Osteoarthritis, also known as degenerative joint disease, is a common condition in pets, affecting an estimated 25 percent at some point in their life. While the term arthritis refers to inflammation of the joints, osteoarthritis refers to inflammation caused by the deterioration of joint cartilage. Osteoarthritis causes loss of bone cartilage, a thickening of the joint capsule, and osteophytosis, or new bone formation around the joint.
In humans, osteoarthritis is typically associated with aging and the general wear and tear on joints. This is not usually the case in pets, with most cases of osteoarthritis occurring secondary to underlying conditions such as elbow or hip dysplasia, ligament tears and ruptures, or broken bones that involve the joints. Primary cases of osteoarthritis do occur, though the exact cause is not understood. Potential risk factors for primary osteoarthritis can include age, breed, obesity, repetitive stress, and hormones.
Signs your pet may suffer from osteoarthritis can include limping, a decrease in normal activity, stiffness in the limbs, inability to jump, a change in normal gait, and pain when you touch the affected area.3
Current treatments for osteoarthritis focus on alleviating symptoms and trying to slow the progression of damage. Current treatment options include:
• Nonsteroidal Anti-Inflammatory Drugs or Disease Modulating Agents – Nonsteroidal anti-inflammatory drugs, such as meloxicam or ketoprofen, are administered to help manage the pain associated with osteoarthritis. Disease modulating agents, such as corticosteroids or hyaluronic acid, are administered as injections in the joint to reduce inflammation and/or slow progression of the damage.
• Weight Management – Maintaining a healthy weight is essential in the management of osteoarthritis. High levels of body fat produce inflammatory mediators that contribute to joint inflammation. Additional weight also puts excess force on the damaged joints.
• Activity Modification and Rehabilitation – Avoiding high-impact activities like running or jumping should be limited and replaced with activities such as short leash walks. Rehabilitation includes range of motion exercises and aqua therapy to help improve joint mobility and increase muscle mass. Other rehabilitation therapies can include acupuncture and laser therapy.
• Surgical Intervention – In some cases, the best form of treatment is surgical intervention. In many cases, this may mean treating the underlying condition responsible for the osteoarthritis, such as a knee cranial cruciate ligament rupture. Total joint replacement surgery is also considered usually in cases where osteoarthritis affects the hips.
Mesenchymal stem cell (MSC) therapy targets osteoarthritis in multiple ways. It was first believed that the main benefit of stem cells would be regeneration of the articular cartilage within the affected joint. While this does occur, researchers and veterinarians discovered this was not the main benefit of stem cells in osteoarthritis.
When your pet suffers from osteoarthritis, inflammatory markers from within the immune system become active in the affected joint, as well as throughout the entire body. This increased inflammation contributes to the degenerative damage within the affected joint. Mesenchymal stem cells work to reduce inflammation. MSC therapy helps reduce pain levels and reduce or even reverse the damage to the affected joints.
An early study published in Veterinary Therapeutics in 2007 was the first randomized, blinded, placebo-controlled clinical trial that showed the effectiveness of stem cell therapy for dogs with osteoarthritis of the hip.4 The study included 21 dogs ranging in age from one to 11 years old. All dogs showed the presence of bilateral hip joint osteoarthritis with a minimum duration of at least six months. Before the trial began, all dogs underwent a full examination including an evaluation of gait, lameness, range of motion, and pain from passive manipulation. Autologous adipose-derived stem cells were collected from all dogs in the study, including those that would eventually receive a placebo treatment. Each dog then received either a saline placebo or a suspension of 4.2 million to 5 million viable stem cells in a saline solution. The solutions were injected into the hip joints. At the end of 90 days, all the dogs were evaluated on gait, lameness, range of motion, and pain. Control animals showed no significant improvement in any of these areas. However, those treated with MSCs showed significant improvement in lameness, pain on manipulation, and range of motion.
