Purpose: We have isolated pluripotent mesenchymal progenitor cells in large numbers from liposuction aspirates (processed lipoaspirate cells or PLAs). This study examines the osteogenic potential of PLAs and bone marrow aspirate cells (BMAs), when exposed to either recombinant human bone morphogenetic protein (BMP)‐2 (rh‐BMP‐2) or adenovirus containing BMP‐2 cDNA (Ad‐BMP‐2).Methods: Liposuction aspirates underwent proteolytic digestion to obtain PLAs. After exposure to exogenous rh‐BMP‐2 or Ad‐BMP‐2 for four or seven days, PLAs and BMAs were assessed by histochemistry, spectrophotometry and RT‐PCR. Western blotting and ELISA confirmed BMP gene transduction. Results were compared to osteoblasts and cells in osteogenic media only. PLA‐Ad‐BMP‐2 cells were seeded on matrices and implanted in the hind limbs of SCID mice.Results: Analysis of quantified bone precursor assays including extracellular ALP histomorphometry, intracellular ALP spectrophotometry, and calcified extracellular matrix (von Kossa) histomorphometry revealed that PLAs treated with exogenous rh‐BMP‐2 or transduced with a BMP‐2 containing adenovirus (PLA‐Ad‐BMP‐2) produced more bone precursors than osteoblasts (p = 0.001). PLAs treated with exogenous rh‐BMP‐2 or PLA‐Ad‐BMP‐2 also produced more bone precursors than BMAs (p = 0.001), except for day 7 ALP histomorphometry (p = 0.343). ELISA confirmed successful BMP‐2 production by both progenitor cell groups transduced with Ad‐BMP‐2. H&E sections from collagen I matrices seeded with PLA‐Ad‐BMP‐2 cells confirmed bone formation at six weeks.Conclusions: Liposuction aspirates contain PLAs that can be transfected with the BMP‐2 gene, with rapid induction into the osteoblast phenotype at a rate comparable to rh‐BMP‐2 and osteoblast groups. Transduced PLAs produce more bone precursors with faster onset of calcified extracellular matrix than transduced BMAs. PLAs may be an ideal source of mesenchyme‐lineage stem cells for gene therapy and tissue engineering. © 2003 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.

Background: Intra-articular corticosteroids relieve osteoarthritis pain, but rapid systemic absorption limits efficacy. FX006, a novel, microsphere-based, extended-release triamcinolone acetonide (TA) formulation, prolongs TA joint residence and reduces systemic exposure compared with standard TA crystalline suspension (TAcs). We assessed symptomatic benefits and safety of FX006 compared with saline-solution placebo and TAcs. Methods: In this Phase-3, multicenter, double-blinded, 24-week study, adults ≥40 years of age with knee osteoarthritis (Kellgren-Lawrence grade 2 or 3) and average-daily-pain (ADP)-intensity scores of ≥5 and ≤9 (0 to 10 numeric rating scale) were centrally randomized (1:1:1) to a single intra-articular injection of FX006 (32 mg), saline-solution placebo, or TAcs (40 mg). The primary end point was change from baseline to week 12 in weekly mean ADP-intensity scores for FX006 compared with saline-solution placebo. Secondary end points were area-under-effect (AUE) curves of the change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with saline-solution placebo, AUE curves of the change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with TAcs, change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with TAcs, and AUE curves of the change in weekly mean ADP-intensity scores from baseline to week 24 for FX006 compared with saline-solution placebo. Exploratory end points included week-12 changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Knee Injury and Osteoarthritis Outcome Score Quality of Life (KOOS-QOL) subscale scores for FX006 compared with saline-solution placebo and TAcs. Adverse events were elicited at each inpatient visit. Results: The primary end point was met. Among 484 treated patients (n = 161 for FX006, n = 162 for saline-solution placebo, and n = 161 for TAcs), FX006 provided significant week-12 improvement in ADP intensity compared with that observed for saline-solution placebo (least-squares mean change from baseline: −3.12 versus −2.14; p < 0.0001) indicating ∼50% improvement. FX006 afforded improvements over saline-solution placebo for all secondary and exploratory end points (p < 0.05). Improvements in osteoarthritis pain were not significant for FX006 compared with TAcs using the ADP-based secondary measures. Exploratory analyses of WOMAC-A, B, and C and KOOS-QOL subscales favored FX006 (p ≤ 0.05). Adverse events were generally mild, occurring at similar frequencies across treatments. Conclusions: FX006 provided significant, clinically meaningful pain reduction compared with saline-solution placebo at week 12 (primary end point). Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

