How to Engineer a Kidney
Michael Molitch-Hou posted on April 14, 2017 | 12611 views

In 1982, a young student named Dahai Ding sat glumly in his classroom at Worcester Polytechnic Institute when his English professor, Kay Draper, asked him about what appeared to be a deep depression. He told her that his sister, Dadi Ding, was stuck in China, suffering from end-

stage kidney disease, where, without access to dialysis or a kidney transplant, she would die.

It was then that Draper was introduced by the dean of the university to my mother, Dr. Susan Hou, then a nephrologist at Tufts University. Along with my family and her local community, Draper launched a campaign to get Dadi to the United States, where she would receive her first kidney transplant.

Kidney transplants and dialysis are the only methods for treating kidney failure. These solutions, however, have proven problematic for numerous reasons, causing researchers to explore new ways of treating kidney failure, including the construction of artificial, biomechanical kidneys or bioprinting new organs from the patient’s own cells.

Such exciting treatments aren’t yet available to kidney patients, but many people are eagerly waiting for science fiction like artificial and bioprinted kidneys to become a reality. To learn about these technologies and how they could play a role in the lives of people like my godmother, Dadi, and my own mother, I spoke to a variety of researchers in the field.

 

A Kidney Patient in China

Jump back to 1956, in Shanghai. Dadi and her family learned that she had kidney problems when she was just two years old, because there was blood in her urine. Her doctor’s treatment involved a mix of herbal remedies and Western medicine, but the treatment was not successful, and every time she caught a cold, the disease would be exacerbated. The situation did not change until she was about eight years old, when she met a doctor who tried to strengthen her immune system and, therefore, reduce the frequency with which she would have a cold and blood in her urine.

The flyer used to raise funds for Dadi’s kidney transplant.

The flyer used to raise funds for Dadi’s kidney transplant.

The treatment seemed to work for sometime, but, when the Cultural Revolution occurred, her primary doctor was sent to perform custodial work, according to Dadi. Meanwhile, Dadi’s parents, U.S.-educated professors, were sent to labor camps. A 12-year-old living alone in Shanghai, Dadi said that she sought relief from the foul-tasting Chinese herbal medicine she had to take regularly and decided to skip out on the treatment altogether.

After several years, without the proper medication, Dadi’s body became very swollen and she began excreting protein in her urine. By the time the Cultural Revolution was over and her doctor was allowed to return to his practice, there was little he could do to reverse the damage already done to her kidneys. In China at the time, dialysis was not available, while kidney transplants had only been performeda handful of times at an experimental level.

 

“I was admitted to the hospital and there was a girl in the same ward with me, a little bit older than me—in her twenties,” Dadi said. “And she just died. I saw her die in the bed right next to me because of exactly the same disease I had. I realized that that could be me. I saw a lot of a doctors, even went to different cities to see famous doctors, and they all said the same thing.” Without a transplant or dialysis, the consensus opinion from all of the doctors that she saw—even those considered the most qualified experts in the country—was the same: her condition was fatal.

Thankfully, Dahai was already in the U.S. where such treatments were available. Draper was able to set up a nonprofit organization with which to legally raise funds for Dadi. Japan Airlines agreed to fund half of her airfare to travel to the United States and, over the course of a couple of months, Draper managed to raise the over $40,000 necessary to perform a kidney transplant.

 

How Does the Kidney Work?

Made up of about one million filtering units called nephrons, the kidney is essential to filtering the waste that passes through the bloodstream, as well as participating in homeostasis in the body. Within a nephron, the glomeruli are an elaborate tuft of blood vessels that keep proteins inside the blood vessels and filter out other material.

The resulting fluid is passed through a structure called the tubule, where specialized cells in its lining reabsorb water and necessary minerals back into the body, while the remaining waste-containing liquid is sent to the bladder to be excreted as urine.

