A Multifunctional Therapeutic Strategy Using P7C3 as A Countermeasure Against Bone Loss and Fragility in An Ovariectomized Rat Model of Postmenopausal Osteoporosis.

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.

Extracellular Proteins Isolated from L. acidophilus as an Osteomicrobiological Therapeutic Agent to Reduce Pathogenic Biofilm Formation, Regulate Chronic Inflammation, and Augment Bone Formation In Vitro.

Periprosthetic joint infection (PJI) is a challenging complication that can occur following joint replacement surgery. Efficacious strategies to prevent and treat PJI and its recurrence remain elusive. Commensal bacteria within the gut convey beneficial effects through a defense strategy named "colonization resistance" thereby preventing pathogenic infection along the intestinal surface. This blueprint may be applicable to PJI. The aim is to investigate Lactobacillus acidophilus spp. and their isolated extracellular-derived proteins (LaEPs) on PJI-relevant Staphylococcus aureus, methicillin-resistant S. aureus, and Escherichia coli planktonic growth and biofilm formation in vitro. The effect of LaEPs on cultured macrophages and osteogenic, and adipogenic human bone marrow-derived mesenchymal stem cell differentiation is analyzed. Data show electrostatically-induced probiotic-pathogen species co-aggregation and pathogenic growth inhibition together with LaEP-induced biofilm prevention. LaEPs prime macrophages for enhanced microbial phagocytosis via cathepsin K, reduce lipopolysaccharide-induced DNA damage and receptor activator nuclear factor-kappa B ligand expression, and promote a reparative M2 macrophage morphology under chronic inflammatory conditions. LaEPs also significantly augment bone deposition while abating adipogenesis thus holding promise as a potential multimodal therapeutic strategy. Proteomic analyses highlight high abundance of lysyl endopeptidase, and urocanate reductase. Further, in vivo analyses are warranted to elucidate their role in the prevention and treatment of PJIs.

Inorganic Nanoparticles as Radiosensitizers for Cancer Treatment.

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.

A novel multifunctional radioprotective strategy using P7C3 as a countermeasure against ionizing radiation-induced bone loss.

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/ß-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.

Can placement of hook at the upper instrumented level decrease the proximal junctional kyphosis risk in adolescent idiopathic scoliosis?

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.

Nanotechnology enabled radioprotectants to reduce space radiation-induced reactive oxidative species.

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.

Osseointegration reduces aseptic loosening of primary distal femoral implants in pediatric and adolescent osteosarcoma patients: a retrospective clinical and radiographic study.

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.

A novel approach for the prevention of ionizing radiation-induced bone loss using a designer multifunctional cerium oxide nanozyme.

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 (Ce3+) 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.

Macromolecules Absorbed from Influenza Infection-Based Sera Modulate the Cellular Uptake of Polymeric Nanoparticles.

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.

Cerium oxide nanoparticles protect against irradiation-induced cellular damage while augmenting osteogenesis.

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.

Multi-functional cerium oxide nanoparticles regulate inflammation and enhance osteogenesis.

Oxidative stress increases bone loss and limits repair, in part, through immunoregulation and the formation and maintenance of low-grade chronic inflammation. The aim of this study was to investigate the effect of cerium oxide nanoparticles (CeONPs) on (i) macrophage phenotype and cytokine expression under normal and simulated acute and chronic inflammatory conditions and, (ii) human mesenchymal stem cell (hBMSCs) proliferation, osteoinduction and osteogenic differentiation. Spherical particles composed of 60% Ce3+ with a hydrodynamic size of ~35 nm and surface charge of 25.4 mV were internalized within cells. Under both acute and chronic conditions, inducible nitric oxide synthase (iNOS) activity decreased with a significant reduction seen in the 1 and 10 µg/mL groups (p < 0.001). A dose dependent and significant increase in anti-inflammatory cytokine gene expression was observed in all CeONP groups under chronic inflammatory condition. No increase in alkaline phosphatase (ALP) activity or mineral deposits were measured following hBMSCs cultured without osteogenic media in any of the CeONP groups, however, a significant increase in osteogenic-related gene expression, ALP activity and bone mineral deposits was measured when supplemented with both CeONPs and osteogenic media. CeONP activity was multifaceted and exhibited low toxicity. A therapeutic dose of 1 µg/mL delivered a disparate but protective effect when under both acute and chronic inflammatory conditions while at the same dose, potentiated osteogenesis.

