Effects of formulation properties on sol–gel behavior of chitosan/glycerolphosphate hydrogel

Chitosan solution containing glycerolphosphate disodium salt (Gp) is an injectable thermosensitive in situ gel-forming system which undergoes sol–gel transition under certain physiological pH and temperature conditions. When a drug-incorporated chitosan/Gp solution is injected into the body, it forms a three-dimensional gel at 37 °C, which allows the drug to be released in a sustained manner. This hydrogel can be used as a drug delivery system for prolonged release of peptides and glycopeptides. The objective of this work was to investigate the effect of different excipients on the sol–gel behavior of this thermosensitive hydrogel. Chitosan polymeric solutions (2 % w/v) containing Gp and different excipients, such as hydroxypropyl methyl cellulose (HPMC), polyethylene glycol (PEG) with two different molecular weights (PEG200 and PEG1000), and poloxamer (F127) in various concentrations, were prepared, and the pH, sol–gel transition time, and syringeability of the final solutions were evaluated. The obtained results point to HPMC as the best additive for chitosan/Gp solutions in developing an in situ gel-forming drug delivery system with optimum gelling time. A significant decrease was noted in the sol-to-gel transition time (from 90 to 60 s) when HPMC was added to the system. This may have been due to the HPMC structure which acted as a viscosity-enhancing and gel-promoting agent. The in vitro release of vancomycin hydrochloride from chitosan/Gp/HPMC hydrogel was also studied. Vancomycin release studies showed a sustained release profile for over 20 days. It can be concluded that combining chitosan/Gp and HPMC is a promising strategy for preparing a thermally reversible in situ gel-forming delivery system with an optimized gelation time.     

Functionalized silver doped hydroxyapatite scaffolds for controlled simultaneous silver ion and drug delivery

Bacterial infections are a major problem in bone tissue regeneration, thus it is essential to incorporate antibacterial properties within the bone scaffolds. Silver compounds are frequently used as antibacterial agents to prevent bacterial infections and numerous studies have shown that silver ions can be incorporated within the biocompatible and osteoconductive biomaterial hydroxyapatite (HAp) structure, but, so far, no study has thoroughly evaluated silver ion release rates in long term. Therefore, we have established a novel carrier system for local drug delivery based on functionalized silver doped hydroxyapatite with determined long term silver ion release rates. Silver ions from prepared scaffolds were released with a rate of 0.001±0.0005 wt%/h taking into account the incorporated silver amount. Moreover, lidocaine hydrochloride was incorporated in the prepared scaffolds, to provide local anesthetic effect. These scaffolds were functionalized with sodium alginate and chitosan and in vitro drug release rate in simulated body fluid was evaluated. The results suggested that the developed novel composite scaffolds possess the antibacterial activity up to one year as well as controlled anesthetic drug delivery up to two weeks.     

Drug loaded electrospun polymer/ceramic composite nanofibrous coatings on titanium for implant related infections

Developing an effective antibacterial surface with the help of drugs that prevent bacterial adhesion, colonization, and proliferation into the surrounding tissues is of great demand. Rifampicin (Rf) is effective antibiotic drug proved has proved its potential in treating bacteria in biofilms, especially against the microbes causing bone infections. Hydroxyapatite (HA), a biocompatible osteoconductive ceramic, has been verified to be a significant material for bioactivity enhancement. Electrospinning is an effective inexpensive method for incorporating nanoparticles into nanofibers with uniform distribution for the drug delivery system for tissue engineering applications. In the current study, for improving bioactivity and antibacterial properties, novel functional polycaprolactone (PCL) composite nanofibers loaded HA and Rf was developed and coated on titanium (Ti). Different characterization techniques such as SEM, EDS, XRD, FITR were used to analyze these PCL/Rf/HA nanocomposites. The results showed that the bioactivity and tensile strength of the composite scaffold increased with the addition of HA nanoparticles. In vitro bioactivity demonstrated that the PCL/HA/Rf composite nanofibers possess enhanced calcium deposition when compared to the pure sample. Cellular interactive responses such as adhesive and proliferation were evaluated using hFOB human fetal osteoblast cell lines. After 6 days of culturing, the cellular properties on Ti sample coated with PCL/HA/Rf was significantly improved. Antibacterial evaluations on the substrates showed that Rf-loaded PCL/HA fibers displayed >3 log reduction against S.aureus MRSA, and S.epidermidis bacterial strain and >2 log reduction against P.aeruginosa bacteria. In vitro drug release study shows initial burst release of Rf, followed by sustained released of 62% at the end of 32 days. The cell viability, adhesion, and proliferation evaluation suggest that the PCL/HA/Rf coated substrate possess good cytocompatibility. Further incorporation of Rf enhanced the antibacterial property of this nanofibrous scaffold.     

