PubMed Health⌕ Search

Biomedical subjects

P A Netti

Publications and source records attributed to P A Netti.

At least 19 recordsLinked to original sources
PubMed2006

The effective dispersion of nanovectors within the tumor microvasculature.

The effective longitudinal diffusion of nanovectors along non-permeable and permeable capillaries has been studied considering the contribution of molecular and convective diffusion based on the Taylor's theory of shear dispersion. The problem is of importance in the transport of nanovectors used for the intravascular delivery of drugs and contrast agents. It has been shown that for a given capillary size and hemodynamic conditions a critical radius acr exists for which the effective longitudinal diffusion along the capillary has a minimum: Nanovectors with a < acr diffuse mainly by Brownian diffusion whereas nanovectors with a < acr diffuse mainly by convection and the effective diffusion coefficient grows with a. In permeable conduits, the effective diffusion reduces significantly compared to normal non-leaky vessels and it has been derived that acr grows almost linearly with the hydraulic permeability Lp of blood vessels. It has been shown that the blood conduits with the largest effective longitudinal diffusivity could be preferentially targeted by the circulating vectors. Based on these findings, the following strategies are proposed to increase the number of nanovectors targeting the tumor vessels: (i) The use of nanovectors with a critical radius for normal vessels, (ii) the injecting of bolus of nanovectors with different radii, and (iii) the normalization of the tumor vasculature. Finally, it has been emphasized that the size of the vector should be selected depending on the body district where the tumoral mass is developing and on the type, malignancy, and state of the tumor.

Animals↗
PubMed2006

Poly-epsilon-caprolactone/hydroxyapatite composites for bone regeneration: in vitro characterization and human osteoblast response.

Polycaprolactone (PCL), a semicrystalline linear resorbable aliphatic polyester, is a good candidate as a scaffold for bone tissue engineering, due to its biocompatibility and biodegradability. However, the poor mechanical properties of PCL impair its use as scaffold for hard tissue regeneration, unless mechanical reinforcement is provided. To enhance mechanical properties and promote osteoconductivity, hydroxyapatite (HA) particles were added to the PCL matrix: three PCL-based composites with different volume ratio of HA (13%, 20%, and 32%) were studied. Mechanical properties and structure were analysed, along with biocompatibility and osteoconductivity. The addition of HA particles (in particular in the range of 20% and 32%) led to a significant improvement in mechanical performance (e.g., elastic modulus) of scaffold. Saos-2 cells and osteoblasts from human trabecular bone (hOB) retrieved during total hip replacement surgery were seeded onto 3D PCL samples for 1-4 weeks. Following the assessment of cell viability, proliferation, morphology, and ALP release, HA-loaded PCL was found to improve osteoconduction compared to the PCL alone. The results indicated that PCL represents a potential candidate as an efficient substrate for bone substitution through an accurate balance between structural/ mechanical properties of polymer and biological activities.

Alkaline Phosphatase↗
PubMed2006

Synthesis and characterization of macroporous poly(ethylene glycol)-based hydrogels for tissue engineering application.

Peptide activated poly(ethylene glycol) (PEG)-based hydrogels have received wide attention as material for tissue engineering application. However, the close structure of these materials may pose severe barriers to tissue invasion and nutrient transport. The aim of this work was to synthesize highly interconnected macroporous PEG hydrogels, suitable for use as tissue engineering scaffolds, by combining the photocrosslinking reaction with a foaming process. In particular, various porous samples, differing for both the polymer molecular weight and concentration in the starting precursor solution, have been prepared and characterized by means of scanning electron microscopy and mercury porosimetry. Moreover, water swelling properties have been evaluated and compared with those of the conventional nonporous ones, by performing both equilibrium and kinetic swelling measurements in distilled water. Results indicated that foamed hydrogels display a well-interconnected porous network, suitable for tissue invasion and free molecular trafficking within them. Pores dimension as well as swelling rate can be modulated by polymer concentrations and bubbling agent composition in the precursor solution.

Biocompatible Materials↗
PubMed2006

Time and space evolution of transport properties in agarose-chondrocyte constructs.

