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Gaia Zucca,1 Barbara Vigani,1 Caterina Valentino,1 Marco Ruggeri,1 Nicoletta Marchesi,1 Alessia Pascale,1 Giulia Giovilli,2 Lorenzo Malavasi,2 Giuseppina Sandri,1 Silvia Rossi1 1Department of Drug Sciences, University of Pavia, Pavia, 27100, Italy; 2Department of Chemistry and INSTM, University of Pavia, Pavia, 27100, ItalyCorrespondence: Silvia Rossi; Barbara Vigani, Department of Drug Sciences, University of Pavia, Via Taramelli 12, Pavia, 27100, Italy, Email silvia.rossi@unipv.it; barbara.vigani@unipv.itPurpose: The main purpose of the study was the formulation development of nanogels (NHs) composed of chondroitin sulfate (CS) and low molecular weight chitosan (lCH), loaded with a naringenin-β-cyclodextrin complex (NAR/β-CD), as a potential treatment for early-stage diabetic retinopathy.Methods: Different formulations of NHs were prepared by varying polymer concentration, lCH ratio, and pH and, then, characterized for particle size, zeta potential, particle concentration (particles/mL) and morphology. Cytotoxicity and internalization were assessed in vitro using Human Umbilical Vein Endothelial Cells (HUVEC). The NAR/β-CD complex was prepared and evaluated for morphology, complexation efficiency, and solubility. Finally, the most promising NH prototype was loaded with NAR/β-CD (NH@NAR/β-CD) and further characterized for encapsulation efficiency, loading capacity, opacity and cytotoxicity on HUVEC; in vitro release test and DPPH assay were performed to investigate NH capability to sustain NAR release and NH@NAR/β-CD antioxidant properties, respectively.Results: NH properties were influenced by polymer concentration, lCH ratio, and pH. N3 (0.5 mg/mL; lCH=1.5:1; pH = 5) and N9 (0.5 mg/mL; lCH=1:1; pH = 5) showed optimal characteristics, including small size (< 350 nm) and positive zeta potential, facilitating cellular uptake. The NAR/β-CD complex showed 71% complexation efficiency and enhanced NAR solubility. Since characterized by superior properties and better in vitro biocompatibility, N3 was loaded with NAR/β-CD. N3@NAR/β-CD capability to sustain in vitro NAR release, radical scavenging activity and in vitro biocompatibility were finally demonstrated.Conclusion: The physico-chemical properties of N3@NAR/β-CD were responsible for their cell uptake, suggesting their potential to target retinal endothelial cells. The high NAR/β-CD complexation efficiency and the sustained NAR release over 72 hours could guarantee the maintenance of an effective drug concentration at the damage site while reducing the injection number. Further studies about the safety and the effectiveness of the intravitreal injection of NHs@NAR/β-CD will be performed on a diabetic animal model. Keywords: polyelectrolyte complexation, cellular uptake, inclusion complex, antioxidant properties, intravitreal administration

Dalila Miele,1 Marco Ruggeri,1 Barbara Vigani,1 Cesar Viseras,2 Francesca Natali,3 Elena Del Favero,4 Silvia Rossi,1 Giuseppina Sandri1 1Department of Drug Sciences, University of Pavia, Pavia, Italy; 2Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Granada, Granada, Spain; 3Institut Laue-Langevin, Grenoble, France; 4Department of Medical Biotechnology and Translational Medicine, University of Milano, Segrate Milano, ItalyCorrespondence: Giuseppina Sandri, Tel +390382987728, Email giuseppina.sandri@unipv.itBackground: Clay minerals are nanomaterials that have recently been recognized as enabling excipients that can promote cell adhesion, proliferation, and differentiation. When nanoclays are loaded in a 3D polymeric nanostructure, the cell–substrate interaction is enhanced, and other bioactive properties are optimized.Purpose: In this study, hectorite (HEC)- and montmorillonite (MMT)-doped polymeric scaffolds were explored for the treatment of deep and chronic skin lesions.Methods: Scaffolds were manufactured by means of electrospinning and then crosslinked by heating. Physicochemical analyses were correlated with in vitro biopharmaceutical characterization to predict the in vivo fate of the clay-doped scaffolds.Results and Discussion: The addition of MMT or HEC to the polymeric scaffold framework modifies the surface arrangement and, consequently, the potential of the scaffolds to interact with biological proteins. The presence of nanoclays alters the nanofiber morphology and size, and MMT doping increases wettability and protein adhesion. This has an impact on fibroblast behavior in a shorter time since scaffold stiffness facilitates cell adhesion and cell proliferation.Conclusion: MMT proved to perform better than HEC, and this could be related to its higher hydrophilicity and protein adhesion. Keywords: nanomaterials, montmorillonite, hectorite, chitosan, nanofibers, electrospinning, tissue engineering

Barbara Vigani, Caterina Valentino, Giuseppina Sandri, Carla Marcella Caramella, Franca Ferrari, Silvia Rossi Department of Drug Sciences, University of Pavia, Pavia, ItalyCorrespondence: Silvia Rossi, Department of Drug Sciences, University of Pavia, Viale Taramelli 12, Pavia, 27100, Italy, Tel +39 0382987357, Fax +39 0382422975, Email silvia.rossi@unipv.itPurpose: Aim of the work was to develop a potential neural scaffold, endowed with neuroprotective and neuroregenerative potential, to be applied at the site of nervous tissue injuries: nanofibers, consisting of gellan gum (GG), spermidine (SP) and gelatin (GL), were prepared via electrospinning. SP was selected for its neuroprotective activity and cationic nature that makes it an ideal GG cross-linking agent. GL was added to improve the scaffold bioactivity.Methods: Mixtures, containing 1.5% w/w GG and increasing SP concentrations (0– 0.125% w/w), were prepared to investigate GG/SP interaction and, thus, to find the best mixture to be electrospun. Mixture rheological and mechanical properties were assessed. The addition of 0.1% w/w GL was also investigated. The most promising GG/SP/GL mixtures were added with poly(ethylene oxide) (PEO) and poloxamer (P407) and, then, electrospun. The resulting fibers were characterized in terms of size and mechanical properties and fiber morphology was observed after soaking in water for 24 hours. Nanofiber biocompatibility was assessed on Schwann cells.Results: More and more structured GG/SP mixtures were obtained by increasing SP concentration, proving its cross-linking potential. After blending with PEO and P407, the mixture consisting of 1.5% w/w GG, 0.05% w/w SP and 0.1% w/w GL was electrospun. The resulting nanofibers appeared homogenous and characterized by a plastic behavior, suggesting a good mechanical resistance when applied at the injury site. Nanofibers were insoluble in aqueous media and able to form a thin gel layer after hydration. GG/SP/GL nanofibers showed a higher compatibility with Schwann cells than GG/SP ones.Conclusion: SP and GL allowed the production of homogenous GG-based nanofibers, which preserved their structure after contact with aqueous media and showed a good compatibility with a neural cell line. After local application at the injury site, nanofibers should support and guide axonal outgrowth, releasing SP in a controlled manner.Graphical Abstract: Keywords: nervous tissue injuries, electrospinning, hydrogel nanofibers, gelatin, Schwann cells

