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Review

Recent Research on Hybrid Hydrogels for Infection Treatment and Bone Repair

by
Mengjiao Cao
1,†,
Chengcheng Liu
2,†,
Mengxin Li
1,
Xu Zhang
3,
Li Peng
4,
Lijia Liu
1,
Jinfeng Liao
3,* and
Jing Yang
1,*
1
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
2
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
3
State Key Laboratory of Oral Diseases, National Clinical Research Centre for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
4
Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Gels 2022, 8(5), 306; https://doi.org/10.3390/gels8050306
Submission received: 20 April 2022 / Revised: 10 May 2022 / Accepted: 12 May 2022 / Published: 16 May 2022
(This article belongs to the Special Issue Stimuli-Responsive Biomedical Hydrogels)
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Abstract

:
The repair of infected bone defects (IBDs) is still a great challenge in clinic. A successful treatment for IBDs should simultaneously resolve both infection control and bone defect repair. Hydrogels are water-swollen hydrophilic materials that maintain a distinct three-dimensional structure, helping load various antibacterial drugs and biomolecules. Hybrid hydrogels may potentially possess antibacterial ability and osteogenic activity. This review summarizes the recent progress of different kinds of antibacterial agents (including inorganic, organic, and natural) encapsulated in hydrogels. Several representative hydrogels of each category and their antibacterial mechanism and effect on bone repair are presented. Moreover, the advantages and disadvantages of antibacterial agent hybrid hydrogels are discussed. The challenge and future research directions are further prospected.

Graphical Abstract

1. Introduction

With the advancement of society, the occurrence of high-energy injury events and the use of internal implants increased, as did the number of trauma and postoperative bone infection patients [1]. Each year, over 2 million bone transplants are applied nationwide [2]. Bone tissue has a limited capacity for regeneration and healing. For complex fractures and bone defects, early external intervention is frequently needed for successful recovery [3]. Generally speaking, a “critical-sized” defect is one that does not receive adequate blood supply for the callous formation and does not recover spontaneously after surgical stabilization, requiring subsequent intervention [3,4]. Critical-sized bone defects, which are typically associated with high-energy injuries or pathological fractures, remain to be a substantial therapeutic problem and necessitate bone transplantation. The defects might vary in severity depending on the site of the damage [5].
An acute and well-controlled inflammatory response is elicited and beneficial to healing when a bone injury occurs. Once the response is inhibited, dysregulated, or becomes chronic, it could be harmful to the healing process [6,7,8]. Inflammation is a critical physiological activity for pathogen elimination and tissue homeostasis preservation. Infected bone defects (IBDs) are chronic diseases with a complex pathology that typically lasts long and has an uncertain prognosis [9]. The healing time varies affected by the location and size of the defects, as well as the severity of the infection [10,11]. IBDs are frequently caused by a combination of acute high-energy injuries and contamination. These types of acute bone infections can occasionally lead to osteomyelitis and chronic infection. Opening fractures, soft tissue or bone tissue loss, infection following internal fixation, and a bone tumor are common causes [11]. Acute bone infections are typically treated with routine systemic antibiotics. Chronic infections and osteomyelitis often necessitate surgical debridement of necrotic tissues in combination with local antibiotic therapy [12].
Efficient elimination of inflammatory stimulants and the release of anti-inflammatory and reparative cytokines are required to treat infected diseases and restore tissue homeostasis [13]. However, the sequence of events can be changed by the presence of a pro-inflammatory stimulus, and the condition may turn to chronic inflammation. Immune cells, particularly macrophages, are important in regulating inflammation. Research on the interconnection between the immune system and bone metabolism led to the term “osteoimmunology” being coined to describe this new field [14]. The presence of both hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) in bone marrow emphasizes the strong connection between these two systems [15]. Bone-resorbing osteoclasts and immunomodulatory macrophages originate from HSCs, and bone-forming osteoblasts develop from MSCs [16]. Because of the shared origin of cytokines, receptors, signaling molecules, and transcription factors, osteoblasts and bone-resorbing osteoclasts of a monocyte/macrophage cell regulate one another [17,18].
Because of bacterial colonization and osteonecrosis, clinical treatment of IBDs has always been complex [19,20]. Surgical treatment of the infected bone frequently results in significant disabling defects. The implantation of bone grafting materials and antibiotic therapy are common treatment modalities for IBDs in clinic [21]. The presence of bacteria in infected bone and surrounding tissues can cause the release of inflammatory and tissue destructive mediators, interfering with osteogenesis [22]. One of the most difficult challenges in modern orthopedics is to eliminate bacterial infection and provide a biocompatible microenvironment for bone repair in bone defects. Because of the inadequate local blood supply, antibiotics in high concentrations are needed in the area of infection. However, conventional routes of drug administration are challenging to achieve excellent antibiotic effects and exacerbate serious side effects [23].
Bone grafts used to treat IBDs should act as osteoinductive bone substitutes and antimicrobial carriers [12]. Autologous bone, also known as autograft, is still regarded as the clinical “gold standard” for bone repair. However, there are several limitations to autogenous grafting associated with the harvesting process. The shortcomings include morbidity of the donor site, increased blood loss, and longer operating times [24]. Furthermore, the allograft is a limited supply of autologous bone substitutes because of the high expenses and dangers of viral transmission [24,25,26]. Fortunately, bone substitutes or synthetic grafts are intended to overcome the drawbacks of autologous and allogeneic bone grafts. When used to restore contaminated bone tissue, bone grafts should ideally inhibit local bacterial growth. Simultaneously, it should stimulate cellular infiltration and immunomodulatory effects in host reparative cells [27,28].
Fabrication of biomedical materials with good antimicrobial and osteogenic activities is critical for promoting the repair effects of bone substitutes on IBDs [29]. Several common materials have been extensively used in bone tissue engineering, including nanofibrous materials, coatings, and hydrogels [30]. In particular, hydrogels have porous network structures and good biocompatibility to mimic the extracellular matrix (ECM) [31]. As a distinct class of soft materials, hydrogels are composed of hydrophilic networks that can maintain moisture. Hydrogel is a suitable candidate to be used as carrier materials for cells or bone growth to facilitate growth factors released and can be easily loaded with antibacterial agents [32]. Hydrogels can be fabricated from polymer chains connected by physical interactions or chemical bonds, and varying crosslinking methods and degrees can easily control the degradation rate, porosity, or release profile [33]. Additionally, hydrogels can self-assemble with self-complementary amphiphilic peptides by gelation. Furthermore, they can be tailored to meet the optimum geometry for implantation or injection [34]. Hydrogels are appealing therapeutic delivery materials, presenting the great potential to encapsulate agents in the water-swollen network [35]. Additionally, some types of hydrogels have inherent antibacterial properties, such as chitosan (CS) and polyethyleneimine (PEI) [32,36,37]. So hydrogels are scaffolds that have been widely researched as a potential alternative material for antibacterial tissue engineering.
Antibacterial agents can be classified into three types: inorganic antibacterial agents, organic antibacterial agents, and natural antibacterial agents based on their composition, source, and nature. Additionally, each type is sorted into different categories, as summarized in Figure 1.
Antibacterial agents administered systemically have a lot of drawbacks, such as low concentrations in the infected area and side effects. In comparison, local delivery of antimicrobial agents may offer appropriate antibacterial dosages [38]. Sustainable local delivery of antibacterial agents via a delivery carrier avoids many disadvantages of systemic side effects. Due to the excellent water content, great bioactivity, and convenience of drug-loading, hydrogels have been extensively researched as drug carriers for targeted delivery [39]. Antibacterial agents can be used in conjunction with hydrogels to slow down the kinetics of drug release and deliver the medication to the target site. Moreover, the hydrogels’ degradation rate can also be controlled, providing this material system the characteristics of a prolonged-release cycle and reducing administration dosage [40,41]. Therefore, hydrogels can encapsulate agents or agent-loaded nano-/microcarriers to provide sustained localized antimicrobial drug release for excellent antibacterial and bone repair performance [42]. This review will focus on recent research on antibacterial hydrogel systems in infected bone regeneration. The features of hybrid hydrogels in antibacterial mechanism and their effect on bone repair will be systemically presented.

2. Hybrid Hydrogels with Inorganic Antibacterial Agents for Infected Bone Repair

Inorganic antibacterial agents are classified based on their modes of action: metal ion elements (e.g., silver (Ag), gold (Au), copper (Cu), zinc (Zn)), and inorganic light-mediated antibacterial materials (e.g., reduced graphene oxide (rGO), carbon-based nanomaterial, titanium dioxide (TiO2), zinc oxide (ZnO) [43]. Light-mediated antibacterial activity can be achieved through photothermal therapy (PTT), photodynamic therapy (PDT), and sunlight-mediated antibacterial treatments [44]. There are few studies on sunlight-activated nanomaterials to date, so this review will focus on the PTT and PDT related inorganic light-mediated antibacterial agents.

2.1. Hydrogels with Metal Nanomaterials

The antibacterial action of nanoparticles is achieved in a number of ways. Several factors, such as the released metal ions and the physicochemical characterization of nanoparticles, may lead to membrane disruption or cell wall penetration, which can contribute to nanoparticles’ antibacterial activity [45,46]. It has been shown that metallic nanoparticles (as in silver, gold, copper, and titanium) have significant antibacterial activity [47,48,49]. The mechanisms of inorganic antibacterial agents of several metal ions are illustrated in Figure 2.
Among the several metal nanomaterials applied in antibacterial therapy, silver nanoparticles (AgNPs) are the most extensively investigated antibacterial nanoagent with a broad antibacterial spectrum [51,52]. AgNPs are typically assumed to perform antibacterially by attaching to the cell wall and membrane, and then destroying the structures and biomolecules within the cell with AgNPs and silver ions [53,54,55]. At the same time, AgNPs can promote bone formation and accelerate the rehabilitation of injured tissues. Mahmood M et al. demonstrated that AgNPs could regulate many osteogenic genes related to bone growth [56]. Han et al. described a method to synthesize AgNPs-loaded hydrogels using gelatin (Gel) as a stabilizing agent in a simple way under sunlight, which improved the survivability and proliferation of osteoblasts on the hydrogels for bone fracture treatment [57].
Gold nanoparticles (GNPs) are also gaining immense attention since their antimicrobial activity has been reported [58]. After intracellular uptake, GNPs have been demonstrated to stimulate osteogenic differentiation and mineralization in cells [59,60]. For example, Zhang et al. prepared PEG-hydrogels with GNPs of 4 nm, 18 nm, and 45 nm in size. The results indicated that hydrogels containing GNPs of 45 nm could efficiently induce bone regeneration in vivo by increasing the osteogenic gene expression, mineralization, and alkaline phosphatase (ALP) activity [61]. In another case, Lee D et al. designed a hydrogel that tyramine (Ty) bound with the Gel backbone (Gel-Ty) containing GNPs attached to N-acetyl cysteine (NAC) (Gel-Ty/G-NAC) for effective bone regeneration [62]. Furthermore, GNPs can be utilized for PTT to treat tumors when exposed to near-infrared light [63]. In addition, copper nanoparticles show excellent antibacterial ability for both Gram-positive bacteria (GPB) and Gram-negative bacteria (GNB) [64]. For example, Dai Q et al. fabricated a unique 3D-printed Ty-modified Gel/silk fibroin (SF)/copper (Cu)-doped bioactive glass (BG) hydrogel [65]. The hydrogel with 1 wt% Cu-BG can effectively modulate osteogenesis and vascularization’s spatiotemporal coupling.
Like antibiotics, prolonged usage of AgNPs results in the development of multidrug-resistant microorganisms [66]. Unfortunately, inorganic nanoparticles are difficult to biodegrade in vivo. So the toxicity of inorganic nanoparticles should be reduced by surface modification.

