Health and Healthcare

30 years of tissue engineering, what has been achieved?

Research scientist Dan Galperin works on Purified Recombinant Zika Enveloped Protein at his laboratory where they are working on developing a vaccine for the Zika virus based on production of recombinant variations of the E protein from the Zika virus at the Protein Sciences Inc. headquarters in Meriden, Connecticut, U.S., June 20, 2016. Picture taken June 20, 2016. REUTERS/Mike Segar - S1BEUEYZGUAA

Scientists have developed small versions of organs that could be used in drug screening. Image: REUTERS/Mike Segar

Daniel Heath
Lecturer, Biomedical Engineering, University of Melbourne
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The idea of tissue engineering emerged just over 30 years ago, in 1988. The two men credited with doing the seminal work in this field are Joseph Vacanti, a surgeon, and Robert Langer, a professor at the Massachusetts Institute of Technology. However, the term “tissue engineering” was not a mainstream buzzword until almost a decade later when the infamous “Vacanti mouse” – the mouse with a human ear on its back – was revealed.

The mouse evoked backlash from animal rights activists, and fear of genetic engineering from many who did not understand the science. For many others, the reaction was one of excitement and wonder. “If we can grow a human ear, why not a kidney, a liver, an eye?” And thus emerged an era of tissue engineering filled with hope – and hype.

The Vacanti mouse is still impressive to this day, and represented a major step forward in science. However, many still don’t understand what exactly the researchers did. The ear was actually a mesh of biodegradable plastic that was moulded into the desired shape, sprinkled with cartilage cells collected from a cow, and implanted under the skin of the mouse. The researchers removed the ‘ears’ after 12 weeks, and found that some new cartilage had been generated within the structure.

The basic premise of tissue engineering remains the same today. In general, a biodegradable material is formed into the shape of a target organ or tissues, this structure is often referred to as a “scaffold”. The scaffold is then seeded with the appropriate cell types. After implantation or maturation in a lab, it is hoped that the scaffold will slowly degrade away and, as it does, the cells will organise themselves and reconstruct a functional organ or tissue.

Tissue engineering in orthopaedic sports medicine Image: Journal of ISAKOS

However, despite 30 years of dedicated research, we are still relying on organ donation rather than growing kidneys, livers, and hearts in the lab. So the question is – what real-world applications has this research produced?

We interviewed Professor Andrea O’Connor, a tissue engineering expert and the Head of the Department of Biomedical Engineering at the University of Melbourne, to find out.

Daniel Heath – Has tissue engineering made any real clinical impact?

Andrea O'Connor – Oh, definitely. Two of the most successful examples are INTEGRA and Osteopore. INTEGRA is used to help repair skin. The material is placed over a damaged section of skin, usually after a burn. The material has two layers. The inner layer, the one that is in contact with the damaged tissue, is a matrix of collagen. The collagen helps new skin cells and blood vessels grow into the injury to aid in repair. The outer layer is a non-degradable film that acts as a barrier to help prevent infection and loss of fluids from the injury site. A couple of weeks after treatment, the outer layer is peeled off, revealing a newly regenerated dermis [the inner layer of skin]. Osteopore is another success story. This is a porous biodegradable material that is used to repair bone during craniofacial surgery.

DH – What are the main roadblocks that are preventing tissue engineering from making a bigger impact and how can these challenges be addressed?

AO – In my opinion, one of the biggest challenges is vascularisation. In the body, cells in almost all of our tissues are within about 200 micrometers of a blood vessel. These blood vessels are critical to the survival of the cells. Without them, the cells don’t receive enough oxygen or nutrients and they die. 200 micrometers is a very short distance, we’re talking about the width of a few human hairs. Researchers have actually become pretty good at engineering tissues in the lab that contain a blood vessel network. However, when we implant these structures, the vessels are not able to connect to the patient’s blood vessels fast enough. This means that the tissue we worked so hard to construct in the lab may not survive the implantation process.

I think 3D printing and similar technologies will really help answer these questions. A lot of researchers around the world are looking at fabricating structures that contain preformed vascular channels that can be rapidly connected to a blood supply. I’m hopeful that this will let us build larger and more successful tissue engineered structures.

She said other challenges exist, such as sourcing the appropriate type and number of cells needed to populate the scaffold.

AO: If you’re trying to grow a kidney, for instance, you need a large number of the cell types that are found in the kidney. However, where do you get them from? Most people are quite attached to their kidneys! Additionally, there are many different types of cell present in a kidney, and they are organised in very complicated structures, and without this structure, a tissue engineered kidney wouldn’t function correctly.

Currently, a lot of people are looking at isolating stem cells from a patient, growing these to large cell numbers, differentiating them into the appropriate cell types, and then using these cells to populate the tissue engineering scaffold. I’m also hopeful that 3D printing will play a role in helping organise these cells into the right structures so that we can build more functional tissues.

Other big hurdles that slow the implementation of tissue engineering in the clinic are regulatory and commercial. New technologies have to go through many years of clinical trials. We have to make sure that these treatments are safe and beneficial before we can use them regularly as a treatment. However, this rigorous testing does slow the speed at which new treatments can be used to help the general population.

Also, these clinical trials costs millions of dollars. To make that happen, you have to be able to convince a large company or venture capitalists to invest in the development of the technology. Many very promising advances aren’t able to find sufficient funding to carry the invention all the way to the clinic. We call the stage between development in the lab and clinical trials “the valley of death”, and many technologies don’t make their way through that valley.

DH – What is the current state of the art in the field and where will tissue engineering go in the next five years?

AO – In addition to efforts to continue engineering whole organs or tissues for therapeutic application, exciting areas of development are organoids and microphysiological systems. While it’s challenging to generate a whole kidney and other organs, we can grow smaller versions of them in the lab that replicate some of their key functions.

Many research groups are connecting these organoids together using microfluidics to create something approaching aspects of a “human body on a chip”. These systems have a lot of potential in the areas of drug screening and personalised medicine.

Currently, drugs are still tested in animals. However, this is ethically difficult and it’s very well known that most animals do not respond the same way to many drugs as humans. We have the potential here to create platforms that allow drugs to be screened in a very human-like system before they’re actually tested in a person. This will likely help us reduce the number of animal experiments that are required and provide us with much better information on how a drug interacts with human physiology.

Thirty years is a short time in the development of a completely new field of science, especially one that operates in the complex and highly regulated medical space. To date, tissue engineering advances have been very successfully translated from the lab bench to the clinic, and thousands of individuals have benefitted.

With continued research, the field will continue to mature, and new and exciting treatments will make their way into clinical practice. However, this will require continued funding in this area of science, concerted efforts from gifted scientists and engineers to address the outstanding challenges in the field, and championing of these technologies by industry to make sure that they successfully navigate through the valley of technological death.

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