Barbara Vigani,1 Silvia Rossi,1 Giuseppina Sandri,1 Maria Cristina Bonferoni,1 Giulia Milanesi,1 Giovanna Bruni,2 Franca Ferrari1 1Department of Drug Sciences, University of Pavia, Pavia, Italy; 2Department of Chemistry, University of Pavia, Pavia, Italy Aim: The aim of the present work was to develop biodegradable alginate (ALG)-containing fibrous membranes intended for tissue repair, acting as both drug delivery systems and cell growth guidance. Methods: Membranes were prepared by electrospinning. Since ALG can be electrospun only when blended with other spinnable polymers, dextran (DEX) and polyethylene oxide (PEO) were investigated as process adjuvants. ALG/DEX mixtures, characterized by different rheological and conductivity properties, were prepared in phosphate buffer or deionized water; surfactants were added to modulate polymer solution surface tension. The Design of Experiments (DoE) approach (full factorial design) was used to investigate the role of polymer solution features (rheological properties, surface tension, and conductivity) on electrospun fiber morphology. A high viscosity at 1,000 s-1 (1.3–1.9 Pa.s) or a high pseudoplasticity index (≥1.7), combined with a low surface tension (30–32 mN/m) and a low conductivity (800–1,000 µS/cm), was responsible for the production of ALG/DEX homogeneous fibers. Such ranges were successfully employed for the preparation of ALG-containing fibers, using PEO, instead of DEX, as process adjuvant. ALG/DEX and ALG/PEO fibers were subsequently subjected to cross-linking/coating processes to make them slowly biodegradable in aqueous medium. In particular, ALG/PEO fibers were cross-linked and coated with CaCl2/chitosan solutions in water/ethanol mixtures. Due to DEX high content, ALG/DEX fibers were soaked in a polylactide-co-glycolide (PLGA) solution in ethyl acetate. Results: Both cross-linking and coating processes made fibers insoluble in physiological medium and produced an increase in their mechanical resistance, assessed by means of a tensile test. PLGA-coated ALG/DEX and chitosan-coated ALG/PEO fibers were biocompatible and able to support fibroblast adhesion. Conclusion: The DoE approach allowed to draw up guidelines useful for the preparation of homogeneous fibers, starting from mixtures of ALG and non-ionic polymers. Such fibers, upon coating, resulted to be good cell substrates, allowing cell adhesion and growth. Keywords: DoE approach, ALG-based fibers, rheological properties, conductivity, surface tension, chitosan, PLGA

Francesca Saporito,1 Giuseppina Sandri,1 Maria Cristina Bonferoni,1 Silvia Rossi,1 Cinzia Boselli,1 Antonia Icaro Cornaglia,2 Barbara Mannucci,3 Pietro Grisoli,1 Barbara Vigani,1 Franca Ferrari1 1Department of Drug Sciences, University of Pavia, Pavia, 2Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, 3Centro Grandi Strumenti, University of Pavia, Pavia, Italy Abstract: Chronic wounds and severe burns are diseases responsible for severe morbidity and even death. Wound repair is a crucial process and tissue regeneration enhancement and infection prevention are key factors to minimize pain, discomfort, and scar formation. The aim of this work was the development of lipid nanoparticles (solid lipid nanoparticles and nanostructured lipid carriers [NLC]), to be loaded with eucalyptus or rosemary essential oils and to be used, as medical devices, to enhance healing of skin wounds. Lipid nanoparticles were based on natural lipids: cocoa butter, as solid lipid, and olive oil or sesame oil, as liquid lipids. Lecithin was chosen as surfactant to stabilize nanoparticles and to prevent their aggregation. The systems were prepared by high shear homogenization followed by ultrasound application. Nanoparticles were characterized for physical–chemical properties, bioadhesion, cytocompatibility, in vitro proliferation enhancement, and wound healing properties toward normal human dermal fibroblasts. Antimicrobial activity of nanoparticles was evaluated against two reference microbial strains, one of Staphylococcus aureus, the other of Streptococcus pyogenes. Finally, the capability of nanoparticles to promote wound healing in vivo was evaluated on a rat burn model. NLC based on olive oil and loaded with eucalyptus oil showed appropriate physical–chemical properties, good bioadhesion, cytocompatibility, in vitro proliferation enhancement, and wound healing properties toward fibroblasts, associated to antimicrobial properties. Moreover, the in vivo results evidenced the capability of these NLC to enhance the healing process. Olive oil, which is characterized by a high content of oleic acid, proved to exert a synergic effect with eucalyptus oil with respect to antimicrobial activity and wound repair promotion. Keywords: lipid nanoparticles, eucalyptus essential oil, antimicrobial properties, wound healing