Poly(ε‐caprolactone) composites containing gentamicin‐loaded β‐tricalcium phosphate/gelatin microspheres as bone tissue supports

In this work, novel antibacterial composites were prepared by using poly(ε‐caprolactone) (PCL) as the main matrix material, and gentamicin‐loaded microspheres composed of β‐tricalcium phosphate (β‐TCP) and gelatin. The purpose is to use this biodegradable material as a support for bone tissue. This composite system is expected to enhance bone regeneration by the presence of β‐TCP and prevent a possible infection that might occur around the defected bone region by the release of gentamicin. The effects of the ratio of the β‐TCP/gelatin microspheres on the morphological, mechanical, and degradation properties of composite films as well as in vitro antibiotic release and antibacterial activities against Escherichia coli and Staphylococcus aureus were investigated. The results showed that the composites of PCL and β‐TCP/gelatin microspheres had antibacterial activities for both bacteria. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Salmon calcitonin‐loaded PLGA microspheres/calcium phosphate cement composites for osteoblast proliferation

To improve the efficacy of salmon calcitonin (SCT) on disuse osteoporosis‐induced bone fracture, the sustained‐release vehicles delivered to bone fractures should be developed. In this study, SCT‐loaded poly(d ,l ‐lactic‐co‐glycolic acid) microspheres (SCT‐PLGA MS) with 20 kDa‐COOH and 40 kDa‐COOH (SCT‐PLGA‐20 COOH MS and SCT‐PLGA‐40 COOH MS) are incorporated into calcium phosphate cement (CPC) at various mass ratios. The cumulative release and mechanical properties of SCT‐PLGA MS/CPC composites decrease as PLGA MS/CPC mass ratio increase. Scanning electron microscopy images and the mass loss of composites indicate the MS from 20% SCT‐PLGA MS/CPC composites have mostly degraded after 8 weeks. In addition, SCT released from the 20% SCT‐PLGA‐20 MS/CPC composites significantly facilitate proliferation and differentiation of MC3T3‐E1 cells. In conclusion, 20% SCT‐PLGA‐20 COOH MS/CPC composites exhibit the sustained drug release, proper CPC degradation, good mechanical properties, and preferable osteoblast proliferation, which would be beneficial to their in vivo applications. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 45486.     

Electrostatic immobilization of cetylpyridinium chloride to poly(vinyl alcohol) hydrogels for the simple fabrication of wound dressings with the suppressed release of antibacterial agents

Polymeric systems for antibacterial wound dressings require chemical reactions or syntheses for attaching or incorporating antibacterial moieties into polymer backbones. However, these materials often fail to satisfy the basic requirements, such as easy and inexpensive synthesis. We speculated that a positively charged organic antibacterial agent would be attracted to the polar groups of poly(vinyl alcohol) (PVA) hydrogels and would show suppressed release. PVA hydrogels containing cetylpyridinium chloride (CPC) were prepared by γ irradiation. CPC was barely released from the hydrogels, probably because of electrostatic interactions, and was stable upon γ irradiation. The suppressed release of CPC conferred antibacterial activity against Escherichia coli to the surface of the hydrogels, whereas no inhibition zone was observed around the hydrogels. The CPC‐containing PVA hydrogels were easy to prepare and contained known and safe materials. The simplicity and safety of this procedure for achieving the suppressed release of antibacterial agents were advantages of these CPC‐containing PVA hydrogels. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40456.     

