NACA and LRP6 Are Part of a Common Genetic Pathway Necessary for Full Anabolic Response to Intermittent PTH

PTH induces phosphorylation of the transcriptional coregulator NACA on serine 99 through Gαs and PKA. This leads to nuclear translocation of NACA and expression of the target gene Lrp6, encoding a coreceptor of the PTH receptor (PTH1R) necessary for full anabolic response to intermittent PTH (iPTH) treatment. We hypothesized that maintaining enough functional PTH1R/LRP6 coreceptor complexes at the plasma membrane through NACA-dependent Lrp6 transcription is important to ensure maximal response to iPTH. To test this model, we generated compound heterozygous mice in which one allele each of Naca and Lrp6 is inactivated in osteoblasts and osteocytes, using a knock-in strain with a Naca99 Ser-to-Ala mutation and an Lrp6 floxed strain (test genotype: Naca99S/A; Lrp6+/fl;OCN-Cre). Four-month-old females were injected with vehicle or 100 μg/kg PTH(1-34) once daily, 5 days a week for 4 weeks. Control mice showed significant increases in vertebral trabecular bone mass and biomechanical properties that were abolished in compound heterozygotes. Lrp6 expression was reduced in compound heterozygotes vs. controls. The iPTH treatment increased Alpl and Col1a1 mRNA levels in the control but not in the test group. These results confirm that NACA and LRP6 form part of a common genetic pathway that is necessary for the full anabolic effect of iPTH.

Biomechanical Analyses of Porous Designs of 3D-Printed Titanium Implant for Mandibular Segmental Osteotomy Defects

Clinically, a reconstruction plate can be used for the facial repair of patients with mandibular segmental defects, but it cannot restore their chewing function. The main purpose of this research is to design a new three-dimensionally (3D) printed porous titanium mandibular implant with both facial restoration and oral chewing function reconstruction. Its biomechanical properties were examined using both finite element analysis (FEA) and in vitro experiments. Cone beam computed tomography images of the mandible of a patient with oral cancer were selected as a reference to create 3D computational models of the bone and of the 3D-printed porous implant. The pores of the porous implant were circles or hexagons of 1 or 2 mm in size. A nonporous implant was fabricated as a control model. For the FEA, two chewing modes, namely right unilateral molar clench and right group function, were set as loading conditions. Regarding the boundary condition, the displacement of both condyles was fixed in all directions. For the in vitro experiments, an occlusal force (100 N) was applied to the abutment of the 3D-printed mandibular implants with and without porous designs as the loading condition. The porous mandibular implants withstood higher stress and strain than the nonporous mandibular implant, but all stress values were lower than the yield strength of Ti-6Al-4V (800 MPa). The strain value of the bone surrounding the mandibular implant was affected not only by the shape and size of the pores but also by the chewing mode. According to Frost’s mechanostat theory of bone, higher bone strain under the porous implants might help maintain or improve bone quality and bone strength. The findings of this study serve as a biomechanical reference for the design of 3D-printed titanium mandibular implants and require confirmation through clinical investigations.

Evaluation of remodeling and geometry on the biomechanical properties of nacreous bivalve shells

Mollusks have developed a broad diversity of shelled structures to protect against challenges imposed by biological interactions(e.g., predation) and constraints (e.g., $$pCO_2$$ p C O 2 -induced ocean acidification and wave-forces). Although the study of shell biomechanical properties with nacreous microstructure has provided understanding about the role of shell integrity and functionality on mollusk performance and survival, there are no studies, to our knowledge, that delve into the variability of these properties during the mollusk ontogeny, between both shells of bivalves or across the shell length. In this study, using as a model the intertidal mussel Perumytilus purpuratus to obtain, for the first time, the mechanical properties of its shells with nacreous microstructure; we perform uniaxial compression tests oriented in three orthogonal axes corresponding to the orthotropic directions of the shell material behavior (thickness, longitudinal, and transversal). Thus, we evaluated whether the shell material’s stress and strain strength and elastic modulus showed differences in mechanical behavior in mussels of different sizes, between valves, and across the shell length. Our results showed that the biomechanical properties of the material building the P. purpuratus shells are symmetrical in both valves and homogeneous across the shell length. However, uniaxial compression tests performed across the shell thickness showed that biomechanical performance depends on the shell size (aging); and that mechanical properties such as the elastic modulus, maximum stress, and strain become degraded during ontogeny. SEM observations evidenced that compression induced a tortuous fracture with a delamination effect on the aragonite mineralogical structure of the shell. Findings suggest that P. purpuratus may become vulnerable to durophagous predators and wave forces in older stages, with implications in mussel beds ecology and biodiversity of intertidal habitats.

