Spatial control of bone formation using a porous polymer scaffold co-delivering anabolic rhBMP-2 and anti-resorptive agents.

Current clinical delivery of recombinant human bone morphogenetic proteins (rhBMPs) utilises freeze-dried collagen. Despite effective new bone generation, rhBMP via collagen can be limited by significant complications due to inflammation and uncontrolled bone formation. This study aimed to produce an alternative rhBMP local delivery system to permit more controllable and superior rhBMP-induced bone formation. Cylindrical porous poly(lactic-co-glycolic acid) (PLGA) scaffolds were manufactured by thermally-induced phase separation. Scaffolds were encapsulated with anabolic rhBMP-2 (20 µg) ± anti-resorptive agents: zoledronic acid (5 µg ZA), ZA pre-adsorbed onto hydroxyapatite microparticles, (5 µg ZA/2% HA) or IkappaB kinase (IKK) inhibitor (10 µg PS-1145). Scaffolds were inserted in a 6-mm critical-sized femoral defect in Wistar rats, and compared against rhBMP-2 via collagen. The regenerate region was examined at 6 weeks by 3D microCT and descriptive histology. MicroCT and histology revealed rhBMP-induced bone was more restricted in the PLGA scaffolds than collagen scaffolds (-92.3% TV, p < 0.01). The regenerate formed by PLGA + rhBMP-2/ZA/HA showed comparable bone volume to rhBMP-2 via collagen, and bone mineral density was +9.1% higher (p < 0.01). Local adjunct ZA/HA or PS-1145 significantly enhanced PLGA + rhBMP-induced bone formation by +78.2% and +52.0%, respectively (p ≤ 0.01). Mechanistically, MG-63 human osteoblast-like cells showed cellular invasion and proliferation within PLGA scaffolds. In conclusion, PLGA scaffolds enabled superior spatial control of rhBMP-induced bone formation over clinically-used collagen. The PLGA scaffold has the potential to avoid uncontrollable bone formation-related safety issues and to customise bone shape by scaffold design. Moreover, local treatment with anti-resorptive agents incorporated within the scaffold further augmented rhBMP-induced bone formation.

Osteoblast attachment to hydroxyapatite micro-tube scaffolds.

Tissue engineering offers a novel route for repairing damaged or diseased tissue by incorporating the patient's own healthy cells or donated cells into temporary scaffolds that act as a matrix for cell cultivation. Tissue scaffolds that are biocompatible and are porous with interconnected porous channels for cell ingrowth with a suitable degradation rate would be advantageous. In this study hydroxyapatite micro-tubes produced using the biomimetic coating technique will be pressed into a tissue scaffold. A compaction and sintering study will be done to observe appropriate pressure and heat treatment to produce a mechanically stable scaffold material. The ideal pressure was found to be 2.5 MPa where the tube-like structure was maintained, high porosity was achieved and suitable strength was possible. Sintering between 1,000 and 1,100 °C was found to produce good results. The average porosity for the chosen pressure of 2.5 MPa was 68%. The scaffold was observed with SEM, micro tomography (micro-CT), chemical analysis and degradation testing. Porous channels were established using micro-CT where the porous channels were roughly 100 µm. Chemical analysis showed constant release of calcium and phosphorous, and far below toxic levels of heavy metals from the die. Degradation testing showed high degradation compared to tested commercially available materials. Cell culturing was done on the scaffold to characterise the biological performance of the scaffolds. Cell culturing was done in a 7 and 24 day cell culture to examine cell morphology and cell ingrowth. The results showed cell ingrowth into a micro-tube and cell orientation in a longitudinal direction. SEM, confocal microscopy and histology were employed as characterisation tools for observing cell ingrowth.

Feasibility of Postoperative Home Monitoring Using Video Consultation and Vital Sign Monitoring of Bariatric Patients.

