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Ensanya Ali Abou Neel,1–3 Anas Aljabo,3 Adam Strange,3 Salwa Ibrahim,3 Melanie Coathup,4 Anne M Young,3 Laurent Bozec,3 Vivek Mudera4 1Division of Biomaterials, Operative Dentistry Department, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia; 2Biomaterials Department, Faculty of Dentistry, Tanta University, Tanta, Egypt; 3Department of Biomaterials and Tissue Engineering, UCL Eastman Dental Institute, London, UK; 4UCL Institute of Orthopaedics and Musculoskeletal Sciences, Royal National Orthopaedic Hospital, Stanmore, London, UK Abstract: Biomineralization is a dynamic, complex, lifelong process by which living organisms control precipitations of inorganic nanocrystals within organic matrices to form unique hybrid biological tissues, for example, enamel, dentin, cementum, and bone. Understanding the process of mineral deposition is important for the development of treatments for mineralization-related diseases and also for the innovation and development of scaffolds. This review provides a thorough overview of the up-to-date information on the theories describing the possible mechanisms and the factors implicated as agonists and antagonists of mineralization. Then, the role of calcium and phosphate ions in the maintenance of teeth and bone health is described. Throughout the life, teeth and bone are at risk of demineralization, with particular emphasis on teeth, due to their anatomical arrangement and location. Teeth are exposed to food, drink, and the microbiota of the mouth; therefore, they have developed a high resistance to localized demineralization that is unmatched by bone. The mechanisms by which demineralization–remineralization process occurs in both teeth and bone and the new therapies/technologies that reverse demineralization or boost remineralization are also scrupulously discussed. Technologies discussed include composites with nano- and micron-sized inorganic minerals that can mimic mechanical properties of the tooth and bone in addition to promoting more natural repair of surrounding tissues. Turning these new technologies to products and practices would improve health care worldwide. Keywords: demineralization, remineralization, teeth, bone and calcium phosphates

Summary Polyetheretherketone (PEEK) is an alternative to metallic implants in orthopedic applications; however, PEEK is bioinert and does not osteointegrate. In this study, an accelerated neutral atom beam technique (ANAB) was employed to improve the bioactivity of PEEK. The aim was to investigate the growth of human mesenchymal stem cells (hMSCs), human osteoblasts (hOB), and skin fibroblasts (BR3G) on PEEK and ANAB PEEK. Methods The surface roughness and contact angle of PEEK and ANAB PEEK was measured. Cell metabolic activity, proliferation and alkaline phosphatase (ALP) was measured and cell attachment was determined by quantifying adhesion plaques with cells. Results ANAB treatment increased the surface hydrophilicity [91.74 ± 4.80° (PEEK) vs. 74.82 ± 2.70° (ANAB PEEK), p < 0.001] but did not alter the surface roughness. Metabolic activity and proliferation for all cell types significantly increased on ANAB PEEK compared to PEEK ( p < 0.05). Significantly increased cell attachment was measured on ANAB PEEK surfaces. MSCs seeded on ANAB PEEK in the presence of osteogenic media, expressed increased levels of ALP compared to untreated PEEK ( p < 0.05) Conclusion Our results demonstrated that ANAB treatment increased the cell attachment, metabolic activity, and proliferation on PEEK. ANAB treatment may improve the osteointegration of PEEK implants. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1438-1446, 2017. [ABSTRACT FROM AUTHOR]

Hemorrhage is one of the leading causes of preventable death. While minor injuries can be treated mainly by conventional methods, deep and irregular wounds with profuse bleeding present significant challenges, some of which can be life-threatening and fatal. This underscores the need to develop easily applicable FDA-approved hemostatic treatments that can effectively stanch blood loss at the point of care before professional medical care. A silicone-based bandage system (SilFoam), a non-compressible, self-expanding, antibacterial hemostatic treatment, is reported here. Its two-component system reacts in situ upon mixing to form a stretchable sponge that acts as a 'tamponade' by expanding within seconds with the evolution of oxygen gas from the interaction of the reactive components present in the formulation. This generates autogenous pressure on the wound that can effectively arrest heavy bleeding within minutes. Possessing optimal adhesive properties, the expanded sponge can be easily removed, rendering it optimal for hemostatic wound dressing. With recent advances in biotechnological research, there is a growing awareness of the potential issues associated with in vivo trials, spanning ethical, psychological, economic, and physiological concerns like burnout and fatigue. Bearing this in mind, a unique manikin system simulating a deep abdominal wound has been employed to investigate SilFoam's hemostatic efficacy with different blood-flow rates using a non-invasive model that aims to provide an easy, fast, and economical route to test hemostatic treatments before in vivo studies. This is the first time an Ag 2 O-based oxygen-induced foaming system has been reported as a hemostatic agent.