Spheronization of solid lipid extrudates

The objective of this study was the examination and development of a solvent-free spheronization process as a manufacturing tool for sustained release matrix spheres. Extrudates prepared from a binary lipid mixture with different amounts of Dynasan 114® and Witocan 42/44® and theophylline as model drug were processed in systematic spheronization experiments by varying pellet formulation and spheronizer-jacket temperature. The rounding procedure of the pellets was investigated by analyzing spot samples after different processing times. The obtained pellets were characterized according to their shape, size distribution, porosity and drug release properties. Round lipid pellets with a mean aspect ratio below 1.1 and a narrow particle size distribution with median equivalent diameters around 1.5 mm could be obtained. The pellets showed sustained drug release properties and porosities below 1%. The spheronization process was shown to be strongly temperature- and formulation dependent. The material temperature during the process was influenced by the adjusted jacket temperature and friction- and shear forces between the rounded particles; control of material temperature seems to pose the challenge in the investigated process.     

具有药物缓释功能的磷酸钙骨水泥的研究进展

磷酸钙骨水泥作为一种新型的骨修复材料,以其生物相容性高和易塑形的特点得到了材料界和医学界的广泛关注.利用药物定点缓释,将抗癌或消炎等药物引入磷酸钙骨水泥中,能达到骨修复与冶疗的双重目的.本文综述了具有药物缓释功能的磷酸钙骨水泥的研究进展,包括材料的理化特性和药物缓释机理的研究.研究表明,对不同药物采取合适的包埋技术,并通过调节骨水泥的厚度、药物包埋量等条件可达到药物控制释放的目的.     

Controlled release and absorption of cetylpyridinium chloride using polymer hydrogels

Interest in the biocide cetylpyridinium chloride (CPC) has resurged based on new studies showing its effectiveness against a wide variety of pathogens. Hydroxyethyl methacrylate (HEMA)‐based hydrogels have been developed for the controlled release of CPC. Initial burst release of the biocide can be controlled and sustained release can be achieved for more than two weeks. The burst and sustained release can be adjusted by varying the amount of anionic monomer (AMPSA), crosslink content (DEGDMA), release media, hydrogel surface area, and CPC loading. After removing the CPC‐loaded hydrogel from solution and drying, the release of CPC can also be reactivated. Very interesting swelling behavior was observed for CPC‐loaded hydrogels due to the electrostatic and hydrophobic interactions between the polymer hydrogel and CPC. In addition, HEMA‐based hydrogels can be used to recover or absorb CPC from aqueous solutions. By increasing the amount of AMPSA in the HEMA‐based hydrogel, more CPC can be absorbed from solution. The absorption is also enhanced by agitating the solution. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci, 2006     

A Bioglass-Based Antibiotic (Vancomycin) Releasing Bone Void Filling Putty to Treat Osteomyelitis and Aid Bone Healing

While the infection rate after primary total joint replacements (TJR) sits at 1–2%, for trauma-related surgery, it can be as high as 3.6 to 21.2% based on the type of trauma; the risk of reinfection after revision surgery is even higher. Current treatments with antibiotic-releasing PMMA-based bone cement/ beads and/or systemic antibiotic after surgical debridement do not provide effective treatment due to fluctuating antibiotic levels at the site of infection, leading to insufficient local antibiotic concentration. In addition, non-biodegradable PMMA does not support bone regrowth in the debrided void spaces and often must be removed in an additional surgery. Here, we report a bioactive glass or bioglass (BG) substrate-based biodegradable, easy to fabricate “press fitting” antibiotic-releasing bone void filling (ABVF-BG) putty to provide effective local antibiotic release at the site of infection along with support for bone regeneration. The ABVF-BG putty formulation had homogenously distributed BG particles, a porous structure, and showed putty-like ease of handling. Furthermore, the ABVF-BG putty demonstrated in vitro antibacterial activity for up to 6 weeks. Finally, the ABVF-BG putty was biodegradable in vivo and showed 100% bacterial eradication (as shown by bacterial cell counts) in the treatment group, which received ABVF-BG putty, compared to the infection control group, where all the rats had a high bacterial load (4.63 × 10⁶ ± 7.9 × 10⁵ CFU/gram bone) and sustained osteomyelitis. The ABVF-BG putty also supported bone growth in the void space as indicated by a combination of histology, µCT, and X-ray imaging. The potential for simultaneous infection treatment and bone healing using the developed BG-based ABVF-BG putty is promising as an alternative treatment option for osteomyelitis.     

