Startseite Hydrogel promotes bone regeneration through various mechanisms: a review
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Hydrogel promotes bone regeneration through various mechanisms: a review

  • Yuanyuan Zheng , Zengguang Ke EMAIL logo , Guofeng Hu und Songlin Tong
Veröffentlicht/Copyright: 22. November 2024
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Biomedical Engineering / Biomedizinische Technik
Aus der Zeitschrift Biomedical Engineering / Biomedizinische Technik Band 70 Heft 2

Abstract

Large defects in bone tissue due to trauma, tumors, or developmental abnormalities usually require surgical treatment for repair. Numerous studies have shown that current bone repair and regeneration treatments have certain complications and limitations. With the in-depth understanding of bone regeneration mechanisms and biological tissue materials, a variety of materials with desirable physicochemical properties and biological functions have emerged in the field of bone regeneration in recent years. Among them, hydrogels have been widely used in bone regeneration research due to their biocompatibility, unique swelling properties, and ease of fabrication. In this paper, the development and classification of hydrogels were introduced, and the mechanism of hydrogels in promoting bone regeneration was described in detail, including the promotion of bone marrow mesenchymal stem cell differentiation, the promotion of angiogenesis, the enhancement of the activity of bone morphogenetic proteins, and the regulation of the microenvironment of bone regeneration tissues. In addition, the future research direction of hydrogel in bone tissue engineering was discussed.

Keywords: hydrogel; bone regeneration; bone marrow mesenchymal stem cells; bone morphogenetic protein; neovascularization; microenvironment

Introduction

The skeleton is one of the major tissues in the human body with multiple physiological functions and plays an important role in maintaining the stability of the internal environment and releasing minerals [1]. Bone defects usually imply the destruction of bone structure and are mostly caused by infection, trauma, tumors, and surgery [2]. Despite the inherent regenerative potential of bone tissue, bone defects exceeding a critical size are difficult to heal naturally and take a long time to heal [3]. The main treatment for severe bone defects is bone grafting, including autologous bone grafting, allogeneic bone grafting, xenografting, and synthetic bone grafting [4]. Autologous bone grafting is considered the gold standard for the treatment of bone defects. However, autologous bone grafts are expensive and may also cause other symptoms such as infection and inflammation [5]. On the other hand, the use of allogeneic bone grafts is limited by factors such as tissue source, bone defects at the donor site, immune response, and infection [6].

Bone regeneration (Figure 1) is a highly complex bio regulatory process involving multiple cell types and coordination of different signaling pathways [7]. The factors affecting bone regeneration mainly include primitive cells with the ability to differentiate and proliferate, various cytokines that regulate bone formation, a microenvironment that is suitable for cell growth and conducive to the restoration of the original bone morphology and continuity, as well as an adequate blood supply and nutrients [8], [9], [10]. The mechanisms of bone regeneration mainly include three types: osteogenesis (cells carried by the graft can form new bone in the area of grafted bone), inducing osteogenesis (bioactive substances in the graft can induce host mesenchymal stem cells (MSCs) to aggregate and differentiate into osteoblasts to form new bone), and conductive osteogenesis (the graft can provide a scaffold structure to guide the growth of blood vessels and osteoblasts toward the grafted bone and form new bone) [11], [12], [13], [14]. With the development of biomaterials, stem cells, and bone tissue engineering technology, various materials with good biological functions have appeared in the field of bone regeneration in recent years [15]. Ideal bone regeneration materials should exhibit excellent cytocompatibility, biodegradability, bioactivity, and appropriate biomechanical characteristics, as well as promote cell adhesion and proliferation [16].

Figure 1: The main factors affecting bone regeneration.
Figure 1:

The main factors affecting bone regeneration.

Hydrogels are extremely hydrophilic three-dimensional network gel formed by physical or chemical crosslinking of hydrophilic polymers [17]. They are widely used in bone tissue engineering because of their good biocompatibility, flexibility, designability and versatility, can be formed into different shapes and sizes to meet specific requirements under different conditions [18]. The water content of hydrogel exceeds 90 % compared to other types of gels. When the polymer network is permeated by water, hydrogels become flexible and deformable like a fluid [19]. In addition, hydrogel has no side effects on biological tissues. Its softness and high water content provide a microenvironment similar to the natural extracellular matrix, which provides nutrients to cells and serves as a platform for cell proliferation and differentiation [20]. The development of hydrogels can be divided into four generations (Table 1). The first-generation hydrogels include polymers formed by free radical-induced chain reaction of vinyl monomers, covalently crosslinked hydrophilic polymers, and cellulose-based hydrogels. The second-generation hydrogels are mainly polyethylene glycol (PEG)/polyester block copolymers. The third-generation hydrogels mainly modulate the mechanical and degradation properties of hydrogels through stereo complexation, inclusion, and metal-ligand coordination. The fourth-generation hydrogels combine organic, polymer chemistry, and nanotechnology for more precise targeting properties [38], 39].

