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PubMed1998

Gelatin/chondroitin 6-sulfate microspheres for the delivery of therapeutic proteins to the joint.

OBJECTIVE: To develop a biodegradable, inflammation-responsive microsphere system for the intraarticular delivery of therapeutic proteins. METHODS: Microspheres were synthesized by complex coacervation. Radiolabeled protein release and microsphere degradation were assessed by exposing the microspheres to human synovial fluids (SF) and recombinant gelatinase. Microsphere degradation was confirmed by scanning electron microscopy (SEM). Microsphere biocompatibility was evaluated in vitro by incubating the microspheres with human synoviocytes, and in vivo by injection into mouse joints. RESULTS: Optimal microsphere formulation was developed. Significant (up to 100%) release of encapsulated protein occurred in SF samples with measurable metalloprotease activity, while release was minimal in SF with negligible activity. Dissolution of microspheres exposed to gelatinase was confirmed by SEM. Microspheres were found to be noncytotoxic in vitro, and noninflammatory in vivo. CONCLUSION: Microsphere encapsulation is an inflammation-responsive and biocompatible system of protein delivery that holds promise for use in the delivery of therapeutic proteins to the joint.

Arthritis, Rheumatoid↗
PubMed2001

Limited adhesion of biodegradable microspheres to E- and P-selectin under flow.

In a variety of disease settings the expression of the endothelial selectins E- and P-selectin appears to be increased. This feature makes these molecules attractive targets around which to design directed drug-delivery schemes. One possible approach for achieving such delivery is to use polymeric biodegradable microspheres bearing a humanized monoclonal antibody (MAb) for E- and P-selectin, MAb HuEP5C7.g2. Perhaps the simplest technique for "coupling" HuEP5C7.g2 to the microspheres is via nonspecific adsorption. Previous studies suggest, however, that the adsorption of proteins onto microspheres fabricated in the presence of a stabilizer such as poly(vinyl alcohol) (PVA) is limited. It is unclear to what extent this limited level of adsorbed HuEP5C7.g2 would be able to support adhesion to E- and P-selectin under flow conditions. To explore this issue, we prepared microspheres from the biodegradable polymer, poly(epsilon-caprolactone) (PCL), using a single emulsion process and PVA as a stabilizer. We then incubated the PCL microspheres with HuEP5C7.g2 and studied the adhesion of the resulting HuEP5C7.g2 microspheres to E- and P-selectin under in vitro flow conditions. We found that the HuEP5C7.g2 PCL microspheres exhibit specific adhesion to Chinese hamster ovary cells stably expressing P-selectin (CHO-P) and 4-h IL-1beta-activated human umbilical vein endothelial cells (HUVEC). In contrast, HuEP5C7.g2 PCL microspheres exhibit little adhesion to parental CHO cells or unactivated HUVEC. The attachment efficiency to the selectin substrates was quite low, with appreciable attachment occurring only at low shear (0.3 dyn/cm(2)). Other supporting data strongly suggest that the limited attachment efficiency is due to a low level of HuEP5C7.g2 adsorbed to the PCL microspheres. Although the attachment was limited, a significant percentage of the HuEP5C7.g2 PCL microspheres were able to remain adherent at relatively high shear (8 dyn/cm(2)). Combined, our data suggest that HuEP5C7.g2 PCL microspheres exhibit selective limited adhesion to cellular substrate expressing E- and P-selectin.

Adsorption↗
PubMedDate not supplied

Characterization of the in vitro adherence behavior of ultrasound responsive double-shelled microspheres targeted to cellular adhesion molecules.