By 2060, an estimated one in four Americans will be elderly. Consequently, the prevalence of osteoporosis and fragility fractures will also increase. Presently, no available intervention definitively prevents or manages osteoporosis. This study explores whether Pool 7 Compound 3 (P7C3) reduces progressive bone loss and fragility following the onset of ovariectomy (OVX)-induced osteoporosis. Results confirm OVX-induced weakened, osteoporotic bone together with a significant gain in adipogenic body weight. Treatment with P7C3 significantly reduced osteoclastic activity, bone marrow adiposity, whole-body weight gain, and preserved bone area, architecture, and mechanical strength. Analyses reveal significantly upregulated platelet derived growth factor-BB and leukemia inhibitory factor, with downregulation of interleukin-1 R6, and receptor activator of nuclear factor kappa-B (RANK). Together, proteomic data suggest the targeting of several key regulators of inflammation, bone, and adipose turnover, via transforming growth factor-beta/SMAD, and Wingless-related integration site/be-catenin signaling pathways. To the best of the knowledge, this is first evidence of an intervention that drives against bone loss via RANK. Metatranscriptomic analyses of the gut microbiota show P7C3 increased Porphyromonadaceae bacterium, Candidatus Melainabacteria, and Ruminococcaceae bacterium abundance, potentially contributing to the favorable inflammatory, and adipo-osteogenic metabolic regulation observed. The results reveal an undiscovered, and multifunctional therapeutic strategy to prevent the pathological progression of OVX-induced bone loss., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Reducible metal oxide nanozymes (rNZs) are a subject of intense recent interest due to their catalytic nature, ease of synthesis, and complex surface character. Such materials contain surface sites which facilitate enzyme-mimetic reactions via substrate coordination and redox cycling. Further, these surface reactive sites are shown to be highly sensitive to stresses within the nanomaterial lattice, the physicochemical environment, and to processing conditions occurring as part of their syntheses. When administered in vivo, a complex protein corona binds to the surface, redefining its biological identity and subsequent interactions within the biological system. Catalytic activities of rNZs each deliver a differing impact on protein corona formation, its composition, and in turn, their recognition, and internalization by host cells. Improving the understanding of the precise principles that dominate rNZ surface-biomolecule adsorption raises the question of whether designer rNZs can be engineered to prevent corona formation, or indeed to produce "custom" protein coronas applied either in vitro, and preadministration, or formed immediately upon their exposure to body fluids. Here, fundamental surface chemistry processes and their implications in rNZ material performance are considered. In particular, material structures which inform component adsorption from the application environment, including substrates for enzyme-mimetic reactions are discussed., (© 2023 Wiley-VCH GmbH.)

This study investigates the effect of porosity and pore shape on the biological and mechanical behavior of additively manufactured scaffolds for bone tissue engineering (BTE). Polylactic acid scaffolds with varying porosity levels (15-78%) and pore shapes, including regular (rectangular pores), gyroid, and diamond (triply periodic minimal surfaces) structures, are fabricated by fused filament fabrication. Murine-derived macrophages and human bone marrow-derived mesenchymal stromal cells (hBMSCs) are seeded onto the scaffolds. The compressive behavior and surface morphology of the scaffolds are characterized. The results show that scaffolds with 15%, 30%, and 45% porosity display the highest rate of macrophage and hBMSC growth. Gyroid and diamond scaffolds exhibit a higher rate of macrophage proliferation, while diamond scaffolds exhibit a higher rate of hBMSC proliferation. Additionally, gyroid and diamond scaffolds exhibit better compressive behavior compared to regular scaffolds. Of particular note, diamond scaffolds have the highest compressive modulus and strength. Surface morphology characterization indicates that the surface roughness of diamond and gyroid scaffolds is greater than that of regular scaffolds at the same porosity level, which is beneficial for cell attachment and proliferation. This study provides valuable insights into porosity and pore shape selection for additively manufactured scaffolds in BTE., (© 2023 Wiley-VCH GmbH.)

Aim: The challenge of distal femoral replacement (DFR) longevity remains a priority for orthopaedic oncologists as the overall survival and activity level of young patients with osteosarcoma continues to improve. This study hypothesized that increased extracortical osseointegration at the bone-implant shoulder (i.e., where the metal implant shaft abuts the femur) will improve stress transfer adjacent to the implant, as evidenced by reduced cortical bone loss, radiolucent line progression and implant failure in young patients (< 20 years) following DFR surgery., Methods: Twenty-nine patients of mean age 13.09 ± 0.56 years received a primary DFR. The clinical outcome of 11 CPS®, 10 GMRS®, 5 Stanmore® and 3 Repiphysis® implants was evaluated over a mean follow-up period of 4.25 ± 0.55 years. The osseous response to a bone-implant shoulder composed of either a hydroxyapatite-coated grooved ingrowth collar (Stanmore®), a porous metal coating (GMRS®) or a polished metal surface (Repiphysis®) was quantified radiographically., Results: All (100.0%) of the Stanmore® implants, 90.0% of GMRS®, 81.8% of CPS® and 33.3% of the Repiphysis® implants survived. Significantly increased extracortical bone and osseointegration were measured adjacent to the Stanmore® bone-implant shoulder when compared with the GMRS® and Repiphysis® implants (p < 0.0001 in both cases). Significantly decreased cortical loss was identified in the Stanmore® group (p = 0.005, GMRS® and p < 0.0001, Repiphysis®) and at 3 years, the progression of radiolucent lines adjacent to the intramedullarly stem was reduced when compared with the GMRS® and Repiphysis® implants (p = 0.012 and 0.026, respectively)., Conclusions: Implants designed to augment osseointegration at the bone-implant shoulder may be critical in reducing short- (≤ 2 years) to mid- (≤ 5 years) term aseptic loosening in this vulnerable DFR patient group. Further longer-term studies are required to confirm these preliminary findings., (© 2023. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Nanotechnology has expanded what can be achieved in our approach to cancer treatment. The ability to produce and engineer functional nanoparticle formulations to elicit higher incidences of tumor cell radiolysis has resulted in substantial improvements in cancer cell eradication while also permitting multi-modal biomedical functionalities. These radiosensitive nanomaterials utilize material characteristics, such as radio-blocking/absorbing high-Z atomic number elements, to mediate localized effects from therapeutic irradiation. These materials thereby allow subsequent scattered or emitted radiation to produce direct (e.g., damage to genetic materials) or indirect (e.g., protein oxidation, reactive oxygen species formation) damage to tumor cells. Using nanomaterials that activate under certain physiologic conditions, such as the tumor microenvironment, can selectively target tumor cells. These characteristics, combined with biological interactions that can target the tumor environment, allow for localized radio-sensitization while mitigating damage to healthy cells. This review explores the various nanomaterial formulations utilized in cancer radiosensitivity research. Emphasis on inorganic nanomaterials showcases the specific material characteristics that enable higher incidences of radiation while ensuring localized cancer targeting based on tumor microenvironment activation. The aim of this review is to guide future research in cancer radiosensitization using nanomaterial formulations and to detail common approaches to its treatment, as well as their relations to commonly implemented radiotherapy techniques.

