A miniaturized multicellular platform to mimic the 3D structure of the alveolar-capillary barrier.

Several diseases affect the alveoli, and the efficacy of medical treatments and pharmaceutical therapies is hampered by the lack of pre-clinical models able to recreate in vitro the diseases. Microfluidic devices, mimicking the key structural and compositional features of the alveoli, offer several advantages to medium and high-throughput analysis of new candidate therapies. Here, we developed an alveolus-on-a-chip recapitulating the microanatomy of the physiological tissue by including the epithelium, the fibrous interstitial layer and the capillary endothelium. A PDMS device was obtained assembling a top layer and a bottom layer obtained by replica molding. A polycaprolactone/gelatin (PCL-Gel) electrospun membrane was included within the two layers supporting the seeding of 3 cell phenotypes. Epithelial cells were grown on a fibroblast-laden collagen hydrogel located on the top side of the PCL-Gel mats while endothelial cells were seeded on the basolateral side of the membrane. The innovative design of the microfluidic device allows to replicate both cell-cell and cell-extracellular matrix interactions according to the in vivo cell arrangement along with the establishment of physiologically relevant air-liquid interface conditions. Indeed, high cell viability was confirmed for up to 10 days and the formation of a tight endothelial and epithelial barrier was assessed by immunofluorescence assays.

Development of biomimetic co-culture and tri-culture models to mimic the complex structure of the alveolar-capillary barrier.

Alveoli are the functional area of respiratory system where the gaseous exchanges take place at level of the alveolar-capillary barrier. The development of safe and effective therapeutic approaches for treating lung disease is currently limited due to the lack of realistic preclinical models for their testing and validation. In this work, tissue engineering approaches were exploited to develop a biomimetic platform that provide an appropriate mimicking of the extracellular environment and the multicellular architecture of human alveoli. Here, we propose the implementation of two biomimetic in vitro models to reproduce the features of the main anatomic portions of the physiological alveolar-capillary barrier. First, a co-culture barrier model was obtained by integrating an electrospun polycaprolactone-gelatin (PCL-Gel) membrane in a modified transwell insert (PCL-Gel TW) to mimic the alveolar basement membrane (coded as thin model). Alveolar epithelial (A549) and lung microvascular endothelial (HULEC-5a) cells were cultured on the apical and basolateral side of the PCL-Gel membrane, respectively, under physiologic air-liquid interface (ALI) conditions for 7 days. The ALI condition promoted the expression of type I and type II alveolar epithelial cell markers and the secretion of mucus in A549 cells. Increased cell viability and barrier properties in co-cultures of A549 and HULEC-5a compared to mono-cultures revealed the effectiveness of the model to reproduce in vitro physiological-relevant features of the alveolar-capillary barrier. The second portion of the alveolar-capillary barrier was developed implementing a tri-culture model (coded as thick model) including a type I collagen (COLL) hydrogel formulated to host lung fibroblasts (MRC-5). The thick barrier model was implemented by seeding HULEC-5a on the basolateral side of PCL-Gel TW and then pouring sequentially MRC-5-laden COLL hydrogel and A549 cells on the apical side of the electrospun membrane. The thick model was maintained up to 7 days at ALI and immunofluorescence staining of tight and adherent junctions demonstrated the formation of a tight barrier. Lastly, the ability of models to emulate pathological inflammatory conditions was validated by exposing the apical compartment of the PCL-Gel TW to lipopolysaccharide (LPS). The damage of A549 tight junctions, the increase of barrier permeability and IL-6 pro-inflammatory cytokine release was observed after 48 h exposure to LPS.

PDAC-on-chip for in vitro modeling of stromal and pancreatic cancer cell crosstalk.

