Although parental vaccines offer long-term protection against homologous strains, they rely exclusively on adaptive immune memory to produce neutralizing antibodies that are ineffective against emerging viral variants. Growing evidence highlights the multifaceted functions of trained immunity to elicit a rapid and enhanced innate response against unrelated stimuli or pathogens to subsequent triggers. This review discusses the protective role of trained immunity against respiratory pathogens and the experimental models essential for evaluating novel inducers of trained immunity. The review further elaborates on the potential of trained immunity to leverage protection against pathogens via the molecular patterns of antigens by pathogen recognition receptors (PPRs) on innate immune cells. The review also focuses on integrating trained innate memory with adaptive memory to shape next-generation vaccines by coupling each one’s unique characteristics.
Bone defects pose a heavy burden on patients, orthopedic surgeons, and public health resources. Various pathological conditions cause bone defects including trauma, tumors, inflammation, osteoporosis, and so forth. Auto‐ and allograft transplantation have been developed as the most commonly used clinic treatment methods, among which autologous bone grafts are the golden standard. Yet the repair of bone defects, especially large‐volume defects in the geriatric population or those complicated with systemic disease, is still a challenge for regenerative medicine from the clinical perspective. The fast development of biomaterials and nanomedicine favors the emergence and promotion of efficient bone regeneration therapies. In this review, we briefly summarize the progress of novel biomaterial and nanomedical approaches to bone regeneration and then discuss the current challenges that still hinder their …
Oral delivery of insulin is of great convenience in treating diabetes but is still subject to the harsh gastrointestinal tract. Herein, we developed an intelligent oral insulin platform based on glucose- responsive polymeric nanoparticles (NPs), which possess the following advantages: (1) protect the integrity and bioavailability of loaded insulin against gastrointestinal tract, (2) overcome the intestinal epithelial barriers via neonatal Fc receptor-mediated transport, and (3) on-demand release of insulin dependent solely on blood glucose levels to avoid hyperglycemia and hypoglycemia caused by unsafe doses of insulin. Notably, our oral NPs extended the therapeutic effect to up to 16 h in type 1 diabetic mice. To our knowledge, this is the longest effective time among such types of oral insulin platforms reported to date and may reduce the frequency of insulin administration to once daily. This platform might be useful for the …
The nasal cavity is a primary checkpoint for the invasion of respiratory pathogens. Numerous pathogens, including SARS-CoV-2, S. pneumoniae, S. aureus, etc., can adhere/colonize nasal lining to trigger an infection. Secretory IgA (sIgA) serves as the first line of immune defense against foreign pathogens. sIgA facilitates clearance of pathogenic microbes by intercepting their access to epithelial receptors and mucus entrapment through immune exclusion. Elevated levels of neutralizing IgA at the mucosal surfaces are associated with a high level of protection following intranasal immunizations. This review summarizes recent advances in intranasal vaccination technology and challenges in maintaining nominal IgA levels at the mucosal surface. Overall, the review emphasizes the significance of IgA-mediated nasal immunity, which holds a tremendous potential to mount protection against respiratory pathogens
Emerging therapies based on localized delivery of siRNA to lungs have opened up exciting possibilities for treatment of different lung diseases. Localized delivery of siRNA to lungs has shown to result in severalfold higher lung accumulation than systemic route, while minimizing non-specific distribution in other organs. However, to date, only 2 clinical trials have explored localized delivery of siRNA for pulmonary diseases. Here we systematically reviewed recent advances in the field of pulmonary delivery of siRNA using non- viral approaches. We firstly introduce the routes of local administration and analyze the anatomical and physiological barriers towards effective local delivery of siRNA in lungs. We then discuss current progress in pulmonary delivery of siRNA for respiratory tract infections, chronic obstructive pulmonary diseases, acute lung injury, and lung cancer, list outstanding questions, and highlight …
Recent advances in coronary stents have all been distinctively focused towards directing re- endothelialization with minimal in-stent restenosis, potentially via alterations in surface topographical cues, for augmenting the efficacy of vascular implants. This perspective was proven by our group utilizing a simple and easily scalable nanosurface modification strategy on metallic stents devoid of any drugs or polymers. In the present work, we explore the impact of surface characteristics in modulating this cell response in-vitro and in-vivo, using titania coated cobalt-chromium (CC) stents, with and without nanotopography, in comparison to commercial controls. Interestingly, titania nanotopography facilitated a preferential cell response in-vitro as against the titania coated and bare CC surfaces, which can be attributed to surface topography, hydrophilicity, and roughness. This in turn altered the cellular adhesion, proliferation …
