Mini-review

Targeted and nontargeted bone remodeling: relationship to basic multicellular unit origination and progression

Strain energy density (SED) is considered to be the primary remodelling stimulus influencing the process of bone growth into porous implants. A bone remodelling algorithm incorporating the concept of bone connectivity, that newly formed bone should only grow from existing bone, was developed to provide a more biologically realistic simulation of bone growth. Results showed that the new algorithm prevented the occurrence of unconnected mature bone within porous implants, an unrealistic phenomenon observed using conventional adaptive elasticity theories. The bone connectivity algorithm had minimal effect (0.67% difference) on the final bone density distribution for standard bending and torsional moment cases. For a porous implant model, both algorithms, with and without bone connectivity implementation, reached the same final stiffness, with a difference of less than 0.01%. The bone connectivity algorithm predicted a slower and more gradual bone remodelling process, requiring at least 50% additional time for full remodelling compared to the conventional adaptive elasticity algorithm, which should be accounted for in the planning of rehabilitation strategies. The developed modelling can be employed to improve porous implant designs to achieve better clinical outcomes.

Bone can adapt its microstructure to mechanical loads through mechanoregulation of the (re)modeling process. This process has been investigated in vivo using time-lapsed micro-computed tomography (micro-CT) and micro-finite element (FE) analysis using surface-based methods, which are highly influenced by surface curvature. Consequently, when trying to investigate mechanoregulation in tissue engineered bone constructs, their concave surfaces make the detection of mechanoregulation impossible when using surface-based methods. In this study, we aimed at developing and applying a volumetric method to non-invasively quantify mechanoregulation of bone formation in tissue engineered bone constructs using micro-CT images and FE analysis. We first investigated hydroxyapatite scaffolds seeded with human mesenchymal stem cells that were incubated over 8 weeks with one mechanically loaded and one control group. Higher mechanoregulation of bone formation was measured in loaded samples with an area under the curve for the receiver operating curve (AUC_formation) of 0.633–0.637 compared to non-loaded controls (AUC_formation: 0.592–0.604) during culture in osteogenic medium (p < 0.05). Furthermore, we applied the method to an in vivo mouse study investigating the effect of loading frequencies on bone adaptation. The volumetric method detected differences in mechanoregulation of bone formation between loading conditions (p < 0.05). Mechanoregulation in bone formation was more pronounced (AUC_formation: 0.609–0.642) compared to the surface-based method (AUC_formation: 0.565–0.569, p < 0.05). Our results show that mechanoregulation of formation in bone tissue engineered constructs takes place and its extent can be quantified with a volumetric mechanoregulation method using time-lapsed micro-CT and FE analysis.

Many efforts have been directed towards optimizing bone scaffolds for tissue growth. However, the impact of the scaffolds mechanical environment on bone growth is still poorly understood, requiring accurate assessment of its mechanoregulation. Existing surface-based methods were unable to detect mechanoregulation in tissue engineered constructs, due to predominantly concave surfaces in scaffolds. We present a volumetric approach to enable the precise and non-invasive quantification and analysis of mechanoregulation in bone tissue engineered constructs by leveraging time-lapsed micro-CT imaging, image registration, and finite element analysis. The implications of this research extend to diverse experimental setups, encompassing culture conditions, and material optimization, and investigations into bone diseases, enabling a significant stride towards comprehensive advancements in bone tissue engineering and regenerative medicine.

There is a genetic component to the minimum effective strain (MES)—a threshold which determines when bone will adapt to function—which suggests ancestry should play a role in bone (re)modelling. Further elucidating this is difficult in living human populations because of the high global genetic admixture. We examined femora from an anthropological skeletal assemblage (Mán Bạc, Vietnam) representing distinct ancestral groups. We tested whether femur morphological and histological markers of modelling and remodelling differed between ancestries despite their similar lifestyles.

