Ok so at VetMedLink at Nottingham uni in April we were given the chance to do a stem cells paper on a topic of our choice here's mine!
Stem Cell Treatment In Dogs
With
Severe Osteoarthritis
BY
LUCY CLOUGH
RESEARCH PAPER
BASED ON
PATHOLOGY LECTURES
AT MEDISIX AND VET-MEDLINK 2012
ABSTRACT
In this paper I will discuss the possibilities of stem cell
cartilage replacement therapy in the joints of dogs affected by osteoarthritis
(OA). In my time spent at many small animal practices I noticed that a lot of
dogs were suffering from OA and it is a very common problem especially in
larger breeds such as Labradors and German Shepherds. I have researched into
different methods and drugs already being tested or used both in animals and in
people as there is usually a link between human and animal medicine. This link
could prove vital as there are many treatments for OA in human medicine that
could be potentially used in veterinary medicine. Stem cell research plays a
big role in finding new treatments in the medical world and I will look into
some detail of stem cells themselves. From what I have found in my research the
use of stem cells for treatment of OA is already being trialled and could be a
very useful and common treatment in the future of both human and veterinary
medicine.
INTRODUCTION
Stem cells
have played an important part in many medical and scientific advances over the
past 50 years. From successfully cloning Dolly the sheep, to regenerating new
nerve tissue in damaged spinal cords, stem cells clearly show great potential
in medicine because of the sheer diversity of things that are possible with
stem cell treatment (Ryan, et al.,
2005) .
Stem
cells are undifferentiated cells that allow the development of an animal to
occur, and in adult animals, allow the repair of damaged tissue
Totipotent
stem cells can be manipulated to differentiate into a specific cell by putting
them in a culture of the type of cells you want them to differentiate into.
This means that stem cells are useful for repairing damaged tissues as they can
be injected into the damaged area in the hope that they will mend the damage.
Stem
cells are already being used in many aspects of modern day medicine; they have
been used to repair damaged areas of spinal column and other tissues such as
tendons. This research has also been shown to work in rats (McDonald, et al., 1999) . In the McDonald, et
al. study, they transplanted embryonic stem cells, which differentiated into
nervous tissue and helped promote recovery in injured rat spinal cord. Stem
cells provide an effective way to grow new healthy organs and tissues for
transplant with reduced rate of rejection as the cells are the patient’s own
cells (Ryan, et al., 2005) . The totipotent stem cells for human
use are created from donated human eggs and sperm or a donated egg and a
nucleus from an adult cell. The cells are then allowed to divide until they are
a hollow ball of stem cells called a blastocyst; the cells inside this hollow
ball are the totipotent stem cells. High potency stem cells can also be
harvested from cord blood from a new born and companies exist that will store
these cells in case they are ever needed in the child’s future. These cells can
be then stimulated to differentiate into any cell of the body. Alternatively more specific stem cells can be
harvested from the bone marrow, blood or adipose (fat) tissue.
Stem
cell research itself is carried out by removing these stem cells from the body
in the case of multipotent autologous research and cord blood research. These
multipotent stem cells are then stimulated to differentiate with chemicals or
by their surroundings. In the case of totipotent stem cell research a sample of
donated eggs are fertilised in vitro and allowed to develop and these stem cells
are then used by trying to induce specific differentiation either with a
chemical cocktail to simulate natural stimuli to differentiate or by placing
them in a surrounding of tissue that you want them to differentiate into, e.g.
putting them into some spinal cord tissue to stimulate nerve cell
differentiation. This is different from the McDonald, et al. study where they
instead transplanted stem cells that were already differentiating into nervous
tissue. Totipotent stem cells can also be created by the removal of an egg cell
nucleus and replacing it with an adult cell nucleus and allowing it to divide
creating a clone blastocyst.
DISCUSSION
Osteoarthritis (OA) is a degenerative disease of the joints such
as the knees, elbows, shoulders and hips. OA is classed as a degenerative
disease as a result of wear and tear which is why it is mostly older dogs that
are affected
It is difficult for this cartilage to be replaced on its own as
cartilage has no blood supply thus repairs very slowly especially in older age.