2.2. Light-Mediated Inorganic Antibacterial Hydrogels

In comparison to traditional antibiotics, PTT would not induce bacterial resistance [67]. Aside from metal NPs, various photothermal agents (PTAs) have been successfully used in the antimicrobial field. PTAs can convert light into heat, resulting in rupture of the cell membrane, protein denaturation, and microbial death [68]. PTT has demonstrated significant promise in antibacterial and bone regeneration treatment due to the rapid development of different PTAs. The inorganic nanomaterials with PPT abilities include metal nanomaterials (Au, Pt), carbon-based nanomaterials (graphene, fullerene, rGO), black phosphorus (BP), and other metal oxide nanoparticles [44,69,70]. Unlike PTT, PDT generates reactive oxygen species (ROS) to generate cytotoxicity. Three elements are required for PDT: light, molecular oxygen, and photosensitizers (PSs). When the PSs are irradiated with light whose wavelength meets the PSs’ absorption, singlet oxygen (1O2), hydroxyl radicals, or oxygen-free radicals can be produced. These radicals can destroy cell membranes and DNA molecules [71].
Nanoparticles with photothermal and photodynamic ability have recently received much attention as a potential treatment for bacterial infections and bone healing. Geng et al. developed a multifunctional biodegradable gelatin/methacrylate anhydride (GelMA) hydrogel by controlling the surface charge and preventing the positive- and negative- charged carbon quantum dots (CQD)from aggregating [72]. They deposited positively charged carbon quantum dots (p-CQDs) on the surface of tungsten disulfide (WS2) nanosheets. Additionally, Geng et al. incorporated (p-CQDs)/WS2 with antimicrobial effects and negatively charged CQDs (n-CQDs) with bone induction ability in GelMA hydrogels. Not only can the hydrogels effectively kill multidrug-resistant bacteria (MDR), but they also considerably accelerate bone regeneration. Graphene, a typical carbon-based nanomaterial, has been extensively investigated for its ability to stimulate bone formation through interaction with osteoprogenitors and other skeletal progenitors. rGO is the product of treating graphene oxide (GO) under thermal, chemical, or UV [73]. In addition to improving mechanical properties, graphene family materials uniformly dispersed into polymers to produce materials can also promote cell proliferation and differentiation, hence facilitating bone regeneration [74]. Wang et al. fabricated the NIR light-responsive, rGO-loaded CS hydrogel films by electrodeposition [75]. The histological and radiological examination revealed that the films promoted bone regeneration in calvarial defect osteoporotic models. Li et al. developed hybrid hydrogels containing gelatin methacrylate, β-cyclodextrin-modified rGO, and acryloyl-β-cyclodextrin for infected skull defects [76]. These hydrogels exhibited ideal antibacterial photothermal properties, as well as unswelling and mechanical properties.
The difficult biodegradation of GO limits its biomedical applications, particularly in vivo [77]. Conversely, BP can degrade in aqueous conditions, generating harmless phosphates and phosphonates that promote biomineralization and regulate osteogenesis [78,79]. As a recently emerged 2D nanomaterial, BP has stimulated widespread research interest. For example, Miao et al. reported that the BP/Gel hydrogel could promote osteogenesis in vitro without osteoinductive factors. In the Sprague Dawley rat model, they also found considerable newborn cranial bone tissue growth [80].
The human body is capable of withstanding high heat for a brief period of time, but normal cells in the surrounding area could be damaged [81,82]. The NIR light frequently employed for PTT therapy has a limited penetration depth [83]. In comparison to NIR-I light (650–1000 nm), the NIR-II window (1000–1700 nm) exhibits a greater penetration depth in tissue and lower energy attenuation [84,85]. Additionally, the combination of PDT and PTT can significantly enhance the antibacterial efficiency of phototherapy. As shown in Figure 3, Zhang et al. designed a NIR-II phototherapy system using ytterbium (Yb), erbium (Er), and holmium(Ho) co-doped TiO2 nanorods (TiO2 NRs) (TiO2:FYH)/curcumin (Cur)/hyaluronic acid (HA)/bone morphogenetic protein-2 (BMP-2) [86]. It had antibiofilm, anti-inflammatory, and osteogenic capabilities in vitro and in vivo. The temperature increased to 47 °C when the 1060 nm laser was used, which was higher by about 7.2 °C than that of the 808 nm laser in the rabbit femur. Furthermore, the system exhibited great antibiofilm capability in the rabbit femur when irradiated with a 1060 nm laser, while numerous microorganisms lived when irradiated with an 808 nm laser. Then, on a titanium bone implant, they constructed a NIR-II-triggered nano-platform made of Yb and Er-doped TiO2 nano-shovel (TiO2@UCN)/quercetin (Qr)/L-arginine (LA) [87]. When irradiated with a 1060 nm laser, the nanoplatform can eradicate biofilms on the titanium implants at 45 °C. Furthermore, the nano-platform enhanced revascularization and osteogenic differentiation, reduced inflammation, and promoted the generation of bone structures.
High temperatures and 1O2 from the phototherapy could easily destroy adjacent tissues, such as the periosteum and blood vessels [88]. PSs can also be developed to be activated by enzyme-mediated luminescence techniques in addition to external sources of excitation, allowing them to address depth constraints [89]. Developing near-infrared light-triggered nanomaterials with extremely prolonged luminescence lifetimes, allowing for continuous activation of PSs for phototherapy, may provide another way to avoid external light irradiation [70].

3. Hybrid Hydrogels with Organic Antibacterial Agents for Infected Bone Repair

Organic antibacterial agents including glutaraldehyde, quaternary ammonium salt compounds, and chlorhexidine (CHX), have been extensively studied [90,91,92]. Metal-organic frameworks (MOFs) are effective against bacteria. MOFs usually refer to composites with a network structure by the self-assembly of metal ions and organic ligands. In comparison to traditional bactericidal materials, MOFs exhibit larger specific surface areas, more adjustable pore structures, and controllable ion release rates. As a result, MOFs have a promising future in infected bone regeneration [93]. In addition to the inorganic photothermal materials mentioned above, organic photothermal agents have received much attention in recent years.

3.1. Hybrid Hydrogels with Organic Antibacterial Agents

Most inorganic antibacterial agents appear in the form of metal ions to kill GNB, whereas GPB are sensitive to organic antibacterial compounds via organelle modification and disruption of metabolic processes [50]. There are many organic antibacterial agents, such as CHX, organic acids, phenols, and quaternary ammonium compounds [94,95].
Quaternary ammonium salts (QAS) are important synthetic organic antimicrobials with a broad antimicrobial spectrum. QASs’ hydrophobic and ionic interactions with biological membranes damage microorganisms’ barriers [96,97]. For example, Lin et al. used quaternary ammonium chitosan (QTS) as a liquid phase in conjunction with calcium silicate (CaSi) powder to form cement [98]. When considering the osteogenic capacity, the antibacterial ability, and the setting time, the results revealed that CaSi cement with1% QTS might be a promising choice for bone regeneration.
Like QAS, CHX is commonly applied by healthcare personnel for general disinfection and hand hygiene [99]. CHX is a broad-spectrum antimicrobial material that inhibits the formation of biofilms and GPB/GNB growth, particularly against E. faecalis [100]. The antibacterial effect of CHX is mediated by the cation’s electrostatic interaction with the negatively charged portions of the bacterial surface, interfering with physiological activities and osmotic regulation in bacteria [101]. Xu L et al. developed a novel injectable hydrogel composed of nanohydroxyapatite particles and CHX (nHA/CHX) loaded in gellan gum (GG), which has the potential to enhance the repair of IBDs [102]. Bacteria counts were considerably lower in the surrounding bone tissue of rats treated with surgical debridement and GG/nHA/CHX transplantation than in the control group. Additionally, at 4 and 8 weeks, rats in the hydrogel group demonstrated considerably abundant new bone formation compared to the control group.
The antibacterial actions of the various organic antibacterial agents encompass a variety of distinct methods, including breaking down cell membranes or oxidizing the proteins and amino acids inside bacteria [103]. However, organic antimicrobials have some limitations in biodegradability, stability, and lifetimes [104]. For overcoming these problems, MOFs may be the solution.

3.2. Hybrid Hydrogels with Metal-Organic Frameworks

Due to the rapid rate of evolution of bacteria, the resistance of bacteria to many organic antimicrobial agents is increasing, which is an urgent problem in the healthcare system [105]. MOFs have attracted substantial attention recently as an innovative and fast-evolving group of organic-inorganic hybrid materials [106]. The majority of MOFs display antimicrobial properties by decomposing metal-ligand bonds and releasing ligands or metal ions into the bacteria. Additionally, they can be used as medication carriers through the adsorption or binding of medicines to their surfaces [107,108]. Various metal ions have been shown to have different effects on osteogenesis and bone mineralization, and their mechanisms of action have also been investigated. As a result, it was established that MOFs enhance osteogenic differentiation in vitro. In vivo studies were less common, which means that the application of MOFs for orthopaedic implants is just starting to be investigated [109].
As an essential member of MOFs, zeolitic imidazolate frameworks-8 (ZIF-8) is a monocrystal constructed of Zn2+ that connects to each other [110]. Recently, Zhang’s study generated antibacterial ZIF-8 using the diethanolamine template and solvent techniques [111]. The ZIF-8 synthesized in these two techniques exhibits remarkable antibacterial activity and is biocompatible at low concentrations. Taking advantage of its prolonged release of Zn2+, which is essential in bone regeneration, revascularization, and antimicrobial activities, ZIF-8 has the promise to be applied as a modification material in bone tissue engineering. When applied to rat bone marrow stromal cells (rBMSCs), ZIF-8 activated the extracellular-signal-regulated kinase (ERK) pathway primarily, and eventually activated the classical mitogen-activated protein kinase (MAPK) signaling and promoted osteogenesis. [112]. For example, Liu et al. designed ZIF-8 nanoparticles (ZIF-8 NPs) functionalized catechol-chitosan (CA-CS) hydrogels (CA-CS/Z) to guarantee adequate blood supply, maintain the stabilization of the bone transplant environment, enhance osteogenesis, and promote bone regeneration (Figure 4) [113]. The hydrogel demonstrated satisfactory adhesion and antimicrobial activities. ZIF-8 discharged from hydrogels may also increase the release and formation of osteocalcin, collagen I, and ALP, hence enhancing rBMSCs’ osteogenic differentiation.
Nonetheless, excessive metal ions produced by MOFs may be toxic to human cells [51,114]. Numerous institutions are researching ways to improve the stability of metal ions as a solution to this issue. Zheng et al. fabricated a nanoplate with a gallic-acid-magnesium-based MOFs (Mg-MOF) core and a biodegradable calcium phosphate (CaP) shell [115]. With the shell in place, the core was less susceptible to degradation, and the bioactive components contained within were more likely to reach a prolonged release under low-pH conditions stimulated by cytokine interleukin-4 (IL4). Then, IL4-MOF@CaP was integrated into collagen (Col) to create a biodegradable scaffold with significant bone regeneration. In addition to being composed of metal ions with antibacterial properties to exert antibacterial effects, MOFs can be loaded with various antibacterial agents as carriers [116]. For instance, Huang et al. successfully constructed an intelligent and long-lasting agent carrier of MOFs(HKUST-1)@carboxymethyl chitosan (HKUST-1@CMCS) [117]. These results indicated that dimethyl fumarate-loaded carrier had enhanced and long-lasting antibacterial action.

3.3. Light-Mediated Organic Antibacterial Hydrogels

Organic photothermal agents are categorized into two types: organic nanoparticles (such as porphyrin–lipid conjugate porphysome and organic semiconducting polymer nanoparticles) and organic dye molecules (such as indocyanine green (ICG), IR820, IR780) [70,118,119]. These photothermal conversion materials are biodegradable but easily photodegradable or photobleached [120].
Kuang et al. developed an injectable multifunctional hydrogel for NIR-triggered release for bone regeneration. This hydrogel consisted of poly (dimethylaminoethyl methacrylate-co-2-hydroxyethyl methacrylate)-coordinated situ-generated CaP nanoparticle (ICPN) (poly (DMAEMA-co-HEMA)/ICPN) (DHCP) hydrogel loaded with poly (N-acryloyl glycinamide-co-acrylamide) (PNAm)-ICG- parathyroid hormone (PTH) microspheres (PIP MSs) [121]. Through the photothermal activity of ICG and the thermal polymerization of PNAm, the temperature was rapidly raised, so that PTH can be released accurately and controlled. The injectable NIR (808nm)-light-responsive hydrogel may stimulate osteoblast and osteoclast activity simultaneously and repair cranial defects successfully.
Additionally, served as PTAs, Polydopamine (PDA) exhibits excellent photothermal conversion and adhesion abilities [121,122]. Luo et al. combined immobilized cisplatin with PDA-modified nano-hydroxyapatite (HA) in an injectable hydrogel composed of oxidized sodium alginate and CS. In animals, the hydrogel had photothermal anticancer effects and facilitated the growth of new bone structures [123]. Yao et al. prepared HA, PDA, and carboxymethyl chitosan (CMCS) composite scaffolds [124]. In vitro, the scaffolds with PDA may stimulate higher BMSCs’ osteogenic differentiation than scaffolds lacking PDA. Additionally, the effect of the photothermal process on the osteogenic differentiation was not affected.
The disadvantage of organic photothermic agents is their susceptibility to photobleaching. Not only are conventional organic NIR-absorbing compounds difficult to synthesize, but they are also prone to photobleaching when exposed to light. These disadvantages result in increased costs and the possibility of performance degradation in PTT. Organic photothermal agents must therefore be modified or packaged to maintain their photothermal capabilities [125].

4. Hybrid Hydrogels with Natural Antibacterial Agents for Bone Defect Repair

Natural antibacterial agents can be classified according to their sources, including microorganism origin (antibiotics such as vancomycin [126], Aspergillomarasmine A [127]), plant origin (curcumin (Cur) [128], quercetin [91]), and animal origin (antimicrobial peptides (AMPs) [129]). As a matter of fact, the majority of antibiotics currently used or under investigation are produced from secondary metabolites extracted from microbial pathogens, including gentamicin, penicillin, erythromycin, and chloramphenicol [130]. Plant extracts are diverse in composition because even from the same plant, numerous extracts with varying compositions can be prepared by altering the extraction conditions. Due to the inherent activity of natural antibiotics, the extracts of lysozymes, AMPs, and antimicrobial proteins from natural substances are a crucial focus of animal origin antimicrobial agent development [131]. AMPs, which are also called host defense peptides (HDPs), are found in all living animals. They are essential parts of the innate immune system’s response to pathogens [132,133]. In vivo, AMPs have the primary biological function of eliminating harmful microbes such as GPB and GNB, fungi, and viruses [134]. Aside from their antibacterial effect, it has also been shown that AMPs are essential in intracellular processes such as angiogenesis, inflammation, and cell signaling, making them potential candidates for creating new medications [135].

4.1. Hybrid Hydrogels with Microorganism Origin Natural Antibacterial Agents

Antibiotics are antibacterial organic compounds derived from natural microorganisms or synthesized in the laboratory. Antibiotics are the most frequently prescribed treatments in hospitals and clinics for bacterial illnesses. Both in therapy and prevention, they are frequently employed in clinical care. Antibiotics have a wide range of antibacterial mechanisms at their disposal. Aside from affecting cell walls and proteins, they can also harm DNA replication and disrupt metabolic processes [136]. Traditionally, broad-spectrum antibiotics are applied systemically to treat bone infections. Antibiotics such as gentamicin and vancomycin are commonly utilized in clinic to treat IBDs [137,138].
Internal encapsulation/physical entrapment through the hydrogels is a strategy for achieving prolonged, localized antibiotic release, hence minimizing systemic adverse effects of antibiotic treatment [139]. This is particularly critical for managing osteomyelitis, which often requires prolonged courses of antibiotics at high doses. Some antibiotics affect osteogenic activities in vitro. According to recent research, a low dose of doxycycline can promote osteogenic differentiation during the initial stages of the procedure [140]. Park JB. et al. showed that increasing tetracycline levels could result in a dose-dependent inhibition in osteogenesis and cell differentiation [141]. A co-delivery system can be built to deliver antibacterial and osteoinductive medicines concurrently or sequentially. Jung et al. fabricated an alginates (ALG)/hyaluronic acid (HA) hydrogel that gelled in situ and comprised BMP-2 and vancomycin [142]. The hydrogel successfully inhibited bacteria proliferation of osteomyelitis and promoted bone repair without the use of supplemental bone transplants. Additionally, the femur treated with the hydrogel regenerated bone more densely compared to the other groups. Only checking the influence of antibiotics on osteogenic activities is insufficient for antibiotics with osteogenic and antibacterial capabilities. The impact of their different concentrations on osteogenesis activity should also be investigated. Liu et al. composited calcium phosphate bone cement (CPC) with gelatin–alginate hydrogels impregnated with gentamicin (GS) in various ratios of 0, 12.5, 25, and 50 vol% [143]. As a result of the findings, the C/0.5-GS complex had the most excellent antibacterial effect and was non-cytotoxic. However, it decreased cell mineralization. The result indicated that high levels of GS in CPC inhibited the capacity of ALP. As a result, C/0.25-GS could be chosen as the best composite due to its adequate strength, steady and sustainable antibiotic release ability, antibacterial activity, and bio-reactivity. An ideal balance between growth factor and drug is necessary for bone formation because high antibiotic doses may hinder osteoblastic differentiation [144].
Antibiotic-resistant bacteria have been increasingly prevalent during the last few decades [145]. Antibiotic therapy is frequently ineffective in osteomyelitis as a result of impaired local vasculature [146]. Furthermore, antibiotics have been proven to be harmful to mammalian cells, resulting in mitochondrial malfunction [147]. The high occurrence of severe bone infections and the increasing risk that antibiotics may become less effective necessitates the development of non-antibiotic-based treatments to replace antibiotics.

