Precision targeting in hepatocellular carcinoma: Exploring ligand-receptor mediated nanotherapy.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and poses a major challenge to global health due to its high morbidity and mortality. Conventional chemotherapy is usually targeted to patients with intermediate to advanced stages, but it is often ineffective and suffers from problems such as multidrug resistance, rapid drug clearance, nonspecific targeting, high side effects, and low drug accumulation in tumor cells. In response to these limitations, recent advances in nanoparticle-mediated targeted drug delivery technologies have emerged as breakthrough approaches for the treatment of HCC. This review focuses on recent advances in nanoparticle-based targeted drug delivery systems, with special attention to various receptors overexpressed on HCC cells. These receptors are key to enhancing the specificity and efficacy of nanoparticle delivery and represent a new paradigm for actively targeting and combating HCC. We comprehensively summarize the current understanding of these receptors, their role in nanoparticle targeting, and the impact of such targeted therapies on HCC. By gaining a deeper understanding of the receptor-mediated mechanisms of these innovative therapies, more effective and precise treatment of HCC can be achieved.

The effect of age on outpatient pediatric procedural sedation with intranasal dexmedetomidine and oral midazolam.

Procedural sedation for diagnostic examination is a common practice in children. The study aims to analyze the sedative effect and safety of intranasal dexmedetomidine combined with oral midazolam in outpatient pediatric procedural sedation across different age groups and to assess the incidence of sedation failure. From February 2021 to September 2021, children who underwent procedural sedation were retrospectively enrolled. The children were divided into 4 groups based on age: the infant group (0 to 1 year old), toddler group (1 to 3 years old), preschool group (3 to 6 years old), and school-age group (6 to 12 years old). Two-mcg/kg intranasal dexmedetomidine and 0.5-mg/kg oral midazolam were used for sedation. The sedation success rate after rescue, sedation success rate, onset time of sedation, and the sedation time were recorded. The incidence of adverse events and the risk factors for sedation failure were also analyzed. A total of 4758 patients were identified. After exclusion, 3149 patients were ultimately enrolled. The combination of 2-mcg/kg intranasal dexmedetomidine and 0.5-mg/kg oral midazolam resulted in a total success rate of 99.7% and a sedation success rate of 91.4%. The sedation success rate varied among the four groups: 90.2% in the infant group, 93.1% in the toddler group, 92.7% in the preschool group, and 78.4% in the school-age group. The sedation success rate was significantly lower in the school-age group compared to the other three groups (P < 0.001). The onset time of sedation was shorter in infant (22 min, IQR: 18-28 min, P < 0.001) and longer in the school-age group (30 min, IQR: 25-35 min, P < 0.05). Additionally, the infants had a longer sedation time (110 min, IQR: 90-135 min, P < 0.001) and a higher rate of delayed recovery (27.5%, all P < 0.001). The incidence of adverse events was low (4.70%), which bradycardia (2.03%) being the most common. Age (0-1 year and > 6 years), weight, ASA class II, and history of failed sedation were identified as risk factors of sedation failure.   Conclusion: Intranasal administration of 2-mcg/kg dexmedetomidine combined with oral administration of 0.5-mg/kg midazolam was found to be efficient and safety for pediatric procedural sedation. Different age groups of children exhibited distinct sedation characteristics, and age was identified as a risk factor affecting the efficacy of sedation. What is Known: • Procedural sedation for diagnostic examination is a common practice in children. • The combination of dexmedetomidine with midazolam can improve sedative effects. What is New: • The success rate of sedation using a combination of 2-mcg/kg intranasal dexmedetomidine and 0.5-mg/kg oral midazolam was significantly lower in school-age children as compared to infants, toddlers, and preschoolers. • The onset time of sedation increased with age, and the sedation time was found to be longer in infant patients.

Fabrication and Evaluation of Porous dECM/PCL Scaffolds for Bone Tissue Engineering.