This study aims to present an ultrasound-mediated nanobubble (NB)-based gene delivery system that could potentially be applied in the future to treat bone disorders such as osteoporosis. NBs are sensitive to ultrasound (US) and serve as a controlled-released carrier to deliver a mixture of Cathepsin K (CTSK) siRNA and cerium oxide nanoparticles (CeNPs). This platform aimed to reduce bone resorption via downregulating CTSK expression in osteoclasts and enhance bone formation via the antioxidant and osteogenic properties of CeNPs. CeNPs were synthesized and characterized using transmission electron microscopy and X-ray photoelectron spectroscopy. The mixture of CTSK siRNA and CeNPs was adsorbed to the surface of NBs using a sonication method. The release profiles of CTSK siRNA and CeNPs labeled with a fluorescent tag molecule were measured after low-intensity pulsed ultrasound (LIPUS) stimulation using fluorescent spectroscopy. The maximum release of CTSK siRNA and the CeNPs for 1 mg/mL of NB-(CTSK siRNA + CeNPs) was obtained at 2.5 nM and 1 µg/mL, respectively, 3 days after LIPUS stimulation. Then, Alizarin Red Staining (ARS) was applied to human bone marrow-derived mesenchymal stem cells (hMSC) and tartrate-resistant acid phosphatase (TRAP) staining was applied to human osteoclast precursors (OCP) to evaluate osteogenic promotion and osteoclastogenic inhibition effects. A higher mineralization and a lower number of osteoclasts were quantified for NB-(CTSK siRNA + CeNPs) versus control +RANKL with ARS ( p < 0.001) and TRAP-positive staining ( p < 0.01). This study provides a method for the delivery of gene silencing siRNA and CeNPs using a US-sensitive NB system that could potentially be used in vivo and in the treatment of bone fractures and disorders such as osteoporosis.

Objective: Proximal junctional kyphosis is a commonly encountered clinical and radiographic phenomenon after pediatric and adolescent spinal deformity surgery that may lead to postoperative deformity, pain, and dissatisfaction. The purpose of the study was to identify whether the placement of transverse process hooks is an effective way to prevent PJK., Methods: Adolescent idiopathic scoliosis patients who underwent posterior spinal fusion between November 2015 and May 2019 were retrospectively analyzed. A minimum 2-year follow-up was required. Demographic and surgical data included UIV level type of instrumentation (hook vs screw) were reported. Radiologic parameters included main curve Cobb angle, thoracic kyphosis (TK), lumbar lordosis (LL), pelvic incidence (PI), and proximal junctional angle (PJA) were assessed. Patients were divided into two groups based on the type of instrumentation at the UIV level whether placement of hook versus pedicle screw., Results: Three hundred and thirty-seven patients were included with the mean age 14.2 ± 1.9 years. Thirty patients (8.9%) were diagnosed with proximal junctional kyphosis radiographically. PJK incidence was found 3.2% (5/154) in the hook group and 13.3% (23/172) in the screw group and the difference found statistically significant. In the PJK group, preoperative thoracic kyphosis and the degree of kyphosis correction were also significantly higher than non-PJK patients., Conclusion: Placement of transverse process hooks at the UIV level in posterior spinal fusion surgery for AIS patients was associated with decreased risk of PJK. A larger preoperative kyphosis and greater degree of kyphosis correction correlated with PJK., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Interest in space exploration has seen substantial growth following recent launch and operation of modern space technologies. In particular, the possibility of travel beyond low earth orbit is seeing sustained support. However, future deep space travel requires addressing health concerns for crews under continuous, longer-term exposure to adverse environmental conditions. Among these challenges, radiation-induced health issues are a major concern. Their potential to induce chronic illness is further potentiated by the microgravity environment. While investigations into the physiological effects of space radiation are still under investigation, studies on model ionizing radiation conditions, in earth and micro-gravity conditions, can provide needed insight into relevant processes. Substantial formation of high, sustained reactive oxygen species (ROS) evolution during radiation exposure is a clear threat to physiological health of space travelers, producing indirect damage to various cell structures and requiring therapeutic address. Radioprotection toward the skeletal system components is essential to astronaut health, due to the high radio-absorption cross-section of bone mineral and local hematopoiesis. Nanotechnology can potentially function as radioprotectant and radiomitigating agents toward ROS and direct radiation damage. Nanoparticle compositions such as gold, silver, platinum, carbon-based materials, silica, transition metal dichalcogenides, and ceria have all shown potential as viable radioprotectants to mitigate space radiation effects with nanoceria further showing the ability to protect genetic material from oxidative damage in several studies. As research into space radiation-induced health problems develops, this review intends to provide insights into the nanomaterial design to ameliorate pathological effects from ionizing radiation exposure. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Nanotechnology Approaches to Biology > Cells at the Nanoscale Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease., (© 2023 Wiley Periodicals LLC.)

