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Biomedical subjects

Abraham J Domb

Publications and source records attributed to Abraham J Domb.

At least 19 recordsLinked to original sources
PubMed2006

Biodegradable injectable in situ depot-forming drug delivery systems.

The scope of drug-delivery systems has expanded significantly in recent years providing new ways to deliver life saving therapeutics to patients. The development of new injectable drug-delivery systems has provided new vistas and opened up unexplored horizons in the field of science, particularly in controlled drug delivery since these systems possess unique advantages over traditional ones, which include ease of application, and localized and prolonged drug delivery. In the past few years, an increasing number of such systems has been reported in the literature for various biomedical applications, including drug delivery, cell encapsulation, and tissue repair. These are injectable fluids that can be introduced into the body in a minimally invasive manner prior to solidifying or gelling within the desired site. For this purpose both natural (chitosan, alginates) as well as synthetic polymers (PEGylated polyesters, ricinoleic acid-based polymers) have been utilized. These systems have been explored widely for the delivery of various therapeutic agents ranging for anti-neoplastic agents like paclitaxel to proteins and peptides such as insulin, almost covering every segment of the pharmaceutical field. This manuscript focuses on the recent advancements in the area of in situ forming biodegradable polymeric drug-delivery systems.

Antineoplastic Agents, Phytogenic↗
PubMed2006

PEG-PLA block copolymer as potential drug carrier: preparation and characterization.

Diblock and multiblock copolymers composed of a poly(D,L-lactide) (PLA) or poly(trimethylene carbonate) (PTMC) core with a hydrophilic chain of poly(ethylene glycol) (PEG) were prepared. These copolymers, in which the core is connected to PEG through a polyfunctional molecule such as citric, mucic, or tartaric acid, may be used to form nanoparticles for drug delivery applications. Branched copolymers were prepared by direct amidation between the polyfunctional acid and methoxy PEGamine, followed by ring-opening polymerization of lactide or trimethyl carbonate to form the PLA and PTMC block copolymers. In addition, a complex multiblock copolymer of biotin-PEG-poly[lactic-co-(glycolic acid)] (PLGA) for application in an avidin-biotin system was prepared for possible design of nanospheres with targeting properties. Studies of drug release from polymeric systems containing multiblock copolymers and studies of polymer degradation were also performed.

Biocompatible Materials↗
PubMed2006

Long acting local anesthetic-polymer formulation to prolong the effect of analgesia.

Prolonged postoperative analgesia cannot be achieved using single injections of local anesthetic solutions. The study objective was to evaluate the efficacy and toxicity of a new formulation of bupivacaine loaded in an injectable fatty acid based biodegradable polymer poly(sebacic-co-ricinoleic acid) for producing motor and sensory block when injected near the sciatic nerve. Bupivacaine was dissolved in poly(fatty ester-anhydride) paste and tested for drug release in vitro and in vivo after injection in mice. The efficacy and toxicity of the polymer-drug combination was determined by injecting the polymer formulation near the sciatic nerve of mice and measure the sensory and motor nerve blockade for 48 h, while monitoring the animal general health and the injection site. Seventy percent of the incorporated drug was released during 1 week in vitro. Single injection of 10% bupivacaine in the polymer caused motor and sensory block that lasted 30 h. Microscopic examination of the injection sites revealed only mild infiltration in three of eight examined tissues with no pathological findings for internal organs were found. In conclusion the polymer poly(sebacic-co-ricinoleic acid) is a safe carrier for prolonged activity of bupivacaine.

Anesthetics, Local↗
PubMed2006

Gentamicin extended release from an injectable polymeric implant.

Gentamicin sulfate, a potent antibiotic agent, is currently used for treatment of osteomyelitis mainly by intravenous injection with a long-term indwelling catheter, local implant of antibiotic containing polymethylmethacrylate beads or calcium phosphate (bone cements). Searching for more effective treatments, this study was designed to evaluate biodegradable injectable gelling polymeric devices for the controlled release of gentamicin sulfate in the treatment of invasive bacterial infections. Gentamicin sulfate was incorporated in poly(sebacic-co-ricinoleic-ester-anhydride P(SA-RA)) paste at 10-20% w/w and its release in buffer solution was monitored. The in vitro activity of the formulations was determined against Staphylococcus aureus. A constant release of active gentamicin for over 28 days was found. The stability of the formulation was determined under different storage conditions. The formulations were stable to sterilization by gamma-irradiation and long term storage under freezing. The toxicity of the polymer and the formulations with gentamicin was examined by subcutaneous injection to rats. Four weeks after implantation, histopathological examination of the tissues surrounding the implant showed no inflammation. A preliminary study revealed positive effect of gentamicin containing P(SA-RA) on established osteomyelitis in a rat model. In conclusion this study suggests that poly(sebacic-co-ricinoleic-ester-anhydride) 3:7 loaded with 10%-20% gentamicin sulfate, might be used as an injectable biodegradable device for in situ treatment of osteomyelitis induced by S. aureus.

