Interstitial fluid pressure in soft tissue as a result of an externally applied contact pressure

Manipulation of interstitial fluid pressure (IFP) has a clinical potential when used in conjunction with near-infrared spectroscopy for the detection of breast cancer. In order to better interpret how the applied pressure alters the vascular space and interstitial water volumes in breast tissue, a study on tissue-mimicking, gelatin phantoms was carried out to mimic the translation of external force into internal pressures. A complete set of three-dimensional (3D) pressure maps were obtained for the interior volumes of phantoms as an external force of 10 mmHg was applied, using mixtures of elastic moduli 19 and 33 kPa to simulate adipose and fibroglandular values of breast tissue. Corresponding linear elastic finite element analysis (FEA) cases were formulated. Shear stress, nonlinear mechanical properties, gravity and tissue geometry were all observed to contribute to internal pressure distribution, with surface shear stresses increasing internal pressures near the surface to greater than twice the applied external pressure. Average pressures by depth were predicted by the linear elastic FEA models. FEA models were run for cases mimicking a 93 kPa tumor inclusion within regions of adipose, fibroglandular tissue, and a composite of the two tissue types to illustrate the localized high fluid pressures caused by a tumor when an external force is applied. The conclusion was that external contact forces can generate potentially clinically useful fluid pressure magnitudes in regions of sharp effective elastic modulus gradients, such as tumor boundaries.     

“Artificial Lymphatic System”: A New Approach to Reduce Interstitial Hypertension and Increase Blood Flow, pH and pO2 in Solid Tumors

A mechanical drainage system, the artificial lymphatic system (ALS), consisting of a vacuum source and drain, is evaluated for its ability to aspirate the interstitial fluids responsible for the elevated interstitial fluid pressure (IFP) observed in solid tumors. IFP, pH, and pO₂ radial profiles were measured before and after aspiration using wick-in-needle (WIN) probes, needle pH and oxygen electrodes, respectively. Laser Doppler flowmetry measured temporal changes in blood flow rate (BFR) at the tumor surface during aspiration. The WIN probe and IFP profile data were analyzed using numerical simulation and distributed mathematical models, respectively. The model parameter, p _E reflecting central tumor IFP, was reduced from 15.3 to 5.7 mm Hg in neuroblastoma and from 13.3 to 12.1 mm Hg in Walker 256, respectively, following aspiration. The simulation demonstrated that spatial averaging inherent in WIN measurements reduced the calculated magnitude of the model parameter changes. IFP was significantly lower (p < 0.05), especially in regions surrounding the drain, and BFR was significantly higher (p < 0.05) following 25 and 45 min of aspiration, respectively; pH and pO₂ profiles increased following aspiration. The experimental and mathematical findings suggest that ALS aspiration may be a viable way of reducing IFP and increasing BFR, pO₂ and pH and should enhance solid tumor chemo and radiation therapy. © 2000 Biomedical Engineering Society. PAC00: 8719Tt, 8715Vv, 8719Uv, 8780-y, 8719Xx     

各向异性传导系数对实体肿瘤间质流体流动影响的二维边界元模拟

目的研究实体肿瘤组织间质各向异性传导系数对流体流动的影响。方法用图像处理方法建立具有实体肿瘤微血管形态和分布特征的二维微血管网络模型, 应用边界元方法数值计算多连通区域内组织液的流动及水力传导系数变化的影响。结果横向与纵向间质水力传导系数的不同, 对整个肿瘤内组织间质压强的分布有明显的影响; 不同函数形式分布的水力传导系数, 影响肿瘤局部区域内间质流体压强的分布。结论各向异性水力传导系数对实体肿瘤组织间质压强有明显影响, 与传导系数变化的范围和肿瘤内微血管网络的形态有关。     

Compliance of the interstitial space in rats I. Studies on hindlimb skeletal muscle