The influence of corneal density and thickness on tonometry measurement with goldmann applanation, non-contact and iCare tonometry methods

Purpose To evaluate the effect of corneal density and thickness on the accuracy of tonometry readings obtained via three most used techniques. Method Intraocular pressures of 45 patients’ right eyes were measured using Goldmann Applanation, iCare, and non-contact tonometry methods. Corneal parameters were obtained using the Pentacam Camera System. Data obtained were analyzed using Paired t Test, Pearson’s correlation coefficient, multiple linear regression analysis, and Bland–Altman plots. Results The mean corneal thickness was 545.4 ± 3.93 μm. The mean corneal density of total, stromal, 0–2 mm, and 2–6 mm zones were 27.85 ± 6.23 GSU, 24.61 ± 6.05 GSU, 20.76 ± 2.96 GSU, and 20.81 ± 3.51 GSU respectively. IOP readings had a statistically significant correlation with corneal stromal thickness, as well as with total and stromal density. The stromal density, however, showed higher correlation with the three tonometry methods than did the total density (iCare: − .482 (0.001) stromal density versus− .464 (0.001) total density, NCT: − .376 (0.011) versus − .353 (0.017), GAT: − .306 (0.041) versus − .296 (0.048)). Statistical differences were found in comparing the iCare readings with GAT (P < 0,00) and with NCT (P < 0,00), with mean differences of 1.8 mmHg ± 2.6 and 2.0 mmHg ± 2.6 respectively. GAT and NCT measurements showed no statistical difference (P > 0.05). Conclusion This study shows that both central corneal thickness and stromal density are significant influential factors of reliable IOP readings. It is necessary to consider more corneal biomechanical properties, as well as exercise a high degree of caution in any new attempts towards adjusting an IOP-correction equation.

Biomechanical Performance Analysis of the Monolateral External Fixation Devices with Steel and Composite Material Frames under the Impact of Axial Load

This paper describes comparative analysis of the biomechanical performances conducted on the external fixation devices whose frames are made out of two different material (stainless steel and composite material). Biomechanical properties were determined with experimental and FEM (finite element method) models which are used to study the movement of the fracture crack, establish stiffness of the design solutions and monitor generated stresses on the zones of interest. Geometric modeling of two fixation devices configurations B50 and C50 is used as a basis for structural analysis under the impact of axial load. Structural analysis results are confirmed with an experimental setup. Analyzed deflection values in the load and fracture zones are used to define the exact values of the stiffness for the construction design and fracture, respectively. The carbon frame device configuration has 28% lower construction stiffness than the one with the steel frame (for B50 configuration), i.e., 9% (for C50 configuration). In addition, fracture stiffness values for the composite frame application are approximately 23% lower (B50 configuration), i.e., 13% lower (C50 configuration), compared to steel frame. The carbon frame device has about 33% lower stresses at the critical zones compared to the steel frame at the control zone MM+ and, similarly, 35% lower stresses at the control zone MM-. With an exhausting analysis of the biomechanical properties of the fixation devices, it can be concluded that steel frame fixation device is superior, meaning it has better biomechanical characteristics compared to carbon frame fixation device, regarding obtained data for stresses and stiffnesses of the frame construction and fracture. Considering stresses at the critical zones of the fixation device construction, the carbon frame device has better biomechanical performances compared to steel frame devices.

The Effects of Healthy Aging on Right Ventricular Structure and Biomechanical Properties: A Pilot Study

Healthy aging has been associated with alterations in pulmonary vascular and right ventricular (RV) hemodynamics, potentially leading to RV remodeling. Despite the current evidence suggesting an association between aging and alterations in RV function and higher prevalence of pulmonary hypertension in the elderly, limited data exist on age-related differences in RV structure and biomechanics. In this work, we report our preliminary findings on the effects of healthy aging on RV structure, function, and biomechanical properties. Hemodynamic measurements, biaxial mechanical testing, constitutive modeling, and quantitative transmural histological analysis were employed to study two groups of male Sprague-Dawley rats: control (11 weeks) and aging (80 weeks). Aging was associated with increases in RV peak pressures (+17%, p = 0.017), RV contractility (+52%, p = 0.004), and RV wall thickness (+38%, p = 0.001). Longitudinal realignment of RV collagen (16.4°, p = 0.013) and myofibers (14.6°, p = 0.017) were observed with aging, accompanied by transmural cardiomyocyte loss and fibrosis. Aging led to increased RV myofiber stiffness (+141%, p = 0.003), in addition to a bimodal alteration in the biaxial biomechanical properties of the RV free wall, resulting in increased tissue-level stiffness in the low-strain region, while progressing into decreased stiffness at higher strains. Our results demonstrate that healthy aging may modulate RV remodeling via increased peak pressures, cardiomyocyte loss, fibrosis, fiber reorientation, and altered mechanical properties in male Sprague-Dawley rats. Similarities were observed between aging-induced remodeling patterns and those of RV remodeling in pressure overload. These findings may help our understanding of age-related changes in the cardiovascular fitness and response to disease.