During the development of de novo synthesized cartilage tissue engineered constructs, transport and biophysical properties are expected to change in time and space. Monitoring and control of the evolution of these parameters are of crucial importance to process biohybrid constructs in vitro. The aim of this work was to measure fluid and macromolecular transport and evolution of mechanical properties of tissue-engineered cartilage constructs as a function of culture time and extracellular matrix (ECM) production. It was found, in agreement with other literature reports, that mechanical and fluid transport properties of the constructs correlated well with time of culture and glycosaminoglycan (GAG) content. Further, diffusion coefficients of 2 probes, dextran (500 kDa) and bovine serum albumin (BSA), correlated well with GAG production. Diffusion coefficients (D) were measured with high spatial and temporal resolution by fluorescent recovery after photobleaching (FRAP). Diffusivity steadily decreases with time while it does not vary through the thickness of the specimen. On the basis of these results, an empirical relationship between diffusion coefficient and GAG content was proposed for the 2 probes analyzed. The results of this study provide useful information to optimize and control the tissue culture process in vitro.

Animals↗
PubMed2004

Hyaluronic-acid-based semi-interpenetrating materials.

In order to enhance the mechanical performances of hyaluronic acid (HA) without compromising its biological activity, HA has been interpenetrating with a fibrillar collagen scaffold. The semi-interpenetrating materials were obtained by mixing HA with different molecular weight and a pepsin-solubilized collagen (atelocollagen) solution, and then by inducing collagen fibrillogenesis. Results indicate that molecular weight of HA significantly influences the mechanical properties of the semi-interpenetrating materials and more specifically stronger material results from the use of low-molecular-weight (LMW) HA. According to the dynamic mechanical data the composite collagen-LMW HA has a higher elastic modulus than collagen, whereas the opposite is true for the high-molecular-weight (HMW) HA. This result highlights the role of specific interactions that occur between collagen and HA during the gel formation in controlling the network mechanical stability. LMW HA may, probably, interact more strongly with collagen during the fibrillogenesis process than HMW HA due to the higher mobility of the chains and the weaker homologous interactions. Moreover, morphological observations showed that LMW HA is intimately interdispersed within the collagen network and completely coated the fibrils, which act as mechanical support.

Biocompatible Materials↗
PubMed2002

Spatial and structural dependence of mechanical properties of porcine intervertebral disc.

Structure-function relationship of natural tissues is crucial to design a device mimicking the structures present in human body. For this purpose, to provide guidelines to design an intervertebral disc (IVD) substitute, in this study the influence of the spatial location and structural components on the mechanical properties of porcine IVD was investigated. Local compressive stiffness (LCS) was measured on the overall disc, also constrained between the two adjacent vertebrae: the dependence on the lumbar position was evaluated. The compliance values in the anterior position (A) were higher than both in the central posterior (CP) and in the lateral-posterior (RP, LP) locations. The values of Young's Modulus (74.67+/-6.03 MPa) and compression break load (1.36x10(4)+/-0.09x10(4)N) of the disc were also evaluated by distributed compression test. The NP rheological behavior was typical of weak-gels, with elastic modulus G' always higher than viscous modulus G" all over the frequency range investigated (G' and G" respectively equal to 320 and 85 Pa at 1 Hz) and with the moduli trends were almost parallel to each other.

Journal Article↗
PubMed2000

Role of extracellular matrix assembly in interstitial transport in solid tumors.

The extracellular matrix (ECM) may contribute to the drug resistance of a solid tumor by preventing the penetration of therapeutic agents. We measured differences in interstitial resistance to macromolecule (IgG) motion in four tumor types and found an unexpected correspondence between transport resistance and the mechanical stiffness. The interstitial diffusion coefficient of IgG was measured in situ by fluorescence redistribution after photobleaching. Tissue elastic modulus and hydraulic conductivity were measured by confined compression of excised tissue. In apparent contradiction to an existing paradigm, these functional properties are correlated with total tissue content of collagen, not glycosaminoglycan. An extended collagen network was observed in the more penetration-resistant tumors. Collagenase treatment of the more penetration-resistant tumors significantly increased the IgG interstitial diffusion rate. We conclude that collagen influences the tissue resistance to macromolecule transport, possibly by binding and stabilizing the glycosaminoglycan component of the ECM. These findings suggest a new method to screen tumors for potential resistance to macromolecule-based therapy. Moreover, collagen and collagen-proteoglycan bonds are identified as potential targets of treatment to improve macromolecule delivery.

Biological Transport↗
PubMed1999

Enhancement of fluid filtration across tumor vessels: implication for delivery of macromolecules.