Radiotherapy is a critical component of cancer care but can cause osteoporosis and pathological insufficiency fractures in surrounding and otherwise healthy bone. Presently, no effective countermeasure exists, and ionizing radiation-induced bone damage continues to be a substantial source of pain and morbidity. The purpose of this study was to investigate a small molecule aminopropyl carbazole named P7C3 as a novel radioprotective strategy. Our studies revealed that P7C3 repressed ionizing radiation (IR)-induced osteoclastic activity, inhibited adipogenesis, and promoted osteoblastogenesis and mineral deposition in vitro. We also demonstrated that rodents exposed to clinically equivalent hypofractionated levels of IR in vivo develop weakened, osteoporotic bone. However, the administration of P7C3 significantly inhibited osteoclastic activity, lipid formation and bone marrow adiposity and mitigated tissue loss such that bone maintained its area, architecture, and mechanical strength. Our findings revealed significant enhancement of cellular macromolecule metabolic processes, myeloid cell differentiation, and the proteins LRP-4, TAGLN, ILK, and Tollip, with downregulation of GDF-3, SH2B1, and CD200. These proteins are key in favoring osteoblast over adipogenic progenitor differentiation, cell matrix interactions, and shape and motility, facilitating inflammatory resolution, and suppressing osteoclastogenesis, potentially via Wnt/β-catenin signaling. A concern was whether P7C3 afforded similar protection to cancer cells. Preliminarily, and remarkably, at the same protective P7C3 dose, a significant reduction in triple-negative breast cancer and osteosarcoma cell metabolic activity was found in vitro. Together, these results indicate that P7C3 is a previously undiscovered key regulator of adipo-osteogenic progenitor lineage commitment and may serve as a novel multifunctional therapeutic strategy, leaving IR an effective clinical tool while diminishing the risk of adverse post-IR complications. Our data uncover a new approach for the prevention of radiation-induced bone damage, and further work is needed to investigate its ability to selectively drive cancer cell death., (© 2023. The Author(s).)

Few studies have investigated the effect of a monosaturated diet high in ω-9 on osteoporosis. We hypothesized that omega-9 (ω-9) protects ovariectomized (OVX) mice from a decline in bone microarchitecture, tissue loss, and mechanical strength, thereby serving as a modifiable dietary intervention against osteoporotic deterioration. Female C57BL/6J mice were assigned to sham-ovariectomy, ovariectomy, or ovariectomy + estradiol treatment prior to switching their feed to a diet high in ω-9 for 12 weeks. Tibiae were evaluated using DMA, 3-point-bending, histomorphometry, and microCT. A significant decrease in lean mass ( p = 0.05), tibial area ( p = 0.009), and cross-sectional moment of inertia ( p = 0.028) was measured in OVX mice compared to the control. A trend was seen where OVX bone displayed increased elastic modulus, ductility, storage modulus, and loss modulus, suggesting the ω-9 diet paradoxically increased both stiffness and viscosity. This implies beneficial alterations on the macro-structural, and micro-tissue level in OVX bone, potentially decreasing the fracture risk. Supporting this, no significant differences in ultimate, fracture, and yield stresses were measured. A diet high in ω-9 did not prevent microarchitectural deterioration, nevertheless, healthy tibial strength and resistance to fracture was maintained via mechanisms independent of bone structure/shape. Further investigation of ω-9 as a therapeutic in osteoporosis is warranted.

Optimizing the biological identity of nanoparticles (NPs) for efficient tumor uptake remains challenging. The controlled formation of a protein corona on NPs through protein absorption from biofluids could favor a biological identity that enables tumor accumulation. To increase the diversity of proteins absorbed by NPs, sera derived from Influenza A virus (IAV)-infected mice were used to pre-coat NPs formed using a hyperbranched polyester polymer (HBPE-NPs). HBPE-NPs, encapsulating a tracking dye or cancer drug, were treated with sera from days 3-6 of IAV infection (VS3-6), and uptake of HBPE-NPs by breast cancer cells was examined. Cancer cells demonstrated better uptake of HBPE-NPs pre-treated with VS3-6 over polyethylene glycol (PEG)-HBPE-NPs, a standard NP surface modification. The uptake of VS5 pre-treated HBPE-NPs by monocytic cells (THP-1) was decreased over PEG-HBPE-NPs. VS5-treated HBPE-NPs delivered a cancer drug more efficiently and displayed better in vivo distribution over controls, remaining stable even after interacting with endothelial cells. Using a proteomics approach, proteins absorbed from sera-treated HBPE-NPs were identified, such as thrombospondin-1 (TSP-1), that could bind multiple cancer cell receptors. Our findings indicate that serum collected during an immune response to infection is a rich source of macromolecules that are absorbed by NPs and modulate their biological identity, achieving rationally designed uptake by targeted cell types.

