Publications

With the aim of healing challenging skin wounds, electro-responsive click-hydrogels made of hyaluronic acid (clickHA) crosslinked with a modified polyethylene glycol precursor (PEG) were prepared by semi- interpenetrating a conducting polymer, poly(hydroxymethyl-3,4-ethylenedioxythiophene) (PEDOT-MeOH) by oxidative polymerization. The porosity and pore size of the mixed hydrogel, clickHA/PEDOT-MeOH, were both higher than those determined for the hydrogel without PEDOT-MeOH, while a honeycomb-like morphology with PEDOT-MeOH covering the pore walls was observed. Although such PEDOT-MeOH-induced changes did not influence the water absorption capacity of clickHA, they drastically affected the mechanical and electrochemical behavior. More specifically, the semi-interpenetration of PEDOT-MeOH into clickHA resulted in an increase of the Young's modulus, the compressive strength and, especially, the electrochemical activity. The biocompatibility and the potential for skin regeneration of clickHA/PEDOT-MeOH were preliminary assessed using viability and wound-healing assays with epithelial cells. Not only is the conducting hydrogel formulation biocompatible, but also promotes efficient cell migration by electrostimulation using a small voltage (0.5 V) for a short time (15 min). Thus, in just 1 h the wound gap was repaired, and a homogeneous monolayer of migrated cells was formed.

JTD Keywords: 4-ethylenedioxythiophene, Car, Click hydrogel, Conducting polymer, Hyaluronic acid, Poly(3, Proliferation, Rational design, Scaffold, Skin, Wound dressing

We report the fabrication and characterization of a highly sensitive pressure sensor that has been successfully tested using 3D-bioprinted skeletal muscle tissue. The proposed pressure sensor consists of two assembled 3D printed specimens, which were obtained using 60/40 v/v poly(3,4-ethylenedioxythiophene):polystyrene sulfonic acid (PEDOT:PSS) / poly(ethylene glycol) diacrylate (PEGDA) mixture, placed between two indium tin oxidecoated polyethylene terephthalate (PET-ITO) films. The printed specimens were shaped with a serrated structure, improving the sensitivity of the contact when pressed against PET-ITO film. Initially, the performance of the fabricated pressure sensor was tested using light cylindrical weights, which corresponded to pressures ranging from 0.99 to 14.71 kPa, and as prove of concept, carefully pressing with the finger (from 2.91 to 6.81 kPa). As the sensitivity and fast response of sensor were compatible with detection of soft muscle contractions, 3D-bioprinted skeletal muscle bioactuators were manufactured using myoblast cells. The contractions of the bioactuators, which were induced using electrical stimulation, exerted a pressure of 1.5 kPa only that was clearly and precisely detected by the sensor. Overall, the potential application of proposed pressure sensor for wearable and biomedical devices is evidenced by demonstrating its fast response time (< 50 ms) and sensitivity.

JTD Keywords: 4-ethylenedioxythiophene), Bioactuator, Healt, Hydrogels, Poly(3, Poly(ethylene glycol) diacrylate, Raman-spectroscopy, Soft electronics, Wearable electronic

To improve the features of alginate-based hydrogels in physiological conditions, Ca2+-crosslinked 2 +-crosslinked semi interpenetrated hydrogels formed by poly(3,4-ethylenedioxythiophene):polystyrene sulfonic acid and alginate (PEDOT/Alg) were subjected to a treatment with glyoxal to form a dual ionic/covalent network. The covalent network density was systematically varied by considering different glyoxalization times (tG). t G ). The content of Ca2+ was significantly higher for the untreated hydrogel than for the glyoxalized ones, while the properties of the hydrogels were found to largely depend on t G . The porosity and swelling capacity decreased with increasing while the stiffness and electrical conductance retention capacity increased with t G . The potentiodynamic response of the hydrogels notably depended on the amount of conformational restraints introduced by the glyoxal, which is a very short crosslinker. Thus, the re-accommodation of the polymer chains during the cyclic potential scans became more difficult with increasing number of covalent crosslinks. This information was used to improve the performance of untreated PEDOT/Alg as electrochemical sensor of hydrogen peroxide by simply applying a tG G of 5 min. Overall, the control of the properties of glyoxalized hydrogels through tG G is very advantageous and can be used as an on-demand strategy to improve the performance of such materials depending on the application.

