The Development of a Magnesium-Releasing and Long-Term Mechanically Stable Calcium Phosphate Bone Cement Possessing Osteogenic and Immunomodulation Effects for Promoting Bone Fracture Regeneration

Bone grafts are commonly used for the treatment of critical sized bone defects. Since the supply of autologous bone is insufficient, allogeneic bone grafts have been used most of the time. However, the poor osteogenic property of allogeneic bone grafts after pretreatment results in delayed union, non-union, or even occasional deformity. Calcium phosphate cement (CPC) is one of the most promising bone filling materials due to its good biocompatibility and similar chemical components as natural bone. However, clinical applications of CPC were hampered by limited osteogenic effects, undesired immune response which results in resorption, and poor mechanical stability in vivo. Magnesium (Mg) has been proven to trigger bone regeneration through modulating cell behaviors of mesenchymal stem cells and macrophages significantly. Unfortunately, the degradation raters of pure Mg and Mg oxide are extremely fast, resulting in early collapse of Mg contained CPC. In this study, we developed a novel magnesium contained calcium phosphate bone cement (Mg-CPC), possessing long-term mechanical stability and osteogenic effects through sustained release of Mg. Furthermore, in vitro studies showed that Mg-CPC had no cytotoxic effects on hBMMSCs and macrophage RAW 264.7, and could enhance the osteogenic differentiation as determined by alkaline phosphate (ALP) activity and calcium nodule staining, as well as suppress the inflammatory as determined by expression of anti-inflammatory cytokine IL-1RA. We also found that Mg-CPC promoted new bone formation and bone maturation in vivo. These results suggest that Mg-CPC should be a good substitute material for bone grafts in clinical use.

Challenges in Treating Genodermatoses: New Therapies at the Horizon

Genodermatoses are rare inherited skin diseases that frequently affect other organs. They often have marked effects on wellbeing and may cause early death. Progress in molecular genetics and translational research has unravelled many underlying pathological mechanisms, and in several disorders with high unmet need, has opened the way for the introduction of innovative treatments. One approach is to intervene where cell-signaling pathways are dysregulated, in the case of overactive pathways by the use of selective inhibitors, or when the activity of an essential factor is decreased by augmenting a molecular component to correct disequilibrium in the pathway. Where inflammatory reactions have been induced by a genetically altered protein, another possible approach is to suppress the inflammation directly. Depending on the nature of the genodermatosis, the implicated protein or even on the particular mutation, to correct the consequences or the genetic defect, may require a highly personalised stratagem. Repurposed drugs, can be used to bring about a “read through” strategy especially where the genetic defect induces premature termination codons. Sometimes the defective protein can be replaced by a normal functioning one. Cell therapies with allogeneic normal keratinocytes or fibroblasts may restore the integrity of diseased skin and allogeneic bone marrow or mesenchymal cells may additionally rescue other affected organs. Genetic engineering is expanding rapidly. The insertion of a normal functioning gene into cells of the recipient is since long explored. More recently, genome editing, allows reframing, insertion or deletion of exons or disruption of aberrantly functioning genes. There are now several examples where these stratagems are being explored in the (pre)clinical phase of therapeutic trial programmes. Another stratagem, designed to reduce the severity of a given disease involves the use of RNAi to attenuate expression of a harmful protein by decreasing abundance of the cognate transcript. Most of these strategies are short-lasting and will thus require intermittent life-long administration. In contrast, insertion of healthy copies of the relevant gene or editing the disease locus in the genome to correct harmful mutations in stem cells is more likely to induce a permanent cure. Here we discuss the potential advantages and drawbacks of applying these technologies in patients with these genetic conditions. Given the severity of many genodermatoses, prevention of transmission to future generations remains an important goal including offering reproductive choices, such as preimplantation genetic testing, which can allow selection of an unaffected embryo for transfer to the uterus.

