This will be the follow up to my previous post on the history of transplantation. Here I will cover the current method of transplantation along with the negatives that come with it. Then I will move to discussing the future of transplantation along with methods that could make traditional methods obsolete.
Current Methods
Transplants are pretty commonplace these days, through the surgical advances made throughout the 20th and 21st centuries. Such things as better equipment, higher sterility during surgery and the development of drugs to prevent rejection. There are still several caveats to transplant surgery that make it almost an art in finding that perfect match.
There are two primary requirements than need to be met for a donor to be considered. The blood types much match or there will be immediate rejection the positive or negative nature of the blood does not matter however.
Secondly the more complicated requirement is a need for matching human leukocyte antigens (HLA). These are special proteins present on all cells in your body that determine what is you compared to what is foreign. If these do not match your immune system will immediately recognise the transplanted tissue as foreign and act to destroy it. Also in some conditions, as mentioned in my previous post, the possibility of the transplant attacking the donor. It is not feasible to acquire a perfect match unless dealing with twins however doctors try to obtain as close a match as is available. This is far more complex than blood matching as there are many different HLA markers on a singular cell to consider. In most cases doctors look to match 8-10 of these markers to a potential donor. Finding a match is far more likely when looking within family as markers are past on from generation to generation. This does not rule out outside donors of course.
Along with finding the necessary match we come across several other issues. The availability of organs is limited and some organs can only be obtained from a deceased donor e.g. the heart. For an organ like the kidney the waiting period can be years and with 6000+ people in the UK alone (NHS Statistics 2019) on the waiting list for transplant, time is limited.
If you do manage to go through surgery, you will need to be put on immuno-suppressant drugs to prevent your immune system from attacking your newly transplanted organ. This is a lifetime commitment which obviously comes with its own risks. By constantly suppressing your immune system you become more susceptible to disease and illness. Now I am not saying that transplantation is a bad thing. It is an incredible leap in our medical history and many, many lives have been saved. Today I am going to talk about how science is aiming to improve this technique. In many cases moving away from the need to receive organs from others and removing the need for donated tissue at all.
Growing Your Own
You would think it science fiction, but we have come a long way. Here I will discuss methods being developed to potentially grow organs for transplantation as well as making our own replacement tissues. This will lightly cover not only transplantation, but the ways we can repair systems without the need for full organ transplants. I will not be covering prosthesis used in amputations, that is an area all to itself.
The key to much of the advances in replacement technology and research are stem cells. You will hear mention of stem cells through this post so a quick, simple explanation will be needed. Stem cells are unique cells with their main property being the ability to become any cell in the body given the right stimulus. They are basically blank sheets with possibility to become anything for example, heart cells, muscle cells or liver cells. These cells hold within them the potential to become entire organs if treated correctly. They are found throughout your body and can be extracted and purified by labs and it is here where our journey to lab grown organs begin.
Future of Skin Grafts
Skin grafts included one of the first historically documented forms of transplant (circa 16th Century). They are a crucial part of many surgeries and in the treatment of several conditions such as burns. For burn victims the treatment is often times just as bad if not worse than receiving the burn in the first place. Many treatment options involve the use of allografts. Skin taken from one area of the body and used to cover another, this will lead to the formation of two wounds that need to be cared for. So studies have been done using stem cells to treat wounds. These stem cells can become new skin cells to eventually help repair that which has been damaged. These applications have been shown to accelerate the wound healing process. Not only repairing the lost skin, but restoring the hair follicles, sebaceous glands and overall improving the look of the area. This improves the psychological state of the patient along with the advanced healing. The treatment has shown such success that some groups have developed stem cell guns that can spray the cells onto the burnt regions.
It’s not just burns that can be treated with steam cells. In 2017 an article was published in Nature documenting the treatment of a young patient with junctional epidermolysis bullosa (JEB). This is a genetic condition causing skin to blister and become damaged easily. Generically modified steam cells grown in the lab were applied to the skin of the patient. These over time eventually replaced the entire epidermis.
Let’s take this further, how about growing substitute skin. One company has developed a material called Stratagraft, a skin substitute entirely grown from living cells in the lab that can be used successfully in transplants. Stratagraft is made from living cells that scientists aim to be universal. To avoid the problem of rejection the tissue is made from keratinocytes. These are the most prevalent cell found in the skin and do not express one of the main markers for the immune system to recognise as foreign. Along with this precaution the fabricated tissue contains no immune cells themselves. The tissue when grown forms a layer almost identical to that of normal human skin. Stratagraft has been used in clinical trials, and is showing great promise in the treatment of injuries that would require skin transplants.
Cellular Construction
The dream of growing organs is a little way off, but there are many who are attempting new and unique approaches to achieving this goal. When we grow cells in the lab they tend to form simple flat structures. Cultured cells will not form three dimensional organs and on top of that organs are not simply made from one cell type. There are a variety of different cells that make up the heart along with the need to form chambers and vessels. These things are complicated and sure we can grow the individual cells that make up a heart but we can’t tell them to make one.
Some groups have looked to scaffolds, creating a skeleton for the cells to grow on and form organs. Again organs are not simple so require so much work to even get close to a functional tissue. However there has been some success in using scaffolds to grow retinal transplants. The technology is very young and the work is still aiming to find the perfect material for implantation. Testing whether is it better to use a degradable scaffold that will eventually disappear or a permanent one. In fact a retinal patch was due to enter phase 3 clinical trials this year after early success in two patients suffering from macular degeneration (blindness due to the loss of a layer in the eye that provides nutrients within the retina). Some say that the use of a scaffold over complicates the surgery, but they are going forward with their patch. Some day treating blindness due to age might be as simple as getting a new retinal layer transplanted.
