Biomaterials.info - Resources for Engineers

Record 3921 to 3940

Synthesis of amorphous carbon nanoparticles and carbon encapsulated metal nanoparticles in liquid benzene by an electric plasma discharge in ultrasonic cavitation field
Sergiienko, R., E. Shibata, et al. (2006), Ultrason Sonochem 13(1): 6-12.
Abstract: A newly-developed method permits an electric plasma discharge to occur with relatively low electric power in insulating organic solutions due to the presence of an ultrasonic cavitation. A stable electric plasma could be generated in an ultrasonic cavitation field containing a thousand tiny activated bubbles, in which the electric conductivity could be improved due to formed radicals and free electrons, using copper electrodes and a titanium ultrasonic horn. This method allowed us to synthesize pyrolytic amorphous carbon nanoparticles smaller than about 30 nm in diameter from benzene liquid. In addition, we synthesized TiC nanoparticles about 50-150 nm in size, and copper nanoparticles smaller than 10 nm, which were encapsulated in multilayered graphite cages. Finally, we used GC-MS and MALDI-TOF-MS to observe and analyze the polymerized compounds and the degree of polymerization of the benzene liquid after the plasma treatment.

Synthesis of bioactive PMMA bone cement via modification with methacryloxypropyltri-methoxysilane and calcium acetate
Mori, A., C. Ohtsuki, et al. (2005), J Mater Sci Mater Med 16(8): 713-8.
Abstract: Bone cement consisting of polymethylmethacrylate (PMMA) powder and methylmethacrylate (MMA) liquid is clinically used for fixation of implants such as artificial hip joints. However, it does not show bone-bonding ability, i.e., bioactivity. The lack of bioactivity would be one of factors which cause loosening between the cement and the implant. The present authors recently showed the potential of bioactive PMMA-based bone cement through modification with gamma-methacryloxypropyltrimethoxysilane (MPS) and calcium acetate. In this study, the effects of the kinds of PMMA powder on setting time, apatite formation and compressive strength were investigated in a simulated body fluid (Kokubo solution). The cement modified with calcium acetate calcined at 220 degrees C could set within 15 min when the PMMA powder had an average molecular weight of 100,000 or less. The addition of calcium acetate calcined at 120 degrees C in the PMMA powder required a much longer period for setting. The modified cements formed an apatite layer after soaking in the Kokubo solution within 1 day for cement starting from PMMA powder with a molecular weight of 100,000 or less. Compressive strengths of the modified cements were more than 70 MPa for cements starting from 100,000 and 56,000 in molecular weight. After soaking in Kokubo solution for 7 days, the modified cement consisting of PMMA powder of 100,000 in molecular weight showed a smaller decrease in compressive strength than that consisting of 56,000 in molecular weight. These results indicate that bioactive PMMA cement can be produced with appropriate setting time and mechanical strength when PMMA powders with a suitable molecular weight are used. Such a type of design of bioactive PMMA bone cement leads to a novel development of bioactive material for bone substitutes.

Synthesis of biodegradable cross-linked poly(beta-amino ester) for gene delivery and its modification, inducing enhanced transfection efficiency and stepwise degradation
Kim, T. I., H. J. Seo, et al. (2005), Bioconjug Chem 16(5): 1140-8.
Abstract: Biodegradable cross-linked poly(beta-amino ester) (CLPAE) was synthesized by Michael addition of pentaerythritol triacrylate and N,N-dimethylethylenediamine and modified with aminohexanoic acid and lysine to CLPAE-Ahx and CLPAE-Lys, respectively, for a gene delivery system. They could self-assemble with plasmid DNA, forming nanosized polyplexes, and CLPAE-Ahx polyplex released plasmid DNA slowly during a week through stepwise degradation. The polymers showed minimal cytotoxicity on 293 cells due to their biodegradability and biocompatibility. Transfection efficiencies of CLPAE-Ahx and CLPAE-Lys were comparable to that of PEI in 293 cells and C2C12 cells. Additionally, high transfection of CLPAE-Ahx on primary rat aorta vascular smooth muscle cells (SMC) and primary mouse embryonic fibroblast cells (MEF) shows a potential for a gene delivery system on primary cells, restenosis treatment of human SMC, and MEF cell function research. In conclusion, CLPAE-Ahx could be used as a nontoxic and highly efficient gene delivery system.