Porous scaffolds play a crucial role in bone tissue regeneration and have been extensively investigated in this field. By incorporating a decellularized extracellular matrix (dECM) onto tissue-engineered scaffolds, bone regeneration can be enhanced by replicating the molecular complexity of native bone tissue. However, the exploration of porous scaffolds with anisotropic channels and the effects of dECM on these scaffolds for bone cells and mineral deposition remains limited. To address this gap, we developed a porous polycaprolactone (PCL) scaffold with anisotropic channels and functionalized it with dECM to capture the critical physicochemical properties of native bone tissue, promoting osteoblast cells' proliferation, differentiation, biomineralization, and osteogenesis. Our results demonstrated the successful fabrication of porous dECM/PCL scaffolds with multiple channel sizes for bone regeneration. The incorporation of 100 µm grid-based channels facilitated improved nutrient and oxygen infiltration, while the porous structure created using 30 mg/mL of sodium chloride significantly enhanced the cells' attachment and proliferation. Notably, the mechanical properties of the scaffolds closely resembled those of human bone tissue. Furthermore, compared with pure PCL scaffolds, the presence of dECM on the scaffolds substantially enhanced the proliferation and differentiation of bone marrow stem cells. Moreover, dECM significantly increased mineral deposition on the scaffold. Overall, the dECM/PCL scaffold holds significant potential as an alternative bone graft substitute for repairing bone injuries.

A novel privacy-preserving biometric authentication scheme.

Most existing secure biometric authentication schemes are server-centric, and users must fully trust the server to store, process, and manage their biometric data. As a result, users' biometric data could be leaked by outside attackers or the service provider itself. This paper first constructs the EDZKP protocol based on the inner product, which proves whether the secret value is the Euclidean distance of the secret vectors. Then, combined with the Cuproof protocol, we propose a novel user-centric biometric authentication scheme called BAZKP. In this scheme, all the biometric data remain encrypted during authentication phase, so the server will never see them directly. Meanwhile, the server can determine whether the Euclidean distance of two secret vectors is within a pre-defined threshold by calculation. Security analysis shows BAZKP satisfies completeness, soundness, and zero-knowledge. Based on BAZKP, we propose a privacy-preserving biometric authentication system, and its evaluation demonstrates that it provides reliable and secure authentication.

Phase separation enabled silver nano-array.

The surface-supported silver nanoparticles have been studied and applied in various applications. Many unique nanostructures have been introduced into this field to improve the functionalities of the surfaces depending on application purposes. We created featured silver nano-array surfaces by utilizing the solvent-mediated phase transition on the surface grafted with poly (acrylic) acids polymer chains and taking advantage of the low temperature of argon gas discharged plasma as a reducing agent. The applied solvents and grafted polymer chain densities affected the phase transition and thus determined the outcome of surface nano-array patterns. However, the total loaded silver ions on the surface affected silver nano-array structures at the sub-micron levels. The featured silver patterned surfaces made in the optimal conditions present a favorable surface-enhanced Raman spectroscopy enhancement as well as recyclability for detection re-usage. This novel method prepares tunable silver nanopatterned surfaces and provides a new approach to various potential applications.

Albumin-Coated Polycaprolactone (PCL)-Decellularized Extracellular Matrix (dECM) Scaffold for Bone Regeneration.

With the emphasis on collagen and hydroxyapatite, the main structural components of bone tissue, synthetic grafts fall short of matching the clinical efficacy of autologous bone grafts. Excluded non-collagenous protein (NCPs) and carbohydrates also participate in critical cell signaling cascades and guide mineral deposition during intermediate stages of bone healing. By mimicking the native fracture repair process, polymeric scaffolds that incorporate calcium-binding moieties present in fibrocartilage can potentially enhance their bioactivity, mineralization, and bone growth. Likewise, coating polymeric fibers with serum albumin is an additional strategy that can impart collagen-like biofunctionality and further increase mineral deposition on the fibrous surface. Here, a combination of electrospun polycaprolactone (PCL) fibers with chondrocyte-derived decellularized extracellular matrix (dECM) and albumin coating were investigated as a fibrocartilage-mimetic scaffold that can serve as a woven bone precursor for bone regeneration. PCL fibrous constructs coated with dECM and albumin are shown to synergistically increase calcium concentration and calcium phosphate (CaP) deposition in a simulated body fluid biomineralization assay. Albumin/dECM coating increased osteoblast proliferation and mineral deposition in culture. In contrast, CaP coating transformed osteoblast bone lining morphology into cuboidal phenotype and arrested their proliferation. Cell sheets of osteoblasts cultured on dECM/albumin/CaP-coated constructs exhibited an increase in calcium deposition and secretion of collagen, osteopontin, osteocalcin, and bone morphogenetic protein. These results highlight the potential of biomolecular coatings to enhance bone-mimetic properties of synthetic nanofibrous scaffolds, stimulate critical protein and mineral deposition, and augment the bone's capacity to heal. Thus, mimicking the intermediate stages of bone regeneration by incorporating calcium-binding moieties may prove to be a useful strategy for improving the clinical outcomes of synthetic bone grafts.

