Preparation and In Vitro Evaluation of Montelukast Sodium-Loaded 3D Printed Orodispersible Films for the Treatment of Asthma.

This research aims to produce orodispersible films (ODFs) and determine their potential use in the oral delivery of montelukast sodium for asthma treatment and allergic rhinitis. ODFs were successfully developed by Three-dimensional (3D) printing using propylene glycol (PG), and hydroxypropyl methylcellulose (HPMC), polyethylene glycol 400 (PEG). Finally, the amount of montelukast sodium in the ODFs was 5% (w/w). Drug-excipients compatibility with Fourier Transformed Infrared (FTIR) spectroscopy, mass uniformity, thickness, disintegration time, folding endurance, moisture absorption, pH, in vitro drug release (dissolution), drug content, moisture loss, moisture content, mechanical properties, and cytotoxicity studies were performed on the prepared films. All formulations disintegrated in approximately 40 s. Over 98% of drug release from all films within 2 min was confirmed. It was reported that Fm1-4 (8% HPMC and 1% PEG) and Fm2-4 (10% HPMC and 3% PEG) are more suitable for drug content, but Fm2-4 may be the ideal formulation considering its durability and transportability properties. Based on the characterization results and in vitro release values, the montelukast sodium ODF can be an option for other dosage forms. It was concluded that the formulations did not show toxic potential by in vitro cytotoxicity study with 3T3 cells. This new formulation can efficiently treat allergic rhinitis and asthma diseases.

Current Strategies for the Regeneration of Skeletal Muscle Tissue.

Traumatic injuries, tumor resections, and degenerative diseases can damage skeletal muscle and lead to functional impairment and severe disability. Skeletal muscle regeneration is a complex process that depends on various cell types, signaling molecules, architectural cues, and physicochemical properties to be successful. To promote muscle repair and regeneration, various strategies for skeletal muscle tissue engineering have been developed in the last decades. However, there is still a high demand for the development of new methods and materials that promote skeletal muscle repair and functional regeneration to bring approaches closer to therapies in the clinic that structurally and functionally repair muscle. The combination of stem cells, biomaterials, and biomolecules is used to induce skeletal muscle regeneration. In this review, we provide an overview of different cell types used to treat skeletal muscle injury, highlight current strategies in biomaterial-based approaches, the importance of topography for the successful creation of functional striated muscle fibers, and discuss novel methods for muscle regeneration and challenges for their future clinical implementation.

Development and characterization of oxaceprol-loaded poly-lactide-co-glycolide nanoparticles for the treatment of osteoarthritis.

Oxaceprol is well-defined therapeutic agent as an atypical inhibitor of inflammation in osteoarthritis. In the present study, we aimed to develop and characterize oxaceprol-loaded poly-lactide-co-glycolide (PLGA) nanoparticles for intra-articular administration in osteoarthritis. PLGA nanoparticles were prepared by double-emulsion solvent evaporation method. Meanwhile, a straightforward and generally applicable high performance liquid chromatography method was developed, and validated for the first time for the quantification of oxaceprol. To examine the drug carrying capacity of nanoparticles, varying amount of oxaceprol was entrapped into a constant amount of polymer matrix. Moreover, the efficacy of drug amount on nanoparticle characteristics such as particle size, zeta potential, morphology, drug entrapment, and in vitro drug release was investigated. Nanoparticle sizes were between 229 and 509 nm for different amount of oxaceprol with spherical smooth morphology. Encapsulation efficiency ranged between 39.73 and 63.83% by decreasing oxaceprol amount. The results of Fourier transform infrared and DSC showed absence of interaction between oxaceprol and PLGA. The in vitro drug release from these nanoparticles showed a sustained release of oxaceprol over 30 days. According to cell culture studies, oxaceprol-loaded nanoparticles had no cytotoxicity with high biocompatibility. This study was the first step of developing an intra-articular system in the treatment of osteoarthritis for the controlled release of oxaceprol. Our findings showed that these nanoparticles can be beneficial for an effective treatment of osteoarthritis avoiding side effects associated with oral administration.

Advancements and applications of upconversion nanoparticles in wound dressings.