We have developed novel adhesion molecule-targeted double-shelled microspheres which encapsulate nitrogen. We report in vitro targeting studies utilizing these microspheres conjugated to target-specific antibodies directed towards ICAM-1 and VCAM-1. In static adherence experiments, the adherence patterns of microspheres conjugated to three different monoclonal antibodies (two targeted to ICAM-1 and one to VCAM-1) to their target surfaces were very different. Maximum microsphere adherence at the lowest target and/or ligand densities was observed with the VCAM-1 system. Differences in target-specific adherence were also observed between anti-ICAM-1 and anti-VCAM-1 microsphere conjugates in flow adherence studies. Equilibrium binding studies of the target proteins in solution to the microsphere-bound ligands showed that the affinity constants of two microsphere-bound monoclonal antibodies for their target proteins are similar. Thus, ligand-target affinity is not the only determinant of microsphere adherence to the target surface in our systems. Shear stress was found to have an effect on the mean diameter of adhered microspheres; a decrease in the mean diameter with increasing shear was observed. The magnitude of this effect was dependent on both microsphere-bound ligand and target surface densities, with a more pronounced change at lower densities. Adhered microspheres were readily detectable using ultrasound at the lowest tested surface density of 40 mm(-2).

Adhesiveness↗
PubMed2006

Characterization of Acanthamoeba-microsphere association by multiparameter flow cytometry and confocal microscopy.

BACKGROUND: Acanthamoebae, in common with other protozoa, readily endocytose particulate material, which in turn may lead to the spread of infectious disease. METHODS: Evaluation and quantification of plain and carboxylate FITC-microsphere association with acanthamoebal trophzoites was undertaken using a combination of flow cytometry and confocal microscopy. Trophozoites from strains and species of Acanthamoeba were exposed to plain and carboxylate FITC-microspheres. Microsphere size and aspects such as trophozoite starvation, maturity, and exposure to metabolic inhibitors were assessed. RESULTS: All species and strains of Acanthamoeba readily endocytosed plain and carboxylate microspheres. Starving trophozoites significantly increased binding and potential ingestion of microspheres, whereas trophozoites of increasing maturity lost such abilities. Trophozoites showed a significant preference for 2.0- and 3.0-microm-diameter microspheres when compared with other sizes, which in turn could occupy much of the cytoplasm. The physiological inhibitors sodium azide, 2,4-dinitrophenol, and cytochalasin B reduced microsphere association with trophozoites; however, some microspheres still bound and associated with trophozoites after inhibitor exposure, a manifestation of both active and inactive agent involvement in microsphere endocytosis. CONCLUSIONS: Even though the origins of microsphere binding by acanthamoebal trophozoite remains shrouded, the combination of flow cytometry and confocal microscopy supported synergistic quantification and qualification of trophozoite-microsphere endocytosis.

Acanthamoeba↗
PubMed2002

In vivo evaluation of a dexamethasone/PLGA microsphere system designed to suppress the inflammatory tissue response to implantable medical devices.

The purpose of this research effort was to evaluate in vivo a newly developed dexamethasone/PLGA microsphere system designed to suppress the inflammatory tissue response to an implanted device, in this case a biosensor. The microspheres were prepared using an oil/water (O/W) emulsion technique. The microsphere system was composed of drug-loaded microspheres (including newly formulated and predegraded microspheres) and free dexamethasone. The combination of the drug and drug-loaded microspheres provided burst release of dexamethasone followed by continuous release from days 2-14. Continuous release to at least 30 days was achieved by mixing predegraded and newly formulated microspheres. The ability of our mixed microsphere system to control tissue reactions to an implant then was tested in vivo using cotton thread sutures to induce inflammation subcutaneously in Sprague-Dawley rats. Two different in vivo studies were performed, the first to find the dosage level of dexamethasone that effectively would suppress the acute inflammatory reaction and the second to show how effective the dexamethasone delivered by PLGA microspheres was in suppressing chronic inflammatory response to an implant. The first in vivo study showed that 0.1 to 0.8 mg of dexamethasone at the site minimized the acute inflammatory reaction. The second in vivo study showed that our mixed microsphere system suppressed the inflammatory response to an implanted suture for at least 1 month. This study has proven the viability of microsphere delivery of an anti-inflammatory to control the inflammatory reaction at an implant site.

