Therapeutic Management of Malignant Wounds: An Update.

OPINION STATEMENT: Malignant fungating wounds (MFW) are severe skin conditions generating tremendous distress in oncological patients with advanced cancer stages because of pain, malodor, exudation, pruritus, inflammation, edema, and bleeding. The classical therapeutic approaches such as surgery, opioids, antimicrobials, and application of different wound dressings are failing in handling pain, odor, and infection control, thus urgently requiring the development of alternative strategies. The aim of this review was to provide an update on the current therapeutic strategies and the perspectives on developing novel alternatives for better malignant wound management. The last decade screened literature evidenced an increasing interest in developing natural treatment alternatives based on beehive, plant extracts, pure vegetal compounds, and bacteriocins. Promising therapeutics can also be envisaged by involving nanotechnology due to either intrinsic biological activities or drug delivery properties of nanomaterials. Despite recent progress in the field of malignant wound care, the literature is still mainly based on in vitro and in vivo studies on small animal models, while the case reports and clinical trials (less than 10 and only one providing public results) remain scarce. Some innovative treatment approaches are used in clinical practice without prior extensive testing in fungating wound patients. Extensive research is urgently needed to fill this knowledge gap and translate the identified promising therapeutic approaches to more advanced testing stages toward creating multidimensional wound care strategies.

3D Propolis-Sodium Alginate Scaffolds: Influence on Structural Parameters, Release Mechanisms, Cell Cytotoxicity and Antibacterial Activity.

In this study, the main aim was to fabricate propolis (Ps)-containing wound dressing patches using 3D printing technology. Different combinations and structures of propolis (Ps)-incorporated sodium alginate (SA) scaffolds were developed. The morphological studies showed that the porosity of developed scaffolds was optimized when 20% (v/v) of Ps was added to the solution. The pore sizes decreased by increasing Ps concentration up to a certain level due to its adhesive properties. The mechanical, swelling-degradation (weight loss) behaviors, and Ps release kinetics were highlighted for the scaffold stability. An antimicrobial assay was employed to test and screen antimicrobial behavior of Ps against Escherichia coli and Staphylococcus aureus strains. The results show that the Ps-added scaffolds have an excellent antibacterial activity because of Ps compounds. An in vitro cytotoxicity test was also applied on the scaffold by using the extract method on the human dermal fibroblasts (HFFF2) cell line. The 3D-printed SA-Ps scaffolds are very useful structures for wound dressing applications.

Development of Graphene Oxide-Based Anticancer Drug Combination Functionalized with Folic Acid as Nanocarrier for Targeted Delivery of Methotrexate.

Graphene has become a prominent material in cancer research in recent years. Graphene and its derivatives also attract attention as carriers in drug delivery systems. In this study, we designed a graphene oxide (GO)-based methotrexate (MTX)-loaded and folic acid (FA)-linked drug delivery system. MTX and FA were bound to GO synthesized from graphite. MTX/FA/GO drug delivery system and system components were characterized using Fourier transform infrared spectroscopy (FTIR), differential calorimetric analysis (DSC), scanning electron microscopy (SEM), transmission electron microscopy (TEM), zeta potential analysis, and dimension measurement (DLS) studies. SEM and TEM images confirmed the nanosheet structure of GO synthesized from graphite, and it was shown that MTX/FA binding to GO transformed the two-dimensional GO into a three-dimensional structure. FTIR and DSC graphs confirmed that oxygen atoms were bound to GO with the formation of carboxylic, hydroxyl, epoxide, and carbonyl groups as a result of the oxidation of graphite, and GO was successfully synthesized. Additionally, these analyses showed that MTX and FA bind physicochemically to the structure of GO. The in vitro Franz diffusion test was performed as a release kinetic test. The release kinetics mathematical model and correlation coefficient (R2) of MTX-loaded GO/FA nanomaterials were found to be the Higuchi model and 0.9785, respectively. Stiffness analyses showed that adding FA to this release system facilitated the entry of the drug into the cell by directing the system to target cells. As a result of the stiffness analyses, the stiffness values of the control cell group, free MTX, and MTX/FA/GO applied cells were measured as 2.34 kPa, 1.87 kPa, and 1.56 kPa, respectively. According to these results, it was seen that MTX/FA/GO weakened the cancer cells. Combined use of the MTX/FA/GO drug delivery system had a higher cytotoxic effect than free MTX on the MDA-MB-231 breast cancer cell line. The results showed that the synthesized MTX/FA/GO material has promising potential in cancer cell-specific targeted therapy for MTX as a drug delivery system.

