
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)12289-X
10.1016/j.heliyon.2024.e36258
e36258
Review Article
Application of gelatin-based composites in bone tissue engineering
Wu Enguang
Huang Lianghui
Shen Yao
Wei Zongyi
Li Yangbiao
Wang Jin ⁎
Chen Zhenhua zhenhuadeai@163.com
⁎⁎
Jiangxi Province Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang, 330013, China
⁎ Corresponding author. author.
⁎⁎ Corresponding author. Jiangxi Province Key Laboratory of Drug Design and Evaluation; School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang, 330013, China. zhenhuadeai@163.com
14 8 2024
30 8 2024
14 8 2024
10 16 e362581 4 2024
25 7 2024
13 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Natural bone tissue has the certain function of self-regeneration and repair, but it is difficult to repair large bone damage. Recently, although autologous bone grafting is the “gold standard” for improving bone repair, it has high cost, few donor sources. Besides, allogeneic bone grafting causes greater immune reactions, which hardly meet clinical needs. The bone tissue engineering (BTE) has been developed to promote bone repair. Gelatin, due to its biocompatibility, receives a great deal of attention in the BTE research field. However, the disadvantages of natural gelatin are poor mechanical properties and single structural property. With the development of BTE, gelatin is often used in combination with a range of natural, synthetic polymers, and inorganic materials to achieve synergistic effects for the complex physiological process of bone repair. The review delves into the fundamental structure and unique properties of gelatin, as well as the excellent properties necessary for bone scaffold materials. Then this review explores the application of modified gelatin three-dimensional (3D) scaffolds with various structures in bone repair, including 3D fiber scaffolds, hydrogels, and nanoparticles. In addition, the review focuses on the excellent efficacy of composite bone tissue scaffolds consisting of modified gelatin, various natural or synthetic polymeric materials, as well as bioactive ceramics and inorganic metallic/non-metallic materials in the repair of bone defects. The combination of these gelatin-based composite scaffolds provides new ideas for the design of scaffold materials for bone repair with good biosafety.

Graphical abstract

Image 1

Keywords

Gelatin
Composite materials
Bone tissue engineering
Bone repair
==== Body
pmc1 Introduction

Bone is a connective tissue composed of non-homogeneous composites that performs a variety of important functions in the body, including movement, support and protection. It functions as a repository for calcium and phosphorus, with its structure primarily composed of a mineral phase known as hydroxyapatite (HAp) alongside and organic phase [1,2]. In addition, the extracellular matrix composition of bone is mainly 85%–90% type I collagen, 5% non-collagenous proteins, 2%–5% lipid and water [3]. In case of skull bone defects less than 8 mm in rat, bone tissue possess the capability to regenerate and self-heal [4]. However large traumas or bone defects caused by tumors, congenital diseases, osteomyelitis, etc., autogenous or allogeneic tissue need to be filled to promote bone healing [5,6]. Autologous bone grafting is considered the gold standard in clinical treatment for bone defect repair. However, it faces several challenges, such as limited bone supply, the risk of disease transmission, and the difficulty of clinical treatment [7,8]. Bone tissue engineering(BTE) is considered an important optimal choice for the development of regenerative bone grafting and repair [9]. BTE consists of three key elements: bone tissue scaffolds, seed cells, and growth factors. The construction of bone scaffolds is a hot and difficult research topic in bone tissue engineering [10,11]. Bone scaffold materials not only need high mechanical properties to support bone defects, but also serve as a medium for information transfer between bone cells, it provides an optimal microenvironment that fosters the growth and proliferation of bone cells as well as facilitates the process of biomineralization [12,13].

Optimal bone scaffold materials should have structural properties similar to natural bone tissue, including excellent biocompatibility, mechanical properties, appropriate porosity and biodegradability [14,15]. Gelatin, a natural polymeric material, has gained widespread application in bone tissue engineering due to its unique properties [16]. The gelatin is obtained by hydrolysis of collagen, and its most abundant sources are pig skin, cow skin, pig bone, and bovine bone. Gelatin is widely used as a drug delivery system for osteogenic active molecules and as a scaffold material [17]. The unique arginine-glycine-aspartate (RGD) sequence of gelatin provides for the promotion of cell adhesion, proliferation and differentiation [18]. In addition, gelatin can be prepared into shapes such as nanofiber scaffolds, hydrogels, and nanoparticles through 3D printing, electrostatic spinning, freeze-drying, and other techniques to better accommodate different shapes of bone defects [19,20]. Fig. 1 shows the process of gelatin-based 3D scaffolds for BTE. The disadvantages of gelatin are also obvious, it is not able to be used for culturing cells alone and has poor mechanical properties, which are not sufficient to be used as a scaffold material. The nature of gelatin as an osteoblast-like matrix analogs and other excellent properties have been fully utilized with the introduction of BTE [21,22]. Currently, due to the easy modification of gelatin, it is commonly used for compounding with various natural polymer materials, synthetic materials as well as inorganic materials such as bioactive ceramics and metal/non-metal inorganic compounds [23,24]. Therefore, modified gelatin or composites with synergistic effects of different physiological functions can be prepared, which not only have high mechanical properties, but also osteoinductive activity and bone microenvironmental regulation [25,26].Fig. 1 Gelatin-based 3D scaffold for BTE.