Wound healing is a complex process that requires effective management to prevent infections and promote efficient tissue regeneration. In recent years, upconversion nanoparticles (UCNPs) have emerged as promising materials for wound dressing applications due to their unique optical properties and potential therapeutic functionalities. These nanoparticles possess enhanced antibacterial properties when functionalized with antibacterial agents, helping to prevent infections, a common complication in wound healing. They can serve as carriers for controlled drug delivery, enabling targeted release of therapeutic agents to the wound site, allowing for tailored treatment and optimal healing conditions. These nanoparticles possess the ability to convert near-infrared (NIR) light into the visible and/or ultraviolet (UV) regions, making them suitable for therapeutic (photothermal therapy and photodynamic therapy) and diagnostic applications. In the context of wound healing, these nanoparticles can be combined with other materials such as hydrogels, fibers, metal-organic frameworks (MOFs), graphene oxide, etc., to enhance the healing process and prevent the growth of microbial infections. Notably, UCNPs can act as sensors for real-time monitoring of the wound healing progress, providing valuable feedback to healthcare professionals. Despite their potential, the use of UCNPs in wound dressing applications faces several challenges. Ensuring the stability and biocompatibility of UCNPs under physiological conditions is crucial for their effective integration into dressings. Comprehensive safety and efficacy evaluations are necessary to understand potential risks and optimize UCNP-based dressings. Scalability and cost-effectiveness of UCNP synthesis and manufacturing processes are important considerations for practical applications. In addition, efficient incorporation of UCNPs into dressings, achieving uniform distribution, poses an important challenge that needs to be addressed. Future research should prioritize addressing concerns regarding stability and biocompatibility, efficient integration into dressings, rigorous safety evaluation, scalability, and cost-effectiveness. The purpose of this review is to critically evaluate the advantages, challenges, and key properties of UCNPs in wound dressing applications to provide insights into their potential as innovative solutions for enhancing wound healing outcomes. We have provided a detailed description of various types of smart wound dressings, focusing on the synthesis and biomedical applications of UCNPs, specifically their utilization in different types of wound dressings.

The comparison of contribution of GO and rGO produced by green synthesis to the properties of CMC-based wound dressing material.

Herein, GO (graphene oxide) or rGO (reduced graphene oxide) which is produced by the green synthesis method using plant extract (Laurus nobilis) was incorporated into a polymeric structure consisting of carboxymethyl cellulose (CMC) and polyethylene glycol (PEG) to produce a wound dressing material with enhanced mechanical and electrical properties. The effect of GO and rGO on the wound dressing features of the produced materials was investigated and compared to each other. Conductivity tests demonstrated that rGO contributed more significantly to the electrical conductivity than GO. While rGO-CMC/PEG/CA reached 3.01 × 10-6 S.cm-1 as the conductivity value, that of GO-CMC/PEG/CA was determined as 0.85 × 10-6 S.cm-1. As for the mechanical tests, it was seen that rGO achieved the best results in terms of elastic modulus (588.62 N/mm2), tensile strength (94.95 MPa) and elongation at break (17.64 %) compared to GO reinforced and pure hydrogel. Curcumin and ascorbic acid were used for antibiotic-free wound treatment and their release kinetics were also modeled. The results showed that rGO reinforced hydrogel provided a more controlled release. All results assured that both the produced GO reinforced and especially rGO reinforced hydrogels could be utilized as modern wound dressing materials with suitable properties to achieve remarkable results for wound healing.

Injectable and self-healing dual crosslinked gelatin/kappa-carrageenan methacryloyl hybrid hydrogels via host-guest supramolecular interaction for wound healing.

