Abstract
Treatment of large bone defects represents a great challenge in orthopedic and craniomaxillofacial surgery. Traditional strategies in bone tissue engineering have focused primarily on mimicking the extracellular matrix (ECM) of bone in terms of structure and composition. However, the synergistic effects of other cues from the microenvironment during bone regeneration are often neglected. The bone microenvironment is a sophisticated system that includes physiological (e.g., neighboring cells such as macrophages), chemical (e.g., oxygen, pH), and physical factors (e.g., mechanics, acoustics) that dynamically interact with each other. Microenvironment-targeted strategies are increasingly recognized as crucial for successful bone regeneration and offer promising solutions for advancing bone tissue engineering. This review provides a comprehensive overview of current microenvironment-targeted strategies and challenges for bone regeneration and further outlines prospective directions of the approaches in construction of bone organoids.
Keywords: Bone regeneration, Physiological microenvironment, Chemical microenvironment, Physical microenvironment, Biomaterials
Graphical abstract
1. Introduction
With the development of an aging society, the incidence of bone-related diseases has dramatically increased worldwide [1]. Bone has the potential to heal and regenerate, but the inability to complete bone healing on its own in large segmental bone defects (>2 cm critical size or >50% loss of bone girth) due to trauma, infection, tumor resection or developmental malformations is a serious problem in orthopedic treatment [2]. Although autologous bone grafting is the “gold standard” for clinical bone repair, it still suffers from secondary surgical injuries, severe donor area injuries and complications [3]. Bone tissue engineering to design material scaffolds, cells and signaling molecules to induce new bone tissue formation by eliminating risks associated with autografting has been a key approach in current bone repair treatments [4]. A variety of different cells in bone (including bone-associated cells, immune cells, endothelial cells, etc.) share the same microenvironment and play an important role in osteogenesis. However, traditional bone tissue engineering studies have focused only on the effects of extracellular matrix (with collagen and hydroxyapatite as the main components [5]) on osteogenesis, ignoring the effects of other cellular and non-cellular cues in the local microenvironment on osteogenesis. Bone microenvironment is a complex structural and biological system that can be distinguished into three parts according to its function and components it contains: physiological microenvironment, chemical microenvironment, and physical microenvironment (Fig. 1). Physiologically, it contains immune cells and endothelial cells, and the physiological microenvironment supports the effective functioning of bone tissue through the integration of cellular energy metabolism exhibiting a tendency to immunosuppression and protection of hematopoietic stem cell components. Recent studies have shown that M2-type macrophages can improve the physiological microenvironment at the site of injury and promote osseointegration by converting the inflammatory microenvironment into an anti-inflammatory microenvironment [6]. Chemically, nutrients such as oxygen and pH as well as various signaling molecules released by different cell types are essential for cell survival and function. Li et al. attempted to enhance the oxygen supply to bone defect areas, and the hypoxic environment was improved, showing a significant increase in osteogenic capacity [7]. Physically, appropriate external stimuli can also influence cell fate, providing new ideas for bone tissue engineering to treat bone defects. By comparing osteoblasts in static culture to those subjected to mechanical stimulation, Brady found that paracrine factors secreted after mechanical stimulation significantly enhanced migration, proliferation, and osteogenesis [8]. In conclusion, engineering of bone microenvironment has emerged as a promising research direction for the design of bone biomaterials. In this review, we elucidate the dynamic regulatory role of cellular and peripheral cues in the bone microenvironment, systematically classify the various cues of the bone microenvironment, and summarize the regulatory role of each class of cues on bone repair. Finally, we discuss the challenges faced in constructing bone microenvironments and future directions for incorporating bone organoids. This work provides solid theoretical support for the construction of advanced bone microenvironments and offers new avenues for the development of bone tissue engineering.
Fig. 1.
The diagram of bone tissue cell microenvironment. Bone microenvironment can be divided into three parts: physiological microenvironment, chemical microenvironment and physical microenvironment.
2. Traditional strategy mimicking ECM
ECM is regarded as a novel regenerative material that not only provides a physical scaffold for cells in tissues but also regulates numerous cellular processes, including growth, migration, differentiation, and morphogenesis [[9], [10], [11], [12]]. The ECM is adynamic structure that undergoes controlled remodeling continually. Maintaining its integrity and homeostasis is essential for tissue growth and organ physiology, while the loss of ECM components or structural changes may result in disease development. A key distinction between bone and other tissues lies in the high percentage of matrix components and the low percentage of cellular components in bone. Heterogeneity is one of the fundamental features of ECM, and numerous studies have shown that different physical properties of biomaterials can influence the differentiation fate and cellular behavior of stem cells [13]. Mesenchymal stem cells have multidirectional differentiation potential and can differentiate into a variety of tissue cells such as adipose, bone, cartilage, muscle, nerve, cardiac muscle, endothelium, etc. [14]. It is also the most widely studied seed cell in bone tissue engineering. Research has supported that biomaterials can achieve stem cell osteogenic differentiation by modulating nanoscale surface morphology in the absence of additional osteogenic supplements [15]. For example, Zhang et al. designed a nanocomposite membrane that mimics endogenous potentials, and a proper electrical microenvironment greatly promotes bone regeneration [16]. In this review, we focus on the field of biomaterials to modulate heterogeneous osteogenic differentiation. The composition of bone tissue ECM can be categorized into organic and inorganic components. The organic component primarily consists of collagen, while the inorganic part is mainly composed of hydroxyapatite (HA). Together, these components constitute the ECM and possess specific biological functions [17]. Mimicking the ECM of bone tissue to promote cellular function and bone regeneration is a reasonable and feasible approach [18]. In this section, the traditional ECM-based repair strategy will be discussed in detail.
2.1. Mimicking component of ECM
2.1.1. Collagen
The ECM of bone tissue is abundant in collagen, which can be cross-linked via functional groups to generate materials with tailored mechanical or biological properties, making it highly applicable in tissue engineering [19,20]. Collagen scaffolds exhibit favorable biological properties, such as hydrophilicity, low antigenicity, and biodegradability [21,22]. However, singular collagen scaffolds lack sufficient mechanical strength, leading to the incorporation of other biomaterials like calcium phosphate, bioceramics, and polymers during scaffold design [23,24]. Zhong et al. developed a collagen-HA co-assembled scaffold, which exhibited strong bioactivity and increased the osteogenic differentiation potential of BMSCs with a similar composition to ECM (Fig. 2A) [25]. Xia's group further combined collagen with calcium phosphate to create a biomimetic composite coating that enhanced cellular affinity and in vivo absorption, supporting osteoblast activity and new bone formation [26].
Fig. 2.
Biomaterials mimic the component and structure of ECM for bone repair. A) Collagen-HA co-assembled scaffolds loaded with immune ions are programmed to promote osteogenic gene expression in BMSCs. Reproduced and adapted with permission [25]. Copyright 2022, Elsevier. B) Bionic HA scaffold regulates the cellular activity of MSCs and enhances the ossification process to promote bone repair. Reproduced and adapted with permission [37]. Copyright 2021, Elsevier. C) Age-specific dECM provides different local environments for BMSCs and promotes microfracture repair in vivo. Reproduced and adapted with permission [40]. Copyright 2021, American Chemical Society. D) HA scaffold with natural bone-mimicking nanopores to improve bone regeneration efficiency. Reproduced and adapted with permission [41]. Copyright 2022, Springer Nature.
Numerous membrane types have been utilized in guided bone regeneration techniques. Collagen membranes, the most prevalent, offer resorbability and in vivo degradation, minimizing inflammatory responses associated with foreign body scaffolds [27,28]. Presently, collagen membranes are frequently employed in the restoration of periodontal defects, obviating the need for secondary surgery [29]. Bio-Gide®, a prominent commercial collagen membrane, exhibits a unique bilayer structure that effectively inhibits epithelial cell infiltration into the defect site and fosters osseointegration [30,31]. To enhance the resistance to degradation and to expand the efficacy of absorbable collagen membranes, many chemical and physical cross-linking methods have been applied to manufacture cross-linked collagen fibers, including UV, glutaraldehyde, hexamethylene diisocyanate, diphenylphosphoryl azide, and enzymatic cross-linking [32]. The principle is to extract collagen into single fibers, which are then reconstituted and cross-linked [33].
2.1.2. Hydroxyapatite
HA possesses exceptional biocompatibility and mechanical properties and demonstrates stable interfacial binding within bone tissue [34,35]. HA surfaces can directly bind to new bone, support osteoblast adhesion, growth, and differentiation, and facilitate new bone deposition by means other than adjacent living bone [36]. Consequently, HA is extensively employed as a bone substitute, metal implant coating, tissue engineering scaffold, and drug delivery carrier, earning the designation of a “bioactive material.” Recent studies have revealed that HA scaffolds can function as osteogenic mediators during osteogenesis via the ZBTB16 and WNT signaling pathways [37]. This phenomenon may be attributed to the integrated microenvironment of specific bioactive materials providing an osteogenic advantage for osteoblasts (Fig. 2B). Ohgushi et al. further corroborated the interaction between HA and bone tissue, demonstrating that the HA surface can support cell differentiation and facilitate cell and bone formation [38]. HA coating combined with metal implants is a widely employed bone repair strategy. Yamada et al. successfully generated nano-polycrystalline HA on the surface of micro-coarsened titanium (Ti) [39]. During the healing phase, the HA-coated Ti significantly enhanced the strength of bone-implant integration compared to uncoated micro-roughing Ti. Thus, the osteogenic scaffold can be optimized by HA coating to improve bone-implant integration and pinpoint specific bone morphogenesis parameters.
