Digitization of Follow-Up Care in Orthopedic and Trauma Surgery With Video Consultations: Health Economic Evaluation Study From a Health Provider's Perspective.

BACKGROUND: Recommendations for health care digitization as issued with the Riyadh Declaration led to an uptake in telemedicine to cope with the COVID-19 pandemic. Evaluations based on clinical data are needed to support stakeholders' decision-making on the long-term implementation of digital health. OBJECTIVE: This health economic evaluation aims to provide the first German analysis of the suitability of video consultations in the follow-up care of patients in orthopedic and trauma surgery, investigate the financial impact on hospital operations and personnel costs, and provide a basis for decisions on digitizing outpatient care. METHODS: We conducted a randomized controlled trial that evaluated video consultations versus face-to-face consultations in the follow-up care of patients in orthopedic and trauma surgery at a German university hospital. We recruited 60 patients who had previously been treated conservatively or surgically for various knee or shoulder injuries. A digital health app and a browser-based software were used to conduct video consultations. The suitability of telemedicine was assessed using the Telemedicine Satisfaction Questionnaire and the EQ-5D-5L questionnaire. Economic analyses included average time spent by physician per consultation, associated personnel costs and capacities for additional treatable patients, and the break-even point for video consultation software fees. RESULTS: After 4 withdrawals in each arm, data from a total of 52 patients (telemedicine group: n=26; control group: n=26) were used for our analyses. In the telemedicine group, 77% (20/26) of all patients agreed that telemedicine provided for their health care needs, and 69% (18/26) found telemedicine an acceptable way to receive health care services. In addition, no significant difference was found in the change of patient utility between groups after 3 months (mean 0.02, SD 0.06 vs mean 0.07, SD 0.17; P=.35). Treatment duration was significantly shorter in the intervention group (mean 8.23, SD 4.45 minutes vs mean 10.92, SD 5.58 minutes; P=.02). The use of telemedicine saved 25% (€2.14 [US $2.35]/€8.67 [US $9.53]) in personnel costs and increased the number of treatable patients by 172 annually, assuming 2 hours of video consultations per week. Sensitivity analysis for scaling up video consultations to 10% of the hospital's outpatient cases resulted in personnel cost savings of €73,056 (US $ 80,275.39) for a senior physician. A total of 23 video consultations per month were required to recoup the software fees of telemedicine through reduced personnel costs (break-even point ranging from 12-38 in the sensitivity analysis). CONCLUSIONS: Our study supports stakeholders' decision-making on the long-term implementation of digital health by demonstrating that video consultations in the follow-up care of patients in orthopedic and trauma surgery result in cost savings and productivity gains for clinics with no negative impact on patient utility. TRIAL REGISTRATION: German Clinical Trials Register DRKS00023445; https://drks.de/search/en/trial/DRKS00023445.

Mesoporous Bioactive Glass-Incorporated Injectable Strontium-Containing Calcium Phosphate Cement Enhanced Osteoconductivity in a Critical-Sized Metaphyseal Defect in Osteoporotic Rats.

In this study, the in vitro and in vivo bone formation behavior of mesoporous bioactive glass (MBG) particles incorporated in a pasty strontium-containing calcium phosphate bone cement (pS100G10) was studied in a metaphyseal fracture-defect model in ovariectomized rats and compared to a plain pasty strontium-containing calcium phosphate bone cement (pS100) and control (empty defect) group, respectively. In vitro testing showed good cytocompatibility on human preosteoblasts and ongoing dissolution of the MBG component. Neither the released strontium nor the BMG particles from the pS100G10 had a negative influence on cell viability. Forty-five female Sprague-Dawley rats were randomly assigned to three different treatment groups: (1) pS100 (n = 15), (2) pS100G10 (n = 15), and (3) empty defect (n = 15). Twelve weeks after bilateral ovariectomy and multi-deficient diet, a 4 mm wedge-shaped fracture-defect was created at the metaphyseal area of the left femur in all animals. The originated fracture-defect was substituted with pS100 or pS100G10 or left empty. After six weeks, histomorphometrical analysis revealed a statistically significant higher bone volume/tissue volume ratio in the pS100G10 group compared to the pS100 (p = 0.03) and empty defect groups (p = 0.0001), indicating enhanced osteoconductivity with the incorporation of MBG. Immunohistochemistry revealed a significant decrease in the RANKL/OPG ratio for pS100 (p = 0.004) and pS100G10 (p = 0.003) compared to the empty defect group. pS100G10 showed a statistically higher expression of BMP-2. In addition, a statistically significant higher gene expression of alkaline phosphatase, osteoprotegerin, collagen1a1, collagen10a1 with a simultaneous decrease in RANKL, and carbonic anhydrase was seen in the pS100 and pS100G10 groups compared to the empty defect group. Mass spectrometric imaging by time-of-flight secondary ion mass spectrometry (ToF-SIMS) showed the release of Sr2+ ions from both pS100 and pS100G10, with a gradient into the interface region. ToF-SIMS imaging also revealed that resorption of the MBG particles allowed for new bone formation in cement pores. In summary, the current work shows better bone formation of the injectable pasty strontium-containing calcium phosphate bone cement with incorporated mesoporous bioactive glass compared to the bioactive-free bone cement and empty defects and can be considered for clinical application for osteopenic fracture defects in the future.