4.2. Hybrid Hydrogels with Plant Origin Natural Antibacterial Agents

As a result of the excellent biocompatibility and biodegradability, natural antibacterial agents are the first antibacterial agents utilized by humans. They are derived from certain animals and plants with antibacterial activity [90].
Curcumin is a polyphenolic organic molecule derived from turmeric [148]. A series of studies revealed that Cur had antibacterial and anti-inflammation activities [128,149], enhanced osteoblasts’ proliferation, and induced osteogenesis-related gene expressions [150,151]. Various investigations have demonstrated that curcumin possesses broad-spectrum antibacterial properties as well as significant biological activity against both GPB and GNB [152]. The antimicrobial mechanistic methods of curcumin typically entail interfering with cellular division as well as the stimulation of the temperature-sensitive protein-filamenting mutant Z. (FtsZ) [153]. The FtsZ protein is related to cell replication in microorganisms, and it is the first protein to appear at sites about to divide [154]. Curcumin is a photosensitizer with phototoxicity that has been shown to have bactericidal effects on various bacteria when exposed to blue light [155,156,157]. Moreover, investigations have demonstrated that methoxy and hydroxyl of Cur are directly related to its antibacterial properties [158]. Unfortunately, it is challenging to combine hydrophobic curcumin with hydrophilic hydrogels. The low solubility and bioavailability restrict the use of curcumin in clinic. So far, many efforts have been made to encapsulate curcumin. Through the use of photocuring and ethanol treatment, Yu et al. were able to develop Cur-loaded CS nanoparticles (CCNP) in SF/hyaluronic acid esterified by methacrylate (HAMA) hydrogel (CCNPs-SF/HAMA) [159]. In vitro study revealed that the hydrogel showed anti-cancer properties while also enhancing osteoblast growth when the concentration of Cur was 150 g/mL. Virk et al. used an electrophoretic deposition technique to create a multilayer coating containing CS and Cur to give orthopedic implants biological and antibacterial abilities. Both characteristics indicate the prospects of the novel material for bone regeneration [160].
Similar to curcumin derived from plants, cannabidiol (CBD) is an ingredient obtained from the Cannabis sativa with anti-inflammatory, antibacterial activity, and the ability of regulating bone metabolism [161,162,163]. CBD has also been found to enhance the migration of MSCs by activating the P42/44 MAPK signaling pathway and subsequently differentiating into osteoblasts [164]. Qi et al. developed a Cu-alginate hydrogel containing CBD (SA@Cu/CBD) for bone regeneration [165]. The hydrogel was antimicrobial and suppressed the inflammatory response while also promoting osteoblast differentiation and exhibiting angiogenic properties.

4.3. Hybrid Hydrogels with Animal Origin Natural Antibacterial Agents

AMPs have broad-spectrum antibacterial activity by cationic and hydrophobic residues [166,167]. Various mammalian cells synthesize AMPs such as defensins, cathelicidins, and histatins [168]. The antimicrobial properties of AMPs were widely believed to be based on their capacity to disrupt membranes via the amphipathic scaffold [169]. AMPs derived from small amino acids would rarely deposit in the human body and could be promptly eliminated from the body [170].
Previous studies demonstrated that AMPs have negligible induction of bacterial resistance. Thus, they can be used to limit microbial contamination in biomedical implants by delivering locally [171]. AMPs cooperated with an appropriate scaffold material to promote bone repair is one of the effective methods in the treatment of IBDs. Yang et al. synthesized a self-assembling hydrogel that RADA16 loaded with AMPs, and the RADA16-AMP had a significant impact on bone growth [172]. Cheng et al. formed a gelatin-based hydrogel containing catechol motifs [173]. Additionally, then, the hydrogel composition was backed with a short cationic antimicrobial peptide (HHC-36) and synthetic silicate nanoparticles (SNs). The hydrogel showed unique features, including strong adhesion, antibacterial activity, and promoting osteogenesis. Sani et al. reported a hydrogel made of gelatin and AMPs that was triggered by visible light [174]. The GelAMP demonstrated excellent antibacterial properties against Porphyromonas gingivalis and promoted bone regeneration in mice.
Some antimicrobial peptides also have an effect on osteogenesis. Due to its broad-spectrum antibacterial activity and multiple bio-functions, particularly osteogenic stimulation, antimicrobial peptides LL37 are regarded as a promising option for bone tissue engineering [175]. LL37 can enhance proliferation, migration, and osteogenic differentiation of MSCs and block bone resorption [176]. Liu et al. fabricated a scaffold for subchondral bone regeneration utilizing LL37-modified layered double hydroxide/CS (LL37@LC) [177]. The study demonstrated that the scaffold might differentiate MSCs into osteoblasts and promote vasculogenesis. Although natural antibacterial agents have a wide range of sources and excellent biodegradable ability, they do have some drawbacks, including insufficient antimicrobial activities or unstable antimicrobial activities.

5. Hydrogels with the Inherent Antibacterial Ability for Bone Defect Repair

Besides the antimicrobial agents, the carrier materials (hydrogels) also have antibacterial activity. CS is a natural biopolymer that resembles hyaluronic acid in structure, which has the inherent antibacterial ability and can disrupt cytomembrane structure, cellular energy metabolism, and protein synthesis [174,178,179]. According to the findings of this study, CS promoted the expression of calcium-binding and mineralization genes, including osteocalcin, osteonectin, osteopontin, and collagen type I alpha 1 (COL1A1) [180]. Typically, CS is frequently mixed with osteogenic agents to form hybrid composites suitable for orthopedic biomedical implants, such as RGD ligand [181]. RGD-modified CS decreased the adhesion of S. epidermidis and S. aureus by 85% and 67%, respectively. Additionally, it promoted the expression of osteogenic markers. Hydroxypropyltrimethyl ammonium chloride chitosan (HACC), a new water-soluble CS derivative, has a broad-spectrum antibacterial activity and has been effectively utilized in bone regeneration as an antibacterial agent. Wang et al. developed the HACC/BMP2-BioCaP complex, which was capable of quickly releasing HACC, accompanied by a sustained release of BMP-2 in critical-sized IBDs [12]. Huang et al. used a photo-crosslinking approach to incorporate hydroxyapatite (HAp)@PDA-F nanoparticles with the quaternized and methacrylated CS (CS/HAp@PDA-F) [182]. The hydrogel system preserved osteogenic differentiation potency and provided an excellent antibacterial activity.
Some chitosan-based composites have been modified to improve their mechanical qualities and antibacterial activity, such as grafting PEI onto chitosan, grafting chitosan onto PEI, or creating a chitosan-PEI composite [183]. PEI includes a 1:2:1 ratio of primary, secondary, and tertiary amino groups. It is known that PEI can improve the bactericidal efficacy of both hydrophilic and hydrophobic antibacterial agents, and it is also a frequently used microbicidal component in its own right in microbiology [184]. They possess permeabilizing properties and are capable of damaging the membranes of bacteria [185,186]. Li et al. reported a self-healing bioactive antibacterial nanocomposite hydrogel based on crosslinking poly polyacrylate/aldehyde-hyaluronic acid (AHA)/PEI/bioactive glass nanoparticles (BGN) (PAPB) in a triple-network configuration. The hydrogel showed favorable biomineralization activity, which facilitated the reconstitution of skull defects (Figure 5) [187].

6. Summary and Challenges

To prevent the bone substitutes from being infected during repair, osteoconductive scaffolds that maintain the release of antibacterial agents over the 4 to 6 week duration for complete vascularization are necessary [188]. As a result, there is an immediate requirement for the development of bone-implant materials that provide long-lasting antibacterial activity and stimulate bone repair [189]. The present review summarizes the current development of the hybrid hydrogel with inorganic, organic, and natural antibacterial agents. Table 1 summarizes the advantages and disadvantages of different antibacterial agent hybrid hydrogels. Although adding antibiotics to hydrogel can enhance the antibacterial properties of materials and increase the speed of bone repair, insufficient long-lasting antimicrobial capability and insufficient osteogenesis properties result in unsatisfactory tissue regeneration [189]. Antibiotics and antibacterial metals, such as Ag, Cu, and Au, have already been implemented into hydrogels to treat and prevent bone infection. However, the risk of antibiotic resistance and tissue toxicity from metal ion release may limit their clinical use [190,191]. Light-mediated antibacterial agents offer a solution to the problem of bacterial resistance and tissue toxicity through their unique antibacterial mechanism.
Recent research indicates that PTT or PDT can promote the proliferation of cells and osteogenesis differentiation, and some nanomaterials possess intrinsic or light-triggered bactericidal properties. Furthermore, the photothermal treatment kills microorganisms by raising the local temperature, causing physical damage to bacteria, and preventing the development of antibiotic resistance. Although light-mediated antibacterial mechanisms have been recognized as one of the most effective antibacterial approaches, their ability to target organisms, oxygen-deprivation-infected tissues, as well as photocatalytic efficiency are still significant variables restricting their antimicrobial effectiveness [192]. To satisfy the future requirements of light-mediated antibacterial agents, it is expected to develop innovative light-mediated antibacterial agents with adequate size, excellent photostability, high photothermal conversion efficiency, and low toxicity for effective PTT and PDT for infection treatment and bone repair. Furthermore, in comparison to PTT or PDT alone, the combination treatment exhibited a synergistic effect, leading to increased efficacy of treatment without noticeable toxic consequences on normal tissues [193]. Therefore, combined PTT and PDT hold desired promise for the treatment of IBDs.
It is to be regretted that the cell and animal investigations of antibacterial agents hybrid hydrogels mentioned above have not yet been applied in clinic. To date, no investigations have described the use of antibacterial hybrid hydrogels for the clinical treatment of IBDs. It is difficult to directly apply the results of successful in-human cell or animal studies to clinical experience. As a result, clinical trials evaluating the safety and functional effectiveness of hybrid hydrogels with antibacterial agents are required in the future. Additionally, a promising future direction is the use of multifunctional materials paired with systemic and local therapy for the treatment of IBDs, and different methods of treatment should be used wherever possible, including multiple drugs, co-delivery, and hyperthermia [194].
In conclusion, antibacterial agents such as antibiotics, metal particles, and AMPs are usually incorporated into hydrogels to endow them with antibacterial activity. For some hydrogels with inherent antibacterial capability, it is convenient to adjust the biocompatibility and antibacterial activity of the hydrogels via chemical modification in various ways. The promising way to treat IBDs is to create a bone graft with antimicrobial and osteogenesis properties in sequential order. Despite significant progress, hydrogels possessing the activities of anti-inflammatory, antibacterial, osteogenic, and angiogenic are desperately needed to treat IBDs.
Table
Table 1. Summary of different antibacterial agents hybrid hydrogels for infected bone repair.
Table 1. Summary of different antibacterial agents hybrid hydrogels for infected bone repair.
CategoryRepresentative AgentAntibacterial MechanismEffect on Bone RepairAdvantagesDisadvantagesRef.
Hydrogels with metal nanomaterialsAgNPs Attach onto the cell wall and membrane, damage intracellular biomolecules and structuresPromote the expression and mineralization of osteogenic proteins, alter microRNA expression associated with bone formation Broad-spectrum antimicrobial properties, stimulate bone growth Long-term use produces multidrug-resistant bacteria and is difficult to biodegrade[51,195]
Light-mediated inorganic antibacterial nanoparticle hybrid hydrogelsrGOMechanical breakage of the cell membrane results in intracellular substance leakagePromote cell proliferation and differentiationDo not elicit bacterial resistanceLow photothermal conversion efficiency, non-biodegradable nature[196,197]
Hydrogels with organic antibacterial agentQuaternary ammonium saltsBinding to the cell membrane, bacteria lysis Promote more osteogenic differentiationCan be used as a modification factorShort-term functionality, environmental toxicity, rapid antimicrobial resistance, and skin penetration[96,97,198]
Hydrogel with MOFsZIF-8Synergistic action, such as Zn2+ and ligand release, ROS production, photothermal effect Activate the ERK pathway primarily, activates MAPK signaling eventually, and promotes the osteogenesis of rBMSCsCan be used as carriers and have electrostatic interaction with negatively charged bacterial cellsExcess metal ions may be harmful to host tissues[112,199]
Light-mediated organic antibacterial agent hybrid hydrogelsICGCombination of PTT and PDT to kill bacteria through ROS generation and thermal ablation Increase ALP activity and enhanced mineralization of osteoblastsWater-soluble, very low cytotoxicityRapid clearance from the body, instability in aqueous solutions, an photobleaching[200,201,202,203,204,205]
Hydrogels with microorganisms origin natural antibacterial agentsDoxycyclineInterfere with prokaryotic protein synthesis at the ribosome level Promote by low concentration, but inhibit by high concentrationBroad-spectrum antibacterial drug Antibiotic-resistant bacteria, toxic to mammalian cells[140,141,206]
Hydrogels with plant origin natural antibacterial agentsCurTarget the bacterial DNA, protein, cell membrane, cell wall, and other biological componentsEnhance osteoblast proliferation, and induce osteogenesis-related gene expressionWide sources and good biodegradabilityPoor solubility and bioavailability [149,150,151,155]
Hydrogels with animal origin natural antibacterial agentsLL37Induce membrane rupture Enhance proliferation, migration, and osteogenic differentiation of MSCs and block bone resorptionBroad-spectrum activity against Insufficient antimicrobial activities or unstable antimicrobial activities[176,207,208]
Hydrogels with inherent self-antibacterial abilityCSDisrupt cytomembrane structure, cellular energy metabolism, and protein synthesisUp-regulate genes associated with calcium binding and mineralization Environmentally friendly agent and cytocompatibility Limited bacterial activity against Gram-negative bacteria [209,210]

Author Contributions

Conceptualization, J.Y. and J.L.; methodology, L.P. and L.L.; writing—original draft preparation, M.C. and C.L.; writing—review and editing, J.Y., X.Z., and J.L.; visualization, M.C., X.Z., and M.L.; supervision, J.Y. and J.L.; funding acquisition, J.Y. and J.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation (NO. 82071108, 32171354), the Fundamental Research Funds for Central Universities, the Project of Science and Technology Department of Sichuan Province (NO. 2021YJ0228), the Science and Technology Application Demonstration Projects in Chengdu (NO. 2021-YF09-00078-SN), and the Research and Develop Program, West China Hospital of Stomatology Sichuan University (NO. LCYJ2020-YJ-3).