Synthesis of CAD/CAM, robotics and biomaterial implant fabrication: single-step reconstruction in computer-aided frontotemporal bone resection
Weihe, S., M. Wehmoller, et al. (2000), Int J Oral Maxillofac Surg 29(5): 384-8.
Abstract: The preoperative manufacturing of individual skull implants, developed by an interdisciplinary research group at Ruhr-University Bochum, is based on the use of titanium as the most common material for implants at present. Using the existing technology for materials that can be milled or moulded, customized implants may be manufactured as well. The goal of the study was to examine biodegradable materials and to evaluate the practicability of intraoperative instrument navigation and robotics. Data acquisition of an adult sheep's head was performed with helical computer tomography (CT). The data were transferred onto a computer aided design/computer aided manufacturing system (CAD/CAM system), and two complex defects in the frontotemporal skull were designed. Standard individual titanium implants were milled for both of the defects. Additionally, for one of the defects a resection template, as well as a mould for the biodegradable poly(D,L-lactide) (PDLLA) implant, were fabricated by the CAD/CAM system. A surgeon carried out the first bone resection (#1) for the prefabricated titanium implant using the resection template and an oscillating saw. The robot system Staubli RX90CR, modified for clinical use, carried out the other resection (#2). Both titanium implants and the PDLLA implant were inserted in their respective defects to compare the precision of their fit. A critical comparison of both implant materials and both resection types shows that fabrication of a PDLLA implant and robot resection are already possible. At present, the titanium implant and resection using a template are more convincing due to the higher precision and practicability.

Synthesis of chitosan-based polymeric surfactants and their adsorption properties for heavy metals and fatty acids
Lee, M. Y., K. J. Hong, et al. (2005), Int J Biol Macromol 36(3): 152-8.
Abstract: Chitosan-based polymeric surfactants (CBPSs) were prepared by N-acylation of chitosans (chitosan 10 and 500) with several acid anhydrides such as hexanoic (C6), lauric (C12), and palmitic (C16) anhydrides. Among the CBPS samples, CBPSs having a good solubility at pH 4.0 were selected and observed for viscosity, surface tension, and adsorption of heavy metals (Cd2+, Co2+, Cr2O7(2-), and Pb2+) as well as the fatty acid (n-octanoic acid). The 1H NMR spectrum of chitosan 10 modified with C16 at the substitution ratio of 0.4 (CBPS10-C16,0.4) showed 85% of acylation in 1% DCl/D2O solutions. CBPS10 with the substitution ratio less than 0.4 showed a good solubility because of shorter repeating units and lesser amounts of hydrophobic substituents. The intrinsic viscosity of CBPS10 was slightly increased, while that of CBPS500 was decreased. As the substitution ratio and length of the carbon chain increased, the surface tension of CBPS10 tended to decrease. CBPS10-C16,0.2 had high adsorption ability for cationic metal ions such as Cd2+, Co2+, and Pb2+ comparable to chitosan. Interestingly, CBPS(10)-C(16,0.2) showed a unique pH optimum for the anionic metal ion such as Cr2O7(2-). In addition, CBPS10-C16,0.2 exhibited the highest adsorption ability for n-octanoic acid among the tested CBPS10 with different carbon chains.

Synthesis of degradable poly(L-lactide-co-ethylene glycol) porous tubes by liquid-liquid centrifugal casting for use as nerve guidance channels
Goraltchouk, A., T. Freier, et al. (2005), Biomaterials 26(36): 7555-63.
Abstract: Biodegradable nerve guidance channels are advantageous, obviating the need for their removal after regeneration; however, most channels lack the appropriate mechanical properties for soft tissue implantation and/or degrade too quickly, resulting in reduced regeneration and necessitating the need for the design of polymers with tunable degradation profiles and mechanical properties. We designed a series of biodegradable polymeric hydrogel tubes consisting of L-lactide (LLA) and polyethylene glycol (PEG) where both the ratio of LLA to PEG and PEG molar mass were varied. By adjusting the PEG:LLA ratio and the molecular weight of the PEG oligomer we were able to control degradation and mechanical properties of our polymers. By incorporating methacrylate (MA) groups on both termini of the linear oligomers, porous tubes were synthesized by a redox-initiated free radical mechanism during a liquid-liquid centrifugal casting process. The tube wall had a bead-like morphology, as determined by SEM, which was reminiscent of previous porous hydrogel tubes synthesized by the same method. Tubes swelled with degradation to 160 vol%, or 640 wt%, and an increased radius calculated at 1.26 times. Those tubes with greater PEG content and PEG molar mass degraded faster than those with greater LLA content, as was expected. Interestingly, the wall morphology changed with degradation to a fiber-like structure and the mechanical properties decreased with degradation. By correlating the accelerated degradation study to a physiologic one, these porous hydrogel tubes were stable for an equivalent of 1.5 months, after which the mechanical properties began to deteriorate. This study demonstrates how porous hydrogel tubes can be designed to meet tissue regeneration criteria by tuning the formulation chemistry and specifically how the ratio of hydrophobic/crystalline LLA and hydrophilic/amorphous PEG impact tube properties.

