Multiscale Modeling of Bone Healing

Bone is a living part of the body that can, in most situations, heal itself after fracture. However, in some situations, healing may fail. Compromised conditions, such as large bone defects, aging, immuno-deficiency, or genetic disorders, might lead to delayed or non-unions. Treatment strategies for those conditions remain a clinical challenge, emphasizing the need to better understand the mechanisms behind endogenous bone regeneration. Bone healing is a complex process that involves the coordination of multiple events at different length and time scales. Computer models have been able to provide great insights into the interactions occurring within and across the different scales (organ, tissue, cellular, intracellular) using different modeling approaches [partial differential equations (PDEs), agent-based models, and finite element techniques]. In this review, we summarize the latest advances in computer models of bone healing with a focus on multiscale approaches and how they have contributed to understand the emergence of tissue formation patterns as a result of processes taking place at the lower length scales

Initial mechanical conditions within an optimized bone scaffold do not ensure bone regeneration – an in silico analysis

Large bone defects remain a clinical challenge because they do not heal spontaneously. 3-D printed scaffolds are a promising treatment option for such critical defects. Recent scaffold design strategies have made use of computer modelling techniques to optimize scaffold design. In particular, scaffold geometries have been optimized to avoid mechanical failure and recently also to provide a distinct mechanical stimulation to cells within the scaffold pores. This way, mechanical strain levels are optimized to favour the bone tissue formation. However, bone regeneration is a highly dynamic process where the mechanical conditions immediately after surgery might not ensure optimal regeneration throughout healing. Here, we investigated in silico whether scaffolds presenting optimal mechanical conditions for bone regeneration immediately after surgery also present an optimal design for the full regeneration process. A computer framework, combining an automatic parametric scaffold design generation with a mechano-biological bone regeneration model, was developed to predict the level of regenerated bone volume for a large range of scaffold designs and to compare it with the scaffold pore volume fraction under favourable mechanical stimuli immediately after surgery. We found that many scaffold designs could be considered as highly beneficial for bone healing immediately after surgery; however, most of them did not show optimal bone formation in later regenerative phases. This study allowed to gain a more thorough understanding of the effect of scaffold geometry changes on bone regeneration and how to maximize regenerated bone volume in the long term

Mechano-Biological Computer Model of Scaffold-Supported Bone Regeneration: Effect of Bone Graft and Scaffold Structure on Large Bone Defect Tissue Patterning

Large segmental bone defects represent a clinical challenge for which current treatment procedures have many drawbacks. 3D-printed scaffolds may help to support healing, but their design process relies mainly on trial and error due to a lack of understanding of which scaffold features support bone regeneration. The aim of this study was to investigate whether existing mechano-biological rules of bone regeneration can also explain scaffold-supported bone defect healing. In addition, we examined the distinct roles of bone grafting and scaffold structure on the regeneration process. To that end, scaffold-surface guided migration and tissue deposition as well as bone graft stimulatory effects were included in an in silico model and predictions were compared to in vivo data. We found graft osteoconductive properties and scaffold-surface guided extracellular matrix deposition to be essential features driving bone defect filling in a 3D-printed honeycomb titanium structure. This knowledge paves the way for the design of more effective 3D scaffold structures and their pre-clinical optimization, prior to their application in scaffold-based bone defect regeneration

BMP2 and mechanical loading cooperatively regulate immediate early signalling events in the BMP pathway

<p>Abstract</p> <p>Background</p> <p>Efficient osteogenic differentiation is highly dependent on coordinated signals arising from growth factor signalling and mechanical forces. Bone morphogenetic proteins (BMPs) are secreted proteins that trigger Smad and non-Smad pathways and thereby influence transcriptional and non-transcriptional differentiation cues. Crosstalk at multiple levels allows for promotion or attenuation of signalling intensity and specificity. Similar to BMPs, mechanical stimulation enhances bone formation. However, the molecular mechanism by which mechanical forces crosstalk to biochemical signals is still unclear.</p> <p>Results</p> <p>Here, we use a three-dimensional bioreactor system to describe how mechanical forces are integrated into the BMP pathway. Time-dependent phosphorylation of Smad, mitogen-activated protein kinases and Akt in human fetal osteoblasts was investigated under loading and/or BMP2 stimulation conditions. The phosphorylation of R-Smads is increased both in intensity and duration under BMP2 stimulation with concurrent mechanical loading. Interestingly, the synergistic effect of both stimuli on immediate early Smad phosphorylation is reflected in the transcription of only a subset of BMP target genes, while others are differently affected. Together this results in a cooperative regulation of osteogenesis that is guided by both signalling pathways.</p> <p>Conclusions</p> <p>Mechanical signals are integrated into the BMP signalling pathway by enhancing immediate early steps within the Smad pathway, independent of autocrine ligand secretion. This suggests a direct crosstalk of both mechanotransduction and BMP signalling, most likely at the level of the cell surface receptors. Furthermore, the crosstalk of both pathways over longer time periods might occur on several signalling levels.</p