Interstitial compliance, defined as the ratio between changes in interstitial fluid volume (ΔIFV) and interstitial fluid pressure (ΔIFP), was determined for rat skeletal muscle. IFV was measured as the extravascular distribution space for ⁵¹Cr-EDTA, while sharpened micropipettes connected to a servo-controlled counterpressure system were used to measure IFP. The experimental protocol was designed to bring about acute (2–4 h) and chronic (24–28h) tissue over- and dehydration. During dehydration, the average compliance was 0.056 ml/g dry weight · mmHg, corresponding to 1.40 ml/100 g wet tissue mmHg, and was not significantly different in acute and chronic experiments. In hydration (acute and chronic), compliance increased several-fold when IFV increased. Even at greatly increased IFV, IFP did not rise more than 1 to 1.5 mmHg above control level. Since control IFV amounts to 10 ml/100 g wet tissue, IFV will decrease by 14% when IFP falls by 1 mmHg from this control level. Provided unchanged interstitial protein mass the dehydration will cause interstitial fluid colloid osmotic pressure to increase by somewhat more than 1 mmHg—from a control level of 9 mmHg. Furthermore, since IFP was not increased by more than 1 to 1.5 mmHg during hydration, an increase in IFP plays a minor role in edema-prevention compared to dilution and/or washout of interstitial proteins.     

Cell Proliferation of Cultured Human Cancer Cells are Affected by the Elevated Tumor Pressures that Exist In Vivo

Elevated interstitial fluid pressure (IFP) is observed in most solid tumors. However, the study of the cellular processes of tumors and the development of chemotherapy are routinely studied using in vitro culture systems at atmospheric pressure. Using a new pressurized cell culture system, we investigated the influence of hydrostatic pressure on population dynamics of three primary osteosarcoma (HOS, U2OS, SaOS2) and two metastatic tumor cell lines (MCF7 breast, H1299 lung) that invade bone. Values of IFP in normal human bone and muscle, and in osteosarcoma tumors obtained during their surgical biopsy established the hydrostatic pressure range for the in vitro cell studies. The IFP values were obtained from a retrospective review of patient records. IFP from confirmed osteosarcoma was 35.9± 16.2 mmHg. Tumor IFP was significantly higher than muscle IFP (p < 0.001) and bone IFP (p < 0.003).The in vitro study measured the cell-line proliferation using hydrostatic pressures of 0, 20, 50 and 100 mmHg. The findings suggest that hydrostatic pressure either increases or decreases tumor proliferation rates depending on cell type. Furthermore, cell death was not associated with apoptosis.     

A biophysical basis of enhanced interstitial fluid pressure in tumors

It is widely accepted that enhanced interstitial fluid pressure (IFP) in tumors is a major obstacle against delivery of therapeutic agents. On the other hand, the origin of enhanced IFP remains controversial. Here, the Van't Hoff equation is applied to examine how glucose breakdown to CO2 and lactate in tumor cells may affect intracellular osmotic pressure. According to the equation, it is found that production of CO2 from glucose lowers osmotic pressure inside cells, while glycolytic production of lactate generates significant increases. Crucial to a net enhancement of pressure in cells is the Warburg ratio, the ratio of the fraction of glucose transformed to lactate divided by the fraction of glucose metabolized to CO2: if (and only if) the ratio is higher than 1.0, there is a resulting increase in intracellular osmotic pressure. Under fully anaerobic glycolysis, the enhancement of intracellular pressure is maximal, namely 19.3 mmHg per mM of glucose metabolized to lactate (Van't Hoff equation). Cells are then biological pressure pumps driven by glycolytic production of lactate, causing IFP to raise. It is proposed that a regulatory feedback loop prevents IFP to raise above microvascular pressure (MVP). Accordingly, enhanced IFP in tumors is the result of high rates of tumor glycolysis, and enhancement of IFP is limited by MVP. It is thus concluded that a high rate of glycolytic production of lactate in tumor cells ultimately prevents both access of therapeutic agents to the malignant cells and immunological surveillance, and that it indirectly drives outward currents of interstitial fluid, thereby propelling both the process of tumor infiltration of surrounding structures and metastatic spread, depending on deformability and proteolytic capacity of the malignant cells.     

