Advances in Material-Based Strategies for Diabetic Bone Regeneration

Abstract

Increased bone fragility and poor bone healing are common and serious complications of diabetes, especially in elderly patients. Long-term hyperglycemia often leads to serious infection and nonunion. Diabetes brings changes to bone microenvironment, including imbalanced immunity, disorder of macrophage polarization, deterioration of microvascular system, excessive advanced glycation end products, reactive oxygen species (ROS), local high levels of glucose, and great tendency to infection. The main traditional managements of diabetic bone involve oral medication and systematic drug administration, which exhibit limited therapeutic efficacy and accompanied side effects. Materials-based strategies have recently been potential alternatives for the treatment of diabetic bone diseases. In this review, we highlight the main material-based strategies for diabetic bone repair deficiency, including regulation of macrophages, elimination of excessive ROS, and resistance to bacterial infection. We also describe the future therapeutic designing approaches for smart biomaterials for diabetic bone regeneration, which would provide new ideas to protect bone health in patients with diabetes.

Graphical Abstract

Graphical Abstract.

Significance Statement.

Complications of diabetes result in great morbidity and mortality for the patient. Diabetes can affect bone microenvironment and lead to the accumulation of reactive oxygen species (ROS) and advanced glycation end products, dysfunction of macrophages, local hyperglycemia, and infectious micromilieu. The combination of cutting-edge technologies together with biomaterials strategies will ultimately provide promising methods for diabetic bone regeneration. In this review, we demonstrate the main advancements of material-based strategies for diabetic bone regeneration, including modulation of macrophages, ROS, and bacteria infection. This review will be valuable for researchers interested in the design strategies for diabetic bone regeneration.

Introduction

With aging aggravated, the prevalence of diabetes mellitus has been elevated dramatically across the world. Although 108 million patients suffered from diabetes in 1980, the World Health Organization (WHO) evaluated that the numbers of patients blew out approximately 4-fold by 2014.¹ The predicted number of patients living with diabetes would be 693 million by 2045.² As a chronic metabolic disease, type 1 (T1DM) and type 2 diabetes mellitus (T2DM) are recognized by elevated blood glucose concentration and chronic inflammatory reaction. Various complications caused by diabetes affect multiple organs and systems, including heart, brain, blood vessels, kidneys, skin, bringing a serious burden to the medical system and patients.³ Recently, the negative impact of diabetes on the skeletal system has received accumulating attention.⁴ Increased bone fragility and deficient bone regeneration become common and serious complications of diabetes, especially in elderly patients. Long-term hyperglycemia deteriorates bone fracture healing, leading to more serious infection and substantial mortality.⁵

For both T1DM and T2DM, diabetes-related bone diseases are frequently concomitant. Specifically, bone mass and bone density decrease, and microstructure of bone changes, such as increased cortical porosity and decreased microvascular blood flow, eventually leading to the decline of bone strength and long-term nonunion of bone defects.⁶ At the same time, diabetes will cause changes in the bone microenvironment, which are mainly manifested in the abnormal function of bone cells (osteoblasts and osteoclasts), increased bone marrow adipose tissue, advanced glycation end products (AGEs), excessive oxidative stress (ROS), disorder of macrophage polarization, lack of oxygen, changes in blood vessels, and chronic inflammation.⁵ Furthermore, when diabetic infectious micromilieu forms, patients would have easy access to local high-glucose condition and bacterial infection. Glucose transporter 4 (GLUT4) has recently been recognized as an important regulator of hyperglycemia because its low concentration or translocation to the cell membrane in patients with T2DM impedes glucose entering cells for energy production. Activation of the insulin-independent GLUT4 signaling pathways is an efficient treatment of diabetes.⁶ To promote diabetic bone regeneration, it is also essential to delve into the molecular and genetic levels to better understand the underlying mechanisms. The most important pathways that make a great impact on diabetic bone diseases include the receptor activator of NF-κB ligand (RANKL), insulin-like growth factor-1 signaling, and the Wnt signaling pathway, along with its inhibitors sclerostin and Dickkopf-1.⁷ For osteoblasts, Wnt signaling and autophagy are downregulated while ferroptosis is enhanced. For osteocytes, sclerostin and senescence are increased while mechanosensing and RANKL are decreased. For osteoclasts, efferocytosis and autophagy are downregulated. For adipocytes, adipsin, PPARγ, and RANKL are increased.⁸ Therefore, understanding the macro-micro changes of bone microenvironment in diabetes would decipher the smart strategies for diabetic bone regeneration. We summarized the major changes in diabetic bone microenvironment in Fig. 1.

Figure 1.

