Search

Refereed/Peer-reviewed BACKGROUND: A nanostructured titanium surface that promotes antimicrobial activity and osseointegration would provide the opportunity to create medical implants that can prevent orthopaedic infection and improve bone integration. Although nanostructured surfaces can exhibit antimicrobial activity, it is not known whether these surfaces are safe and conducive to osseointegration. QUESTIONS/PURPOSES: Using a sheep animal model, we sought to determine whether the bony integration of medical-grade, titanium, porous-coated implants with a unique nanostructured surface modification (alkaline heat treatment [AHT]) previously shown to kill bacteria was better than that for a clinically accepted control surface of porous-coated titanium covered with hydroxyapatite (PCHA) after 12 weeks in vivo. The null hypothesis was that there would be no difference between implants with respect to the primary outcomes: interfacial shear strength and percent intersection surface (the percentage of implant surface with bone contact, as defined by a micro-CT protocol), and the secondary outcomes: stiffness, peak load, energy to failure, and micro-CT (bone volume/total volume [BV/TV], trabecular thickness [Tb.Th], and trabecular number [Tb.N]) and histomorphometric (bone-implant contact [BIC]) parameters. METHODS: Implants of each material (alkaline heat-treated and hydroxyapatite-coated titanium) were surgically inserted into femoral and tibial metaphyseal cancellous bone (16 per implant type; interference fit) and in tibial cortices at three diaphyseal locations (24 per implant type; line-to-line fit) in eight skeletally mature sheep. At 12 weeks postoperatively, bones were excised to assess osseointegration of AHT and PCHA implants via biomechanical push-through tests, micro-CT, and histomorphometry. Bone composition and remodeling patterns in adult sheep are similar to that of humans, and this model enables comparison of implants with ex vivo outcomes that are not permissible with humans. Comparisons of primary and secondary outcomes were undertaken with linear mixed-effects models that were developed for the cortical and cancellous groups separately and that included a random effect of animals, covariates to adjust for preoperative bodyweight, and implant location (left/right limb, femoral/tibial cancellous, cortical diaphyseal region, and medial/lateral cortex) as appropriate. Significance was set at an alpha of 0.05. RESULTS: The estimated marginal mean interfacial shear strength for cancellous bone, adjusted for covariates, was 1.6 MPa greater for AHT implants (9.3 MPa) than for PCHA implants (7.7 MPa) (95% CI 0.5 to 2.8; p = 0.006). Similarly, the estimated marginal mean interfacial shear strength for cortical bone, adjusted for covariates, was 6.6 MPa greater for AHT implants (25.5 MPa) than for PCHA implants (18.9 MPa) (95% CI 5.0 to 8.1; p < 0.001). No difference in the implant-bone percent intersection surface was detected for cancellous sites (cancellous AHT 55.1% and PCHA 58.7%; adjusted difference of estimated marginal mean -3.6% [95% CI -8.1% to 0.9%]; p = 0.11). In cortical bone, the estimated marginal mean percent intersection surface at the medial site, adjusted for covariates, was 11.8% higher for AHT implants (58.1%) than for PCHA (46.2% [95% CI 7.1% to 16.6%]; p < 0.001) and was not different at the lateral site (AHT 75.8% and PCHA 74.9%; adjusted difference of estimated marginal mean 0.9% [95% CI -3.8% to 5.7%]; p = 0.70). CONCLUSION: These data suggest there is stronger integration of bone on the AHT surface than on the PCHA surface at 12 weeks postimplantation in this sheep model. CLINICAL RELEVANCE: Given that the AHT implants formed a more robust interface with cortical and cancellous bone than the PCHA implants, a clinical noninferiority study using hip stems with identical geometries can now be performed to compare the same surfaces used in this study. The results of this preclinical study provide an ethical baseline to proceed with such a clinical study given the potential of the alkaline heat-treated surface to reduce periprosthetic joint infection and enhance implant osseointegration.

Background: Huntington’s disease (HD) is a fatal neurodegenerative autosomal dominant disorder with prevalence of 1 : 20000 that has no effective treatment to date. Translatability of candidate therapeutics could be enhanced by additional testing in large animal models because of similarities in brain anatomy, size, and immunophysiology. These features enable realistic pre-clinical studies of biodistribution, efficacy, and toxicity. Objective and Methods: Here we non-invasively characterized alterations in brain white matter microstructure, neurochemistry, neurological status, and mutant Huntingtin protein (mHTT) levels in cerebrospinal fluid (CSF) of aged OVT73 HD sheep. Results: Similar to HD patients, CSF mHTT differentiates HD from normal sheep. Our results are indicative of a decline in neurological status, and alterations in brain white matter diffusion and spectroscopy metric that are more severe in aged female HD sheep. Longitudinal analysis of aged female HD sheep suggests that the decline is detectable over the course of a year. In line with reports of HD human studies, white matter alterations in corpus callosum correlates with a decline in gait of HD sheep. Moreover, alterations in the occipital cortex white matter correlates with a decline in clinical rating score. In addition, the marker of energy metabolism in striatum of aged HD sheep, shows a correlation with decline of clinical rating score and eye coordination. Conclusion: This data suggests that OVT73 HD sheep can serve as a pre-manifest large animal model of HD providing a platform for pre-clinical testing of HD therapeutics and non-invasive tracking of the efficacy of the therapy.

