The effect of bisphosphonate treatment on the biochemical and cellular events during bone remodelling in response to microinjury stimulation.

Osteoporosis is one of the most prevalent bone diseases worldwide and is characterised by high levels of bone turnover, a marked loss in bone mass and accumulation of microdamage, which leads to an increased fracture incidence that places a huge burden on global health care systems. Bisphosphonates have been used to treat osteoporosis and have shown great success in conserving bone mass and reducing fracture incidence. In spite of the existing knowledge of the in vivo responses of bone to bisphosphonates, the cellular responses to these drugs have yet to be fully elucidated. In vitro model systems that allow the decoupling of complex highly integrated events, such as bone remodelling, provide a tool whereby these biological processes may be studied in a more simplified context. This study firstly utilised an in vitro model system of bone remodelling and comprising all three major cell types of the bone (osteocytes, osteoclasts and osteoblasts), which was representative of the bone's capacity to sense microdamage and subsequently initiate a basic multicellular unit response. Secondly, this system was used to study the effect of two commonly utilised aminobisphosphonate treatments for osteoporosis, alendronate and zoledronate. We demonstrated that microinjury to osteocyte networks being treated with bisphosphonates modulates receptor activator of nuclear factor kappa-B ligand and osteoprotegerin activity, and subsequently osteoclastogenesis. Furthermore, bisphosphonates increased the osteogenic potential following microinjury. Thus, we have shown for the first time that bisphosphonates act at all three stages of bone remodelling, from microinjury to osteoclastogenesis and ultimately osteogenesis.

An actuatable soft reservoir modulates host foreign body response.

The performance of indwelling medical devices that depend on an interface with soft tissue is plagued by complex, unpredictable foreign body responses. Such devices-including breast implants, biosensors, and drug delivery devices-are often subject to a collection of biological host responses, including fibrosis, which can impair device functionality. This work describes a milliscale dynamic soft reservoir (DSR) that actively modulates the biomechanics of the biotic-abiotic interface by altering strain, fluid flow, and cellular activity in the peri-implant tissue. We performed cyclical actuation of the DSR in a preclinical rodent model. Evaluation of the resulting host response showed a significant reduction in fibrous capsule thickness (P = 0.0005) in the actuated DSR compared with non-actuated controls, whereas the collagen density and orientation were not changed. We also show a significant reduction in myofibroblasts (P = 0.0036) in the actuated group and propose that actuation-mediated strain reduces differentiation and proliferation of myofibroblasts and therefore extracellular matrix production. Computational models quantified the effect of actuation on the reservoir and surrounding fluid. By adding a porous membrane and a therapy reservoir to the DSR, we demonstrate that, with actuation, we could (i) increase transport of a therapy analog and (ii) enhance pharmacokinetics and time to functional effect of an inotropic agent. The dynamic reservoirs presented here may act as a versatile tool to further understand, and ultimately to ameliorate, the host response to implantable biomaterials.

Total knee arthroplasty in patients with ankylosing spondylitis.

BACKGROUND: Ankylosing spondylitis is a seronegative spondyloarthropathy that primarily affects the sacroiliac joints, spine, hips, and, less commonly, the knee joints. The purpose of this study was to evaluate the results in a consecutive group of patients with ankylosing spondylitis who underwent total knee arthroplasty. METHODS: The results of thirty total knee arthroplasties in twenty patients with ankylosing spondylitis were reviewed. There were seventeen men and three women, with an average age of fifty-five years (range, twenty-eight to sixty-seven years) at the time of the arthroplasty. The diagnosis of ankylosing spondylitis was established preoperatively with use of the New York criteria. All patients received a cemented condylar-type implant. The average duration of follow-up was 11.2 years (range, three to sixteen years). RESULTS: The average Knee Society pain score improved from 14 points preoperatively to 76.3 points at the time of the latest follow-up. The improvement in the average Knee Society function score was less impressive, with an increase from 16.3 points preoperatively to 58.7 points at the time of the latest follow-up. The average arc of motion was 84.8 degrees prior to the arthroplasty and 86.7 degrees at the time of the final follow-up. Six knees (20%) had heterotopic bone formation. Three knees required manipulation under anesthesia because of poor motion postoperatively. There was one revision, due to loosening of a patellar component. All other components were radiographically stable at the time of the latest follow-up. CONCLUSIONS: Total knee arthroplasty with cement in patients with ankylosing spondylitis provided excellent pain relief and durable fixation at an average of 11.2 years postoperatively. However, patients with ankylosing spondylitis are at increased risk for the development of stiffness and heterotopic bone formation.

Vascularized free fibular transfer combined with autografting for the management of fracture nonunions associated with radiation therapy.

