Calcium phosphate complex of recombinant human thrombomodulin promote bone formation in interbody fusion.

Interbody fusion is an orthopedic surgical procedure to connect two adjacent vertebrae in patients suffering from spinal disc disease. The combination of synthetic bone grafts with protein-based drugs is an intriguing approach to stimulate interbody bone growth, specifically in patients exhibiting restricted bone progression. Recombinant human thrombomodulin (rhTM), a novel protein drug characterized by its superior stability and potency, shows promise in enhancing bone formation.

Delivery of extracellular vesicles loaded with immune checkpoint inhibitors for immunotherapeutic management of glioma.

Glioma is a common primary malignant brain tumor with low survival rate. Immunotherapy with immune checkpoints inhibitors (ICI) can be a choice for glioma management, and extracellular vesicles (EVs) are recognized as a potential drug delivery system for various disease management due to their enhanced barrier permeation ability and immunomodulatory effect. The aim of this study is to develop ICI-loaded EVs (ICI/EV) that have sufficient efficacy in managing glioma.

BMSC loaded photo-crosslinked hyaluronic acid/collagen hydrogel incorporating FG4592 for enhanced cell proliferation and nucleus pulposus differentiation.

Intervertebral disc degeneration arises from damage or degeneration of the nucleus pulposus (NP). In this study, we developed a photo-crosslinkable hydrogel incorporating FG4592 to support the growth and differentiation of bone-marrow-derived mesenchymal stem cells (BMSC). Initially, hyaluronic acid was modified with tyramine and combined with collagen to introduce riboflavin as a photo-crosslinker.

Amphiphilic NLC-Gel formulation loaded with Sebacoyl dinalbuphine ester and Nalbuphine for localized postoperative pain management.

Opioids are powerful analgesics; however, their significant systemic adverse effects and the need for frequent administration restrict their use. Nalbuphine (NA) is a κ-agonist narcotic with limited adverse effects, but needs to be frequently administrated due to its short elimination half-life. Whereas sebacoyl dinalbuphine ester (SDE) is a NA prodrug, which can effectively prolong the analgesic effect, but lacks immediate pain relief.

Long acting tariquidar loaded stearic acid-modified hydroxyapatite enhances brain penetration and antitumor effect of temozolomide.

Temozolomide (TMZ) is the first line chemotherapy for glioblastoma (GBM) treatment, but the P-glycoprotein (P-gp) expressed in blood-brain barrier (BBB) will pump out TMZ from the brain leading to decreased TMZ concentration. Tariquidar (TQD), a selective and potent P-gp inhibitor, may be suitable for combination therapy to increase concentration of TMZ in brain. Hydroxyapatite (HAP) is a biodegradable material with sustained release characteristics, and stearic acid surface-modified HAP (SA-HAP) can increase hydrophobicity to facilitate TQD loading.

Drug delivery of extracellular vesicles: Preparation, delivery strategies and applications.

Extracellular vesicles (EV) are cell-originated vesicles exhibited with characteristics similar to the parent cells. Several studies have suggested the therapeutic potential of EV since they played as an intercellular communicator and modulate disease microenvironment, and thus EV has been widely studied in cancer management and tissue regeneration. However, merely application of EV revealed limited therapeutic outcome in different disease scenario and co-administration of drugs may be necessary to exert proper therapeutic effect.

Porous hydroxyapatite carrier enables localized and sustained delivery of honokiol for glioma treatment.

The objective of this study is to develop hydroxyapatite (HAp) particles for targeted delivery of honokiol to tumor sites after glioma surgical management. Honokiol is released from the HAp-honokiol particles inside cancer cells through endocytosis and subsequent acid lysosomal dissolution. HAp is synthesized using a co-precipitation method, and egg white is added to create porous structures.

Administration of N-Acetylcysteine to Regress the Fibrogenic and Proinflammatory Effects of Oxidative Stress in Hypertrophic Ligamentum Flavum Cells.

Ligamentum flavum hypertrophy (LFH) is a major cause of lumbar spinal stenosis (LSS). In hypertrophic ligamentum flavum (LF) cells, oxidative stress activates intracellular signaling and induces the expression of inflammatory and fibrotic markers. This study explored whether healthy and hypertrophic LF cells respond differently to oxidative stress, via examining the levels of phosphorylated p38 (p-p38), inducible nitric oxide synthase (iNOS), and -smooth muscle actin (-SMA).

Nanostructured Lipid Carrier Gel Formulation of Recombinant Human Thrombomodulin Improve Diabetic Wound Healing by Topical Administration.

Recombinant human thrombomodulin (rhTM), an angiogenesis factor, has been demonstrated to stimulate cell proliferation, keratinocyte migration and wound healing. The objective of this study was to develop nanostructured lipid carrier (NLC) formulations encapsulating rhTM for promoting chronic wound healing. RhTM-loaded NLCs were prepared and characterized.

Enhancing Target Tissue Levels and Diminishing Plasma Clearance of Ionizing Zwitterionic Antidotes in Organophosphate Exposures.

Inhibition of acetylcholinesterase (AChE) by certain organophosphates (OPs) can be life-threatening and requires reactivating antidote accessibility to the peripheral and central nervous systems to reverse symptoms and enhance survival parameters. In considering dosing requirements for oxime antidotes in OP exposures that inactivate AChE, clearance of proton ionizable, zwitterionic antidotes is rapid and proceeds with largely the parent antidotal compound being cleared by renal transporters. Such transporters may also control disposition between target tissues and plasma as well as overall elimination from the body.

Ligand design for human acetylcholinesterase and nicotinic acetylcholine receptors, extending beyond the conventional and canonical.