The disability, mortality and costs due to ionizing radiation (IR)-induced osteoporotic bone fractures are substantial and no effective therapy exists. Ionizing radiation increases cellular oxidative damage, causing an imbalance in bone turnover that is primarily driven via heightened activity of the bone-resorbing osteoclast. We demonstrate that rats exposed to sublethal levels of IR develop fragile, osteoporotic bone. At reactive surface sites, cerium ions have the ability to easily undergo redox cycling: drastically adjusting their electronic configurations and versatile catalytic activities. These properties make cerium oxide nanomaterials fascinating. We show that an engineered artificial nanozyme composed of cerium oxide, and designed to possess a higher fraction of trivalent (Ce 3+ ) surface sites, mitigates the IR-induced loss in bone area, bone architecture, and strength. These investigations also demonstrate that our nanozyme furnishes several mechanistic avenues of protection and selectively targets highly damaging reactive oxygen species, protecting the rats against IR-induced DNA damage, cellular senescence, and elevated osteoclastic activity in vitro and in vivo . Further, we reveal that our nanozyme is a previously unreported key regulator of osteoclast formation derived from macrophages while also directly targeting bone progenitor cells, favoring new bone formation despite its exposure to harmful levels of IR in vitro . These findings open a new approach for the specific prevention of IR-induced bone loss using synthesis-mediated designer multifunctional nanomaterials., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: Joint degeneration and large or complex bone defects are a significant source of morbidity and diminished quality of life worldwide. There is an unmet need for a functional implant with near-native biomechanical properties. The potential for their generation using 3D bioprinting (3DBP)-based tissue engineering methods was assessed. We systematically reviewed the current state of 3DBP in orthoregeneration., Methods: This review was performed using PubMed and Web of Science. Primary research articles reporting 3DBP of cartilage, bone, vasculature, and their osteochondral and vascular bone composites were considered. Full text English articles were analyzed., Results: Over 1300 studies were retrieved, after removing duplicates, 1046 studies remained. After inclusion and exclusion criteria were applied, 114 articles were analyzed fully. Bioink material types and combinations were tallied. Cell types and testing methods were also analyzed. Nearly all papers determined the effect of 3DBP on cell survival. Bioink material physical characterization using gelation and rheology, and construct biomechanics were performed. In vitro testing methods assessed biochemistry, markers of extracellular matrix production and/or cell differentiation into respective lineages. In vivo proof-of-concept studies included full-thickness bone and joint defects as well as subcutaneous implantation in rodents followed by histological and µCT analyses to demonstrate implant growth and integration into surrounding native tissues., Conclusions: Despite its relative infancy, 3DBP is making an impact in joint and bone engineering. Several groups have demonstrated preclinical efficacy of mechanically robust constructs which integrate into articular joint defects in small animals. However, notable obstacles remain. Notably, researchers encountered pitfalls in scaling up constructs and establishing implant function and viability in long term animal models. Further, to translate from the laboratory to the clinic, standardized quality control metrics such as construct stiffness and graft integration metrics should be established with investigator consensus. While there is much work to be done, 3DBP implants have great potential to treat degenerative joint diseases and provide benefit to patients globally., (© 2022. The Author(s).)

The influence of diet on the development of osteoporosis is significant and not fully understood. This study investigated the effect of diets of varying lipid profiles and ω-3, ω-6 and ω-9 composition on the structural and mechanical properties of bone. The hypothesis studied was that a diet high in saturated fat would induce osteoporosis and produce an overall increased detrimental bony response when compared with a diet high in unsaturated ω-6, or ω-9. Male C57BL/6J mice were fed either a control diet, 50:50 mix (saturated:unsaturated) high in ω-9 (HFD50:50), a diet high in saturated fat (HSF) or a polyunsaturated fat diet high in ω-6 (PUFA) over an 8-week duration. Tibiae were retrieved and evaluated using DMA, 3-point-bending, histomorphometry, and microCT. Mice fed a HSF diet displayed key features characteristic of osteoporosis. The loss tangent was significantly increased in the HFD50:50 diet group compared with control (p = 0.016) and PUFA-fed animals (p = 0.049). HFD50:50-fed mice presented with an increased viscous component, longer tibiae, increased loss modulus (p = 0.009), and ultimate stress, smaller microcracks (p < 0.001), and increased trabecular width (p = 0.002) compared with control animals. A diet high in ω-9 resulted in an overall superior bone response and further analysis of its role in bone health is warranted.

Increased bone loss and risk of fracture are two of the main challenges for cancer patients who undergo ionizing radiation (IR) therapy. This decline in bone quality is in part, caused by the excessive and sustained release of reactive oxygen species (ROS). Cerium oxide nanoparticles (CeONPs) have proven antioxidant and regenerative properties and the purpose of this study was to investigate the effect of CeONPs in reducing IR-induced functional damage in human bone marrow-derived mesenchymal stromal cells (hBMSCs). hBMSCs were supplemented with CeONPs at a concentration of either 1 or 10 μg/mL 24 h prior to exposure to a single 7 Gy irradiation dose. ROS levels, cellular proliferation, morphology, senescence, DNA damage, p53 expression and autophagy were evaluated as well as alkaline phosphatase, osteogenic protein gene expression and bone matrix deposition following osteogenic differentiation. Results showed that supplementation of CeONPs at a concentration of 1 μg/mL reduced cell senescence and significantly augmented cell autophagy (p = 0.01), osteogenesis and bone matrix deposition >2-fold (p = 0.0001) while under normal, non-irradiated culture conditions. Following irradiation, functional damage was attenuated and CeONPs at both 1 or 10 μg/mL significantly reduced ROS levels (p = 0.05 and 0.001 respectively), DNA damage by >4-fold (p < 0.05) while increasing autophagy >3.5-fold and bone matrix deposition 5-fold (p = 0.0001 in both groups). When supplemented with 10 μg/mL, p53 expression increased 3.5-fold (p < 0.05). We conclude that cellular uptake of CeONPs offered a significant, multifunctional and protective effect against IR-induced cellular damage while also augmenting osteogenic differentiation and subsequent new bone deposition. The use of CeONPs holds promise as a novel multifunctional therapeutic strategy for irradiation-induced bone loss., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: This study compared the incidence of osteolysis, aseptic loosening, and revision following use of highly cross-linked polyethylene (HXLPE) or conventional polyethylene (CPE) at medium to long-term (>5 to 15 years) follow-up in primary total hip arthroplasty (THA). Incidences were quantified and compared with regard to age and method of implant fixation., Methods: Using the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines, 12 randomized controlled trials and 18 cohort studies were investigated for evidence-based outcomes following HXPLE and CPE use in 2,539 hips over a 5 to 15-year follow-up., Results: Lower rates of osteolysis, aseptic loosening, and implant revision were reported following use of HXLPE liners. Osteolysis was reduced from 25.4% with CPE to 4.05% with HXLPE in young patients, and from 29.7% to 6.6% in the older patient cohort. Similarities in osteolysis rates were observed when cemented (24.9% for CPE and 6.5% for HXLPE) and uncemented components (32.8% for CPE and 7.1% for HXLPE) were compared. No clear advantage in the type of HXLPE used was observed., Conclusions: Over a follow-up period of up to 15 years, when compared with CPE, use of HXLPE liners reduced the incidence of osteolysis, aseptic loosening, and implant revision, regardless of the fixation method and including in younger and potentially more active patients., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The authors indicated that no external funding was received for any aspect of this work. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/G272)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Aims: Periprosthetic joint infection (PJI) is a debilitating condition with a substantial socioeconomic burden. A novel autologous blood glue (ABG) has been developed, which can be prepared during surgery and sprayed onto prostheses at the time of implantation. The ABG can potentially provide an antimicrobial coating which will be effective in preventing PJI, not only by providing a physical barrier but also by eluting a well-known antibiotic. Hence, this study aimed to assess the antimicrobial effectiveness of ABG when impregnated with gentamicin and stem cells., Methods: Gentamicin elution from the ABG matrix was analyzed and quantified in a time-dependent manner. The combined efficiency of gentamicin and ABG as an anti-biofilm coating was investigated on titanium disks., Results: ABG-gentamicin was bactericidal from 10 μg/ml and could release bactericidal concentrations over seven days, preventing biofilm formation. A concentration of 75 μg/ml of gentamicin in ABG showed the highest bactericidal effect up to day 7. On titanium disks, a significant bacterial reduction on ABG-gentamicin coated disks was observed when compared to both uncoated (mean 2-log reduction) and ABG-coated (mean 3-log reduction) disks, at days 3 and 7. ABG alone exhibited no antimicrobial or anti-biofilm properties. However, a concentration of 75 μg/ml gentamicin in ABG sustains release over seven days and significantly reduced biofilm formation. Its use as an implant coating in patients with a high risk of infection may prevent bacterial adhesion perioperatively and in the early postoperative period., Conclusion: ABG's use as a carrier for stem cells was effective, as it supported cell growth. It has the potential to co-deliver compatible cells, drugs, and growth factors. However, ABG-gentamicin's potential needs to be further justified using in vivo studies. Cite this article: Bone Joint Res 2020;9(12):848-856.