Table 1:

The development of hydrogels.

Hydrogel Classification Representation References
First generation hydrogel A polymer synthesized from an olefinic monomer Polyacrylamide (PAM), polyhydroxyethyl methacrylate (pHEMA) [21], 22]
Covalently crosslinked hydrophilic polymer Polyvinyl alcohol (PVA), PEG [23], 24]
Hydrogels based on cellulose Methylcellulose (MC), carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC) [25], [26], [27]
Second generation hydrogel Temperature-responsive thermosensitive hydrogel poly(N-isopropylacrylamide) (PNIPA), poly(n,N-diethylacrylamide) (PDEAM) [28], 29]
pH sensitive hydrogel Polyacrylic acid (PAA), polyacrylamide, chitosan [30], [31], [32]
Biomolecular sensitive hydrogel Glucose oxidase hydrogel [33]
Third generation hydrogel Synthesis through stereo coordination, inclusion complexes, metal ligand coordination, and peptide chain synthesis Poly-l-Lactic acid (PLLA), poly (d-lactic acid) (PDLA) [34], 35]
Fourth generation hydrogel Combining organic and polymer chemistry with nanotechnology Polymer nanocomposite hydrogel [36], 37]

Hydrogels can be categorized into natural hydrogels and synthetic hydrogels according to their origin [40]. Natural hydrogels are obtained directly from nature, while synthetic hydrogels need to be prepared by chemical reactions (Table 2). Hydrogels from natural sources include proteins (gelatin, collagen, fibrin, and fibroin) and polysaccharide (hyaluronic acid, chondroitin sulfate, alginate, and chitosan). In addition, DNA, peptides and proteins hydrogels, as one kind of natural hydrogels, are also widely used in disease treatment due to their unique advantages [56], [57], [58]. Synthetic hydrogels mainly include poly (2-hydroxyethyl methacrylate), PEG, PVA, poly (N-isopropylacrylamide), and polyacrylamide [59]. Compared with synthetic hydrogels, natural hydrogels are biocompatible, environmentally sensitive, and inexpensive, but less stable. To better realize the application of hydrogels in the fields of drug delivery and tissue regeneration, intelligent hydrogels have emerged [60]. The so-called intelligent hydrogels are hydrogels that can respond to the external environment (such as pH and temperature) to achieve hydrogel controllability. Among them, temperature-responsive hydrogels include poly (N-isopropylacrylamide) based hydrogels, poloxamer, etc., and pH-responsive hydrogels include poly (dimethylaminoethyl methacrylate) based hydrogels, poly (allyl acetate) based hydrogels, hydrazone linked hydrogels, etc. [61], 62]. Hydrogels have been widely used in the biomedical field for the study of physiopathological mechanisms and the treatment of regenerative diseases, among which more studies have been conducted on the application of hydrogel in the field of bone regeneration. This article reviewed the application mechanism of hydrogels in bone regeneration (Figure 2).

Table 2:

Hydrogel classification, advantages and disadvantages.

