Elsevier

Research in Veterinary Science

Volume 135, March 2021, Pages 495-503
Research in Veterinary Science

Administration of mesenchymal stem cells from adipose tissue at the hip joint of dogs with osteoarthritis: A systematic review

https://doi.org/10.1016/j.rvsc.2020.11.014Get rights and content

Highlights

  • Dogs with hip OA showed better clinical outcomes after a single intra-articular injection of ADSC in a short follow-up

  • ADSC treatment was effective in reducing pain and improving functional limitation and quality of life in dogs with hip OA.

  • ADSC administration was generally safe and well tolerated in all studies with no adverse effects detected.

  • The results obtained from clinical improvement were similar, using either autologous or allogeneic ADSC.

  • The studies analyzed were heterogeneous for clinical and methodological reasons, and more randomized studies are necessary.

Abstract

This systematic review aimed to determine the effects of intra-articular administration of mesenchymal stem cells from adipose tissue in dogs with hip joint osteoarthritis (OA). Clinical trials were systematically reviewed, using PubMed, EMBASE, Cochrane Library, LILACS, Web of Science, Scopus, Open Grey, Google Scholar, and ProQuest Dissertation and Thesis without publication year restrictions. References were screened and selected based on predefined eligibility criteria by two independent reviewers, according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Clinical outcomes were assessed quantitatively using clinical pain scores, physical examination, imaging examination, questionnaire responses, pain in manipulation, gait analysis, range of joint motion, and adverse effects. The risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist. Out of 1483 articles, six met the inclusion criteria for qualitative analysis, with two randomized controlled trials and four before-and-after studies. All studies reported significantly better clinical outcomes in the adipose tissue stem cells (ADSC) group with improvements in pain and function and decreased evidence of hip OA. The risk of bias was categorized as high in the before-and-after studies and moderate to high in the randomized studies. The studies were considered heterogeneous owing to clinical results and methodology. Because of this heterogeneity, it was not possible to perform meta-analysis. Assessments of ADSC reports yielded positive clinical effects that showed improvements in pain and function and decreased evidence of hip osteoarthritis. More high-level, larger-cohort dog studies that utilize standardized protocols are needed.

Introduction

Osteoarthritis (OA) is one of the most common hip joint diseases in dogs, as well as knee, shoulder, and elbow and despite the extensive research, the treatment is still limited (Little et al., 2016; Meeson et al., 2019). Besides that, canine hip OA shares pathoanatomical characteristics with developmental dysplasia of the hip (DDH) in humans, and therefore have been proposed as the best spontaneous animal model for joint problems (Harman et al., 2016; Meeson et al., 2019). Although the exact cause of OA is not known, it is associated with environmental and genetic factors, such as obesity, age, and dysplasia (Marx et al., 2014). OA is characterized by progressive degeneration of the articular cartilage, synovial inflammation, insufficient repair response, joint space narrowing, and, finally, joint destruction (Cuervo et al., 2014; Marx et al., 2014; Srzentić Dražilov et al., 2018; Vilar et al., 2016; Vilar et al., 2014). It is a major clinical problem, particularly for dogs, since it affects around 20% of these animals (Guercio et al., 2012; Harman et al., 2016). Severe OA causes chronic pain, stiffness of the joint, leading to significantly reduced joint function (Cuervo et al., 2014; Kriston-Pál et al., 2017; Marx et al., 2014; Olsen et al., 2019; Pers and Jorgensen, 2013) with decreased quality of life (Shah et al., 2018). Since the regeneration is limited, current therapeutic approaches are palliative and include physical therapy, weight reduction, oral and injectable medications (Marx et al., 2014; Shah et al., 2018).The diagnosis of hip OA mainly depends on the detailed history of the patient (Cuervo et al., 2014; Pers and Jorgensen, 2013; Rodríguez-Jiménez et al., 2012), together with a complete physical examination (Agung et al., 2006; Vilar et al., 2016). Complementary diagnostic tests can be performed when the diagnosis remains uncertain with clinical features (Cuervo et al., 2014; Marx et al., 2014; Srzentić Dražilov et al., 2018), imaging (Cuervo et al., 2014; Marx et al., 2014; Shah et al., 2018; Vilar et al., 2016), and laboratory testing (Marx et al., 2014). Pain intensity is difficult to accurately assess in dogs, but veterinarians use scoring systems based on various signals, including patient vocalization, activity level, degree of lameness, and reaction to manipulation. In this sense, a variety of multidimensional scales was created for animals from a library of words that humans use to describe their experience of pain. However, in animals, this language is described by the veterinarian and by the tutors' observations after their examination using questionnaires and different scores, and sometimes without standardization. These scales provide quantitative assessments of clinical pain that can provide scores considering the sensory and affective qualities of pain, lameness, and joint movement, in addition to their intensity (Holton et al., 2001). However, all of these signals are subjective and can be influenced by a variety of external factors like fear and stress (Bernardo and Fibbe, 2013; Cuervo et al., 2014; Harman et al., 2016; Mifune et al., 2013; Pers and Jorgensen, 2013).

