Structure driven bio-responsive ability of injectable nanocomposite hydrogels for efficient bone regeneration.

Injectable hydrogels are promising for treatment of bone defects in clinic owing to their minimally invasive procedure. Currently, there is limited emphasis on how to utilize injectable hydrogels to mobilize body's regenerative potential for enhancing bone regeneration. Herein, an injectable bone-mimicking hydrogel (BMH) scaffold assembled from nanocomposite microgel building blocks was developed, in which a highly interconnected microporous structure and an inorganic/organic (methacrylated hydroxyapatite and methacrylated gelatin) interweaved nano structure were well-designed. Compared with hydrogels lacking micro-nano structures or only showing microporous structure, the BMH scaffold enhanced the ingrowth of vessels and promoted the formation of dense cellular networks (including stem cells and M2 macrophages), across the entire scaffold at early stage after subcutaneous implantation. Moreover, the BMH scaffold could not only directly trigger osteogenic differentiation of the infiltrated stem cells, but also provided an instructive osteo-immune microenvironment by inducing macrophages into M2 phenotype. Mechanistically, our results reveal that the nano-rough structure of the BMH plays an essential role in inducing macrophage M2 polarization through activating mechanotransduction related RhoA/ROCK2 pathway. Overall, this work offers an injectable hydrogel with micro-nano structure driven bio-responsive abilities, highlighting harnessing body's inherent regenerative potential to realize bone regeneration.

Development of a multifunctional nano-hydroxyapatite platform (nHEA) for advanced treatment of severely infected full-thickness skin wounds.

The treatment of full-thickness skin injuries complicated by severe infection is hampered by the lack of comprehensive solutions that can regulate the various stages of wound healing. Consequently, there is an urgent need for a multifunctional dressing capable of multi-level regulation. In this study, we propose a novel solution by covalently integrating ε-poly-l-lysine-grafted gallic acid (EG) and in situ bioreduced silver nanoparticles (AgNPs) onto nano-hydroxyapatite (nHAP), thereby developing a multi-layered, multifunctional nanoplatform (nHEA). Cell experiments have shown that, compared to nHAP and nHAP loaded only with EG (nHEG), the addition of AgNPs to nHEA confers excellent antibacterial properties while maintaining optimal biocompatibility. The incorporation of EG onto nHEG and nHEA imparts antioxidation, anti-inflammatory, and pro-angiogenic functions, and the release of Ca2+ and EG further enhances fibroblast migration and collagen secretion. In a rat model of full-thickness skin injury with severe infection, nHEA demonstrates remarkable antibacterial and anti-inflammatory effects, along with promoting collagen remodeling and regeneration. Together, both cell experiments and animal studies confirm the significant potential of this innovative multifunctional nanoplatform in the treatment of full-thickness skin injuries with severe infection. STATEMENT OF SIGNIFICANCE: Treating infected full-thickness skin injuries poses a longstanding challenge due to the lack of comprehensive solutions that can regulate different stages of wound healing. This study introduces a novel multifunctional nanoplatform, nHEA, developed by covalently integrating ε-poly-l-lysine grafted with gallic acid (EG) and in situ bioreduced AgNPs onto nano-hydroxyapatite (nHAP). Cell experiments reveal that the integration of AgNPs enhances nHEA's antibacterial performance while maintaining optimal biocompatibility. The inclusion of EG bestows antioxidant, inflammation-regulating, and angiogenetic properties upon nHEA, and the release of Ca2+ and EG stimulates the migration and collagen secretion of fibroblast cells. Consequently, nHEA exhibits superior antibacterial and inflammation-regulating efficacy, and stimulates collagen remodeling and regeneration in vivo, making it a promising treatment for severely infected skin injuries.

Comparative effectiveness and safety of bolus vs. continuous infusion of loop diuretics: Results from the MIMIC-III Database.