Injectable hydrogels based on natural polymers have shown great potential for various tissue engineering applications, such as wound healing. However, poor mechanical properties and weak self-healing ability are still major challenges. In this work, we introduce a host-guest (HG) supramolecular interaction between acrylate-ß-cyclodextrin (Ac-ß-CD) conjugated on methacrylated kappa-carrageenan (MA-κ-CA) and aromatic residues on gelatin to provide self-healing characteristics. We synthesize an MA-κ-CA to conjugate Ac-ß-CD and fabricate dual crosslinked hybrid hydrogels with gelatin to mimic the native extracellular matrix (ECM). The dual crosslinking occurs on the MA-κ-CA backbone through the addition of KCl and photocrosslinking process, which enhances mechanical strength and stability. The hybrid hydrogels exhibit shear-thinning, self-healing, and injectable behavior, which apply easily under a minimally invasive manner and contribute to shear stress during the injection. In-vitro studies indicate enhanced cell viability. Furthermore, scratch assays are performed to examine cell migration and cell-cell interaction. It is envisioned that the combination of self-healing and injectable dual crosslinked hybrid hydrogels with HG interactions display a promising and functional biomaterial platform for wound healing applications.

Application of Convergent Science and Technology toward Ocular Disease Treatment.

Eyes are one of the main critical organs of the body that provide our brain with the most information about the surrounding environment. Disturbance in the activity of this informational organ, resulting from different ocular diseases, could affect the quality of life, so finding appropriate methods for treating ocular disease has attracted lots of attention. This is especially due to the ineffectiveness of the conventional therapeutic method to deliver drugs into the interior parts of the eye, and the also presence of barriers such as tear film, blood-ocular, and blood-retina barriers. Recently, some novel techniques, such as different types of contact lenses, micro and nanoneedles and in situ gels, have been introduced which can overcome the previously mentioned barriers. These novel techniques could enhance the bioavailability of therapeutic components inside the eyes, deliver them to the posterior side of the eyes, release them in a controlled manner, and reduce the side effects of previous methods (such as eye drops). Accordingly, this review paper aims to summarize some of the evidence on the effectiveness of these new techniques for treating ocular disease, their preclinical and clinical progression, current limitations, and future perspectives.

Optimization of methacrylated gelatin /layered double hydroxides nanocomposite cell-laden hydrogel bioinks with high printability for 3D extrusion bioprinting.

Layered double hydroxides (LDHs) offer unique source of inspiration for design of bone mimetic biomaterials due to their superior mechanical properties, drug delivery capability and regulation cellular behaviors, particularly by divalent metal cations in their structure. Three-dimensional (3D) bioprinting of LDHs holds great promise as a novel strategy thanks to highly tunable physiochemical properties and shear-thinning ability of LDHs, which allow shape fidelity after deposition. Herein, we introduce a straightforward strategy for extrusion bioprinting of cell laden nanocomposite hydrogel bioink of gelatin methacryloyl (GelMA) biopolymer and LDHs nanoparticles. First, we synthesized LDHs by co-precipitation process and systematically examined the effect of LDHs addition on printing parameters such as printing pressure, extrusion rate, printing speed, and finally bioink printability in creating grid-like constructs. The developed hydrogel bioinks provided precise control over extrudability, extrusion uniformity, and structural integrity after deposition. Based on the printability and rheological analysis, the printability could be altered by controlling the concentration of LDHs, and printability was found to be ideal with the addition of 3 wt % LDHs. The addition of LDHs resulted in remarkably enhanced compressive strength from 652 kPa (G-LDH0) to 1168 kPa (G-LDH3). It was shown that the printed nanocomposite hydrogel scaffolds were able to support encapsulated osteoblast survival, spreading, and proliferation in the absence of any osteoinductive factors taking advantage of LDHs. In addition, cells encapsulated in G-LDH3 had a larger cell spreading area and higher cell aspect ratio than those encapsulated in G-LDH0. Altogether, the results demonstrated that the developed GelMA/LDHs nanocomposite hydrogel bioink revealed a high potential for extrusion bioprinting with high structural fidelity to fabricate implantable 3D hydrogel constructs for repair of bone defects.

Biosensor integrated brain-on-a-chip platforms: Progress and prospects in clinical translation.

