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PubMed1996

In vivo colored microspheres in the isolated rat heart for use in NMR.

Myocardial perfusion measurement with colored microspheres may become an alternative for radioactive microsphere techniques. We use and validate a spectrophotometric method that has been previously established for large animals in the isolated perfused rat heart. The perfusion system was adapted for use in a NMR microscope. Hearts were perfused with constant coronary flow that was adjusted to a coronary perfusion pressure of 100 mmHg. Homogeneous coronary inflow of microspheres was represented by equal distribution of microspheres of two different colors after simultaneous injection. Mean regional myocardial blood flow was 17.76 +/- 5.01 ml/min/g, mean wet heart weight was 1.13 +/- 0.34 g and mean global flow was 20.06 +/- 0.60 ml/min. Heart rate was 296 +/- 8.9 beats/min and left ventricular pressure was similar 5 min before (149.1 +/- 14.27 mmHg) and after (147.1 +/- 13.49 mmHg) microsphere injection. Microspheres of four colors that were injected sequentially, at various coronary flows, demonstrated linearity and reproducibility of the technique. A cumulative use of less than 90 000 microspheres showed no effect on hemodynamics especially on left ventricular pressure.

Animals↗
PubMed1985

Hepatic artery administration of degradable starch microspheres. I. Effect on energy charge and incorporation of precursors into rat liver nucleic acids.

The effects of hepatic artery administration of degradable starch microspheres on liver energy charge and nucleic acid anabolism were studied in rats. Liver energy charge was evaluated 20 and 60 min after the injection of degradable starch microspheres. As compared to controls the microspheres had no effect on liver energy charge. The incorporation of orotic acid, uracil, and thymidine into liver RNA or DNA was studied 1 h after hepatic artery injection of precursor alone or together with degradable starch microspheres. Orotic acid and uracil incorporation into RNA was studied in normal rats and the DNA incorporation of thymidine in animals with regenerating livers. Orotic acid and thymidine were given in trace amounts. Uracil was given in amounts corresponding to a therapeutic dose of 5-fluorouracil. The addition of microspheres had no effects on the incorporation of the nucleic acid precursors into RNA or DNA. Thus, in the normal liver degradable starch microspheres administered by the hepatic artery had no influence on liver energy charge or RNA anabolism in the liver. Also the microspheres had no negative effects on the DNA anabolism in proliferating liver cells.

Animals↗
PubMed1995

Microencapsulation of DNA within alginate microspheres and crosslinked chitosan membranes for in vivo application.

Calf thymus DNA was microencapsulated within crosslinked chitosan membranes, or immobilized within chitosan-coated alginate microspheres. Microcapsules were prepared by interfacial polymerization of chitosan, and alginate microspheres formed by emulsification/internal gelation. Diameters ranged from 20 to 500 microns, depending on the formulation conditions. Encapsulated DNA was quantified in situ by direct spectrophotometry (260 nm) and ethidium bromide fluorimetry, and compared to DNA measurements on the fractions following disruption and dissolution of the microspheres. Approximately 84% of the DNA was released upon core dissolution and membrane disruption, with 12% membrane bound. The yield of encapsulation was 96%. Leakage of DNA from intact microspheres/capsules was not observed. DNA microcapsules and microspheres were recovered intact from rat feces following gavage and gastrointestinal transit. Higher recoveries (60%) and reduced shrinkage during transit were obtained with the alginate microspheres. DNA was recovered and purified from the microcapsules and microspheres by chromatography and differential precipitation with ethanol. This is the first report of microcapsules or microspheres containing biologically active material (DNA) being passed through the gastrointestinal tract, with the potential for substantial recovery.

Animals↗
PubMed1995

Assessment of coronary vasodilator reserve by N-13 ammonia PET using the microsphere method and Patlak plot analysis.