Synthesis of nitric oxide-releasing gold nanoparticles
Rothrock, A. R., R. L. Donkers, et al. (2005), J Am Chem Soc 127(26): 9362-3.

Synthesis of novel biomaterials in plants
Moire, L., E. Rezzonico, et al. (2003), J Plant Physiol 160(7): 831-9.
Abstract: Metabolic engineering of plants allows the possibility of using crops for the synthesis of novel polymers having useful material properties. Strong and flexible protein-based polymers, which are based on the structure of silk and elastin have been synthesized in transgenic plants. A wide range of polyhydroxyalkanoates having properties ranging from stiff plastics to soft elastomers and glues have been synthesized in various compartments of plants, such as the cytoplasm, plastid and peroxisome. These plant biomaterials could replace, in part, the synthetic plastics, fibers and elastomers produced from petroleum, thus offering the advantage of renewability, sustainability and biodegradability.

Synthesis of novel folic acid-functionalized biocompatible block copolymers by atom transfer radical polymerization for gene delivery and encapsulation of hydrophobic drugs
Licciardi, M., Y. Tang, et al. (2005), Biomacromolecules 6(2): 1085-96.
Abstract: Two synthetic routes to folic acid (FA)-functionalized diblock copolymers based on 2-(methacryloyloxy)ethyl phosphorylcholine [MPC] and either 2-(dimethylamino)ethyl methacrylate [DMA] or 2-(diisopropylamino)ethyl methacrylate [DPA] were explored. The most successful route involved atom transfer radical polymerization (ATRP) of MPC followed by the tertiary amine methacrylate using a 9-fluorenylmethyl chloroformate (Fmoc)-protected ATRP initiator. Deprotection of the Fmoc groups produced terminal primary amine groups, which were conjugated with FA to produce two series of novel FA-functionalized biocompatible block copolymers. Nonfunctionalized MPC-DMA diblock copolymers have been previously shown to be effective synthetic vectors for DNA condensation; thus, these FA-functionalized MPC-DMA diblock copolymers appear to be well suited to gene therapy applications based on cell targeting strategies. In contrast, the FA-MPC-DPA copolymers are currently being evaluated as pH-responsive micellar vehicles for the delivery of highly hydrophobic anticancer drugs.

Synthesis of photoswitchable amino acids based on azobenzene chromophores: building blocks with potential for photoresponsive biomaterials
Juodaityte, J. and N. Sewald (2004), J Biotechnol 112(1-2): 127-38.
Abstract: Three novel derivatives of azobenzene substituted amino acids have been synthesized. The compounds may serve as photoswitchable building blocks in the synthesis of bicyclic peptides or peptide strands interconnected with a photoisomerizable group.

Synthesis of polyacrylamide gel beads with electrostatic functional groups for the molecular imprinting of bovine serum albumin
Pang, X., G. Cheng, et al. (2006), Anal Bioanal Chem 384(1): 225-30.
Abstract: Synthetic materials capable of recognizing proteins are important in separation, biosensors and biomaterials. In this study, bovine serum albumin-imprinted soft-wet polyacrylamide gel beads were prepared via inverse-phase suspension polymerization, using acrylamide and N,N'-methylene diacrylamide as polymeric matrix components and methacrylic acid as functional monomer. The adsorption study showed, through the imprinting process, that the imprinted gel beads had much higher adsorption capacity than the nonimprinted gel beads, and that the matching of the surface zeta-potential between the templates and the imprinted gel beads can enhance the imprinting effect. Adsorption kinetics indicated that the adsorption process could be described as an apparent first-order kinetic process for the gel beads. From the adsorption isotherm curve, we found that the adsorption of the imprinted gel beads was in agreement with the Langmuir adsorption model. Moreover, selectivity testing of the imprinted gel beads showed that imprinted gel beads exhibited good recognition for BSA as compared to the control protein. We speculate that the formation of complementary shapes and multiple-point electrostatic interactions between the imprinting cavities and the template proteins are the two factors that lead to the imprinting effect.