Because of the brain's complexity, developing effective treatments for neurological disorders is a formidable challenge. Research efforts to this end are advancing as in vitro systems have reached the point that they can imitate critical components of the brain's structure and function. Brain-on-a-chip (BoC) was first used for microfluidics-based systems with small synthetic tissues but has expanded recently to include in vitro simulation of the central nervous system (CNS). Defining the system's qualifying parameters may improve the BoC for the next generation of in vitro platforms. These parameters show how well a given platform solves the problems unique to in vitro CNS modeling (like recreating the brain's microenvironment and including essential parts like the blood-brain barrier (BBB)) and how much more value it offers than traditional cell culture systems. This review provides an overview of the practical concerns of creating and deploying BoC systems and elaborates on how these technologies might be used. Not only how advanced biosensing technologies could be integrated with BoC system but also how novel approaches will automate assays and improve point-of-care (PoC) diagnostics and accurate quantitative analyses are discussed. Key challenges providing opportunities for clinical translation of BoC in neurodegenerative disorders are also addressed.

The effect of LDHs nanoparticles on the cellular behavior of stem cell-laden 3D-bioprinted scaffold.

Three-dimensional (3D)-bioprinting as an emerging approach for tissue engineering possesses the promise to create highly mimicked organs or tissues by using computer-aided design. For biomedical applications in tissue engineering in our previous work, we developed an optimized nanocomposite bioink based on methylacrylated gelatin (GelMA), methylacrylated chitosan (ChitMA), and double-layered hydroxide (LDHs) nanoparticles by using 3D-bioprinting technology. Herein, we used the previous formulation to fabricate human bone marrow mesenchymal stem cells (hBMMSCs)-laden nanocomposite bioinks. The effect of LDHs nanoparticles on the cellular behaviors of the encapsulated-hBMMSCs in the scaffolds was evaluated for the first time. Live/Dead, PrestoBlue, and DAPI/Actin analysis were carried out to assess the cell viability, proliferation rate, and cellular morphology of encapsulated hBMMSCs within the scaffolds. In addition, osteogenic differentiation studies were performed culturing the scaffolds for up to 21 days. Results show that LDHs nanoparticles in the GelMA/ChitMA scaffold formulation increased the viability of hBMMSCs, did not cause any adverse effect on the proliferation rate, cell morphology of the hBMMSCs, and increased the Runx2 protein expression of the encapsulated-hBMMSCs in the scaffolds. This study progresses the LDHs containing nanocomposite bioink for cell printing applications in tissue engineering.

Photocurable silk fibroin-based tissue sealants with enhanced adhesive properties for the treatment of corneal perforations.

Corneal defects are associated with corneal tissue engineering in terms of vision loss. The treatment of corneal defects is an important clinical challenge due to a uniform corneal thickness and the apparent lack of regenerative ability. In this work, we synthesized a biocompatible and photocrosslinkable ocular tissue adhesive composite hydrogel prepared by using methacrylated gelatin (GelMA), which is called the most favorable derivative of gelatin used as a tissue adhesive, silk fibroin (SF), and GelMA/SF (GS) with high adhesion behaviours for use in corneal injuries. The adhesion behaviours of the materials prepared in the presence of silk fibroin were improved. Importantly, the effect of different UV curing times on the adhesion properties of the prepared materials was also investigated. The prepared GS tissue adhesives showed high physiological adhesion. GS can be modulated to increase its adhesive strength up to 3 times compared to G. GS was also found to be biocompatible and have a high healing potential. In addition, the obtained transmission value of GS is also close to that of the human cornea. GS supported cellular adhesion and proliferation. The burst pressure strength for fresh cornea of the GS-60s sealants (144.5 ± 13 kPa) was determined to be higher than that of the G-60s sealants (52.6 ± 33.5 kPa).

Development of mucoadhesive modified kappa-carrageenan/pectin patches for controlled delivery of drug in the buccal cavity.

In this study, modified kappa-carrageenan/pectin hydrogel patches were fabricated for treatment of buccal fungal infections. For this purpose, kappa-carrageenan-g-acrylic acid was modified with different thiolated agents (L-cysteine and 3-mercaptopropionic acid), and the thiol content of the resulting modified kappa-carrageenan was confirmed by elemental analyzer. Then, the hydrogel patches were fabricated, and characterized by Fourier-transform infrared spectroscopy, thermogravimetric analysis, ex vivo mucoadhesion test, and swelling behavior. Triamcinolone acetonide was added either directly or by encapsulating within the poly(lactic-co-glycolic acid) nanoparticles. The release amount of the drug from the directly loaded patch was 7.81 mg/g polymer, while it was 3.28 mg/g polymer for the encapsulated patch with the same content at 7 hr. The hydrogel patches had no cytotoxicity by cell culture studies. Finally, the drug loaded hydrogel patches were demonstrated antifungal activity against Aspergillus fumigatus and Aspergillus flavus. These results provide that the novel modified kappa-carrageenan and pectin based buccal delivery system has promising antifungal property, and could have advantages compared to conventional buccal delivery systems.