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Lima, A.L.L.; Oliveira, P.R.; Carvalho, V.C.; Cimerman, S.; Savio, E.; Diretrizes Panamer Tratamiento, O. Recommendations for the treatment of osteomyelitis. Braz. J. Infect. Dis. 2014, 18, 526–534. [Google Scholar] [CrossRef] [Green Version]
  2. Campana, V.; Milano, G.; Pagano, E.; Barba, M.; Cicione, C.; Salonna, G.; Lattanzi, W.; Logroscino, G. Bone substitutes in orthopaedic surgery: From basic science to clinical practice. J. Mater. Sci. Mater. Med. 2014, 25, 2445–2461. [Google Scholar] [CrossRef]
  3. Agarwal, R.; García, A.J. Biomaterial strategies for engineering implants for enhanced osseointegration and bone repair. Adv. Drug Deliv. Rev. 2015, 94, 53–62. [Google Scholar] [CrossRef] [Green Version]
  4. Keating, J.F.; Simpson, A.H.; Robinson, C.M. The management of fractures with bone loss. J. Bone Jt. Surg. Br. Vol. 2005, 87, 142–150. [Google Scholar] [CrossRef] [Green Version]
  5. Harris, J.S.; Bemenderfer, T.B.; Wessel, A.R.; Kacena, M.A. A review of mouse critical size defect models in weight bearing bones. Bone 2013, 55, 241–247. [Google Scholar] [CrossRef] [Green Version]
  6. O’Keefe, R.J.; Mao, J. Bone tissue engineering and regeneration: From discovery to the clinic—An overview. Tissue Eng. Part B Rev. 2011, 17, 389–392. [Google Scholar] [CrossRef] [Green Version]
  7. Mountziaris, P.M.; Mikos, A.G. Modulation of the inflammatory response for enhanced bone tissue regeneration. Tissue Eng. Part B Rev. 2008, 14, 179–186. [Google Scholar] [CrossRef]
  8. Waters, R.V.; Gamradt, S.C.; Asnis, P.; Vickery, B.H.; Avnur, Z.; Hill, E.; Bostrom, M. Systemic corticosteroids inhibit bone healing in a rabbit ulnar osteotomy model. Acta Orthop. Scand. 2000, 71, 316–321. [Google Scholar] [CrossRef]
  9. Toh, C.L.; Jupiter, J.B. The infected nonunion of the tibia. Clin. Orthop. Relat. Res. 1995, 315, 176–191. Available online: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=ppvovftb&NEWS=N&AN=00003086-199506000-00019 (accessed on 19 April 2022). [CrossRef]
  10. Patzakis, M.J.; Wilkins, J. Factors influencing infection rate in open fracture wounds. Clin. Orthop. Relat. Res. 1989, 243, 36–40. Available online: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=ppvovfta&NEWS=N&AN=00003086-198906000-00006 (accessed on 19 April 2022). [CrossRef]
  11. Patzakis, M.J.; Zalavras, C.G. Chronic posttraumatic osteomyelitis and infected nonunion of the tibia: Current management concepts. J. Am. Acad. Orthop. Surg. 2005, 13, 417–427. [Google Scholar] [CrossRef]
  12. Wang, D.; Liu, Y.; Liu, Y.; Yan, L.; Zaat, S.A.J.; Wismeijer, D.; Pathak, J.L.; Wu, G. A dual functional bone-defect-filling material with sequential antibacterial and osteoinductive properties for infected bone defect repair. J. Biomed. Mater. Res. Part A 2019, 107, 2360–2370. [Google Scholar] [CrossRef]
  13. Serhan, C.N.; Savill, J. Resolution of inflammation: The beginning programs the end. Nat. Immunol. 2005, 6, 1191–1197. [Google Scholar] [CrossRef]
  14. Arron, J.R.; Choi, Y. Bone versus immune system. Nature 2000, 408, 535–536. [Google Scholar] [CrossRef]
  15. Arboleya, L.; Castañeda, S. Osteoimmunology: The study of the relationship between the immune system and bone tissue. Reumatol. Clin. 2013, 9, 303–315. [Google Scholar] [CrossRef]
  16. Takayanagi, H. Osteoimmunology: Shared mechanisms and crosstalk between the immune and bone systems. Nat. Rev. Immunol. 2007, 7, 292–304. [Google Scholar] [CrossRef]
  17. Walsh, M.C.; Kim, N.; Kadono, Y.; Rho, J.; Lee, S.Y.; Lorenzo, J.; Choi, Y. Osteoimmunology: Interplay between the immune system and bone metabolism. Annu. Rev. Immunol. 2006, 24, 33–63. [Google Scholar] [CrossRef] [Green Version]
  18. Loi, F.; Córdova, L.A.; Pajarinen, J.; Lin, T.-h.; Yao, Z.; Goodman, S.B. Inflammation, fracture and bone repair. Bone 2016, 86, 119–130. [Google Scholar] [CrossRef] [Green Version]
  19. Bhattacharya, R.; Kundu, B.; Nandi, S.K.; Basu, D. Systematic approach to treat chronic osteomyelitis through localized drug delivery system: Bench to bed side. Mater. Sci. Eng. C Mater. Biol. Appl. 2013, 33, 3986–3993. [Google Scholar] [CrossRef]
  20. Cheng, T.; Qu, H.; Zhang, G.; Zhang, X. Osteogenic and antibacterial properties of vancomycin-laden mesoporous bioglass/PLGA composite scaffolds for bone regeneration in infected bone defects. Artif. Cells Nanomed. Biotechnol. 2018, 46, 1935–1947. [Google Scholar] [CrossRef] [Green Version]
  21. Lu, H.; Liu, Y.; Guo, J.; Wu, H.; Wang, J.; Wu, G. Biomaterials with Antibacterial and Osteoinductive Properties to Repair Infected Bone Defects. Int. J. Mol. Sci. 2016, 17, 334. [Google Scholar] [CrossRef]
  22. Thomas, M.V.; Puleo, D.A. Infection, Inflammation, and Bone Regeneration: A Paradoxical Relationship. J. Dent. Res. 2011, 90, 1052–1061. [Google Scholar] [CrossRef]
  23. Soundrapandian, C.; Sa, B.; Datta, S. Organic–Inorganic Composites for Bone Drug Delivery. AAPS Pharm. Sci. Tech. 2009, 10, 1158–1171. [Google Scholar] [CrossRef] [Green Version]
  24. Khan, S.N.; Cammisa, F.P., Jr.; Sandhu, H.S.; Diwan, A.D.; Girardi, F.P.; Lane, J.M. The biology of bone grafting. J. Am. Acad. Orthop. Surg. 2005, 13, 77–86. [Google Scholar] [CrossRef]
  25. Roberts, T.T.; Rosenbaum, A.J. Bone grafts, bone substitutes and orthobiologics. Organogenesis 2012, 8, 114–124. [Google Scholar] [CrossRef] [Green Version]
  26. Zimmermann, G.; Moghaddam, A. Allograft bone matrix versus synthetic bone graft substitutes. Injury 2011, 42 (Suppl. 2), S16–S21. [Google Scholar] [CrossRef]
  27. O’Brien, F.J. Biomaterials & scaffolds for tissue engineering. Mater. Today 2011, 14, 88–95. [Google Scholar] [CrossRef]
  28. Koons, G.L.; Diba, M.; Mikos, A.G. Materials design for bone-tissue engineering. Nat. Rev. Mater. 2020, 5, 584–603. [Google Scholar] [CrossRef]
  29. Zhang, S.; Guo, Y.; Dong, Y.; Wu, Y.; Cheng, L.; Wang, Y.; Xing, M.; Yuan, Q. A Novel Nanosilver/Nanosilica Hydrogel for Bone Regeneration in Infected Bone Defects. ACS Appl. Mater. Interfaces 2016, 8, 13242–13250. [Google Scholar] [CrossRef]
  30. Wan, X.; Zhao, Y.; Li, Z.; Li, L. Emerging polymeric electrospun fibers: From structural diversity to application in flexible bioelectronics and tissue engineering. Exploration 2022, 2, 20210029. [Google Scholar] [CrossRef]
  31. Altay, G.; Tosi, S.; García-Díaz, M.; Martínez, E. Imaging the Cell Morphological Response to 3D Topography and Curvature in Engineered Intestinal Tissues. Front. Bioeng. Biotechnol. 2020, 8, 294. [Google Scholar] [CrossRef] [PubMed]
  32. Li, S.; Dong, S.; Xu, W.; Tu, S.; Yan, L.; Zhao, C.; Ding, J.; Chen, X. Antibacterial Hydrogels. Adv. Sci. 2018, 5, 1700527. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Vermonden, T.; Klumperman, B. The past, present and future of hydrogels. Eur. Polym. J. 2015, 72, 341–343. [Google Scholar] [CrossRef]
  34. Bai, X.; Gao, M.; Syed, S.; Zhuang, J.; Xu, X.; Zhang, X.-Q. Bioactive hydrogels for bone regeneration. Bioact. Mater. 2018, 3, 401–417. [Google Scholar] [CrossRef]
  35. Buwalda, S.J.; Vermonden, T.; Hennink, W.E. Hydrogels for Therapeutic Delivery: Current Developments and Future Directions. Biomacromolecules 2017, 18, 316–330. [Google Scholar] [CrossRef]
  36. Liu, M.; Guo, R.; Ma, Y. Construction of a specific and efficient antibacterial agent against Pseudomonas aeruginosa based on polyethyleneimine cross-linked fucose. J. Mater. Sci. 2021, 56, 6083–6094. [Google Scholar] [CrossRef]
  37. Chung, Y.C.; Wang, H.L.; Chen, Y.M.; Li, S.L. Effect of abiotic factors on the antibacterial activity of chitosan against waterborne pathogens. Bioresour. Technol. 2003, 88, 179–184. [Google Scholar] [CrossRef]
  38. Mombelli, A.; Samaranayake, L.P. Topical and systemic antibiotics in the management of periodontal diseases. Int. Dent. J. 2004, 54, 3–14. [Google Scholar] [CrossRef]
  39. Hoare, T.R.; Kohane, D.S. Hydrogels in drug delivery: Progress and challenges. Polymer 2008, 49, 1993–2007. [Google Scholar] [CrossRef] [Green Version]
  40. Mou, J.; Liu, Z.; Liu, J.; Lu, J.; Zhu, W.; Pei, D. Hydrogel containing minocycline and zinc oxide-loaded serum albumin nanopartical for periodontitis application: Preparation, characterization and evaluation. Drug Deliv. 2019, 26, 179–187. [Google Scholar] [CrossRef] [Green Version]
  41. Gil, J.; Natesan, S.; Li, J.; Valdes, J.; Harding, A.; Solis, M.; Davis, S.C.; Christy, R.J. A PEGylated fibrin hydrogel-based antimicrobial wound dressing controls infection without impeding wound healing. Int. Wound J. 2017, 14, 1248–1257. [Google Scholar] [CrossRef] [PubMed]
  42. Zhong, Y.; Shultz, R.B. Hydrogel-based local drug delivery strategies for spinal cord repair. Neural Regen. Res. 2021, 16, 247–253. [Google Scholar] [CrossRef] [PubMed]
  43. Singh, A.; Dubey, A.K. Various Biomaterials and Techniques for Improving Antibacterial Response. ACS Appl. Bio Mater. 2018, 1, 3–20. [Google Scholar] [CrossRef]
  44. Wang, Y.; Yang, Y.; Shi, Y.; Song, H.; Yu, C. Antibiotic-Free Antibacterial Strategies Enabled by Nanomaterials: Progress and Perspectives. Adv. Mater. 2019, 32, e1904106. [Google Scholar] [CrossRef] [PubMed]
  45. Seil, J.T.; Webster, T.J. Antimicrobial applications of nanotechnology: Methods and literature. Int. J. Nanomed. 2012, 7, 2767–2781. [Google Scholar] [CrossRef] [Green Version]
  46. Babu, K.S.; Anandkumar, M.; Tsai, T.Y.; Kao, T.H.; Inbaraj, B.S.; Chen, B.H. Cytotoxicity and antibacterial activity of gold-supported cerium oxide nanoparticles. Int. J. Nanomed. 2014, 9, 5515–5531. [Google Scholar] [CrossRef] [Green Version]
  47. Zhou, Y.; Kong, Y.; Kundu, S.; Cirillo, J.D.; Liang, H. Antibacterial activities of gold and silver nanoparticles against Escherichia coli and bacillus Calmette-Guérin. J. Nanobiotechnol. 2012, 10, 19. [Google Scholar] [CrossRef] [Green Version]
  48. Kruk, T.; Szczepanowicz, K.; Stefańska, J.; Socha, R.P.; Warszyński, P. Synthesis and antimicrobial activity of monodisperse copper nanoparticles. Colloids Surf. B Biointerfaces 2015, 128, 17–22. [Google Scholar] [CrossRef]
  49. Shen, J.; Karges, J.; Xiong, K.; Chen, Y.; Ji, L.; Chao, H. Cancer cell membrane camouflaged iridium complexes functionalized black-titanium nanoparticles for hierarchical-targeted synergistic NIR-II photothermal and sonodynamic therapy. Biomaterials 2021, 275, 120979. [Google Scholar] [CrossRef]
  50. Saidin, S.; Jumat, M.A.; Mohd Amin, N.A.A.; Saleh Al-Hammadi, A.S. Organic and inorganic antibacterial approaches in combating bacterial infection for biomedical application. Mater. Sci Eng. C Mater. Biol. Appl. 2021, 118, 111382. [Google Scholar] [CrossRef]
  51. Sharma, V.K.; Yngard, R.A.; Lin, Y. Silver nanoparticles: Green synthesis and their antimicrobial activities. Adv. Colloid Interface Sci. 2009, 145, 83–96. [Google Scholar] [CrossRef] [PubMed]