Throughout the long, windy structure of each nephron, minerals and other molecules are reabsorbed into the body, while waste is sent to the bladder for excretion. (Image courtesy of Wikipedia.)
Throughout the long, windy structure of each nephron, minerals and other molecules are reabsorbed into the body, while waste is sent to the bladder for excretion. (Image courtesy of Wikipedia.)

The nephrons don’t just arbitrarily reabsorb what the body needs and get rid of what it doesn’t, but do so at levels appropriate for the body to maintain homeostasis. For instance, if you drink too much water, the kidney will send more of the liquid to be excreted as urine. If you drink too little, the kidney will ensure that more water is reabsorbed into the bloodstream. The same is true for molecules like glucose and calcium. If a disease or toxin disrupts the function of the kidneys, waste may not be disposed of properly or homeostasis may be disrupted.


Kidneys in America

When you think about it, even the most rudimentary forms of organ transplant are fascinating. Taking a vital piece of one person’s body and placing it into another’s is mad science at its best, but getting those organs to work isn’t easy. Not only must the blood types of donors and recipients be compatible, but so must their human leukocyte antigen (HLA) type. HLA antigens are what enable the immune system to distinguish between one person and a foreign body, such as a transplanted organ. Once the immune system recognizes the kidney as being foreign, it treats it like bacterial in an infection and tries to destroy it.

Dahai was set to be Dadi’s donor, but the siblings learned that their crossmatch was positive. Upon introducing her blood to his, their antibodies immediately reacted to destroy the foreign element. This positive crossmatch suggested that Dahai’s kidney would be instantly rejected if it were implanted into Dadi. A transplant from her brother was not the only option, however.

Dadi and her brother Dahai in 1982.

Dadi and her brother Dahai in 1982.

“In 1982, a surgeon that received a deceased donor was required to give one kidney to the national waiting list, but was able to give the other to his or her own patient,” my mother explained. “So, when a deceased donor came into Tufts, the surgeon was able to give one of the kidneys to Dadi.”

The donor kidney came from a young person who had died in a motorcycle accident, meaning that the kidney was relatively healthy. Nevertheless, it lasted only a week before Dadi’s body rejected it and the organ had to be removed. “At the time, the immunosuppressants weren’t as effective as what we use today,” Dadi told me. “A new medication called cyclosporine was in experimental trials, but not at Tufts, where I was having my transplant done.”

Dadi was then placed on the national waiting list, as she awaited another deceased donor. This process can take quite a long time; in her case, it was seven years. During that time, Dadi studied to become a nephrology nurse, got married and her life was sustained by peritoneal dialysis (PD).

 

Peritoneal Dialysis vs. Hemodialysis

Outside of actual kidney transplants, any technology used to treat kidney failure attempts to replicate the function of an actual kidney. This is done through the use of a system that features a semipermeable membrane for removing waste and excess water from the blood.

PD is a more affordable form of dialysis because it does not require a machine or specialized dialysis facility for treatment. (Image courtesy of Wikipedia.)

PD is a more affordable form of dialysis because it does not require a machine or specialized dialysis facility for treatment. (Image courtesy of Wikipedia.)

In the case of PD, that membrane is already in the body. PD gets its name because, to replace the function of the kidney, it relies on the peritoneum, a membrane coating the abdomen that is responsible for exchanging fluid and dissolved substances with the blood. A catheter is inserted into the abdominal cavity, which is filled with a specialty solution called dialysate. The membrane ultra filters the blood, causing waste products and excess fluid to flow into the dialysate, which is then drained and replaced with fresh solution.

While on PD and studying at nursing school, Dadi said that it was possible for her to fill her abdomen with fresh dialysate before heading to class until, after about four or five hours, she would go somewhere private, drain the waste fluid, and pour in some new dialysate once again. Although this process of continuous ambulatory peritoneal dialysis made it possible for Dadi to go about her daily life while undergoing treatment, she ultimately began to suffer from complications. The glucose in the solution caused her peritoneum to thicken to the point that it no longer functioned as an effective filter.

