproduced a heart using an off-the-shelf ink jet printer filled with cells suspended in a hydrogel. Their results were reported at the Amer. Assoc. Advan. Sci.Conf. 2007.

An experiment involving mice shows the first steps in creating an artificial pancreas without the use of scaffolding. The work was done by a company called ViaCyte (formerly Novocell). First, stem cells are encapsulated in a membrane. The membrane is porous enough to allow blood and glucose to enter, but fine enough to prevent the cells from leaking into the body. The stem cells are induced to become insulin-producing pancreas cells. Finally, the encapsulated cells are implanted in the mouse. The work was publicized at the Int. Soc. Stem Cell Res. 2010 and reported in Tech. Rev. Jun 2010.

Bioengineered kidneys

Creating an artificial kidney is much more difficult than forming other organs because the kidneys have a complex internal structure that includes items like tubules and glomeruli. However, it may not be necessary to reproduce these features to make a useful therapy. In addition to its well-known filtering functions, the kidneys are also part of the endocrine system. They produce and regulate the level of various hormones, the best known of which is erythropoietin (EPO), which stimulates the production of red blood cells.

Currently, all dialysis patients get injections of EPO as part of their renal replacement therapy, to avoid anemia. But there may be other hormones that they are missing. David Humes at the Univ. of Michigan has shown that an external device filled with kidney cells can be used to regulate the hormone levels of dialysis patients. The work is described in Tech. Rev. Nov 2006. A company named RenaMed Biologics was formed to commercialize the product. The company partnered with Genzyme to perform clinical trials of this renal assist device, but testing was suspended, MassHighTech Oct 2006.

James Yoo and other researchers and Wake Forest University report in Tissue Eng. Feb 2009 (subscription required) that they were able to generate three-dimensional renal structures resembling tubules and glomeruli in vitro using primary kidney cells. These structures produced a liquid that resembled urine. A company called Tengion has licensed the technology and is working on a neo-kidney augment product. However, it is not yet in clinical development and is not commercially available.

Optimistically, all of these techniques for regenerative medicine will come to market within ten years. Bioengineered organs have the potential to reduce the need for live donor organs, allow more deceased donor organs to be used rather than discarded, and shorten the waiting list for transplants. Further, assuming that the patient’s own stem cells are used to seed the acellular matrix, they will ensure HLA compatibility and eliminate the need for the patients to take immunosuppressant medications which should reduce the risk of side effects.