Surgeons treating fractures with many small osteochondral fragments have often expressed the clinical need for an adhesive to join such fragments, as an adjunct to standard implants. If an adhesive would maintain alignment of the articular surfaces and subsequently heal it could result in improved clinical outcomes. However, there are no bone adhesives available for clinical indications and few pre-clinical models to assess safety and efficacy of adhesive biomaterial candidates. A bone adhesive candidate based on water, α-TCP and an amino acid phosphoserine was evaluated in-vivo in a novel murine bone core model (preliminary results presented EORS 2019) in which excised bone cores were glued back in place and harvested @ 0, 3, 7, 14, 28 and 42days. Adhesive pull-out strength was demonstrated 0–28 days, with a dip at 14 days increasing to 11.3N maximum. Histology 0–42 days showed the adhesive progressively remodelling to bone in both cancellous and cortical compartments with no signs of either undesirable inflammation or peripheral ectopic bone formation. These favourable results suggested translation to a large animal model.A porcine dental extraction socket model was subsequently developed where dental implants were affixed only with the adhesive. Biomechanical data was collected @ 1, 14, 28 and 56 days, and histology at 1,14,28 and 56 days. Adhesive strength assessed by implant pull-out force increased out to 28 days and maintained out to 56 days (282N maximum) with failure only occurring at the adhesive bone interface. Histology confirmed the adhesive's biocompatibility and osteoconductive behavior. Additionally, remodelling was demonstrated at the adhesive-bone interface with resorption by osteoclast-like cells and followed by new bone apposition and substitution by bone. Whilst the in-vivo dental implant data is encouraging, a large animal preclinical model is needed (under development) to confirm the adhesive is capable of healing, for example, loaded osteochondral bone fragments.Acknowledgements: The murine study was supported, in part, by the Swedish Foundation for Strategic Research (#RMA15-0110).

Background and Aims: Long-term prospective data on patient-reported outcome after surgical treatment of pelvic ring injuries are scarce. This study aimed at describing results at 5 years post-surgery using validated outcome measures. Patients and Methods: Patients admitted for surgical treatment of pelvic ring injuries were prospectively included and asked to report their outcome at 1, 2 and 5 years post-surgery using two patient-reported outcome measures: the generic Short-Form 36 and the condition-specific pelvic discomfort index. Data were evaluated using mixed-effects linear models. Results: There were 108 patients (68 males and 40 females), mean age 38 years. Injury type according to the AO/OTA-classification was B-type in 68 patients and C-type in 40 patients. No domain of the Short-Form 36 reached norm values at 5 years post-surgery. Females reported a worse outcome than males concerning general health (p < 0.01) at 5 years. Recovery of physical function (p < 0.01), mental health (p = 0.04), and pain (p = 0.01) was observed for males at 5 years compared to earlier assessments, while females on the contrary described more pain at this time-point (p = 0.03). Mean pelvic discomfort index at 5 years was 27, indicating moderate residual pelvic discomfort overall. Males reported less pelvic discomfort than females at 5 years (p = 0.02) and improved when compared to results at 2 years (p = 0.02), while females did not. Influence of age, fracture type, and presence of associated injuries on patient-reported outcome was limited. Conclusion: Surgically treated pelvic ring injuries are associated with long-standing negative effects on patient-reported outcome. Males report a better outcome than females at 5 years post-surgery.

A new class of materials, bone adhesives, could revolutionise the treatment of highly fragmented fractures. We present the first biological safety investigation of a bio-inspired bone adhesive. The formulation was based upon a modified calcium phosphate cement that included the amino acid phosphoserine. This material has recently been described as substantially stronger than other bioresorbable calcium phosphate cements. Four adhesive groups with the active substance (phosphoserine) and two control groups without phosphoserine were selected for in vitro and in vivo biocompatibility testing. The test groups were subject for cell viability assay and subcutaneous implantation in rats that was followed by gene expression analysis and histology assessment after 6 and 12 weeks. All adhesive groups supported the same rate of cell proliferation compared to the α-TCP control and had viability between 45–64% when compared to cell control. There was no evidence of an increased immune response or ectopic bone formation in vivo. To conclude, this bio-inspired bone adhesive has been proven to be safe, in the present study, without any harmful effects on the surrounding soft tissue.