2.2. Mimicking the structure of ECM
2.2.1. Decellularized ECM scaffold
The decellularized extracellular matrix (dECM) is the extracellular part of the tissue that is highly bioactive, low immunogenic and well biodegradable. The main advantage of dECM is that biomolecules in ECM are retained, supporting cell growth and viability. However, the decellularization process presents challenges, particularly maximizing cellular material removal while minimizing ECM damage. To evaluate dECM's potential for promoting the osteogenic process, Hashimoto et al. compared MSC differentiation on three-dimensional dECM and two-dimensional tissue culture polystyrene discs, observing significantly higher alkaline phosphatase (ALP) activity in MSCs grown in decellularized bone matrix [42]. This finding suggests that the decellularized bone matrix facilitates early osteogenic differentiation of MSCs. Furthermore, when rabbit dECM from different age groups, such as neonates, children, and adolescents, was co-cultured with BMSCs, BMSCs exhibited distinct cell morphology, roundness, and proliferation characteristics in vitro (Fig. 2C) [40]. To enhance the osteoinductivity of dECM, researchers have tried to incorporate different materials such as HA, glass-ceramics and Ti in dECM scaffolds, all of which proved to enhance osteogenic differentiation and bone repair [43,44]. These findings indicate that dECM, as a biomaterial, holds the potential for promoting bone regeneration.
2.2.2. Synthetic ECM scaffold
Hydrogels, polymeric materials with water solubility, form three-dimensional network structures through cross-linking reactions between hydrophilic polymers. Owing to their biomimetic properties, hydrogels can emulate the ECM internal structure and provide support for cells to perform physiological functions [45]. Many natural or synthetic materials are used as hydrogel base units for bone repair. In the last decade, hydrogels have been developed in various implantable forms to address different types or locations of bone diseases [46]. Implantable hydrogels are widely used due to their mechanical strength and ease of shape adjustment at pre-designed sites. In-situ injectable hydrogel scaffolds have excellent sol-gel properties allowing filling of defective sites without traditional major surgery [47]. Thus, hydrogels are considered promising candidates for bone tissue engineering. Due to the nanoscale size of natural tissues or organs, nanomaterials have superior physicochemical properties in terms of bionanotechnology, and nanoscale ECM scaffolds are emerging as a developmental direction to promote bone repair potential [48]. Li et al. introduced HA nanoparticles into bone graft materials by varying the sintering temperature to form nanoscale pore scaffolds similar to natural bone [41]. The results demonstrated that the mechanical strength, cell proliferation, and differentiation rates of the scaffolds with nanopores were significantly increased (Fig. 2D).
Electrospinning, a versatile technique facilitating the fabrication of nanofibers with controlled diameters and distinct structures, is employed to construct polymeric nanofiber scaffolds for bone tissue engineering due to its structural resemblance to tissue ECM, straightforward setup, and cost-effective operation [49]. Fibers generated through this method exhibit high homogeneity and mechanical strength, forming porous scaffolds with an elevated surface-to-volume ratio. A diverse array of synthetic biodegradable polymers and natural macromolecules have been utilized to create fibrous scaffolds. While electrospun natural polymers demonstrate enhanced hydrophilicity, synthetic polymers possess greater robustness and superior mechanical properties. Synthetic electrospun fiber scaffolds can be further functionalized to augment cellular activities by incorporating compounds or morphogens such as HA, glycosaminoglycan, and recombinant human BMP-2. Controlled release of these compounds from the scaffolds can be achieved through the meticulous blending of various synthetic biodegradable polymers. Providing both topographical and biochemical signals, the electrospun nanofibrous scaffolds may offer an optimal microenvironment that mimics native ECM for seeded cells [50]. Li et al. developed a novel nanoparticle-embedded electrospun nanofiber scaffold for controlled dual delivery of BMP-2 and DEX [51]. In vivo osteogenesis studies showed that controlled dual delivery of BMP-2 and DEX promotes calvarial bone defect repair; DEX effectively promotes early calcified bone formation, while BMP-2 facilitates long-term new bone formation. In conclusion, dual drug-loaded nanofiber scaffolds may be ideal candidates for bone tissue engineering.
2.3. Limitations of traditional strategy mimicking ECM
A primary focus of conventional bone tissue engineering is the development of biomaterials that emulate the composition and structure of the ECM to modulate bone regeneration. The method of mimicking bone ECM is superior because it is simple and similar to bone ECM. However, in many cases, the importance of the local cellular microenvironment in injury repair is often overlooked, and this simple approach of mimicking bone-like structures may lack the physiological, chemical, and physical cues that provide cells with the ability to form bone [[52], [53], [54]]. It is well known that key components such as collagen and HA provide the environment for osteogenic differentiation of stem cells in the bone structure, but natural ECM contains growth factors that are also necessary for normal bone formation. The dECM retains most of the original structure in biological tissues, yet some inactivation processes during formation irreversibly destroy the active components, such as proteases and growth factors. It has been shown that different oxygen concentrations, pH ranges, and appropriate stress stimulation can promote osteoblast proliferation and matrix secretion. All these studies suggest that we need to focus equally on the non-ECM part of the microenvironment.
Pericellular interactions in the microenvironment are dynamic, and their dynamics not only act as a reservoir for their signaling molecules but also mediate signals from other sources. These signals include a variety of factors, including cell-cell, cell-growth factor, pericellular chemical changes, and physical stimuli [55]. These dynamic processes ultimately determine the equilibrium and potential aberrations of the tissue. In traditional strategy described above, researchers focus more on the simulation of the initial infrastructure, ignoring the signals that cells must receive from the environment as they develop within or on the scaffold to achieve an ordered, specific genetic program that ultimately results in tissue/organ formation. Therefore, we believe that designing the cellular microenvironment requires more attention to the physiological, chemical and physical cues in the microenvironment rather than solely focusing on ECM features, which would be a revolutionary chance for the tissue engineering field.
3. Bone microenvironment
3.1. Composition of bone microenvironment
The bone microenvironment consists of three key components: Physiological (e.g., neighboring cells such as macrophages), chemical (e.g., oxygen, pH), and physical factors (e.g., mechanics, acoustics). These components work in concert to provide functional support for bone growth and development [56].
3.1.1. Physiological microenvironment
The physiological well-being of bone is determined not only by the dynamic equilibrium between osteoblasts and osteoclasts but also by other cells in the local microenvironment, such as immune and endothelial cells. Immune cells, encompassing lymphocytes (B and T cells), macrophages, and dendritic cells, have been demonstrated to secrete active factors that impact bone formation [57,58]. For instance, macrophages promote osteoblastogenesis by releasing interleukin-18 (IL-18) [59,60]. In the event of bone fractures, immune cells, particularly macrophages, are involved throughout the entire healing process, providing defense against pathogens and releasing a diverse array of effectors to regulate bone remodeling. The immune system also contributes to the development of pathological and chronic conditions in osteoporosis [61]. Endothelial cells, which form the blood vessel linings, along with pericytes, are crucial for bone tissue homeostasis by producing paracrine signaling molecules known as angiocrine factors [62]. Research has indicated that endothelial cells secrete several signaling molecules via paracrine interactions, such as platelet-derived growth factor (PDGF)-BB, vascular endothelial growth factor (VEGF), and BMP-2, which play an active role in the regulation of bone homeostasis [63].
3.1.2. Chemical microenvironment
The chemical microenvironment of bone contains numerous soluble factors, such as nutrients (e.g., oxygen, pH) and signaling molecules (e.g., enzymes, cytokines). Oxygen is the most easily depleted nutrient, and its insufficient supply has impeded the success of engineering intricate and sizable tissue constructs. Among soluble signaling molecules, cytokines have garnered significant attention in engineering biomimetic cellular microenvironments. BMPs, a group of structurally similar, highly conserved functional proteins, belong to the TGF-β superfamily [64]. BMP-2, a critical factor in osteogenesis, induces the differentiation of undifferentiated MSCs into chondrocytes and osteoblasts, which participate in bone and cartilage growth, development, and reconstruction processes [65]. Angiogenesis and osteogenesis are intimately connected, with VEGF performing distinct functions at various stages of bone formation, such as recruiting macrophages during the inflammatory phase to promote angiogenesis and stimulating osteoclastogenesis during the repair phase to maintain bone homeostasis [[66], [67], [68]].
3.1.3. Physical microenvironment
Except for the physiological and chemical cues mentioned above, cells interact with and respond to physical stimuli (including mechanical, photo, thermal, electrical, magnetic and acoustic stimuli) [69]. Researchers have adopted this principle to achieve efficient bone repair through the synergistic action of external field stimulation and responsive scaffolds. Mechanical stimuli can affect cell behavior through mechanotransduction. Photic stimuli (e.g., near-infrared light) can upregulate osteogenic gene expression to enhance bone regeneration [70]. Thermally responsive materials respond to temperature and serve to enhance cellular activity [71]. Electrical stimulation promotes migration, proliferation and differentiation of osteoblasts [72]. One possible mechanism is that electrical stimulation upregulates intracellular calcium concentration and subsequently regulates osteogenesis via the calmodulin pathway [73,74]. Magnetic stimulation therapy can be classified into two types: static magnetic fields (SMF) or electromagnetic fields (EMF), although the underlying biological mechanisms are still elusive, in vitro studies have shown that it can significantly enhance osteoblast differentiation [75,76]. Acoustic fields induce material deformation through acoustic radiation forces [77,78]. Although acoustic field stimulation has not been extensively utilized for engineering the bone microenvironment, it possesses considerable potential.
3.2. Importance of bone microenvironment
Over the past decade, comprehensive research has enhanced our understanding of the effects of biochemical and biophysical cues on cellular behavior. The bone microenvironment, as a highly dynamic and complex network, regulates the biological behavior of cells primarily through the following mechanisms: 1) providing physiological and biochemical signals to cells; and 2) providing physical and stimulatory signals to cells. The principal challenge in comprehending the bone microenvironment lies in adapting to its dynamic properties, where cellular feedback plays a significant role. However, the spatial and temporal variations of these cues, as well as their independent or collective actions with cells in forming intricate microenvironmental networks, remain unclear. Gaining insight into the influence of these dynamics on the regulation of cellular behavior is crucial for enhancing the development of bionanomaterials that can be employed in designing cellular microenvironments and facilitating numerous biomedical applications. Below we describe how different cues guide changes in the bone microenvironment and provide tools to interpret the microenvironment.