JTD Keywords: 4-ethylenedioxythiophene), Acid, Behavior, Cell, Conducting hydrogels, Dual networ, Electrochemical biosensor, Fabrication, Gel, Linke, Microspheres, Peroxidase, Poly(3, Polyvinyl-alcohol, Semi-interpenetrated hydrogel

Surgical sutures are long-established medical devices that play an important role closing and healing damaged tissues and organs postoperatively. However, current commercial sutures are not able to detect infections at the wound site, which are quite frequent after surgery. In this work, we present mechanically stable smart sutures for the real-time monitoring of bacterial growth and biofilm formation. For this purpose, a conducting polymer named poly(3,4-ethylenedioxythiophene) (PEDOT), which is able to detect bacteria metabolites, was implemented as a coating onto commercial biostable sutures. A protecting hydrogel layer with adhesive properties, which was made of polydopamine-polyacrylamide (PDA-PAM), was used to prevent the detachment of the sensing coating of PEDOT upon looping and knotting the suture. The protective hydrogel preserved not only the knot mechanical properties of the suture but also the electrochemical response of the PEDOT-coating and, therefore, its ability to detect NADH from bacteria respiration. Ex-vivo assays using sutured swine intestine samples demonstrated that the suture with the PDA-PAM hydrogel layer detects the growth of bacteria in real tissues. As a proof of concept, sutures coated with PEDOT and protected with PDA-PAM were used to inhibit the local growth of bacteria in sutured intestines by applying controlled electrostimuli. Results evidenced that smart electro-responsive sutures can be used as multi-task devices focused on fighting bacterial infections, meaning not only monitoring but also hampering bacteria growth.

JTD Keywords: 4-ethylenedioxythiophene), Bacteria growth detection, Bacteria growth inhibition, Multi-task biomedical devices, Nanoparticles, Pape, Poly(3, Polydopamine-polyacrylamide, Sensor, Smart suture

Biofabrication of three-dimensional (3D) cultures through the 3D Bioprinting technique opens new perspectives and applications of cell-laden hydrogels. However, to continue with the progress, new BioInks with specific properties must be carefully designed. In this study, we report the synthesis and 3D Bioprinting of an electroconductive BioInk made of gelatin/fibrinogen hydrogel, C2C12 mouse myoblast and 5% w/w of conductive poly (3,4-ethylenedioxythiophene) nanoparticles (PEDOT NPs). The influence of PEDOT NPs, incorporated in the cellladen BioInk, not only showed a positive effect in cells viability, differentiation and myotube functionalities, also allowed the printed constructs to behaved as BioCapacitors. Such devices were able to electrochemically store a significant amount of energy (0.5 mF/cm2), enough to self-stimulate as BioActuator, with typical contractions ranging from 27 to 38 mu N, during nearly 50 min. The biofabrication of 3D constructs with the proposed electroconductive BioInk could lead to new devices for tissue engineering, biohybrid robotics or bioelectronics.

JTD Keywords: 3d bioprinting, Animal, Animals, Bioactuator, Bioactuators, Biocapacitor, Biofabrication, Bioprinting, Biosensing techniques, C2c12 myoblasts, Cells, Chemistry, Electric conductivity, Electroconductive, Electroconductive bioink, Ethylenedioxythiophenes, Genetic procedures, Hydrogel, Hydrogels, Mice, Mouse, Pedot nps, Pedot nps,3d bioprinting,electroconductive bioink,bioactuator,biocapacito, Poly (3,4-ethylenedioxythiophene) nanoparticle, Printing, three-dimensional, Procedures, Skeletal-muscle,cytotoxicity,polymer, Synthesis (chemical), Three dimensional printing, Tissue engineering, Tissue scaffolds