  52. Kong, H.; Jang, J. Antibacterial Properties of Novel Poly(methyl methacrylate) Nanofiber Containing Silver Nanoparticles. Langmuir 2008, 24, 2051–2056. [Google Scholar] [CrossRef] [PubMed]
  53. Franci, G.; Falanga, A.; Galdiero, S.; Palomba, L.; Rai, M.; Morelli, G.; Galdiero, M. Silver Nanoparticles as Potential Antibacterial Agents. Molecules 2015, 20, 8856–8874. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Durán, N.; Durán, M.; de Jesus, M.B.; Seabra, A.B.; Fávaro, W.J.; Nakazato, G. Silver nanoparticles: A new view on mechanistic aspects on antimicrobial activity. Nanomed. Nanotechnol. Biol. Med. 2016, 12, 789–799. [Google Scholar] [CrossRef]
  55. Le Ouay, B.; Stellacci, F. Antibacterial activity of silver nanoparticles: A surface science insight. Nano Today 2015, 10, 339–354. [Google Scholar] [CrossRef] [Green Version]
  56. Mahmood, M.; Li, Z.; Casciano, D.; Khodakovskaya, M.V.; Chen, T.; Karmakar, A.; Dervishi, E.; Xu, Y.; Mustafa, T.; Watanabe, F.; et al. Nanostructural materials increase mineralization in bone cells and affect gene expression through miRNA regulation. J. Cell. Mol. Med. 2010, 15, 2297–2306. [Google Scholar] [CrossRef] [Green Version]
  57. Han, X.; He, J.; Wang, Z.; Bai, Z.; Qu, P.; Song, Z.; Wang, W. Fabrication of silver nanoparticles/gelatin hydrogel system for bone regeneration and fracture treatment. Drug Deliv. 2021, 28, 319–324. [Google Scholar] [CrossRef]
  58. Yang, X.; Wei, Q.; Shao, H.; Jiang, X. Multivalent Aminosaccharide-Based Gold Nanoparticles as Narrow-Spectrum Antibiotics in Vivo. ACS Appl. Mater. Interfaces 2019, 11, 7725–7730. [Google Scholar] [CrossRef]
  59. Liang, H.; Jin, C.; Ma, L.; Feng, X.; Deng, X.; Wu, S.; Liu, X.; Yang, C. Accelerated Bone Regeneration by Gold-Nanoparticle-Loaded Mesoporous Silica through Stimulating Immunomodulation. ACS Appl. Mater. Interfaces 2019, 11, 41758–41769. [Google Scholar] [CrossRef]
  60. Yi, C.; Liu, D.; Fong, C.C.; Zhang, J.; Yang, M. Gold nanoparticles promote osteogenic differentiation of mesenchymal stem cells through p38 MAPK pathway. ACS Nano 2010, 4, 6439–6448. [Google Scholar] [CrossRef]
  61. Zhang, Y.; Wang, P.; Mao, H.; Zhang, Y.; Zheng, L.; Yu, P.; Guo, Z.; Li, L.; Jiang, Q. PEGylated gold nanoparticles promote osteogenic differentiation in in vitro and in vivo systems. Mater. Des. 2021, 197, 109231. [Google Scholar] [CrossRef]
  62. Lee, D.; Heo, D.N.; Nah, H.R.; Lee, S.J.; Ko, W.K.; Lee, J.S.; Moon, H.J.; Bang, J.B.; Hwang, Y.S.; Reis, R.L.; et al. Injectable hydrogel composite containing modified gold nanoparticles: Implication in bone tissue regeneration. Int. J. Nanomed. 2018, 13, 7019–7031. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. You, J.; Zhang, P.; Hu, F.; Du, Y.; Yuan, H.; Zhu, J.; Wang, Z.; Zhou, J.; Li, C. Near-infrared light-sensitive liposomes for the enhanced photothermal tumor treatment by the combination with chemotherapy. Pharm. Res. 2014, 31, 554–565. [Google Scholar] [CrossRef] [PubMed]
  64. Usman, M.S.; El Zowalaty, M.E.; Shameli, K.; Zainuddin, N.; Salama, M.; Ibrahim, N.A. Synthesis, characterization, and antimicrobial properties of copper nanoparticles. Int. J. Nanomed. 2013, 8, 4467–4479. [Google Scholar] [CrossRef] [Green Version]
  65. Dai, Q.; Li, Q.; Gao, H.; Yao, L.; Lin, Z.; Li, D.; Zhu, S.; Liu, C.; Yang, Z.; Wang, G.; et al. 3D printing of Cu-doped bioactive glass composite scaffolds promotes bone regeneration through activating the HIF-1α and TNF-α pathway of hUVECs. Biomater. Sci. 2021, 9, 5519–5532. [Google Scholar] [CrossRef]
  66. Panáček, A.; Kvítek, L.; Smékalová, M.; Večeřová, R.; Kolář, M.; Röderová, M.; Dyčka, F.; Šebela, M.; Prucek, R.; Tomanec, O.; et al. Bacterial resistance to silver nanoparticles and how to overcome it. Nat. Nanotechnol. 2018, 13, 65–71. [Google Scholar] [CrossRef]
  67. Lin, J.; He, Z.; Liu, F.; Feng, J.; Huang, C.; Sun, X.; Deng, H. Hybrid Hydrogels for Synergistic Periodontal Antibacterial Treatment with Sustained Drug Release and NIR-Responsive Photothermal Effect. Int. J. Nanomed. 2020, 15, 5377–5387. [Google Scholar] [CrossRef]
  68. Li, J.; Liu, X.; Tan, L.; Cui, Z.; Yang, X.; Liang, Y.; Li, Z.; Zhu, S.; Zheng, Y.; Yeung, K.W.K.; et al. Zinc-doped Prussian blue enhances photothermal clearance of Staphylococcus aureus and promotes tissue repair in infected wounds. Nat. Commun. 2019, 10, 4490. [Google Scholar] [CrossRef]
  69. Chen, Y.; Gao, Y.; Chen, Y.; Liu, L.; Mo, A.; Peng, Q. Nanomaterials-based photothermal therapy and its potentials in antibacterial treatment. J. Control. Release Off. J. Control. Release Soc. 2020, 328, 251–262. [Google Scholar] [CrossRef]
  70. Li, X.; Lovell, J.F.; Yoon, J.; Chen, X. Clinical development and potential of photothermal and photodynamic therapies for cancer. Nat. Rev. Clin. Oncol. 2020, 17, 657–674. [Google Scholar] [CrossRef]
  71. Xu, Z.; Gao, Y.; Meng, S.; Yang, B.; Pang, L.; Wang, C.; Liu, T. Mechanism and In Vivo Evaluation: Photodynamic Antibacterial Chemotherapy of Lysine-Porphyrin Conjugate. Front. Microbiol. 2016, 7, 242. [Google Scholar] [CrossRef]
  72. Geng, B.; Li, P.; Fang, F.; Shi, W.; Glowacki, J.; Pan, D.; Shen, L. Antibacterial and osteogenic carbon quantum dots for regeneration of bone defects infected with multidrug-resistant bacteria. Carbon 2021, 184, 375–385. [Google Scholar] [CrossRef]
  73. Bianco, A.; Cheng, H.-M.; Enoki, T.; Gogotsi, Y.; Hurt, R.H.; Koratkar, N.; Kyotani, T.; Monthioux, M.; Park, C.R.; Tascon, J.M.D.; et al. All in the graphene family—A recommended nomenclature for two-dimensional carbon materials. Carbon 2013, 65, 1–6. [Google Scholar] [CrossRef]
  74. Prasadh, S.; Suresh, S.; Wong, R. Osteogenic Potential of Graphene in Bone Tissue Engineering Scaffolds. Materials 2018, 11, 1430. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Wang, X.; Guo, W.; Li, L.; Yu, F.; Li, J.; Liu, L.; Fang, B.; Xia, L. Photothermally triggered biomimetic drug delivery of Teriparatide via reduced graphene oxide loaded chitosan hydrogel for osteoporotic bone regeneration. Chem. Eng. J. 2020, 413, 127413. [Google Scholar] [CrossRef]
  76. Li, Y.; He, J.; Zhou, J.; Li, Z.; Liu, L.; Hu, S.; Guo, B.; Wang, W. A conductive photothermal non-swelling nanocomposite hydrogel patch accelerating bone defect repair. Biomater. Sci. 2022, 10, 1326–1341. [Google Scholar] [CrossRef] [PubMed]
  77. Ling, S.; Wang, Q.; Zhang, D.; Zhang, Y.; Mu, X.; Kaplan, D.L.; Buehler, M.J. Integration of stiff graphene and tough silk for the design and fabrication of versatile electronic materials. Adv. Funct. Mater. 2018, 28, 1705291. [Google Scholar] [CrossRef]
  78. Yang, B.; Yin, J.; Chen, Y.; Pan, S.; Yao, H.; Gao, Y.; Shi, J. 2D-Black-Phosphorus-Reinforced 3D-Printed Scaffolds:A Stepwise Countermeasure for Osteosarcoma. Adv. Mater. 2018, 30, 1705611. [Google Scholar] [CrossRef]
  79. Dadsetan, M.; Giuliani, M.; Wanivenhaus, F.; Brett Runge, M.; Charlesworth, J.E.; Yaszemski, M.J. Incorporation of phosphate group modulates bone cell attachment and differentiation on oligo(polyethylene glycol) fumarate hydrogel. Acta Biomater. 2012, 8, 1430–1439. [Google Scholar] [CrossRef] [Green Version]
  80. Miao, Y.; Shi, X.; Li, Q.; Hao, L.; Liu, L.; Liu, X.; Chen, Y.; Wang, Y. Engineering natural matrices with black phosphorus nanosheets to generate multi-functional therapeutic nanocomposite hydrogels. Biomater. Sci. 2019, 7, 4046–4059. [Google Scholar] [CrossRef]
  81. Tan, L.; Li, J.; Liu, X.; Cui, Z.; Yang, X.; Zhu, S.; Li, Z.; Yuan, X.; Zheng, Y.; Yeung, K.W.K.; et al. Rapid Biofilm Eradication on Bone Implants Using Red Phosphorus and Near-Infrared Light. Adv. Mater. 2018, 30, 1801808. [Google Scholar] [CrossRef] [PubMed]
  82. Zhang, G.; Zhang, X.; Yang, Y.; Chi, R.; Shi, J.; Hang, R.; Huang, X.; Yao, X.; Chu, P.K.; Zhang, X. Dual light-induced in situ antibacterial activities of biocompatibleTiO(2)/MoS(2)/PDA/RGD nanorod arrays on titanium. Biomater. Sci. 2020, 8, 391–404. [Google Scholar] [CrossRef] [PubMed]
  83. Miao, Q.; Pu, K. Organic Semiconducting Agents for Deep-Tissue Molecular Imaging: Second Near-Infrared Fluorescence, Self-Luminescence, and Photoacoustics. Adv. Mater. 2018, 30, e1801778. [Google Scholar] [CrossRef] [PubMed]
  84. Jiang, Y.; Pu, K. Molecular Fluorescence and Photoacoustic Imaging in the Second Near-Infrared Optical Window Using Organic Contrast Agents. Adv. Biosyst. 2018, 2, 1700262. [Google Scholar] [CrossRef] [PubMed]
  85. Hong, G.; Antaris, A.L.; Dai, H. Near-infrared fluorophores for biomedical imaging. Nat. Biomed. Eng. 2017, 1, 10. [Google Scholar] [CrossRef]
  86. Zhang, G.; Yang, Y.; Shi, J.; Yao, X.; Chen, W.; Wei, X.; Zhang, X.; Chu, P.K. Near-infrared light II—Assisted rapid biofilm elimination platform for bone implants at mild temperature. Biomaterials 2021, 269, 120634. [Google Scholar] [CrossRef]
  87. Zhang, G.; Wu, Z.; Yang, Y.; Shi, J.; Lv, J.; Fang, Y.; Shen, Z.; Lv, Z.; Li, P.; Yao, X.; et al. A multifunctional antibacterial coating on bone implants for osteosarcoma therapy and enhanced osteointegration. Chem. Eng. J. 2022, 428, 131155. [Google Scholar] [CrossRef]
  88. Hu, B.; Berkey, C.; Feliciano, T.; Chen, X.; Li, Z.; Chen, C.; Amini, S.; Nai, M.H.; Lei, Q.L.; Ni, R.; et al. Thermal-Disrupting Interface Mitigates Intercellular Cohesion Loss for Accurate Topical Antibacterial Therapy. Adv. Mater. 2020, 32, e1907030. [Google Scholar] [CrossRef]
  89. Xu, X.; An, H.; Zhang, D.; Tao, H.; Dou, Y.; Li, X.; Huang, J.; Zhang, J. A self-illuminating nanoparticle for inflammation imaging and cancer therapy. Sci. Adv. 2019, 5, eaat2953. [Google Scholar] [CrossRef] [Green Version]
  90. Zheng, L.; Li, S.; Luo, J.; Wang, X. Latest Advances on Bacterial Cellulose-Based Antibacterial Materials as Wound Dressings. Front. Bioeng. Biotechnol. 2020, 8, 593768. [Google Scholar] [CrossRef]
  91. Akca, A.E.; Akca, G.; Topçu, F.T.; Macit, E.; Pikdöken, L.; Özgen, I.Ş. The Comparative Evaluation of the Antimicrobial Effect of Propolis with Chlorhexidine against Oral Pathogens: An In Vitro Study. BioMed Res. Int. 2016, 2016, 3627463. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Lan, T.; Guo, Q.; Shen, X. Polyethyleneimine and quaternized ammonium polyethyleneimine: The versatile materials for combating bacteria and biofilms. J. Biomater. Sci. Polym. Ed. 2019, 30, 1243–1259. [Google Scholar] [CrossRef] [PubMed]
  93. Shen, M.; Forghani, F.; Kong, X.; Liu, D.; Ye, X.; Chen, S.; Ding, T. Antibacterial applications of metal–organic frameworks and their composites. Compr. Rev. Food Sci. Food Saf. 2020, 19, 1397–1419. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Hismiogullari, S.E.; Hismiogullari, A.A.; Sahin, F.; Oner, E.T.; Yenice, S.; Karasartova, D. Investigation of Antibacterial and Cytotoxic Effects of Organic Acids Including Ascorbic Acid, Lactic Acid and Acetic Acids on Mammalian Cells. J. Anim. Vet. Adv. 2008, 7, 681–684. Available online: https://medwelljournals.com/abstract/?doi=javaa.2008.681.684 (accessed on 19 April 2022).