4. Engineered bone microenvironment
The coordinated interplay of physiological, chemical, and physical signaling in the bone microenvironment is crucial for regulating cellular processes in both developing and mature skeletons [79]. Recent progress in bone biology has resulted in a growing interest in using biomaterial scaffolds and bioreactors to engineer microenvironments that mimic natural bone functions [80]. In the following sections, we systematically review how bone biology and tissue engineering have been integrated to create controllable microenvironments at multiple levels (Table 1).
Table 1.
Microenvironment-targeted strategy.
| Types | Pathway | Materials | Function | Ref. |
|---|---|---|---|---|
| Physiological Microenvironment | Immunomodulation | Titanium implant | Micro-rough and hydrophilic surfaces promote the release of anti-inflammatory factors from macrophages | [81] |
| Polyethylene terephthalate | Macrophages adhering to hydrophilic and anionic surfaces selectively produce anti-inflammatory cytokines | [82] | ||
| Magnesium containing microspheres | Mg2+ release upregulates anti-inflammatory genes and triggers immune regulation | [83] | ||
| miR-181b exosomes | Exo-181b activates the PRKCD/AKT signaling pathway to promote M2 polarization | [84] | ||
| Angiogenesis | Sulfated chitosan scaffold | Dual-module scaffold continuously releases rhBMP-2 and VEGF, synergistically promoting osteogenesis and angiogenesis | [85] | |
| Nanofibrous gelatin-silica hybrid scaffold | Vascular-mimicking microchannel scaffold promotes rapid vascularization and bone regeneration | [86] | ||
| Energy metabolism | Bioenergetic-active material scaffold | Scaffold degradation fragments can increase mitochondrial membrane potential to accelerate bone regeneration | [87] | |
| GelMA hydrogel | Mg2+ increases cellular bioenergy levels to promote osteogenesis induction | [88] | ||
| Citrate composite support | Citrate-mediated elevation of cellular energy levels supports metabolic osteogenesis | [89] | ||
| Chemical Microenvironment | Oxygen | Liposomal/hydrogel complexes | ROS-responsive hydrogel releases oxygen to promote bone regeneration | [90] |
| PCL/nHA/CaO2 scaffold | The bionic scaffold releases oxygen continuously to promote bone defect repair | [91] | ||
| Bioactive glass/collagen–glycosaminoglycan scaffold | Co2+ mimics hypoxic signaling to activate the HIF pathway to support osteogenesis | [92] | ||
| pH | MOF@CaP nanoplatform | Nanoplatform mimics low pH environment to enhance bone regeneration and capacity | [93] | |
| Custom Titanium implant | The alkaline microenvironment mediates the osteogenic differentiation of stem cells and promotes new bone formation | [94] | ||
| Enzymes and Cytokines | Chondroitin Sulfate/Polyethylene Glycol hydrogel | Matrix metalloproteinase-mediated degradation of hydrogels regulates stem cell differentiation | [95] | |
| GelMA hydrogel | Mineralized alkaline phosphatase enhances the osteogenic differentiation potential of BMSCs | [96] | ||
| Hyaluronic acid hydrogel | Nanozymes mediate O2 production from endogenous H2O2 and provide a microenvironment for osteogenesis | [97] | ||
| Physical Microenvironment | Mechanical forces | Polydimethylsiloxane substrates | Stiff materials have a higher osteogenic potential than soft materials | [98] |
| The flow loop apparatus | Sustained low-velocity shear stress stimulates the expression of osteogenic markers in stem cells | [99] | ||
| Gelatin hydrogel | Reversibly connected, highly elastic hydrogel adapts to dynamic stresses and supports bone regeneration processes | [100] | ||
| Temperature | light-responsive poly (N-isopropylacrylamide- co -nitrobenzyl methacrylate) | Ultraviolet light stimulates the release of dexamethasone from photosensitive materials to promote bone regeneration | [101] | |
| Poly (vinyl alcohol) fibers | Thermoresponsive fibers improve the toughness of calcium phosphate cement and enhance bone repair | [102] | ||
| Biphasic calcium phosphate scaffold | Regulates drug release by changing the light source wavelength to promote bone repair | [103] | ||
| Electric field | Whitlockite scaffold | Scaffolds provide an endogenous electric field to the defect site and inhibit the activity of osteoclasts. | [104] | |
| Triboelectric nanogenerator | Mediated proliferation and differentiation of osteoblasts by electrical stimulation | [105] | ||
| Magnetic field | Poly(lactide-co-glycolide) scaffold | Magneto-thermal accelerated degradation behavior of magnetic scaffolds under alternating magnetic fields | [106] | |
| Static magnetic field | Magnetic fields can regulate the direction of osteoblast growth | [107] | ||
| Acoustic | Collagen sponge | In situ recruitment of osteogenic factors by ultrasonically shocked microbubbles | [108] | |
| Acoustically responsive scaffold/hydrogel | Pulsed ultrasound recruits BMSCs for bone repair | [109] | ||
| Programming design | Poly(aryl-ether-ether-ketone) (PEEK) implant | Programmed surface coating to release osteogenic drugs over time | [110] | |
| GelMA hydrogel | Programming a two-factor delivery system to match the bone repair healing process | [111] |
4.1. Physiological microenvironment
Maintaining the homeostasis of the physiological microenvironment of bone is paramount for preserving the vitality and functionality of bone-related cells, and is a crucial aspect of bone regeneration [18]. This review focuses on investigations concerning immune regulation, angiogenesis, and energy metabolism within the bone physiological microenvironment.
4.1.1. Immune regulation
Osteoimmunology is a specialized area of research that examines the reciprocal relationship between bone cells and the immune system [112]. Numerous factors typically categorized as immunological agents, such as interleukins (e.g., IL-6, IL-11, IL-17, and IL-23) [[113], [114], [115]], tumor necrosis factor (TNF)-α [116], RANK and its ligand RANKL [117], nuclear factor of activated T cells (NFATc1) [118] have been found to exert a significant influence on osteoclasts and osteoblasts. In particular, macrophages of the innate immune system undergo diverse polarization states, with M1 macrophages exhibiting pro-inflammatory behavior and M2 macrophages demonstrating anti-inflammatory characteristics [119]. These macrophage phenotypes and their polarization are indispensable for biomaterials to stimulate bone regeneration [120].
Biomaterials have been recognized as a promising approach for regulating bone regeneration by altering surface morphology [81,121], stiffness [122], porosity and pore size [123], hydrophilicity [124] and surface charge [82] through physical and chemical modifications, thus affecting macrophage polarization, phenotype and function and contributing to the M1 to M2 phenotype transition. Biomaterials can also provide bioactive molecules, including bioactive ions [83], drugs [6], cytokines [125], and microRNAs(miRNAs) [84], which can activate anti-inflammatory signaling directly or indirectly. For instance, Zinc is an essential trace element in bone formation and plays a critical role in osteogenesis and immune processes. Therefore, it is frequently used to modify biological materials to improve bone immunomodulatory capacity. Huang et al. investigated the role of Zn2+ in osteoinduction and immunomodulation by combining it with a phosphate/poly(l-lactic acid) scaffold (TCP/PLLA) [126]. Compared to a single scaffold, the sustained-release scaffold of Zn2+ showed a stronger effect on bone differentiation while inducing macrophage polarization toward the M2 phenotype, resulting in a favorable osteogenic microenvironment (Fig. 3A).
Fig. 3.
Biomaterials mimic the immune environment to promote bone repair. A) Sustained release of Zn2+ from bioactive ceramics induces M2 macrophages, further promoting periosteal-derived progenitor cells-mediated bone regeneration. Reproduced and adapted with permission [126]. Copyright 2021, Springer Nature. B) Blood-derived hybrid hydrogels promote bone healing by reprogramming the immune environment. Reproduced and adapted with permission [127]. Copyright 2022, American Chemical Society. C) Nanocomplexes deliver miR-21 and IL-4 in layers to promote macrophage polarization to the M2 phenotype. Reproduced and adapted with permission [128]. Copyright 2021， Wiley-VCH GmbH. D) Mg–Al laminated double hydroxide coating induces macrophage polarization to an M2 anti-inflammatory phenotype that exhibits good osteogenic and angiogenic potential. Reproduced and adapted with permission [129]. Copyright 2021, Elsevier. E) Dual-effect coated Ti screws modified with Zn2+ and BMP-2 co-regulate the bone immune microenvironment at the bone-implant interface. Reproduced and adapted with permission [130]. Copyright 2022, Springer Nature.
The incorporation of biomaterials with cytokines has emerged as a direct and effective strategy for promoting bone regeneration. Human blood is naturally rich in various cytokines, and extensive bone injury is often accompanied by a poor regenerative microenvironment, especially an unfavorable immune microenvironment. Studies have shown that autologous blood-derived hydrogels can create the right conditions for osteogenesis by reprogramming the skeletal immune microenvironment, showing great promise in the field of personalized regenerative medicine (Fig. 3B) [127]. To take a more refined perspective, Deng et al. selected the key cytokines IL-4 and miR-21, which inhibit inflammation and delivered them to the site of injury in a programmed manner to modulate the bone immune microenvironment (Fig. 3C) [128]. Surface modifications of bone implants, including coating (Fig. 3D) [129] and molecular click (Fig. 3E) [130] methods, have also been utilized to achieve the same effect. Among the cells of the adaptive immune system, regulatory T cells may be promising candidates for a positive regulatory effect on fracture healing. Chen et al. showed that regulatory T cell exosomes can significantly enhance bone repair, demonstrating that regulatory T cells are promising and effective therapeutic agents for bone reconstruction, but the exact mechanism still needs to be discovered [131].
Despite the obvious progress in the field of bone immunology, many questions remain. For example, the immune system shares a variety of transcription factors, signaling molecules, and membrane receptors during bone repair, and the underlying molecular mechanisms by which it promotes bone regeneration remain unclear. Therefore, it is crucial to identify the molecular mechanisms by which osteoblasts and the immune system interact. In addition, bone injury patients with concomitant autoimmune diseases are commonly seen in the clinic, and autoimmunity may affect bone healing [132]. Future research advances could personalize microenvironmental therapies to address the need for clinical treatment.
