Explore the vast range of titles available.

Bone regeneration requires a well-orchestrated cellular and molecular response including robust vascularization and recruitment of mesenchymal and osteogenic cells. In femoral fractures, angiogenesis and osteogenesis are closely coupled during the complex healing process. Here, we show with advanced longitudinal intravital multiphoton microscopy that early vascular sprouting is not directly coupled to osteoprogenitor invasion during calvarial bone regeneration. Early osteoprogenitors emerging from the periosteum give rise to bone-forming osteoblasts at the injured calvarial bone edge. Microvessels growing inside the lesions are not associated with osteoprogenitors. Subsequently, osteogenic cells collectively invade the vascularized and perfused lesion as a multicellular layer, thereby advancing regenerative ossification. Vascular sprouting and remodeling result in dynamic blood flow alterations to accommodate the growing bone. Single cell profiling of injured calvarial bones demonstrates mesenchymal stromal cell heterogeneity comparable to femoral fractures with increase in cell types promoting bone regeneration. Expression of angiogenesis and hypoxia-related genes are slightly elevated reflecting ossification of a vascularized lesion site. Endothelial Notch and VEGF signaling alter vascular growth in calvarial bone repair without affecting the ossification progress. Our findings may have clinical implications for bone regeneration and bioengineering approaches. Fractured long bones regenerate through osteo-angiogenic coupling, but how calvarial bone healing occurs is not yet clear. Here they show that regenerating blood vessels separate from co-migrating progenitors in calvarial bones, resulting in osteoblasts mineralizing a previously vascularized lesion.

While low-intensity blood flow restriction (LI-BFR) training has recently been shown to improve bone health, there remains limited evidence regarding its impact on older adults. This meta-analysis aimed to quantitatively identify the effects of LI-BFR training on bone mineral density (BMD) and bone biomarkers compared with conventional resistance training programs. Studies were identified through searches of four databases: PubMed, Scopus, SPORTDiscus, and Web of Science. R packages were utilized for this meta-analysis. The results indicated that compared to low-intensity (LI) training, LI-BFR significantly increased BMD (ES = 0.25, 95% Confidence Interval [CI]: [0.08, 0.41], p  < 0.01), osteotropic hormones (i.e., GH, ES = 1.18, 95%CI: [0.66, 1.70]), p  < 0.001; IGF-1, ES = 0.89, 95% CI: [0.44, 1.33], p  < 0.001), but resulted in a smaller increase in bone resorption markers (i.e., CTX, ES = -0.77, 95%CI: [-1.16, -0.37], p  < 0.001). LI-BFR training demonstrated similar effects on BMD improvement as high-intensity (HI) resistance training (ES = -0.1, 95%CI: [-0.66, 0.41], p  = 0.64). Furthermore, sex and training frequency moderated the secretion of osteotropic hormones (male vs. female: IGF-1, 0.51 vs. 1.64, p  < 0.01; ≤ 3 times per week vs. > 3 times per week: GH, 1.62 vs. 0.68, p  < 0.01, and IGF-1, 1.13 vs. 0.39, p  < 0.05). In conclusion, LI-BFR training shows promise for enhancing bone health in older adults, offering benefits comparable to HI training.

Since the proposal of Paul Ehrlich’s magic bullet concept over 100 years ago, tremendous advances have occurred in targeted therapy. From the initial selective antibody, antitoxin to targeted drug delivery that emerged in the past decades, more precise therapeutic efficacy is realized in specific pathological sites of clinical diseases. As a highly pyknotic mineralized tissue with lessened blood flow, bone is characterized by a complex remodeling and homeostatic regulation mechanism, which makes drug therapy for skeletal diseases more challenging than other tissues. Bone-targeted therapy has been considered a promising therapeutic approach for handling such drawbacks. With the deepening understanding of bone biology, improvements in some established bone-targeted drugs and novel therapeutic targets for drugs and deliveries have emerged on the horizon. In this review, we provide a panoramic summary of recent advances in therapeutic strategies based on bone targeting. We highlight targeting strategies based on bone structure and remodeling biology. For bone-targeted therapeutic agents, in addition to improvements of the classic denosumab, romosozumab, and PTH1R ligands, potential regulation of the remodeling process targeting other key membrane expressions, cellular crosstalk, and gene expression, of all bone cells has been exploited. For bone-targeted drug delivery, different delivery strategies targeting bone matrix, bone marrow, and specific bone cells are summarized with a comparison between different targeting ligands. Ultimately, this review will summarize recent advances in the clinical translation of bone-targeted therapies and provide a perspective on the challenges for the application of bone-targeted therapy in the clinic and future trends in this area.