While the previous study used autologous stem cells, a 2016 study in Veterinary Regenerative Medicine evaluated the use of allogeneic adipose-derived MSCs in dogs with osteoarthritis.5 The study was randomized, blinded, and placebo controlled. Participants were divided into two groups. The control group received a placebo injection into one or two affected joints while the treatment group received a single injection of MSCs. This study revealed statistically impressive results. Veterinary pain manipulation scores improved by 92.8 percent in treated dogs compared to 50.2 percent in placebo controls. Veterinary global scores improved by 86.9 percent in treated dogs versus 30.8 percent in placebo controls. Neither group experienced adverse effects as a result of treatment.
Just like humans, pets are susceptible to injuries such as broken bones or muscle and ligament damage. For example, a common injury among people is a torn or ruptured anterior cruciate ligament, or ACL, in the knee. In dogs, this ligament is known as the cranial cruciate ligament (CCL) and is the most common cause of hindlimb lameness in dogs. While, like humans, dogs can tear or rupture this ligament in an injury, the more common causes are excessive strain or a progressive degenerative disease. A CCL tear is the most common orthopedic disease seen in dogs and repairing this ligament is the most common surgical procedure performed by veterinary surgeons. The cranial cruciate ligament prevents cranial displacement of the tibia, prevents knee hyperextension, and prevents the internal rotation of the tibia. When this ligament is damaged, symptoms will depend on the type of injury. An acute tear or rupture will likely cause pain and the avoidance of weight-bearing on the affected hind limb. This may improve with rest or in time. With a partial tear, you dog may experience lameness after exercise, but will recover with rest. Unfortunately, the ligament is likely to continue to weaken and become unstable. With chronic rupture of the ligament, lameness may be persistent. The knee may appear swollen as the body creates scar tissue around the joint. Arthritis is also likely to develop.6
The goal of CCL treatment is to stabilize the joint, alleviate pain, and increase mobility. Conservative treatment begins with weight control, rest, and anti-inflammatory medications. This treatment is often enough for dogs weighing under 25 pounds. However, surgical intervention is the preferred method of treatment in dogs over 25 pounds. There are four main surgical intervention options: extra-capsular stabilizing suture, TightRope procedure, Tibial plateau leveling osteotomy, and tibial tuberosity advancement.
• Extra-Capsular Stabilizing Suture – This surgical procedure is designed to try and mimic the natural function of a stable CCL. A heavy gauge suture is placed across the outside of the stifle joint. This procedure works well on dogs under 40 pounds, though in heavier dogs is not as predictable and the suture has a higher percentage of breakage.
• TightRope Cruciate Repair – The TightRope repair system is a newer treatment option for CCL injuries that uses a strong synthetic ligament that is directly anchored to the bones on either side of the joint.7
• Tibial Plateau Leveling Osteotomy (TPLO) – When the CCL no longer supports the joint, the tibia can shift forward in relationship to the femur when weight is placed on the limb. The TPLO procedure works to reduce the amount of this shift by making a semicircular cut through the top of the tibia and rotating it. A metal plate is then attached to the medial surface to stabilize the new position. This flattens the tibial plateau and prevents the femur from sliding backwards.
• Tibial Tuberosity Advancement (TTA) – This procedure is similar to the TPLO in that it changes the mechanics and shape of the stifle joint. In this procedure, the cranial surface of the tibia, where the patellar ligament attaches, is cut. This section of bone is then advanced in a forward position and stabilized with a titanium plate and screws.
In cases of cranial cruciate ligament injuries, mesenchymal stem cell therapy offers an alternative treatment in both cases of partial and complete rupture. In a partial rupture, where the ligament is still intact, the introduction of mesenchymal stem cells helps generate new tissue and aids in the development of new blood vessels, or angiogenesis. They work as immunomodulators to help regulate and normalize the immune system, reducing the levels of inflammation in the area and bringing down pain levels. This stimulation of new growth aids in the repair of the ligament, often eliminating the need for surgical intervention. In cases where the tendon is completely ruptured, the use of mesenchymal stem cells in connection with surgical repair can greatly accelerate healing, reduce post-surgical pain, and decrease the development of arthritis in the joint.
When it comes to stem cell therapy for canine orthopedic conditions, there are studies and case reports that show promising results. Many veterinarians are now turning to stem cell treatments as a front-line option, especially when it comes to partial cranial cruciate ligament tears.