4.1.2. Angiogenesis
Bone tissue is heavily reliant on the vascular system to receive oxygen and nutrients, as it is highly vascularized. The skeletal system is known to receive a substantial amount of blood output from the heart, estimated to be 10–15%. Thus, angiogenesis serves a key function in driving the development of bone tissue. Multiple approaches have been suggested to improve angiogenesis in bone tissue regeneration, such as administering angiogenic growth factors like VEGF and FGF, selecting appropriate seed cells like stem cells or mature vascular cells, and designing three-dimensional (3D) bionic scaffolds. The effectiveness of tissue engineering repair is closely related to the design of the biomaterial, which creates an environment suitable for cell growth, adhesion and differentiation. To promote vascularized osteogenesis, scaffold materials used for tissue engineering must possess similar biological properties to natural bone. For instance, natural collagen, fibrin gels, and bone cement exhibit good osteoconductivity, but are fragile and have poor mechanical properties. In contrast, materials such as bioactive glass and polylactic acid have good degradation properties but limited hydrophilicity and histocompatibility. Given these limitations, using a single material for vascularized bone regeneration is challenging.
Tang et al. developed a dual modular scaffold that was designed to release different growth factors with different characteristics while maintaining their biological activity to promote angiogenesis and osteogenic capacity (Fig. 4A) [133]. Apart from the scaffold structure and composition, cytokines and ionic components also play critical roles in angiogenesis and bone regeneration. Therefore, scaffold properties can be improved by incorporating these components to enhance vascularized bone tissue engineering. Angiogenesis is mediated by a complex interplay of molecular signals involving various cytokines and ions, including VEGF, Angiopoietin (ANG), Silicon (Si), Magnesium (Mg), and Calcium (Ca). BMP-2, which is the most potent osteogenic agent, was loaded into poly(lactic acid)-glycolic acid copolymer tubes by Bouyer et al., resulting in intact defect bridging and vascularized bone tissue formation [134]. This indicates that BMP-2 has the potential to promote vascularized osteogenesis. Additionally, dimethyl oxalyl glycine (DMOG) has gained considerable attention in vascularized osteogenesis. Bionic scaffolds loaded with DMOG have been shown to exhibit excellent angiogenesis and stable bone formation both in vitro and in vivo (Fig. 4B) [135]. Ha et al. co-loaded DMOG, an osteogenic factor, and a pro-angiogenic factor into nanofibrous scaffolds with an interconnected perfusable microchannel network (Fig. 4C) [86]. The microchannel structure provided the necessary foundation for nutrient transport and improved degradation, serving as a model for in vivo pre-vascularization.
Fig. 4.
Biomaterials enhance angiogenesis to promote bone repair. A) 26SCS-functionalized bimodular scaffolds deliver BMP-2 and VEGF for synergistic osteogenesis and angiogenesis. Reproduced and adapted with permission [133]. Copyright 2020, Elsevier. B) 3D-printed two-factor delivery scaffolds sequentially release DMOG and Sr ions that match the angiogenic and osteogenic processes. Reproduced and adapted with permission [135]. Copyright 2023, American Chemical Society. C) Nanofibrous gelatin-silica hybrid scaffold with the spatiotemporal release of DMOG and bone-forming peptide to enhance angiogenesis and improve bone regeneration. Reproduced and adapted with permission [86]. Copyright 2022, Wiley-VCH GmbH. D) Dynamic DNA hydrogels loaded with black phosphorus nanosheets continuously release VEGF and promote mature vessel growth to induce osteogenesis. Reproduced and adapted with permission [136]. Copyright 2022, Elsevier.
The primary benefit of revascularization is the ability to achieve perfusion immediately after implantation, accelerating the development of the entire capillary network. In a rabbit model, it was shown that revascularized grafts enhanced the formation of new bone and capillaries. Tissue engineering commonly employs 3D printing technology as a strategy. 3D bioprinting technology enables precise localization of biomaterials, biochemistry, and living cells. Inspired by this technology, Miao et al. designed a nano-dynamic hydrogel scaffold with the aid of 3D printing. VEGF-decorated black phosphorus nanosheets (BPNSs) and DNA impart functionality to the hydrogel, enhancing angiogenesis and osteogenic activity (Fig. 4D) [136].
The greatest challenge for angiogenic strategies is that newly formed capillaries after stent implantation are transient and require continuous supplementation with exogenous nutrients [137]. Therefore, an in-depth understanding of cellular dynamics, cellular microenvironment and cell-cell interactions may guide the design of next-generation angiogenic scaffolds.
4.1.3. Energy metabolism
Cellular energy homeostasis involves the regulation of energy production and consumption in cells during normal physiological processes, achieved through nutrient uptake and biosynthesis (Fig. 5A) [138,139]. Two main metabolic pathways that convert nutrients to adenosine triphosphate (ATP) for energy to support biosynthetic activities are glycolysis and oxidative phosphorylation. The skeleton requires a significant amount of ATP to maintain its health, normal differentiation, and physiological functions. Cells follow a strict mechanism to regulate metabolic fluxes to maintain metabolic homeostasis [140]. This involves the regulation of gene expression, mRNA transcription and translation, and the expression of transporter proteins and metabolic enzymes in response to extracellular factors such as hormones and intertissued signals [141]. In this way, metabolic activities and pathways are regulated to support desired physiological functions. For example, osteoblast progenitors increase glucose uptake by upregulating the expression of glucose transporter protein 1 (GLUT1) in response to osteogenic signals, thereby meeting the energy requirements for osteogenic differentiation [136]. Additionally, in a hypoxic in vivo environment, undifferentiated MSCs exhibit higher glycolytic activity and lower oxidative phosphorylation activity, which suggests that cells may implement self-protective mechanisms to prevent aging caused by oxidative contingencies [142].
Fig. 5.
Biomaterials improve energy metabolism for bone repair. A) Bioenergetic regulation and signaling during osteoblast differentiation. Reproduced and adapted with permission [139]. Copyright 2022, Elsevier. B) Bioenergetically active material scaffolds that accelerate bone formation by degradation-mediated increases in mitochondrial membrane potential. Reproduced and adapted with permission [87]. Copyright 2020, American Association for the Advancement of Science. C) Mg2+ energy drive improved low-dose BMP-2-induced bone regeneration. Reproduced and adapted with permission [88]. Copyright 2022, Elsevier. D) Citrate-based biomaterials support osteogenic differentiation by providing degradation products during degradation and regulating the metabolic pathway of energy production. Reproduced and adapted with permission [89]. Copyright 2018, National Academy of Sciences.
Recent evidence indicates that modulating cellular metabolism can influence gene expression and signaling pathways to promote bone regeneration. One approach to achieve this is through the use of materials that induce material-derived cellular signaling. or instance, a bioenergetically active scaffold was designed by Liu et al. to release degradation debris in a controlled manner and produce metabolic intermediates, which enter the mitochondria and enhance the tricarboxylic acid (TCA) cycle, thereby increasing mitochondrial membrane potential and promoting bone regeneration (Fig. 5B) [87]. Similarly, ion-doped biomaterials can effectively modulate metabolism to regulate cellular function by controlling the release of metal ions that act as cofactors for metabolic enzymes or indirectly affect enzyme activity. Lin et al. demonstrated that a Mg2+-based bioenergy-driven strategy improved BMP-2-driven bone regeneration by increasing mitochondrial membrane potential and upregulating metabolic enzyme activity through the Akt signaling pathway (Fig. 5C) [88]. In addition, the regulation of metabolites, cofactors, and key substrates can influence intracellular metabolic events, with citrate from citrate-based biomaterials shown to promote osteogenic differentiation (Fig. 5D) [89]. The regulation of cellular energy metabolism may be a determinant of cell survival, proliferation, differentiation, and specific functions. Thus, understanding the specific energetic and biosynthetic requirements of different cell types is crucial for the design of effective regenerative engineering strategies.
Current research in bone tissue engineering in terms of cellular energy metabolism lags behind the neurological and cardiovascular fields. One of the main difficulties is that osteogenic differentiation exhibits a high proliferation rate in the initial stages and a synthesis and deposition phase in the later stages mainly by mechanisms. Different cellular stages require different metabolic signals and energy allocation. This would be a great challenge to match the dynamic formation process with inactive biomaterials.
4.2. Chemical microenvironment
In the bone microenvironment, cellular interactions are critical, and there exists a plethora of nutrients and signaling molecules that play significant roles in bone regeneration. This section outlines some of the essential factors, including nutrients such as oxygen and pH, as well as signaling molecules like enzymes and cytokines.
4.2.1. Oxygen
Oxygen is an indispensable molecule for the maintenance of cell viability, growth, metabolism, differentiation, and intercellular communication [143]. In healthy tissues, capillaries ensure the provision of sufficient oxygen to cells. Hypoxia arises when the distance between cells and blood vessels surpasses 100–200 μm [144]. The primary cause of tissue hypoxia is disruption of the vascular network at the injury site, which results in delayed oxygen delivery to the adjacent cells. Simultaneously, chronic hypoxia frequently contributes to widespread cell death and tissue necrosis. Notably, various skeletal cells exhibiting high metabolic activity and oxygen demand exhibit heightened sensitivity to hypoxic conditions. Consequently, it is imperative to ensure adequate oxygen supply to hypoxic tissues and regulate cellular metabolism to adapt to the hypoxic environment [145].
Tissue engineering facilitates in situ oxygen production by incorporating oxygen-generating components into biological materials. Oxygen production based on hemoglobin and peroxides has achieved remarkable results, but emerging technologies such as oxygen microbubbles, nanosponges and photosynthetic algae are equally worthy of in-depth study (Fig. 6A). Sun et al. developed an innovative composite hydrogel material capable of converting ROS to O2, with the capacity to accelerate O2 production in response to excess ROS based on the requirements of the affected region [90]. This hydrogel demonstrates effective oxygen generation capacity, promoting angiogenesis, inhibiting osteoclast differentiation, and enhancing osteoblast differentiation under hypoxic conditions (Fig. 6B). Wang et al. incorporated CaO2 in 3D printed scaffolds that exhibited good cytocompatibility and oxygen release, thus significantly improving cell survival and growth under hypoxic conditions (Fig. 6C) [91].