Natural hydrogels Advantages Disadvantages References
Gelatin Biocompatibility, non-toxic, adjustable degradation, and easy modification Risk of triggering immunogenic reactions [41]
Collagen Biocompatibility, biodegradability, and good bone conduction activity Poor mechanical performance, unsatisfactory processing conditions, and risk of denaturation during the processing [42]
Fibrin Good biocompatibility and biodegradability, renewability, flexibility, and high mechanical strength Poor solubility [43]
Silk heart protein Good mechanical properties, biocompatibility, and bio-absorbability Brittleness is high [44]
Hyaluronic acid Non-toxic, non-allergenic, biocompatible, and biodegradable Easy to induce allergic reactions [45]
Chondroitin sulfate Good biocompatibility, low toxicity, and good biodegradability Poor mechanical performance [46]
Alginate Biocompatibility, lack of immunogenicity, mild cross-linking, adjustable mechanical properties Lack of cell adhesion sites and slow degradation [47]
Chitosan Biocompatibility, ease of processing, antibacterial properties, adjustable degradation rate Poor mechanical performance and stability [48]
Agarose Good biodegradability, biocompatibility, antibacterial properties, and high hydrophilicity High gelation temperature and high rigidity [49]
Proteins and peptides Superior biocompatibility and lower immunogenicity Poor mechanical performance [50]
DNA Good stability, biocompatibility, biodegradability, and adjustable functionality Low sensitivity and quantitative barriers [51]
Synthetic hydrogel Advantage Disadvantage References
2-Hydroxyethyl methacrylate Hydrophilicity, biocompatibility, and non-toxicity Has allergenicity that irritates the skin and mucous membranes [52]
Polyethylene glycol(PEG) Biocompatibility, non-toxic, easy to functionalize and modify Slow degradation rate, able to resist protein and cell adhesion [53]
Poly (N-isopropylacrylamide) Good biocompatibility and temperature sensitivity Low mechanical strength, limited drug loading, and low biodegradability [54]
PVA Biodegradable, biocompatible, and easy to functionalize Lack of cell adhesion sites [55]
Figure 2: Hydrogel promotes the differentiation of bone marrow mesenchymal stem cells into osteoblasts to achieve bone regeneration.
Figure 2:

Hydrogel promotes the differentiation of bone marrow mesenchymal stem cells into osteoblasts to achieve bone regeneration.

Mechanism of hydrogel in bone regeneration

Promoting the differentiation of MSCs into osteoblasts

Although bone marrow MSCs have the potential for multi-directional differentiation, they do not differentiate into osteocytes on their own and need to be stimulated to complete the transformation into chondrocytes [63]. Hydrogel is capable of encapsulating bone marrow MSCs and has no toxic effects. It can promote the aggregation of bone marrow hematopoietic stem cells and enhance cell migration and proliferation [64]. In addition, the reticular structure inside the hydrogel facilitates the directional transport of cells and accelerates the osteogenic differentiation ability and speed of stem cells [65]. A recent study on hydrogels in small animals found that MSCs encapsulated in hydrogels had good temperature sensitivity and could promote bone regeneration and repair of cranial defects [66]. Wise et al. utilized collagen/chitosan hydrogels to encapsulate bone marrow MSCs from different sources and compared the osteogenic ability of the stem cells. The results showed that both freshly isolated rat bone marrow MSCs and purified cultured rat MSCs could be well encapsulated by the hydrogel and produced large amounts of osteocalcin within 21 days, increasing calcium deposition and phosphate mineralization with a similar degree of osteogenesis [67]. A study on the use of a novel hydrogel found that polysaccharide hybrid hydrogels can promote the proliferation and migration of rabbit bone marrow MSCs and enhance the aggregation of bone marrow MSCs in vitro [67]. Another study found that a novel temperature-sensitive hydrogel fortified with platelet-rich plasma can capture adipose-derived stem cells, induce their osteogenesis, promote calcium deposition and extracellular matrix mineralization, and upregulate the expression of osteogenic marker genes by increasing the cell proliferation rate and alkaline phosphatase activity [68]. Meanwhile, hydrogels were implanted into rabbit cranial defects, and new bone formation was found at the defects, confirming that temperature-sensitive composite hydrogels could promote osteogenesis of rabbit adipose-derived stem cells [69].