We detail here distinctive departures from lead classical cholinesterase re-activators, the pyridinium aldoximes, to achieve rapid CNS penetration and reactivation of AChE in the CNS (brain and spinal cord). Such reactivation is consistent with these non-canonical re-activators enhancing survival parameters in both mice and macaques following exposure to organophosphates. Thus, the ideal cholinesterase re-activator should show minimal toxicity, limited inhibitory activity in the absence of an organophosphate, and rapid CNS penetration, in addition to its nucleophilic potential at the target, the conjugated AChE active center.

Topical application of sebacoyl dinalbuphine ester-loaded nanostructured lipid carriers alleviate pruritus in scratching mouse model.

Sebacoyl dinalbuphine ester (SDE) is a nalbuphine (NA) prodrug capable of biotransformation in vivo and prolong the duration of NA, maximize its effect in pain and pruritus management. However, the large molecular weight, low skin penetration, and stability concerns of SDE make it difficult to be used in local skin delivery. Nanostructured lipid carrier (NLC) is a lipid-based nanoparticulate system that has the potential for formulating SDE in order to promote drug delivery through the skin.

Oxidative stress mediates age-related hypertrophy of ligamentum flavum by inducing inflammation, fibrosis, and apoptosis through activating Akt and MAPK pathways.

The role of oxidative stress in ligamentum flavum (LF) hypertrophy has not been elucidated. We hypothesize that oxidative stress induces inflammatory responses and the subsequent fibrotic processes in LF, via activation of the Akt and MAPK pathways. Specimens of LFs were collected during surgeries for lumbar disc herniation (LDH) or lumbar spinal stenosis (LSS).

Development of an In Vitro 3D Model for Investigating Ligamentum Flavum Hypertrophy.

Background: Ligamentum flavum hypertrophy (LFH) is among the most crucial factors in degenerative lumbar spinal stenosis, which can cause back pain, lower extremity pain, cauda equina syndrome and neurogenic claudication. The exact pathogenesis of LFH remains elusive despite extensive research. Most in vitro studies investigating LFH have been carried out using conventional two-dimensional (2D) cell cultures, which do not resemble in vivo conditions, as they lack crucial pathophysiological factors found in three-dimensional (3D) LFH tissue, such as enhanced cell proliferation and cell cluster formation.

Assessment of ionizable, zwitterionic oximes as reactivating antidotal agents for organophosphate exposure.

Since the development in the 1950's of 2-PAM (Pralidoxime), an antidote that reactivates organophosphate conjugated acetylcholinesterase in target tissues upon pesticide or nerve agent exposure, improvements in antidotal therapy have largely involved congeneric pyridinium aldoximes. Despite seminal advances in detailing the structures of the cholinesterases as the primary target site, progress with small molecule antidotes has yet to define a superior agent. Two major limitations are immediately apparent.

Calcium phosphate particles stimulate exosome secretion from phagocytes for the enhancement of drug delivery.

Exosomes are attractive potential carriers for drug delivery because of their natural function of transferring biomolecules among cells without eliciting immune responses. However, an obstacle to the application of exosomes for drug delivery is the difficulty in collecting sufficient numbers of these vesicles. In this study, we demonstrate treatment with calcium phosphate (CaP) particles could increase over two-fold the number of exosomes secreted from macrophage-like RAW264.

Post-exposure treatment with the oxime RS194B rapidly reactivates and reverses advanced symptoms of lethal inhaled paraoxon in macaques.

Fatalities from organophosphate (OP) insecticide result from both occupational and deliberate exposure; significantly impacting human health. Like nerve agents, insecticides are neurotoxins which target and inhibit acetylcholinesterases (AChE) in central and peripheral synapses in the cholinergic nervous system. Post-exposure therapeutic countermeasures generally include administration of atropine with a pyridinium aldoxime e.

Mesoporous hydroxyapatite as a carrier of olanzapine for long-acting antidepression treatment in rats with induced depression.

An antidepressant carrier, mesoporous hydroxyapatite olanzapine (mesoHAP-OLZ), was designed to maintain 3weeks of constant medication release. The carrier was intramuscularly (IM) injected, where cellular activity played a role in achieving the goal of constant release. The efficiency of the treatment was evaluated from 3 perspectives in in vivo studies: locomotor activities, biomarkers, and learning and memory ability.

Development of gelatin nanoparticles conjugated with phytohemagglutinin erythroagglutinating loaded with gemcitabine for inducing apoptosis in non-small cell lung cancer cells.

Gelatin is an efficient drug delivery vehicle for attaching targeting molecules like phytohemagglutinin erythroagglutinating (PHA-E) and carrying the chemotherapeutic agent gemcitabine (GEM). Fluorescent gelatin nanoparticles (GNPs) conjugated with PHA-E and carrying gemcitabine (GNP-(PHA-E)-GEM) were synthesized by nanoprecipitation for guiding gemcitabine-loaded gelatin nanoparticles to NSCLC by PHA-E targeting. GNPs have a uniform narrow size distribution and spherical shape, and their particle size is about 290 nm.

Mesoporous Hydroxyapatite as Olanzapine Carrier Provides a Long-Acting Effect in Antidepression Treatment.

An antidepressant carrier was designed to maintain over 2 weeks of constant medication release. The carrier was injected into muscle, where cellular activity was employed to achieve the goal of constant release. Mesoporous hydroxyapatite (mesoHAP) was synthesized into an adequate size by a coprecipitation method; it then went through a series of hydrophobic surface modifications for olanzapine (OLZ) loading by physical absorption to produce mesoHAP-OLZ.