Fig. 6.
Biomaterials release oxygen to promote bone repair. A) Oxygen release mechanisms of various oxygen-producing biomaterials. Reproduced and adapted with permission [147]. Copyright 2021, Elsevier. B) A novel composite hydrogel scavenges ROS and prolongs oxygen production to reverse the hypoxic microenvironment in areas of bone defects. Reproduced and adapted with permission [90]. Copyright 2022, Elsevier. C) 3D-printed bionic oxygen-containing scaffolds enhance the expression of osteogenic regulatory transcription factors and accelerate osteogenesis. Reproduced and adapted with permission [91]. Copyright 2022, American Chemical Society.
Hypoxia-inducible transcription factor (HIF) is among the most well-known transcription factors that mediate oxygen-sensitive signaling pathways, stimulating the transcription of numerous genes and thereby influencing angiogenesis, precursor cell recruitment, and differentiation [146]. The development of tissue-engineered scaffolds capable of emulating local hypoxia within an environment exhibiting normal oxygen levels constitutes a rational approach, and this has emerged as a contemporary research direction to incorporate key oxygen-dependent HIF signaling pathways in scaffold design and fabrication. Quinlan et al. incorporated cobalt ions into bioactive glass/collagen-glycosaminoglycan scaffolds, which mimic hypoxia and artificially stabilize HIF-1α transcription factors [92]. The results demonstrated a significant enhancement of vascular endothelial growth factor expression, highlighting the ability to activate the HIF pathway under normoxic conditions.
However, during tissue engineering development, the material cannot be considered an adequate oxygenation mechanism due to its limited diffusion capacity and solubility in aqueous solutions. Therefore, the development of durable and homogeneous oxygen-releasing materials is critical for translation into clinical solutions.
4.2.2. pH
The natural human microenvironment is mildly alkaline. It is established that systemic acidosis in humans results in bone loss, potentially due to the physicochemical dissolution of bone minerals [148]. There are two common forms of acidosis, metabolic acidosis and respiratory acidosis. During metabolic acidosis, bones release buffered acids (protons) and calcium. During metabolic acidosis, bones release buffered acids (protons) and calcium. David et al. investigated the effects of metabolic acidosis on bone in mice [149]. The results show that metabolic acidosis can lead to the occurrence of bone resorption. Bone tissue pH can also be affected by inflammatory bone disease, tumor environment, and local acidic microenvironments due to immune cell enrichment. The acidic microenvironment further decreases pH, promoting increased bone resorption. Yuan et al. designed a composite hydrogel with selective toxicity to osteosarcoma tissues [150]. The loaded curcumin can be released in a pH-responsive manner at acidic osteosarcoma sites through the breakage of subamine bonds in the hydrogel, achieving selective toxicity to osteosarcoma cells. This selective toxicity and differentiation-promoting ability of pH-responsive hydrogels have been demonstrated in osteosarcoma cells and normal osteoblasts (Fig. 7A). The effective proton microenvironment boundary of degradable biomaterials was recently found to be 400 ± 50 μm, exceeding generally accepted value of 300 μm [151]. This further corroborates that biomaterials can significantly impact the cellular microenvironment (Fig. 7B). Consequently, some researchers have leveraged these microenvironment characteristics to develop smart reactive biomaterials with therapeutic and regenerative functions. Zheng et al. aimed to design multifunctional nanoplatforms capable of releasing a low pH microenvironment [93]. These nanoplatforms can continuously release encapsulated bioactive factors at low pH conditions to actively and precisely establish a reparative microenvironment for bone regeneration. Moreover, slow degradation during nanoparticle healing provides sufficient in situ magnesium and silica for angiogenesis and calcium and phosphate for osteogenesis (Fig. 7C). Alternatively, another study focused on the impact of an alkaline microenvironment on bone regeneration. The researchers constructed a weakly alkaline inner layer of Ca–O–Ti and a strongly alkaline outer membrane of MgO with Ti as the substrate [94]. This customizable alkaline microenvironment surface exhibited sustained resistance to infection and osseointegration, offering novel insights into bone implant surface design (Fig. 7D).
Fig. 7.
pH-responsive biomaterials promote bone repair. A) pH-responsive hydrogel targets selective osteosarcoma cells to release pro-bone repair drugs. Reproduced and adapted with permission [150]. Copyright 2022, American Chemical Society. B) Schematic diagram of the microenvironment of nearby cells affected by the implanted biomaterial. Reproduced and adapted with permission [151]. Copyright 2019, American Chemical Society. C) A nanoscale drug delivery system that reduces pH and can actively build a bone regenerative repair microenvironment. Reproduced and adapted with permission [93]. Copyright 2020, Elsevier. D) Customizable alkaline surface to enhance the osteogenic properties of Ti implants. Reproduced and adapted with permission [94]. Copyright 2021, Elsevier.
In the above study, different acid-base microenvironments showed different restorative effects in different pathological environments. It is still difficult to determine the optimal pH range, and further in-depth studies are needed in the future.
4.2.3. Enzymes and cytokines
Enzymes are specific macromolecular biocatalysts, and all metabolic processes lin the body require the participation of enzymes [152]. In recent years, enzyme-based biomaterials have received a lot of attention [153]. For example, enzyme-responsive hydrogels typically utilize natural enzymes present in organisms or abnormally overexpressed at lesion sites, such as matrix metalloproteinases (MMP) [154], phosphatases [155], and tyrosinases [156]. Anjum et al. prepared a natural hydrogel based on an enzymatic reaction by grafting MMP in a hybrid system to maintain cell viability, proliferation, and migration through MMP-mediated degradation of the hydrogel to regulate cell growth factor delivery and stem cell differentiation [95]. However, MMP overexpression in bone and chondrocytes can result in pathological changes in bone, such as osteoarthritis (OA), osteoporosis, and rheumatoid arthritis (RA) [157]. In another study, mineralized ALP nanoparticles were incorporated into hydrogels to assess their bone repair effects in vivo. The osteogenic differentiation properties of BMSCs were significantly enhanced while retaining ALP enzyme activity (Fig. 8A) [96].
Fig. 8.
Biomaterials release enzymes and cytokines to promote bone repair. A) Mineralase-based hydrogels promote BMSC osteogenic differentiation to induce in situ mineralization. Reproduced and adapted with permission [96]. Copyright 2022, American Chemical Society. B) Enzymatic multifunctional scaffold loaded with GOx and catalase alleviates hyperglycemic environment and promotes bone regeneration. Reproduced and adapted with permission [158]. Copyright 2021, Wiley-VCH GmbH. C) Nanoenzyme-enhanced hydrogel improves the hypoxic environment for osseointegration at the RA prosthesis interface. Reproduced and adapted with permission [97]. Copyright 2022, Springer Nature Limited. D) Multifunctional microcarriers with sequential delivery of BMP-2 and VEGF. Reproduced and adapted with permission [168]. Copyright 2020, Springer Nature Limited.
Enzymes can not only be used as cofactors to enhance scaffold bioactivity but also be employed to create functionalized scaffolds via 3D printing. Chen et al. designed an enzyme-functionalized scaffold that releases glucose oxidase to alleviate the hyperglycemic environment and enhance bone regeneration in diabetic patients(Fig. 8B) [158]. Nanozymes, a new generation of artificial enzymes, possess unique nanomaterial properties, such as high catalytic activity, good stability, and low cost. Introducing nanozymes into hydrogels can create highly advanced bioactive platforms to address complex tissue-specific physiological challenges. A recent study demonstrated that composite hydrogels loaded with nanozymes not only scavenged endogenous overexpressed ROS but also synergistically generated dissolved oxygen. The effects of inhibiting local inflammatory cytokines and improving osseointegration were validated through in vivo and in vitro experiments (Fig. 8C) [97]. Despite these promising results, the question of how enzymes with overlapping substrates can react more precisely remains to be addressed.
Various growth factors play crucial roles in the bone repair process. Their effectiveness relies on the dose and release rate in vivo, as well as the drug delivery system, encompassing vectors, cells, and gene therapy. BMP and VEGF are the most extensively studied growth factors in bone tissue engineering. Various BMP2-loaded scaffolds have been investigated, including liposomes [159], gelatin sponges [160], hydrogels [161], exosomes [162], immune complexes [163], 3D printed scaffolds [164], etc., all of which demonstrate remarkable bone regeneration capabilities. Previous research on angiogenic factors has emphasized the role of VEGF in neovascularization and osteogenic recruitment, revealing that VEGF delivery increases vascular density and stimulates minor bone regeneration in rabbits and rats with bone defects [[165], [166], [167]]. Recent studies have indicated that the co-delivery of VEGF with osteogenic growth factors synergistically enhances osteogenesis (Fig. 8D) [168]. Bone-associated growth factors are diverse and numerous, with dynamic concentrations and distributions under varying physiological and pathological conditions, playing vital roles in promoting systemic or local bone formation. Presently, the most significant challenge in tissue engineering is delivering appropriate growth factors in a temporally and tightly regulated sequence during the repair cascade, holding immense potential for advancing bone repair medical interventions.
4.3. Physical microenvironment
Physical stimuli can significantly influence bone formation and are typically categorized into two primary classifications: internal and external bone stimuli. Internal stimuli predominantly stem from mechanical alterations, while external stimuli encompass factors such as photothermal, electrical, magnetic, and acoustic. Moreover, by integrating external stimuli with internal responses, a programmed spatiotemporally bone regeneration system can be designed and implemented.