Pancreatic ductal adenocarcinoma (PDAC) mainly develops in the head of the pancreas, within the acino-ductal unit composed of acinar and ductal cells surrounded by pancreatic stellate cells (PSCs). PSCs strongly influence the tumor microenvironment by triggering an intense stromal deposition, which plays a key role in tumor progression and limits drug perfusion. We have developed a microfluidic in vitro model recreating the in vivo tumor-stroma crosstalk to replicate the steps of PDAC evolution towards the establishment of an efficient in vitro platform for innovative therapy validation. The multilayer PDAC-on-chip was designed to culture the PDAC cells and the PSCs embedded in a type I collagen gel in the top and bottom layers, respectively. The presence of a biomimetic nanofibrous membrane in the middle of the chip permits the control of interactions between the two cell lines and the easy analysis of the effects of the crosstalk on cell behavior. First, the PDAC-stromal cell relationship was evaluated under co-culture conditions on 24-well inserts including the PCL/Gel electrospun membrane. This simplified model shows that human fibroblasts change their morphology and secrete larger amounts of IL-6 cytokines in the presence of tumor cells, confirming the activation of stromal cells under co-culture. Then, the PDAC-on-chip system was validated by demonstrating that human fibroblasts seeded in a 3D collagen matrix in the bottom microchannel also change to a myofibroblast-like shape with increased expression of α-SMA and secrete larger amounts of IL-6 cytokines. This microfluidic system is suitable for the evaluation of drug efficacy and serves as a powerful tool for understanding the early evolution steps of PDAC.

Antimicrobial peptide-based materials: opportunities and challenges.

The multifunctional properties of antimicrobial peptides (AMPs) make them attractive candidates for the treatment of various diseases. AMPs are considered as alternatives to antibiotics due to the increasing number of multidrug-resistant (MDR) bacteria. However, bare AMPs have limited therapeutic potentials due to a low residence time in the blood circulatory system and susceptibility to proteases and an alkaline wound environment. These limitations are the major hurdles for AMPs to succeed as commercial drugs. In contrast, AMP-based materials, for instance, NPs, hydrogels, electrospun fibres, dressings and implants, could overcome these challenges and provide therapeutic efficacies to the conjugated AMPs superior to those of bare AMPs in different disease models. In this review, we discuss the preparation of different compositions of AMP-based materials and their therapeutic potential for the treatment of microbial infections in the brain, eyes, mouth, skin, lungs, and gastrointestinal and urinary tracts. Apart from antimicrobial potential, the applications of AMP-based materials in the regeneration of skin/bone, prevention of implant-associated infections, detection/imaging of bacteria, cancer therapy and gene delivery are discussed in this review. Lastly, we discuss different challenges that hinder the commercialization of AMP-based materials. Overall, this review provides a comprehensive account of the current progress and prospects of AMP-based materials for clinical applications.

Biocompatible Electrospun Polycaprolactone-Polyaniline Scaffold Treated with Atmospheric Plasma to Improve Hydrophilicity.

Conductive polymers (CPs) have recently been applied in the development of scaffolds for tissue engineering applications in attempt to induce additional cues able to enhance tissue growth. Polyaniline (PANI) is one of the most widely studied CPs, but it requires to be blended with other polymers in order to be processed through conventional technologies. Here, we propose the fabrication of nanofibers based on a polycaprolactone (PCL)-PANI blend obtained using electrospinning technology. An extracellular matrix-like fibrous substrate was obtained showing a good stability in the physiological environment (37 °C in PBS solution up 7 days). However, since the high hydrophobicity of the PCL-PANI mats (133.5 ± 2.2°) could negatively affect the biological response, a treatment with atmospheric plasma was applied on the nanofibrous mats, obtaining a hydrophilic surface (67.1 ± 2°). In vitro tests were performed to confirm the viability and the physiological-like morphology of human foreskin fibroblast (HFF-1) cells cultured on the plasma treated PCL-PANI nanofibrous scaffolds.

Embedding Ordered Mesoporous Carbons into Thermosensitive Hydrogels: A Cutting-Edge Strategy to Vehiculate a Cargo and Control Its Release Profile.

