The two syringes on the left contain a very small amount of antibiotics. The large syringe is used for intravenous (IV) administration of stem cells. It contains approximately a quarter of the total VF fraction (SVF) diluted in sterile saline. The four syringes on the right contain a combination of platelet rich plasma (PRP) and SVF and are injected into the joints and intervertebral spaces.
Little did I know about this time last year that animal stem cell therapy was a thing. Looking for a job that would capitalize on my biological background and love for animals, I found a position for a stem cell technician at a local veterinary office. I got the job! and found that there are few things as exciting as changing a dog that was in so much pain that it could barely move to become one who is able to frolic and that To enjoy life again.
Stem cell therapy is an effective tool for treating degenerative or other diseases as well as injuries. This is an effective way to use cells from the dog's own body to regenerate damaged or diseased tissue. It was first used in the veterinary context in 2002 to repair tendons and ligaments in horses.1 Since severe leg injuries can be harmful to horses, especially those involved in racing and jumping, stem cell therapy was a key factor. The results were remarkable most of the horses treated were able to return to their previous activity.
Eventually, stem cell therapy has been used in the treatment of pets, mostly for the same tendon or ligament repair problems, but has largely focused on arthritis. While stem cell therapy is not a panacea, it is a low risk approach to treating injuries and degenerative diseases that provides our dogs with a better quality of life without being dependent on medication.
STEM CELL BASICS
What is a stem cell? It's not quite as easy a question as it sounds. There are different types of stem cells, but the first main characteristic of a stem cell (SC) is that it can become one of several different cell types (called differentiation), creating different tissues. Stem cells are also very proliferative, which means they divide quickly and produce more cells, but at different rates depending on the type of SC.
There is a difference between embryonic and adult stem cells. Embryonic stem cells (ESCs) are responsible for embryonic development. They are pluripotent, which means that they can develop into any type of cell in the adult body. And they are very proliferative, more so than adult SCs. ESCs do not exist in the organism after birth.
An embryo develops from a single cell into a complex organism made up of several tissues. The process of development goes through many stages, but in short, some cells multiply and eventually develop into specialized cells that make up all of the different tissues in the body. ESCs in the early embryo multiply or divide to produce more cells very quickly. They are pluripotent, which means that they can become any type of cell in the organism. Eventually, as development proceeds, the cells become more specialized and less proliferative. There are many levels or levels as PCs move toward specialization.
At the beginning of development, ESCs differentiate into one of three germ layers, from which certain parts of the fetus arise. The endoderm (endo = inner) leads to many internal organs, including the lungs, pancreas, stomach and liver. The mesoderm (meso = middle) leads to bones, cartilage, tendons, ligaments, muscles, heart, fat and some nerve tissue. The ectoderm (ecto = external) leads to neurons, outer layers of skin and hair. When ESCs share, they produce new SCs that specialize in one of these layers. These SCs produce more SCs as well as "progenitor cells", the precursors for specialized cells that make up different tissues.
The Mesoderm line produces mesenchymal stem cells (MSCs) that are used for therapy. The MSCs are considered multipotent (as opposed to pluripotent) because they can result in a limited number of tissues. MSCs and SCs from the other two lineages are present in the fully developed organism, but are dormant or inactive until needed. They are activated by injuries or illnesses and begin to multiply and differentiate.
Undisputed
When friends hear what I do for a living now, they sometimes ask me: Isn't stem cell therapy controversial? In our context, no! The controversy concerns the use of embryonic stem cells. There are ethical and religious objections to their use in humans. From a clinical point of view, ESC have proven difficult and in some cases dangerous. Because of their highly proliferative nature, they can actually replicate too much. This can lead to mutations in the cells that can lead to cancer.
What we are using are adult stem cells. There are no ethical concerns as the cells can be extracted from a living organism with minimal risk. For SC therapy in a veterinary context, the cells are taken from the same animal that uses them for therapeutic purposes. And because adult stem cells are less hot in terms of proliferation, their genome stays much more stable, essentially eliminating concern about cancer development.
PUTTING STEM CELLS INTO THERAPEUTIC WORK
There are many adult SCs in an adult organism. They are typically dormant and activated in response to tissue damage or disease, starting a complex cascade of cellular and chemical signals. The local SCs are activated and migrate to the specific area and multiply to produce more stem cells as well as progenitor cells to replace impaired specialized cells (such as cartilage or bone).
Importantly, MSCs can be used to treat tissues to which they do not lead. Their main function in these cases is to activate the SCs in that tissue. SCs also modulate the immune system and decrease the inflammatory response. The main function of the stem cells used for therapy is to regenerate healthy tissue directly (for tissues of the mesoderm line) or indirectly (for endoderm or ectoderm lines) to replace what is damaged or diseased.