Static histomorphometry data collected from subperiosteal cortical bone of the femoral midshaft, and gross morphometric measures of femur robusticity, were studied in 17 individuals from the Mán Bạc collection dated to 1906–1523 cal. BC. This assemblage represents agricultural migrants with affinity to East Asian groups, who integrated with the local hunter-gatherers with affinity to Australo-Papuan groups during the mid-Holocene. Femur robusticity and histology data were compared between groups of ‘Migrant’ (n = 8), ‘Admixed’ (n = 4), and ‘Local’ (n = 5).

Local individuals had more robust femoral diaphyses with greater secondary osteon densities, and relatively large secondary osteon and Haversian canal parameters than the migrants. The Migrant group showed gracile femoral shafts with the least dense bone made up of small secondary osteons and Haversian canals. The Admixed individuals fell between the Migrant and Local categories in terms of their femoral data. However, we also found that measures of how densely bone is remodelled per unit area were in a tight range across all three ancestries.

Bone modelling and remodelling markers varied with ancestral histories in our sample. This suggests that there is an ancestry related predisposition to bone optimising its metabolic expenditure likely in relation to the MES. Our results stress the need to incorporate population genetic history into hierarchical bone analyses. Understanding ancestry effects on bone morphology has implications for interpreting biomechanical loading history in past and modern human populations.

Bone and cartilage are two highly specialized connective tissues. Bones are rigid and strong tissues due to their mineralized extracellular components and contribute to the skeletal structure of human and animal bodies. Stem cells have promising potential for the repair and regeneration of bone, cartilage, and other body tissues. Stem cells can be used to develop multiple regenerative medicine approaches for the treatment of several bone and cartilage diseases and disorders. They are, therefore, a valuable and promising tool for the repair and regeneration of bone and cartilage. In this chapter, we briefly describe the structure and function of joint and bone as well as the bone remodeling process. We also discuss recent advances in stem cell application in the repair and regeneration of joint, cartilage, and bone.

West Nusa Tenggara Province has the fifth-highest prevalence of stunting cases in Indonesia. So far, limited research is available to understand the likelihood of stunting in this region. Transforming Growth Factor-Beta 1 (TGF-β1), an immunoregulatory cytokine, may affect the stunting progression. Knowledge of messenger mRNA expression in the TGF-β1 gene in stunted toddlers could help to determine therapeutic targets to catch up on their growth.

This study compared the expression of TGF- β1 mRNA and TGF-β1 concentrations in the stunted and the non-stunted toddlers. The nutritional status of all participants was also gathered and linked to the stunting issue.

A cross-sectional study was conducted on 48 toddlers aged 12–36 months. The stunting case was defined as a Z-Score of less than −2 of length/height for age according to WHO. The serum TGF-β1 and TGF-β1 gene mRNA were measured using ELISA and RT-PCR, respectively. The nutritional status data were collected through interviewer-administered structured questionnaire to the toddlers' parents and 48-h food recalls. Descriptive analyses were applied to determine the distribution of participants’ macronutrient and micronutrient levels.

Results show that there were significant differences in expressions of the TGF- β1 gene mRNA of the stunted and the non-stunted toddlers. The expression of the TGF- β1 mRNA gene in the non-stunted toddlers was also higher with 13.7 ± 0.859 fold change than those of the stunted toddlers with 9.01 ± 1.76 fold change with a p-value <0.001. The serum TGF-β1 concentrations in the stunted toddler (6.20 ± 3.60 pg/ml) were significantly lower than the ones in the non-stunted toddlers (14.3 ± 1.05 pg/ml) with p-value <0.001. However, there was no clear relationship between the likelihood of stunting and the nutritional status from the obtained data.

Overall findings demonstrate the significantly lower both the TGF-β1 gene mRNA expression and serum TGF-β1 for the stunted toddlers than the non-stunted toddlers, impacting bone formation and resorption. The outcomes of this study encourage the development of interventional therapy for stunted toddlers by increasing the serum TGF-β1 concentrations.