Gramicidin-S-Inspired Cyclopeptidomimetics as Potent Membrane-Active Bactericidal Agents with Therapeutic Potential

Antimicrobial peptides (AMPs) are promising antibacterial agents often hindered by their undesired hemolytic activity. Inspired by gramicidin S (GS), a well-known cyclodecapeptide, we synthesized a panel of antibacterial cyclopeptidomimetics using β,γ-diamino acids (β,γ-DiAAs). We observed that peptidomimetic CP-2 displays a bactericidal activity similar to that of GS while possessing lower side-effects. Moreover, extensive studies revealed that CP-2 likely kills bacteria through membrane disruption. Altogether, CP-2 is a promising membrane-active antibiotic with therapeutic potential.     

Long-term release of chlorhexidine from dental adhesive resin system using human serum albumin nanoparticles

A functional dental adhesive resin system with antimicrobial properties was developed using human serum albumin (HSA) nanoparticles as the drug delivery carrier. HSA nanoparticles loaded with chlorhexidine (CHX) diacetate, a model antimicrobial drug, were prepared using a desolvation technique. The resulting CHX-loaded HSA nanoparticles were incorporated into a commercial methyl methacrylate (MMA)-based resin. The size of the nanoparticles ranged 50–300 nm, and the nanoparticles were dispersed homogeneously in the resin matrix. The CHX-loaded HSA nanoparticles showed an early release burst of ~20 % of the total CHX by day 5, followed by the sustained release of the remaining CHX over the next 20 days. In contrast, the resin matrix containing the HSA nanoparticles showed a sustained release of CHX without an early release burst in a 4-week immersion study. In the agar diffusion test, the resin matrix incorporating the CHX-loaded HAS nanoparticles showed a larger growth inhibition zone against Streptococcus mutans than the resin matrix alone, indicating that this delivery platform potently imparts antibacterial activity to the resins. These results also suggest that CHX, which inhibits the growth of oral bacteria, can be incorporated efficiently into the MMA-based resin matrix using HSA nanoparticles.     

Prospects use of hybrid layered double hydroxides‐polyacrylamide as controlled release media for antibiotic molecules

Some controlled‐release media containing two commercial antibiotic molecules, viz. Amoxicillin (AMX) and Ampicillin (AMP), were prepared using layered double hydroxides (LDH) intercalated and extended by polyacrylamide. The polycarylamide was prepared in situ by polymerization of acrylamide monomer intercalated in the interlayers of LDH. The LDH‐polyacrylamide‐antibiotic hybrid nanocomposites were characterized by various techniques like Fourier transform infrared (FT‐IR), powder X‐ray diffraction (XRD), thermogravimetric analysis (TGA), and field emission scanning electron microscopy (FE‐SEM). The results from these characterizations have shown the successful incorporation of the antibiotics in the interlayers and provided important information regarding their interlayer structure. The nanocomposites showed increased thermal stability in TGA. The loading of antibiotic in the PAM/Mg‐Al nanocomposite was found to be 36.33% for AMX and 52.38% for AMP. The improved antibacterial activity of hybrid nanocomposite was evaluated against Escherichia coli using the wells diffusion technique. The aliquot samples in agar media drug release study were found to be highly effective against microorganisms. The sustained release of antibiotic drug from the hybrid nanocomposite was also verified. The release rate at pH 7.4 phosphate buffer was found slower than that at pH 4.6. It can be concluded that hybrid nanocomposites of LDH extended by in situ polymerized acrylamide are very suitable materials to host different antibiotics and their controlled release. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 45442.     