UNLABELLED: Noninvasive quantification of regional myocardial blood flow (MBF) has been successfully achieved with N-13 ammonia. The microsphere method as a simple method for quantifying regional myocardial blood flow was reevaluated in comparison with Patlak graphical analysis. In addition coronary vasodilator reserve (CVR) was estimated by both methods. METHODS: Dynamic N-13 ammonia PET studies were performed in 10 healthy volunteers and 10 patients with coronary artery disease at baseline and after dipyridamole infusion (0.56 mg/kg). MBF was estimated by the microsphere method at various times and by Patlak graphical analysis. In order to reduce the noise level in the microsphere method, MBF estimates were also performed after data in 10-40 seconds were averaged. RESULTS: In the studies on normal subjects MBF (ml/min/g) determined by the microsphere method significantly differs from time to time. However, MBF determined by the modified microsphere method [with average (Extraction fraction) x MBF values obtained between 100 and 120 sec] linearly correlated well with MBF by Patlak graphical analysis (r = 0.97, slope = 0.98, intercept = 0.20). In the studies on patients with coronary artery disease a good agreement of the MBF estimates was also observed (r = 0.97, slope = 0.98, intercept = 0.22). In the studies on the normal subjects and patients with coronary artery disease, CVR obtained by the modified microsphere method after correcting the overestimated MBF values also correlated well with that by Patlak graphical analysis (r = 0.90, slope = 1.14, intercept = -0.15, and r = 0.92, slope = 0.82, intercept = 0.25, respectively). CONCLUSION: The modified microsphere method is a very simple and reliable approach for quantifying MBF with N-13 ammonia PET which is comparable to Patlak graphical analysis. It also makes possible CVR assessment as accurate as Patlak graphical analysis.

Adult↗
PubMed2005

Evaluation of chitosan/beta-tricalcium phosphate microspheres as a constituent to PMMA cement.

Two methods, a traditional emulsion technique and a high voltage electrostatically modified encapsulation system, were used to fabricate degradable chitosan/beta -tricalcium phosphate (beta-TCP) microspheres. The two distinct kinds of microspheres both exhibited good sphericity and the beta-TCP was trapped well inside the chitosan gel. The microspheres prepared by high voltage electrostatic system exhibited a rougher outer surface and narrower size distribution. These microspheres were then used as an added constituent to commercially available PMMA bone cement. Four modified cement composites that were prepared with different composition ratios of the two kinds of chitosan/beta-TCP microspheres that were made from emulsion technique (C1P1 and C2P1) and from a process by a high voltage electrostatic system (EC1P1 and EC2P1) were compared with the PMMA cement (Pure P). The characteristics of these materials indicate that with the addition of chitosan/beta-TCP microspheres as a constituent into the PMMA cement significantly decreases the curing peak temperature. Furthermore, the setting time increases from 3.5 min to 9 min, as compared to the PMMA cement. These changes could be beneficial for the handling of the bone cement paste and causing less damage to the surrounding tissues. Understandably, the presence of chitosan/beta-TCP microspheres in the prepared composites reduced the ultimate compressive strength and bending strength. From the degradation test and SEM observations, the modified chitosan/beta -TCP/PMMA composites could be degraded gradually and create rougher surfaces that would be beneficial to cell adherence and growth.

Biocompatible Materials↗
PubMed2005

Microsphere of apatite-gelatin nanocomposite as bone regenerative filler.

In this study, we developed novel microspheres comprised of an apatite-gelatin nanocomposite. This microsphere formulation is considered to be useful as a bone regenerative filler, either directly or combined with polymeric matrices. Using the water-in-oil emulsion technique, the apatite-gelatin viscous nanocomposite solution was successfully formulated into microspheres with an average diameter of approximately 110 microm. The microspheres were composed of apatite nanocrystallines precipitated within the gelatin matrix, revealing a typical nanocomposite internal structure. This nanocomposite structure contrasted markedly with that of the conventional composite microspheres which were obtained by directly mixing gelatin with apatite powder. Initial cellular assays showed that the microspheres maintained the adhesion and proliferation of the osteoblastic cells, suggesting the usefulness of the apatite-gelatin nanocomposite microspheres in the bone regeneration field.

Apatites↗
PubMed1981

Selective distribution of microspheres injected into the umbilical veins and inferior venae cavae of fetal sheep.