A scheme demonstration of macro-micro changes of bone microenvironment in diabetes. Created with BioRender.com.

Recently, biomaterials have been extensively applicated in bone tissue regeneration. Biomaterials with different regulatory strategies have made important contributions to the rapid development of bone tissue engineering.^9,10 However, the existing bone repair strategies of biomaterials mainly focus on healthy people, which may not be satisfied to patients with diabetes. Therefore, it is necessary to explore novel biomaterials that can enhance diabetic bone repair and improve the application potential of materials in the pathological microenvironment. At present, the material-based strategies in diabetic bone regeneration deficiency mainly include regulation of abnormal immunity, reversing acidic milieu, ameliorating local hyperglycemia, eliminating overproduced AGEs and ROS, restoring damaged vascular system, and fighting bacterial infection. In this review, we focused on the principal materials-based strategies, involving managing local chronic inflammation (targeting macrophages), scavenging excessive reactive oxygen species (ROS), and resisting bacterial infection. Moreover, we elucidate the advancements of intelligent biomaterials that can be used for solving problems of diabetic bone regeneration, which potentially offer personalized novel strategies for diabetic bone regeneration deficiency.

Materials-Based Strategy for Diabetic Bone Diseases

With the development of biomaterials, the research on bone tissue engineering biomaterials about diabetes is gradually increasing. Compared with traditional drug therapy, alternative strategies based on biomaterials show great potential to combat diabetic bone diseases with less complications. Due to their precise targeting ability, lower doses are required. This helps alleviate or even eliminate the adverse effects of systemic drug administration. Currently, material-based designing methods in diabetic bone repair primarily involve regulation of dysfunctional immune microenvironment,¹¹ neutralization of low PH,¹² mitigation of high glucose levels,¹³ clearance of accumulated AGEs and ROS,¹⁴ promotion of deteriorated microvascular,¹⁵ and resistance of bacterial infection.¹⁶ We have compared the advantages and disadvantages of traditional drug therapy and materials-based therapy in Fig. 2. In this review, we focused on the essential materials-based strategies, including reducing local chronic inflammation (targeting macrophages), scavenging excessive radical oxygen species (ROS), and striving against bacterial infection. The latest studies have focused on intelligent biological response materials, which endeavor functional regeneration and are responsive to pathological microenvironment. Here, we discussed the applications of different materials used for the promotion of diabetic bone regeneration based on the microenvironment changes of bone, and elucidated challenges of material-based therapeutic strategies.

Figure 2.

Comparison between materials-based therapy and traditional drug therapy for diabetic bone diseases. Created with BioRender.com.

Macrophage-Targeted Strategy

Macrophages are widely present in tissues, assisting in maintaining bone homeostasis during embryonic development and maturation.¹⁷ Macrophages are involved in regulating immune responses and osteogenic processes at all procedures of bone reconstruction.¹⁸ With sufficient plasticity, macrophages integrate various clues from the microenvironment of bone tissue while in regeneration process, and differentiate into corresponding phenotypes and functions to adapt to changes of niche.¹⁹ During bone regeneration, the extracellular microenvironment is highly dynamic, deciding the reversible property of macrophage polarization. Therefore, the function and the polarization of macrophages exhibit diverse states at different bone repair stages.²⁰ Under physiological condition, macrophages can switch from pro-inflammatory M1 phenotype to pro-repair M2 phenotype from the inflammatory stage, primary callus stage, and finally to the regeneration stage. Moreover, macrophages have sophisticated cooperation with osteoblast-related cells, and thus regulating bone reconstruction. Specifically, in the early stage, the role of macrophages is to clear away infectious substances and microorganisms such as bacteria. Meanwhile, stimulated by inflammatory factors such as tumor necrosis factor-α, interleukin-1β (IL-1β), and IL-6 in the microenvironment, infiltrating monocytes in the bone repair area can differentiate into pro-inflammatory macrophages. In the primary callus stage, macrophages resident in bone recruit bone marrow mesenchymal stem cells (BMMSCs) via paracrine cytokines, which could induce BMMSCs differentiate into osteogenic lineage cells, thus improving bone regeneration. The homeostasis of the M1/M2-like macrophage paradigm largely improves osteogenesis in the regeneration phase, which finally makes a great impact on reconstruction effect of new-bone-like tissue.^18,21