Currently there are no standard models with which to evaluate the biomechanical performance of calcified tissue adhesives, in vivo. We present, herein, a pre-clinical murine distal femoral bone model for evaluating tissue adhesives intended for use in both osseous and osteochondral tissue reconstruction. Cylindrical cores (diameter (Ø) 2 mm (mm) × 2 mm depth), containing both cancellous and cortical bone, were fractured out from the distal femur and then reattached using one of two tissue adhesives. The adhesiveness of fibrin glue (Tisseeltm), and a novel, biocompatible, calcium phosphate-based tissue adhesive (OsStictm) were evaluated by pullout testing, in which glued cores were extracted and the peak force at failure recorded. The results show that Tisseel weakly bonded the metaphyseal bone cores, while OsStic produced > 30-fold higher mean peak forces at failure (7.64 Newtons (N) vs. 0.21 N). The failure modes were consistently disparate, with Tisseel failing gradually, while OsStic failed abruptly, as would be expected with a calcium-based material. Imaging of the bone/adhesive interface with microcomputed tomography revealed that, for OsStic, failure occurred more often within cancellous bone (75% of tested samples) rather than at the adhesive interface. Despite the challenges associated with biomechanical testing in small rodent models the preclinical ex-vivo test model presented herein is both sensitive and accurate. It enabled differences in tissue adhesive strength to be quantified even for very small osseous fragments (<Ø4mm). Importantly, this model can easily be scaled to larger animals and adapted to fracture fragment fixation in human bone. The present model is also compatible with other long-term in vivo evaluation methods (i.e. in vivo imaging, histological analysis, etc.).

Designing strategies to deliver functional proteins at physiologically relevant concentrations using chemically cross-linked biocompatible hydrogels is a major field of research. However, the impact of cross-linking chemistry on the encapsulated protein bioactivity is rarely studied. Here we examine the two well-known cross-linking reactions namely; hydrazone cross-linking chemistry and thiol-Michael addition reaction to form hyaluronic acid (HA) hydrogels. As a therapeutic protein, we employed recombinant human bone morphogenetic protein-2 (rhBMP-2) for this study. Incubation of rhBMP-2 with HA functionalized with a thiol diminished phosphorylation of Smad 1/5/8, a signal transducer for osteogenic differntiation, whereas an aldehyde functionalized HA had no effect. This indicates that thiol functionalized polymers indeed has an impact on protein function. To validate this result in an in vivo setting we performed BMP-2 induced bone formation in a rat ectopic model. These experiments revealed that the hydrazone-cross-linked HA-hydrogel induced significantly higher bone formation (18.90 ± 4.25 mm3) as compared to the HA-thiol-Michael hydrogels (1.25 ± 0.52 mm3) after 8 weeks as determined by micro-computed tomography. The histological examination of the neo-bone indicated that hydrazone-hydrogels promoted a better quality of bone formation with improved mineralization and collagen formation as compared to the thiol-Michael hydrogels. We believe such a direct comparison of two cross-linking chemistries will provide new insight for developing biomaterials for protein delivery for in vivo applications.

Background Mutations of the endoplasmic reticulum (ER) stress transducer OASIS (encoded by CREB3L1), cause severe recessive osteogenesis imperfecta (OI) not compatible with surviving the neonatal period, as has been shown in two unrelated families through a whole gene deletion vs. a qualitative alteration of OASIS Heterozygous carriers in the described families have exhibited a mild phenotype. OASIS is a transcription factor highly expressed in osteoblasts, and OASIS(-/-) mice exhibit severe osteopenia and spontaneous fractures. Here, we expand the clinical spectrum by a detailed phenotypic characterization of the first case of OASIS-associated OI surviving the neonatal period, with heterozygous family members being unaffected. Methods: All OI-associated genes were sequenced. Primary human osteoblast-like cell (hOB) and fibroblast (FB) cultures were obtained for qPCR, and steady-state collagen biochemistry. FB, hOB and skin biopsies were ultrastructurally analyzed. Bone was analyzed by |mu CT, histomorphometry, quantitative backscattered electron imaging (qBEI), and Raman microspectroscopy. Results: The proband, a boy with severe OI, had blue sclera and tooth agenesis A homozygous CREB3L1 stop codon mutation was detected by sequencing, while several family members were heterozygotes Markedly low levels of CREB3L1 mRNA were confirmed by qPCR in hOBs (16%) and FB (21%), however, collagen I levels were only reduced in hOBs (5-10%) Electron microscopy of hOBs showed pronounced alterations, with numerous myelin figures and diminished RER vs. normal ultrastructure of FB. Bone histomorphometry and qBEI were similar to collagen I OI, with low trabecular thickness and mineral apposition rate, and increased bone matrix mineralization. Raman microspectroscopy revealed low level of glycosaminoglycans. Clinical response to lifelong bisphosphonate treatment was as expected in severe OI with steadily increasing bone mineral density, but despite this the boy suffered repeated childhood fractures. Conclusions: Deficiency of OASIS can cause severe OI compatible with surviving the neonatal period A marked decrease of collagen type I transcription was noted in bone tissue, but not in skin, and ultrastructure of hOBs was pathological. Results also suggested OASIS involvement in glycosaminoglycan secretion in bone.

