COVID-19 orthopaedic trauma volumes: a Canadian experience during lockdown and staged reopening.

OBJECTIVES: The aim of this study is to report the impact of public health measures (PHM), including their relaxation, on surgical orthopaedic trauma volumes. We hypothesize an initial reduction in orthopaedic trauma volumes during lockdown followed by a surge as Stages 1 and 2 of reopening progressed in Summer 2020. METHODS: All unscheduled surgical orthopaedic trauma cases from March through August were retrospectively reviewed in Calgary, Alberta, Canada, from 2008 to 2020. Trauma volumes from 2008 to 2019 were used to model expected 2020 volumes, and multivariable Poisson regression was used to determine the effect of PHM on orthopaedic trauma volumes. RESULTS: A total of 22,331 trauma orthopaedic surgeries were included. During lockdown, there was a significant decrease in trauma volume compared with expected (-14.2%, -25.7 to -10.5%, P < .001) and there were significantly fewer ankle fractures (-17.8%, -30.9 to -2.2%, P = .027). During reopening Stage 2, there was a significant increase in trauma volume (+8.9%, +2.2 to +16.1%, P = .009). There was no change in the incidence of polytrauma, hip fracture, or wrist fracture during the pandemic. CONCLUSIONS: This study provides the first report of a surge in trauma volumes as PHM are relaxed during the COVID-19 pandemic. The ability to predict decreases in trauma volumes with strict PHM and subsequent surges with reopening can help inform operating room time management and staffing in future waves of COVID-19 or infectious disease pandemics. LEVEL OF EVIDENCE: Prognostic - Level III.

Cartilage boundary lubrication synergism is mediated by hyaluronan concentration and PRG4 concentration and structure.

BACKGROUND: Proteoglycan 4 (PRG4) and hyaluronan (HA) are key synovial fluid constituents that contribute synergistically to cartilage boundary lubrication; however, the effects of their concentrations as well as their structure, both of which can be altered in osteoarthritis, on this functional synergism are unknown. The objectives of this study were to evaluate cartilage boundary lubricating ability of 1) PRG4 + HA in solution at constant HA concentration in a range of PRG4 concentrations, 2) constant PRG4 concentration in a range of HA concentrations, 3) HA + reduced/alkylated (R/A) PRG4, and 4) hylan G-F 20 + PRG4. METHODS: Static and kinetic friction coefficients (µ(static,Neq), <µ(kinetic,Neq)>) were measured using a previously characterized cartilage-cartilage boundary mode friction test for the following concentrations of purified PRG4 and HA: Test 1: HA (1.5 MDa, 3.3 mg/mL) + PRG4 from 4.5 - 1500 µg/mL; Test 2: PRG4 (450, 150, 45 µg/mL) + HA (1.5 MDa) from 0.3 - 3.3 mg/mL. Test 3: hylan G-F 20 (3. 3 mg/mL) + PRG4 (450 µg/mL). Test 4: HA (3.3 mg/mL) + R/A PRG4 (450 µg/mL). ANOVA was used to compare lubricants within (comparing 6 lubricants of interest) and between (comparing 3 lubricants of interest) test sequences, with Tukey and Fishers post-hoc testing respectively. RESULTS: This study demonstrates that both PRG4 and HA concentration, as well as PRG4 disulfide-bonded structure, can alter the cartilage boundary lubricating ability of PRG4 + HA solutions. The boundary lubricating ability of high MW HA + PRG4 solutions was limited by very low concentrations of PRG4. Decreased concentrations of high MW HA also limited the cartilage boundary lubricating ability of HA + PRG4 solutions, with the effect exacerbated by low PRG4 concentrations. The reduction of friction by addition of PRG4 to a cross-linked HA viscosupplement product, but not with addition of R/A PRG4 to HA, is consistent with a non-covalent mechanism of interaction where tertiary and quaternary PRG4 structure are important. CONCLUSIONS: Collectively, these results demonstrate that deficiency of either or both PRG4 and HA, or alterations in PRG4 structure, may be detrimental to SF cartilage boundary lubricating function. This study provides further insight into the nature of cartilage boundary lubrication and advancement towards potential formulation of new intra-articular biotherapeutic treatments for osteoarthritis using PRG4 ± HA.