Animals↗
PubMed2004

Development of biodegradable poly(propylene fumarate)/poly(lactic-co-glycolic acid) blend microspheres. I. Preparation and characterization.

We developed poly(propylene fumarate)/poly(lactic-co-glycolic acid) (PPF/PLGA) blend microspheres and investigated the effects of various processing parameters on the characteristics of these microspheres. The advantage of these blend microspheres is that the carbon-carbon double bonds along the PPF backbone could be used for their immobilization in a PPF scaffold. Microspheres containing the model drug Texas red dextran were fabricated using a double emulsion-solvent extraction technique. The effects of the following six processing parameters on the microsphere characteristics were investigated: PPF/PLGA ratio, polymer viscosity, vortex speed during emulsification, amount of internal aqueous phase, use of poly(vinyl alcohol) (PVA) in the internal aqueous phase, and PVA concentration in the external aqueous phase. Our results showed that the microsphere surface morphology was affected most by the viscosity of the polymer solution. Microspheres fabricated with a kinematic viscosity of 39 centistokes had a smooth, nonporous surface. In most microsphere formulations, the model drug was dispersed uniformly in the polymer matrix. For all fabricated formulations, the average microsphere diameter ranged between 19.0 and 76.9 microm. The external PVA concentration and vortex speed had most effect on the size distribution. Entrapment efficiencies varied from 60 to 98% and were most affected by the amount of internal aqueous phase, vortex speed, and polymer viscosity. Overall, we demonstrated the ability to fabricate PPF/PLGA blend microspheres with similar surface morphology, entrapment efficiency, and size distribution as conventional PLGA microspheres.

Biocompatible Materials↗
PubMed2005

Skin regeneration using keratinocytes and dermal fibroblasts cultured on biodegradable microspherical polymer scaffolds.

Bioartificial skin sheet grafts have been utilized to treat large burns and chronic ulcers. However, the trypsinization step to harvest cultured skin grafts from culture dishes damages the cells by breaking the anchoring proteins and lowers their uptake ratio after transplantation. In addition, epidermal sheet grafts require a long fabrication period. To overcome these limitations, we utilized biodegradable poly(lactide-co-glycolide) (PLGA) microspheres as both cell culture matrix and transplantation vehicle of skin cells for skin regeneration in this study. This method could avoid the trypsinization step and have a relatively short preparation period. Human keratinocytes and dermal fibroblasts cultured on PLGA microspheres in spinner flasks proliferated by 3.0-fold and 9.4-fold, respectively, after 10 days. When both types of cells cultured on PLGA microspheres were reinoculated onto culture dishes, the cells migrated from the PLGA microspheres to the culture dish surface, grew, and formed a confluent cell layer within 5 days, showing the growth and migration abilities of the cells cultured on PLGA microspheres. Full-thickness skin wounds created on the back of athymic mice were either treated with transplantation of keratinocytes and dermal fibroblasts cultured on microspheres (cell-transplanted group), treated with PLGA microspheres alone (microsphere-implanted group), or covered with dressing materials without treatment (untreated group). Three weeks after the treatments, differentiated epithelium that stained positively for cytokeratin, a marker of epidermis, was observed in the cell-transplanted group, while the microsphere-implanted group and untreated group showed incomplete reepithelialization. Dermal regeneration with positive staining for vimentin, a marker of dermal fibroblast, was observed in the cell-transplanted group. Regenerated dermis with positive staining for vimentin was partly observed in the microsphere-implanted group and untreated group. These results suggest that transplantation of keratinocytes and dermal fibroblasts cultured on PLGA microspheres could be potentially useful as an alternative to bioartificial skin grafts for the treatment of skin wounds.

Animals↗
PubMed1986

Measurement of active phagocytosis by polymorphonuclear leukocytes by fluorescence liberation from phagocytized microspheres.

