Effects of Bioactive Glasses (BGs) on Exosome Production and Secretion: A Critical Review.

There is an increasing trend toward the application of bioactive glasses in different areas of biomedicine, including tissue engineering and oncology. The reason for this increase is mostly attributed to the inherent properties of BGs, such as excellent biocompatibility, and the ease of tailoring their properties by changing, for example, the chemical composition. Previous experiments have demonstrated that the interactions between BGs and their ionic dissolution products, and mammalian cells, can affect and change cellular behaviors, and thereby govern the performance of living tissues. However, limited research exists on their critical role in the production and secretion of extracellular vesicles (EVs) such as exosomes. Exosomes are nanosized membrane vesicles that carry various therapeutic cargoes such as DNA, RNA, proteins, and lipids, and thereby can govern cell-cell communication and subsequent tissue responses. The use of exosomes is currently considered a cell-free approach in tissue engineering strategies, due to their positive roles in accelerating wound healing. On the other hand, exosomes are known as key players in cancer biology (e.g., progression and metastasis), due to their capability to carry bioactive molecules between tumor cells and normal cells. Recent studies have demonstrated that the biological performance of BGs, including their proangiogenic activity, is accomplished with the help of exosomes. Indeed, therapeutic cargos (e.g., proteins) produced in BG-treated cells are transferred by a specific subset of exosomes toward target cells and tissues, and lead to a biological phenomenon. On the other hand, BGs are suitable delivery vehicles that can be utilized for the targeted delivery of exosomes to cells and tissues of interest. Therefore, it seems necessary to have a deeper understanding of the potential effects of BGs in the production of exosomes in cells that are involved in tissue repair and regeneration (mostly mesenchymal stem cells), as well as in those that play roles in cancer progression (e.g., cancer stem cells). This review aims to present an updated report on this critical issue, to provide a roadmap for future research in the fields of tissue engineering and regenerative medicine.

Nanostructured bioactive glasses: A bird's eye view on cancer therapy.

Bioactive glasses (BGs) arewell known for their successful applications in tissue engineering and regenerative medicine. Recent experimental studies have shown their potential usability in oncology, either alone or in combination with other biocompatible materials, such as biopolymers. Direct contact with BG particles has been found to cause toxicity and death in specific cancer cells (bone-derived neoplastic stromal cells) in vitro. Nanostructured BGs (NBGs) can be doped with anticancer elements, such as gallium, to enhance their toxic effects against tumor cells. However, the molecular mechanisms and intracellular targets for anticancer compositions of NBGs require further clarification. NBGs have been successfully evaluated for use in various well-established cancer treatment strategies, including cancer hyperthermia, phototherapy, and anticancer drug delivery. Existing results indicate that NBGs not only enhance cancer cell death, but can also participate in the regeneration of lost healthy tissues. However, the application of NBGs in oncology is still in its early stages, and numerous unanswered questions must be addressed. For example, the impact of the composition, biodegradation, size, and morphology of NBGs on their anticancer efficacy should be defined for each type of cancer and treatment strategy. Moreover, it should be more clearly assessed whether NBGs can shrink tumors, slow/stop cancer progression, or cure cancer completely. In this regard, the use of computational studies (in silico methods) is highly recommended to design the most effective glass formulations for cancer therapy approaches and to predict, to some extent, the relevant properties, efficacy, and outcomes. This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Antioxidant Effects of Bioactive Glasses (BGs) and Their Significance in Tissue Engineering Strategies.

Elevated levels of oxidative stress are usually observed following injuries, leading to impaired tissue repair due to oxidation-related chronic inflammation. Several attempts have been made to manage this unfavorable situation, and the use of biomaterials with antioxidant activity is showing great promise in tissue engineering and regenerative medicine approaches. Bioactive glasses (BGs) are a versatile group of inorganic substances that exhibit an outstanding regenerative capacity for both hard and soft damaged tissues. The chemical composition of BGs provides a great opportunity for imparting specific biological activities to them. On this point, BGs may easily become antioxidant substances through simple physicochemical modifications. For example, particular antioxidant elements (mostly cerium (Ce)) can be added to the basic composition of the glasses. On the other hand, grafting natural antioxidant substances (e.g., polyphenols) on the BG surface is feasible for making antioxidant substitutes with promising results in vitro. Mesoporous BGs (MBGs) were demonstrated to have unique merits compared with melt-derived BGs since they make it possible to load antioxidants and deliver them to the desired locations. However, there are actually limited in vivo experimental studies on the capability of modified BGs for scavenging free radicals (e.g., reactive oxygen species (ROS)). Therefore, more research is required to determine the actual potential of BGs in decreasing oxidative stress and subsequently improving tissue repair and regeneration. The present work aims to highlight the potential of different types of BGs in modulating oxidative stress and subsequently improving tissue healing.