Very recently, the controlled release of dopamine (DA), a neurotransmitter whose deficiency is associated with Parkinson's disease, has been postulated as a good alternative to the oral administration of levodopa (L-Dopa), a dopamine precursor, to combat the effects of said disease. However, this is still a very little explored field and there are very few carriers that are capable of releasing DA, a small and water-soluble molecule, in an efficient and controlled manner. In this work, we report a carrier based on a conductive hydrogel capable of loading DA and releasing it progressively and efficiently (100 % release) in a period of five days by applying small electrical stimuli (-0.4 V) daily for a short time (1 min). The hydrogel (CMC/PEDOT), which is electrically active, has been prepared from sodium carboxymethylcellulose and poly(3,4-ethylenedioxythiophene) microparticles, using citric acid as a cross-linking agent. Furthermore, the results have shown that when relatively hydrophobic small molecules, such as chloramphenicol, are loaded, the electrostimulated release is significantly less efficient, demonstrating the usefulness of CMC/PEDOT as a carrier for neurotransmitters.

JTD Keywords: Amines, Carboxymethyl cellulose, Carboxymethylcellulose, Conducting hydrogels, Conducting polymers, Controlled release, Crosslinking, Dopamine, Drug-delivery system, Electrostimulation, Hydrogels, Joining, Levodopa, Loading, Molecules, Neurophysiology, Neurotransmitter release, Neurotransmitters release, Oral administration, Parkinson's disease, Parkinsons-disease, Poly(3,4-ethylenedioxythiophene), Release, Sodium, Transport, Water-soluble molecule

Virtually, all implantable medical devices are susceptible to infection. As the main healthcare issue concerning implantable devices is the elevated risk of infection, different strategies based on the coating or functionalization of biomedical devices with antiseptic agents or antibiotics are proposed. In this work, an alternative approach is presented, which consists of the functionalization of implantable medical devices with sensors capable of detecting infection at very early stages through continuous monitoring of the bacteria metabolism. This approach, which is implemented in surgical sutures as a representative case of implantable devices susceptible to bacteria colonization, is expected to minimize the risk of worsening the patient's clinical condition. More specifically, non-absorbable polypropylene/polyethylene (PP/PE) surgical sutures are functionalized with conducting polymers using a combination of low-pressure oxygen plasma, chemical oxidative polymerization, and anodic polymerization, to detect metabolites coming from bacteria respiration. Functionalized suture yarns are used for real-time monitoring of bacteria growth, demonstrating the potential of this strategy to fight against infections.© 2023 Wiley-VCH GmbH.

JTD Keywords: adhesion, biofilm, conducting polymers, contamination, derivatives, detections, functionalized sutures, nadh, poly(3,4-ethylenedioxythiophene), Bacteria growth, Conducting polymers, Detections, Functionalized sutures, Monofilament, Nadh

JTD Keywords: 4-ethylenedioxythiophene), carbon nanoparticles, conductive hydrogel, manganese oxide poly(3, sensors, supercapacitor, supercapacitors, temperature sensor, Alginate, Carbon nanotubes

In addition of a key catecholamine neurotransmitter, dopamine is is the metabolite predominantly produced by specific types of tumors (e.g. paragangliomas and neuroblastomas), which cannot be diagnosed using conven-tional sensitive tests. Within this context, development of flexible electrochemical sensors to monitor dopamine levels in physiological fluids for the early diagnosis and control of diseases related to abnormal levels of such compound, is necessary. In this work, a flexible self-supported membrane, which acts directly as electrode, has been developed to detect dopamine. The membrane consists of three nanoperforated polylactic acid (PLA) layers, which provide flexibility and mechanical integrity, separated by two layers of an electroactive copolymer, which are obtained by electrochemical copolymerization of 3,4-ethylenedioxythiophene and aniline. The sensitivity and detection limit provided by the electroactive copolymer, which is accessible to dopamine molecules through the nanoperforations of the PLA outer layers, is 1.846 mu A/(cm2.mu M) and 1.7 mu M, respectively, in a urea-rich environments that mimics urine. These values allow us to propose the self-standing flexible electrodes devel-oped in this study for the detection of dopamine in patients affected by paragangliomas and neuroblastomas tumors, which typically present dopamine concentrations between 2 and 7 mu M.

