PEGylated Micro/Nanoparticles Based on Biodegradable Poly(Ester Amides): Preparation and Study of the Core-Shell Structure by Synchrotron Radiation-Based FTIR Microspectroscopy and Electron Microscopy.

Surface modification of drug-loaded particles with polyethylene glycol (PEG) chains is a powerful tool that promotes better transport of therapeutic agents, provides stability, and avoids their detection by the immune system. In this study, we used a new approach to synthesize a biodegradable poly(ester amide) (PEA) and PEGylating surfactant. These were employed to fabricate micro/nanoparticles with a core-shell structure. Nanoparticle (NP)-protein interactions and self-assembling were subsequently studied by synchrotron radiation-based FTIR microspectroscopy (SR-FTIRM) and transmission electron microscopy (TEM) techniques. The core-shell structure was identified using IR absorption bands of characteristic chemical groups. Specifically, the stretching absorption band of the secondary amino group (3300 cm-1) allowed us to identify the poly(ester amide) core, while the band at 1105 cm-1 (C-O-C vibration) was useful to demonstrate the shell structure based on PEG chains. By integration of absorption bands, a 2D intensity map of the particle was built to show a core-shell structure, which was further supported by TEM images.

A Color Indicator Based on 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Bromide (MTT) and a Biodegradable Poly(ester amide) for Detecting Bacterial Contamination.

Bacterial contamination is a hazard in many industries, including food, pharmaceuticals, and healthcare. The availability of a rapid and simple method for detecting this type of contamination in sterile areas enables immediate intervention to avoid or reduce detrimental effects. Among these methods, colorimetric indicators are becoming increasingly popular due to their affordability, ease of use, and quick visual interpretation of the signal. In this article, a bacterial contamination indicator system was designed by incorporating MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) into an electrospun PADAS matrix, which is a biodegradable poly(ester amide) synthesized from L-alanine, 1,12-dodecanediol, and sebacic acid. Uniaxial stress testing, thermogravimetric analysis and scanning electron microscopy were used to examine the mechanical properties, thermal stability, and morphology of the mats, respectively. The capacity for bacterial detection was not only analyzed with agar and broth assays but also by replicating important environmental conditions. Among the MTT concentrations tested in this study (0.2%, 2%, and 5%), it was found that only with a 2% MTT content the designed system produced a color response visible to the naked eye with optimal intensity, a sensitivity limit of 104 CFU/mL, and 86% cell viability, which showed the great potential for its use to detect bacterial contamination. In summary, by means of the process described in this work, it was possible to obtain a simple, low-cost and fast-response bacterial contamination indicator that can be used in mask filters, air filters, or protective clothing.

Nylons with Applications in Energy Generators, 3D Printing and Biomedicine.

Linear polyamides, known as nylons, are a class of synthetic polymers with a wide range of applications due to their outstanding properties, such as chemical and thermal resistance or mechanical strength. These polymers have been used in various fields: from common and domestic applications, such as socks and fishing nets, to industrial gears or water purification membranes. By their durability, flexibility and wear resistance, nylons are now being used in addictive manufacturing technology as a good material choice to produce sophisticated devices with precise and complex geometric shapes. Furthermore, the emergence of triboelectric nanogenerators and the development of biomaterials have highlighted the versatility and utility of these materials. Due to their ability to enhance triboelectric performance and the range of applications, nylons show a potential use as tribo-positive materials. Because of the easy control of their shape, they can be subsequently integrated into nanogenerators. The use of nylons has also extended into the field of biomaterials, where their biocompatibility, mechanical strength and versatility have paved the way for groundbreaking advances in medical devices as dental implants, catheters and non-absorbable surgical sutures. By means of 3D bioprinting, nylons have been used to develop scaffolds, joint implants and drug carriers with tailored properties for various biomedical applications. The present paper aims to collect evidence of these recently specific applications of nylons by reviewing the literature produced in recent decades, with a special focus on the newer technologies in the field of energy harvesting and biomedicine.

Development of Responsive Nanoparticles for Cancer Therapy.

Great efforts are focused on the development of safe nano-carriers for the treatment of cancer in order to overcome some of the typical limitations of conventional therapies [...].

Copolymers and Blends Based on 3-Hydroxybutyrate and 3-Hydroxyvalerate Units.

