Machine learning instructed microfluidic synthesis of curcumin-loaded liposomes.

The association of machine learning (ML) tools with the synthesis of nanoparticles has the potential to streamline the development of more efficient and effective nanomedicines. The continuous-flow synthesis of nanoparticles via microfluidics represents an ideal playground for ML tools, where multiple engineering parameters - flow rates and mixing configurations, type and concentrations of the reagents - contribute in a non-trivial fashion to determine the resultant morphological and pharmacological attributes of nanomedicines. Here we present the application of ML models towards the microfluidic-based synthesis of liposomes loaded with a model hydrophobic therapeutic agent, curcumin. After generating over 200 different liposome configurations by systematically modulating flow rates, lipid concentrations, organic:water mixing volume ratios, support-vector machine models and feed-forward artificial neural networks were trained to predict, respectively, the liposome dispersity/stability and size. This work presents an initial step towards the application and cultivation of ML models to instruct the microfluidic formulation of nanoparticles.

An in silico model of the capturing of magnetic nanoparticles in tumour spheroids in the presence of flow.

One of the main challenges in improving the efficacy of conventional chemotherapeutic drugs is that they do not reach the cancer cells at sufficiently high doses while at the same time affecting healthy tissue and causing significant side effects and suffering in cancer patients. To overcome this deficiency, magnetic nanoparticles as transporter systems have emerged as a promising approach to achieve more specific tumour targeting. Drug-loaded magnetic nanoparticles can be directed to the target tissue by applying an external magnetic field. However, the magnetic forces exerted on the nanoparticles fall off rapidly with distance, making the tumour targeting challenging, even more so in the presence of flowing blood or interstitial fluid. We therefore present a computational model of the capturing of magnetic nanoparticles in a test setup: our model includes the flow around the tumour, the magnetic forces that guide the nanoparticles, and the transport within the tumour. We show how a model for the transport of magnetic nanoparticles in an external magnetic field can be integrated with a multiphase tumour model based on the theory of porous media. Our approach based on the underlying physical mechanisms can provide crucial insights into mechanisms that cannot be studied conclusively in experimental research alone. Such a computational model enables an efficient and systematic exploration of the nanoparticle design space, first in a controlled test setup and then in more complex in vivo scenarios. As an effective tool for minimising costly trial-and-error design methods, it expedites translation into clinical practice to improve therapeutic outcomes and limit adverse effects for cancer patients.

Coupling tumor growth and bio distribution models.

We couple a tumor growth model embedded in a microenvironment, with a bio distribution model able to simulate a whole organ. The growth model yields the evolution of tumor cell population, of the differential pressure between cell populations, of porosity of ECM, of consumption of nutrients due to tumor growth, of angiogenesis, and related growth factors as function of the locally available nutrient. The bio distribution model on the other hand operates on a frozen geometry but yields a much refined distribution of nutrient and other molecules. The combination of both models will enable simulating the growth of a tumor in a whole organ, including a realistic distribution of therapeutic agents and allow hence to evaluate the efficacy of these agents.

A monolithic multiphase porous medium framework for (a-)vascular tumor growth.

We present a dynamic vascular tumor model combining a multiphase porous medium framework for avascular tumor growth in a consistent Arbitrary Lagrangian Eulerian formulation and a novel approach to incorporate angiogenesis. The multiphase model is based on Thermodynamically Constrained Averaging Theory and comprises the extracellular matrix as a porous solid phase and three fluid phases: (living and necrotic) tumor cells, host cells and the interstitial fluid. Angiogenesis is modeled by treating the neovasculature as a proper additional phase with volume fraction or blood vessel density. This allows us to define consistent inter-phase exchange terms between the neovasculature and the interstitial fluid. As a consequence, transcapillary leakage and lymphatic drainage can be modeled. By including these important processes we are able to reproduce the increased interstitial pressure in tumors which is a crucial factor in drug delivery and, thus, therapeutic outcome. Different coupling schemes to solve the resulting five-phase problem are realized and compared with respect to robustness and computational efficiency. We find that a fully monolithic approach is superior to both the standard partitioned and a hybrid monolithic-partitioned scheme for a wide range of parameters. The flexible implementation of the novel model makes further extensions (e.g., inclusion of additional phases and species) straightforward.

Evaluating the influence of mechanical stress on anticancer treatments through a multiphase porous media model.