Selection of natural biomaterials for micro-tissue and organ-on-chip models.

The desired organ in micro-tissue models of organ-on-a-chip (OoC) devices dictates the optimum biomaterials, divided into natural and synthetic biomaterials. They can resemble biological tissues' biological functions and architectures by constructing bioactivity of macromolecules, cells, nanoparticles, and other biological agents. The inclusion of such components in OoCs allows them having biological processes, such as basic biorecognition, enzymatic cleavage, and regulated drug release. In this report, we review natural-based biomaterials that are used in OoCs and their main characteristics. We address the preparation, modification, and characterization methods of natural-based biomaterials and summarize recent reports on their applications in the design and fabrication of micro-tissue models. This article will help bioengineers select the proper biomaterials based on developing new technologies to meet clinical expectations and improve patient outcomes fusing disease modeling.

Enzyme-Mediated Alleviation of Peroxide Toxicity in Self-Oxygenating Biomaterials.

Oxygen releasing biomaterials can facilitate the survival of living implants by creating environments with a viable oxygen level. Hydrophobic oxygen generating microparticles (HOGMPs) encapsulated calcium peroxide (CPO) have recently been used in tissue engineering to release physiologically relevant amounts of oxygen for several weeks. However, generating oxygen using CPO is mediated via the generation of toxic levels of hydrogen peroxide (H2 O2 ). The incorporation of antioxidants, such as catalases, can potentially reduce H2 O2 levels. However, the formulation in which catalases can most effectively scavenge H2 O2 within oxygen generating biomaterials has remained unexplored. In this study, three distinct catalase incorporation methods are compared based on their ability to decrease H2 O2 levels. Specifically, catalase is incorporated within HOGMPs, or absorbed onto HOGMPs, or freely laden into the hydrogel entrapping HOGMPs and compared with control without catalase. Supplementation of free catalase in an HOGMP-laden hydrogel significantly decreases H2 O2 levels reflecting a higher cellular viability and metabolic activity of all the groups. An HOGMP/catalase-laden hydrogel precursor solution containing cells is used as an oxygenating bioink allowing improved viability of printed constructs under severe hypoxic conditions. The combination of HOGMPs with a catalase-laden hydrogel has the potential to decrease peroxide toxicity of oxygen generating tissues.

Combination therapy using nanomaterials and stem cells to treat spinal cord injuries.

As a part of the central nervous system, the spinal cord (SC) provides most of the communications between the brain and other parts of the body. Any damage to SC interrupts this communication, leading to serious problems, which may remain for the rest of their life. Due to its significant impact on patients' quality of life and its exorbitant medical costs, SC injury (SCI) is known as one of the most challengeable diseases in the world. Thus, it is critical to introduce highly translatable therapeutic platforms for SCI treatment. So far, different strategies have been introduced, among which utilizing various types of stem cells is one of the most interesting ones. The capability of stem cells to differentiate into several types of cell lines makes them promising candidates for the regeneration of injured tissues. One of the other interesting and novel strategies for SCI treatment is the application of nanomaterials, which could appear as a carrier for therapeutic agents or as a platform for culturing the cells. Combining these two approaches, stem cells and nanomaterials, could provide promising therapeutic strategies for SCI management. Accordingly, in this review we have summarized some of the recent advancements in which the applications of different types of stem cells and nanomaterials, alone and in combination forms, were evaluated for SCI treatment.

Layered double hydroxide-based nanocomposite scaffolds in tissue engineering applications.