In addition, the specific properties of hydrogel can directly affect the signaling pathway of osteoblastic differentiation, thus promoting the differentiation of bone marrow MSCs into osteoblasts. A study on phenolic alginate gel revealed that it contains collagen nanoparticles and hydroxyapatite, with good mechanical characteristics. The addition of hydroxyapatite reduces collagen degradation, increases the swelling rate and stiffness of the hydrogel in tandem, and reduces elasticity and pore size, which is beneficial for the differentiation of bone marrow MSCs into osteoblasts. Various experimental methods confirmed that Wnt signal pathway related protein expression is induced during the process of phenolic alginate saline gel inducing stem cells to osteoblasts, indicating that the Wnt signal is involved in this process [70]. Ji et al. explored the osteogenic induction ability of newly synthesized temperature-sensitive hydroxypropyl chitacean hydrogel (HPCH). It was found to be non-toxic to cells and has good mechanical properties, which can stimulate stem cells to secrete angiogenic factors and osteogenic growth factors. By loading bone marrow MSCs and macrophages to the hydrogel, stem cells can promote the transformation of macrophages to anti-inflammatory M2 type, inhibit the secretion of inflammatory factors, upregulate the expression of osteogenic proteins osteocalcin, osteopontin and runt-related transcription factor 2, and promote cartilage solidification and the generation of angiogenic factors. Moreover, its unique 3D structure shows excellent compressive strength, creating a favorable microenvironment for vascularization and osteogenesis [71]. A study on multifunctional hydrogel found voltage and mechanical signaling effects. It can activate the downstream p-extracellular signal-regulated kinase (ERK) signaling pathway through multiple signaling proteins like mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase (JNK), P38, and transforming growth factor beta (TGF-β), ultimately promoting the differentiation of bone marrow MSCs into osteoblasts [72]. Yang et al. prepared collagen hydrogel with electrical properties by using methacrylic anhydride and succinic anhydride, this hydrogel has a triple helical structure and electrochemical characteristics. It can make bone marrow MSCs better adhere and spread on the hydrogel surface by affecting hydrophilicity, protein diffusion rate, and binding speed. It also promotes bone marrow MSCs to secrete sulfate mucopolysaccharide (sGAG) and further cartilage differentiation by improving integrin gene expression. Similar results were observed for in vivo subcutaneous implantation of this hydrogel, where significantly higher expression levels of sGAG, SOX9, and type II collagen were found in collagen hydrogels with higher negative charge [73]. In conclusion, hydrogels from various sources can promote the differentiation of bone marrow MSCs into osteoblasts, thus achieving bone regeneration (Figure 2).

Promote neovascularization in bone tissue

The vascular system is the body’s pipeline system in the human body and plays a crucial role in bone regeneration through its main functions of transporting oxygen and nutrients, maintaining blood flow and blood pressure, participating in immune reactions, recruiting cells in bone tissue, and regulating osteogenesis [74]. The key to successful bone regeneration is the establishment of a strong vascular network at the repair site to deliver the necessary nutrients and oxygen to the injured site. Thus, angiogenesis is a prerequisite and necessary factor for bone regeneration. since bone is a calcified tissue it has a limited blood supply and if blood supply is disturbed, new growth of blood vessels is time sensitive as it requires bone remodeling [75]. Therefore, the development of biomaterials that can promote the construction of functional vascular networks at defect sites is crucial in bone regeneration research. Another mechanism by which hydrogels promote bone regeneration is to promote angiogenesis in bone tissue [76]. Hydrogels have no toxic effect on vascular endothelial cells and can serve as vascular scaffolds and protective layers to protect neovascularization from damage and provide better protection against risk factors in the microenvironment [77]. Hydrogels can carry cells that promote angiogenesis and crosslink various cellular particles and cytokines. In addition, hydrogels can form a biphasic system with stem cells, which act directly on the bone defect site to simulate the normal biological environment around the bone and achieve bone and vascular regeneration, thus accelerating the repair of bone defects [76]. A study showed that implanting hydrogels co-cultured with human umbilical vein endothelial cells (HUVEC) into bone defect sites could enhance the formation of endothelial cell tubular structures and the number of branches, stimulate angiogenesis, and better promote bone tissue regeneration [78]. At the same time, Zhang et al. encapsulated exosomes derived from umbilical cord MSCs in hyaluronic acid hydrogel and combined them with customized nano scaffolds to repair cranial defects in rats. Imaging and histological evaluations indicated that this composite can enhance the proliferation, migration, and differentiation of vascular endothelial cells, further promoting bone regeneration [79]. Furthermore, many studies on the mechanism of bone regeneration and repair have shown that the novel hydrogel obtained after the implantation of multiple metal ions in the hydrogel has a better role in promoting angiogenesis. For example, when magnesium ions were implanted into hydrogels to repair cranial defects in rats, the novel hydrogel significantly promoted angiogenesis and bone regeneration in bone tissue, which was characterized by the upregulation of the expression of platelet endothelial cell adhesion molecule (CD31) and platelet endothelial cell adhesion molecule (VEGF), and the increase in vascular density [80], [81], [82].