Respiratory pathogens transmit primarily through particles such as droplets and aerosols. Although often overlooked, the resuspension of settled droplets is also a key facilitator of disease transmission. In this review, we discuss the three main mechanisms of aerosol generation: direct generation such as coughing and sneezing, indirect generation such as medical procedures, and resuspension of settled droplets and aerosols. The size of particles and environmental factors influence their airborne lifetime and ability to cause infection. Specifically, humidity and temperature are key factors controlling the evaporation of suspended droplets, consequently affecting the duration in which particles remain airborne. We also suggest material‐based approaches for effective prevention of disease transmission. These approaches include electrostatically charged virucidal agents and surface coatings, which have been …
Targeted drug delivery systems hold the remarkable potential to improve the therapeutic index of anticancer medications markedly. Here, we report a targeted delivery platform for cancer treatment using clathrin light chain (CLC)‐conjugated drugs. We conjugated CLC to paclitaxel (PTX) through a glutaric anhydride at high efficiency. Labeled CLCs localized to 4T1 tumors implanted in mice, and conjugation of PTX to CLC enhanced its delivery to these tumors. Treatment of three different mouse models of cancer— melanoma, breast cancer, and lung cancer—with CLC‐PTX resulted in significant growth inhibition of both the primary tumor and metastatic lesions, as compared to treatment with free PTX. CLC‐ PTX treatment caused a marked increase in apoptosis of tumor cells and reduction of tumor angiogenesis. Our data suggested HSP70 as a binding partner for CLC. Our study demonstrates that CLC‐based drug …
The present study demonstrates an original approach by which Au nanoparticles (∼10 nm) are embedded into TiO2 fibers via electrospinning. The photocatalytic performance of the resultant fibrous material was studied and related to the architecture and the nature of the internal interfaces in the composite. It was found that embedment of nano Au particles into the TiO2 fiber significantly improved the photocatalytic performance as compared to non-embedded ones. Electrospun fibers with the Au nanoparticles (∼10 nm) showed an average fiber diameter of ∼380 nm. The photocatalytic studies of Au embedded TiO2 fibers using ultra-violet (UV) visible spectroscopy showed ∼35% increase in photocatalytic activity when compared to the TiO2 fibers without the Au nanoparticles after 7 hrs of UV irradiation. This increase in photocatalysis was attributed to the ability of Au to increase charge separation in TiO2 and also
Nanohydroxyapatite (nanoHA) is a well-established synthetic bone substitute with excellent osteoconduction and osteointegration. However, brittleness coupled with slow degradation curtails its load-bearing and bone regeneration potential, respectively. To address these limitations, nanoHA composite matrix reinforced with electrospun fibrous yarns was fabricated and tested in vitro and in vivo. Different weight percentages (5, 10, 15 wt%) and varying lengths (short and continuous) of poly(l-lactic acid) yarns were randomly dispersed in a gelatinous matrix containing nanoHA. This significantly improved the compressive strength as well as work of fracture, especially for continuous yarns at high weight percentages (10 and 15 wt%). Incorporation of yarns did not adversely affect the pore size (50–350 μm) or porosity of the scaffolds as well as the in vitro cellular response. Finally, when tested in a critical-sized …
Stainless steel (SS) coronary stents continue to present risk of in‐stent restenosis that impact its long term safety and efficacy. The present work focuses on developing a drug‐free and polymer‐less surface on coronary stents by utilizing a titania (TiO2) nanotexturing approach through hydrothermal processing, that will offer improved stent performance in vivo. Mechanically stable and durable nanotextured coatings are obtained on SS stents that also offer good corrosion resistance. In vitro vascular cell (endothelial and smooth muscle cells) studies on surface modified SS show preferential rapid endothelialization with enhanced nitric oxide production and reduce smooth muscle cell proliferation, in comparison to unmodified SS. In vivo evaluation of the nanotextured stents after subcutaneous implantation in rabbits show reduced irritability and minimal localized inflammatory response. These beneficial effects …
