This work aimed to develop new antibiotic-coated/ antibiotic-loaded hydroxyapatite (HAp) scaffolds for orthopaedic trauma, specifically to treat the infection after fixation of skeletal fracture. The HAp scaffolds were fabricated from the Nile tilapia (Oreochromis niloticus) bones and fully characterized. The HAp scaffolds were coated with 12 formulations of poly (lactic-co-glycolic acid) (PLGA) or poly (lactic acid) (PLA), blended with vancomycin. The vancomycin release, surface morphology, antibacterial properties, and the cytocompatibility of the scaffolds were conducted. The HAp powder contains elements identical to those found in human bones. This HAp powder is suitable as a starting material to build scaffolds. After the scaffold fabrication, The ratio of HAp to β-TCP changed, and the phase transformation of β-TCP to α-TCP was observed. All antibiotic-coated/ antibiotic-loaded HAp scaffolds can release vancomycin into the phosphate-buffered saline (PBS) solution. PLGA-coated scaffolds obtained faster drug release profiles than PLA-coated scaffolds. The low polymer concentration in the coating solutions (20%w/v) gave a faster drug release profile than the high polymer concentration (40%w/v). All groups showed a trace of surface erosion after being submerged in PBS for 14 days. Most of the extracts can inhibit Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA). The extracts not only caused no cytotoxicity to Saos-2 bone cells but also can increase cell growth. This study demonstrates that it is possible to use these antibiotic-coated/ antibiotic-loaded scaffolds in the clinic as an antibiotic bead replacement.

Extracellular vesicles (EVs) are a collective term for nanoscale or microscale vesicles secreted by cells that play important biological roles. Mesenchymal stem cells are a class of cells with the potential for self-healing and multidirectional differentiation. In recent years, numerous studies have shown that EVs, especially those secreted by mesenchymal stem cells, can promote the repair and regeneration of various tissues and, thus, have significant potential in regenerative medicine. However, due to the rapid clearance capacity of the circulatory system, EVs are barely able to act persistently at specific sites for repair of target tissues. Hydrogels have good biocompatibility and loose and porous structural properties that allow them to serve as EV carriers, thereby prolonging the retention in certain specific areas and slowing the release of EVs. When EVs are needed to function at specific sites, the EV-loaded hydrogels can stand as an excellent approach. In this review, we first introduce the sources, roles, and extraction and characterization methods of EVs and describe their current application status. We then review the different types of hydrogels and discuss factors influencing their abilities to carry and release EVs. We summarize several strategies for loading EVs into hydrogels and characterizing EV-loaded hydrogels. Furthermore, we discuss application strategies for EV-loaded hydrogels and review their specific applications in tissue regeneration and repair. This article concludes with a summary of the current state of research on EV-loaded hydrogels and an outlook on future research directions, which we hope will provide promising ideas for researchers.

Thrombogenesis remains the primary failure of synthetic vascular grafts. Endothelial coverage is crucial to provide an antithrombogenic surface. However, most synthetic materials do not support cell adhesion, and transanastomotic endothelial migration is limited. Here, a surface modification strategy using fucoidan and topography was developed to enable fast in situ endothelialization of polyvinyl alcohol, which is not endothelial cell-adhesive. Among three different immobilization approaches compared, conjugation of aminated-fucoidan promoted endothelial monolayer formation while minimizing thrombogenicity in both in vitro platelet rich plasma testing and ex vivo non-human primate shunt assay. Screening of six topographical patterns showed that 2 μm gratings increased endothelial cell migration without inducing inflammation responses of endothelial cells. Mechanistic studies demonstrated that fucoidan could attract fibronectin, enabling integrin binding and focal adhesion formation and activating focal adhesion kinase (FAK) signaling, and 2 μm gratings further enhanced FAK-mediated cell migration. In a clinically relevant rabbit carotid artery end-to-side anastomosis model, 60% in situ endothelialization was observed throughout the entire lumen of 1.7 mm inner diameter modified grafts, compared to 0% of unmodified graft, and the four-week graft patency also increased. This work presents a promising strategy to stimulate in situ endothelialization on synthetic materials for improving long-term performance.