At this point, she switched to hemodialysis. Instead of an organic membrane within the body, hemodialysis relies on an external machine. Blood flows from a surgically altered blood vessel called a fistula in a patient’s arm into the dialysis machine, which includes a dialyzer made up of hollow synthetic fibers that ultrafilter out waste and excess fluid while dialysate cleans the blood. The cleaned blood is then returned to the body through a second needle. This process continues for three to four hours and must be performed at least three times a week to effectively clean the blood.

In hemodialysis, blood is pumped out of the patient into a filtering system, where the blood is cleaned and sent back into the patient’s body. The process only removes about 15 percent of the body’s necessary waste. (Image courtesy of Wikipedia.)
In hemodialysis, blood is pumped out of the patient into a filtering system, where the blood is cleaned and sent back into the patient’s body. The process only removes about 15 percent of the body’s necessary waste. (Image courtesy of Wikipedia.)

Switching to hemodialysis, Dadi was able to trade in the complications of PD for a whole new set. Although hemodialysis is more efficient at removing waste from the body and causes no risk to the abdomen, as with PD, it is necessary in this process for the patient to receive treatment at specific facilities overseen by trained staff.

By this time, Dadi actually became one of these trained staff members as a registered nurse who oversaw a dialysis unit. As it is for all such dialysis patients, she found it difficult to both work and dialyze three to four hours three days a week. Fortunately for her, she adopted home hemodialysis. This has allowed her to perform the treatment during flexible hours, usually at night while she tries to sleep.

Dadi explained that dialysis is only capable of removing about 15 percent of the waste that must be removed from her body. My mom pointed out that this can be improved by dialyzing longer, more frequently or through improvements in the machine technology. “The efficiency of a dialysis machine is determined by the size and how fast the blood moves through the dialyzer,” my mom explained, “as well as how big the holes are in the dialyzer. They have to be big enough to get rid of the waste, but without removing blood cells and proteins.”

 

The Artificial Kidney: The Future of Dialysis?

Dr. Shuvo Roy, of the University of California San Francisco, and Dr. William H. Fissell IV, of Vanderbilt University Medical Center, are in the process of developing a unique device that acts almost as a biomechanical, implantable dialysis machine. While it is mechanical in nature, the “artificial kidney” uses kidney cells and silicon membranes to replicate the function of a kidney, providing additional functions beyond current dialysis machines. I asked Dr. Roy to explain exactly how it works.

The artificial kidney will be roughly the size of a coffee cup and powered by the pumping of the body’s own blood. (Image courtesy of UCSF.)
The artificial kidney will be roughly the size of a coffee cup and powered by the pumping of the body’s own blood. (Image courtesy of UCSF.)

“The artificial kidney device consists of two implanted modules that work together to get rid of wastes,” Dr. Roy said. “First, a hemofilter module processes incoming blood to create a watery ultrafiltrate that contains dissolved toxins as well as sugars and salts. Second, a bioreactor of kidney cells processes the ultrafiltrate and sends the sugars and salts back into the blood. In the process, water is also reabsorbed back into the body, concentrating the ultrafiltrate into ‘urine,’ which will be directed to the bladder for excretion.”

Key to the device is the use of actual kidney proximal tubule cells, which are grown on silicon nanomembranes, according to Dr. Roy. This makes it possible for water, salts, glucose, amino acids and other small molecules to pass through the device freely. “These nourish the kidney cells, and the porous nature of the membranes also allows the cells to dispose of small wastes, such as carbon dioxide,” Dr. Roy explained. “The silicon nanomembranes also provides immunoisolation for the kidney cells. The immune system relies on fairly large molecules (antibodies) to identify and attach foreign intruders, which are a thousand times larger than small nourishing components such as glucose. These molecules are too large to penetrate the sieve of the membrane supporting the kidney cells.”

