Microcin C7-laden modified gelatin based biocomposite hydrogel for the treatment of periodontitis

AUTHORS

Shuo Zhou, Di Miao, Jinpeng Wen, Qianqian Zhang, Datao Hu, Na Liu, Jinyang Li, Yifan Zhang, Ke Wang, Yue Chen

ABSTRACT

Periodontitis is an oral disease with the highest incidence globally, and plaque control is the key to its treatment. In this study, Microcin C7 was used to treat periodontitis, and a novel injectable temperature-sensitive sustained-release hydrogel was synthesized as an environmentally sensitive carrier for drug delivery. First, modified gelatin was formed from gelatin and glycidyl methacrylate. Then, Microcin C7-laden hydrogel was formed from cross-linking with double bonds between modified gelatin, N-isopropyl acrylamide, and 2-Methacryloyloxyethyl phosphorylcholine through radical polymerization, and the model drug Microcin C7 was loaded by electrostatic adsorption. The hydrogel has good temperature sensitivity, self-healing, and injectable properties. In vitro results showed that the hydrogel could slowly and continuously release Microcin C7 with good biocompatibility and biodegradability, with a remarkable antibacterial effect on Porphyromonas gingivalis. It also confirmed the antibacterial and anti-inflammatory effects of Microcin C7-laden hydrogel in a periodontitis rat model. The results showed that Microcin C7-laden hydrogel is a promising candidate for local drug delivery systems in periodontitis.

Development of miR-26a-activated scaffold to promote healing of critical-sized bone defects through angiogenic and osteogenic mechanisms

AUTHORS

Author links open overlay panelJoanna M. Sadowska a 1, Monika Ziminska b 1, Cole Ferreira c 1, Austyn Matheson a, Auden Balouch c, Jasmine Bogle c, Samantha Wojda c, John Redmond d, Ahmed Elkashif b, Nicholas Dunne b d e f g, Helen O. McCarthy b, Seth Donahue c, Fergal J. O'Brien

ABSTRACT

Very large bone defects significantly diminish the vascular, blood, and nutrient supply to the injured site, reducing the bone's ability to self-regenerate and complicating treatment. Delivering nanomedicines from biomaterial scaffolds that induce host cells to produce bone-healing proteins is emerging as an appealing solution for treating these challenging defects. In this context, microRNA-26a mimics (miR-26a) are particularly interesting as they target the two most relevant processes in bone regeneration-angiogenesis and osteogenesis. However, the main limitation of microRNAs is their poor stability and issues with cytosolic delivery. Thus, utilising a collagen-nanohydroxyapatite (coll-nHA) scaffold in combination with cell-penetrating peptide (RALA) nanoparticles, we aimed to develop an effective system to deliver miR-26a nanoparticles to regenerate bone defects in vivo. The microRNA-26a complexed RALA nanoparticles, which showed the highest transfection efficiency, were incorporated into collagen-nanohydroxyapatite scaffolds and in vitro assessment demonstrated the miR-26a-activated scaffolds effectively transfected human mesenchymal stem cells (hMSCs) resulting in enhanced production of vascular endothelial growth factor, increased alkaline phosphatase activity, and greater mineralisation. After implantation in critical-sized rat calvarial defects, micro CT and histomorphological analysis revealed that the miR-26a-activated scaffolds improved bone repair in vivo, producing new bone of superior quality, which was highly mineralised and vascularised compared to a miR-free scaffold. This innovative combination of osteogenic collagen-nanohydroxyapatite scaffolds with multifunctional microRNA-26a complexed nanoparticles provides an effective carrier delivering nanoparticles locally with high efficacy and minimal off-target effects and demonstrates the potential of targeting osteogenic-angiogenic coupling using scaffold-based nanomedicine delivery as a new "off-the-shelf" product capable of healing complex bone injuries.

Injectable sericin based nanocomposite hydrogel for multi-modal imaging-guided immunomodulatory bone regeneration

AUTHORS

Li-Bo Jiang, Sheng-Long Ding, Wang Ding, Di-Han Su, Fang-Xue Zhang, Tai-Wei Zhang, Xiao-Fan Yin, Lan Xiao, Yu-Lin Li, Feng-Lai Yuan, Jian Dong

ABSTRACT

Irregular bone defects, where the inflammation and immune microenvironment confronted with implanted biomaterials, remain a prominent challenge for bone regeneration. In this study, we fabricated an injectable alginate/sericin/graphene oxide (Alg/Ser/GO) hydrogel based on the Alg–Tyramine framework with HRP/H2O2 enzymatic crosslinking. This hydrogel exhibited bioimaging property and controlled degradation behavior upon releasing sericin and GO. Importantly, synergistic effects on bone regeneration between sericin and GO were demonstrated. GO significantly enhanced the spreading, osteogenic differentiation, and mineralization of encapsulated rat BMSCs, whereas the released sericin promoted M2 polarization and migration via the NF-κB and MAPK pathways. The M2 polarization of macrophages induced osteogenic differentiation of BMSCs via several secreted cytokines. Both in vivo and in vitro experiments showed that the Alg/Ser/GO hydrogel induced macrophage infiltration into the surrounding tissues and inhibited inflammation and fibrous capsule thickening. Last, the injected Alg/Ser/GO hydrogels with BMSCs promptly repaired established distal femoral defects in rats. Therefore, the fabricated Alg/Ser/GO hydrogel, along with macrophages and BMSCs, is a promising biomaterial for bone healing, especially the irregular bone defects.