RATIONALE: The length of hospital stay after bariatric surgery has decreased rapidly in recent years to an average of 1 day (one midnight). The transition from a controlled hospital environment to home environment may be a big step for patients. For these patients, home monitoring can be a substitute. METHODS: A pilot study of 84 morbidly obese patients undergoing either laparoscopic Roux-Y gastric bypass (LRYGB) or laparoscopic sleeve gastrectomy (LGS) was performed. Home monitoring consisted of daily contact via video consultation and measurement of vital signs at home. The primary outcome was feasibility of home monitoring. Secondary outcomes were complications and patient satisfaction measured with a questionnaire (PSQ-18). RESULTS: In 77 of the 84 patients (92%), videoconference was possible on day 1, 74 patients (88%) on day 2 and 76 patients (90%) on day 3. Four patients (5%) were never reached. On day 1, 52 patients (62%) performed all instructed measurements, on day 2, 49 patients (58%) and on day 3, 63 patients (75%). Only 47 out of 84 patients (56%) measured the instructed amount of times on all 3 days. High satisfaction rates were reported in the patients receiving home monitoring. CONCLUSION: Our first experience with home monitoring was disappointing since home monitoring of vital signs had poor compliance and not all patients were able to use the application. Further refinement of the home monitoring tool is needed to increase compliance and utility of the tool.

Validity of a simple sleep monitor for diagnosing OSA in bariatric surgery patients.

BACKGROUND: One third of bariatric surgery patients have an apnea-hypopnea index (AHI)>15/hr, representing moderate and severe forms of obstructive sleep apnea (OSA). Treating these forms of OSA is recommended to reduce the risk of perioperative complications. The AHI derived from poly(somno)graphy [P(S)G] is the gold standard for OSA diagnosis. However, performing P(S)G in all patients scheduled for bariatric surgery is time consuming and expensive. An accurate and simple screening tool able to rule out moderate to severe OSA would reduce the number of patients needing mandatory P(S)Gs. OBJECTIVES: To assess the validity of a simple sleep monitor (Checkme Health Monitor) as a screening tool for OSA in bariatric surgery patients. SETTING: Obesity Center Amsterdam, OLVG-West, Amsterdam, the Netherlands METHODS: Patients scheduled for bariatric surgery were prospectively enrolled in this study. All patients underwent preoperative P(S)G and simultaneously used the Checkme to assess the oxygen desaturation index. The diagnostic performance of the Checkme for AHI ≥15/hr was assessed using receiver operating characteristic curve analysis. RESULTS: A total of 50 patients were analyzed. Sensitivity and negative predictive value were 100% and 100%, respectively, specificity and positive predictive value were 69% and 64%, respectively, for the optimal cutoff value of Checkme-3% oxygen desaturation index ≥9/hr for P(S)G-AHI ≥15. The area under the curve value expressed by the receiver operating characteristic curve was .95. CONCLUSION: The Checkme is valid for exclusion of moderate and severe OSA in bariatric surgery patients. The Checkme enables bariatric clinics not to perform P(S)G in all patients scheduled for bariatric surgery.

Mechanical design and driving mechanism of an isokinetic functional electrical stimulation-based leg stepping trainer.

The mechanical design of a constant velocity (isokinetic) leg stepping trainer driven by functional electrical stimulation-evoked muscle contractions was the focus of this paper. The system was conceived for training the leg muscles of neurologically-impaired patients. A commercially available slider crank mechanism for elliptical stepping exercise was adapted to a motorized isokinetic driving mechanism. The exercise system permits constant-velocity pedalling at cadences of 1-60 rev x min(-1). The variable-velocity feature allows low pedalling forces for individuals with very weak leg muscles, yet provides resistance to higher pedalling effort in stronger patients. In the future, the system will be integrated with a computer-controlled neuromuscular stimulator and a feedback control unit to monitor training responses of spinal cord-injured, stroke and head injury patients.

An interpenetrating network composite for a regenerative spinal disc application.