Development of bilayer tissue-engineered scaffolds: combination of 3D printing and electrospinning methodologies.

Although different fabrication methods and biomaterials are used in scaffold development, hydrogels and electrospun materials that provide the closest environment to the extracellular matrix have recently attracted considerable interest in tissue engineering applications. However, some of the limitations encountered in the application of these methods alone in scaffold fabrication have increased the tendency to use these methods together. In this study, a bilayer scaffold was developed using 3D-printed gelatin methacryloyl (GelMA) hydrogel containing ciprofloxacin (CIP) and electrospun polycaprolactone (PCL)-collagen (COL) patches. The bilayer scaffolds were characterized in terms of chemical, morphological, mechanical, swelling, and degradation properties; drug release, antibacterial properties, and cytocompatibility of the scaffolds were also studied. In conclusion, bilayer GelMA-CIP/PCL-COL scaffolds, which exhibit sufficient porosity, mechanical strength, and antibacterial properties and also support cell growth, are promising potential substitutes in tissue engineering applications.

Blend Electrospinning of Nigella sativa-Incorporating PCL/PLA/HA Fibers and Its Investigation for Bone Healing Applications.

One of the well-known postoperative complications that requires a number of prophylactic and curative treatments is infection. The implications of postsurgical infections are further exacerbated by the emergence of antibiotic-resistant strains. Reduced effectiveness of synthetic antibiotics has led to an interest in plant-based substances. Extracts obtained from Nigella sativa have been shown to possess effective anti-infectious agents against bacteria frequently seen in bone infections. In this study, a fiber-based bone scaffold containing polycaprolactone, poly(lactic acid), and hydroxyapatite with N. sativa oil at varying concentrations was developed. Solvent electrospinning was used to fabricate the fibers with the specified composition. According to FE-SEM analysis, fibers with average diameters of 751 ± 82, 1000 ± 100, 1020 ± 90, and 1223 ± 112 nm were formed and successful integration of N. sativa oil into the fiber's structure was confirmed via FTIR. Staphylococcus aureus showed moderate susceptibility against the fibers with a maximum inhibition zone diameter of 11.5 ± 1.6 mm. MTT assay analysis exhibited concentration-dependent cell toxicity against fibroblast cells. In short, the antibacterial fibers synthesized in this study possessed antibacterial properties while also allowing moderate accommodation of CDD fibroblast cells at low oil concentrations, which can be a potential application for bone healing and mitigating postsurgical infections.

Three-Dimensional-Printed GelMA-KerMA Composite Patches as an Innovative Platform for Potential Tissue Engineering of Tympanic Membrane Perforations.

Tympanic membrane (TM) perforations, primarily induced by middle ear infections, the introduction of foreign objects into the ear, and acoustic trauma, lead to hearing abnormalities and ear infections. We describe the design and fabrication of a novel composite patch containing photocrosslinkable gelatin methacryloyl (GelMA) and keratin methacryloyl (KerMA) hydrogels. GelMA-KerMA patches containing conical microneedles in their design were developed using the digital light processing (DLP) 3D printing approach. Following this, the patches were biofunctionalized by applying a coaxial coating with PVA nanoparticles loaded with gentamicin (GEN) and fibroblast growth factor (FGF-2) with the Electrohydrodynamic Atomization (EHDA) method. The developed nanoparticle-coated 3D-printed patches were evaluated in terms of their chemical, morphological, mechanical, swelling, and degradation behavior. In addition, the GEN and FGF-2 release profiles, antimicrobial properties, and biocompatibility of the patches were examined in vitro. The morphological assessment verified the successful fabrication and nanoparticle coating of the 3D-printed GelMA-KerMA patches. The outcomes of antibacterial tests demonstrated that GEN@PVA/GelMA-KerMA patches exhibited substantial antibacterial efficacy against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. Furthermore, cell culture studies revealed that GelMA-KerMA patches were biocompatible with human adipose-derived mesenchymal stem cells (hADMSC) and supported cell attachment and proliferation without any cytotoxicity. These findings indicated that biofunctional 3D-printed GelMA-KerMA patches have the potential to be a promising therapeutic approach for addressing TM perforations.