Cancer therapies using genes and other macromolecules might realize their full clinical potential if they could be delivered to tumor tissue in optimal quantities. Unfortunately, the compromised circulation within tumors poses a formidable resistance to adequate and uniform penetration of these agents. Previously, we have proposed elevated interstitial fluid pressure (IFP) as a major physiological barrier to delivery of macromolecules. Here we postulate that modulation of tumor microvascular pressure (MVP) and associated changes in IFP would enhance macromolecular delivery into a solid tumor. To test our hypothesis, we altered tumor MVP by either periodic injection or continuous infusion of angiotensin II (AII) and measured the resulting changes in IFP and uptake of macromolecules. We used the nicotinyl hydrazine derivative of human polyclonal IgG (HYNIC-IgG) as a nonspecific macromolecule and CC49 antibody as a specific macromolecule. We found that both chronic and periodic modulation of tumor MVP enhances transvascular fluid filtration, leading to a 40% increase in total uptake of the specific antibody within 4 hr of its administration. Conversely, neither continuous nor periodic infusion of AII induced any increase in uptake of nonspecific antibodies. Strategies to improve delivery of macromolecules and limitations of this approach are identified.

Animals↗
PubMed1999

Diffusion of macromolecules in agarose gels: comparison of linear and globular configurations.

The diffusion coefficients (D) of different types of macromolecules (proteins, dextrans, polymer beads, and DNA) were measured by fluorescence recovery after photobleaching (FRAP) both in solution and in 2% agarose gels to compare transport properties of these macromolecules. Diffusion measurements were conducted with concentrations low enough to avoid macromolecular interactions. For gel measurements, diffusion data were fitted according to different theories: polymer chains and spherical macromolecules were analyzed separately. As chain length increases, diffusion coefficients of DNA show a clear shift from a Rouse-like behavior (DG congruent with N0-0.5) to a reptational behavior (DG congruent with N0-2.0). The pore size, a, of a 2% agarose gel cast in a 0.1 M PBS solution was estimated. Diffusion coefficients of the proteins and the polymer beads were analyzed with the Ogston model and the effective medium model permitting the estimation of an agarose gel fiber radius and hydraulic permeability of the gels. Not only did flexible macromolecules exhibit greater mobility in the gel than did comparable-size rigid spherical particles, they also proved to be a more useful probe of available space between fibers.

Animals↗
PubMed1999

Mechanics of interstitial-lymphatic fluid transport: theoretical foundation and experimental validation.

Interstitial fluid movement is intrinsically linked to lymphatic drainage. However, their relationship is poorly understood, and associated pathologies are mostly untreatable. In this work we test the hypothesis that bulk tissue fluid movement can be evaluated in situ and described by a linear biphasic theory which integrates the regulatory function of the lymphatics with the mechanical stresses of the tissue. To accomplish this, we develop a novel experimental and theoretical model using the skin of the mouse tail. We then use the model to demonstrate how interstitial-lymphatic fluid movement depends on a balance between the elasticity, hydraulic conductivity, and lymphatic conductance as well as to demonstrate how chronic swelling (edema) alters the equipoise between tissue fluid balance parameters. Specifically, tissue fluid equilibrium is perturbed with a continuous interstitial infusion of saline into the tip of the tail. The resulting gradients in tissue stress are measured in terms of interstitial fluid pressure using a servo-null system. These measurements are then fit to the theory to provide in vivo estimates of the tissue hydraulic conductivity, elastic modulus, and overall resistance to lymphatic drainage. Additional experiments are performed on edematous tails to show that although chronic swelling causes an increase in the hydraulic conductivity, its greatly increased distensibility (due to matrix remodeling) dampens the driving forces for fluid movement and leads to fluid stagnation. This model is useful for examining potential treatments for edema and lymphatic disorders as well as substances which may alter tissue fluid balance and/or lymphatic drainage.

Animals↗
PubMed1998

Viscoelastic behavior of composite ligament prostheses.