组织液压波在大白鼠胃经皮下组织传送规律的研究

注射０．９％的生理盐水到麻醉的大白鼠胃经的皮下，形成一个水泡，然后给予一个机械压力，由此产生一个组织液压波，测量组织液压在胃经上和胃经外的变化，发现了五种基本的组织液型及亚型，这些波型基于组织不同的粘弹性特性，组织液压波在经线上与经线外幅度差异与距离的线性回归方程为Ｙ＝－０．３５Ｘ＋１．９６，具有统计学显著性（Ｐ＜０．０１）。表明经脉线组织可能具有较好的渗透性和柔性。     

一种针刺补泻法对小型猪皮下组织液压的影响

目的研究《灵枢》卷首《九针十二原》针刺补泻法对小型猪皮下组织液压(interstitial fluid pressure,IFP)的作用,探讨其调节组织液的生物力学机制。方法在9只健康实验用小型猪腹部随机取点行补法(提/按法)和泻法(摇大针孔),观察正常状态(normal state,NS)、抽取组织液的低组织液量(low volume,LV)状态和注入生理盐水的高组织液量(high volume,HV)状态下针刺前后IFP。结果 NS下提/按法可极显著升高IFP;泻法可极显著降低IFP,针后5 min泻法组IFP降低较快。LV状态提/按法均能升高IFP,针后10 min二者IFP下降较慢。HV状态下泻法可极显著降低IFP,针后5 min与对照组变化趋势不同。结论该补泻法可升高或降低IFP,证明其对IFP有相反方向的调节作用。研究结果为针灸临床使用补泻手法提供新的科学依据。     

Compression Induced Cell Damage in Engineered Muscle Tissue: An <Emphasis Type="Italic">In Vitro</Emphasis> Model to Study Pressure Ulcer Aetiology

The aetiology of pressure ulcers is poorly understood. The complexity of the problem, involving mechanical, biochemical, and physiological factors demands the need for simpler model systems that can be used to investigate the relative contribution of these factors, while controlling others. Therefore, an in vitro model system of engineered skeletal muscle tissue constructs was developed. With this model system, the relationship between compressive tissue straining and cell damage initiation was investigated under well-defined environmental conditions. Compression of the engineered muscle tissue constructs revealed that cell death occurs within 1–2 h at clinically relevant straining percentages and that higher strains led to earlier damage initiation. In addition, the uniform distribution of dead cells throughout the constructs suggested that sustained deformation of the cells was the principle cause of cell death. Therefore, it is hypothetised that sustained cell deformation is an additional mechanism that plays a role in the development of pressure ulcers. © 2003 Biomedical Engineering Society. PAC2003: 8719Rr, 8719Ff, 8718La, 8780Rb     

Pressure-volume relationship for rat dermis: compression studies

The relationship between tissue hydrostatic pressure and fluid content is an important determinant of the response of the microvascular exchange system to perturbations. However, only a limited number of studies relating these parameters have been reported. To add to this body of information, fully swollen rat dermis in vitro was subjected to successive compressive loads in an apparatus in which tissue thickness changes were monitored. At steady-state the mechanical load on the tissue was balanced by the interstitial fluid pressure within the tissue while the fluid content of the tissue was determined from the unstressed tissue fluid content and changes in tissue thickness. The range of conditions investigated was from moderate overhydration through normal tissue fluid content to significant dehydration. From the relationship between interstitial fluid pressure and tissue fluid content (expressed as mass of fluid per mass of fat-free dry tissue) the tissue compliance was determined. Compliance, defined as the rate of change of the tissue fluid content with changes in interstitial pressure, increased with tissue hydration. The compliance determined using compressive loads and steady-state response of tissue thickness compares favourably with the limited amount of information available about this tissue property which is critical in the determination of tissue fluid balance. Compliance ranged over one order of magnitude for the conditions studied and at normal hydration, tissue fluid volume changed by about 6.6% per mmHg in tissue hydrostatic pressure.     