The high drug loading capacity, cytocompatibility and easy functionalization of ordered mesoporous carbons (OMCs) make them attractive nanocarriers to treat several pathologies. OMCs' efficiency could be further increased by embedding them into a hydrogel phase for an in loco prolonged drug release. In this work, OMCs were embedded into injectable thermosensitive hydrogels. In detail, rod-like (diameter ca. 250 nm, length ca. 700 nm) and spherical (diameter approximately 120 nm) OMCs were synthesized by nanocasting selected templates and loaded with ibuprofen through a melt infiltration method to achieve complete filling of their pores (100% loading yield). In parallel, an amphiphilic Poloxamer® 407-based poly(ether urethane) was synthesized (Mn¯ 72 kDa) and solubilized at 15 and 20% w/v concentration in saline solution to design thermosensitive hydrogels. OMC incorporation into the hydrogels (10 mg/mL concentration) did not negatively affect their gelation potential. Hybrid systems successfully released ibuprofen at a slower rate compared to control gels (gels embedding ibuprofen as such), but with no significant differences between rod-like and spherical OMC-loaded gels. OMCs can thus work as effective drug reservoirs that progressively release their payload over time and also upon encapsulation in a hydrogel phase, thus opening the way to their application to treat many different pathological states (e.g., as topical medications).

Towards 3D Multi-Layer Scaffolds for Periodontal Tissue Engineering Applications: Addressing Manufacturing and Architectural Challenges.

Reduced periodontal support, deriving from chronic inflammatory conditions, such as periodontitis, is one of the main causes of tooth loss. The use of dental implants for the replacement of missing teeth has attracted growing interest as a standard procedure in clinical practice. However, adequate bone volume and soft tissue augmentation at the site of the implant are important prerequisites for successful implant positioning as well as proper functional and aesthetic reconstruction of patients. Three-dimensional (3D) scaffolds have greatly contributed to solve most of the challenges that traditional solutions (i.e., autografts, allografts and xenografts) posed. Nevertheless, mimicking the complex architecture and functionality of the periodontal tissue represents still a great challenge. In this study, a porous poly(ε-caprolactone) (PCL) and Sr-doped nano hydroxyapatite (Sr-nHA) with a multi-layer structure was produced via a single-step additive manufacturing (AM) process, as a potential strategy for hard periodontal tissue regeneration. Physicochemical characterization was conducted in order to evaluate the overall scaffold architecture, topography, as well as porosity with respect to the original CAD model. Furthermore, compressive tests were performed to assess the mechanical properties of the resulting multi-layer structure. Finally, in vitro biological performance, in terms of biocompatibility and osteogenic potential, was evaluated by using human osteosarcoma cells. The manufacturing route used in this work revealed a highly versatile method to fabricate 3D multi-layer scaffolds with porosity levels as well as mechanical properties within the range of dentoalveolar bone tissue. Moreover, the single step process allowed the achievement of an excellent integrity among the different layers of the scaffold. In vitro tests suggested the promising role of the ceramic phase within the polymeric matrix towards bone mineralization processes. Overall, the results of this study demonstrate that the approach undertaken may serve as a platform for future advances in 3D multi-layer and patient-specific strategies that may better address complex periodontal tissue defects.

DLP 3D Printing Meets Lignocellulosic Biopolymers: Carboxymethyl Cellulose Inks for 3D Biocompatible Hydrogels.

The development of new bio-based inks is a stringent request for the expansion of additive manufacturing towards the development of 3D-printed biocompatible hydrogels. Herein, methacrylated carboxymethyl cellulose (M-CMC) is investigated as a bio-based photocurable ink for digital light processing (DLP) 3D printing. CMC is chemically modified using methacrylic anhydride. Successful methacrylation is confirmed by 1H NMR and FTIR spectroscopy. Aqueous formulations based on M-CMC/lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) photoinitiator and M-CMC/Dulbecco's Modified Eagle Medium (DMEM)/LAP show high photoreactivity upon UV irradiation as confirmed by photorheology and FTIR. The same formulations can be easily 3D-printed through a DLP apparatus to produce 3D shaped hydrogels with excellent swelling ability and mechanical properties. Envisaging the application of the hydrogels in the biomedical field, cytotoxicity is also evaluated. The light-induced printing of cellulose-based hydrogels represents a significant step forward in the production of new DLP inks suitable for biomedical applications.

