Use of Stem Cells for the Treatment of Musculoskeletal Injuries in Horses.

Mesenchymal stem cells (MSCs) are used as a regenerative therapy in horses for musculoskeletal injury since the late 1990s and in some regions are standard of care for certain injuries. Yet, there is no Food and Drug Administration-approved MSC therapeutic in the United States for horses. In humans, lack of regulatory approval in the United States has been caused by failure of late-phase clinical trials to demonstrate consistent efficacy, perhaps because of nonuniformity of MSC preparation and application techniques. This article discusses clinical evidence for musculoskeletal applications of MSCs in the horse and current challenges to marketing approval.

Current use of biologic therapies for musculoskeletal disease: A survey of board-certified equine specialists.

OBJECTIVE: To evaluate the use of mesenchymal stem cells (MSCs), autologous conditioned serum (ACS), platelet-rich plasma (PRP), and autologous protein solution (APS) for the treatment of equine musculoskeletal disease by diplomates of the American College of Veterinary Surgery (ACVS), and American College of Veterinary Sports Medicine and Rehabilitation (ACVSMR). STUDY DESIGN: Cross-sectional study. SAMPLE POPULATION: Diplomates (n = 423). METHODS: An email link was sent to ACVS and ACVMR diplomates. A survey contained 59 questions regarding demographics, as well as indications, frequency, adverse effects, and limitations of use. Responses were analyzed using Fisher's exact test. RESULTS: One hundred and fifty four surveys were analyzed. Years in practice and type of practice were not associated with biologic therapy use. PRP was the most used therapy (120/137; 87.5%). PRP and MSCs were most often administered intralesionally while ACS and APS were most often administered intra-articularly. ACS (50/104; 48.1%) treatment was repeated commonly within 2 weeks of initial injection. MSCs (39/90; 43.3%) and PRP (38/100; 38%) were commonly repeated 1-2 months after initial injection and APS was typically repeated >4 months after initial injection (21/53; 39.6%). Local inflammation and expense were the most common adverse effect and limitation of use. CONCLUSION: Diplomates most commonly utilized PRP and MSC intralesionally for soft-tissue injuries, and ACS and ACP intra-articularly for joint injury. Protocols for repeated administration varied widely. Local inflammation was a clinical concern with the use of biologics. CLINICAL SIGNIFICANCE: Biologic therapies are used commonly by ACVS and ACVSMR diplomates for soft tissue and joint disease.

Use of Negative Pressure Wound Therapy in the Treatment of Limb Wounds: A Case Series of 42 Horses.

Traumatic limb injuries are common in horses. Negative pressure wound therapy (NPWT) has been proven to promote wound healing in human medicine. It has also been described for the treatment of wounds in horses. In this retrospective study, clinical records of 42 (n = 42) animals were assessed. Categories of wounds, duration of NPWT application, frequency of resetting the NPWT device, technical complications, and tolerance to the procedure were recorded. 42 wounds were classified as bony (n = 15; 36 %), articular (n = 14; 33 %), tenosynovial (n = 9; 21%), muscular (n = 2; 5%) and cutaneous (n = 2; 5 %). NPWT was used to help (1) first intention healing by preoperative (n = 3; 7 %) or postoperative (n = 7; 17%) application, (2) second intention healing (n = 31; 74%), and (3) delayed primary closure (n = 1; 2%). Duration of NPWT application ranged from 2 to 36 days (mean 11.5), with the system staying in place for periods ranging from 1 to 7 days (mean 4.5). In 69% (n = 29) of the cases, healing was considered satisfactory at discharge. 26 % (n = 11) of horses were discharged whilst ideally NPWT should have been continued. 2 animals (n = 2; 5%) were euthanized after surgery due to unrelenting pain. The procedure was well tolerated except in 1 horse who showed signs of discomfort at the first application. This study demonstrated that NPWT with long periods of application can be used successfully to manage various types of limb wounds.

The Role of Mesenchymal Stem Cells (MSCs) in Veterinary Medicine and Their Use in Musculoskeletal Disorders.

Regenerative medicine is a dynamically developing field of human and veterinary medicine. The animal model was most commonly used for mesenchymal stem cells (MSCs) treatment in experimental and preclinical studies with a satisfactory therapeutic effect. Year by year, the need for alternative treatments in veterinary medicine is increasing, and other applications for promising MSCs and their biological derivatives are constantly being sought. There is also an increase in demand for other methods of treating disease states, of which the classical treatment methods did not bring the desired results. Cell therapy can be a realistic option for treating human and animal diseases in the near future and therefore additional research is needed to optimize cell origins, numbers, or application methods in order to standardize the treatment process and assess its effects. The aim of the following work was to summarize available knowledge about stem cells in veterinary medicine and their possible application in the treatment of chosen musculoskeletal disorders in dogs and horses.

