Sara Feldman

Structural analysis of the human tibia by tomographic (pQCT) serial scans

This study analyses the evaluation of tomographic indicators of tibia structure, assuming that the usual loading pattern shifts from uniaxial compression close to the heel to a combined compression, torsion and bending scheme towards the knee. To this end, pQCT scans were obtained at 5% intervals of the tibia length (S5–S95 sites from heel to knee) in healthy men and women (10/10) aged 20–40 years. Indicators of bone mass [cortical area, cortical/total bone mineral content (BMC)], diaphyseal design (peri/endosteal perimeters, cortical thickness, circularity, bending/torsion moments of inertia – CSMIs), and material quality [(cortical vBMD (bone mineral density)] were determined. The longitudinal patterns of variation of these measures were similar between genders, but male values were always higher except for cortical vBMD. Expression of BMC data as percentages of the minimal values obtained along the bone eliminated those differences. The correlative variations in cortical area, BMC and thickness, periosteal perimeter and CSMIs along the bone showed that cortical bone mass was predominantly associated with cortical thickness toward the mid‐diaphysis, and with bone diameter and CSMIs moving more proximally. Positive relationships between CSMIs (y) and total BMC (x) showed men’s values shifting to the upper‐right region of the graph and women’s values shifting to the lower‐left region. Total BMC decayed about 33% from S5 to S15 (where minimum total BMC and CSMI values and variances and maximum circularity were observed) and increased until S45, reaching the original S5 value at S40. The observed gender‐related differences reflected the natural allometric relationships. However, the data also suggested that men distribute their available cortical mass more efficiently than women. The minimum amount and variance of mass indicators and CSMIs, and the largest circularity observed at S15 reflected the assumed adaptation to compression pattern at that level. The increase in CSMIs (successively for torsion, A–P bending, and lateral bending), the decrease in circularity values and the changes in cortical thickness and periosteal perimeter toward the knee described the progressive adaptation to increasing torsion and bending stresses. In agreement with the biomechanical background, the described relationships: (i) identify the sites at which some changes in tibial stresses and diaphyseal structure take place, possibly associated with fracture incidence; (ii) allow prediction of mass indicators at any site from single determinations; (iii) establish the proportionality between the total bone mass at regions with highly predominant trabecular and cortical bone of the same individual, suitable for a specific evaluation of changes in trabecular mass; and (iv) evaluate the ability of bone tissue to self‐distribute the available cortical bone according to specific stress patterns, avoiding many anthropometric and gender‐derived influences.

Characterization of Hybrid Bioactive Glass-polyvinyl Alcohol Scaffolds Containing a PTHrP-derived Pentapeptide as Implants for Tissue Engineering Applications

Hybrid foam (BG-PVA) with 50 % Bioactive glass (BG) and 50 % polyvinyl alcohol (PVA) was prepared by sol-gel process to produce scaffolds for bone tissue engineering. The pore structure of hydrated foams was evaluated by 3-D confocal microscopy, confirming 70% porosity and interconnected macroporous network. In this study, we assessed the putative advantage of coating with osteostatin pentapeptide into BG-PVA hybrid scaffolds to improve their bioactivity. In vitro cell culture experiments were performed using mouse pre-osteoblastic MC3T3-E1 cell line. The exposure to osteostatin loaded-BG-PVA scaffolds increase cell proliferation in contrast with the unloaded scaffolds. An in vivo study was selected to implant BG-PVA scaffolds, non-coated (Group A) or coated (Group B) with osteostatin into non critical bone defect at rabbit femur. Both groups showed new compact bone formation on implant surface, with lamellae disposed around a haversian canal forming osteons-like structure. We observed signs of inflammation around the implanted unloaded scaffold at one month, but resolved at 3 months. This early inflammation did not occur in Group B; supporting the notion that osteostatin may act as anti-inflammatory inhibitor. On the other hand, Group B showed increased bone formation, as depicted by many new trabeculae partly mineralized in the implant regenerating area, incipient at 1 month and more evident at 3 months after implantation. PVA/BG hybrid scaffolds present a porous structure suitable to support osteoblast proliferation and differentiation. Our in vitro and in vivo findings indicate that osteostatin coating improves the osteogenic features of these scaffolds

Absorptiometric assessment of muscle-bone relationships in humans: reference, validation, and application studies.

This report summarizes some preliminary absorptiometric (DXA, QCT/pQCT) studies from our laboratory, supporting the following assumptions. 1. InHomo sapiens at all ages, natural proportionality between DXA-assessed bone mineral mass (bone mineral content, BMC) and muscle mass (lean mass, LM) of the whole body or limbs is specific for ethnicity, gender, and reproductive status, but not for body weight, height, or body mass index. 2. This proportionality is sensitive to many kinds of endocrine-metabolic perturbations. 3. Percentilized or Z-scored charts of the BMC/LM correlations as determined in large samples of healthy individuals can provide a diagnostic reference for evaluating proportionality in different conditions. 4. Employing exclusively DXA, this methodology can be applied to discriminate between “disuse-related” and “metabolic” osteopenias based on the finding of normal or low BMC/LM percentiles or Z-scores respectively, with important therapeutic and monitoring implications.