Fig. 1

The review delves into the fundamental structure and unique properties of gelatin, and the excellent properties necessary for bone scaffold materials. Then comprehensively explores the application of modified gelatin 3D scaffolds with various structures in bone repair, including 3D fiber scaffolds, hydrogels, and nanoparticles. The paper primarily reviews the exceptional effectiveness demonstrated by composite bone tissue scaffolds composed of modified gelatin and various natural or synthetic polymeric materials, as well as bioactive ceramics and inorganic metal/non-metal materials, in the repair of bone defects. This review provides new perspectives and ideas for gelatin research in the field of BTE.

2 Structure and properties of gelatin and bone scaffold materials

2.1 Structure and properties of gelatin

Gelatin is obtained by partial hydrolysis of insoluble collagen originating from pigs, cows, fish, etc., followed by pretreatment and extraction procedures [27,28]. Gelatin can be categorized into different types based on different preparation processes. Among these, collagen is treated by acid to obtain type I gelatin, which has an isoelectric point (PI = 8–9), while type II gelatin obtained by treatment with alkali has an isoelectric point (PI = 4–5) [17,29]. These differences stem from the different chemicals used in the treatment process, resulting in subtle changes in gelatin properties. Furthermore, controlling the temperature during the processing allows the triple-helical collagen to be fragmented into gelatin with different molecular weights, thus producing gelatin with varying degrees of mechanical strength [16,30,31]. Due to its excellent biocompatibility, biodegradability, low toxicity, and low allergenicity, gelatin has emerged as an ideal choice for bone tissue scaffold materials [32,33]. Furthermore, as an analogue of the extracellular matrix, gelatin possesses a unique RGD sequence, as shown in Fig. 2, which provides a favorable biological environment for bone cell adhesion, proliferation, and biomineralization [34,35].Fig. 2 Constitution and structure of gelatin.

Fig. 2

2.2 Structure and properties of bone scaffold materials

In order to successfully repair and support the bone regeneration process, a good bone scaffold material should have structural properties similar to those of natural bone, including good biocompatibility, biodegradability, porosity and mechanical strength. Moreover, it should have good cell adsorption and tissue adhesion, which is conducive to the proliferation and differentiation of seed cells and osteogenic regeneration [36,37].

The degradation rate of bone scaffolds had an important influence in the process of bone repair. Too fast degradation rate will lead to the bone scaffold unable to support the proliferation of host cells of bone tissue, resulting in the obstacle of new bone regeneration, while too slow degradation rate will be unable to make enough space for the regeneration of new bone, which is not conducive to the continuous regeneration of bone tissue [38]. Therefore, the rate of explanation of bone scaffolds should match the rate of new bone regeneration. For example, Tariq et al. prepared composite scaffolds using gelatin and PCL as the main materials by electrostatic spinning technique, which showed that the single PCL scaffold had no degradation in 28 days, while the introduction of hydrophilic gelatin resulted in the degradation of its composite scaffolds from day 7 to day 28 at a rate of ∼31 %–∼68%, which was matched with the average periosteum recovery time of 2–4 weeks, respectively [39]. Under the action of matrix metalloproteinase (MMP) in vivo, gelatin molecules were degraded to collagen fragments and tripeptides, and several studies have been conducted to show that gelatin not only possesses excellent biocompatibility, but its degradation products are also beneficial in promoting bone repair. For example, Hatakeyama et al. cultured human umbilical vein endothelial cells (HUVECs) with gelatin degradation products, which showed that gelatin degradation products significantly promoted the formation of capillary-like structures in HUVECs, stimulating angiogenesis and bone regeneration [40].

The porosity, mechanical strength and shape of bone scaffolds affect the bone repair process to varying degrees as well [41]. Porosity was a key element in evaluating whether the bone scaffold had the performance of new bone molding. Too high porosity leaded to lower mechanical strength of the scaffold, while too low porosity might be detrimental to the growth of new osteoblasts and vascularization of tissues. The proper porosity and pore size distribution played a key role in osteoblast attachment, migration, regeneration, as well as nutrient and metabolic waste transfer [42]. The small pore size (≈100 μm) bioscaffolds have been shown to be effective for in vitro bone tissue regeneration in cultured bone, with interconnected pores capable of meeting the oxygen, nutrient, and cell attachment requirements of the bone regeneration process. While larger pore sizes (≥300 μm) have also been found to have good tissue permeability, allowing for vascularization within the body, which is beneficial for bone regeneration [43,44]. The optimal scale of porosity and mechanical strength has been a challenge for scaffold materials. Porosity and mechanical strength similar to bone composition were able to have a more positive impact on the bone repair process [45]. El-Bahrawy et al. prepared gelatin composite scaffolds with porous hybrid structure by adjusting different gelatin/PVA ratios, which showed that gelatin/PVA porous hybrid scaffolds not only had the high porosity and pore size, but also the mechanical properties were close to the compressive strength of cancellous bone, and the scaffolds had the potential to repair the damage of cancellous bone [46].