Hydroxyapatite Nanoparticles for Improved Cancer Theranostics.

Beyond their well-known applications in bone tissue engineering, hydroxyapatite nanoparticles (HAp NPs) have also been showing great promise for improved cancer therapy. The chemical structure of HAp NPs offers excellent possibilities for loading and delivering a broad range of anticancer drugs in a sustained, prolonged, and targeted manner and thus eliciting lower complications than conventional chemotherapeutic strategies. The incorporation of specific therapeutic elements into the basic composition of HAp NPs is another approach, alone or synergistically with drug release, to provide advanced anticancer effects such as the capability to inhibit the growth and metastasis of cancer cells through activating specific cell signaling pathways. HAp NPs can be easily converted to smart anticancer agents by applying different surface modification treatments to facilitate the targeting and killing of cancer cells without significant adverse effects on normal healthy cells. The applications in cancer diagnosis for magnetic and nuclear in vivo imaging are also promising as the detection of solid tumor cells is now achievable by utilizing superparamagnetic HAp NPs. The ongoing research emphasizes the use of HAp NPs in fabricating three-dimensional scaffolds for the treatment of cancerous tissues or organs, promoting the regeneration of healthy tissue after cancer detection and removal. This review provides a summary of HAp NP applications in cancer theranostics, highlighting the current limitations and the challenges ahead for this field to open new avenues for research.

Stem cell-mediated angiogenesis in skin tissue engineering and wound healing.

The timely management of skin wounds has been an unmet clinical need for centuries. While there have been several attempts to accelerate wound healing and reduce the cost of hospitalisation and the healthcare burden, there remains a lack of efficient and effective wound healing approaches. In this regard, stem cell-based therapies have garnered an outstanding position for the treatment of both acute and chronic skin wounds. Stem cells of different origins (e.g., embryo-derived stem cells) have been utilised for managing cutaneous lesions; specifically, mesenchymal stem cells (MSCs) isolated from foetal (umbilical cord) and adult (bone marrow) tissues paved the way to more satisfactory outcomes. Since angiogenesis plays a critical role in all four stages of normal wound healing, recent therapeutic approaches have focused on utilising stem cells for inducing neovascularisation. In fact, stem cells can promote angiogenesis via either differentiation into endothelial lineages or secreting pro-angiogenic exosomes. Furthermore, particular conditions (e.g., hypoxic environments) can be applied in order to boost the pro-angiogenic capability of stem cells before transplantation. For tissue engineering and regenerative medicine applications, stem cells can be combined with specific types of pro-angiogenic biocompatible materials (e.g., bioactive glasses) to enhance the neovascularisation process and subsequently accelerate wound healing. As such, this review article summarises such efforts emphasising the bright future that is conceivable when using pro-angiogenic stem cells for treating acute and chronic skin wounds.

Iron (Fe)-doped mesoporous 45S5 bioactive glasses: Implications for cancer therapy.