Drug resistance is one of the leading causes of poor therapy outcomes in cancer. As several chemotherapeutics are designed to target rapidly dividing cells, the presence of a low-proliferating cell population contributes significantly to treatment resistance. Interestingly, recent studies have shown that compressive stresses acting on tumor spheroids are able to hinder cell proliferation, through a mechanism of growth inhibition. However, studies analyzing the influence of mechanical compression on therapeutic treatment efficacy have still to be performed. In this work, we start from an existing mathematical model for avascular tumors, including the description of mechanical compression. We introduce governing equations for transport and uptake of a chemotherapeutic agent, acting on cell proliferation. Then, model equations are adapted for tumor spheroids and the combined effect of compressive stresses and drug action is investigated. Interestingly, we find that the variation in tumor spheroid volume, due to the presence of a drug targeting cell proliferation, considerably depends on the compressive stress level of the cell aggregate. Our results suggest that mechanical compression of tumors may compromise the efficacy of chemotherapeutic agents. In particular, a drug dose that is effective in reducing tumor volume for stress-free conditions may not perform equally well in a mechanically compressed environment.

Averaging Theory for Description of Environmental Problems: What Have We Learned?

Advances in Water Resources has been a prime archival source for implementation of averaging theories in changing the scale at which processes of importance in environmental modeling are described. Thus in celebration of the 35th year of this journal, it seems appropriate to assess what has been learned about these theories and about their utility in describing systems of interest. We review advances in understanding and use of averaging theories to describe porous medium flow and transport at the macroscale, an averaged scale that models spatial variability, and at the megascale, an integral scale that only considers time variation of system properties. We detail physical insights gained from the development and application of averaging theory for flow through porous medium systems and for the behavior of solids at the macroscale. We show the relationship between standard models that are typically applied and more rigorous models that are derived using modern averaging theory. We discuss how the results derived from averaging theory that are available can be built upon and applied broadly within the community. We highlight opportunities and needs that exist for collaborations among theorists, numerical analysts, and experimentalists to advance the new classes of models that have been derived. Lastly, we comment on averaging developments for rivers, estuaries, and watersheds.

Global sensitivity analysis based on Gaussian-process metamodelling for complex biomechanical problems.

Biomechanical models often need to describe very complex systems, organs or diseases, and hence also include a large number of parameters. One of the attractive features of physics-based models is that in those models (most) parameters have a clear physical meaning. Nevertheless, the determination of these parameters is often very elaborate and costly and shows a large scatter within the population. Hence, it is essential to identify the most important parameters (worth the effort) for a particular problem at hand. In order to distinguish parameters which have a significant influence on a specific model output from non-influential parameters, we use sensitivity analysis, in particular the Sobol method as a global variance-based method. However, the Sobol method requires a large number of model evaluations, which is prohibitive for computationally expensive models. We therefore employ Gaussian processes as a metamodel for the underlying full model. Metamodelling introduces further uncertainty, which we also quantify. We demonstrate the approach by applying it to two different problems: nanoparticle-mediated drug delivery in a complex, multiphase tumour-growth model, and arterial growth and remodelling. Even relatively small numbers of evaluations of the full model suffice to identify the influential parameters in both cases and to separate them from non-influential parameters. The approach also allows the quantification of higher-order interaction effects. We thus show that a variance-based global sensitivity analysis is feasible for complex, computationally expensive biomechanical models. Different aspects of sensitivity analysis are covered including a transparent declaration of the uncertainties involved in the estimation process. Such a global sensitivity analysis not only helps to massively reduce costs for experimental determination of parameters but is also highly beneficial for inverse analysis of such complex models.

Tumour growth: An approach to calibrate parameters of a multiphase porous media model based on in vitro observations of Neuroblastoma spheroid growth in a hydrogel microenvironment.

To unravel processes that lead to the growth of solid tumours, it is necessary to link knowledge of cancer biology with the physical properties of the tumour and its interaction with the surrounding microenvironment. Our understanding of the underlying mechanisms is however still imprecise. We therefore developed computational physics-based models, which incorporate the interaction of the tumour with its surroundings based on the theory of porous media. However, the experimental validation of such models represents a challenge to its clinical use as a prognostic tool. This study combines a physics-based model with in vitro experiments based on microfluidic devices used to mimic a three-dimensional tumour microenvironment. By conducting a global sensitivity analysis, we identify the most influential input parameters and infer their posterior distribution based on Bayesian calibration. The resulting probability density is in agreement with the scattering of the experimental data and thus validates the proposed workflow. This study demonstrates the huge challenges associated with determining precise parameters with usually only limited data for such complex processes and models, but also demonstrates in general how to indirectly characterise the mechanical properties of neuroblastoma spheroids that cannot feasibly be measured experimentally.