To investigate the extent of streaming of umbilical venous blood in the venous and arterial circulations of normal and hypoxic sheep fetuses and to experimentally determine its effect on determinations of blood flow by means of the microsphere method, we injected 15 mu microspheres labeled with different radionuclides into the umbilical veins (UVs) and distal inferior venae cavae (DIVC) of 21 chronically catheterized near-term sheep fetuses. We determined the ratio of the radioactive counts from the UV-injected microspheres to the radioactive counts from the DIVC-injected microspheres (UV/DIVC count ratio) in each fetal tissue in 40 experiments. In 75% of the normal fetuses and 58% of the hypoxic fetuses, UV-injected microspheres streamed preferentially through the foramen ovale to the left atrium and ventricle when compared with DIVC-injected microspheres. Fetal hypoxia was associated with a significant decrease in the extent of preferential streaming. In the arterial circulation, we found no evidence for preferential streaming of UV-injected and DIVC-injected microspheres.

Animals↗
PubMed1984

Magnetic targeting of microspheres in blood flow.

Magnetically responsive albumin microspheres can be targeted to the vasculature of specific organs, using extracorporeal magnetic sources. Experiments have been performed on targeting these microspheres to specific regions of normal and tumorous rat tails. This paper quantitatively analyzes the relationship between magnetic forces and the observed microsphere holding. The magnetic forces are determined by the magnetic responsiveness of the microspheres, and by the spatial field of the magnet; both of these are measured. The microsphere holding is defined as that fraction of the microspheres perfusing the tail which are held at a particular site; this is measured at various positions in the tail. The holding as a function of magnetic force is thereby established. To interpret the data, the dynamics of microspheres in blood flow is considered, including motion to a vessel wall, shear forces at the wall, and intersphere attraction. Overall, the method appears favorable for targeting therapeutic drugs to tumor sites in humans.

Animals↗
PubMed1983

Simple methods for determining the accuracy of tumor blood flow measurements using radioactive microspheres in rats.

Two simple methods are presented which allow positive identification of the accuracy and precision of the microsphere technique and a quick verification of sphere entrapment in tumor vessels. A known flow of Ringer's solution from a motor-driven syringe is perfused through the rat's isolated systemic circulation from left ventricle to right atrium and collected in a funnel. Using this preparation, total blood flow in rats measured with radioactive microspheres injected into the left ventricle was 97% of actual flow. The coefficient of variation (standard deviation/mean) of the microsphere measurements was 0.22. In the same preparation, nonentrapment of microspheres in subcutaneous tumor nodules grown on a hind limb could be measured from the difference in counts collected in venous effluent before and after placement of a tourniquet proximal to the tumor. For example, in two types of transplantable carcinoma, we found nonentrapment of less than 0.1% of the injected microspheres. Such a shunt would correspond to less than 10% of microspheres entering a typical tumor nodule and, in turn, less than 10% underestimation of true flow to the tumor. These two techniques may be helpful to other investigators in testing the accuracy of microsphere methods in various small animal tumor models.

Animals↗
PubMed1991

Biodegradable microspheres as a vaccine delivery system.

The utility of biodegradable and biocompatible microspheres as a vaccine delivery system for the induction of systemic and disseminated mucosal antibody responses was investigated. Intraperitoneal (ip) injection into mice of 1-10 microns microspheres, constructed of the copolymer poly(DL-lactide-coglycolide) (DL-PLG) which contained approximately 1% by weight a formalinized toxoid vaccine of staphylococcal enterotoxin B (SEB), dramatically potentiated the circulating IgG anti-toxin antibody response as compared to the free toxoid. The initiation of vaccine release was delayed in larger microspheres, and a mixture of 1-10 and 20-50 microns microspheres stimulated both a primary and an anamnestic secondary anti-toxin response following a single injection. However, neither free nor microencapsulated SEB toxoid induced a detectable mucosal IgA anti-toxin response following systemic injection. In contrast, three peroral immunizations with toxoid-microspheres stimulated circulating IgM, IgG and IgA anti-toxin antibodies and a concurrent mucosal IgA response in saliva, gut washings and lung washings. Systemic immunization with microencapsulated toxoid primed for the induction of disseminated mucosal IgA responses by subsequent oral or intratracheal (it) boosting in microspheres, while soluble toxoid was ineffective at boosting. These results indicate that biodegradable and biocompatible microspheres represent an adjuvant system with potentially widespread application in the induction of both circulating and mucosal immunity.