The utilization of bioactive glasses (BGs) in cancer therapy has recently become quite promising; herein, a series of Fe-doped mesoporous 45S5-based BGs (MBGs) were synthesized via the sol-gel method in the presence of Pluronic P123 as a soft template. The physico-chemical and biological properties of the prepared glasses were well-characterized through structural assessments, thermal analyses, and electron microscopic studies. Electrochemical analyses, including cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), were also performed to investigate the actual potential of the Fe2O3-containing MBGs in modulating the Fenton's reaction. The XRD results confirmed the glassy state of the Fe-doped samples before immersion in simulated body fluid (SBF). The prepared Fe-doped MBGs exhibited a particle size in the range of 11-86 nm, surface charge of 27-30 mV, SBET of 95-306 m2/g, and Ms of 0.08 to 0.2 emu/g. The incorporation of Fe2O3 led to a negligible decrease in the bioactivity of the glasses. The CV analysis indicated that the Fe-doped MBGs could generate H2O2 in a cathodic potential higher than -0.2 V (vs. Ag/AgCl) in the O2-saturated Na2SO4 solution. Additionally, the data of the EIS test revealed that the Fe2O3-doped MBGs could increase the standard rate constant of Electro-Fenton's (EF) reaction up to 38.44 times as compared with the Fe-free glasses. In conclusion, Fe-doped 45S5-derived glasses may be useful in cancer therapy strategies due to their capability of activating Fenton's reaction and subsequent production of reactive oxygen species (ROS) such as •OH free radicals.

Osteogenic Potential of Magnesium (Mg)-Doped Multicomponent Bioactive Glass: In Vitro and In Vivo Animal Studies.

The use of bioactive glasses (BGs) has been quite fruitful in hard tissue engineering due to the capability of these materials to bond to living bone. In this work, a melt-derived magnesium (Mg)-doped BG (composition: 45SiO2-3P2O5-26CaO-15Na2O-7MgO-4K2O (mol.%)) was synthesized for being used in bone reconstruction. The prepared BGs were then manufactured as three-dimensional (3D) scaffolds by using the sponge replica approach. The microstructure of the samples was assessed by X-ray diffraction (XRD) and the surface morphology was observed by using scanning electron microscopy (SEM). The in vitro bioactivity and the release of osteo-stimulatory Mg2+ ions from the prepared samples were investigated over 7 days of incubation in simulated body fluids (SBF). In vitro cellular analyses revealed the compatibility of the Mg-doped BGs with human osteosarcoma cells (MG-63 cell line). Moreover, the Mg-doped BGs could induce bone nodule formation in vitro and improve the migratory ability of human umbilical vein endothelial cells (HUVECs). In vivo osteogenic capacity was further evaluated by implanting the BG-derived scaffolds into surgically-created critical-size bone defects in rats. Histological and immunohistological observations revealed an appropriate bone regeneration in the animals receiving the glass-based scaffolds after 12 weeks of surgery. In conclusion, our study indicates the effectiveness of the Mg-doped BGs in stimulating osteogenesis in both in vitro and in vivo conditions.

Mesoporous Silica Nanoparticles and Mesoporous Bioactive Glasses for Wound Management: From Skin Regeneration to Cancer Therapy.

Exploring new therapies for managing skin wounds is under progress and, in this regard, mesoporous silica nanoparticles (MSNs) and mesoporous bioactive glasses (MBGs) offer great opportunities in treating acute, chronic, and malignant wounds. In general, therapeutic effectiveness of both MSNs and MBGs in different formulations (fine powder, fibers, composites etc.) has been proved over all the four stages of normal wound healing including hemostasis, inflammation, proliferation, and remodeling. The main merits of these porous substances can be summarized as their excellent biocompatibility and the ability of loading and delivering a wide range of both hydrophobic and hydrophilic bioactive molecules and chemicals. In addition, doping with inorganic elements (e.g., Cu, Ga, and Ta) into MSNs and MBGs structure is a feasible and practical approach to prepare customized materials for improved skin regeneration. Nowadays, MSNs and MBGs could be utilized in the concept of targeted therapy of skin malignancies (e.g., melanoma) by grafting of specific ligands. Since potential effects of various parameters including the chemical composition, particle size/morphology, textural properties, and surface chemistry should be comprehensively determined via cellular in vitro and in vivo assays, it seems still too early to draw a conclusion on ultimate efficacy of MSNs and MBGs in skin regeneration. In this regard, there are some concerns over the final fate of MSNs and MBGs in the wound site plus optimal dosages for achieving the best outcomes that deserve careful investigation in the future.

Gum Tragacanth (GT): A Versatile Biocompatible Material beyond Borders.

