Bioactivity of Chitosan-Based Particles Loaded with Plant-Derived Extracts for Biomedical Applications: Emphasis on Antimicrobial Fiber-Based Systems.

Marine-derived chitosan (CS) is a cationic polysaccharide widely studied for its bioactivity, which is mostly attached to its primary amine groups. CS is able to neutralize reactive oxygen species (ROS) from the microenvironments in which it is integrated, consequently reducing cell-induced oxidative stress. It also acts as a bacterial peripheral layer hindering nutrient intake and interacting with negatively charged outer cellular components, which lead to an increase in the cell permeability or to its lysis. Its biocompatibility, biodegradability, ease of processability (particularly in mild conditions), and chemical versatility has fueled CS study as a valuable matrix component of bioactive small-scaled organic drug-delivery systems, with current research also showcasing CS's potential within tridimensional sponges, hydrogels and sutures, blended films, nanofiber sheets and fabric coatings. On the other hand, renewable plant-derived extracts are here emphasized, given their potential as eco-friendly radical scavengers, microbicidal agents, or alternatives to antibiotics, considering that most of the latter have induced bacterial resistance because of excessive and/or inappropriate use. Loading them into small-scaled particles potentiates a strong and sustained bioactivity, and a controlled release, using lower doses of bioactive compounds. A pH-triggered release, dependent on CS's protonation/deprotonation of its amine groups, has been the most explored stimulus for that control. However, the use of CS derivatives, crosslinking agents, and/or additional stabilization processes is enabling slower release rates, following extract diffusion from the particle matrix, which can find major applicability in fiber-based systems within ROS-enriched microenvironments and/or spiked with microbes. Research on this is still in its infancy. Yet, the few published studies have already revealed that the composition, along with an adequate drug release rate, has an important role in controlling an existing infection, forming new tissue, and successfully closing a wound. A bioactive finishing of textiles has also been promoting high particle infiltration, superior washing durability, and biological response.

Functionalization of Crosslinked Sodium Alginate/Gelatin Wet-Spun Porous Fibers with Nisin Z for the Inhibition of Staphylococcus aureus-Induced Infections.

Nisin Z, an amphipathic peptide, with a significant antibacterial activity against Gram-positive bacteria and low toxicity in humans, has been studied for food preservation applications. Thus far, very little research has been done to explore its potential in biomedicine. Here, we report the modification of sodium alginate (SA) and gelatin (GN) blended microfibers, produced via the wet-spinning technique, with Nisin Z, with the purpose of eradicating Staphylococcus aureus-induced infections. Wet-spun SAGN microfibers were successfully produced at a 70/30% v/v of SA (2 wt%)/GN (1 wt%) polymer ratio by extrusion within a calcium chloride (CaCl2) coagulation bath. Modifications to the biodegradable fibers' chemical stability and structure were then introduced via crosslinking with CaCl2 and glutaraldehyde (SAGNCL). Regardless of the chemical modification employed, all microfibers were labelled as homogeneous both in size (≈246.79 µm) and shape (cylindrical and defect-free). SA-free microfibers, with an increased surface area for peptide immobilization, originated from the action of phosphate buffer saline solution on SAGN fibers, were also produced (GNCL). Their durability in physiological conditions (simulated body fluid) was, however, compromised very early in the experiment (day 1 and 3, with and without Nisin Z, respectively). Only the crosslinked SAGNCL fibers remained intact for the 28 day-testing period. Their thermal resilience in comparison with the unmodified and SA-free fibers was also demonstrated. Nisin Z was functionalized onto the unmodified and chemically altered fibers at an average concentration of 178 µg/mL. Nisin Z did not impact on the fiber's morphology nor on their chemical/thermal stability. However, the peptide improved the SA fibers (control) structural integrity, guaranteeing its stability for longer, in physiological conditions. Its main effect was detected on the time-kill kinetics of the bacteria S. aureus. SAGNCL and GNCL loaded with Nisin Z were capable of progressively eliminating the bacteria, reaching an inhibition superior to 99% after 24 h of culture. The peptide-modified SA and SAGN were not as effective, losing their antimicrobial action after 6 h of incubation. Bacteria elimination was consistent with the release kinetics of Nisin Z from the fibers. In general, data revealed the increased potential and durable effect of Nisin Z (significantly superior to its free, unloaded form) against S. aureus-induced infections, while loaded onto prospective biomedical wet-spun scaffolds.

Sodium alginate-based multifunctional sandwich-like system for treating wound infections.

Microbial colonization and development of infections in wounds is a sign of chronicity. The prevailing approach to manage and treat these wounds involves dressings. However, these often fail in effectively addressing infections, as they struggle to both absorb exudates and maintain optimal local moisture. The system here presented was conceptualized with a three-layer design: the outer layer made of a fibrous polycaprolactone (PCL) film, to act as a barrier for preventing microorganisms and impurities from reaching the wound; the intermediate layer formed of a sodium alginate (SA) hydrogel loaded with ampicillin (Amp) for fighting infections; and the inner layer comprised of a fibrous film of PCL and polyethylene glycol (PEG) for facilitating cell recognition and preventing wound adhesion. Thermal evaluations, degradation, wettability and release behavior testing confirmed the system resistance overtime. The sandwich demonstrated the capability for absorbing exudates (≈70 %) and exhibited a controlled release of Amp for up to 24 h. Antimicrobial testing was performed against Staphylococcus aureus and Escherichia coli, as representatives of Gram-positive and Gram-negative bacteria: >99 % elimination of bacteria. Cell cytotoxicity assessments showed high cytocompatibility levels, confirming the safety of the proposed sandwich system. Adhesion assays confirmed the system ease of detaching without mechanical effort (0.37 N). Data established the efficiency of the sandwich-like system, suggesting promising applications in infected wound care.