A 2016 study published in Frontiers of Veterinary Science evaluated 36 dogs with partial cranial cruciate ligament tears.8 The dogs were treated with either autologous bone marrow aspirate concentrate (BMAC) or adipose-derived progenitor cells (ADPC) in combination with a platelet-rich plasma. Of the 36 dogs that started in the study, only 13 owners remained in contact for the 90-day post-treatment evaluation. Of those 13, nine dogs showed a fully intact CCL through arthroscopy findings. The CCL was marked with neovascularization (new blood vessels) and a normal fiber pattern, demonstrating complete healing. One dog experienced significant improvement and received a second injection to promote continued healing. The three remaining dogs showed a tear of greater than 50 percent and required a TPLO. Of these dogs, eight were performance or sporting dogs and all were able to return to the sport or sport conditioning after treatment.
While CCL injury is the most common canine orthopedic injury, bone fractures and injury also occur. Three case reports published in the Taiwan Veterinary Journal in 2017 looked at the use of adipose-derived stem cells combined with autologous cancellous bone or synthetic bone substitutes in the treatment of non-union fractures.9 All three dogs had bone fractures that were unsuccessfully treated with surgical intervention and bone plates. One developed a bone infection after two bone plate attempts. All three dogs received stem cell therapy and within a few months, all three experienced full bone union and recovery.
Keratoconjunctivitis Sicca (KCS) is a condition similar to Sjogren’s syndrome in humans. “Kerato” refers to the cornea of the eye. “Conjunctivae” refers to the membranes of the eye socket. “Itis” refers to inflammation and “sicca” means dry. Dogs with KCS have a deficiency in tear production. This deficiency contributes to dry eyes, which can lead to changes and damage to the cornea and conjunctiva, which can lead to blindness. There are two types of KCS: quantitative and qualitative. Quantitative KCS is a reduction in the aqueous layer of the tear film while qualitative KCS has a decrease in the mucin or oily layers of the tear film.
The most common cause of KCS is immune mediated inflammation of the lacrimal gland in the eyes. Like in humans, it is considered to be of autoimmune disease origin where the immune system mistakenly attacks the glands responsible for tear production. However, other possible causes include congenital alacrima, drug toxicity, third eyelid extension, and metabolic diseases, such as diabetes or canine distemper.
The most common clinical signs of KCS are painful red eyes with a thick mucous discharge. It commonly occurs in both eyes. Dry eyes can lead to secondary corneal ulceration or bacterial conjunctivitis. If uncontrolled, it can cause corneal pigmentation, vascularization, and scarring of the eye. Any of these conditions can lead to visual impairment or loss of the eye completely.
Diagnosis of KCS is made using the Schirmer tear test (SST) or the Tear Break Up Time test (TBUT). The SST tests for quantitative KCS and uses paper strips to test for tear production levels. Normal tear production in dogs should be over 15mm/min. The TBUT uses a fluorescein stain in the eye to measure how long it takes for the tear film to break up the fluorescein layer. A normal TBUT is greater than 20 seconds.
While KCS can affect any dog, certain breeds are more likely to develop dry eye. These breeds include Cavalier King Charles Spaniel, English Bulldog, Lhasa Apso, Pug, Shih Tzu, and West Highland White Terrier.
Current treatment for KCS is lifelong and involves the daily application of a topical eye medication that helps reduce inflammation. In many cases, lubricating drops are used as well to help improve comfort. While most dogs respond well to this treatment, it is necessary to maintain daily drops two to three times a day for their lifetime. For dogs that do not respond well to drop, surgical intervention may be necessary. A parotid duct transposition redirects the parotid salivary duct from the mouth to the eye.
While immunosuppressive eye drops work for most cases of KCS, this treatment method requires multiple drops per day, for the duration of the dog’s life. Mesenchymal stem cells injected into the lacrimal glands provide similar immunosuppressive properties and cause the body’s immune system to reset. After treatment with MSCs, tests show reductions in inflammatory markers CD-4, IL-1, IL-6 and TNF-a. In addition, MSCs stimulate neighboring parenchymal cells to repair damage within the eye tissue.