The use of naturally occurring materials in biomedicine has been increasingly attracting the researchers' interest and, in this regard, gum tragacanth (GT) is recently showing great promise as a therapeutic substance in tissue engineering and regenerative medicine. As a polysaccharide, GT can be easily extracted from the stems and branches of various species of Astragalus. This anionic polymer is known to be a biodegradable, non-allergenic, non-toxic, and non-carcinogenic material. The stability against microbial, heat and acid degradation has made GT an attractive material not only in industrial settings (e.g., food packaging) but also in biomedical approaches (e.g., drug delivery). Over time, GT has been shown to be a useful reagent in the formation and stabilization of metal nanoparticles in the context of green chemistry. With the advent of tissue engineering, GT has also been utilized for the fabrication of three-dimensional (3D) scaffolds applied for both hard and soft tissue healing strategies. However, more research is needed for defining GT applicability in the future of biomedical engineering. On this object, the present review aims to provide a state-of-the-art overview of GT in biomedicine and tries to open new horizons in the field based on its inherent characteristics.

Biomedical Radioactive Glasses for Brachytherapy.

The fight against cancer is an old challenge for mankind. Apart from surgery and chemotherapy, which are the most common treatments, use of radiation represents a promising, less invasive strategy that can be performed both from the outside or inside the body. The latter approach, also known as brachytherapy, relies on the use of implantable beta-emitting seeds or microspheres for killing cancer cells. A set of radioactive glasses have been developed for this purpose but their clinical use is still mainly limited to liver cancer. This review paper provides a picture of the biomedical glasses developed and experimented for brachytherapy so far, focusing the discussion on the production methods and current limitations of the available options to their diffusion in clinical practice. Highly-durable neutron-activatable glasses in the yttria-alumina-silica oxide system are typically preferred in order to avoid the potentially-dangerous release of radioisotopes, while the compositional design of degradable glass systems suitable for use in radiotherapy still remains a challenge and would deserve further investigation in the near future.

Copper-containing bioactive glasses and glass-ceramics: From tissue regeneration to cancer therapeutic strategies.

Copper is one of the most used therapeutic metallic elements in biomedicine, ranging from antibacterial approaches to cancer theranostics. This element could be easily incorporated into different types of biomaterials; specifically, copper-doped bioactive glasses (BGs) provide great opportunities for biomedical engineers and clinicians as regards their excellent biocompatibility and regenerative potential. Although copper-incorporated BGs are mostly used in bone tissue engineering, accelerated soft tissue healing is achievable, too, with interesting potentials in wound treatment and skin repair. Copper can modulate the physico-chemical properties of BGs (e.g., reactivity with bio-fluids) and improve their therapeutic potential. Improving cell proliferation, promoting angiogenesis, reducing or even prohibiting bacterial growth are counted as prominent biological features of copper-doped BGs. Recent studies have also suggested the suitability of copper-doped BGs in cancer photothermal therapy (PTT). However, more research is needed to determine the extent to which copper-doped BGs are actually applicable for tissue engineering and regenerative medicine strategies in the clinic. Moreover, copper-doped BGs in combination with polymers may be considered in the future to produce relatively soft, pliable composites and printable inks for use in biofabrication.

Stem cell-based therapies for cardiac diseases: The critical role of angiogenic exosomes.

Finding effective treatments for cardiac diseases is among the hottest subjects in medicine; cell-based therapies have brought great promises for managing a broad range of life-threatening heart complications such as myocardial infarction. After clarifying the critical role of angiogenesis in tissue repair and regeneration, various stem/progenitor cell were utilized to accelerate the healing of injured cardiac tissue. Embryonic, fetal, adult, and induced pluripotent stem cells have shown the appropriate proangiogenic potential for tissue repair strategies. The capability of stem cells for differentiating into endothelial lineages was initially introduced as the primary mechanism involved in improving angiogenesis and accelerated heart tissue repair. However, recent studies have demonstrated the leading role of paracrine factors secreted by stem cells in advancing neo-vessel formation. Genetically modified stem cells are also being applied for promoting angiogenesis regarding their ability to considerably overexpress and secrete angiogenic bioactive molecules. Yet, conducting further research seems necessary to precisely identify molecular mechanisms behind the proangiogenic potential of stem cells, including the signaling pathways and regulatory molecules such as microRNAs. In conclusion, stem cells' pivotal roles in promoting angiogenesis and consequent improved cardiac healing and remodeling processes should not be ignored, especially in the case of stem cell-derived extracellular vesicles.

