Magnetically Active Bicontinuous Polymer Structures for Multiple Controlled Drug Delivery.

The targeted delivery of drugs using wireless navigable magnetic robots, allows the delivery of drug molecules to be controlled non only in time but also in space, improving medical outcomes. The main disadvantages behind their use lies in the low amount of drug that can be transported and the single nature of drug that can be loaded (hydrophilic or hydrophobic). These considerations limit their use in co-delivery systems, now recognized to be very promising for many different pathologies. We developed a magnetic bijel-like structure to load and release different types of molecules (hydrophilic and hydrophobic). In this work, we explored the use of ε-caprolactone, which can polymerize, forming hydrophobic domains (oil phase). After mixing with iron oxide nanoparticles (NPs), the water dispersion creates a magnetic biphasic porous structure without phase separation. The resulting device showed good performance both in magnetic actuation and as a drug delivery system. This article is protected by copyright. All rights reserved.

Towards bone regeneration: Understanding the nucleating ability of proline-rich peptides in biomineralisation.

Obtaining rapid mineralisation is a challenge in current bone graft materials, which has been attributed to the difficulty of guiding the biological processes towards osteogenesis. Amelogenin, a key protein in enamel formation, inspired the design of two intrinsically disordered peptides (P2 and P6) that enhance in vivo bone formation, but the process is not fully understood. In this study, we have elucidated the mechanism by which these peptides induce improved mineralisation. Our molecular dynamics analysis demonstrated that in an aqueous environment, P2 and P6 fold to interact with the surrounding Ca2+, PO43- and OH- ions, which can lead to apatite nucleation. Although P2 has a less stable backbone, it folds to a stable structure that allows for the nucleation of larger calcium phosphate aggregates than P6. These results were validated experimentally in a concentrated simulated body fluid solution, where the peptide solutions accelerated the mineralisation process compared to the control and yielded mineral structures mimicking the amorphous calcium phosphate crystals that can be found in lamella bone. A pH drop for the peptide groups suggests depletion of calcium and phosphate, a prerequisite for intrinsic osteoinduction, while S/TEM and SEM suggested that the peptide regulated the mineral nucleation into lamella flakes. Evidently, the peptides accelerate and guide mineral formation, elucidating the mechanism for how these peptides can improve the efficacy of P2 or P6 containing devices for bone regeneration. The work also demonstrates how experimental mineralisation study coupled with molecular dynamics is a valid method for understanding and predicting in vivo performance prior to animal trials.

From Basic Science to Clinical Practice: A Review of Current Periodontal/Mucogingival Regenerative Biomaterials.

Periodontitis is a dysbiosis-driven inflammatory disease affecting the tooth-supporting tissues, characterized by their progressive resorption, which can ultimately lead to tooth loss. A step-wise therapeutic approach is employed for periodontitis. After an initial behavioral and non-surgical phase, intra-bony or furcation defects may be amenable to regenerative procedures. This review discusses the regenerative technologies employed for periodontal regeneration, highlighting the current limitations and future research areas. The search, performed on the MEDLINE database, has identified the available biomaterials, including biologicals (autologous platelet concentrates, hydrogels), bone grafts (pure or putty), and membranes. Biologicals and bone grafts have been critically analyzed in terms of composition, mechanism of action, and clinical applications. Although a certain degree of periodontal regeneration is predictable in intra-bony and class II furcation defects, complete defect closure is hardly achieved. Moreover, treating class III furcation defects remains challenging. The key properties required for functional regeneration are discussed, and none of the commercially available biomaterials possess all the ideal characteristics. Therefore, research is needed to promote the advancement of more effective and targeted regenerative therapies for periodontitis. Lastly, improving the design and reporting of clinical studies is suggested by strictly adhering to the Consolidated Standards of Reporting Trials (CONSORT) 2010 statement.

Biphasic Porous Bijel-Like Structures with Hydrogel Domains as Controlled Drug Delivery Systems.