Flexible Osteogenic Glue as an All-In-One Solution to Assist Fracture Fixation and Healing

AUTHORS

Jincheng Tang, Kun Xi, Hao Chen, Lingjun Wang, Dongya Li, Yun Xu, Tianwen Xin, Liang Wu, Yidi Zhou, Jiang Bian, Zhengwei Cai, Huilin Yang, Lianfu Deng, Yong Gu, Wenguo Cui, Liang Chen

ABSTRACT

Osteogenic glue that reproduces the natural bone composition represents the final frontier of orthopedic adhesives with the potential to revolutionize surgical strategies against comminuted fractures. However, it is difficult to achieve an all-in-one formula, which could provide flexible and reliable adhesiveness while avoiding interfering with or even promoting the healing of glued fractures. Herein, an osteogenic glue characterized by inorganic-in-organic integration between amine-modified mesoporous bioactive glass nanoparticles (AMBGN) and bioadhesive gelatin-dextran network (GelDex) is introduced as an all-in-one tool to flexibly adhere and splice bone fragments and subsequently guide fracture healing during degradation. Relying on such integration, a 4-fold improvement in cohesiveness is presented, followed by a nearly 5-fold enhancement in adhesive strength in ex vivo porcine bone samples. The reversible and re-adjustable adhesiveness also enables glue to effectively splice intricate fragments from highly comminuted fractures in the rabbit radius in an in vivo environment. Moreover, well-preserved organic–inorganic integrity during degradation of the glue guides sustained interfacial osteogenesis and achieve satisfying healing outcomes in glued fractures, as observed by the 2-fold improvement in biomechanical and radiological performance compared with commercially available cyanoacrylate adhesives. The current findings propose an all-in-one solution for the fixation of bone fragments during surgery.

Bi-directional regulation functions of lanthanum-substituted layered double hydroxide nanohybrid scaffolds via activating...

AUTHORS

Min Chu, Zhenyu Sun, Zhanghao Fan, Degang Yu, Yuanqing Mao, Yaping Guo

ABSTRACT

Rationale: Osteoporotic patients suffer symptoms of excessive osteoclastogenesis and impaired osteogenesis, resulting in a great challenge to treat osteoporosis-related bone defects. Based on the positive effect of rare earth elements on bone metabolism and bone regeneration, we try to prove the hypothesis that the La3+ dopants in lanthanum-substituted MgAl layered double hydroxide (La-LDH) nanohybrid scaffolds simultaneously activate osteogenesis and inhibit osteoclastogenesis.

Methods: A freeze-drying technology was employed to construct La-LDH nanohybrid scaffolds. The in vitro osteogenic and anti-osteoclastogenic activities of La-LDH nanohybrid scaffolds were evaluated by using ovariectomized rat bone marrow stromal cells (rBMSCs-OVX) and bone marrow-derived macrophages (BMMs) as cell models. The in vivo bone regeneration ability of the scaffolds was investigated by using critical-size calvarial bone defect model of OVX rats.

Results: La-LDH nanohybrid scaffolds exhibited three-dimensional macroporous structure, and La-LDH nanoplates arranged perpendicularly on chitosan organic matrix. The La3+ dopants in the scaffolds promote proliferation and osteogenic differentiation of rBMSCs-OVX by activating Wnt/β-catenin pathway, leading to high expression of ALP, Runx-2, COL-1 and OCN genes. Moreover, La-LDH scaffolds significantly suppressed RANKL-induced osteoclastogenesis by inhibiting NF-κB signaling pathway. As compared with the scaffolds without La3+ dopants, La-LDH scaffolds provided more favourable microenvironment to induce new bone in-growth along macroporous channels.

Conclusion: La-LDH nanohybrid scaffolds possessed the bi-directional regulation functions on osteogenesis and osteoclastogenesis for osteoporotic bone regeneration. The modification of La3+ dopants in bone scaffolds provides a novel strategy for osteoporosis-related bone defect healing.

Three-dimensional-printed individualized porous implants: A new “implant-bone” interface fusion concept for large bone defect treatment

AUTHORS

Teng Zhang, Qingguang Wei, Hua Zhou, Zehao Jing, Xiaoguang Liu, Yufeng Zheng, Hong Cai, Feng Wei, Liang Jiang, Miao Yu, Yan Cheng, Daoyang Fan, Wenhao Zhou, Xinhong Lin, Huijie Leng, Jian Li, Xinyu Li, Caimei Wang, Yun Tian, Zhongjun Liu

ABSTRACT

Bone defect repairs are based on bone graft fusion or replacement. Current large bone defect treatments are inadequate and lack of reliable technology. Therefore, we aimed to investigate a simple technique using three-dimensional (3D)-printed individualized porous implants without any bone grafts, osteoinductive agents, or surface biofunctionalization to treat large bone defects, and systematically study its long-term therapeutic effects and osseointegration characteristics. Twenty-six patients with large bone defects caused by tumor, infection, or trauma received treatment with individualized porous implants; among them, three typical cases underwent a detailed study. Additionally, a large segmental femur defect sheep model was used to study the osseointegration characteristics. Immediate and long-term biomechanical stability was achieved, and the animal study revealed that the bone grew into the pores with gradual remodeling, resulting in a long-term mechanically stable implant-bone complex. Advantages of 3D-printed microporous implants for the repair of bone defects included 1) that the stabilization devices were immediately designed and constructed to achieve early postoperative mobility, and 2) that osseointegration between the host bone and implants was achieved without bone grafting. Our osseointegration method, in which the “implant-bone” interface fusion concept was used instead of “bone-bone” fusion, subverts the traditional idea of osseointegration.