This review presents a comprehensive update of the biopolymer poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), emphasizing its production, properties, and applications. The overall biosynthesis pathway of PHBV is explored in detail, highlighting recent advances in production techniques. The inherent physicochemical properties of PHBV, along with its degradation behavior, are discussed in detail. This review also explores various blends and composites of PHBV, demonstrating their potential for a range of applications. Finally, the versatility of PHBV-based materials in multiple sectors is examined, emphasizing their increasing importance in the field of biodegradable polymers.

Lanthanides-Substituted Hydroxyapatite for Biomedical Applications.

Lately, there has been an increasing demand for materials that could improve tissue regenerative therapies and provide antimicrobial effects. Similarly, there is a growing need to develop or modify biomaterials for the diagnosis and treatment of different pathologies. In this scenario, hydroxyapatite (HAp) appears as a bioceramic with extended functionalities. Nevertheless, there are certain disadvantages related to the mechanical properties and lack of antimicrobial capacity. To circumvent them, the doping of HAp with a variety of cationic ions is emerging as a good alterative due to the different biological roles of each ion. Among many elements, lanthanides are understudied despite their great potential in the biomedical field. For this reason, the present review focuses on the biological benefits of lanthanides and how their incorporation into HAp can alter its morphology and physical properties. A comprehensive section of the applications of lanthanides-substituted HAp nanoparticles (HAp NPs) is presented to unveil the potential biomedical uses of these systems. Finally, the need to study the tolerable and non-toxic percentages of substitution with these elements is highlighted.

Hydroxyapatite Biobased Materials for Treatment and Diagnosis of Cancer.

Great advances in cancer treatment have been undertaken in the last years as a consequence of the development of new antitumoral drugs able to target cancer cells with decreasing side effects and a better understanding of the behavior of neoplastic cells during invasion and metastasis. Specifically, drug delivery systems (DDS) based on the use of hydroxyapatite nanoparticles (HAp NPs) are gaining attention and merit a comprehensive review focused on their potential applications. These are derived from the intrinsic properties of HAp (e.g., biocompatibility and biodegradability), together with the easy functionalization and easy control of porosity, crystallinity and morphology of HAp NPs. The capacity to tailor the properties of DLS based on HAp NPs has well-recognized advantages for the control of both drug loading and release. Furthermore, the functionalization of NPs allows a targeted uptake in tumoral cells while their rapid elimination by the reticuloendothelial system (RES) can be avoided. Advances in HAp NPs involve not only their use as drug nanocarriers but also their employment as nanosystems for magnetic hyperthermia therapy, gene delivery systems, adjuvants for cancer immunotherapy and nanoparticles for cell imaging.

Drug-Biopolymer Dispersions: Morphology- and Temperature- Dependent (Anti)Plasticizer Effect of the Drug and Component-Specific Johari-Goldstein Relaxations.

Amorphous molecule-macromolecule mixtures are ubiquitous in polymer technology and are one of the most studied routes for the development of amorphous drug formulations. For these applications it is crucial to understand how the preparation method affects the properties of the mixtures. Here, we employ differential scanning calorimetry and broadband dielectric spectroscopy to investigate dispersions of a small-molecule drug (the Nordazepam anxiolytic) in biodegradable polylactide, both in the form of solvent-cast films and electrospun microfibres. We show that the dispersion of the same small-molecule compound can have opposite (plasticizing or antiplasticizing) effects on the segmental mobility of a biopolymer depending on preparation method, temperature, and polymer enantiomerism. We compare two different chiral forms of the polymer, namely, the enantiomeric pure, semicrystalline L-polymer (PLLA), and a random, fully amorphous copolymer containing both L and D monomers (PDLLA), both of which have lower glass transition temperature (Tg) than the drug. While the drug has a weak antiplasticizing effect on the films, consistent with its higher Tg, we find that it actually acts as a plasticizer for the PLLA microfibres, reducing their Tg by as much as 14 K at 30%-weight drug loading, namely, to a value that is lower than the Tg of fully amorphous films. The structural relaxation time of the samples similarly depends on chemical composition and morphology. Most mixtures displayed a single structural relaxation, as expected for homogeneous samples. In the PLLA microfibres, the presence of crystalline domains increases the structural relaxation time of the amorphous fraction, while the presence of the drug lowers the structural relaxation time of the (partially stretched) chains in the microfibres, increasing chain mobility well above that of the fully amorphous polymer matrix. Even fully amorphous homogeneous mixtures exhibit two distinct Johari-Goldstein relaxation processes, one for each chemical component. Our findings have important implications for the interpretation of the Johari-Goldstein process as well as for the physical stability and mechanical properties of microfibres with small-molecule additives.