One of the first studies to examine the effects of MSCs on canine KCS was published in BioMed Research International in 2015.10 Researchers implanted adipose-derived MSCs into the lacrimal glands of 12 dogs. They measured results at three-month intervals using the Schirmer tear test as well as evaluating ocular surface integrity. The baseline mean STT value was around 4.96 before treatment. By the first evaluation at three months, the STT values increased significantly to around 11.16 and continued to increase, ending at 12.66 at the nine-month evaluation. Decreases were seen in ocular discharge, hyperaemia (eye redness), and corneal changes.
Another study published in Cell Medicine in 2016 examined 15 dogs of different breeds and followed results out to 12 months post MSC treatment.11 Similar to the previous study, all dogs experienced statistically significant improvements in STT scores as well as ocular surface improvements. They discovered that all of the patients with mild to moderate KCS were able to achieve normal SST values. Those with more severe cases of KCS saw significant improvements in tear production and eye health but did not experience a complete reversion. However, compared to daily drops of immunosuppressive medication, one single MSC transplantation was able to provide treatment for at least a 12-month period. This eliminated the need for daily medications and returned the tear production to normal levels in most dogs.
Canine atopic dermatitis is the second most common skin condition in dogs, with veterinarians reporting as many as 15 percent of patients in a traditional setting and as many as 30 percent in specialty dermatology practices. It is a genetically predisposed inflammatory allergic skin disease associated with IgE antibodies to common environmental allergens.12 Symptoms of canine atopic dermatitis can include severe itching, excessive scratching, excessive chewing of the paws and areas around the groin and armpits, hair loss, and greasy or flaky skin with a strong foul odor. The excessive scratching and chewing can lead to hot spots, or areas of raw and inflamed skin, which can become infected. As a dog ages, the sensitivity to allergens increases. While atopic dermatitis may start out as seasonal, with age it can progress to a year-round condition. While all dog breeds can develop canine atopic dermatitis, some breeds are more prone than others. These breeds include Boxer, Boston Terrier, Chinese Shar-Pei. Golden Retriever, Dalmatian, Labrador Retriever, Lhasa Apso, Scottish Terrier, Shih Tzu, West Highland White Terrier, and the Wirehaired Fox Terrier.
Canine atopic dermatitis is a lifelong condition without a cure. Lifelong treatment and management is necessary. If specific allergens can be identified, avoidance is the first line of treatment. Unfortunately, this is often difficult. Treatments focus on relieving the symptoms and reducing the risk of secondary infections. These treatments can include:
• Anti-itch medications
• Allergen-specific immunotherapy medications
• Antimicrobial shampoos
• Topical corticosteroids
• Omega-3 and Omega-6 fatty acid supplements
Atopic dermatitis is associated with an inflammatory response associated with IgE antibodies, but its exact pathogenesis is not completely understood. Researchers do know that it involves a reaction between the skin structure, the immune system, and environmental influences. Mesenchymal stem cells demonstrate the ability to provide immunosuppressive properties and essentially reset the immune system. Preliminary studies using MSCs as a therapy show promising results, including temporary remission of the disease.
Clinical trials are looking at the benefits of MSCs for dogs with canine atopic dermatitis. A 2018 study published in The Veterinary Record evaluated 26 dogs suffering from atopic dermatitis for at least 12 months that did not respond well to conventional therapies.13 Each dog received an intravenous dose of allogenic adipose-derived MSCs and were assessed at a 6-month follow up exam and evaluated based on the Canine Atopic Dermatitis Extent and Severity Index (CADESI). Pruritus, or itching, and CADESI scores decreased significantly as early as one week after treatment and remained stable for six months. They concluded that this simple therapy offered remission of clinical symptoms for at least six months with no adverse side effects.
The kidneys are an essential organ for dog health as they help excrete toxins, maintain normal levels of blood electrolytes, maintain blood pressure, and produce urine. Acute kidney injuries (AKI) occur when something causes sudden or acute kidney damage. This can happen in dogs diagnosed with chronic kidney disease or in otherwise healthy dogs. Common causes of acute kidney injury can include ingestion of toxins, such as antifreeze, certain medications, and tainted foods. Decreased blood flow and oxygen delivery to the kidneys can also affect function, as can infections or urinary tract obstruction.