Quantum Dots: A Review from Concept to Clinic.

Quantum dots (QDs) are semiconductor materials that have gained great interest due to their unique characteristics like optical properties. They are extensively being used in different areas, including solar cells, light-emitting diodes, laser technology, as well as biological and biomedical applications. In this review, comprehensive information about different aspects of QDs is provided, including their types and classifications, synthesis approaches, in vitro and in vivo toxicity, biological applications, and potentials in clinical applications. With a focus on the biological aspects, the respective in vitro and in vivo studies are collected and presented. Various surface modifications on QDs are discussed as directly influencing their properties like toxicity and optical abilities. Given the promising results, these materials are clinically used for targeted molecular therapy and imaging. However, there are a large number of questions that should be addressed before the wide application of QDs in a clinical setting. Regarding the existing barriers to QDs, suggestions are given and discussed to present an appropriate route for the clinical use of these materials.

Nanotechnology for angiogenesis: opportunities and challenges.

Angiogenesis plays a critical role within the human body, from the early stages of life (i.e., embryonic development) to life-threatening diseases (e.g., cancer, heart attack, stroke, wound healing). Many pharmaceutical companies have expended huge efforts on both stimulation and inhibition of angiogenesis. During the last decade, the nanotechnology revolution has made a great impact in medicine, and regulatory approvals are starting to be achieved for nanomedicines to treat a wide range of diseases. Angiogenesis therapies involve the inhibition of angiogenesis in oncology and ophthalmology, and stimulation of angiogenesis in wound healing and tissue engineering. This review aims to summarize nanotechnology-based strategies that have been explored in the broad area of angiogenesis. Lipid-based, carbon-based and polymeric nanoparticles, and a wide range of inorganic and metallic nanoparticles are covered in detail. Theranostic and imaging approaches can be facilitated by nanoparticles. Many preparations have been reported to have a bimodal effect where they stimulate angiogenesis at low dose and inhibit it at higher doses.

Decellularization and preservation of human skin: A platform for tissue engineering and reconstructive surgery.

A matrix derived from natural tissue functions as a highly biocompatible and versatile scaffold for tissue engineering applications. It can act as a supportive construct that provides a niche for colonization by host cells. In this work, we describe a cost-effective, reliable and reproducible protocol for decellularization and preservation of human skin as a potential soft tissue replacement. The decellularized human skin is achieved using purely chemical agents without any enzymatic steps. The suitability of the proposed method for the preservation of the extracellular matrix (ECM) structure and its main components and integrity were evaluated using histological and immunohistochemical analysis. Cryopreservation and final sterility were conducted using programmable freeze-drying and gamma irradiation. The architecture, basement membrane and 3D structure of ECM can be successfully preserved after decellularization. Our protocol was found to be appropriate to maintain key proteins such as collagen type I, III, IV and laminin in the structure of final scaffold. This protocol offers a novel platform for the preparation of a dermal substitute for potential clinical applications. STATEMENT OF SIGNIFICANCE: Clinical application of naturally-based scaffolds for verity of health problems obliges development of a reproducible and effective technology that does not change structural and compositional material properties during scaffold preparation and preservation. Lack of an effective protocol for the production of biological products using decellularization method is still remaining. This effort is directing to solve this challenge in order to accomplish the off-the -shelf availability of decellularized dermal scaffold in market for clinical application.

Curcumin in tissue engineering: A traditional remedy for modern medicine.

Curcumin is the principal polyphenolic compound present in turmeric with broad applications in tissue engineering and regenerative medicine. It has some important inherent properties with the potential to facilitate tissue healing, including anti-inflammatory, anti-oxidant, and antibacterial activities. Therefore, curcumin has been used for the treatment of various damaged tissues, especially wound injuries. There are different forms of curcumin, among which nano-formulations are of a great importance in regenerative medicine. It is also important to design sophisticated delivery systems for controlled/localized delivery of curcumin to the target tissues and organs. Although there are many reports on the advantages of this compound, further research is required to fully explore its clinical usage. The review describes the physicochemical and biological properties of curcumin and the current state of the evidence on its applications in tissue engineering. © 2018 BioFactors, 45(2):135-151, 2019.

