Stem Cell treatment for articular cartilage lesions for Osteoarthritic patients- Can it solve the problem? (Make Hyaline cartilage great again)
Stem cell treatment in articular cartilage regeneration is a relatively new concept that is being developed in trials in an attempt to regain normal cartilage and joint function. This method has yielded some interesting and partially successful early small scale trials. With current treatments only providing limiting relief, there is an onus on improving these techniques. So, can stem cells ultimately help in repairing cartilage and regaining function?
Articular Cartilage degeneration is one of the leading causes of osteoarthritis (OA) in the general population. Osteoarthritis is an extremely common condition which affects inflamed joints by bone rubbing together, primarily as a result of worn down degenerated articular cartilage. It can lead to a range of problems with mobility causing cessation of physical activity as well as difficulty with daily tasks and in the most serious cases, morbidity (nhs.uk, 2019). According to the American Arthritis foundation, OA is said to affect over 27 million Americans with an increasing presence in elderly people. Furthermore, current treatments offered which are available are not completely effective in dealing with regenerating cartilage and are likely to lead to osteoarthritic problems in the long-term. However, while current treatments have not been successful in restoring physiological cartilage function, there has been research done in the scientific and orthopaedic community into stem cell therapy as a potential avenue for repairing and regenerating damaged Articular cartilage. This has been met with varying success in small scale studies. Therefore, can stem cell therapy be the key in what is needed to successfully regenerate articular cartilage? And therefore can it improve patients quality of life and pain relief, and avoid the need for expensive and invasive surgery?
Articular cartilage is found covering the ends of bones of synovial joints such as the hip, knee and ankle. It functions to provide a smooth lubricated surface to prevent rubbing together of bone surfaces and acts as a shock absorber by absorbing much of the mechanical load instead of the bone such as when running for example (Fox, Bedei & Rodeo, 2009). It consists of smooth Hyaline cartilage which is ball-bearing and is well hydrated; this gives the cartilage its shock absorber properties. Articular Cartilage consists of an extracellular matrix which contains a large number of cartilage cells- known as chondrocytes- as well as water, proteins and type 11 collagen (Fox, Bedei & Rodeo, 2009). Type 11 collagen plays a key role in enabling the cartilage to deal with compressive loads, as it can retain high concentrations of the protein aggrecan which forms a network (Smith et al, 2019). This is a key part of hyaline cartilage composition. Articular cartilage has a poor potential for repair due to its poor blood supply and the fact that the cartilage cells have limited potential for regeneration (Fox, Bedei & Rodeo, 2009). When damaged, there are two different classes of defects which determine how articular cartilage is repaired by the body. A chondral defect is one in which the defect has not reached the bone and because the defect is within the avascular cartilage, there will be limited repair. The fact that the surrounding chondrocytes have limited regeneration potential also aids poor repair (Karuppal, 2017). However, once the defect has reached the underlying bone beneath the cartilage then the bones blood supply will kickstart repair (Karappal, 2017). This is known as an osteochondral defect. A small number of nearby bone marrow cells from the bone will arrive at the defect site and differentiate to form cartilage which is generally fibrous. Fibrous cartilage contains less type 11 collagen – aggrecan networks and consists of a mix of type 1 and type 11 collagen, therefore being not as mechanically strong as before (peedia.com, 2019). This is weaker than the previous hyaline cartilage so will break down and damage the cartilage even further leading to painful osteoarthritis.
While there is not a specific cause of breakdown of Articular Cartilage, there are several different factors which attribute to it. Many sportspeople who take part in high impact sport like football and running are more likely to wear down their articular cartilage; this is often due to the wear and tear effect on the cartilage of dealing with high forces being loaded onto it. Long-term wear and tear will lead to cessation of sport and surgery. Articular Cartilage degeneration is also more common in people in later life who have previously injured the joint previously- for example twisting of the knee. Additionally, OA and cartilage degeneration is very common in the older population due to wear and tear over a long period of time leading to inevitable damage. From my experience, the number of patients visiting orthopaedic clinics with OA prevalent in joints is very common, especially in older people. Current treatments are not great with efficiently repairing the cartilage. The main problem with methods of articular cartilage repair is that fibrocartilage forms in the damaged area instead of hyaline cartilage. This weaker cartilage type will break down and eventually cause serious osteoarthritis. Microfracture arthroscopy, in which an osteochondral fracture is made in the cartilage, causes formation of this fibrocartilage. Autologous Chondrocyte Implantation is another treatment which has shown some promise in generating hyaline cartilage. However, this procedure involves two operations, is expensive and the risk of infection is greater. There is a need to find a treatment that can avoid the number of serious cases of OA which require a joint replacement which is the last line in dealing with OA. So, how can stem cell therapy revolutionise osteoarthritis treatment?
Stem cell therapy has been reported as a much heralded and publicized treatment for many physiological conditions. Indeed, recent studies in Nature have pointed to some promising research in regards to using stem cells in treating HIV (nature.com, 2019). There are many different types of stem cells that are available and Mesenchymal Stem cells are the most commonly used in treating articular cartilage lesions. Mesenchymal Stem cells are pluripotent cells which can differentiate into a number of type of cells such as bone cells and cartilage cells. It is because of their ability to differentiate into cartilage cells readily and that they can be produced in high numbers that give Stem cells an advantage over other treatments. There have been several sources of Mesenchymal Stem cells that have been identified such as bone marrow (most common), adipose tissue and umbilical cord cells. Stem cell studies that have been done are generally autologous; meaning that they are unlikely to be rejected as the cells are taken from the patient. Additionally, using mesenchymal stem cells for cartilage repair has been demonstrated to be a safe procedure in both short and long-term studies (Hossein et al, 2010; Karuppal, 2017).