Altogether, the device may be more effective than dialysis, not only because it provides continuous blood filtration, but also because it does so with silicon nanomembranes and actual kidney cells. These silicon nanomembranes make it possible to shrink the device down to an implantable size, but also perform better than the plastic components used in existing dialysis machines. Whereas hemofilters for dialysis machines have a surface area of about 2 square meters, the silicon filters that Roy’s lab uses are one-twentieth of the size.

“Traditional dialysis machines remove blood from the patient, filter it through an external machine, and then return the blood to the patient,” Dr. Roy said. “The implanted artificial kidney will allow the filtration to occur continuously, and within the patient’s body, removing the need to be tethered to an external machine. Human kidneys conduct these functions through hundreds of thousands of kidney cells. The artificial kidney performs blood filtration through the use of silicon nanomembranes instead of polymer membranes that are used in conventional dialysis. In addition, the artificial kidney contains kidney cells in the bioreactor to provide biological functions that dialysis simply cannot.”

For the team, the long-term challenges associated with the artificial kidney are keeping it operational and troublefree after implantation. All of the potential issues won’t be known until clinical trials begin in the next year or so. For the time being, Dr. Roy is examining ways for increasing the lifetime of the kidney cells and methods for

ensuring the absence of blood clots. This includes coating the nanomembranes with molecules that make them “blood-friendly.”

As a part of a three-phase program, the lab has already established concept feasibility for externally testing the hemofilter and bioreactor in ICU patients before shrinking the size of the device so that it can be small enough for permanent implantation.

“Currently, we are in Phase II,” Dr. Roy explained. “We are working on engineering refinements to the device components, continuing experiments on the bioreactor to study the conditions that allow the kidney cells to grow and remain healthy, and we have begun a rigorous series of preclinical animal studies for the hemofilter.”

Phase III will begin in late 2017 or in 2018, at which point clinical trials of the hemofilter will begin to demonstrate the device’s safety. This may expedite clinical trials of the combined hemofilter and bioreactor design and, ultimately, pave the way for more streamlined testing of the combined device.

“Once the bioreactor has completed its own set of rigorous preclinical animal studies, we will begin the combined device clinical trials. During clinical trials, we will work with manufacturers to discuss and manage the details of production. Once the clinical trials are complete, we anticipate that the device will be available for patients shortly thereafter,” Dr. Roy said.

Although Dr. Roy’s team uses 3D printing to create plastic housing for the lab’s prototypes and evaluate surgical considerations for the implanted design, no bioprinting is currently used for the kidney cells. That possibility has not yet been ruled out, however. “Bioprinting may be an interesting tool to use in the development of the bioreactor,” Dr. Roy explained. “As bioprinting technology matures for various kidney cells, we could explore it as an advanced tactic to creating a bioartificial kidney.”

Kidney Transplant #2

By 1989, when Dadi’s name was at the top of the waiting list, antirejection medicine had come a long way. Doctors were able to transplant a deceased donor kidney successfully into Dadi, and the new generation of immunosuppressive medication was able to prevent her body from destroying the foreign organ. However, once hooked up to Dadi’s blood supply, the donor kidney was unable to produce urine.

“There are several reasons that could have caused the kidney not to make urine,” said Dadi, now a retired nephrology nurse. “Rejection is one thing. The body tries to destroy the kidney as a foreign body. Secondly, the kidney could have been damaged before getting to me. If the donor died from a certain disease, before the kidney was removed, the organ could already have been damaged; usually, people who have unfortunately died from accidents have kidneys with the best quality because the donor was otherwise healthy. The last issue is how long the kidney was on ice. The longer the organ is on ice, the longer it takes for it to recover.”