Animals↗
PubMed2006

An in vitro quantitative antibacterial analysis of amalgam and composite resins.

OBJECTIVES: Antibacterial properties of restorative dental materials such as amalgam and composite resins may improve the restorative treatment outcome. This study evaluates the antibacterial properties of three composite resins: Z250, Tetric Ceram, P60 and a dental amalgam in vitro. METHODS: Streptococcus mutans and Actinomyces viscosus served as test microorganisms. Three quantitative microtiter spectrophotometric assays were used to evaluate the effect of the restorative materials on: (i) early-stage biofilm using a direct contact test (DCT); (ii) planktonic bacterial growth; (iii) bacterial growth in the materials' elute. For comparison purposes, agar diffusion test (ADT) was also performed. RESULTS: The effect of the composite resins on bacterial growth was minimal and limited to a few days only. One-week-aged composites promoted growth of S. mutans and A. viscosus. The antibacterial properties in direct contact were more potent than in planktonic bacterial growth. Amalgam showed complete inhibition of both bacteria in all phases, and the effect lasted for at least 1 week. The materials' elute had no effect on both bacterial growth with the exception of complete inhibition of S. mutans in amalgam. The later results correlated with the ADT. CONCLUSIONS: The present findings demonstrate potent and lasting antibacterial properties of amalgam, which are lacking in composite resins. This may explain the clinical observation of biofilm accumulated more on composites compared to amalgams. It follows that the assessment of antibacterial properties of poorly-soluble materials has to employ more than one assay.

Actinomyces viscosus↗
PubMed2006

Hydrolytic degradation and drug release of ricinoleic acid-lactic acid copolyesters.

A systematic study on the degradation and drug release from L-lactic acid and ricinoleic-acid-based copolyesters is reported. These copolyesters were synthesized by ring opening polymerization (ROP), melt condensation (COND) and transesterification (TRANS) of high molecular weight poly(lactic acid) (PLA) with ricinoleic acid (PLA-RA), and repolymerization by condensation to yield random and block copolymers of weight average molecular weights (Mw) between 3000 and 13,000. All polymers showed an almost zero-order weight loss, with a 20-40% loss after 60 days of incubation. Lactic acid release to the degradation solution is proportional to weight loss of the polymer samples. The main decrease in molecular weight was observed during the first 20 days, followed by a slow degradation phase, which kept the number average molecular weight (Mn) at 4000-2000 for another 40 days. Water-soluble 5FU was released from ricinoleic-acid-based polymers faster than slightly water-soluble triamcinolone. Drug release into phosphate-buffered saline (pH 7.4, 0.1 M) at 37 degrees C from P(LA-RA) 60:40 prepared by condensation of the acids was faster than from pasty P(PLA-RA) 60:40 synthesized by transesterification for both drugs.

Antimetabolites, Antineoplastic↗
PubMed2006

n-Alkanoic acid monolayers on 316L stainless steel promote the adhesion of electropolymerized polypyrrole films.

The formation of a self-assembled monolayer significantly promotes the adhesion of electrodeposited polypyrrole on stainless steel. The monolayer affects the nucleation and growth mechanism of polypyrrole as a result of its hydrophobic nature. This was confirmed by analyzing current-time transients of the initial stages of electropolymerization and was in agreement with AFM images.

Electrochemistry↗
PubMed2006

Combination of 3D tissue engineered scaffold and non-viral gene carrier enhance in vitro DNA expression of mesenchymal stem cells.