3 Gelatin 3D scaffold

From the bionic perspective, scaffold materials for bone tissue engineering require a 3D structure [47].To mimic the complexity of the extracellular matrix structure and to promote normal cell growth, many scaffold fabrication techniques, such as solvent casting, particle leaching, gas foaming, phase separation, freeze-drying, self-assembly, and electrostatic spinning, have been developed for gelatin 3D scaffolds [[48], [49], [50]]. Gelatin 3D scaffolds not only provided mechanical support and microenvironment for osteoblasts, but also, compared with traditional tissue engineering, cell-based strategies of gelatin-based scaffold materials were currently attracting a lot of attention by carrying progenitor cells, cytokines, or biologically active molecules in order to achieve the recruitment of cells and accelerate the induction of new bone regeneration [51,52]. MSCs with differentiation ability were the most ideal seed cells for tissue engineering. MSCs were able to be closely integrated with gelatin scaffolds and implanted into bone injury sites to effectively stimulate the regenerative and osteogenic differentiation effects of bone cells [53]. Cytokines or bioactive molecules and gelatin scaffolds were adsorbed and mixed through the scaffolds, leading to a slow release, which were widely used in bone repair. Three cytokines, BMP-2, BMP-7 and PGDF-BB, which have been clinically approved for use in bone grafts for the treatment of hard-to-heal bone repair surgery [54]. There are three main types of gelatin 3D scaffolds (Fig. 3), which are nanofiber scaffolds, hydrogels and nanoparticles [55,56].Fig. 3 Gelatin 3D scaffolds including nanofiber scaffolds, hydrogels and nanoparticles.

Fig. 3

3.1 Nanofiber scaffold

Nanofiber scaffolds with a 3D porous structure provide a supportive matrix for cell attachment, differentiation, and new bone formation [57,58]. The scaffolds have a high specific surface area, increasing the ability of the scaffolds to attach a large number of cells. Scaffolds with varied pore sizes are fabricated by various methods such as freeze-drying and electrostatic spinning [59,60]. Scaffolds with pore sizes of 200 μm facilitate bone regeneration because they facilitate nutrient transport and metabolite drainage, as well as provide space for new bone formation and vascularization [61]. The mechanical properties of nanofiber scaffolds should be similar to those of natural tissues to protect cells from tensile forces. Electrostatic spinning is currently the most widely used method for fabricating nanofiber scaffolds [62,63]. Within this method, a polymer solution is mixed with an appropriate volatile solvent and loaded into a syringe. The polymer is ejected under mechanical pressure, when a voltage is applied, the droplet at the needle changes from a sphere to a cone (Taylor cone) and extends from the tip of the cone to obtain fibrous filaments, which pile up in a reciprocal manner to form a porous scaffold [64,65]. The size of the pores in the scaffolds is changed by varying the current, flow rate, voltage, and the distance between the collection plate and the syringe. For example, Sneh et al. prepared Gelatin-PCL-nHAp nanocomposite scaffold materials by electrostatic spinning technique, which showed a significant increase in cell survival rate and enhanced cell adhesion and proliferation [66].

3.2 Hydrogel

Hydrogel is a polymeric material with a 3D mesh structure which can swell in water and retain a large amount of water [25,67]. Gelatin hydrogels contain a large number of hydrophilic groups such as hydroxyl, carboxyl and amino groups in the molecular chain segments which absorb a large amount of water to maintain the soft physical properties and provide more possibilities for modification [68,69]. Modified gelatin hydrogels can be prepared by physical cross-linking, enzymatic cross-linking, and chemical cross-linking [70]. The common methods for physical cross-linking are plasma, UV radiation and dehydrogenation heat treatment, which produce no potentially cytotoxic chemicals. However, the modified gelatin hydrogel network prepared by physical cross-linking has a low degree of crosslinking [71]. Chemical cross-linking can be achieved by adding a cross-linking agent to activate a gelatin molecule and the activated gelatin molecule is directly bonded to another gelatin molecule by chemical bonding, or the cross-linking agent is chemically bonded to the active functional group of the gelatin and is stabilized in that form in the structure of the gelatin [68,72]. Commonly used cross-linking agents include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, EDC, aldehydes (such as formaldehyde, glutaraldehyde), epoxy compounds (such as ethylene oxide, glycidyl ether), plant polyphenols (such as tannic acid, ferulic acid), etc. Currently, enzyme cross-linking is mainly used for polymeric materials with glutamine aminotransferase, tyrosinase, and horseradish peroxidase. Enzyme cross-linking can not only improve the mechanical properties of modified gelatin scaffolds but also enhance their osteogenic effects, which forming a dense 3D network structure through cross-linking with amino acid residues of gelatin polymers without the use of chemical cross-linking agents and organic solvents [73,74].