JTD Keywords: 4-ethylenedioxythiophene), Conducting polymer, Electrochemical sensor, Electrodes, Hydrogels, Poly(3, Polyaniline, Polylactic acid, Selective detection, Sensors, Supercapacitors

Innovative insulin delivery systems contemplate combining multi-pharmacokinetic profiles for glycemic control. Two device configurations have been designed for the controlled release of insulin using the same chemical compounds. The first insulin delivery system, which displays a rapid release response that, in addition, is enhanced on a short time scale by electrical stimulation, consists on an insulin layer sandwiched between a conducting poly(3,4-ethylenedioxythiophene) (PEDOT) film and a poly-gamma-glutamic acid (gamma-PGA) hydrogel. The second system is constituted by gamma-PGA hydrogel loaded with insulin and PEDOT nanoparticles by in situ gelation. In this case, the insulin release, which only starts after the degradation of the hydrogel over time (i.e. on a long time scale), is slow and sustained. The combination of an on-demand and fast release profile with a sustained and slow profile, which act on different time scales, would result in a very efficient regulation of diabetes therapy in comparison to current systems, allowing to control both fast and sustained glycemic events. Considering that the two systems developed in this work are based on the same chemical components, future work will be focused on the combination of the two kinetic profiles by re-engineering a unique insulin release device using gamma-PGA, PEDOT and insulin.

JTD Keywords: Conducting polymer, Constant, Diabetes, Diabetes-mellitus, Drug-delivery, Electrodes, Electrostimulation, Glucose-responsive hydrogels, Hydrogel, Molecular dynamics, Molecular-dynamics, Nanogels, Nanoparticles, Poly(3,4-ethylenedioxythiophene), Risk

A hydrogel/nanoparticle-loaded system for the controlled delivery of small hydrophobic drugs has been prepared using poly(gamma-glutamic acid) (PGGA), a naturally occurring biopolymer made of glutamic acid units connected by amide linkages between alpha-amino and gamma-carboxylic acid groups, and poly(3,4-ethylenedioxythiophene) (PEDOT), a very stable conducting polymer with excellent electrochemical response. Specifically, curcumin (CUR)-loaded PEDOT nanoparticles (PEDOT/CUR) were incorporated to the PGGA hydrogel during the crosslinking reaction. After chemical, morphological and electrochemical characterization, the release profiles of PEDOT/CUR and PGGA/PEDOT/CUR system have been compared in absence and presence of electrical stimuli, which consisted on the application of a voltage of -0.5 V for 15 min every 24 h. Results show that the release is higher for electrically stimulated systems by more than twice, even though due to its hydrophobicity and poor solubility in water the release was relatively slow in both cases. This feature could be advantageous when the therapeutic treatment requires slow, controlled and sustained CUR release.

JTD Keywords: 4-ethylenedioxythiophene), Acid, Controlled-release, Curcumi n, Curcumin, Electrostimulated release, Nanocarriers, Pedotpss, Poly( ?-glutamic acid), Poly(3

Rapid detection of bacterial presence on implantable medical devices is essential to prevent biofilm formation, which consists of densely packed bacteria colonies able to withstand antibiotic-mediated killing. In this work, a smart approach is presented to integrate electrochemical sensors for detecting bacterial infections in biomedical implants made of isotactic polypropylene (i-PP) using chemical assembly. The electrochemical detection is based on the capacity of conducting polymers (CPs) to detect extracellular nicotinamide adenine dinucleotide (NADH) released from cellular respiration of bacteria, which allows distinguishing prokaryotic from eukaryotic cells. Oxygen plasma-functionalized free-standing i-PP, coated with a layer (≈1.1 µm in thickness) of CP nanoparticles obtained by oxidative polymerization, is used as working electrode for the anodic polymerization of a second CP layer (≈8.2 µm in thickness), which provides very high electrochemical activity and stability. The resulting layered material, i-PP /CP , detects the electro-oxidation of NADH in physiological media with a sensitivity 417 µA cm and a detection limit up to 0.14 × 10 m, which is below the concentration of extracellular NADH found for bacterial cultures of biofilm-positive and biofilm-negative strains. f 2 −2 −3