Phagocytosis by polymorphonuclear leukocytes (PMN) was determined by a newly developed technique based on measurement of liberation of a fluorescence substance from PMN phagosomes; 4-methylumbelliferyl-beta-D-glucuronide (4MUGL), which is a substrate of beta-glucuronidase in lysosome, was conjugated with a microsphere, and 4-methylumbelliferone (4MU) liberated from phagocytized 4MUGL-microspheres was measured. The microspheres were composed of glyceryl-methacrylate having a diameter of 2.0 micron. Liberating activity of six kinds of 4MUGL-microspheres containing various amounts of amino and carboxyl groups was compared. Among these six kinds of 4MUGL-microspheres, four kinds showed activity similar to that of morphological phagocytosis. These four kinds of 4MUGL-microspheres liberated 4MU into the extracellular fluid from PMN during phagocytosis. Furthermore, they were recognized as a substrate of purified beta-glucuronidase. 4MUGL-MS610 showed the highest liberating activity among the four kinds of microspheres. Optimal conditions for phagocytosis by PMN were determined using 4MUGL-MS610. Total liberation of 4MU from the microspheres increased almost linearly with incubation time with PMN from 0 to 60 min and was linear with 4MUGL-MS in concentrations up to 4 X 10(8) microspheres/ml. This liberation was parallel to phagocytosis in a dose-dependent fashion. During 10-min incubation 20.4% of 4MU was liberated from 4MUGL-microspheres with phagocytosis. Seventy-five percent of the liberated 4MU was distributed in the extracellular fluid. 4MU distributed in the extracellular fluid was not attributable to hydrolysis of unphagocytized microspheres by beta-glucuronidase extracellularly leaked from PMN by phagocytosis. Also phagocytized 4MUGL-MS610 by PMN was observed by scanning electron microscopy. These results indicate that 4MU was liberated from 4MUGL-MS by hydrolysis due to beta-glucuronidase released into phagosomes with phagocytosis by PMN. Sensitivity of this assay was limited to about 50 pmol/ml, being less than 0.5-1 microsphere phagocytized into one cell.

Cell Membrane Permeability↗
PubMed1991

Polymer-coated albumin microspheres as carriers for intravascular tumour targeting of cisplatin.

We used a poly-lactide-co-glycolide polymer (PLAGA 50:50) to formulate cisplatin (cDDP) into microspheres designed for intravascular administration. Two systems were developed. PLAGA-coated albumin microspheres and microspheres consisting of PLAGA only. PLAGA-coated microspheres displayed a mean diameter of 31.8 +/- 0.9 microns and a payload of 7.5% cDDP (w/w). Solid PLAGA microspheres exhibited a mean diameter of 19.4 +/- 0.6 microns and a payload of 20% cDDP. Release characteristics and in vitro effects on L1210 leukemia and B16 melanoma cell lines were investigated. Both types of microsphere overcame the initial rapid release of cDDP (burst effect), and PLAGA-coated albumin microspheres also showed a lag phase of approximately 30 min before cDDP release began. PLAGA-coated albumin microspheres released most of their payload through diffusion, and the coating eventually cracked after 7 days' incubation in saline supplemented with 0.1% Tween at 37 degrees C, enabling the release of any cDDP remaining. Effects of platinum, pre-released from PLAGA-coated albumin microspheres on the in vitro growth of L1210 cells were comparable with those of standard formulations (dissolved) of cDDP. Material released from non-drug-loaded PLAGA microspheres had no effect on L1210 cell growth, suggesting the absence of cytotoxic compounds in the matrix. The colony-forming ability of B16 cells was also equally inhibited by standard cDDP and pre-released drug. These studies show that formulation of cDDP in PLAGA-based microspheres prevents the rapid burst effect of cDDP seen in previous preparations and offers an improved system of administration for hepatic artery infusion or adjuvant therapy, enabling better clinical handling and the promise of a higher ratio of tumour tissue to normal tissue.

Animals↗
PubMedDate not supplied

Validation studies for the use of the microsphere method in cats and young minipigs.