Multifunctional Scaffolds Based on Emulsion and Coaxial Electrospinning Incorporation of Hydroxyapatite for Bone Tissue Regeneration.

Tissue engineering is nowadays a powerful tool to restore damaged tissues and recover their normal functionality. Advantages over other current methods are well established, although a continuous evolution is still necessary to improve the final performance and the range of applications. Trends are nowadays focused on the development of multifunctional scaffolds with hierarchical structures and the capability to render a sustained delivery of bioactive molecules under an appropriate stimulus. Nanocomposites incorporating hydroxyapatite nanoparticles (HAp NPs) have a predominant role in bone tissue regeneration due to their high capacity to enhance osteoinduction, osteoconduction, and osteointegration, as well as their encapsulation efficiency and protection capability of bioactive agents. Selection of appropriated polymeric matrices is fundamental and consequently great efforts have been invested to increase the range of properties of available materials through copolymerization, blending, or combining structures constituted by different materials. Scaffolds can be obtained from different processes that differ in characteristics, such as texture or porosity. Probably, electrospinning has the greater relevance, since the obtained nanofiber membranes have a great similarity with the extracellular matrix and, in addition, they can easily incorporate functional and bioactive compounds. Coaxial and emulsion electrospinning processes appear ideal to generate complex systems able to incorporate highly different agents. The present review is mainly focused on the recent works performed with Hap-loaded scaffolds having at least one structural layer composed of core/shell nanofibers.

Medicated Scaffolds Prepared with Hydroxyapatite/Streptomycin Nanoparticles Encapsulated into Polylactide Microfibers.

The preparation, characterization, and controlled release of hydroxyapatite (HAp) nanoparticles loaded with streptomycin (STR) was studied. These nanoparticles are highly appropriate for the treatment of bacterial infections and are also promising for the treatment of cancer cells. The analyses involved scanning electron microscopy, dynamic light scattering (DLS) and Z-potential measurements, as well as infrared spectroscopy and X-ray diffraction. Both amorphous (ACP) and crystalline (cHAp) hydroxyapatite nanoparticles were considered since they differ in their release behavior (faster and slower for amorphous and crystalline particles, respectively). The encapsulated nanoparticles were finally incorporated into biodegradable and biocompatible polylactide (PLA) scaffolds. The STR load was carried out following different pathways during the synthesis/precipitation of the nanoparticles (i.e., nucleation steps) and also by simple adsorption once the nanoparticles were formed. The loaded nanoparticles were biocompatible according to the study of the cytotoxicity of extracts using different cell lines. FTIR microspectroscopy was also employed to evaluate the cytotoxic effect on cancer cell lines of nanoparticles internalized by endocytosis. The results were promising when amorphous nanoparticles were employed. The nanoparticles loaded with STR increased their size and changed their superficial negative charge to positive. The nanoparticles' crystallinity decreased, with the consequence that their crystal sizes reduced, when STR was incorporated into their structure. STR maintained its antibacterial activity, although it was reduced during the adsorption into the nanoparticles formed. The STR release was faster from the amorphous ACP nanoparticles and slower from the crystalline cHAp nanoparticles. However, in both cases, the STR release was slower when incorporated in calcium and phosphate during the synthesis. The biocompatibility of these nanoparticles was assayed by two approximations. When extracts from the nanoparticles were evaluated in cultures of cell lines, no cytotoxic damage was observed at concentrations of less than 10 mg/mL. This demonstrated their biocompatibility. Another experiment using FTIR microspectroscopy evaluated the cytotoxic effect of nanoparticles internalized by endocytosis in cancer cells. The results demonstrated slight damage to the biomacromolecules when the cells were treated with ACP nanoparticles. Both ACP and cHAp nanoparticles were efficiently encapsulated in PLA electrospun matrices, providing functionality and bioactive properties.