Chen et al. conducted MgO nanoparticles were introduced into a newly synthesized aqueous water-soluble phosphocreatine-functionalized chitosan (CSMP) solution to form an injectable CSMP–MgO hydrogel. The combination of phosphate groups in CSMP and magnesium in MgO nanoparticles promotes angiogenesis in bone tissue and ultimately osteogenic differentiation. HUVEC cells were co-cultured with the hydrogel to evaluate its pro-angiogenic effect in vitro by observing the formation of a capillary network. It was found that HUVEC cells in the CSMP–MgO hydrogel group showed a rich vascular tubular network structure and revealed the largest capillary length, confirming the pro-angiogenic effect of the CSMP–MgO hydrogel [83]. Another study on multifunctional piezoelectric hydrogel discovered that it not only generates electricity but also promotes angiogenesis and bone regeneration by regulating the immune response. In this study, the effect of different stimulations on the angiogenic capacity of HUVEC cells was tested. It was found that the piezoelectric hydrogel promoted the chemotaxis and migration of HUVEC cells by inhibiting the immune response. Moreover, it enhanced the tube-forming ability of HUVEC cells by increasing vascular branch and tube formation and increased the expression of vascular function related protein CD31. All these results confirm the pro-angiogenic effect of the piezoelectric hydrogel [84]. Gao et al. successfully constructed a silk fibroin hydrogel compounded with nanoparticles and applied it to bone regeneration research. This hydrogel has excellent bioactivity and can promote the adhesion and spreading of HUVEC cells. At the same time, it can enhance angiogenesis and osteogenic differentiation. In the rat cranial regeneration model, transplanting the hydrogel significantly accelerated the cranial regeneration process. After 8 weeks of implantation, the healing rate can reach 86.77 ± 8.91 %, the pro-angiogenic effect shows that the number and branches of new blood vessels in HUVEC cells in the hydrogel group increase. Among them, the number of new blood vessels increases by 1.77 times, increased expression of VEGF and CD31 proteins. The results confirm that the hydrogel can accelerate bone regeneration by promoting angiogenesis [85]. Therefore, accelerating angiogenesis in bone tissue is another important mechanism by which hydrogels promote bone regeneration (Figure 3).

Figure 3: Accelerating angiogenesis in bone tissue is the main mechanism of hydrogel to promote bone regeneration.
Figure 3:

Accelerating angiogenesis in bone tissue is the main mechanism of hydrogel to promote bone regeneration.

Enhance bone morphogenetic protein (BMP) activity

BMP are a class of transforming growth factors involved in various processes of bone tissue repair and are capable of inducing the differentiation of bone marrow mesenchymal cells into osteoblasts and chondrocytes [86]. Among them, BMP2 is the most important regulator of bone formation, inducing the differentiation of bone precursor cells into mature stem cells [87], 88]. As a growth factor, BMP has a short half-life, is prone to inactivation and degradation in vivo, and requires excessive physiological doses to achieve the effect of promoting bone formation. However, excessive amounts of BMP can lead to side effects such as bone swelling, osteolysis, and bone resorption [89]. Therefore, there is a need for a biological delivery material in combination with BMP that reduces the dosage of BMP while increasing the activity and stability of BMP to better achieve the effect of promoting bone regeneration. It has been confirmed that combining BMP with hydrogel for bone defects not only maintains the stability of BMP and delays the degradation time of BMP, but also prolongs the activity time of osteoblasts and promotes bone regeneration [90]. Another study also found that by increasing or decreasing the number and type of anions in the hydrogel composition and changing the solid-liquid transition period and internal pore size, BMP2 can be released slowly and continuously, thus better promoting bone regeneration [91]. For example, when BMP2 was implanted into fibrin hydrogel containing macromolecular heparin, BMP2 could adhere well to the hydrogel to maintain its stability and activity, avoiding its sudden release and prolonging the action time of BMP2, thus enabling BMP2 to act directly on mesenchymal cells, accelerating their differentiation to osteoblasts, and promoting bone regeneration [92]. Similarly, Xu et al. first combined BMP2 with microspheres to prepare BMP2 microspheres and then implanted the microspheres into chitosan/polyethylene glycol hydrogels to prepare composite hydrogels. This composite hydrogel provides an environment and space for new bone growth, and the pore diameter of the hydrogel scaffold also provides exchange space for materials needed for bone regeneration. Microspheres can slowly release BMP2 and generate large amounts of calcium and phosphate ions to promote bone formation [93]. In addition, BMP7 and BMP9 can also be slowly released in the hydrogel, accelerating the aggregation, proliferation, and differentiation of osteoblast at the bone defects, contributing to the fusion of newly formed bone and surrounding bone tissues, and upregulating the expression of bone-related factors, and ultimately achieve the purpose of promoting bone regeneration [94], 95].