Hybrid Injectable Sol-Gel Systems Based on Thermo-Sensitive Polyurethane Hydrogels Carrying pH-Sensitive Mesoporous Silica Nanoparticles for the Controlled and Triggered Release of Therapeutic Agents.

Injectable therapeutic formulations locally releasing their cargo with tunable kinetics in response to external biochemical/physical cues are gaining interest in the scientific community, with the aim to overcome the cons of traditional administration routes. In this work, we proposed an alternative solution to this challenging goal by combining thermo-sensitive hydrogels based on custom-made amphiphilic poly(ether urethane)s (PEUs) and mesoporous silica nanoparticles coated with a self-immolative polymer sensitive to acid pH (MSN-CS-SIP). By exploiting PEU chemical versatility, Boc-protected amino groups were introduced as PEU building block (PEU-Boc), which were then subjected to a deprotection reaction to expose pendant primary amines along the polymer backbone (PEU-NH2, 3E18 -NH2/gPEU-NH2) with the aim to accelerate system response to external acid pH environment. Then, thermo-sensitive hydrogels were designed (15% w/v) showing fast gelation in physiological conditions (approximately 5 min), while no significant changes in gelation temperature and kinetics were induced by the Boc-deprotection. Conversely, free amines in PEU-NH2 effectively enhanced and accelerated acid pH transfer (pH 5) through hydrogel thickness (PEU-Boc and PEU-NH2 gels covered approximately 42 and 52% of the pH delta between their initial pH and the pH of the surrounding buffer within 30 min incubation, respectively). MSN-CS-SIP carrying a fluorescent cargo as model drug (MSN-CS-SIP-Ru) were then encapsulated within the hydrogels with no significant effects on their thermo-sensitivity. Injectability and in situ gelation at 37°C were demonstrated ex vivo through sub-cutaneous injection in rodents. Moreover, MSN-CS-SIP-Ru-loaded gels turned out to be detectable through the skin by IVIS imaging. Cargo acid pH-triggered delivery from PEU-Boc and PEU-NH2 gels was finally demonstrated through drug release tests in neutral and acid pH environments (in acid pH environment approximately 2-fold higher cargo release). Additionally, acid-triggered payload release from PEU-NH2 gels was significantly higher compared to PEU-Boc systems at 3 and 4 days incubation. The herein designed hybrid injectable formulations could thus represent a significant step forward in the development of multi-stimuli sensitive drug carriers. Indeed, being able to adapt their behavior in response to biochemical cues from the surrounding physio-pathological environment, these formulations can effectively trigger the release of their payload according to therapeutic needs.

Light Processable Starch Hydrogels.

Light processable hydrogels were successfully fabricated by utilizing maize starch as raw material. To render light processability, starch was gelatinized and methacrylated by simple reaction with methacrylic anhydride. The methacrylated starch was then evaluated for its photocuring reactivity and 3D printability by digital light processing (DLP). Hydrogels with good mechanical properties and biocompatibility were obtained by direct curing from aqueous solution containing lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) as photo-initiator. The properties of the hydrogels were tunable by simply changing the concentration of starch in water. Photo-rheology showed that the formulations with 10 or 15 wt% starch started curing immediately and reached G' plateau after only 60 s, while it took 90 s for the 5 wt% formulation. The properties of the photocured hydrogels were further characterized by rheology, compressive tests, and swelling experiments. Increasing the starch content from 10 to 15 wt% increased the compressive stiffness from 13 to 20 kPa. This covers the stiffness of different body tissues giving promise for the use of the hydrogels in tissue engineering applications. Good cell viability with human fibroblast cells was confirmed for all three starch hydrogel formulations indicating no negative effects from the methacrylation or photo-crosslinking reaction. Finally, the light processability of methacrylated starch by digital light processing (DLP) 3D printing directly from aqueous solution was successfully demonstrated. Altogether the results are promising for future application of the hydrogels in tissue engineering and as cell carriers.

