Application of exosomes in tumor immunity: recent progresses.

Exosomes are small extracellular vesicles secreted by cells, ranging in size from 30 to 150 nm. They contain proteins, nucleic acids, lipids, and other bioactive molecules, which play a crucial role in intercellular communication and material transfer. In tumor immunity, exosomes present various functions while the following two are of great importance: regulating the immune response and serving as delivery carriers. This review starts with the introduction of the formation, compositions, functions, isolation, characterization, and applications of exosomes, and subsequently discusses the current status of exosomes in tumor immunotherapy, and the recent applications of exosome-based tumor immunity regulation and antitumor drug delivery. Finally, current challenge and future prospects are proposed and hope to demonstrate inspiration for targeted readers in the field.

Engineered Vasculature for Cancer Research and Regenerative Medicine.

Engineered human tissues created by three-dimensional cell culture of human cells in a hydrogel are becoming emerging model systems for cancer drug discovery and regenerative medicine. Complex functional engineered tissues can also assist in the regeneration, repair, or replacement of human tissues. However, one of the main hurdles for tissue engineering, three-dimensional cell culture, and regenerative medicine is the capability of delivering nutrients and oxygen to cells through the vasculatures. Several studies have investigated different strategies to create a functional vascular system in engineered tissues and organ-on-a-chips. Engineered vasculatures have been used for the studies of angiogenesis, vasculogenesis, as well as drug and cell transports across the endothelium. Moreover, vascular engineering allows the creation of large functional vascular conduits for regenerative medicine purposes. However, there are still many challenges in the creation of vascularized tissue constructs and their biological applications. This review will summarize the latest efforts to create vasculatures and vascularized tissues for cancer research and regenerative medicine.

Preparation of 3D printed calcium sulfate filled PLA scaffolds with improved mechanical and degradation properties.

Scaffold is one of the key components for tissue engineering application. Three-dimensional (3D) printing has given a new avenue to the scaffolds design to closely mimic the real tissue. However, material selection has always been a challenge in adopting 3D printing for scaffolds fabrication, especially for hard tissue. The fused filament fabrication technique is one of the economical 3D printing technology available today, which can efficiently fabricate scaffolds with its key features. In the present study, a hybrid polymer-ceramic scaffold has been prepared by combining the benefit of synthetic biodegradable poly (lactic acid) (PLA) and osteoconductive calcium sulphate (CaS), to harness the advantage of both materials. Composite PLA filament with maximum ceramic loading of 40 wt% was investigated for its printability and subsequently scaffolds were 3D printed. The composite filament was extruded at a temperature of 160 °C at a constant speed with an average diameter of 1.66 ± 0.34 mm. PLA-CaS scaffold with ceramic content of 10%, 20%, and 40% was 3D printed with square pore geometry. The developed scaffolds were characterized for their thermal stability, mechanical, morphological, and geometrical accuracy. The mechanical strength was improved by 29% at 20 wt% of CaS. The porosity was found to be 50-60% with an average pore size of 550 µm with well-interconnected pores. The effect of CaS particles on the degradation behaviour of scaffolds was also assessed over an incubation period of 28 days. The CaS particles acted as porogen and improved the surface chemistry for future cellular activity, while accelerating the degradation rate.

Engineering biomaterials to 3D-print scaffolds for bone regeneration: practical and theoretical consideration.

There are more than 2 million bone grafting procedures performed annually in the US alone. Despite significant efforts, the repair of large segmental bone defects is a substantial clinical challenge which requires bone substitute materials or a bone graft. The available biomaterials lack the adequate mechanical strength to withstand the static and dynamic loads while maintaining sufficient porosity to facilitate cell in-growth and vascularization during bone tissue regeneration. A wide range of advanced biomaterials are being currently designed to mimic the physical as well as the chemical composition of a bone by forming polymer blends, polymer-ceramic and polymer-degradable metal composites. Transforming these novel biomaterials into porous and load-bearing structures via three-dimensional printing (3DP) has emerged as a popular manufacturing technique to develop engineered bone grafts. 3DP has been adopted as a versatile tool to design and develop bone grafts that satisfy porosity and mechanical requirements while having the ability to form grafts of varied shapes and sizes to meet the physiological requirements. In addition to providing surfaces for cell attachment and eventual bone formation, these bone grafts also have to provide physical support during the repair process. Hence, the mechanical competence of the 3D-printed scaffold plays a key role in the success of the implant. In this review, we present various recent strategies that have been utilized to design and develop robust biomaterials that can be deployed for 3D-printing bone substitutes. The article also reviews some of the practical, theoretical and biological considerations adopted in the 3D-structure design and development for bone tissue engineering.