I cannot really avoid talking about scaffolds without mentioning the controversial surgeries that took place back in 2011. The world was in awe at the miraculous treatment performed by Dr. Paolo Macchiarini. The first ever tracheal transplant successfully completed using an entirely synthetic windpipe. However it was not joy for too long. Andemariam Beyene lived for 3 years after the surgery and was the longest surviving patient of this surgery. Several other transplants were performed all leading to the deaths of the patients. Those who survived had their synthetic windpipes removed in replacement of a living donor version. Macchiarini seemed ignorant of these failures and continued his work in clinical trials in Russia. Investigations were underway unearthing false research claims in past publications and medical negligence on the part of Macchiarini. Sadly no crime could be proven as the patients may have died under any other treatment. The Swedish national scientific review board did find misconduct in his publications and had his papers retracted. So why didn’t these synthetic windpipes work? They couldn’t integrate correctly with the body, causing inflammation of the living windpipe, and although they were sown with living cells no true tissue really grew back.
Making Miniature Organs
Let us move to the really exciting advances. We have covered replacement methods and using scaffolds with stem cells. So it’s time to talk about making organs and tissues ourselves. Dr Jim Wells and his team have put together methods of taking stem cells and coaxing them to become specific cells and then work together to form effectively miniature organs called organoids. These are very small and around the size of a pea, but they stand as a huge step in developing methods that could eventually grow organs. Currently they are incredibly useful to medical research and patient treatment in rather unique ways. These organoids possess much of the complexity of the original organ, they possess various cell types and are layered. They also have the same functions as the organ they are derived from.
This functionality makes them ideal for the testing of drugs. Many drugs fail to reach the level of clinical trial or fail before getting to consumers approximately 90% of drugs in fact fail. Drug development takes many years of research and much of the early testing goes on in animals. However we are humans not rats or monkeys we are all genetically different. A drug that may treat arthritis in a rat may have no effect on a human. So these organoids stand as a method of reducing animal testing as well as having an artificial human test subject for new therapeutic treatments. Not only that but these organoids have been used to create personalised treatments for patients. Taking a sample of the patient’s stem cells allows the growth of an organoid unique to them. Drugs can then be tested without any harm to the patient, generating individual treatment plans.
Bioprinting
With the rise of 3D printing within the manufacturing industry. Along with the ability for people to craft things from desktop printers, this technology has leapt forward in the past few years. It is now the turn of scientists to jump on the bandwagon. Swapping out the plastics for bio-ink. There is now a huge amount of investment into the development of bioprinters that have the capability of printing cells to form shapes and 3D structures similar to blood vessels and the trachea. The cells are threaded together within a string the size of a hair. The string is then layered to form these structure. They have produced replicas of an asthmatic trachea that will relax and contract in response to irritation and drug therapy. This technology along with the organoids can also be used highly within the drug development field. In a few years time we may be able to print new tissue to replace damaged organs or at least parts of organs together with blood vessels.
Summary
The area of transplantation is ever changing we started back in the 1900s with the first successful kidney transplant and now we perform surgery with ease. The next hurdles for us to cross are the problems of rejection and the limited supply of organs for those in need. The advancement of this technology aims to remove rejection as a problem by providing the patient’s own cells as transplants and then help with the supply by growing replacement organs in the future. Some groups are even looking into using donor organs and removing all the cells from it leaving behind only the nature scaffold then filling it with the recipient’s cells, as a sort of stop gap between these methods I have discussed. We also have advancements in the way we are conducting drug development using human based tissues as a replacement for animals. In a couple more years who knows how things may have advanced. The future of bio-engineering is truly exciting and one day we may be waiting only a month to grow a new kidney that is our very own.
Reading Sources
- The future of organ transplantation. Cascalho. M et al.
- Individual cell-only bioink and photocurable supporting medium for 3D printing and generation of engineered tissues with complex geometries.
- Bioengineered stem cells as an alternative for islet cell transplantation. Moore S. et al.
- Scaffolds for retinal pigment epithelial cell transplantation in age-related macular degeneration. White and Olabisi.
- Evaluation of culture conditions for in vitro meniscus repair model systems using bone marrow-derived mesenchymal stem cells. Hidalgo Perea, et al.
- Scaffold-free trachea regeneration by tissue engineering with bio-3D printing. Taniguchi et al.
- Tissue-engineered trachea from a 3D-printed scaffold enhances whole-segment tracheal repair. Gao et al.
- Bioartificial Organ Manufacturing Technologies. Xiaohong Wang.
- Stem Cells for Skin Tissue Engineering and Wound Healing. Chen et al.
- Regeneration of the entire human epidermis using transgenic stem cells. Hirsch et al.
- Stratagraft clinical trials
- StrataGraft skin substitute is well-tolerated and is not acutely immunogenic in patients with traumatic wounds: results from a prospective, randomized, controlled dose escalation trial. Centanni et al.
- The effects of stem cells on burn wounds: a review. Francis et al.
- Stem Cell Treatment in Retinal Diseases: Recent Developments. Ayşe Öner.
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