In cases of arthritis or dysplasia where the bones or cartilage are damaged, the MSCs produce and become these cells. If the ligament is damaged, they produce ligament cells. In the cases of the other two lines, the MSCs stimulate the SCs on that line to produce new cells such as liver cells or skin cells. As the body regenerates new, healthy cells as a result, SC therapy is often referred to as regenerative medicine.
In order to perform stem cell therapy we must first extract the MSCs, concentrate them, and then bring them to the area of injury or disease. The closer the cells can be placed to the specific problem area, the better. In arthritis, the MSCs are injected into the diseased joint; MSCs are given intravenously for areas or organs where injection is not possible. As the SCs travel through the blood to reach various organs, they are available to respond to specific areas of stress in those tissues.
Most dogs receiving SC therapy will need multiple treatments. The time between treatments depends on the person. Repeated treatments are carried out at intervals of one to two months to a year. In my work I have seen a few cases where the problem has stopped after treatment. This is not common, but it does happen.
TREATMENT PROCESS
For SC therapy, MSCs are extracted from the body of the animal to be treated. They are present in tissues such as bone, fat, skin, brain, and heart.2 First, SCs were extracted from the bone marrow. However, there is a greater abundance of MSCs in adipose tissue and this tissue is less traumatic to harvest, so this is the most common source used.
There are several sources of adipose tissue in a dog. Some veterinarians ingest fat from the shoulder blade area. Others, including the veterinarian I work for, Dr. Robert Hagler of Lafayette, Calif., Prefer to use navel fat. This is a relatively simple procedure, but it requires general anesthesia.
Once removed, the fat is processed to extract the stem cells from the tissue (that's my job!). The tissue goes through several mechanical and chemical digestion and separation steps. After a few hours, the exit is the stromal vascular fraction (SVF), which has concentrated mesenchymal SCs as well as other cells and components that aid the MSCs' action. Depending on the veterinarian, the SVF can be extracted on site. In this case, the dog will be treated on the same day (in the clinic where I work, the processing is done internally). The majority of vets send the fat off for processing and the SVF is sent back for treatment on the second day after harvest. At this point it is given to the dog.
Usually there are many cells from the fatty tissue for multiple treatments, depending on the condition being treated. The SVF required for initial treatment is slightly diluted in sterile saline and divided to account for the number of injections to be performed. Platelet rich plasma (PRP, more on this below) is usually added to the SVF to further support the stem cell response. We usually save a small portion of SVF to be given intravenously. Extra fat, containing cells for future treatments, is sent for processing and the cells are cryogenically frozen.
In most cases, the dog will be sedated for injection. If you've ever had an injection in a joint you know that these are very painful and that it is much easier for the dog to be sedated. If MSCs are administered via IV only, sedation is usually not required. Once the injections are complete, the sedation will reverse and the dog can go home after a full recovery.
Future treatments are easier because fat and cell extraction is already complete. In our office, the dog comes to the office in the morning and has taken blood for PRP. The blood is processed to obtain the PRP, while thawed SVF goes through steps to wash and activate the MSCs. Once both components are made, they are administered as described above.
With joint injections, the first few days after treatment can be more painful than before treatment. The time it takes to see positive results varies from dog to dog. The average is a matter of weeks, but in some cases we've had positive results within a few days and sometimes it takes a month or two.
PLATELET PLASMA
Many veterinarians accompany the MSCs with platelet-rich plasma. This substance amplifies the signals from the injured or damaged area and directs the MSCs to that area. It helps to get the most out of the MSCs in use. PRP also uses the dog's tissue in this case, blood drawn on the day of treatment. It is processed using a series of separation steps to concentrate platelets and a number of growth factors present in the blood, and then the PRP is activated. It is combined with the SVF and administered with it when injected.
In our office, we sometimes use PRP outside of SC therapy to promote healing. The most striking example of effectiveness I've seen was when two dogs had TPLO (Tibia Plateau Leveling Osteotomy) surgery for a broken ACL on the same day. Both had previously had TPLO surgery on the other hind leg. Upon completion of the procedure, PRP was administered to the surgical site. According to the owners and Dr. Hagler, both dogs had shorter recovery times compared to their previous surgeries and used the surgical legs much earlier.
RISKS
Stem cell therapy is very safe. The MSCs used for therapy are autologous, meaning they come from the same dog who will receive them, so there is no risk of rejection. There are essentially no side effects from the treatment itself. The treatment process is rooted in the animal's biology and uses the natural healing powers of its own cells.
