Gentamicin-eluting bioresorbable composite fibers for wound healing applications

New gentamicin-eluting bioresorbable core/shell fiber structures were developed and studied. These structures were composed of a polyglyconate core and a porous poly(DL-lactic-co-glycolic acid) (PDLGA) shell loaded with the antibiotic agent gentamicin, prepared using freeze drying of inverted emulsions. These unique fibers are designed to be used as basic elements of bioresorbable burn and ulcer dressings. The investigation focused on the effects of the emulsion's composition (formulation) on the shell's microstructure, on the drug release profile from the fibers, and on bacterial inhibition. The release profiles generally exhibited an initial burst effect accompanied by a decrease in release rates with time. Albumin was found to be the most effective surfactant for stabilizing the inverted emulsions. All three formulation parameters had a significant effect on gentamicin's release profile. An increase in the polymer and organic:aqueous phase ratio or a decrease in the drug content resulted in a lower burst release and a more moderate release profile. The released gentamicin also resulted in a significant decrease in bacterial viability and practically no bacteria survived after 2 days when using bacterial concentrations of 1 x 10(7) CFU/mL. Thus, our new fiber structures are effective against the relevant bacterial strains and can be used as basic elements of bioresorbable drug-eluting wound dressings.     

Paclitaxel-eluting composite fibers: drug release and tensile mechanical properties

New core/shell fiber structures loaded with paclitaxel were developed and studied. These composite fibers are ideal for forming thin, delicate, biomedically important structures for various applications. Possible applications include fiber-based endovascular stents that mechanically support blood vessels while delivering drugs for preventing restenosis directly to the blood vesel wall, or drug delivery systems for treatment of cancer. The core/shell fiber structures were formed by "coating" dense core fibers with porous paclitaxel-containing poly(DL-lactic-co-glycolic acid) (PDLGA) structures. Shell preparation ("coating") was performed by freeze-drying water in oil emulsions. The present study focused on the effects of the emulsion's formulation (composition) and processing conditions on the paclitaxel release profile and on the fibers' tensile mechanical properties. In general, the porous PDLGA shell released approximately 40% of the paclitaxel, with most of the release occurring during the first 30 days. The main release mechanism during the tested period is diffusion, rather than polymer degradation. The release rate and quantity increased with increased drug content or decreased polymer content, whereas the organic:aqueous phase ratio had practically no effect on the release profile. These new composite fibers are strong and flexible enough to be used as basic elements for stents. We demonstrated that proper selection of processing conditions based on kinetic and thermodynamic considerations can yield polymer/drug systems with the desired drug release behavior and good mechanical properties.     

Lysostaphin-functionalized cellulose fibers with antistaphylococcal activity for wound healing applications

With the emergence of "super bacteria" that are resistant to antibiotics, e.g., methicillin-resistant Staphylococcus aureus, novel antimicrobial therapies are needed to prevent associated hospitalizations and deaths. Bacteriophages and bacteria use cell lytic enzymes to kill host or competing bacteria, respectively, in natural environments. Taking inspiration from nature, we have employed a cell lytic enzyme, lysostaphin (Lst), with specific bactericidal activity against S. aureus, to generate anti-infective bandages. Lst was immobilized onto biocompatible fibers generated by electrospinning homogeneous solutions of cellulose, cellulose-chitosan, and cellulose-poly(methylmethacrylate) (PMMA) from 1-ethyl-3-methylimidazolium acetate ([EMIM][OAc]), room temperature ionic liquid. Electron microscopic analysis shows that these fibers have submicron-scale diameter. The fibers were chemically treated to generate aldehyde groups for the covalent immobilization of Lst. The resulting Lst-functionalized cellulose fibers were processed to obtain bandage preparations that showed activity against S. aureus in an in vitro skin model with low toxicity toward keratinocytes, suggesting good biocompatibility for these materials as antimicrobial matrices in wound healing applications.     