Severe degeneration of the intervertebral disc has an immensely debilitating effect on quality of life that has become a serious health and economic burden throughout the world. The disc plays an integral role in biomechanical movement and support within the spine. The emergence of tissue engineering endeavours to restore the structural characteristics and functionality of the native tissue. Hydrogels have been widely investigated as a candidate for regeneration of the gelatinous nucleus pulposus due to its architectural resemblance and fluid retention characteristics. However, hydrogels are often limited due to small compressive stiffness and tear resistance, leading to extrusion complications. Reinforcement of the hydrogel network using polymeric scaffolds may address these issues of inadequate mechanical properties and implant instability. This study investigates the potential of a carrageenan gel-infused polycaprolactone scaffold for nucleus pulposus tissue engineering. Mechanical properties were characterised using viscoelastic and poroelastic frameworks via microindentation. The incorporation of polymeric reinforcement within the gels increased material stiffness to that comparable to the native nucleus pulposus, however permeability was significantly greater than native values. A preliminary cell evaluation culturing NIH 3T3s over 21 days suggested the incorporation of polymeric networks also enhanced cellular proliferation compared to gels alone.

Sintering effects on the strength of hydroxyapatite.

Mechanisms underlying temperature-strength interrelations for dense (> 95% dense, pores closed) hydroxyapatite (HAp) were investigated by comparative assessment of temperature effects on tensile strength, Weibull modulus, apparent density, decomposition (HAp:tricalcium phosphate ratio), dehydroxylation and microstructure. Significant dehydroxylation occurred above approximately 800 degrees C. Strength peaked at approximately 80 MPa just before the attainment of closed porosity (approximately 95% dense). For higher temperatures (closed porosity), the strength dropped sharply to approximately 60 MPa due to the closure of dehydroxylation pathways, and then stabilized at approximately 60 MPa. At very high temperatures (> 1350 degrees C), the strength dropped catastrophically to approximately 10 MPa corresponding to the decomposition of HAp to tricalcium phosphate and the associated sudden release of the remaining bonded water.

Effects of nandrolone decanoate on bone mass in established osteoporosis.

A double-blind, randomized, placebo-controlled study was conducted in 46 postmenopausal women with established osteoporosis in order to assess the long-term effects of nandrolone decanoate on the bone mineral density (BMD) of the lumbar vertebrae and of the distal third of the radius and on the biochemical markers of bone turnover. The patients received intramuscular injections of placebo or 50 mg nandrolone decanoate every 3 weeks for 18 months. Thirty-two of the initial 46 patients completed 1 year of study and 25 completed the whole study period of 18 months. Overall, vertebral BMD increased by 2.9% in the nandrolone decanoate group and fell by 2.3% in the placebo group. Radial BMD showed a slight but transient improvement, with a subsequent return to basal levels in the nandrolone decanoate group, whereas there was a progressive decrease in the placebo group. Patients treated with nandrolone decanoate also complained less of bone pain. Urinary hydroxyproline decreased significantly in treated patients, whereas osteocalcin tended to increase, but the change was not significant. HDL cholesterol concentrations decreased only slightly and haemoglobin increased significantly in the nandrolone decanoate group. Two patients treated with nandrolone decanoate withdrew from the study because of hirsutism and hoarseness. The results indicate that nandrolone decanoate exerts positive effects on vertebral BMD and on bone pain in patients with established postmenopausal osteoporosis.

Radiological staging in patients with hilar cholangiocarcinoma: a systematic review and meta-analysis.

OBJECTIVE: To obtain diagnostic performance values of CT, MRI, ultrasound and 18-fludeoxyglucose positron emission tomography (PET)/CT for staging of hilar cholangiocarcinoma. METHODS: A comprehensive systematic search was performed for articles published up to March 2011 that fulfilled the inclusion criteria. Study quality was assessed with the quality assessment of diagnostic accuracy studies tool. RESULTS: 16 articles (448 patients) were included that evaluated CT (n=11), MRI (n=3), ultrasound (n=3), or PET/CT (n=1). Overall, their quality was moderate. The accuracy estimates for evaluation of CT for ductal extent of the tumour was 86%. The sensitivity and specificity estimates of CT were 89% and 92% for evaluation of portal vein involvement, 83% and 93% for hepatic artery involvement, and 61% and 88% for lymph node involvement, respectively. Data were too limited for adequate comparisons of the different techniques. CONCLUSION: Diagnostic accuracy studies of CT, MRI, ultrasound or PET/CT for staging of hilar cholangiocarcinoma are sparse and have moderate methodological quality. Data primarily concern CT, which has an acceptable accuracy for assessment of ductal extent, portal vein and hepatic artery involvement, but low sensitivity for nodal status.