BACKGROUND: The purpose of this study was to evaluate the functional results, rates of union, and complications associated with vascularized free fibular transfer combined with autografting for the treatment of nonunions in previously irradiated bone. METHODS: Seventeen patients who had had eighteen vascularized free fibular transfers combined with autografting for the treatment of nonunion of a fracture in previously irradiated bone were included in this study. There were eleven female patients and six male patients. Eight patients had a bone neoplasm and nine, a soft-tissue neoplasm. The diagnosis was Ewing sarcoma in four patients; lymphoma, malignant fibrous histiocytoma, and rhabdomyosarcoma in two patients each; and cavernous hemangioma, metastatic breast carcinoma, reticulum-cell sarcoma, myxosarcoma, hemangiopericytoma, and fibrosarcoma in one patient each. The remaining patient had a soft-tissue tumor for which the diagnosis was not known. All patients received radiation therapy. The average dose was 5564 centigray. There were no recurrent tumors. The average interval between the radiation therapy and the original fracture was 111 months. The fracture was in the femur in thirteen patients, in the humerus in three, and in the tibia in one. All patients had operative or nonoperative treatment, or both, of the initial fracture, and two had iliac-crest bone-grafting after the initial open reduction and internal fixation procedure. The ages of the patients ranged from thirteen to eighty-two years at the time of the vascularized free fibular transfer. All fibular transfers were applied as onlay grafts because no nonunion was associated with a large segmental defect. Cancellous autogenous bone graft from the iliac crest was used as an additional graft at the proximal and distal junctions of the graft with the bone and at the fracture site in all patients. The average duration of follow-up after the vascularized free fibular transfer was fifty-seven months (range, twenty-eight to 112 months). RESULTS: Sixteen of the eighteen fracture sites united, after an average of 9.4 months (range, three to twenty-four months). Thirteen patients had an excellent result, one had a good result, two had a fair result, and one had a failure of treatment. Four patients had an infection, including one who continued to have a nonunion. The other three patients had union after treatment with antibiotics, debridement, and removal of the hardware. Another patient who had a recalcitrant nonunion eventually required an above-the-knee amputation. CONCLUSIONS: On the basis of this review, we suggest that microvascular fibular transfer combined with autografting is an appropriate treatment option for difficult nonunions associated with previously irradiated bone.

Total knee arthroplasty in patients who have pigmented villonodular synovitis.

We reviewed the results of all eighteen total knee arthroplasties that had been performed at the Mayo Clinic between 1974 and 1992 for the treatment of pigmented villonodular synovitis. The diagnosis had been confirmed histologically in all patients. Fourteen patients had diffuse disease, which was active in eleven and inactive in three, and four had focal disease. In addition to the arthroplasty, the eleven patients who had active diffuse disease were managed with a complete synovectomy and the four patients who had focal disease had a partial synovectomy. The three remaining patients had a history of diffuse pigmented villonodular synovitis but had no evidence of disease at the time of the arthroplasty, so a synovectomy was not performed. At an average of 9.9 years (range, 3.6 to 20.1 years) after the arthroplasty, fourteen of the eighteen total knee prostheses were well fixed and functioning satisfactorily. The average knee score was 89 points (range, 80 to 99 points) and the average functional score was 77 points (range, 20 to 100 points) for these fourteen patients. The four failures were in patients who had active diffuse disease at the time of the arthroplasty. Three of the failures were due to aseptic loosening, and one was due to recurrence of the disease. Sixteen patients had no evidence of recurrence when they were last seen, at an average of 10.3 years (range, 3.6 to 20.1 years) after the arthroplasty. The two patients who had a recurrence were among the eleven who had active diffuse disease. In one of these patients, the recurrence was diagnosed at the time of a revision arthroplasty performed because of aseptic loosening. The other patient had two recurrences, necessitating an above-the-knee amputation.

The delayed addition of human mesenchymal stem cells to pre-formed endothelial cell networks results in functional vascularization of a collagen-glycosaminoglycan scaffold in vivo.

This paper demonstrates a method to engineer, in vitro, a nascent microvasculature within a collagen-glycosaminoglycan scaffold with a view to overcoming the major issue of graft failure due to avascular necrosis of tissue-engineered constructs. Human umbilical vein endothelial cells (ECs) were cultured alone and in various co-culture combinations with human mesenchymal stem cells (MSCs) to determine their vasculogenic abilities in vitro. Results demonstrated that the delayed addition of MSCs to pre-formed EC networks, whereby MSCs act as pericytes to the nascent vessels, resulted in the best developed vasculature. The results also demonstrate that the crosstalk between ECs and MSCs during microvessel formation occurs in a highly regulated, spatio-temporal fashion, whereby the initial seeding of ECs results in platelet derived growth factor (PDGF) release; the subsequent addition of MSCs 3 days later leads to a cessation in PDGF production, coinciding with increased vascular endothelial cell growth factor expression and enhanced vessel formation. Functional assessment of these pre-engineered constructs in a subcutaneous rat implant model demonstrated anastomosis between the in vitro engineered vessels and the host vasculature, with significantly increased vascularization occurring in the co-culture group. This study has thus provided new information on the process of in vitro vasculogenesis within a three-dimensional porous scaffold for tissue engineering and demonstrates the potential for using these vascularized scaffolds in the repair of critical sized bone defects.

