A Multimodal Scaffold for SDF1 Delivery Improves Cardiac Function in a Rat Subacute Myocardial Infarct Model.

Ischemic heart disease is one of the leading causes of death worldwide. The efficient delivery of therapeutic growth factors could counteract the adverse prognosis of post-myocardial infarction (post-MI). In this study, a collagen hydrogel that is able to load and appropriately deliver pro-angiogenic stromal cell-derived factor 1 (SDF1) was physically coupled with a compact collagen membrane in order to provide the suture strength required for surgical implantation. This bilayer collagen-on-collagen scaffold (bCS) showed the suitable physicochemical properties that are needed for efficient implantation, and the scaffold was able to deliver therapeutic growth factors after MI. In vitro collagen matrix biodegradation led to a sustained SDF1 release and a lack of cytotoxicity in the relevant cell cultures. In vivo intervention in a rat subacute MI model resulted in the full integration of the scaffold into the heart after implantation and biocompatibility with the tissue, with a prevalence of anti-inflammatory and pro-angiogenic macrophages, as well as evidence of revascularization and improved cardiac function after 60 days. Moreover, the beneficial effect of the released SDF1 on heart remodeling was confirmed by a significant reduction in cardiac tissue stiffness. Our findings demonstrate that this multimodal scaffold is a desirable matrix that can be used as a drug delivery system and a scaffolding material to promote functional recovery after MI.

Effects of the Haemodynamic Stimulus on the Location of Carotid Plaques Based on a Patient-Specific Mechanobiological Plaque Atheroma Formation Model.

In this work, we propose a mechanobiological atheroma growth model modulated by a new haemodynamic stimulus. To test this model, we analyse the development of atheroma plaques in patient-specific bifurcations of carotid arteries for a total time of 30 years. In particular, eight geometries (left or right carotid arteries) were segmented from clinical images and compared with the solutions obtained computationally to validate the model. The influence of some haemodynamical stimuli on the location and size of plaques is also studied. Plaques predicted by the mechanobiological models using the time average wall shear stress (TAWSS), the oscillatory shear index (OSI) and a new index proposed in this work are compared. The new index predicts the shape index of the endothelial cells as a combination of TAWSS and OSI values and was fitted using data from the literature. The mechanobiological model represents an evolution of the one previously proposed by the authors. This model uses Navier-Stokes equations to simulate blood flow along the lumen in the transient mode. It also employs Darcy's law and Kedem-Katchalsky equations for plasma and substance flow across the endothelium using the three-pore model. The mass balances of all the substances that have been considered in the model are implemented by convection-diffusion-reaction equations, and finally the growth of the plaques has been computed. The results show that by using the new mechanical stimulus proposed in this study, prediction of plaques is, in most cases, better than only using TAWSS or OSI with a minimal and maximal errors on stenosis ratio of 2.77 and 32.89 %, respectively. However, there are a few geometries in which haemodynamics cannot predict the location of plaques, and other biological or genetic factors would be more relevant than haemodynamics. In particular, the model predicts correctly eleven of the fourteen plaques presented in all the geometries considered. Additionally, a healthy geometry has been computed to check that plaque is not developed with the model in this case.

On the use of machine learning techniques for the mechanical characterization of soft biological tissues.

Motivated by the search for new strategies for fitting a material model, a new approach is explored in the present work. The use of numerical and complex algorithms based on machine learning techniques such as support vector machines for regression, bagged decision trees, and artificial neural networks is proposed for solving the parameter identification of constitutive laws for soft biological tissues. First, the mathematical tools were trained with analytical uniaxial data (circumferential and longitudinal directions) as inputs, and their corresponding material parameters of the Gasser, Ogden, and Holzapfel strain energy function as outputs. The train and test errors show great efficiency during the training process in finding correlations between inputs and outputs; besides, the correlation coefficients were very close to 1. Second, the tool was validated with unseen observations of analytical circumferential and longitudinal uniaxial data. The results show an excellent agreement between the prediction of the material parameters of the strain energy function and the analytical curves. Finally, data from real circumferential and longitudinal uniaxial tests on different cardiovascular tissues were fitted; thus, the material model of these tissues was predicted. We found that the method was able to consistently identify model parameters, and we believe that the use of these numerical tools could lead to an improvement in the characterization of soft biological tissues.