The objective of this study is to enhance the expression of a plasmid DNA for mesenchymal stem cells (MSC) by combination of 3-dimensional (3D) tissue engineered scaffolds and non-viral gene carrier. As a carrier of plasmid DNA, dextran-spermine cationic polysaccharide was prepared by means of reductive-amination between oxidized dextran and the natural oligoamine, spermine. As the MSC scaffold, collagen sponges reinforced by incorporation of poly(glycolic acid) (PGA) fibers were used. A complex of the cationized dextran and plasmid DNA of BMP-2 was impregnated into the scaffolds. MCS were seeded into each scaffold and cultured by a 3D culture method. When MSC were cultured in the PGA-reinforced sponge, the level of BMP-2 expression was significantly enhanced by the cationized dextran-plasmid DNA complex impregnated into the scaffold than by the cationized dextran-plasmid DNA complex in 2-dimensional (2D) (tissue culture plate) culture method. The alkaline phosphatase activity and osteocalcin content of transfected MSC cultured in the PGA-reinforced sponge were significantly higher compared with 2D culture method. We conclude that combination of cationized dextran plasmid DNA complex and 3D tissue engineered scaffold was promising to promote the in vitro gene expression for MSC.

Animals↗
PubMed2006

Antibacterial activity of dental composites containing quaternary ammonium polyethylenimine nanoparticles against Streptococcus mutans.

The antibacterial activity of quaternary ammonium polyethylenimine (PEI) nanoparticles embedded at 1%w/w with clinically used bonding, flowable and hybrid dental composite resins and cured by light polymerization was studied. The antibacterial activity was tested with Streptoccocus mutans by: (i) the agar diffusion test (ADT); (ii) the direct contact test; (iii) bacterial growth in the materials elute; (iv) and scanning electron microscope (SEM). Using the direct contact test, antibacterial activity (p<0.001) was found in all three types of composite resins incorporated with the synthesized nanoparticles. The effect lasted for at least 1 month. SEM demonstrated bacterial debris and no streptococcal chains at 24h of bacterial contact. The addition of 1%w/w of nanoparticles did not affect the flexural modulus and the flexural strength of the dental composite materials. The results indicate that quaternary ammonium PEI nanoparticles immobilized in resin-based materials have a strong antibacterial activity upon contact without leach-out of the nanoparticles and without compromise in mechanical properties.

Anti-Bacterial Agents↗
PubMed2006

Site-specific delivery of dexamethasone from biodegradable implants reduces formation of pericardial adhesions in rabbits.

Repeated sternotomy often leads to serious complications in patients due to the formation of cardiac adhesions. In this study we characterized dexamethasone-loaded biodegradable poly(lactide)-poly(ethyleneglycol) copolymer films for site-specific drug delivery and examined their efficacy in the rabbit model of postoperative cardiac adhesions. Tritiated dexamethasone-loaded films were used to determine the in vitro release and in vivo drug distribution. Dexamethasone release in serum was biphasic with 69% drug released after 72 hr. The implants produced sustained drug levels at the implantation site with low distribution into the peripheral tissues. The matrices were implanted in rabbits between the epicardium and the sternum following sternotomy, pericardiectomy and epicardium abrasion, with the drug-releasing surface facing the epicardium. The tenacity and density of the adhesions was examined 21 days post procedure in comparison to both groups of untreated and rabbits implanted with blank matrices. Similarly tenacious and dense adhesions were observed in both control groups. In contrast, epicardial adhesions' formation was significantly reduced and the anatomy was preserved in the treated animals. It is concluded that local delivery of dexamethasone from biodegradable implants provides a promising approach for the prevention of pericardial adhesions while potentially minimizing the systemic adverse effects inherent to systemic therapy or high blood levels of the drug.

Animals↗
PubMed2006

Poly(sebacic acid-co-ricinoleic acid) biodegradable injectable in situ gelling polymer.

The investigated polymers, poly(sebacic acid-co-ricinoleic acid) containing > or =70% ricinoleic acid, may be injected via a 22 gauge needle and become gel upon contact with aqueous medium, both in vitro and in vivo. Various properties of the polymers including viscosity, thermal analysis, and in vivo behavior, before and after exposure to aqueous medium, were determined. These polymers were observed using scanning electron microscopy (SEM) at dry and wet states. It was found that the viscosity and melting temperature of P(SA:RA) increased after exposure to buffer. The viscosity at 37 degrees C of P(SA:RA)3:7 had the highest increase: from 4200 cP before to 8940 cP after exposure to buffer; in the case of P(SA:RA)25:75 before exposure to buffer the viscosity was 1150 cP while after it raised to 3200 cP. The viscosity of P(SA:RA)2:8 also increased from 400 cP before exposure to buffer to 1000 cP after. On the other hand polymer without sebacic acid, (poly(ricinoleic acid)), did not show gelation properties. Thermal analysis also showed an increase in the melting point of the polymers exposed to the aqueous medium during the first 24 h of incubation. Images obtained by SEM showed formation of a three-dimensional network in polymers exposed to buffers. When injected into animals, P(SA:RA) forms a solid implant in the injection site already at 8 h postinjection.