Bioresorbable nanofiber-based systems for wound healing and drug delivery: optimization of fabrication parameters

Wound healing is a complex process that often requires treatment with antibiotics. This article reports the initial development of a biodegradable polymeric nanofiber-based antibiotic delivery system. The functions of such a system would be (a) to serve as a biodegradable gauze, and (b) to serve as an antibiotic delivery system. The polymer used in this study was poly(lactide-co-glycolide) (PLAGA), and nanofibers of PLAGA were fabricated with the use of the electrospinning process. The objective of this study was to determine the effect of fabrication parameters: orifice diameter (needle gauge), polymer solution concentration, and voltage per unit length, on the morphology and diameter of electrospun nanofibers. The needle gauges studied were 16 (1.19 mm), 18 (0.84 mm), and 20 (0.58 mm), and the range of polymer solution concentration studied was from 0.10 g/mL to 0.30 g/mL. The effect of voltage was determined by varying the voltage per unit electrospinning distance, and the range studied was from 0.375 kV/cm to 1.5 kV/cm. In addition, the mass per unit area of the electrospun nanofibers as a function of time was determined and the feasibility of antibiotic (cefazolin) loading into the nanofibers was also studied. The results indicate that the diameter of nanofibers decreased with an increase in needle gauge (decrease in orifice diameter), and increased with an increase in the concentration of the polymer solution. The voltage study demonstrated that the average diameter of the nanofibers decreased with an increase in voltage. However, the effect of voltage on fiber diameter was less pronounced as compared to polymer solution concentration. The results of the areal density study indicated that the mass per unit area of the electrospun nanofibers increased linearly with time. Feasibility of drug incorporation into the nanofibers was demonstrated with the use of cefazolin, a broad-spectrum antibiotic. Overall, these studies demonstrated that PLAGA nanofibers can be tailored to desired diameters through modifications in processing parameters, and that antibiotics such as cefazolin can be incorporated into these nanofibers. Therefore, PLAGA nanofibers show potential as antibiotic delivery systems for the treatment of wounds.     

Chitosan nanoparticle/PCL nanofiber composite for wound dressing and drug delivery

Many investigations of wound dressings equipped with drug delivery systems have recently been conducted. Chitosan is widely used not only as a material for wound dressing by the efficacy of its own, but also as a nanoparticle for drug delivery. In this study, an electrospun polycaprolactone nanofiber composite with chitosan nanoparticles (ChiNP–PCLNF) was fabricated and then evaluated for its drug release and biocompatibility to skin fibroblasts. ChiNP–PCLNF complexes showed no cytotoxicity and nanoparticles adsorbed by van der Waals force were released into aquatic environments and then penetrated into rat primary fibroblasts. Our studies demonstrate the potential for application of ChiNP–PCLNF as a wound dressing system with drug delivery for skin wound healing without side effects.     

Protein-loaded bioresorbable fibers and expandable stents: Mechanical properties and protein release

There is an increasing interest in bioresorbable polymeric stents for coronary, urethral and tracheal applications. These stents can support body conduits during their healing process and release biologically active agents from an internal reservoir to the surrounding tissue. A removal operation is not needed. Bioresorbable poly(L-lactic acid) fibers were prepared through melt spinning accompanied by a postpreparation drawing process. Novel expandable bioresorbable stents were developed from these fibers. Bioresorbable microspheres containing albumin were prepared and attached to the stents, to serve as a protein reservoir coating. The controlled release of albumin from the microsphere-loaded stent was studied. The fibers combine high strength and modulus, together with good ductility and flexibility. An increase in draw ratio increases the tensile strength and modulus and decreases the ultimate strain. The stents demonstrated excellent initial radial compression strength and good in vitro degradation resistivity, which makes them applicable for supporting blood vessels for at least 20 weeks. Microspheres bound to these stents enable effective protein loading, without reducing the stent's mechanical properties. The protein release from the microsphere-loaded stent occurs by diffusion, is determined mainly by the initial molecular weight of the bioresorbable polymer and its erosion rate, and is strongly affected by the microsphere structure.     