Sost deficiency leads to reduced mechanical strains at the tibia midshaft in strain-matched in vivo loading experiments in mice.

Sclerostin, a product of the Sost gene, is a Wnt-inhibitor and thus negatively regulates bone accrual. Canonical Wnt/ß-catenin signalling is also known to be activated in mechanotransduction. Sclerostin neutralizing antibodies are being tested in ongoing clinical trials to target osteoporosis and osteogenesis imperfecta but their interaction with mechanical stimuli on bone formation remains unclear. Sost knockout (KO) mice were examined to gain insight into how long-term Sost deficiency alters the local mechanical environment within the bone. This knowledge is crucial as the strain environment regulates bone adaptation. We characterized the bone geometry at the tibial midshaft of young and adult Sost KO and age-matched littermate control (LC) mice using microcomputed tomography imaging. The cortical area and the minimal and maximal moment of inertia were higher in Sost KO than in LC mice, whereas no difference was detected in either the anterior-posterior or medio-lateral bone curvature. Differences observed between age-matched genotypes were greater in adult mice. We analysed the local mechanical environment in the bone using finite-element models (FEMs), which showed that strains in the tibiae of Sost KO mice are lower than in age-matched LC mice at the diaphyseal midshaft, a region commonly used to assess cortical bone formation and resorption. Our FEMs also suggested that tissue mineral density is only a minor contributor to the strain distribution in tibial cortical bone from Sost KO mice compared to bone geometry. Furthermore, they indicated that although strain gauging experiments matched strains at the gauge site, strains along the tibial length were not comparable between age-matched Sost KO and LC mice or between young and adult animals within the same genotype.

Machine learning techniques for the optimization of joint replacements: 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.

Femoral head necrosis: A finite element analysis of common and novel surgical techniques.

BACKGROUND: Femoral head necrosis is a common cause of secondary osteoarthritis. At the early stages, treatment strategies are normally based on core decompression techniques, where the number, location and diameter of the drilling holes varies depending on the selected approach. The purpose of this study was to investigate the risk of femoral head, neck and subtrochanteric fracture following six different core decompression techniques. MATERIALS: Five common and a newly proposed techniques were analyzed in respect to their biomechanical consequences using finite element analysis. The geometry of a femur was reconstructed from computed-tomography images. Thereafter, the drilling configurations were simulated. The strains in the intact and drilled femurs were determined under physiological, patient-specific, muscle and joint contact forces. FINDINGS: The following results were observed: i) - an increase in collapse and fracture risk of the femur head by disease progression ii) - for a single hole approach at the subtrochanteric region, the fracture risk increases with the diameter iii) - the highest fracture risks occur for an 8mm single hole drilling at the subtrochanteric region and approaches with multiple drilling at various entry points iv) - the proposed novel approach resulted in the most physiological strains (closer to the experienced by the healthy bone). INTERPRETATION: Our results suggest that all common core decompression methods have a significant impact on the biomechanical competence of the proximal femur and impact its mechanical potential. Fracture risk increases with drilling diameter and multiple drilling with smaller diameter. We recommend the anterior approach due to its reduced soft tissue trauma and its biomechanical performance.

Strain shielding inspired re-design of proximal femoral stems for total hip arthroplasty.

A large number of hip prosthesis with different designs have been developed. However, the influence of hip implant design changes on the strains induced in the bone remains unclear. The purpose of this study is to better understand the mechanics of short stem total hip arthroplasty. Specifically, it investigates whether strain shielding can be avoided by changing implant shape and/or material properties. It is hypothesized that the re-design of existing implant designs can result in further reduction of strain shielding and thus keep bone loss minimal following total hip replacement. Finite element methods were used to compare healthy and implanted models. The local mechanics strains/stresses in the intact and implanted femurs were determined under patient-specific muscle and joint contact forces. Results suggest that small changes in implant geometry and material properties have no major effect on strain shielding. Furthermore, it was found that improvement depends on a dramatic re-design of the original implant design. Whereas the benefit of this strategy of modification of the original geometry of a given short-stemmed hip consists in reduced bone remodeling, care should be taken with regard to long-term bone anchorage and implant fatigue strength. It is also shown that geometrical and material changes have a limited potential in avoiding strain shielding even in short-stemmed implants. Finally, it is suggested that an understanding of the influence of these changes on the strain distribution within the bone can guide in the process of optimizing the current stem designs toward minimal strain shielding effects. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2534-2544, 2017.