4.3.1. Mechanical alterations
Bone, a mechanosensitive tissue, responds to mechanical signals from its environment through a process known as mechanotransduction [169]. Extensive research demonstrates that mechanical stimulation significantly impacts the development and remodeling of skeletal structures and offers a novel, drug-free approach to bone regeneration [170,171]. In bone tissue engineering, biological scaffolds are frequently required as temporary structural supports to fill bone defects, withstand early mechanical loading, and guide new bone formation [172]. Consequently, the efficacy of bone repair is strongly correlated with the mechanical properties of the scaffold, including stiffness, shear stress, and dynamic stress, which can influence osteogenic effects.
Current research has focused on investigating the impact of various materials and scaffold stiffnesses on osteogenesis. In a study by Zhang et al., polydimethylsiloxane substrates with different stiffnesses were prepared to explore the potential mechanisms of mechanotransduction [98]. The results indicated that rat primary osteoblast differentiation was more favorable on rigid substrates, with higher expression of ALP and runt-related transcription factor 2 (Runx2) observed on substrates with a stiffness of 134 kPa. In another study, researchers compared the orientation of collagen fibers in bone tissue microstructure and found that longitudinally aligned, dark-colored bone was more mineralized, containing a higher ratio of inorganic to organic matrix components and exhibiting increased stiffness and resistance to plastic deformation under compression. In contrast, brighter-colored bone, containing a higher proportion of collagen, provided enhanced ductility and energy dissipation due to lower stiffness and rigidity (Fig. 9A) [173]. These findings suggest that both intrinsic material properties and anisotropy affect surface stiffness, warranting further in-depth comparative research.
Fig. 9.
Mechanical properties of biomaterials promote bone regeneration. A) Effect of different arrangements of collagen fibers on bone stiffness. Reproduced and adapted with permission [173]. Copyright 2021, American Chemical Society. B) Comparison of bone formation under different shear stresses. Reproduced and adapted with permission [174]. Copyright 2019, Biomedical Engineering Society. C) Microfluidic chip generates constant shear stress to verify the effect of shear force on osteogenic differentiation and shear stress distribution schematic. Reproduced and adapted with permission [178]. Copyright 2014, plos.org. D) Pressure clouds and flow distribution of spiral structure brackets with the different modulus of elasticity. Reproduced and adapted with permission [183]. Copyright 2019, Elsevier.
Under physiological conditions, bone cells are constantly exposed to mechanical loads, such as shear stresses, which stimulate osteocytes and lead to changes in bone volume and structure to maintain an optimal skeletal structure (Fig. 9B) [174]. Fluid shear stresses are predicted to range from 0.8 to 3 Pa [175,176], and they have been shown to initiate a series of osteogenic signaling events, including calcium release [177], and nitric oxide [176] synthesis and release. Krekea et al. exposed planar cultures of BMSCs to shear flow [99]. The results demonstrated that expression of late phenotypic markers of osteoblast differentiation increased with the duration of exposure to shear flow, with significant enhancement of bone sialoprotein (BSP) and osteopontin (OPN) genes observed at 30 and 120 min of shear flow. Similarly, Kim et al. subjected MSCs to constant, very low shear stress generated by flow and observed increased osteogenic differentiation of MSCs (Fig. 9C) [178]. These findings suggest that immature osteoblasts are mechanosensitive and are associated with shear strength or shear patterns [179]. Therefore, shear stress is deemed an essential factor in bone scaffold development, contributing to osseointegration between the host and implant, a prerequisite for implant stability.
The dynamic stress microenvironment offers cells the capacity to influence behavior and fate through stress relaxation and remodeling [[180], [181], [182]]. Traditional bone tissue engineering strategies aim to develop a bone scaffold with an elastic modulus and yield strength comparable to human bone, employing helical structures and optimizing cell inoculation efficiency by varying porosity and pore size (Fig. 9D) [183]. In recent decades, adaptive hydrogels with reversible connections have garnered significant attention. These hydrogels are characterized by spatial dynamics of the matrix with reversible connections, providing plasticity and stress relaxation to adapt biophysical signals during the repair process [184]. Supramolecular chemistry offers numerous non-covalent interactions for obtaining reversible connections, including macrocyclic host-guest interactions [100], hydrogen bonding [185], electrostatic interactions [186], and hydrophobic interactions [187]. Additionally, dynamic covalent chemistry presents several options, such as reversible Diels-Alder reactions [188], hydrazone bonding [189], thioester exchange [190], and borate bonding [191]. Qian et al. prepared a supramolecular gelatin macromolecule [100]. The resulting hydrogels can withstand excessive compressive and tensile strains and rapidly self-repair after mechanical damage. Hydrogels with altered mechanical stress were shown to be promising carrier materials for bone tissue repair.
4.3.2. Photothermal effect
Photo and thermal reactions serve as external stimulation treatments and significantly contribute to bone regeneration promotion. Current research explores various types of light, including ultraviolet (UV), visible (Vis), near-infrared (NIR), and distinct wavelengths of laser light [192]. Notably, NIR light, with its high tissue penetration depth and photothermal effect, serves as an efficacious approach to foster osteogenesis [193,194].
UV light is frequently employed in photoresponsive biomaterial systems, as its short wavelength facilitates drug release from biomaterials [195]. In one study, a light-responsive microgel was synthesized, which, under UV irradiation, promoted the release of DEX, inducing osteogenic differentiation of hMSC [101]. AlamarBlue assay and standardized ALP activity assay results indicated that DEX released from microgels has the potential for inducing osteogenic differentiation of hMSC. By toggling the UV light source on and off, drug release can be controlled, supporting clinical drug requirements. Furthermore, zirconia surfaces treated with UV light significantly enhanced osteogenesis, potentially due to accelerated cell attachment and spreading increased cytoskeleton development, and proliferation [196]. Blue light irradiation of the photosensitive material g-C3N4/rGO generated photocurrent, rapidly inducing BMSCs into osteoblasts. The researchers co-cultured photosensitive material with BMSC and the cell culture dishes were simultaneously irradiated with blue light for 30 min per day. The spectroscopic results showed that photocurrent generation from π-π* orbitals in visible light could provide a stronger driving force for osteogenesis [197].
Temperature change also impacts bone formation. Thermally responsive systems are powerful activation mechanisms for biomedical and biomaterial applications, as body temperature typically ranges from 35 to 37°C, and temperature shifts induce functional changes [198]. Thermally responsive biomaterials play a significant role in bone regeneration, such as smart fibers and hydrogels. The researchers incorporated thermally responsive poly(N-isopropylacrylamide) fiber brushes with calcium phosphate [102]. This brush has a dual thermo-responsive transition, with the fibers dispersing in hydrophilic calcium phosphate bone cement at 21°C and transforming to a hydrophobic state at 37°C to toughen this bone cement. Thermo-responsive hydrogels are a key biomaterial in that they exhibit temperature-dependent gel-sol transition in water [199]. Many thermally responsive hydrogels based on synthetic and natural copolymers have been successfully prepared and further investigated [200,201].
The synergistic effects of photo and thermo stimulation have proven efficacious in promoting bone regeneration. NIR light-generated photothermal effects facilitate osteogenesis, offering the advantages of non-invasiveness and high spatial and temporal accuracy [202]. Photothermal agents are capable of converting light energy into heat energy under NIR illumination, allowing for adjustments to photothermal hydrogels by modulating the concentration and ratio of the photothermal agent, irradiation time, and laser intensity [203]. Gentle local heating promotes cell proliferation, angiogenesis, wound healing, and bone regeneration [204], while moderate heat (45°C–50°C) causes minimal damage to normal tissue cells but inflicts lethal damage to tumor cells [205]. For the healing of infected wounds, heat therapy (>50°C) is effective in inhibiting bacterial proliferation. Therefore, the photothermal effect can be controlled according to different temperatures for various applications [206]. In recent studies, upconversion nanoparticles have garnered attention as efficient photo-responsive platforms. Yan [207] and Ye's [208] teams employed NIR light-mediated photothermal reactions to release Epimedium(Fig. 10A) and NO(Fig. 10B), respectively, as effective drugs against osteoporosis, with both experiments exhibiting favorable osteogenic differentiation. Photo-responsive systems can also achieve co-control of multiple targets. Qin Zhao et al. developed a dual-targeting nanoscaffold (BCP-GNC) that modulates drug release by altering the light source wavelength, thereby influencing scaffold temperature [103]. BCP-GNC releases IL-4 at 690 nm and DEX at 808 nm, modulating innate and adaptive immune responses and promoting osteoinduction. Yang et al. designed a multifunctional composite scaffold using 3D printing technology, unifying photothermal ablation of osteosarcoma, osteogenic differentiation of progenitor stem cells, and enhanced angiogenesis through bioactive ions (Fig. 10C) [209].
Fig. 10.
Biomaterials respond to photo and thermal stimulation to promote bone repair. A) Upconversion nanoparticle loaded with epimedium promotes MSC osteogenic differentiation. Reproduced and adapted with permission [207]. Copyright 2022, American Chemical Society. B) Targeted treatment of osteoporosis by upconversion nanoparticles releasing NO. Reproduced and adapted with permission [208]. Copyright 2021, American Chemical Society. C) Wesselsite nanosheet functionalized scaffold repairs tumor-induced bone defects. Reproduced and adapted with permission [209]. Copyright 2021, Wiley-VCH GmbH. D) Carboxy-capped dendrimer-mediated photothermal response inhibits bone tumor growth and tumor-associated osteolysis. Reproduced and adapted with permission [210]. Copyright 2018, American Chemical Society.
Another study reported that NIR-mediated photothermal responses inhibited osteolysis and promoted bone regeneration (Fig. 10D) [210]. Accumulating evidence supports the efficacy of NIR-mediated photothermal responses for targeted bone tumor treatment. Black phosphorus (BP), a cutting-edge two-dimensional material, exhibits exceptional photothermal properties, biocompatibility, and biodegradability [211]. Research has demonstrated that NIR-mediated photothermal heating of BP induces its oxidation in the presence of oxygen and water, effectively degrading it into phosphate ions [212]. These phosphate ions subsequently attract nearby calcium ions to form HA, thereby achieving in situ biomineralization [213]. Harnessing BP to enhance biomineralization represents an innovative approach to fostering bone formation and regeneration.
