Polyglycerol Sebacate Elastomer: A Critical Overview of Synthetic Methods and Characterisation Techniques.

Poly (glycerol sebacate) is a widely studied elastomeric copolymer obtained from the polycondensation of two bioresorbable monomers, glycerol and sebacic acid. Due to its biocompatibility and the possibility to tailor its biodegradability rate and mechanical properties, PGS has gained lots of interest in the last two decades, especially in the soft tissue engineering field. Different synthetic approaches have been proposed, ranging from classic thermal polyesterification and curing to microwave-assisted organic synthesis, UV crosslinking and enzymatic catalysis. Each technique, characterized by its advantages and disadvantages, can be tailored by controlling the crosslinking density, which depends on specific synthetic parameters. In this work, classic and alternative synthetic methods, as well as characterisation and tailoring techniques, are critically reviewed with the aim to provide a valuable tool for the reproducible and customized production of PGS for tissue engineering applications.

Investigation on Electrospun and Solvent-Casted PCL-PLGA Blends Scaffolds Embedded with Induced Pluripotent Stem Cells for Tissue Engineering.

The design, production, and characterisation of tissue-engineered scaffolds made of polylactic-co-glycolic acid (PLGA), polycaprolactone (PCL) and their blends obtained through electrospinning (ES) or solvent casting/particulate leaching (SC) manufacturing techniques are presented here. The polymer blend composition was chosen to always obtain a prevalence of one of the two polymers, in order to investigate the contribution of the less concentrated polymer on the scaffolds' properties. Physical-chemical characterization of ES scaffolds demonstrated that tailoring of fibre diameter and Young modulus (YM) was possible by controlling PCL concentration in PLGA-based blends, increasing the fibre diameter from 0.6 to 1.0 µm and reducing the YM from about 22 to 9 MPa. SC scaffolds showed a "bubble-like" topography, caused by the porogen spherical particles, which is responsible for decreasing the contact angles from about 110° in ES scaffolds to about 74° in SC specimens. Nevertheless, due to phase separation within the blend, solvent-casted samples displayed less reproducible properties. Furthermore, ES samples were characterised by 10-fold higher water uptake than SC scaffolds. The scaffolds suitability as iPSCs culturing support was evaluated using XTT assay, and pluripotency and integrin gene expression were investigated using RT-PCR and RT-qPCR. Thanks to their higher wettability and appropriate YM, SC scaffolds seemed to be superior in ensuring high cell viability over 5 days, whereas the ability to maintain iPSCs pluripotency status was found to be similar for ES and SC scaffolds.

Influence of Electrospun Fibre Secondary Morphology on Antibiotic Release Kinetic and Its Impact on Antimicrobic Efficacy.

Vascular graft infections are a severe complication in vascular surgery, with a high morbidity and mortality. Prevention and treatment involve the use of antibiotic- or antiseptic-impregnated artificial vascular grafts, but currently, there are no commercially available infection-proof small-diameter vascular grafts (SDVGs). In this work we investigated the antimicrobic activity of two SDVGs prototypes loaded with tobramycin and produced via the electrospinning of drug-doped PLGA (polylactide-co-glycolide) solutions. Differences in rheological and conductivity properties of the polymer solutions resulted in non-identical fibre morphology that deeply influenced the hydration profile and consequently the in vitro cumulative drug release, which was investigated by using a spectrofluorimetric technique. Using DDSolver Excel add-in, modelling of the drug release kinetic was performed to evaluate the release mechanism involved: Prototype 1 showed a sustained and diffusive driven drug release, which allowed for the complete elution of tobramycin within 2 weeks, whereas Prototype 2 resulted in a more extended drug release controlled by both diffusion and matrix relaxation. Time-kill assays performed on S. aureus and E. coli highlighted the influence of burst drug release on the decay rate of bacterial populations, with Prototype 1 being more efficient on both microorganisms. Nevertheless, both prototypes showed good antimicrobic activity over the 5 days of in vitro testing.

Graphene Nanoplatelets-Based Textured Polymeric Fibrous Fabrics for the Next-Generation Devices.

Graphene is a 2D crystal composed of carbon atoms in a hexagonal arrangement. From their isolation, graphene nanoplatelets (nCD) have revolutionized material science due to their unique properties, and, nowadays, there are countless applications, including drug delivery, biosensors, energy storage, and tissue engineering. Within this work, nCD were combined with PLA, a widely used and clinically relevant thermoplastic polymer, to produce advanced composite texturized electrospun fabric for the next-generation devices. The electrospinning manufacturing process was set-up by virtue of a proper characterization of the composite raw material and its solution. From the morphological point of view, the nCD addition permitted the reduction of the fiber diameter while the texture allowed more aligned fibers. After that, mechanical features of fabrics were tested at RT and upon heating (40 °C, 69 °C), showing the reinforcement action of nCD mainly in the texturized mats at 40 °C. Finally, mats' degradation in simulated physiological fluid was minimal up to 30 d, even if composite mats revealed excellent fluid-handling capability. Moreover, no toxic impurities and degradation products were pointed out during the incubation. This work gains insight on the effects of the combination of composite carbon-based material and texturized fibers to reach highly performing fabrics.