Gene therapy continues to be a promising contender for the treatment of cystic fibrosis (CF) airway disease. We have previously demonstrated that airway conditioning with lysophosphatidylcholine (L...

The study aimed to evaluate the comparative osteoconductivity of three commercially available bone void fillers containing gentamicin with respect to new bone, growth, host tissue response and resorption of the implant material. Defects were created in the cancellous bone of the distal femur and proximal tibia of 12-skeletally mature sheep and filled with three commercially available bone void fillers containing gentamicin (Stimulan-G, Cerament-G, Herafill-G). Peripheral blood was taken pre-operatively and at the time of implantation, as well as at intermittent timepoints following surgery to determine systemic gentamicin levels (5-,15- and 30- minutes, 1, 2, 3, 6, 12, 24, 48- and 72-hours, 3-, 6- and 12-weeks). Decalcified, embedded samples were stained with haematoxylin and eosin (H&E) and used to assess the host tissue response and the formation of new bone in the presence of test implant materials. No adverse reactions were noted at harvest at any time points for any cancellous implantation sites with the various implant materials. Comparative microCT analysis of the Stimulan-G, Cerament-G and Herafill-G test materials revealed a similar increase in bone surface area and volume between animals implanted with Stimulan-G or Cerament-G test materials. Animals implanted with Herafill-G test materials demonstrated the lowest increases in bone volume and surface area of the test materials tested, at levels similar to the negative control sites. By 12-weeks, Stimulan-G defects were completely closed with mature bone and bone marrow whilst the Cerament-G material was still present after 12 weeks by histological examination. In conclusion, this study demonstrated differences in the bone regenerative capacity of a range of bone void fillers in an in vivo setting.

Introduction Evidence suggests treatments guided by brain oxygen levels improve patient outcomes following severe traumatic brain injury; however, brain oxygen levels are not routinely monitored as an effective non-invasive method has not been established. We undertook a study, in a sheep model of acute brain injury, to assess a new non-invasive brain oximeter. The monitor uses the principles of pulse oximetry to record a pulse and oxygen levels. Methods We studied 8 sheep. An acute increase in intracranial pressure was induced with an injection of blood into the cranial vault. The temporal changes in the brain oximeter, intracranial pressure and cerebral perfusion pressure were recorded. Simultaneous conventional skin pulse oximetry was also recorded to assess the possible influence of skin blood flow on the brain oximeter signal. Results At baseline, a pulsatile waveform consistent with the brain circulation was obtained in 7 animals. The baseline brain pulse was quite distinct from the simultaneous conventional skin pulse and similar in shape to a central venous pressure waveform. Injection of blood into the cranial vault triggered an immediate increase in intracranial pressure and fall in cerebral perfusion pressure, by 60-s cerebral perfusion pressure recovered. The brain oximeter oxygen levels demonstrated similar changes with an immediate fall and recovery by 60 s. Periods of high intracranial pressure were also associated with high-frequency oscillations in the brain pulse waveform; there was, however, no change in the conventional skin pulse oximeter pulse waveform. Conclusion The brain oximeter detected acute changes in both oxygen levels and the brain pulse waveform following an increase in intracranial pressure levels. The brain oximeter could assist clinicians in the management of acute brain injury.

Background In our earlier study on the functional limits of the aneurysmal aortic root we determined the pig root is susceptible to failure at high aortic pressures levels. We established a pig rupture model using cardiopulmonary bypass to determine the most susceptible region of the aortic root under the highest pressures achievable using continuous flow, and what changes occur in these regions on a macroscopic and histological level. This information may help guide clinical management of aortic root and ascending aorta pathology. Methods Five pigs underwent 4D flow MRI imaging pre surgery to determine vasopressor induced wall sheer stress and flow parameters. All pigs were then placed on cardiopulmonary bypass (CPB) via median sternotomy, and maximal aortic root and ascending aorta flows were initiated until rupture or failure, to determine the most susceptible region of the aorta. The heart was explanted and analysed histologically to determine if histological changes mirror the macroscopic observations. Results The magnetic resonance imaging (MRI) aortic flow and wall sheer stress (WSS) increased significantly in all regions of the aorta, and the median maximal pressures obtained during cardiopulmonary bypass was 497 mmHg and median maximal flows was 3.96 L/m. The area of failure in all experiments was the non-coronary cusp of the aortic valve. Collagen and elastin composition (%) was greatest in the proximal regions of the aorta. Collagen I and III showed greatest content in the inner aortic root and ascending aorta regions. Conclusions This unique porcine model shows that the aortic root is most susceptible to failure at high continuous aortic pressures, supported histologically by different changes in collagen content and subtypes in the aortic root. With further analysis, this information could guide management of the aortic root in disease.

