RESUMEN
The atomic force microscopy (AFM) nanoindentation regarding biological samples is a challenging procedure. Biological samples at the nanoscale can be considered as purely elastic materials under the condition that the indentation depth is very small and the indenter is smooth. However, the indenters that are commonly used are pyramidal and in several cases the indentation depths are big comparing to the dimensions of the tip apex. Hence, pyramidal indenters usually cause a permanent damage to the sample. In this case, the best model that can be applied for the data processing is the Oliver-Pharr model which takes into account the elastic-plastic behavior of the sample. The Oliver-Pharr model is based on the fitting of the unloading load-indentation data to a power law equation. In this paper a simplified procedure which ensures the accurate fitting of the unloading load-indentation data to the Oliver-Pharr model is presented and validated on experimental data obtained from a human glioma cell line. It should be noted that the proposed method can be also applied for the data fitting in the case of purely elastic response.
Asunto(s)
Línea Celular/citología , Módulo de Elasticidad/fisiología , Glioma/fisiopatología , Microscopía de Fuerza Atómica/métodos , Animales , Microscopía de Fuerza Atómica/instrumentación , Modelos BiológicosRESUMEN
The experimental evidence that a feedback exists between growth and stress in tumors poses challenging questions. First, the rheological properties (the "constitutive equations") of aggregates of malignant cells are still a matter of debate. Secondly, the feedback law (the "growth law") that relates stress and mitotic-apoptotic rate is far to be identified. We address these questions on the basis of a theoretical analysis of in vitro and in vivo experiments that involve the growth of tumor spheroids. We show that solid tumors exhibit several mechanical features of a poroelastic material, where the cellular component behaves like an elastic solid. When the solid component of the spheroid is loaded at the boundary, the cellular aggregate grows up to an asymptotic volume that depends on the exerted compression. Residual stress shows up when solid tumors are radially cut, highlighting a peculiar tensional pattern. By a novel numerical approach we correlate the measured opening angle and the underlying residual stress in a sphere. The features of the mechanobiological system can be explained in terms of a feedback of mechanics on the cell proliferation rate as modulated by the availability of nutrient, that is radially damped by the balance between diffusion and consumption. The volumetric growth profiles and the pattern of residual stress can be theoretically reproduced assuming a dependence of the target stress on the concentration of nutrient which is specific of the malignant tissue.
RESUMEN
Gliomas are highly invasive brain tumours characterised by poor prognosis and limited response to therapy. There is an ongoing debate on the therapeutic potential of vaso-modulatory interventions against glioma invasion. Prominent vasculature-targeting therapies involve tumour blood vessel deterioration and normalisation. The former aims at tumour infarction and nutrient deprivation induced by blood vessel occlusion/collapse. In contrast, the therapeutic intention of normalising the abnormal tumour vasculature is to improve the efficacy of conventional treatment modalities. Although these strategies have shown therapeutic potential, it remains unclear why they both often fail to control glioma growth. To shed some light on this issue, we propose a mathematical model based on the migration/proliferation dichotomy of glioma cells in order to investigate why vaso-modulatory interventions have shown limited success in terms of tumour clearance. We found the existence of a critical cell proliferation/diffusion ratio that separates glioma responses to vaso-modulatory interventions into two distinct regimes. While for tumours, belonging to one regime, vascular modulations reduce the front speed and increase the infiltration width, for those in the other regime, the invasion speed increases and infiltration width decreases. We discuss how these in silico findings can be used to guide individualised vaso-modulatory approaches to improve treatment success rates.