Inhibition of TGF-beta modulates macrophages and vessel maturation in parallel to a lowering of interstitial fluid pressure in experimental carcinoma

A pathologically elevated interstitial fluid pressure (IFP) is a characteristic of both clinical and experimental carcinoma. The soluble TGF-beta receptor type II-murine Fc:IgG2A chimeric protein (Fc:TbetaRII) lowers IFP in the KAT-4 experimental model for anaplastic thyroid carcinoma. Analyses of messenger RNA (mRNA) expressions by Affymetrix microarrays and RNase protection assays, as well as of protein expressions identified tumor macrophages as targets for Fc:TbetaRII. Treatment with Fc:TbetaRII reduced albumin extravasation, increased coverage of alpha-smooth muscle actin-positive cells and reduced expression of NG2, a marker of activated pericytes, in KAT-4 carcinoma blood vessels. Specific inhibition of interleukin-1 (IL-1), a major cytokine produced by activated macrophages, lowered carcinoma IFP to a similar degree as Fc:TbetaRII but had no significant effect on the parameters of blood vessel maturation. Neither Fc:TbetaRII nor inhibition of IL-1 changed blood vessel density. Finally, pretreatment of KAT-4 carcinomas with Fc:TbetaRII increased the antitumor efficacy of doxorubicin. Our data emphasize a potential role of tumor macrophages in carcinoma physiology and identify these cells as potential stromal targets for treatment aimed to improve efficacy of chemotherapy.     

Subcutaneous interstitial pressure in man and dogs exposed to heat and exercise stress

Summary Interstitial fluid pressure (IFP) was measured by the wick method in six young men. During exercise in the heat, IFP progressively decreased, and this decrease was maintained after cessation of exercise. In two men working in the same conditions after heat acclimatisation IFP became initially positive before steadily declining. In three anaesthetised dogs exposed to heat IFP also declined, but in a thermoneutral environment it rose towards atmospheric pressure. It is suggested that IFP could be used as a measure of filtration forces operating across the capillary wall. Fluid dynamics in the interstitial space of heat acclimatised man differed, however, from that of unacclimatised man and heat exposed dogs. It is postulated that these changes may be related to movement of protein from the interstitial to the plasma compartments during exercise after acclimatisation.     

A Model of Fluid Flow in Solid Tumors

Solid tumors consist of a porous interstitium and a neoplastic vasculature composed of a network of capillaries with highly permeable walls. Blood flows across the vasculature from the arterial entrance point to the venous exit point, and enters the tumor by convective and diffusive extravasation through the permeable capillary walls. In this paper, an integrated theoretical model of the flow through the tumor is developed. The flow through the interstitium is described by Darcy's law for an isotropic porous medium, the flow along the capillaries is described by Poiseuille's law, and the extravasation flux is described by Starling's law involving the pressure on either side of the capillaries. Given the arterial, the venous, and the ambient pressure, the problem is formulated in terms of a coupled system of integral and differential equations for the vascular and interstitial pressures. The overall hydrodynamics is described in terms of hydraulic conductivity coefficients for the arterial and venous flow rates whose functional form provides an explanation for the singular behavior of the vascular resistance observed in experiments. Numerical solutions are computed for an idealized case where the vasculature is modeled as a single tube, and charts of the hydraulic conductivities are presented for a broad range of tissue and capillary wall conductivities. The results in the physiological range of conditions are found to be in good agreement with laboratory observations. It is shown that the assumption of uniform interstitial pressure is not generally appropriate, and predictions of the extravasation rate based on it may carry a significant amount of error. © 2003 Biomedical Engineering Society. PAC2003: 8719Tt, 8710+e     