Incidence of Osteolysis and Aseptic Loosening Following Metal-on-Highly Cross-Linked Polyethylene Hip Arthroplasty: A Systematic Review of Studies with Up to 15-Year Follow-up.

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.

A novel antimicrobial coating to prevent periprosthetic joint infection.

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.

The development of a novel autologous blood glue aiming to improve osseointegration in the bone-implant interface.

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.

Multidrug chemotherapy causes early radiological signs of loosening in distal femoral replacements.

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.

A carboxymethyl cellulose bone graft carrier delays early bone healing in an ovine model.

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.

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.

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.

Revision shoulder arthroplasty for failed humeral head resurfacing hemiarthroplasty.

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.

Non-invasive massive growing prostheses reduce infection in paediatric cancer patients.

PURPOSE: In this study, we asked the question of whether non-invasive (NI) extendible bone tumour implants are as reliable and reduce infection when compared with patients who received a minimally invasive (MI) extendible implant. METHODS: Forty-two NI extendible bone tumour implants were investigated at a mean follow-up of 22 months (range, 1-87 months) and 63 MI implants at a mean follow-up of 49 months (range, 1-156 months). RESULTS: Kaplan-Meier analysis showed that the probability of MI implant survival was 58.8% compared with 78.6% in NI patients. No significant difference between these two patient groups was found. Infection was the main reason for failure in the MI implant group where nine (35%) implants were revised. However, only one (11%) NI implant was revised for infection ( p = 0.042). None of the NI implants failed due to aseptic loosening; however, six (23%) MI implants were revised for aseptic loosening of the intramedullary stem. Four (15%) of the failed MI implants were revised due to full extension and five (56%) of failed NI implants were replaced as the implant had been fully extended where the patient still required growth. CONCLUSION: Where possible, an NI massive prosthesis should be used in this patient group. Our results suggest that MI prostheses should be infrequently used due to the high incidence of infection. Lengthening of NI prostheses is painless, can be carried out in the clinic and is more cost-effective. However, further work is required to increase the amount of growth potential available in these implants.

A novel ceramic coating for reduced metal ion release in metal-on-metal hip surgery.

An ovine total hip arthroplasty model was developed to evaluate metal ion release, wear, the biological response and adverse tissue reaction to metal-on-metal (MoM) bearing materials. The performance of an advanced superlattice ceramic coating (SLC) was evaluated as a bearing surface and experimental groups divided into; (1) MoM articulating surfaces coated with a SLC coating (SLC-MoM), (2) uncoated MoM surfaces (MoM), and (3) metal on polyethylene (MoP) surfaces. Implants remained in vivo for 13 months and blood chromium (Cr) and cobalt (Co) metal ion levels were measured pre and postoperatively. Synovial tissue was graded using an ALVAL scoring system. When compared with the MoM group, sheep with SLC-MoM implants showed significantly lower levels of chromium and cobalt metal ions within blood over the 13-month period. Evidence of gray tissue staining was observed in the synovium of implants in the MOM group. A significantly lower ALVAL score was measured in the SLC-MoM group (3.88) when compared with MoM components (6.67) (p = 0.010). ALVAL results showed no significant difference when SLC-MOM components were compared to MoP (5.25). This model was able to distinguish wear and the effect of released debris between different bearing combinations and demonstrated the effect of a SLC coating when applied onto the bearing surface. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1760-1771, 2019.