Economic and Environmental Impact of Digital Health App Video Consultations in Follow-up Care for Patients in Orthopedic and Trauma Surgery in Germany: Randomized Controlled Trial.

BACKGROUND: Following the Riyadh Declaration, digital health technologies were prioritized in many countries to address the challenges of the COVID-19 pandemic. Digital health apps for telemedicine and video consultations help reduce potential disease spread in routine health care, including follow-up care in orthopedic and trauma surgery. In addition to the satisfaction, efficiency, and safety of telemedicine, its economic and environmental effects are highly relevant to decision makers, particularly for the goal of reaching carbon neutrality of health care systems. OBJECTIVE: This study aims to provide the first comprehensive health economic and environmental analysis of video consultations in follow-up care after knee and shoulder interventions in an orthopedic and trauma surgery department of a German university hospital. The analysis is conducted from a societal perspective. We analyze both economic and environmental impacts of video consultations, taking into account the goal of carbon neutrality for the German health care system by 2030. METHODS: We conducted a prospective randomized controlled trial comparing follow-up care with digital health app video consultations (intervention group) to conventional face-to-face consultations in the clinic (control group). Economic impact included the analysis of travel and time costs and production losses. Examination of the environmental impact comprised the emissions of greenhouse gases, carbon monoxide, volatile hydrocarbons, nitrogen oxides, and particulates, and the calculation of environmental costs. Sensitivity analysis included calculations with a higher cost per ton of carbon dioxide equivalent, which gives equal weight to the welfare of present and future generations. RESULTS: Data from 52 patients indicated that, from the patients' point of view, telemedicine helped reduce travel costs, time costs, and production losses, resulting in mean cost savings of €76.52 per video consultation. In addition, emissions of 11.248 kg of greenhouse gases, 0.070 kg of carbon monoxide, 0.011 kg of volatile hydrocarbons, 0.028 kg of nitrogen oxides, and 0.0004 kg of particulates could be saved per patient through avoided travel. This resulted in savings of environmental costs between €3.73 and €9.53 per patient. CONCLUSIONS: We presented the first comprehensive analysis of economic and environmental effects of telemedicine in the follow-up care of patients in orthopedic and trauma surgery in Germany. Video consultations were found to reduce the environmental footprint of follow-up care; saved travel costs, travel time, and time costs for patients; and helped to lower production losses. Our findings can support the decision-making on the use of digital health during and beyond the COVID-19 pandemic, providing decision makers with data for both economic and environmental effects. Thanks to the pragmatic design of our study, our findings can be applied to a wide range of clinical contexts and potential digital health applications that substitute outpatient hospital visits with video consultations. TRIAL REGISTRATION: German Clinical Trials Register DRKS00023445; https://tinyurl.com/4pcvhz4n.

Assessing Telemedicine Efficiency in Follow-up Care With Video Consultations for Patients in Orthopedic and Trauma Surgery in Germany: Randomized Controlled Trial.