Clinical application of mesenchymal stem cells therapy in musculoskeletal injuries in dogs-a review of the scientific literature.

Mesenchymal stem cells (MSCs) are multipotent, which is defined by their ability to self-renew while maintaining the capacity to differentiate into a certain number of cells, presumably from their own germinal layer. MSCs therapy is based on their anti-inflammatory, immunomodulatory (immunosuppressive), and regenerative potential. This review aims to provide a clinical overview of the MSCs potential as a therapeutic option for orthopedic diseases in dogs. A total of 25 clinical studies published in the scientific literature in the last 15 years on various diseases will be presented: semitendinosus myopathy, supraspinatus tendinopathy, cruciate ligament rupture, bone fractures and defects, and also osteoarthritis (OA). All articles involved in this study include only diseases that have naturally occurred in canine patients. MSCs therapy in the veterinary orthopedic field has great potential, especially for OA. All studies presented promising results. However, MSCs bone healing capacity did not reveal such favorable outcomes in the long term. Besides, most of these clinical studies did not include immunohistochemistry, immunofluorescence, and histopathology to confirm that MSCs have differentiated and incorporated into the injured tissues. This review summarizes the current knowledge of canine MSCs biology, immunology, and clinical application in canine orthopedic diseases. Despite the positive results in its use, there is still a lack of defined protocols, heterogeneous samples, and concomitant medications used with MSCs therapy compromising therapeutic effects. Further studies are needed in the hope of overcoming its limitation in upcoming trials.

Biomechanical effects of a titanium intervertebral cage as a stand-alone device, and in combination with locking plates in the canine caudal cervical spine.

OBJECTIVE: To evaluate the change in ex vivo biomechanical properties of the canine cervical spine, due to an intervertebral cage, both as a stand-alone device and in combination with plates. STUDY DESIGN: Experimental ex vivo study. ANIMALS: Cervical spinal segments (C5-C7) from eight canine cadavers. METHODS: The range of motion (ROM) and elastic zone stiffness (EZS) of the spines were determined with a four-point bending device in flexion/extension, lateral bending, and axial rotation for four conditions: native, discectomy, cage (at C6-C7), and cage with plates (at C6-C7). The disc height index (DHI) for each condition was determined using radiography. RESULTS: Discectomy resulted in overall increased ROM (p < .01) and EZS (p < .05) and decreased DHI (p < .005) when compared to the native condition. Placement of the cage increased DHI (p < .001) and restored total ROM during flexion/extension, lateral bending and axial rotation, and EZS during flexion/extension to the level of the native spine. Application of the plates further reduced the total ROM during flexion/extension (p < .001) and lateral bending (p < .001), but restored ROM in extension and EZS during lateral bending. No implant failure, subsidence, or significant cage migration occurred during loading. CONCLUSION: An anchorless intervertebral cage used as a stand-alone device was able to restore the disc height and spinal stability to the level of the native cervical spine, whereas the addition of plates further reduced the spinal unit mobility. CLINICAL SIGNIFICANCE: This study implies that the intervertebral cage may be used as a stand-alone device in the spinal unit fixation in the canine cervical spine.

A RETROSPECTIVE REVIEW OF POST-METAMORPHIC MOUNTAIN CHICKEN FROG (LEPTODACTYLUS FALLAX) NECROPSY FINDINGS FROM EUROPEAN ZOOLOGICAL COLLECTIONS, 1998 TO 2018.

The mountain chicken frog (Leptodactylus fallax) is the largest endemic amphibian species in the Western Hemisphere. Since 1998, this critically endangered species has been maintained as a European Endangered Species Programme, but low breeding success and a high mortality rate threaten the sustainability of the captive frog population. In the current study, we analyzed gross and histopathologic postmortem information from 212 mountain chicken frogs that died in European zoological collections from 1998 to 2018. Thin body condition was the most commonly reported finding across all submissions, observed in 125 frogs. The gastrointestinal and urinary systems were reported to have the highest prevalence of pathologic findings on gross and histopathologic examination. Inflammatory disease was the most frequent diagnosis after histopathologic examination of relevant tissues, with intestinal inflammatory disease (n = 76) followed by tubulointerstitial nephritis (n = 26) being the most commonly reported. Neoplasia was reported in 42 of 212 (19.8%) frogs, all of which were adults. A defined cause of death, or reason for euthanasia, was proposed for 164 of 212 (77.4%) frogs, with inflammatory diseases processes (74 of 212; 34.9%) most commonly implicated. Intestinal adenocarcinoma, seemingly restricted to the colon, caused the deaths of 31 adult frogs. Further investigations to determine factors contributing to the high incidence of inflammatory disease processes and neoplasia are advocated to improve the health and sustainability of the captive mountain chicken frog population.