The Degradation of Synthetic Polymeric Scaffolds With Strut-like Architecture Influences the Mechanics-dependent Repair Process of an Osteochondral Defect in Silico

Current clinical treatments of osteochondral defects in articulating joints are frequently not successful in restoring articular surfaces. Novel scaffold-based tissue engineering strategies may help to improve current treatment options and foster a true regeneration of articulating structures. A frequently desired property of scaffolds is their ability to degrade over time and allow a full restoration of tissue and function. However, it remains largely unknown how scaffold degradation influences the mechanical stability of the tissue in a defect region and, in turn, the regenerative process. Such differing goals-supporting regeneration by degrading its own structure-can hardly be analyzed for tissue engineered constructs in clinical trials and in vivo preclinical experiments. Using an in silico analysis, we investigated the degradation-induced modifications in material and architectural properties of a scaffold with strut-like architecture over the healing course and their influence on the mechanics-dependent tissue formation in osteochondral defects. The repair outcome greatly varied depending on the degradation modality, i.e. surface erosion or bulk degradation with and without autocatalysis, and of the degradation speed, i.e. faster, equal or slower than the expected repair time. Bulk degradation with autocatalysis, independently of degradation speed, caused the mechanical failure of the scaffold prior to osteochondral defect repair and was thereby deemed inappropriate for further application. On the other hand, scaffolds with strut-like architecture degrading by both surface erosion and bulk degradation with slow degradation speed resulted in comparably good repair outcomes, thereby indicating such degradation modalities as favorable for the application in osteochondral defects

Overstretching Expectations May Endanger the Success of the “Millennium Surgery”

Total hip arthroplasty (THA) is an extremely successful treatment strategy. Patient expectations, however, have increased; if not properly guided by surgeons, at present, patients expect next to pain-free restoration of the joint and a fast return to work and sports. While the revision rates after THA also increased in younger patients, knowledge on musculoskeletal loads still remains sparse, and the current recommendations on postoperative rehabilitation are based on expert opinions only. The aim of this study was to unravel biomechanical contact conditions in "working age" (60 years, 67.7 +/- 8.6 years) patients during activities recommended post-THA. We hypothesized that working age patients would show substantially increased hip contact loads compared to older patients. The in vivo joint contact force (F-res) and torsion torque (M-tors), reflecting the main contact load situation, experienced during activities of daily living and sports activities were measured in a unique group of 16 patients with instrumented THA. We summarized patient activities and sports recommendations after THA mentioned within the literature using PubMed (without claim of completeness). The measurements showed that younger working age patients experienced significant (p = 0.050) increased M-tors (21.52 +/- 9.11 Nm) than older retirement age patients (13.99 +/- 7.89 Nm) by walking. Bowling, as a recommended low-impact sport, was associated with F-res of up to 5436 N and M-tors of up to 108 Nm in the working age group, which were higher than the F-res (5276 N) and M-tors (71 Nm) during high-impact soccer. Based on our results, age was proven to be a discriminator in joint loading, with working age patients presenting with increased loads compared to retirement age patients, already during daily activities. The current patient recommendations have led to further increased joint loadings. If THA cannot be delayed in a patient, we propose counselling patients on a carefully considered return to sports, focusing on low-impact activities, as indicated hereby. The findings from this work illustrate the need to provide critical feedback to patient expectations when returning to work and sports activities. Patients returning to more intensive sports activities should be carefully monitored and advised to avoid as much overloading as possible

Multiscale Modeling of Bone Healing: Toward a Systems Biology Approach

Bone is a living part of the body that can, in most situations, heal itself after fracture. However, in some situations, healing may fail. Compromised conditions, such as large bone defects, aging, immuno-deficiency, or genetic disorders, might lead to delayed or non-unions. Treatment strategies for those conditions remain a clinical challenge, emphasizing the need to better understand the mechanisms behind endogenous bone regeneration. Bone healing is a complex process that involves the coordination of multiple events at different length and time scales. Computer models have been able to provide great insights into the interactions occurring within and across the different scales (organ, tissue, cellular, intracellular) using different modeling approaches [partial differential equations (PDEs), agent-based models, and finite element techniques]. In this review, we summarize the latest advances in computer models of bone healing with a focus on multiscale approaches and how they have contributed to understand the emergence of tissue formation patterns as a result of processes taking place at the lower length scales