BACKGROUND: Telemedicine can help mitigate important health care challenges, such as demographic changes and the current COVID-19 pandemic, in high-income countries such as Germany. It gives physicians and patients the opportunity to interact via video consultations, regardless of their location, thus offering cost and time savings for both sides. OBJECTIVE: We aimed to investigate whether telemedicine can be implemented efficiently in the follow-up care for patients in orthopedic and trauma surgery, with respect to patient satisfaction, physician satisfaction, and quality of care. METHODS: We conducted a prospective randomized controlled trial in a German university hospital and enrolled 60 patients with different knee and shoulder conditions. For follow-up appointments, patients received either an in-person consultation in the clinic (control group) or a video consultation with their physician (telemedicine group). Patients' and physicians' subsequent evaluations of these follow-up appointments were collected and assessed using separate questionnaires. RESULTS: On the basis of data from 52 consultations after 8 withdrawals, it was found that patients were slightly more satisfied with video consultations (mean 1.58, SD 0.643) than with in-clinic consultations (mean 1.64, SD 0.569), although the difference was not statistically significant (P=.69). After excluding video consultations marred by technical problems, no significant difference was found in physician satisfaction between the groups (mean 1.47, SD 0.516 vs mean 1.32, SD 0.557; P=.31). Further analysis indicated that telemedicine can be applied to broader groups of patients and that patients who have prior experience with telemedicine are more willing to use telemedicine for follow-up care. CONCLUSIONS: Telemedicine can be an alternative and efficient form of follow-up care for patients in orthopedic and trauma surgery in Germany, and it has no significant disadvantages compared with in-person consultations in the clinic. TRIAL REGISTRATION: German Clinical Trials Register DRKS00023445; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00023445.

Influence of Thoracic Trauma on Fracture Healing in Long Bones-A Retrospective Analysis.

PURPOSE: Pre-clinical studies indicate that concomitant thoracic trauma impairs fracture healing of long bones and reduces callus formation. The aim of this study was to investigate whether patients with accompanying chest trauma suffer from delayed fracture healing of long bones in comparison with patients with fractures of two long bones or isolated fractures. PATIENTS AND METHODS: This is a clinical retrospective study from a level I trauma center. The patients were divided into three groups: (1) thoracic trauma and fracture of a long bone, (2) fractures of two long bones, (3) isolated fracture of a long bone. The fracture consolidation was defined using the radiographic union scale in tibial fractures (RUST). A RUST value of ≥10 six-to-eight months after definitive operative intervention represented complete fracture healing. RESULTS: In the first group 19 (43.2%) fractures did not show full consolidation, in the second group 14 (45.2%) and 13 (41.9%) and in the third group 14 (36.8%). The analysis revealed no statistically significant differences between the groups regarding consolidation of the fractures six-to-eight months after definitive operative intervention (p = 0.84). CONCLUSIONS: Unlike previously reported pre-clinical data, this study did not demonstrate a negative effect on fracture consolidation in long bones when accompanied by thoracic trauma. Furthermore, the results demonstrated that concomitant fractures of two long bones does not have a negative effect on fracture consolidation.

Gelatin-Modified Calcium/Strontium Hydrogen Phosphates Stimulate Bone Regeneration in Osteoblast/Osteoclast Co-Culture and in Osteoporotic Rat Femur Defects-In Vitro to In Vivo Translation.

The development and characterization of biomaterials for bone replacement in case of large defects in preconditioned bone (e.g., osteoporosis) require close cooperation of various disciplines. Of particular interest are effects observed in vitro at the cellular level and their in vivo representation in animal experiments. In the present case, the material-based alteration of the ratio of osteoblasts to osteoclasts in vitro in the context of their co-cultivation was examined and showed equivalence to the material-based stimulation of bone regeneration in a bone defect of osteoporotic rats. Gelatin-modified calcium/strontium phosphates with a Ca:Sr ratio in their precipitation solutions of 5:5 and 3:7 caused a pro-osteogenic reaction on both levels in vitro and in vivo. Stimulation of osteoblasts and inhibition of osteoclast activity were proven during culture on materials with higher strontium content. The same material caused a decrease in osteoclast activity in vitro. In vivo, a positive effect of the material with increased strontium content was observed by immunohistochemistry, e.g., by significantly increased bone volume to tissue volume ratio, increased bone morphogenetic protein-2 (BMP2) expression, and significantly reduced receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio. In addition, material degradation and bone regeneration were examined after 6 weeks using stage scans with ToF-SIMS and µ-CT imaging. The remaining material in the defects and strontium signals, which originate from areas exceeding the defect area, indicate the incorporation of strontium ions into the surrounding mineralized tissue. Thus, the material inherent properties (release of biologically active ions, solubility and degradability, mechanical strength) directly influenced the cellular reaction in vitro and also bone regeneration in vivo. Based on this, in the future, materials might be synthesized and specifically adapted to patient-specific needs and their bone status.

In Vitro and In Vivo Biocompatibility Studies of a Cast and Coated Titanium Alloy.