Gelatin hydrogels can be used to protect cells as well as to load certain growth factors or functional drugs to promote bone tissue repair. In recent years, smart injectable hydrogels have received increasing attention because they can be used for minimally invasive treatments [75]. The smart injectable hydrogel system is a liquid at room temperature and forms a hydrogel when injected into the location of bone cracks to fill intricately shaped defects [2,76]. The smart injectable hydrogels are able to shorten surgery time, reduce pain after surgery, lessen scar size and allow patients to recover quickly in an economical way. For example, Zhe et al. utilized nano-HAp and nano-silicate (SN) compounded with gelatin to prepare MSC-loaded GelMA-HAp-SN composite hydrogel scaffold, which was able to activate the highest expression of new bone formation and vascularized tissue [77].

3.3 Nanoparticles

Nanoparticles are be used to deliver drugs and growth factors that exhibit excellent slow release with effective promotion of bone regeneration [78]. In addition, nanoparticles could modify the properties of scaffolds, such as superior mechanical properties and osteoinductive activity. For stance, Schrade et al. prepared an alginate dialdehyde-gelatin nanoparticle scaffold loaded with clindamycin and growth factors, which showed that the modified gelatin scaffold could effectively promote the proliferation of MG-63 cells and enhance the inhibition of staphylococcus aureus [79].

BTE is a rapidly developing field. The gelatin composite scaffolds have been widely studied in nanofiber scaffolds, hydrogels, and nanoparticles, in addition to the application of new technologies such as 4D scaffolds and organoids based on gelatin materials, which have demonstrated unique advantages in recent years [80,81]. 4D printing is based on the 3D structure to add a time dimension, so that the printed scaffold automatically changes over time with internal and external stimuli, with its unique responsiveness and shape change ability will better match the physiological environment of bone defects, which is expected to achieve a more accurate and individualized treatment [82]. However, in the process of bone repair was usually accompanied by the regulation of multiple cellular activities, the 4D printed scaffolds hardly were respond to multiple synergistic effects, so the design of 4D printed scaffolds with multiple stimulus responsed to meet the dynamic changes of the microenvironment in the process of bone repair is an important breakthrough point [83]. For example, Chakraborty et al. used SF-gelatin bioink doped with magnetic nanoparticles to achieve mechanically actuated and thermally responsive mechanical stimulation of cartilage regeneration under prolonged driving by a magnetic field [84]. Bone organoids are bionic bone tissues with spatial structure and capable of self-renewal through directed differentiation of stem cells, and are genomically stable in long-term expansion in vitro. Bone organoids were usually based on bioactive material scaffolds and extracellular matrices to provide strong mechanical supportt [85]. Wang et al. prepared GelMA/AlgMA/HAP Scaffolds loaded with bone marrow mesenchymal stem cells through 3D printing, through in vivo cultivation, the organoid formed trabecular-like structural features of bone by self-mineralization, and its mechanical properties were comparable to those of natural spongy bone [86]. However, bone organoids were influenced by the physiological microenvironment of normal tissues, the complexity and sophistication of neural networks, blood vessels and other physiological functions, as well as the normal developmental and maturation environment of osteoid organs has not been satisfied at present, which still need to be invested in more comprehensive research [87].

4 Modified gelatin and its composite materials

Given the abundance of readily modifiable groups in gelatin, such as hydroxyl, amino and carboxyl groups, gelatin-based scaffolds with excellent mechanical properties and outstanding osteoinductive activity can be successfully produced through clever modification by chemical reactions or physical methods [16,47]. These include the modification of gelatin with methacrylic anhydride (MA), dopamine, polyphenols, adipic dihydrazide and maleic anhydrideto optimize its properties for specific applications [88]. The structure of the compounds used for gelatin modification is shown in Fig. 4. And for example, Yang et al. prepared a hydrogel biomimetic periosteum by combining dopamine-modified gelatin with oxidized hyaluronan and doped with micro/nanobioactive glass, which showed excellent adhesion to bone tissue and formed a stable barrier in the region of bone defects [89]. Moreover, Honda et al. used epigallocatechin gallate (EGCG) for gelatin modification, which showed a significant increase in the degradation time of the scaffold and improved osteoinductivity of the scaffold material with significant bone repair effect [90].Fig. 4 The structure of the compounds used for gelatin modification.

