Elimination of intracellular Ca2+ overload by BAPTA­AM liposome nanoparticles: A promising treatment for acute pancreatitis.

Calcium overload, a notable instigator of acute pancreatitis (AP), induces oxidative stress and an inflammatory cascade, subsequently activating both endogenous and exogenous apoptotic pathways. However, there is currently lack of available pharmaceutical interventions to alleviate AP by addressing calcium overload. In the present study, the potential clinical application of liposome nanoparticles (LNs) loaded with 1,2­bis(2­aminophenoxy)ethane­N,N,N',N'­tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA­AM), a cell­permeant calcium chelator, was investigated as a therapeutic approach for the management of AP. To establish the experimental models in vitro, AR42J cells were exposed to high glucose/sodium oleate (HGO) to induce necrosis, and in vivo, intra­ductal taurocholate (TC) infusion was used to induce AP. The findings of the present study indicated that the use of BAPTA­AM­loaded LN (BLN) effectively and rapidly eliminated excessive Ca2+ and reactive oxygen species, suppressed mononuclear macrophage activation and the release of inflammatory cytokines, and mitigated pancreatic acinar cell apoptosis and necrosis induced by HGO. Furthermore, the systemic administration of BLN demonstrated promising therapeutic potential in the rat model of AP. Notably, BLN significantly enhanced the survival rates of rats subjected to the TC challenge, increasing from 37.5 to 75%. This improvement was attributed to the restoration of pancreatic function, as indicated by improved blood biochemistry indices and alleviation of pancreatic lesions. The potential therapeutic efficacy of BLN in rescuing patients with AP is likely attributed to its capacity to inhibit oxidative stress, prevent premature activation of zymogens and downregulate the expression of TNF­α, IL­6 and cathepsin B. Thus, BLN demonstrated promising value as a novel therapeutic approach for promptly alleviating the burden of intracellular Ca2+ overload in patients with AP.

Combined release of LL37 peptide and zinc ion from a mussel-inspired coating on porous titanium for infected bone defect repairing.

Implant-associated infections impose great burden on patient health and public healthcare. Antimicrobial peptides and metal ions are generally incorporated onto implant surface to deter bacteria colonization. However, it is still challenging to efficiently prevent postoperative infections at non-cytotoxic dosages. Herein, a scaffold based on porous titanium coated with a mussel-inspired dual-diameter TiO2 nanotubes is developed for loading dual drugs of LL37 peptide and Zn2+ with different sizes and characteristics. Benefiting from in-situ formed polydopamine layer and dual-diameter nanotubular structure, the scaffold provides an efficient platform for controllable drugs elution: accelerated release under acidic condition and sustained release for up to 28 days under neutral/alkalescent circumstances. Such combination of dual drugs simultaneously enhanced antibacterial efficacy and osteogenesis. In antibacterial test, LL37 peptide serving as bacteria membrane puncture agent, and Zn2+ acting as ROS generator, cooperatively destroyed bacterial membrane integrity and subsequently damaged bacterial DNA, endowing dual-drug loaded scaffold with remarkable bactericidal efficiency of > 92 % in vitro and > 99 % in vivo. Noteworthily, dual-drug loaded scaffold promoted bone-implant osteointegration under infectious microenvironment, overmatching single-drug load ones. It provides a promising strategy on surface modification of implant for infected bone defect repairing.

Preparation and Hemostatic Effect of Micro-Nanograded Porous Particles Doped with Dopamine-Based Water-Triggered Intelligent Composite Adhesives.

The wet environment of water or tissue in bleeding wounds poses significant challenges to the adhesion performance of existing hemostatic adhesives. An intelligent composite adhesive prepared by doping starch-based silicate micro-nanograded porous particles (MBC@CMS) with dopamine-hyperbranched polymers (HPD, 7800 Mw) synthesized by the Michael addition reaction could be triggered by water to form a glue (MBC@CMS-HPD). The results indicated that MBC@CMS-HPD could still have adhesion properties under running water washing and water immersion and could effectively seal the water outlet. The results of the glue-forming mechanism showed that MBC@CMS-HPD had better wettability than water, which could eliminate water molecules at the wet adhesive surface. When contacted with water, the agglomeration of the HPD hydrophobic chain increases the exposure of the catechol group, and the relative atomic mass of the N element on the surface increases from 2.8 to 4.8%. The adhesion of MBC@CMS-HPD was enhanced and stable. MBC@CMS-HPD showed significant hemostasis effects in five injury bleeding models of Sprague-Dawley (SD) rats and New Zealand rabbits. Especially in the fatal femoral artery bleeding model of New Zealand rabbits, MBC@CMS-HPD reduced the amount of bleeding by 75% and shortened the bleeding time by 78% compared with the a-cyanoacrylate adhesives. The results of the coagulation mechanism showed that compared with HPD, MBC@CMS-HPD could activate both endogenous and exogenous coagulation pathways. Among them, after contact with blood, HPD formed a gel to close the blood outlet, and MBC@CMS entered the wound to activate the internal and external coagulation pathways. In addition, HPD and MBC@CMS had good histocompatibility and degradability, which has the potential to be applied to different wounds.

The contribution of pore size and porosity of 3D printed porous titanium scaffolds to osteogenesis.