This study investigates the unique properties, fabrication technique, and vascular applications of woven nanotextiles made from low-strength nanoyarns, which are bundles of thousands of nanofibers. An innovative robotic system was developed to meticulously interweave nanoyarns in longitudinal and transverse directions, resulting in a flexible, but strong woven product. This is the only technique for producing seamless nanotextiles in tubular form from nanofibers. The porosity and the mechanical properties of nanotextiles could be substantially tuned by altering the number of nanoyarns per unit area. Investigations of the physical and biological properties of the woven nanotextile revealed remarkable and fundamental differences from its nonwoven nanofibrous form and conventional textiles. This enhancement in the material property was attributed to the multitude of hierarchically arranged nanofibers in the …
Ultrasound (US)‐mediated sonodynamic therapy (SDT) has emerged as a superior modality for cancer treatment owing to the non‐invasiveness and high tissue‐penetrating depth. However, developing biocompatible nanomaterial‐based sonosensitizers with efficient SDT capability remains challenging. Here, we employed a liquid‐phase exfoliation strategy to obtain a new type of two‐dimensional (2D) stanene‐based nanosheets (SnNSs) with a band gap of 2.3 eV, which is narrower than those of the most extensively studied nano‐sonosensitizers, allowing a more efficient US‐triggered separation of electron (e−)‐hole (h+) pairs for reactive oxygen species (ROS) generation. In addition, we discovered that such SnNSs could also serve as robust near‐infrared (NIR)‐mediated photothermal therapy (PTT) agents owing to their efficient photothermal conversion, and serve as nanocarriers for anticancer drug …
We report a unique one-dimensional (1-D) morphology of TiO2 having TiO2 nanoparticles decorating the surface of TiO2 nanofibers fabricated by a simultaneous electrospinning and electrospraying technique. The composite made by both nanofibers and nanoparticles is used as a photoanode material for dye-sensitized solar cells (DSCs) which helped in overcoming the limitations associated with nanofibers and nanoparticles when employed separately. The DSC showed an excellent efficiency of 7.89% (for a square-shaped cell of area 0.2 cm2) in comparison to 6.87% for the nanoparticulate DSC and 5.21% for the nanofiber DSC (for cells of the same area and thickness) which is an impressive value when literature on DSC fabrication with 1-D nanostructures for DSCs is concerned.
Small interfering RNA (siRNA)–based therapeutics can mitigate the long-term sequelae of traumatic brain injury (TBI) but suffer from poor permeability across the blood-brain barrier (BBB). One approach to overcoming this challenge involves treatment administration while BBB is transiently breached after injury. However, it offers a limited window for therapeutic intervention and is applicable to only a subset of injuries with substantially breached BBB. We report a nanoparticle platform for BBB pathophysiology–independent delivery of siRNA in TBI. We achieved this by combined modulation of surface chemistry and coating density on nanoparticles, which maximized their active transport across BBB. Engineered nanoparticles injected within or outside the window of breached BBB in TBI mice showed threefold higher brain accumulation compared to nonengineered PEGylated nanoparticles and 50% gene silencing …
Bare metal stents (BMSs) of stainless steel (SS) were surface engineered to develop nanoscale titania topography using a combination of physical vapor deposition and thermochemical processing. The nanoleafy architecture formed on the stent surface remained stable and adherent upon repeated crimping and expansion, as well as under flow. This titania nanoengineered stent showed a preferential proliferation of endothelial cells over smooth muscle cells in vitro, which is an essential requirement for improving the in vivo endothelialization, with concurrent reduction of intimal hyperplasia. The efficacy of this surface-modified stent was assessed after implantation in rabbit iliac arteries for 8 weeks. Significant reduction in neointimal thickening and thereby in-stent restenosis with complete endothelial coverage was observed for the nanotextured stents, compared to BMSs, even without the use of any …
Cancer patients with malignant involvement of tumor-draining lymph nodes (TDLNs) and distant metastases have the poorest prognosis. A drug delivery platform that targets the primary tumor, TDLNs, and metastatic niches simultaneously, remains to be developed. Here, we generated a novel monoclonal antibody (MHA112) against peripheral node addressin (PNAd), a family of glycoproteins expressed on high endothelial venules (HEVs), which are present constitutively in the lymph nodes (LNs) and formed ectopically in the tumor stroma. MHA112 was endocytosed by PNAd-expressing cells, where it passed through the lysosomes. MHA112 conjugated antineoplastic drug Paclitaxel (Taxol) (MHA112-Taxol) delivered Taxol effectively to the HEV-containing tumors, TDLNs, and metastatic lesions. MHA112-Taxol treatment significantly reduced primary tumor size as well as metastatic lesions in a number of mouse …