Novel experimental effects on bone material properties and the pre- and postyield behavior of bones may be independent of bone mineralization

In this article, we summarize the results of six different tomographic/biomechanical rat studies involving hypophysectomy (Hx), ovariectomy, treatment with rhGH, olpadronate, alendronate, and toxic doses of aluminum and the development of a genetic diabetes in theeSS strain. All these conditions induced some interesting and rarely reported effects on postyield bone strength. These effects were generally related neither to the degree of mineralization or the elastic modulus of the bone tissue nor to the preyield behavior of the bones. In two particular cases (Hx,eSS), the elastic modulus of bone tissue varied independently of its degree of mineralization. These results suggest the involvement of some microstructural factor(s) of bone tissue resistance to crack progression (a postyield feature of bone behavior), rather than to crack initiation (the yield-determining factor) in the corresponding mechanism. Changes in collagen or crystal structure may play that role. These changes are relevant to the mechanism of fracture production during plastic deformation, a feature of bone strength that might be independent from mineralization. Therefore, these changes might help to explain some effects of novel treatments on bone strength unrelated to bone mineralization. This questions the belief that the remaining bone mass in metabolic osteopenias is biologically and mechanically normal.

Hybrid Matrix Grafts to Favor Tissue Regeneration in Rabbit Femur Bone Lesions

At present, typical approaches employed to repair fractures and other bone lesions tend to use matrix grafts to promote tissue regeneration. These grafts act as templates, which promote cellular adhesion, growth and proliferation, osteoconduction, and even osteoinduction, which commonly results in de novo osteogenesis. The present work aimed to study the bone-repairing ability of hybrid matrixes (HM) prepared with polyvinyl alcohol (PVA) and bioactive glass in an experimental rabbit model. The HM were prepared by combining 30% bioactive glass (nominal composition of 58% SiO2 -33 % CaO - 9% P2O5) and 70% PVA. New Zealand rabbits were randomly divided into the control group (C group) and two groups with bone lesions, in which one received a matrix implant HM (Implant group), while the other did not (no Implant group). Clinical monitoring showed no altered parameters from either the Implant or the no Implant groups as compared to the control group, for the variables of diet grades, day and night temperatures and hemograms. In the Implant group, radiologic and tomographic studies showed implanted areas with clean edges in femoral non-articular direction, and radio-dense images that suggest incipient integration. Minimum signs of phlogosis could be observed, whereas no signs of rejection at this imaging level could be identified. Histological analysis showed evidence of osteo-integration, with the formation of a trabecular bone within the implant. Together, these results show that implants of hybrid matrixes of bioactive glass are capable of promoting bone regeneration.

Bone regeneration mediated by a bioactive and biodegradable extracellular matrix-like hydrogel based on elastin-like recombinamers

The morbidity of bone fractures and defects is steadily increasing due to changes in the age pyramid. As such, novel biomaterials that are able to promote the healing and regeneration of injured bones are needed to overcome the limitations of auto-, allo-, and xenografts, while providing a ready-to-use product that may help to minimize surgical invasiveness and duration. In this regard, recombinant biomaterials, such as elastin-like recombinamers (ELRs), are very promising as their design can be tailored by genetic engineering, thus allowing scalable production and batch-to-batch consistency, among others. Furthermore, they can self-assemble into physically crosslinked hydrogels above a certain transition temperature, in this case body temperature, but are injectable below this temperature, thereby markedly reducing surgical invasiveness. In this study, we have developed two bioactive hydrogel-forming ELRs, one including the osteogenic and osteoinductive bone morphogenetic protein-2 (BMP-2) and the other the Arg-Gly-Asp (RGD) cell adhesion motif. The combination of these two novel ELRs results in a BMP-2-loaded extracellular matrix-like hydrogel. Moreover, elastase-sensitive domains were included in both ELR molecules, thereby conferring biodegradation as a result of enzymatic cleavage and avoiding the need for scaffold removal after bone regeneration. Both ELRs and their combination showed excellent cytocompatibility, and the culture of cells on RGD-containing ELRs resulted in optimal cell adhesion. In addition, hydrogels based on a mixture of both ELRs were implanted in a pilot study involving a femoral bone injury model in New Zealand white rabbits, showing complete regeneration in six out of seven cases, with the other showing partial closure of the defect. Moreover, bone neoformation was confirmed using different techniques, such as radiography, computed tomography, and histology. This hydrogel system therefore displays significant potential in the regeneration of bone defects, promoting self-regeneration by the surrounding tissue with no involvement of stem cells or osteogenic factors other than BMP-2, which is released in a controlled manner by elastase-mediated cleavage from the ELR backbone.

MMPs are involved in osteoporosis and are correlated with cardiovascular diseases

Osteoporosis and cardiovascular diseases are common causes of morbidity and mortality worldwide, especially in people aged over 60 years. Osteoporosis is characterized by low bone mineral density, which deteriorates the microarchitecture of bones and increases the risk of bone fractures. Other pathologies also constitute risk factors for the development of osteoporosis, mainly cardiovascular diseases. In fact, a growing number of reports have shown a positive correlation between cardiovascular diseases and low bone mineral density. MMPs are proteases that participate in the organized degradation of the extracellular matrix (ECM) and which play essential physiological roles, such as cardiovascular and bone tissue remodeling. Overexpression of MMPs underlies pathological processes like osteoporosis and cardiovascular diseases. MMP-1, -2, -9, -13, and -14 are expressed in bone tissue and are key players in the digestion of bone matrix by osteoblasts. Considering this relationship between osteometabolic and cardiovascular pathologies and MMPs, this review focuses on the involvement of MMPs in osteoporosis and on their participation in cardiovascular diseases; it also deals with the positive correlation between osteoporosis and cardiovascular diseases. Although there are many drugs to treat osteoporosis, controversies exist. Here, we will describe these controversies and will discuss how inhibition of MMPs could be an alternative strategy to or an adjuvant therapy in the current treatment of osteoporosis.