Machine learning-augmented and microspectroscopy-informed multiparametric MRI for the non-invasive prediction of articular cartilage composition.

BACKGROUND: Articular cartilage degeneration is the hallmark change of osteoarthritis, a severely disabling disease with high prevalence and considerable socioeconomic and individual burden. Early, potentially reversible cartilage degeneration is characterized by distinct changes in cartilage composition and ultrastructure, while the tissue's morphology remains largely unaltered. Hence, early degenerative changes may not be diagnosed by clinical standard diagnostic tools. METHODS: Against this background, this study introduces a novel method to determine the tissue composition non-invasively. Our method involves quantitative MRI parameters (i.e., T1, T1ρ, T2 and [Formula: see text] maps), compositional reference measurements (i.e., microspectroscopically determined local proteoglycan [PG] and collagen [CO] contents) and machine learning techniques (i.e., artificial neural networks [ANNs] and multivariate linear models [MLMs]) on 17 histologically grossly intact human cartilage samples. RESULTS: Accuracy and precision were higher in ANN-based predictions than in MLM-based predictions and moderate-to-strong correlations were found between measured and predicted compositional parameters. CONCLUSION: Once trained for the clinical setting, advanced machine learning techniques, in particular ANNs, may be used to non-invasively determine compositional features of cartilage based on quantitative MRI parameters with potential implications for the diagnosis of (early) degeneration and for the monitoring of therapeutic outcomes.

Computer-Controlled Biaxial Bioreactor for Investigating Cell-Mediated Homeostasis in Tissue Equivalents.

Soft biological tissues consist of cells and extracellular matrix (ECM), a network of diverse proteins, glycoproteins, and glycosaminoglycans that surround the cells. The cells actively sense the surrounding ECM and regulate its mechanical state. Cell-seeded collagen or fibrin gels, so-called tissue equivalents, are simple but powerful model systems to study this phenomenon. Nevertheless, few quantitative studies document the stresses that cells establish and maintain in such gels; moreover, most prior data were collected via uniaxial experiments whereas soft tissues are mainly subject to multiaxial loading in vivo. To begin to close this gap between existing experimental data and in vivo conditions, we describe here a computer-controlled bioreactor that enables accurate measurements of the evolution of mechanical tension and deformation of tissue equivalents under well-controlled biaxial loads. This device allows diverse studies, including how cells establish a homeostatic state of biaxial stress and if they maintain it in response to mechanical perturbations. It similarly allows, for example, studies of the impact of cell and matrix density, exogenous growth factors and cytokines, and different types of loading conditions (uniaxial, strip-biaxial, and biaxial) on these processes. As illustrative results, we show that NIH/3T3 fibroblasts establish a homeostatic mechanical state that depends on cell density and collagen concentration. Following perturbations from this homeostatic state, the cells were able to recover biaxial loading similar to homeostatic. Depending on the precise loads, however, they were not always able to fully maintain that state.

Experimental characterization of the biaxial mechanical properties of porcine gastric tissue.

Health problems related to the stomach are among the most important sources of morbidity in industrialized countries. There is evidence that mechanics may play an important role in various such pathologies. However, so far experimental data characterizing the mechanical properties of gastric tissue remain scarce, which significantly limits our understanding of the mechanics of the stomach. To help close this gap, we performed biaxial mechanical tests of porcine gastric tissue patches. Our experiments reveal a considerable anisotropy and different mechanical properties in the three major regions of the stomach (fundus, corpus, antrum). Moreover, they demonstrate that the mechanical properties of the gastric wall and the physiological function of the different regions of the stomach are closely related. This finding suggests that further examination of the mechanics of the gastric wall may indeed be a promising avenue of research towards a better understanding of the organic causes of frequent health problems related to the stomach.

Growth and Remodeling of Load-Bearing Biological Soft Tissues.

The past two decades reveal a growing role of continuum biomechanics in understanding homeostasis, adaptation, and disease progression in soft tissues. In this paper, we briefly review the two primary theoretical approaches for describing mechano-regulated soft tissue growth and remodeling on the continuum level as well as hybrid approaches that attempt to combine the advantages of these two approaches while avoiding their disadvantages. We also discuss emerging concepts, including that of mechanobiological stability. Moreover, to motivate and put into context the different theoretical approaches, we briefly review findings from mechanobiology that show the importance of mass turnover and the prestressing of both extant and new extracellular matrix in most cases of growth and remodeling. For illustrative purposes, these concepts and findings are discussed, in large part, within the context of two load-bearing, collagen dominated soft tissues - tendons/ligaments and blood vessels. We conclude by emphasizing further examples, needs, and opportunities in this exciting field of modeling soft tissues.

Homogenized constrained mixture models for anisotropic volumetric growth and remodeling.