The biocompatibility of a cast porous and with a calcium titanate reaction layer functionalized titanium alloy (Ti-6Al-7Nb) was tested by means of cell culture, and a small (rat) and large animal (sheep) model. The uncoated titanium material served as a control. In-vitro tests included the validation of osteoblast-like cells attached to the surface of the material with scanning electron microscopy and immunofluorescence of cytoskeletal actin as well as their osteogenic development, the ability to mineralize, and their vitality. Following the in-vitro tests a small animal (rat) and big animal (sheep) model were accomplished by inserting a cylindrical titanium implant into a drill hole defect in the femoral condyle. After 7, 14, and 30 days (rat) and 6 months (sheep) the condyles were studied regarding histological and histomorphometrical characteristics. Uncoated and coated material showed a good biocompatibility both in cell culture and animal models. While the defect area in the rat is well consolidated after 30 days, the sheep show only little bone inside the implant after 6 months, possibly due to stress shielding. None of the executed methods indicated a statistically significant difference between coated and uncoated material.

A new small animal model for simulating a two-stage-revision procedure in implant-related methicillin-resistant Staphylococcus aureus bone infection.

BACKGROUND: Implant-related bone infections with methicillin-resistant Staphylococcus aureus (MRSA) remain a challenge for orthopedic surgeons. This devasting complication may lead to functional impairment and loss of the affected limbs. High failure rates in treatment make improvement of surgical treatment necessary. Beside an already established demanding and costly large animal model, a small animal model of a two-stage revision does not exist, yet. Thus, the purpose of this study was to establish a preclinical small animal model to simulate a two-stage revision in implant-related MRSA infection. MATERIALS AND METHODS: In twelve rabbits Steel K-wires were implanted into the intramedullary canal of the left tibia, followed by inoculation with MRSA. Two different clinical isolates of MRSA-strains were used in two different concentrations (CFUs; 105 and 107 colony forming units (CFUs). This led to four groups of three rabbits each. Eleven rabbits survived the whole study period. After four weeks the inoculated K-wires were removed and replaced with vancomycin loaded PMMA-spacers (stage 1). Twenty-eight days later new K-wire implants were placed intramedullary (stage 2). After 84 days all animals were sacrificed. Tibiae were analyzed microbiologically, radiologically and histologically. RESULTS: In every rabbit K-wire associated infection could be established within the first four weeks. After irrigation and debridement at revision one (stage 1), infection could be eradicated in 67% of group I, in 50% of group II and in 33% of group III and IV. Recurrence of the infection could be determined in all animals of group I and IV at day 84. X-ray analysis and histology both demonstrated clear signs of osteomyelitis after twelve weeks. Survival, clinical observations and weight assessment confirmed the ethical justifiable stress of the animals during the experiment. CONCLUSION: The presented small animal model of a two-stage revision in implant-related infection is a promising preclinical set-up for assessment of new treatment strategies of implant-related infections. Both high survival as well as reinfection rates were possible by simulating the clinical gold standard of two-stage revision surgery in an MRSA implant-related infection model. Therefore, the model can be deemed suitable for further preclinical in vivo testing.

Radiocarpal fusion and midcarpal resection interposition arthroplasty: long-term results in severely destroyed rheumatoid wrists.

BACKGROUND: The aim of this retrospective study is to evaluate distal resection interposition arthroplasty of the wrist as a tool to restore mobility as well as to restore stability in severely destroyed wrist joints. METHODS: Thirty-four wrists in 28 rheumatoid arthritis patients were included. The mean follow-up time was 9 years after surgical treatment with clinical and radiological examination. The results were accessed based on a modification of Clayton ́s scoring system as well as a functional questionnaire. RESULTS: 71% patients were satisfied with pain, function and activities of daily life. Better results were reported by patients with a young age, early surgical intervention, a shorter duration of the disease, and lesser involvement of other joints. CONCLUSIONS: The results for radiocarpal arthrodesis were comparable to those of synovectomy or arthrodesis of the wrist. The results after total wrist joint arthroplasty varies probably as the result of different patient groups, implant types and evolution of prosthetic designs, and are not comparable with the present study.

Diaphyseal long bone nonunions - types, aetiology, economics, and treatment recommendations.