PLLA-gelatin composite fiber membranes incorporated with functionalized CeNPs as a sustainable wound dressing substitute promoting skin regeneration and scar remodeling.

The need for a wound dressing material that can accelerate wound healing is increasing and will last for a long time. In this study, cerium oxide nanoparticle (CeNP) incorporated poly-L-lactic acid (PLLA)-gelatin composite fiber membranes were fabricated using established electrospinning techniques for use as a low-cost sustainable wound dressing material. The obtained membranes were characterized for their morphology, and physical, mechanical and biological properties. The results showed that the membranes maintained an integrated morphology, and demonstrated water absorption and improved mechanical properties. An in vitro cell proliferation test confirmed that the cells presented better activities over the composite fiber membranes. In the rat scalding model, rapid wound recombination was observed. All these data suggested that electrospun CeNP incorporated PLLA-gelatin composite fiber membranes can be an ideal dressing substitute that can be used for wound healing applications. Furthermore, the use of biodegradable polymers and environmentally sustainable production technologies presented better sustainability for the commercial production of these composite membranes promoting tissue regeneration and scar remodeling.

Design and finite element analysis of femoral stem prosthesis using functional graded materials.

Conventionally biometals were used for design and development of bioimplants. However, the Young's Modulus (YM) of these bioimplants is higher than that of a natural bone. Asymmetric load transfer from a bone to the bioimplant results in aseptic loosening and stress shielding. Here-in, the use of functionally graded materials (FGM) has been introduced to design the femoral stem prosthesis as a model bioimplant using computational biomechanics. The material properties variations in these FGMs in longitudinal and radial directions are explored to minimize the aseptic loosening and stress-shielding that plays a vital role in defining the performance and longevity of the prosthesis. Three groups of FGM (Ti-HA, SS316L-HA and CoCr alloy-HA) have been explored to design the stem prosthesis and the finite element analysis (FEA) was carried out using computational biomechanics. The stress distribution profile in the designed stem prosthesis demonstrated an increase in the stress values with an increase in the volume fraction exponent. The results corroborated with the stress distribution obtained from the simulation results of a cortico-cancellous bone. The stress distribution in the Ti-HA prosthesis is observed to be more uniform than CoCr-HA and SS316L-HA prosthesis. In addition, the reduced number of stress shielding points were observed for the Ti-HA prosthesis when compared with the CoCr-HA and SS 316 L-HA stem prostheses. Hence, the results suggested that the Ti-HA prosthesis could be considered as a mechanically stable prosthesis and the same could offer safe design for further development of a femoral bioimplant.

Exosomes, a New Star for Targeted Delivery.

Exosomes are cell-secreted nanoparticles (generally with a size of 30-150 nm) bearing numerous biological molecules including nucleic acids, proteins and lipids, which are thought to play important roles in intercellular communication. As carriers, exosomes hold promise as advanced platforms for targeted drug/gene delivery, owing to their unique properties, such as innate stability, low immunogenicity and excellent tissue/cell penetration capacity. However, their practical applications can be limited due to insufficient targeting ability or low efficacy in some cases. In order to overcome these existing challenges, various approaches have been applied to engineer cell-derived exosomes for a higher selectivity and effectiveness. This review presents the state-of-the-art designs and applications of advanced exosome-based systems for targeted cargo delivery. By discussing experts' opinions, we hope this review will inspire the researchers in this field to develop more practical exosomal delivery systems for clinical applications.

Finite element analysis of fixed bone plates over fractured femur model.

The development of prosthetic bioimplants for fracture fixation using curved bone plates has been used as an established procedure for treatment in orthopedic. Here-in, we propose a novel curved bone plate fixation strategy to fix the designed biocompatible plates in different fracture models. Various biocompatible metallic biomaterials such as Ti-alloy (Ti-6Al-4V), stainless steel (SS 316L), and Co-alloy (Co-Cr) were created in SOLID works and used for the design of the bone plates. The typical fracture models (transverse and oblique) were created over a standard femur bone (models created using Materialize MIMIC/MAGIC) and two bone plates of similar materials were fixed side-by-side over the fractured femur using the screws made from Ti-6Al-4V. The finite element analysis (FEA) was carried out to evaluate the interface deformation, stress, and strain generated at the bone-bioimplant interface. The results from FEA demonstrated that the interface deformation and stress for a bone-bioimplant assembly are significantly reduced when natural anisotropic condition (functionally graded materials properties) of the human femur was well considered. Based on the analysis, Ti-6AL-4V and SS 316L were found as the best fit metallic biomaterials for the design and development of bone plate prosthetic bioimplants for fixation of an oblique fracture and transverse fracture respectively.