Management of osseous and soft tissue dead space can be a significant challenge in the clinical setting. Calcium sulphate and calcium phosphate-based biomaterials are increasingly being used as alternatives to PMMA for local release of antibiotics, in particular to fill dead space following surgical debridement. This study aims to observe the in-vivo absorption characteristics and tissue response of three commercially available calcium sulphate-based materials combined with gentamicin in an established soft tissue rabbit model. The implant materials (1cc) were placed into four intramuscular sites in 18 New Zealand White rabbits (n = 6). In-life blood samples and radiographs were taken from each animal following implantation. Animals were sacrificed at 0, 1, 7, 21, 42 and 63 days post-operatively (n = 3) and implant sites analysed by micro-computed tomography and histology. Radiographically and histologically, recrystallized calcium sulphate (RCS) absorbed the fastest with complete absorption by day 21. Calcium sulphate/HA composite (CSHA) and Calcium sulphate/calcium carbonate (CSCC) absorbed slower and were detectable at day 63. Residual bead analysis revealed the presence of detectable gentamicin at 24 h and 7 days for CSHA and RCS but none in CSCC. Systemic levels of gentamicin were only detected between 1 h and 24 h. Serological inflammatory cytokine expression for IL-6, TNF-α and IL-1β indicated no unusual inflammatory response to the implanted materials. Calcium sulphate materials loaded with gentamicin are effective in resolving a surgically created dead space without eliciting any adverse host response.

Background Context Degenerative disc disease (DDD) is a common, widespread socioeconomic problem. Appropriate large animal models of DDD are required for improved understanding and to serve as preclinical test beds for therapeutic strategies. Purpose To evaluate the effects of short and medium duration immobilization on the sheep lumbar intervertebral disc (IVD) and facet joints (FJs), and to establish a large animal model for DDD research. Study Design An in vivo sheep model evaluating the effect of short- and medium-term immobilization on disc degeneration. Methods Eighteen sheep were equally randomized into three groups: short-term (6-week) immobilization (n=6), medium-term (26-week) immobilization (n=6), and control (no surgery) (n=6). Immobilization of L3–L4 was achieved with pedicle screw and rod implantation, the IVD was kept intact, and the annulus and end plates were not disrupted. The IVD and FJs were assessed with planar radiography, computerized tomography (CT), magnetic resonance imaging (MRI), pure moment biomechanical testing, and histologic analysis. Results Disc height was reduced for 6- and 26-week immobilization groups. The MRI and histologic analysis demonstrated significant disc degeneration for both immobilized groups compared with control, but no statistical difference was detected between short- and medium-term duration. Progressive degenerative changes in FJs were observed with micro-CT and histologic end points. Immobilization significantly reduced lateral bending and flexion-extension range of motion. Conclusions The mechanical environment set up by immobilization alone is capable of inducing lumbar disc degeneration at both 6 and 26 weeks in sheep. Longer duration immobilization did not advance disc degeneration process beyond of that found with short duration. The present model produces a degenerative disc with intact annulus and without acute injury, more closely representing the scenario common in human disc degeneration. This provides a suitable large animal in vivo model for the evaluation of the new therapies for disc degeneration. Further studies would do well to examine the effect of remobilization after immobilization in this model.

Increasing bone ongrowth and ingrowth of polyether ether ketone (PEEK) interbody fusion devices has the potential to improve clinical outcomes.This study evaluated the in vivo response of promoting new bone growth and bone apposition with NanoMetalene (NM) compared with PEEK alone in a cancellous implantation site with an empty aperture.This is a randomized control animal study.Implants and funding for this study were provided by SeaSpine (60,000 USD). Cylindrical dowels with two apertures were prepared as PEEK with a sub-micron layer of the titanium (NM). The titanium coating was applied over the entire implant (Group 1) or just the apertures (Group 2). Polyether ether ketone implants with no coating served as controls (Group 3). Implants were placed in the cancellous bone of the distal femur or proximal tibia with no graft material placed in the apertures in eight adult sheep. Bone ongrowth to the surface of the implant and ingrowth into the apertures was assessed at 4 and 8 weeks after surgery with micro-computed tomography (CT) and undecalcified histology.The apertures in the implants were notably empty in the PEEK group at 4 and 8 weeks. In contrast, new bone formation into the apertures was found in samples coated with NM even though no graft material was placed into the defect. The bone growing into the aperture tracked along the titanium layer. Apertures with the titanium coating demonstrated significantly more bone by micro-CT qualitative grading compared with PEEK with average bone coverage scores of Group 1 (NM) 1.62±0.89, Group 2 (NM apertures only) 1.62±0.77, and Group 3 (PEEK) 0.43±0.51, respectively, at 4 weeks (p.01) and Group 1 (NM) 1.79±1.19, Group 2 (NM apertures only) 1.98±1.18, and Group 3 (PEEK) 0.69±0.87, respectively, at 8 weeks (p.05). The amount of bone in the apertures (ingrowth) quantified using the volumetric data from the micro-CT supported an overall increase in bone volume inside the apertures with the titanium coating compared with PEEK. Histology showed newly formed woven bone tracked along the surface of the titanium in the apertures. The PEEK interface presented the typical nonreactive fibrous tissue inside the apertures at 4 weeks and some focal contact with bone on the outside at 4 weeks and 8 weeks.Micro-CT and histology demonstrated bone ongrowth to the surfaces coated with NM where the newly formed bone tracked along the thin titanium-coated surfaces. Polyether ether ketone surfaces presented the nonreactive fibrous tissue at the interface as previously reported in preclinical scenarios.