Interstitial fluid pressure correlates with intravoxel incoherent motion imaging metrics in a mouse mammary carcinoma model

The effective delivery of a therapeutic drug to the core of a tumor is often impeded by physiological barriers, such as the interstitial fluid pressure (IFP). There are a number of therapies that can decrease IFP and induce tumor vascular normalization. However, a lack of a noninvasive means to measure IFP hinders the utilization of such a window of opportunity for the maximization of the treatment response. Thus, the purpose of this study was to investigate the feasibility of using intravoxel incoherent motion (IVIM) diffusion parameters as noninvasive imaging biomarkers for IFP. Mice bearing the 4T1 mammary carcinoma model were studied using diffusion‐weighted imaging (DWI), immediately followed by wick‐in‐needle IFP measurement. Voxelwise analysis was conducted with a conventional monoexponential diffusion model, as well as a biexponential model taking IVIM into account. There was no significant correlation of IFP with either the median apparent diffusion coefficient from the monoexponential model (r = 0.11, p = 0.78) or the median tissue diffusivity from the biexponential model (r = 0.30, p = 0.44). However, IFP was correlated with the median pseudo‐diffusivity (D_p) of apparent vascular voxels (r = 0.76, p = 0.02) and with the median product of the perfusion fraction and pseudo‐diffusivity (f_pD_p) of apparent vascular voxels (r = 0.77, p = 0.02). Although the effect of IVIM in tumors has been reported previously, to our knowledge, this study represents the first direct comparison of IVIM metrics with IFP, with the results supporting the feasibility of the use of IVIM DWI metrics as noninvasive biomarkers for tumor IFP. Copyright © 2011 John Wiley & Sons, Ltd.     

循经低流阻通道组织液压的初步观察

目的 测量循经低流阻通道与周围的组织液压,观察其差异及变化情况。方法 在麻醉的小型猪上,使用连续流阻测量仪测出低流阻点和非低流阻点,然后采取针中芯方法测量组织液压。结果 统计结果表明,小型猪胃经、肾经和任脉的低流阻通道平均压力均显著低于旁开的高流阻区域,其压力差分别为1.06、0.70、3.69 mmHg（1 mmHg=0．133 kPa）,总压力差为1.44 mmHg,压力梯度为1.44~2.88 mmHg/cm。在一些低流阻点上发现了与呼吸频率一致的压力波。结论 外周皮下组织中存在着指向经脉低流阻通道的压力差,可能构成组织液向经脉流动的动力。     

Quantification and localisation of damage in rat muscles after controlled loading; a new approach to study the aetiology of pressure sores.

To obtain more insight in the aetiology of deep pressure sores, an animal model was developed to relate controlled external loading to local muscle damage. The tibialis anterior muscle (TA) and overlying skin of a rat were compressed between indentor and tibia. Loads of 10, 70 and 250kPa at skin surface were applied for 2 or 6h. During half of the 10 and 250kPa experiments interstitial fluid pressure (IFP) in the TA was measured. The TAs were excised 24h after load application. Both amount and location of damage were assessed by histological examination using a semi-automated image-processing program. In six of eleven loaded muscles damage was found. The damage was located from superficial to deep muscle tissue in a zone never exceeding the diameter of the indentor. The IFP measurements interfered with the occurrence of damage; application of 10 and 70kPa loads only caused damage when combined with IFP measurements, whereas IFP measurements increased damage at 250kPa loads. The results showed that the developed animal model can be used to provoke local damage by applying a controlled load and that the amount and location of damage can be assessed using the newly developed techniques.     