Chitosan (CS), a biopolymer known for its wound-healing properties, has garnered significant interest in biomedical research. This study explores the potential of two Hermetia illucens-derived CS types-unbleached CS and bleached CS-as novel biomaterials for wound-healing applications, in comparison with commercial CS derived from the shells of Pandalus borealis (cold-water shrimp). CS was extracted from pupal exuviae, a byproduct of insect farming, which supports a circular economy by converting waste into valuable molecules for biomedical applications. Unbleached CS exhibited viscosity and viscoelastic properties comparable to those of commercial CS. The critical entanglement concentration (CEC) of unbleached CS (1.15 ± 0.05 % w/v) was similar to that of commercial CS (1.18 ± 0.09 % w/v). Moreover, both Hermetia illucens-derived CS types (unbleached and bleached) demonstrated a greater capability to enhance fibroblast viability (135 ± 7 % and 123 ± 6 %, respectively) compared to commercial CS (115 ± 7 %). Further investigation revealed that unbleached CS exhibited increased antioxidant activity, reversing >30 % of the loss of viability caused by H 2 O 2 treatment, and demonstrated anti-inflammatory properties, decreasing IL-6 levels by 66 ± 2 %. Sponge-like scaffolds based on unbleached CS and commercial CS were prepared via freeze-drying. When comparing structural and functional properties of commercial and unbleached CS scaffolds, the unbleached CS scaffolds exhibited higher porosity (67.9 ± 2.7 %), smaller pore size (216 ± 35 nm), higher swelling ratio (25.4 ± 1.9), greater resistance to degradation, and enhanced fibroblast proliferation. These findings underscore the potential of insect-derived CS as a sustainable and bioactive material for wound healing. However, further research is required to fully understand its interactions and mechanisms in tissue repair., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Respiratory tract infections (RTIs) represent a significant global health issue, particularly for vulnerable population, such as children, the elderly, or patients with immunosuppression. In this context, the aim of the present work was the development of Chitosan/Hydrolyzed Collagen-based microparticles (Mps) as a pulmonary drug delivery system (PDDS) for the treatment of RTIs. Mps were produced via spray-drying and composed of chitosan (Cs), one of the most widely used polysaccharides in PDDS, and hydrolyzed collagen (HC), another promising material for the development of PDDS that has not yet been fully explored. The formation of an interaction product between Cs and HC occurred during the spray-drying process and was confirmed by infrared spectroscopy and thermal analysis. Mps were characterized in terms of morphology, particle size, zeta potential, aerodynamic performance, swelling behavior and biodegradation profile in simulated lung fluid. Mps biocompatibility was also assessed on adenocarcinomic human alveolar basal epithelial (A549) cells. Finally, Mps were characterized in vitro for antibacterial properties and their ability to inhibit bacterial adhesion to S. aureus and P. aeruginosa. An enhanced antibacterial effect was observed for Mps with respect to the pristine materials (Cs and HC) and their physical mixture. Moreover, Mps were also able to inhibit bacteria adhesion to epithelial cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The work aims to develop mucoadhesive and thermo-responsive in situ gelling systems, using hydrophobically-modified hydroxypropyl-methyl cellulose (Sangelose, SG) and beta-cyclodextrin (β-CD) derivatives, for preventing viral respiratory infections. Eight SG/CD systems with varying CD concentrations were evaluated for rheological properties, mucoadhesiveness, spreadability and sprayability via nasal devices; cytotoxicity was in vitro investigated on reconstituted nasal epithelia. Additionally, droplet size distribution and spray deposition were assessed for the most promising systems. The addition of β-CD derivatives to SG solution was responsible for a rapid sol-gel transition within a physiological temperature range (29-34 °C). SG/CD systems were characterized by a prevalence of the elastic properties on the viscous ones at 37 °C, functional to the formation of a protective gel barrier on the mucosa. The most promising systems showed sprayability and spreadability suitable for nasal administration, while in vitro tests demonstrated their non-toxicity. All the sprays were characterized by droplets with size >100 μm, functional to avoid droplet exhalation or lung deposition; spray deposition studies confirmed uniform distribution across nasal turbinates, crucial for trapping inhaled particles. In conclusion, a mucoadhesive and thermo-responsive in situ gelling system consisting of SG and β-CD derivatives was successfully developed as promising nasal spray for the prevention of respiratory infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.)

Thermoplastic polymers provide a versatile platform to mimic various aspects of physiological extracellular matrix properties such as chemical composition, stiffness, and topography for use in cell and tissue engineering applications. In this review, we provide a brief overview of the most promising thermoplastic polymers, and in particular the thermoplastic polyesters, such as poly(lactic acid), poly(glycolic acid), and polycaprolactone, and the thermoplastic elastomers, such as polyurethanes, polyhydroxyalkanoates, and poly(butyl cyanoacrylate). A particular focus has been made on the synthesis processes, the processability and the biocompatibility. We also discuss how these materials can be applied in tissue engineering, mimicking tissues' structure and function, and stimulate mesenchymal stem cells differentiation and mechanotransduction., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors.)

Alginate biopolymer is widely employed in many industrial fields thanks to its pleasing features of biodegradability, biocompatibility, low toxicity, and relatively low cost. The gelling process of alginate with divalent cations is fairly simple and thus it is used as a versatile biomaterial to tailor the desired mechanical and moisture properties. This study focused on developing new gel formulations to enhance the properties of calcium-alginate hydrogel (CA). The newly synthesized hydrogels, referred to as CA-CHEM gels, were chemically cross-linked with different ratios of pentaerythritol tris[3-(1-aziridinyl)propionate] (PTAP) through the reaction between the carboxylic groups of alginate and aziridines of PTAP. The reaction was successfully monitored by NMR. The new CA-CHEM gels were chemically characterized using FTIR-ATR, while SEM analysis confirmed the changes in the porosity and homogeneity of the network. Additionally, thermogravimetric analyses and mechanical properties showed improvement in degradation stability and in structural strength, compared to plain CA, with an increasing PTAP content up to 1 % w/w. Finally, the new CA-CHEM gels effectively controlled water absorption and release. In particular, CA-CHEM-1 performed as the most controlled system, making it promising for delivering aqueous cleaning solutions on water-sensitive surfaces such as a wooden historical musical instrument., (© 2024 The Author(s). ChemPlusChem published by Wiley-VCH GmbH.)