The most significant predictors of reoperation following operative management of fractures are the presence of a third degree open fracture, remaining fracture gaps and a transverse fracture. However clinical studies provide no information regarding the involvement of various soft tissues or how the mechanical environment affects revascularisation and bone healing. Here the results of experimental and numerical mechano-biological studies on fracture healing are summarized to provide guidance toward clinical treatment of fractures. In experimental studies, isolated muscle crush appeared to only temporarily impair fracture healing, with no significant effect to the final bone healing, whereas a more severe muscle trauma significantly reduced callus formation and biomechanical properties of the healed bones. An intraoperative trauma can furthermore impede vascularization. Surgical removal of the haematoma or periosteum disturbs fracture healing. While reaming for intramedullary nailing reduced blood flow in the bone during the early phase of bone healing, it did not affect the stiffness or strength of the final bone healing. The optimal conditions for rapid vascularization and bone healing result from fracture fixation that minimizes shearing movements in the healing zone while allowing moderate compressive movements. Bone healing is increasingly delayed with increasing fracture gap size and critical-size defects do not heal sufficiently independent of the mechanical environment. The stiffness of fracture fixation systems like nails and external fixators applied in clinical treatments frequently display a too low stiffness, whereas plate systems often cause a too stiff fixation that suppresses bone healing.

Blood platelets are formed by fragmentation of long membrane extensions from bone marrow megakaryocytes in the blood flow. Using lattice-Boltzmann/immersed boundary simulations we propose a biological Rayleigh–Plateau instability as the biophysical mechanism behind this fragmentation process. This instability is akin to the surface tension-induced breakup of a liquid jet but is driven by active cortical processes including actomyosin contractility and microtubule sliding. Our fully three-dimensional simulations highlight the crucial role of actomyosin contractility, which is required to trigger the instability, and illustrate how the wavelength of the instability determines the size of the final platelets. The elasto-hydrodynamic origin of the fragmentation explains the strong acceleration of platelet biogenesis in the presence of an external flow, which we observe in agreement with experiments. Our simulations then allow us to disentangle the influence of specific flow conditions: While a homogeneous flow with uniform velocity leads to the strongest acceleration, a shear flow with a linear velocity gradient can cause fusion events of two developing platelet-sized swellings during fragmentation. A fusion event may lead to the release of larger structures which are observable as preplatelets in experiments. Together, our findings strongly indicate a mainly physical origin of fragmentation and regulation of platelet size in flow-accelerated platelet biogenesis.

Despite considerable advances in knowledge of the anatomy, ecology and evolution of early mammals, far less is known about their physiology. Evidence is contradictory concerning the timing and fossil groups in which mammalian endothermy arose. To determine the state of metabolic evolution in two of the earliest stem-mammals, the Early Jurassic Morganucodon and Kuehneotherium , we use separate proxies for basal and maximum metabolic rate. Here we report, using synchrotron X-ray tomographic imaging of incremental tooth cementum, that they had maximum lifespans considerably longer than comparably sized living mammals, but similar to those of reptiles, and so they likely had reptilian-level basal metabolic rates. Measurements of femoral nutrient foramina show Morganucodon had blood flow rates intermediate between living mammals and reptiles, suggesting maximum metabolic rates increased evolutionarily before basal metabolic rates. Stem mammals lacked the elevated endothermic metabolism of living mammals, highlighting the mosaic nature of mammalian physiological evolution. Modern mammals are endothermic, but it has not been clear when this type of metabolism evolved. Here, Newham et al. analyse tooth and bone structure in Early Jurassic stem-mammal fossils to estimate lifespan and blood flow rates, which inform about basal and maximum metabolic rates, respectively, and show these stem-mammals had metabolic rates closer to modern ectothermic reptiles than to endothermic mammals.

Among the factors that are important in successful bone tissue regeneration through scaffolds are permeability and fluid flow-induced wall shear stress (WSS) because of the direct contribution of these factors to cell bioactivities. The permeability of scaffolds is usually measured using fluids such as water, which are characterized as Newtonian materials with constant viscosity. However, using the fluid properties of blood as bases in measuring permeability can lead to more realistic results given that scaffolds are implanted in the body, where the only flowing fluid (i.e., blood) is a non-Newtonian fluid. Moreover, the linear relationship of WSS with fluid viscosity challenges the use of Newtonian fluids in determining WSS magnitude. With consideration for these issues, we investigated permeability and WSS through computational fluid dynamics (CFD) analyses of lattice-based and gyroid scaffold architectures with Newtonian and non-Newtonian blood flow properties. With reference to geometrical parameters and the pressure drops derived from the CFD analyses, the permeability levels of the Newtonian and non-Newtonian models were calculated by exploiting the classic and modified Darcy's equations, respectively. Results showed that both scaffold architectures were several times more permeable in the Newtonian blood flow models than in their non-Newtonian counterparts. Within the scaffolds, the non-Newtonian flow of blood caused almost twice the magnitude of WSS originating from Newtonian blood flow. These striking discrepancies in permeability and WSS between the two blood models were due to differences in their viscosity behaviors.