A major barrier to the successful application of nanotechnology for cancer treatment is the suboptimal delivery of therapeutic payloads to metastatic tumor deposits. We previously discovered that cabozantinib, a tyrosine kinase inhibitor, triggers neutrophil-mediated anticancer innate immunity, resulting in tumor regression in an aggressive PTEN/p53-deficient genetically engineered murine model of advanced prostate cancer. Here, we specifically investigated the potential of cabozantinib-induced neutrophil activation and recruitment to enhance delivery of BSA-coated polymeric nanoparticles (BSA-NPs) into murine PTEN/p53-deficient prostate tumors. On the basis of the observation that BSA coating of NPs enhanced association and internalization by activated neutrophils by approximately 6-fold in vitro, relative to uncoated NPs, we systemically injected BSA-coated, dye-loaded NPs into prostate-specific PTEN/p53 …
Despite four decades of research in intra-articular drug delivery systems (DDS) and two decades of advances in disease-modifying osteoarthritis drugs (DMOADs), there is still no clinically available disease-modifying therapy for osteoarthritis (OA). Multiple barriers compromise intra-articular DMOAD delivery. Although multiple exciting approaches have been developed to overcome these barriers, there are still outstanding questions. We make several recommendations that can help in fully overcoming these barriers. Considering OA heterogeneity, we also propose a patient-centered, bottom-up workflow to guide preclinical development of DDS-based intra-articular DMOAD therapies. Overall, we expect this review to inspire paradigm-shifting innovations for developing next-generation DDS that can enable clinical translation of intra-articular DMOADs.
Electrospinning apparatus and method for producing multi-dimensional structures such as one-dimensional continuous yarns, two-dimensional mats and three-dimensional cotton-like fluffy scaffolds is disclosed. Further, electrospinning apparatus and method with single collector geometry for producing multi-dimensional structures and core-sheath yarns are disclosed.
The present invention relates to woven tubular nanotextiles, fabrication thereof using a weaving apparatus, and use thereof in vascular graft applications. The woven nanotextile conduit is 0.1 to 50 mm in diameter and includes a multitude of hierarchically arranged nanofibers. They are made from low strength bundled nanoyarns containing thousands of nanofibers with improved mechanical strength. The weaving apparatus interweaves the warp and weft yarns in longitu dinal and transverse directions, resulting in a flexible and strong woven product. The physical and biological proper ties of the woven nanotextile were significantly enhanced when compared to non-woven nanofibrous form and con ventional medical textiles. The nanotextile displayed super hydrophilic behavior in an otherwise hydrophobic material and when implanted as a vascular graft was robust, sutur able, kink-proof and non-thrombogenic …
Human saphenous vein (hSV) and synthetic grafts are commonly used conduits in vascular grafting, despite high failure rates. Decellularising hSVs (D-hSVs) to produce vascular scaffolds might be an effective alternative. We assessed the effectiveness of a detergent-based method using 0% to 1% sodium dodecyl sulphate (SDS) to decellularise hSV. Decellularisation effectiveness was measured in vitro by nuclear counting, DNA content, residual cell viability, extracellular matrix integrity and mechanical strength. Cytotoxicity was assessed on human and porcine cells. The most effective SDS concentration was used to prepare D-hSV grafts that underwent preliminary in vivo testing using a porcine carotid artery replacement model. Effective decellularisation was achieved with 0.01% SDS, and D-hSVs were biocompatible after seeding. In vivo xeno-transplantation confirmed excellent mechanical strength and …
This study details the design and fabrication of woven electrospun nanotextile patches for vascular applications that meet the mechanical and biological requirements. Nanotextile vascular patches based on biodegradable polymers such as poly‐l‐lactic acid (PLLA) and poly(caprolactone)/collagen (PCL/Col) are fabricated by integrating the techniques of electrospinning and weaving. Fibrous polymeric nanoyarns obtained by electrospinning are strengthened via different postprocessing techniques of heat‐stretching and plying, to generate interwoven nanotextiles that are tightly packed, mechanically strong, yet flexible. The unique pattern of nanofibers within the nanotextile results in its exceptional anisotropic mechanical behavior, appropriate for a vascular patch material. Moreover, these matrices exhibit good hydrophilicity, protein adsorption, and hemocompatibility, when compared to the commercial controls …
Electrospinning apparatus and method for producing multi-dimensional structures such as one-dimensional continuous yarns, two-dimensional mats and three-dimensional cotton-like fluffy scaffolds is disclosed. Further, electrospinning apparatus and method with single collector geometry for producing multi-dimensional structures and core-sheath yarns are disclosed.