Towards the modelling of ageing and atherosclerosis effects in ApoE(-/-) mice aortic tissue.

The goal of this work consists in a quantitative analysis and constitutive modelling of ageing processes associated to plaque formation in mice arteries. Reliable information on the characteristic evolution of pressure-stretch curves due to the ageing effects is extracted from previous inflation test experiments. Furthermore, characteristic age-dependent material parameters are identified on the basis of a continuum-mechanics-based parameter optimisation technique. The results indicate that the aorta-stiffness of the healthy control mice remains basically constant irrespective of the diet-time and age. In contrast, significant differences exist within the material response and in consequence within the material parameters between the ApoE(-/-) and the control mice as well as for the different locations over the aorta which is underlined by our experimental observations. With regard to the temporal evolution of the material parameters, we observe that the material parameters for the ApoE(-/-) mice aortas exhibit a saturation-type increase with respect to age.

Epicardial delivery of collagen patches with adipose-derived stem cells in rat and minipig models of chronic myocardial infarction.

Although transplantation of adipose-derived stem cells (ADSC) in chronic myocardial infarction (MI) models is associated with functional improvement, its therapeutic value is limited due to poor long-term cell engraftment and survival. Thus, the objective of this study was to examine whether transplantation of collagen patches seeded with ADSC could enhance cell engraftment and improve cardiac function in models of chronic MI. With that purpose, chronically infarcted Sprague-Dawley rats (n = 58) were divided into four groups and transplanted with media, collagen scaffold (CS), rat ADSC, or CS seeded with rat ADSC (CS-rADSC). Cell engraftment, histological changes, and cardiac function were assessed 4 months after transplantation. In addition, Göttingen minipigs (n = 18) were subjected to MI and then transplanted 2 months later with CS or CS seeded with autologous minipig ADSC (CS-pADSC). Functional and histological assessments were performed 3 months post-transplantation. Transplantation of CS-rADSC was associated with increased cell engraftment, significant improvement in cardiac function, myocardial remodeling, and revascularization. Moreover, transplantation of CS-pADSC in the pre-clinical swine model improved cardiac function and was associated with decreased fibrosis and increased vasculogenesis. In summary, transplantation of CS-ADSC resulted in enhanced cell engraftment and was associated with a significant improvement in cardiac function and myocardial remodeling.

Mathematical modelling of atheroma plaque formation and development in coronary arteries.

Atherosclerosis is a vascular disease caused by inflammation of the arterial wall, which results in the accumulation of low-density lipoprotein (LDL) cholesterol, monocytes, macrophages and fat-laden foam cells at the place of the inflammation. This process is commonly referred to as plaque formation. The evolution of the atherosclerosis disease, and in particular the influence of wall shear stress on the growth of atherosclerotic plaques, is still a poorly understood phenomenon. This work presents a mathematical model to reproduce atheroma plaque growth in coronary arteries. This model uses the Navier-Stokes equations and Darcy's law for fluid dynamics, convection-diffusion-reaction equations for modelling the mass balance in the lumen and intima, and the Kedem-Katchalsky equations for the interfacial coupling at membranes, i.e. endothelium. The volume flux and the solute flux across the interface between the fluid and the porous domains are governed by a three-pore model. The main species and substances which play a role in early atherosclerosis development have been considered in the model, i.e. LDL, oxidized LDL, monocytes, macrophages, foam cells, smooth muscle cells, cytokines and collagen. Furthermore, experimental data taken from the literature have been used in order to physiologically determine model parameters. The mathematical model has been implemented in a representative axisymmetric geometrical coronary artery model. The results show that the mathematical model is able to qualitatively capture the atheroma plaque development observed in the intima layer.

Does microcalcification increase the risk of rupture?