So far, the literature around stem cell treatment has been primarily early clinical trials and pre-clinical research. However, there has been some potential that should be studied further in trials. Early studies have shown some encouraging results with stem cell treatment. In a 2006 research study, bone marrow mesenchymal stem cells were implanted in a 31 year old male competitive judo player to treat an osteochondral articular cartilage defect located at the medial femoral condyle (knee joint). They found that within 7 months of treatment with bone marrow stem cells, the defect was fully filled with repair tissue and histologically the tissue had hyaline-like properties. Furthermore, the patients clinical symptoms had improved substantially with the patient being able to return to their previous activity level. Surely this would be classed as a success and a massive clinical breakthrough? While this case study has appeared successful, there was only one participant in the study and there was no l
ong-term follow up to see if repaired tissue would be stable; despite its hyaline like properties. Additionally, an MRI scan of the patient one year after treatment with stem cells still found chondral and subchondral irregularities in repaired area. This again highlights the need to review this patient over a longer period of time to check the efficacy of this treatment. On a side note, this patient was an active judo player who was relatively young meaning could older people who are less active respond well to this treatment?
The above study showed promise in that stem cell therapy could regenerate damaged cartilage tissue and repair it with hyaline properties. Another study in 2013 focused on again giving bone marrow mesenchymal stem cells in articular cartilage defects in the ankle; this time in 49 patients, varying from ages 18-50. This study involved the use of a hyaluronic acid scaffold with stem cell implantation. So and so found that after 6 months, there was a significant improvement in clinical scores in patients which were greatest at 24 months post treatment. Hyaline-like cartilage was also found in much of the repair tissue- around 78%. However, within the following 2 years, there was significant decline recorded in clinical scores although the scores were still greater than those 6 months post treatment. This again questions the long-term efficacy of this treatment as the ability of stem cells to last 15-20 years is still untested. Another study in 2014 found disappointing results when injecting autologous bone marrow stem cells intra-articularly, finding substantial fibrocartilage repair as opposed to hyaline. Additionally, there was also a lack of significant results in this study when comparing stem cell group to a control group. However, this was a longer-term study and 10 year follow up scores for stem cell treatment were better than pre-operative scores showing potential for stem cells to be beneficial clinically to patients over a long period of time.
In order to improve long-term outlook and to enhance stem cell treatment, there is still work to be done. While there is promise with hyaline like cartilage being regenerated, it doesn’t seem that its 100%.
Other Stem Cell techniques/New research
There are new techniques that are being applied in order to enhance stem cell treatment. One of these techniques involves co-delivery of stem cells with another substance. This was done in an animal study on rats using adipose-derived MSCs co-delivered with a substance called Matrilin-3. Matrilin-3 is an ECM component found in cartilaginous tissues which regulates anti-inflammatory function and ECM components (Muttigi et al, 2017). Co-deliver of stem cells with Matrilin-3 induced type 11 collagen-aggrecan expression which as stated earlier plays a key role in strong cartilage. Furthermore, co-delivery implanted at the defect site at a low dose yielded good results in rats, showing hyaline-like cartilage repair and good quality repair. This was one of the first studies to look at matrilin-3 co-delivery with stem cells in animals and yielded strong results and evidence of articular cartilage repair. When stem cells were added without matrilin-3 being added, there was fibrous cartilage formation in the defect. This represents a positive method of further research which could then be extended into human studies. However, this was a very early study, no evidence of long-term and at high doses of matrilin-3, there was less hyaline cartilage repair in defects to which the writers could not provide a reason at this stage. Yet, it provides promise and excitement as a future potential treatment.
In the studies that I have read, Stem cell therapy has shown promising results in articular cartilage repair, reporting good clinical outcomes and growth of hyaline-like cartilage. However, these treatments have not been made widely available as treatment. Ultimately, more studies/bigger trials will need to be carried out in order to see if this promising outcome can be used clinically. The lack of long-term follow up as well remains to be seen if this treatment will be more effective than others in the long run. A treatment though which can produce hyaline cartilage rather than fibrous is in theory a better and more durable cartilage treatment for patients. However, the long-term aspects of this still need to be assessed.
References
Fox, A.J.S; Bedi, A & Rodeo, S.A. (2009). The Basic Science of Articular Cartilage. Sports Health. 1(6), 461-468. [Accessed 24 Feb 2019.]
nhs.uk. 2019. Osteoarthritis – NHS. [ONLINE] Available at: https://www.nhs.uk/conditions/osteoarthritis/. [Accessed 07 March 2019].
arthritis.org. 2019. What is Osteoarthritis?. [ONLINE] Available at: https://www.arthritis.org/about-arthritis/types/osteoarthritis/what-is-osteoarthritis.php. [Accessed 07 March 2019].
Pediaa.Com. 2019. Difference Between Fibrocartilage and Hyaline Cartilage | Definition, Characteristics, Function, Similarities and Differences. [ONLINE] Available at: http://pediaa.com/difference-between-fibrocartilage-and-hyaline-cartilage/. [Accessed 07 March 2019].
Second patient free of HIV after stem-cell therapy. 2019. Second patient free of HIV after stem-cell therapy. [ONLINE] Available at: https://www.nature.com/articles/d41586-019-00798-3. [Accessed 07 March 2019].
Smith, D; Gardiner, B.S; Zhang, L & Grodinzky, A.J. 2019. Articular Cartilage Dynamics. 1st ed. Singapore: Springer.