What is tissue engineering?

Tissue engineering is an important tool in understanding how certain conditions progress and how they can be treated. Therapies based on tissue engineering techniques have already been approved within Europe. So what is tissue engineering?

What is tissue engineering?

Tissue engineering is part of the field of bioengineering. Bioengineering is a broad discipline, which combines principles from both biology and engineering. It is sometimes described as taking an engineering approach to the study of biology.

Within healthcare, bioengineers contribute in areas such as device design (eg., considering all the mechanical forces a joint implant will have to withstand), physical therapy (eg., studying how weight-bearing affects the healing of a broken bone), and drug delivery (eg., understanding how quickly the coating of a tablet breaks down and how rapidly it will start to have an effect).

Tissue engineering involves investigating the biological, physical, and chemical forces involved in tissue development, injury, and wound healing. The goal of tissue engineering is to restore, maintain, improve, or replace biological tissues. This requires understanding what the healthy condition looks like, and how to return damaged tissue to this state with treatment. To study this, tissue engineers must grow cells in a laboratory which behave like healthy cells grown in the body (‘native tissue’).

Tissue samples grown outside the body using tissue engineering techniques are often referred to as ‘tissue-engineered constructs’.

What is the difference between tissue engineering and regenerative medicine?

The terms ‘tissue engineering’ and ‘regenerative medicine’ are often used interchangeably.  Both focus on the repair, maintenance and restoration of biological tissues. The key difference is that tissue engineering focuses on growing tissues outside the body. Regenerative medicine specifically focuses on how tissue-engineering techniques can be used in a healthcare setting to repair tissue within the body.

A lot of research in tissue engineering has the long-term goal of developing a construct that can be used in the clinic. Tissue engineering research is a necessary first step in regenerative medicine therapies.

What are the principles of tissue engineering?

The three defining elements of tissue engineering are the use of:

• Stem cells
• A biocompatible, three-dimensional scaffold
• Bioactive molecules

Stem cells are cells which are capable of developing (differentiating) into more than one cell type. The best-known examples are embryonic stem cells, which can turn into any type of cell in the body. Stem cells in adults can differentiate into several different cell types, depending where they originate within the body. For example, adipose-derived stem cells, which are found in fat tissue, can differentiate into bone, cartilage, fat, and several other tissue types. The path a cell takes depends on many factors, including mechanical forces (such as muscle movement in the developing embryo) or exposure to chemicals (such as signalling molecules in the bloodstream).

Scaffolds are three-dimensional structures which support the growth of stem cells into the desired cell or tissue type. Cells in the lab are often grown on flat surfaces, or suspended within a liquid. A 3D scaffold is a closer match to the 3D environment of the body.

It is important that the material used in a scaffold is biocompatible – that it will not damage the tissue it comes into contact with. This means the material must not be toxic, but also that it must not break down over time into small parts which might irritate the tissue. Materials used in tissue engineering scaffolds include collagen, or certain protein chains (proteoglycans).

Scaffolds for tissue engineering must also be porous. Stem cells can only be coated (seeded) onto the outside of the scaffold, so it is important that the scaffold is porous enough for the cells to move inwards towards the core as they grow. If the construct has cells only on the outside, and none at the core, it will not behave like normal tissue.

Bioactive molecules are substances which have an effect on living tissue. In tissue engineering, this may mean signalling molecules or growth factors which can influence how a stem cell differentiates. These bioactive molecules may be in the nutrient mix used to grow the cell in a lab. They may also be incorporated into the 3D scaffold during the manufacturing stage.

Researchers are also investigating how bioactive molecules might be used to make tissue engineered implants more effective. For example, a scaffold could release a drug which reduces inflammation, or which helps the implanted cells embed at the implant site.

How can tissue engineering be used in research in developing gene and cell therapies?

Tissue engineering techniques are used to grow ‘models’ of tissue in the lab. These have many uses in research.

• Studying normal tissue development. Engineering tissue can allow researchers to see how certain tissue types develop from stem cells. By controlling the environment, they can observe how certain changes affect the developing tissue. This allows them to answer very specific questions. When conducting a study in animals or humans, there will always be unknown factors which can’t be controlled. In a tissue-engineered model, researchers can control changes to the environment and can measure the results precisely.
• Studying diseases at a tissue level. Scientists can tailor the lab environment to resemble a particular condition. (For example, to understand how arthritis affects cartilage development and repair, scientists may add inflammatory molecules to the nutrient mix.) Another way to study a condition at a tissue level is to collect cells from patients with the condition, and compare the development of their tissue with cells from healthy patients.
• Testing therapies. Tissue-engineered constructs can be used to test drugs to confirm that they are safe for a particular tissue type, or to see what effect they have on a disease model.

Current and potential therapeutic uses

Tissue engineering is used in the following approved therapies:

• Spherox (CO.DON.AG, approved in the EU in 2017), used to treat cartilage defects in knee joints. This therapy, involves collecting cells from the patient, then isolating cells capable of turning into cartilage. In the lab, these are grown into spherical clumps of cells (spheroids). These spheroids are implanted into the cartilage defects, where they attach to the cartilage. Alongside a physiotherapy programme, these implants can fill in the defect over time, reducing pain and improving mobility.

Researchers are also investigating whether engineered tissue might be used for tissue grafts or implants, including:

• Engineering skin to treat severe burn injuries
• Engineering heart valves for people with heart valve disease
• Engineering nervous tissue to repair damaged or severed nerves
• Engineering blood vessel tissue
• Engineering bone tissue to replace bone lost to injury or infection
• Engineering Bowel Tissue to treat Short Bowel Syndrome

This list is by no means exhaustive. Tissue engineering research has implications in treating congenital conditions, diseased tissue, and injuries.

What are the challenges in using tissue engineering to develop therapies?

• Collecting suitable cells. As tissues are a mix of different cell types, researchers need to develop methods for collecting and isolating other the right kind of undifferentiated cell from patients or donors; otherwise the right tissue type will not develop.

• Understanding what factors affect cell differentiation. The human body is a much more complicated environment for cells than a lab, where all the chemicals, nutrients and physical forces can be controlled. This means that a tissue grown in the lab will be exposed to a different environment when implanted into the body. Scientists need to understand the environment of the body to avoid the implant differentiating into the wrong cell type (for example, bone instead of cartilage).

• Recreating the native features of a tissue. Being able to grow a particular type of tissue is not necessarily enough; some tissues behave differently in different regions of the body. For example, the mechanical properties of cartilage at the surface of a joint are different from the cartilage immediately beside the bone. This means that an implant for a deep cartilage defect would have the same range as native cartilage.

• Cell integration at the implant site. In order to fully secure the implant in place, the engineered tissue and the native tissue need to ‘grow into’ each other and become enmeshed. If a tissue-engineered implant does not integrate into the body, the site may not heal properly.

• Assessing the long-term effects of implanted cells. As with any new technology, researchers will need to monitor implanted tissue-engineered constructs over the long-term to ensure that they are safe and predictable.

Find out more

Tissue Engineering and Regenerative Medicine (National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health)