The cells are instead supplied by diffusion. Cartilage is made up of cells
called Chondrocytes; these Chondrocytes are held in place in a matrix called
the lacunae. As the Chondrocytes are held in place this means that they cannot
migrate to repair areas of damage which is another reason why cartilage is so
difficult to repair (Dominici, et al., 2001) .
When a pup is developing inside the bitch it is the multipotent mesenchymal stem
cell that forms the cartilage in the joints. If the pup develops
normally it should have smooth cartilage that fits together and has minimal
friction. As OA is degenerative it is not until the pup is older, usually at least
after the age of 5, that the signs of OA start to appear. They may find trouble
getting up, jumping into cars, exercising or moving in general. The cartilage
wears down and is not replaced quickly enough due to its slowly-repairing nature.
Current treatments for OA include drugs such as non-steroidal anti-inflammatory
drugs (NSAIDs) and a specialised drug called Cartrophen (Vasseur, et al., 1995) as well as many
other supplements such as omega 3, etodolac and chondroitin sulphate (Aragon, et al., 2007) . Other more
intrusive treatments include joint clearing and joint replacement using
stainless steel alloy pegs into the bone and ball with high density
polyethylene socket to mimic the original joint (Olmstead, 1987) . These surgical procedures are invasive
and costly so if a stem cell treatment can be developed to be cheaper and less
invasive than this it benefits both dog and owner.
Cartrophen is
a very interesting drug for medicinal treatment of OA, I have seen it being
used a lot in practice and all of the owners said they noticed a big change in
the comfort of their dog after a few doses of the drug. It is given as an
injection in the back of the neck much like a vaccination once a month. (Anon., 2003) It works by acting
on the pathology in the joint thus reducing the pain. It also supports the
recovery of new cartilage formation and is said to be just as effective and
also longer lasting than NSAIDS. Drugs like Cartrophen and NSAIDS should
definitely be tried before any major surgical actions are taken as the drugs
are a lot safer and less invasive and expensive than surgery. However, if all
drug options have been tried and none have improved the dog’s condition
surgical options may be looked into. First the dog would have to have X-rays of
the affected joints and maybe even a surgical exploration of the joint using
fibre optic cameras. If the joint is found to be unclear of debris of damaged
tissues this must first be cleaned and neatened up before any further action
can be taken. (Moseley, et al., 2002) . The removal of this
debris alone may improve the functioning of the joint but if not the dog may be
a prime candidate for stem cell therapy, providing the joint is otherwise
healthy other than the osteoarthritis (no hip dysplasia etc.). Fig3 shows and
X-ray of a dog with severe hip dysplasia where the ‘ball’ of the joint does not
fit into the ‘socket’ properly as the joint is deformed. In this case the joint
has tried to regrow a new socket edge as the arrow is pointing to a bone spur
of new bone growth (BVA & TheKennelClub, 2010) .
Cartilage is formed from the differentiation of the mesenchymal stem
cell, it is these stem cells that would be used in the possible
treatment of OA. To attain the mesenchymal stem cells a sample of fat is taken
from the dog and the stem cells can be isolated. These are autologous cells as
they are removed from the same dog they are going back into, this means there
is less chance of rejection
For the procedure to be performed, skilled surgeons would be
needed and also skilled technicians that are trained in finding and isolating
the specific stem cells. The veterinary surgeon will have to have the knowledge
to be able to decide whether stem cell therapy would have a good chance of
being successful in each case. Research and trial surgeries have already begun
in cats and dogs, a company called Vet-Stem in America (Harman & Dale, 2011) have trialled over
3000 cats and dogs using stem cell treatments for OA. The company uses the
animal’s own adipose (fat) tissue to derive the stem cells for treatments. Results
showed that 70% of dogs would show dramatic improvement in mobility after 4-8
weeks and another 20% showed some improvement. This shows that stem cells are a
viable treatment for OA and they could become more widely used in the
veterinary world. Vet-Stem started off in the equine sector where stem cells
were used to repair tendon damage that could have otherwise ended a race
horse’s career. They also offer a ‘StemInsure’ service in which an owner can
have some of their pet’s stem cells harvested and stored in case they will ever
be needed in the future. The cost of these treatments are however very
expensive, $3500-$4000 for each treatment (Harman & Dale, 2011) . If we can master
the technique to raise success rate even higher and find a way to cut the costs
down, stem cell therapy could be a less invasive and less costly treatment for severe
OA than joint replacement.