Mechanical characterization of a customized decellularized scaffold for vascular tissue engineering.

Several challenges persist when attempting to utilize decellularized tissue as a scaffold for vascular tissue engineering. Namely: poor cell infiltration/migration, excessive culture times associated with repopulating the scaffolds, and the achievement of a quiescent medial layer. In an attempt to create an optimum vascular scaffold, we customized the properties of decellularized porcine carotid arteries by: (i) creating cavities within the medial layer to allow direct injection of cells, and (ii) controlling the amount of collagen digestion to increase the porosity. Histological examination of our customized scaffold revealed a highly porous tissue structure containing consistent medial cavities running longitudinally through the porous scaffold wall. Mechanical testing of the customized scaffold showed that our minimal localized disruption to the ECM does not have a detrimental effect on the bulk mechanical response of the tissue. The results demonstrate that an increased stiffness and reduced distensibility occurs after decellularization when compared to the native tissue, however post scaffold customization we can revert the scaffold tensile properties back to that of the native tissue. This most noteworthy result occurs in the elastin dominant phase of the tensile response of the scaffold, indicating that no disruption has occurred to the elastin network by our decellularization and customization techniques. Additionally, the bulk seeding potential of the customized scaffold was demonstrated by direct injection of human smooth muscle cells through the medial cavities. The optimum cell dispersion was observed in the highest porosity scaffold, with large cell numbers retained within the medial layer after 24 h static culture. In summary, this study presents a novel customized decellularized vascular scaffold that has the capability of bulk seeding the media, and in tandem to this method, the porosity of the scaffold has been increased without compromising the mechanical integrity.

The "warning leak" in spontaneous subarachnoid haemorrhage.

A clear history of a warning leak was obtained in 28% of patients with ruptured intracranial aneurysms admitted to a Department of Neurosurgery. The ultimate outcome in these patients was worse than in other patients who were in good condition after initial haemorrhage. There are also cases in which symptoms suggesting a warning leak are found not to be due to haemorrhage, and CT scanning cannot be relied upon to determine accurately whether a warning leak has actually occurred in patients with suggestive symptoms. The frequency and significance of the warning leak should be recognized. Such recognition would improve the outcome after the rupture of an intracranial aneurysm.

Lumbar puncture in the presence of raised intracranial pressure.

Study of 30 patients with raised intracranial pressure whose condition worsened after lumbar puncture emphasizes the danger of carrying this out in the presence of raised intracranial pressure. In half the cases deterioration was immediate and dramatic, and in the other half it occurred within 12 hours. Probably a tentorial or cerebellar pressure cone, or both, had formed before lumbar puncture, and the procedure made this worse and caused the clinical deterioration.A history of progressive headache associated with mental changes, and the development and progression of localizing neurological signs were the two features suggestive of varied intracranial pressure found most constantly in this series. A good quality plain x-ray film is important in the diagnosis of this condition.

Lumbar puncture in spontaneous subarachnoid haemorrhage.

Seventy-four patients with proved spontaneous subarachnoid haemorrhage were studied. Sixty-four underwent computed tomography and 55 underwent lumbar puncture. Seven cases deteriorated dramatically after lumbar puncture, six of these showing evidence of cerebral dislocation on further investigation. Four of the seven had not undergone computed tomography and three underwent computed tomography after lumbar puncture. Computed tomography of the brain could determine patients at risk of coning. It is suggested that computed tomography is the investigation of choice after spontaneous subarachnoid haemorrhage and that lumbar puncture, if still then necessary, should be avoided until computed tomography has been undertaken.

Total knee arthroplasty in patients with parkinson's disease.

A retrospective review of 24 consecutive patients with Parkinson's disease who underwent 33 primary cemented condylar total knee arthroplasties was performed. The average follow-up period was 33 months, with a minimum follow-up period of 2 years. The pain score improved from 34 points before surgery to 89 points at the latest follow-up examination. The functional score improved from 42 points before surgery to 68 points at the latest follow-up examination. In patients whose Parkinson's disease progressed, the latest functional score was 49.5 points, significantly lower than the scores of those patients who did not progress. The results show that total knee arthroplasty is successful in patients with Parkinson's disease. Unfortunately in some patients. Parkinson's disease progresses and functional results decrease, but the benefit of pain relief persists.

Total knee arthroplasty in patients 55 years old or younger. 10- to 17-year results.