Porous titanium implants were popularly fabricated to promote bone formation. A desirable porous scaffold was recommended to be with porosity of >60% or/and pore size of >300 µm for better osteointegration. However, whether the pore size and porosity could be randomly selected within the recommended values? And what is the correlation between pore size and porosity for accelerating osteointegration? In this study, porous titanium with cubic cell structure was produced by selective laser melting. The designed porosities of scaffolds with 700-µm pore size were 40%, 70% and 90%; and the pore sizes of scaffolds with 70% porosity were 400, 700 and 900 µm. The in vitro osteogenic potential and in vivo bone formation were investigated. Results showed that porosity and pore size could be tuned by altering strut size, which was further directly responsible for mechanical properties. Besides, pore size and porosity synergistically contributed to osteogenic activity in vitro and new bone formation in vivo. In regard to pore sizes herein, the optimized one for better osteogenic response and bone forming ability was ~600-700 µm (p70). Too smaller or too larger pore size might more or less hinder cellular behaviors and bone regeneration, even if both pore size (300-900 µm) and porosity (70%) were within the recommended value range. At a constant pore size (~600-700 µm), p70 and p90 with higher porosity was more conductive to biological effects, compared with p40. As a result, pore-size variation revealed more significant influence on osteogenesis, compared with variation of porosity within recommended values. However, the applicable porosity within recommended values should be designed with the consideration of specific load-bearing conditions. This study helps to provide guidance for designing porous scaffolds with appropriate mechanical strengths and effective bone-forming ability, so as to develop better custom-made bone substitutes.

Degradable and self-luminescence porous silicon particles as tissue adhesive for wound closure, monitoring and accelerating wound healing.

Tissue adhesives have received much attention for their effectiveness in sealing wounds or incisions in clinical surgery, especially in minimally invasive surgery. To meet the safe and smart wound management requirements, ideal tissue adhesives are expected to have high biocompatibility, and be able to accelerate wound closing and healing, and monitor wound healing process. However, few adhesives fit all of the above descriptions. It has been demonstrated that inorganic nanoparticles can directly glue biological tissue based on nano-bridging effect. In this study, self-luminescence porous silicon (LPSi) particles were prepared with degradable and biocompatible properties. In addition, the self-luminescence property of LPSi particles was discovered by In Vivo Imaging System (IVIS) for the first time, which can avoid the limitations of photoluminescence imaging. Due to the oxidation and degradation reaction, LPSi particles not only can be degraded completely in several days, but also showed satisfactory biocompatibility. And their degradation product could promote tube formation of HUVECs. Moreover, owing to the high specific surface area and the outer oxide layer of LPSi particles, LPSi tissue adhesive exhibited strong adhesive strength to pig livers. Furthermore, this adhesive closed wound rapidly, promoted angiogenesis and epidermal regeneration, and facilitated wound healing in a mouse skin incision model. Importantly, the wound healing ratio can be monitored by measuring the self-luminescence intensity of LPSi particles in the wound site. This study reveals that LPSi particles could be employed as a safe and smart wound management tissue adhesive for wound closure, as well as accelerating and monitoring wound healing.

Study on hemostatic effect and mechanism of starch-based nano-microporous particles.

The powdered hemostatic particles have broad application prospects in large open wounds, internal organ injuries and penetrating injuries of the body. In this study, nanoscale mescoporous and macroporous silica (MMSN), nanoscale mescoporous and macroporous bioactive glass (MBG), micron-scale cross-linked corn starch porous microspheres (CMS), MMSN@CMS and MBG@CMS starch-based nano-microporous particles were synthesized and their hemostatic effect and hemostatic mechanism were studied. The results showed that comparted with the single particle of CMS, the combination particles MBG@CMS and MMSN@CMS significantly increased the water absorption rate, activated both internal and external coagulation pathways, significantly shortened CBT, as well as the improved hemostatic effects in vitro. The immediately released Ca2+ from MBG@CMS in the blood to participate in the coagulation pathway, and MMSN@CMS activated platelets by concentrating blood coagulation factors, might be the main hemostatic mechanisms for the starch-based nano-microporous particles. Furthermore, the hemostatic efficacy of particles, both in the model of tail-amputation and liver injury in SD rats, showed the starch-based nano-microporous particles, especial MBG@CMS, could significantly reduce the weight of blood loss and shorten the bleeding time. Our research work stated that the starch-based nano-microporous particles MBG@CMS might be a hemostasis biomaterial with the potential applications for the emergency bleeding.

Research status and development potential of composite hemostatic materials.

Bleeding is a serious incident that can occur in people's daily lives or clinics. Bleeding can be caused by accidental trauma, surgery, congenital diseases, or blood disorders caused by drugs. Excessive bleeding in the body can lead to illness or death. Adequate hemostasis is an essential strategy to prevent bleeding to avoid death and is the first step in wound healing. With rapid developments in science and technology, various hemostatic materials have been developed with the hope of enhancing the hemostatic effect by activating different coagulation mechanisms. Some examples are the formation of physical barriers, platelet aggregation, concentration of blood components, and release of clotting factors. The design of composite hemostatic materials should conform to the requirement according to which multiple coagulation mechanisms can be simultaneously activated in order to enhance the hemostatic effect. Combined with the research status of composite hemostatic materials, it has been found that there is still a lack of materials that exhibit high biocompatibility, shape variability, simultaneous usability for both internal and external bleeding, in vivo degradability, ability to camouflage platelets or blood cells, and other clotting-related factors. Therefore, the future development potential and optimization direction for composite hemostatic materials have been proposed through an in-depth discussion on their characteristics and coagulation mechanisms. It is hoped that this review can provide a worthwhile reference for research into hemostatic materials.