Although it wouldn’t produce urine, Dadi kept the kidney in her body for six months, hoping it would start waking up, continuing dialysis all the while. Then, Dadi began developing pemphigoid blisters on her body, in her mouth and down her throat. Her immune system was reacting to the kidney, without the ability to actually reject it. Against her doctor’s objections, Dadi pushed for an elective surgery to remove the kidney. Anesthetized from the abdomen down, she witnessed the surgeon open her up and pull out an entirely black organ.

Dadi recalled, “He said, ‘The kidney was completely rotten. Thank god we did this surgery; otherwise, this organ could have ruptured and caused an infection all throughout your body.’” The experience was so traumatic that Dadi decided to avoid the transplant waiting list. Even if she were on the list, the odds of receiving a transplant would be rare.

"With two transplants, you keep getting foreign body and your body starts to develop antibodies against these foreign antigens," Dadi said. "I have become very sensitized. The doctors performed a test matching me against the general population and I’m 99 percent sensitized. That means that only 1 percent of the people in this country would be able to give me a kidney."

Without functioning kidneys, she has continued to live a long life thanks to home hemodialysis. Combined with her initial time on PD, my godmother has been on dialysis for 35 years. This is nearly a record for a dialysis patient, but the treatment has significant issues. 

For Dadi, the fistula, which provides a permanent location for the intravenous needles needed in dialysis, has caused so much scarring that her arm is suffering from nerve damage and her skin is cannot heal properly to stop bleeding at the needle site. More importantly, the scarring may limit how much time she has left on dialysis.

Bioprinting Organ Patches

Because Dr. Roy’s artificial kidney features renal proximal tubule cells, it’s not hard to imagine one potential partner in a firm called Organovo, which recently demonstrated the ability to 3D print renal proximal tubule epithelial cells (RPTECs).

Many bioprinting processes extrude a biocompatible gel infused with tissue cells to build a structure. Keith Murphy, co-founder and former CEO of Organovo, described how the company’s technology differs from many of these methods. “In contrast to that,” Murphy said, “what Organovo has focused on is making a structure that is cellular. In some cases we use gels as complements to what we’re doing for short-term structural components, but always with the goal to remove them quickly and to get to something that is 100 percent cellular and I think that’s the major difference with most of what’s out there. We strive to have a structure that is fully cellular as fast as possible.”

Organovo began by commercializing 3D-printed liver tissues for pharmaceutical research and drug safety testing as one step toward the ultimate goal of, one day in the future, bioprinting complete organs. 3D-printed tissues may make it possible to more quickly and accurately test medications, bridging the drug discovery and clinical trial phases of development. After successfully commercializing human bioprinted liver tissue, the California-based firm went on to do the same with kidney cells, releasing ExViveTM Human Kidney Tissue for researching nephrotoxicity.

ExVive Human Kidney Tissue is made up of “an apical layer of polarized primary RPTECs supported by a collagen IV-rich tubulointerstitial interface of primary renal fibroblasts and endothelial cells.” The tissue is able to demonstrate such kidney functions as the tubular transport of xenobiotics, proteins and ions and which can be used to assess kidney toxicity and tissue injury. Such behavior made it possible for Organovo to study the nephrotoxicity of the chemotherapy medication cisplatin, as well as its mediation by the drug cimetidine.

As a milestone along the road to actual organs, Organovo has conceived of an interesting middle ground: organ patches. Until it’s possible to bioprint an actual liver, Organovo is working on creating liver patches that can be used as a temporary treatment to provide relief to patients on organ waiting lists. The research so far is quite promising. In December 2016, the company presented its first data demonstrating survival and sustained functionality of bioprinted human liver tissue implanted into animal models.

Researchers implanted liver patches made up of human hepatocytes and select non-parenchymal cells onto the livers of mice. Over the course of several weeks, the tissue was rapidly vascularized and engrafted into the host organ, where it exhibited the production of key liver proteins and enzymes. As Organovo continues to study the technology, the company plans to submit an Investigational New Drug application to the U.S. Food and Drug Administration in 2020.