In diabetes, the metabolic disturbance in the bone marrow microenvironment significantly affects the metabolic pattern and functional plasticity of macrophages, which impedes macrophages involved in bone repair from transforming into M2 macrophages.²² For M1 macrophages, predominant metabolic pattern is that the glucose uptake is upregulated and the predominant pathway turns to glycolysis. For M2 macrophages, the metabolic manners are mainly through oxidative phosphorylation (OxPhos) and fatty acid oxidation. The possible reason relies on that glucose metabolism is necessary for inflammatory macrophage activation.^23,24 Macrophages are essential parts in the progress of diabetes and boost inflammatory response by releasing proinflammatory cytokines and proteases. Studies have revealed that the formation of ROS in monocytes and macrophages in diabetes is aggravated due to the change of glycolysis.²⁵ The response to upregulated glucose transporter type 1 sensor to elevated glucose is significant to macrophage aging, which is a potential mechanism of diabetes periodontitis deterioration.²⁶ Increased toll-like receptor 2/4 level in the blood of patients with diabetes activated NF-κB signaling, thus upregulating the expression level of various cytokines, thereby affecting the stability of the bone microenvironment.²⁷ White adipose tissue obtained from patients with diabetes is characterized by fat cell hypertrophy and high infiltration of proinflammatory macrophages. The results indicate that targeting macrophages via a mixture of glucose, insulin, and palmitic acid (ie, “metabolic activation”) generates a complicated macrophage phenotype that differs in mechanism from classical activation, indicating that metabolic disease-specific pathways promote inflammation through mechanisms unlike which during infection.²⁸

Given the importance of macrophages in diabetic bone repair, developing strategies aiming to regulate biological functions and macrophage phenotype is a promising choice. However, the intrinsic microenvironment is complex in diabetes, and the niches of macrophages shift dramatically, the therapeutic ways under physiological conditions are not satisfied to build the bone repair in diabetes. Engineered biomaterials have been recently used as a promising method to enhance bone reconstruction by repairing the pathological phase in diabetes via regulation of macrophage behaviors. Microsphere delivery system has been emphasized as effective drug vector to assure the continuous release of effective factors for bone regeneration. A study developed bioinspired injectable microsphere that was consistent of nanofibrous heparin-modified gelatin microsphere (NHG-MS). Additionally, IL4, which is the main cytokine contributing to the polarization of M1 into an M2 macrophage, was embedded into the NHG-MS. This immunomodulatory injectable system could accurately control the release of IL4, thus modulating M1 macrophage to transform into anti-inflammatory M2 macrophage and restoring bone regeneration in diabetes.²⁹ Similarly, delayed tooth extraction socket (TES) healing is prolonged in diabetes. Delayed healing is often attributed to the turbulent inflammatory response modulated by either M1 pro-inflammatory or M2 pro-healing phenotypes. A study designed a gelatin/β-TCP scaffold with sustained release of IL-4 to induce a phenotype switch to M2 macrophages, which improved osteogenesis and angiogenesis, thus promoting TES healing in diabetes.¹¹ Li et al³⁰ constructed a physically crosslinked DNA hydrogel with sustained release of cytokine IL-10 to promote diabetic alveolar bone reconstruction. The mechanism was that the ILGel induced M2 macrophage polarization, inhibited periodontal inflammation, and enhanced osteogenic differentiation of mesenchymal stem cells (MSCs). Sun et al³¹ fabricated 3D bioprinted scaffolds with modified bioinks, which consisted of gelatin, gelatin methacryloyl (GelMA), and 4-arm poly(ethylene glycol) (PEG) acrylate. Loaded with BMSCs, RAW264.7 macrophages, and BMP-4-loaded mesoporous silica nanoparticles (MSNs), this scaffold was implanted in diabetic bone defects, promoting osteogenic differentiation of BMSCs and regulating macrophage polarization to accelerate bone repair in diabetes. Chen et al³² built a hydrogel scaffold with high mechanical strength and an intrinsic porous 3D networks, which consists of hydroxyapatite (HA) nanocrystals, osteoinductive magnesium oxide (MgO) nanocrystals, and cysteine-modified γ-polyglutamic acid (PGA-Cys). This nanocrystal hybrid hydrogel (HA/MgO-H) successfully combates diabetes-related bone regeneration via the controlled release of Mg²⁺. The mechanism was that the scaffold downregulated infiltration of M1-like macrophages (CD80⁺) and upregulated angiogenesis (CD31⁺). Xiang et al³³ injected macroporous silk gel scaffolds loaded with sitagliptin at the bone-implant interface under diabetes conditions. The results showed that the silk/sitagliptin gel scaffolds could regulate polarization of M2 macrophages, and thus promoting osteointegration.