Fabrication of channeled scaffolds through polyelectrolyte complex (PEC) printed sacrificial templates for tissue formation.

One of the pivotal factors that limit the clinical translation of tissue engineering is the inability to create large volume and complex three-dimensional (3D) tissues, mainly due to the lack of long-range mass transport with many current scaffolds. Here we present a simple yet robust sacrificial strategy to create hierarchical and perfusable microchannel networks within versatile scaffolds via the combination of embedded 3D printing (EB3DP), tunable polyelectrolyte complexes (PEC), and casting methods. The sacrificial templates of PEC filaments (diameter from 120 to 500 µm) with arbitrary 3D configurations were fabricated by EB3DP and then incorporated into various castable matrices (e.g., hydrogels, organic solutions, meltable polymers, etc.). Rapid dissolution of PEC templates within a 2.00 M potassium bromide aqueous solution led to the high fidelity formation of interconnected channels for free mass exchange. The efficacy of such channeled scaffolds for in vitro tissue formation was demonstrated with mouse fibroblasts, showing continuous cell proliferation and ECM deposition. Subcutaneous implantation of channeled silk fibroin (SF) scaffolds with a porosity of 76% could lead to tissue ingrowth as high as 53% in contrast to 5% for those non-channeled controls after 4 weeks. Both histological and immunofluorescence analyses demonstrated that such channeled scaffolds promoted cellularization, vascularization, and host integration along with immunoregulation.

Blood circulation activating effect of Sanqi (Radix Notoginseng) on venous thromboembolism rat.

OBJECTIVE: To explore the blood circulation activating effect and mechanism of Sanqi (Radix Notoginseng) in vivo, using a venous thromboembolism (VTE) rat model. METHODS: We established the VTE rat model, and then intervened with low molecular weight heparin (LMWH), as well as low, medium and high doses of Sanqi (Radix Notoginseng), to observe the blood circulation activating effect of Sanqi (Radix Notoginseng) on VTE rats. RESULTS: After the treatment with high concentrations of Sanqi (Radix Notoginseng), the pulmonary thromboembolism was alleviated, and the lower limb thrombosis was markedly improved. Moreover, the expression quantities of plasma activated partial thromboplastin time, prothrombin time and D-dimer, as well as endothelin, von Willebrand factor, and plasminogen activator inhibitor-1 in thrombosis segment tissues were markedly down-regulated; while those of nitric oxide and tissue-type plasminogen activator were up-regulated. After low and medium concentration Sanqi (Radix Notoginseng) treatment, no obvious improvement was observed in each index. Moreover, the high concentration Sanqi (Radix Notoginseng) showed comparable efficacy to the positive drug LMWH. CONCLUSION: This data suggests that high concentration of Sanqi (Radix Notoginseng) is effective in preventing and treating VTE.

Efficacy of Sanqi (Radix Notoginseng) in treating cerebral hemorrhage in rats with traumatic brain injury.