Muscle Fascicles Exhibit Limited Passive Elongation Throughout the Rehabilitation of Achilles Tendon Rupture After Percutaneous Repair

Achilles tendon rupture (ATR) results in long-term functional and structural deficits, characterized by reduced ankle mobility and plantarflexor muscle atrophy. However, it remains unclear how such functional impairments develop after surgical repair. While it is known that this injury negatively affects the tendon's function, to date, limited work has focused on the short-term effect of ATR on the structure of the muscles in series. The aim of this study was to characterize changes in medial gastrocnemius architecture and its response to passive lengthening during the post-surgical rehabilitative period following ATR. Both injured and contralateral limbs from 10 subjects (1 female, BMI: 27.2 ± 3.9 kg/m2; age: 46 ± 10 years) with acute, unilateral ATR were assessed at 8, 12, and 16 weeks after percutaneous surgical repair. To characterize the component tissues of the muscle-tendon unit, resting medial gastrocnemius muscle thickness, fascicle length, and pennation angle were determined from ultrasound images with the ankle in both maximal plantarflexion and dorsiflexion. The ankle range of motion (ROM) was determined using motion capture; combined ultrasound and motion capture determined the relative displacement of the musculotendinous junction (MTJ) of the AT with the medial gastrocnemius. The ATR-injured gastrocnemius muscle consistently exhibited lower thickness, regardless of time point and ankle angle. Maximal ankle plantarflexion angles and corresponding fascicle lengths were lower on the injured ankle compared to the contralateral throughout rehabilitation. When normalized to the overall ankle ROM, both injured fascicles and MTJ displacement exhibited a comparably lower change in length when the ankle was passively rotated. These results indicate that when both ankles are passively exposed to the same ROM following ATR surgery, both ipsilateral Achilles tendon and gastrocnemius muscle fascicles exhibit limited lengthening compared to the contralateral MTU tissues. This appears to be consistent throughout the rehabilitation of gait, suggesting that current post-operative rehabilitative exercises do not appear to induce muscle adaptations in the affected MTU

Short-run dynamics of income disparities and regional cycle synchronization in the U.S.

Since the 1990s, the issue of regional income convergence and its long-term tendencies has been thoroughly and heatedly discussed. Much less attention, however, has been devoted to the short-run dynamics of regional convergence. In particular, three important aspects have not yet been adequately addressed. First, it is indeed essential to understand whether regional disparities manifest a tendency to move systematically along the national cycle. Then, if this happens to be the case, it becomes crucial to know whether 1) these movements are pro- or counter-cyclical,2) the cyclical evolution of the disparities is a consequence of differences in the timing with which the business cycle is felt in regions or it is motivated by the amplitude differences across local cyclical swings. In this paper, we shed light on these issues using data on personal income for the 48 coterminous U.S. states between 1969 and 2008. Our results indicate that income disparities do not move randomly in the short run but follow a distinct cyclical pattern, moving either pro- or counter-cyclically depending on the period of analysis. These patterns are probably explained by the changes in the direction of capital and labor flows that favor developed or poorer states in different periods. As for the underlying mechanism, it appears that the short-run evolution of the disparities in recent years is largely a consequence of differences in the timing with which the business cycle is felt across states rather than the outcome of amplitude differences across local cyclical swings

Application to a short-stem hip implant

Today, different implant designs exist in the market; however, there is not a clear understanding of which are the best implant design parameters to achieve mechanical optimal conditions. Therefore, the aim of this project was to investigate if the geometry of a commercial short stem hip prosthesis can be further optimized to reduce stress shielding effects and achieve better short- stemmed implant performance. To reach this aim, the potential of machine learning techniques combined with parametric Finite Element analysis was used. The selected implant geometrical parameters were: total stem length (L), thickness in the lateral (R1) and medial (R2) and the distance between the implant neck and the central stem surface (D). The results show that the total stem length was not the only parameter playing a role in stress shielding. An optimized implant should aim for a decreased stem length and a reduced length of the surface in contact with the bone. The two radiuses that characterize the stem width at the distal cross-section in contact with the bone were less influential in the reduction of stress shielding compared with the other two parameters; but they also play a role where thinner stems present better results