In-vivo lung biomechanical modeling for effective tumor motion tracking in external beam radiation therapy.

Lung cancer is the most common cause of cancer-related death in both men and women. Radiation therapy is widely used for lung cancer treatment; however, respiratory motion presents challenges that can compromise the accuracy and/or effectiveness of radiation treatment. Respiratory motion compensation using biomechanical modeling is a common approach used to address this challenge. This study focuses on the development and validation of a lung biomechanical model that can accurately estimate the motion and deformation of lung tumor. Towards this goal, treatment planning 4D-CT images of lung cancer patients were processed to develop patient-specific finite element (FE) models of the lung to predict the patients' tumor motion/deformation. The tumor motion/deformation was modeled for a full respiration cycle, as captured by the 4D-CT scans. Parameters driving the lung and tumor deformation model were found through an inverse problem formulation. The CT datasets pertaining to the inhalation phases of respiration were used for validating the model's accuracy. The volumetric Dice similarity coefficient between the actual and simulated gross tumor volumes (GTVs) of the patients calculated across respiration phases was found to range between 0.80 ± 0.03 and 0.92 ± 0.01. The average error in estimating tumor's center of mass calculated across respiration phases ranged between 0.50 ± 0.10 (mm) and 1.04 ± 0.57 (mm), indicating a reasonably good accuracy of the proposed model. The proposed model demonstrates favorable accuracy for estimating the lung tumor motion/deformation, and therefore can potentially be used in radiation therapy applications for respiratory motion compensation.

4D-CT Hyper-Elastography Using a Biomechanical Model.

Low dose computed tomography (LDCT) is the current gold-standard for lung cancer diagnosis. However, accuracy of diagnosis is limited by the radiologist's ability to discern cancerous from non-cancerous nodules. To assist with diagnoses, a 4D-CT lung elastography method is proposed to distinguish nodules based on tissue stiffness properties. The technique relies on a patient-specific inverse finite element (FE) model of the lung solved using an optimization algorithm. The FE model incorporates hyperelastic material properties for tumor and healthy regions and was deformed according to respiration physiology. The tumor hyperelastic parameters and trans-pulmonary pressure were estimated using an optimization algorithm that maximizes similarity between the actual and simulated tumor and lung image data. The proposed technique was evaluated using an in-silico study where the lung tumor elastic properties were assumed. Following that evaluation, the technique was applied to clinical 4D-CT data of two lung cancer patients. Results from the evaluation study show that the elastography technique recovered known tumor parameters with only 6% error. Tumor hyperelastic properties from the clinical data are also reported. Results from this proof of concept study demonstrate the ability to perform lung elastography with 4D-CT data alone. Advancements in the technique could lead to improved diagnoses and timely treatment of lung cancer.

A Composite Material Based Neural Network for Tissue Mechanical Properties Estimation Toward Stage Assessment of Infarction.

Cardiac biomechanical modelling is a promising new tool to be used in prognostic medicine and therapy planning for patients suffering from a variety of cardiovascular diseases and injuries. In order to have an accurate biomechanical model, personalized parameters to define loading, boundary conditions and mechanical properties are required. Achieving personalized modelling parameters often requires inverse optimization which is computationally expensive; hence techniques to reduce the multivariable complexity are in need. Presented in this paper is the fundamental blueprint to create a library of scar tissue mechanical properties to be used in modelling the healing mechanics of hearts that have suffered acute myocardial infarction. This library can be used to reduce the number of variables necessary to capture the scar tissue mechanical properties down to 1. This single parameter also carries information pertaining to staging of the scar tissue healing, predict its rate, and predict its collagen density. This information can be potentially used as valuable biomarkers to adjust existing or develop new treatment plans for patients.

4DCT Ventilation Map Construction Using Biomechanics-base Image Registration and Enhanced Air Segmentation.

Current lung radiation therapy (RT) treatment planning algorithms used in most centers assume homogeneous lung function. However, co-existing pulmonary dysfunctions present in many non-small cell lung cancer (NSCLC) patients, particularly smokers, cause regional variations in both perfusion and ventilation, leading to inhomogeneous lung function. An adaptive RT treatment planning that deliberately avoids highly functional lung regions can potentially reduce pulmonary toxicity and morbidity. The ventilation component of lung function can be measured using a variety of techniques. Recently, 4DCT ventilation imaging has emerged as a cost-effective and accessible method. Current 4DCT ventilation calculation methods, including the intensity-based and Jacobian models, suffer from inaccurate estimations of air volume distribution and unreliability of intensity-based image registration algorithms. In this study, we propose a novel method that utilizes a biomechanical model-based registration along with an accurate air segmentation algorithm to calculate 4DCT ventilation maps. The results show a successful development of ventilation maps using the proposed method.