With the development of biomaterial science, the smart materials which could respond to the changes of microenvironment have become a promising tool for diabetic bone diseases. Li et al³⁴ designed a responsive dual-logic-based hydrogel that consists of reversibly cross-linked poly(vinyl alcohol) (PVA) network with a colloidal network electrostatically assembled from gelatin nanoparticles, to improve diabetic bone regeneration. Based on the level of glucose, ROS, and MMPs pathological clues, this hydrogel can intelligently regulate the time and type of drug release from biomaterials, and modulate macrophage polarization by remodeling the antioxidative system. Lee et al³⁵ reported that Titanium (Ti) discs with hydrophilic-modified SLA (modSLA) surfaces regulated M2 macrophages in the early osseous healing stage under physiological and diabetic condition. They also demonstrated that modSLA surface suppressed the inflammatory response and enhanced promoted M2 macrophage phenotype polarization, which promoted osseous healing in diabetes.³⁶

Extracellular vesicles, which transport noncoding RNA, mRNA, DNA, protein, and other bioactive substances, playing an important role in tissue regeneration engineering via mediating intercellular signaling. Nowadays, Multiple studies have found that extracellular vesicles orchestrate the osteogenic differentiation function of MSCs, including miR-29a, miR-29c, miR218, and thus playing a predictive and suggestive role in bone regeneration.³⁷ Wang et al³⁸ demonstrated that M2-exosomes dramatically downregulated the proportion of M1 macrophages, thus improving fracture healing in diabetes. They also found that M2-exosomes promoted the shift of M1 phenotype into M2 phenotype through regulating PI3K/AKT pathway. Ying et al³⁹ found that M2 bone marrow-derived macrophages (M2 BMDM Exos) can secrete extracellular vesicles containing miRNA, improving insulin sensitivity in obese mice. Overexpression of miR-690 (highly expressed in M2 BMDM Exos) in miRNA-depleted BMDMs could produce Exos that simulate the function of M2 BMDM Exos on metabolic patterns. Zhang et al⁴⁰ demonstrated that miR-144-5p was highly expressed in diabetic bone marrow-derived macrophages (dBMDM-exos), and it could be carried into BMSCs to improve bone formation via Smad1 pathway.

Recently, the roles of electrical microenvironment have been hotspots in bone tissue engineering. It has been revealed that electrical cues play an important part in orchestrating migration, physiological activity, and cytokine production of macrophages.^41,42 However, the application of electrical characteristics in diabetic bone regeneration is still limited. Dai et al⁴³ fabricated a ferroelectric BaTiO₃/poly(vinylidene fluoridetrifluoroethylene) (BTO/P(VDF-TrFE)) nanocomposite membrane to simulate the electrical microenvironment of natural bone. The polarized BTO/P(VDF-TrFE) membranes suppressed M1 macrophage polarization induced by high glucose level and promoted bone regeneration in diabetic rats. The mechanism was that the polarized electrical membranes suppressed PI3K-AKT signaling pathway, and thus attenuating pro-inflammatory M1 phenotype polarization under hyperglycemic conditions. Table 1 summarized the biomaterial-based macrophage targeting strategies.

Table 1.

Summary of biomaterial-based strategies targeting macrophage.

Biomaterials	Mechanisms	Animal models	References
A double-network hydrogel consisting of PBA-cross-linked PVA and gelatin colloids	Regulation of macrophage polarization by remodeling the mitochondria-related antioxidative system	Calvarial bone defect in diabetic rat model	18
Bioprinted gelatin/β-TCP scaffold with sustained release of IL-4	Regulation of macrophage polarization	TES healing in T2DM mice model	11
3D bioprinted scaffolds with modified bioinks, which consisted of gelatin, GelMA, and 4-arm PEG acrylate, loading BMP-4-loaded MSNs	Regulation of macrophage polarization	Calvarial bone defect in diabetic rat model	31
HA/MgO nanocrystal PGA-Cys hybrid hydrogel (HA/MgO-H)	Reducing infiltration of pro-inflammatory macrophages (CD80+) and higher angiogenesis (CD31+)	Femoral defects of diabetic rats	32
Silk gel scaffolds loaded with sitagliptin	Recruitment of M2 macrophages to the sites of Ti implants	Femoral defects of diabetic rats	33
PBA-cross-linked PVA and gelatin colloids	Regulation of macrophage polarization by remodeling the mitochondria-related antioxidative system	Calvarial bone defect in diabetic rat model	34
M2 macrophage-derived exosomes	Inducing the conversion of M1 macrophages into M2 macrophages by stimulating the PI3K/AKT pathway	Femoral defects of diabetic C57BL/6	38
Suppression of miR-144-5p in dBMDM-exos	Be transferred into BMSCs to regulate bone regeneration by targeting Smad1	Femoral defects of diabetic rats	40
Piezoelectric BaTiO3/Ti6Al4V (BT/Ti) scaffold	1. Promoting M2 polarization of macrophages 2. Inhibiting the inflammatory MAPK/JNK signaling cascade and activated OxPhos and ATP synthesis in macrophages	Cervical corpectomy and artificial vertebral body implantation of diabetic sheep	42
Ferroelectric BTO/P(VDF-TrFE) nanocomposite membrane	1. Inhibiting high glucose-induced M1-type inflammation under hyperglycemic conditions by suppressing expression of AKT2 and IRF5 within the PI3K-AKT signaling pathway 2. Switching macrophage phenotype from the pro-inflammatory (M1) into the pro-healing (M2) phenotype	Calvarial bone defect in diabetic rat model	43

