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•Cylindrical scaffolds were designed with CAD and produced using RP.•3D scaffolds were produced with a TCP/AA mixture and functionalized with GO.•GO inclusion led to porous yet stiff ...scaffolds with a controlled swelling profile.•TCP/AA_GO scaffolds promoted calcium deposition and increased the ALP activity.•All scaffolds displayed a biocompatible profile and promoted osteoblast adhesion.
The incidence of fractures and bone-related diseases like osteoporosis has been increasing due to aging of the world’s population. Up to now, grafts and titanium implants have been the principal therapeutic approaches used for bone repair/regeneration. However, these types of treatment have several shortcomings, like limited availability, risk of donor-to-recipient infection and tissue morbidity. To overcome these handicaps, new 3D templates, capable of replicating the features of the native tissue, are currently being developed by researchers from the area of tissue engineering. These 3D constructs are able to provide a temporary matrix on which host cells can adhere, proliferate and differentiate. Herein, 3D cylindrical scaffolds were designed to mimic the natural architecture of hollow bones, and to allow nutrient exchange and bone neovascularization. 3D scaffolds were produced with tricalcium phosphate (TCP)/alginic acid (AA) using a Fab@home 3D printer. Furthermore, graphene oxide (GO) was incorporated into the structure of some scaffolds to further enhance their mechanical properties. The results revealed that the scaffolds incorporating GO displayed greater porosity, without impairing their mechanical properties. These scaffolds also presented a controlled swelling profile, enhanced biomineralization capacity and were able to increase the Alkaline Phosphatase (ALP) activity. Such characteristics make TCP/AA scaffolds functionalized with GO promising 3D constructs for bone tissue engineering applications.
Three‐dimensional cell culture models, such as spheroids, can be used in the process of the development of new anticancer agents because they are able to closely mimic the main features of human ...solid tumors, namely their structural organization, cellular layered assembling, hypoxia, and nutrient gradients. These properties imprint to the spheroids an anticancer therapeutics resistance profile, which is similar to that displayed by human solid tumors. In this review, an overview of the drug resistance mechanisms observed in 3D tumor spheroids is provided. Furthermore, comparisons between the therapeutics resistance profile exhibited by spheroids, and 2D cell cultures are presented. Finally, examples of the therapeutic approaches that have been developed to surpass the drug resistance mechanisms exhibited by spheroids are described.
Drug resistance phenotype acquired by the cancer cells is still the major cause of the patient’s low survival rates. Spheroids in vitro models represent more closely the characteristics of the human tumors, which prompted its use in the development of new therapeutics. In this review, the structural and functional similarities between spheroids and in vivo human solid tumors are reviewed, highlighting the common drug resistance mechanisms, as well as the therapeutic approaches explored to surpass this resistance.
HIGHLIGHTS
The suitability of 3D cell culture models for drug screening purposes is highlighted.
Spheroids and in vivo human solid tumors structural and functional similarities are emphasized.
The drug resistance mechanisms exhibited by spheroids are described.
Therapeutic approaches used to surpass spheroids’ drug resistance mechanisms are described.
The design of nanocarriers for the delivery of drugs and nucleic-acids remains a very challenging goal due to their physicochemical differences. In addition, the reported accelerated clearance and ...immune response of pegylated nanomedicines highlight the necessity to develop carriers using new materials. Herein, we describe the synthesis of amphiphilic triblock poly(2-ethyl-2-oxazoline)-PLA-g-PEI (PEOz-PLA-g-PEI) micelles for the delivery of minicircle DNA (mcDNA) vectors. In this copolymer the generally used PEG moieties are replaced by the biocompatible PEOz polymer backbone that assembles the hydrophilic shell. The obtained results show that amphiphilic micelles have low critical micellar concentration, are hemocompatible and exhibit stability upon incubation in serum. The uptake in MCF-7 cells was efficient and the nanocarriers achieved 2.7 fold higher expression than control particles. Moreover, mcDNA-loaded micelleplexes penetrated into 3D multicellular spheroids and promoted widespread gene expression. Additionally, to prove the concept of co-delivery, mcDNA and doxorubicin (Dox) were simultaneously encapsulated in PEOz-PLA-g-PEI carriers, with high efficiency. Dox-mcDNA micelleplexes exhibited extensive cellular uptake and demonstrated anti-tumoral activity. These findings led us to conclude that this system has a potential not only for the delivery of novel mcDNA vectors, but also for the co-delivery of drug-mcDNA combinations without PEG functionalization.