Synthesis of SiO2-coated ZnMnFe2O4 nanospheres with improved magnetic properties
Wang, J., K. Zhang, et al. (2005), J Nanosci Nanotechnol 5(5): 772-5.
Abstract: A core-shell structured composite, SiO2 coated ZnMnFe2O4 spinel ferrite nanoparticles (average diameter of approximately 80 nm), was prepared by hydrolysis of tetraethyl orthosilicate (TEOS) in the presence of ZnMnFe2O4 nanoparticles (average diameter of approximately 10 nm) synthesized by a hydrothermal method. The obtained samples were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), and field emission scanning electron microscopy (FESEM). The magnetic measurements were carried out on a vibrating sample magnetometer (VSM), and the measurement results indicate that the core-shell samples possess better magnetic properties at room temperature, compared with paramagnetic colloids with a magnetic core by a coprecipitation method. These core-shell nanospherical particles with self-assembly under additional magnetic fields could have potential application in biomedical systems.

Synthesis of thromboxane B2 and prostaglandin F2 alpha by human platelets after contact with biomaterials used in vascular surgery
Pizzoferrato, A., M. D'Addato, et al. (1983), Life Support Syst 1 Suppl 1: 251-4.

Synthesis of well-defined amphiphilic block copolymers having phospholipid polymer sequences as a novel biocompatible polymer micelle reagent
Yusa, S., K. Fukuda, et al. (2005), Biomacromolecules 6(2): 663-70.
Abstract: To realize safer and effective drug administration, novel well-defined and biocompatible amphiphilic block copolymers containing phospholipid polymer sequences were synthesized. At first, the homopolymer of 2-methacryloyloxyethylphosphorylcholine (MPC) was synthesized in water by reversible addition-fragmentation chain transfer (RAFT) controlled radical polymerization. The "living" polymerization was confirmed by the fact that the number-average molecular weight increased linearly with monomer conversion while the molecular weight distribution remained narrow independent of the conversion. The poly(MPC) thus prepared is end-capped with a dithioester moiety. Using the dithioester-capped poly(MPC) as a macro chain transfer agent, AB diblock copolymers of MPC and n-butyl methacrylate (BMA) were synthesized. Associative properties of the amphiphilic block copolymer (pMPC(m)-BMA(n)) with varying poly(BMA) block lengths were investigated using NMR, fluorescence probe, static light scattering (SLS), and quasi-elastic light scattering (QELS) techniques. Proton NMR data in D2O indicated highly restricted motions of the n-butyl moieties, arising from hydrophobic associations of poly(BMA) blocks. Fluorescence spectra of N-phenyl-1-naphthylamine indicated that the probes were solubilized in the polymer micelles in water. The formation of polymer micelles comprising a core with poly(BMA) blocks and shell with hydrophilic poly(MPC) blocks was suggested by SLS and QELS data. The size and mass of the micelle increased with increasing poly(BMA) block length. With an expectation of a pharmaceutical application of pMPC(m)-BMA(n), solubilization of a poorly water-soluble anticancer agent, paclitaxel (PTX), was investigated. PTX dissolved well in aqueous solutions of pMPC(m)-BMA(n) as compared with pure water, implying that PTX is incorporated into the hydrophobic core of the polymer micelle. Since excellent biocompatible poly(MPC) sequences form an outer shell of the micelle, pMPC(m)-BMA(n) may find application as a promising reagent to make a good formulation with a hydrophobic drug.

