Regenerative medicine in orthopaedic practice

Regenerative medicine has been defined as the branch of medicine that aims at repair, replacement or regeneration of cells, tissues, or organs to restore impaired function. Tissues essentially consist of cells, which are the basic living units, surrounded by a matrix or scaffold, which helps the cells in their function. A rough analogy would be to compare the cells to bricks, and the matrix, to the mortar that holds the wall together.

The human body consists of over 200 different cell types. Many of these cell types are incapable of self renewal. The cell numbers are maintained by certain cells known as stem cells, which have two basic characteristics - They have the capacity of self renewal, and under appropriate conditions, to differentiate into different cell lineages. This essentially means that they can replicate themselves, and if appropriately stimulated, can develop different tissues. Given their versatile nature, one may be surprised that they have not already become more popular in treating medical conditions. The reason for this is that the technology for  extensive cell expansion in vitro, that is, outside the body, has taken time to develop, along with the understanding of the growth factors, the ‘triggers’ required to induce the development of different cell lines. There have also been various moral and ethical constraints, compounded by the fact that the regulatory bodies world over have had no uniform opinion on the legality of the extent of stem cell use.

Stem cells are basically of two types: Embryonic stem cells, which are derived from the embryo, and Adult (or non embryonic) stem cells. The embryonic stem cells are described as pluripotent, as they can differentiate into almost all the cell types in an adult. (Researchers have successfully cloned several animals, including Dolly the sheep, a cat, a horse and several others using techniques involving embryonic stem cells.)  Their enormous therapeutic potential is limited by ethical and moral concerns which have generated an unresolved debate, with strong opinions being held by both sides of the argument.

Adult stem cells, on the other hand, are multipotent, as they can differentiate only into specific cell types and can be derived from various sources such as umbilical cord blood, bone marrow, skin and fat (adipose tissue). Cells can also be derived from specific tissues, called unipotent cells, such as from cartilage tissue, which can then be cultured to develop that specific tissue.

The existence of cells that could differentiate into different tissues was known since the 1930s.

Stem cells were first studied in the 1960s. In the seventies attempts were made, at that time unsuccessfully, to generate new cartilage.

In orthopaedic practice, regenerative medicine has been used to solve problems that have defied satisfactory solution by conventional means. The main uses of regenerative medicine in orthopaedics have been to regenerate cartilage that lines the joints ( Articular Cartilage). This is specially suited to large, weight bearing joints like the knee, in younger patients with localised damage to the cartilage.  The other main use is in the treatment of fractures that have failed to heal satisfactorily by conventional means (non- unions), where stem cells may be used to achieve healing, or union of the fractures, in conjunction with fixation modalities.

 Stem cells have also been used in the treatment of segmental bone loss, and in the management of spinal injuries, where stem cells may be used to attempt to regenerate damaged nerve cells. As this science is still in its infancy, other uses, currently being experimented with may also become available with time.

The knee joint is the most commonly involved joint in wear and tear. The causes for this are numerous, and especially in the younger patient, it is usually following trauma when the damage tends to be focal. Cartilage has no blood supply, and so is incapable of healing. The usual symptoms of such wear are sharp pain, especially in certain positions of the joint, when loaded. The patient may or may not recall a history of trauma. Some patients have pain in front of the knee, when one of the most common causes is wear under the knee cap or patella. Conventional imaging techniques such as radiographs ( X rays) may not reveal any abnormality.

The diagnosis is made by a good history and a clinical examination, followed by specialised investigations such as the MRI, where indicated. Other causes of similar symptoms, such as a damaged meniscus or ligaments should be excluded, although they may co exist with articular cartilage damage. For an accurate assessment of the extent of damage, however, the best tool is arthroscopy, or ‘key- hole surgery’. This enables the surgeon to survey the inside of the joint, and accurately assess the nature, and extent of damage. It is at this point that a decision can be made about the suitability for cartilage regeneration.

Several protocols for cartilage regeneration have been developed. The most commonly used protocol is ACI, or Autologous Chondrocyte Implantation which was developed in Sweden in the early 1990s. Simply put, it is the technique of implantation of cartilage cells ( Chondrocytes) derived from the patient ( autologous).

In this technique, cartilage cells are harvested from the joint during ‘key- hole’ surgery, from a non load bearing aspect of the joint, after the surgeon has assessed the suitability of the patient for ACI, and accurately mapped the area and extent of the wear. These cartilage cells are subsequently cultured in highly specialised laboratories, and multiplied, to generate several thousands of such cells. This process normally takes about three weeks. Three weeks later, when the cells are ready, the surgeon performs an open operation to access the area of damaged cartilage, and implants the cells in that area. Several means of securing these cells to that particular area have been developed.

The original technique involved the harvest of a patch of membrane lining the top part of the shin bone, the tibia. This is called the ‘periosteal patch technique’. More recent techniques that do not require the harvest of a periosteal patch, such as Chondro Gide® or MACI®, have evolved. These chondrocytes then generate cartilage tissue, which heals the damaged area. As an extension of this technique, it is now also possible to perform a ‘biological knee replacement’, where all the worn aspects of the joint, including the damaged menisci are replaced.

Various recent studies using this technique have reported 80-85 per cent  success rates, with up to five years of follow up. Studies have also shown that this technique is most successful when performed in the younger patient, with focal damage to the cartilage in specific aspects of the joint.

The other common use of stem cells is in healing fractures that have failed to unite by conventional treatment modalities. The causes of non-union may be numerous, and may include bone loss, poor blood supply, inappropriate fixation or immobilisation and infection. The use of stem cells in this situation depends on eradicating infection, obtaining bone ends with good blood supply, and then re fixing the fracture with appropriate immobilization, and implanting stem cells, usually derived from the bone marrow, in a scaffold of a calcium  based matrix with appropriate growth factors such as bone morphogenetic protein (BMP). Good results have been achieved and segmental bone loss of up to 4 -7 cms have been regenerated with this technique.

Regenerative medicine is still in relative infancy, when compared to several conventional methods that were used to deal with these problems in the past. Currently there are few centres dedicated to the development of stem cell based technology for treatment.  While it is not a panacea for all ills, there is no doubt that it holds great promise for treatment of certain orthopaedic and other conditions. There are several interesting lines of research being pursued in this area, based on a better understanding of growth factors and development of genetic engineering techniques. These may form the basis of treatment modalities in the future that are unthinkable presently.

As with any such new idea, despite its relative infancy, there have been several instances of this technology falling into disrepute owing to inappropriate use and unsubstantiated claims made by practitioners the world over.  It is, therefore important to stress that judicious and legal use of this new technology should be strictly adhered to.