In vitro and in vivo evaluation of the chitosan/Tur composite film for wound healing applications

We have developed tourmaline/chitosan (Tur/CS) composite films for wound healing applications. The characteristics of composite films were studied by optical microscope, infrared spectra and X-ray diffraction. Tur particles were uniformly distributed in the CS film and the crystal structure of CS was not remarkably changed except the decrease of crystallinity. The influence of Tur on wound healing applications was characterized by modulating Tur concentrations in the Tur/CS composite film prepared by loading Tur powder into CS matrix with different proportion (0, 1/40 and 1/10). Then L929 cells were co-cultured on the composite films to access the cytotoxicity in vitro. Tur concentrations strongly influenced cell process extension. Tur/CS composite film with 1/40 mass ratio could promote the cell adhesion and proliferation. Fewer and shorter processes were observed at high Tur density. When the composite films were transplanted on porcine full-thickness burn wounds, histological results demonstrated that the Tur/CS group with 1/40 mass ratio had a significantly higher number of newly-formed and mature blood vessels, and fastest regeneration of dermis. Based on the observed facts these films can be tailored for their potential utilization in wound healing and skin tissue engineering applications.     

High strength bioresorbable bone plates: preparation, mechanical properties and in vitro analysis

Biodegradable bone plates were prepared as semi-interpenetrating networks (SIPN) of crosslinked polypropylene fumarate (PPF) within a host matrix of either poly(lactide-co-glycolide)-85:15 (PLGA) or poly(1-lactide-co-d,l-lactide)-70:30 (PLA) using N-vinylpyrrolidone (NVP), ethylene glycol dimethacrylate (EGDMA), 2-hydroxyethyl methacrylate (HEMA), and methyl methacrylate (MMA) as crosslinking agents. Hydroxyapatite (HAP), an inorganic filler material, was used to further augment mechanical strength. The control crosslinking agent (NVP) was replaced partially and totally with other crosslinking agents. The amount of crosslinking agent lost, the characterization change in the mechanical properties and the dimensional stability of the bone plates after in vitro treatment was calculated. The optimum crosslinking agent was selected on the basis of low in vitro release of NVP from SIPN matrix. Bone plates were then prepared using this crosslinking agent at 5 MPa pressure and at temperatures between 100-140 degrees C to determine if there was any augmentation of mechanical properties in the presence of the crosslinked network. In vitro analysis showed that 90% of the crosslinking agent was lost on plates using NVP as a crosslinking agent. This loss was reduced to 50% when NVP was partially replaced with EGDMA or MMA. EGDMA was determined to be superior because (1) its low release as a crosslinking agent, (2) flexural plate strength of 50-67 MPa, (3) flexural modulus of 7-13 GPa, and (4) manufacturability stiffness of 300-600 N/m. HAP-loading resulted in an additional increase in values of mechanical parameters. Substituting PLGA with PLA in the PPF-SIPN did not show any additional improvement of mechanical properties.     

Surface-modified nanocrystalline ceramics for drug delivery applications

Drug delivery systems comprised of various types of carriers have long been the object of pharmacological investigation. The search has been stimulated by the belief that carriers will lead to reduced drug toxicity, dosage requirements, enhanced cellular targeting and improved shelf-life. Among the carriers investigated are complex polymeric carbohydrates, synthetic proteins and liposomal structures. For the past four years, we have been experimenting with a radically new class of carriers comprised of surface-modified nanocrystalline ceramics. While the ceramics provide the structural stability of a largely immutable solid, the surface modification creates a glassy molecular stabilization film to which pharmacological agents may be bound non-covalently from an aqueous phase with minimal structural denaturation. As a consequence of maintained structural integrity and owing to concentration effects afforded by the surfaces of the nanocrystalline materials, drug activity following surface immobilization is preserved. We have used successfully surface-modified nanocrystalline ceramics to deliver viral antigens for the purpose of evoking an immune response, oxygenated haemoglobin for cell respiration and insulin for carbohydrate metabolism. The theoretical principles, technical details and experimental results are reviewed. Surface-modified nanocrystalline materials offer an exciting new approach to the well-recognized challenges of drug delivery. Biomaterials (1994) 15, 1201–1207     

Resorbable composites with bioresorbable glass fibers for load-bearing applications. In vitro degradation and degradation mechanism

