Clinically relevant redifferentiation of fibroblast-like chondrocytes into functional chondrocytes by the low molecular weight fraction of human serum albumin.

OBJECTIVES: Traumatic joint injury induces chondrocyte dysfunction and progressive breakdown of articular cartilage, leading to post-traumatic osteoarthritis (PTOA). In this condition, dysfunctional fibroblast-like chondrocytes (FLCs) no longer express proteins required for cartilage maintenance, such as SOX9 and collagen-type II (COL2). Interleukin-6 (IL-6) has been demonstrated to downregulate expression of these two critical proteins in chondrocytes, and increased IL-6 levels have been measured in patients with PTOA. The <5kDa fraction of human serum albumin (LMWF5A) has been suggested to modulate this pathway, as decreased levels of IL-6 are secreted by immunostimulated LMWF5A-treated macrophages. Our objective was to determine whether LMWF5A induces an in vitro model of FLCs to redifferentiate into functional chondrocytes. METHODS: SOX9 and COL2 were monitored via western blot, and COL2 was detected with immunofluorescence. Aggrecan and IL-6 were quantified by ELISA. Glycosaminoglycan (GAG) levels were quantified with alcian blue. RESULTS: We found that LMWF5A significantly increases the principal cartilage transcription factor SOX9 and the SOX9 target protein COL2 in monolayer-cultured FLCs. Multiple LMWF5A treatments of 3-D pellet FLC cultures over 2wks resulted in a significant decrease in IL-6 and significant increases in the major players of articular cartilage mechanics, aggrecan and highly-sulfated GAGs. CONCLUSIONS: These data support the hypothesis and clinical outcomes of two phase III clinical trials that LMWF5A-treatment induces chondrogenesis and supports functional cartilage. We propose that LMWF5A could maintain articular cartilage integrity in all joints following traumatic injury.

Incidence of total knee replacement subsequent to intra-articular injection of the anti-inflammatory compound LMWF-5A versus saline: a long-term follow-up study to a randomized controlled trial.

BACKGROUND: The disease modifying potential of osteoarthritis therapies are of increasing interest, including their effects on delaying total knee replacement (TKR). To date, there have been no studies to determine the effect of LMWF-5A, a novel anti-inflammatory compound derived from human serum albumin, on delaying TKR. METHODS: We evaluated time to TKR three years after patients participated in a randomized trial of three intra-articular injections of LMWF-5A or saline. Patients were contacted via last known phone number and were asked to participate in a short nine item telephone questionnaire; verbal consent was obtained. The primary endpoint was incidence of TKR (%). RESULTS: In total, 39 of 45 patients responded (87% response rate). The overall incidence of TKR was 38.5% (15/39). TKR rates were higher in patients with more severe osteoarthritis defined by Kellgren-Lawrence grade 4, compared to patients with moderate osteoarthritis defined by Kellgren-Lawrence grade 3 (56% vs. 26%, p = 0.06). Overall, there were no differences in TKR rates by treatment arm (39% LMWF-5A vs. 38% saline, p = 0.92). In the severe osteoarthritis subset (n = 16), treatment with LMWF-5A resulted in a lower incidence of TKR compared to saline vehicle arm (40% vs. 83%, p = 0.15). TKR rates were significantly lower with LMWF-5A in patients who responded to treatment (14% with LMWF-5A, vs. 100% with saline, p = 0.03). CONCLUSION: This study demonstrates significant delays in TKR for patients with severe osteoarthritis treated with LMWF-5A, suggesting that LMWF-5A has the potential to provide structure modifying/preserving therapy in this population.

Is after-hours orthopaedic surgery associated with adverse outcomes? A prospective comparative study.