Radioactive microspheres are suitable for measuring cardiac output, its distribution and organ blood flow if certain criteria are met. Cardiac output may be determined with the reference flow method if microspheres do not recirculate. In case 10 micron microspheres were extracted completely by the lungs. The use of microspheres for the determination of cardiac output is therefore not limited by recirculation of microspheres down to this size. Under baseline conditions we found no preferential streaming with 50 micron spheres in young minipigs and with 25 and 15 micron spheres in cats At high cardiac output values induced by the administration of 0.4 mg/kg of Dihydralazine in cats, 25 micron but not 15 micron microspheres showed a small, non significant tendency to stream preferentially into the upper body. Thus, under rapid flow conditions 15 micron microspheres may be preferable to larger ones from the rheological point of view. Under baseline conditions the distribution of cardiac output to a wide range of organs was very similar when comparing 25 and 15 micron microspheres in cats and 50 and 15 micron microspheres in minipigs, whereas 10 micron microspheres were poorly extracted by most organ in cats. 15 micron microspheres were found to be suitable for the determination of cardiac output and its distribution in both species provided that bronchial and arteriovenous shunt flows can be neglected.

Animals↗
PubMedDate not supplied

Catecholamine-containing biodegradable microsphere implants as a novel approach in the treatment of CNS neurodegenerative disease. A review of experimental studies in DA-lesioned rats.

Biodegradable controlled-release microsphere systems made with the biocompatible biodegradable polyester excipient poly(DL-lactide-co-glycolide) constitute an exciting new technology for drug delivery to the central nervous system (CNS). Implantable controlled-release microspheres containing dopamine (DA) or norepinephrine (NE) provide a novel means to compare DA- or NE -induced restitution of function in unilateral 6-hydroxydopamine lesioned rats. A suspension of 3 microL of DA- or NE-containing microspheres or empty microspheres was implanted in 2 sites of the DA denervated striatum of rats previously unilaterally lesioned with 6-hydroxydopamine. Contralateral-rotational behavior induced by apomorphine was used as an index of lesion success and, following implantation of the microspheres, also as an index of functional recovery. Interestingly, both DA- and NE-microsphere-implanted rats displayed a 30-50% reduction in the number of apomorphine-induced rotations up to 8 wk postimplantation. Rats implanted with empty microspheres did not demonstrate significant changes in contralateral rotational behavior. Behavioral studies following implantation of a mixture of DA and NE microspheres revealed an 80% decrease in the number of apomorphine induced rotations up to 4 wk. On conclusion of the studies, immunocytochemical examination revealed growth of DA and tyrosine hydroxylase immunoreactive fibers in the striatum of DA and NE microsphere-implanted rats. Functional behavior appeared to correlate with the degree of fiber growth. Preliminary electron microscopic studies showed signs of axonal sprouting in the vicinity of the implanted microspheres. No growth was noted in rats implanted with empty microspheres. This report reviews the abilities of both microencapsulated NE and DA to assure functional recovery and to promote DA fiber (re)growth in parkinsonian rats. This novel means to deliver these substances to the central nervous system could be of therapeutic usefulness in Parkinson's disease.

Animals↗
PubMed2006

Protocell-like microspheres from thermal polyaspartic acid.