Seventy-four consecutive total knee arthroplasties in 54 patients who were 55 years of age or younger (average age 43 years) were reviewed. All patients had a minimum followup of 10 years with an average followup of 13 years (range, 10-17 years). No patients died or were lost to followup. The preoperative diagnosis was rheumatoid arthritis in 47, gonarthrosis in 12, posttraumatic arthritis in six, osteonecrosis in three, hemophilia in two, and one patient each with pigmented villonodular synovitis, tuberculosis, systemic lupus erythematosus, and achondroplasia. The knee score improved from an average of 36 points (range, 10-80 points) preoperatively to 84 points (range, 37-100 points) at latest followup. The functional score improved from 45 points (range, 0-100 points) to 60 points (range, 0-100 points) at latest followup. Two patients had their implants revised: one at 3 years because of ligamentous laxity and one at 13 years because of aseptic loosening of the tibial component. There were no deep infections. There were no radiographically loose implants at latest followup. The implant survival to revision at 10 years was estimated at 99% (confidence limit, 96%-100%). The implant survival to revision at 15 years was estimated at 95% confidence limit, 88%-100%). Cemented total knee arthroplasty in the young patient is a reliable procedure and has excellent results at 13-year followup with an estimated survivorship of 99% at 10 years.

Femoral component failure in hybrid total knee arthroplasty.

From 1986 to 1991, 74 consecutive hybrid total knee arthroplasties (in 65 patients) of a single design were performed at the authors' institution. Seven patients (eight knees) died with well functioning replacements during the surveillance period. One patient refused to participate in any followup efforts because of billing disputes. This left 65 total knee arthroplasties (57 patients) for review. There were 35 men and 22 women with an average age of 60 years (range, 27-83 years) at the time of arthroplasty. The underlying diagnosis was osteoarthritis in 46 knees, rheumatoid arthritis in six knees, and other in four knees. The average length of followup was 7.4 years (range, 5-10 years), and no patients were lost to followup. The Knee Society scores improved from an average of 37 preoperatively to 84 at latest followup. The functional score improved from 49 to 69 at latest followup. Ten (13.8%) knees required revision surgery. Eight of the nine knees that were revised had femoral component problems, including a loose component in six and a fractured component in two. One knee was revised for polyethylene wear with secondary osteolysis and one was revised elsewhere in which the operative details are unknown. The implant survival to revision at 5 years was 89% and 85% at final followup. Femoral component fixation in hybrid total knee arthroplasty in unreliable with this component design. In light of the excellent 10- to 15-year results of cemented condylar knee designs it is thought that hybrid fixation should be abandoned.

Cement versus cementless fixation in total knee arthroplasty.

A prospectively studied group of 55 uncemented Press Fit Condylar total knee arthroplasties was compared retrospectively with a matched group of 51 cemented Press Fit Condylar total knee arthroplasties at a mean of 10 years after operation. For the cemented group, the pain and function scores improved from 32 and 45 preoperatively to 95 and 77, respectively. For the uncemented group the scores improved from 33 and 50 preoperatively to 93 and 60, respectively. There were 10 revisions in the uncemented group for femoral or tibial aseptic loosening or osteolysis compared with two revisions in the cemented group. Exclusive of problems related to patellar metal backing, survival to revision for aseptic failure or radiographic loosening was 72% in the uncemented group and 94% in the cemented group at 10 years. A significantly higher revision rate was found in the uncemented compared with cemented total knee arthroplasty of the Press Fit Condylar design.

Primary uncemented total hip arthroplasty in patients <40 years old: 10- to 14-year results using first-generation proximally porous-coated implants.

Eighty-two consecutive primary first-generation uncemented total hip arthroplasties (72 patients) performed in patients <40 years old were reviewed with minimum follow-up of 10 years. Of 82 hips, 24 (29.3%) have been revised to date. The estimated survival free of aseptic revision or radiographic failure was 81.3% at 10 years for the acetabular components. The estimated survival free of aseptic revision or radiographic failure was 84.9% at 10 years for the femoral component. In this exclusively young patient cohort, there was a high failure rate of the acetabular component and the femoral component. The data in this report can serve as a baseline for comparison of newer implants and operative methods.

A critical assessment of proximal macrotexturing on cemented femoral components.

We analyzed the cement-metal interface of 3 different types of femoral components that had proximal macrotexturing after in vitro insertion and after fatigue testing designed to produce debonding and micromotion. These components were compared with clinical retrieval specimens. The cement did not flow into the macrotexturing; rather, hollow, brittle volcanoes or calderas were formed. These fragile protrusions of cement become worn down or abraded by debonded components. This abrasion of cement may contribute to the early and aggressive osteolysis seen in some of these early failures with proximal macrotextured components. The formation of these volcanos and calderas can be aborted by placing bone-cement onto the macrotexturing before stem insertion. This simple technique allows the macrotexturing to be filled with cement.