Administration, Oral↗
PubMed1990

Measurement of blood flow to the adrenal capsule, cortex and medulla in dogs after hemorrhage by fluorescent microspheres.

Changes in adrenal medullary and total cortical blood flow after hemorrhage have been described using radioactive microspheres. To assess changes in adrenal capsular and in intracortical adrenal blood flow, a method was used based on microscopic detection of non-radioactive microspheres. Injection of microspheres labelled with fluorescent dyes permitted multiple determinations of blood flow. Pentobarbital anesthetized dogs (n = 6) were prepared acutely with left ventricular and aortic catheters for injection and collection of microspheres, respectively. Adrenal denervation was done unilaterally by cutting the thoracic splanchnic nerve. Injections of 16-microns spheres were made prior to and immediately after 18 ml/kg hemorrhage done over 6 min. Dogs were killed with KCl and adrenals were removed, fixed and sectioned at 80 microns. Using fluorescence microscopy, microspheres were counted in the adrenal capsule, zona glomerulosa, inner cortex (zona facsiculata and reticularis), and the medulla. The majority (95%) of microspheres in the adrenal cortex were trapped in the zona glomerulosa, precluding an independent estimate of blood flow to the inner cortex. Thus, total cortical blood flow was determined by summing the number of 16-microns microspheres in the zona glomerulosa and inner cortex. Prior to hemorrhage, blood flow was greater in the capsule (5.4 +/- 1.6 ml/min/g) compared to the cortex (1.8 +/- 0.9 ml/min/g) and the medulla (2.9 +/- 1.8 ml/min/g). Splanchnicotomy did not change blood flow in the resting state. Following hemorrhage, in innervated glands, medullary blood flow increased to 8.6 +/- 3.1 ml/min/g, whereas blood flow to other zones was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗
PubMed2004

Functionalisation of allergen-loaded microspheres with wheat germ agglutinin for targeting enterocytes.

In this study, we constructed particles applicable for oral immunotherapy of type I allergy by protecting allergens from digestion and supporting intestinal antigen uptake. Therefore, birch-pollen allergens were entrapped in poly(d,l-lactic-co-glycolic acid) microspheres by spray-drying rendering microspheres with a main population of 1-3microm. Microspheres were further coated with wheat germ agglutinin (WGA) to target enterocytes. Coating with WGA did not alter the surface characteristics of the microspheres as demonstrated in scanning electron microscopy. Binding of WGA was specific and could be inhibited by chitotriose to 14.7+/-6.9%. Comparable amounts of allergen were released from both particle-types with 46.3+/-1.7% and 44.5+/-2.6% during 21 days. Simulating gastric digestion in vitro, antigenicity of allergens entrapped in WGA-microspheres was preserved to 59.8+/-1.5% even after 2h. Feedings of BALB/c mice with WGA-microspheres induced higher levels of allergen-specific IgG-levels than gavages of uncoated microparticles or naked protein. Thus, we conclude that WGA-microspheres are suitable vehicles for oral delivery and mucosal targeting due to lectin-mediated bioadhesion.

Allergens↗
PubMed2004

Mechanistic evaluation of the glucose-induced reduction in initial burst release of octreotide acetate from poly(D,L-lactide-co-glycolide) microspheres.