The intention of the current article is to review the epidemiology with related socioeconomic costs, pathophysiology, and treatment options for diaphyseal long bone delayed unions and nonunions. Diaphyseal nonunions in the tibia and in the femur are estimated to occur 4.6-8% after modern intramedullary nailing of closed fractures with an even much higher risk in open fractures. There is a high socioeconomic burden for long bone nonunions mainly driven by indirect costs, such as productivity losses due to long treatment duration. The classic classification of Weber and Cech of the 1970s is based on the underlying biological aspect of the nonunion differentiating between "vital" (hypertrophic) and "avital" (hypo-/atrophic) nonunions, and can still be considered to represent the basis for basic evaluation of nonunions. The "diamond concept" units biomechanical and biological aspects and provides the pre-requisites for successful bone healing in nonunions. For humeral diaphyseal shaft nonunions, excellent results for augmentation plating were reported. In atrophic humeral shaft nonunions, compression plating with stimulation of bone healing by bone grafting or BMPs seem to be the best option. For femoral and tibial diaphyseal shaft fractures, dynamization of the nail is an atraumatic, effective, and cheap surgical possibility to achieve bony consolidation, particularly in delayed nonunions before 24 weeks after initial surgery. In established hypertrophic nonunions in the tibia and femur, biomechanical stability should be addressed by augmentation plating or exchange nailing. Hypotrophic or atrophic nonunions require additional biological stimulation of bone healing for augmentation plating.

Strontium and bisphosphonate coated iron foam scaffolds for osteoporotic fracture defect healing.

The purpose of this work was to investigate new bone formation in macroporous iron foams coated with strontium (FeSr) or bisphosphonate (FeBiP) compared to plain iron foam (Fe) and empty defect in a critical size metaphyseal bone defect model in ovariectomized rats. 60 female rats were subjected to bilateral ovariectomy and multi-deficient diet for 3 months. A 4 mm wedge shaped metaphyseal osteotomy was created, fixed with a mini-plate and subsequently filled with Fe, FeSr, FeBiP or left empty. After 6 weeks, µCt analysis revealed a statistically significant increased bone formation at the implant interface in FeSr compared to FeBiP (p = 0.035) and Fe (p = 0.002), respectively. Increased mineralized tissue was also seen within the pores in FeSr (p = 0.023) compared to Fe. Histomorphometry revealed significantly increased bone formation at the implant interface in FeSr (p < 0.001) and FeBiP (p = 0.006) compared to plain Fe with increased osteoblast and decreased osteoclast activity in combination with increased BMP2 and decreased RANKL/OPG in immunohistochemistry. ToF-SIMS analysis showed overlapping Ca signals with Fe for both FeSr and FeBiP thereby indicating tissue in-growth into the scaffolds. In conclusion, iron foam with strontium or bisphosphonate coating are of further interest in metaphyseal fracture defects in osteopenic bone.

Postembedding Decalcification of Mineralized Tissue Sections Preserves the Integrity of Implanted Biomaterials and Minimizes Number of Experimental Animals.

Bone histology of decalcified or undecalcified samples depends on the investigation. However, in research each method provides different information to answer the scientific question. Decalcification is the first step after sample fixation and governs what analysis is later feasible on the sections. Besides, decalcification is favored for immunostaining and in situ hybridization. Otherwise, sample decalcification can be damaging to bone biomaterials implants that contains calcium or strontium. On the other hand, after decalcification mineralization cannot be assessed using histology or imaging mass spectrometry. The current study provides a solution to the hardship caused by material presence within the bone tissue. The protocol presents a possibility of gaining sequential and alternating decalcified and undecalcified sections from the same bone sample. In this manner, investigations using histology, protein signaling, in situ hybridization, and mass spectrometry on the same sample can better answer the intended research question. Indeed, decalcification of sections and grindings resulted in well-preserved sample and biomaterials integrity. Immunostaining was comparable to that of classically decalcified samples. The study offers a novel approach that incites correlative analysis on the same sample and reduces the number of processed samples whether clinical biopsies or experimental animals.

Bone formation and degradation behavior of nanocrystalline hydroxyapatite with or without collagen-type 1 in osteoporotic bone defects - an experimental study in osteoporotic goats.