In-vitro Characterization of a Hernia Mesh Featuring a Nanostructured Coating.

Abdominal hernia repair is a frequently performed surgical procedure worldwide. Currently, the use of polypropylene (PP) surgical meshes for the repair of abdominal hernias constitutes the primary surgical approach, being widely accepted as superior to primary suture repair. Surgical meshes act as a reinforcement for the weakened or damaged tissues and support tissue restoration. However, implanted meshes could suffer from poor integration with the surrounding tissues. In this context, the present study describes the preliminary evaluation of a PCL-Gel-based nanofibrous coating as an element to develop a multicomponent hernia mesh device (meshPCL-Gel) that could overcome this limitation thanks to the presence of a nanostructured biomimetic substrate for enhanced cell attachment and new tissue formation. Through the electrospinning technique, a commercial PP hernia mesh was coated with a nanofibrous membrane from a polycaprolactone (PCL) and gelatin (Gel) blend (PCL-Gel). Resulting PCL-Gel nanofibers were homogeneous and defect-free, with an average diameter of 0.15 ± 0.04 µm. The presence of Gel decreased PCL hydrophobicity, so that membranes average water contact angle dropped from 138.9 ± 1.1° (PCL) to 99.9 ± 21.6°, while it slightly influenced mechanical properties, which remained comparable to those of PCL (E = 15.7 ± 2.7 MPa, σ R = 7.7 ± 0.6 ε R = 118.8 ± 13.2%). Hydrolytic and enzymatic degradation was conducted on PCL-Gel up to 28 days, with maximum weight losses around 20 and 40%, respectively. The meshPCL-Gel device was obtained with few simple steps, with no influences on the original mechanical properties of the bare mesh, and good stability under physiological conditions. The biocompatibility of meshPCL-Gel was assessed by culturing BJ human fibroblasts on the device, up to 7 days. After 24 h, cells adhered to the nanofibrous substrate, and after 72 h their metabolic activity was about 70% with respect to control cells. The absence of detectable lactate dehydrogenase in the culture medium indicated that no necrosis induction occurred. Hence, the developed nanostructured coating provided the meshPCL-Gel device with chemical and topographical cues similar to the native extracellular matrix ones, that could be exploited for enhancing the biological response and, consequently, mesh integration, in abdominal wall hernia repair.

Reviewing recently developed technologies to direct cell activity through the control of pore size: From the macro- to the nanoscale.

Scaffold pore size plays a fundamental role in the regeneration of new tissue since it has been shown to direct cell activity in situ. It is well known that cellular response changes in relation with pores diameter. Consequently, researchers developed efficient approaches to realize scaffolds with controllable macro-, micro-, and nanoporous architecture. In this context, new strategies aiming at the manufacturing of scaffolds with multiscale pore networks have emerged, in the attempt to mimic the complex hierarchical structures found in living systems. In this review, we aim at providing an overview of the fabrication methods currently adopted to realize scaffolds with controlled, multisized pores highlighting their specific influence on cellular activity.

Potential of Manuka Honey as a Natural Polyelectrolyte to Develop Biomimetic Nanostructured Meshes With Antimicrobial Properties.

