As most if you know, Trooper managed to injure his tendon at the start of September. I recently had to choose a topic to make a presentation on for a module called "Emerging Veterinary Science". I therefore thought it would be interesting to choose the subject of recent enhances in the treatment of tendon injuries. I am mainly going to focus on the use to stem cells as this is a recent are of research with a lot of work being carried out in the area.
Tendon injuries are a big problem in a number of species, the horse however is particularly prone. Horses can also be used as models for human research; this has led to interest into developing new methods to treat tendon injuries in the horse (Caniglia et al, 2011).There are three stages of healing after a tendon injury. During the acute phase there is inflammation, haemorrhage, swelling and break down of collagen fibres, this phase lasts a few days. The next phase is the sub-acute phase, there is granulation (healing), and repair by fibrosis and scar tissue formation, this phase lasts a few weeks. The final phase is the chronic phase, during this phase there is maturation and remodelling of scar tissue. This stage can be ongoing until it has healed, it may last for months. These stages of healing and what happens during them should be taken into account when researching potential new methods as their natural healing mechanisms may be exploited (Fessel et al, 2012). The aims of treatment are to reduce scar inflammation, scar formation and restore structure and function (Bedi et al, 2012).
One problem in the horse is that they have a poor blood supply in their lower limb. This can lead to the injury taking longer to heal as there will not be as many cells reaching the area and having the desired effect. Another problem that happens when the injury is healing is due to the formation of scar tissue. This is not as elastic as the normal tendon tissue and therefore may be likely to reduce the performance of the horse and increase the likelihood of re-injury. Reducing the formation of scar tissue is one of the major factors looked for in these regenerative treatments such as the use of stem cells.
Traditional treatments of tendon injuries include rest, anti-inflammatory drugs, hosing, bandaging etc. It has been suggested that all of these methods help to reduce the symptoms but do not help with the actual healing process in the tendon.
The table below summarises some of the other new treatments that are becoming available. Trooper had the platelet rich plasma injection during his treatment. These treatments are injected into the site of the injury, this may be done using an ultrasound scan. They all encourage the growth cells and healing.
Stem cells are essentially immature cells that have not yet developed into a specific type of cell. Mesenchymal stem cells (MSCs) are the ones most talked about in research and have an indirect effect on tissue homeostasis (keeping everything the same and in working order). They are involved with hormone activity, anti-inflammatory effects, anti-apoptotic effects (prevents cells bursting) and the attraction of additional stem cells from the surrounding tendon (Uccell et al, 2011).
Stem cells can come from a variety of origins. In the adult they may come from the bone marrow, in horses this has only been researched in recent years as before they had no need to obtain stem cells as disorders such as leukaemia in the horse are rare. They can be taken from the pelvis or the sternum. Once stem cells have been obtained via a needle they are cultured then injected into the site of injury on the tendon (Kasashima et al, 2011). Stem cells are also present in the foetus, placenta and the umbilical cord (Ranera et al, 2011). It has been found the MSCs may be species specific, however, within a species the MSCs are non-specific and the recipients and donors may not need to be matched (Young et al, 2012). A second injection did not elicit a greater response than the first suggesting no hypersensitivity (allergic) reactions took place. However, there has been conflicting research in this area (Carrade et al, 2011).
Below is an image to show the different types of cells a stem cell can turn into once it has been taken and cultured in the lab. These include fat cells (adipocytes), bone cells (osteocytes), muscle cells (myocytes) and tendon cells (tenocytes). Once a stem cell has turned into a tenocyte it will be involved in the production of collagen and proteoglycans which help to heal the tendon. They have also been found to increase the tensile strength of the tendon.
Image from Nixon et al (2012)
Godwin et al (2011) looked into the long term effects of using MSCs and found it was safe to use in horses with tendon injury and reduced the re-injury rate compared to those who were not treated. No effects such as tumour formations were seen. MSCs were also found to reduce the re-injury rate compared to some other treatments.
Foetal derived embryonic stem cells have been researched by Watts et al (2011). The flexor tendons of 8 Thoroughbreds were looked at in a blind, randomised trial. MRI scans were used to assess the tendon. It was found that it induced muscular-skeletal regeneration but there was low long-term survival of cells.
There have been some contrasting results as to whether treating tendon injuries with MSC helped the injury to heal. Caninglia et al (2011) used 6 horses and gave them MSCs from bone marrow 4 weeks after their injury. They found no significant differences in the collagen fibrils measured between the treated and control group. In this study, the control group were given bone marrow supernatant. This raised the question that the supernatant may have contained growth factors that were having an effect on the healing and not the actual stem cells. This treatment was also given at 4 weeks which may have not been the most beneficial time to give the treatment, more research would be needed into when the ideal time to treat horses with tendon injuries is.
There may be a relationship between where the cell has come from and what type of cell it will differentiate into. Therefore it may be more ideal to use stem cells taken from the tendon. Ni et al (2011) treated tendon injuries in rats with tendon derived stem cells, it was found to lead to earlier and better repair. Some common properties were found between the different MSCs but there were also unique characteristics of the tendon derived stem cells such as the expression of tenogenic and chondrogenic markers which help with tendon healing.
A possible link with tumour induction has been found with stem cells, however Godwin et al (2011) did not find this. Infections may be a problem due to the injection into the sterile tendon sheath. These are both problems that can also arise with the other treatments in the table above. There are also ethical issues with the use of a foetus to aid the healing of an injured horse (Ni et al, 2011).
There are still many unanswered questions such as which type of stem cell may be best to use. A combination of treatments may be the best way forward. The concentrations of cells given and at which day they should be given also needs to be looked into. Cell-based treatments offer great potential due their ability to regenerate connective tissues. These treatments hold great promise but further research is still needed.
A full bibliography can be given if anyone would like it.
If anyone reads this before Monday the 27th morning and has any questions then please ask because I get asked questions at the end of my presentation and I am trying to do extra research so I will be able to answer them!