The intention of the current work is to assess new bone formation and degradation behavior of nanocrystalline hydroxyapatite with (HA/col-1) or without collagen-type I (HA) in osteoporotic metaphyseal bone defects in goats. After ovariectomy and special low-calcium diet for three months, 3 drill hole defects in the vertebrae of L3, L4, L5, 4 drill hole defects in the right and left iliac crest and 1 drill hole defect at the distal femur were created in three Chinese mountain goats with a total of 24 defects. The defects were either filled with one of the biomaterials or left empty (empty defect control group). After 42 days, the animals were euthanized and the samples were assessed for new bone formation using high-resolution peripheral quantitative computed tomography (HR-pQCT) and histomorphometry with 2 regions of interest. Detail histology, enzymehistochemistry and immunohistochemistry as well as connexin-43 in situ hybridization and transmission electron microscopy were carried out for evaluation of degradation behavior of the materials and cellular responses of the surrounding tissue in respect to the implants. HR-pQCT showed the highest BV/TV ratio (p = 0.008) and smallest trabecular spacing (p = 0.005) for HA compared to the other groups in the region of interest at the interface with 1mm distance to the initially created defect. The HA/col-1 yielded the highest connectivity density (Conn.D) (p = 0.034) and the highest number of trabeculae (Tb.N) (p = 0.002) compared to the HA and the control group. Histomorphometric analysis for the core region of the initially created defect revealed a statistically higher new bone formation in the HA (p = 0.001) and HA/col-1 group (p = 0.001) compared to the empty defect group including all defect sites. This result was confirmed for site specific analysis with significant higher new bone formation for the HA group for vertebral defects compared to the empty defect group (p = 0.029). For the interface region, no statistically significant differences were found between the three groups (p = 0.08). Histology revealed a good biocompatibility without inflammatory reaction for the HA- and HA/col-1 implants with a higher fragmentation of the HA-implant compared to the HA/col-1 biomaterial and formation of new bone in the region between the biomaterial fragments by osteoblasts. Fragmentation was shown by transmission electron microscopy to be caused by multinuclear osteoclast-like cells with degradation of the implant via intracellular incorporation of degraded implant material particles. In conclusion, both nanoparticulate HA with and without collagen type-1 showed better new bone formation compared to untreated drill hole defects in metaphyseal regions of this osteoporotic Chinese mountain goat model with good biocompatibility.

Effects of macroporous, strontium loaded xerogel-scaffolds on new bone formation in critical-size metaphyseal fracture defects in ovariectomized rats.

New bone formation was studied in a metaphyseal fracture-defect in ovariectomized rats stimulated by a plain and a strontium-enriched macroporous silica/collagen scaffold (ScB30 and ScB30Sr20) and a compact silica/collagen xerogel (B30). 45 female Sprague-Dawley rats were randomly assigned to three different treatment groups: (1) ScB30 (n=15), (2) ScB30Sr20 (n=15), and (3) B30 (n=15). 12 weeks after bilateral ovariectomy and multi-deficient diet, a 4 mm wedge-shaped fracture-defect was created at the metaphyseal area of the left femur. A 7-hole T-shaped plate at the lateral aspect of the femur stabilized the bone and the defect was filled with ScB30, ScB30Sr20 or B30 subsequently. After six weeks, histomorphometrical analysis revealed a statistically significant higher bone volume/tissue volume ratio in the ScB30Sr20 group compared to ScB30 (p=0.043) and B30 (p=0.0001) indicating an improved formation of new bone by the strontium-enriched macroporous silica/collagen scaffold. Furthermore, immunohistochemical results showed increased expression of BMP2 and OPG and a decreased RANKL expression in the ScB30Sr20 group. This was further confirmed with the gene expression analysis where an increase in prominent bone formation markers (ALP, OCN, Runx2, Col1a1 and Col10a1) was seen. No material remnants were found in the scaffold group indicating an almost complete degradation process of the biomaterials. This is confirmed by ToF-SIMS analysis that did not detect any strontium in the ScB30Sr20 group neither in the defect nor in the surrounding tissue. Taken together, this study shows the stimulating effects of strontium through increased bone formation by up regulation of osteoanabolic markers. This work also indicates the importance of material porosity, geometry and biodegradability in bone healing.

Neovascularization of osteoporotic metaphyseal bone defects: A morphometric micro-CT study.

PURPOSE: Neovascularization is essential for bone regeneration in fractures. This study aimed to investigate the microvascular morphology and distribution in the non-injured femur and the neovascularization of the metaphyseal critical size defect in a small animal model of osteoporosis. MATERIALS AND METHODS: Female rats (n=7) were ovariectomized (OVX) and received a multideficiency diet. Three months after OVX, a 5mm wedge shaped critical size defect was cut at the distal femoral metaphysis and stabilized with a T-shaped mini-plate. After six weeks, the animals were euthanized, and femora were removed and decalcified for micro-CT measurement of fracture neovascularization. RESULTS: No fracture healing was observed along the critical size defects. In the non-injured bone, micro-vessel distribution showed a specific pattern, thereby enabling a differentiation between epi-, meta- and diaphysis. Micro-CT based morphometry revealed a significant reduction of the vascular volume fraction as well as the vascular thickness (p<0.001) in the critical size defect compared to the intact contralateral femur. Blood volume related vascular surface (vascular surface/volume) increased significantly (p<0.001). Connectivity density and tissue volume related vascular surface (vascular surface density) did not change significantly. CONCLUSIONS: Micro-CT based vascular morphometry demonstrated differences between epi-, meta- and diaphysis in the non-injured bone as well as differences between the critical size defect and the non-injured metaphysis. As angiogenesis is a crucial prerequisite that precedes osteogenesis, our results may influence further evaluation of osteoconductive or osteogenic biomaterials in this small animal model of osteoporosis.