Tumors of the cerebellopontine angle (CPA) represent an heterogeneous group which can arise extradural, intradural-extraaxial or intraaxial compartment. Hemangioblastomas of the cerebellopontine angle (CPA) are extremely rare. Computed tomography (CT) and magnetic resonance imaging (MRI) are often the gold-standard radiological imaging modalities used in characterizing the lesion\'s features, and its relationship with the surrounding structures. They are vascular lesions and may cause profuse bleeding intraoperatively, that is why angiography remains a crucial diagnostic and therapeutic tool, by reducing both the presurgical differential diagnosis, as well as the intraoperative bleeding by providing capability of embolization of this vascular tumor. We present the case of a 65 year old patient with a cystic-solid variety of HMB at the right CPA, which was successfully treated by a combination of an endovascular preoperative embolization and surgery without major complications or neurological deficits.

UNASSIGNED: To evaluate the clinical outcomes of transcatheter arterial embolization (TAE) with n-butyl-2-cyanoacrylate (NBCA) for treatment of bleeding in cirrhotic patients.
UNASSIGNED: A total of 35 cirrhotic patients (26 men, 9 women; mean age, 48.4 ± 11.1) who underwent TAE with NBCA for bleeding from January 2011 to December 2020 were retrospectively analysed. Only cirrhotic patients with active arterial bleeding confirmed on computed tomography (CT) were included. Fifteen patients were hemodynamically unstable before embolization procedure, and coagulopathy was observed in 32 patients. The mean MELD score and Child Pugh score were 24 ± 9.9 and 9.9 ± 2.2, respectively. The mean haemoglobin level and mean number of RBC units transfused before embolization were 7.4 ± 1.4 g/dL and 10.2 ± 4, respectively. The technical, clinical success rate and 30-day mortality rate were evaluated.
UNASSIGNED: Technical success and clinical success rates were achieved in 100% and 82.8% of patients, respectively. Overall 30-day mortality rate was 48%. No major complications related to the embolization procedure was seen. Only the greater number of RBC units transfused before the embolization procedure (OR = 1.81, 95% CI = 1.17-2.80, P = 0.007) was significantly associated with clinical failure. Greater number of RBC units transfused (OR = 1.53, 95% CI: 1.00-2.34, P = 0.004) and higher Child Pugh score (OR 2.44, 95% CI 1.26-4.71, P = 0.008) were significantly associated with higher 30-day mortality rate.
UNASSIGNED: Transcatheter arterial embolization using NBCA can be used as the effective treatment option for bleeding in cirrhotic patients which has a high technical and clinical success despite the grave prognosis associated with cirrhosis.

Chronic diabetic wounds are an important healthcare challenge. High concentration glucose, high level of matrix metalloproteinase-9 (MMP-9), and long-term inflammation constitute the special wound environment of diabetic wounds. Tissue necrosis aggravates the formation of irregular wounds. All the above factors hinder the healing of chronic diabetic wounds. To solve these issues, a glucose and MMP-9 dual-response temperature-sensitive shape self-adaptive hydrogel (CBP/GMs@Cel&INS) was designed and constructed with polyvinyl alcohol (PVA) and chitosan grafted with phenylboric acid (CS-BA) by encapsulating insulin (INS) and gelatin microspheres containing celecoxib (GMs@Cel). Temperature-sensitive self-adaptive CBP/GMs@Cel&INS provides a new way to balance the fluid-like mobility (self-adapt to deep wounds quickly, approximately 37 °C) and solid-like elasticity (protect wounds against external forces, approximately 25 °C) of self-adaptive hydrogels, while simultaneously releasing insulin and celecoxib on-demand in the environment of high-level glucose and MMP-9. Moreover, CBP/GMs@Cel&INS exhibits remodeling and self-healing properties, enhanced adhesion strength (39.65 ± 6.58 kPa), down-regulates MMP-9, and promotes cell proliferation, migration, and glucose consumption. In diabetic full-thickness skin defect models, CBP/GMs@Cel&INS significantly alleviates inflammation and regulates the local high-level glucose and MMP-9 in the wounds, and promotes wound healing effectively through the synergistic effect of temperature-sensitive shape-adaptive character and the dual-responsive system.

