David C. Ayers

The prevention of heterotopic ossification in high-risk patients by low-dose radiation therapy after total hip arthroplasty.

A prospective study was done to evaluate the efficacy of treatment with 1,000 rads of radiation in the prevention of heterotopic ossification after total hip arthroplasty in patients who are at high risk. In a previous prospective study, patients who were at high risk for heterotopic ossification after total hip arthroplasty were identified and an effective regimen for its prevention was established. It was demonstrated that treatment with 2,000 rads of radiation that was initiated within four days after the total hip arthroplasty was highly effective in the prevention of heterotopic ossification and in the prevention of recurrence after resection of existing ossification. In the present study, 1,000 rads of radiation was administered in increments of 200 rads over a period of five to seven days and was as effective as treatment with 2,000 rads. The protocol of 1,000 rads is preferable because it reduces the risk of malignancy and the duration of hospitalization.

Instructional Course Lectures, The American Academy of Orthopaedic Surgeons - Common Complications of Total Knee Arthroplasty*†

The success of a total joint arthroplasty is contingent on a clear understanding of the potential complications of the procedure. This Instructional Course Lecture presents a review of specific problems related to wound-healing, neurovascular injuries, infections, thromboembolic disease, the extensor mechanism, stiffness, and periprosthetic fractures to provide the reader with a clear understanding of ways to avoid and treat these common complications. Primary wound-healing is critical for the success of any total knee arthroplasty. Any delay in wound-healing increases the risk of infection and failure of the arthroplasty214,216. The prevention of soft-tissue problems through the selection of the proper skin incision, an understanding of the vascular anatomy and patient-related risk factors, and prompt treatment of wound problems (should they arise) are imperative if a good result is to be achieved. ### Vascular Anatomy The blood supply to the soft tissues of the anterior aspect of the knee is completely random, with contributions from multiple vessels2,23,43,161,203,258,295. This blood supply arises predominantly from the terminal branches of the peripatellar anastomotic arterial ring, which has numerous contributing arterial branches, including the medial and lateral superior genicular arteries, the medial and lateral inferior genicular arteries, the supreme genicular artery, the anterior tibial recurrent artery, and a branch of the profunda femoris artery. In contrast to the skin circulation of the thigh proximal to the knee, there is no underlying muscle or intermuscular septum directly anterior to the knee to provide a direct pathway for arterial perforators43,161. Skin circulation in this area is dependent on the dermal plexus, which originates directly from arterioles traveling within the subcutaneous fascia. Any operative dissection performed superficial to this subcutaneous fascia disrupts the arterial supply to the skin and increases …

Prevention of Deep-Vein Thrombosis after Total Hip Arthroplasty. Comparison of Warfarin and Dalteparin*

The effectiveness and safety of warfarin were compared with those of a low-molecular-weight heparin (dalteparin) for the prevention of deep-vein thrombosis after total hip arthroplasty in a prospective, randomized, multi-institutional trial. Patients who were older than eighteen years of age and were scheduled to have an elective primary or revision total hip arthroplasty were eligible; 580 patients were randomized, 550 had the operation and received prophylaxis, and 382 had evaluable venograms. Prophylaxis was provided either with warfarin beginning the night before the operation or with dalteparin beginning two hours before the operation and was continued until venography was performed. Bleeding was assessed on the basis of intraoperative blood loss, transfusion requirements, a decrease in hematocrit, and clinically identified bleeding complications. The prevalence of deep-vein thrombosis was found to be significantly lower in the patients who had received dalteparin than in those who had received warfarin (twenty-eight [15 per cent] of 192 patients compared with forty-nine [26 per cent] of 190 patients; p = 0.006). Deep-vein thrombosis occurred in the calf veins of twenty-one patients (11 per cent) who had received dalteparin and of forty-three patients (23 per cent) who had received warfarin; this difference was significant (p = 0.003). Proximal deep-vein thrombosis occurred in ten patients (5 per cent) who had received dalteparin and in sixteen patients (8 per cent) who had received warfarin; however, with the numbers available, no significant difference could be detected (p = 0.185). We also could not detect a significant difference with regard to the intraoperative and postoperative blood loss, the decrease in hematocrit, and the prevalence of major bleeding complications between the two groups; however, the patients who had received dalteparin had a significantly higher prevalence of bleeding complications involving the operative site (p = 0.03), and a significantly greater percentage required postoperative transfusions (p = 0.001). We concluded that preoperative prophylaxis with dalteparin is significantly more effective than that with warfarin in preventing deep-vein thrombosis after total hip arthroplasty. The greater effectiveness of dalteparin must be considered, however, in light of an increased need for postoperative transfusions and an increase in the prevalence of wound-related bleeding complications.