BACKGROUND: Treatment of fractures is sometimes performed after normal daytime operating hours and in such instances may be performed under less than ideal conditions. The consequence of performing operations under such conditions is largely unknown and was therefore studied in the context of intramedullary nail fixation of tibial and femoral shaft fractures. METHODS: Two hundred and three consecutive patients with either a femoral or tibial shaft fracture (Orthopaedic Trauma Association classification 32 or 42) treated with intramedullary nail fixation were included in a prospective, multicenter, nonrandomized study. Patients were divided into an after-hours group defined as an operation beginning from 4:00 P.M. to 6:00 A.M. or a daytime group defined as an operation beginning from 6:00 A.M. to 4:00 P.M. These groups were further divided on the basis of the injured bone into the following subgroups: after-hours femoral fracture (fifty-five patients), daytime femoral fracture (forty-four patients), after-hours tibial fracture (forty-eight patients), and daytime tibial fracture (fifty-six patients). The demographic and fracture characteristics were similar among the subgroups. All patients were treated with the same type of femoral antegrade, femoral retrograde, or tibial nail fixation with reaming. Data for fracture-healing, complications, operative time, and fluoroscopy time were collected prospectively. RESULTS: The healing rates were similar between daytime and after-hours surgery groups for both the tibial and femoral nailing. On the basis of univariate analysis, operative times were shorter in the after-hours group compared with the daytime group for both the tibial and femoral nail fixation groups (p < 0.02), but regression analysis failed to identify time of surgery as an independent variable associated with operative time. Radiation exposure was similar for the after-hours group and the daytime group for both tibial and femoral nail fixation (p > 0.05). The after-hours group had more unplanned reoperations than the daytime group (p < 0.02). Removal of painful hardware was more frequent in the after-hours femoral fracture group (27%) than in the daytime femoral fracture group (3%) (p < 0.02), and after-hours surgery was an independent variable associated with the need for removal of painful femoral fracture hardware (p < 0.05). CONCLUSIONS: Rates of nonunion, infectious complications, and radiation exposure are similar for after-hours and daytime surgery for intramedullary nail fixation of both femoral and tibial fractures. After-hours femoral nail fixation was associated with an increased frequency for removal of painful hardware, which may be related to technical errors associated with nonideal conditions and shorter operative times. An increase in the allocated amount of daytime operative time for orthopaedic trauma surgery has the potential to reduce minor complication rates for intramedullary nail fixation.

Results of femoral intramedullary nailing in patients who are obese versus those who are not obese: a prospective multicenter comparison study.

OBJECTIVES: Antegrade femoral nailing through a piriformis fossa starting point in patients who are obese has been demonstrated to be problematic. Retrograde femoral nailing therefore has been advocated in this patient population, but little data exist to support such a recommendation. The purpose of this study was to evaluate and compare antegrade and retrograde femoral nailing technique in both patients who are and are not obese. DESIGN: Prospective, multicenter, nonrandomized, internal review board (IRB)-approved study. SETTING: Four Level 1 trauma centers. PATIENTS: Patients (151) with a femoral shaft fracture (OTA 32) treated with intramedullary nailing were studied. Thirty-two with a body mass index (BMI) of >or=30 comprised the obese group (OG), and 119 with a BMI of <30 comprised the nonobese group (NOG). Antegrade nailing was performed in 15 patients from the OG and 84 from the NOG. Retrograde nailing was performed in 17 patients from the OG and 35 from the NOG. INTERVENTION: Reamed intramedullary nailing of a femoral shaft fracture. MAIN OUTCOME MEASURES: Patient and fracture characteristics, operative time, fluoroscopy time, healing, complications, and functional outcome based on the lower extremity measure (LEM) were evaluated. RESULTS: Antegrade technique in the OG was associated with a 52% greater average operative time (94 minutes) compared with antegrade nailing in the NOG (62 minutes; P < 0.003). For retrograde nailing technique, there was no difference in the average operative time between the OG (67 minutes) and NOG (62 minutes; P = 0.51). Antegrade technique in the OG was associated with a 79% greater average radiation exposure time (247 seconds) compared with antegrade nailing in the NOG (135 seconds; P < 0.03). For retrograde nailing technique, average fluoroscopy time was similar between the OG (76 seconds) and the NOG (63 seconds; P = 0.44). Within the OG, antegrade nailing required 40% greater average operative time (94 minutes versus 67 minutes, P < 0.02) and more than 3 times more average fluoroscopy time (242 seconds versus 76 seconds, P < 0.002) than retrograde nailing. Thirty-eight patients from the original cohort were not available for follow-up. Of the 113 patients followed (average 9 months, range: 4 to 25 months), healing complications occurred similarly between the 2 groups, with 1 nonunion and 2 delayed unions in the OG (12%), and 3 nonunions and 9 delayed unions in the NOG (14%). CONCLUSIONS: This study provides evidence, in the form of decreased operative and radiation exposure times, to support the use of retrograde nailing technique for the treatment of femoral shaft fractures in patients who are obese. Also, antegrade nailing was found to require significantly more operative and radiation exposure time in the patient who is obese as opposed to the patients who is not obese. Although having similar baseline functional scores, patients who are obese recovered at a slower rate and more incompletely than patients who are not obese.