Bone defects are a common challenge in the clinical setting. Bone tissue engineering (BTE) is an effective treatment for the clinical problem of large bone defects. In this study, we fabricated silk fibroin (SF)/hydroxyapatite (HAp) scaffolds inlaid with naringin poly lactic-co-glycolic acid (PLGA) microspheres, investigating the feasibility of their application in BTE. Naringin PLGA microspheres were manufactured and adhered to the SF/HAp scaffold. Bone mesenchymal stem cells (BMSCs) were inoculated onto the SF/HAp scaffold containing naringin PLGA microsphere to examine the biocompatibility of the SF/HAp scaffolds. A rabbit femoral distal bone defect model was used to evaluate the in vivo function of the SF/HAp scaffolds containing naringin-loaded PLGA microspheres. The current study demonstrated that SF/HAp scaffolds containing naringin-loaded PLGA microspheres show promise as osteo-modulatory biomaterials for bone regeneration.

Pulmonary administration route has been extensively exploited for the treatment of local lung diseases such as asthma, chronic obstructive pulmonary diseases and respiratory infections, and systemic diseases such as diabetes. Most inhaled medicines could be cleared rapidly from the lungs and their therapeutic effects are transit. The inhaled medicines with extended pulmonary exposure may not only improve the patient compliance by reducing the frequency of drug administration, but also enhance the clinical benefits to the patients with improved therapeutic outcomes. This article systematically reviews the physical and chemical strategies to extend the pulmonary exposure of the inhaled medicines. It starts with an introduction of various physiological and pathophysiological barriers for designing inhaled medicines with extended lung exposure, which is followed by recent advances in various strategies to overcome these barriers. Finally, the applications of the inhaled medicines with extended lung exposure for the treatment of various diseases and the safety concerns associated to various strategies to extend the pulmonary exposure of the inhaled medicines are summarized.

The need for long-term treatments of chronic diseases has motivated the widespread development of long-acting parenteral formulations (LAPFs) with the aim of improving drug pharmacokinetics and therapeutic efficacy. LAPFs have been proven to extend the half-life of therapeutics, as well as to improve patient adherence; consequently, this enhances the outcome of therapy positively. Over past decades, considerable progress has been made in designing effective LAPFs in both preclinical and clinical settings. Here we review the latest advances of LAPFs in preclinical and clinical stages, focusing on the strategies and underlying mechanisms for achieving long acting. Existing strategies are classified into manipulation of in vivo clearance and manipulation of drug release from delivery systems, respectively. And the current challenges and prospects of each strategy are discussed. In addition, we also briefly discuss the design principles of LAPFs and provide future perspectives of the rational design of more effective LAPFs for their further clinical translation.

Breast cancer brain metastases (BCBMs) are one of the most difficult malignancies to treat due to the intracranial location and multifocal growth. Chemotherapy and molecular targeted therapy are extremely ineffective for BCBMs due to the inept brain accumulation because of the formidable blood‒brain barrier (BBB). Accumulation studies prove that low density lipoprotein receptor-related protein 1 (LRP1) is promising target for BBB transcytosis. However, as the primary clearance receptor for amyloid beta and tissue plasminogen activator, LRP1 at abluminal side of BBB can clear LRP1-targeting therapeutics. Matrix metalloproteinase-1 (MMP1) is highly enriched in metastatic niche to promote growth of BCBMs. Herein, it is reported that nanoparticles (NPs-K-s-A) tethered with MMP1-sensitive fusion peptide containing HER2-targeting K and LRP1-targeting angiopep-2 (A), can surmount the BBB and escape LRP1-mediated clearance in metastatic niche. NPs-K-s-A revealed infinitely superior brain accumulation to angiopep-2-decorated NPs-A in BCBMs bearing mice, while comparable brain accumulation in normal mice. The delivered doxorubicin and lapatinib synergistically inhibit BCBMs growth and prolongs survival of mice bearing BCBMs. Due to the efficient BBB penetration, special and remarkable clearance escape, and facilitated therapeutic outcome, the fusion peptide-based drug delivery strategy may serve as a potential approach for clinical management of BCBMs.