Fibro-porous PLLA/gelatin composite membrane doped with cerium oxide nanoparticles as bioactive scaffolds for future angiogenesis.

Functionalized cerium oxide nanoparticle (CeNP)-loaded fibro-porous poly-l-lactic acid (PLLA)/gelatin composite membranes were prepared via an electrospinning technology. Considering the importance of such membrane scaffolds for promoting angiogenesis in tissue engineering and drug screening, a series of PLLA/gelatin composite fiber membranes loaded with different doses of CeNPs was prepared. The prepared composite membranes demonstrated hydrophilicity, water absorption, and improved mechanical properties compared to a PLLA and PLLA/gelatin membrane. Also, cell viability assay using somatic hybrid endothelial cells (EA.hy926) proved the biocompatible nature of the scaffolds. The biocompatibility was further supported by in vivo chick embryo angiogenesis assay using fertilized eggs. Our initial results support that these membrane scaffolds could be useful for angiogenesis-related disease treatment after further investigations.

Photocurable platelet rich plasma bioadhesives.

Closure of wounds with tissue adhesives has many advantages over sutures, but existing synthetic adhesives are toxic and have poor workability. Blood-derived adhesives display complete resorption but have adhesion too weak for reliable wound dressings. We propose a semi-synthetic design that combines the positive attributes of synthetic and blood-derived tissue adhesives. PAMAM-g-diazirine (PDz) is a rapidly gelling bioadhesive miscible in both aqueous and organic solvents. PDz blended with platelet-rich plasma (PRP) forms PDz/PRP composite, a semi-synthetic formulation that combines PDz's wet tissue adhesion with PRP's potent wound healing properties. Light-activated PDz/PRP bioadhesive composite has similar elasticity to soft tissues and behaves as an induced hemostat-an unmet clinical need for rapid wound dressings. PDz/PRP composite applied to in-vivo full-thickness wounds observed a 25% reduction in inflammation, as assessed by the host-cell response.

Science-Based Strategies of Antiviral Coatings with Viricidal Properties for the COVID-19 Like Pandemics.

The worldwide, extraordinary outbreak of coronavirus pandemic (i.e., COVID-19) and other emerging viral expansions have drawn particular interest to the design and development of novel antiviral, and viricidal, agents, with a broad-spectrum of antiviral activity. The current indispensable challenge lies in the development of universal virus repudiation systems that are reusable, and capable of inactivating pathogens, thus reducing risk of infection and transmission. In this review, science-based methods, mechanisms, and procedures, which are implemented in obtaining resultant antiviral coated substrates, used in the destruction of the strains of the different viruses, are reviewed. The constituent antiviral members are classified into a few broad groups, such as polymeric materials, metal ions/metal oxides, and functional nanomaterials, based on the type of materials used at the virus contamination sites. The action mode against enveloped viruses was depicted to vindicate the antiviral mechanism. We also disclose hypothesized strategies for development of a universal and reusable virus deactivation system against the emerging COVID-19. In the surge of the current, alarming scenario of SARS-CoV-2 infections, there is a great necessity for developing highly-innovative antiviral agents to work against the viruses. We hypothesize that some of the antiviral coatings discussed here could exert an inhibitive effect on COVID-19, indicated by the results that the coatings succeeded in obtaining against other enveloped viruses. Consequently, the coatings need to be tested and authenticated, to fabricate a wide range of coated antiviral products such as masks, gowns, surgical drapes, textiles, high-touch surfaces, and other personal protective equipment, aimed at extrication from the COVID-19 pandemic.

CaproGlu: Multifunctional tissue adhesive platform.

Driven by the clinical need for a strong tissue adhesive with elastomeric material properties, a departure from legacy crosslinking chemistries was sought as a multipurpose platform for tissue mending. A fresh approach to bonding wet substrates has yielded a synthetic biomaterial that overcomes the drawbacks of free-radical and nature-inspired bioadhesives. A food-grade liquid polycaprolactone grafted with carbene precursors yields CaproGlu. The first-of-its-kind low-viscosity prepolymer is VOC-free and requires no photoinitiators. Grafted diazirine end-groups form carbene diradicals upon low energy UVA (365 nm) activation that immediately crosslink tissue surfaces; no pre-heating or animal-derived components are required. The hydrophobic polymeric environment enables metastable functional groups not possible in formulations requiring solvents or water. Activated diazirine within CaproGlu is uniquely capable of crosslinking all amino acids, even on wet tissue substrates. CaproGlu undergoes rapid liquid-to-biorubber transition within seconds of UVA exposure-features not found in any other bioadhesive. The exceptional shelf stability of CaproGlu allows gamma sterilization with no change in material properties. CaproGlu wet adhesiveness is challenged against current unmet clinical needs: anastomosis of spliced blood vessels, anesthetic muscle patches, and human platelet-mediating coatings. The versatility of CaproGlu enables both organic and inorganic composites for future bioadhesive platforms.