Synthesis of zinc-crosslinked thiolated alginic acid beads and their in vitro evaluation as potential enteric delivery system with folic acid as model drug
Taha, M. O., K. M. Aiedeh, et al. (2005), Pharmazie 60(10): 736-42.
Abstract: The aim of this study is to explore the potential of synthetic modifications of alginic acid as a method to enhance the stability of its complexes with divalent cations under physiological conditions. A fraction of algin's carboxylic acid moieties was substituted with thiol groups to different substitution degrees through conjugating alginate to cysteine to produce alginate-cysteine (AC) conjugates. Infrared spectrophotometry and iodometry were used to characterize the resulting polymeric conjugates in terms of structure and degree of substitution. Moreover, zinc ions were used to crosslink the resulting AC polymers. Folic acid loaded beads were prepared from Zinc-crosslinked AC polymers (AC-Zn) of different cysteine substitution degrees. The generated beads were then investigated in vitro for their capacity to modify folic acid release. AC-Zn polymeric beads resisted drug release under acidic conditions (pH 1.0). However, upon transfer to a phosphate buffer solution (pH 7.0) they released most of their contents almost immediately. This change in drug release behavior is most probably due to the sequestering of zinc cations by phosphate ions within the buffer solution to form insoluble chelates and, to a lesser extent, the ionization of the carboxylic acid and thiol moieties. Removal of zinc ions from the polymeric matrix seems to promote polymeric disintegration and subsequent drug release. A similar behavior is expected in vivo due to the presence of natural zinc sequestering agents in the intestinal fluids. AC-Zn polymers provided a novel approach for enteric drug delivery as drug release from these matrices complied with the USP specifications for enteric dosage forms.

Synthesis, characterization and cytocompatibility of polyurethaneurea elastomers with designed elastase sensitivity
Guan, J. and W. R. Wagner (2005), Biomacromolecules 6(5): 2833-42.
Abstract: In designing a synthetic scaffold for engineering soft, mechanically active tissues, desirable properties include elasticity, support of cell adhesion and growth, ease of processability, and responsiveness to in vivo remodeling. To achieve these properties, we have developed a family of thermoplastic elastomers, polyurethaneureas (PUs), that possess enzymatic remodeling capabilities in addition to simple hydrolytic lability. PUs were synthesized using either polycaprolactone or triblock copolymer polycaprolactone-b-poly(ethylene glycol)-b-polycaprolactone as the soft segment, 1,4-butanediisocyanate as the hard segment, and the peptide Ala-Ala-Lys as a chain extender. The synthesized PUs had high molecular weights, low glass transition temperatures (< -54 degrees C), and were flexible with breaking strains of 670-890% and tensile strengths of 15-28 MPa. Incubation in buffered saline without elastase for 8 weeks resulted in mass loss from 12% to 18% depending on soft segment composition. The degradation significantly increased (p < 0.05) in the presence of elastase, ranging from 19% to 34% with degradation products showing no cytotoxicity. To encourage cell adhesion, PUs were surface-modified with radio frequency glow discharge followed by coupling of Arg-Gly-Asp-Ser (RGDS). Endothelial cell adhesion was >140% of tissue culture polystyrene on PU surfaces and >200% on RGDS-modified surfaces. The synthesized PUs thus combine mechanical, chemical, and bioresponsive properties that might be employed in soft-tissue engineering applications.

Synthesis, characterization and cytotoxicity of poly(ethylene glycol)-graft-trimethyl chitosan block copolymers
Mao, S., X. Shuai, et al. (2005), Biomaterials 26(32): 6343-56.
Abstract: PEGylated trimethyl chitosan (TMC) copolymers were synthesized in an attempt to both increase the solubility of chitosan in water, and improve the biocompatibility of TMC. A series of copolymers with different degrees of substitution were obtained by grafting activated poly(ethylene glycol)s (PEG) of different MW onto TMC via primary amino groups. Structure of the copolymers was characterized using 1H, 13C NMR spectroscopy and GPC. Solubility experiments demonstrated that PEG-g-TMC copolymers were completely water-soluble over the entire pH range of 1-14 regardless of the PEG MW, even when the graft density was as low as 10%. Using the methyl tetrazolium (MTT) assay, the effect of TMC molecular weight, PEGylation ratio, PEG and TMC molecular weight in the copolymers, and complexation with insulin on the cytotoxicity of TMC was examined, and IC50 values were calculated with L929 cell line. All polymers exhibited a time- and dose-dependent cytotoxic response that increased with molecular weight. PEGylation can decrease the cytotoxicity of TMC to a great extent in the case of low molecular weight TMCs. According to the cytotoxicity results, PEG 5 kDa is superior for PEGylation when compared to PEG 550 Da at similar graft ratios. Complexation with insulin further increased cell viability. In addition, Lactate dehydrogenase (LDH) assays were performed to quantify the membrane-damaging effects of the copolymers, which is in line with the conclusion drawn from MTT assay. Moreover, the safety of the copolymers was corroborated by observing the morphological change of the cells with inverted phase contrast microscopy. Based upon these results PEG-g-TMC merits further investigations as a drug delivery vehicle.

