Tissue engineered vascular grafts transform into autologous neovessels capable of native function and growth

Background Tissue-engineered vascular grafts (TEVGs) have the potential to advance the surgical management of infants and children requiring congenital heart surgery by creating functional vascular conduits with growth capacity. Methods Herein, we used an integrative computational-experimental approach to elucidate the natural history of neovessel formation in a large animal preclinical model; combining an in vitro accelerated degradation study with mechanical testing, large animal implantation studies with in vivo imaging and histology, and data-informed computational growth and remodeling models. Results Our findings demonstrate that the structural integrity of the polymeric scaffold is lost over the first 26 weeks in vivo, while polymeric fragments persist for up to 52 weeks. Our models predict that early neotissue accumulation is driven primarily by inflammatory processes in response to the implanted polymeric scaffold, but that turnover becomes progressively mechano-mediated as the scaffold degrades. Using a lamb model, we confirm that early neotissue formation results primarily from the foreign body reaction induced by the scaffold, resulting in an early period of dynamic remodeling characterized by transient TEVG narrowing. As the scaffold degrades, mechano-mediated neotissue remodeling becomes dominant around 26 weeks. After the scaffold degrades completely, the resulting neovessel undergoes growth and remodeling that mimicks native vessel behavior, including biological growth capacity, further supported by fluid–structure interaction simulations providing detailed hemodynamic and wall stress information. Conclusions These findings provide insights into TEVG remodeling, and have important implications for clinical use and future development of TEVGs for children with congenital heart disease.

Characterization of Exercise-Induced Myocardium Growth Using Finite Element Modeling and Bayesian Optimization

Cardiomyocyte growth can occur in both physiological (exercised-induced) and pathological (e.g., volume overload and pressure overload) conditions leading to left ventricular (LV) hypertrophy. Studies using animal models and histology have demonstrated the growth and remodeling process at the organ level and tissue–cellular level, respectively. However, the driving factors of growth and the mechanistic link between organ, tissue, and cellular growth remains poorly understood. Computational models have the potential to bridge this gap by using constitutive models that describe the growth and remodeling process of the myocardium coupled with finite element (FE) analysis to model the biomechanics of the heart at the organ level. Using subject-specific imaging data of the LV geometry at two different time points, an FE model can be created with the inverse method to characterize the growth parameters of each subject. In this study, we developed a framework that takes in vivo cardiac magnetic resonance (CMR) imaging data of exercised porcine model and uses FE and Bayesian optimization to characterize myocardium growth in the transverse and longitudinal directions. The efficacy of this framework was demonstrated by successfully predicting growth parameters of 18 synthetic LV targeted masks which were generated from three LV porcine geometries. The framework was further used to characterize growth parameters in 4 swine subjects that had been exercised. The study suggested that exercise-induced growth in swine is prone to longitudinal cardiomyocyte growth (58.0 ± 19.6% after 6 weeks and 79.3 ± 15.6% after 12 weeks) compared to transverse growth (4.0 ± 8.0% after 6 weeks and 7.8 ± 9.4% after 12 weeks). This framework can be used to characterize myocardial growth in different phenotypes of LV hypertrophy and can be incorporated with other growth constitutive models to study different hypothetical growth mechanisms.

Hydrostatic Mechanical Stress Regulates Growth and Maturation of The Atrioventricular Valve

During valvulogenesis, cytoskeletal, secretory, and transcriptional events drive endocardial cushions growth and remodeling into thin fibrous leaflets. Genetic disorders play an important role in understanding valve malformations but only account for a minority of clinical cases. Mechanical forces are ever-present, but how they coordinate molecular and cellular decisions remains unclear. In this study, we used osmotic pressure to interrogate how compressive and tensile stresses influence valve growth and shaping maturation. We found that compressive stress drives a growth phenotype whereas tensile stress increases compaction. We identified a mechanically activated switch between valve growth and maturation, by which compression induces cushion growth via BMP-pSMAD1/5 while tension induces maturation via pSer-19 mediated MLC2 contractility. The compressive stress acts through BMP signaling to increase cell proliferation and decrease cell contractility, and MEK-ERK is essential for both compressive stress and BMP mediation of compaction. We further showed that the effects of osmotic stress are conserved through the condensation and elongation stages of development. Together, our results demonstrate that compressive/tensile stress regulation of BMP-pSMAD1/5 and MLC2 contractility orchestrates valve growth and remodeling.