The slinging of sheep is a commonly reported, yet poorly described procedure, which is useful for the advancement of veterinary and medical preclinical research. We have described a novel, flexible and repeatable method of suspending sheep to varying degrees while not affecting mobility and thereby improving animal husbandry and welfare.

Global gene delivery to the CNS has therapeutic importance for the treatment of neurological disorders that affect the entire CNS. Due to direct contact with the CNS, cerebrospinal fluid (CSF) is an attractive route for CNS gene delivery. A safe and effective route to achieve global gene distribution in the CNS is needed, and administration of genes through the cisterna magna (CM) via a suboccipital puncture results in broad distribution in the brain and spinal cord. However, translation of this technique to clinical practice is challenging due to the risk of serious and potentially fatal complications in patients. Herein, we report development of a gene therapy delivery method to the CM through adaptation of an intravascular microcatheter, which can be safely navigated intrathecally under fluoroscopic guidance. We examined the safety, reproducibility, and distribution/transduction of this method in sheep using a self-complementary adeno-associated virus 9 (scAAV9)-GFP vector. This technique was used to treat two Tay-Sachs disease patients (30 months old and 7 months old) with AAV gene therapy. No adverse effects were observed during infusion or post-treatment. This delivery technique is a safe and minimally invasive alternative to direct infusion into the CM, achieving broad distribution of AAV gene transfer to the CNS.

As spinal fusions require large volumes of bone graft, different bone graft substitutes are being investigated as alternatives. A subclass of calcium phosphate materials with submicron surface topography has been shown to be a highly effective bone graft substitute. In this work, a commercially available biphasic calcium phosphate (BCP) with submicron surface topography (MagnetOs; Kuros Biosciences BV) was evaluated in an Ovine model of instrumented posterolateral fusion. The material was implanted stand-alone, either as granules (BCPgranules) or as granules embedded within a fast-resorbing polymeric carrier (BCPputty) and compared to autograft bone (AG). Twenty-five adult, female Merino sheep underwent posterolateral fusion at L2-3 and L4-5 levels with instrumentation. After 6, 12, and 26 weeks, outcomes were evaluated by manual palpation, range of motion (ROM) testing, micro-computed tomography, histology and histomorphometry. Fusion assessment by manual palpation 12 weeks after implantation revealed 100% fusion rates in all treatment groups. The three treatment groups showed a significant decrease in lateral bending at the fusion levels at 12 weeks (P < 0.05) and 26 weeks (P < 0.001) compared to the 6 week time-point. Flexion-extension and axial rotation were also reduced over time, but statistical significance was only reached in flexion-extension for AG and BCPputty between the 6 and 26 week time-points (P < 0.05). No significant differences in ROM were observed between the treatment groups at any of the time-points investigated. Histological assessment at 12 weeks showed fusion rates of 75%, 92%, and 83% for AG, BCPgranules and BCPputty, respectively. The fusion rates were further increased 26 weeks postimplantation. Similar trends of bone growth were observed by histomorphometry. The fusion mass consisted of at least 55% bone for all treatment groups 26 weeks after implantation. These results suggest that this BCP with submicron surface topography, in granules or putty form, is a promising alternative to autograft for spinal fusion.

Posterolateral spinal fusion (PLF) is a common procedure in orthopedic surgery that is performed to fuse adjacent vertebrae to reduce symptoms related to spinal conditions. In the current study, a novel synthetic calcium phosphate with submicron surface topography was evaluated as an autograft extender in a validated rabbit model of PLF. Fifty‐nine skeletally mature New Zealand white rabbits were divided into three groups and underwent single‐level intertransverse process PLF at L4‐5 using (1) autologous bone graft (ABG) alone or in a 1:1 combination with (2) calcium phosphate granules (ABG/BCPgranules), or (3) granules embedded in a fast‐resorbing polymeric carrier (ABG/BCPputty). After 6, 9, and 12 weeks, animals were sacrificed and spinal fusion was assessed by manual palpation, Radiographs, micro‐CT, mechanical testing (12 weeks only), histology, and histomorphometry. Based on all endpoints, all groups showed a gradual progression in bone formation and maturation during time, leading to solid fusion masses between the transverse processes after 12 weeks. Fusion assessments by manual palpation, radiography and histology were consistent and demonstrated equivalent fusion rates between groups, with high bilateral fusion rates after 12 weeks. Mechanical tests after 12 weeks indicated substantially lower range of motion for all groups, compared to non‐operated controls. By histology and histomorphometry, the gradual formation and maturation of bone in the fusion mass was confirmed for each graft type. With these results, we describe the equivalent performance between autograft and a novel calcium phosphate material as an autograft extender in a rabbit model of PLF using an extensive range of evaluation techniques. © 2019 The Authors. Journal of Biomedical Materials Research Part B: Applied Biomaterials published by Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 2080–2090, 2019.