Bioprinting functional kidney patches is not quite as easy as liver patches, according to Murphy. “The challenge with kidney is the level of complexity of the kidney in that you need some of the finer details to be present in order to get some of the basic function,” Murphy said. “What Organovo has produced to date is a kidney proximal tubule, which is only one small part of the kidney anatomy. The proximal tubule is an important part because toxicity from drugs often occurs here. That’s why we’ve launched that product even though it’s not a full kidney issue. To get to more complex kidney tissue you need to have the ability to represent the greater set of cell types and some initial architecture.”

In fact, Murphy didn’t previously consider a kidney patch to be feasible. That is, until Organovo started working with Melissa Little, of the University of Queensland and the Murdoch Childrens Research Institute. In 2015, Little and her team first published research detailing the ability to grow “mini-kidneys” from induced pluripotent stem cells (iPSCs), that is, stem cells derived from adults instead of embryos.

Using signaling factors, the team was able to cause iPSCs to differentiate into two kidney precursor cells: those that become collecting ducts and those that become functional nephrons. As a result, the organoids were made up of a collecting duct network with connective tissue, blood vessel progenitor cells and nephrons. The mini-kidneys functioned similarly to kidneys in a first-trimester human fetus, with in-vitro structures damaged by renal toxins.

Little is pushing her work further with the help of Organovo and the Methuselah Foundation. Using an Organovo bioprinter, Little believes that it may be possible to bioprint a more accurate kidney model. Organovo is also licensing her research for potential commercialization.

“Before the work that Prof. Melissa Little did, I don’t think I would have said that there could be a patch for the kidney,” Murphy explained. “We sponsored her believing that it could be done. Seeing that work as successful as it was means that we can start a timeline to think about when we can have a kidney patch, as well. I can’t give you an exact timeline because it depends on resources and how the science proceeds. We were probably at a similar point with liver tissue a couple years ago as we are with kidney now and we’ve spent maybe two years getting to where we are today with liver tissue—some solid prototype tissues. I think it’s not unreasonable to think that we could be at the same point with the kidney in a couple of years.”

A Family of Donors

Even if Dadi’s transplants had taken, there was no promise that her kidney failure would be entirely remediated. Long periods of exposure to immunosuppressive drugs have a toxic effect on the body.

Just ask my mom, not only because she is a nephrologist at Loyola University Medical Center in Illinois, but because she is a transplant patient and a kidney donor.

My mother got into nephrology while in medical school, where she saw a best friend and colleague suffer from acute renal disease. It was then that she knew that she would one day donate her own kidney. That day came when she was presented with a new patient, who, at 4 ft 7 in and 93 lb, just so happened to be roughly the same size as my own petite mom. I’m proud to say that, on October 10, 2002, my mother became the first known doctor in the U.S. to give a kidney to an unrelated patient.

A 2002 clipping discussing the transplant between my mom and her patient. (Image courtesy of People Magazine.)
A 2002 clipping discussing the transplant between my mom and her patient. (Image courtesy of People Magazine.)

That gesture would be repaid after my mom developed pulmonary fibrosis in 2011. Exactly 12 years after she donated her kidney, my mom received a lung transplant from a deceased donor, potentially making her the only doctor to be both an organ donor and recipient. Soon, she would experience what her own patients had when taking immunosuppressants to protect the health of her donor organ. The first drug she tried, tacrolimus, caused unmanageable hallucinations. I remember one night when my mom went from searching for invisible rings in her pockets to urging me to call the police to keep a squad of fascists from blowing up a raccoon with a bazooka.

She then turned to the same medication Dadi had taken in 1989, cyclosporine. The drug ultimately proved too powerful, causing toxicity to her remaining kidney, ultimately resulting in kidney failure. The only qualified donor in my family was my brother, who gave our mother his kidney this past February.

Dr. Susan Hou with her 37-year-old son, Ethan.
Dr. Susan Hou with her 36-year-old son, Ethan. 