Aims: For cementless implants, stability is initially attained by an interference fit into the bone and osteo-integration may be encouraged by coating the implant with bioactive substances. Blood based autologous glue provides an easy, cost-effective way of obtaining high concentrations of growth factors for tissue healing and regeneration with the intention of spraying it onto the implant surface during surgery. The aim of this study was to incorporate nucleated cells from autologous bone marrow (BM) aspirate into gels made from the patient's own blood, and to investigate the effects of incorporating three different concentrations of platelet rich plasma (PRP) on the proliferation and viability of the cells in the gel., Methods: The autologous blood glue (ABG) that constituted 1.25, 2.5, and 5 times concentration PRP were made with and without equal volumes of BM nucleated cells. Proliferation, morphology, and viability of the cells in the glue was measured at days 7 and 14 and compared to cells seeded in fibrin glue., Results: Overall, 2.5 times concentration of PRP in ABG was capable of supporting the maximum growth of cells isolated from the BM aspirate and maintain their characteristics. Irrespective of PRP concentration, cells in ABG had statistically significantly higher viability compared to cells in fibrin glue., Conclusion: In vitro this novel autologous gel is more capable of supporting the growth of cells in its structure for up to 14 days, compared to commercially available fibrin-based sealants, and this difference was statistically significant.Cite this article: Bone Joint Res 2020;9(7):402-411., (© 2020 Author(s) et al.)

Aims: Limb salvage in bone tumour patients replaces the bone with massive segmental prostheses where achieving bone integration at the shoulder of the implant through extracortical bone growth has been shown to prevent loosening. This study investigates the effect of multidrug chemotherapy on extracortical bone growth and early radiological signs of aseptic loosening in patients with massive distal femoral prostheses., Methods: A retrospective radiological analysis was performed on adult patients with distal femoral arthroplasties. In all, 16 patients were included in the chemotherapy group with 18 patients in the non-chemotherapy control group. Annual radiographs were analyzed for three years postoperatively. Dimensions of the bony pedicle, osseointegration of the hydroxyapatite (HA) collar surface, bone resorption at the implant shoulder, and radiolucent line (RLL) formation around the cemented component were analyzed., Results: A greater RLL score (p = 0.041) was observed at three years postoperatively, with those receiving chemotherapy showing greater radiological loosening compared with those not receiving chemotherapy. Chemotherapy patients experience osteolysis at the shoulder of the ingrowth collar over time (p < 0.001) compared with non-chemotherapy patients where osteolysis was not observed. A greater median percentage integration of the collar surface was observed in the non-chemotherapy group (8.6%, interquartile range (IQR) 0.0% to 37.9%; p = 0.021) at three years. Bone growth around the collar was observed in both groups, and no statistical difference in amount of extracortical bony bridging was seen., Conclusion: Multidrug chemotherapy affects the osseointegration of ingrowth collars and accelerates signs of radiological loosening. This may increase the risk of aseptic loosening in patients with massive segmental implants used to treat bone cancer.Cite this article: Bone Joint Res 2020;9(7):333-340., (© 2020 Author(s) et al.)

A limitation in the use of calcium phosphate (CaP) is that in its raw form, it comprises blocks or granules, which are limited in their utility for orthopedic surgery and a number of commercial bone grafts are supplied within an aqueous based carboxymethyl cellulose (CMC) putty. Our hypothesis was that CMC combined with a porous silicate-substituted CaP (SiCaP) scaffold would have no negative effect on bone formation after implantation in an ovine femoral condyle. Defects were either (a) empty or filled with (b) SiCaP granules, (c) CMC-SiCaP Putty or (d) a SiCaP press-fit dry block. Scaffolds were identical in composition and remained in vivo for 4, 8, and 12 weeks. Bone apposition rates, bone area, percentage of bone-implant contact and graft area were quantified. At 4 and 8 weeks, significantly more new bone and percentage of bone-implant contact was measured within granules when compared with both putty and block scaffolds. At 12 weeks, significantly increased bone was measured for the granules when compared with blocks and no significant difference was found when the granules and putty scaffolds were compared. Results showed the disadvantageous effect that CMC may have on early bone growth and that granules increased new bone formation when compared with a press-fit block composed of the same material., (© 2019 Wiley Periodicals, Inc.)