Olive mill wastewater (OMWW) is a byproduct of olive oil extraction that represents a critical environmental concern due to its potential adverse effects on ecosystems. Given these premises, spray-dried microparticles were designed and developed using maltodextrins as carriers to encapsulate OMWW bioactive compounds. The microparticles were manufactured using an easily scalable and sustainable spray-drying process. The resulting microparticles were smooth, spherical, and exhibited a mean particle size of about 18 μm. The systems demonstrated notable antioxidant properties with a DPPH radical scavenging activity higher than 60 %, due to the polyphenolic compounds of OMWW (about 24 g gallic acid equivalents per g of sample). In addition, the microparticles supported fibroblast and macrophage viability at concentrations up to 1 mg/mL. They also determined a 4-fold inflammation reduction in macrophages, improved collagen expression in fibroblasts, and modulated oxidative stress on aged fibroblasts. In conclusion, these microparticles could be considered as promising medical devices in wound healing, while offering a sustainable solution for valorizing OMWW., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Giuseppina Sandri reports financial support was provided by The National Recovery and Resilience Plan (NRRP). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

Chronic wounds are non-healing lesions characterized by a high degree of inflammation, posing significant challenges in clinical management due to the increased risk of severe infection. This study focuses on developing a powder for cutaneous application to enhance the healing and prevent infections in chronic wounds. The smart nanocomposites-based biomimetic microparticles here developed combine the properties of chitosan and of clays and represent a significant innovation in the field of biomaterials for skin regeneration since they possess enhanced antimicrobial properties, are multi-functional scaffolds and promote cell proliferation, support tissue reconstruction by mimicking the natural extracellular matrix, and provide hemostatic properties to control bleeding during wound closure. The microparticles were made of chitosan and doped with clay minerals, specifically montmorillonite or layered double hydroxides, containing copper ions. The synergistic combination of biomimetic polymers and clays aims to regulate cellular responses, angiogenesis, and extracellular matrix (ECM) deposition, leveraging the bioactive properties of both components to promote wound healing. Montmorillonite and layered double hydroxides were enriched with copper ions through intercalation or coprecipitation methods, respectively. The water-insoluble microparticles were prepared using a chitosan derivative, chitosan carbamate, synthesized to obtain chitosan-based microparticles via spray-drying without crosslinkers. Physico-chemical characterization confirmed the successful doping of Cu-clay interaction products in the microparticles. In addition to enhanced cell proliferation and hemostatic properties, the presence of Cu-clays boosted the microparticles' antibacterial properties. Encouraging preclinical in vitro and in vivo results suggest that these smart nanocomposite biomimetic microparticles doped with Cu-enriched clay minerals could be promising candidates for simultaneously enhancing healing and controlling infections in chronic wounds., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Giuseppina Sandri reports financial support was provided by The National Recovery and Resilience Plan (NRRP). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

The high rate of rejection and failure of orthopedic implants is primarily attributed to incomplete osseointegration and stress at the implant-to-bone interface due to significant differences in the mechanical properties of the implant and the surrounding bone. Various surface treatments have been developed to enhance the osteoconductive properties of implants. The aim of this work was the in vitro characterization of titanium alloy modified with a nanocrystalline hydroxyapatite surface layer in relative comparison to unmodified controls. This investigation focused on the behavior of the surface treatment in relation to the physiological environment. Moreover, the osteogenic response of human osteoblasts and adipose stem cells was assessed. Qualitative characterization of cellular interaction was performed via confocal laser scanning microscopy focusing on the cell nuclei and cytoskeletons. Filipodia were assessed using scanning electron microscopy. The results highlight that the HA treatment promotes protein adhesion as well as gene expression of osteoblasts and stem cells, which is relevant for the inorganic and organic components of the extracellular matrix and bone. In particular, cells grown onto HA-modified titanium alloy are able to promote ECM production, leading to a high expression of collagen I and non-collagenous proteins, which are crucial for regulating mineral matrix formation. Moreover, they present an impressive amount of filipodia having long extensions all over the test surface. These findings suggest that the HA surface treatment under investigation effectively enhances the osteoconductive properties of Ti6Al4V ELI.

Alternative approaches to laser fusion for the additive manufacturing (AM) of metals are often hampered by the need for long sintering cycles. Typical sintering cycles require heating at temperatures above 80% of the melting point for several hours. The process is time- and energy-consuming, particularly when high-melting materials are involved. Applying pressure can drastically reduce the time and temperature required for densification. Recently, a particular kind of pressure-assisted sintering process known as spark plasma sintering (SPS) or field-assisted sintering (FAST) received considerable attention in academia and industry due to its ability to enhance densification. However, conventional SPS/FAST techniques cannot be directly applied to the densification of objects presenting a complex geometry. This work shows how a modified SPS/FAST setup, operating in a pseudoisostatic mode, can be used for debinding and sinter objects produced by material extrusion. This approach can be applied to metals and metal-based and ceramic-based composites when their geometry does not include closed cavities. Depending on the characteristics of the pressure-transfer medium, some level of anisotropy in the volume reduction associated with the densification can be observed. Still, it can easily be corrected by appropriately compensating sintering deformation during printing. Using this approach, the time required for the debinding and sintering can be reduced considerably. It represents an alternative approach to the AM of a wide range of inorganic materials characterized by a relatively low-cost, high material flexibility, and low environmental impact., (Copyright 2023, Mary Ann Liebert, Inc., publishers.)

