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Multiple biological therapies for orthopedic injuries are marketed to veterinarians, despite a lack of rigorous comparative biological activity data to guide informed decisions in selecting a most effective compound. Therefore, the goal of this study was to use relevant bioassay systems to directly compare the anti-inflammatory and immunomodulatory activity of three commonly used orthobiological therapies (OTs): mesenchymal stromal cells (MSC), autologous conditioned serum (ACS), and platelet rich plasma (PRP). Equine monocyte-derived macrophages were used as the readout system to compare therapies, including cytokine production and transcriptomic responses. Macrophages were stimulated with IL-1ß and treated 24 h with OTs, washed and cultured an additional 24 h to generate supernatants. Secreted cytokines were measured by multiplex immunoassay and ELISA. To assess global transcriptomic responses to treatments, RNA was extracted from macrophages and subjected to full RNA sequencing, using an Illumina-based platform. Data analysis included comparison of differentially expressed genes and pathway analysis in treated vs. untreated macrophages. All treatments reduced production of IL-1ß by macrophages. Secretion of IL-10 was highest in MSC-CM treated macrophages, while PRP lysate and ACS resulted in greater downregulation of IL-6 and IP-10. Transcriptomic analysis revealed that ACS triggered multiple inflammatory response pathways in macrophages based on GSEA, while MSC generated significant downregulation of inflammatory pathways, and PRP lysate induced a mixed immune response profile. Key downregulated genes in MSC-treated cultures included type 1 and type 2 interferon response, TNF-α and IL-6. PRP lysate cultures demonstrated downregulation of inflammation-related genes IL-1RA, SLAMF9, ENSECAG00000022247 but concurrent upregulation of TNF-α, IL-2 signaling, and Myc targets. ACS induced upregulation of inflammatory IL-2 signaling, TNFα and KRAS signaling and hypoxia, but downregulation of MTOR signaling and type 1 interferon signaling. These findings, representing the first comprehensive look at immune response pathways for popular equine OTs, reveal distinct differences between therapies. These studies address a critical gap in our understanding of the relative immunomodulatory properties of regenerative therapies commonly used in equine practice to treat musculoskeletal disease and will serve as a platform from which further comparisons may build.

Background The frequency of surgical site infection (SSI) following orthopaedic implant placement in horses has been reported but not compared with respect to specific antibiotic protocols administered. Objectives To determine factors associated with SSI in horses undergoing proximal interphalangeal joint (PIPJ) arthrodesis including perioperative antibiotic protocols. Methods Records were evaluated (2010–2019), and horses undergoing PIPJ arthrodesis were identified. Patient signalment, supervising surgeon, reason for surgery, limb, implants placed, anaesthetic time, duration casting/coaptation postoperatively, antibiotic regimen and incidence/onset SSI were recorded. Bayesian and frequentist logistic regressions were used to estimate the contribution of covariates to infection occurrence. Results Fifty‐four PIPJ arthrodeses were performed. SSI occurred in 2/54 (3.7%) on day 15,30. Arthrodesis was performed most commonly for osteoarthritis (33/54, 61.1%), fracture (11/54, 20.4%), and subluxation (5/54, 9.3%). Perioperative systemic antibiotics were administered 1–3 days (15/54, 27.8%) or > 3 days (39/54, 72.2%). Antibiotic protocols included cefazolin/gentamicin (20/54, 37%), cefazolin/gentamicin/doxycycline (14/54, 25.9%) and potassium penicillin/gentamicin (10/54, 18.5%). Regional limb perfusion was performed preoperatively 31/54 (57.4%) and postoperatively 7/54 (13%). Survival to dismissal was 98.1% (53/54 horses) with one horse euthanized due to support limb laminitis. No association was identified between antibiotic selection or duration (1–3 vs. > 3 days), pre‐operative regional antibiotic perfusion, intraoperative antibiotic lavage or anaesthetic time (< or > 3 h) and SSI; however, modelling was complicated by quasi‐complete or complete separation of the data. Bayesian analysis (but not frequentist analysis) indicated an association between post‐operative regional antibiotic perfusion and SSI. Limitations include the retrospective nature of data collection and the low rate of infection overall. Conclusions The prevalence of SSI in this population was lower than that in previous reports of equine orthopaedic internal fixation. There was no difference in SSI rate in cases administered systemic antibiotics for 1–3 days or >3 days, or for those horses that did or did not receive preoperative regional antibiotic perfusion. The frequency of surgical site infection (SSI) following orthopedic implant placement in horses has been reported but not compared with respect to specific antibiotic protocols administered. The objective of this study was determine factors assocaited with SSI in horses undergoing proximal interphalangeal joint arthrodesis including perioperative antibiotic protocols. No association was identified between antibiotic selection or duration, pre‐operative regional antibiotic perfusion, intraoperative antibiotic lavage or anaesthetic time and SSI.