Metastatic spine disease (MSD) is a severe event in cancer patients. Experimental data indicate that bone metastasis is mostly mediated by blood flow-dependent, passive arrest of circulating tumor cells to the bone metastatic niche (BMN). Here, we have set out to test these experimental observations in a clinical, human setting to improve our understanding of MSD. 507 patients, treated on spinal metastases in our institution from 2005 to  2015 were retrospectively evaluated. We identified 259 patients with accessible staging reports of the skeleton before and at initial diagnosis of MSD. Data analysis comprised localizations of bone metastases, underlying malignancy and time to development of MSD. Dissemination pattern of bone metastasis was correlated with red bone marrow (RBM) content of the respective bone as a measure of blood flow. Spinal metastases occurred most frequently in lung cancer (21%), prostate cancer (19%), and breast cancer (12%). At the diagnosis of MSD, majority of patients have multiple extra-spinal bone metastases (2/3). The distribution of metastases to extra-spinal bones and to the spine is mostly proportional to the RBM content of the involved bone. Corresponding to the high RBM content, thoracic spine, pelvic bones and ribs represent a predilection site for bone metastasis. We confirm a distinct preference of cancer types to metastasize to bones. When it comes to bone metastases all primaries show uniform distribution pattern, which supports the hypothesis of a predominantly blood flow-dependent distribution of tumor cells and passive arrest to the BMN rather than a spine-specific homing mechanism.

Understanding the mechanisms underlying vascular regeneration in the heart is crucial for developing novel therapeutic strategies for myocardial ischemia. This study investigates the contribution of bone marrow-derived cells to endothelial cell populations in the heart, and their role in cardiac function and coronary circulation following repetitive ischemia (RI). Chimeric rats were created by transplanting BM cells from GFP female rats into irradiated male recipients. After engraftment chimeras were subjected to RI for 17 days. Vascular growth was assessed from recovery of cardiac function and increases in myocardial blood flow during LAD occlusion. After sorting GFP+ BM cells from heart and bone of Control and RI rats, single-cell RNA sequencing was implemented to determine the fate of BM cells. Our in vivo RI model demonstrated an improvement in cardiac function and myocardial blood flow after 17 days of RI with increased capillary density in the rats subjected to RI compared to Controls. Single-cell RNA sequencing of bone marrow cells isolated from rats' hearts identified distinct endothelial cell (EC) subpopulations. These ECs exhibited heterogeneous gene expression profiles and were enriched for markers of capillary, artery, lymphatic, venous, and immune ECs. Furthermore, BM-derived ECs in the RI group showed an angiogenic profile, characterized by upregulated genes associated with blood vessel development and angiogenesis. This study elucidates the heterogeneity of bone marrow-derived endothelial cells in the heart and their response to repetitive ischemia, laying the groundwork for targeting specific subpopulations for therapeutic angiogenesis in myocardial ischemia.

Sigmoid sinus wall dehiscence (SSWD) is a common pathophysiology of patients with pulsatile tinnitus (PT). However, the pathological mechanism of SSWD is unclear. This study aimed to investigate the relationship between the position of the SSWD and blood flow pattern of the transverse sinus and sigmoid sinus (TS–SS) junction. The impact of the blood flow was hypothesized to be the pathological mechanism of SSWD. Twenty patients and two healthy volunteers were analyzed retrospectively, and transient computer fluid dynamics was used to verify this hypothesis. A 4D flow magnetic resonance imaging experiment was performed to validate the numerical simulation. The position of high-velocity blood flow impacting the vessel wall (17/20) was consistent with SSWD. In healthy volunteers, the temporal bone was thin where the blood flow impacted the blood vessel wall. The average wall shear stress (20/20) and pressure (18/20) of the SSWD area (peak) were higher than those of sigmoid sinus wall anomalies (the contact area between the vessel wall and the temporal bone at the TS–SS junction). The average wall pressure percentage differences of 16/20, 11/20, and 4/20 patients were more than 5%, 10%, and 20%, respectively. The average wall shear stress percentage differences of 20/20, 18/20, and 16/20 patients were more than 5%, 10%, and 20%, respectively. In brief, the blood flow of the TS–SS junction impacted the vessel wall and increased wall pressure, which might be an important pathological mechanism of SSWD. This study could serve as a basis for the diagnosis and SSWD resurfacing surgery of patients with PT induced by SSWD.