Nowadays, chronic wounds are the major cause of morbidity worldwide and the healthcare costs related to wound care are a billion-dollar issue; chronic wounds involve a non-healing process that makes necessary the application of advanced wound dressings to promote skin integrity recovery. Functionally Graded Scaffolds (FGSs) are currently driving interest as promising candidates in mimicking the skin tissue environment and, thus, in enhancing a faster and more effective wound healing process. Aim of the present work was to design and develop a porous FGS based on κ-carrageenan (κCG) for the management of chronic skin wounds; a freeze-drying process was optimized to obtain in a single-step a three-layered FGS characterized by a pore size gradient functional to mimic the structure of native skin tissue. In addition to κCG, arginine and whey protein isolate were used as multifunctional agents for FGS preparation; these substances can not only intervene in some stages of wound healing but are able to establish non-covalent interactions with κCG, which were responsible for the production of layers with different pore size, water content capability and mechanical properties. Cell migration, adhesion and proliferation within the FGS structure were evaluated in vitro on fibroblasts and FGS wound healing potential was also studied in vivo on a murine model., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Chronic wounds represent silent epidemic affecting a large portion of the world population, especially the elders; in this context, the development of advanced bioactive dressings is imperative to accelerate wound healing process, while contrasting or preventing infections. The aim of the present work was to provide a deep characterization of the functional and biopharmaceutical properties of a sustainable thin and flexible films, composed of whey proteins alone (WPI) and added with nanostructured zinc oxide (WPZ) and intended for the management of chronic wounds. The potential of whey proteins-based films as wound dressings has been confirmed by their wettability, hydration properties, elastic behavior upon hydration, biodegradation propensity and, when added with nanostructured zinc oxide, antibacterial efficacy against both Gram-positive and Gram-negative pathogens, i.e. Staphylococcus aureus and Escherichia coli. In-vitro experiments, performed on normal human dermal fibroblasts, confirmed film cytocompatibility, also revealing the possible role of Zn 2+ ions in promoting fibroblast proliferation. Finally, in-vivo studies on rat model confirmed film suitability to act as wound dressing, since able to ensure a regular healing process while providing effective protection from infections. In particular, both films WPI and WPZ are responsible for the formation in the wound bed of a continuous collagen layer similar to that of healthy skin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Tendon disorders are common injuries, which can be greatly debilitating as they are often accompanied by great pain and inflammation. Moreover, several problems are also related to the laceration of the tendon-to-bone interface (TBI), a specific region subjected to great mechanical stresses. The techniques used nowadays for the treatment of tendon and TBI injuries often involve surgery. However, one critical aspect of this procedure involves the elevated risk of fail due to the tissues weakening and the postoperative alterations of the normal joint mechanics. Synthetic polymers, such as thermoplastic polyurethane, are of special interest in the tissue engineering field as they allow the production of scaffolds with tunable elastic and mechanical properties, that could guarantee an effective support during the new tissue formation. Based on these premises, the aim of this work was the design and the development of highly porous 3D scaffolds based on thermoplastic polyurethane, and doped with chondroitin sulfate and caseinophosphopeptides, able to mimic the structural, biomechanical, and biochemical functions of the TBI. The obtained scaffolds were characterized by a homogeneous microporous structure, and by a porosity optimal for cell nutrition and migration. They were also characterized by remarkable mechanical properties, reaching values comparable to the ones of the native tendons. The scaffolds promoted the tenocyte adhesion and proliferation when caseinophosphopetides and chondroitin sulfate are present in the 3D structure. In particular, caseinophosphopeptides' optimal concentration for cell proliferation resulted 2.4 mg/mL. Finally, the systems evaluation in vivo demonstrated the scaffolds' safety, since they did not cause any inflammatory effect nor foreign body response, representing interesting platforms for the regeneration of injured TBI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The synthesis and characterization of a novel film-forming organic cage and of its smaller analogue are here described. While the small cage produced single crystals suitable for X-ray diffraction studies, the large one was isolated as a dense film. Due to its remarkable film-forming properties, this latter cage could be solution processed into transparent thin-layer films and mechanically stable dense self-standing membranes of controllable thickness. Thanks to these peculiar features, the membranes were also successfully tested for gas permeation, reporting a behavior similar to that found with stiff glassy polymers such as polymers of intrinsic microporosity or polyimides. Given the growing interest in the development of molecular-based membranes, for example for separation technologies and functional coatings, the properties of this organic cage were investigated by thorough analysis of their structural, thermal, mechanical and gas transport properties, and by detailed atomistic simulations., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Introduction: Recently, mycelia of Ganoderma lucidum and Pleurotus ostreatus , edible fungi, have been characterized in vitro as self-growing biomaterials for tissue engineering since they are constituted of interconnected fibrous networks resembling the dermal collagen structure. Aim: This work aims to investigate the biopharmaceutical properties of G. lucidum and P. ostreatus mycelia to prove their safety and effectiveness in tissue engineering as dermal substitutes. Methods: The mycelial materials were characterized using a multidisciplinary approach, including physicochemical properties (morphology, thermal behavior, surface charge, and isoelectric point). Moreover, preclinical properties such as gene expression and in vitro wound healing assay have been evaluated using fibroblasts. Finally, these naturally-grown substrates were applied in vivo using a murine burn/excisional wound model. Conclusions: Both G. lucidum and P. ostreatus mycelia are biocompatible and able to safely and effectively enhance tissue repair in vivo in our preclinical model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ruggeri, Miele, Contardi, Vigani, Boselli, Icaro Cornaglia, Rossi, Suarato, Athanassiou and Sandri.)

Herein we developed a hydrogel based porous cross-linked scaffold intended for the treatment of chronic skin ulcers. It is made of collagen, the most abundant protein of mammals ECM, and chitosan, a natural polysaccharide endowed with numerous positive cues for wound repair. Different cross-linking methods, namely UV irradiation with the addition of glucose, addition of tannic acid as cross-linking agent and ultrasonication, were employed to prepare a cross-linked hydrogel with a highly interconnected 3D internal structure. The variables considered critical to obtain a suitable system for the envisaged application are the composition of hydrogels, especially the concentration of chitosan, and the concentration ratio between chitosan and collagen. Stable systems, characterized by high porosity, were obtained thanks to the use of freeze-drying process. To assess the influence of the above-mentioned variables on scaffold mechanical properties, a Design of Experiments (DoE) approach was exploited, which resulted in the identification of the best hydrogel composition. In vitro and in vivo assays on a fibroblast model cell line and on a murine model, respectively, demonstrated scaffold biocompatibility, biomimicry, and safety., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Periodontal regeneration is extremely limited and unpredictable due to structural complications, as it requires the simultaneous restoration of different tissues, including cementum, gingiva, bone, and periodontal ligament. In this work, spray-dried microparticles based on green materials (polysaccharides - gums - and a protein - silk fibroin) are proposed to be implanted in the periodontal pocket as 3D scaffolds during non-surgical treatments, to prevent the progression of periodontal disease and to promote the healing in mild periodontitis. Arabic or xanthan gum have been associated to silk fibroin, extracted from Bombyx mori cocoons, and loaded with lysozyme due to its antibacterial properties. The microparticles were prepared by spray-drying and cross-linked by water vapor annealing, inducing the amorphous to semi-crystalline transition of the protein component. The microparticles were characterized in terms of their chemico-physical features (SEM, size distribution, structural characterization - FTIR and SAXS, hydration and degradation properties) and preclinical properties (lysozyme release, antibacterial properties, mucoadhesion, in vitro cells adhesion and proliferation and in vivo safety on a murine incisional wound model). The encouraging preclinical results highlighted that these three-dimensional (3D) microparticles could provide a biocompatible platform able to prevent periodontitis progression and to promote the healing of soft tissues in mild periodontitis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Tendon disorders are common medical conditions, which can be greatly debilitating as they are often accompanied by great pain and inflammation. The techniques used nowadays for the treatment of chronic tendon injuries often involve surgery. However, one critical aspect of this procedure involves the scar tissue, characterized by mechanical properties that vary from healthy tissue, rendering the tendons inclined to reinjury or rupture. Synthetic polymers, such as thermoplastic polyurethane, are of special interest in the tissue engineering field as they allow the production of scaffolds with controlled elastic and mechanical properties, which could guarantee an effective support during the new tissue formation. The aim of this work was the design and the development of tubular nanofibrous scaffolds based on thermoplastic polyurethane and enriched with cerium oxide nanoparticles and chondroitin sulfate. The scaffolds were characterized by remarkable mechanical properties, especially when tubular aligned, reaching values comparable to the ones of the native tendons. A weight loss test was performed, suggesting a degradation in prolonged times. In particular, the scaffolds maintained their morphology and also remarkable mechanical properties after 12 weeks of degradation. The scaffolds promoted the cell adhesion and proliferation, in particular when in aligned conformation. Finally, the systems in vivo did not cause any inflammatory effect, representing interesting platforms for the regeneration of injured tendons.