A pH-Triggered Polymer Degradation or Drug Delivery System by Light-Mediated Cis/Trans Isomerization of o-Hydroxy Cinnamates.

A new methodology for the pH-triggered degradation of polymers or for the release of drugs under visible light irradiation based on the cyclization of ortho-hydroxy-cinnamates (oHC) to coumarins is described. The key oHC structural motif can be readily incorporated into the rational design of novel photocleavable polymers via click chemistry. This main-chain moiety undergoes a fast photocleavage when irradiated with 455 nm light provided that a suitable base is added. A series of polyethylene glycol-alt-ortho-hydroxy cinnamate (polyethylene glycol (PEG)n -alt-oHC)-based polymers are synthesized and the time-dependent visible-light initiated cleavage of the photoactive monomer and polymer is investigated in solution by a variety of spectroscopic and chromatographic techniques. The photo-degradation behavior of the water-soluble poly(PEG2000 -alt-oHC) is investigated within a broad pH range (pH = 2.1-11.8), demonstrating fast degradation at pH 11.8, while the stability of the polymer is greatly enhanced at pH 2.1. Moreover, the neat polymer shows long-term stability under daylight conditions, thus allowing its storage without special precautions. In addition, two water-soluble PEG-based drug-carrier molecules (mPEG2000 -oHC-benzhydrol/phenol) are synthesized and used for drug delivery studies, monitoring the process by UV-vis spectroscopy in an ON/OFF intermittent manner.

Recent Progress on Biodegradable Tissue Engineering Scaffolds Prepared by Thermally-Induced Phase Separation (TIPS).

Porous biodegradable scaffolds provide a physical substrate for cells allowing them to attach, proliferate and guide the formation of new tissues. A variety of techniques have been developed to fabricate tissue engineering (TE) scaffolds, among them the most relevant is the thermally-induced phase separation (TIPS). This technique has been widely used in recent years to fabricate three-dimensional (3D) TE scaffolds. Low production cost, simple experimental procedure and easy processability together with the capability to produce highly porous scaffolds with controllable architecture justify the popularity of TIPS. This paper provides a general overview of the TIPS methodology applied for the preparation of 3D porous TE scaffolds. The recent advances in the fabrication of porous scaffolds through this technique, in terms of technology and material selection, have been reviewed. In addition, how properties can be effectively modified to serve as ideal substrates for specific target cells has been specifically addressed. Additionally, examples are offered with respect to changes of TIPS procedure parameters, the combination of TIPS with other techniques and innovations in polymer or filler selection.

Poly(aspartic acid) Biohydrogel as the Base of a New Hybrid Conducting Material.

In the present study, a composite made of conducting polymer, poly(3,4-ethylenedioxythiophene) (PEDOT), and a biodegradable hydrogel of poly(aspartic acid) (PASP) were electrochemically interpenetrated with poly(hydroxymethyl-3,4-ethylenedioxythiophene) (PHMeDOT) to prepare a new interpenetrated polymer network (IPN). Different cross-linker and PEDOT MPs contents, as well as different electropolymerization times, were studied to optimize the structural and electrochemical properties. The properties of the new material, being electrically conductive, biocompatible, bioactive, and biodegradable, make it suitable for possible uses in biomedical applications.

Doped photo-crosslinked polyesteramide hydrogels as solid electrolytes for supercapacitors.

High-performance hydrogels play a crucial role as solid electrolytes for flexible electrochemical supercapacitors (ESCs). More specifically, all solid-state ESCs based on renewable, biodegradable and/or biocompatible hydrogels doped with inorganic salts as electrolytes are attractive not only because of their contribution to reducing resource consumption and/or the generation of electronic garbage, but also due to their potential applicability in the biomedical field. Here, computer simulations have been combined with experimental measurements to probe the outstanding capability as solid electrolytes of photo-crosslinked unsaturated polyesteramide hydrogels containing phenylalanine, butenediol and fumarate, and doped with NaCl (UPEA-Phe/NaCl). Atomistic molecular dynamics simulations have shown the influence of the hydrogel pore structure in the migration of Na+ and Cl- ions, suggesting that UPEA-Phe/NaCl hydrogels prepared without completing the photo-crosslinking reaction will exhibit better behavior as solid electrolytes. Theoretical predictions have been confirmed by potentiodynamic and galvanostatic studies on ESCs fabricated using poly(3,4-ethylenedioxythiophene) electrodes and UPEA-Phe/NaCl hydrogels, which were obtained using different times of exposure to UV radiation (i.e. 4 and 8 h for incomplete and complete photo-crosslinking reaction). Moreover, the behavior as a solid electrolyte of the UPEA-Phe/NaCl hydrogel prepared using a photo-polymerization time of 4 h has been found to be significantly superior to those exhibited by different polypeptide and polysaccharide hydrogels, which were analyzed using ESCs with identical electrodes and experimental conditions.