Lavandula stoechas extract incorporated polylactic acid nanofibrous mats as an antibacterial and cytocompatible wound dressing.

In recent years, great efforts have been devoted to the design and production of bioactive wound dressings that promote skin regeneration and prevent infection. Many plant extracts and essential oils have been widely accepted in traditional medicine for a wide variety of medicinal purposes, especially wound healing. Over the past decade, many studies have focused on manufacturing and designing wound dressings containing plant compounds and extracts. In this study, Lavandula stoechas extract (LSE) (0.25 %, 0.5 %, and 1%wt) incorporated-polylactic acid (PLA) nanofibrous mats were successfully produced and characterized. Microstructural analysis by SEM revealed that the fiber diameter changed with the increase in the amount of LSE. Also, the nanofibrous mats were evaluated for their in vitro antibacterial, cytotoxicity, and wound healing properties for their use as a wound dressing material. According to the results of the disc diffusion test, PLA nanofibrous mats containing LSE %1 showed 9.65 ± 0.46 and 7.37 ± 0.03 inhibition zone (mm) against E. coli and S. aureus, respectively. According to the results of the in vitro wound healing assay, mats containing 0.5 % LSE showed better-wound closure activity compared to the control. Our results show that LSE-incorporated nanofibrous dressings can be an effective alternative with good antimicrobial activity.

Fabrication and optimization of 3D printed gelatin methacryloyl microneedle arrays based on vat photopolymerization.

Microneedles (MNs) are micrometer-sized arrays that can penetrate the skin in a minimally invasive manner; these devices offer tremendous potential for the transdermal delivery of therapeutic molecules. Although there are many conventional techniques for manufacturing MNs, most of them are complicated and can only fabricate MNs with specific geometries, which restricts the ability to adjust the performance of the MNs. Herein, we present the fabrication of gelatin methacryloyl (GelMA) MN arrays using the vat photopolymerization 3D printing technique. This technique allows for the fabrication of high-resolution and smooth surface MNs with desired geometries. The existence of methacryloyl groups bonded to the GelMA was verified by 1H NMR and FTIR analysis. To examine the effects of varying needle heights (1000, 750, and 500 µm) and exposure times (30, 50, and 70 s) on GelMA MNs, the height, tip radius, and angle of the needles were measured; their morphological and mechanical properties were also characterized. It was observed that as the exposure time increased, the height of the MNs increased; moreover, sharper tips were obtained and tip angles decreased. In addition, GelMA MNs exhibited good mechanical performance with no breakage up to 0.3 mm displacement. These results indicate that 3D printed GelMA MNs have great potential for transdermal delivery of various therapeutics.

Biocompatible polyvinyl alcohol nanofibers loaded with amoxicillin and salicylic acid to prevent wound infections.

Diabetic wounds are one of the most challenging clinical conditions in diabetes, necessitating the development of new treatments to foster healing and prevent microbial contamination. In this study, polyvinyl alcohol was used as a matrix polymer, and amoxicillin (AMX) and salicylic acid (SA) were selected as bioactive compounds with antimicrobial (with AMX) and anti-inflammatory action (with SA) to obtain innovative drug-loaded electrospun nanofiber patches for the management of diabetic wounds. Scanning electron microscope images revealed the uniform and beadless structure of the nanofiber patches. Mechanical tests indicated that AMX minimally increased the tensile strength, while SA significantly reduced it. The patches demonstrated effective antibacterial activity against both gram-positive (Staphylococcus aureus) and gram-negative (Escherichia coli) strains. The potential of these patches in the development of novel wound dressings is highlighted by the excellent biocompatibility with fibroblast cells maintained for up to 7 d.