Trabecular Shear Stresses Predict <Emphasis Type="Italic">In Vivo</Emphasis> Linear Microcrack Density but not Diffuse Damage in Human Vertebral Cancellous Bone

Linear microcracks and diffuse damage (staining over a broad region) are two types of microscopic damage known to occur in vivo in human vertebral trabecular bone. These damage types might be associated with vertebral failure. Using microcomputed tomography and finite element analysis for specimens of cancellous bone, we estimated the stresses in the trabeculae of human vertebral tissue for inferosuperior loading. Microdamage was quantified histologically. The density of in vivo linear microcracks was, but the diffuse damage area was not, related to the estimates of von Mises stress distribution in the tissue. In vivo linear microcrack density increased with increasing coefficient of variation of the trabecular von Mises stress and with increasing average trabecular von Mises stress generated per superoinferior apparent axial stress. Nonlinear increase in linear crack density, similar to the increase of the coefficient of variation of trabecular shear stresses, with decreasing bone stiffness and bone volume fraction suggests that damage may accumulate rather rapidly in diseases associated with low bone density due to the dramatic increase of shear stresses in the tissue. © 2003 Biomedical Engineering Society. PAC2003: 8719Rr, 8719Xx, 8759Ls, 8759Fm, 8710+e     

Modeling the transmural stress distribution during healing of bioresorbable vascular prostheses

Little attention has been given to the stresses within the wall of bioresorbable vascular prostheses and how they might affect the resorption process. We modeled the graft “complex” (inner tissue capsule, residual graft, and outer tissue capsule) as a three-layered compound tube under internal pressure. Using this biomechanical model, we studied the effects of alterations in the geometry (i. e., radius and thickness) and mechanical properties of each stratum on the overall transmural stress distribution. Hypothetical simulations were performed to investigate the possible-sequence of and alterations in the radial and circumferential stresses during the resorption process. Our results suggest that early in the resorption phase, the inner tissue capsule is subjected to compressive hoop stresses and concentrated, largemagnitude compressive radial stresses. This distribution gives way to the more typical distribution for a thick-walled tube when equilibration (i.e., complete resorption) is approached. The prediction of the compressive stresses in the pseudo-intima during early resorption parallels findings of an elevated mitotic index in that region at that time. This leads to a new hypothesis, namely, that compressive stresses, both in-plane and out-of-plane with respect to the regenerated vascular cells, participate in the resorption process of bioresorbable vascular grafts by modulating elevated cellular proliferative activity and may play an important role in other aspects of vascular cell biology. Results of recent experimentation support this hypothesis.     

Sympathectomy decreases size and invasiveness of tongue cancer in rats

The sympathetic nervous system plays a role in carcinogenesis wherein locally released sympathetic neurotransmitters affect proliferation, angiogenesis, vessel permeability, lymphocyte traffic and cytokine production. The present in vivo study was designed to investigate whether surgical sympathectomy, both unilateral and bilateral, had an effect on tumor growth, interstitial fluid pressure (IFP) and lymphatics in rat tongue cancer. We used 4-nitroquinoline-1-oxide (4-NQO) in drinking water for 19 weeks to induce tongue cancer in 20 Dark Agouti rats. After 11 weeks, one group underwent unilateral sympathectomy and another underwent bilateral sympathectomy, while the third group underwent sham surgery. By 19 weeks, tumors in the bilaterally sympathectomized (BL-SCGx) rats were significantly smaller (P<0.05), more diffuse in appearance and less invasive (P<0.05) compared with the large exophytic tumors in the sham-operated rats. The relative lymphatic area was significantly decreased (P<0.05) in tumors in the BL-SCGx rats compared with the sham group. Interestingly, the tumors in rats that underwent unilateral or bilateral sympathectomy had a significantly lower (P<0.05) IFP than those in sham rats. Lack of tyrosine hydroxylase (TH) immunoreactive nerves and few neuropeptide Y (NPY) positive fibers indicate absence of sympathetic nerve fibers in the bilateral sympathectomized group. The peritumoral lymph vessel area was correlated with the tumor size (P<0.001), depth of invasion (P<0.001), weight of rats (P<0.005) and IFP (P<0.05). In conclusion, the present study presents evidence that deprivation of sympathetic nerves decreases tumor growth in rat tongue, probably caused by decreasing IFP and lymph vessel area.