Distal tibial fracture repair in a neurofibromatosis type 1-deficient mouse treated with recombinant bone morphogenetic protein and a bisphosphonate.

Congenital pseudarthrosis of the tibia is an uncommon manifestation of neurofibromatosis type 1 (NF1), but one that remains difficult to treat due to anabolic deficiency and catabolic excess. Bone grafting and more recently recombinant human bone morphogenetic proteins (rhBMPs) have been identified as pro-anabolic stimuli with the potential to improve the outcome after surgery. As an additional pharmaceutical intervention, we describe the combined use of rhBMP-2 and the bisphosphonate zoledronic acid in a mouse model of NF1-deficient fracture repair. Fractures were generated in the distal tibiae of neurofibromatosis type 1-deficient (Nf1(+/-)) mice and control mice. Fractures were open and featured periosteal stripping. All mice received 10 µg rhBMP-2 delivered in a carboxymethylcellulose carrier around the fracture as an anabolic stimulus. Bisphosphonate-treated mice also received five doses of 0.02 mg/kg zoledronic acid given by intraperitoneal injection. When only rhBMP but no zoledronic acid was used to promote repair, 75% of fractures in Nf1(+/-) mice remained ununited at three weeks compared with 7% of controls (p < 0.001). Systemic post-operative administration of zoledronic acid halved the rate of ununited fractures to 37.5% (p < 0.07). These data support the concept that preventing bone loss in combination with anabolic stimulation may improve the outcome following surgical treatment for children with congenital pseudarthosis of the tibia and NF1.

Multidisciplinary management of hilar cholangiocarcinoma (Klatskin tumor): extended resection is associated with improved survival.

BACKGROUND: Effective diagnosis and treatment of patients with hilar cholangiocarcinoma (HCCA) is based on the synergy of endoscopists, interventional radiologists, radiotherapists and surgeons. This report summarizes the multidisciplinary experience in management of HCCA over a period of two decades at the Academic Medical Center in Amsterdam, with emphasis on surgical outcome. METHODS: From 1988 until 2003, 117 consecutive patients underwent resection on the suspicion of HCCA. Preoperative work-up included staging laparoscopy, preoperative biliary drainage, assessment of volume/function of future remnant liver and radiation therapy to prevent seeding metastases. More aggressive surgical approach combining hilar resection with extended liver resection was applied as of 1998. Outcomes of resection including actuarial 5-year survival were assessed. RESULTS: Eighteen patients (15.3%) appeared to have a benign lesion on microscopical examination of the specimen, leaving 99 patients with histologically proven HCCA. These 99 patients were analysed according to three 5-year time periods of resection, i.e. period 1 (1988-1993, n=45), 2 (1993-1998, n=25) and 3 (1998-2003, n=29). The rate of R0 resections increased and actuarial five-year survival significantly improved from 20±5% for the periods 1 and 2, to 33±9% in period 3 (p<0.05). Postoperative morbidity and mortality in the last period were 68% and 10%, respectively. CONCLUSION: Extended surgical resection resulted in increased rate of R0 resections and significantly improved survival. Candidates for resection should be considered by a specialized, multidisciplinary team.

The influence of surface chemistry and topography on the contact guidance of MG63 osteoblast cells.