Heparin is a highly sulfated anionic polysaccharide composed of repeating glycoamine and uronic acid residues and has anticoagulant function. Due to the presence of a large number of negatively charged sulfate and carboxyl groups, it can bind to various proteins and positively charged cationic compounds. The heparin-conjugated fibrin (HCF) hydrogel is synthesized from adipose-derived pericytes (ADPs) and BMP2. The heparin sulfate groups of this hydrogel interact with the BMP2 protein to form a stable strong polyanionic complex, which not only protects heparin from hydrolysis but also delays the release of BMP2 from the hydrogel and maintains its biological activity. In vitro release experiments show that the continuous release time of BMP2 from the HCF hydrogel exceeds 4 weeks and can enhance the activity of alkaline phosphatase (ALP) protein in newly generated osteoblasts of rats and induce osteogenesis of osteoblasts in rat skull [96]. Alginate is a natural biopolymer. In the presence of divalent cations, alginate is easily ionically cross-linked to form a stable hydrogel. Although alginate biomaterials lack osteoconductivity and osteoinductivity, the addition of BMP2 can enhance its osteogenic induction ability. A new type of hydrogel synthesized from BMP2-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles and alginate shows excellent mechanical properties and can continuously release BMP2 for up to 2 weeks. In addition, this hydrogel can significantly enhance calcium deposition and alkaline phosphatase activity and upregulate the expression of osteogenic genes in MSCs [97]. In addition, a 3D-printed hydrogel scaffold is used to encapsulate BMP2-engineered human MSCs cells. MSCs cells can continuously express BMP2 and differentiate into osteoblasts. When implanted into severely immunodeficient mice, at 14 days after implantation, bone formation in mice increases, and mature trabecular bone structure and a large number of new blood vessels appear [97]. Chitosan has biocompatibility and biodegradability and can be used for bone transplantation. The presence of amino and hydroxyl groups in chitosan improves the absorption capacity of drugs, ions and growth factors. These groups are also modifiable positions for connecting additional functional groups to further enhance covalent adsorption. Methyl acrylate-modified chitosan was used to deliver BMP2 for bone regeneration research. The results showed that about 30 % of BMP2 was released on the first day, and then 70 % was released in the following week. The tibial defect in rats recovered by 3 mm within 4 weeks, indicating that chitosan-delivered BMP2 has important value in bone repair. In addition, sulfated chitosan can maintain a beneficial immune microenvironment by regulating immune function, enhance the connection between immune cells and stem cells, promote the osteogenic induction ability of stem cells and BMP2, and promote the chemotaxis of bone marrow stromal cells by upregulating bone morphogenetic protein receptor IA (BMPR-IA) expression and amplifying BMP2/Smad signal transduction [98]. Therefore, the enhancement of BMP2 activity is another mechanism by which hydrogels promote bone regeneration (Figure 4).

Figure 4: Enhancement of BMP2 activity is another mechanism by which hydrogels promote bone regeneration.
Figure 4:

Enhancement of BMP2 activity is another mechanism by which hydrogels promote bone regeneration.