Voltaglue Bioadhesives Energized with Interdigitated 3D-Graphene Electrodes.

Soft tissue fixation of implant and bioelectrodes relies on mechanical means (e.g., sutures, staples, and screws), with associated complications of tissue perforation, scarring, and interfacial stress concentrations. Adhesive bioelectrodes address these shortcomings with voltage cured carbene-based bioadhesives, locally energized through graphene interdigitated electrodes. Electrorheometry and adhesion structure activity relationships are explored with respect to voltage and electrolyte on bioelectrodes synthesized from graphene 3D-printed onto resorbable polyester substrates. Adhesive leachates effects on in vitro metabolism and human-derived platelet-rich plasma response serves to qualitatively assess biological response. The voltage activated bioadhesives are found to have gelation times of 60 s or less with maximum shear storage modulus (G') of 3 kPa. Shear modulus mimics reported values for human soft tissues (0.1-10 kPa). The maximum adhesion strength achieved for the ≈50 mg bioelectrode films is 170 g cm-2 (17 kPa), which exceeds the force required for tethering of electrodes on dynamic soft tissues. The method provides the groundwork for implantable bio/electrodes that may be permanently incorporated into soft tissues, vis-à-vis graphene backscattering wireless electronics since all components are bioresorbable.

Nonthrombogenic Hydrogel Coatings with Carbene-Cross-Linking Bioadhesives.

Bioadhesives are a current unmet clinical need for mending of blood contacting soft tissues without inducing thrombosis. Recent development of carbene precursor bioadhesives with the advantages of on-demand curing, tuneable modulus, and wet adhesion have been synthesized by grafting diazirine onto poly (amidoamine) (PAMAM-G5) dendrimers. Herein, the structure activity relationships of platelet adhesion and activation is evaluated for the first time on the cured PAMAM-g-diazirine bioadhesives. Three strategies were employed to prevent healthy human donor platelets from adhering and activating on light-cured bioadhesive surfaces: (1) Attenuation of cationic surface charge, (2) antifouling composites by incorporating heparin and alginate in uncured formulation, and (3) heparin wash of cured bioadhesive surface. Topographical imaging of cured and ethanol dehydrated bioadhesive surfaces was used to quantify the adhered and activated platelets with scanning electron microscopy, whose resolution allowed identification of round senescent, short dendritic, and long dendritic platelets. Cured surfaces of PAMAM-g-diazirine (15%) had 10300 ± 500 adhered platelets mm-2 with 99.7% activation into short/long dendritic cells. Reduction of primary amines by higher degree of diazirine grafting or capping of free amines by acetylation reduces platelet adherence (2400 ± 200 vs 3000 ± 300, respectively). Physical incorporation of heparin and alginate in the formulations reduced the activated platelet; 1300 ± 300 and 300 ± 50, activated platelets mm-2, in comparison with additive free adhesive formulation. Similarly, heparin rinse of the surface of additive free bioadhesive reduced the activated platelet to platelets of heparin composites at 600 ± 100 platelets mm-2. PAMAM-g-diazirine (15%) bioadhesive retained the photocured mechanical properties and lap shear adhesion despite the addition of heparin and alginate additives.

Functionalized nanoceria exhibit improved angiogenic properties.

The growth of new blood vessels from the pre-existing vasculature known as angiogenesis has a vital role in various physiological and pathological processes. In the present study, we demonstrate the pro-angiogenic properties of functional nanoconjugates of organosilane functionalized cerium oxide (CeO2) nanoparticles (nanoceria). Aqueous dispersible CeO2 and trivalent metal (samarium) ion-doped CeO2 (SmCeO2) nanoparticles conjugated with hydrophilic biocompatible and antifouling (6-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-hexyl)triethoxysilane moieties were prepared. These functional nanoconjugates were prepared via an in situ synthesis and functionalization procedure using an ammonia-induced ethylene glycol-assisted precipitation method. The prepared nanoconjugates were thoroughly characterized using various physico-chemical techniques such as transmission electron microscopy (TEM), X-ray diffraction (XRD) analysis, dynamic light scattering (DLS), Fourier-transform infrared (FTIR) spectroscopy, 13C high-resolution solid-state nuclear magnetic resonance (NMR) spectroscopy, and X-ray photoelectron spectroscopy (XPS). The pro-angiogenic properties of the prepared nanoconjugates were evaluated by employing various angiogenesis assays (in vitro and in vivo). The results of the present study illustrate that the functional nanoconjugates of SmCeO2 triggered endothelial cell proliferation and induced the growth of blood vessels in a chick embryo. The enhanced expression of pro-angiogenic markers (p38 MAPK/HIF-1α) by these functional nanoconjugates might be a plausible signaling mechanism underlying their pro-angiogenic properties. Considering all the observations, we believe that (6-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-hexyl)triethoxysilane conjugated SmCeO2 nanoparticles could be developed as potential candidates for the treatment of cardiovascular, ischemic and ocular diseases where angiogenesis is the principal phenomenon.