Fig. 4

Currently, gelatin-based bone scaffold materials are usually combined with various natural or synthetic polymeric materials as well as bioceramics and inorganic metallic/non-metallic materials to achieve synergistic effects and are widely used in the field of bone tissue engineering for their many performance advantages, such as more mechanical properties, osteoinductive activity, and anti-infection [[91], [92], [93]].

4.1 Organic polymer materials

With the introduction of BTE techniques, gelatin-based materials are often composited with functional organic polymers, aiming to cope with the diverse and complex physiological demands faced during bone injury healing. The emergence of such composites, which often exhibit superior mechanical properties, as well as anti-inflammatory effects and low immunogenicity, has attracted close attention and in-depth studies by a wide range of researchers.

4.1.1 Natural polymer materials

Natural polymer materials generally have good biocompatibility and biodegradability, which not only promote the adhesion of osteoblasts to bone but also promote cell proliferation. Natural polymers include polysaccharide biomolecules, polyphenols, and protein polymers, which can modify gelatin by chemical surface modification, physical modification, or enzymatic cross-linking to improve the osteoinductive activity and mechanical properties of modified gelatin scaffold materials [94,95]. The major natural polymer bone scaffold materials that are commonly used for gelatin modification include chitosan (CS), Alg, silk fibroin (SF) and peptide.

CS, a product of chitin deacetylation, is similar in structure to glycosaminoglycan, the molecular chain is a copolymer composed of β-(1,4)-2-acetylamino-D-glucan unit and β-(1,4)-2-amino-D-glucan unit. Chitosan has good biocompatibility, biodegradability, and antibacterial activity. It is often used in various skin, nerve, and soft tissue engineering [96,97]. However, the mechanical properties and stability of single CS limit application of tissue engineering. Gel-CS based composites are obtained by chemical cross-linking [98]. The CS molecular chain contains abundant –NH2 and –OH reactive groups, while the gelatin molecular chain contains –NH2, –OH, –COOH reactive groups. Therefore, CS and Gelatin are cross-linked by covalent bonds to obtain Gel-CS based composites. What's importantly, compared with single gelatin or CS materials, the gelatin-CS composite scaffolds have significant advantages in porosity, swelling rate, degradation rate, mechanical properties, biomineralization and cell adsorption capacity [2,99]. For instance, Ranganathan et al. prepared Gel-CS composites, which showed significant superiority compared to single CS and gelatin in affecting the properties of bone regeneration [100]. Moreover, Gel-CS composites can be used as scaffold materials to load seed cells or growth factors for more efficient application in BTE.

SF is a natural polymeric fibrous protein extracted from silk, which can be obtained by degumming the natural silk [101]. SF with 18 amino acids and has amphoteric charge. Compared with other natural or synthetic fibers, it has unique mechanical properties, such as good flexibility, tensile strength and breathability, which has been widely used in the field of tissue engineering [102]. SF can be prepared into thin films, hydrogels, and porous sponge materials by using chemical or physical modification methods. In combination with gelatin, it can effectively compensate for the poor mechanical properties of gelatin and be better used in BTE. Gel-SF scaffolds have good mechanical properties, thermal stability and degradation rate, which can not only provide suitable mechanical support for traumatic bone injury, but also accelerate bone regeneration by adsorbing cells on the scaffold [103]. For example, Luetchfork et al. prepared a variety of Gel-SF scaffolds in different ratios, which supported the adhesion of MSCs with high efficiency compared to single Gel or SF, and had a broad therapeutic potential for bone injury repair [104].

Alg, a kind of natural polysaccharide polymers rich in β-D-mannuronic acid and α-L-guluronic acid structural fragments, is extracted from the brown algae kelp and Sargassum [105]. Alg shows the advantages of high hydrophilicity, good biocompatibility and biodegradability. However, Alg has the weak mechanical properties, lack of intercellular interaction and uncontrolled degradation. Compositing sodium alginate with gelatin is able to compensate the shortcomings of both sides and improve the utilization rate and therapeutic effect of bone defect repair [106]. For instance, Cheng et al. prepared 3D bio-printed Alg-Gel composites, which promoted the expression of osteogenic genes and proteins. The mechanical strength of the scaffold was similar to that of mouse dermal tissue structure with a more regular pore structure [107]. The advantages and disadvantages of common single natural polymers for bone repair and the material properties of the compounds with gelatin are summarized in Table 1.Table 1 Characteristics of modified gelatin and natural polymers composite for BTE.

