Time-Dependent Collagen Fibered Structure in the Early Distraction Callus: Imaging Characterization and Mathematical Modeling

Collagen is a ubiquitous protein present in regenerating bone tissues that experiences multiple biological phenomena during distraction osteogenesis until the deposition of phosphate crystals. This work combines fluorescence techniques and mathematical modeling to shed light on the mechano-structural processes behind the maturation and accommodation-to-mineralization of the callus tissue. Ovine metatarsal bone calluses were analyzed through confocal images at different stages of the early distraction osteogenesis process, quantifying the fiber orientation distribution and mean intensity as fiber density measure. Likewise, a mathematical model based on the experimental data was defined to micromechanically characterize the apparent stiffening of the tissue within the distracted callus. A reorganization of the fibers around the distraction axis and increased fiber density were found as the bone fragments were gradually separated. Given the degree of significance between the mathematical model and previous in vivo data, reorganization, densification, and bundle maturation phenomena seem to explain the apparent mechanical maturation observed in the tissue theoretically.This work was supported by the Spanish Ministry of Economy, Industry and Competitiveness [Grant No. DPI2017-82501-P]; the Spanish State Research Agency (AEI) [Grant No. PID2020-113790RB-I00/AEI/ 10.13039/501100011033]; and the European Regional Development Fund (FEDER) with the Junta de Andalucı ´a [Grant No. US-1261691]

Real-Time Wireless Platform for In Vivo Monitoring of Bone Regeneration

For the monitoring of bone regeneration processes, the instrumentation of the fixation is an increasingly common technique to indirectly measure the evolution of bone formation instead of ex vivo measurements or traditional in vivo techniques, such as X-ray or visual review. A versatile instrumented external fixator capable of adapting to multiple bone regeneration processes was designed, as well as a wireless acquisition system for the data collection. The design and implementation of the overall architecture of such a system is described in this work, including the hardware, firmware, and mechanical components. The measurements are conditioned and subsequently sent to a PC via wireless communication to be in vivo displayed and analyzed using a developed real-time monitoring application. Moreover, a model for the in vivo estimation of the bone callus stiffness from collected data was defined. This model was validated in vitro using elastic springs, reporting promising results with respect to previous equipment, with average errors and uncertainties below 6.7% and 14.04%. The devices were also validated in vivo performing a bone lengthening treatment on a sheep metatarsus. The resulting system allowed the in vivo mechanical characterization of the bone callus during experimentation, providing a low-cost, simple, and highly reliable solution.Junta de Andalucía US-1261691Ministerio de Economía y Competitividad DPI2017-82501-PMinisterio de Economía y Competitividad PGC2018-097257-B-C3

Correction : Chaparro et al. Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain: Large-Scale Epidemiological Study. J. Clin. Med. 2021, 10, 2885

The authors wish to make the following corrections to this paper [...]

Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain : Large-Scale Epidemiological Study

(1) Aims: To assess the incidence of inflammatory bowel disease (IBD) in Spain, to describe the main epidemiological and clinical characteristics at diagnosis and the evolution of the disease, and to explore the use of drug treatments. (2) Methods: Prospective, population-based nationwide registry. Adult patients diagnosed with IBD-Crohn's disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U)-during 2017 in Spain were included and were followed-up for 1 year. (3) Results: We identified 3611 incident cases of IBD diagnosed during 2017 in 108 hospitals covering over 22 million inhabitants. The overall incidence (cases/100,000 person-years) was 16 for IBD, 7.5 for CD, 8 for UC, and 0.5 for IBD-U; 53% of patients were male and median age was 43 years (interquartile range = 31-56 years). During a median 12-month follow-up, 34% of patients were treated with systemic steroids, 25% with immunomodulators, 15% with biologics and 5.6% underwent surgery. The percentage of patients under these treatments was significantly higher in CD than UC and IBD-U. Use of systemic steroids and biologics was significantly higher in hospitals with high resources. In total, 28% of patients were hospitalized (35% CD and 22% UC patients, p < 0.01). (4) Conclusion: The incidence of IBD in Spain is rather high and similar to that reported in Northern Europe. IBD patients require substantial therapeutic resources, which are greater in CD and in hospitals with high resources, and much higher than previously reported. One third of patients are hospitalized in the first year after diagnosis and a relevant proportion undergo surgery