ROS-Targeted Strategy

Under physiological condition, intrinsic cellular antioxidant mechanisms are adequate to resist oxidative stress and the consequent impact. This balance is orchestrated via sophisticated and elaborate signaling pathways.⁴⁴ Under diabetic condition, the homeostasis between the generation of ROS and the scavenging capacity of antioxidant defense system was disturbed. Once the balance is broken, the intrinsic antioxidant defense system is transcended by markable upregulation of ROS. Increased glucose level induces additional ROS, thus aggravating complications of diabetes and delaying diabetic bone healing.⁴⁵ In diabetes, the underlying mechanism of increased ROS may be attributed in the accumulation of AGEs, increased glucose autoxidation, activation of protein kinase C isoforms, polyol pathway flux, and mitochondrial overproduction of superoxide results in increased oxidative stress.⁴⁶ The expression of free fatty acids and leptin is upregulated, contributing to accumulation of ROS.⁴⁷ Moreover, tendency of insulin resistance also leads to the excess generation of ROS.⁴⁸

Multiple studies on the effectiveness of antioxidants in 2 types of diabetes have revealed that antioxidants should be part of the treatment process. The modern treatment strategy for diabetes aims to develop new methods of personalized antioxidant treatment, including the combination of ROS source targeting and new methods of antioxidant delivery.

Multiple studies suggested that effective antioxidants targeting ROS should be an efficient treatment option for diabetes. The modern strategy improving diabetic bone defect healing is to design personalized antioxidants, including the scavenging ROS and regulating anti-inflammatory activities.^45,49 Zhang et al⁵⁰ designed an antioxidant alpha-lipoic acid (ALA)-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres which could release ALA sustainedly. The biodegradable PLGA microspheres loaded with ALA cleared ROS and partially rescued the impaired osteogenic differentiation capacity of MSCs under diabetic condition. Singh et al⁵¹ decorated nanoceria on nanofibrous or 3D-printed scaffolds, which enhanced bone regeneration in diabetic conditions via scavenging ROS and activating TGF-β-SMAD2/3/-P38 pathway. Li et al⁴⁹ developed a scaffold to promote the diabetic periodontal bone regeneration, which consists of polydopamine (PDA)-mediated graphene oxide (PGO), PDA-modified HA nanoparticles (PHA), and alginate/gelatin (AG). This PGO-PHA-AG scaffold owns excellent antioxidative property to clear intrinsic ROS in RAW 264.7 cells. Moreover, this scaffold enhances M2 macrophage and promotes osteogenic differentiation of BMMSCs via elevated osteogenic-related cytokines from M2 macrophages. The specific mechanism is mediated by glycolytic and RhoA/ROCK pathways in macrophages. Yang et al¹³ constructed a 3D printed enzyme-functionalized scaffold, which used alginate, glucose oxidase (GOx), and catalase-assisted biomineralized calcium phosphate nanosheets (CaP@CAT NSs). Gluconic acid and hydrogen peroxide (H₂O₂) could be catalyzed by this scaffold, and the hyperglycemia environment in diabetes could be ameliorated. The role of CaP@CAT NSs is to scavenge H₂O₂ in diabetes, and thus creating hypoxic microenvironment to improve neovascularization. Furthermore, CaP@CAT NSs promote the mechanical performance of the scaffolds, and degraded Ca²⁺ and PO₄³⁻ ions enhance diabetic bone repair. Lao et al⁵² constructed a metformin (Met)-loaded zeolitic imidazolate frameworks (nanoparticles-Met@ZIF-8) modified GelMA hydrogel, which could release Met and Zn⁺. This composite hydrogel responded the changes of PH in diabetic environment to eliminated excessive ROS, alleviated inflammation and mitochondria damage, as well as promoting M2 macrophage polarization.