Synthesis, characterization and melt spinning of a block copolymer of L-lactide and epsilon-caprolactone for potential use as an absorbable monofilament surgical suture
Baimark, Y., R. Molloy, et al. (2005), J Mater Sci Mater Med 16(8): 699-707.
Abstract: This paper describes the synthesis and characterization of a block copolymer of L-lactide (LL) and epsilon -caprolactone (CL) and its subsequent melt spinning into a monofilament fiber. The synthesis reaction was a two-step process. In the first step, an approximately 50:50 mol% random copolymer, P(LL-co-CL), was synthesized via bulk copolymerization of LL and CL. This first-step prepolymer then became the macroinitiator in the second-step reaction in which more LL monomer was added to form a block copolymer, PLL-b-P(LL-co-CL)-b-PLL. Both the prepolymer and block copolymer were characterized by a combination of analytical techniques comprising dilute-solution viscometry, GPC, 1H and 13C NMR, DSC and TG. The block copolymer was then processed into a monofilament fiber using a small-scale melt spinning apparatus. The fiber was spun with a minimum amount of chain orientation and crystallinity so that its semi-crystalline morphology could be constructed under more controlled conditions in subsequent off-line hot-drawing and annealing steps. In this way, the fiber's tensile properties and dimensional stability were developed, as indicated by the changes in its stress-strain curve. The final drawn and annealed fiber had a tensile strength (>400 MPa) approaching that of a commercial PDS II suture of similar size. It is considered that this type of block copolymer has the potential to be developed further as a lower-cost alternative to the current commercial monofilament surgical sutures.

Synthesis, characterization, and antitumoral activity of polyoxometalate loaded starch nanocomplexes
Wang, X., L. Xu, et al. (2005), J Nanosci Nanotechnol 5(6): 905-8.
Abstract: Using a reverse-phase microemulsion polymerization method and an encapsulating method, polyoxometalates (POMs) K6SiW11TiO40 incorporating starch microspheres have been prepared and structurally characterized by elemental analyses, IR, UV-vis, and NMR spectroscopy. The size of SiW11TiO40/starch particles is about 40-60 nm. The polyoxometalate encapsulated by a starch microsphere retains the parent structure. The starch microsphere is a good carrier, as it is able to enhance the antitumoral activity of POMs and decrease the toxicity of POMs as well.

Synthesis, characterization, biodegradation, and drug delivery application of biodegradable lactic/glycolic acid polymers: Part III. Drug delivery application
Wu, X. S. (2004), Artif Cells Blood Substit Immobil Biotechnol 32(4): 575-91.
Abstract: Lactic/glycolic acid polymers (PLGA) are widely used for drug delivery systems. The microsphere formulation is the most interesting dosage form of the PLGA-based controlled release devices. In this study, the previously reported PLGA were used to prepare drug-containing microspheres. Progesterone was used as a model drug. The progesterone microspheres were prepared from PLGA having varied compositions and varied molecular weight. The microscopic characterization shows that the microspheres are spherical, nonaggregated particles. The progesterone-containing PLGA microspheres possess a Gaussian size distribution, having average size from 70-134 microm. A solvent extraction method was employed to prepare the microspheres. The microencapsulation method used in this study has high drug encapsulation efficiency. The progesterone release from the PLGA microspheres and the factors affecting the drug release were studied. The release of progesterone from the PLGA microspheres is affected by the properties of the polymer used. The drug release is more rapid from the microspheres prepared using the PLGA having higher fraction of glycolic acid moiety. The drug release from the microspheres composed of higher molecular weight PLGA is faster. The drug content in microspheres also has an effect on the drug release. Higher progesterone content in microspheres yields a quicker initial burst release of the drug.

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