There are clinical situations in fracture repair, e.g. osteochondral fragments, where current implant hardware is insufficient. The proposition of an adhesive enabling fixation and healing has been...

Rational Design of Biomaterials for Growth Factor Delivery: Impact of Hydrogel Crosslinking Chemistry on the In Vitroand In VivoBioactivity of Recombinant Human Bone Morphogenetic Protein-2

Objective: We sought to study the anatomic variations of the cochlear aqueduct and its accessory canals in human temporal bones using micro-CT and a 3D reconstruction paradigm. More knowledge about the anatomic variations of these structures, particularly at the basal turn of the cochlea and round window niche, may be important to better preserve residual hearing as well as the neural supply during cochlear implant surgery. Methods: An archival collection of 30 human temporal bones underwent micro-CT and 3D reconstruction. A surface enhancement paradigm was applied. The application displays reconstructed slices as a 3D object with realistic 3D visualization of scanned objects. Virtual sectioning or “cropping” of the petrous bone presented subsequent areas. Thereby, the bony canals could be followed from inside the basal turn of cochlea and middle ear to the jugular foramen. Results: The cochlear aqueduct was always paralleled by an accessory canal containing the inferior cochlear vein. It ran from the basal turn of the cochlea and exited laterally in the jugular foramen. In 70% of the cases, a secondary accessory canal was observed and it derived mostly from a depression or infundibulum located in the floor of the round window niche. This canal also exited in the jugular foramen. The secondary accessory canal occasionally anastomosed with the primary accessory canal suggesting that it contains a vein that drains middle ear blood to the cranial sinus. Conclusion: Micro-CT with 3D surface reconstruction paradigm offers new possibilities to study the topographic anatomy of minor details in the human inner ear. The technique creates simulated transparent “castings” of the labyrinth with a coinciding surface view through enhancement of contrast between boundaries. Accessory canals that drain blood from the cochlea, spiral ganglion, and middle ear could be characterized three-dimensionally.

Localizing and removing the infected sequestrum in long-standing trauma-related chronic osteomyelitis remains a clinical challenge. PET/CT with 18F-fluorodeoxyglucose (FDG-PET) has a high sensitivity for chronic osteomyelitis and 18F-sodium-fluoride PET/CT (NaF-PET) has a high specificity for identifying non-viable bone. Combining both, high signal on FDG-PET in the bone without signal on NaF-PET could potentially guide surgery to become more precise with curative intent.

INTRODUCTION:This study aimed to evaluate clinical results after plaster cast fixation for 10 days versus 1 month of moderately displaced and reduced distal radius fractures.MATERIAL AND METHODS:In a prospective randomized study, 109 patients with moderately displaced and conservatively treated distal radius fractures (age ≥50 years) were randomized 10 days after reduction to either removal of the plaster cast and immediate mobilization (active group) or to continued plaster cast fixation for another 3 weeks (control group). Grip strength, pincer strength, range of motion, and pain were assessed at 1, 4, and 12 months after reduction. Clinical outcome was evaluated using three functional assessment scores at 12 months.RESULTS:Treatment failed in 3/54 (6%) patients in the active group. One of these patients had the plaster cast reinstituted because of feelings of instability. The fractures in the other two patients displaced severely after mobilization and were therefore treated surgically. For the remaining 51 patients in the active group, the range of wrist motion was slightly better at 1 month compared with the controls, but there were no differences in grip or pincer strength or pain at the 1-month follow-up. There were no differences between the active and control group in any outcome at 4 or 12 months, including functional assessment scores at 12 months.CONCLUSION:Treatment with mobilization 10 days after reduction of moderately displaced distal radius fractures resulted in a few treatment failures compared with none among controls. The only functional benefit for the remaining patients was a small and transient increase in range of motion at the 1-month follow-up. Plaster cast removal 10 days after reduction in moderately displaced distal radius fractures is therefore not recommended.