Despite the compelling need for artificial connective tissue replacements for orthopedic applications, to date, there is no material which can adequately reproduce the mechanical behavior of natural tissue with necessary long-term endurance. In this work, we introduce a novel soft composite material as a more suitable candidate for connective tissue replacement. The material proposed is based on a hydrogel-polymer matrix reinforced with poly(ethylene terephthalate) fibers wound helically to mimic the architecture of the collagen fibers in natural tissue. Macroscopic behaviors such as static stress-strain, stress relaxation, and dynamic frequency responses can be modulated with choice of the components and design of the composite structure. In doing so, the mechanical characteristics of natural ligaments can be qualitatively reproduced and sustained over time.

Composite Resins↗
PubMed1998

Intratumoral infusion of fluid: estimation of hydraulic conductivity and implications for the delivery of therapeutic agents.

We have developed a new technique to measure in vivo tumour tissue fluid transport parameters (hydraulic conductivity and compliance) that influence the systemic and intratumoral delivery of therapeutic agents. An infusion needle approximating a point source was constructed to produce a radially symmetrical fluid source in the centre of human tumours in immunodeficient mice. At constant flow, the pressure gradient generated in the tumour by the infusion of fluid (Evans blue-albumin in saline) was measured as a function of the radial position with micropipettes connected to a servo-null system. To evaluate whether the fluid infused was reabsorbed by blood vessels, infusions were also performed after circulatory arrest. In the colon adenocarcinoma LS174T with a spherically symmetrical distribution of Evans blue-albumin, the median hydraulic conductivity in vivo and after circulatory arrest at a flow rate of 0.1 microl min(-1) was, respectively, 1.7x10(-7) and 2.3x10(-7) cm2 mmHg(-1) s. Compliance estimates were 35 microl mmHg(-1) in vivo, and 100 microl mmHg(-1) after circulatory arrest. In the sarcoma HSTS 26T, hydraulic conductivity and compliance were not calculated because of the asymmetric distribution of the fluid infused. The technique will be helpful in identifying strategies to improve the intratumoral and systemic delivery of gene targeting vectors and other therapeutic agents.

Absorption↗
PubMed1997

Transmural coupling of fluid flow in microcirculatory network and interstitium in tumors.

The growth of tumors and their response to treatment are determined by delivery of diffusible substances to cancer cells and hence by their blood supply. Relative to most normal tissues, tumor blood flow is highly heterogeneous. Several hypotheses have been postulated to explain this anomalous behavior of tumor microcirculation, but the underlying mechanisms for these heterogeneities are not fully understood. In this study we consider a potential source of nonuniformity in the blood flow: the enhanced fluid exchange between the vascular and interstitial space mediated by the high leakiness of tumor vessels which could lead to a coupling between vascular, transvascular, and interstitial fluid flow. A simple network model is presented to describe the basic features of flow through a network of permeable and compliant vessels embedded in an isotropic porous medium. Two vascular geometries are considered: a regular mesh of identical vessels and a pair of countercurrent vessels of equal diameter. In each case, the flow through each vessel of the network is described by Poiseuille's law; the transmural flow between the vessels and the external porous medium is governed by Starling's law; the fluid movement through the porous medium is described by Darcy's law; and the vessel wall is assumed to be elastic. Our results show that the behavior of microcirculation may be strongly modified as a result of vascular compliance and enhanced vascular leakiness of tumor vessels. We found not only that the vascular pressure generates the well-known, high central interstitial fluid pressure, but also that the elevated interstitial pressure in turn alters the vascular pressure distribution. These changes in vascular pressure distribution result in a modification of the blood flow pattern. As the leakiness and compliance of the vessels increase, the blood is diverted away from the center of the tumor to a more peripheral path. The clinical significance of these results is that drug delivery for chemotherapy and oxygenation needed for radiotherapy may well be hampered in the central region of the tumor, despite the presence of highly permeable vessels in these regions.

Biological Transport↗
PubMed1997

Solid stress inhibits the growth of multicellular tumor spheroids.

In normal tissues, the processes of growth, remodeling, and morphogenesis are tightly regulated by the stress field; conversely, stress may be generated by these processes. We demonstrate that solid stress inhibits tumor growth in vitro, regardless of host species, tissue of origin, or differentiation state. The inhibiting stress for multicellular tumor spheroid growth in agarose matrices was 45 to 120 mm Hg. This stress, which greatly exceeds blood pressure in tumor vessels, is sufficient to induce the collapse of vascular or lymphatic vessels in tumors in vivo and can explain impaired blood flow, poor lymphatic drainage, and suboptimal drug delivery previously reported in solid tumors. The stress-induced growth inhibition of plateau-phase spheroids was accompanied, at the cellular level, by decreased apoptosis with no significant changes in proliferation. A concomitant increase in the cellular packing density was observed, which may prevent cells from undergoing apoptosis via a cell-volume or cell-shape transduction mechanism. These results suggest that solid stress controls tumor growth at both the macroscopic and cellular levels, and thus influences tumor progression and delivery of therapeutic agents.