One major obstacle for development of injectable biodegradable microspheres for controlled peptide and protein delivery is the high initial burst of drug release occurring over the first day of incubation. We describe here the significant reduction in initial burst release of a highly water-soluble model peptide, octreotide acetate, from poly(D,L-lactide-co-glycolide) microspheres by the co-encapsulation of a small amount of glucose (e.g., 0.2%w/w), i.e., from 30+/-20% burst - glucose to 8+/-3% + glucose (mean+/-SD, n=4). This reduction is unexpected since hydrophilic additives are known to increase porosity of microspheres, causing an increase in permeability to mass transport and a higher burst. Using the double emulsion-solvent evaporation method of encapsulation, the effect of glucose on initial burst in an acetate buffer pH 4 was found to depend on polymer concentration, discontinuous phase/continuous phase ratio, and glucose content. Extensive characterization studies were performed on two microsphere batches, +/-0.2% glucose, to elucidate the mechanism of this effect. However, no significant difference was observed with respect to specific surface area, porosity, internal and external morphology and drug distribution. Continuous monitoring of the first 24-h release of octreotide acetate from these two batches disclosed that even though their starting release rates were close, the microspheres + glucose exhibited a much lower release rate between 0.2 and 24h compared to those - glucose. The microspheres + glucose showed a denser periphery and a reduced water uptake at the end of 24-h release, indicating decreased permeability. However, this effect at times was offset as glucose content was further increased to 1%, causing an increase in surface area and porosity. In summary, we conclude that the effect of glucose on initial burst are determined by two factors: (1) increased initial burst due to increased osmotic pressure during encapsulation and drug release, and (2) decreased initial burst due to decreased permeability of microspheres.

Coated Materials, Biocompatible↗
PubMed2004

Effects of the controlled-released TGF-beta 1 from chitosan microspheres on chondrocytes cultured in a collagen/chitosan/glycosaminoglycan scaffold.

The objectives of this study were (1) to develop a three-dimensional collagen/chitosan/glycosaminoglycan (GAG) scaffold in combination with transforming growth factor-beta1 (TGF-beta 1)-loaded chitosan microspheres, and (2) to evaluate the effect of released TGF-beta 1 on the chondrogenic potential of rabbit chondrocytes in such scaffolds. TGF-beta 1 was loaded into chitosan microspheres using an emulsion-crosslinking method. The controlled release of TGF-beta 1, as measured by enzyme-linked immunosorbent assay (ELISA), was monitored for 7 days. The porous scaffolds containing collagen and chitosan were fabricated by using a freeze drying technique and crosslinked using 1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide (EDC) in the presence of chondroitin sulfate (CS), as a GAG component. The TGF-beta 1 microspheres were encapsulated into the scaffold at a concentration of 10 ng TGF-beta 1/scaffold and then chondrocytes were seeded in the scaffold and incubated in vitro for 3 weeks. Both proliferation rate and glycosaminoglycan (GAG) production were significantly higher in the TGF-beta 1 microsphere-incorporated scaffolds than in the control scaffolds without microspheres. Extracellular matrix staining by Safranin O and immunohistochemistry for type II collagen were elevated in the scaffold with TGF-beta 1 microspheres. These results suggest that TGF-beta 1 microspheres when incorporated into a scaffold have the potential to enhance cartilage formation.

Animals↗
PubMed2004

Fabrication and characterizations of a novel drug delivery device liposomes-in-microsphere (LIM).

In the present work, we developed a novel drug delivery system, liposomes-in-microsphere (LIM) of biodegradable polymers, which is conceived from a combination of the polymer- and the lipid-based delivery systems and can thus integrate the advantages and avoid the drawbacks of the two systems. Liposomes were encapsulated into microspheres of biodegradable polymers by the solvent extraction/evaporation process to form LIMs. The integrity of the liposomes was preserved by modifying the microencapsulation process and coating the liposomes with chitosan. We demonstrated by scanning electron microscopy, laser light scattering and fluorescence spectroscopy that the particle size and surface morphology of the polymeric microspheres did not change significantly with the liposomes encapsulated, the liposomes remained intact within the polymeric matrix of the microspheres, and the encapsulated liposomes could be released from the microspheres in a controlled manner at a nearly constant release rate after an initial off-release period. Decreasing the particle size of liposomes and increasing the pore size of the polymeric matrix shortened the initial off-release period and increased the liposome release rate. In conclusion, a novel drug delivery system, liposomes-in-microsphere, was successfully developed and characterized. The liposome release kinetics could be controlled by the composition and fabrication parameters of the liposomes and polymeric microspheres. Such a novel controlled release system may have potential to be applied for drug delivery and gene therapy.

Coated Materials, Biocompatible↗
PubMed2005

Poly(lactide-co-glycolide) microspheres as a moldable scaffold for cartilage tissue engineering.