One of the most prominent amino acids to appear in monomer-generating origin-of-life experiments is aspartic acid. Hugo Schiff found in 1897 that aspartic acid polymerizes when heated to form polyaspartylimide which hydrolyzes in basic aqueous solution to form thermal polyaspartic acid which is a branched polypeptide. We recently reported at the ISSOL 2005 Conference that commercially made thermal polyaspartic acid forms microspheres when heated in boiling water and allowed to cool. In a new experiment we heated aspartic acid at 180 degrees C for up to 100 h to form thermal polyaspartylimide which when heated in boiling water without addition of base hydrolyzed to form thermal polyaspartic acid which upon cooling formed microspheres. Thermal polyaspartic acid microspheres appear protocell-like in the sense of being prebiotically plausible lattices or containers that could eventually have been filled with just the right additions of primordial proteins, nucleic acids, lipids, and metabolites so as to constitute protocells capable of undergoing further chemical and biological evolution. Thermal polyaspartic acid microspheres are extremely simple models of protocells that are more amenable to precise quantitative experimental investigation than the proteinoid microspheres of Sidney W. Fox. We present here scanning electron microscope images of such thermal polyaspartic acid microspheres. Figure 1 shows thermal polyaspartic acid microspheres from L: -aspartic acid heated at 180 degrees C for 50 h, at a magnification of 3,500x. Figure 2 shows thermal polyaspartic acid microspheres from the same sample at a magnification of 7,000x. The thermal polyaspartic acid microspheres have a diameter of approximately 1 mum These images were viewed with a Hitachi S2460N scanning electron microscope at 20 kV acceleration voltage. Figure 1 Thermal polyaspartic acid microspheres from L: -aspartic acid heated at 180 degrees C for 50 h, at a magnification of 3,500x. Figure 2 Thermal polyaspartic acid microspheres from L: -aspartic acid heated at 180 degrees C for 50 h, at a magnification of 7,000x.

Evolution, Chemical↗
PubMed2006

Heparin immobilized porous PLGA microspheres for angiogenic growth factor delivery.

PURPOSE: Heparin immobilized porous poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres were prepared for sustained release of basic fibroblast growth factor (bFGF) to induce angiogenesis. MATERIALS AND METHODS: Porous PLGA microspheres having primary amine groups on the surface were prepared using an oil-in-water (O/W) single emulsion method using Pluronic F-127 as an extractable porogen. Heparin was surface immobilized via covalent conjugation. bFGF was loaded into the heparin functionalized (PLGA-heparin) microspheres by a simple dipping method. The bFGF loaded PLGA-heparin microspheres were tested for in vitro release and in vivo angiogenic activity. RESULTS: PLGA microspheres with an open-porous structure were formed. The amount of conjugated amine group onto the microspheres was 1.93+/-0.01 nmol/mg-microspheres, while the amount of heparin was 95.8 pmol/mg-microspheres. PLGA-heparin microspheres released out bFGF in a more sustained manner with a smaller extent of initial burst than PLGA microspheres, indicating that surface immobilized heparin controlled the release rate of bFGF. Subcutaneous implantation of bFGF loaded PLGA-heparin microspheres in mice significantly induced the formation of new vascular microvessels. CONCLUSIONS: PLGA microspheres with an open porous structure allowed significant amount of heparin immobilization and bFGF loading. bFGF loaded PLGA-HP microspheres showed sustained release profiles of bFGF in vitro, demonstrating reversible and specific binding of bFGF to immobilized heparin. They also induced local angiogenesis in vivo in an animal model.

Amines↗
PubMed1993

An investigation of the filtration capacity and the fate of large filtered sterically-stabilized microspheres in rat spleen.

Earlier we demonstrated that coating the surface of large model polystyrene microspheres (220-300 nm in diameter) with the block co-polymer polyoxyethylene/polyoxypropylene poloxamine-908 triggered their accumulation in the rat spleen by a filtration mechanism following intravenous administration [Moghimi, S.M., Porter, C.J.H., Muir, I.S., Illum, L. and Davis, S.S. (1991) Biochem. Biophys. Res. Commun. 177, 861-866]. We have now demonstrated that the macrophages of the red-pulp can effectively phagocytose the filtered poloxamine-coated microspheres 24 h post-administration. This could be the result of either the loss of the surface absorbed poloxamine, and hence the steric barrier, or 'neutralization' of the effect of the anti-phagocytic material poloxamine-908 within the spleen. In order to assess the capacity of the splenic uptake mechanism(s), rats received daily intravenous administration of unlabelled large poloxamine-908 coated microspheres (220 nm in diameter) for 4 days (daily-dosed animals). Control rats received daily saline injection. On the fifth day all animals were injected with either radiolabelled large (220 nm) or small (60 nm in diameter) poloxamine-coated polystyrene microspheres. Predosing dramatically decreased the splenic uptake of the large test microspheres but had no effect on the uptake of small test-microspheres. The failure of the spleen to take up particles was not associated with an increased circulatory level of microspheres. Surprisingly, both small and large coated microspheres were sequestered by the liver and accumulated in Kupffer cells as demonstrated by electron microscopy in daily-dosed animals. In contrast, the liver of control animals did not effectively sequester poloxamine-coated microspheres. Here, microspheres predominantly remained in blood. Sequestration of poloxamine-908 coated microspheres by Kupffer cells of the liver of daily-dosed animals was the result of opsonization by an unknown serum component.