The purpose of the present study was to determine in vitro the effects of different surface topographies and chemistries of commercially pure titanium (cpTi) and diamond-like carbon (DLC) surfaces on osteoblast growth and attachment. Microgrooves (widths of 2, 4, 8 and 10 microm and a depth of 1.5-2 microm) were patterned onto silicon (Si) substrates using microlithography and reactive ion etching. The Si substrates were subsequently vapor coated with either cpTi or DLC coatings. All surfaces were characterized using atomic force microscopy (AFM), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and contact angle measurements. Using the MG63 Osteoblast-Like cell line, we determined cell viability, adhesion, and morphology on different substrates over a 3 day culture period. The results showed cpTi surfaces to be significantly more hydrophilic than DLC for groove sizes larger than 2 microm. Cell contact guidance was observed for all grooved samples in comparison to the unpatterned controls. The cell viability tests indicated a significantly greater cell number for 8 and 10 microm grooves on cpTi surfaces compared to other groove sizes. The cell adhesion study showed that the smaller groove sizes, as well as the unpatterned control groups, displayed better cell adhesion to the substrate.

Calcium phosphate fibres synthesized from a simulated body fluid.

The biomimetic coating method was used for fabricating calcium phosphate fibres for biomedical applications such as bone defect fillers. Natural cotton substrate was pre-treated with phosphorylation and a Ca(OH)2 saturated solution. The pre-treated samples were then soaked in simulated body fluid (SBF) of two different concentrations, 1.5 times and 5.0 times the ion concentration of blood plasma. The cotton was then burnt out via sintering of the ceramic coating at 950 degrees C, 1050 degrees C, 1150 degrees C, and 1250 degrees C. The results demonstrated that osteoblastic cells were able to cover the entire surface cotton fibres, and the cell coverage appeared to be independent of surface roughness and Ca/P ratio of fibres.

Hydroxyapatite-coated metals: interfacial reactions during sintering.

Electrophoretic deposition (EPD) is a low cost flexible process for producing HA coatings on metal implants. Its main limitation is that it requires heating the coated implant in order to densify the HA. HA typically sinters at a temperature below 1150 degrees C, but metal implants are degraded above 1000 degrees C. Further, the metal induces the decomposition of the HA coating upon sintering. Recent developments have enabled EPD of metathesis-synthesised uncalcined HA which sinters at approximately 1000 degrees C. The effects of temperature on HA-coated Ti, Ti6Al4V, and 316L stainless steel were investigated for dual coatings of metathesis HA sintered at 1000 degrees C. The use of dual HA coatings (coat, sinter, coat, sinter) enabled decomposition to be confined to the "undercoat" (HA layer 1), with the surface coating decomposition free. The tensile strength of the three metals was not significantly affected by the high sintering temperatures (925 degrees C < T < 1000 degrees C). XRD/SEM/EDS analyses of the interfacial zones revealed that 316L had a negligible HA:metal interfacial zone (approximately 1 microm) while HA:Ti and HA:Ti6Al4V had large interfacial zones (>10 microm) comprising a TiO2 oxidation zone and a CaTiO2 reaction zone.

Precipitation of hydroxyapatite nanoparticles: effects of precipitation method on electrophoretic deposition.

Electrophoretic deposition is a low-cost, simple, and flexible coating method for producing hydroxyapatite (HA) coatings on metal implants with a broad range of thicknesses, from < 1 microm to > 500 microm. As for many other HA coating techniques, densification of electrophoretically deposited coatings involves heating the coated metal to temperatures above 1000 degrees C. Metal substrates tend to react with HA coatings at such temperatures inducing decomposition at temperatures below 1050 degrees C (decomposition for pure HA normally occurs above 1300 degrees C). Therefore, densification of these coatings needs to be conducted at temperatures lower than 1050 degrees C, and this necessitates the use of high-surface-area HA nano-precipitates, rather than commercially available pre-calcined powders, which densify at temperatures typically higher than 1200 degrees C. HA nano-precipitates were prepared by three methods and deposited on metal substrates by electrophoresis: (1) the acid base method, which produced plate-like nano-particles with a 2.5:1 aspect ratio, and severely cracked coatings; (2) the calcium acetate method, which produced needle-like nano-particles with a 10:1 aspect ratio, and slightly cracked coatings; (3) the metathesis method, which produced rounded nano-particles with a 2:1 aspect ratio, and high-quality crack-free coatings. The results suggested that the less equiaxed the nano-particles, the more cracked the coatings obtained by the electrophoretic deposition technique.