Preparation and Biocompatible Surface Modification of Redox Altered Cerium Oxide Nanoparticle Promising for Nanobiology and Medicine.

The biocompatible surface modification of metal oxide nanoparticles via surface functionalization technique has been used as an important tool in nanotechnology and medicine. In this report, we have prepared aqueous dispersible, trivalent metal ion (samarium)-doped cerium oxide nanoparticles (SmCNPs) as model redox altered CNPs of biological relevance. SmCNP surface modified with hydrophilic biocompatible (6-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-hexyl) triethoxysilane (MEEETES) were prepared using ammonia-induced ethylene glycol-assisted precipitation method and were characterized using a variety of complementary characterization techniques. The chemical interaction of functional moieties with the surface of doped nanoparticle was studied using powerful 13C cross polarization magic angle sample spinning nuclear magnetic resonance spectroscopy. The results demonstrated the production of the extremely small size MEEETES surface modified doped nanoparticles with significant reduction in aggregation compared to their unmodified state. Moreover, the functional moieties had strong chemical interaction with the surface of the doped nanoparticles. The biocompatible surface modification using MEEETES should also be extended to several other transition metal ion doped and co-doped CNPs for the production of aqueous dispersible redox altered CNPs that are promising for nanobiology and medicine.

Collagen microgel-assisted dexamethasone release from PLLA-collagen hybrid scaffolds of controlled pore structure for osteogenic differentiation of mesenchymal stem cells.

Directed stem cell differentiation over three-dimensional porous scaffolds capable of releasing bioactive instructive cues is an important tool in tissue engineering. In this research, we have prepared dexamethasone (Dex)-releasing collagen microbead-functionalized poly(L-Lactide)-collagen hybrid scaffolds as an osteoinductive platform for human bone marrow-derived mesenchymal stem cells (MSCs). The scaffolds were prepared by a combined method of emulsion freeze-drying and porogen-leaching using pre-prepared ice collagen particulates as a porogen material. Dex release from the hybrid scaffolds was studied at 37 °C under shaking condition and the impact of released Dex towards osteogenic lineage differentiation was investigated by 3 week in vitro culture of MSCs. The results showed that hybrid scaffolds had controlled pore structure and interconnected pores deposited with collagen fibers. The hybrid scaffold facilitated cell seeding and the spatial localization of Dex/collagen microbeads facilitated a microgel-assisted spatio-temporal control of Dex release. The released Dex was useful for osteogenic differentiation of MSCs, which was confirmed from the elevated expression of osteogenic-specific gene-encoded proteins. The hybrid scaffolds should be useful for regeneration of a functional bone tissue.

Collagen scaffolds with controlled insulin release and controlled pore structure for cartilage tissue engineering.

Controlled and local release of growth factors and nutrients from porous scaffolds is important for maintenance of cell survival, proliferation, and promotion of tissue regeneration. The purpose of the present research was to design a controlled release porous collagen-microbead hybrid scaffold with controlled pore structure capable of releasing insulin for application to cartilage tissue regeneration. Collagen-microbead hybrid scaffold was prepared by hybridization of insulin loaded PLGA microbeads with collagen using a freeze-drying technique. The pore structure of the hybrid scaffold was controlled by using preprepared ice particulates having a diameter range of 150-250 µ m. Hybrid scaffold had a controlled pore structure with pore size equivalent to ice particulates and good interconnection. The microbeads showed an even spatial distribution throughout the pore walls. In vitro insulin release profile from the hybrid scaffold exhibited a zero order release kinetics up to a period of 4 weeks without initial burst release. Culture of bovine articular chondrocytes in the hybrid scaffold demonstrated high bioactivity of the released insulin. The hybrid scaffold facilitated cell seeding and spatial cell distribution and promoted cell proliferation.