Regulating the microenvironment of bone regeneration tissue

Bone injuries from various causes can lead to changes in the microenvironment of bone defects. Among them, the hypoxic environment caused by blood interruption due to microvascular rupture at the defect site is the main reason affecting bone regeneration [99]. It is well known that hypoxia not only affects the proliferation and activity of bone marrow MSCs, but also inhibits their metabolic transformation and tube-forming ability, and further reduces the expression of osteogenic markers and mineralization [100]. In addition to directly decreasing cell activity, hypoxia increases the release of reactive oxygen species (ROS). High concentrations of ROS induce the death of osteoblast precursor cells and mature osteoblasts and inhibit the expression of ALP/BMP and tubular markers [101]. In addition, short-term over-oxygenation can lead to high oxygen tension and affect osteoblast activity [102]. Therefore, reasonable oxygenation and removal of ROS are important for promoting bone tissue regeneration. Hydrogels can improve the microenvironment of bone defects. On the one hand, specific components in the microenvironment activate the release of drugs and growth factors loaded in hydrogels. On the other hand, hydrogels can improve the stability of the microenvironment, promote osteoblast differentiation, and accelerate osteogenesis [103]. Sun et al. designed a composite hydrogel to meet the needs of bone defects, which has the potential to responsively clear ROS and prolong the duration of oxygen supply, thereby generating large amounts of oxygen to improve the hypoxic microenvironment at the site of bone defects, and also promotes the regeneration and repair of bone tissues by facilitating the formation of vascular rings and osteoblast differentiation, as well as by inhibiting osteoclast differentiation [104]. Zhou et al. also developed an antioxidant hydrogel to accelerate bone tissue regeneration through a similar mechanism of action [105]. Notably, due to the presence of hyperglycemia, the blood vessels of diabetic patients usually exhibit abnormal function and are prone to hypoxia and ROS overproduction, which induces the production of inflammatory factors and harmful substances resulting in the disturbance of the microenvironment at the bone defects. Therefore, bone regeneration in diabetic patients faces greater challenges. Li et al. designed a dual-network adaptive hydrogel composed of phenylboronic acid crosslinked polyvinyl alcohol and gelatin gel. This network hydrogel reversibly decomposed upon exposure to a high glucose environment and ROS, decreased the ROS content in the microenvironment, increased oxygen content by inhibiting inflammatory reactions, and improved the imbalanced microenvironment, which in turn promoted bone regeneration [106].

Hydrogels can bind to host cells through specific molecular pathways and regulate the bone regeneration microenvironment to promote bone hyperplasia. Sun et al. developed a smart responsive hydrogel. It can increase the expression of the brain and muscle arntlike 1(BMAL1) gene in osteoblasts by releasing oxygen, upregulate the expression levels of autophagy related proteins Beclin1 and LC3, and regulate the microenvironment in the bone regeneration process to promote osteogenesis [107]. Zhang et al. developed a new type of ultrasound-triggered biomimetic ultrashort peptide nanofiber hydrogel. This hydrogel can promote the healing of bone defects by constructing a microenvironment conducive to bone regeneration. Exploring its mechanism reveals that this hydrogel can change the polarization state of macrophages, reduce the number of M1 types and increase the number of M2 types. At the same time, interleukin-4 activates the transcription factor Signal Transducer and Activator of Transcription 6 (STAT6), which further binds to specific target genes and increases the number of peroxisome proliferator-activated receptor gamma (PPAR-γ) heterodimerization and M2 macrophages. More interestingly, the nanofibers released by this hydrogel can also inhibit the release of ROS by regulating macrophage mitochondrial energy metabolism and secrete BMP2 and insulin-like growth factor 1(IGF-1) proteins to accelerate the osteogenic differentiation ability of bone marrow MSCs [108]. A study on immunomodulatory blood-derived hybrid hydrogel found that it can regulate the bone regeneration microenvironment in multiple ways to enhance bone regeneration ability. This double-network hybrid hydrogel is composed of platelet-rich fibrin and polycaprolactone/hydroxyapatite composite nanofibers, with polydopamine (PDA) as an anchor. The polycaprolactone in hydrogel has good mechanical properties to stimulate osteoblast differentiation in an appropriate biomechanical microenvironment. PDA can not only improve the adhesion ability of growth factors but also continuously create a suitable biochemical and immune microenvironment for osteoblasts and promote bone healing by inducing M2 macrophage polarization [109]. Yang et al. developed a 3D printed composite hydrogel scaffold, this hydrogel can provide a suitable microenvironment for bone regeneration and angiogenesis. In addition, the CS (Ca and Si) molecules released from this 3D printed composite hydrogel scaffold endow the scaffold with multiple functions. Firstly, it promotes the differentiation of bone mesenchymal MSCs into osteoblasts and blood vessels. Secondly, it induces the transformation of macrophages to M2 type by inhibiting the expression of Smad six and Smad seven proteins. At the same time, it remodels the immune microenvironment conducive to bone and angiogenesis. The rabbit skull defect experiment confirmed that the scaffold can promote osteogenesis and neovascularization by regulating the bone regeneration microenvironment. In general, the strong osteoinductive ability and good bone immune regulation characteristics of the scaffold are considered a promising strategy for treating bone defects [110]. Therefore, regulating the microenvironment of bone tissue is another mechanism by which hydrogels promote bone regeneration (Figure 5).