JTD Keywords: bacteria respiration, bacteria sensors, biomedical implants, flexible sensors, poly(3,4-ethylenedioxythiophene), Bacteria respiration, Bacteria sensors, Biomedical implants, Flexible sensors, Poly(3,4-ethylenedioxythiophene)

Flexible electrochemical sensors based on electroactive materials have emerged as powerful analytical tools for biomedical applications requiring bioanalytes detection. Within this context, 3D printing is a remarkable technology for developing electrochemical devices, due to no design constraints, waste minimization, and batch manufacturing with high reproducibility. However, the fabrication of 3D printed electrodes is still limited by the in-house fabrication of conductive filaments, which requires the mixture of the electroactive material with melted of thermoplastic polymer (e.g., polylactic acid, PLA). Herein, a simple approach is presented for preparing electrochemical dopamine (DA) biosensors. Specifically, the surface of 3D-printed PLA specimens, which exhibit an elastic modulus and a tensile strength of 3.7 +/- 0.3 GPa and 47 +/- 1 MPa, respectively, is activated applying a 0.5 m NaOH solution for 30 min and, subsequently, poly(3,4-ethylenedioxythiophene) is polymerized in situ using aqueous solvent. The detection of DA with the produced sensors has been demonstrated by cyclic voltammetry, differential pulse voltammetry, and chronoamperometry. In summary, the obtained results reflect that low-cost electrochemical sensors, which are widely used in medicine and biotechnology, can be rapidly fabricated using the proposed approach that, although based on additive manufacturing, does not require the preparation of conductive filaments.

JTD Keywords: 3d printers, Additive manufacturing, Amines, Batch manufacturing, Biomedical applications, Chronoamperometry, Conducting polymer, Conducting polymers, Conductive filaments, Conservation, Cyclic voltammetry, Differential pulse voltammetry, Electroactive material, Electrochemical biosensor, Electrochemical devices, Electrochemical sensors, Electrodes, Electron emission, Flexible electrode, High reproducibility, Medical applications, Neurophysiology, Poly-3 ,4-ethylenedioxythiophene, Polyesters, Polylactic aci, Sodium hydroxide, Tensile strength, Thermoplastic polymer

© 2020 Elsevier B.V. Semi-interpenetrated nanogels (NGs) able to release and sense diclofenac (DIC) have been designed to act as photothermal agents with the possibility to ablate cancer cells using mild-temperatures (<45 °C). Combining mild heat treatments with simultaneous chemotherapy appears as a very promising therapeutic strategy to avoid heat resistance or damaging the surrounding tissues. Particularly, NGs consisted on a poly(N-isopropylacrylamide) (PNIPAM) and dendritic polyglycerol (dPG) mesh containing a semi-interpenetrating network (SIPN) of poly(hydroxymethyl 3,4-ethylenedioxythiophene) (PHMeEDOT). The PHMeEDOT acted as photothermal and conducting agent, while PNIPAM-dPG NG provided thermoresponsivity and acted as stabilizer. We studied how semi-interpenetration modified the physicochemical characteristics of the thermoresponsive SIPN NGs and selected the best condition to generate a multifunctional photothermal agent. The thermoswitchable conductiveness of the multifunctional NGs and the redox activity of DIC could be utilized for its electrochemical detection. Besides, as proof of the therapeutic concept, we investigated the combinatorial effect of photothermal therapy (PTT) and DIC treatment using the HeLa cancer cell line in vitro. Within 15 min NIR irradiation without surpassing 45 °C we were able to kill 95% of the cells, demonstrating the potential of SIPN NGs as drug carriers, sensors and agents for mild PTT.

JTD Keywords: cells, cellulose, conducting polymers, controlled delivery, diclofenac, efficiency, electrochemical oxidation, electrochemical sensors, nanogels, nanoparticles, photothermal therapy, pnipam, poly(3,4-ethylenedioxythiophene), Conducting polymers, Electrochemical sensors, Nanogels, Photothermal therapy