In cases of moderate and advanced hip OA, where palliative interventions are insufficient, surgical intervention, such as osteotomy, is performed as the last approach. Novel therapeutic options have focused on reversing the pathophysiology of OA, including cartilage repair. In this sense, regenerative medicine, in particular, has brought new approaches to repair damaged cartilage in joints, as demonstrated by several research articles and clinical trials focusing on the role of mesenchymal stem cells (MSC) and chondrocytes in treating OA (Cuervo et al., 2014; Kriston-Pál et al., 2017; Marx et al., 2014; Srzentić Dražilov et al., 2018). MSC have garnered significant attention because of their self-renewal properties, multilineage differentiation potential, immunomodulatory capacity, and anti-inflammatory potential (Cuervo et al., 2014; Harman et al., 2016; Olsen et al., 2019; Srzentić Dražilov et al., 2018; Vilar et al., 2016). In veterinary medicine, previous studies have shown clinical improvement in dogs with orthopedic conditions after autologous and/or allogeneic adipose tissue stem cells (ADSC) therapy (Harman et al., 2016; Vilar et al., 2014; Zuk et al., 2001). As a result, ADSC have been characterized as promising for the treatment of OA (Guercio et al., 2012; Jorgensen and Noël, 2012; Kriston-Pál et al., 2017; Shah et al., 2018). Morever, a previous narrative review showed the effectiveness that MSC in OA treatment and suggested their use for patients resistant to standard treatments (de Bakker et al., 2013; Shah et al., 2018). Therefore, establishing the start, duration and efficacy of ADSC therapy in canine OA is important (Harman et al., 2016; Marx et al., 2014; Vilar et al., 2016). Besides, this is the first systematic review of in vivo studies concerning the therapeutic potential of single intra-articular administration ADSC in hip join OA in dogs.

Section snippets

Protocol and registration

A systematic review protocol based on PRISMA-P was prepared and registered in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42020141513. This systematic review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis checklist (PRISMA) (Shamseer et al., 2015).

Inclusion criteria

The question was formulated using the acronym PICOS (Population, Intervention, Comparison, Outcomes, Studies design) in which P) = dogs with hip

Results

The studies were considered heterogeneous for clinical (differences about participants, type of interventions and results) and methodological (design and risk of bias) reasons and therefore, the meta-analysis was not justified. To clarify the qualitative results, studies were separated into “before-and-after” and “randomized controlled trials”.

Discussion

OA is a degenerative disease with low repair capacity that might affect all joint structures (Cuervo et al., 2014) and is a critical unresolved clinical problem in veterinary medicine (Kong et al., 2017; Marx et al., 2014; Shah et al., 2018; Srzentić Dražilov et al., 2018). Therefore, this review aimed to investigate reliable published evidence to support the efficacy of the use of ADSC for the treatment of dogs with hip OA. Six articles that used intra-articular inoculation of these cells were

Conclusion

Autologous or allogeneic mesenchymal stem cells derived from adipose tissue represent a very promising therapy for hip OA in dogs. The studies analyzed here reported positive effects of ADSC, with improved scores for lameness, pain, and range of motion with a single dose of cells. However, the assessments were performed in a short follow-up period. Therefore, treatment protocols need to include more randomized studies, and results should be evaluated for an extended time.

Declaration of Competing Interest

The authors declare that they have no conflict of interest.

Acknowledgments

This study was supported by the Federal University of Santa Catarina (UFSC), and Federal Institute of Santa Catarina – Concórdia Campus (IFC). BLT received a fellowship from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil). We would like to thank the Brazilian Center for Evidence-based Research (COBE-UFSC), UFSC Librarian (BU-UFSC) Gorete Savi, and the Stem Cell and Tissue Regeneration Laboratory (LACERT-UFSC).

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