Symptoms of acute kidney injury vary depending on the severity of the illness. In many cases, symptoms are not noticeable until the dog is in acute renal failure. Clinical signs include lethargy, vomiting, diarrhea, abdominal pain, weight loss, decreased appetite, and a change in urination. If the underlying cause is determined to be infection or blockage, treatment must begin immediately. In many cases, however, the underlying cause is never determined, and treatment focuses on supportive care. Unfortunately, the mortality rates of acute kidney injury are high, ranging from 47 to 61 percent.
Traditional treatment for acute kidney injury focuses on addressing any underlying causes first. Once that is treated, or no cause is determined, treatment focuses on supportive care. The veterinarian provides fluids, manages blood pressure abnormalities, offers pain medications, anti-nausea medications, and monitors bloodwork to check electrolyte balances. In severe cases, dialysis or blood purification can help keep dogs stable and allow time for the kidneys to heal. In some cases, this medical management is enough to allow the kidneys time to heal and restore kidney blood values to within normal range. However, even with recovery from an acute kidney injury, many dogs that survive end up with permanent kidney damage and chronic kidney disease.
Numerous studies in rat models have focused on the short-term effects that bone marrow or adipose-derived mesenchymal stem cells provide in cases of acute renal failure. Evidence suggests that MSCs help to preserve renal function, as well as reduce tubular injury and fibrosis. While controversial, many propose that MSC may actually differentiate into functional renal tubular epithelial cells. Another theory is that paracrine effects (cell signaling from one cell to another, changing the behavior of a cell) from the MSCs offer a greater effect than direct cellular incorporation into the kidneys and help to greatly suppress intra-renal inflammation.
In cases of chronic kidney disease, rodent models show that MSCs reduce intra-renal inflammation and suppress fibrosis and glomerulosclerosis.14
A 2017 study published in In Vivo, looked at the effects of MSC therapy on a canine model of acute kidney injury.15 The study included 14 male beagles, with half receiving umbilical cord MSCs. All dogs treated with MSCs showed decreased levels of blood urea nitrogen and creatinine levels and survived the acute kidney injury. This suggests that MSC treatment could be an effective treatment option for acute kidney injury.
In March of 2019, the Journal of Veterinary Internal Medicine published a Phase 1 clinical trial looking at the use of MSCs for the treatment of chronic kidney disease in cats.16 While this study is still ongoing and results have not been published, they report that intra-arterial infusion of MSCs into the renal artery was feasible and safe within the 3-month post-operative period.
It has been 15 years since the first animals were treated with stem cell therapy. Currently, stem cell therapy for dogs is mostly used to alleviate conditions such as osteoarthritis, bone and ligament injuries, and Keratoconjunctivitis Sicca. But this is only the beginning. Research continues to investigate the use of stem cells in veterinary medicine for conditions such as spinal injuries, cardiac defects, gastrointestinal issues, renal conditions, and bone repair.
A promising study from The Journal of Veterinary Medicine in 2009 evaluated the use of adipose-derived stem cells in dogs with spinal cord injuries.17 Results showed significant improvement in nerve conduction velocity and neurological function in the group of dogs that received the stem cells.
A preliminary study from Stem Cells International in 2014 looked at the use of adipose derived stem cells and autologous stromal vascular fraction in dogs with hip dysplasia.18 In this study, researchers injected stem cells into acupuncture points. During the clinical evaluation one week after injection, the dogs showed marked improvement. By days 15 and 30, all dogs showed increased range of motion, reduced pain on manipulation, and lameness. While they point out further studies are needed, they believe stem cells may represent an important therapeutic alternative for treating joint diseases.
In a report from Andrew Hoffman, D.V.M., D.V.Sc. from the Regenerative Medicine Laboratory at the Cummings School of Veterinary Medicine he discusses many of the conditions currently being evaluated and undergoing trials for stem cell therapy.19 In addition to osteoarthritis and the other conditions already mentioned, other conditions include:
This is a common condition in smaller chondrodystrophic dog breeds, such as Dachshunds, often leading to paralysis. A 2015 study published in Turkish Neurosurgery treated seven dogs with MSCs in paraplegic dogs without deep pain perception due to intervertebral disc disease.20 Most of the dogs experienced improvement and researchers believe that the use of MSCs may be a promising approach to IVDD.