She is now recovering, but the fate of her kidney remains uncertain. Initially, it performed with the gusto of a 36-year-old man. Now, the toxicity levels in her kidney have started to slowly creep up. Finding another match like my brother may not be so easy, leaving dialysis as potentially the only other option if anything should happen to the organ.

The Path to Complete Organs

Both Wake Forest Institute for Regenerative Medicine (WFIRM) and its director, Dr. Anthony Atala, are legendary in the tissue engineering space. In 1999, Atala and his team created the first lab-grown organ, a bladder, to be implanted into a human. After the successful implantation of artificial bladders into seven children using their own cells, Atala took his team to WFIRM, where he oversees approximately 300 researchers working to develop over 30 different replacement tissues and organs.

In the case of bladder transplantats, Dr. Atala was able to use progenitor cells from the patient’s own tissues, ensuring that there would be no rejection; however, he has also discovered a new class of stem cells derived from amniotic fluid. These may be valuable in future cases where a patient’s own cells cannot be used, but an organ transplant is necessary—for instance, when a patient has cancer. In order to prevent rejection, using a patient’s own cells is always preferable.

Several bioprinted scaffolds, including a kidney structure. (Image courtesy of WFIRM.)
Several bioprinted scaffolds, including a kidney structure. (Image courtesy of WFIRM.)

WFIRM is still working to produce an artificial kidney that can actually benefit patients. Though there is much progress yet to be made, WFIRM has embarked upon several promising strategies. WFIRM initially began by growing cells with the characteristics of kidney cells and then placing them on an artificial kidney device that included a tubular component, collection system and a reservoir. Implanted in animals, the cells formed kidney-like structures that produced urine-like fluid.

The research then evolved to use bioprinting, first with an inkjet-style printer and then with a pneumatic extrusion device. By converting a patient’s CT scan into a 3D model, it may be possible to create a patient-specific kidney scaffold that would be seeded with the patient’s own cells.

Alternatively, WFIRM will place a deceased donor kidney into a washing machine-like device to rinse away the original donor cells, leaving only the structure in place. This architecturally intact organ template would then be infiltrated with the patient’s own cells.

WFIRM’s Integrated Tissue-Organ Printing System at Dr. Atala’s TED Talk in 2011. (Image courtesy of TED.)
WFIRM’s Integrated Tissue-Organ Printing System at Dr. Atala’s TED Talk in 2011. (Image courtesy of TED.)

Engineering kidneys presents unique challenges, according to Atala. “As a solid organ, the kidney is very dense with cells, which means that it has high requirements for oxygen,” Atala explained. “The challenges in engineering functional replacement kidneys are many, from growing the millions of cells required to engineer the organ to finding a way to supply the organ structure with oxygen until it can integrate with the body. Of course, these are the obvious challenges. Our work on this organ is a long-term effort, and I have no doubt that we will encounter a variety of obstacles along the way. Engineering solid organs, after all, is considered the holy grail of regenerative medicine, and we do not expect it to be simple.”

One issue that has been brought up in bioprinting is the ability to vascularize tissue, so that nutrients can be brought to the organ. Both Keith Murphy, of Organovo, and Dr. Atala said that vascularization has been achieved on a smaller scale. The problem may be scaling this up, according to Dr. Atala.

“Our team has bioprinted human-sized cartilage, bone and muscle constructs that, when implanted in experimental models, developed a system of blood vessels and nerves,” Dr. Atala said. “The key to supplying the constructs with oxygen until they developed blood vessels was to print tiny channels into the structures that allowed oxygen and nutrients from nearby structures to diffuse into the printed structures. While this technique is successful for smaller structures, supplying solid organs such as the kidney is more challenging.”

WFIRM continues to make progress on the technology. In fact, Dr. Atala 3D printed a prototype kidney structure on stage during a TED Talk in 2011. The printer used in the process was an upgrade of an earlier inkjet platform, which was essentially a 2D inkjet printer that was hacked to print biological tissue. Since printing the kidney on stage in 2011, Dr. Atala said that WFIRM has enhanced the system.