➤ The selection of an agent for prophylaxis against venous thromboembolism (VTE) is a balance between efficacy and safety. The goal is to prevent symptomatic VTE while limiting the risk of bleeding. ➤ The optimal agent for VTE prophylaxis has not been identified. The American College of Chest Physicians guidelines recommend that, after total hip or total knee arthroplasty, patients receive at least 10 to 14 days of 1 of the following prophylaxis agents: aspirin, adjusted-dose vitamin K antagonist, apixaban, dabigatran, fondaparinux, low-molecular-weight heparin, low-dose unfractionated heparin, rivaroxaban, or portable home mechanical compression. ➤ The use of aspirin for VTE prophylaxis has increased in popularity over the past decade because it is effective, and it is an oral agent that does not require monitoring. The true efficacy of aspirin needs to be determined in multicenter randomized clinical trials. ➤ Validated risk stratification protocols are essential to identify the safest and most effective regimen for VTE prophylaxis for individual patients. There is no consensus regarding the optimal method for risk stratification; the selection of a prophylaxis agent should be determined by shared decision-making with the patient to balance the risk of thrombosis versus bleeding. ➤ Patients with atrial fibrillation being treated with chronic warfarin therapy or direct oral anticoagulants should stop the agent 3 to 5 days prior to surgery. Patients do not typically require bridging therapy prior to surgery.

Cal-sized femoral defect in rats. Methods: Critical-sized femoral defects were created in Lewis rats, and the rats were randomized into four groups. The sclerostin antibody (Scl-Ab) treatment groups included the continuous Scl-Ab group (twenty-one animals), the early Scl-Ab group (fifteen animals), and the delayed Scl-Ab group (fifteen animals), which received sclerostin antibody (25 mg/kg) twice weekly for weeks 0 through 12; weeks 0 through 2; and weeks 2 through 4; respectively. Twenty-one animals in the control group received vehicle from weeks 0 through 12. In a subsequent study, bone turnover markers were measured at zero, two, six, and twelve weeks after surgery in rats receiving vehicle or sclerostin neutralizing antibody for twelve weeks (fifteen rats per group). The quality of bone formed was evaluated with radiographs, microcomputed tomography, biomechanical testing, and histologic and histomorphometric analysis. Results: In the primary study, four of fifteen defects in the continuous (zero to twelve-week) Scl-Ab group, three of fifteen defects in the early (zero to two-week) Scl-Ab group, and four of fifteen defects in the delayed (two to four-week) Scl-Ab group healed at twelve weeks, while none of the defects healed in the control group. In both studies, treatment with sclerostin antibody for twelve weeks demonstrated a significant increase in new bone formation (p < 0.05) compared with the control group. The three treatment groups did not differ significantly with respect to the healing rates and the quality of new bone formed in the defect. The serum markers of bone formation were significantly elevated in the animals in the continuous Scl-Ab group (p < 0.05) compared with the controls. Conclusions: Administration of sclerostin neutralizing antibody led to increased bone formation, resulting in complete healing of femoral defects in a small subset of rats, with a majority of the animals not healing the defect by twelve weeks. Clinical Relevance: Sclerostin neutralizing antibody is a systemically delivered agent that exerts an anabolic effect during fracture repair and has the potential to be used as an adjuvant to enhance bone-healing in difficult bone-repair scenarios....

The management and definitive treatment of segmental bone defects in the setting of acute trauma, fracture non-union, revision joint arthroplasty, and tumor surgery are challenging clinical problems with no consistently satisfactory solution. Orthopaedic surgeons are developing novel strategies to treat these problems, including three-dimensional (3D) printing combined with growth factors and/or cells. This article reviews the current strategies for management of segmental bone loss in orthopaedic surgery, including graft selection, bone graft substitutes, and operative techniques. Furthermore, we highlight 3D printing as a technology that may serve a major role in the management of segmental defects. The optimization of a 3D-printed scaffold design through printing technique, material selection, and scaffold geometry, as well as biologic additives to enhance bone regeneration and incorporation could change the treatment paradigm for these difficult bone repair problems.