Impaired extracellular matrix structure resulting from malnutrition in ovariectomized mature rats.

Bone loss is a symptom related to disease and age, which reflects on bone cells and ECM. Discrepant regulation affects cell proliferation and ECM localization. Rat model of osteoporosis (OVX) was investigated against control rats (Sham) at young and old ages. Biophysical, histological and molecular techniques were implemented to examine the underlying cellular and extracellular matrix changes and to assess the mechanisms contributing to bone loss in the context of aging and the widely used osteoporotic models in rats. Bone loss exhibited a compromised function of bone cells and infiltration of adipocytes into bone marrow. However, the expression of genes regulating collagen catabolic process and adipogenesis was chronologically shifted in diseased bone in comparison with aged bone. The data showed the involvement of Wnt signaling inhibition in adipogenesis and bone loss due to over-expression of SOST in both diseased and aged bone. Further, in the OVX animals, an integrin-mediated ERK activation indicated the role of MAPK in osteoblastogenesis and adipogenesis. The increased PTH levels due to calcium and estrogen deficiency activated osteoblastogenesis. Thusly, RANKL-mediated osteoclastogenesis was initiated. Interestingly, the data show the role of MEPE regulating osteoclast-mediated resorption at late stages in osteoporotic bone. The interplay between ECM and bone cells change tissue microstructure and properties. The involvement of Wnt and MAPK pathways in activating cell proliferation has intriguing similarities to oncogenesis and myeloma. The study indicates the importance of targeting both pathways simultaneously to remedy metabolic bone diseases and age-related bone loss.

Histological Comparison of New Biodegradable Magnesium-Based Implants for Maxillofacial Applications.

BACKGROUND: A variety of materials have been used for bone augmentation, distraction osteotomy, and in post-cancer patients following tumor removal. However, a temporary metal implant that would resorb after successful treatment is a new concept. Magnesium was suggested as a suitable material for these purposes because it is biocompatible, has better mechanical properties than titanium, and stimulates new bone formation. This study evaluates histological appearance of magnesium-based implants and the surrounding bone. MATERIALS AND METHODS: Three magnesium-based biomaterials were tested in a rabbit bone defect model: magnesium-hydroxyapatite (Mg-HA), W4 (96 % magnesium, 4 % yttrium), and pure magnesium (pure Mg). Animals were sacrificed after 6 and 12 weeks and the samples were analyzed histologically and histomorphometrically. RESULTS: Mg-HA had the highest mean amount of tartrate-resistant acid phosphatase (TRAP) positive cells at the implantation site of all groups. It had shown the fastest degradation rate already at 6 weeks but the least amount of new bone formation. New bone was seen forming in direct contact with pure Mg and W4. The mean gas volume was highest in W4 compared to pure Mg and Mg-HA but this difference was not statistically significant. W4 had the lowest mean number of TRAP-positive cells of all materials. CONCLUSION: Pure Mg and W4 were shown to be the most promising materials in this study in respect to the bone response to the implant material. They could be used for screws and plates in bone augmentation procedures.

Impact of prophylactic CpG Oligodeoxynucleotide application on implant-associated Staphylococcus aureus bone infection.