A continuum mechanical framework for modeling tumor growth and treatment in two- and three-phase systems.

The growth and treatment of tumors is an important problem to society that involves the manifestation of cellular phenomena at length scales on the order of centimeters. Continuum mechanical approaches are being increasingly used to model tumors at the largest length scales of concern. The issue of how to best connect such descriptions to smaller-scale descriptions remains open. We formulate a framework to derive macroscale models of tumor behavior using the thermodynamically constrained averaging theory (TCAT), which provides a firm connection with the microscale and constraints on permissible forms of closure relations. We build on developments in the porous medium mechanics literature to formulate fundamental entropy inequality expressions for a general class of three-phase, compositional models at the macroscale. We use the general framework derived to formulate two classes of models, a two-phase model and a three-phase model. The general TCAT framework derived forms the basis for a wide range of potential models of varying sophistication, which can be derived, approximated, and applied to understand not only tumor growth but also the effectiveness of various treatment modalities.

Validation and parameter optimization of a hybrid embedded/homogenized solid tumor perfusion model.

The goal of this paper is to investigate the validity of a hybrid embedded/homogenized in-silico approach for modeling perfusion through solid tumors. The rationale behind this novel idea is that only the larger blood vessels have to be explicitly resolved while the smaller scales of the vasculature are homogenized. As opposed to typical discrete or fully resolved 1D-3D models, the required data can be obtained with in-vivo imaging techniques since the morphology of the smaller vessels is not necessary. By contrast, the larger vessels, whose topology and structure is attainable noninvasively, are resolved and embedded as one-dimensional inclusions into the three-dimensional tissue domain which is modeled as a porous medium. A sound mortar-type formulation is employed to couple the two representations of the vasculature. We validate the hybrid model and optimize its parameters by comparing its results to a corresponding fully resolved model based on several well-defined metrics. These tests are performed on a complex data set of three different tumor types with heterogeneous vascular architectures. The correspondence of the hybrid model in terms of mean representative elementary volume blood and interstitial fluid pressures is excellent with relative errors of less than 4%. Larger, but less important and explicable errors are present in terms of blood flow in the smaller, homogenized vessels. We finally discuss and demonstrate how the hybrid model can be further improved to apply it for studies on tumor perfusion and the efficacy of drug delivery.

Extension of a multiphase tumour growth model to study nanoparticle delivery to solid tumours.

One of the main challenges in increasing the efficacy of conventional chemotherapeutics is the fact that they do not reach cancerous cells at a sufficiently high dosage. In order to remedy this deficiency, nanoparticle-based drugs have evolved as a promising novel approach to more specific tumour targeting. Nevertheless, several biophysical phenomena prevent the sufficient penetration of nanoparticles in order to target the entire tumour. We therefore extend our vascular multiphase tumour growth model, enabling it to investigate the influence of different biophysical factors on the distribution of nanoparticles in the tumour microenvironment. The novel model permits the examination of the interplay between the size of vessel-wall pores, the permeability of the blood-vessel endothelium and the lymphatic drainage on the delivery of particles of different sizes. Solid tumours develop a non-perfused core and increased interstitial pressure. Our model confirms that those two typical features of solid tumours limit nanoparticle delivery. Only in case of small nanoparticles is the transport dominated by diffusion, and particles can reach the entire tumour. The size of the vessel-wall pores and the permeability of the blood-vessel endothelium have a major impact on the amount of delivered nanoparticles. This extended in-silico tumour growth model permits the examination of the characteristics and of the limitations of nanoparticle delivery to solid tumours, which currently complicate the translation of nanoparticle therapy to a clinical stage.

Drug delivery: Experiments, mathematical modelling and machine learning.

We address the problem of determining from laboratory experiments the data necessary for a proper modeling of drug delivery and efficacy in anticancer therapy. There is an inherent difficulty in extracting the necessary parameters, because the experiments often yield an insufficient quantity of information. To overcome this difficulty, we propose to combine real experiments, numerical simulation, and Machine Learning (ML) based on Artificial Neural Networks (ANN), aiming at a reliable identification of the physical model factors, e.g. the killing action of the drug. To this purpose, we exploit the employed mathematical-numerical model for tumor growth and drug delivery, together with the ANN - ML procedure, to integrate the results of the experimental tests and feed back the model itself, thus obtaining a reliable predictive tool. The procedure represents a hybrid data-driven, physics-informed approach to machine learning. The physical and mathematical model employed for the numerical simulations is without extracellular matrix (ECM) and healthy cells because of the experimental conditions we reproduce.