Drug-coated sutures are widely used as delivery depots for antibiotics and anti-inflammatory drugs at surgical wound sites. Although drug-laden coating provides good localized drug concentration, variable loading efficiency and release kinetics limits its use. Alternatively, drug incorporation within suture matrices is hampered by the harsh fabrication conditions required for suture-strength enhancement. To circumvent these limitations, we fabricated mechanically robust electrospun core–sheath yarns as sutures, with a central poly-l-lactic acid core, and a drug-eluting poly-lactic-co-glycolic acid sheath. The electrospun sheath was incorporated with aceclofenac or insulin to demonstrate versatility of the suture in loading both chemical and biological class of drugs. Aceclofenac and insulin incorporated sutures exhibited 15% and 4% loading, and release for 10 and 7 days, respectively. Aceclofenac sutures …
Globally, millions of patients are affected by myocardial infarction or lower limb gangrene/amputation due to atherosclerosis. Available surgical treatment based on vein and synthetic grafts provides sub-optimal benefits. We engineered a highly flexible and mechanically robust nanotextile-based vascular graft (NanoGraft) by interweaving nanofibrous threads of poly-L-lactic acid to address the unmet need. The NanoGrafts were rendered impervious with selective fibrin deposition in the micropores by pre-clotting. The pre-clotted NanoGrafts (4 mm diameter) and ePTFE were implanted in a porcine carotid artery replacement model. The fibrin-laden porous milieu facilitated rapid endothelization by the transmural angiogenesis in the NanoGraft. In-vivo patency of NanoGrafts was 100% at 2- and 4-weeks, with no changes over time in lumen size, flow velocities, and minimal foreign-body inflammatory reaction. However, the patency of ePTFE at 2-week was 66% and showed marked infiltration, neointimal thickening, and poor host tissue integration. The study demonstrates the in-vivo feasibility and safety of a thin-layered vascular prosthesis, viz., NanoGraft, and its potential superiority over the commercial ePTFE.
A major impediment to the development of small diameter vascular grafts is to achieve an optimal balance between its mechanical properties and cellular response. To address this, the technique of cylindrical weaving has been combined with electrospinning to fabricate a seamless bilayered conduit (∼3 mm) having an inner cell-friendly nanofibrous layer of poly(caprolactone)/collagen and an outer mechanically compliant woven silk layer. Mechanical characteristics such as burst strength, suture retention, compliance and leak resistance were found to be improved for this bilayered conduit when compared to the commercial standard. In-vitro studies revealed that the lumen of the conduit was non- hemolytic and could support adhesion and viability of endothelial cells. Overall, our studies suggest that the proposed bilayer construct could be a suitable candidate for small diameter vascular prosthesis.
The present study describes a unique way of integrating substrateless electrospinning process with textile technology. We developed a new collector design that provided a pressure-driven, localized cotton-wool structure in free space from which continuous high strength yarns were drawn. An advantage of this integration was that the textile could be drug/dye loaded and be developed into a core–sheath architecture with greater functionality. This method could produce potential nanotextiles for various biomedical applications.