Animals↗
PubMed2006

Impact of aldehyde content on amphotericin B-dextran imine conjugate toxicity.

The biocompatibility of oxidized dextran (40 kDa) was investigated in vitro. The contribution of aldehyde groups to the toxicity of polymer-drug conjugates, such as dextran-amphotericin B (AmB) was evaluated. Oxidized dextran was proved to be toxic against the RAW 264.7 cell line with an IC50 of 3 micromol/mL aldehydes. Modification of aldehyde groups and their reaction with ethanolamine reduced the toxicity at least 15-fold. Accordingly, the antifungal and antileishmanial dextran-AmB imine conjugate, which contains unreacted aldehyde groups, was modified with ethanolamine and compared to dextran-AmB amine and imine conjugates. Modification of the imine conjugate with ethanolamine reduced its toxicity toward the RAW cell line by 100%. The effect on Leishmania major parasites was 5 times higher than that of the dextran-AmB amine conjugate. The dextran-AmB-ethanolamine conjugate was at least 15 times less hemolytic than free AmB. Stability and drug release profiles in buffer solution were investigated. The imine conjugates released free AmB while the amine conjugate did not. It is concluded that aldehyde groups may contribute to cell toxicity. This toxicity is reduced by converting the aldehyde groups into imine conjugates with ethanolamine. The results have direct implications toward the safety of AmB-polysaccharide conjugates used against fungal and leishmanial infections.

Aldehydes↗
PubMed2006

Citrus oil and MgCl2 as antibacterial and anti-inflammatory agents.

BACKGROUND: The antibacterial and anti-inflammatory properties of Dead Sea magnesium chloride (MgCl(2)), citrus oil, and their combination were investigated. Citrus oil is composed of monoterpenes, in particular D-limonene, which is known to inhibit growth of bacteria, fungi, and certain parasites. METHODS: Inhibition of Porphyromonas gingivalis in vitro was used to evaluate the antibacterial effect of a mixture of Dead Sea magnesium chloride and citrus oil and of each of the components. A subcutaneous chamber model in mice was used to assess the anti-inflammatory effect of the mixture and the individual components. Leukocyte migration, tumor necrosis factor-alpha (TNF-alpha) secretion, and interleukin (IL)-10 secretion were determined. Hydrocortisone was used as a positive control. RESULTS: Citrus oil had an antibacterial effect with a minimal inhibitory concentration (MIC) of 1 mg/ml, whereas MgCl(2) at concentrations up to 10 mg/ml did not exhibit any antibacterial activity. However, a mixture of 10 mg/ml MgCl(2) and 0.25 mg/ml citrus oil dramatically increased inhibition of bacterial growth. The combination of MgCl(2) and the citrus oil resulted in lower levels of TNF-alpha and leukocyte migration while maintaining the levels of IL-10 compared to the control. CONCLUSION: These findings suggest that a mixture of citrus oil and MgCl(2) could be used as a natural antibacterial and anti-inflammatory agent.

Animals↗
PubMed2005

Iontophoresis: a non-invasive ocular drug delivery.

Iontophoresis as a non-invasive technique for ocular drug delivery has been investigated for many years. This paper provides an overview of the approaches currently used in the development of the ocular iontophoretic device, the essential features of this procedure and the reported toxicity. This review focuses on the experimental results after transcorneal and transscleral iontophoresis of different drugs, emphasizing the current density applied and the treatment duration used by the investigators.

Administration, Topical↗
PubMed2005

PLA stereocomplexes for controlled release of somatostatin analogue.

Reversible stereoselective complexes were spontaneously formed from mixing acetonitrile solutions of enantiomeric D-poly(lactide) (D-PLA), L-poly(lactide) (L-PLA), and octreotide (an octapeptide, somatostatin analogue). Hetero-stereocomplexes of poly (D-lactide) and L-octreotide were obtained by spray freezing of solution of D-PLA and octreotide. An additional transition temperature close to the melting point of enantiomeric PLA was observed in DSC thermogram. The same phenomenon was observed in stereocomplex of D-PLA/L-PLA and octreotide. The enthalpy of both transition temperatures correlate with peptide content in the hetero-stereocomplex. The spray method produced compact and smooth micro particles compared to particles formed by precipitation in acetonitrile solution. The particle size of stereocomplexes was in the range of 1.5 to 4 microm for all formations. Increasing peptide concentration in the stereocomplex increases the release rate of the peptide, and increases polymer degradation rate as monitored by lactic acid release form stereocomplexes.