Incorporating Pathology-Induced Heterogeneities in a Patient-Specific Biomechanical Model of the Lung for Accurate Tumor Motion Estimation.

Radiation therapy (RT) is an important component of treatment for lung cancer. However, the accuracy of this method can be affected by the complex respiratory motion/deformation of the target tumor during treatment. To improve the accuracy of RT, patient-specific biomechanical models of the lung have been proposed for estimating the tumor's respiratory motion/deformation. Chronic obstructive pulmonary disease (COPD) has a high incidence among lung cancer patients and is associated with heterogeneous destruction of lung parenchyma. This key heterogeneity element, however, has not been incorporated in lung biomechanical models developed in previous studies. In this work, we have developed a physiologically and patho-physiologically realistic lung biomechanical model that accounts for lung tissue heterogeneity. Four-dimensional computed tomography (4DCT) images were used to build a patient-specific finite element (FE) model of the lung. Image information was used to identify and incorporate inhomogeneities within the model. Mechanical properties of normal and diseased regions in the lung and the transpulmonary pressure driving the respiratory motion were estimated using an optimization algorithm that maximizes the similarity between the actual and simulated tumor and lung image data. Results from this proof of concept study on a lung cancer patient indicated improved accuracy of tumor motion estimation when COPD-induced lung tissue heterogeneities were incorporated in the model.

Controlling Differentiation of Stem Cells for Developing Personalized Organ-on-Chip Platforms.

Organ-on-chip (OOC) platforms have attracted attentions of pharmaceutical companies as powerful tools for screening of existing drugs and development of new drug candidates. OOCs have primarily used human cell lines or primary cells to develop biomimetic tissue models. However, the ability of human stem cells in unlimited self-renewal and differentiation into multiple lineages has made them attractive for OOCs. The microfluidic technology has enabled precise control of stem cell differentiation using soluble factors, biophysical cues, and electromagnetic signals. This study discusses different tissue- and organ-on-chip platforms (i.e., skin, brain, blood-brain barrier, bone marrow, heart, liver, lung, tumor, and vascular), with an emphasis on the critical role of stem cells in the synthesis of complex tissues. This study further recaps the design, fabrication, high-throughput performance, and improved functionality of stem-cell-based OOCs, technical challenges, obstacles against implementing their potential applications, and future perspectives related to different experimental platforms.

Skin Diseases Modeling using Combined Tissue Engineering and Microfluidic Technologies.

In recent years, both tissue engineering and microfluidics have significantly contributed in engineering of in vitro skin substitutes to test the penetration of chemicals or to replace damaged skins. Organ-on-chip platforms have been recently inspired by the integration of microfluidics and biomaterials in order to develop physiologically relevant disease models. However, the application of organ-on-chip on the development of skin disease models is still limited and needs to be further developed. The impact of tissue engineering, biomaterials and microfluidic platforms on the development of skin grafts and biomimetic in vitro skin models is reviewed. The integration of tissue engineering and microfluidics for the development of biomimetic skin-on-chip platforms is further discussed, not only to improve the performance of present skin models, but also for the development of novel skin disease platforms for drug screening processes.

Microfluidic-Based Multi-Organ Platforms for Drug Discovery.

Development of predictive multi-organ models before implementing costly clinical trials is central for screening the toxicity, efficacy, and side effects of new therapeutic agents. Despite significant efforts that have been recently made to develop biomimetic in vitro tissue models, the clinical application of such platforms is still far from reality. Recent advances in physiologically-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling, micro- and nanotechnology, and in silico modeling have enabled single- and multi-organ platforms for investigation of new chemical agents and tissue-tissue interactions. This review provides an overview of the principles of designing microfluidic-based organ-on-chip models for drug testing and highlights current state-of-the-art in developing predictive multi-organ models for studying the cross-talk of interconnected organs. We further discuss the challenges associated with establishing a predictive body-on-chip (BOC) model such as the scaling, cell types, the common medium, and principles of the study design for characterizing the interaction of drugs with multiple targets.