Secreted frizzled related protein 1 regulates Wnt signaling for BMP2 induced chondrocyte differentiation

Canonical Wnt signaling (β‐catenin/TCF) has emerged as a key regulator of skeletogenesis. In this study, chondrogenesis is examined in a mouse model in which the Wnt antagonist secreted frizzled related protein 1 (sFRP1) is non‐functional and results in a high bone mass phenotype and activation through the canonical pathway of the Runx2 transcription factor that is essential for bone formation. We find during the period of rapid post‐natal growth, shortened height of the growth plate and increased calcification of the hypertrophic zone (HZ) in the sFRP1−/− mouse, indicating accelerated endochondral ossification. Using mouse embryo fibroblasts (MEFs) induced into the chondrogenic lineage, increased chondrogenesis and accelerating differentiation of hypertrophic chondrocytes in the sFRP1−/− MEFs was observed compared to WT cells. The induced maturation of hypertrophic chondrocytes in sFRP1−/− MEFs was inversely correlated to phospho‐β‐catenin levels, indicating involvement of activated canonical Wnt signaling characterized by an increased expression of collagen type 2a1 and Sox 9. However, an absence of Indian hedgehog expression which occurs in WT cells was found. SFRP1−/− cells also exhibited an early induction of collagen type 10a1. Thus, these modifications in gene expression are contributing mechanism(s) for increased chondrocyte differentiation in SFRP1−/− cells. These studies have identified sFRP1 as a critical negative regulator of Wnt signaling for the normal progression of chondrocyte differentiation. Microarray gene profiling provided additional novel insights into the regulatory factors for appropriate Wnt signaling necessary for the control of chondrocyte maturation.

Total knee replacement outcome and coexisting physical and emotional illness

Despite widespread acceptance of total knee replacement surgery’s clinical effectiveness, variation persists in long-term functional outcome. Our aim was to quantify the relative contributions of physical and emotional coexisting conditions to the variation in improvement in 12-month post-total knee replacement physical function. Data from 165 patients who had primary total knee replacement (62% women; mean age 68 years) were evaluated. Eighty-four percent had at least one comorbid illness, with cardiovascular conditions the most prevalent (61%). Mean improvement in 12-month general function (Short Form-36 Physical Component Score) and knee-specific function (Western Ontario and McMaster Universities Osteoarthritis Index) was similar for patients with and without comorbid medical diagnoses. Adding coexisting conditions to age, gender, and baseline physical function did not improve the model’s ability to explain variation in 12-month physical function as measured by either Short Form-36 Physical Component Score or Western Ontario and McMaster Universities Osteoarthritis Index. Although coexisting medical conditions did not predict the degree of 12 month post-total knee replacement functional improvement, poorer pre-total knee replacement emotional health (Short Form-36 Mental Component Score) was associated with smaller improvements in Short Form-36 Physical Component Score and Western Ontario and McMaster Universities Osteoarthritis Index. The lack of a relationship between the presence of coexisting medical diagnoses and 12-month physical function in this study is important for patients and orthopedic surgeons. Level of Evidence: Prognostic study, Level 1 (prospective study). See the Guidelines for Authors for a complete description of levels of evidence.

Periprosthetic osteolysis: Characterizing the innate immune response to titanium wear-particles

Osteolysis of bone following total hip replacement is a major clinical problem. Examination of the areas surrounding failed implants has indicated an increase in the bone‐resorption‐inducing cytokine, interleukin 1β (IL‐1β). NALP3, a NOD‐like receptor protein located in the cytosol of macrophages, signals the cleavage of pro‐IL‐1β into its mature, secreted form, IL‐1β. Here we showed that titanium particles stimulate the NALP3 inflammasome. We demonstrated that titanium induces IL‐1β secretion from macrophages. This response depended on the expression of components of the NALP3 inflammasome, including NALP3, ASC, and Caspase‐1. We also showed that titanium particles trigger the recruitment of neutrophils and that this acute inflammatory response depends on the expression of the IL‐1 receptor and IL‐1α/β. Moreover, administration of the IL‐1 receptor antagonist (IL‐1Ra) diminished neutrophil recruitment in response to titanium particles. Together, these results suggest that titanium particle‐induced acute inflammation is due to activation of the NALP3 inflammasome, which leads to increased IL‐1β secretion and IL‐1‐associated signaling, including neutrophil recruitment. Efficacy of IL‐1Ra treatment introduces the potential for antagonist‐based therapies for implant osteolysis.