Copper was manufactured by using a low-cost 3D printing device and copper oxide water-based colloids. The proposed method avoids the use of toxic volatile solvents (used in metal-based robocasting), adopting copper oxide as a precursor of copper metal due to its lower cost and higher chemical stability. The appropriate rheological properties of the colloids have been obtained through the addition of poly-ethylene oxide-co-polypropylene-co-polyethylene oxide copolymer (Pluronic P123) and poly-acrylic acid to the suspension of the oxide in water. Mixing of the components of the colloidal suspension was performed with the same syringes used for the extrusion, avoiding any material waste. The low-temperature transition of water solutions of P123 is used to facilitate the homogenization of the colloid. The copper oxide is then converted to copper metal through a reductive sintering process, performed at 1000°C for a few hours in an atmosphere of Ar-10%H 2 . This approach allows the obtainment of porous copper objects (up to 20%) while retaining good mechanical properties. It could be beneficial for many applications, for example current collectors in lithium batteries., Competing Interests: No competing or personal financial interests exist., (Copyright 2023, Mary Ann Liebert, Inc., publishers.)

Several nanomedicine based medicinal products recently reached the market thanks to the drive of the COVID-19 pandemic. These products are characterized by criticality in scalability and reproducibility of the batches, and the manufacturing processes are now being pushed towards continuous production to face these challenges. Although the pharmaceutical industry, because of its deep regulation, is characterized by slow adoption of new technologies, recently, the European Medicines Agency (EMA) took the lead in pushing for process improvements using technologies already established in other manufacturing sectors. Foremost among these technologies, robotics is a technological driver, and its implementation in the pharma field should cause a big change, probably within the next 5 years. This paper aims at describing the regulation changes mainly in aseptic manufacturing and the use of robotics in the pharmaceutical environment to fulfill GMP (good manufacturing practice). Special attention is therefore paid at first to the regulatory aspect, explaining the reasons behind the current changes, and then to the use of robotics that will characterize the future of manufacturing especially in aseptic environments, moving from a clear overview of robotics to the use of automated systems to design more efficient processes, with reduced risk of contamination. This review should clarify the regulation and technological scenario and provide pharmaceutical technologists with basic knowledge in robotics and automation, as well as engineers with regulatory knowledge to define a common background and language, and enable the cultural shift of the pharmaceutical industry.

Clay minerals are historically among the most used materials with a wide variety of applications. In pharmaceutical and biomedical fields, their healing properties have always been known and used in pelotherapy and therefore attractive for their potential. In recent decades, the research has therefore focused on the systematic investigation of these properties. This review aims to describe the most relevant and recent uses of clays in the pharmaceutical and biomedical field, especially for drug delivery and tissue engineering purposes. Clay minerals, which are biocompatible and non-toxic materials, can act as carriers for active ingredients while controlling their release and increasing their bioavailability. Moreover, the combination of clays and polymers is useful as it can improve the mechanical and thermal properties of polymers, as well as induce cell adhesion and proliferation. Different types of clays, both of natural (such as montmorillonite and halloysite) and synthetic origin (layered double hydroxides and zeolites), were considered in order to compare them and to assess their advantages and different uses.

Peripheral nerve injury is one of the most debilitating pathologies that severely impair patients' life. Although many efforts have been made to advance in the treatment of such a complex disorder, successful strategies to ensure full recovery are still scarce. The aim of the present work was to develop flexible and mechanically resistant platforms intended to act as a support and guide for neural cells during the regeneration process of peripheral nerve injury. For this purpose, poly(lactic- co -glycolic acid) (PLGA)/poly(d,l-lactic acid) (PDLLA)/poly(ethylene glycol) 400 (PEG)-multichannel-based scaffolds (MCs) were prepared through a multistep process involving electrospun microfibers coated with a polymer blend solution and used as a sacrificial mold. In particular, scaffolds characterized by random (MCR) and aligned (MCA) multichannel were obtained. A design of experiments approach (DoE) was employed to identify a scaffold-optimized composition. MCs were characterized for morphological and mechanical properties, suturability, degradability, cell colonization, and in vivo safety. A new biodegradable, biocompatible, and safe microscale multichannel scaffold was developed as the result of an easy multistep procedure.