BACKGROUND:The Uppsala collection of human temporal bones and molds is a unique resource for education and international research collaboration. Micro-computerized tomography (micro-CT) and synchrotron imaging are used to investigate the complex anatomy of the inner ear. Impaired microcirculation is etiologically linked to various inner ear disorders, and recent developments in inner ear surgery promote examination of the vascular system. Here, for the first time, we present three-dimensional (3D) data from investigations of the major vascular pathways and corresponding bone channels.METHODS:We used the archival Uppsala collection of temporal bones and molds consisting of 324 inner ear casts and 113 macerated temporal bones. Micro-CT was used to investigate vascular bone channels, and 26 fresh human temporal bones underwent synchrotron radiation phase contrast imaging (SR-PCI). Data were processed by volume-rendering software to create 3D reconstructions allowing orthogonal sectioning, cropping, and soft tissue analyses.RESULTS:Micro-CT with 3D rendering was superior in reproducing the anatomy of the vascular bone channels, while SR-PCI replicated soft tissues. Arterial bone channels were traced from scala vestibuli (SV) arterioles to the fundus, cochlea, and vestibular apparatus. Drainage routes along the aqueducts were examined.CONCLUSION:Human inner ear vessels are difficult to study due to the adjoining hard bone. Micro-CT and SR-PCI with 3D reconstructions revealed large portions of the micro-vascular system in un-decalcified specimens. The results increase our understanding of the organization of the vascular system in humans and how altered microcirculation may relate to inner ear disorders. The findings may also have surgical implications.

Increased precision in the measurement of dorsal angulation in distal radius fractures using the dorsal-ulnar cornaer as the reference point versus Lister’s tubercle

OBJECTIVE:The aim was to study the relationship between the labyrinthine portion (LP) of the facial canal and the cochlea in human inner ear molds and temporal bones using micro-CT and 3D rendering. A reduced cochlea-facial distance may spread electric currents from the cochlear implant to the LP and cause facial nerve stimulation. Influencing factors may be the topographic anatomy and otic capsule properties.METHODS:An archival collection of human temporal bones underwent micro-CT and 3D reconstruction. In addition, cochlea-facial distance was assessed in silicone and polyester resin molds, and the association between the LP and upper basal turn of the cochlea was analyzed.RESULTS:Local thinning of the otic capsule and local anatomy may explain the development of cochlea-facial dehiscence, which was found in 1.4%. A reduced cochlea-facial distance was noted in 1 bone with a superior semicircular canal dehiscence but not in bones with superior semicircular canal "blue line." The otic capsule often impinged upon the LP and caused narrowing.CONCLUSION:Micro-CT with 3D rendering offers new possibilities to study the topographic anatomy of the human temporal bone. The varied shape of the cross-section of the LP could often be explained by an "intruding" cochlea.

Site-specific administration of bone morphogenetic protein-2 (BMP-2) at the site of a bone fracture via scaffolds can minimise systemic side-effects and exhibit sustained biological effects. While ...

The aim of this study was to examine whether reduced distal radius fractures can be treated with early mobilisation without affecting the radiographic results.

There are an increasing number of fragility fractures, which present a surgical challenge given the reduced bone quality of underlying osteoporosis. Particularly in aged patients, there is a need for early weight bearing and mobilization to avoid further complications such as loss of function or autonomy. As an attempt to improve fracture stability and ultimate healing, the use of biomaterials for augmentation of osseous voids and fracture fixation is a promising treatment option. Augmentation techniques can be applied in various locations, and fractures of the metaphyseal regions such as proximal humerus, femur, tibia and the distal radius remain the most common areas for its use. The current review, based on the available mechanical and biological data, provides an overview of the relevant treatment options and different composites used for augmentation of osteoporotic fractures.