Dexamethasone modulates BMP‐2 effects on mesenchymal stem cells in vitro

Dexamethasone/ascorbic acid/glycerolphosphate (DAG) and bone morphogenic protein (BMP)‐2 are potent agents in cell proliferation and differentiation pathways. This study investigates the in vitro interactions between dexamethasone and BMP‐2 for an osteoblastic differentiation of mesenchymal stem cells (MSCs). Bone marrow‐derived human MSCs were cultured with DAG (group A), BMP‐2 + DAG (group B), and DAG + BMP‐2 combined with a porous collagen I/III scaffold (group C). RT‐PCR, ELISA, immuncytochemical stainings and flow cytometry analysis served to evaluate the osteogenic‐promoting potency of each of the above conditions in terms of cell morphology/viability, antigen presentation, and gene expression. DAG induced collagen I secretion from MSCs, which was further increased by the combination of DAG + BMP‐2. In comparison, the collagen scaffold and the control samples showed no significant influence on collagen I secretion of MSCs. DAG stimulation of MSCs led also to a steady but not significant increase of BMP‐2 level. A DAG and more, a DAG + BMP‐2, stimulation increased the number of mesenchymal cells (CD105+/CD73+). All samples showed mRNA of ALP, osteopontin, Runx2, Twist 1 and 2, Notch‐1/2, osteonectin, osteocalcin, BSP, and collagen‐A1 after 28 days of in vitro culture. Culture media of all samples showed a decrease in Ca2+ and PO  42− concentration, whereas a collagen‐I‐peak only occurred at day 28 in DAG‐ and DAG + BMP‐2‐stimulated bone marrow cells. In conclusion, BMP‐2 enhances DAG‐induced osteogenic differentiation in mesenchymal bone marrow cells. Both agents interact in various ways and can modify osteoblastic bone formation.

Prevention of heterotopic ossification in high-risk patients by radiation therapy.

Heterotopic ossification (HO) is a frequent occurrence after cemented and cementless total hip arthroplasty (THA). Patients at risk for this complication include those with preexisting ipsilateral or contralateral HO, diffuse idiopathic skeletal hyperostosis, hypertrophic osteoarthrosis, posttraumatic arthritis, and ankylosing spondylitis. Low-dose radiation therapy effectively prevents HO in this high-risk group when treatment is begun early in the postoperative period. A prospective evaluation has established the efficacy of fractionated and single-dose radiation therapy protocols. Limited radiation portals are used in patients receiving cementless prostheses. A rectangular radiation portal obliquely oriented to the prosthesis enables radiation treatment of the periarticular soft tissues while avoiding exposure of the bone-prosthesis interface. Radiation therapy to this interface may inhibit or delay bony ingrowth. Radiation therapy is the only treatment used to prevent HO that is delivered locally and not systemically. Low-dose radiation therapy using a limited radiation portal is the treatment of choice to prevent HO in high-risk patients after cementless THA.

Blood salvage after total hip arthroplasty.

We performed a prospective, randomized study to determine the effect of postoperative collection and reinfusion of unwashed, filtered, salvaged blood on the transfusion requirements of 232 patients managed with a total hip replacement. Patients who were scheduled to have a primary or revision procedure were advised to predeposit two or four units of autologous blood, respectively, before the operation. In addition, intraoperative blood salvage was performed for all patients who had a revision procedure. The patients were randomly assigned to one of two groups: the first group was managed with postoperative blood salvage with use of the Autovac Postoperative Orthopaedic Autotransfusion Canister and the second, with closed suction drainage with use of the Hemovac system. In the first group, blood was collected from wound drains for four hours postoperatively; if at least 300 milliliters of blood was collected, the unwashed blood was reinfused through a microaggregate filter during a two-hour period. A maximum of 1000 milliliters of salvaged blood was reinfused; any blood that had not been reinfused within six hours after the beginning of collection was discarded. No complications or episodes of hypotension, confusion, cardiac or pulmonary compromise, febrile reaction, or coagulopathy were observed during or after the reinfusion of the unwashed, filtered, salvaged blood. No reinfusions were interrupted or discontinued. We found that postoperative reinfusion of unwashed, filtered, salvaged blood was associated with a decreased prevalence of homologous transfusion after a total hip replacement among patients for whom preoperatively donated autologous blood was not available.(ABSTRACT TRUNCATED AT 250 WORDS)

Secreted frizzled related protein 1 is a target to improve fracture healing

Genetic studies have identified a high bone mass of phenotype in both human and mouse when canonical Wnt signaling is increased. Secreted frizzled related protein 1 (sFRP1) is one of several Wnt antagonists and among the loss‐of‐function mouse models in which 32‐week‐old mice exhibit a high bone mass phenotype. Here we show that impact fracture healing is enhanced in this mouse model of increased Wnt signaling at a physiologic level in young (8 weeks) sFRP1−/− mice which do not yet exhibit significant increases in BMD. In vivo deletion of sFRP1 function improves fracture repair by promoting early bone union without adverse effects on the quality of bone tissue reflected by increased mechanical strength. We observe a dramatic reduction of the cartilage callous, increased intramembranous bone formation with bone bridging by 14 days, and early bone remodeling during the 28‐day fracture repair process in the sFRP1−/− mice. Our molecular analyses of gene markers indicate that the effect of sFRP1 loss‐of‐function during fracture repair is to accelerate bone healing after formation of the initial hematoma by directing mesenchymal stem cells into the osteoblast lineage via the canonical pathway. Further evidence to support this conclusion is the observation of maximal sFRP1 levels in the cartilaginous callus of a WT mouse. Hence sFRP1−/− mouse progenitor cells are shifted directly into the osteoblast lineage. Thus, developing an antagonist to specifically inhibit sFRP1 represents a safe target for stimulating fracture repair and bone formation in metabolic bone disorders, osteoporosis and aging. J. Cell. Physiol. 220: 174–181, 2009.