Electrically Polarized Hydroxyapatite: Influence of the Polarization Process on the Microstructure and Properties.

Semipermanently polarized hydroxyapatite, named SP/HAp(w), is obtained by applying a constant dc electric field of 1-10 kV/cm at 300-850 °C to the samples previously sintered in water vapor, while permanently polarized hydroxyapatite, PP/HAp(a), is produced by applying a dc electric field of 3 kV/cm at 1000 °C to the samples sintered in air. SP/HAp(w) has been used for biomedical applications, while PP/HAp(a) has been proved to be a valuable catalyst for N2 and CO2 fixation. In this work, structural differences between SP/HAp(w) and PP/HAp(a) have been ascertained using Raman microscopy, wide-angle X-ray diffraction, scanning electronic microscopy, high-resolution transmission electron microscopy, and grazing incidence X-ray diffraction. Results prove the existence of crystal distortion in the form of amorphous calcium phosphate and ß-tricalcium phosphate (ß-TCP) phases close to the surface because of the atmosphere used in the sintering process. The existence of an amorphous layer in the surface and the phase transition through ß-TCP of SP/HAp(w) are the structural factors responsible for the differences with respect to PP/HAp(a). Moreover, a superstructure has been identified in PP/HAp(a) samples, which could be another structural factor associated with enhanced conductivity, permanent polarization, and catalytic activity of this material.

Biominerals Formed by DNA and Calcium Oxalate or Hydroxyapatite: A Comparative Study.

Biominerals formed by DNA and calcium oxalate (CaOx) or hydroxyapatite (HAp), the most important and stable phase of calcium phosphate) have been examined and compared using a synergistic combination of computer simulation and experimental studies. The interest of this comparison stems from the medical observation that HAp- and CaOx-based microcalcifications are frequently observed in breast cancer tissues, and some of their features are used as part of the diagnosis. Molecular dynamics simulations show that (1) the DNA double helix remains stable when it is adsorbed onto the most stable facet of HAp, whereas it undergoes significant structural distortions when it is adsorbed onto CaOx; (2) DNA acts as a template for the nucleation and growth of HAp but not for the mineralization of CaOx; and (3) the DNA double helix remains stable when it is encapsulated inside HAp nanopores, but it becomes destabilized when the encapsulation occurs into CaOx nanopores. Furthermore, CaOx and HAp minerals containing DNA molecules inside and/or adsorbed on the surface have been prepared in the lab by mixing solutions containing the corresponding ions with fish sperm DNA. Characterization of the formed minerals, which has been focused on the identification of DNA using UV-vis spectroscopy, indicates that the tendency to adsorb and, especially, encapsulate DNA is much smaller for CaOx than for HAp, which is in perfect agreement with results from molecular dynamics simulations. Finally, quantum mechanical calculations have been performed to rationalize these results in terms of molecular interactions, evidencing the high affinity of Ca2+ toward oxalate anions in an aqueous environment.

Incorporation of Chloramphenicol Loaded Hydroxyapatite Nanoparticles into Polylactide.