The greatest risk with therapy is general anesthesia, which is required to surgically remove some fat from the dog. There is always some risk involved in surgical procedures that require anesthesia, especially in older or frail dogs. In addition, there is some risk of infection as injections are often given into joints. To reduce this risk, injections of MSC are often accompanied by a small dose of antibiotic.
Rocco's transformation
Ten year old Rocco goes for a walk two days after his second stem cell treatment. He has seen great benefits from stem cell therapy, including less pain, more energy, improvements in his muscles, and a reduction in this drug.
Rocco is a 10 year old black Labrador Retriever. He had his first stem cell treatment thirteen months ago, during which he treated a number of problems including arthritis in both hips and a neurological problem that resulted in weakness in his rear end. The pain from his hips combined with the weakness of the rear end made it increasingly difficult for him to move. Rocco's owner Vicki says he would crouch to urinate and would not be able to get up.
He also had chewing myositis an autoimmune disease that causes the muscles involved in chewing to become inflamed and very painful. Rocco couldn't open his mouth without terrible pain. In addition, he had neurological problems affecting his head and neck that resulted in laryngeal paralysis. He had so many neurological symptoms that it was difficult to make a definitive diagnosis.
Before his conditions hindered him, Rocco was an active dog with a lot of vigor. He loved his long walks in a local park. He let his family know he was ready for a walk by putting his leash in his mouth. He caught treats that were thrown at him. And he jumped on the couch to hang out with his family. Vicki describes the heartache of seeing Rocco so painful that he couldn't pick up his leash or jump to the couch, and when they got to their favorite spot, Rocco didn't get out of the car. With the loss of the muscles in his head, he looked very different, as if his eyes were sunken. She describes him like a skeleton. Rocco was given medication for pain and prednisone for myositis, but got little relief. Vicki was afraid that this would be the end of Rocco's life.
You and Dr. Hagler decided to try stem cell therapy and the results were amazing. Rocco received injections in both hips, intervertebral injections in his lumbar and sacral spine, and stem cells via IV for the head, jaw, and neck. The day after his treatment, he was cheerful and happy. He returned to his usual exuberance about his daily walks. And his kaumyositis and larynx paralysis resolved and have not been recognizable since then.
While Rocco wasn't exactly a target of his SC therapy, he also had a long history of digestive problems. Despite years of trying to identify and treat the problem, nothing seemed to be helping. Rocco had diarrhea about every other week. He has not had an episode of diarrhea since his SC treatment. In addition to the success of the targeted symptoms, this was an unexpected and wonderful surprise!
Rocco was just returning for follow-up treatment when Vicki noticed that some signs of his hip pain and weakness at the rear end were returning. Again he received injections in his hips and between the vertebrae and stem cells over IV. The next day, Vicki described him as "super spunky" for the walk they had just been on. She describes Rocco's experience as "like a miracle" and is so grateful to have her lucky dog back. She notes that Rocco's improved health has been therapeutic for the whole family.
EXPECTATIONS
As mentioned earlier, SC therapy has been the most widely used in the treatment of arthritis and has resulted in significant improvements in pain levels, range of motion and functional mobility. Our practice has also used it in many cases of hip or elbow dysplasia, with excellent results in very young dogs with severe dysplasia.
One example is Tugboat, a chocolate laboratory that was weakened by elbow dysplasia when it was only four months old. Its owner tried everything including costly surgery, pain medication, therapy, etc.
In search of other options, she decided on SC therapy. After treatment, Tugboat is a different dog! He used to find it hard to stand walking, but now he walks for over an hour a day and plays on the beach. He comes in for repeat treatments about every six months if he shows signs of pain and reduced mobility and soon returns to normal activities.
MSCs are also used to treat damaged tendons and ligaments. SC therapy is helpful for partial tears, but not when the ligament is completely torn. There just isn't enough material to bridge a full crack. In the clinic where I work, we have used SCs to treat degenerative myelopathy with good results. There have been a number of small studies (n = 10 or less in most cases) that found that SC therapy improved the condition of dogs with arthritis, dysplasia, disc disease, perianal fistulas, inflammatory bowel disease, and keratoconjunctivitis sicca. 3
Some dogs show improvement very early after treatment; others take longer and the degree of improvement varies. Dr. However, Hagler says, "I've never seen a dog that hasn't improved."
Overall, the literature3 agrees that SC therapy is effective, although many studies or reports based on practitioners' data and experiences are anecdotal. Few clinical studies have been completed, although the companies whose technology will be used to extract the SCs have studies in the works.
THE FUTURE OF STEM CELL THERAPY
The exciting opportunities for future directions in stem cell therapy mainly concern the source of cells used to treat patients. Currently, the dog being treated must be the source of the cells used for treatment otherwise the treatment would be legally considered a drug and must first be approved by the U.S. Food and Drug Administration (FDA).