4.3.3. Electricity and magnetism
Application of electrical or magnetic stimulation in bone tissue engineering offers a promising strategy for bone regeneration [214]. Bone inherently exhibits piezoelectric properties, generating electrical and biochemical signals in response to mechanical activity for bone remodeling and repair [215]. Integrating smart materials with piezoelectric properties into bone implants can enhance bone regeneration [216]. Piezoelectric materials facilitate bone regeneration by accumulating electrical charge in response to mechanical stress, manifesting as a voltage generated by mechanical stress (the positive piezoelectric effect) or a mechanical response to an applied voltage (the converse piezoelectric effect) (Fig. 11A) [217,218]. While both effects are crucial, the positive piezoelectric effect has been predominantly investigated for bone implant applications. Common piezoelectric biomaterials include piezoelectric ceramics, piezoelectric polymers, and their composites [216,219].
Fig. 11.
Biomaterials respond to electrical and magnetic stimulation to promote bone repair. A) Schematic diagram of piezoelectric material surface mechanical strain induced charge generation triggering cell signaling pathway. Reproduced and adapted with permission [218]. Copyright 2020, WILEY-VCH Verlag GmbH. B) Composite scaffold with piezoelectric properties provides an endogenous electric field to promote bone regeneration in bone defects. Reproduced and adapted with permission [104]. Copyright 2022, Elsevier. C) Bionic piezoelectric bone membranes doped with polydopamine-modified hydroxyapatite (PHA) and barium titanate (PBT) synergistically promote osteogenesis and immunity. Reproduced and adapted with permission [220]. Copyright 2023, American Chemical Society. D) Schematic diagram of magnetron degradation in polymer implants. Reproduced and adapted with permission [106]. Copyright 2021, Wiley-VCH GmbH. E) Electromagnetic co-stimulation of bionic 3D scaffolds synergistically promotes bone repair. Reproduced and adapted with permission [226]. Copyright 2019, American Chemical Society.
Recent research has focused on designing composite scaffolds with piezoelectric properties and sustained Mg2+ release using 3D printing technology, which can restore the local endogenous electrical microenvironment and promote osteogenic differentiation (Fig. 11B) [104]. Additionally, multifunctional composite synergistic osteogenesis can be achieved with piezoelectric materials, combining piezoelectric osteogenesis with immunomodulation for rapid in situ bone regeneration (Fig. 11C) [220]. Nanogenerators can also convert environmental mechanical energy into electrical energy [221]. One study proposed a self-powered electrical system consisting of a triboelectric nanogenerator (TENG) and a flexible forked-finger electrode for in vitro osteogenesis, significantly promoting osteogenesis and demonstrating potential for clinical treatment of osteoporosis and related fractures [105]. The authors demonstrated that this electrical stimulator can clearly promote osteogenesis and has considerable potential for clinical treatment. Magnetically active biomaterials exploit external magnetic fields or direct magnetic forces to enhance bone tissue regeneration [222]. A prevailing trend in magnetically responsive biomaterials is the incorporation of iron oxide nanoparticles, as nanoparticles smaller than 100 nm exhibit superparamagnetic properties that prevent particle agglomeration [223]. One study verified that magnetic nanoparticles generate magnetothermia in alternating magnetic fields, providing crucial guidance for scaffold degradation (Fig. 11D) [106]. Magnetic fields with varying parameters may differentially affect osteogenesis in the magnetic response regime [224]. The direction and strength of the magnetic field influence bone regeneration. One study reported that cultured MC3T3-E1 cells aligned parallel to the static magnetic field (SMF) after 60 h of exposure, marking the first evidence that the growth direction of apposed cells can be regulated by the magnetic field [107]. Moreover, the biological effect of the magnetic field became more pronounced with increasing magnetic field strength within a specific range, but beyond that range, the effect diminished or even became inhibitory. Yang et al. examined the induction of osteoblasts by SMFs at three different intensities (500 nT, 0.2 T, and 16 T) and found that iron concentration and mRNA expression of transferrin receptor 1 were affected, suggesting iron involvement in the magnetic field's effect on osteoblasts [225].
Electrical and magnetic synergy can also benefit bone regeneration. Fernandes et al. demonstrated the feasibility of electromagnetic co-stimulation by assembling piezoelectric polymers and magnetostrictive nanoparticles in response to magnetic stimulation, constructing a bionic three-dimensional magnetically active scaffold for tissue recovery through co-stimulation (Fig. 11E) [226]. The applicability of pulsed electromagnetic fields (PEMF) has been evaluated using a rat cranial defect model [227]. In an 8 mm diameter rat cranial defect model, the experimental group receiving PEMF exhibited a significant effect on bone regeneration by applying a 12 μs width, a 60 Hz pulse frequency, and a 10 G magnetic field strength. However, the complex biological effects of electromagnetic fields and the underlying mechanisms of PEMF pose challenges in defining treatment options, necessitating extensive research to overcome this issue.
4.3.4. Acoustic
In vivo and in vitro studies have shown that ultrasound stimulation (e.g., low-intensity pulsed ultrasound (LIPUS), shock waves) is beneficial in promoting bone healing or reactivating failed healing processes [228]. Ultrasound-responsive biomaterials can deliver signaling molecules directly or indirectly with the help of ultrasound stimulation [229,230]. Functional fracture healing has been reported by ultrasound-mediated delivery of target genes (Fig. 12A) [108]. At present, LIPUS is the most extensively studied and researched technique in the domain of ultrasound stimulation for bone repair [231]. The biological response to LIPUS is intricate, involving numerous cell types and multiple pathways. Known mechanotransduction pathways implicated in cellular responses include MAPK [232], other kinase signaling pathways, gap junction intercellular communication [233], upregulation and aggregation of integrins, involvement of COX-2/PGE2 [234], iNOS/NO pathways [235], and activation of ATI mechanoreceptors. A recent study discovered that by altering the radiation frequency of pulsed ultrasound, not only could the release of bioactive molecules for recruiting endogenous BMSC be controlled, but also the capture of recruited BMSC into the stent could be facilitated through resonant gradient field-induced trapping forces (Fig. 12B) [109]. Similarly, several other studies have reported some effects of LIPUS on cell differentiation and protein responses. Although clinical and experimental studies have shown enhanced effects of LIPUS on bone regeneration, the physiological mechanisms involved in the complex bone healing process remain unclear and warrant further investigation (Fig. 12C–D) [[236], [237], [238], [239]].
Fig. 12.
Biomaterials respond to ultrasound stimulation to promote bone repair. A) Schematic diagram of ultrasound-mediated targeted gene delivery to the fracture site. Reproduced and adapted with permission [108]. Copyright 2017, American Association for the Advancement of Science. B) Schematic diagram of endogenous cell recruitment by pulsed ultrasound remote stimulation. Reproduced and adapted with permission [109]. Copyright 2022, Elsevier. C) Schematic diagram of LIPUS stimulation of periodontal stem cells to promote osteogenic differentiation. Reproduced and adapted with permission [238]. Copyright 2020, Springer Nature. D) Schematic diagram of LIPUS stimulated micro-arc oxidized Ti implants for bone repair. Reproduced and adapted with permission [239]. Copyright 2019, American Chemical Society.
4.3.5. Programmed spatiotemporally design
On-demand delivery of chemotactic and osteogenic biomolecules for bone regeneration is an appealing yet challenging endeavor, as it requires meeting the varying demands of distinct bone regeneration phases. Existing bone tissue engineering approaches face limitations in coordinating appropriate biomolecule concentrations and treatment time points on-demand due to insufficient spatial separation. Consequently, designing a programmable regulated delivery system remains a formidable task. In a recent study, researchers combined thermoresponsiveness with photothermal response to achieve rapid response concentrations in the initial burst release of the primary response, followed by precise modulation of therapeutic effects using photoresponsiveness [240]. The results suggest that a controlled and stable promotion of osteogenic differentiation can be achieved (Fig. 13A). Other researchers have sought to integrate immunomodulation with osteogenic process programming. By coating the programmed surface with poly(aryl ether ether ketone) (PEEK), IL-10 was released rapidly within the first week, followed by slow release of DEX for up to four weeks [110]. Suitable immunomodulatory activity sets the stage for osteogenesis, while the stable release of DEX promotes subsequent bone regeneration. Zhou et al. designed a hybrid dual growth factor delivery system with basic fibroblast growth factor (bFGF) and BMP-2 to further mimic the natural bone healing process and promote bone regeneration by synergizing osteogenic and angiogenic functions. It provides a simple and effective alternative method for bone defect treatment (Fig. 13B) [111].
Fig. 13.
Programmable design of biomaterials for bone repair. A) Thermally responsive hydrogels are combined with light-responsive nanoparticles to construct programmed delivery systems for on-demand growth factor release. Reproduced and adapted with permission [240]. Copyright 2022, Elsevier. B) Composite hydrogel that mimics the natural cascade reaction of bone healing for spatiotemporally regulated release of cytokines. Reproduced and adapted with permission [111]. Copyright 2021, Springer Nature. C) Multiple bioprinting technologies for bone repair. Reproduced and adapted with permission [244]. Copyright 2021, Elsevier. D) Constructing multi-responsive bilayers using 4D printing technology to precisely regulate stem cell fate and optimize bone repair. Reproduced and adapted with permission [258]. Copyright 2021, Wiley-VCH GmbH.