OBJECTIVE: To evaluate the protective efficacy of Sanqi (Radix Notoginseng) on cerebral hemorrhage in a rat model of traumatic brain injury (TBI) by investigating plasminogen activator inhibitor-1 (PAI-1), tissue-type plasminogen activator (t-PA), nuclear factor-κB (NF-κB, p-p65), nitric oxide (NO), endothelin (ET), cluster differentiation (CD61CD62), and coagulation. METHODS: The free-fall method was used to create a rat model of TBI. Forty-eight rats were randomly divided into six groups: the blank group, sham group, model group, low-dose Sanqi (Radix Notoginseng) group, middle-dose Sanqi (Radix Notoginseng) group, and high-dose Sanqi (Radix Notoginseng) group. At 24 h after the model was created, we investigated brain MRI, brain tissue morphology using HE staining, flow cytometry, and immunohistochemical changes. RESULTS: Cerebral hemorrhage was aggravated in TBI rats (observed in brain specimens, brain MRI, and brain tissue HE). Cerebral immunohistochemistry results demonstrated that the expression of t-PA, PAI-1 and p-p65 increased significantly in TBI rats, while t-PA/PAI-1 had a significant decrease. In addition, CD61CD62, D2D, and ET were significantly increased in TBI rats, and PT and APTT were significantly prolonged; in contrast, NO was significantly decreased. Sanqi (Radix Notoginseng) decreased cerebral hemorrhage in TBI rats (observed in brain MRI and brain tissue HE), and increased t-PA/PAI-1, CD61CD62 significantly. It also significantly decreased the expression of t-PA, PAI-1, and p-p65 in brain immunohistochemistry and significantly decreased PT, APTT, D2D, and ET. However, there were no differences in NO between the model group and the Sanqi (Radix Notoginseng) group. CONCLUSION: Sanqi (Radix Notoginseng) can decrease the expression of p-p65, increase t-PA/PAI-1, and stem traumatic intracranial hemorrhage in a TBI rat model.

Panax notoginseng protects the rat brain function from traumatic brain injury by inhibiting autophagy via mammalian targeting of rapamycin.

Traumatic brain injury (TBI) remains one of the leading causes of death and disability worldwide. Our previous studies have found that traditional Chinese medicine, Panax notoginseng (P. notoginseng) can reduce cerebral hemorrhage in rats with TBI. Yet, the exact mechanism still remains unclear. According to the random number table, 36 SD rats were randomly divided into six groups: Sham group (negative control group), Model group, PIK inhibitor group (positive group), P. notoginseng group (experimental group), Rapamycin group, and Panax notoginseng+Rapamycin group (experimental group). In the Model group (M group, the group showing signs of TBI without any treatment), the neural function defect score was significantly decreased, while sequestosome 1 (P62), Beclin 1, and microtubule-associated protein 1 light chain 3 (LC3-II) were significantly increased. The brain tissue was significantly damaged, and many autophagosomes were observed in the cytoplasm. Compared with the Model group and the Rapamycin group (M+Rapa group, the group showing signs of TBI with Rapamycin treatment), P62, Beclin 1, and LC3-II were significantly decreased, the score of neural function defect was significantly improved, and the brain tissue damage was significantly reduced in the PIK (phosphatidylinositol 3-kinase) inhibitor group (M+LY group, the group showing signs of TBI with PIK inhibitor treatment). Compared with the Model group, mTOR was decreased and LC3-II was increased; however, there were no significant changes in neural function defect score, HE staining, Nissl staining, and transmission electron microscopy in the Rapamycin group. Compared with the Model group, the neural function defect score at 72h was significantly improved, mTOR was significantly increased, P62, Beclin 1, and LC3-II significantly decreased, brain tissue damage was reduced in HE staining and Nissl staining, autophagosomes were reduced in cytoplasm by transmission electron microscopy in the P. notoginseng group (M+PN group, the group showing signs of TBI with P. notoginseng treatment). Also, there was no significant difference between P. notoginseng group and P. notoginseng+Rapamycin group (M+PN+Rapa group, the group showing signs of TBI with P. notoginseng+Rapamycin treatment). P. notoginseng protects the rat brain function from TBI by inhibiting autophagy through the mTOR signaling pathway and other autophagy pathways.

Fabrication of polylactic acid (PLA)-based porous scaffold through the combination of traditional bio-fabrication and 3D printing technology for bone regeneration.