  95. Weber, D.J.; Rutala, W.A.; Sickbert-Bennett, E.E. Outbreaks associated with contaminated antiseptics and disinfectants. Antimicrob. Agents Chemother. 2007, 51, 4217–4224. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Lenoir, S.; Pagnoulle, C.; Galleni, M.; Compère, P.; Jérôme, R.; Detrembleur, C. Polyolefin Matrixes with Permanent Antibacterial Activity:  Preparation, Antibacterial Activity, and Action Mode of the Active Species. Biomacromolecules 2006, 7, 2291–2296. [Google Scholar] [CrossRef] [PubMed]
  97. Huang, Z.; Liuyang, R.; Dong, C.; Lei, Y.; Zhang, A.; Lin, Y. Polymeric quaternary ammonium salt activity against Fusarium oxysporum f. sp. cubense race 4: Synthesis, structure-activity relationship and mode of action. React. Funct. Polym. 2017, 114, 13–22. [Google Scholar] [CrossRef]
  98. Lin, M.C.; Chen, C.C.; Wu, I.T.; Ding, S.J. Enhanced antibacterial activity of calcium silicate-based hybrid cements for bone repair. Mater. Sci. Eng. C Mater. Biol. Appl. 2020, 110, 110727. [Google Scholar] [CrossRef]
  99. McClure, J.-A.; Zaal DeLongchamp, J.; Conly, J.M.; Zhang, K. Novel Multiplex PCR Assay for Detection of Chlorhexidine-Quaternary Ammonium, Mupirocin, and Methicillin Resistance Genes, with Simultaneous Discrimination of Staphylococcus aureus from Coagulase-Negative Staphylococci. J. Clin. Microbiol. 2017, 55, 1857–1864. [Google Scholar] [CrossRef] [Green Version]
  100. Chen, F.; Wang, D. Novel technologies for the prevention and treatment of dental caries: A patent survey. Expert Opin. Ther. Pat. 2010, 20, 681–694. [Google Scholar] [CrossRef] [Green Version]
  101. Barbour, M.E.; Gandhi, N.; el-Turki, A.; O’Sullivan, D.J.; Jagger, D.C. Differential adhesion of Streptococcus gordonii to anatase and rutile titanium dioxide surfaces with and without functionalization with chlorhexidine. J. Biomed. Mater. Res. Part A 2009, 90, 993–998. [Google Scholar] [CrossRef] [PubMed]
  102. Xu, L.; Ye, Q.; Xie, J.; Yang, J.; Jiang, W.; Yuan, H.; Li, J. An injectable gellan gum-based hydrogel that inhibits Staphylococcus aureus for infected bone defect repair. J. Mater. Chem. B 2022, 10, 282–292. [Google Scholar] [CrossRef] [PubMed]
  103. Alavijeh, R.K.; Beheshti, S.; Akhbari, K.; Morsali, A. Investigation of reasons for metal-organic framework’s antibacterial activities. Polyhedron 2018, 156, 257–278. [Google Scholar] [CrossRef]
  104. Zane, A.; Zuo, R.; Villamena, F.A.; Rockenbauer, A.; Digeorge Foushee, A.M.; Flores, K.; Dutta, P.K.; Nagy, A. Biocompatibility and antibacterial activity of nitrogen-doped titanium dioxide nanoparticles for use in dental resin formulations. Int. J. Nanomed. 2016, 11, 6459–6470. [Google Scholar] [CrossRef] [Green Version]
  105. Tsai, D.-S.; Yang, T.-S.; Huang, Y.-S.; Peng, P.-W.; Ou, K.-L. Disinfection effects of undoped and silver-doped ceria powders of nanometer crystallite size. Int. J. Nanomed. 2016, 11, 2531–2542. [Google Scholar] [CrossRef] [Green Version]
  106. Yang, J.; Yang, Y. Metal–Organic Frameworks for Biomedical Applications. Small 2020, 16, e1906846. [Google Scholar] [CrossRef]
  107. Restrepo, J.; Serroukh, Z.; Santiago-Morales, J.; Aguado, S.; Gómez-Sal, P.; Mosquera, M.E.G.; Rosal, R. An Antibacterial Zn–MOF with Hydrazinebenzoate Linkers. Eur. J. Inorg. Chem. 2016, 2017, 574–580. [Google Scholar] [CrossRef]
  108. Tamames-Tabar, C.; Imbuluzqueta, E.; Guillou, N.; Serre, C.; Miller, S.R.; Elkaim, E.; Horcajada, P.; Blanco-Prieto, M.J. A Zn azelate MOF: Combining antibacterial effect. Crystengcomm 2015, 17, 456–462. [Google Scholar] [CrossRef]
  109. Zhu, Z.; Jiang, S.; Liu, Y.; Gao, X.; Hu, S.; Zhang, X.; Huang, C.; Wan, Q.; Wang, J.; Pei, X. Micro or nano: Evaluation of biosafety and biopotency of magnesium metal organic framework-74 with different particle sizes. Nano Res. 2020, 13, 511–526. [Google Scholar] [CrossRef]
  110. Zheng, H.; Zhang, Y.; Liu, L.; Wan, W.; Guo, P.; Nyström, A.M.; Zou, X. One-pot Synthesis of Metal-Organic Frameworks with Encapsulated Target Molecules and Their Applications for Controlled Drug Delivery. J. Am. Chem. Soc. 2016, 138, 962–968. [Google Scholar] [CrossRef]
  111. Zhang, Y.; Li, T.T.; Shiu, B.C.; Lin, J.H.; Lou, C.W. Two methods for constructing ZIF-8 nanomaterials with good bio compatibility and robust antibacterial applied to biomedical. J. Biomater. Appl. 2022, 36, 1042–1054. [Google Scholar] [CrossRef] [PubMed]
  112. Gao, X.; Xue, Y.; Zhu, Z.; Chen, J.; Liu, Y.; Cheng, X.; Zhang, X.; Wang, J.; Pei, X.; Wan, Q. Nanoscale Zeolitic Imidazolate Framework-8 Activator of Canonical MAPK Signaling for Bone Repair. ACS Appl. Mater. Interfaces 2021, 13, 97–111. [Google Scholar] [CrossRef] [PubMed]
  113. Liu, Y.; Zhu, Z.; Pei, X.; Zhang, X.; Cheng, X.; Hu, S.; Gao, X.; Wang, J.; Chen, J.; Wan, Q. ZIF-8-Modified Multifunctional Bone-Adhesive Hydrogels Promoting Angiogenesis and Osteogenesis for Bone Regeneration. ACS Appl. Mater. Interfaces 2020, 12, 36978–36995. [Google Scholar] [CrossRef] [PubMed]
  114. Liu, J.; Sonshine, D.A.; Shervani, S.; Hurt, R.H. Controlled Release of Biologically Active Silver from Nanosilver Surfaces. ACS Nano 2010, 4, 6903–6913. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Zheng, Z.; Chen, Y.; Guo, B.; Wang, Y.; Liu, W.; Sun, J.; Wang, X. Magnesium-organic framework-based stimuli-responsive systems that optimize the bone microenvironment for enhanced bone regeneration. Chem. Eng. J. 2020, 396, 125241. [Google Scholar] [CrossRef]
  116. Soomro, N.A.; Wu, Q.; Amur, S.A.; Liang, H.; Ur Rahman, A.; Yuan, Q.; Wei, Y. Natural drug physcion encapsulated zeolitic imidazolate framework, and their application as antimicrobial agent. Colloids Surf. B Biointerfaces 2019, 182, 110364. [Google Scholar] [CrossRef]
  117. Huang, G.; Li, Y.; Qin, Z.; Liang, Q.; Xu, C.; Lin, B. Hybridization of carboxymethyl chitosan with MOFs to construct recyclable, long-acting and intelligent antibacterial agent carrier. Carbohydr. Polym. 2020, 233, 115848. [Google Scholar] [CrossRef]
  118. Li, J.; Rao, J.; Pu, K. Recent progress on semiconducting polymer nanoparticles for molecular imaging and cancer phototherapy. Biomaterials 2018, 155, 217–235. [Google Scholar] [CrossRef]
  119. Li, J.; Pu, K. Development of organic semiconducting materials for deep-tissue optical imaging, phototherapy and photoactivation. Chem. Soc. Rev. 2019, 48, 38–71. [Google Scholar] [CrossRef]
  120. Lu, R.; Zhu, J.; Yu, C.; Nie, Z.; Gao, Y. Cu(3)BiS(3) Nanocrystals as Efficient Nanoplatforms for CT Imaging Guided Photothermal Therapy of Arterial Inflammation. Front. Bioeng. Biotechnol. 2020, 8, 981. [Google Scholar] [CrossRef]
  121. Kuang, L.J.; Huang, J.H.; Liu, Y.T.; Li, X.L.; Yuan, Y.; Liu, C.S. Injectable Hydrogel with NIR Light-Responsive, Dual-Mode PTH Release for Osteoregeneration in Osteoporosis. Adv. Funct. Mater. 2021, 31, 2105383. [Google Scholar] [CrossRef]
  122. Liu, Y.; Ai, K.; Liu, J.; Deng, M.; He, Y.; Lu, L. Dopamine-melanin colloidal nanospheres: An efficient near-infrared photothermal therapeutic agent for in vivo cancer therapy. Adv. Mater. 2013, 25, 1353–1359. [Google Scholar] [CrossRef] [PubMed]
  123. Luo, S.; Wu, J.; Jia, Z.; Tang, P.; Sheng, J.; Xie, C.; Liu, C.; Gan, D.; Hu, D.; Zheng, W.; et al. An Injectable, Bifunctional Hydrogel with Photothermal Effects for Tumor Therapy and Bone Regeneration. Macromol. Biosci. 2019, 19, e1900047. [Google Scholar] [CrossRef] [PubMed]
  124. Yao, M.Y.; Zou, Q.X.; Zou, W.W.; Xie, Z.Z.; Li, Z.H.; Zhao, X.J.; Du, C. Bifunctional scaffolds of hydroxyapatite/poly(dopamine)/carboxymethyl chitosan with osteogenesis and anti-osteosarcoma effect. Biomater. Sci. 2021, 9, 3319–3333. [Google Scholar] [CrossRef]
  125. Lü, B.; Chen, Y.; Li, P.; Wang, B.; Müllen, K.; Yin, M. Stable radical anions generated from a porous perylenediimide metal-organic framework for boosting near-infrared photothermal conversion. Nat. Commun. 2019, 10, 767. [Google Scholar] [CrossRef]
  126. Eirich, J.; Orth, R.; Sieber, S.A. Unraveling the Protein Targets of Vancomycin in Living S. aureus and E. faecalis Cells. J. Am. Chem. Soc. 2011, 133, 12144–12153. [Google Scholar] [CrossRef]
  127. King, A.M.; Reid-Yu, S.A.; Wang, W.; King, D.T.; De Pascale, G.; Strynadka, N.C.; Walsh, T.R.; Coombes, B.K.; Wright, G.D. Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance. Nature 2014, 510, 503–506. [Google Scholar] [CrossRef] [Green Version]
  128. Moghadamtousi, S.Z.; Kadir, H.A.; Hassandarvish, P.; Tajik, H.; Abubakar, S.; Zandi, K. A review on antibacterial, antiviral, and antifungal activity of curcumin. BioMed Res. Int. 2014, 2014, 186864. [Google Scholar] [CrossRef]
  129. Clardy, J.; Fischbach, M.A.; Walsh, C.T. New antibiotics from bacterial natural products. Nat. Biotechnol. 2006, 24, 1541–1550. [Google Scholar] [CrossRef]
  130. Genilloud, O. Actinomycetes: Still a source of novel antibiotics. Nat. Prod. Rep. 2017, 34, 1203–1232. [Google Scholar] [CrossRef]
  131. Ibrahim, H.R.; Aoki, T.; Pellegrini, A. Strategies for new antimicrobial proteins and peptides: Lysozyme and aprotinin as model molecules. Curr. Pharm. Des. 2002, 8, 671–693. [Google Scholar] [CrossRef] [PubMed]
  132. Habermann, E. Bee and wasp venoms. Science 1972, 177, 314–322. [Google Scholar] [CrossRef]
  133. Lehrer, R.I.; Lichtenstein, A.K.; Ganz, T. Defensins: Antimicrobial and cytotoxic peptides of mammalian cells. Annu. Rev. Immunol. 1993, 11, 105–128. [Google Scholar] [CrossRef]
  134. Mahlapuu, M.; Håkansson, J.; Ringstad, L.; Björn, C. Antimicrobial Peptides: An Emerging Category of Therapeutic Agents. Front. Cell. Infect. Microbiol. 2016, 6, 194. [Google Scholar] [CrossRef] [Green Version]
  135. Diamond, G.; Beckloff, N.; Weinberg, A.; Kisich, K.O. The roles of antimicrobial peptides in innate host defense. Curr. Pharm. Des. 2009, 15, 2377–2392. [Google Scholar] [CrossRef] [Green Version]
  136. Rudramurthy, G.R.; Swamy, M.K.; Sinniah, U.R.; Ghasemzadeh, A. Nanoparticles: Alternatives Against Drug-Resistant Pathogenic Microbes. Molecules 2016, 21, 836. [Google Scholar] [CrossRef]
  137. Wei, S.; Jian, C.; Xu, F.; Bao, T.; Lan, S.; Wu, G.; Qi, B.; Bai, Z.; Yu, A. Vancomycin-impregnated electrospun polycaprolactone (PCL) membrane for the treatment of infected bone defects: An animal study. J. Biomater. Appl. 2018, 32, 1187–1196. [Google Scholar] [CrossRef]
  138. Giavaresi, G.; Bertazzoni Minelli, E.; Sartori, M.; Benini, A.; Della Bora, T.; Sambri, V.; Gaibani, P.; Borsari, V.; Salamanna, F.; Martini, L.; et al. Microbiological and pharmacological tests on new antibiotic-loaded PMMA-based composites for the treatment of osteomyelitis. J. Orthop. Res. Off. Publ. Orthop. Res. Soc. 2012, 30, 348–355. [Google Scholar] [CrossRef]