Bijels are a peculiar type of Pickering emulsion that have a bicontinuous morphology and are stabilised by a jammed layer of nanoparticles (NPs). Due to their double nature, their usage has increased in recent years in various fields, such as biological and food applications. In fact, they can release both hydrophilic and hydrophobic compounds simultaneously. An improvement to this structure is the use of a hydrophobic monomer like polycaprolactone as the organic phase, which is able to polymerise during the formation of the structure. Unfortunately, the structures formed in this way always have some drawbacks, such as their thermal stability or degradation when submerged in an aqueous medium. A number of studies have been carried out in which some parameters, such as the NPs or the monomer, were changed and their effect on the final product evaluated. In this work, the effect of modifying the aqueous phase was studied. In particular, the effect of adding alginate, a biopolymer capable of forming a stable hydrogel in the presence of divalent cations, was analysed, as was the difference between soaking or not in CaCl2, the final system. Specific attention was paid to their swelling behaviour (150% vs. 25% of the blank sample), rheological properties (G' 100 kPa vs. 20 kPa of the blank sample) and their release performances. In this framework, complete release of hydrophilic drug vs. 20% in the blank sample was observed together with improved release of the hydrophobic one with 35% in 8 h vs. 5% in the case of the blank sample. This strategy has been proven to influence bijels' properties, opening the doors to many different uses.

Synergistic Pharmacological Therapy to Modulate Glial Cells in Spinal Cord Injury.

Current treatments for modulating the glial-mediated inflammatory response after spinal cord injury (SCI) have limited ability to improve recovery. This is quite likely due to the lack of a selective therapeutic approach acting on microgliosis and astrocytosis, the glia components most involved after trauma, while maximizing efficacy and minimizing side effects. A new nanogel that can selectively release active compounds in microglial cells and astrocytes is developed and characterized. The degree of selectivity and subcellular distribution of the nanogel is evaluated by applying an innovative super-resolution microscopy technique, expansion microscopy. Two different administration schemes are then tested in a SCI mouse model: in an early phase, the nanogel loaded with Rolipram, an anti-inflammatory drug, achieves significant improvement in the animal's motor performance due to the increased recruitment of microglia and macrophages that are able to localize the lesion. Treatment in the late phase, however, gives opposite results, with worse motor recovery because of the widespread degeneration. These findings demonstrate that the nanovector can be selective and functional in the treatment of the glial component in different phases of SCI. They also open a new therapeutic scenario for tackling glia-mediated inflammation after neurodegenerative events in the central nervous system.

Biomaterials and Cell Therapy Combination in Central Nervous System Treatments.

Current pharmacological and surgical therapies for the central nervous system (CNS) show a limited capacity to reduce the damage progression; that together with the intrinsic limited capability of the CNS to regenerate greatly reduces the hopes of recovery. Among all the therapies proposed, the tissue engineering strategies supplemented with therapeutic stem cells remain the most promising. Neural tissue engineering strategies are based on the development of devices presenting optimal physical, chemical, and mechanical properties which, once inserted in the injured site, can support therapeutic cells, limiting the effect of a hostile environment and supporting regenerative processes. Thus, this review focuses on the employment of hydrogel and nanofibrous scaffolds supplemented with stem cells as promising therapeutic tools for the central and peripheral nervous systems in preclinical and clinical applications.

On the role of polymeric hydrogels in the thermal response of gold nanorods under NIR laser irradiation.

Hydrogels are 3D cross-linked networks of polymeric chains designed to be used in the human body. Nowadays they find widespread applications in the biomedical field and are particularly attractive as drug delivery vectors. However, despite many good results, their release performance is sometimes very quick and uncontrolled, being forced by the high in vivo clearance of body fluids. In this direction, the development of novel responsive nanomaterials promises to overcome the drawbacks of common hydrogels, inducing responsive properties in three-dimensional polymeric devices. In this study, we synthesized and then loaded gold nanorods (Au NRs) within an agarose-carbomer (AC)-based hydrogel obtained from a microwave-assisted polycondensation reaction between carbomer 974P and agarose. The photothermal effect of the composite device was quantified in terms of maximum temperature and spatial-temporal temperature distribution, also during consecutive laser irradiations. This work shows that composite Au NRs loaded within AC hydrogels can serve as a stable photothermal treatment agent with enhanced photothermal efficiency and good thermal stability after consecutive laser irradiations. These results confirm that the composite system produced can exhibit an enhanced thermal effect under NIR laser irradiation, which is expected to lead to great therapeutic advantages for the localized treatment of different diseases.