Fiber spinning technologies attracted a great interest since the beginning of the last century. Among these, electrospinning is a widely diffuse technique; however, it presents some drawbacks such as low fiber yield, high energy demand and the use of organic solvents. On the contrary, centrifugal spinning is a more sustainable method and allows to obtain fiber using centrifugal force and melted materials. The aim of the present work was the design and the development of polydioxanone (PDO) microfibers intended for tissue engineering, using centrifugal spinning. PDO, a bioresorbable polymer currently used for sutures, was selected as low melting polyester and DES (deep eutectic solvents), either choline chloride/citric acid (ChCl/CA) or betaine/citric acid (Bet/CA) 1:1 M ratio, were used to improve PDO spinnability. Physical mixtures of DES and PDO were prepared using different weight ratios. These were then poured into the spinneret and melted at 140 °C for 5 min. After the complete melting, the blends were spun for 1 min at 700 rpm. The fibers were characterized for physico chemical properties (morphology; dimensions; chemical structure; thermal behavior; mechanical properties). Moreover, the preclinical investigation was performed in vitro (biocompatibility, adhesion and proliferation of fibroblasts) and in vivo (murine burn/excisional model to assess safety and efficacy). The multidisciplinary approach allowed to obtain an extensive characterization to develop PDO based microfibers as medical device for implant to treat full thickness skin wounds., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Tendon disorders are common medical conditions that could lead to significant disability, pain, healthcare costs, and a loss of productivity. Traditional approaches require long periods of treatment, and they largely fail due to the tissues weakening and the postoperative alterations of the normal joint mechanics. To overcome these limitations, innovative strategies for the treatment of these injuries need to be explored. The aim of the present work was the design of nano-fibrous scaffolds based on poly(butyl cyanoacrylate) (PBCA), a well-known biodegradable and biocompatible synthetic polymer, doped with copper oxide nanoparticles and caseinphosphopeptides (CPP), able to mimic the hierarchical structure of the tendon and to improve the tissue healing potential. These were developed as implants to be sutured to reconstruct the tendons and the ligaments during surgery. PBCA was synthetized, and then electrospun to produce aligned nanofibers. The obtained scaffolds were characterized for their structure and physico-chemical and mechanical properties, highlighting that CuO and CPP loading, and the aligned conformation determined an increase in the scaffold mechanical performance. Furthermore, the scaffolds loaded with CuO showed antioxidant and anti-inflammatory properties. Moreover, human tenocytes adhesion and proliferation to the scaffolds were assessed in vitro. Finally, the antibacterial activity of the scaffolds was evaluated using Escherichia coli and Staphylococcus aureus as representative of Gram-negative and Gram-positive bacteria, respectively, demonstrating that the CuO-doped scaffolds possessed a significant antimicrobial effect against E. coli . In conclusion, scaffolds based on PBCA and doped with CuO and CPP deserve particular attention as enhancers of the tendon tissue regeneration and able to avoid bacterial adhesion. Further investigation on the scaffold efficacy in vivo will assess their capability for enhancing the tendon ECM restoration in view of accelerating their translation to the clinic.

Neurological disorders affecting both CNS and PNS still represent one of the most critical and challenging pathologies, therefore many researchers have been focusing on this field in recent decades. Spinal cord injury (SCI) and peripheral nerve injury (PNI) are severely disabling diseases leading to dramatic and, in most cases, irreversible sensory, motor, and autonomic impairments. The challenging pathophysiologic consequences involved in SCI and PNI are demanding the development of more effective therapeutic strategies since, as yet, a therapeutic strategy that can effectively lead to a complete recovery from such pathologies is not available. Drug delivery systems (DDSs) based on polysaccharides have been receiving more and more attention for a wide range of applications, due to their outstanding physical-chemical properties. This review aims at providing an overview of the most studied polysaccharides used for the development of DDSs intended for the repair and regeneration of a damaged nervous system, with particular attention to spinal cord and peripheral nerve injury treatments. In particular, DDSs based on chitosan and their association with alginate, dextran, agarose, cellulose, and gellan were thoroughly revised.

Insects, especially crickets, have been proposed as a novel source of nutrients in human nutrition since they possess bioactive molecules, including high protein content, lipids, chitin, vitamins and minerals. In this work, the nutritional and functional properties of a novel Italian spray-dried (SD) cricket powder were evaluated. The powder was characterized by physico-chemical properties (morphology, size distribution, solid state, thermal profiles, and surface zeta potential), and antioxidant properties. Moreover, preclinical properties (cytocompatibility and pro-inflammatory immune response) were assessed. The powder was characterized by microparticle structure with bulges and rough surfaces, showing distinctive antioxidant properties. The preclinical results suggested that the SD crickets were biocompatible towards Caco-2 and macrophages without immune response, representing an interesting material for the food industry that could provide health benefits in addition to the basic nutritional value of traditional foods.

The cleaning of some wooden artefacts can be challenging due to peculiar surface roughness and/or particular finishing treatments that favour the deposition of dirt and contaminants. The most common cleaning system used by conservators is agar gel, characterized by its rigidity and brittleness, which challenges the cleaning of rough and irregular surfaces typical of most wooden artefacts. In this work, alginate crosslinked with calcium (CA) and konjac glucomannan crosslinked with borax (KGB) gels were proposed to solve this issue. They were prepared and applied to smooth- and rough-surfaced mock-ups replicating wooden musical instruments' surfaces that had been subsequently covered by artificial soiling and sweat contaminants. The mechanical properties of CA and KGB gels, including their stability over a 60-day storage time, were evaluated by a texture analyzer, while cleaning efficacy was analytically evaluated by non-invasive X-ray fluorescence mapping and profilometric investigation. CA gel appeared to have a higher tensile strength and elongation at break. KGB gel was shown to be soft and resilient, indicating its suitability for cleaning rough surfaces. After repeating the cleaning application three times on the rough-surfaced mock-ups, both the CA and KGB gels were shown to have cleaning efficacy. The results obtained with CA and KGB were compared with those from the Agar application.

