PDA-BPs integrated mussel-inspired multifunctional hydrogel coating on PPENK implants for anti-tumor therapy, antibacterial infection and bone regeneration.

Currently, many cancer patients with bone defects are still threatened by tumor recurrence, postoperative bacterial infection, and massive bone loss. Many methods have been studied to endow bone implants with biocompatibility, but it is difficult to find an implant material that can simultaneously solve the problems of anticancer, antibacterial and bone promotion. Here, a multifunctional gelatin methacrylate/dopamine methacrylate adhesive hydrogel coating containing 2D black phosphorus (BP) nanoparticle protected by polydopamine (pBP) is prepared by photocrosslinking to modify the surface of poly (aryl ether nitrile ketone) containing phthalazinone (PPENK) implant. The multifunctional hydrogel coating works in conjunction with pBP, which can deliver drug through photothermal mediation and kill bacteria through photodynamic therapy at the initial phase followed by promotion of osteointegration. In this design, photothermal effect of pBP control the release of doxorubicin hydrochloride loaded via electrostatic attraction. Meanwhile, pBP can generate reactive oxygen species (ROS) to eliminate bacterial infection under 808 nm laser. In the slow degradation process, pBP not only effectively consumes excess ROS and avoid apoptosis induced by ROS in normal cells, but also degrade into PO43- to promote osteogenesis. In summary, nanocomposite hydrogel coatings provide a promising strategy for treatment of cancer patients with bone defects.

Stabilization of Apatite Coatings on PPENK Surfaces by Mechanical Interlocking to Promote Bioactivity and Osseointegration In Vivo.

Apatite coatings with high stability can effectively improve the surface bioactivity and osteogenic activity of implant materials. In clinical practice, the ability of apatite coatings to bond with the substrate is critical to the effect of implants. Here, we propose a strategy to construct a three-dimensional (3D) nanoporous structure on the surface of a poly(phthalazinone ether nitrile ketone) (PPENK) substrate and introduce a polydopamine (PDA) coating with grafted phosphonate groups to enhance the overall deposition of a bone-like apatite coating in the 3D nanoporous structure during mineralization. This method leads to a mechanical interlocking between the apatite coating and the substrate, which increases the stability of the apatite coating. The apatite coating confers a better bioactive surface to PPENK and also promotes osteogenic differentiation and adhesion of MC3T3-E1 osteoblasts in vitro. The samples are then implanted into rat femurs to characterize in vivo osseointegration. Micro-CT data and histological staining of tissue sections reveal that PPENK with a stable apatite coating induces less fibrous capsule formation and no inflammatory response and promotes osteogenic differentiation and bone-bonding strength. This enhances the long-term use of PPENK implant materials and shows great potential for clinical application as orthopedic implants.

Cardiotoxicity of immune checkpoint inhibitors: A frequency network meta-analysis.

Immune checkpoint inhibitors (ICIs) in combination withother anti-cancer treatments have been approved for a variety of cancers. While the difference in the incidence of cardiovascular adverse events has not been fully investigated. We aimed to assess the the differences in cardiotoxicity among cancer patients receiving different ICI therapies. PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov. websites were searched for all randomized controlled trials (RCTs) of ICI. The primary outcomes were any grade cardiotoxicity and Grade 3-5 cardiotoxicity, the secondary outcomes were any grade myocarditis and Grade 3-5 myocarditis, with sub-analyses based on cancer type and does of ICI. A systematic review and frequency network meta-analysis were then performed for cardiotoxicity events. 91 RCTs (n=52247) involving 12 treatment arms were finally included. We observed that PD-L1 + CTLA-4 had the highest risk among all therapies inducing any grade cardiotoxicity, and the differences were significant except PD-1 + CTLA-4, PD-1 + TTD and PD-L1 + TTD. In addition, CTLA-4 had a higher risk of Grade 3-5 cardiotoxicity than PD-1 and anit-PD-L1. For Grade 1-5 myocarditis and Grade 3-5 myocarditis, no significant difference was found among differences therapies. No differences were observed in subgroup analyses according to does and cancer type. There were differences in the incidence of cardiotoxicity among different ICI therapies. For ICI monotherapy, CTLA-4 may be linked to Grade 3-5 cardiotoxicity than PD-1 or PD-L1. For dual therapy, the cardiotoxicity of dual ICI therapy seems to be higher than that of chemotherapy or targeted therapy.

Tunicate inspired gelatin-based tough hydrogel wound dressing containing twisted phthalazinone with adhesive, self-healing and antibacterial properties.