Table 1Natural
Polymers	Advantages of single material	Disadvantages of single material	Characteristics of composite materials	Ref.	
CS	Biocompatibility; biodegradability; antibacterial properties.	Stability; mechanical strength; osteoinductivity.	Improved mechanical strength; osteoconductivity; significant biomineralization effect; and enhanced cell adhesion.	[108]	
SF	Good biocompatibility, good mechanical strength; and high thermal stability.	Slow biodegradation, high fragility; and presence of residual contaminants.	Good biodegradability; flexibility; tensile strength and mechanical properties.	[109]	
Alg	Good biocompatibility; simple gelation and easy functionalization.	Poor mechanical properties; uncontrolled degradation; and hard to sterilize.	Improved mechanical properties; regular pore structure; good biodegradability; and beneficial to cell growth.	[110]	
Hyaluronic acid (HA)	Good biocompatibility, biodegradability; good viscoelasticity and easy functionalization.	Poor mechanical properties; difficult to process by electrostatic spinning.	Good biocompatibility, biodegradability and mechanical strength; strong cell adhesion is conducive to osteoblast growth.	[111]	
Cellulose	Good biocompatibility and easy to functionalize.	Poor mechanical properties and slow biodegradation.	Good mechanical strength; proper porosity; and strong cell adhesion.	[112]	
Fucoidan	Good biocompatibility, osteoinductivity; easy functionalization; easy gelation.	Slow degradation and poor mechanical properties.	Good antibacterial activity; antioxidant; cytocompatibility and hemostatic properties.	[113]	

4.1.2 Synthetic polymer

Synthetic polymers are formed by the polymerization of repeating monomers. Through designing the polymer functional groups and molecular weights appropriately, synthetic polymers exhibit specific structures and properties, such as controlled products and suitable mechanical properties. However, compared to natural polymers, synthetic polymers are usually poorer in degradability. The modification of gelatin with synthetic polymer materials not only compensates for the weak mechanical properties of gelatin, but also can prepare scaffold materials with adjustable properties according to the growth characteristics of bone cells. The major bone regeneration synthetic polymer scaffolds, such as PCL, PLA, poly (lactic-co-glycolic acid) (PLGA), and HAp are used for gelatin modification.

PCL is made by ring-opening polymerization of ε-caprolactone, which is a non-toxic, biodegradable polyester with certain rigidity and strength. However, its degradation rate is slow, and the hydrophobicity of PCL is not conducive to cell adhesion and proliferation [114]. For instance, Yuan et al. prepared a series of composite fiber membranes with different ratios of PCL and gelatin by electrospinning, which showed that a higher PCL content was beneficial to maintain the fiber structure of electrospun membranes, while a higher gelatin content could effectively improve the degradation rate of the scaffolds [115]. In addition, Liu et al. prepared modified gelatin scaffolds with different degradation rates according to the different degradation rates of PCL and gelatin, showed that the composite scaffold material could increase the adhesion of osteoblasts to bone and could effectively promote the regeneration of alveolar bone [116].

PLA is composed of polymerized lactic acid monomers that possess several essential characteristics for bone regeneration, such as cytocompatibility, thermal stability, and non-toxic degradation products [117,118]. For example, Yu et al. designed bioactive resveratrol PLA-Gel porous nanofiber scaffolds with good properties by electrostatic spinning technique, which had effective in cartilage injury repair [119].

PLGA is a random polymerization of lactic acid and hydroxyacetic acid monomers with good biocompatibility and biodegradability [120,121]. PLGA is the most widely used synthetic polymer for bone regeneration applications. Besides, the degradation rate of PLGA is able to be regulated from weeks to months by simply changing the ratio of the two monomers [122,123]. For instance, Li et al. prepared an injectable PLGA-Gel hydrogel scaffold loaded with simvastatin for enhancing osteogenic healing of alveolar bone. The composite hydrogel scaffold was shown to have excellent mobility at 37 °C with improved degradation rate and sustained osteogenic effect on the regeneration of new bone cells [124]. The advantages and disadvantages of other synthetic polymer materials for bone repair as well as the characteristics of composites with gelatin are summarized in Table 2.Table 2 Characteristics of modified gelatin and synthetic polymers composite for BTE.

Table 2Synthetic
Polymers	Advantages of single material	Disadvantages of single material	Characteristics of composite materials	Ref.	
Polyglycolic acid	Controllable degradation rat; osteoinductivity.	Poor Biocompatibility; adhesion.	Mechanical strength; osteoinductivity; biomineralization effect.	[125]	
Polyethylene glycol (diol) diacrylate	Flexibility; modifiable;	Adhesion; fragile.	Mechanical enhancement good biodegradability; flexibility.	[126]	
Ethyl phthalate	Good plasticity; good mechanical strength; and high thermal stability	Uncontrolled degradation.	Improved mechanical properties, regular pore structure; Shape control.	[127]	
N-allylglycine	Controllable mechanical properties; good plasticity; Good thermal stability.	Poor biocompatibility; osteoinductivity.	Controllable degradation and mechanical strength.	[128]	
Poly (vinyl alcohol)	Mechanical strength and plasticity.	Poor degradation and biocompatibility.	Good biocompatibility mechanical strength; and degradation.	[129]	
Polyorthoesters	Mechanical strength; plasticity; biocompatibility; stabilization.	Degradation; osteoinductivity.	Biocompatibility; mechanical strength.	[130,131]	

4.2 Inorganic materials

Inorganic materials used for bone repair mainly include bioceramics, metallic materials and other inorganic materials, which usually have excellent mechanical properties and osteoinductive activity to compensate for the shortcomings of natural gelatin [132,133]. The following mainly introduced the common inorganic materials composited with gelatin such as HAp, bioactive glasses (BGs), silver nanoparticles (AgNPs) and black phosphorus (BP) nanosheets [[134], [135], [136]]. The advantages and disadvantages of other common inorganic materials for bone repair applications and the properties of gelatin composites are summarized in Table 3.Table 3 Characteristics of modified gelatin and inorganic materials composite for BTE.