Layered double hydroxides (LDHs), when incorporated into biomaterials, provide a tunable composition, controllable particle size, anion exchange capacity, pH-sensitive solubility, high-drug loading efficiency, efficient gene and drug delivery, controlled release and effective intracellular uptake, natural biodegradability in an acidic medium, and negligible toxicity. In this review, we study potential applications of LDH-based nanocomposite scaffolds for tissue engineering. We address how LDHs provide new solutions for nanostructure stability and enhance in vivo studies' success.

Advancements and future directions in the antibacterial wound dressings - A review.

Wound repair is a complex process that has not been entirely understood. It can conclude in several irregularities. Hence, designing an appropriate wound dressing that can accelerate the healing period is critical. Infections, a major obstacle to wound repair, cause an elevated inflammatory responses and result in ultimate outcome of incomplete and prolonged wound repair. To overcome these shortcomings, there is a growing requirement for antibacterial wound dressings. Dressings with antibacterial activities and multifunctional behaviors are highly anticipated to avoid the wound infection for successful healing. The aim of this review is not only to concentrate on the importance of antibacterial dressings for wound healing applications but also to discuss recent studies and some future perspectives about antibacterial wound dressings.

Tissue Adhesives: From Research to Clinical Translation.

Sutures, staples, clips and skin closure strips are used as the gold standard to close wounds after an injury. In spite of being the present standard of care, the utilization of these conventional methods is precarious amid complicated and sensitive surgeries such as vascular anastomosis, ocular surgeries, nerve repair, or due to the high-risk components included. Tissue adhesives function as an interface to connect the surfaces of wound edges and prevent them from separation. They are fluid or semi-fluid mixtures that can be easily used to seal any wound of any morphology - uniform or irregular. As such, they provide alternatives to new and novel platforms for wound closure methods. In this review, we offer a background on the improvement of distinctive tissue adhesives focusing on the chemistry of some of these products that have been a commercial success from the clinical application perspective. This review is aimed to provide a guide toward innovation of tissue bioadhesive materials and their associated biomedical applications.

Design of an amphiphilic hyperbranched core/shell-type polymeric nanocarrier platform for drug delivery.

An amphiphilic core/shell-type polymer-based drug carrier system (HPAE- PCL-b -MPEG), composed of hyperbranched poly(aminoester)-based polymer (HPAE) as the core building block and poly(ethylene glycol)-b - poly(ε-caprolactone) diblock polymers (MPEG-b -PCL) as the shell building block, was designed. The synthesized polymers were characterized with FTIR, 1 H NMR, 13 C NMR, and GPC analysis. Monodisperse HPAE-PCL-b - MPEG nanoparticles with dimensions of < 200 nm and polydispersity index of < 0.5 were prepared by nanoprecipitation method and characterized with SEM, particle size, and zeta potential analysis. 5-Fluorouracil was encapsulated within HPAE-PCL-b -MPEG nanoparticles. In vitro drug release profiles and cytotoxicity of blank and 5-fluorouracil-loaded nanoparticles were examined against the human colon cancer HCT116 cell line. All results suggest that HPAE-PCL-b - MPEG nanoparticles offer an alternative and effective drug nanocarrier system for drug delivery applications.

Current Strategies and Future Perspectives of Skin-on-a-Chip Platforms: Innovations, Technical Challenges and Commercial Outlook.

The skin is the largest and most exposed organ in the human body. Not only it is involved in numerous biological processes essential for life but also it represents a significant endpoint for the application of pharmaceuticals. The area of in vitro skin tissue engineering has been progressing extensively in recent years. Advanced in vitro human skin models strongly impact the discovery of new drugs thanks to the enhanced screening efficiency and reliability. Nowadays, animal models are largely employed at the preclinical stage of new pharmaceutical compounds development for both risk assessment evaluation and pharmacokinetic studies. On the other hand, animal models often insufficiently foresee the human reaction due to the variations in skin immunity and physiology. Skin-on-chips devices offer innovative and state-of-the-art platforms essential to overcome these limitations. In the present review, we focus on the contribution of skin-on-chip platforms in fundamental research and applied medical research. In addition, we also highlighted the technical and practical difficulties that must be overcome to enhance skin-on-chip platforms, e.g. embedding electrical measurements, for improved modeling of human diseases as well as of new drug discovery and development.