This study demonstrates the use of biodegradable poly(lactide-co-glycolide) (PLG) microspheres as a moldable scaffold for cartilage tissue engineering. Chondrocytes were delivered to a cylindrical mold with or without PLG microspheres and cultured in vitro for up to 8 weeks. Cartilagenous tissue formed using chondrocytes and microspheres maintained thickness, shape, and chondrocyte collagen type II phenotype, as indicated by type II collagen staining. The presence of microspheres further enhanced total tissue mass and the amount of glycosaminoglycan that accumulated. Evaluation of microsphere composition demonstrated effects of polymer molecular weight, end group chemistry, and buffer inclusion on tissue-engineered cartilage growth. Higher molecular weight PLG resulted in a larger mass of cartilage-like tissue formed and a higher content of proteoglycans. Cartilage-like tissue formed using microspheres made from low molecular weight and free carboxylic acid end groups did not display increases in tissue mass, yet a modest increased proteoglycan accumulation was detected. Microspheres comprised of PLG with methyl ester end groups yielded a steady increase in tissue mass, with no real increase in matrix accumulation. The microencapsulation of Mg(OH)(2) had negative effects on tissue mass and matrix accumulation. The data herein reflect the potential utility of a moldable PLG-chondrocyte system for tissue-engineering applications.

Absorbable Implants↗
PubMed2005

A delivery strategy for rotenone microspheres in an animal model of Parkinson's disease.

In order to study the pathogenesis of Parkinson's disease (PD), and explore therapeutic drug or approaches, the accurate animal model of PD with inexpensive, biocompatible and convenient administration was necessary. The aim of the present work was to investigate a delivery strategy for rotenone microspheres in an animal model of PD. The rotenone microspheres were prepared by solvent evaporation technique. The rotenone microspheres showed high entrapment efficiency (97.4+/-2.2%) with particle size about 100 microm. In vitro release of rotenone microspheres demonstrated different profiles from medium with different pH or concentration of isopropyl alcohol. The most consistent medium with in vivo rotenone levels in rat plasma was PBS (pH 5.8) with 20% isopropyl alcohol, and the cumulated release amount of rotenone over 30 days was 95.4% in it. The rotenone microspheres (9 mg/kg) produced typical PD symptoms in rats, for example, the cataleptic behavior test demonstrated a obviously prolonged descent latency compared with control animals after administration, and the tyrosine hydroxylase (TH) immunohistochemistry tests showed typical histological evidence of selective degeneration of the nigrostriatal dopaminergic system (striatum and substantia nigra) in rotenone microspheres-treated rats. In addition, this delivery system for rotenone model showed many noticeable advantages such as inexpensive, biocompatible and expedient administration by direct subcutaneous injection. This information suggested that rotenone microspheres as a delivery strategy for setting up an ideal animal model of PD was feasible.

Animals↗
PubMed2005

Controlled release of bioactive TGF-beta 1 from microspheres embedded within biodegradable hydrogels.

Transforming growth factor-beta1 (TGF-beta1) is of great relevance to cartilage development and regeneration. A delivery system for controlled release of growth factors such as TGF-beta1 may be therapeutic for cartilage repair. We have encapsulated TGF-beta1 into poly(DL-lactide-co-glycolide) (PLGA) microspheres, and subsequently incorporated the microspheres into biodegradable hydrogels. The hydrogels are poly(ethylene glycol) based, and the degradation rate of the hydrogels is controlled by the non-toxic cross-linking reagent, genipin. Release kinetics of TGF-beta1 were assessed using ELISA and the bioactivity of the released TGF-beta1 was evaluated using a mink lung cell growth inhibition assay. The controlled release of TGF-beta1 encapsulated within microspheres embedded in scaffolds is better controlled when compared to delivery from microspheres alone. ELISA results indicated that TGF-beta1 was released over 21 days from the delivery system, and the burst release was decreased when the microspheres were embedded in the hydrogels. The concentration of TGF-beta1 released from the gels can be controlled by both the mass of microspheres embedded in the gel, and by the concentration of genipin. Additionally, the scaffold permits containment and conformation of the spheres to the defect shape. Based on these in vitro observations, we predict that we can develop a microsphere-loaded hydrogel for controlled release of TGF-beta1 to a cartilage wound site.

Absorbable Implants↗