Production of 3D Printed Bi-Layer and Tri-Layer Sandwich Scaffolds with Polycaprolactone and Poly (vinyl alcohol)-Metformin towards Diabetic Wound Healing.

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by impaired insulin secretion, sensitivity, and hyperglycemia. Diabetic wounds are one of the significant complications of T2DM owing to its difficulty in normal healing, resulting in chronic wounds. In the present work, PCL/PVA, PCL/PVA/PCL, and metformin-loaded, PCL/PVA-Met and PCL/PVA-Met/PCL hybrid scaffolds with different designs were fabricated using 3D printing. The porosity and morphological analysis of 3D-printed scaffolds were performed using scanning electron microscopy (SEM). The scaffolds' average pore sizes were between 63.6 ± 4.0 and 112.9 ± 3.0 µm. Molecular and chemical interactions between polymers and the drug were investigated with Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD). Mechanical, thermal, and degradation analysis of the scaffolds were undertaken to investigate the physico-chemical characteristics of the scaffolds. Owing to the structure, PCL/PVA/PCL sandwich scaffolds had lower degradation rates than the bi-layer scaffolds. The drug release of the metformin-loaded scaffolds was evaluated with UV spectrometry, and the biocompatibility of the scaffolds on fibroblast cells was determined by cell culture analysis. The drug release in the PCL/PVA-Met scaffold was sustained till six days, whereas in the PCL/PVA-Met/PCL, it continued for 31 days. In the study of drug release kinetics, PCL/PVA-Met and PCL/PVA-Met/PCL scaffolds showed the highest correlation coefficients (R2) values for the first-order release model at 0.8735 and 0.889, respectively. Since the layered structures in the literature are mainly obtained with the electrospun fiber structures, these biocompatible sandwich scaffolds, produced for the first time with 3D-printing technology, may offer an alternative to existing drug delivery systems and may be a promising candidate for enhancing diabetic wound healing.

In-depth drug delivery to tumoral soft tissues via pH responsive hydrogel.

A pH responsive nanoparticle-hydrogel hybrid drug delivery system was investigated for in-depth anticancer drug delivery to solid tumours. It consists of acid susceptible polymer nanoparticles loaded in a chitosan hydrogel. The hybrid formulation was characterized by UV-visible spectroscopy, FTIR, SEM, TEM, particle size analysis, zeta potential measurement and viscosity measurement. Drug encapsulation and nanoparticle loading efficiencies were found to be 48% and 72% respectively which describes the efficient interaction of the chemical entities in this hybrid drug delivery system. The hydrogel exhibited pH responsive behaviour: minimal drug and nanoparticle release at physiological pH but an increase in viscosity under acidic conditions and fast nanoparticle and drug release. The cytotoxicity of the drug loaded hydrogel was investigated against the MCF-7 breast cancer cell line along with the drug and nanoparticles without hydrogel. The drug loaded hydrogel showed a better cytotoxic effect on MCF-7 cancer cells. Thus, drug loaded nanoparticles containing hydrogel could be a better option for maximum drug distribution in tumours.

3D printing in the battle against COVID-19.

Coronavirus disease 2019 (COVID-19) that is SARS-CoV-2, previously called 2019-nCoV, is a kind of human infectious disease caused by severe acute respiratory syndrome coronavirus. Based on the prompt increase of human infection rate, COVID-19 outbreak was distinguished as a pandemic by the World Health Organization (WHO). By 2020, COVID-19 becomes a major health problem all around the world. Due to the battle against COVID-19, there are some adversities that are encountered with. The most significant difficulty is the lack of equipment for the COVID-19 battle. Lately, there is not sufficient personal protective equipment (PPE) for hospital workers on the front lines in this terrifying time. All around the world, hospitals are overwhelmed by the volume of patients and the lack of personal protective equipment including face masks, gloves, eye protection and clothing. In addition, the lack of nasal swabs, which are necessary components, that are used for testing is another issue that is being faced. There are a small number of respirators, which are emergency devices that help patients breathe for a short period of time. To overcome the limited number of equipment available, the foremost solution can be 3D printing that allows three-dimensional renderings to be realized as physical objects with the use of a printer and that revolutionized prototyping. Low-cost desktop 3D printers allow economical 3D models and guides but have less quality approvals. 3D printing is already well integrated into the process of COVID-19 battle by manufacturing the equipment that are convenient. The goals of this review are to explore the techniques of 3D printing for the equipment that are used for COVID-19 battle and evaluate the materials that are used for manufacturing and the manufactured equipment. Lastly, the advantages and disadvantages of 3D printing are figured out.