The development of a successful strategy to ensure a full recovery in patients affected by peripheral nerve injury (PNI), one of the most debilitating pathologies, is, still today, a major clinical challenge. Herein, spermidine (SP), an endogenous polyamine, is employed with a dual role: as cross-linking agent for alginate (ALG) and as antioxidant and anti-inflammatory compound. In particular, micro/nanogels based on the ionic interaction between ALG and SP were obtained via ionotropic gelation. Different ALG concentrations and viscosity grades and different SP concentrations were considered. The influence of such variables on micro/nanogels size was investigated by means of a Design of Experiments (DoE) approach (full factorial design). The formation of micro/nanogels was proved by Scanning Electron Microscope (SEM) analysis and by rheological and profilometry measurements. Fourier Transform Infrared (FTIR) measurements performed on nanogels of optimal composition confirmed SP-ALG interaction. The addition of trehalose as cryoprotectant agent to nanogel dispersion was considered in view of the employment of freeze-drying process to obtain a stable product. Moreover, in vitro studies on Schwann cells proved the ability of SP of expressing antioxidant and anti-inflammatory properties, even if involved in the formation of nanogels., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The enthesis is an extremely specific region, localized at the tendon-bone interface (TBI) and made of a hybrid connection of fibrocartilage with minerals. The direct type of enthesis tissue is commonly subjected to full laceration, due to the stiffness gradient between the soft tissues and hard bone, and this often reoccurs after surgical reconstruction. For this purpose, the present work aimed to design and develop a tubular scaffold based on pullulan (PU) and chitosan (CH) and intended to enhance enthesis repair. The scaffold was designed with a topographical gradient of nanofibers, from random to aligned, and hydroxyapatite (HAP) nanoparticles along the tubular length. In particular, one part of the tubular scaffold was characterized by a structure similar to bone hard tissue, with a random mineralized fiber arrangement; while the other part was characterized by aligned fibers, without HAP doping. The tubular shape of the scaffold was also designed to be extemporarily loaded with chondroitin sulfate (CS), a glycosaminoglycan effective in wound healing, before the surgery. Micro CT analysis revealed that the scaffold was characterized by a continuous gradient, without interruptions from one end to the other. The gradient of the fiber arrangement was observed using SEM analysis, and it was still possible to observe the gradient when the scaffold had been hydrated for 6 days. In vitro studies demonstrated that human adipose stem cells (hASC) were able to grow and differentiate onto the scaffold, expressing the typical ECM production for tendon in the aligned zone, or bone tissue in the random mineralized part. CS resulted in a synergistic effect, favoring cell adhesion/proliferation on the scaffold surface. These results suggest that this tubular scaffold loaded with CS could be a powerful tool to support enthesis repair upon surgery.

Chronic wounds (resulting from underlying disease, metabolic disorders, infections, trauma, and even tumours) pose significant health problems. In this work, microparticles, based on polysaccharides (maltodextrin or dextran) and amino acids, and doped with antibacterial nanoparticles (CuO or ZnO NPs) are designed. Smart nano-in-microparticles with a hierarchical 3D structure are developed. The ultimate goal aims at an innovative platform to achieve skin repair and to manage skin colonization by avoiding infection that could delay and even impair the healing process. The microparticles are prepared by spray-drying and cross-linked by heating, to obtain insoluble scaffolds able to facilitate cell proliferation in the wound bed. The nano-in-microparticles are characterized using a multidisciplinary approach: chemico-physical properties (SEM, SEM-EDX, size distribution, swelling and degradation properties, structural characterization - FTIR, XRPD, SAXS - mechanical properties, surface zeta potential) and preclinical properties (in vitro biocompatibility and whole-blood clotting properties, release studies and antimicrobial properties, and in vivo safety and efficacy on murine burn/excisional wound model) were assessed. The hierarchical 3D nano-in microparticles demonstrate to promote skin tissue repair in a preclinical study, indicating that this platform deserves particular attention and further investigation will promote the prototypes translation to clinics., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

In this paper, we report on the preparation of Imidazole-functionalized glass surfaces, demonstrating the ability of a dinuclear Cu(II) complex of a macrocyclic ligand to give a "cascade" interaction with the deprotonated forms of grafted imidazole moieties. In this way, we realized a prototypal example of an antimicrobial surface based on a supramolecular approach, obtaining a neat microbicidal effect using low amounts of the described copper complex., Competing Interests: The authors declare no conflict of interest.

In recent decades, the demand for replacement of damaged or broken tissues has increased; this poses the attention on problems related to low donor availability. For this reason, researchers focused their attention on the field of tissue engineering, which allows the development of scaffolds able to mimic the tissues' extracellular matrix. However, tissue replacement and regeneration are complex since scaffolds need to guarantee an adequate hierarchical structured morphology as well as adequate mechanical, chemical, and physical properties to stand the stresses and enhance the new tissue formation. For this purpose, the use of inorganic materials as fillers for the scaffolds has gained great interest in tissue engineering applications, due to their wide range of physicochemical properties as well as their capability to induce biological responses. However, some issues still need to be faced to improve their efficacy. This review focuses on the description of the most effective inorganic nanomaterials (clays, nano-based nanomaterials, metal oxides, metallic nanoparticles) used in tissue engineering and their properties. Particular attention has been devoted to their combination with scaffolds in a wide range of applications. In particular, skin, orthopaedic, and neural tissue engineering have been considered.

The spontaneous healing of a tendon laceration results in the formation of scar tissue, which has lower functionality than the original tissue. Moreover, chronic non-healing tendon injuries frequently require surgical treatment. Several types of scaffolds have been developed using the tissue engineering approach, to complement surgical procedures and to enhance the healing process at the injured site. In this work, an electrospun hybrid tubular scaffold was designed to mimic tissue fibrous arrangement and extracellular matrix (ECM) composition, and to be extemporaneously loaded into the inner cavity with human platelet lysate (PL), with the aim of leading to complete post-surgery functional regeneration of the tissue for functional regeneration of the osteo-tendon interface. For this purpose, pullulan (P)/chitosan (CH) based polymer solutions were enriched with hydroxyapatite nanoparticles (HP) and electrospun. The nanofibers were collected vertically along the length of the scaffold to mimic the fascicle direction of the tendon tissue. The scaffold obtained showed tendon-like mechanical performance, depending on HP content and tube size. The PL proteins were able to cross the scaffold wall, and in vitro studies have demonstrated that tenocytes and osteoblasts are able to adhere to and proliferate onto the scaffold in the presence of PL; moreover, they were also able to produce either collagen or sialoproteins, respectively-important components of ECM. These results suggest that HP and PL have a synergic effect, endorsing PL-loaded HP-doped aligned tubular scaffolds as an effective strategy to support new tissue formation in tendon-to-bone interface regeneration.