Tobramycin Nanoantibiotics and Their Advantages: A Minireview.

Nowadays, antimicrobial resistance (AMR) represents a challenge for antibiotic therapy, mostly involving Gram-negative bacteria. Among the strategies activated to overcome AMR, the repurposing of already available antimicrobial molecules by encapsulating them in drug delivery systems, such as nanoparticles (NPs) and also engineered NPs, seems to be promising. Tobramycin is a powerful and effective aminoglycoside, approved for complicated infections and reinfections and indicated mainly against Gram-negative bacteria, such as Pseudomonas aeruginosa, Escherichia coli, Proteus, Klebsiella, Enterobacter, Serratia, Providencia, and Citrobacter species. However, the drug presents several side effects, mostly due to dose frequency, and for this reason, it is a good candidate for nanomedicine formulation. This review paper is focused on what has been conducted in the last 20 years for the development of Tobramycin nanosized delivery systems (nanoantibiotics), with critical discussion and comparison. Tobramycin was selected as the antimicrobial drug because it is a wide-spectrum antibiotic that is effective against both Gram-positive and Gram-negative aerobic bacteria, and it is characterized by a fast bactericidal effect, even against multidrug-resistant microorganisms (MDR).

Tobramycin Supplemented Small-Diameter Vascular Grafts for Local Antibiotic Delivery: A Preliminary Formulation Study.

Peripheral artery occlusive disease is an emerging cardiovascular disease characterized by the blockage of blood vessels in the limbs and is associated with dysfunction, gangrene, amputation, and a high mortality risk. Possible treatments involve by-pass surgery using autologous vessel grafts, because of the lack of suitable synthetic small-diameter vascular prosthesis. One to five percent of patients experience vascular graft infection, with a high risk of haemorrhage, spreading of the infection, amputation and even death. In this work, an infection-proof vascular graft prototype was designed and manufactured by electrospinning 12.5% w/v poly-L-lactic-co-glycolic acid solution in 75% v/v dichloromethane, 23.8% v/v dimethylformamide and 1.2% v/v water, loaded with 0.2% w/wPLGA. Polymer and tobramycin concentrations were selected after viscosity and surface tension and after HPLC-UV encapsulation efficiency (EE%) evaluation, respectively. The final drug-loaded prototype had an EE% of 95.58% ± 3.14%, with smooth fibres in the nanometer range and good porosity; graft wall thickness was 291 ± 20.82 µm and its internal diameter was 2.61 ± 0.05 mm. The graft's antimicrobic activity evaluation through time-kill assays demonstrated a significant and strong antibacterial activity over 5 days against Staphylococcus aureus and Escherichia coli. An indirect cell viability assay on Normal Human Dermal Fibroblasts (NHDF) confirmed the cytocompatibility of the grafts.

Tubular Electrospun Vancomycin-Loaded Vascular Grafts: Formulation Study and Physicochemical Characterization.

This work aimed at formulating tubular grafts electrospun with a size < 6 mm and incorporating vancomycin as an antimicrobial agent. Compared to other papers, the present study succeeded in using medical healthcare-grade polymers and solvents permitted by ICH Topic Q3C (R4). Vancomycin (VMC) was incorporated into polyester synthetic polymers (poly-L-lactide-co-poly-ε-caprolactone and poly lactide-co-glycolide) using permitted solvents; moreover, a surfactant was added to the formulation in order to avoid the precipitation of VMC on fiber surface. A preliminary preformulation study was carried out to evaluate solubility of VMC in different aqueous and organic solvents and its stability. To reduce size of fibers and their orientation, we studied a solvent system based on methylene chloride and acetone (DCM/acetone), at different ratios (80:20, 70:30, and 60:40). Considering conductivity of solutions and their spinnability, solvent system at a 80:20 ratio was selected for the study. SEM images demonstrated that size of fibers, their distribution, and their orientation were affected by the incorporation of VMC and surfactant into polymer solution. Surfactant allowed for the reduction of precipitates of VMC on fiber surface, which are responsible of the high burst release in the first six hours; the release was mainly dependent on graft structure porosity, number of pores, and graft absorbent capability. A controlled release of VMC was achieved, covering a period from 96 to 168 h as a function of composition and structure; the concentration of VMC was significantly beyond VMC minimum inhibitory concentration (MIC, 2 ug/mL). These results indicated that the VMC tubular electrospun grafts not only controlled the local release of VMC, but also avoided onset of antibiotic resistance.