Management of dead space (DS) is a fundamental aspect of surgery. Residual DS following surgery can fill with hematoma and provide an environment for bacterial growth, increasing the incidence of postoperative infection. Materials for managing DS include polymethyl-methacrylate (PMMA), which is nonresorbing and requires removal in a second surgical procedure. The use of calcium sulfate (CS) offers the advantage of being fully absorbed and does not require subsequent surgical removal. As CS has historically been used as a bone void filler, there are some concerns for the risk of heterotopic ossification (HO) when implanted adjacent to soft tissue. This study assessed the osteoinductive potential of CS and identified and characterised residual material present in muscle tissue using histology, energy-dispersive X-ray spectroscopy analysis, and scanning electron microscopy (SEM). CS beads with and without antibiotic were implanted in intramuscular sites in both athymic rats and New Zealand white rabbits. At 28 days after implantation in the rat model, no signs of osteoinduction were observed. In the rabbit model, at 21 days after implantation, almost complete bead absorption and presence of a “halo” of material in the surrounding muscle tissue were confirmed. Our results suggested that the halo of material was a calcium phosphate precipitate, not HO.

SummaryObjective: To compare the initial biomechanical properties of olecranon osteotomies stabilized with intramedullary pins and a Nitinol bone staple to osteotomies stabilized with pin and tension band wire fixation.Study design: Ex vivo mechanical evaluation on cadaveric bones.Material and methods: Ten pairs of cadaveric forelimbs from skeletally mature Greyhounds with an olecranon osteotomy stabilized with either a pin and Nitinol bone staple or a pin and tension band wire. A single load to failure was applied to each specimen through the triceps tendon. Biomechanical properties were compared based on stiffness, yield load, and maximum load to failure and load at 2 mm of axial displacement.Results: Specimens stabilized with the bone staple were biomechanically superior in all the variables tested. There was significantly greater stiffness (118.0 ± 25.9 N/mm versus 70.1 ± 40.4 N/mm; p = 0.005), yield load (319.0 ± 99.8 N versus 238.0 ± 42.5 N; p = 0.03), maximum load sustained (385.0 ± 99.2 N versus 287.0 ± 37.4 N; p = 0.009), and load at 2 mm of axial displacement (218.0 ± 51.5 N versus 138.0 ± 48.7 N; p = 0.002) in specimens stabilized with pins and a Nitinol bone staple than specimens stabilized with pin and tension band wire fixation.Clinical significance: The pin and Nitinol bone staple construct provides a biomechanically superior alternative to pin and tension band wire fixation for stabilization of olecranon osteotomies, and its use warrants further clinical investigation.Supplementary material for this article is available at https://doi.org/10.3415/VCOT-17-02-0025

Background context The ideal tissue-engineered solution for any bone graft substitute is to assist in the rapid formation of bone and facilitate fusion. Purpose The present study aims to evaluate this E-BMP-2 (Escherichia coli–derived human bone morphogenetic protein-2) in ovine posterolateral lumbar fusion (PLF) to examine the influence of dose and overall performance in a model with similar graft size and diffusive challenges to the human. Study design/setting In vivo large animal model study. Methods An adult ovine PLF was performed in 30 animals with groups of E-BMP-2 with a beta-tricalcium phosphate (β-TCP) carrier at three different dosages, β-TCP alone, and autograft from the iliac crest. The fusions were assessed by radiography (X-ray and microcomputed tomography), mechanical testing, and hard-tissue histology with bone labels at 6, 8, and 10 weeks along with routine paraffin histology at 12 weeks. Results Results showed increasing new bone and fusion rate with E-BMP-2 dose, whereas β-TCP alone was largely resorbed and did not achieve fusion in this model at 12 weeks. Autograft showed similar grading for the amount of bone between the transverse processes but a lower fusion rate than β-TCP/E-BMP-2 groups. Bone labels revealed new bone formation at all time points for the E-BMP2 groups, whereas the autograft group showed active bone formation at 10 weeks. Beta-tricalcium phosphate displayed reliable incorporation into the decorticated host bone, whereas limited new bone was found between the transverse processes. At the center of the fusion mass, increased E-BMP-2 dose led to increased incorporation of β-TCP by new bone. Conclusions These results suggest that E-BMP-2 was capable of producing posterolateral fusion in the ovine model that is equal to or superior to autologous graft in terms of fusion rate and mechanical strength. E-BMP-2 dose had considerable influence on β-TCP granule resorption.