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Mechanobiology of bone regeneration: distraction osteogenesis and tissue engineering

Bone regeneration is the natural process of bone reconstruction during the continuous adult remodeling, fracture healing, or complex clinical treatments of bone defects. In this biological problem, the role of engineering is essential for several aspects, including the control of the callus mechanical environment, predicting the complex mineralization phenomena, or designing materials and structures to optimize angiogenesis. The aim of this thesis is to find mechanical solutions to current challenging limitations in this field: the current mechanical incompatibility between brittle implants and external fixations in load-bearing models; the insufficient knowledge of the surrounding soft tissues’ mechanics during the elongation; the lack of understanding of the mechanical environment that promotes mineralization; or the need of quantitative tools for better clinical control of the processes. Distraction osteogenesis and tissue engineering experiments were carried out on merino sheep. A flexible Ilizarov-type external fixator was initially implanted in their right-back metatarsus. The distraction group underwent an osteotomy in a middle cross-section of the bone that, after a latency period of 7 days, was elongated to a final length of 15 mm (distraction rate of 1 mm/day). By cons, the tissue engineering group had 15 mm of bone directly replaced with a porous bioceramic scaffold biologically enhanced with cancellous bone autograft. Animals were slaughtered at different time-points of the consolidation phase. Before surgeries, an instrumented external fixator was devised to control bone formation through mechanical parameters indirectly. By working with a low-cost and size-optimized real-time wireless acquisition system, they reported promising results in estimating callus forces and stiffening. The resulting versatile system offers mechanobiological comparisons of the evolutions of different treatments. Concerning the scaffold design, a standardized optimization problem was defined and applied to optimize their inner architecture by covering biological parameters (porosity, pore size, and surface area) and mechanical constraints to ensure its structural integrity in vivo. During the distraction phase, higher viscoelastic forces with a similar relaxation rate were quantified compared to other distraction processes without limb elongation. After applying rheological models to the raw data, the mechano-structural changes suffered by this bone callus and its surrounding soft tissues were estimated. The contribution of these tissues to the distraction forces was limited to elongations above 4% of the original length when anatomical changes were evidenced. Likewise, the quantified elastic callus stiffening was mathematically modeled to elucidate the mechano-structural phenomena behind the callus accommodation-to-mineralization. It was based on ex vivo confocal imaging data applied to non-mineralized callus samples. The continuous collagen reorientation, densification and maturation seemed to control this problem. In the consolidation stage, several in vivo monitoring techniques were employed to build an exhaustive comparison between processes: gait analysis, internal force distribution, callus stiffening, x-rays, and CT imaging. All the parameters analyzed tended to healthy values in both groups but at different rates. In the short-term, the bone callus recovered its loading capacity and it exponentially increased its stiffness, being faster in the tissue engineering group. The healthy callus mineral density and limb bearing capacity were reached around 5-6 months after surgery. However, the recovery time of this last parameter seems to have been influenced by the walking conditions acquired by the animals due to pain and low confidence in the treated limb in the early stages. Finally, both the apparent geometry of the callus and its trabecular microstructure seemed to recover in the long remodeling phase

Mechanobiology of Bone Consolidation During Distraction Osteogenesis: Bone Lengthening Vs. Bone Transport

Bone lengthening and bone transport are regeneration processes that commonly rely on distraction osteogenesis, a widely accepted surgical procedure to deal with numerous bony pathologies. Despite the extensive study in the literature of the influence of biomechanical factors, a lack of knowledge about their mechanobiological differences prevents a clinical particularization. Bone lengthening treatments were performed on sheep metatarsus by reproducing the surgical and biomechanical protocol of previous bone transport experiments. Several in vivo monitoring techniques were employed to build an exhaustive comparison: gait analysis, radiographic and CT assessment, force measures through the fixation, or mechanical characterization of the new tissue. A significant initial loss of the bearing capacity, quantified by the ground reaction forces and the limb contact time with the ground, is suffered by the bone lengthening specimens. The potential effects of this anomaly on the musculoskeletal force distribution and the evolution of the bone callus elastic modulus over time are also analyzed. Imaging techniques also seem to reveal lower bone volume in the bone lengthening callus than in the bone transport one, but an equivalent mineralization rate. The simultaneous quantification of biological and mechanical parameters provides valuable information for the daily clinical routine and numerical tools development