Artificial bone grafts possess the advantages of good biodegradability, customizable dimensions, and sufficient mechanical properties, which can promote cell proliferation and differentiation in bone tissue regeneration. 3D printing is a delicate approach that endows the scaffolds with excellent controllability and repeatability when compared with conventional bio-fabrication methods. However, the limitation of printing resolution somehow makes it difficult to prepare bone defect substitution with high porosity and hierarchical construct. In this study, we utilized polylactic acid (PLA) as printing materials and developed a smart strategy to combine 3D printing technology with bio-fabrication methods. A porous planar scaffold was printed and then rolled up into a spiral structure with adjustable pore size and porosity. The topographic features and morphology of the artificial scaffolds were examined through stereomicroscope and SEM, respectively. The porous spiral scaffold presented good mechanical properties in a set of mechanical testing. Later, the human fetal osteoblasts (hFOB) were cultured on the porous spiral scaffold and its control groups for a total of 28 days. The MTS analysis, alkaline phosphatase (ALP) assay, and alizarin red S (ARS) staining were used to analyze the cell proliferation, osteogenic differentiation, and mineral deposition after a certain period of time. The results indicated that compared with the other two scaffolds, the porous spiral scaffold with larger surface area and better interconnections between internal porous networks could significantly improve the spatial cell compartment and promote cell growth and differentiation. The porous spiral scaffold may see versatile applications in large-volume bone defects regeneration.

Nanofibrous Nerve Conduits with Nerve Growth Factors and Bone Marrow Stromal Cells Pre-Cultured in Bioreactors for Peripheral Nerve Regeneration.

Peripheral nerve injury (PNI) was the leading cause of permanent dysfunction in movement and sensation. Synthesized nerve guide conduits (NGCs) with Schwann Cells (SCs) can help peripheral nerve regeneration. However, poor accessibility of SCs and lack of full coverage of seeded cells on NGCs can lead to failure of nerve regeneration across long gaps and full functional recovery. To overcome these limitations, bone marrow stromal cells (BMSCs) and a novel culture method were proposed in the current study. BMSCs were harvested and seeded on a never growth factor (NGF)-loaded PCL nanofibrous NGCs and cultured with a rotary cell culture system (RCCS) before implantation. The NGCs were tested in vitro with PC-12 cells to validate the bioactivity of released NGF and to access its ability to promote neurite extension. Also, the NGCs were tested in vivo with rat sciatic nerve model to exam its potential in bridging the long gap (15 mm segmental defect). The efficacy of the NGCs was investigated based on the results of the functional test, electrophysiology test, muscle atrophy, and histological analysis. The results of in vitro PC-12 cell study confirmed the bioactivity of released NGF and showed a significant increase in the neurite extension with the help of PEG-diamine and BSA. These results showed that the novel loading method could preserve the bioactivity of growth factors and achieve a sustained release in vitro. Besides, the results of the in vivo study exhibited a significant increase with the combination of all additives. These results showed that with the help of NGF and RCCS, the NGCs with the seeded BMSCs could enhance peripheral nerve regeneration across long nerve injury gaps.

Controlled released of drug from doubled-walled PVA hydrogel/PCL microspheres prepared by single needle electrospraying method.

Poly(vinyl alcohol) (PVA) hydrogels have been extensively studied as drug delivery systems. However, due to the high hydrophilicity of PVA, these hydrogels have weak abilities to efficiently load drugs and control the initial burst release. In this study, we present a one-step simple and rapid single needle electrospraying (SNESy) method that combines PVA hydrogels with another biocompatible polymer polycaprolactone (PCL). A distinct core-shell structure was obtained with the PVA hydrogel core and PCL shell after the system was properly set up. The results revealed that the volume ratio between PVA hydrogel and PCL played an important role in determining the particle size and the formation of a spherical structure. The double-walled structure of the microsphere was confirmed by taking the fluorescent images and conducting the ATR-FTIR method. Furthermore, doxorubicin hydrochloride was used as a model drug to evaluate the drug loading capacity and the in vitro release behavior of this PVA hydrogel/PCL microsphere. The results indicated that coating a layer of PCL polymer significantly enhanced the drug loading capacity and reduced the drug initial burst release compared to the single-layer PVA hydrogel nanoparticles, demonstrating these biocompatible double-walled microspheres can be applied as excellent drug delivery carriers.

Stereochemical Strategy Advances Microbially Antiadhesive Cotton Textile in Safeguarding Skin Flora.