Animals↗
PubMed1996

Effect of transvascular fluid exchange on pressure-flow relationship in tumors: a proposed mechanism for tumor blood flow heterogeneity.

Tumor blood flow (TBF) is characterized by spatial and temporal heterogeneities. Despite the crucial role of TBF in tumor growth, metastasis, and therapy, the mechanisms underlying these heterogeneities are not fully understood. Tumor vessels are, in general, more leaky than normal vessels and this may enhance the efficiency of fluid exchange between the vascular and the interstitial space. The coupling between transvascular fluid exchange and hemodynamics in tumors has not been explored previously. To investigate the role of transvascular fluid exchange on afferent and efferent blood flow, we modeled the tumor vasculature as an equivalent single vessel which is permeable and deformable and embedded in a fluid medium with uniform pressure. Simulations were carried out to examine the effects of vessel leakiness, vessel compliance, and interstitial fluid pressure on (a) pressure-flow relationship, (b) arterial-venous pressure relationship, and (c) pressure profile along the vessel. Experiments suggested by model simulations required an independent control of arterial and venous pressure and tumor blood flow. To this end, we perfused tissue-isolated tumors ex vivo and obtained data on perfusate flow rate vs arterial and venous pressures. The simulations predicted the following trends as a result of an enhanced fluid filtration across the vessel wall: (a) for a fixed arterial-venous pressure difference, efferent flow decreases with increasing venous pressure, (b) changes in venous pressure are not completely transmitted to the arterial side, and (c) the pressure profile along the vessel becomes less steep. The experimental results confirmed these trends and indicated that vascular and interstitial flow are coupled in isolated tumors. The implications of this coupling for the spatial and temporal heterogeneity in TBF are discussed.

Adenocarcinoma↗
PubMed1996

Compatibility and the genesis of residual stress by volumetric growth.

The equations of compatibility which are pertinant for growth strain fields are collected and examples are given in simply-connected and multiply-connected regions. Compatibility conditions for infinitesimal strains are well known and the possibilities of Volterra dislocations in multiply-connected regions are enumerated. For finite growth strains in a multiply-connected regions, each case must be examined individually and no generalizations in terms of Volterra dislocations are available. Any incompatible growth strains give rise to residual stresses which are known to occur in many tissues such as the heart, arterial wall, and solid tumors.

Animals↗
PubMed1995

Time-dependent behavior of interstitial fluid pressure in solid tumors: implications for drug delivery.

Elevated interstitial fluid pressure (IFP) may constitute a significant physiological barrier to drug delivery in solid tumors. Strategies for overcoming this barrier have not been developed to date. To identify and characterize various mechanisms regulating IFP and to develop strategies for overcoming the IFP barrier, we modeled the tumor as a poroelastic solid. We used this model to simulate the effect of changes in microvascular pressure and tumor blood flow (TBF) on IFP. To test model predictions, the effects of changes in arterial pressure and TBF on IFP were measured using a tissue-isolated tumor preparation. IFP in the center of an isolated tumor was predicted to follow variation of the arterial pressure with a time delay of the order of magnitude of 10 s, and this delay was found to be 11 +/- 6 s experimentally. Following a cessation of TBF, the time constant of the drop in IFP was predicted to be of the order of 1000 s and was found to be 1500 +/- 900 s experimentally. The former time scale is characteristic of transcapillary fluid exchange, and the latter of percolation of fluid through the interstitial matrix. Relying on the good agreement between theoretical predictions and experimental data, we estimated the effect of blood pressure modulation on macromolecular uptake in solid tumors. Our results show that no appreciable increase of macromolecular uptake should occur either by an acute or by a chronic increase of blood pressure. On the other hand, higher uptake would result from periodic modulation of blood pressure. Therefore, the effectiveness of a vasoconstrictor such as angiotensin II to increase macromolecular delivery should be significantly enhanced by periodic rather than bolus or continuous administration of the vasoactive agent.

Animals↗