Table 3Inorganic materials	Advantages of single material	Disadvantages of single material	Characteristics of composite materials	Ref.	
Calcium octaphosphate	Oteoinductivity; mechanical strength and biocompatibility.	Low solubility; slow degradation.	High rate of osteogenesis; mechanical enhancement.	[137]	
Graphene oxide	Mechanical strength; high optical transparency; electrical conductivity;	Slow degradation and low swelling rate	Excellent osteogenic effect and mechanical strength.	[138]	
Hydrotalcite	Excellent adsorbability; adjustable structure; antimicrobial activity.	Poor dispersion; biocompatibility; mechanical strength.	Anti-infection; plasticity; biocompatibility; Osteogenic induction	[139,140]	
AuNPs	Antimicrobial activity; mechanical strength; osteoinductivity.	Poor dispersion; slow degradation.	Anti-infection; Osteogenic; Adjustable performance; mechanical strength.	[141,142]	
Calcium sulfate	Tolerance; osteoinductivity; plasticity	Poor anti-infection; hyperbiodegradation.	Osteoinductivity Excellent biodegradability	[[143], [144], [145]]	
Carbon nanotubes	Excellent toughness; electroconductibility; high specific surface area.	Biocompatibility.	Osteogenic induction; Biocompatibility; excellent biodegradability.	[146,147]	

HAp is a material with high similarity to the mineral composition of bone and is an attractive source of artificial bone material for BTE, with good compressive strength, biocompatibility and corrosion resistance [148]. It is commonly used as a replacement material for teeth and skeletons. The porous structure of HAp is beneficial as a bone scaffold to support cartilage repair and osteogenic regeneration. However, single HAp is brittle, poorly stiffened, slowly degraded, and has poor adhesion to cells. While composites of HAp with gelatin are beneficial for cell adhesion and growth, which can also improve its biodegradability and stability [149]. For example, Zhu et al. used glutaraldehyde as a cross-linking agent to synthesize porous Gel-HAp scaffold materials with different concentrations, which could effectively support, cell adhesion and proliferation [72]. What's more, Conrad et al. made a modified gelatin bone scaffold material by incorporating nano-HAp into gelatin-based micro-ribbon hydrogel, which was able to rapidly induce endogenous cranial bone regeneration with increased osteoclast activity [150].

BGs are silicate glasses composed of basic components such as Na2O, SiO2, CaO and P2O5. Bioactive glass will slowly release soluble Si、P、Na and Ca ions when in contact with body fluids, which is conducive to promoting bone repair and angiogenesis [151]. In addition, Ce、Mg、Zn、Fe、Sr、Ag、B and other beneficial elements for bone repair can be added to the preparation of bioactive glass. For example, Mostajeran et al. prepared SA-Gel-BG/Ce scaffolds by compositing cerium-doped bioactive glass with SA/gelatin, which showed a significant increase in the mechanical properties and showed outstanding anti-inflammatory, antimicrobial, osteogenic as well as angiogenic properties [152,153].

Bacterial infections during bone injury impair the healing and repairing ability of bone tissues. The high use of antibiotics in the clinic may lead to bacterial resistance, while the unique antibacterial mechanism of AgNPs is almost non-resistant to bacteria and has a wide range of antibacterial properties [154]. In addition, AgNPs have photothermal conversion ability, which enhances the antibacterial performance and osteoinductive activity, and the composite with gelatin can improve the mechanical properties of composite scaffolds [116]. For example, Ou et al. composited nanosilver (nAg), halloysite nanotubes (HNTs) with GelMA to prepare nAg/HNTs/GelMA composite hydrogels. The addition of nAg not only improved the mechanical and antimicrobial properties of the composite hydrogel, but also regulated the macrophage inflammatory reaction and accelerated bone regeneration.

BP nanosheets, as a novel two-dimensional nanomaterial, have been widely studied in BTE due to the special physicochemical properties, such as excellent electrical conductivity, photothermal conversion ability and excellent biodegradability [155]. Moreover, in physiological environment, the degradation products of black phosphorus nanosheets are phosphates, which contribute to bone tissue mineralization. For instance, Jing et al. incorporated magnesium-modified BP into GelMA to prepare a photosensitive and conductive composite hydrogel, which exhibited effective antimicrobial properties under near-infrared irradiation and induced nerve fiber regeneration to promote bone repair [156].