The use of antibiotics has been the cornerstone to prevent bacterial infections; however, the emergency of antibiotic-resistant bacteria is still an open challenge. This work aimed to develop a delivery system for treating soft tissue infections for: (1) reducing the released antimicrobial amount, preventing drug-related systemic side effects; (2) rediscovering the beneficial effects of naturally derived agents; and (3) preserving the substrate functional properties. For the first time, Manuka honey (MH) was proposed as polyelectrolyte within the layer-by-layer assembly. Biomimetic electrospun poly(ε-caprolactone) meshes were treated via layer-by-layer assembly to obtain a multilayered nanocoating, consisting of MH as polyanion and poly-(allylamine-hydrochloride) as polycation. Physicochemical characterization demonstrated the successful nanocoating formation. Different cell lines (human immortalized and primary skin fibroblasts, and primary endothelial cells) confirmed positively the membranes cytocompatibility, while bacterial tests using Gram-negative and Gram-positive bacteria demonstrated that the antimicrobial MH activity was dependent on the concentration used and strains tested.

The interplay between chondrocyte spheroids and mesenchymal stem cells boosts cartilage regeneration within a 3D natural-based hydrogel.

Articular cartilage (AC) lacks the ability to self-repair and cell-based approaches, primarily based on using chondrocytes and mesenchymal stem cells (MSCs), are emerging as effective technology to restore cartilage functionality, because cells synergic functionality may support the maintenance of chondrogenic phenotype and promote extracellular matrix regeneration. This work aims to develop a more physiologically representative co-culture system to investigate the influence of MSCs on the activity of chondrocytes. A thermo-sensitive chitosan-based hydrogel, ionically crosslinked with ß-glycerophosphate, is optimised to obtain sol/gel transition at physiological conditions within 5 minutes, high porosity with pores diameter <30 µm, and in vitro mechanical integrity with compressive and equilibrium Young's moduli of 37 kPa and 17 kPa, respectively. Live/dead staining showed that after 1 and 3 days in culture, the encapsulated MSCs into the hydrogels are viable and characterised by round-like morphology. Furthermore chondrocyte spheroids, seeded on top of gels that contained either MSCs or no cells, show that the encapsulated MSCs stimulate chondrocyte activity within a gel co-culture, both in terms of maintaining the coherence of chondrocyte spheroids, leading to a larger quantity of CD44 (by immunofluorescence) and a higher production of collagen and glycosaminoglycans (by histology) compared with the mono-culture.

Multilayer nanoscale functionalization to treat disorders and enhance regeneration of bone tissue.

The coatings application onto medical devices has experienced a continuous growth in the last few years. Medical device coating market is expected to grow at a CAGR of 5.16% to reach USD 10 million by 2023 due to the increasing geriatric population and the growing demand for continuous innovation. Layer-by-Layer (LbL) assembly represents a versatile method to modify the surface properties, in order to control cell interaction and thus enhance biological functions. Furthermore, LbL is environmentally friendly, able to coat all types of surfaces with the creation of homogenous film and to include and control the release of biomolecules/drugs. This feature review provides a critical overview on recent progresses in functionalizing materials by LbL assembly for bone regeneration and disorder treatment. An overview of emerging and visionary opportunities on LbL technologies and further combination with other existing methods used in biomedical field, is also discussed to evidence the new challenges and potential developments in bone regenerative medicine.

Quartz Crystal Microbalance With Dissipation Monitoring: A Powerful Method to Predict the in vivo Behavior of Bioengineered Surfaces.

The Quartz Crystal Microbalance with dissipation monitoring (QCM-D) is a tool to measure mass and viscosity in processes occurring at or near surfaces, or within thin films. QCM-D is able to detect extremely small chemical, mechanical, and electrical changes taking place on the sensor surface and to convert them into electrical signals which can be investigated to study dynamic process. Surface nanotopography and chemical composition are of pivotal importance in biomedical applications since interactions of medical devices with the physiological environment are mediated by surface features. This review is intended to provide readers with an up-to-date summary of QCM-D applications in the study of cell behavior and to discuss the future trends for the use of QCM-D as a high-throughput method to study cell/surface interactions overcoming the current challenges in the design of biomedical devices.

Nanostructured scaffold with biomimetic and antibacterial properties for wound healing produced by 'green electrospinning'.