Background Polyetheretherketone (PEEK) has a wide range of clinical applications but does not directly bond to bone. Bulk incorporation of osteoconductive materials including hydroxyapatite (HA) into the PEEK matrix is a potential solution to address the formation of a fibrous tissue layer between PEEK and bone and has not been tested. Questions/purposes Using in vivo ovine animal models, we asked: (1) Does PEEK-HA improve cortical and cancellous bone ongrowth compared with PEEK? (2) Does PEEK-HA improve bone ongrowth and fusion outcome in a more challenging functional ovine cervical fusion model? Methods The in vivo responses of PEEK-HA Enhanced and PEEK-OPTIMA® Natural were evaluated for bone ongrowth in the form of dowels implanted in the cancellous and cortical bone of adult sheep and examined at 4 and 12 weeks as well as interbody cervical fusion at 6, 12, and 26 weeks. The bone-implant interface was evaluated with radiographic and histologic endpoints for a qualitative assessment of direct bone contact of an intervening fibrous tissue later. Gamma-irradiated cortical allograft cages were evaluated as well. Results Incorporating HA into the PEEK matrix resulted in more direct bone apposition as opposed to the fibrous tissue interface with PEEK alone in the bone ongrowth as well as interbody cervical fusions. No adverse reactions were found at the implant–bone interface for either material. Radiography and histology revealed resorption and fracture of the allograft devices in vivo. Conclusions Incorporating HA into PEEK provides a more favorable environment than PEEK alone for bone ongrowth. Cervical fusion was improved with PEEK-HA compared with PEEK alone as well as allograft bone interbody devices. Clinical Relevance Improving the bone–implant interface with a PEEK device by incorporating HA may improve interbody fusion results and requires further clinical studies.

Background The field of orthopaedics is a constantly evolving discipline. Despite the historical success of plates, pins and screws in fracture reduction and stabilisation, there is a continuing search for more efficient and improved methods of fracture fixation. The aim of this study was to evaluate shape-memory staples and to compare them to a currently used implant for internal fracture fixation. Multi-plane bending stability and interfragmentary compression were assessed across a simulated osteotomy using single and double-staple fixation and compared to a bridging plate. Methods Transverse osteotomies were made in polyurethane blocks (20 × 20 × 120 mm) and repairs were performed with one (n = 6), or two (n = 6) 20 mm nitinol staples, or an eight-hole 2.7 mm quarter-tubular plate (n = 6). A pressure film was placed between fragments to determine contact area and compressive forces before and after loading. Loading consisted of multi-planar four-point bending with an actuator displacement of 3 mm. Gapping between segments was recorded to determine loads corresponding to a 2 mm gap and residual post-load gap. Results Staple fixations showed statistically significant higher mean compressive loads and contact areas across the osteotomy compared to plate fixations. Double-staple constructs were superior to single-staple constructs for both parameters (p

We compared two locomotion techniques in an immersive CAVE-like display in order to determine which one promotes better performance in a wayfinding task. One method, commonly found in computer games, allows participants to steer through the 3D scene according to their gaze direction while the other uncouples the gaze direction from the direction of travel. In both cases tracked physical head movements determined the gaze direction. In order to provide a realistic scenario for comparing these methods we devised a task in which participants had to navigate to various houses of a virtual village that was previously seen on a map. The 2D coordinates of paths taken by participants were recorded together with their success rates in finding the targets, and the time taken to reach their destination. Participants showed better results with the pointing method of motion control, reaching the targets faster and with fewer errors. Results are interpreted with respect to the benefits afforded by large field of view displays.

Navigation in large-scale virtual environments is composed of locomotion and wayfinding. We compared two locomotion techniques in an immersive CAVE-like display in order to determine which one promotes better performance in children in a wayfinding task. A ‘treasure hunt’ game scenario was devised in which participants had to navigate to various houses of a virtual village that was previously seen only on a map. The 2D coordinates of paths taken by participants were recorded together with their success rates in finding the targets, and the time taken to reach their destination. Children showed that although the pointing method allowed them better control in locomotion, neither method was preferred in terms of success rates and timing.

Human responses to crowds were investigated with a simulation of a busy street scene using virtual reality. Both psychophysiological measures and a memory test were used to assess the influence of large crowds or individual agents who stood close to the participant while they performed a memory task. Results from most individuals revealed strong orienting responses to changes in the crowd. This was indicated by sharp increases in skin conductance and reduction in peripheral blood volume amplitude. Furthermore, cognitive function appeared to be affected. Results of the memory test appeared to be influenced by how closely virtual agents approached the participants. These findings are discussed with respect to wearable affective computing which seeks robust identifiable correlates of autonomic activity that can be used in everyday contexts.