“We have continued to improve and refine the printer,” Dr. Atala explained. “For example, we have reduced the size of the printing nozzles to allow for more precise structures. The printer is able to deposit both biodegradable, plastic-like materials to form the tissue ‘shape’ and water-based gels that contain the cells. In addition, we have optimized the water-based ink that contains the cells so that it promotes the cells’ health and growth. We also print a lattice of microchannels throughout structures that allow nutrients and oxygen from the body to diffuse into the structures and keep them alive until the tissues develop their own system of blood vessels. The results of studies in experimental models suggest that the printing system can print viable human-scale structures that have the right size, strength and function for future clinical use.”

The Future of Kidneys

Whereas Keith Murphy reluctantly gave a timeline of a few years before a kidney patch might be viable, Dr. Atala was unable to venture a guess as to when bioprinted organs might become a reality.  Instead, he said, “In science, it is never easy to predict how soon a new technology will become clinically available to patients. The results of our research indicate the feasibility of printing bone, muscle and cartilage for patients, and we will be using similar strategies to print solid organs. Our goal is to make patients better, so we are also pursuing other technologies, including cell therapies.”

In a paired exchange, multiple incompatible donors are matched with compatible recipients to create a donation chain. (Image courtesy of Kidney Link.)
In a paired exchange, multiple incompatible donors are matched with compatible recipients to create a donation chain. (Image courtesy of Kidney Link.)

Until then, organizations like the National Kidney Registry, Be the Match and The Alliance for Paired Kidney Donation have been developing new strategies for managing the organ crisis in the U.S. With paired organ exchange, it’s possible for patients with incompatible donors to be placed into a larger pool to be matched so that multiple patients can receive organs from compatible strangers. However, in such a network, the donors must volunteer to donate a kidney to someone they don’t know, which can be a potential psychological hindrance.

For widespread organ donation to be truly successful, there are a lot of cultural and political obstacles to overcome. Efforts to institute an opt-out system of organ donation, in which organ donation occurs automatically after death unless an individual specifically requests otherwise, have struggled in the United States. Without such a system, would-be donors often have false biases against organ donation, mistakenly believing that doctors won’t work as hard to save the lives of organ donors or that the organs might be harvested for the black market.

As of January 2016, there were 121,678 people in the U.S. in need of an organ transplant, 100,791 of which were awaiting kidney transplants. For kidney patients, there is a race against time, on the one hand waiting for cultural attitudes to shift to increase the number of eligible donors and, on the other hand, for technology to improve to the point where there are newer, better treatment options, like artificial or bioprinted kidneys.

The author with his godparents, Tien (left) and Dadi (right). (Image courtesy of Le Voyager Photography.)

The author with his godparents, Tien (left) and Dadi (right). (Image courtesy of Le Voyager Photography.)

I asked my godmother if, given the hardship she has gone through with her first two transplants, whether she’d be open to the idea of receiving a bioprinted kidney made from her own cells, in the hopes of limiting the chances of rejection.

“Based on my experience,” Dadi said, “of course, I am eagerly waiting for something like a printable kidney or an artificial kidney. The needle access site in my arm is becoming too scarred to use, leaving only the vessels in my neck or legs—areas that are highly problematic and prone to infection. If I run out of dialysis access, I need something to live on. Timing is very important. If I have to wait another 10 years, I don’t think my vessel can last that long.”

She added, “I hope the scientists that are working on these projects have something out sooner. It’s not just me that needs it. There are a lot of other patients. I’ve been a nurse for kidney patients for all of these years. I know that many people out there are waiting for something because they can’t get a transplant. They’re miserable on dialysis or some of them, like me, might not be able to do dialysis anymore. There’s really a big need there. It’s really a life or death issue.”

Recommended For You