Cetylpyridinium chloride cationic finishing improves the dyeing and antibacterial properties of madder dyed cotton

In this work, after cationic pretreatment of cotton fabric with cetylpyridinium chloride (CPC), the compound of citric acid (CA) and succinic acid (SUA) were used as crosslinking agents to dye cotton fabrics with natural madder dye to improve the dyeing and antibacterial properties and realise the multifunctional finishing of cotton fabric. The effects of mordant dyeing, CA + SUA crosslinked dyeing, and CPC/CA + SUA crosslinked dyeing on the microstructure and properties of cotton fabrics were compared. The dyeing by the three processes occurred primarily in the amorphous zone of the fibres, and all kept the original crystalline form of the cotton. CA + SUA crosslinked dyeing and CPC/CA + SUA crosslinked dyeing increased the thermal stability of the cotton fabric. CPC/CA + SUA crosslinked dyed cotton obtained excellent dyeing results with the colour depth value (K/S) of 12.3 and rubbing fastness and washing fastness of levels 4–5, and the levelness and dye permeability were acceptable. Furthermore, the antibacterial rate against Escherichia coli and Staphylococcus aureus reached 99.99%, and the ultraviolet protection factor (UPF) reached 50+. Moreover, the wrinkle recovery angle (WRA) increased by 55% compared with raw cotton. This showed that CPC/CA + SUA crosslinked dyed cotton had excellent antibacterial, anti-ultraviolet, and anti-wrinkle performances.     

Gentamicin‐loaded poly(acrylic acid)‐grafted cotton fibers,part 1: Synthesis,characterization, and preliminary drug release study

This study describes preparation of poly (acrylic acid)‐grafted cotton fibers and release of antibiotic drug gentamicin sulfate from them under physiological conditions. Poly(acrylic acid) has been grafted onto cellulose backbone of cotton fibers via Ce(IV)‐initiated polymerization in aqueous medium. The conditions obtained for optimum grafting were as follows: initiation time 30 min; initiation temperature 37°C; monomer concentration 27.8 mM; grafting temperature 30°C; nitric acid (catalyst) concentration 0.1M. The grafted fibers were characterized by FTIR, TGA, and SEM analysis. The antibiotic drug gentamicin sulfate (GS) was loaded into the grafted fibers by equilibration method and release was studied under physiological conditions. The kinetic release data was interpreted by first‐order kinetic model. Finally, drug‐loaded fibers showed fair antibacterial action against Escherichia coli. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Facile Fabrication of Povidone Iodine-Embedded Polytetrafluoroethylene Superhydrophobic Films with Improved Antiadhesive and Bactericidal Properties in Bacterial Environments

It remains a challenge to maintain the antiadhesion properties of superhydrophobic films after exposure to bacterial environments. In this work, superhydrophobic bactericidal polymer films via the simple incorporation of polyvinylpyrrolidone-iodine (PVP-I) or iodine into polytetrafluoroethylene (PTFE) are fabricated to improve their antiadhesive and antibacterial capability. Superhydrophobic iodine-embedded films, polytetrafluoroethylene/polyvinylpyrrolidone-iodine and polytetrafluoroethylene-iodine (PTFE/PVP-I and PTFE-I), show excellent antiadhesive and bactericidal performances even post exposure to bacterial solutions as compared to iodine-free counterparts by controlling the release of iodine. Especially, superhydrophobic PTFE/PVP-I films display a more sustained iodine release profile and significant antibacterial properties against gram-positive (S. aureus, methicillin-resistant S. aureus (MRSA)) and gram-negative (E. coli) bacteria. Such a facile combination of antiseptic agents and superhydrophobic surface could be widely used for antiseptic biomedical applications.     