Antineoplastic Agents, Hormonal↗
PubMed2005

Relationships between chemical composition, physical properties and transfection efficiency of polysaccharide-spermine conjugates.

Biodegradable water-soluble polysaccharide-spermine (SPM) polycation conjugates for nucleic acid delivery were synthesized by oxidizing polysaccharides using potassium periodate, followed by SPM conjugation. The polycations differ in their polysaccharide type, arabinogalactan (AG) or dextran (D), and/or in the IO(4)- /saccharide mole ratio used for polysaccharide oxidation (1:1, 1:3, or 1:5), resulting in either D(1:1)-SPM, AG(1:1)-SPM, D(1:3)-SPM, AG(1:3)-SPM, or AG(1:5)-SPM. Chemical structure of the conjugates was characterized for total nitrogen and primary amino groups. Surface pH and electrical surface potential were determined by means of spectral changes of covalently attached 7-hydroxycoumarin (HC, a pH- and electrical surface potential-sensitive fluorophore). The binding and the electrostatic neutralization of the polycations by plasmid DNA, as well as the relationship between chemical structure, physical parameters, and transfection of NIH3T3 cells, were also studied. D(1:1)-SPM, the only polycation that showed efficient cell transfection in culture, was shown to have: (1) high SPM content (2000 nmol/mg); (2) high levels of cross-linked SPM (39-51%); (3) at DNA P-/NH3+ ratio of 2.0, a plateau in neutralization of cationic groups (+48 mV, as determined by HC-labeled D(1:1)-SPM titration with DNA), and a drop in zeta-potential from +42 mV for the polymer alone to 0 mV for the polyplex, suggesting that some of the charges are hidden from the DNA; (4) pH(surface) value of 9.2, suggesting that at physiological bulk pH the polymer is only partially ionized, and therefore can act as a "proton sponge" in the endosome; and (5) high sensitivity to serum-rich growth medium. An oleyl derivative, N-oleyl-dextran-spermine (ODS), was synthesized and demonstrated improved transfection efficiency in serum-rich medium.

Animals↗
PubMed2005

Dextran-spermine-based polyplexes--evaluation of transgene expression and of local and systemic toxicity in mice.

Gene delivery using self-assembled polyplexes, formed between negatively charged nucleic acids and cationic polymers, have several drawbacks including low transgene expression and toxicity effects related to their positive charge. Recently, a novel cationic polymer based on dextran-spermine (D-SPM) was developed for gene delivery. This polymer showed systemic biodistribution upon local administration (intramuscular (i.m.) and intranasal (i.n.)) followed by transgene expression in organs remote from the site of injection (liver and lungs). Polyplexes based on D-SPM were administered both i.m. and i.n. to BALB/c female mice. LacZ expression in the liver, lungs, and muscles was assessed using whole-mount 5-bromo-4-chloro-3-indolyl beta-d-galactopyranoside (X-gal) staining and paraffin sectioning. The local toxicity in these organs was evaluated from hematoxylin and eosin stained sections. The systemic toxicity of the polymer and polyplexes was estimated by comparing the mice total weight, major organ weights, blood counts (primarily white blood cells (WBC) and platelets), and serum transaminases, to those of control animals (which received PBS). Transgene expression using D-SPM polyplexes was dependent upon the dosage and the polyplexes (+/-) charge ratio. Using the i.m. and i.n. routes of administration the transfection occurred primarily in the bronchial epithelial cells, pneumocytes, and bronchial alveoli of the lungs; in the muscle's fibrocytes; and in the liver's hepatocytes. Histopathological assays revealed mild toxicity in muscle and no abnormal findings in liver and lung. No systemic toxicity was obtained, as we did not find decrease in WBC count or platelet and no increase in serum transaminases. In addition, mice body weights and major organ weights were similar to the control group at both 2 and 28 days post-administration. This study demonstrates systemic transfection efficacy upon local administration of D-SPM complexes with good tolerability and low toxicity.

Animals↗