Real-Time Wireless Platform for In Vivo Monitoring of Bone Regeneration

For the monitoring of bone regeneration processes, the instrumentation of the fixation is an increasingly common technique to indirectly measure the evolution of bone formation instead of ex vivo measurements or traditional in vivo techniques, such as X-ray or visual review. A versatile instrumented external fixator capable of adapting to multiple bone regeneration processes was designed, as well as a wireless acquisition system for the data collection. The design and implementation of the overall architecture of such a system is described in this work, including the hardware, firmware, and mechanical components. The measurements are conditioned and subsequently sent to a PC via wireless communication to be in vivo displayed and analyzed using a developed real-time monitoring application. Moreover, a model for the in vivo estimation of the bone callus stiffness from collected data was defined. This model was validated in vitro using elastic springs, reporting promising results with respect to previous equipment, with average errors and uncertainties below 6.7% and 14.04%. The devices were also validated in vivo performing a bone lengthening treatment on a sheep metatarsus. The resulting system allowed the in vivo mechanical characterization of the bone callus during experimentation, providing a low-cost, simple, and highly reliable solution

Structural optimization of 3D-printed patient-specific ceramic scaffolds for in vivo bone regeneration in load-bearing defects.

Tissue engineering has recently gained popularity as an alternative to autografts to stimulate bone tissue regeneration through structures called scaffolds. Most of the in vivo experiments on long-bony defects use internally-stabilized generic scaffolds. Despite the wide variety of computational methods, a standardized protocol is required to optimize ceramic scaffolds for load-bearing bony defects stabilized with flexible fixations. An optimization problem was defined for applications to sheep metatarsus defects. It covers biological parameters (porosity, pore size, and the specific surface area) and mechanical constraints based on in vivo and in vitro results reported in the literature. The optimized parameters (59.30% of porosity, 5768.91 m-1 of specific surface area, and 360.80 μm of pore size) and the compressive strength of the selected structure were validated in vitro by means of tomographic images and compression tests of six 3D-printed samples. Divergences between the design and measured values of the optimized parameters, mainly due to manufacturing defects, are consistent with the previous studies. Using the mixed experimental-mathematical scaffold-design procedure described, they could be implanted in vivo with instrumented external fixators, therefore facilitating biomechanical monitoring of the regeneration process

Mechanobiology of Bone Consolidation During Distraction Osteogenesis: Bone Lengthening Vs. Bone Transport.

Bone lengthening and bone transport are regeneration processes that commonly rely on distraction osteogenesis, a widely accepted surgical procedure to deal with numerous bony pathologies. Despite the extensive study in the literature of the influence of biomechanical factors, a lack of knowledge about their mechanobiological differences prevents a clinical particularization. Bone lengthening treatments were performed on sheep metatarsus by reproducing the surgical and biomechanical protocol of previous bone transport experiments. Several in vivo monitoring techniques were employed to build an exhaustive comparison: gait analysis, radiographic and CT assessment, force measures through the fixation, or mechanical characterization of the new tissue. A significant initial loss of the bearing capacity, quantified by the ground reaction forces and the limb contact time with the ground, is suffered by the bone lengthening specimens. The potential effects of this anomaly on the musculoskeletal force distribution and the evolution of the bone callus elastic modulus over time are also analyzed. Imaging techniques also seem to reveal lower bone volume in the bone lengthening callus than in the bone transport one, but an equivalent mineralization rate. The simultaneous quantification of biological and mechanical parameters provides valuable information for the daily clinical routine and numerical tools development