Combating COVID-19 with tissue engineering: a review.

The ongoing COVID-19 pandemic triggered by SARS-CoV-2 emerged from Wuhan, China, firstly in December 2019, as well spread to almost all around the world rapidly. The main reason why this disease spreads so many people in a short time is that the virus could be transmitted from an infected person to another by infected droplets. The new emergence of diseases usually may affect multiple organs; moreover, this disease is such an example. Numerous reported studies focus on acute or chronic organ damage caused by the virus. At this point, tissue engineering (TE) strategies can be used to treat the damages with its interdisciplinary approaches. Tissue engineers could design drug delivery systems, scaffolds, and especially biomaterials for the damaged tissue and organs. In this review, brief information about SARS-CoV-2, COVID-19, and epidemiology of the disease will be given at first. After that, the symptoms, the tissue damages in specific organs, and cytokine effect caused by COVID-19 will be described in detail. Finally, it will be attempted to summarize and suggest the appropriate treatments with suitable biomaterials for the damages via TE approaches. The aim of this review is to serve as a summary of currently available tissue damage treatments after COVID-19.

3D bioprinting applications in neural tissue engineering for spinal cord injury repair.

Spinal cord injury (SCI) is a disease of the central nervous system (CNS) that has not yet been treated successfully. In the United States, almost 450,000 people suffer from SCI. Despite the development of many clinical treatments, therapeutics are still at an early stage for a successful bridging of damaged nerve spaces and complete recovery of nerve functions. Biomimetic 3D scaffolds have been an effective option in repairing the damaged nervous system. 3D scaffolds allow improved host tissue engraftment and new tissue development by supplying physical support to ease cell function. Recently, 3D bioprinting techniques that may easily regulate the dimension and shape of the 3D tissue scaffold and are capable of producing scaffolds with cells have attracted attention. Production of biologically more complex microstructures can be achieved by using 3D bioprinting technology. Particularly in vitro modeling of CNS tissues for in vivo transplantation is critical in the treatment of SCI. Considering the potential impact of 3D bioprinting technology on neural studies, this review focus on 3D bioprinting methods, bio-inks, and cells widely used in neural tissue engineering and the latest technological applications of bioprinting of nerve tissues for the repair of SCI are discussed.

Evaluation of current diagnostic methods for COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent responsible for the coronavirus disease of 2019 (COVID-19), which triggers lung failure, pneumonia, and multi-organ dysfunction. This enveloped, positive sense and single-stranded RNA virus can be transmitted through aerosol droplets, direct and indirect contacts. Thus, SARS-CoV-2 is highly contagious and has reached a pandemic level in a few months. Since COVID-19 has caused numerous human casualties and severe economic loss posing a global threat, the development of readily available, accurate, fast, and cost-effective diagnostic techniques in hospitals and in any places where humans spread the virus is urgently required. COVID-19 can be diagnosed by clinical findings and several laboratory tests. These tests may include virus isolation, nucleic acid-based molecular assays like real-time polymerase chain reactions, antigen or antibody-based immunological assays such as rapid immunochromatographic tests, enzyme-linked immunosorbent assays, immunofluorescence techniques, and indirect fluorescent antibody techniques, electrochemical sensors, etc. However, current methods should be developed by novel approaches for sensitive, specific, and accurate diagnosis of COVID-19 cases to control and prevent this outbreak. Thus, this review will cover an overview and comparison of multiple reports and commercially available kits that include molecular tests, immunoassays, and sensor-based diagnostic methods for diagnosis of COVID-19. The pros and cons of these methods and future perspectives will be thoroughly evaluated and discussed.