Animals↗
PubMed2006

Degradation behavior of dextran hydrogels composed of positively and negatively charged microspheres.

This paper reports on the degradation behavior of in situ gelling hydrogel matrices composed of positively and negatively charged dextran microspheres. Rheological analysis showed that, once the individual microspheres started to degrade, the hydrogel changed from a mainly elastic to a viscoelastic network. It was shown with gels composed of equal amounts of cationic and anionic microspheres, that both a higher crosslink density of the particles and a decrease in water content of the hydrogels resulted in a slower degradation, ranging from 65 to 140 days. Dispersions containing cationic, neutral or anionic microspheres completely degraded within 30, 55 or 120 days, respectively. The microspheres were loaded with rhodamine-B-dextran and degradation was studied with confocal microscopy and fluorescence spectroscopy. After a lag time of 3 days rhodamine-B-dextran started to release from the positive microspheres with a 50% release after 16 days. In contrast, release of rhodamine-B-dextran from the negative microspheres started after 10 days with a 50% release after 36 days. The faster degradation of the positively charged microspheres as compared to the negatively charged microspheres is attributed to stabilization of the transition state in the hydrolysis process by the protonated tertiary amine groups present in the cationic microspheres. On the other hand, the presence of negatively charged groups causes repulsion of hydroxyl anions resulting in a slower degradation. Combining the oppositely charged microspheres in different ratios makes it possible to tailor the network properties and the degradation behavior of these hydrogels, making them suitable for various applications in drug delivery and tissue engineering.

Anions↗
PubMed2006

Modification of poly(glycidyl methacrylate-divinylbenzene) porous microspheres with polyethylene glycol and their adsorption property of protein.

Rigid porous poly(glycidyl methacrylate-divinylbenzene) (P(GMA-DVB)) microspheres were synthesized through suspension polymerization with a mixture of isooctane and 4-methyl-2-pentonal as the porogen. The microspheres were intended to use as column packing materials for protein separation. However, irreversible adsorption of protein was found on the polymer microsphere. To circumvent the problem, polyethylene glycol (PEG) was coupled to the microspheres. The coupling reaction took place between the hydroxyl group of PEG and the epoxy group of the P(GMA-DVB) solid medium in the presence of boron trifluoride. The density of PEG immobilized onto the P(GMA-DVB) can be determined easily by saponification of modified microsphere firstly and then titration of glycerol-PEG. The effect of the cross-linker content of microsphere on the density of PEG immobilization was investigated. Molecular weight of PEG was found to influence the PEG-immobilization density, which subsequently affects the hydrophilicity of the modified P(GMA-DVB). Bovine serum albumin (BSA) and trypsin were used as model proteins to examine the adsorption and desorption properties of the modified P(GMA-DVB) microspheres. The results demonstrated that P(GMA-DVB) porous microsphere with 20% DVB and modified with PEG4000 showed excellent adsorption and desorption properties. Adsorption capacity of BSA on the modified microsphere attained to 51.6 mg/g microsphere, and BSA mass recovery and trypsin activity recovery was up to 97.6% and 98.7%, respectively. The modified microsphere was demonstrated to be a promising hydrophobic interaction chromatography material for purification of protein.