Constrained mixture models for soft tissue growth and remodeling have attracted increasing attention over the last decade. They can capture the effects of the simultaneous presence of multiple constituents that are continuously deposited and degraded at in general different rates, which is important to understand essential features of living soft tissues that cannot be captured by simple kinematic growth models. Recently the novel concept of homogenized constrained mixture models was introduced. It was shown that these models produce results which are very similar (and in certain limit cases even identical) to the ones of constrained mixture models based on multi-network theory. At the same time, the computational cost and complexity of homogenized constrained mixture models are much lower. This paper discusses the theory and implementation of homogenized constrained mixture models for anisotropic volumetric growth and remodeling in three dimensions. Previous constrained mixture models of volumetric growth in three dimensions were limited to the special case of isotropic growth. By numerical examples, comparison with experimental data and a theoretical discussion, we demonstrate that there is some evidence raising doubts whether isotropic growth models are appropriate to represent growth and remodeling of soft tissue in the vasculature. Anisotropic constrained mixture models, as introduced in this paper for the first time, may be required to avoid unphysiological results in simulations of vascular growth and remodeling.

A homogenized constrained mixture (and mechanical analog) model for growth and remodeling of soft tissue.

Most mathematical models of the growth and remodeling of load-bearing soft tissues are based on one of two major approaches: a kinematic theory that specifies an evolution equation for the stress-free configuration of the tissue as a whole or a constrained mixture theory that specifies rates of mass production and removal of individual constituents within stressed configurations. The former is popular because of its conceptual simplicity, but relies largely on heuristic definitions of growth; the latter is based on biologically motivated micromechanical models, but suffers from higher computational costs due to the need to track all past configurations. In this paper, we present a temporally homogenized constrained mixture model that combines advantages of both classical approaches, namely a biologically motivated micromechanical foundation, a simple computational implementation, and low computational cost. As illustrative examples, we show that this approach describes well both cell-mediated remodeling of tissue equivalents in vitro and the growth and remodeling of aneurysms in vivo. We also show that this homogenized constrained mixture model suggests an intimate relationship between models of growth and remodeling and viscoelasticity. That is, important aspects of tissue adaptation can be understood in terms of a simple mechanical analog model, a Maxwell fluid (i.e., spring and dashpot in series) in parallel with a "motor element" that represents cell-mediated mechanoregulation of extracellular matrix. This analogy allows a simple implementation of homogenized constrained mixture models within commercially available simulation codes by exploiting available models of viscoelasticity.

Vascular homeostasis and the concept of mechanobiological stability.

Vascular mechanics has been studied in depth since the early 1970s mainly following classical concepts from continuum mechanics. Yet, an important distinction of blood vessels, in contrast to typical engineering materials, is the continuous degradation and deposition of material in these living tissues. In this paper we examine mechanical consequences of such mass turnover. Motivated by Lyapunov's stability theory, we introduce the new concepts of mechanobiological equilibrium and stability and demonstrate that blood vessels can maintain their structure and function under physiological conditions only if new material is deposited at a certain prestress and the vessels are both mechanically and mechanobiologically stable. Moreover, we introduce the concept of mechanobiological adaptivity as a third corner stone to understand vascular behavior on a continuum level. We demonstrate that adaptivity represents a key difference between the stability of mechanobiological and typical human-made systems. Based on these ideas, we suggest a change of paradigm that can be illustrated by considering a common arterial pathology. We suggest that aneurysms can be interpreted as mechanobiological instabilities and that predictions of their rupture risk should not only consider the maximal diameter or wall stress, but also the mechanobiological stability. A mathematical analysis of the impact of the different model parameters on the so-called mechanobiological stability margin, a single scalar used to characterize mechanobiological stability, reveals that this stability increases with the characteristic time constant of mass turnover, material stiffness, and capacity for stress-dependent changes in mass production. As each of these parameters may be modified by appropriate drugs, the theory developed in this paper may guide both prognosis and the development of new therapies for arterial pathologies such as aneurysms.

Mechanobiological stability: a new paradigm to understand the enlargement of aneurysms?

Static and dynamic mechanical instabilities were previously suggested, and then rejected, as mediators of aneurysmal development, which leaves open the question of the underlying mechanism. In this paper, we suggest as a new paradigm the interpretation of aneurysms as mechanobiological instabilities. For illustrative purposes, we compare analytical calculations with computational simulations of the growth and remodelling of idealized fusiform abdominal aortic aneurysms and experimental and clinical findings. We show that the concept of mechanobiological stability is consistent with the impact of risk factors such as age, smoking or diabetes on the initiation and enlargement of these lesions as well as adaptive processes in the healthy abdominal aorta such as dilatation during ageing or in hypertension. In general, high stiffness, an increased capacity for stress-mediated matrix production, and slow matrix turnover all improve the mechanobiological stability of blood vessels. This theoretical understanding may help guide prognosis and the development of future therapies for aneurysms as it enables systematic ways to attenuate enlargement.