  139. Feng, K.; Sun, H.; Bradley, M.A.; Dupler, E.J.; Giannobile, W.V.; Ma, P.X. Novel antibacterial nanofibrous PLLA scaffolds. J. Control. Release Off. J. Control. Release Soc. 2010, 146, 363–369. [Google Scholar] [CrossRef] [Green Version]
  140. Park, J.-B. Low dose of doxycyline promotes early differentiation of preosteoblasts by partially regulating the expression of estrogen receptors. J. Surg. Res. 2012, 178, 737–742. [Google Scholar] [CrossRef]
  141. Park, J.-B. Effects of Doxycycline, Minocycline, and Tetracycline on Cell Proliferation, Differentiation, and Protein Expression in Osteoprecursor Cells. J. Craniofacial Surg. 2011, 22, 1839–1842. [Google Scholar] [CrossRef] [PubMed]
  142. Jung, S.W.; Oh, S.H.; Lee, I.S.; Byun, J.H.; Lee, J.H. In Situ Gelling Hydrogel with Anti-Bacterial Activity and Bone Healing Property for Treatment of Osteomyelitis. Tissue Eng. Regen. Med. 2019, 16, 479–490. [Google Scholar] [CrossRef] [PubMed]
  143. Liu, S.-M.; Chen, W.-C.; Ko, C.-L.; Chang, H.-T.; Chen, Y.-S.; Haung, S.-M.; Chang, K.-C.; Chen, J.-C. In Vitro Evaluation of Calcium Phosphate Bone Cement Composite Hydrogel Beads of Cross-Linked Gelatin-Alginate with Gentamicin-Impregnated Porous Scaffold. Pharmaceuticals 2021, 14, 1000. [Google Scholar] [CrossRef] [PubMed]
  144. Shi, X.; Wang, Y.; Ren, L.; Huang, W.; Wang, D.A. A protein/antibiotic releasing poly(lactic-co-glycolic acid)/lecithin scaffold for bone repair applications. Int. J. Pharm. 2009, 373, 85–92. [Google Scholar] [CrossRef]
  145. Davies, J.; Davies, D. Origins and evolution of antibiotic resistance. Microbiol. Mol. Biol. Rev. 2010, 74, 417–433. [Google Scholar] [CrossRef] [Green Version]
  146. Wright, J.A.; Nair, S.P. Interaction of staphylococci with bone. Int. J. Med. Microbiol. 2010, 300, 193–204. [Google Scholar] [CrossRef] [Green Version]
  147. Kalghatgi, S.; Spina Catherine, S.; Costello James, C.; Liesa, M.; Morones-Ramirez, J.R.; Slomovic, S.; Molina, A.; Shirihai Orian, S.; Collins James, J. Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells. Sci. Transl. Med. 2013, 5, 192ra185. [Google Scholar] [CrossRef] [Green Version]
  148. Reddy, R.C.; Vatsala, P.G.; Keshamouni, V.G.; Padmanaban, G.; Rangarajan, P.N. Curcumin for malaria therapy. Biochem. Biophys. Res. Commun. 2005, 326, 472–474. [Google Scholar] [CrossRef]
  149. Kant, V.; Gopal, A.; Pathak, N.N.; Kumar, P.; Tandan, S.K.; Kumar, D. Antioxidant and anti-inflammatory potential of curcumin accelerated the cutaneous wound healing in streptozotocin-induced diabetic rats. Int. Immunopharmacol. 2014, 20, 322–330. [Google Scholar] [CrossRef]
  150. Wang, Z.; Zhang, K.; Zhu, Y.; Wang, D.; Shao, Y.; Zhang, J. Curcumin inhibits hypoxia-induced proliferation and invasion of MG-63 osteosarcoma cells via downregulating Notch1. Mol. Med. Rep. 2017, 15, 1747–1752. [Google Scholar] [CrossRef] [Green Version]
  151. Chen, P.; Wang, H.; Yang, F.; Chen, H.; He, W.; Wang, J. Curcumin Promotes Osteosarcoma Cell Death by Activating miR-125a/ERRα Signal Pathway. J. Cell. Biochem. 2016, 118, 74–81. [Google Scholar] [CrossRef]
  152. Hussain, Y.; Alam, W.; Ullah, H.; Dacrema, M.; Daglia, M.; Khan, H.; Arciola, C.R. Antimicrobial Potential of Curcumin: Therapeutic Potential and Challenges to Clinical Applications. Antibiotics 2022, 11, 322. [Google Scholar] [CrossRef]
  153. Morão, L.G.; Polaquini, C.R.; Kopacz, M.; Torrezan, G.S.; Ayusso, G.M.; Dilarri, G.; Cavalca, L.B.; Zielińska, A.; Scheffers, D.J.; Regasini, L.O.; et al. A simplified curcumin targets the membrane of Bacillus subtilis. MicrobiologyOpen 2019, 8, e00683. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Kaur, S.; Modi, N.H.; Panda, D.; Roy, N. Probing the binding site of curcumin in Escherichia coli and Bacillus subtilis FtsZ--a structural insight to unveil antibacterial activity of curcumin. Eur. J. Med. Chem. 2010, 45, 4209–4214. [Google Scholar] [CrossRef] [PubMed]
  155. Zheng, D.; Huang, C.; Huang, H.; Zhao, Y.; Khan, M.R.U.; Zhao, H.; Huang, L. Antibacterial Mechanism of Curcumin: A Review. Chem. Biodivers. 2020, 17, e2000171. [Google Scholar] [CrossRef] [PubMed]
  156. Leite, D.P.; Paolillo, F.R.; Parmesano, T.N.; Fontana, C.R.; Bagnato, V.S. Effects of photodynamic therapy with blue light and curcumin as mouth rinse for oral disinfection: A randomized controlled trial. Photomed. Laser Surg. 2014, 32, 627–632. [Google Scholar] [CrossRef] [Green Version]
  157. Koon, H.K.; Leung, A.W.N.; Yue, K.; Mak, N.K. Photodynamic Effect of Curcumin on NPC/CNE2 Cells. J. Environ. Pathol. Toxicol. Oncol. 2006, 25, 205–216. [Google Scholar] [CrossRef]
  158. Han, S.; Yang, Y. Antimicrobial activity of wool fabric treated with curcumin. Dyes Pigment. 2005, 64, 157–161. [Google Scholar] [CrossRef]
  159. Yu, Q.; Meng, Z.; Liu, Y.; Li, Z.; Sun, X.; Zhao, Z. Photocuring Hyaluronic Acid/Silk Fibroin Hydrogel Containing Curcumin Loaded CHITOSAN Nanoparticles for the Treatment of MG-63 Cells and ME3T3-E1 Cells. Polymers 2021, 13, 2302. [Google Scholar] [CrossRef]
  160. Virk, R.S.; Rehman, M.A.U.; Munawar, M.A.; Schubert, D.W.; Goldmann, W.H.; Dusza, J.; Boccaccini, A.R. Curcumin-Containing Orthopedic Implant Coatings Deposited on Poly-Ether-Ether-Ketone/Bioactive Glass/Hexagonal Boron Nitride Layers by Electrophoretic Deposition. Coatings 2019, 9, 572. [Google Scholar] [CrossRef] [Green Version]
  161. Martín-Moreno, A.M.; Reigada, D.; Ramírez, B.G.; Mechoulam, R.; Innamorato, N.; Cuadrado, A.; de Ceballos, M.L. Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: Relevance to Alzheimer’s disease. Mol. Pharmacol. 2011, 79, 964–973. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  162. Hernández-Cervantes, R.; Méndez-Díaz, M.; Prospéro-García, Ó.; Morales-Montor, J. Immunoregulatory Role of Cannabinoids during Infectious Disease. Neuroimmunomodulation 2017, 24, 183–199. [Google Scholar] [CrossRef] [PubMed]
  163. Bab, I.; Ofek, O.; Tam, J.; Rehnelt, J.; Zimmer, A. Endocannabinoids and the Regulation of Bone Metabolism. J. Neuroendocr. 2008, 20, 69–74. [Google Scholar] [CrossRef] [PubMed]
  164. Schmuhl, E.; Ramer, R.; Salamon, A.; Peters, K.; Hinz, B.J.B.p. Increase of mesenchymal stem cell migration by cannabidiol via activation of p42/44 MAPK. Biochem. Pharmacol. 2014, 87, 489–501. [Google Scholar] [CrossRef] [PubMed]
  165. Qi, J.; Zheng, Z.; Hu, L.; Wang, H.; Tang, B.; Lin, L. Development and characterization of cannabidiol-loaded alginate copper hydrogel for repairing open bone defects in vitro. Colloids Surf. B Biointerfaces 2022, 212, 112339. [Google Scholar] [CrossRef] [PubMed]
  166. Izadpanah, A.; Gallo, R.L. Antimicrobial peptides. J. Am. Acad. Dermatol. 2005, 52, 381–390. [Google Scholar] [CrossRef] [PubMed]
  167. Hilchie, A.L.; Wuerth, K.; Hancock, R.E. Immune modulation by multifaceted cationic host defense (antimicrobial) peptides. Nat. Chem. Biol. 2013, 9, 761–768. [Google Scholar] [CrossRef]
  168. De Smet, K.; Contreras, R. Human antimicrobial peptides: Defensins, cathelicidins and histatins. Biotechnol. Lett. 2005, 27, 1337–1347. [Google Scholar] [CrossRef]
  169. Lee, J.; Kang, D.; Choi, J.; Huang, W.; Wadman, M.; Barron, A.E.; Seo, J. Effect of side chain hydrophobicity and cationic charge on antimicrobial activity and cytotoxicity of helical peptoids. Bioorganic. Med. Chem. Lett. 2018, 28, 170–173. [Google Scholar] [CrossRef]
  170. Jantaruk, P.; Roytrakul, S.; Sitthisak, S.; Kunthalert, D. Potential role of an antimicrobial peptide, KLK in inhibiting lipopolysaccharide-induced macrophage inflammation. PLoS ONE 2017, 12, e0183852. [Google Scholar] [CrossRef] [Green Version]
  171. Kazemzadeh-Narbat, M.; Kindrachuk, J.; Duan, K.; Jenssen, H.; Hancock, R.E.; Wang, R. Antimicrobial peptides on calcium phosphate-coated titanium for the prevention of implant-associated infections. Biomaterials 2010, 31, 9519–9526. [Google Scholar] [CrossRef] [PubMed]
  172. Yang, G.; Huang, T.; Wang, Y.; Wang, H.; Li, Y.; Yu, K.; Dong, L. Sustained Release of Antimicrobial Peptide from Self-Assembling Hydrogel Enhanced Osteogenesis. J. Biomater. Sci. Polym. Ed. 2018, 29, 1812–1824. [Google Scholar] [CrossRef] [PubMed]
  173. Cheng, H.; Yue, K.; Kazemzadeh-Narbat, M.; Liu, Y.; Khalilpour, A.; Li, B.; Zhang, Y.S.; Annabi, N.; Khademhosseini, A. Mussel-Inspired Multifunctional Hydrogel Coating for Prevention of Infections and Enhanced Osteogenesis. ACS Appl. Mater. Interfaces 2017, 9, 11428–11439. [Google Scholar] [CrossRef] [Green Version]
  174. Sani, E.S.; Lara, R.P.; Aldawood, Z.; Bassir, S.H.; Nguyen, D.; Kantarci, A.; Intini, G.; Annabi, N. An Antimicrobial Dental Light Curable Bioadhesive Hydrogel for Treatment of Peri-Implant Diseases. Matter 2019, 1, 926–944. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  175. Yu, X.; Quan, J.; Long, W.; Chen, H.; Wang, R.; Guo, J.; Lin, X.; Mai, S. LL-37 inhibits LPS-induced inflammation and stimulates the osteogenic differentiation of BMSCs via P2X7 receptor and MAPK signaling pathway. Exp. Cell Res. 2018, 372, 178–187. [Google Scholar] [CrossRef] [PubMed]
  176. Zhu, Y.; Lu, F.; Zhang, G.; Liu, Z. Overview of signal transduction between LL37 and bone marrow-derived MSCs. Histochem. J. 2022, 1–9. [Google Scholar] [CrossRef]
  177. Liu, P.; Li, M.; Yu, H.; Fang, H.; Yin, J.; Zhu, D.; Yang, Q.; Ke, Q.; Huang, Y.; Guo, Y.; et al. Biphasic CK2.1-coated β-glycerophosphate chitosan/LL37-modified layered double hydroxide chitosan composite scaffolds enhance coordinated hyaline cartilage and subchondral bone regeneration. Chem. Eng. J. 2021, 418, 129531. [Google Scholar] [CrossRef]
  178. Raafat, D.; von Bargen, K.; Haas, A.; Sahl, H.G. Insights into the mode of action of chitosan as an antibacterial compound. Appl Env. Microbiol. 2008, 74, 3764–3773. [Google Scholar] [CrossRef] [Green Version]
  179. Nair, L.S.; Laurencin, C.T. Polymers as biomaterials for tissue engineering and controlled drug delivery. Adv. Biochem. Eng. Biotechnol. 2006, 102, 47–90. [Google Scholar] [CrossRef]
  180. Mathews, S.; Gupta, P.K.; Bhonde, R.; Totey, S. Chitosan enhances mineralization during osteoblast differentiation of human bone marrow-derived mesenchymal stem cells, by upregulating the associated genes. Cell Prolif. 2011, 44, 537–549. [Google Scholar] [CrossRef]
  181. Shi, Z.; Neoh, K.G.; Kang, E.T.; Poh, C.; Wang, W. Bacterial adhesion and osteoblast function on titanium with surface-grafted chitosan and immobilized RGD peptide. J. Biomed. Mater. Res. Part A 2008, 86, 865–872. [Google Scholar] [CrossRef] [PubMed]
  182. Huang, B.; Chen, M.; Tian, J.; Zhang, Y.; Dai, Z.; Li, J.; Zhang, W. Oxygen-Carrying and Antibacterial Fluorinated Nano-hydroxyapatite Incorporated Hydrogels for Enhanced Bone Regeneration. Adv. Healthc. Mater. 2022, e2102540. [Google Scholar] [CrossRef]
  183. Xu, K.J.; Dai, Q.Y.; Dong, K.Q.; Wei, N.S.; Qin, Z.Y. Double noncovalent network chitosan/hyperbranched polyethylenimine/Fe3+ films with high toughness and good antibacterial activity. RSC Adv. 2022, 12, 5255–5264. [Google Scholar] [CrossRef] [PubMed]