The ion to neutral ratio of the sputtered material have been studied for high power pulsed magnetron sputtering and compared with a continuous direct current (dc) discharge using the same experimental setup except for the power source. Optical emission spectroscopy (OES) was used to study the optical emission from the plasma through a side window. The emission was shown to be dominated by emission from metal ions. The distribution of metal ionized states clearly differed from the distribution of excited states, and we suggest the presence of a hot dense plasma surrounded by a cooler plasma. Sputtered material was ionized close to the target and transported into a cooler plasma region where the emission was also recorded. Assuming a Maxwell–Boltzmann distribution of excited states the emission from the plasma was quantified. This showed that the ionic contribution to the recorded spectrum was over 90% for high pulse powers. Even at relatively low applied pulse powers, the recorded spectra were dominated by emission from ions. OES analysis of the discharge in a continuous dc magnetron discharge was also made, which demonstrated much lower ionization.

A segmental tibial defect model in a large animal can provide a basis for testing materials and techniques for use in nonunions and severe trauma. This study reports the rationale behind establishing such a model and its design and conclusions. After ethics approval of the study, aged ewes (older than 5 y; n = 12) were enrolled. A 5-cm mid diaphyseal osteoperiosteal defect was made in the left tibia and was stabilized by using an 8-mm stainless-steel cross-locked intramedullary nail. Sheep were euthanized at 12 wk after surgery and evaluated by using radiography, microCT, and soft-tissue histology techniques. Radiology confirmed a lack of hard tissue callus bridging across the defect. Volumetric analysis based on microCT showed bone growth across the 16.5 cm(3) defect of 1.82 ± 0.94 cm(3). Histologic sections of the bridging tissues revealed callus originating from both the periosteal and endosteal surfaces, with fibrous tissue completing the bridging in all instances. Immunohistochemistry was used to evaluate the quality of the healing response. Clinical, radiographic, and histologic union was not achieved by 12 wk. This model may be effective for the investigation of surgical techniques and healing adjuncts for nonunion cases, where severe traumatic injury has led to significant bone loss.

On activation, platelets secrete an array of growth factors that contribute to bone regeneration. Combining platelet-rich plasma (PRP) with bone graft substitutes has the potential to reduce or replace the reliance on autografts. Lack of standardization and improper use may contribute to the conflicting outcomes reported within both preclinical and clinical investigations using PRP. This study investigates the effect of PRP dose on bone augmentation. Eighty critical-sized defects were created in the cancellous bone of the medial proximal tibia and the distal femur of 20 five-year-old female sheep. The defects were treated with three doses of an autologous thrombin-activated PRP combined with a biphasic calcium phosphate (BCP) or autograft and empty defects. Radiography, micro-computed tomography, histology, histomorphometry, and fluorochrome bone labels were examined at 4 weeks. The empty defects did not spontaneously heal. The highest dose of PRP treatment had a significantly greater micro-CT bone volume/total volume compared with the BCP alone (PRP: 30.6%±1.8%; BCP: 24.5%±0.1%). All doses of PRP treatment were significantly greater than the BCP alone for histomorphometric new bone area (PRP: 14.5%±1.3%; BCP: 9.7%±1.5%) and bone ingrowth depth (PRP: 2288±210 μm; BCP:1151±268 μm). From week 2 onward, PRP had a significant effect on the weekly bone ingrowth compared with BCP; however, autografts had the highest amount of weekly fluorescent bone labeling. PRP induces new bone formation with a dose-dependent response at 4 weeks when used with a BCP in sheep.

An immersive first-person 3D computer game was designed and developed to investigate if the visual characteristics of a player's avatar influences their behavior. Two types of gender-matched biped avatar were used: Normal looking Humanoids and tougher looking Aliens. In the game, players had to block incoming projectiles fired from two canons with their hands. The number of times the players were hit as well as a measure of how hard they hit the projectiles was recorded. Results show differences in these measures dependent on the type of avatar used, in line with previous findings whereby people appear to be influenced by the perceived characteristics of their digital representation.

It is clear that humans have mental representations of their spatial environments and that these representations are useful, if not essential, in a wide variety of cognitive tasks such as identification of landmarks and objects, guiding actions and navigation and in directing spatial awareness and attention. Determining the properties of mental representation has long been a contentious issue (see Pinker, 1984). One method of probing the nature of human representation is by studying the extent to which representation can surpass or go beyond the visual (or sensory) experience from which it derives. From a strictly empiricist standpoint what is not sensed cannot be represented; except as a combination of things that have been experienced. But perceptual experience is always limited by our view of the world and the properties of our visual system. It is therefore not surprising when human representation is found to be highly dependent on the initial viewpoint of the observer and on any shortcomings thereof. However, representation is not a static entity; it evolves with experience. The debate as to whether human representation of objects is view-dependent or view-invariant that has dominated research journals recently may simply be a discussion concerning how much information is available in the retinal image during experimental tests and whether this information is sufficient for the task at hand. Here we review an approach to the study of the development of human spatial representation under realistic problem solving scenarios. This is facilitated by the use of realistic virtual environments, exploratory learning and redundancy in visual detail.