As a hydrolytic product of collagen, gelatin is a polypeptide of biological origin. Gelatin hydrogels emerge as promising material candidates for traditional dressings due to good biocompatibility and the ability to keep wounds moist. However, it is difficult to simultaneously achieve gelatin hydrogel with robust mechanical property for long-term usage, reliable tissue adhesion, self-healing and antibacterial properties. Herein, we propose a simply synthesized strategy of a multifunctional gelatin hydrogel dressing, which is constructed by conjugating a newly synthesized 2-(4'-aldehydephenyl)-4-(2',3',4'-trihydroxyphenyl)-2,3-phthalazine-1(2H)-one (THPZB) to gelatin with Schiff base and chelating with Fe3+ ions (termed G/THPZB/Fe hydrogel). The twisted structure of phthalazinone in THPZB leads to entanglement of gelatin molecular chains, which resolves the stiffness-toughness conflict of the hydrogel. Furthermore, the strong tissue adhesion and fast self-healing capability mainly originate from the hydrogen bonding of the pyrogallol in THPZB. In vitro study shows that the hydrogels possess good biocompatibility with L929 cells, hemostatic and antibacterial activity. In the rat model of skin infection, the hydrogel dressing not only have no adverse effects on vital organs, but also can effectively promote wound healing of bacterial infection. Considering that it has multiple functions, G/THPZB/Fe hydrogel can be used as a promising wound dressing for biomedical applications.

Apatite Formation Induced by Chitosan/Gelatin Hydrogel Coating Anchored on Poly(aryl ether nitrile ketone) Substrates to Promote Osteoblastic Differentiation.

Bone-like apatite is a promising coating of poly(ether ether ketone) (PEEK) for bone implantation. Poly(aryl ether nitrile ketone) containing phthalazinone moiety (PPENK) is a novel alternative for its easy synthesis. Here, chitosan/gelatin hybrid hydrogel coating is applied to induce the formation of apatite on the surface of PPENK substrate through biomineralization to improve its biocompatibility and osteogenic property. PPENK possessing allyl groups (PPENK-d) are synthesized and spin-coated on PPENK substrate to impart reactive groups. The hydrogel coating is prepared by the ultraviolet crosslinking of gelatin methacrylate (GelMA) and chitosan methacrylate (CSMA) on PPENK substrate. PPENK-d, GelMA, and CSMA are characterized by 1 H-NMR to confirm the designed structures. The presence of chitosan increases the chelation of calcium ions and thus induces the nucleation of apatite. The microstructural and compositional results reveal that the chitosan-containing hydrogel coating induced apatite coating yields a higher apatite quantity compared to the gelatin hydrogel coating. The apatite coatings on PPENK substrate promote the cytocompatibility and osteogenesis of MC3T3-E1 preosteoblasts in vitro.

Enhancing Tissue Adhesion and Osteoblastic Differentiation of MC3T3-E1 Cells on Poly(aryl ether ketone) by Chemically Anchored Hydroxyapatite Nanocomposite Hydrogel Coating.

Tissue adhesion to bone implant and osteoblastic differentiation are the key factors to achieve poly(aryl ether ketone) (PAEK) implant osseointegration. However, physical interaction of implant with tissue and hydroxyapatite coating suffers from slow implant tissue integration and lack of long-term stability. In this study, a novel poly(phthalazinone ether sulfone ketone) containing allyl groups (APPBAESK) is coated onto PPBESK sheet for reacting with the allyl groups of the hydrogel coating to enhance its stability. N-Succinimidyl (NHS)-ester activated group and nano-hydroxyapatite (nano-HA) are introduced into the hydrogel synthesized from gelatin methacrylate (GelMA) and acrylic acid to construct a nanocomposite hydrogel coating on PPBESK which is a promising PAEK implant material. The hydrophilicity of the PPBESK sheet is improved by the hydrogel coating. The chemical components of the nanocomposite hydrogel coating are confirmed by X-ray photoelectron spectroscope, Attenuated total reflection infrared, and X-ray powder diffraction. The tissue shear adhesion strength of the hydrogel coating toward pig skin is enhanced due to the synergism of NHS-ester activated group and nano-HA. The osteogenic differentiation of MC3T3-E1 preosteoblasts is promoted by nano-HA in nanocomposite hydrogel coating. Therefore, the bifunctional nanocomposite hydrogel coating provides a great application prospect in the surface modification of PAEK implants in bone tissue engineering.

RhBMP-2 immobilized on poly(phthalazinone ether nitrile ketone) via chemical and physical modification for promoting in vitro osteogenic differentiation.

Poly(ether ether ketone) (PEEK) is a polyaryletherketone commonly used for bone implants, but it is difficult to modify the PEEK surface. Conversely, poly(phthalazinone ether nitrile ketone) (PPENK) is a polyaryletherketone whose surface can be modified by using chemical reactions owing to its cyano group. In this paper, two types of materials, P-BMP-2 and PH-BMP-2, were prepared by covalent immobilization and heparin binding of rhBMP-2 respectively to enhance the osteogenic activity of PPENK. X-ray photoelectron spectroscopy and water contact-angle measurement were used to demonstrate the hydrolysis of the cyano groups on PPENK, amine group grafting and immobilization of rhBMP-2. Immunohistochemical staining and evaluation of loading and release behaviour were used to demonstrate the existence of rhBMP-2 on PPENK surfaces. The biological activity of MC3T3-E1 preosteoblast cells on the samples were evaluated using cell adhesion, viability and proliferation tests. The genetic expression of genes associated with osteogenic activity was assessed by reverse transcription polymerase chain reaction. Based on the obtained in vitro experimental results, both P-BMP-2 and PH-BMP-2 exhibit good cytocompatibility and promote differentiation of MC3T3-E1 preosteoblast cells. In particular, the favourable biocompatibility can be obtained using the heparin-binding method.