Nanoparticle Synthesis and Their Integration into Polymer-Based Fibers for Biomedical Applications.

The potential of nanoparticles as effective drug delivery systems combined with the versatility of fibers has led to the development of new and improved strategies to help in the diagnosis and treatment of diseases. Nanoparticles have extraordinary characteristics that are helpful in several applications, including wound dressings, microbial balance approaches, tissue regeneration, and cancer treatment. Owing to their large surface area, tailor-ability, and persistent diameter, fibers are also used for wound dressings, tissue engineering, controlled drug delivery, and protective clothing. The combination of nanoparticles with fibers has the power to generate delivery systems that have enhanced performance over the individual architectures. This review aims at illustrating the main possibilities and trends of fibers functionalized with nanoparticles, focusing on inorganic and organic nanoparticles and polymer-based fibers. Emphasis on the recent progress in the fabrication procedures of several types of nanoparticles and in the description of the most used polymers to produce fibers has been undertaken, along with the bioactivity of such alliances in several biomedical applications. To finish, future perspectives of nanoparticles incorporated within polymer-based fibers for clinical use are presented and discussed, thus showcasing relevant paths to follow for enhanced success in the field.

Sodium alginate/polycaprolactone co-axial wet-spun microfibers modified with N-carboxymethyl chitosan and the peptide AAPV for Staphylococcus aureus and human neutrophil elastase inhibition in potential chronic wound scenarios.

In chronic wound (CW) scenarios, Staphylococcus aureus-induced infections are very prevalent. This leads to abnormal inflammatory processes, in which proteolytic enzymes, such as human neutrophil elastase (HNE), become highly expressed. Alanine-Alanine-Proline-Valine (AAPV) is an antimicrobial tetrapeptide capable of suppressing the HNE activity, restoring its expression to standard rates. Here, we proposed the incorporation of the peptide AAPV within an innovative co-axial drug delivery system, in which the peptide liberation was controlled by N-carboxymethyl chitosan (NCMC) solubilization, a pH-sensitive antimicrobial polymer effective against Staphylococcus aureus. The microfibers' core was composed of polycaprolactone (PCL), a mechanically resilient polymer, and AAPV, while the shell was made of the highly hydrated and absorbent sodium alginate (SA) and NCMC, responsive to neutral-basic pH (characteristic of CW). NCMC was loaded at twice its minimum bactericidal concentration (6.144 mg/mL) against S. aureus, while AAPV was loaded at its maximum inhibitory concentration against HNE (50 µg/mL), and the production of fibers with a core-shell structure, in which all components could be detected (directly or indirectly), was confirmed. Core-shell fibers were characterized as flexible and mechanically resilient, and structurally stable after 28-days of immersion in physiological-like environments. Time-kill kinetics evaluations revealed the effective action of NCMC against S. aureus, while elastase inhibitory activity examinations proved the ability of AAPV to reduce HNE levels. Cell biology testing confirmed the safety of the engineered fiber system for human tissue contact, with fibroblast-like cells and human keratinocytes maintaining their morphology while in contact with the produced fibers. Data confirmed the engineered drug delivery platform as potentially effective for applications in CW care.

Tunable Spun Fiber Constructs in Biomedicine: Influence of Processing Parameters in the Fibers' Architecture.

Electrospinning and wet-spinning have been recognized as two of the most efficient and promising techniques for producing polymeric fibrous constructs for a wide range of applications, including optics, electronics, food industry and biomedical applications. They have gained considerable attention in the past few decades because of their unique features and tunable architectures that can mimic desirable biological features, responding more effectively to local demands. In this review, various fiber architectures and configurations, varying from monolayer and core-shell fibers to tri-axial, porous, multilayer, side-by-side and helical fibers, are discussed, highlighting the influence of processing parameters in the final constructs. Additionally, the envisaged biomedical purposes for the examined fiber architectures, mainly focused on drug delivery and tissue engineering applications, are explored at great length.

Spun Biotextiles in Tissue Engineering and Biomolecules Delivery Systems.

Nowadays, tissue engineering is described as an interdisciplinary field that combines engineering principles and life sciences to generate implantable devices to repair, restore and/or improve functions of injured tissues. Such devices are designed to induce the interaction and integration of tissue and cells within the implantable matrices and are manufactured to meet the appropriate physical, mechanical and physiological local demands. Biodegradable constructs based on polymeric fibers are desirable for tissue engineering due to their large surface area, interconnectivity, open pore structure, and controlled mechanical strength. Additionally, biodegradable constructs are also very sought-out for biomolecule delivery systems with a target-directed action. In the present review, we explore the properties of some of the most common biodegradable polymers used in tissue engineering applications and biomolecule delivery systems and highlight their most important uses.