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Tissue engineering - great hope for medicine. Part II: Stem cells and scaffolds

Tissue engineering - great hope for medicine. Part II: Stem cells and scaffolds

The opening ceremony of the academic year 2017/2018 at the Jagiellonian University included a special lecture by Dr hab. Justyna Drukała from the JU Faculty of Biochemistry, Biophysics, and Biotechnology, a biologist, head of the JU Cell Bank.

Here is the English translation of second part of the lecture, which takes the reader on a fascinating journey into the world of transplantation and regenerative medicine.

See also: Part I: From prostheses to transplants

Stem cells’ potential

Due to their properties, stem cells have long been a focus of interest for physicians and researchers specialising in tissue and organ regeneration. Studies on stem cells together with the dynamic development of synthetic materials and biomaterials gave birth to a new dynamically developing field of science tissue engineering.

Transplantation has proved to be an important means of fulfilling the most important objectives of medicine – serving human life. Although today it’s still a widely used method and a standard in treatment of life-threatening organ damage, the problem with finding donors is becoming more and more prevalent. Besides, in spite of the advancements in immunosuppression, complications related to its use and the risk of transplant rejection remain a major challenge.

Stem cells of human mesenchyme (embryonic connective tissue)

Photo: Rose Spear/ Flickr, license CC BY

It’s well established that tissues in a mature body continue to retain the ability to regenerate and it’s possible thanks to different types of stem cells which stay active throughout life. However, their number is small, so they don’t suffice to restore functional tissue in case of an extensive damage, related to a severe physiological stress. It should also be remembered that besides regenerative mechanisms that lead to the full reconstruction of the structure and function of a damaged organ, other, parallel mechanisms are activated in response to the damage. They often protect the tissue against further negative consequences of the damage by creating a scar, at the cost of depriving the tissue of its specific functions.

Due to their properties, stem cells have long been a focus of interest for physicians and researchers specialising in tissue and organ regeneration. The late 20th century was marked by a renaissance in studies on stem cells, including the possibility of their isolation and reproduction outside the body. At the same time, there was a dynamic development of synthetic materials and biomaterials applicable in reconstructive surgery. The marriage of these two disciplines, stimulated by the needs of transplantation medicine, gave birth to a new dynamically developing field of science – tissue engineering, whose main goal is to produce a living tissue outside the body.  

Pioneering achievements in this field have been made by Richard Langer, an American biotechnologist, biochemist and Joseph Vacanti, a transplantation surgeon, who together proposed a definition of tissue engineering and initiated rapid development of this field of research, which is part of regeneration medicine.

The main goal of tissue engineering is to create and develop substitutes for tissues and organs as a functional alternative to conventional organ and tissue transplants.

Intense basic research into the possibility of in vitro cell and tissue culture is related to the growing clinical needs. The current state of knowledge, which allows optimisation of cell isolation technology and reconstruction of three-dimensional tissue structure, raises hopes that it’s possible to reconstruct tissues for clinical purposes. Hence, there is a growing need for continuous improvement of these technologies and the development of strategies of their clinical application.

Human stem cell. Photo: Public Domain

Learning about the structure of tissues and organs from histological research and analysing stages of tissue development during embryogenesis, researchers intend to use isolated cells and three-dimensional scaffolds – matrices, on which cell division and differentiation takes place, with the aim of reconstructing the expected tissue structure and factors determining the process of such reconstruction. As far as cells are concerned, stem cells are the most desired population, as they are crucial for tissue regeneration. Embryonic stem cells are most flexible in this respect, but they can’t be used in treatment for many different reasons.

Building scaffolds

We already know that stem cells can be found in all tissues of a mature organism. Yet, they largely differ in terms of number, potential, as well as possibility of isolation and reproduction. The patient’s own tissues are the optimal source of cells, since they do not trigger immune response. However, it is not always possible to harvest stem cells, and not every patient can wait for their reproduction and graft. Hence, there is an ongoing search for more universal stem cells, capable of regenerating different types of tissues.

An important breakthrough in this field was made by Shin’ya Yamanaka and John B. Gordon, who proved that diverse cells taken from a mature organism can be genetically modified so that they can play the role of embryonic stem cells. In that way, the researchers found a new potential source of autologous stem cells which are universal in terms of differentiation capability and can be used in regeneration medicine. For their achievements, Yamanaka and Gordon were awarded Nobel Prize in 2012.

However, to correctly reconstruct the structure of an organ it is necessary to accurately place differentiating stem cells in a three-dimensional arrangement. The use of proper three-dimensional scaffolds can also facilitate this process.  

In native tissues, the scaffolding for cells is made of protein, mainly collagens, as well as proteoglycans, whose composition varies depending on the tissue. On the one hand, they form the backbone of the tissue, which gives it specific mechanical and physical properties. On the other hand, they influence the behaviour of cells that reconstruct the tissue by controlling various processes that finally lead to tissue maturation outside the body.

The substance from which the matrix is built is produced and secreted by cells, so it isn’t necessary to faithfully reconstruct constituent parts of the scaffold. During the tissue maturation in an in vitro culture in a bioreactor, cells themselves transform the scaffold according to the tissue’s intended role, in response to external signals, i.e. molecules delivered via the growth medium in which the reconstructed living tissue is immersed. Matrices can be produced from both natural and synthetic biopolymers, the latter of which are already clinically used to produce surgical stitches, prostheses, drug carriers, as well as valves.

As the effectiveness of putting cells on the scaffolding determines the effectiveness of reconstructing the tissue, key factors in this process are: the cross-linking of cells, the size of pores, the thickness of fibers and the presence of domains recognised by cells. The scaffoldings are produced with various chemical and physical methods. The recent research has been mostly focused on the bioprinting method, which consists in creating three-dimensional structures from diluted parts of scaffoldings and living cells. Bioprinting is conducted according to an accurate computer model, generated on the basis of computed tomography or magnetic resonance imaging.

The size of tissues and organs produced outside the body is the bottleneck of tissue engineering, as they don’t contain arteries supplying them with nutrients. During culturing, the cells’ nutrition is dependent on the growth medium, which is pumped inside the three-dimensional structure of the tissue. To be able to survive after transplantation, the produced tissue substitute needs to be quickly put within the network of patient’s blood vessels, which determines its integration with the transplant recipient’s tissues and the survival of its cells. A perfect solution to this problem would be to reconstruct the tissue or organ together with its own network of vessels, which could be linked to the main blood vessel of patient after the transplant. This is becoming possible thanks to bioprinting.

Delivering the cells to the injured area is not an effective solution in itself when the matrix has been destroyed. In such case, it’s also necessary to provide the regenerating tissue with a scaffolding, so that it is properly “inhabited” by cells, which, in response to the received signals, will start to differentiate and perform their desired function.

Regenerative medicine uses some or all of the abovementioned elements of this tissue engineering triad - cells, scaffold, and signals. Depending on the tissue damage, its regeneration can be induced by delivering cells themselves or factors activating reserves of dormant stem cells, which will reconstruct the tissue.  

See also: Part III: A price worth paying

Original Text by Dr hab. Justyna Drukała: www.nauka.uj.edu.pl (all three parts)

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