Increasingly, the rat femoral fracture model is being used for preclinical investigations of fracture healing, however, the effect of gap size and its influence on mechanobiology is not well understood. We aimed to evaluate the influence of osteotomy gap on osteotomy healing between the previously published extremes of guaranteed union (0.5 mm) and non-union (3 mm) using this model. A femoral osteotomy in 12-14 week old female Wistar rats was stabilised with a micro fixator (titanium blocks, carbon fiber bars) with an osteotomy gap of 1.0 mm (n = 5), 1.5 mm (n = 7), 2.0 mm (n = 6). After five weeks, the left femur was retrieved. The osteotomy gap was scanned using X-ray microtomography and then histologically evaluated. The radiographic union rate (complete mineralised bone bridging across the osteotomy) was three times higher for the 1.0 mm than the 2.0 mm gap. The 1.0 mm gap had the largest callus (0.069μm 3 ) and bone volume (0.035μm 3 ). Callus and bone volume were approximately 50% smaller within the 2.0 mm gap. Using cadaveric rat femurs stabilised with the external fixator, day 0 mechanical assessment of construct stiffness was calculated on materials testing machine displacement vs load output. The construct stiffness for the 1.0, 1.5 and 2.0 mm gaps was 32.6 ± 5.4, 32.5 ± 2.4, and 32.4 ± 8.3 N/mm (p = 0.779). Interfragmentary strain (IFS) was calculated using the change in osteotomy gap displacement as measured using microstrain miniature differential reluctance transducer spanning the osteotomy gap. Increasing the gap size significantly reduced the IFS (p = 0.013). The mean 'day 0' IFS for the 1.0, 1.5 and 2.0 mm gaps were 11.2 ± 1.3, 8.4 ± 1.5 and 6.1 ± 1.2% respectively. A 1.5 mm gap resulted in a delayed fracture healing by 5 weeks and may represent a useful test environment for fracture healing therapy. Increasing gap size did not affect construct stiffness, but did reduce the 'day 0' IFS, with a doubling of non-union and halving of bone volume measured between 1.0 and 2.0 mm gaps., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Mesenchymal stem cells (MSCs) are of growing interest in terms of bone regeneration. Most preclinical trials utilize bone-marrow-derived mesenchymal stem cells (bMSCs), although this is not without isolation and expansion difficulties. The aim of this study was: to compare the characteristics of bMSCs and adipose-derived mesenchymal stem cells (AdMSCs) from juvenile, adult, and ovarectomized (OVX) rats; and to assess the effect of human parathyroid hormone (hPTH) 1-34 on their osteogenic potential and migration to stromal cell-derived factor-1 (SDF-1)., Methods: Cells were isolated from the adipose and bone marrow of juvenile, adult, and previously OVX Wistar rats, and were characterized with flow cytometry, proliferation assays, osteogenic and adipogenic differentiation, and migration to SDF-1. Experiments were repeated with and without intermittent hPTH 1-34., Results: Juvenile and adult MSCs demonstrated significantly increased osteogenic and adipogenic differentiation and superior migration towards SDF-1 compared with OVX groups; this was the case for AdMSCs and bMSCs equally. Parathyroid hormone (PTH) increased parameters of osteogenic differentiation and migration to SDF-1. This was significant for all cell types, although it had the most significant effect on cells derived from OVX animals. bMSCs from all groups showed increased mineralization and migration to SDF-1 compared with AdMSCs., Conclusion: Juvenile MSCs showed significantly greater migration to SDF-1 and significantly greater osteogenic and adipogenic differentiation compared with cells from osteopenic rats; this was true for bMSCs and AdMSCs. The addition of PTH increased these characteristics, with the most significant effect on cells derived from OVX animals, further illustrating possible clinical application of both PTH and MSCs in bone regenerative therapies. Cite this article :L. Osagie-Clouard, A. Sanghani-Kerai, M. Coathup, R. Meeson, T. Briggs, G. Blunn. The influence of parathyroid hormone 1-34 on the osteogenic characteristics of adipose- and bone-marrow-derived mesenchymal stem cells from juvenile and ovarectomized rats. Bone Joint Res 2019;8:397-404. DOI: 10.1302/2046-3758.88.BJR-2019-0018.R1.

Impact Statement: Currently ∼10% of fractures progress to delayed or nonunion with significant morbidity and economic impact. Endogenous mobilization of stem cells by pharmacological antagonism of their homing and migration receptor CXCR4 with AMD3100 experimentally reduced delayed union development. Endogenous mobilization may, therefore, translate as a low risk means to boost healing and could potentially be given as a prophylaxis to patients with fractures at risk of delayed healing or nonunion. These patients may include fragility fractures, comminuted tibial fractures, or when treating established nonunions. This approach could have promise for other conditions that may benefit from stem cell treatments.