Notably, overproduced ROS induced by diabetic microenvironment makes side effect on bone regeneration and hinders the osseointegration of implants. Ma et al⁵³ reported that silk fibrous (SF)-coated Ti implants (STIs) improved the osteoblast biological dysfunctions caused by diabetes via ROS-mediated NF-κB signaling pathway. Then, they coated a silk fibroin-based HA (SF/HA) hybrid material to Ti implant (SHT), finding that this scaffold inhibits ROS overproduction via PI3K/Akt signaling, and thus promoting osseointegration of the TI implant under diabetic condition.⁵⁴ Tao et al⁵⁵ investigated the role of silibinin (SIL)-modified HA coating on osseointegration in diabetes, reporting that this coating could reduce the level of ROS to improve osseointegration of diabetic rats via activation SIRT1/SOD2 signaling pathway. Wang et al⁵⁶ used electrospinning technology to fabricate a nanofiber and encapsulated melatonin (MT) in PLGA to generate a coating on a PDA-modified Ti surface. The incorporated MT downregulated the expression of ROS. This coating improved osteogenic differentiation on the titanium-bone (Ti-B) interface by BMP-4/WNT pathway to promote osteointegration in T1DM mice with tibial bone defects.

Since chitosan has showed great antioxidant activity, Li et al⁵⁷ explored the effect of chitosan-coated porous Ti alloy implant (CTI) on diabetes-induced impaired osseointegration. They found CTI could attenuate ROS level via PI3K/AKT pathway. These coating strategies provide effective surface functionalization methods for underlying clinical application of Ti implant of patients with diabetes. Semaphorin 3A (Sema3A) has been recognized as a positive gene for promoting osteogenesis, especially on surface-mediated osteogenic differentiation.⁵⁸ Wang and Wei⁵⁹ reported that treatment with Sema3A on HA-coated Ti rod could promote osseointegration in diabetic rat model, through downregulating the oxidative stress of osteoblasts. Wu et al¹⁴ investigated that proanthocyanidin (PC) loading in phenyl sulfide mesoporous silica nanoparticles (PMS) could be triggered by ROS in microenvironment and then diminished overproductive ROS, which reached dynamic ROS orchestration and homeostasis ultimately. Wang et al⁶⁰ constructed a dual nutrient elements (ZnO and Sr(OH)₂) coating onto the sulfonated polyetheretherketone (SPEEK) implant surface (Zn&Sr-SPEEK). This coating-implant rescued osteogenic differentiation of osteoblasts under diabetic conditions, via suppressing the overexpression of Drp1 gene and eliminating excessive ROS, as well as restoring mitochondrial function. Huang et al⁶¹ found that TiO₂ nanotube (TNT) coating on Ti implants directly promoted osteogenesis of BMMSCs and osseointegration under diabetic conditions. The mechanism was that TNT coating improved the activity of superoxide dismutase 2, neutralized intracellular ROS, and inhibited apoptosis, via upregulation of forkhead box transcription factor O1 (FoxO1). Moreover, TNT coating ameliorated oxidative stress in macrophages, upregulating the portion of M2 phenotype under diabetic microenvironment with increased secretion of the anti-inflammatory factors, thus enhancing the osseo-immunity capacity. Table 2 summarized the biomaterial-based ROS targeting strategies.

Table 2.

Summary of biomaterial-based strategies targeting ROS.