Machine learning in knee arthroplasty: specific data are key—a systematic review

Purpose Artificial intelligence (AI) in healthcare is rapidly growing and offers novel options of data analysis. Machine learning (ML) represents a distinct application of AI, which is capable of generating predictions and has already been tested in different medical specialties with various approaches such as diagnostic applications, cost predictions or identification of risk factors. In orthopaedics, this technology has only recently been introduced and the literature on ML in knee arthroplasty is scarce. In this review, we aim to investigate which predictions are already feasible using ML models in knee arthroplasty to identify prerequisites for the effective use of this novel approach. For this reason, we conducted a systematic review of ML algorithms for outcome prediction in knee arthroplasty. Methods A comprehensive search of PubMed, Medline database and the Cochrane Library was conducted to find ML applications for knee arthroplasty. All relevant articles were systematically retrieved and evaluated by an orthopaedic surgeon and a data scientist on the basis of the PRISMA statement. The search strategy yielded 225 articles of which 19 were finally assessed as eligible. A modified Coleman Methodology Score (mCMS) was applied to account for a methodological evaluation. Results The studies presented in this review demonstrated fair to good results (AUC median 0.76/range 0.57–0.98), while heterogeneous prediction models were analysed: complications (6), costs (4), functional outcome (3), revision (2), postoperative satisfaction (2), surgical technique (1) and biomechanical properties (1) were investigated. The median mCMS was 65 (range 40–80) points. Conclusion The prediction of distinct outcomes with ML models applying specific data is already feasible; however, the prediction of more complex outcomes is still inaccurate. Registry data on knee arthroplasty have not been fully analysed yet so that specific parameters have not been sufficiently evaluated. The inclusion of specific input data as well as the collaboration of orthopaedic surgeons and data scientists are essential prerequisites to fully utilize the capacity of ML in knee arthroplasty. Future studies should investigate prospective data with specific and longitudinally recorded parameters. Level of evidence III.

Fibro-adipogenesis in Injured Rotator Cuff Muscle

Purpose of Review Fibro-adipogenic progenitors were first characterized in 2010 and later found to contribute significantly to muscle regeneration and mediate degenerative changes in muscle following injury. These progenitors were also found to have an influence on the rotator cuff muscle’s response to chronic injury which is defined by fibrosis accompanied by massive fatty degeneration. The purpose of this review is to highlight progenitor cells, their contribution to fibro-adipogenesis in rotator cuff tissue, and the factors influencing fibro-adipogenesis in this tissue. Recent Findings Fibro-adipogenic progenitors are a key mediator of the fatty infiltration notably prevalent in rotator cuff injury. Relative to other muscle groups, the rotator cuff has relatively high rates of fibro-adipogenesis following massive chronic rotator cuff tears. This may be linked to the pre-injury density of fibro-adipogenic progenitors in muscle tissue affecting post-injury levels of fibro-adipogenesis. In addition, suprascapular nerve injury in rat models of rotator cuff tears has demonstrated worse, histologic, and biomechanical properties and lower healing rates of rotator cuff repairs. However, fatty infiltration in the rotator cuff following suprascapular nerve compression has been shown to be reversible following release of the nerve compression. Summary The fibro-adipogenic response to acute and chronic injury in rotator cuff tissue is determined by a complex array of factors including progenitor cell influence, transcriptional pathways, chronicity of the injury, anatomic location of injury, microenvironmental influences, and the severity of nerve involvement. Elucidating the complex interactions of these factors will provide potential targets for therapeutic intervention in vivo.

The synthetic artificial stem cell (SASC): Shifting the paradigm of cell therapy in regenerative engineering

Stem cells are of great interest in tissue regeneration due to their ability to modulate the local microenvironment by secreting bioactive factors (collectively, secretome). However, secretome delivery through conditioned media still requires time-consuming cell isolation and maintenance and also may contain factors antagonistic to targeted tissue regeneration. We have therefore engineered a synthetic artificial stem cell (SASC) system which mimics the paracrine effect of the stem cell secretome and provides tailorability of the composition for targeted tissue regeneration. We report the first of many applications of the SASC system we have formulated to treat osteoarthritis (OA). Choosing growth factors important to chondrogenesis and encapsulating respective recombinant proteins in poly (lactic-coglycolic acid) 85:15 (PLGA) we fabricated the SASC system. We compared the antiinflammatory and chondroprotective effects of SASC to that of adipose-derived stem cells (ADSCs) using in vitro interleukin 1B-induced and in vivo collagenase-induced osteoarthritis rodent models. We have designed SASC as an injectable therapy with controlled release of the formulated secretome. In vitro, SASC showed significant antiinflammatory and chondroprotective effects as seen by the up-regulation of SOX9 and reduction of nitric oxide, ADAMTS5, and PRG4 genes compared to ADSCs. In vivo, treatment with SASC and ADSCs significantly attenuated cartilage degeneration and improved the biomechanical properties of the articular cartilage in comparison to OA control. This SASC system demonstrates the feasibility of developing a completely synthetic, tailorable stem cell secretome which reinforces the possibility of developing a new therapeutic strategy that provides better control over targeted tissue engineering applications.