Background: The purpose of the present study was to analyze and report the clinical outcomes following revision shoulder arthroplasty for failed humeral head resurfacing hemiarthroplasty (HHRH)., Methods: All patients who underwent revision shoulder arthroplasty for failed HHRH at our institution were retrospectively reviewed. Twenty-two shoulders in 20 patients were available for analysis. Mean age at the time of HHRH was 60 years (range 42 years to 75 years). The cohort consisted of 17 females and three males., Results: The mean time from HHRH to revision was 5 years (range 1 year to 8 years). Mean age at the time of revision surgery was 62 years (range 44 years to 80 years). Patients were followed-up for a mean of 3.3 years (range 2 years to 4 years) after revision. Following revision surgery, there was an increase in forward elevation from 67° (range 0° to 130°) to 97° (range 40° to 160°) ( p  = 0.04). This was accompanied by an improvement in both the Oxford Shoulder Score and the subjective shoulder value, which increased from 13 (range 2 to 28) to 39 (range 24 to 48) ( p  = 0.000) and from 23 (range 0 to 65) to 79 (range 25 to 100) ( p  = 0.000) respectively., Conclusions: Revision shoulder arthroplasty for failed HHRH improves functional outcome.

A significant number of fractures develop non-union. Mesenchymal stem cell (MSC) therapy may be beneficial, however, this requires cell acquisition, culture and delivery. Endogenous mobilization of stem cells offers a non-invasive alternative. The hypothesis was administration of VEGF and the CXCR4 antagonist AMD3100 would increase the circulating pool of available MSCs and improve fracture healing. Ex-breeder female wistar rats received VEGF followed by AMD3100, or sham PBS. Blood prepared for culture and colonies were counted. P3 cells were analyzed by flow cytometry, bi-differentiation. The effect of mobilization on fracture healing was evaluated with 1.5 mm femoral osteotomy stabilized with an external fixator in 12-14 week old female Wistars. The mobilized group had significantly greater number of cfus/ml compared to controls, p = 0.029. The isolated cells expressed 1.8% CD34, 35% CD45, 61% CD29, 78% CD90, and differentiated into osteoblasts but not into adipocytes. The fracture gap in animals treated with VEGF and AMD3100 showed increased bone volume; 5.22 ± 1.7 µm 3 and trabecular thickness 0.05 ± 0.01 µm compared with control animals (4.3 ± 3.1 µm 3 , 0.04 ± 0.01 µm, respectively). Radiographic scores quantifying fracture healing (RUST) showed that the animals in the mobilization group had a higher healing score compared to controls (9.6 vs. 7.7). Histologically, mobilization resulted in significantly lower group variability in bone formation (p = 0.032) and greater amounts of bone and less fibrous tissue than the control group. Clinical significance: This pre-clinical study demonstrates a beneficial effect of endogenous MSC mobilization on fracture healing, which may have translation potential to prevent or treat clinical fractures at risk of delayed or non-union fractures. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:1294-1302, 2019., (© 2018 The Authors. Journal of Orthopaedic Research1® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society.)

The use of external fixators allows for the direct investigation of newly formed interfragmentary bone, and the radiographic evaluation of the fracture. We validated the results of a finite element (FE) model with the in vitro stiffness' of two widely used external fixator devices used for in vivo analysis of fracture healing in rat femoral fractures with differing construction (Ti alloy ExFix1 and PEEK ExFix2). Rat femoral fracture fixation was modeled using two external fixators. For both constructs an osteotomy of 2.75 mm was used, and offset maintained at 5 mm. Tufnol, served as standardized substitutes for rat femora. Constructs were loaded under axial compression and torsion. Overall axial and torsional stiffness were compared between the in vitro models and FE results. FE models were also used to compare the fracture movement and overall pattern of von Mises stress across the external fixators. In vitro axial stiffness of ExFix1 was 29.26 N/mm ± 3.83 compared to ExFix2 6.31 N/mm ± 0.67 (p* < 0.05). Torsional stiffness of ExFix1 was 47.5 Nmm/° ± 2.71 compared to ExFix2 at 19.1 Nmm/° ±1.18 (p* < 0.05). FE results predicted similar comparative ratios between the ExFix1 and 2 as the in vitro studies. FE results predicted considerably larger interfragmentary motion in the ExFix2 comparing to ExFix1. We demonstrated significant differences in the stiffness' of the two external fixators as one would expect from such variable designs; yet, importantly we validated the utility of an FE model for the analysis and prediction of changes in fracture mechanics dependent on fixator choice. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:293-298, 2019., (© 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Periprosthetic joint infection (PJI) is associated with high patient morbidity and a large financial cost. This study investigated Photodynamic Therapy (PDT) as a means of eradicating bacteria that cause PJI, using a laser with a 665-nm wavelength and methylene blue (MB) as the photosensitizer. The effectiveness of MB concentration on the growth inhibition of methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Pseudomonas aeruginosa and Acinetobacter baumannii was investigated. The effect of laser dose was also investigated and the optimized PDT method was used to investigate its bactericidal effect on species within planktonic culture and following the formation of a biofilm on polished titanium and hydroxyapatite coated titanium discs. Results showed that Staphylococci were eradicated at the lowest concentration of 0.1 mM methylene blue (MB). With P. aeruginosa and A. baumannii, increasing the MB concentration improved the bactericidal effect. When the laser dose was increased, results showed that the higher the power of the laser the more bacteria were eradicated with a laser power ≥ 35 J/cm 2 and an irradiance of 35 mW/cm 2 , eradicating all S. epidermidis. The optimized PDT method had a significant bactericidal effect against planktonic MRSA and S. epidermidis compared to MB alone, laser alone, or control (no treatment). When biofilms were formed, PDT treatment had a significantly higher bactericidal effect than MB alone and laser alone for all species of bacteria investigated on the polished disc surfaces. P. aeruginosa grown in a biofilm was shown to be less sensitive to PDT when compared to Staphylococci, and a HA-coated surface reduced the effectiveness of PDT. This study demonstrated that PDT is effective for killing bacteria that cause PJI.

Increasing innovation in rapid prototyping (RP) and additive manufacturing (AM), also known as 3D printing, is bringing about major changes in translational surgical research. This review describes the current position in the use of additive manufacturing in orthopaedic surgery. Cite this article: Bone Joint J 2018;100-B:455-60.