Articular Joint Lubricants during Osteoarthritis and Rheumatoid Arthritis Display Altered Levels and Molecular Species.

BACKGROUND: Hyaluronic acid (HA), lubricin, and phospholipid species (PLs) contribute independently or together to the boundary lubrication of articular joints that is provided by synovial fluid (SF). Our study is the first reporting quantitative data about the molecular weight (MW) forms of HA, lubricin, and PLs in SF from cohorts of healthy donors, patients with early (eOA)- or late (lOA)-stage osteoarthritis (OA), and patients with active rheumatoid arthritis (RA). METHODS: We used human SF from unaffected controls, eOA, lOA, and RA. HA and lubricin levels were measured by enzyme-linked immunosorbent assay. PLs was quantified by electrospray ionization tandem mass spectrometry. Fatty acids (FAs) were analyzed by gas chromatography, coupled with mass spectrometry. The MW distribution of HA was determined by agarose gel electrophoresis. RESULTS: Compared with control SF, the concentrations of HA and lubricin were lower in OA and RA SF, whereas those of PLs were higher in OA and RA SF. Moreover, the MW distribution of HA shifted toward the lower ranges in OA and RA SF. We noted distinct alterations between cohorts in the relative distribution of PLs and the degree of FA saturation and chain lengths of FAs. CONCLUSIONS: The levels, composition, and MW distribution of all currently known lubricants in SF--HA, lubricin, PLs--vary with joint disease and stage of OA. Our study is the first delivering a comprehensive view about all joint lubricants during health and widespread joint diseases. Thus, we provide the framework to develop new optimal compounded lubricants to reduce joint destruction.

Metabolic analysis of knee synovial fluid as a potential diagnostic approach for osteoarthritis.

Osteoarthritis (OA) is a leading cause of chronic joint pain in the older human population. Diagnosis of OA at an earlier stage may enable the development of new treatments to one day effectively modify the progression and prognosis of the disease. In this work, we explore whether an integrated metabolomics approach could be utilized for the diagnosis of OA. Synovial fluid (SF) samples were collected from symptomatic chronic knee OA patients and normal human cadaveric knee joints. The samples were analyzed using (1)H nuclear magnetic resonance (NMR) spectroscopy and gas chromatography-mass spectrometry (GC-MS) followed by multivariate statistical analysis. Based on the metabolic profiles, we were able to distinguish OA patients from the controls and validate the statistical models. Moreover, we have integrated the (1)H NMR and GC-MS results and we found that 11 metabolites were statistically important for the separation between OA and normal SF. Additionally, statistical analysis showed an excellent predictive ability of the constructed metabolomics model (area under the receiver operating characteristic curve = 1.0). Our findings indicate that metabolomics might serve as a promising approach for the diagnosis and prognosis of degenerative changes in the knee joint and should be further validated in clinical settings.

Effects of concentration and structure on proteoglycan 4 rheology and interaction with hyaluronan.

BACKGROUND: The contribution of proteoglycan 4 (PRG4) to synovial fluid and hyaluronan (HA) solution rheology are poorly understood. The effects of PRG4 disulfide-bonded structure on viscosity and viscosity of newly available full-length recombinant human PRG4 (rhPRG4) have not previously been reported. OBJECTIVE: This study determined the viscosity of PRG4 and rhPRG4, R/A (reduced and alkylated) PRG4 and rhPRG4, and PRG4 and rhPRG4+HA solutions. METHODS: Steady shear viscosities of 1.5 MDa HA, PRG4 from bovine cartilage explant culture, rhPRG4 and (rh)PRG4+HA solutions were measured with 40 mm parallel plate fixtures. RESULTS: PRG4 demonstrated shear-dependent viscosity at high concentrations, but Newtonian behaviour at low concentrations and when disulfide-bonded/multimeric structure was disrupted by R/A. rhPRG4 demonstrated Newtonian behaviour over all concentrations tested and upon R/A. At high HA concentrations, rhPRG4 reduced solution viscosity, suggesting a binding interaction. At low HA concentrations, solution viscosity was increased relative to HA alone, possibly due to self-association of rhPRG4. Effects of PRG4 on HA solution viscosity were dependent on PRG4's disulfide-bonded structure. CONCLUSIONS: The finding that rhPRG4 can increase the viscosity of low concentration HA solutions suggests that supplementation with rhPRG4 may help mitigate the loss in synovial fluid viscosity experienced with decreased HA concentration in osteoarthritis.