Bioprinting technology presents a promising approach to achieving programmable bio-design. By loading cells and bioactive cues directly into bioink, bioprinting can create structures that mimic natural tissue while allowing for programmability (Fig. 13C) [[241], [242], [243], [244]]. This advancement enables personalized treatment of bone-related diseases. Bioinks for bone tissue bioprinting are categorized into natural bioinks (collagen [245], chitosan [246], fibrin [247], gelatin [248], agarose [249] and alginate [250], etc.) and synthetic bioinks (Pluronic F-127 [251], methylated gelatin [252], PEG [253], etc.). Numerous challenges remain for clinical application of conventional 3D bioprinting in bone tissue engineering, such as reconstructing large and irregular bone tissue for individualized needs, achieving vascularization and nerve regeneration when repairing extensive bone defects, and addressing mechanical properties [254,255]. Four-dimensional (4D) bioprinting, which integrates the concept of time as a fourth dimension with 3D bioprinting, permits printed objects to alter their shape or function in response to external stimuli, cell fusion, or self-assembly after printing. This innovative approach offers a next-generation solution for tissue engineering, providing the potential to construct complex functional structures [256]. For instance, smart, renewable bioscaffolds synthesized using PCL and crosslinkers with predetermined amounts of castor oil demonstrated favorable shape memory effects and shape recovery at physiological temperatures [257]. Another study employed 4D printing technology to dynamically regulate stem cell fate, enabling precise switching between proliferation and differentiation phases to better promote bone regeneration (Fig. 13D) [258]. The synthesized smart polymers exhibited satisfactory surface morphology, shape memory, mechanical properties, biocompatibility, and biodegradability. In recent years, bioprinting has garnered considerable attention in the biomedical field and clinical applications due to the emergence of stimulus-responsive biomaterials and a deeper understanding of tissue regeneration. While various stimulus-responsive biomaterials and innovative strategies have been developed, 4D bioprinting remains in its infancy, necessitating further research to address numerous challenges [259].
Although responsive biomaterials have been developed for mechanical force, photothermal, electromagnetic and ultrasonic stimulation associated with the physical microenvironment, they are still in their infancy and have some common issues that need to be urgently addressed. The first is that these novel biomaterials, their immune responses and metabolic pathways have not been systematically explored. Secondly, the manufacturing process of reactive materials is complex and the specific mechanisms still need to be studied in detail. The optimal parameters of external stimuli and changes in the internal environment cannot be determined quickly in real-time and require the selection of suitable animal models for evaluation. Despite the enormous challenges, physical microenvironmental stimulation of biomaterials has far-reaching clinical applications in the future.
5. Bone microenvironment and bone organoids
Organoids, defined as in vitro 3D cell clusters derived from induced pluripotent stem cells, embryonic stem cells, or primitive tissues, rely on artificial microenvironmental matrices for self-renewal and self-organization. These formations emulate natural tissue structures and exhibit organ functions akin to native tissues [260]. Despite the variability resulting from their self-organizing nature, organoids represent the closest in vitro model system to in vivo tissue conditions and offer a promising avenue for personalized medicine. To date, organoids have been developed to simulate various human organs, including the brain [261], lung [262], kidney [263], liver [264], pancreas [265], intestine [266], and prostate [267]. However, the development of bone organoids remains in its infancy, due to limited understanding of bone-related disease mechanisms and challenges in directing stem cell differentiation [268]. Bone organoids combine stem cells with bioactive materials to form three-dimensional bone-mimicking tissue with self-renewal and self-organizing properties [260]. The successful establishment of bone organoids depends not only on the selection of stem cells but, more importantly, on the capacity of introduced biomaterials to provide the requisite microenvironmental matrix for 3D cell model growth and differentiation (Fig. 14A).
Fig. 14.
Engineered bone microenvironments assist in building bone organoids. A) Schematic diagram of the process of building bone organoids. Reproduced and adapted with permission [268]. Copyright 2022, Elsevier. B) The hydrogel-based construction of bone organoids bionically mimics the physiological microenvironment and promotes cell adhesion, proliferation and differentiation. Reproduced and adapted with permission [270]. Copyright 2022, Elsevier. C) BMSC and EC cells can form a pseudo-vascularized network within the mesenchymal compartment to generate bone marrow-like organs with in situ functional characteristics. Reproduced and adapted with permission [272]. Copyright 2022, American Institute of Physics. D) Composite hydrogel sensory electrical stimulation reconstructs the bone's physical microenvironment to promote bone regeneration. Reproduced and adapted with permission [274]. Copyright 2022, Elsevier.
As aforementioned, the bone microenvironment can be classified into physiological, chemical, and physical microenvironments, with dynamic interactions between the physiological microenvironment and bone organoids seed cells playing a critical role in regulating cellular behavior and tissue regeneration [269]. This dynamic process involves the continuous generation, degradation, and remodeling of ECM components. Matrigel, a natural physiological microenvironmental component derived from mouse tumors, is the most prevalent substrate for organoid cultures. It provides multiple physiological cues to induce stem cell differentiation, supports bone organoids growth, maintains extracellular and intercellular junctions, and facilitates self-organization into organoid tissues. Despite its widespread use in organoid cultures, Matrigel possesses certain drawbacks, such as heterogeneous origin, variable composition, and complexity, which impede its clinical advancement. Consequently, alternative biomaterials are urgently required for bone organoids development. Bone tissue engineering techniques have identified hydrogels as a viable alternative to matrix gels for bone organoids cultivation [270]. Hydrogels can provide a three-dimensional aqueous microenvironment to activate cell adhesion and proliferation, enhance cell differentiation, more closely mimic the functionality of natural tissues, and allow modulation of their properties through functional group modifications (Fig. 14B). It is anticipated that the biomimetic physiological microenvironment furnished by hydrogels will significantly advance overall regulation, thereby facilitating bone organoids culture.
The chemical microenvironment, encompassing various soluble factors, plays a crucial role in maintaining development and homeostasis during bone organoids construction. Existing in vitro skeletal models are frequently limited to basic osteogenic functions. Nevertheless, by integrating engineered microenvironmental tissue engineering strategies, organoids can present gradients of nutrients, gases, and signaling molecules, thereby achieving a comprehensive integration of immune regulation, angiogenesis, and osteogenic functions [271]. Recent research has demonstrated that bone marrow-like organoids can be formed on a hydrogel microporous platform, aided by components of the natural bone niche [272]. Morphologically, these organoids form self-organized, vascular-like networks, which strongly support the further construction of vascularized bone organoids (Fig. 14C) [273].
Constructing bone organoids with responsive physical microenvironments enables rapid detection of and response to disease environments and therapeutic effects. Various diseases exhibit distinct pathological microenvironments, such as excess reactive oxygen species and weak acidity in tumors, specific pH reductions and bacterially secreted enzymes in severe infections, and negative potential and specific ion concentrations at bone defect sites [157]. Leveraging these unique pathological characteristics, reversible or irreversible transformations in physical properties or chemical structures of biomaterials can be induced by stimulating the surrounding physical microenvironment, subsequently influencing cell fate and enhancing bone tissue healing and regeneration. Recent studies have similarly shown that re-establishing the physical microenvironment through electrical stimulation can significantly accelerate bone regeneration (Fig. 14D). [274].
In summary, the bone microenvironment is inherently linked to the development of bone organoids. Engineered bone microenvironments hold considerable potential for multifunctional co-regulation of bone organoids in simulating bone development and diseases. However, the currently reported bone organoids can only represent a single function of bone, such as bone formation, bone resorption, or hematopoiesis. Achieving multifunctional integrated bone organoids remains a great difficulty due to the different requirements of different types of stem cells for co-culture microenvironments. Future research can be conducted by constructing bone organoids with responsive microenvironments and integrating engineered microenvironmental tissue engineering strategies that can better mimic the complexity of bone tissue, create more accurate in vitro models, and ultimately facilitate advances in bone tissue regeneration and personalized medicine.
6. Summary and prospect
Bone tissue regeneration constitutes a multifaceted process that necessitates the emulation of the natural bone microenvironment, engaging various cells and factors to optimize new bone formation. This presents a critical opportunity for bone tissue engineering, which endeavors to integrate diverse physiological, chemical, and physical factors to replicate the microarchitecture and microenvironment of bone, ultimately facilitating tissue regeneration and repair. Recent advancements in the field have harnessed innovative techniques and materials to mimic the bone microenvironment, demonstrating its potential as a promising therapeutic target to promote functional bone tissue regeneration.
However, several challenges remain to be addressed in bone tissue engineering. Foremost is the attainment of multifunctional integration while emulating the bone microenvironment. The regulation of the bone healing process is stage-specific, dynamic, and coordinated, necessitating a research focus not only on the direct regulation of osteoblast cell lineage by the microenvironment but also on the interconnected systems of angiogenesis and immune regulation therein. By modulating the biological effects of these cells, a multifunctionally regulated microenvironment can be established in concordance with the natural healing process, thus enhancing bone regeneration more effectively.
Secondly, the nascent field of time-modulated four-dimensional (4D) bone microenvironments warrants further exploration. In recent years, time regulation has garnered substantial attention in biomedical research and clinical applications due to the emergence of stimuli-responsive biomaterials and enhanced comprehension of tissue regeneration. Morrison et al. showcased the successful implementation of personalized 4D printed medical devices in the treatment of pediatric tracheobronchi [275]. 4D implants possess the capacity to self-transform and self-mature over time, yielding significant benefits in the management of adolescent patients with congenital malformations. The 4D concept holds immense potential for personalized treatment and precision medicine, emerging as a leading trend within the realm of bone tissue engineering.
To fully harness the potential of bone tissue engineering, it is imperative that researchers address these challenges, focusing on the development of multifunctional integration and time-modulated 4D bone microenvironments. The successful incorporation of these advances will not only contribute to a deeper understanding of the bone healing process but also propel the field toward more effective and personalized therapeutic solutions for bone tissue regeneration.
Declaration of competing interest
We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service, and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled, “Microenvironment-Targeted Strategy Steers Advanced Bone Regeneration”.
Acknowledgments
S.Y.H., M.K.W., and Z.F.Y. contributed equally to this work. This work was financially supported by the National Natural Science Foundation of China (82230071, 82172098), Shanghai Committee of Science and Technology (23141900600, Laboratory Animal Research Project).
Contributor Information
Yingying Jing, Email: jingy4172@shu.edu.cn.
Long Bai, Email: bailong@shu.edu.cn.
Jiacan Su, Email: drsujiacan@163.com.
Data availability
No data was used for the research described in the article.
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