Rupture of atherosclerotic plaque, which is related to maximal stress conditions in the plaque among others, is a major cause of mortality. More careful examination of stress distributions in atherosclerotic plaques reports that it could be due to local stress behaviors at critical sites caused by cap thinning, inflammation, macroscopic heterogeneity, and recently, the presence of microcalcifications. However, the role of microcalcifications is not yet fully understood, and most finite element models of blood vessels with atheroma plaque ignore the heterogeneity of the plaque constituents at the microscale. The goal of this work is to investigate the effect of microcalcifications on the stress field of an atheroma plaque vessel section. This is achieved by performing a parametric finite element study, assuming a plane strain hypothesis, of a coronary artery section with eccentric atheroma plaque and one microcalcification incorporated. The geometrical parameters used to define and design the idealized coronary plaque anatomy and the microcalcification were the fibrous cap thickness and the microcalcification ratio, angle and eccentricity. We could conclude that microcalcifications should be considered in the modeling of this kind of problems since they cause a significant alteration of the vulnerable risk by increasing the maximum maximal principal stress up to 32%, although this increase of stress is not uniform (12% on average). The obtained results show that the fibrous cap thickness, the microcalcification ratio and the microcalcification eccentricity, in combination with the microcalcification angle, appear to be the key morphological parameters that play a determinant role in the maximal principal stress and accordingly in the rupture risk of the plaque.

Preparation and characterization of collagen-based ADSC-carrier sheets for cardiovascular application.

The use of scaffolds composed of natural biodegradable matrices represents an attractive strategy to circumvent the lack of cell engraftment, a major limitation of stem cell therapy in cardiovascular diseases. Bovine-derived non-porous collagen scaffolds with different degrees of cross-linking (C0, C2, C5 and C10) were produced and tested for their mechanical behavior, in vitro biocompatibility with adipose-derived stem cells (ADSCs) and tissue adhesion and inflammatory reaction. Uniaxial tensile tests revealed an anisotropic behavior of collagen scaffolds (2×0.5cm) and statistically significant differences in the mechanical behavior between cross-linked and non-cross-linked scaffolds (n=5). In vitro, ADSCs adhered homogenously and showed a similar degree of proliferation on all four types of scaffolds (cells×10(3)cm(-2) at day 7: C0: 94.7±37.1; C2: 91.7±25.6; C5: 88.2±6.8; C10: 72.8±10.7; P=n.s.; n=3). In order to test the in vivo biocompatibility, a chronic myocardial infarction model was performed in rats and 1.2×1.2cm size collagen scaffolds implanted onto the heart 1month post-infarction. Six animals per group were killed 2, 7 and 30days after transplant. Complete and long-lasting adhesion to the heart was only observed with the non-cross-linked scaffolds with almost total degradation 1month post-transplantation. After 7 and 30days post-implantation, the degree of inflammation was significantly lower in the hearts treated with non-cross-linked scaffolds (day 7: C0: 10.2±2.1%; C2: 16.3±2.9%; C5: 15.9±4.8%; C10: 17.4±4.1%; P<0.05 vs. C0; day 30: C0: 1.3±1.3%; C2: 9.4±3.0%; C5: 7.0±2.1%; C10: 9.8±2.5%; P<0.01 vs. C0). In view of the results, the non-cross-linked scaffold (C0) was chosen as an ADSC-carrier sheet and tested in vivo. One week post-implantation, 25.3±7.0% of the cells transplanted were detected in those animals receiving the cell-carrier sheet whereas no cells were found in animals receiving cells alone (n=3 animals/group). We conclude that the biocompatibility and mechanical properties of the non-cross-linked collagen scaffolds make them a useful cell carrier that greatly favors tissue cell engraftment and may be exploited for cell transplantation in models of cardiac disease.

Machine learning techniques as a helpful tool toward determination of plaque vulnerability.

Atherosclerotic cardiovascular disease results in millions of sudden deaths annually, and coronary artery disease accounts for the majority of this toll. Plaque rupture plays main role in the majority of acute coronary syndromes. Rupture has been usually associated with stress concentrations, which are determined mainly by tissue properties and plaque geometry. The aim of this study is develop a tool, using machine learning techniques to assist the clinical professionals on decisions of the vulnerability of the atheroma plaque. In practice, the main drawbacks of 3-D finite element analysis to predict the vulnerability risk are the huge main memories required and the long computation times. Therefore, it is essential to use these methods which are faster and more efficient. This paper discusses two potential applications of computational technologies, artificial neural networks and support vector machines, used to assess the role of maximum principal stress in a coronary vessel with atheroma plaque as a function of the main geometrical features in order to quantify the vulnerability risk.