Global Sensitivity Analysis of a Homogenized Constrained Mixture Model of Arterial Growth and Remodeling

Growth and remodeling in arterial tissue have attracted considerable attention over the last decade. Mathematical models have been proposed, and computational studies with these have helped to understand the role of the different model parameters. So far it remains, however, poorly understood how much of the model output variability can be attributed to the individual input parameters and their interactions. To clarify this, we propose herein a global sensitivity analysis, based on Sobol indices, for a homogenized constrained mixture model of aortic growth and remodeling. In two representative examples, we found that 54–80% of the long term output variability resulted from only three model parameters. In our study, the two most influential parameters were the one characterizing the ability of the tissue to increase collagen production under increased stress and the one characterizing the collagen half-life time. The third most influential parameter was the one characterizing the strain-stiffening of collagen under large deformation. Our results suggest that in future computational studies it may - at least in scenarios similar to the ones studied herein - suffice to use population average values for the other parameters. Moreover, our results suggest that developing methods to measure the said three most influential parameters may be an important step towards reliable patient-specific predictions of the enlargement of abdominal aortic aneurysms in clinical practice.

Architecture-Dependent Mechano-Adaptation in Single Vascular Smooth Muscle Cells

Arteries grow and remodel following mechanical perturbation. Vascular smooth muscle cells (VSMCs) within the artery undergo hyperplasia, hypertrophy, or change their contractility following sustained changes in loading. Experimental evidence suggests that VSMCs grow and remodel to maintain a constant transmural stress, or "target" stress. This behavior is often described using a stress-dependent finite growth framework. Typically, computational models of arterial growth and remodeling account for VSMC behavior in constrained mixture formulations that incorporate behavior of each component of the artery. However, these models do not account for differential VSMC architecture observed in situ, which may significantly influence growth and remodeling. Here, we used Cellular Microbiaxial Stretching (CµBS) to characterize how VSMCs with different cytoskeletal architectures respond to a sustained step-change in strain. We find that VSMC F-actin architecture becomes more aligned immediately following stretch and retains this alignment after 24 hours. Further, we find that VSMC stress magnitude depends on cellular architecture. Qualitatively, however, stress behavior following stretch is consistent across cell architectures - stress increases following stretch and returns to pre-stretch magnitudes after 24 hours. Lastly, we formulated an architecture-dependent targeted-growth law that accounts for experimentally measured cytoskeletal alignment and attributes stress evolution to individual fiber growth and find that this model robustly captures long-term stress evolution in single VSMCs. These results suggest that VSMC mechano-adaptation depends on cellular architecture, which has implications for growth and remodeling in regions of arteries with differential architecture, such as at bifurcations.

Rho/ROCK-MYOCD in regulating airway smooth muscle growth and remodeling

Abnormal airway remodeling is a common pathologic change seen in chronic respiratory diseases. Altered proliferation and differentiation of airway smooth muscle cells (ASMCs) are the major component of airway remodeling, and the resultant structural abnormalities are difficult to restore. Understanding of airway smooth muscle regulation is urgently needed in order to identify potential intervention targets. MYOCD (or Myocardin) and Myocardin related transcription factors (MRTFs) are key co-transcription factors in muscle growth, which have not been extensively investigated in airway smooth muscle cells. In addition, the RhoA/ROCK signaling pathway is known to play an important role in airway remodeling partly through regulating the proliferation and differentiation of ASMCs, which may be connected with MYOCD/MRTF co-transcription factors. This minireview focuses on this newly recognized and potentially important RhoA/ROCK-MYOCD/MRTFs pathway in controlling airway smooth muscle growth and remodeling.