As of yet the only common surgical procedure for treatment of
severe OA is joint replacement. This is a highly invasive and costly procedure
and for a hip replacement for example a metal rod is implanted into the hollowed
femoral bone after the damaged head is removed and the metal ball protrudes
from the top forming the new ‘ball’ for the ‘ball and socket’ model. The socket
must be cleared of all damaged cartilage and unsmooth bone before a high
density plastic socket can be implanted (Cluett M.D, 2010) . The femoral implant and socket have a
rough outer layer to allow the bone to adhere to its surface. Fig5 shows a
completed joint replacement in a human hip.
The dog must then rest the joint until it has all healed and is
strong again. Here it is not only the cost of the surgery time it is also the
cost of the implant and drugs that will be needed for pain relief, physiotherapy
and antibiotics. However all this may still work out cheaper than having to
isolate and inject stem cells in what is still a new area of medicine and not
everything is known about them.
Stem cell
treatment would be especially beneficial to the larger dogs such as German Shepherds
and Labradors where genetics means they have an increased risk of OA. As they
are larger they are also at more risk as they have more weight to carry on
their joints so wear and tear can progress more rapidly and lead to OA and
other problems in other joints such as knees, shoulders, hips and spine.
Obesity is also a contributing factor to OA due to the extra weight being
carried. Many Labradors especially are becoming obese due to their greed and
owners feeding them more and exercising them less, this means that OA is
becoming more common in younger dogs
Another
possible use for mesenchymal stem cells is that they could be used to culture
cartilage tissue outside the body. With these cartilage cells outside the body
new drugs can be tested on them without damaging a living animal. This way
drugs can be tested to see if they will cause any regeneration of new cartilage
or strengthen the existing cartilage. Carrying out tests on tissues outside of
the body first is beneficial as it is cheaper and many different cultures and
tests can be done at the same time without having to test on the live animals
and care for the live animals (Bremer & Hartung, 2004) . It is also more
ethical to first test new drugs on living tissue outside the body before
testing on live animals, this reduces the risk of the drug causing harm to the
animal.
CONCLUSION
Things could go wrong, stem cells have not been used widely and
long enough for us to fully know how they will stand in the long term when
placed in an area artificially. They could overgrow and possibly cause a
cancerous growth in the area they are put. If a cancer does occur this will
just cause more discomfort and pain for the dog and if it is an old dog it may
not survive any treatments for cancer. It is also possible that the stem cells
don’t differentiate into the right type of cell so may develop into many
different types of cells forming a teratoma where the growth is made of many
different cells and has to be removed. If the growth is made only of the
cartilage cells but just too many of them this type of cancer is called a
chondroma (Lichtenstein & Hall, 1952) . Cancer research
could possibly come up with a solution to cancerous growths in the future and
this could reduce the risk of fatality from stem cells that have become
cancerous in the future.
Ethical reasons to do with stem cell research are always an issue
and have to be taken into consideration. The stem cells must be taken from the
dog requiring treatment in a safe manner without harming the dog further,
taking the stem cells from the same dog also means embryonic stem cells are not
needed and there is less chance of rejection and further stress to the dog.
It also must be made sure that the stem cell therapy can be
covered by insurance providers to insure that owners can afford the treatment.
If owners cannot afford the treatment it will not be a viable idea as it will
not be used widely enough and will not be economical. A way of reducing the
costs involved with the treatment must be found for insurance companies to be
willing to pay out on a claim. The therapy will also need to be trialled more
and have a good success rate so that more owners will consider stem cell
treatment for their dog. Stem cell treatment must be successful enough to be
able to compete with the cheaper more common other drug treatment such as NSAIDS and provide a more long term and better quality treatment.
Stem Cells are already used in many different areas of human
medicine and if the trend between animal and human medicine is correct they
should be more widely used in the veterinary world very soon. Fig6 shows some
of the areas in which stem cells can be used in human medicine. Most of these
potential uses, including treatments for OA are still being researched and are
not fully established in medicine. There have been some trials in humans where
human mesenchymal and embryonic stem cells have been used to repair degenerative
intervertebral discs
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