HYPOTHESIS: Wound healing is a complex process that often requires treatment with antibacterial agents to avoid infection, which affects the optimal tissue regeneration process. Ideal scaffolds for wound healing treatment should combine biomimetic features to ensure the tissue growth on properly designed extracellular matrix (ECM)-like scaffolds and antibacterial properties in order to avoid bacterial colonization. EXPERIMENTS: In this work, gelatin cross-linked nanofibers (GL-nanofibres), with diameters ranging from 200 to 300 nm, were prepared via a "green electrospinning technique" to mimic the structure and composition of the extracellular matrix (ECM), and promote the normal skin wound healing process. Nanofibres were doped with two antibacterial agents (gentamicin sulphate or silver nanoparticles) to achieve an antibacterial effect against Gram + and Gram- bacteria. FINDINGS: The ECM-mimicking structure of GL-nanofibres was not affected by the presence of the antibacterial agents, which were homogeneously distributed within the mats as shown by SEM and EDS. The antibacterial properties of the developed matrices were confirmed using 4 strains (S. aureus, S. epidermidis, P. aeruginosa and E. coli) while the biocompatibility of the developed substrates and their ability to induce cell growth was assessed using Neonatal Normal Human Dermal Fibroblasts (NHDF-Neo).

Combined Influence of Gelatin Fibre Topography and Growth Factors on Cultured Dorsal Root Ganglia Neurons.

Nerve guidance channels facilitate nerve regeneration and represent an attractive alternative to nerve graft. Actually, nano- and microstructured biomaterials for nerve reconstruction have gained much attention, thanks to recent discoveries about topography effects on cell behavior and morphology. Electrospun fibres have been proposed as filler or structural component for nerve guidance channels, principally due to their similarity with extracellular matrices which facilitate nerve regeneration. Among several tested biomaterials, gelatin has been used to prepare fibres able to support Schwann cell migration and neurite outgrowth. In this work, the effects of gelatin fibre size on axon elongation and Schwann cell migration have been tested using dorsal root ganglia cultures. Moreover, we analyzed how fibres might affect the expression of specific neuronal subtype markers in sensory neuron cultures and how the combined effect of substrate and biological cues affects neurite growth and gene expression. Data show that fibre topography differentially affects both neurite outgrowth and gene expression and suggest that fibre size and topography associated to specific growth factor exposure might be used to select neuron subpopulations and favor the axonal growth of specific neurons. Anat Rec, 301:1668-1677, 2018. © 2018 Wiley Periodicals, Inc.

Current Limitations in the Treatment of Parkinson's and Alzheimer's Diseases: State-of-the-Art and Future Perspective of Polymeric Carriers.

Alzheimer's and Parkinson's diseases are the most common neurodegenerative diseases worldwide and their incidence is increasing due to the aging population. At the moment, the available therapies are not disease modifying and have several limitations, some of which are discussed in this review. One of the main limitations of these treatments is the low concentration that drugs reach in the central nervous system after systemic administration. Indeed, the presence of biological barriers, particularly the blood-brain barrier (BBB), hinders the effective drug delivery to the brain, reducing the potential benefit coming from the administration of the medication. In this review, the mechanisms of transport across the BBB and new methods to improve drug passage across the BBB are discussed. These methods include non-invasive solutions such as intranasal and intravitreal administration, and the use of nanotechnology solutions based on polymeric carriers when the drug is intravenously injected, orally taken for intestine adsorption or delivered through the dermal mucosa. Also, it provides an analysis of more invasive solutions that include intracranially injected hydrogels and implanted devices for local drug delivery. Efforts in finding new therapeutic drugs blocking neurodegenerative disease progression or reverting their course should be coupled with efforts addressed to efficient drug delivery systems. Hence, new pharmacology discoveries together with advancements in nanotechnologies and biomaterials for regenerative medicine are required to effectively counteract neurodegenerative diseases.