Feline musculoskeletal ageing: How are we diagnosing and treating musculoskeletal impairment?

PRACTICAL RELEVANCE: An understanding of the process of musculoskeletal ageing - which all senior and geriatric cats will experience - is vital to maintaining the health and welfare of our ageing cat population. CLINICAL CHALLENGES: Assessment of the feline musculoskeletal system is not always straightforward. Diagnosis of impairment relies on input from owners and veterinarians in terms of visual observation, and clinical and orthopaedic examination, in addition to diagnostic imaging. AUDIENCE: This review is written for the primary care veterinary team. AIMS: The goals are to raise awareness and improve clinical diagnosis of musculoskeletal impairment as a result of ageing. The article also reviews therapeutic options and considers the evidence available for the prevention/deceleration of musculoskeletal ageing and impairment. EVIDENCE BASE: There is good evidence of a high prevalence of osteoarthritis (OA) and degenerative joint disease (DJD) in older cats. There is also good evidence to indicate that functional impairment and chronic pain are sequelae of musculoskeletal disease. However, there is a paucity of information for what is best practice for the management and treatment of musculoskeletal impairment in a clinical situation. There is also a lack of evidence on how prevention of central stimulation of the nervous system caused by musculoskeletal impairment and, in turn the development of chronic pain, can be avoided.

Veterinary Regenerative Medicine for Musculoskeletal Disorders: Can Mesenchymal Stem/Stromal Cells and Their Secretome Be the New Frontier?

Regenerative medicine aims to restore the normal function of diseased or damaged cells, tissues, and organs using a set of different approaches, including cell-based therapies. In the veterinary field, regenerative medicine is strongly related to the use of mesenchymal stromal cells (MSCs), which belong to the body repair system and are defined as multipotent progenitor cells, able to self-replicate and to differentiate into different cell types. This review aims to take stock of what is known about the MSCs and their use in the veterinary medicine focusing on clinical reports on dogs and horses in musculoskeletal diseases, a research field extensively reported in the literature data. Finally, a perspective regarding the use of the secretome and/or extracellular vesicles (EVs) in the veterinary field to replace parental MSCs is provided. The pharmaceuticalization of EVs is wished due to the realization of a Good Manufacturing Practice (GMP product suitable for clinical trials.

Mesenchymal stem cells for treatment of musculoskeletal disease in horses: Relative merits of allogeneic versus autologous stem cells.

Mesenchymal stem cells (MSCs) are widely used for treatment of musculoskeletal diseases in horses, but there is ongoing debate regarding the relative safety and efficacy of allogeneic MSCs, compared with autologous equine MSCs. This review summarises the currently available published data regarding the therapeutic use of autologous and allogeneic MSCs in horses. Arguments that have been advanced against the use of allogeneic MSCs include higher risk of immunological reactions and shorter cell survival times following injection. Arguments favouring the use of allogeneic MSCs include the ability to bank cells and reduce the time to treatment, to collect MSCs from younger donor animals and the ability to manipulate banked cells prior to administration. In vitro studies and a limited set of experimental in vivo studies have indicated that adverse immunological reactions may occur when allogeneic MSCs are administered to horses. However, newer studies lack evidence of inflammatory reactions or adverse clinical responses when allogeneic MSCs are administered and compared with autologous MSCs. Thus, while the relative merits of allogeneic vs autologous MSCs for treatment of musculoskeletal injuries in horses have not been fully established, accumulating evidence from studies in horses suggests that allogeneic MSCs maybe a safe alternative to autologous MSCs. Large, properly designed, randomised trials in addition to careful immunological evaluation of short-term and long-term, local and systemic immune responses are needed to more fully resolve the issue.

Cranial cruciate ligament disease in cats: an epidemiological retrospective study of 50 cats (2011-2016).