Background Prophylactic perioperative antimicrobial protocols in equine synovial endoscopy have been described but not compared with respect to post‐operative outcomes and complications. Increasing antimicrobial resistance in equine practice and interest in promoting judicious use of antimicrobials has prompted reevaluation of drug selection and dosing strategies. Objectives To determine the frequency of and compare post‐operative complications following elective synovial endoscopy between horses receiving different perioperative antimicrobial protocols. Methods Records from the Colorado State University Veterinary Teaching Hospital were evaluated (2014–2018) and equine patients undergoing elective synovial endoscopy were identified. Patients undergoing endoscopy for sepsis or internal fixation were excluded. Patient signalment, clinician, joint and limb involved, perioperative antimicrobial regimen, number endoscopic portals and closure technique, and post‐operative complications including incidence of joint infection were recorded. Generalized linear models were used to estimate the odds of post‐operative complications. Results Elective synovial endoscopies of 516 horses in 537 procedures evaluating 761 synovial structures were performed. No horses developed post‐operative septic synovitis. Administration of post‐operative antimicrobials, type used and patient sex were all significantly associated with increased risk of complications, which were predominantly gastrointestinal‐related. Complication rates in horses receiving a single preoperative dose of cefazolin were lower than in horses receiving potassium penicillin, gentamicin or multiple doses. Complication rates were lower in females compared to castrated or intact males. Other factors evaluated (breed, age, surgeon, anaesthesia duration or hospitalization, joint/limb operated, number endoscopic portals) were not associated with increased risk of complications post‐operatively in this case population. Conclusions Prophylactic perioperative antimicrobial protocols in equine practice deserve periodic reconsideration due to increased antimicrobial resistance. Prolonged antimicrobial usage beyond the time of surgery was unnecessary to prevent septic synovitis following synovial endoscopy in this case population and was furthermore associated with an increased risk of gastrointestinal complications. Prophylactic perioperative antimicrobial protocols in equine practice deserve periodic reconsideration due to increased antimicrobial resistance. Prolonged antimicrobial usage beyond the time of surgery was unnecessary to prevent septic synovitis following synovial endoscopy in this case population and was furthermore associated with an increased risk of gastrointestinal complications.

Septic arthritis causes significant morbidity and mortality in veterinary and human clinical practice and is increasingly complicated by multidrug-resistant infections. Intra-articular (IA) antibiotic administration achieves high local drug concentrations but is considered off-label usage, and appropriate doses have not been defined. Using an equine joint model, we investigated the effects of amikacin injected at three different doses (500, 125, and 31.25 mg) on the immune and cartilage responses in tibiotarsal joints. Synovial fluid (SF) was sampled at multiple time points over 24 h, the cell counts determined, and amikacin concentrations measured by liquid chromatography-mass spectrometry. Cytokine concentrations and collagen degradation products in SF were measured by ELISA and multiplex immunoassays. The mean amikacin concentrations in SF were greater than or equal to the minimum inhibitory concentration (MIC) (0.004 mg/ml) for most common equine joint pathogens at all time points tested to 24 h for all three amikacin doses evaluated. The inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) increased significantly in SF in the highest amikacin dose group, despite the fact that increases in SF cell counts were not observed. Similarly, the biomarkers of cartilage type II collagen cleavage (C2C and C12C) were increased in SF following amikacin injection. Mechanistically, we further demonstrated using in vitro studies that chondrocytes and synoviocytes killed by exposure to amikacin underwent apoptotic cell death and were phagocytosed by macrophages in a non-inflammatory process resembling efferocytosis. Neutrophils and T cells were susceptible to amikacin cytotoxicity at clinically relevant doses, which may result in blunting of cellular inflammatory responses in SF and account for the lack of increase in total nucleated cell counts following amikacin injection. In summary, decisions on whether to inject cytotoxic antibiotics such as aminoglycosides intra-articularly and what doses to use should take into account the potential harm that antibiotics may cause and consider lower doses than those previously reported in equine practice.