Atopic dermatitis is an inflammatory skin disease that affects nearly 8.7 percent of dogs. Current treatment options require frequent administration of topical medications that can come with serious side effects. Current clinical trials, such as one currently enrolling by VetCell Therapeutics and Western University Health Center are looking at how MSCs may change treatment options.21
Similar to the fistulas experienced by human Crohn’s patients, perianal fistulas, or anal furunculosis, is a serious medical condition that commonly affects German Shepherds. These tunnel-like lesions appear in the skin and tissue surrounding the anal area and can cause severe pain. Current treatments include anti-inflammatory and immunosuppressive drugs but can progress to the need for surgical intervention. A 2016 study in Regenerative Medicine treated six dogs with canine anal furunculosis with human embryonic stem cells.22 At three months, all six dogs were completely free of fistulas. This study was the first to show evidence of the safety and therapeutic potential. While this is encouraging for canine treatment, this also provides hope for people suffering from Crohn’s disease.
Dogs may suffer from one of several inflammatory bowel diseases including histiocytic ulcerative colitis, lymphocytic-plasmacytic colitis, and eosinophilic colitis. These conditions cause inflammation in the walls of the gastrointestinal tract and may cause vomiting, decreased appetite, weight loss, and liquid or bloody stool. Dietary changes and anti-inflammatory medicines can help, but this is often a lifelong condition. A 2015 study in Veterinary Journal evaluated the use of a single intravenous infusion of adipose-derived MSCs in 11 dogs with IBD.23 After 120 days, results showed significant improvement in gastrointestinal lesions and reduced inflammation.
Dilated Cardiomyopathy is a disease of the cardiac muscle that decreases the ability of the heart to generate enough pressure to pump blood through the body. It is more common in Doberman Pinschers, Great Danes, boxers, and Cocker Spaniels. This causes a lack of blood flow, decreased delivery of oxygenated blood, and congestion of blood in the lungs. Symptoms such as lethargy, weakness, coughing, abdominal distention, and cardiac arrhythmias are common. These arrhythmias can predispose dogs to sudden death. Current treatment is cardiac medications directed at improving the systolic function of the heart. Unfortunately, this can be a devastating disease. A 2013 study published in the Journal of Small Animal Practice looked at the use of adipose-derived MSCs in Dobermans with dilated cardiomyopathy.24 While they determined that the use of stem cells appear safe, however, it did not show any significant improvement. This is an area however they are continuing to research.
Studies not specific to veterinary use also have possible implications for our companions. Research is currently underway using stem cell therapy in mice to correct damaged tissues in the heart and brain that were caused by congenital birth defects.25 There is also evidence from studies with mice showing that stem cell treatment holds the power to reverse diabetes.26 Scientists are also working on achieving more control over growing stem cells into specific cells to repair damaged organs such as the heart, liver, kidneys and brain. This could help treat or prevent strokes, dementia, and various terminal illnesses on a grand scale. Research out of the University of Pennsylvania indicates that stem cells could potentially be used to restore areas of the retina damaged due to vision diseases and disorders. We could soon see stem cell therapy being used to treat cancer, heart disease, diabetes, blindness and more in our furry friends.
Stem cells also hold the potential to be used as preventative medicine in the near future—delaying or eliminating the onset of degenerative diseases such as osteoarthritis and spinal cord disorders while extending the lives of dogs. Current research shows that young stem cells have the ability to extend the lifespan of geriatric mice.27 The future of veterinary care is likely to include once-yearly stem cell infusions in an effort to promote longevity and health of your pet’s cells and tissues.
Alderman, Donna, and Robert W. Alexander. “Advances in Stem Cell Therapy: Application to Veterinary Medicine.” Today's Veterinary Practice, 25 June 2019, todaysveterinarypractice.com/advances-in-stem-cell-therapy-application-to-veterinary-medicine/
“Stem Cell FAQs.” Texas A&M Veterinary Medical Teaching Hospital, vethospital.tamu.edu/small-animal/orthopedics/stem-cell-faqs/.