Characterization of proteoglycan 4 and hyaluronan composition and lubrication function of ovine synovial fluid following knee surgery.

The objective of this study was to determine changes in (1) proteoglycan 4 (PRG4) and hyaluronan (HA) concentration, (2) HA molecular weight (MW) distribution, and (3) cartilage boundary lubricating ability of synovial fluid (SF) from surgical sham (SHAM), anterior cruciate ligament (ACL)/medial collateral ligament (MCL) transection, and lateral meniscectomy (MEN) in a post-knee surgery ovine model. Ovine SF (oSF) was collected at euthanization 20 weeks after surgery, with the contralateral joint serving as the non-operative control. PRG4 and HA concentration in oSF was measured by sandwich enzyme-linked immunosorbent assay, and HA MW distribution by agarose gel electrophoresis. Cartilage boundary lubricating ability of oSF was measured by a cartilage-cartilage friction test. PRG4 and HA concentration in SHAM, ACL/MCL, and MEN oSF were similar in comparison to the contralateral control (CTRL) oSF. The HA MW distribution in the operated oSF for all ranges were similar to the respective CTRL oSF. The kinetic coefficients of friction in operated and CTRL oSF were similar in all groups, and were significantly lower than saline. These results indicate oSF lubricant composition and function at 20 weeks post-knee surgery were similar to contralateral CTRL, and suggest earlier time points post surgery warrant further investigation.

Diminished cartilage-lubricating ability of human osteoarthritic synovial fluid deficient in proteoglycan 4: Restoration through proteoglycan 4 supplementation.

OBJECTIVE: The purposes of this study were 1) to quantify the proteoglycan 4 (PRG4) and hyaluronan (HA) content in synovial fluid (SF) from normal donors and from patients with chronic osteoarthritis (OA) and 2) to assess the cartilage boundary-lubricating ability of PRG4-deficient OA SF as compared to that of normal SF, with and without supplementation with PRG4 and/or HA. METHODS: OA SF was aspirated from the knee joints of patients with symptomatic chronic knee OA prior to therapeutic injection. PRG4 concentrations were measured using a custom sandwich enzyme-linked immunosorbent assay (ELISA), and HA concentrations were measured using a commercially available ELISA. The molecular weight distribution of HA was measured by agarose gel electrophoresis. The cartilage boundary-lubricating ability of PRG4-deficient OA SF, PRG4-deficient OA SF supplemented with PRG4 and/or HA, and normal SF was assessed using a cartilage-on-cartilage friction test. Two friction coefficients (µ) were calculated: static (µ(static, Neq) ) and kinetic (<µ(kinetic, Neq) >) (where N(eq) represents equilibrium axial load and angle brackets indicate that the value is an average). RESULTS: The mean ± SEM PRG4 concentration in normal SF was 287.1 ± 31.8 µg/ml. OA SF samples deficient in PRG4 (146.5 ± 28.2 µg/ml) as compared to normal were identified and selected for lubrication testing. The HA concentration in PRG4-deficient OA SF (mean ± SEM 0.73 ± 0.08 mg/ml) was not significantly different from that in normal SF (0.54 ± 0.09 mg/ml). In PRG4-deficient OA SF, the molecular weight distribution of HA was shifted toward the lower range. The cartilage boundary-lubricating ability of PRG4-deficient OA SF was significantly diminished as compared to normal (mean ± SEM <µ(kinetic, Neq) > = 0.043 ± 0.008 versus 0.025 ± 0.002; P < 0.05) and was restored when supplemented with PRG4 (<µ(kinetic, Neq) > = 0.023 ± 0.003; P < 0.05). CONCLUSION: These results indicate that some OA SF may have decreased PRG4 levels and diminished cartilage boundary-lubricating ability as compared to normal SF and that PRG4 supplementation can restore normal cartilage boundary lubrication function to these OA SF.