OBJECTIVES: The aim of this study was to describe the characteristics and long-term outcome of surgically and conservatively treated cats with cranial cruciate ligament disease (CCLD). METHODS: A retrospective cohort study of cats with CCLD, diagnosed at two university animal hospitals between January 2011 and December 2016, was performed. Signalment, history, treatment and follow-up information were retrieved. Cat owners were contacted for additional long-term follow-up information. The cases were divided into two groups: one conservatively managed and one surgically treated with the lateral fabellotibial suture technique. A quality of life questionnaire, the Feline Musculoskeletal Pain Index (FMPI), was distributed to the owners of cats alive at follow-up for assessment of chronic pain as a long-term outcome. Univariable statistical methods were used to evaluate the data. RESULTS: Fifty cats were identified and were followed for a median of 41 months after diagnosis of CCLD. Seven cats (14%) developed bilateral CCLD. Twenty-eight cats (56%) were treated conservatively and 22 (44%) surgically. All surgically treated cats in which arthrotomy was performed (19/22) had total cranial cruciate ligament rupture and 9/19 (47%) had meniscal injuries. Postoperative surgical complications were recorded in 6/22 cats (27%). Owners of 24/29 (83%) cats still alive at follow-up completed the FMPI questionnaire. The conservatively treated cats had a lower FMPI score, indicating less chronic pain, than those cats treated surgically (P = 0.017). CONCLUSIONS AND RELEVANCE: Conservatively treated cats with CCLD experienced less chronic pain at long-term follow-up than surgically treated cats. Bilateral disease is not uncommon in cats with CCLD.

Breed susceptibility for common surgically treated orthopaedic diseases in 12 dog breeds.

BACKGROUND: A retrospective case-control study was conducted to estimate breed predisposition for common orthopaedic conditions in 12 popular dog breeds in Norway and Sweden. Orthopaedic conditions investigated were elbow dysplasia (ED); cranial cruciate ligament disease (CCLD); medial patellar luxation (MPL); and fractures of the radius and ulna. Dogs surgically treated for the conditions above at the Swedish and Norwegian University Animal Hospitals between the years 2011 and 2015 were compared with a geographically adjusted control group calculated from the national ID-registries. Logistic regression analyses (stratified for clinic and combined) were used to calculate odds ratios (OR) and 95% confidence intervals. Mixed breed dogs were used as reference. RESULTS: Breeds found at-risk for ED were the Labrador retriever (OR = 5.73), the Rottweiler (OR = 5.63), the German shepherd dog (OR = 3.31) and the Staffordshire bull terrier (OR = 3.08). The Chihuahua was the only breed where an increased risk for MPL (OR = 2.80) was identified. While the Rottweiler was the only breed predisposed for CCLD (OR = 3.96), the results were conflicting for the Labrador retriever (OR = 0.44 in Sweden, 2.85 in Norway); the overall risk was identical to mixed-breed dogs. CONCLUSIONS: Most results are in concordance with earlier studies. However, an increased risk of CCLD was not identified for the Labrador retriever, the Staffordshire bull terrier was found to have an increased risk of ED and some country-specific differences were noted. These results highlight the importance of utilising large caseloads and appropriate control groups when breed susceptibility is reported.

Comparison of ground reaction force measurements in a population of Domestic Shorthair and Maine Coon cats.

Current research on gait analysis mostly involves horses and dogs. Feline kinetics and kinematics are being investigated and receiving more clinical interest at present. Ground reaction forces measured on pressure-sensitive mattresses have been established in healthy Domestic Shorthair cats (DSH). Currently, no further information exists on either breed-specific measured gait reaction forces or comparisons among breeds. Because Maine Coon (MC) cats appear to be over-represented with orthopaedic diseases of the hind limb (hip dysplasia, patellar luxation), we evaluated ground reaction force GRF measurements in MC cats and compared them with those of DSH cats. Pre-evaluation radiological and clinical exams determined that the cats were not lame. The parameters evaluated were peak vertical force (PFz), vertical impulse (IFz), time to PFz (TPFz), step length (SL), paw contact area (PCA), stance phase duration (SPD) and symmetry index (SI) for the fore- and hind limbs. In both breeds, PFz and IFz were greater in forelimbs than in hind limbs. The PFz and IFz in Newtons were higher in the MC cats compared to the DSH cats, but not after normalisation for total force (%TF) and body mass (%BM). Furthermore, due to their body conformation, MC cats have a longer SL, larger PCA, and higher body weight than DSH cats. No other parameters differed significantly, except that the TPFz displayed an earlier value in the MC hind limbs. Measured symmetry indices were similar to those reported in dogs and did not differ between breeds. This is the first study to report GRF values and temporospatial parameters in a healthy MC cat population. However, our results could not confirm differences between normalized PFz and IFz and temporospatial parameters between the breeds. The authors therefore conclude that genetic or other causes may be involved in orthopaedic hind limb pathogenesis seen in MC cats more often than in other breeds.