Survival Rates of Dental Implants in Autogenous and Allogeneic Bone Blocks: A Systematic Review

Background and Objectives: Preliminary studies emphasize the similar performance of autogenous bone blocks (AUBBs) and allogeneic bone blocks (ALBBs) in pre-implant surgery; however, most of these studies include limited subjects or hold a low level of evidence. The purpose of this review is to test the hypothesis of indifferent implant survival rates (ISRs) in AUBB and ALBB and determine the impact of various material-, surgery- and patient-related confounders and predictors. Materials and Methods: The national library of medicine (MEDLINE), Excerpta Medica database (EMBASE) and Cochrane Central Register of Controlled Trials (CENTRAL) were screened for studies reporting the ISRs of implants placed in AUBB and ALBB with ≥10 participants followed for ≥12 months from January 1995 to November 2021. The review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The risk of bias was assessed via several scoring tools, dependent on the study design. Means of sub-entities were presented as violin plots. Results: An electronic data search resulted in the identification of 9233 articles, of which 100 were included in the quantitative analysis. No significant difference (p = 0.54) was found between the ISR of AUBB (96.23 ± 5.27%; range: 75% to 100%; 2195 subjects, 6861 implants) and that of ALBB (97.66 ± 2.68%; range: 90.1% to 100%; 1202 subjects, 3434 implants). The ISR in AUBB was increased in blocks from intraoral as compared to extraoral donor sites (p = 0.0003), partially edentulous as compared to totally edentulous (p = 0.0002), as well as in patients younger than 45 as compared to those older (p = 0.044), cortical as compared to cortico-cancellous blocks (p = 0.005) and in delayed implantations within three months as compared to immediate implantations (p = 0.018). The ISR of ALBB was significantly increased in processed as compared to fresh-frozen ALBB (p = 0.004), but also in horizontal as compared to vertical augmentations (p = 0.009). Conclusions: The present findings widely emphasize the feasibility of achieving similar ISRs with AUBB and ALBB applied for pre-implant bone grafting. ISRs were negatively affected in sub-entities linked to more extensive augmentation procedures such as bone donor site and dentition status. The inclusion and pooling of literature with a low level of evidence, the absence of randomized controlled clinical trials (RCTs) comparing AUBB and ALBB and the limited count of comparative studies with short follow-ups increases the risk of bias and complicates data interpretation. Consequently, further long-term comparative studies are needed.

Tratamiento de la laminitis crónica en equinos utilizando células troncales mesenquimales alogénicas de la médula ósea

Chronic laminitis is a disabling condition that affects the laminar corium of the horse’s hooves. Commonly, it develops as a collateral injury of numerous primary systemic diseases. It is believed that the critical physiopathological event that renders a hoof laminitic is the loss of mesenchymal stem cells. This loss greatly impairs the ability of the laminar corium to regenerate. Although previous work provides credibility to this notion, there remain unsettled issues that must be addressed before accepting it as a well-founded fact. Here, it was reexamined the central tenet of the physiopathological model of laminitis by infusing allogeneic bone marrow-derived mesenchymal stem cells (ABM-MSCs), through the digital palmar vein, into the hooves of horses afflicted by chronic laminitis. Horses were clinically monitored during 6 mo by evaluating them monthly using the lameness-modified Obel-Glasgow’s scale and hooves thermography. Venograms and lamellar biopsies were taken at the beginning and at the end of the study period to gathered evidence on vascular remodeling and laminar corium regeneration. The results showed that ABM-MSCs infusion promotes vascular remodeling and laminar corium regeneration, further supporting that the loss of stem cells is the critical event leading to chronic laminitis. This work also demonstrated that the infusion of ABM-MSCs is safe since the treated horses did not develop local or systemic, negative clinical manifestations attuned with rejection reactions, at least during the 6-mo period they were follow up and under the therapeutic scheme proposed.

rBMSC osteogenic differentiation enhanced by graphene quantum dots loaded with immunomodulatory layered double hydroxide nanoparticles