A Circular Approach to Finished Tanned Leather: Regeneration by Cryogenic Technology.

Finished tanned leather is usually covered by a thin polymeric layer. This layer has the scope to change the morphological aspect of the last leather layer as well as improve the impermeabilization properties. Often, the finished product is refused by the final client, and tanneries must restore significant quantities of materials. Therefore, it is very important to remove this finished polymeric layer, recover the underneath tanned leather, and predispose it to a new finishing. The bonding between the polymeric film and leather is so strong that, today, only a blade shaving process can perform this separation at the expense of also removing a layer of tanned leather and consequently reducing the leather thickness. Here, a novel separation method was developed based on the significant difference in the dilation properties between the tanned hide and the polymeric film at low temperatures. The use of cryogenic fluids, in particular the direct application of liquid nitrogen, can freeze the polymeric layer below the glass transition temperature, inducing brittle behavior. The result is an easy separation without any alteration of the tanned leather layer; for a demonstration of that, some techniques were used, such as FTIR, SEM, Tensile strength evaluation, DSC, and TGA. By this last analysis, it is possible to check how a decrease of weight to 90% happened for the polymeric layer at about 400 °C against the complete blank at about 600 °C. A similar great distance of results exists in the case of tensile strength, where an average value of 34.5% is the deformation stress for blank samples, against 34.8% for processed samples. Thus, the process here developed allows the reuse of the tanned leather towards a new life in respect of the principles of the circular economy.

ß-Cyclodextrin functionalized agarose-based hydrogels for multiple controlled drug delivery of ibuprofen.

Agarose hydrogels are three-dimensional hydrophilic polymeric frameworks characterised by high water content, viscoelastic properties, and excellent ability as cell and drug delivery systems. However, their hydrophilicity as gel systems makes loading of hydrophobic drugs difficult and often ineffective. The incorporation of amphiphilic molecules (e.g. cyclodextrins) into hydrogels as hosts able to form inclusion complexes with hydrophobic drugs could be a possible solution. However, if not properly confined, the host compounds can get out of the network resulting in uncontrolled release. Therefore, in this work, ß-cyclodextrins-based host-guest supramolecular hydrogel systems were synthesised, with ß-cyclodextrins (ß-CD) covalently bound to the polymeric network, preventing leakage of the host molecules. Hydrogels were prepared at two different ß-CD-functionalized polyvinyl alcohol (PVA)/agarose ratios, and characterised chemically and physically. Then ibuprofen, a drug often used as a gold standard in studies involving ß-CD both in its hydrophilic and hydrophobic forms, was selected to investigate the release behavior of the synthesised hydrogels and the influence of ß-CD on the release. The presence of ß-CD linked to the polymeric 3D network ensured a higher and prolonged release profile for the hydrophobic drug and also seemed to have some influence on the hydrophilic one.

Design of Functional Pluronic-Based Precursors for Tailoring Hydrogel Thermoresponsiveness and Cell-Adhesive Properties.

In this study, functional Pluronic F127 precursors were designed and synthesized for the preparation of thermosensitive hydrogels. Using linear Pluronic thioacetate and Pluronic multi-acrylate precursors, F127-based hydrogels were prepared through thioacetate deprotection-mediated Michael-type addition. The properties of these gels were compared to those obtained through free radical crosslinking of F127 diacrylate. Temperature was found to have a clear influence on gel swelling as a result of F127 thermoresponsiveness. The macromolecular architecture and functionality of the precursors were also optimized and characterized in terms of gelation kinetics and drug diffusion. In vitro tests were conducted on fibroblasts and endothelial cells to assess their response to cellular adhesion with Pluronic gels that were functionalized with an RGD peptide or pretreated with serum proteins to promote cell adhesion. This study provides a method for creating tailored hydrogels suitable for various biomedical applications, such as soft-tissue engineering, cell encapsulation, wound healing, and sustained delivery of therapeutic molecules.