A stem cell bank would be of great help in dogs lacking enough fat to harvest or in dogs too frail to undergo general anesthesia for surgical fat removal. Just as dogs can be universal blood recipients, they can also safely receive stem cells obtained from another dog. One study even found that MSCs can be extracted from human adipose tissue and transplanted into dogs.4 (Does anyone have any fat you'd like to donate?)
Transplanting MSCs from another animal would be a game changer. There are cases when the dog with bank cells no longer needs them, either because they stopped therapy or because they passed away. It would be ideal if the dog's owner could make the bank cells available to other dogs. This is not currently legal.
It is possible to grow MSCs (but not support cells) in a laboratory to increase their numbers and reduce the need to harvest fat more than once. A company is doing that now.
Getting started with stem cells
You may think this sounds like something that could help your dog. Here are the next steps.
The first is to find a veterinarian who offers SC therapy. All veterinarians offering this therapy work with one of two companies that provide the equipment, reagents, processing and storage of cells: VetStem Biopharma and MediVet Biologics. The details of the service offered depend to some extent on the company with which the veterinarian's office works.
VetStem has been providing SC therapy for animals for a long time. VetStem is currently cultivating the MSCs of the beast, but MediVet is not, although they are working in that direction. VetStem does all the processing in its own facility.
MediVet offers training, equipment and reagents for veterinary clinics that process cells internally. Not all hospitals that work with MediVet choose it. In these cases MediVet takes over the processing. The nice thing about the processing on site is that the fat and the initial therapy can be carried out on the same day. If you have to travel a distance to a veterinarian for SC therapy, it is certainly not ideal to make several trips from one another within a few days for initial therapy.
PRP can also be carried out on site. VetStem does not include PRP in its SC therapy.
Both companies save SCs for future use and can bank cells before treatment is required. If your dog is anesthetized for some other procedure such as a spay or neuter, your veterinarian may harvest fat at this point and send it to the company so they can extract and freeze the cells your dog may need for future use. If you have the forethought (and the money) to do this, it could eliminate the need to have your dog undergo fat loss surgery later when they may be less able to tolerate general anesthesia. When I'm ready to have my dog neutered, I probably will.
Depending on where you are, the choice of company to use for SC processing can be easily narrowed down for you by the veterinarians offering SC therapy in your area. Ask your veterinarian. You can also check the VetStem and MediVet websites. They can put you in touch with one of their partner veterinarians in your area.
PRE-PROCEDURE CONSIDERATIONS
In some cases, SC therapy is contraindicated. Because of the proliferative and immunomodulatory effects of SCs, therapy should not be given in dogs known or suspected of having cancer. Dogs with an active infection should also not receive therapy.
SC therapy may also not be an option for dogs that are lacking enough fat (until there is a stem cell bank for dogs!) Or dogs that are too frail to withstand general anesthesia.
Stem cell therapy isn't cheap; The cost of initial treatment, including harvesting fat, is near $ 2,500. Follow-up treatments can cost anywhere from $ 500 to $ 1,000. These numbers vary from vet to vet. The good news is that many pet insurance policies now cover SC therapy. Even without insurance, it's much cheaper and less invasive than more drastic measures like joint replacements.
SC therapy is not a panacea and to achieve the greatest benefit requires basic, but sometimes overlooked, measures. It is important to support the health of the entire dog: keep its nails trimmed so that they do not interfere with walking. Feed them a good quality diet that supports overall health. Take precautions to prevent infection after surgery. Keep up to date with follow-up treatments in a timely manner to minimize the dog's pain or dysfunction. Supporting the general health of the dog and providing quality care are essential to getting the most out of treatment.
Joanne Osburn is a stem cell technician at Mt. Diablo Veterinary Medical Center in Lafayette, CA. After spending nine years as a biology technician in a government laboratory, she is excited to work in the veterinary field where she can help improve the lives of pets. She lives in San Francisco Bay with her husband Paul and their super stupid dog Guster.
References
1 Fortier LA, Travis AJ. "Stem cells in veterinary medicine." Stem Cell Research & Therapy 2011; 2: 9.
2 Markoski MM. "Advances in the Use of Stem Cells in Veterinary Medicine: From Basic Research to Clinical Practice." Scientifica 2016; 2016: 4516920.
3 Hoffman AM, Dow SW. "Brief overview: Stem cell experiments with models for pets." Stem cells 2016; 34: 1709- 1729.
4 Lee SH, Setyawan EMN, Choi YB et al. "Clinical Evaluation After Human Fat Stem Cell Transplantation in Dogs." J Vet Sci 2018; 19 (3): 452- 461.
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