BACKGROUND: It is unclear whether fluid management goals are best achieved by bolus injection or continuous infusion of loop diuretics. In this study, we compared the effectiveness and safety of a continuous infusion with that of a bolus injection when an increased loop diuretic dosage is required in intensive care unit (ICU) patients. METHODS: We obtained data from the MIMIC-III database for patients who were first-time ICU admissions and required an increased diuretic dosage. Patients were excluded if they had an estimated glomerular filtration rate <15 ml/min/1.73 m2, were receiving renal replacement therapy, had a baseline systolic blood pressure <80 mmHg, or required a furosemide dose <120 mg. The patients were divided into a continuous group and a bolus group. Propensity score matching was used to balance patients' background characteristics. RESULTS: The final dataset included 807 patients (continuous group, n = 409; bolus group, n = 398). After propensity score matching, there were 253 patients in the bolus group and 231 in the continuous group. The 24 h urine output per 40 mg of furosemide was significantly greater in the continuous group than in the bolus group (234.66 ml [95% confidence interval (CI) 152.13-317.18, p < 0.01]). There was no significant between-group difference in the incidence of acute kidney injury (odds ratio 0.96, 95% CI 0.66-1.41, p = 0.85). CONCLUSIONS: Our results indicate that a continuous infusion of loop diuretics may be more effective than a bolus injection and does not increase the risk of acute kidney injury in patients who need an increased diuretic dosage in the ICU.

A chitosan-based multifunctional hydrogel containing in situ rapidly bioreduced silver nanoparticles for accelerating infected wound healing.

Generally, bacterial infection seriously hinders the wound healing process, so it is crucial to safeguard the wound from severe infection. Besides, multifunctional hydrogel dressings (self-healing, injectable, antibacterial and adaptable) seem to be conducive to meet the needs of wound healing. Here, a double-crosslinked multifunctional hydrogel (COC hydrogel) based on quaternized chitosan, methacrylate anhydride-modified collagen and oxidized dextran was developed. The double-crosslinked network improved the stability of the hydrogel while not destroying the functionality of the Schiff base bond. More importantly, silver ions were rapidly in situ bioreduced to silver nanoparticles (AgNPs) during the formation of the COC hydrogel, which can essentially avoid the dispersion and agglomeration problems. The obtained COC@AgNP hydrogel had good biocompatibility compared with that loaded with silver ions and excellent antibacterial properties compared with that loaded with the same amount of commercial AgNPs. In vivo results indicated that the COC@AgNP hydrogel accelerated the healing process of infected full-thickness skin defects through anti-infection, anti-inflammation, stimulating collagen deposition, and promoting the formation of epithelia and blood vessels. Collectively, the COC@AgNP hydrogel has good potential for clinical infected wound dressing applications.

Constructing a biomimetic nanocomposite with the in situ deposition of spherical hydroxyapatite nanoparticles to induce bone regeneration.

Inspired by the nanostructure of bone, biomimetic nanocomposites comprising natural polymers and inorganic nanoparticles have gained much attention for bone regenerative applications. However, the mechanical and biological performances of nanocomposites are largely limited by the inhomogeneous distribution, uncontrolled size and irregular morphology of inorganic nanoparticles at present. In this work, an innovative in situ precipitation method has been developed to construct a biomimetic nanocomposite which consists of spherical hydroxyapatite (HA) nanoparticles and gelatin (Gel). The homogeneous dispersion of HA nanoparticles in nHA-Gel endowed it with a low swelling ratio, enhanced mechanical properties and slow degradation. Moreover, strontium (Sr) was incorporated into HA nanoparticles to further enhance the bioactivity of nanocomposites. In vitro experiments suggested that nHA-Gel and Sr-nHA-Gel facilitated cell spreading and promoted osteogenic differentiation of bone-marrow-derived mesenchymal stem cells (BMSCs) as compared to pure Gel and mHA-Gel conventional composites developed by mechanical mixing. In vivo rat critical-sized calvarial defect repair further confirmed that nHA-Gel and Sr-nHA-Gel possessed relatively effective bone regenerative abilities among the four groups. Collectively, the biomimetic nanocomposites of nHA-Gel and Sr-nHA-Gel have good efficacy in inducing bone regeneration and would be a promising alternative to bone grafts for clinical applications.