In summary, Gelatin had the ability to be compounded with a variety of other bioactive materials in order to prepare gelatin composite scaffolds with excellent performance, which could be used to meet different types of bone defects. In addition, bone defects in different pathologic states are also worthy of attention, such as postmenopausal osteoporosis and diabetic osteoporosis patients. Gelatin composite scaffolds effectively promoted the adhesion and proliferation of osteoblasts, which was contributed to alleviate the pathological conditions of bone microstructure degradation and bone mineral density loss in postmenopausal osteoporosis patients [157]. Moreover, gelatin scaffold materials were capable of loading active molecules, such as BMP-2, estrogen and other active molecules, which accelerated the regeneration process of the bone microenvironment [158]. For the treatment of patients with diabetic osteoporosis, gelatin scaffolds loaded with anti-inflammatory active molecules or osteogenesis-related growth factors were used to improve osteoblast proliferation and differentiation and metabolic processes [159]. At present, although there is no clear case of gelatin scaffolds in the research of clinical treatment, it can be found that modified gelatin scaffolds show great potential in preclinical treatment in the field of tissue engineering and regenerative medicine from the current research. In particular, gelatin and hyaluronic acid/hydroxyapatite composite scaffold materials have been widely used in preclinical studies of cartilage regeneration and wound healing [160].

5 Summary and prospect

Gelatin, a natural hydrophilic polymer, has excellent biocompatibility, biodegradability, and superior biological properties in the field of bone tissue engineering. To compensate for the insufficient mechanical properties of gelatin, researchers have modified gelatin or compounded it with other various natural or synthetic polymeric materials, as well as bioactive ceramics and inorganic metal/non-metal materials to obtain more superior performance of bone tissue engineering scaffold materials. Although the clinical practice research on gelatin-based composite scaffold materials in the field of bone tissue regeneration is still in its infancy, mainly focusing on preclinical studies such as in vitro cell experiments, mechanical property tests, and animal experiments, this field is undergoing rapid development. With the continuous emergence and maturity of advanced technologies such as electrospinning, additive manufacturing, 3D printing, 4D printing, and bone organoids, scientists have been able to customize biological scaffolds with high biocompatibility and excellent matching to the shape of bone defects. These meticulously developed scaffold materials aim to produce bone tissue repair materials with higher degrees of matching and functionality for more effective treatment of bone tissue injuries. Therefore, gelatin-based composite scaffold materials are gradually becoming one of the most promising scaffold materials in the field of bone tissue regeneration [161,162].

Data availability statement

The authors declare that no data associated with our study has been deposited into a publicly available repository since no data was used for the research described in the article.

Funding

This review was funded by Outstanding 10.13039/100003536 Youth Foundation of Jiangxi Province [grant number 20224ACB216019 ], Doctoral startup fund of 10.13039/501100013798 Jiangxi Science and Technology Normal University [grant number 2022BSQD22 ], Science and Technology Research Project of 10.13039/501100009102 Jiangxi Provincial Department of Education [grant number GJJ2201359 ], 10.13039/501100004479 Jiangxi Provincial Natural Science Foundation [grant number 20232BAB216130 ], Jiangxi Province 2023 Graduate Innovation special fund project by the Education Department of Jiangxi Province [grant number YC2023–S909 ], Provincial Innovation Training Program for College Students [grant number S202311318068 ].

Ethics declarations

Review and/or approval by an ethics committee was not needed for this study because it don't include any human or animal participation.

Consent to publish

All authors agree to the submission and publication of the manuscript.

CRediT authorship contribution statement

Enguang Wu: Writing – review & editing, Writing – original draft, Conceptualization. Lianghui Huang: Writing – review & editing, Conceptualization. Yao Shen: Supervision. Zongyi Wei: Methodology. Yangbiao Li: Methodology. Jin Wang: Validation, Investigation, Funding acquisition, Formal analysis, Data curation. Zhenhua Chen: Validation, Supervision, Investigation, Funding acquisition, Formal analysis, Data curation.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Abbreviations

AgNPs Silver nanoparticles

Alg Alginate

BGs Bioactive glasses

BP Nanosheets black phosphorus nanosheets

BTE Bone tissue engineering

CS Chitosan

EGCG Epigallocatechin gallate

Gly Glycine

Gel Gelatin

HAp Hydroxyapatite

HUVECs Human umbilical vein endothelial cells

Hyp Hydroxyproline

MSCs Mesenchymal stem cells

PCL Polycaprolactone

PLA Polylactic acid

PLGA Poly (lactic-co-glycolic acid)

Pro Proline

PVA Polyvinyl Alcohol

SF Silk fibroin

3D Three-dimensional

4D Four-dimensional

Acknowledgements

Not applicable.
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