“Small Animal Topics.” ACVS, www.acvs.org/small-animal/osteoarthritis-in-dogs.
Black, Linda L, et al. “Effect of Adipose-Derived Mesenchymal Stem and Regenerative Cells on Lameness in Dogs with Chronic Osteoarthritis of the Coxofemoral Joints: a Randomized, Double-Blinded, Multicenter, Controlled Trial.” Veterinary Therapeutics: Research in Applied Veterinary Medicine, U.S. National Library of Medicine, 2007, www.ncbi.nlm.nih.gov/pubmed/18183546.
Harman, Robert, et al. “A Prospective, Randomized, Masked, and Placebo-Controlled Efficacy Study of Intraarticular Allogeneic Adipose Stem Cells for the Treatment of Osteoarthritis in Dogs.” Frontiers in Veterinary Science, Frontiers Media S.A., 16 Sept. 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC5025432/.
“Cranial Cruciate Ligament Rupture.” Small Animal Hospital, smallanimal.vethospital.ufl.edu/clinical-services/surgery/orthopedic-surgery/cranial-cruciate-ligament-rupture/.
“Tightrope Cruciate Repair.” Roscoe Village Animal Hospital, www.roscoevillageanimalhospital.com/tightrope-cruciate-repair/.
Canapp Jr., Sherman O., et al. “Partial Cranial Cruciate Ligament Tears Treated with Stem Cell and Platelet-Rich Plasma Combination Therapy in 36 Dogs: A Retrospective Study.” Frontiers, Frontiers, 28 Nov. 2016, www.frontiersin.org/articles/10.3389/fvets.2016.00112/full.
Tsai, Kun-Lung. “CASE REPORT: Three Cases of Non-Union Fracture in Dogs Treated with Adipose-Derived Adult Stem Cells Combines with Autologous Cancellous Bone and Synthetic Bone Substitutes.” Taiwan Veterinary Journal, 2017, www.worldscientific.com/doi/abs/10.1142/S1682648516720033?journalCode=tvj.
Villatoro, Antonio J., et al. “Use of Adipose-Derived Mesenchymal Stem Cells in Keratoconjunctivitis Sicca in a Canine Model.” BioMed Research International, Hindawi, 23 Feb. 2015, www.hindawi.com/journals/bmri/2015/527926/.
Bittencourt, Maura K W, et al. “Allogeneic Mesenchymal Stem Cell Transplantation in Dogs with Keratoconjunctivitis Sicca.” Cell Medicine, Cognizant Communication Corporation, 18 Oct. 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC5165646/.
Lund, Elizabeth. “The Epidemiology of Atopic Dermatitis.” Banfield DataSavant, 24 Mar. 2008, www.banfield.com/getmedia/34ffd1bf-65e2-4d73-9d81-493231df3d91/4_2-The-epidemiology-of-atopic-dermatitis.
Villatoro, Antonio José, et al. “Allogeneic Adipose-Derived Mesenchymal Stem Cell Therapy in Dogs with Refractory Atopic Dermatitis: Clinical Efficacy and Safety.” The Veterinary Record, U.S. National Library of Medicine, 1 Dec. 2018, www.ncbi.nlm.nih.gov/pubmed/30158120.
Quimby DVM, PhD, DACVIM, Jessica. “Applications of Stem Cell Therapy in Kidney Disease.” VIN, 27 June 2013, www.vin.com/AppUtil/Project/DefaultAdv1.aspx?pId=99&catId=14649&id=6133833.
Lee, Seung-Jun, et al. “Mesenchymal Stem Cells Contribute to Improvement of Renal Function in a Canine Kidney Injury Model.” In Vivo (Athens, Greece), International Institute of Anticancer Research, 3 Nov. 2017, www.ncbi.nlm.nih.gov/pmc/articles/PMC5756639/.