An in vitro degradation study of three bioresorbable glass fiber-reinforced poly(l-lactide-co-dl-lactide) (PLDLA) composites was carried out in simulated body fluid (SBF), to simulate body conditions, and deionized water, to evaluate the nature of the degradation products. The changes in mechanical and chemical properties were systematically characterized over 52 weeks dissolution time to determine the degradation mechanism and investigate strength retention by the bioresorbable glass fiber-reinforced PLDLA composite. The degradation mechanism was found to be a combination of surface and bulk erosion and does not follow the typical core-accelerated degradation mechanism of poly(α-hydroxyacids). Strength retention by bioresorbable glass fiber-reinforced PLDLA composites can be tailored by changing the oxide composition of the glass fibers, but the structure–property relationship of the glass fibers has to be understood and controlled so that the phenomenon of ion leaching can be utilized to control the degradation rate. Therefore, these high performance composites are likely to open up several new possibilities for utilizing resorbable materials in clinical applications which could not be realized in the past.     

靶向光热抗菌纳米材料及其在伤口愈合中的应用研究进展EI北大核心CSCD

随着光热纳米材料的开发,基于近红外光激发的光热疗法在细菌感染的伤口治疗中显示出巨大的潜力。同时,为提高伤口感染部位的光热抗菌效果,降低光热对健康组织的高温损伤,靶向细菌策略也逐渐被应用于伤口的光热治疗中。本文分类介绍了常用的光热纳米材料及其靶向细菌策略,阐述了它们在光热抗菌治疗,尤其是在细菌感染伤口中的应用,分析了靶向光热抗菌疗法在伤口愈合应用中面临的难题与挑战,最后对靶向光热抗菌材料的发展提出展望,以期为伤口光热治疗提供一条新的思路。     

In vitro degradation, flexural, compressive and shear properties of fully bioresorbable composite rods

Several studies have investigated self-reinforced polylactic acid (SR-PLA) and polyglycolic acid (SR-PGA) rods which could be used as intramedullary (IM) fixation devices to align and stabilise bone fractures. This study investigated totally bioresorbable composite rods manufactured via compression moulding at ∼100 °C using phosphate glass fibres (of composition 50P₂O₅–40CaO–5Na₂O–5Fe₂O₃ in mol%) to reinforce PLA with an approximate fibre volume fraction (v_f) of 30%. Different fibre architectures (random and unidirectional) were investigated and pure PLA rods were used as control samples.The degradation profiles and retention of mechanical properties were investigated and PBS was selected as the degradation medium. Unidirectional (P50 UD) composite rods had 50% higher initial flexural strength as compared to PLA and 60% higher in comparison to the random mat (P50 RM) composite rods. Similar initial profiles for flexural modulus were also seen comparing the P50 UD and P50 RM rods. Higher shear strength properties were seen for P50 UD in comparison to P50 RM and PLA rods. However, shear stiffness values decreased rapidly (after a week) whereas the PLA remained approximately constant. For the compressive strength studies, P50 RM and PLA rods remained approximately constant, whilst for the P50 UD rods a significantly higher initial value was obtained, which decreased rapidly after 3 days immersion in PBS.However, the mechanical properties decreased after immersion in PBS as a result of the plasticisation effect of water within the composite and degradation of the fibres. The fibres within the random and unidirectional composite rods (P50 RM and P50 UD) degraded leaving behind microtubes as seen from the SEM micrographs (after 28 days degradation) which in turn created a porous structure within the rods. This was the main reason attributed for the increase seen in mass loss and water uptake for the composite rods (∼17% and ∼16%, respectively).     