Human spatial encoding of three-dimensional navigable space was studied, using a virtual environment simulation. This allowed subjects to become familiar with a realistic scene by making simulated rotational and translational movements during training. Subsequent tests determined whether subjects could generalize their recognition ability by identifying novel-perspective views and topographic floor plans of the scene. Results from picture recognition tests showed that familiar direction views were most easily recognized, although significant generalization to novel views was observed. Topographic floor plans were also easily identified. In further experiments, novel-view performance diminished when active training was replaced by passive viewing of static images of the scene. However, the ability to make self-initiated movements, as opposed to watching dynamic movie sequences, had no effect on performance. These results suggest that representation of navigable space is view dependent and highlight the importance of spatial-temporal continuity during learning.

We investigated shape constancy in human shape from shading under variations of illuminant direction using a local attitude probe in conjunction with a perturbation analysis. Stimuli were computer generated and depicted ellipsoids in a structured setting. Even with these simple shapes subjects settings were systematically biased in the illuminant direction and were consistent with a regression to image luminance gradients. These biases were reduced for high albedo scenes where interreflections make image illuminance more dependent on scene geometry. Adding texture to the surface reduced but did not eliminate this bias. These results suggest that we can expect little constancy in shape from shading under variations of illuminant direction without constraints from other cues. © 1997 Elsevier Science Ltd.

Pictorial relief was measured for a series of pictures of a smooth solid object. The scene was geometrically identical for all pictures, but the rendering was different. Whereas all pictures were monochrome full-scale photographs, they were taken under different illuminations of the scene, the source being frontal and displaced towards either the upper left, the upper right, the lower right, or the lower left. It was found that different illuminations led to significantly different, systematic alterations of pictorial relief. It is concluded that though shape constancy under changes in illumination might be said to rule in the first rough approximation, the deviations from true constancy are indeed both significant and systematic. Different from either stimulus-reduction or cue-conflict paradigms, this ‘perturbation analysis’ shows that shading is used as an important source of information even if the particular illumination appears to be ignored at first blush. For all subjects, brighter parts in the stimulus were consistently interpreted as being nearer in pictorial space, both for the global layout and for the subsidiary relief.

Sophisticated computer graphics were used to generate images of three-dimensional blocks-world scenes to investigate the perception of surface attitude. Three types of surface primitive (planar blocks, cylinders, and ellipsoids) were combined to form structured settings. The experiments were designed to investigate whether surface-based information such as gradients in shading and texture provide any significant advantage in attitude judgments over information derived from object contours. Images of shaded, textured, and line-drawn surfaces formed the stimulus set. The subjects' task consisted of setting an attitude probe on different parts of the scene so that the probe appeared to be locally coplanar with the perceived surfaces. Analysis of settings according to attitude components, slant and tilt, shows remarkable agreement in slant settings for the shaded and line-drawn scenes but poor correlation between shaded and textured scenes. Similarly, tilt was also easily judged in shaded and line-drawn scenes and the experiments indicate that explicit surface boundaries are important for stable tilt perception. In general, the results suggest that, for the simple surfaces employed here, surface cues provide little extra information beyond that which is derived from contours.

Virtual Reality is implemented by a combination of technologies that are used in order to visualize and provide interaction with a virtual environment. These environments often depict three-dimensional space which may be realistic or imaginary, macroscopic or microscopic and based on realistic physical laws of dynamics, or on imaginary dynamics. The multitude of scenarios that VR may be used to depict make it broadly applicable to the many areas in education. A key feature of VR is that it allows multi-sensory interaction with the space being visualized. Here we look at how this combination of multi-sensory visualization and interactivity make VR ideally suited for effective learning and try to explain this effectiveness in terms of the advantages afforded by active learning through experiences. We also consider some of the applications of VR in education and also some of its drawbacks.

We describe the development and evaluation of a large-scale multimodal virtual reality simulation suitable for the visualization of cultural heritage sites and architectural planning. The system is demonstrated with a reconstruction of an ancient Greek temple in Messene that was created as part of a EU funded cultural heritage project (CREATE). The system utilizes a CAVE-like theatre consisting of head-tracked user localization, a haptic interface with two arms, and 3D sound. The haptic interface was coupled with a realistic physics engine allowing users to experience and fully appreciate the effort involved in the construction of architectural components and their changes through the ages. Initial user-based studies were carried out, to evaluate the usability and performance of the system. A simple task of stacking blocks was used to compare errors and timing in a haptics-enabled system with a haptics-disabled system. In addition, a qualitative study of the final system took place while it was installed in a museum.

The perception and recognition of spatial layout of objects within a three-dimensional setting was studied using a virtual reality (VR) simulation. The subject's task was to detect the movement of one of several objects across the surface of a tabletop after a retention interval during which time all objects were occluded from view. Previous experiments have contrasted performance in this task after rotations of the observer's observation point with rotations of just the objects themselves. They found that subjects who walk or move to new observation points perform better than those whose observation point remains constant. This superior performance by mobile observers has been attributed to the influence of non-visual information derived from the proprioceptive or vestibular systems. Our experimental results show that purely visual information derived from simulated movement can also improve subject's performance, although the performance differences manifested themselves primarily in improved response times rather than accuracy of the responses themselves.