Adsorption↗
PubMed2004

Pathologic response and microdosimetry of (90)Y microspheres in man: review of four explanted whole livers.

INTRODUCTION: Radioactive microsphere (90)Y therapy is increasingly used for primary and metastatic solid tumors in the liver. We present an analysis of 4 explanted livers previously treated with (90)Y microsphere agents (glass or resin). One tumor nodule was analyzed with submillimeter three-dimensional microdosimetry. METHODS AND MATERIALS: Four patients received hepatic artery delivery of (90)Y microspheres for unresectable hepatocellular and colon cancers. Whole livers were explanted as part of lifesaving cadaveric transplant in 2 patients with hepatoma. These patients had received glass microspheres as a procedural bridge to transplant. Autopsy was performed on 2 patients with colon cancer who died of progressive metastatic disease and who had been treated with resin microspheres. Complete pathologic review was performed on each whole liver, including estimation of the response of the tumor to therapy, distribution of microspheres in the tumor and normal liver tissues, and normal-tissue radiation response. A biopsy taken from the edge of a tumor nodule was sectioned serially for three-dimensional radiation dosimetry analyses. Three-dimensional microsphere coordinates within the biopsy specimen were used to calculate dosage using a three-dimensional dose kernel. Isodose coverage of tumor and normal liver areas and total dose delivered were determined. RESULTS: Preferential and heterogeneous deposition of microspheres was noted at the edge of tumor nodules compared with the center portion of the tumor or normal liver parenchyma. Both glass and resin microspheres delivered high cumulative doses to the tumor, which varied from 100 Gy to more than 3000 Gy. No veno-occlusive disease or widespread radiation hepatitis was seen. CONCLUSION: Microsphere ((90)Y) therapy delivers high numbers of spheres with resulting high total doses of radiation, preferentially in the periphery of tumors. Normal liver parenchyma showed little radiation effect away from the tumors. Heterogeneous high-dose regions in the tumor were produced by both glass and resin microspheres.

Algorithms↗
PubMed2004

Microwave-treated gelatin microspheres as drug delivery system.

The crosslinking process of natural macromolecules with microwave energy should have the potentiality to overcome the problems due to the toxicity of the residuals of chemical crosslinking agents and moreover of the "in vivo" biodegradation products of the chemical crosslinked macromolecule. To evaluate the effective crosslinking of the gelatin forming the microspheres, the water-soluble fraction at 37 degrees C, the water absorption capability, the free amino and free carboxylic acid groups of the gelatin were determined. The structural change in the gelatin microspheres has been detected by the porosity studies. Moreover, both the "in vitro" biodegradability and the biocompatibility of the gelatin microspheres microwave-treated after a subcutaneous injection into female albino guinea pigs were tested. As the results suggest only the gelatin microspheres microwave-treated for 10 min at an inlet temperature of 250 degrees C could have been modified by the crosslink formation among the macromolecular chains. The gelatin microspheres treated with the microwave energy were very well biodegraded as indicated both by the "in vitro" enzymatic degradation studies and mainly by the histopathological examination. This latter study has also demonstrated the biocompatibility of the gelatin microspheres crosslinked with the microwave energy. In order to evaluate the feasibility of the microwave crosslinking process for pharmaceutical applications, both the drug loading and the drug release processes were evaluated using diclofenac as drug model, either as acidic form or as sodium salt. The microspheres were swollen in aqueous solution of diclofenac sodium salt, followed by a washing procedure with cool water to maintain the sodium salt into the microspheres or with pH 1.5 HCl to induce the diclofenac precipitation. To increase the amount of diclofenac acid form in the microspheres, the procedure was repeated three times washing with pH 1.5 HCl after each swelling process. Both the X-ray diffractometry and thermal analysis investigations showed a different physical state of the two drug forms in the microspheres, i.e. the amorphous state of the sodium salt and the crystalline state of the acidic form. According to the experimental results, the drug is released from gelatin microspheres according to the drug loading and the drug solubility.

Animals↗