脂肪组织来源干细胞构建皮肤复合组织修复创面缺损

BACKGROUND: There is no clear understanding on the effects of subcutaneous fat and stem cells on wound healing. OBJECTIVE: To explore the therapeutic effects of skin composite prepared with adipose tissue-derived stem cells on skin defects. METHODS: Epidermal cells, fibroblasts, adipose tissue-derived stem cells as seed cells and bovine collagen gel as a scaffold were used to build a complex with a variety of cells. A 6-mm diameter circular skin defect was made on the both sides of the rat back. The right side as experimental side was implanted with an 8-mm diameter multilayer skin composite, and the left side (control side) was only treated with a simple dressing. RESULTS AND CONCLUSION: For the constructed multi-layer skin composite, the epidermal layer was continuously merged into the multi-layer, the fibroblasts evenly distributed in the corium layer, and lipid droplets existed in the fat layer in which the cells distributed uniformly. Cell aggregation was obviously observed at the junction of different layers. In the experimental side, the rate of wound healing, granulation tissue thickness, the thickness of dermis and the capillary density were significantly higher than those in the control side. Taken together, we can construct multilayer skin composites with a variety of cells as seed cells, such as epidermal cells, fibroblasts and adipose tissue-derived stem cells, and bovine collagen gel as a scaffold, which promote wound healing and increase the thickness of dermis.        

Electrospinning: applications in drug delivery and tissue engineering

Despite its long history and some preliminary work in tissue engineering nearly 30 years ago, electrospinning has not gained widespread interest as a potential polymer processing technique for applications in tissue engineering and drug delivery until the last 5-10 years. This renewed interest can be attributed to electrospinning's relative ease of use, adaptability, and the ability to fabricate fibers with diameters on the nanometer size scale. Furthermore, the electrospinning process affords the opportunity to engineer scaffolds with micro to nanoscale topography and high porosity similar to the natural extracellular matrix (ECM). The inherently high surface to volume ratio of electrospun scaffolds can enhance cell attachment, drug loading, and mass transfer properties. Various materials can be electrospun including: biodegradable, non-degradable, and natural materials. Electrospun fibers can be oriented or arranged randomly, giving control over both the bulk mechanical properties and the biological response to the scaffold. Drugs ranging from antibiotics and anticancer agents to proteins, DNA, and RNA can be incorporated into electrospun scaffolds. Suspensions containing living cells have even been electrospun successfully. The applications of electrospinning in tissue engineering and drug delivery are nearly limitless. This review summarizes the most recent and state of the art work in electrospinning and its uses in tissue engineering and drug delivery.     

Styrenic block copolymers for biomaterial and drug delivery applications

The use of styrenic block copolymers has undergone a renaissance as a biomaterial and drug delivery matrix. The early promise posed by the physical and biological properties of these block copolymers for implantable medical devices was not met. However, there has been an increased understanding of the role of microphase separation on the mediation of the biological response. Poly (styrene-b-isobutylene-b-styrene) (SIBS) block copolymer has critical enabling properties related to processing, vascular compatibility and bio-stability that has resulted in its use as the matrix for paclitaxel delivery from Boston Scientific's TAXUS coronary stent. These enabling properties will allow the continuing development of medical devices based on SIBS that meet demanding physical and biological requirements.     

Mechanical properties and in vitro degradation of bioresorbable fibers and expandable fiber-based stents

Bioresorbable polymeric support devices (stents) are being developed in order to improve the biocompatibility and drug reservoir capacity of metal stents, as well as to offer a temporary alternative to permanent metallic stents. These temporary devices may be utilized for coronary, urethral, tracheal, and other applications. The present study focuses on the mechanical properties of bioresorbable fibers as well as stents developed from these fibers. Fibers made of poly(L-lactide) (PLLA), polydioxanone (PDS), and poly(glycolide-co-epsilon-caprolactone) (PGACL) were studied in vitro. These fibers combine a relatively high initial strength and modulus together with sufficient ductility and flexibility, and were therefore chosen for use in stents. The effect of degradation on the tensile mechanical properties and morphology of these fibers was examined. The expandable stents developed from these fibers demonstrated excellent initial radial compression strength. The PLLA stents exhibited excellent in vitro degradation resistance and can therefore support body conduits such as blood vessels for prolonged periods of time. PDS and PGACL stents can afford good support for 5 and 2 weeks, respectively, and can therefore be utilized for short-term applications. The degradation resistance of the stents correlates with the profile of mechanical property deterioration of the corresponding bioresorbable fibers.     