Biomaterials	Mechanisms	Animal models	References
ALA-loaded PLGA microspheres	Scavenging ROS and partially recovering the mesenchymal stem cell proliferation and differentiation	Calvarial bone defect model of diabetic rats	50
Nanoceria decorated on nanofibrous or 3D-printed scaffolds	Scavenging ROS and activating TGF-β-SMAD2/3/-P38 pathway	Calvarial bone defect model of diabetic rats	51
PHA-incorporated conductive AG scaffold	1. Transferring endogenous electrical signals to cells and activating Ca2+ channels 2. ROS-scavenging, promoting M2 polarization via glycolytic and RhoA/ROCK pathways in macrophages	Periodontal bone defects of diabetic rats	49
Alginate, GOx, and CaP@CAT NSs scaffold	1. GOx alleviates the hyperglycemia environment by catalyzing glucose and oxygen into gluconic acid and H2O2 2. CaP@CAT NSs scavenge H2O2 3. The initiated hypoxic microenvironment stimulates neovascularization 4. CaP@CAT NSs enhance the mechanical property, and facilitate bone regeneration by the degraded Ca2+ and PO43− ions	Calvarial bone defect model of diabetic rats	13
A Met-loaded zeolitic imidazolate frameworks (nanoparticles-Met@ZIF-8) modified GelMA hydrogel	Eliminating excessive ROS, alleviating inflammation and mitochondria damage, as well as promoting M2 macrophage polarization	Calvarial bone defect model of diabetic rats	52
STIs	Improving the osteoblast biological dysfunctions caused by diabetes via ROS-mediated NF-κB signaling pathway	Crista iliaca of the diabetic sheep	53
SHT	Activation of ROS-mediated PI3K/Akt signaling pathway to promote osseointegration of implant	Critical-sized defect of femoral bone in diabetic rabbits	54
SIL-modified HA coating on osseointegration	Reducing ROS through activation of SIRT1/SOD2 signaling pathway	Femoral bone of diabetic rats	55
PLGA@MT-Ti	Activation of the BMP-4/WNT pathway and attenuates ROS overproduction to promote osteointegration at the Ti-B interface	T1DM mice with tibial bone defects	56
CTI	ROS-mediated reactivation of PI3K/AKT pathway	Ilium defects of diabetic sheep	57
Sema3A on HA-coated Ti rod	Sema3A reduces the oxidative stress of osteoblasts and enhancing the function of osteoblasts in a diabetic rat	Femoral bone defects of diabetic rats	59
Injectable local drug delivery system (LDDS) which consists of OD and PBA-PEI, loading Doxy and Met	1. The LDDS improves drug-loading efficiency (Doxy and Met) through B-N coordination 2. Achievement of ROS-triggered drug release locally 3. Remarkable antibacterial effect	Chronic periodontitis model of maxillae in STZ-induced diabetic rats	16
ROS reactive PMS/PC system	1. PC was released from the ROS-reactive PMS/PC triggered by peripheral ROS and then eliminated excessive ROS 2. Promoting the angiogenesis-osteogenesis coupling via downregulating the expression of nicotinamide adenine dinucleotide phosphate oxidase 2 to suppress ROS overproduction, preventing vascular oxidative stress	Tibia defects of db/db type 2 diabetes model mice diabetic mouse	14
Zn&Sr-SPEEK	1. Downregulation of dynamin-related protein 1 (Drp1) gene 2. Regulation of mitochondrial membrane potential (MMP) resurgence 3. Elimination of ROS	Femoral defects of diabetic rats	60
TNT coating on Ti implants	1. Promoting superoxide dismutase 2 activity, neutralizing of ROS, and inhibiting apoptosis, via upregulation of FoxO1 2. Alleviating oxidative stress in macrophages upregulating the portion of M2 phenotype	Femoral defects of diabetic rats	61

Antibacterial Strategy

The main properties of diabetes infection microenvironment (DIM) are local high glucose level and susceptibility of bacteria. These 2 characteristics will affect bone metabolism and suppress osseointegration, thus increasing the failure rate of implants and the risk of complications in patients with diabetes.⁶² At present, conventional implant surface modification strategies mainly focus on the research and development of antibacterial coating or regulating the dynamic equilibrium functional interface of bone-implant. A number of surface modification methods have been proposed to promote diabetic bone regeneration,⁶³ such as HA, nutrient metals. Due to their effectiveness against bacteria, bioactive factors such as antimicrobial peptides and antibiotics⁶⁴ have been extensively used in clinical and research applications. However, bacterial resistance and the insensitivity of biofilms to drugs make anti-infection even more difficult.⁶⁵ Although these bioactive materials have obtained good therapeutic effects in the noninfectious environment of diabetes models, it is difficult to achieve good antibacterial effects in the face of the complex and changeable diabetic infectious microenvironment. Zhao et al¹⁶ developed a novel drug delivery system (LDDS) using oxidized dextran (OD) and phenylboronic acid-functionalized poly(ethylene imine) (PBA-PEI). This injectable (LDDS) could not only elevate drug loading efficiency (doxycycline (Doxy) and Met) by B-N coordination, but also locally release ROS-triggered drug. Notably, this system exhibited significant antibacterial function against S. aureus, E. coli, and Porphyromonas gingivalis. Recently, phototherapy has been extensively used for anti-infection dynamic therapeutic strategy, including photothermal therapy and photodynamic therapy.⁶⁶ In addition, chemodynamic therapy is also a prospective option for anti-bacteria under a special acidic micromilieu, because Fenton (-like) reaction produces a multitude of hydroxyl radicals (·OH).^67,68 Li et al⁶⁹ designed a strategy for implant surface modification, using copper sulfide (CuS), graphene oxide (GO) biological heterojunction (CuS/GO), and GOx coating polyetheretherketone (PEEK) implants (SP-Cu/G@GOx) to achieve antibacterial effects under DIM and promoting osseointegration of implants. This strategy transformed disadvantages into engine power of antibacterial and osteogenesis, and enhance the osseointegration of implants in the microenvironment of diabetes infection. Lee et al¹² developed a pH-responsive cinnamaldehyde-TNT coating (TNT-CIN), which speedily released in the low PH condition caused by diabetes. This coating promoted diabetic bone repair by facilitating osteogenic differentiation of MSCs, M2 polarization of macrophages, as well as resisting P. gingivalis and Streptococcus mutans effectively. Huang et al⁷⁰ modified PEEK by an advanced layer-by-layer construction method to make multifunctional PEEK (SP@(TA-GS/PF)*3), loading with tannic acid (TA), gentamicin sulfate (GS), and Pluronic F127 (PF127) on the basis of porous sulfonation (SPEEK). This scaffold showed great antibacterial property and improved the osteogenesis of MC3T3-E1. In addition, it scavenged overproductive oxidative stress to improve the HUVEC growth, promoting neovascularization via upregulated secretion of VEGF (Table 3).