Figure 5: Regulating the microenvironment of bone tissue is another mechanism by which hydrogels promote bone regeneration.
Figure 5:

Regulating the microenvironment of bone tissue is another mechanism by which hydrogels promote bone regeneration.

Summary

Repairing bone tissue defects has long been a major challenge in the field of bone regeneration, and biomaterials for bone regeneration need high biocompatibility and low immunogenicity. With in-depth research on the mechanism of bone regeneration and the application of bio-tissue materials, a variety of bio-functional materials with excellent performance have appeared in the field of bone regeneration, which has brought new hope for the repair of large-scale bone defects. Because of their unique physical and biological properties, hydrogels play an important role in numerous diseases such as tumors, wound healing, neurological diseases, digestive diseases, and motor system diseases. Among them, hydrogels show significant advantages in the fields of bone regeneration and repair due to their good biocompatibility and modifiable properties. This article summarized the main mechanisms of hydrogel to promote bone regeneration, including inducing the differentiation of bone marrow MSCs to osteoblasts and angiogenesis, enhancing the activity of bone morphogenetic proteins, and improving the microenvironment of bone regeneration tissues. The different mechanisms interact with each other to jointly promote bone regeneration and repair. Through an in-depth understanding of the mechanism of hydrogel promoting bone regeneration, this paper provides a research direction for the development of novel hydrogels and other bio-tissue materials. Certainly, there are still more mechanisms and functions of hydrogels for bone regeneration that need to be further summarized and studied.

Corresponding author: Zengguang Ke, Department of Orthopaedic Surgery, Affiliated Cixi Hospital, Wenzhou Medical University, No. 999, South Second Ring Road, Hushan Street, Cixi, Ningbo, 315300, China, E-mail:

  1. Research ethics: Not applicable.

  2. Informed consent: Not applicable.

  3. Author contributions: Conceptualization: Zengguang Ke; writing and original draft preparation: Yuanyuan Zheng; writing and editing: Guofeng Hu and Songlin Tong. All authors have read and agreed to the published version of the manuscript.

  4. Use of Large Language Models, AI and Machine Learning Tools: Not applicable.

  5. Conflict of interest: The authors state no conflict of interest.

  6. Research funding: Not applicable.

  7. Data availability: Not applicable.

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Received: 2024-08-16
Accepted: 2024-11-05
Published Online: 2024-11-22
Published in Print: 2025-04-28

© 2024 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

Artikel in diesem Heft

  1. Frontmatter
  2. Review
  3. Hydrogel promotes bone regeneration through various mechanisms: a review
  4. Research Articles
  5. Wear investigation of implant-supported upper removable prothesis with electroplated gold or PEKK secondary crowns
  6. Straight and helical plating with locking plates for proximal humeral shaft fractures – a biomechanical comparison under physiological load conditions
  7. Integration of neuromuscular control for multidirectional horizontal planar reaching movements in a portable upper limb exoskeleton for enhanced stroke rehabilitation
  8. Recognition analysis of spiral and straight-line drawings in tremor assessment
  9. Combination of edge enhancement and cold diffusion model for low dose CT image denoising
  10. High-performance breast cancer diagnosis method using hybrid feature selection method
  11. A multimodal deep learning-based algorithm for specific fetal heart rate events detection
https://doi.org/10.1515/bmt-2024-0391
Schlagwörter für diesen Artikel
hydrogel; bone regeneration; bone marrow mesenchymal stem cells; bone morphogenetic protein; neovascularization; microenvironment
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Frontmatter
  2. Review
  3. Hydrogel promotes bone regeneration through various mechanisms: a review
  4. Research Articles
  5. Wear investigation of implant-supported upper removable prothesis with electroplated gold or PEKK secondary crowns
  6. Straight and helical plating with locking plates for proximal humeral shaft fractures – a biomechanical comparison under physiological load conditions
  7. Integration of neuromuscular control for multidirectional horizontal planar reaching movements in a portable upper limb exoskeleton for enhanced stroke rehabilitation
  8. Recognition analysis of spiral and straight-line drawings in tremor assessment
  9. Combination of edge enhancement and cold diffusion model for low dose CT image denoising
  10. High-performance breast cancer diagnosis method using hybrid feature selection method
  11. A multimodal deep learning-based algorithm for specific fetal heart rate events detection
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