Practical considerations for clinical use of mesenchymal stem cells: From the laboratory to the horse.

Since the clinical use of mesenchymal stem cells (MSCs) for treating musculoskeletal injuries is gaining popularity, practitioners should be aware of the factors that may affect MSCs from tissue harvesting for MSC isolation to cell delivery into the injury site. This review provides equine practitioners with up-to-date, practical knowledge for the treatment of equine patients using MSCs. A brief overview of laboratory procedures affecting MSCs is provided, but the main focus is on shipping conditions, routes of administration, injection methods, and which commonly used products can be combined with MSCs and which products should be avoided as they have deleterious effects on cells. There are still several knowledge gaps regarding MSC-based therapies in horses. Therefore, it is important to properly manage the factors which are currently known to affect MSCs, to further strengthen the evidence basis of this treatment.

Surgical Management of Orthopedic and Musculoskeletal Diseases of Feedlot Calves.

Injuries, infections, and disorders of the musculoskeletal system are common in feedlot calves. These conditions often are amenable to surgical treatment with return of the calf to productivity. Weight gain and carcass quality are expected to be significantly adversely affected by pain and debilitation. The goal of surgical management of disorders of the joints, muscles, and feet should be resolution of the inciting cause, mitigation of pain, and restoration of form and function. If these are achieved, calves should return to acceptable, if not normal, feed intake, rate of gain, and carcass quality.

[Ultrasonographic examination of the stifle joint in the dog. Part 2: Impaired wound healing and neoplastic, congenital, developmental, degenerative and traumatic disorders]. / Die sonographische Untersuchung des Kniegelenks beim Hund. Teil 2: Wundheilungsstörungen, Neoplasien, kongenitale, entwicklungsbedingte, degenerative und traumatische Veränderungen.

Ultrasonography is a cost-effective, non-invasive technique, which can be performed in conscious dogs. It frequently contributes valuable and even crucial diagnostic information in patients with lameness attributed to the stifle joint. Within the first part of this article, technical requirements and limitations as well as the standardized scanning protocol and ultrasonographic anatomy of the stifle joint are described. Additionally, ultrasonographic features of common pathologies of the stifle joint, including cranial cruciate ligament rupture and meniscal pathologies, are discussed. The second part of the article focuses on the ultrasonographic approach to other, less common pathologies of the canine stifle joint, including impaired wound healing and congenital, neoplastic, developmental and traumatic disorders.

The current 'state of play' of regenerative medicine in horses: what the horse can tell the human.

The horse is an attractive model for many human age-related degenerative diseases of the musculoskeletal system because it is a large animal species that both ages and exercises, and develops naturally occurring injuries with many similarities to the human counterpart. It therefore represents an ideal species to use as a 'proving ground' for new therapies, most notably regenerative medicine. Regenerative techniques using cell-based therapies for the treatment of equine musculoskeletal disease have been in use for over a decade. This review article provides a summary overview of the sources, current challenges and problems surrounding the use of stem cell and non-cell-based therapy in regenerative medicine in horses and is based on presentations from a recent Havemeyer symposium on equine regenerative medicine where speakers are selected from leading authorities in both equine and human regenerative medicine fields from 10 different countries.

Diseases of the tendons and tendon sheaths.

Contracted flexor tendon leading to flexural deformity is a common congenital defect in cattle. Arthrogryposis is a congenital syndrome of persistent joint contracture that occurs frequently in Europe as a consequence of Schmallenberg virus infection of the dam. Spastic paresis has a hereditary component, and affected cattle should not be used for breeding purposes. The most common tendon avulsion involves the deep digital flexor tendon. Tendon disruptions may be successfully managed by tenorrhaphy and external coaptation or by external coaptation alone. Medical management alone is unlikely to be effective for purulent tenosynovitis.

Mesenchymal stem cell therapy in horses: useful beyond orthopedic injuries?

In the past decade, mesenchymal stem cells (MSC) have received much attention in equine veterinary medicine. The first therapeutic use of equine MSC was reported in 2003. Since then, the clinical application of MSC has been exploding with thousands of horses now treated worldwide. At present, MSC are mainly used in veterinary medicine to treat musculoskeletal diseases based on their ability to differentiate into various tissues of mesodermal origin. This is in marked contrast to human medicine, where MSC therapies are primarily focused on immune-mediated, inflammatory, and ischemic diseases. In this review, both orthopedic as well as non-orthopedic clinical applications of equine MSC are discussed. A brief overview is provided on the potential of MSC for non-orthopedic injuries with emphasis on those diseases, which occur in both humans and horses.