  184. Khalil, H.; Chen, T.; Riffon, R.; Wang, R.; Wang, Z. Synergy between polyethylenimine and different families of antibiotics against a resistant clinical isolate of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2008, 52, 1635–1641. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  185. Azevedo, M.M.; Ramalho, P.; Silva, A.P.; Teixeira-Santos, R.; Pina-Vaz, C.; Rodrigues, A.G. Polyethyleneimine and polyethyleneimine-based nanoparticles: Novel bacterial and yeast biofilm inhibitors. J. Med. Microbiol. 2014, 63, 1167–1173. [Google Scholar] [CrossRef]
  186. Haldar, J.; An, D.; Alvarez de Cienfuegos, L.; Chen, J.; Klibanov, A.M. Polymeric coatings that inactivate both influenza virus and pathogenic bacteria. Proc. Natl. Acad. Sci. USA 2006, 103, 17667–17671. [Google Scholar] [CrossRef] [Green Version]
  187. Li, Y.; Ge, J.; Luo, M.; Niu, W.; Ling, X.; Xu, K.; Lin, C.; Lei, B.; Zhang, X. Elastomeric self-healing antibacterial bioactive nanocomposites scaffolds for treating skull defect. Appl. Mater. Today 2022, 26, 101254. [Google Scholar] [CrossRef]
  188. Kundu, B.; Soundrapandian, C.; Nandi, S.K.; Mukherjee, P.; Dandapat, N.; Roy, S.; Datta, B.K.; Mandal, T.K.; Basu, D.; Bhattacharya, R.N. Development of New Localized Drug Delivery System Based on Ceftriaxone-Sulbactam Composite Drug Impregnated Porous Hydroxyapatite: A Systematic Approach for In Vitro and In Vivo Animal Trial. Pharm. Res. 2010, 27, 1659–1676. [Google Scholar] [CrossRef]
  189. Wenke, J.C.; Guelcher, S.A. Dual delivery of an antibiotic and a growth factor addresses both the microbiological and biological challenges of contaminated bone fractures. Expert Opin. Drug Deliv. 2011, 8, 1555–1569. [Google Scholar] [CrossRef]
  190. Qayoom, I.; Teotia, A.K.; Panjla, A.; Verma, S.; Kumar, A. Local and Sustained Delivery of Rifampicin from a Bioactive Ceramic Carrier Treats Bone Infection in Rat Tibia. ACS Infect. Dis. 2020, 6, 2938–2949. [Google Scholar] [CrossRef]
  191. Zheng, K.; Setyawati, M.I.; Leong, D.T.; Xie, J. Antimicrobial silver nanomaterials. Coord. Chem. Rev. 2018, 357, 1–17. [Google Scholar] [CrossRef]
  192. Mei, L.; Zhu, S.; Yin, W.; Chen, C.; Nie, G.; Gu, Z.; Zhao, Y. Two-dimensional nanomaterials beyond graphene for antibacterial applications: Current progress and future perspectives. Theranostics 2020, 10, 757–781. [Google Scholar] [CrossRef] [PubMed]
  193. Wei, G.; Yang, G.; Wang, Y.; Jiang, H.; Fu, Y.; Yue, G.; Ju, R. Phototherapy-based combination strategies for bacterial infection treatment. Theranostics 2020, 10, 12241–12262. [Google Scholar] [CrossRef] [PubMed]
  194. Zhou, J.; Zhang, Z.; Joseph, J.; Zhang, X.; Ferdows, B.E.; Patel, D.N.; Chen, W.; Banfi, G.; Molinaro, R.; Cosco, D.; et al. Biomaterials and nanomedicine for bone regeneration: Progress and future prospects. Exploration 2021, 1, 20210011. [Google Scholar] [CrossRef]
  195. He, W.; Zheng, Y.; Feng, Q.; Elkhooly, T.A.; Liu, X.; Yang, X.; Wang, Y.; Xie, Y. Silver nanoparticles stimulate osteogenesis of human mesenchymal stem cells through activation of autophagy. Nanomedicine 2020, 15, 337–353. [Google Scholar] [CrossRef]
  196. Choudhary, P.; Parandhaman, T.; Ramalingam, B.; Duraipandy, N.; Kiran, M.S.; Das, S.K. Fabrication of Nontoxic Reduced Graphene Oxide Protein Nanoframework as Sustained Antimicrobial Coating for Biomedical Application. ACS Appl. Mater. Interfaces 2017, 9, 38255–38269. [Google Scholar] [CrossRef]
  197. Jodati, H.; Yilmaz, B.; Evis, Z. In vitro and in vivo properties of graphene-incorporated scaffolds for bone defect repair. Ceram. Int. 2021, 47, 29535–29549. [Google Scholar] [CrossRef]
  198. Lei, Y.F.; Zhou, S.W.; Dong, C.Y.; Zhang, A.Q.; Lin, Y.L. PDMS tri-block copolymers bearing quaternary ammonium salts for epidermal antimicrobial agents: Synthesis, surface adsorption and non-skin penetration. React. Funct. Polym. 2018, 124, 20–28. [Google Scholar] [CrossRef]
  199. Li, P.; Li, J.; Feng, X.; Li, J.; Hao, Y.; Zhang, J.; Wang, H.; Yin, A.; Zhou, J.; Ma, X.; et al. Metal-organic frameworks with photocatalytic bactericidal activity for integrated air cleaning. Nat. Commun. 2019, 10, 2177. [Google Scholar] [CrossRef]
  200. Mamoon, A.M.; Gamal-Eldeen, A.M.; Ruppel, M.E.; Smith, R.J.; Tsang, T.; Miller, L.M. In vitro efficiency and mechanistic role of indocyanine green as photodynamic therapy agent for human melanoma. Photodiagn. Photodyn. Ther. 2009, 6, 105–116. [Google Scholar] [CrossRef]
  201. Genina, E.A.; Bashkatov, A.N.; Simonenko, G.V.; Odoevskaya, O.D.; Tuchin, V.V.; Altshuler, G.B. Low-intensity indocyanine-green laser phototherapy of acne vulgaris: Pilot study. J. Biomed. Opt. 2004, 9, 828–834. [Google Scholar] [CrossRef] [PubMed]
  202. Kirchherr, A.K.; Briel, A.; Mäder, K. Stabilization of indocyanine green by encapsulation within micellar systems. Mol. Pharm. 2009, 6, 480–491. [Google Scholar] [CrossRef] [PubMed]
  203. Saxena, V.; Sadoqi, M.; Shao, J. Degradation kinetics of indocyanine green in aqueous solution. J. Pharm. Sci. 2003, 92, 2090–2097. [Google Scholar] [CrossRef] [PubMed]
  204. Ateş, G.B.; Ak, A.; Garipcan, B.; Gülsoy, M. Indocyanine green-mediated photobiomodulation on human osteoblast cells. Lasers Med. Sci. 2018, 33, 1591–1599. [Google Scholar] [CrossRef] [PubMed]
  205. Ni, Z.; Hu, J.; Zhu, H.; Shang, Y.; Chen, D.; Chen, Y.; Liu, H. In situ formation of a near-infrared controlled dual-antibacterial platform. New J. Chem. 2022, 46, 1569–1576. [Google Scholar] [CrossRef]
  206. Rempe, S.; Hayden, J.M.; Robbins, R.A.; Hoyt, J.C. Tetracyclines and pulmonary inflammation. Endocr. Metab. Immune Disord. Drug Targets 2007, 7, 232–236. [Google Scholar] [CrossRef]
  207. Lakshmaiah Narayana, J.; Chen, J.Y. Antimicrobial peptides: Possible anti-infective agents. Peptides 2015, 72, 88–94. [Google Scholar] [CrossRef]
  208. Vandamme, D.; Landuyt, B.; Luyten, W.; Schoofs, L. A comprehensive summary of LL-37, the factotum human cathelicidin peptide. Cell. Immunol. 2012, 280, 22–35. [Google Scholar] [CrossRef]
  209. Zhou, C.; Ao, H.Y.; Han, X.; Jiang, W.W.; Yang, Z.F.; Ma, L.; Deng, X.Y.; Wan, Y.Z. Engineering a novel antibacterial agent with multifunction: Protocatechuic acid-grafted-quaternized chitosan. Carbohydr. Polym. 2021, 258, 117683. [Google Scholar] [CrossRef]
  210. Ao, H.; Yang, S.; Nie, B.; Fan, Q.; Zhang, Q.; Zong, J.; Guo, S.; Zheng, X.; Tang, T. Improved antibacterial properties of collagen I/hyaluronic acid/quaternized chitosan multilayer modified titanium coatings with both contact-killing and release-killing functions. J. Mater. Chem. B 2019, 7, 1951–1961. [Google Scholar] [CrossRef]
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Figure 1. Antibacterial agents and their categories for infected bone defects.
Figure 1. Antibacterial agents and their categories for infected bone defects.
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Figure 2. Possible antibacterial mechanisms for inorganic antibacterial agents of Ag, Cu, Au, and Zn. R-SH, sulfhydryls (Reprinted with permission from Ref. [50] Copyright 2021 Elsevier).
Figure 2. Possible antibacterial mechanisms for inorganic antibacterial agents of Ag, Cu, Au, and Zn. R-SH, sulfhydryls (Reprinted with permission from Ref. [50] Copyright 2021 Elsevier).
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Figure 3. Schematic illustration of the crafting process of the TiO2: FYH/Cur/BMP-2 NRs on Ti implant towards biofilm elimination, anti-inflammation, and bone regeneration. OCN, osteocalcin; OPN, osteopontin; RUNX2, runt-related transcription factor 2; QSI, quorum-sensing inhibitors; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6 (Reprinted with permission from Ref. [86]. Copyright 2021 Elsevier).
Figure 3. Schematic illustration of the crafting process of the TiO2: FYH/Cur/BMP-2 NRs on Ti implant towards biofilm elimination, anti-inflammation, and bone regeneration. OCN, osteocalcin; OPN, osteopontin; RUNX2, runt-related transcription factor 2; QSI, quorum-sensing inhibitors; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6 (Reprinted with permission from Ref. [86]. Copyright 2021 Elsevier).
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Figure 4. Scheme of the fabrication of CA-CS/Z hydrogels with acceptable adhesion properties and antibacterial properties, enhancing the stability of the implanting environment after bone transplantation. HCA, hydrocaffeic acid; 2-Mclm, 2-methylimidazole; VEGF, vascular endothelial growth factor (Reprinted with permission from Ref. [113]. Copyright 2020 American Chemical Society).
Figure 4. Scheme of the fabrication of CA-CS/Z hydrogels with acceptable adhesion properties and antibacterial properties, enhancing the stability of the implanting environment after bone transplantation. HCA, hydrocaffeic acid; 2-Mclm, 2-methylimidazole; VEGF, vascular endothelial growth factor (Reprinted with permission from Ref. [113]. Copyright 2020 American Chemical Society).
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Figure 5. Schematic illustration showing the synthesis process of multifunctional PAPB hydrogel and the effective application. (A) The synthesis process of multifunctional PAPB hydrogel, (B) potential biomedical applications of multifunctional PAPB hydrogel; (C) Intuitive optical images of before and after gelation; (D) Intuitive optical images of bending and elongation; (E) Intuitive optical images of before and after swelling. AA, acrylic acid (Reprinted with permission from Ref. [187] Copyright 2022 Elsevier).
Figure 5. Schematic illustration showing the synthesis process of multifunctional PAPB hydrogel and the effective application. (A) The synthesis process of multifunctional PAPB hydrogel, (B) potential biomedical applications of multifunctional PAPB hydrogel; (C) Intuitive optical images of before and after gelation; (D) Intuitive optical images of bending and elongation; (E) Intuitive optical images of before and after swelling. AA, acrylic acid (Reprinted with permission from Ref. [187] Copyright 2022 Elsevier).
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Cao, M.; Liu, C.; Li, M.; Zhang, X.; Peng, L.; Liu, L.; Liao, J.; Yang, J. Recent Research on Hybrid Hydrogels for Infection Treatment and Bone Repair. Gels 2022, 8, 306. https://doi.org/10.3390/gels8050306

AMA Style

Cao M, Liu C, Li M, Zhang X, Peng L, Liu L, Liao J, Yang J. Recent Research on Hybrid Hydrogels for Infection Treatment and Bone Repair. Gels. 2022; 8(5):306. https://doi.org/10.3390/gels8050306

Chicago/Turabian Style

Cao, Mengjiao, Chengcheng Liu, Mengxin Li, Xu Zhang, Li Peng, Lijia Liu, Jinfeng Liao, and Jing Yang. 2022. "Recent Research on Hybrid Hydrogels for Infection Treatment and Bone Repair" Gels 8, no. 5: 306. https://doi.org/10.3390/gels8050306

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