Thomson, Abigail L., et al. “Intra‐Arterial Renal Infusion of Autologous Mesenchymal Stem Cells for Treatment of Chronic Kidney Disease in Cats: Phase I Clinical Trial.” Wiley Online Library, John Wiley & Sons, Ltd (10.1111), 29 Mar. 2019, onlinelibrary.wiley.com/doi/full/10.1111/jvim.15486.
Ryu, Hak Hyun, et al. “Functional Recovery and Neural Differentiation after Transplantation of Allogenic Adipose-Derived Stem Cells in a Canine Model of Acute Spinal Cord Injury.” Journal of Veterinary Science, The Korean Society of Veterinary Science, Dec. 2009, www.ncbi.nlm.nih.gov/pubmed/19934591/.
Marx, Camila, et al. “Acupoint Injection of Autologous Stromal Vascular Fraction and Allogeneic Adipose-Derived Stem Cells to Treat Hip Dysplasia in Dogs.” Stem Cells International, Hindawi Publishing Corporation, 2014, www.ncbi.nlm.nih.gov/pubmed/25180040/.
Hoffman, Andrew M., and Steven W. Dow. “Concise Review: Stem Cell Trials Using Companion Animal Disease Models.” Stem Cells Journals (AlphaMed Press), John Wiley & Sons, Ltd, 3 May 2016, stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/stem.2377.
Besalti, Omer, et al. “Intraspinal Transplantation of Autologous Neurogenically-Induced Bone Marrow-Derived Mesenchymal Stem Cells in the Treatment of Paraplegic Dogs without Deep Pain Perception Secondary to Intervertebral Disk Disease.” Turkish Neurosurgery, U.S. National Library of Medicine, 2015, www.ncbi.nlm.nih.gov/pubmed/26242341.
Kaur, Gagandeep. “Novel Stem Cell Treatment for Canine Atopic Dermatitis.” Western University Pet Health Center, VetCell Therapeutics, www.westernu.edu/mediafiles/veterinary/research/ClinicalTrialAtopicDermatitis.pdf.
Ferrer, Lluís, et al. “Treatment of Perianal Fistulas with Human Embryonic Stem Cell-Derived Mesenchymal Stem Cells: a Canine Model of Human Fistulizing Crohn's Disease.” Regenerative Medicine, U.S. National Library of Medicine, Jan. 2016, www.ncbi.nlm.nih.gov/pubmed/26387424.
Pérez-Merino, E M, et al. “Safety and Efficacy of Allogeneic Adipose Tissue-Derived Mesenchymal Stem Cells for Treatment of Dogs with Inflammatory Bowel Disease: Endoscopic and Histological Outcomes.” Veterinary Journal (London, England : 1997), U.S. National Library of Medicine, Dec. 2015, www.ncbi.nlm.nih.gov/pubmed/26526521.
Pogue, B, et al. “Stem-Cell Therapy for Dilated Cardiomyopathy: A Pilot Study Evaluating Retrograde Coronary Venous Delivery.” The Journal of Small Animal Practice, U.S. National Library of Medicine, July 2013, www.ncbi.nlm.nih.gov/pubmed/23731226.
Hebrew University of Jerusalem. "Brain Birth Defects Successfully Reversed Through Stem Cell Therapy." ScienceDaily. ScienceDaily, 30 December 2008. <www.sciencedaily.com/releases/2008/12/081228191056.htm>.
Reversal of Diabetes in Non-Obese Diabetic Mice Without Spleen Cell-Derived ß Cell Regeneration By Anita S. Chong, Jikun Shen, Jing Tao, Dengping Yin, Andrey Kuznetsov, Manami Hara, Louis H. Philipson Science24 Mar 2006 : 1774-1775
Kovina MV, Karnaukhov AV, Krasheninnikov ME, Kovin AL, Gazheev ST, Sergievich LA, Karnaukhova EV, Bogdanenko EV, Balyasin MV, Khodarovich YM, Dyuzheva TG and Lyundup AV (2019) Extension of Maximal Lifespan and High Bone Marrow Chimerism After Nonmyeloablative Syngeneic Transplantation of Bone Marrow From Young to Old Mice. Front. Genet. 10:310. doi: 10.3389/fgene.2019.00310
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