Microbial contamination on cotton textiles (CT) negatively affects people's health as well as the textile itself during use and storage. Using antimicrobial CT in a body-safe manner is currently still a challenge because it is difficult to balance killing microbes and protecting skin flora. Herein, a borneol-decorated CT (BDCT) through coupling of borneol 4-formylbenzoate molecules onto the amino-modified CT is reported. This BDCT shows strong and broad-spectrum microbially antiadhesive activities against gram-positive bacteria (Staphylococcus aureus and S. epidermidis), gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and fungi (Aspergillus niger, Mucor racemosus, and Candida albicans). Because of its unique stereochemical microbial antiadhesion mechanism, BDCT is harmless to skin flora. In addition, BDCT exhibits prominent durability of microbially antiadhesive capability by bearing 50 times of accelerated laundering. Therefore, this stereochemical BDCT strategy shows great potential for applications in the new generation of textiles, food packaging, and medical protection.

Polydopamine-Decorated Orlistat-Loaded Hollow Capsules with an Enhanced Cytotoxicity against Cancer Cell Lines.

Orlistat, an FDA-approved antiobesity drug, has recently been shown to have anticancer effects. However, orlistat is extremely hydrophobic with low absorption. Therefore, new approaches are needed to effectively deliver orlistat for cancer therapy. Herein, we developed a fast and simple method to use polydopamine-coated hollow capsule (PHC) as a drug nanocarrier for enhancing the therapeutic effects of orlistat. Orlistat-loaded PHC had an average size of 200 nm, which was characterized by using dynamic light scattering and scanning electron microscope. Furthermore, the polydopamine layer provided an excellent control of orlistat release because it was extremely sensitive to pH values. The cellular uptake and cytotoxicity experiments were performed to show that orlistat packaged in PHC could be endocytosed into cells and then significantly improved the cytotoxic activity against cancer cell lines in a short time compared with free orlistat. Moreover, dynamic study of cell membrane lysis was performed by staining with the LIVE/DEAD kit to demonstrate the cancer-killing mechanism. The size of the cell surface area has also been proven to be a key parameter which affected drug efficacy. Taken all together, these results present that orlistat-loaded PHC is a very promising formula for cancer treatments.

Dynamic agent of an injectable and self-healing drug-loaded hydrogel for embolization therapy.

Embolic agents are crucial for trans-catheter arterial embolization (TAE) in the treatment of various unresectable malignant tumors. Although solid particles, liquid oils, and some polymeric hydrogels have proved their capacities for embolic therapies, the low efficiency, time sensitivity, and cytotoxicity are still considered as challenges. In this study, we developed a three-component dynamic self-healing hydrogel to overcome these limitations. With the help of the Schiff-base bonding, both glycol-chitosan and carbazochrome, containing amine groups, react with dibenzaldehyde-terminated poly(ethylene-glycol) (DF-PEG), forming the dynamic self-healing hydrogels under a mild condition within 200 s. 1H NMR and rheology test were used to characterize the Schiff-base formation and mechanical strength. Controlled-release of carbazochrome from different gelator concentrations of DF-PEG was also studied. Furthermore, in vivo evaluation of the embolization on rats showed the superior embolic effects of the injectable and self-healing hydrogel. Therefore, this new dynamic agent demonstrated the potential for application as a simple, inexpensive, and tunable embolic agent for cancer treatment and drug delivery system.

Anti-cancer activity of camptothecin nanocrystals decorated by silver nanoparticles.

The emergence of multidrug resistant cancer phenotypes dramatically attenuates the efficiency of a variety of anti-cancer drugs. Silver nanoparticles (AgNPs) display excellent anti-cancer activity and dramatic inhibitory effect on drug resistance related proteins like P-glycoprotein (Pgp). Here we developed a novel drug nanocrystal formulation of Camptothecin (CPT), a broad spectrum anti-cancer agent, decorated by AgNPs. The resulting combinational formulation of CPT and AgNPs, named as CPT/Ag nanocrystals, demonstrated excellent dispersion properties and an improved dissolution rate, drug stability and cellular uptake rate. Because CPT nanocrystals are able to bypass Pgp recognition and AgNPs inhibit both Pgp expression and activity, CPT/Ag nanocrystals showed extreme and indiscriminate cytotoxicity against a variety of both drug sensitive and drug resistant cancer cells. Moreover, the quickly and plenty of released CPT from the CPT/Ag nanocrystals triggered by the tumor microenvironment led to a relaxed and cleavable chromatin structure, facilitating DNA damage and apoptotic potential of AgNPs that were subsequently released.