Table 3.

Summary for biomaterial-based strategies targeting bacterial infection.

Biomaterials	Mechanisms	Animal models	References
Injectable local drug delivery system (LDDS) which consists of OD and PBA-PEI, loading Doxy and Met	Inhibition of E. coli, S. aureus, and P. gingivalis	Chronic periodontitis model of maxillae in STZ-induced diabetic rats	16
Bioheterojunction-engineered orthopedic PEEK implant consisting of CuS/GO bioheterojunctions (bioHJs) and GOx	Inhibition of S. aureus and E. coli under NIR	Femoral defects of STZ-induced diabetic rats	69
Multifunctional PEEK (SP@(TA-GS/PF)*3) by the assembly of TA, GS, and PF127 on the basis of prepared porous PEEK through sulfonation (SPEEK)	Scavenged excessive ROS for enhanced neovascularization; Inhibition of S. aureus	Femoral defects of STZ-induced diabetic rats	70

Conclusion and Future Perspectives

Diabetes is one of the major chronic diseases threatening the global human health. The high prevalence of osteopenia and osteoporosis in patients with diabetes has brought difficulties to the implementation of clinical strategies. Meanwhile, the increase of the prevalence of diabetes directly leads to the increment of the tooth loss rate, which results in a surge in demand for dental implant. Recently, with the deepening understanding of the diabetic pathological microenvironment, it has been revealed that except high glucose and persistent chronic inflammation, local excessive oxidative stress and immune homeostasis imbalance will eventually interfere with the diabetic bone regeneration by interfering with the energy metabolism of macrophages, destroying the activity of endogenous growth factors, and damaging the regenerative potential of related cells. Therefore, the current strategies for diabetic bone reconstruction are mainly regulating macrophage polarization, scavenging ROS, and combating bacteria infection. However, besides macrophages, the roles of regulatory T cells (Tregs)-mediated immune management in regulating microenvironment for periodontal tissue regeneration are attractive, which results in the enrichment and expansion of functional Tregs in the defect region and reconstructed the local immune microenvironment.⁷¹ This Tregs-targeted strategy affords us lessons that would merit designing thoughts for diabetic bone regeneration. With the development of advanced materials and nanotechnology, the application of intelligent responsive biomaterials in diabetic bone regeneration has gradually become a hotspot. Intelligent responsive biomaterials include pH, redox reaction, enzyme, glucose, ions, temperature, electricity, and engineered nanoparticles, but the applications in diabetes bone repair are still limited.⁷² Presently, there are few studies on glucose-responsive smart biomaterials to promote diabetic bone regeneration.¹³ This field may be an important direction in treatment of diabetic bone diseases in the future. Additionally, in diabetic bone regeneration, the orchestration of microenvironment involving bone, blood vessels, and various cells is complicated. Four-dimensional printed stimulus-responsive biomaterials can accurately achieve the spatial distribution and sequence release of tissue engineering seed cells and bioactive substances, which is conducive to the establishment of bone regeneration microenvironment. However, for the development and application of new biomaterials related to diabetic bone regeneration, more extensive basic research and preclinical experimental exploration are needed to obtain more safe and effective treatment.

Funding

This work was supported by the National Natural Science Foundation of China (82201023), Open Research Project of State Key Laboratory of Oral Disease (SKLOD2023OF04), and Research Foundation of Peking University School and Hospital of Stomatology (PKUSS20210102).

Conflict of Interest

All the authors declared no potential conflicts of interest. Graphical abstract, Fig. 1 and Fig. 2 were created with Biorender.com.

Author Contributions

Z.L.: study conceptualization, investigation, visualization, writing—original draft. M.Y.: writing—review and editing. Y.Z.: study conceptualization, supervision, investigation, project administration, writing—review and editing.

Data Availability

No new data were generated or analyzed in support of this research.