An approach for vascular tumor growth based on a hybrid embedded/homogenized treatment of the vasculature within a multiphase porous medium model.

The aim of this work is to develop a novel computational approach to facilitate the modeling of angiogenesis during tumor growth. The preexisting vasculature is modeled as a 1D inclusion and embedded into the 3D tissue through a suitable coupling method, which allows for nonmatching meshes in 1D and 3D domain. The neovasculature, which is formed during angiogenesis, is represented in a homogenized way as a phase in our multiphase porous medium system. This splitting of models is motivated by the highly complex morphology, physiology, and flow patterns in the neovasculature, which are challenging and computationally expensive to resolve with a discrete, 1D angiogenesis and blood flow model. Moreover, it is questionable if a discrete representation generates any useful additional insight. By contrast, our model may be classified as a hybrid vascular multiphase tumor growth model in the sense that a discrete, 1D representation of the preexisting vasculature is coupled with a continuum model describing angiogenesis. It is based on an originally avascular model which has been derived via the thermodynamically constrained averaging theory. The new model enables us to study mass transport from the preexisting vasculature into the neovasculature and tumor tissue. We show by means of several illustrative examples that it is indeed capable of reproducing important aspects of vascular tumor growth phenomenologically.

Predicting the role of microstructural and biomechanical cues in tumor growth and spreading.

A continuum porous media model is developed for elucidating the role of the mechanical cues in regulating tumor growth and spreading. It is shown that stiffer matrices and higher cell-matrix adhesion limit tumor growth and spreading toward the surrounding tissue. Higher matrix porosities, conversely, favor the growth and the dissemination of tumor cells. This model could be used for predicting the response of malignant masses to novel therapeutic agents affecting directly the tumor microenvironment and its micromechanical cues.

Predicting the growth of glioblastoma multiforme spheroids using a multiphase porous media model.

Tumor spheroids constitute an effective in vitro tool to investigate the avascular stage of tumor growth. These three-dimensional cell aggregates reproduce the nutrient and proliferation gradients found in the early stages of cancer and can be grown with a strict control of their environmental conditions. In the last years, new experimental techniques have been developed to determine the effect of mechanical stress on the growth of tumor spheroids. These studies report a reduction in cell proliferation as a function of increasingly applied stress on the surface of the spheroids. This work presents a specialization for tumor spheroid growth of a previous more general multiphase model. The equations of the model are derived in the framework of porous media theory, and constitutive relations for the mass transfer terms and the stress are formulated on the basis of experimental observations. A set of experiments is performed, investigating the growth of U-87MG spheroids both freely growing in the culture medium and subjected to an external mechanical pressure induced by a Dextran solution. The growth curves of the model are compared to the experimental data, with good agreement for both the experimental settings. A new mathematical law regulating the inhibitory effect of mechanical compression on cancer cell proliferation is presented at the end of the paper. This new law is validated against experimental data and provides better results compared to other expressions in the literature.

Optimizing particle size for targeting diseased microvasculature: from experiments to artificial neural networks.

BACKGROUND: Nanoparticles with different sizes, shapes, and surface properties are being developed for the early diagnosis, imaging, and treatment of a range of diseases. Identifying the optimal configuration that maximizes nanoparticle accumulation at the diseased site is of vital importance. In this work, using a parallel plate flow chamber apparatus, it is demonstrated that an optimal particle diameter (d(opt)) exists for which the number (n(s)) of nanoparticles adhering to the vessel walls is maximized. Such a diameter depends on the wall shear rate (S). Artificial neural networks are proposed as a tool to predict n(s) as a function of S and particle diameter (d), from which to eventually derive d(opt). Artificial neural networks are trained using data from flow chamber experiments. Two networks are used, ie, ANN231 and ANN2321, exhibiting an accurate prediction for n(s) and its complex functional dependence on d and S. This demonstrates that artificial neural networks can be used effectively to minimize the number of experiments needed without compromising the accuracy of the study. A similar procedure could potentially be used equally effectively for in vivo analysis.