On the Sorbent Ability and Reusability of Graphene-Oxide-Chitosan Aerogels for the Removal of Dyes from Wastewater.

One of the most persistent issues affecting people worldwide is water contamination due to the indiscriminate disposal of pollutants, causing severe environmental problems. Dyes are among the most harmful contaminants because of their high chemical stability and consequently difficult degradation. To remove contaminants from water, adsorption is the most widely used and effective method. In this work, we recall the results already published about the synthesis, the characterization and the use of porous graphene-oxide-chitosan aerogels as a sorbent material. Those systems, prepared by mixing GO sheets and CS chains, using APS as a cross-linking agent, and by further lyophilization, were further characterized using nano-computed tomography, supplying more understanding about their micro and nano-structure. Their sorbent ability has been investigated also by the study of their isotherm of adsorption of two different anionic dyes: Indigo Carmine and Cibacron Brilliant Yellow. Those analyses confirmed the potentialities of the aerogels and their affinity for those anionic dyes. Moreover, the possibility of regenerating and reusing the material was evaluated as a key aspect for applications of this kind. The treatment with NaOH, to promote the desorption of adsorbed dyes, and subsequent washing with HCl, to re-protonate the system, ensured the regeneration of the gels and their use in multiple cycles of adsorption with the selected water contaminants.

Hyaluronic acid-based hydrogels: Drug diffusion investigated by HR-MAS NMR and release kinetics.

Hydrogels based on hyaluronic acid (HA) and agarose-carbomer (AC) raised an increasing interest as drug delivery systems. The complex architecture of the polymer network, such as mesh size, HA molecular weight and drug-polymer non covalent interactions across the 3D polymer matrix strongly influence the release capability/profile of these materials. In this study, AC-HA hydrogels with different mesh sizes have been prepared and characterised. High Resolution Magic Angle Spinning (HR-MAS) NMR spectroscopy has been used to investigate the motion of two drugs, such as ethosuximide (neutral molecule) and sodium salicylate (net negative charge) within the AC and AC-HA hydrogel networks. Analysis of the experimental data provides evidence of superdiffusive motion for all formulations containing sodium salicylate, while ethosuximide molecules undergo unrestricted diffusion within the gel matrix. We further speculate that the superdiffusive motion, observed at the nanoscale, can be responsible for the faster release of sodium salicylate from all hydrogel formulations.

Editorial on the Special Issue "Advances in Nanogels".

In recent decades, the rise of nanotechnology has led to the design of innovative nano-biomaterials which are used to improve pharmacological therapies and assist with disease diagnosis [...].

Bijels as a Fluid Labyrinth for Drugs: The Effect of Nanoparticles on the Release Kinetics of Ethosuximide and Dimethyl Fumarate.

Bijels (bicontinuous interfacially jammed emulsion gels) raised an increasing interest as biomaterials for controlled drug delivery due to their biphasic nature organized in mesoscopic tortuous domains. Two bijel formulations were prepared and explored as delivery systems for both hydrophilic and lipophilic drugs, ethosuximide and dimethyl fumarate. The two bijel-like structures, based on polymerized ε-caprolactone/water, differ in the stabilizing nanoparticle hydroxyapatite (inorganic) and nanogel-based nanoparticles (organic). Diffusion nuclear magnetic resonance spectroscopy has been used to characterize the bijel structure and the transport behavior of the drug molecules confined within the water/organic interconnected domains. A reduced diffusion coefficient is observed for several concentrations of the drugs and both bijel formulations. Moreover, in vitro release profiles also reveal the effect of the microstructure and drug-nanoparticle interactions.

Biomaterial-Mediated Factor Delivery for Spinal Cord Injury Treatment.