Bone tissue defects caused by disease, trauma, aging or genetic factors emerged as one of the main factors that endanger human health. At present, advanced development of bone tissue engineering and regenerative medicine focused on the biomaterials regulated stem cell for responsive differentiation. In vivo transplantation of allogeneic bone materials has the needs of both osteogenic and immune regulation function. In this study, we utilized the extensively proved biocompatible layered double hydroxide (LDH) nanoparticles as the nanocarrier of graphene quantum dots (GQD), the functional loading was validated by characteristics analysis of scanning electron microscopy, surface zeta potential, X-ray diffraction and fourier transform infrared spectroscopy. Further, we investigated the cellular uptake of nanoparticles in rat bone marrow derived mesenchymal stem cells, the significant enhanced endocytosis was occurred in LDH-GQD treated groups. The enhanced osteogenic differentiation abilities of LDH-GQD were systematically investigated through alkaline phosphatase staining, alizarin red staining and qPCR analysis. In addition, the anti-inflammatory regulation of LDH facilitated the phenotypic transition of macrophage in LDH-GQD nanocomposites. Overall, the successful construction and functional validation of nanomaterials in this study will provide clinical therapeutic potential in bone defects regeneration.

Allogeneic Bone-Marrow Mesenchymal Stem Cell with Moldable Cryogel for Craniofacial Bone Regeneration

Allogeneic bone-marrow mesenchymal stem cells (BMSCs) can promote bone regeneration and substitute for autologous BMSCs if autologous sources are unavailable, but the efficacy of bone regeneration by allogeneic BMSCs is still inconsistent. A Lewis rat cranium defect model was used to investigate the efficacy of bone regeneration between autologous and allogeneic BMSCs in gelatin-nanohydroxyapatite cryogel scaffolds. BMSCs from Wistar rats served as the allogeneic cell lineage. The full-thickness cranium defects were treated by either blank control, cryogel only, allogeneic BMSC-seeded cryogel, or autologous BMSC-seeded cryogel (n = 5). Bone regeneration was monitored by micro-computed tomography and examined histologically at week 12. In addition, we assessed the immune responses in vitro by mixed lymphocyte reaction (MLR) assay and CD4+ immunochemistry staining ex vivo. The MLR showed that allogeneic BSMCs elicited a weak immune response on day 14 that progressively attenuated by day 28. In vivo, the bone regeneration in allogeneic BMSCs was inferior at week 4, but progressively matched the autologous BMSCs by week 12. Our results suggest that allogeneic BMSCs can serve as an alternative source for bone regeneration.

In vivo experimental study of the arterial supply of the rabbit posterior limb

Background: The use of bone graft has been a successful step in the treatment of a large number of diseases of the osteoarticular system. But a massive bone defect remains a dilemma for modern reconstructive surgery. Present methods used have a high level of morbidity and complication. Literature indicates the absence of an optimal solution in massive bone defects healing. The aim of this study: to perform an in vivo preliminary study of vascularization of the hind limb in the rabbit model, for obtaining a graft able for further inclusion in the host blood circulation, without immunosuppression by decellularization. Material and methods: The study was performed on the 12 laboratory rabbits. After euthanasia of the rabbit, the femoral and tibiofibular bone was collected without soft tissue, only with the vascular pedicle, and keeping the passage through the vessels. In the abdominal aorta was injected contrast material, with the subsequent preparation of the arterial vessels, succeeded by anatomical, morphological, radiography, and microangiography study of this vascularized bone segment. Results: The principal nutrient artery of the rabbit femur springs from the lateral circumflex femoral artery. The optimal segment for vascularized allografting (the rabbit model) was determined the upper third of the femur with the up to the level of the internal iliac artery. So, it could be used as a bone graft for further conservation and decellularization. Conclusions: The vascularized allogeneic bone without immunosuppression would be a perfect alternative in the treatment of the massive bone defects.