Bone grafts have been predominated used to treat bone defects, delayed union or non-union, and spinal fusion in orthopaedic clinically for a period of time, despite the emergency of synthetic bone graft substitutes. Nevertheless, the integration of allogeneic grafts and synthetic substitutes with host bone was found jeopardized in long-term follow-up studies. Hence, the enhancement of osteointegration of these grafts and substitutes with host bone is considerably important. To address this problem, addition of various growth factors, such as bone morphogenetic proteins (BMPs), parathyroid hormone (PTH) and platelet rich plasma (PRP), into structural allografts and synthetic substitutes have been considered. Although clinical applications of these factors have exhibited good bone formation, their further application was limited due to high cost and potential adverse side effects. Alternatively, bioinorganic ions such as magnesium, strontium and zinc are considered as alternative of osteogenic biological factors. Hence, this paper aims to review the currently available bone grafts and bone substitutes as well as the biological and bio-inorganic factors for the treatments of bone defect.

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Ag/Ag@AgCl/ZnO hybrid nanostructures are embedded in a hydrogel by a simple two-step technique. The Ag/Ag@AgCl nanostructures are assembled in the hydrogel via ultraviolet light chemical reduction followed by incorporation of ZnO nanostructures by NaOH precipitation. The hydrogel accelerates wound healing and exhibits high antibacterial efficiency against both Escherichia coli and Staphylococcus aureus under visible light irradiation. The Ag/Ag@AgCl nanostructures enhance the photocatalytic and antibacterial activity of ZnO due to the enhancement of reactive oxygen species by visible light. This hydrogel system kills 95.95% of E. coli and 98.49% of S. aureus within 20 min upon exposure to simulated visible light, and rapid sterilization plays a crucial role in wound healing. In addition, this system provides controllable, sustained release of silver and zinc ions over a period of 21 days arising from the reversible swelling-shrinking transition of the hydrogel triggered by the changing pH value in the biological environment. About 90% Zn release is observed in the acidic environment after 3 days, whereas only 10% Zn release occurs in the neutral environment after 21 days. In vivo results show that release of Ag and Zn stimulates the immune function to produce a large number of white blood cells and neutrophils (2-4 times more than the control), thereby producing the synergistic antibacterial effects and accelerated wound healing.

Magnesium and its alloys may potentially be applied as degradable metallic materials in orthopaedic implantations due to their degradability and resemblance to human cortical bone. However, the high corrosion rate and accumulation of hydrogen gas upon degradation hinders its clinical application. In this study, we adopt a new approach to control the corrosion rate by coating a controllable polymeric membrane fabricated by polycaprolactone and dichloromethane onto magnesium alloys, in which the pore size was controlled during the manufacturing process. The addition of the polymeric membrane was found to reduce the degradation rate of magnesium, and the bulk mechanical properties were shown to be maintained upon degradation. The in-vitro studies indicated good cytocompatibility of eGFP and SaOS-2 osteoblasts with the polymer-coated samples, which was not observed for the uncoated samples. The in-vivo study indicated that the uncoated sample degraded more rapidly than that of the polymer-coated samples. Although new bone formation was found on both samples, as determined by Micro-CT, higher volumes of new bone were observed on the polymer-coated samples. Histological analysis indicated no inflammation, necrosis or hydrogen gas accumulation on either of the samples during degradation. Collectively, these data suggest that the use of polymeric membrane may be potentially applied for future clinical use.

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Bone-implant-associated infections are common after orthopedic surgery due to impaired host immune response around the implants. In particular, when a biofilm develops, the immune system and antibiotic treatment find it difficult to eradicate, which sometimes requires a second operation to replace the infected implants. Most strategies have been designed to prevent biofilms from forming on the surface of bone implants, but these strategies cannot eliminate the biofilm when it has been established in vivo. To address this issue, a nonsurgical, noninvasive treatment for biofilm infection must be developed. Herein, a red-phosphorus-IR780-arginine-glycine-aspartic-acid-cysteine coating on titanium bone implants is prepared. The red phosphorus has great biocompatibility and exhibits efficient photothermal ability. The temperature sensitivity of Staphylococcus aureus biofilm is enhanced in the presence of singlet oxygen ( O ) produced by IR780. Without damaging the normal tissue, the biofilm can be eradicated through a safe near-infrared (808 nm) photothermal therapy at 50 °C in vitro and in vivo. This approach reaches an antibacterial efficiency of 96.2% in vivo with 10 min of irradiation at 50 °C. Meanwhile, arginine-glycine-aspartic-acid-cysteine decorated on the surface of the implant can improve the cell adhesion, proliferation, and osteogenic differentiation.

Despite the development of advanced antibacterial materials, bacterial infection is still a serious problem for wound healing because it usually induces severe complications and cannot be eradicated completely. Most current materials cannot simultaneously provide antibacterial activity, reusability, and biocompatibility as well as participate in stimulating cell behaviors to promote bacteria-accompanied wound healing. This work fabricated a hybrid hydrogel embedded with two-dimensional (2D) few-layer black phosphorus nanosheets (BPs) via simple electrostatic interaction. Within 10 min, 98.90% Escherichia coli and 99.51% Staphylococcus aureus can be killed rapidly by this hybrid, due to its powerful ability to produce singlet oxygen (O) under simulated visible light. In addition, this hydrogel also shows a high repeatability; that is, the antibacterial efficacy can still reach up to 95.6 and 94.58% against E. coli and S. aureus, respectively, even after challenging bacteria up to four times repeatedly. In vitro and in vivo results reveal that BPs in this hybrid hydrogel can promote the formation of the fibrinogen at the early stages during the tissue reconstruction process for accelerated incrustation. In addition, BPs can also trigger phosphoinositide 3-kinase (PI3K), phosphorylation of protein kinase B (Akt), and extracellular signal-regulated kinase (ERK1/2) signaling pathways for enhanced cellular proliferation and differentiation. Moreover, the hydrogel causes no appreciable abnormalities or damage to major organs (heart, liver, spleen, lung, and kidney) in rats during the wound healing process. Therefore, this BP-based hydrogel will have great potential as a safe multimodal therapeutic system for active wound healing and sterilization.

Wound healing is affected by bacterial infection and related inflammation, cell proliferation and differentiation, and tissue remodeling. Current antibiotics therapy cannot promote wound healing and kill bacteria at the same time. Herein, hybrid nanosheets of g-C 3 N 4 -Zn 2+ @graphene oxide (SCN-Zn 2+ @GO) are prepared by combining Zn 2+ doped sheet-like g-C 3 N 4 with graphene oxide via electrostatic bonding and π-π stacking interactions to assist wound healing and kill bacteria simultaneously by short-time exposure to 660 and 808 nm light. The gene expressions of matrix metalloproteinase-2, type I collagen, type III collagen, and interleukin β in fibroblasts are regulated by GO and released Zn 2+ , which can accelerate wound healing. Co-irradiation produces an antibacterial ratio over 99.1% within a short time because of the synergistic effects of both photodynamic antibacterial and photothermal antibacterial treatments. The hyperthermia produced by 808 nm light illumination can weaken the bacterial activity. And these bacteria can be easily killed by membrane destruction, protein denaturation, and disruption of bacterial metabolic pathways due to reactive oxygen species produced under 660 nm light irradiation. This strategy of Zn 2+ and GO modification can increase the antibacterial efficacy of SCN and accelerate wound healing at the same time, which makes this SCN-Zn 2+ @GO be very promising in bacteria-infected wound healing therapy.