Size- and surface-dependent uptake of colloid particles into the lymphatic system.

PURPOSE: To examine the effect of particle size and surface characteristics on colloidal particle uptake from subcutaneous tissue into the lymphatic system. MATERIALS AND METHODS: Perfluorocarbon emulsion ZY13163 (median particle diameter, 0.08 micron; surfactant, egg yolk phospholipid), ZY13164 (median particle diameter, 0.36 micron; surfactant, egg yolk phospholipid), ZY13199 (0.18 micron, surfactants Tetronic904) and ZY14001 (0.11 micron, surfactant Pluronic L121) were individually injected into the dorsal skin of the hind foot of rabbits. Lymph flow rates and particle concentrations were determined in prenodal lymph fluid after injection, with and without massage of the skin over the injection site. RESULTS: In the first 24 hours after injection, the decreasing order of colloid flux without massage was as follows: ZY13199 > ZY14001 > ZY13163 > ZY13164. Lymph flow rates, lymph leukocyte concentrations and colloid concentrations increased substantially with mechanical skin massage. CONCLUSIONS: Transport of colloids into lymphatic vessels depends on particle size and surface characteristics. Without massage, colloids with egg yolk phospholipid exhibit size dependent decrease in uptake into lymphatics, while with massage only a weak correlation with particle size is present.

Mechanism of colloidal particle uptake into the lymphatic system: basic study with percutaneous lymphography.

PURPOSE: To examine the extracellular (dispersed particles) and intracellular (phagocytosed particles) colloidal particle transport from subcutaneous tissue into the lymphatic system. MATERIALS AND METHODS: Perfluorocarbon emulsions LA11063 (mean particle diameter, 0.34 micron) and ZY12149 (mean particle diameter, 0.06 micron) were individually injected into the dorsal skin of the hind foot of rabbits. Lymph flow rates and particle concentrations were determined in prenodal lymph fluid after injection, with and without massage of the skin over the injection site. RESULTS: In the first 24 hours after injection, extracellular colloid flux was substantially larger than intracellular flux. Lymph flow rates and colloid concentrations increased substantially with massage. Extracellular LA11063 flux was smaller than ZY12149 flux, whereas intracellular LA11063 flux exceeded ZY12149 flux. CONCLUSION: Transport of colloids into lymphatic vessels is dependent on particle size. Both extracellular and intracellular pathways are utilized. External tissue movement contributes substantially to the rate of particle uptake via both pathways.

Percutaneous CT lymphography with perflubron: imaging efficacy in rabbits and monkeys.

PURPOSE: To evaluate the imaging efficacy of percutaneous lymphography performed with injection of perflubron emulsions and computed tomography (CT). MATERIALS AND METHODS: Thin-section CT was used to image lymph nodes in 116 rabbits and six monkeys. Quantitative measures of regional lymph node enhancement were obtained 4 hours to 21 days after subcutaneous injection of perflubron (0.1-0.5 mL per injection site). Lymph node enhancement was calculated in Hounsfield units and converted to bromine concentration with standards that were imaged at the same time. RESULTS: Excellent enhancement of regional lymph nodes in both groups of animals was obtained. Nodal enhancement was linearly related to dose and was sustained for 20 days; maximum enhancement was seen 2 days after injection. Massage of the injection site increased delivery of the perflubron emulsion to regional lymph nodes. CONCLUSION: In rabbits and monkeys, percutaneous CT lymphography effectively depicts the intranodal distribution of macrophages in normal lymph nodes.

Development of highly fluid, concentrated and stable fluorocarbon emulsions for diagnosis and therapy.

A challenging aim in developing injectable fluorocarbon emulsions is to combine good flow characteristics (especially at low shear rates) with the high fluorocarbon concentration required for high oxygen delivery or effective contrast in imaging, long shelf life, and biological acceptability. A good balance of these sometimes conflicting objectives has been achieved with 90% w/v concentrated emulsions of various fluorocarbons, including the radiopaque oxygen carrier perfluorooctylbromide (PFOB, perflubron). The sterile emulsions have viscosities of about 20 cPs at a shear rate of 1 sec-1; the viscosity decreases rapidly with fluorocarbon concentration, and at 60% w/v the viscosity is less than that of human blood. The emulsions are suitable for injection as prepared, and are stable unfrozen for over a year.

Application of computer-based experimental design to optimization of processing conditions for perfluorocarbon emulsion.

Response surface methodology was applied during process optimization of a parenteral emulsion formulation containing perfluorocarbon (PFC). E-Chip, a computer software program, was used to design and analyze the optimization experiments. The levels of eight process variables of interest were varied: pre-emulsification temperature and mixing time, mixer speed, generator type, rate of PFC addition, homogenization temperature, pressure and number of passes. Dependent variables evaluated included emulsion median diameter, viscosity and percent unemulsified PFC. A predictive model describing the relationship between the dependent and process variables was developed. Median diameter of the emulsion was affected significantly by homogenization temperature and pressure, and marginally by the rate of addition of the PFC. Viscosity was not influenced by any of the process variables. Percent unemulsified PFC was slightly influenced by the number of homogenization passes. The model was then used to set optimum process conditions.

Drop size stability assessment of fluorocarbon emulsions.

The aging of fluorocarbon emulsions prepared with natural egg yolk phospholipids (EYP) has been studied and a linear variation (r2 greater than 0.95) of the mean average volume of the droplets with time has been observed. The slope of the experimental lines, called "Stability Parameter, S" can thus be taken as a representation of the rate of aging of the emulsions. Examples are given of use of parameter S to assess the effect of formulation and processing parameters on the stability of diverse fluorocarbon emulsions. S is a useful tool to compare emulsions and ascertain any factors of stabilization/destabilization.