The development of polyanhydrides for drug delivery applications

This paper reviews the development of the polyanhydrides as bioerodible polymers for drug delivery applications. The topics include design and synthesis of the polymer, physical properties, techniques to fabricate the polymer into drug delivery devices, evaluation of biocompatibility, and example applications of the polyanhydrides. Discussion of the interrelationship between the physical-chemical properties of the polyanhydrides, fabrication methods, and drug release rates is included. One section is devoted to a case study to provide a historical perspective of the development a polyanhydride-based drug delivery treatment from the conception of the idea to the final stages of human clinical trials. This section includes an outline of the extensive in vitro and in vivo testing that is necessary for development of a new material for biomedical applications.     

Hydrogels for buccal drug delivery: properties relevant for muco-adhesion

In order to develop a muco-adhesive hydrogel for buccal drug delivery it is necessary to understand fully the properties determining adhesiveness as well as mechanisms involved. In this study we measured glass transition temperatures, water contact angles and the peel- and shear detachment forces from porcine oral mucosa, of acrylic acid and butyl acrylate copolymers. The contact angle maximizes at 50% butyl acrylate content. The glass transition temperature decreases from 0% to 100% butyl acrylate. There seems to exist a certain combination of contact angle and glass transition temperature which is related to adhesiveness. This strongly suggests that, in order to obtain a muco-adhesive hydrogel, at least two properties have to be optimized: (1) the polarity of the polymer surface and (2) the molecular mobility of the polymer groups.     

Synthesis and properties of waterborne polyurethane hydrogels for wound healing dressings

To accomplish ideal wound healing dressing, a series of waterborne polyurethane (WBPU) hydrogels based on polyethylene glycol (PEG) were synthesized by polyaddition reaction in an emulsion system. The stable WBPU hydrogels which have remaining weight of above 85% were obtained. The effect of the soft segment (PEG) content on water absorbability of WBPU hydrogels was investigated. Water absorption % and equilibrium water content (%) of the WBPU hydrogel significantly increased in proportion to PEG content and the time of water-immersion. The maximum water absorption % and equilibrium water content (%) of WBPU hydrogels containing various PEG contents were in the range of 409-810% and 85-96%, respectively. The water vapor transmission rate of the WBPU hydrogels was found to be in the range of 1490-3118 g/m(2)/day. These results suggest that the WBPU hydrogels prepared in this study may have high potential as new wound dressing materials, which provide and maintain the adequate moist environment required to prevent scab formation and dehydration of the wound bed. By the wound healing evaluation using full-thickness rat model experiment, it was found that the wound covered with a typical WBPU hydrogel (HG-78 sample) was completely filled with new epithelium without any significant adverse reactions.     

The mechanical properties of individual,electrospun fibrinogen fibers

We used a combined atomic force microscopic (AFM)/fluorescence microscopic technique to study the mechanical properties of individual, electrospun fibrinogen fibers in aqueous buffer. Fibers (average diameter 208 nm) were suspended over 12 μm-wide grooves in a striated, transparent substrate. The AFM, situated above the sample, was used to laterally stretch the fibers and to measure the applied force. The fluorescence microscope, situated below the sample, was used to visualize the stretching process. The fibers could be stretched to 2.3 times their original length before breaking; the breaking stress was 22 × 10⁶ Pa. We collected incremental stress–strain curves to determine the viscoelastic behavior of these fibers. The total stretch modulus was 17.5 × 10⁶ Pa and the relaxed elastic modulus was 7.2 × 10⁶ Pa. When held at constant strain, electrospun fibrinogen fibers showed a fast and slow stress relaxation time of 3 and 55 s.Our fibers were spun from the typically used 90% 1,1,1,3,3,3-hexafluoro-2-propanol (90-HFP) electrospinning solution and re-suspended in aqueous buffer. Circular dichroism spectra indicate that α-helical content of fibrinogen is ～70% higher in 90-HFP than in aqueous solution.These data are needed to understand the mechanical behavior of electrospun fibrinogen structures. Our technique is also applicable to study other nanoscopic fibers.