Glass-ceramics for cancer treatment: So close, or yet so far?

After years of research on the ability of glass-ceramics in bone regeneration, this family of biomaterials has shown revolutionary potentials in a couple of emerging applications such as cancer treatment. Although glass-ceramics have not yet reached their actual potential in cancer therapy, the relevant research activity is significantly growing in this field. It has been projected that this idea and the advent of magnetic bioactive glass-ceramics and mesoporous bioactive glasses could result in major future developments in the field of cancer. Undoubtedly, this strategy needs further developments to better answer the critical questions essential for clinical usage. This review aims to address the existing research developments on glass-ceramics for cancer treatment, starting with the current status and moving to future advances. STATEMENT OF SIGNIFICANCE: Although glass-ceramics have not yet reached their potential in cancer therapy, research activity is significantly growing. It has been speculated that this idea and the advent of modern glass-ceramics could result in significant future advances. Undoubtedly, this strategy needs further investigations and many critical questions have to be answered before it can be successfully applied for cancer treatment. This paper reviews the current state-of-the-art, starting with current products and moving onto recent developments in this field. According to our knowledge, there is a lack of a systematic review on the importance and developments of magnetic bioactive glass-ceramics and mesoporous bioactive glasses for cancer treatment, and it is expected that this review will be of interest to those working in this area.

Biomedical applications of nanoceria: new roles for an old player.

The use of different biomaterials with the ability to accelerate the repair and regeneration processes is of great importance in tissue engineering strategies. On this point, cerium oxide nanoparticles (CNPs or nanoceria) have recently attracted much attention due to their excellent biological properties including anti-oxidant, anti-inflammation and antibacterial activities as well as high angiogenic potential. The results of incorporation of these nano-sized particles into various constructs and scaffolds designed for tissue engineering applications have proven the success of this strategy in terms of improving healing process of different tissues. In this review, we first summarize the physicochemical and biological properties of nanoceria in brief and then present its usability in tissue engineering strategies based on the currently available published reports.

Sustained release of TGF-ß1 via genetically-modified cells induces the chondrogenic differentiation of mesenchymal stem cells encapsulated in alginate sulfate hydrogels.

Strategies based on growth factor (GF) delivery have attracted considerable attention in tissue engineering applications. Among different GFs, transforming growth factor beta 1 (TGF-ß1) is considered to be a potent factor for inducing chondrogenesis. In the present study, an expression cassette encoding the TGF-ß1 protein was prepared and transfected into the SP2/0-Ag14 cell line. The confocal microscopy of the transfected cells was performed to confirm the correct transfection process. The expression and in vitro release kinetics of the recombinant TGF-ß1 were assessed by western blot analysis and ELISA, respectively. Moreover, the biological activity of the expressed protein was compared with that of a commercially available product. The chondrogenic effects of the sustained release of the recombinant TGF-ß1 in an in vitro co-culture system were evaluated using a migration assay and real-time PCR. Results of confocal microscopy confirmed the successful transfection of the vector-encoding TGF-ß1 protein into the SP2/0-Ag14 cells. The bioactivity of the produced protein was in the range of the commercial product. The sustained release of the TGF-ß1 protein via SP2/0-Ag14 cells encapsulated in hydrogels encouraged the migration of adipose-derived MSCs. In addition, the expression analysis of chondrogenesis-related genes revealed that the pretreatment of encapsulated Ad-MSCs cells in alginate sulfate hydrogels through their exposure to the sustained release of TGF-ß1 is an efficient approach before transplantation of cells into the body.

Bioactive glasses entering the mainstream.

Over the past decade, the extended research on bioactive glasses (BGs) has drastically grown because of their bioactive nature and unique ability to deliver therapeutics in tissue engineering, regenerative medicine and even cancer research. These strategies mostly rely on the inherent potential of BGs regarding bonding to the living tissues and accelerating the healing process. All the possibilities are strongly associated with releasing various therapeutic ions from the BG structures into the biological environment. Additionally, some types of glasses [i.e., mesoporous bioactive glasses (MBGs)] can serve as suitable platforms for the delivery of various small molecules and pharmaceutical agents. This class of biomaterials is recognised as a highly versatile delivery system, playing a crucial part in the future of medicine.