Methoxy polyethylene glycol–cholesterol modified soy lecithin liposomes for poorly water-soluble anticancer drug delivery

Soy lecithin liposomes (SLP) were prepared and partially surface modified with methoxy polyethylene glycol-cholesterol conjugate (mPEG-Chol) to improve its poorly-soluble-water-anticancer-drugs delivery efficiency. Paclitaxel (PTX) was used as the model drug and the PTX/SLP@mPEG was successfully developed with the optimal mass ratio of mPEG-Chol determined at 4% in the SLP@mPEG formulation. The optimal SLP@mPEG formulation had a particle size range of 161.80 ± 1.51 nm and a negative surface charge of −54.30 ± 1.40 mV. Besides, a sustained drug release profile of 72 h and an encapsulation efficiency of 87.48 ± 0.70% was recorded. Moreover, in vitro cytotoxicity assays demonstrated that SLP@mPEG is nontoxic and cytocompatible. Overall, these obtained results provide insights into the potential of SLP@mPEG as a platform for the development of more effective therapies against cancers.     

快释型磷酸钙骨水泥性能和释药机理

磷酸钙骨水泥(calcium phosphate cement,CPC)是一种具有临床应用前景的抗生素载体材料,但抗生素长期残留易导致发生耐药性,本研究的目的是制备和表征快释型磷酸钙骨水泥(fast-releasing calcium phosphate cement,FRCPC),并研究其快速释放机理。采用在CPC中加入易溶于水的物质制备FRCPC,测试其凝结时间、抗压强度、药物体外释放及释放过程中易溶于水的物质的溶出,观察骨水泥断面微观形貌。结果表明:FRCPC初凝时间为(8±0.33)min,终凝时间为(16±0.50)min,抗压强度为(2.6±0.23)MPa。药物体外释放结果表明:FRCPC中的药物释放明显快于CPC中的,能在7d内完全释放。在药物释放不同时间点的X射线衍射谱和采用沉淀滴定法测试易溶于水的物质溶出量的结果均表明:FRCPC中,易溶于水的物质迅速溶出,与扫描电镜观察结果(FRCPC相对于CPC孔隙率增加和孔径增大)相吻合,利于FRCPC中药物快速释放;且释放符合以扩散控释为主的Higuchi模型。FRCPC可实现防止耐药性发生的目的,通过进一步性能改进有望应用于临床。     

Mixed solvent system as binder for the production of silicified microcrystalline cellulose-based pellets

Silicified microcrystalline cellulose pellets with hydroxypropyl methylcellullose (HPMC) as modifier were prepared using a mixed solvent as liquid binder. Pellets were produced using extrusion-spheronization with a mixed solvent consisting of water and isopropanol as liquid binder. The key spheronization aid was Prosolv® SMCC 90. Low viscosity grade HPMC was incorporated aiming to modify release of indometacin. Physical characteristics including breaking load, apparent density and flow properties, particle size distribution and shape were determined. Drug loaded pellets were also tested for dissolution profiles. By adjusting liquid binder property, at isopropanol to water ratio of 3.5 to 6.5, pellets of desirable size and shape with reasonable yields were obtained. Pellets exhibited good flow property and they were mechanically strong. Pellet with higher HPMC content displayed a faster drug dissolution profile. This was because low viscosity grade HPMC was not enough to create strong gel. Instead hydration of HPMC molecules increased matrix's hydrophilicity and weakened the structure of pellet faster. The release of indometacin was partly based on the erosion of hydrated matrix. The presence of HPMC in the pellets would require a mixed solvent to produce desirable shape. Incorporation of HPMC had modified drug release from the pellets without further coating. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47924.     

New hybrid agarose/Cu-Bioglass® biomaterials for antibacterial coatings

Agarose hydrogels, combined with 45S5 Bioglass®, were elaborated to serve as copper delivery systems. Our aim was to study the antibacterial properties of these hydrogels. The results show that the amount of glass does not influence the stiffness properties, but it improves the hydrophilicity and the swelling profile of agarose hydrogel. Two bacterial strains, Bacillus sp. 4J6 and Pseudomonas aeruginosa sp. PAO1, were chosen. Their retention on the substrates was analyzed by confocal laser scanning microscopy. The mechanical characteristics and the release of copper have an effect on the bacterial adhesion and the biofilm formation. All the obtained results indicate that these hydrogels could be adapted to a potential application to the antibacterial coatings