Chloramphenicol (CAM) has been encapsulated into hydroxyapatite nanoparticles displaying different morphologies and crystallinities. The process was based on typical precipitation of solutions containing phosphate and calcium ions and the addition of CAM once the hydroxyapatite nuclei were formed. This procedure favored a disposition of the drug into the bulk parts of the nanoparticles and led to a fast release in aqueous media. Clear antibacterial activity was derived, being slightly higher for the amorphous samples due to their higher encapsulation efficiency. Polylactide (PLA) microfibers incorporating CAM encapsulated in hydroxyapatite nanoparticles were prepared by the electrospinning technique and under optimized conditions. Drug release experiments demonstrated that only a small percentage of the loaded CAM could be delivered to an aqueous PBS medium. This amount was enough to render an immediate bacteriostatic effect without causing a cytotoxic effect on osteoblast-like, fibroblasts, and epithelial cells. Therefore, the prepared scaffolds were able to retain CAM-loaded nanoparticles, being a reservoir that should allow a prolonged release depending on the polymer degradation rate. The studied system may have promising applications for the treatment of cancer since CAM has been proposed as a new antitumor drug.

Non-Isothermal Crystallization Kinetics of Poly(4-Hydroxybutyrate) Biopolymer.

The non-isothermal crystallization of the biodegradable poly(4-hydroxybutyrate) (P4HB) has been studied by means of differential scanning calorimetry (DSC) and polarizing optical microscopy (POM). In the first case, Avrami, Ozawa, Mo, Cazé, and Friedman methodologies were applied. The isoconversional approach developed by Vyazovkin allowed also the determination of a secondary nucleation parameter of 2.10 × 105 K2 and estimating a temperature close to 10 °C for the maximum crystal growth rate. Similar values (i.e., 2.22 × 105 K2 and 9 °C) were evaluated from non-isothermal Avrami parameters. All experimental data corresponded to a limited region where the polymer crystallized according to a single regime. Negative and ringed spherulites were always obtained from the non-isothermal crystallization of P4HB from the melt. The texture of spherulites was dependent on the crystallization temperature, and specifically, the interring spacing decreased with the decrease of the crystallization temperature (Tc). Synchrotron data indicated that the thickness of the constitutive lamellae varied with the cooling rate, being deduced as a lamellar insertion mechanism that became more relevant when the cooling rate increased. POM non-isothermal measurements were also consistent with a single crystallization regime and provided direct measurements of the crystallization growth rate (G). Analysis of the POM data gave a secondary nucleation constant and a bell-shaped G-Tc dependence that was in relative agreement with DSC analysis. All non-isothermal data were finally compared with information derived from previous isothermal analyses.

Hydroxyapatite with Permanent Electrical Polarization: Preparation, Characterization, and Response against Inorganic Adsorbates.

Permanently polarized hydroxyapatite (HAp) particles have been prepared by applying a constant DC of 500 V at 1000 °C for 1 h to the sintered mineral. This process causes important chemical changes, as the formation of OH- defects (vacancies), the disappearance of hydrogenophosphate ions at the mineral surface layer, and structural variations reflected by the increment of the crystallinity. As a consequence, the electrochemical properties and electrical conductivity of the polarized mineral increase noticeably compared with as-prepared and sintered samples. Moreover, these increments remain practically unaltered after several months. In addition, permanent polarization favours significantly the ability of HAp to adsorb inorganic bioadsorbates in comparison with as-prepared and sintered samples. The adsorbates cause a significant increment of the electrochemical stability and electrical conductivity with respect to bare polarized HAp, which may have many implications for biomedical applications of permanently polarized HAp.

Tuning the Kinetic Stability of the Amorphous Phase of the Chloramphenicol Antibiotic.

We employ broadband dielectric spectroscopy to study the relaxation dynamics and crystallization kinetics of a broad-spectrum antibiotic, chloramphenicol, in its supercooled liquid form. Two dynamic processes are observed: the structural α relaxation, which becomes kinetically frozen at Tg = 302 ± 1 K, and an intramolecular secondary relaxation. Under isothermal conditions, the supercooled drug displays interconversion between different isomers, followed by recrystallization. Recrystallization follows the Avrami law with Avrami exponent n = 1.3 ± 0.1, consistent with a one-dimensional growth of crystalline platelets, as observed by electron microscopy. Exposure to humid atmosphere and subsequent heating to high temperature is found to degrade the compound. The partially degraded sample displays a much lower tendency to crystallize, likely because the presence of the degradation products results in spatial frustration. This sample exhibits enhanced conductivity and an additional relaxation, intermediate to the ones observed in the pure sample, which likely corresponds to the noncooperative dynamics of the main degradation product. We find that dispersing the antibiotic in polylactic acid results in an amorphous sample, which does not crystallize at room temperature for relatively long times.