Recently, the biomedical scientists who are working in the skin regeneration area have proposed asymmetric membranes as ideal wound dressings, since they are able to reproduce both layers of skin and ...improve the healing process as well as make it less painful. Herein, an electrospinning technique was used to produce new asymmetric membranes. The protective layer was composed of a blending solution between polycaprolactone and polylactic acid, whereas the underlying layer was comprised of methacrylated gelatin and chitosan. The chemical/physical properties, the in vitro hemo- and biocompatibility of the nanofibrous membranes were evaluated. The results obtained reveal that the produced membranes exhibited a wettability able to provide a moist environment at wound site. Moreover, the membranes' hemocompatibility and fibroblast cell adhesion, spreading and proliferation at the surface of the membranes were also noticed in the in vitro assays. Such results highlight the suitability of these asymmetric membranes for wound dressing applications.
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Gold core mesoporous silica shell (AuMSS) nanorods are multifunctional nanomedicines that can act simultaneously as photothermal, drug delivery, and bioimaging agents. Nevertheless, ...it is reported that once administrated, nanoparticles can be coated with blood proteins, forming a protein corona, that directly impacts on nanomedicines’ circulation time, biodistribution, and therapeutic performance. Therefore, it become crucial to develop novel alternatives to improve nanoparticles’ half-life in the bloodstream. In this work, Polyethylenimine (PEI) and Red blood cells (RBC)-derived membranes were combined for the first time to functionalize AuMSS nanorods and simultaneously load acridine orange (AO). The obtained results revealed that the RBC-derived membranes promoted the neutralization of the AuMSS’ surface charge and consequently improved the colloidal stability and biocompatibility of the nanocarriers. Indeed, the in vitro data revealed that PEI/RBC-derived membranes’ functionalization also improved the nanoparticles’ cellular internalization and was capable of mitigating the hemolytic effects of AuMSS and AuMSS/PEI nanorods. In turn, the combinatorial chemo-photothermal therapy mediated by AuMSS/PEI/RBC_AO nanorods was able to completely eliminate HeLa cells, contrasting with the less efficient standalone therapies. Such data reinforce the potential of AuMSS nanomaterials to act simultaneously as photothermal and chemotherapeutic agents.
Hydrogels are considered to be the most ideal materials for the production of wound dressings since they display a three-dimensional structure that mimics the native extracellular matrix of skin as ...well as a high-water content, which confers a moist environment at the wound site. Until now, different polymers have been used, alone or blended, for the production of hydrogels aimed for this biomedical application. From the best of our knowledge, the application of a xanthan gum-konjac glucomannan blend has not been used for the production of wound dressings. Herein, a thermo-reversible hydrogel composed of xanthan gum-konjac glucomannan (at different concentrations (1% and 2%
/
) and ratios (50/50 and 60/40)) was produced and characterized. The obtained data emphasize the excellent physicochemical and biological properties of the produced hydrogels, which are suitable for their future application as wound dressings.