Spinal cord injury (SCI) is an injurious process that begins with immediate physical damage to the spinal cord and associated tissues during an acute traumatic event. However, the tissue damage expands in both intensity and volume in the subsequent subacute phase. At this stage, numerous events exacerbate the pathological condition, and therein lies the main cause of post-traumatic neural degeneration, which then ends with the chronic phase. In recent years, therapeutic interventions addressing different neurodegenerative mechanisms have been proposed, but have met with limited success when translated into clinical settings. The underlying reasons for this are that the pathogenesis of SCI is a continued multifactorial disease, and the treatment of only one factor is not sufficient to curb neural degeneration and resulting paralysis. Recent advances have led to the development of biomaterials aiming to promote in situ combinatorial strategies using drugs/biomolecules to achieve a maximized multitarget approach. This review provides an overview of single and combinatorial regenerative-factor-based treatments as well as potential delivery options to treat SCIs.

Droplet-based microfluidic synthesis of nanogels for controlled drug delivery: tailoring nanomaterial properties via pneumatically actuated flow-focusing junction.

Conventional batch syntheses of polymer-based nanoparticles show considerable shortcomings in terms of scarce control over nanomaterials morphology and limited lot-to-lot reproducibility. Droplet-based microfluidics represents a valuable strategy to overcome these constraints, exploiting the formation of nanoparticles within discrete microdroplets. In this work, we synthesized nanogels (NGs) composed of hyaluronic acid and polyethyleneimine using a microfluidic flow-focusing device endowed with a pressure-driven micro-actuator. The actuator achieves real-time modulation of the junction orifice width, thereby regulating the microdroplet diameter and, as a result, the NG size. Acting on process parameters, NG hydrodynamic diameter could be tuned in the range 92-190 nm while preserving an extremely low polydispersity (0.015); those values are hardly achievable in batch syntheses and underline the strength of our toolbox for the continuous in-flow synthesis of nanocarriers. Furthermore, NGs were validated in vitro as a drug delivery system in a representative case study still lacking an effective therapeutic treatment: ovarian cancer. Using doxorubicin as a chemotherapeutic agent, we show that NG-mediated release of the drug results in an enhanced antiblastic effect vs. the non-encapsulated administration route even at sublethal dosages, highlighting the wide applicability of our microfluidics-enabled nanomaterials in healthcare scenarios.

Design and clinical application of injectable hydrogels for musculoskeletal therapy.

Musculoskeletal defects are an enormous healthcare burden and source of pain and disability for individuals. With an aging population, the proportion of individuals living with these medical indications will increase. Simultaneously, there is pressure on healthcare providers to source efficient solutions, which are cheaper and less invasive than conventional technology. This has led to an increased research focus on hydrogels as highly biocompatible biomaterials that can be delivered through minimally invasive procedures. This review will discuss how hydrogels can be designed for clinical translation, particularly in the context of the new European Medical Device Regulation (MDR). We will then do a deep dive into the clinically used hydrogel solutions that have been commercially approved or have undergone clinical trials in Europe or the United States. We will discuss the therapeutic mechanism and limitations of these products. Due to the vast application areas of hydrogels, this work focuses only on treatments of cartilage, bone, and the nucleus pulposus. Lastly, the main steps toward clinical translation of hydrogels as medical devices are outlined. We suggest a framework for how academics can assist small and medium MedTech enterprises conducting the initial clinical investigation and post-market clinical follow-up required in the MDR. It is evident that the successful translation of hydrogels is governed by acquiring high-quality pre-clinical and clinical data confirming the device mechanism of action and safety.

Polymer-based thermoresponsive hydrogels for controlled drug delivery.

INTRODUCTION: Controlled drug delivery through hydrogels is generally limited by the poor barrier that polymeric network can create to diffusion mechanism. Stimuli responsive polymers can help in this way guaranteeing that delivery can be sustained and finely controlled using an external stimulus. AREA COVERED: This review provides an overview of recent studies about the use of temperature as an external stimulus able to work as an efficient new route of drug's administration. Thermoresponsive hydrogels are discussed and compared in terms of physical properties and mechanism of drug release considering their classification in intrinsical (formed by thermosensitive polymers) and non-intrinsical (polymers with thermosensitive moieties) hydrogels. EXPERT OPINION: Thermoresponsive hydrogels can be developed by using different polymers added or not with micro/nanoparticles of organic or inorganic origin. In both cases, the final system represents an innovative way for the local and sustained drug delivery in a specific site of the body. In particular, it is possible to obtain an on-demand release of drug by applying a local increase of temperature to the system.