Tissue engineering and regenerative medicine (TERM).

Exciting developments appear to be taking place with regard to the healing of the tissues of the body damaged or destroyed by injury or degeneration.

At a relatively early stage of its development the human embryo consists of three layers from which all the cells of the body develop. This being so the cells within these layers are called ‘germ’cells. The cells of the upper layer (ectodermal layer) give rise to the skin and nervous system. Those of the middle (mesenchymal layer) give rise to the bones, muscles and blood vessels. Those of the lower layer (endodermal layer) give rise to the bowel and its associated parts.

It was originally thought that once the cells of these layers had developed to form a definitive tissue or organ within the embryo that they were no longer able to multiply to replace the damaged parts within the developed body. Typically damaged tissues of the body heal by way of scar tissue, although this often leads to pain, stiffness and deformity

Over the last few years, however, promising research has taken place which shows that under the right circumstances some undifferentiated cells of the body can be stimulated and made to multiply and differentiate into cells  specific for the area. Following this process these cells can be inserted into the affected area in which they produce the   to replace the tissues in the damaged area with relatively normal cells which then with normal, or as close to normal as can be obtained; the aim of which is to restore the damaged tissue or prevent progression of the disease.

While this exciting research is still considered experimental, it shows great potential to achieve the aims of replacing damaged or injured tissues with relatively normal tissue rather than scar tissue or a prosthesis, to fill large tissue defects, or to simply to improve the function of the damaged tissue. Tissue engineering is the development of cell based substitutes to restore, maintain or improve tissue function

As they mimic the mechanisms of normal tissue repair these processes are put under the general term of  ’Regenerative Medicine’.

While experimental investigations are taking place with regard to several tissues and organs of the body, the main investigations with regard to damage within the musculo-skeletal system are in connection with restorative procedures of the tendon and ligament, fascia, bone, cartilage and skin.

The main techniques and components used in the restoration of musculo-skeletal tissues include one or more of the following:

 

  • Stem cells

It has, however, now been shown that it is indeed possible, by using certain techniques, to stimulate some cells within the adult body to cause them to multiply and differentiate once again to form the specific tissues of the body. Because these cells can develop into a number of different tissues they are termed ‘stem cells’.

Two main types of cell lines are used viz. Embyonic and Mesenchymal. The ‘embyonic’ cells are derived from the blastocyst formed by the fertilised ovum in its early stage of development. They can develop into any tissue of the body and, as such, are very useful in studies of human development and disease.

The stem line more often used for testing musculo-skeletal tissue engineering and regeneration techniques are the ‘mesenchymal stem cells’ MSC’s which are obtained from a number of sources, including fat,  bone marrow and cord blood, ligaments, synovium and tendons. Similarly they have been shown to proliferate and differentiate into a wide range of lineages and are being tested in the  treatment of a number of conditions.

  • Drugs and Growth Factors Bioactive agents

In addition to the stem cells, it has been found that there are a number of normal biological substances which stimulate the stem cells to differentiate and grow into the required tissue. These substances are termed ‘growth factors’ (GF). GFs can be used in their isolated form in injured tissue/organ, as a ‘pool’ of GF’s or in association with scaffolds and/or cells within the body or in the laboratory.

Simplicity of application and affordable price are the main reasons by which GFs have been widely applied for treatment of different injuries in orthopaedics

In a body injury, platelets participate in the natural healing process, being responsible for haemostasis and releasing of bioproteins or GFs that are crucial to the wound-healing process.

Bone morphogenetic proteins (BMPs) are members of the human transforming growth factor-b (TGF-b) superfamily and similarly to PRP have been demonstrated to have many therapeutic possibilities, particularly with their effect in regeneration of body tissues, specially bone and cartilage.

  • Scaffolds

Tissues can be ‘engineered’ by applying stem cells to a 3-dimensional, porous ‘scaffold’ of synthetic or natural materials which is shaped to replace the deficit in the tissue, either within the body or in the laboratory. Scaffolds can be combined with stem cells or GF in a in vivo approach (to permit the self-regeneration of small tissue lesions or used alone.

The stem cells adhere to this scaffold while they proliferate into the required tissue, often stimulated by some bioactive agent, such as a physical stimulus or a biological ‘growth factor’. The scaffold is biodegradable and is gradually replaced by the natural ‘ground substance’ of that particular tissue secreted by the now differentiated cells.

Applications of TERM techniques

The main musculo-skeletal tissues which benefit from tissue engineering and regenerative medicine strategies are bone, tendon and fascia, and skin.

  • Bone repair Some technologies combining the use of GFs (namely BMPs), cells and/or scaffolds, adapted or not to a surgical intervention, have achieved promising results in cases where several previous surgeries have failed systematically.

BMPs, specifically BMP-2, BMP-4 and BMP-7, have been known for over a decade for inducing osteogenic bone cell differentiation in vitro and in vivo.

  • Cutaneous ulcers around the ankle, secondary to trauma, vascular insufficiency or diabetes are injuries that require special attention mainly owing to low vascular supply. Cell-seeded scaffolds have been shown to be beneficial when treating ulcers as it improves wound healing.
  • Tendon Repair Several GFs have been found to be useful in tendon wound healing, like TGF-b [44], BMP, fibroblast growth factor (FGF) and insulin-like growth factor (IGF).

The aim of TERM is the substitution of the missing tissue with a tissue-engineered construct. Stem cell-based TERM strategies require three main steps:

(i) cells are harvested, isolated and expanded in a tissue culture

(ii) scaffolds are seeded with the induced cells,

(iii) cell-seeded scaffolds are re-implanted in the damaged area.