Bioinspired and adhesive multilayer membranes are produced using the layer-by-layer (LbL) assembly of chitosan (CHT), alginate (ALG) and hyaluronic acid modified with dopamine (HA-DN). Freestanding ...multilayer membranes without DN are also produced as a control. The success of the synthesis of HA-DN was confirmed using UV-visible spectroscopy. Scanning electron microscopy images indicate that the surface of the DN-containing membranes is more porous than the control ones; they also present a higher average thickness value for the same number of CHT/ALG/CHT/HA(-DN) tetralayers (n = 100). Also, water uptake, mechanical strength and adhesion are enhanced with the introduction of DN moieties along the nano-layers. Besides, human dermal fibroblast viability, enhanced adhesion and proliferation were confirmed by immunofluorescence assays and by measuring both the metabolic activity and DNA content. Moreover, in vivo assays with such kinds of DN-containing multilayer membranes were performed; the application of these membranes in the treatment of dermal wounds induced in Wistar rats results in the highest decrease of inflammation of rat skin, compared with the control conditions. Overall, this investigation suggests that these mussel-inspired freestanding multilayer membranes may enhance either their mechanical performance or cellular adhesion and proliferation, leading to an improved wound healing process, being a promising material to restore the structural and functional properties of wounded skin.
The wound healing process involves highly complex and dynamic events that allow the re-establishment of skin's structural integrity. To further improve or to overcome the drawbacks associated with ...this process, researchers have been focused on the development of new therapeutics. Among them, asymmetric membranes are currently one of the most promising approaches to be used in wound healing due to its structural similarities with the epidermal and dermal layers of the native skin. The outer layer of asymmetric membranes provides a barrier that protects the wound from external damages (e.g. microorganisms and chemical agents), whereas the interior porous layer acts as template for supporting cell adhesion, migration and proliferation. Among the different materials used to produce these distinct layers, the chitosan arises as one of the preeminent materials due to its inherent biocompatibility, antibacterial, hemostatic, and healing properties. Therefore, in this review, it is provided an overview of the different chitosan-based asymmetric membranes developed for wound dressing applications. Further, the chitosan modifications to enhance its bioactivity as well as the asymmetric membranes general properties and production techniques are also described.
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•The asymmetric membranes' properties make them good candidates to be used as wound dressings.•The different techniques used to produce asymmetric membranes are described.•Different approaches followed to improve chitosan bioactivity are highlighted.•Chitosan-based asymmetric membranes application in wound healing is overviewed.
Cancer photothermal therapy (PTT) has captured the attention of researchers worldwide due to its localized and trigger-activated therapeutic effect. In this field, nanomaterials capable of converting ...the energy of the irradiation light into heat have been showing promising results in several pre-clinical and clinical assays. Such a therapeutic modality takes advantage of the innate capacity of nanomaterials to accumulate in the tumor tissue and their capacity to interact with NIR laser irradiation to exert a therapeutic effect. Therefore, several nanostructures composed of different materials and organizations for mediating a photothermal effect have been developed. In this review, the most common inorganic nanomaterials, such as gold, carbon-based materials, tungsten, copper, molybdenum, and iron oxide, which have been explored for mediating a tumor-localized photothermal effect, are summarized. Moreover, the physicochemical parameters of nanoparticles that influence the PTT effectiveness are discussed and the recent clinical advances involving inorganic nanomaterial-mediated cancer photothermal therapy are also presented.
Cancer photothermal therapy (PTT) has captured the attention of researchers worldwide due to its localized and trigger-activated therapeutic effect.
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•HA is a biocompatible and biodegradable ECM compound that encourage the wound healing.•HA-based wound dressings present excellent performance in treatment of wounds.•The synthesis of ...HA-derivatives augments its stability and mechanical properties.•The biomolecules loading into HA wound dressings improves the biological activity.
Hyaluronic acid (HA), a non-sulfated glycosaminoglycan (GAG), is a major component of skin extracellular matrix (ECM) and it is involved in the inflammatory response, angiogenesis, and tissue regeneration process. Due to the intrinsic properties of HA (such as biocompatibility, biodegradability and hydrophilic character), it has been used to produce different wound dressings, namely sponges, films, hydrogels, and electrospun membranes. Herein, an overview of the different HA-based wound dressings that have been produced so far is provided as well as the future directions regarding the strategies aimed to improve the mechanical stability of HA-based wound dressings, along with the incorporation of biomolecules intended to ameliorate their biological performance during the healing process.
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