TLR-9 ligand CpG oligodeoxynucleotide type B (CpG ODN) induces a proinflammatory environment. We evaluated the effects of a preoperative CpG ODN application in an implant-associated Staphylococcus aureus bone infection model by monitoring bacterial loads and cytokine and chemokine levels. A total of 95 rats were used in four different groups: CpG ODN group (group 1; n=25), non-CpG-ODN group (group 2; n=25); saline pretreatment (group 3; n=25), and one uninfected group (group 4; n=20). A single dose of CpG-ODN was administered to the left tibialis anterior muscle 3days prior to surgery and the tibia midshaft was osteotomized, stabilized by an intramedullary implant and subsequently contaminated with 10(3) colony forming units (CFUs) of S. aureus in groups 1-3. The osteotomy gap in animals of group 4 was not contaminated with S. aureus and those animals did not receive any pretreatment. CpG ODN administration resulted in significant reduction of the bacterial load in tibia tissue homogenate and on the implant surface on day 1 post-infection compared to non-CpG-ODN pretreatment (p<0.05; p<0.05). Reductions in bacterial CFUs, compared to non-treated (saline) controls, were approximately 67% and 77% for bone tissue homogenates and implants. No bacteria were detected in uninfected rats. Early reduction of bacterial CFUs in the tibia was accompanied by increased levels of proinflammatory mediators MIP-2, IL-1ß and RANTES in bone tissue milieu of the CpG ODN treated group compared to controls. At day 42 post-infection, bone marrow tissue of rats pretreated with CpG ODN had comparable high bacterial CFU numbers as the non-CpG ODN or saline treated groups. Microbiological analysis of implants removed from CpG ODN treated rats showed high bacterial growth densities on their surfaces which were not different from those observed in controls. In histology, all animals of groups 1-3 showed established infected non-unions. Additionally, inflammatory mediator profiles in bone marrow homogenates of CpG ODN treated rats resembled those seen in infected controls. In this rat model, prophylactic administration of a single dose of CpG ODN, resulted in marked reduction of S. aureus load in the infected tibia during the initial stage of infection but failed to prevent development of chronic infection over time.

The biocompatibility of degradable magnesium interference screws: an experimental study with sheep.

Screws for ligament reconstruction are nowadays mostly made of poly-L-lactide (PLLA). However, magnesium-based biomaterials are gathering increased interest in this research field because of their good mechanical property and osteoanabolic influence on bone metabolism. The aim of this pilot study was to evaluate the biocompatibility of an interference screw for ligament reconstruction made of magnesium alloy W4 by diecasting and milling and using different PEO-coatings with calcium phosphates. PLLA and titanium screws were used as control samples. The screws were implanted in the femur condyle of the hind leg of a merino sheep. The observation period was six and twelve weeks and one year. Histomorphometric, immunohistochemical, immunofluorescence, and molecular biological evaluation were conducted. Further TEM analysis was done. In all magnesium screws a clinically relevant gas formation in the vicinity of the biomaterial was observed. Except for the PLLA and titanium control samples, no screw was fully integrated in the surrounding bone tissue. Regarding the fabrication process, milling seems to produce less gas liberation and has a better influence on bone metabolism than diecasting. Coating by PEO with calcium phosphates could not reduce the initial gas liberation but rather reduced the bone metabolism in the vicinity of the biomaterial.

Application of F-18-sodium fluoride (NaF) dynamic PET-CT (dPET-CT) for defect healing: a comparison of biomaterials in an experimental osteoporotic rat model.

BACKGROUND: The aim of the current study was to measure and compare the effect of various biomaterials for the healing of osteoporotic bone defects in the rat femur using 18F-sodium fluoride dPET-CT. MATERIAL AND METHODS: Osteoporosis was induced by ovariectomy and a calcium-restricted diet. After 3 months, rats were operated on to create a 4-mm wedge-shaped defect in the distal metaphyseal femur. Bone substitution materials of calcium phosphate cement (CPC), composites of collagen and silica, and iron foams with interconnecting pores were inserted. Strontium or bisphosphonate, which are well known for having positive effects in osteoporosis treatment, were added into the materials. Eighteen weeks after osteoporosis induction and 6 weeks following femoral surgery, dPET-CT studies scan were performed with 18F-Sodium Fluoride. Standardized uptake values (SUVs) and a 2-tissue compartmental learning-machine model (K1-k4, vessel density [VB], influx [ki]) were used for quantitative analysis. RESULTS: k3, reflecting the formation of fluoroapatite, revealed a statistically significant increase at the biomaterial-bone interface due to the Sr release from strontium-modified calcium phosphate cement (SrCPC) compared to CPC, which demonstrated enhanced new bone formation. In addition, k3 as measured in the porous scaffold silica/collagen xerogel (Sc-B30), showed a significant increase based on Wilcoxon rank-sum test (p<0.05) as compared with monolithic silica/collagen xerogel (B30) in the defect region. Furthermore, ki, reflecting the net plasma clearance of tracer to bone mineral measured in the iron foam with coating of the bisphosphonate zoledronic acid (Fe-BP), was enhanced as compared with plain iron foam (Fe) in the defect region. CONCLUSIONS: k3 was the most significant parameter for the characterization of healing processes and revealed the best differentiation between the 2 different biomaterials. PET scanning using 18F-sodium fluoride seems to be a sensitive and useful method for evaluation of bone healing after replacement with these biomaterials.