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锌基生物降解材料: Comparison
Please note this is a comparison between Version 2 by Yang Liu and Version 1 by Yang Liu.

用于内固定的传统惰性材料引起了许多并发症，通常需要通过二次手术去除。可生物降解的材料，如镁（Mg）、铁（Fe）和锌（Zn）基合金，为解决这些问题开辟了新的途径。在过去的几十年中，镁基合金引起了研究人员的广泛关注。然而，仍然需要克服过快的降解速度和氢气释放的问题。Zn合金具有与传统金属材料（例如钛（Ti））相当的机械性能，并且具有中等的降解速率，可能作为内部固定材料的良好候选者，特别是在骨架的承重部位。近年来，新兴的Zn基合金和复合材料被开发出来，并进行了体外和体内研究，以探索其生物降解性，机械性能和生物相容性，以朝着骨折固定临床应用的最终目标迈进。本文对Zn基生物降解材料的相关研究进展进行综述，以期为今后Zn基生物降解材料在骨科内固定中的应用提供有益的参考。

  • Zinc-based biodegradable materials
  • orthopedic implant
  • biodegradability
  • mechanical property
  • biocompatibility

1. Introduction简介

Bone fractures are becoming increasingly common with the rapid increases in aging population, traffic accidents, sports injuries and metabolic diseases 随着人口老龄化、交通事故、运动损伤和代谢性疾病的迅速增加，骨折变得越来越普遍[1,，2,，3]. Fractures have a lifetime prevalence of 。骨折终生患病率为~40% and an annual incidence of 3.6% ，年发病率为3.6%[4]. The most common and burdensome fractures are lower leg fractures of the patella, tibia or fibula, or ankle 。最常见和累赘的骨折是髌骨、胫骨或腓骨或踝关节的小腿骨折[5]. Fracture healing is the process of reconstructing bone and restoring its biological and biomechanical functions 。骨折愈合是重建骨骼并恢复其生物和生物力学功能的过程[6,，7]. As one of the common surgical treatments, internal fixation using screws, pins, plates, etc., provides mechanical stability for a fractured bone, allowing weight bearing, early use of the limb, and bone healing 。作为常见的外科治疗之一，使用螺钉、销钉、板等进行内固定可为骨折提供机械稳定性，允许负重、早期肢体使用和骨愈合[8]. Success in fracture healing is closely related to the internal fixation implants used.。骨折愈合的成功与所使用的内固定植入物密切相关。
Implants used for internal fixation can be divided into several categories: wires, pins and screws, plates, and intramedullary nails or rods 用于内固定的植入物可分为几类：导丝、针和螺钉、板和髓内钉或棒[9]. Staples and clamps are also used occasionally for osteotomy or fracture fixation 。订书钉和夹具偶尔也用于截骨术或骨折固定术[9]. Traditional fixation materials are generally nondegradable, including inert stainless steel (。传统的固定材料通常是不可降解的，包括惰性不锈钢（SS), titanium (Ti) and its alloys, and cobalt-chromium (Co-Cr) alloys ）、钛（Ti）及其合金和钴铬（Co-Cr）合金[10]. They possess satisfactory biocompatibility, high wear resistance, and adequate mechanical strength (Table 。它们具有令人满意的生物相容性、高耐磨性和足够的机械强度（表1) ）[11,，12,，13]. However, they have notable shortcomings when being applied in fracture fixation. For example, metallic materials have much higher elastic modulus values (190–2。然而，它们在应用于骨折固定时具有明显的缺点。例如，与骨组织（3-300 GPa for GPa）相比，金属材料的弹性模量值要高得多（316L SS, 210–240 GPa for Co-Cr alloys, and 90–为190-200 GPa，Co-Cr合金为210-240 GPa，钛合金为90-110 GPa for Ti alloys) compared with bone tissues (3–30 GPa). Although a rigid fixation is required at the beginning of the healing process to provide a sufficient mechanical stability, a large discrepancy in stiffness between bone and the implant can lead to stress shielding and therefore can delay healing ）。虽然在愈合过程开始时需要进行刚性固定以提供足够的机械稳定性，但骨与植入物之间的刚度差异较大会导致应力屏蔽，从而延迟愈合[14]. Even for a successful bone healing, a secondary surgery is often required to remove the implant 。即使骨愈合成功，也经常需要二次手术来移除植入物[15].。
Biodegradable materials are well suited to solve the issues above. Fixation implants made of biodegradable materials can provide a strong mechanical support of the fracture site at earlier stages of the healing process, and later on degrade naturally as the healed bone takes over the mechanical loading and their by-products can be absorbed and metabolized 可生物降解材料非常适合解决上述问题。由可生物降解材料制成的固定植入物可以在愈合过程的早期阶段为骨折部位提供强大的机械支撑，后来随着愈合的骨接管机械负荷，其副产物可以被吸收和代谢而自然降解[16]. Degradable polymers are intended for applications in soft tissue graft fixation and meniscus repair due to their low strength 。可降解聚合物强度低，可用于软组织移植固定和半月板修复[17,，18,，19]. Compared to polymers, Mg-based biodegradable materials have higher strength and modulus that are close to cortical bone (Table 。与聚合物相比，镁基生物降解材料具有更高的强度和模量，接近皮质骨（表1). Also, ）。此外，基于Mg ions released from Mg-based biodegradable implants have beneficial effects on bone regeneration 的可生物降解植入物释放的镁离子对骨再生有益[20]. Due to their appropriate mechanical property, biocompatibility and biodegradability, 。由于其适当的机械性能、生物相容性和生物降解性，镁基金属在过去几十年中引起了体外和体内研究的极大关注。几种基于Mg-based metals have attracted a great deal of attention of in vitro and in vivo research during the last decades. Several Mg-based implants (bone screws, pins, plates) have been available in clinic or undergoing clinical trials 的植入物（骨螺钉、针、板）已投入临床或正在进行临床试验[15,，21]. However, the issues with an over-fast degradation rate and generation of hydrogen still need to be overcome. Additionally, current Mg alloys (ultimate tensile strength (。然而，仍然需要克服过快的降解速度和氢气产生的问题。此外，目前的镁合金（极限抗拉强度（UTS) 350 MPa) have relatively low mechanical strength and are only limited to non- or low-load-bearing applications, such as fixation of small bones and cancellous fragments, meniscus repair and soft tissue fixation ）350MPa）具有相对较低的机械强度，并且仅限于非承重或低承重应用，例如小骨和松质碎片的固定，半月板修复和软组织固定[21]. Clearly, there remains a critical need for development of biodegradable materials for fixation of fractures at heavy load-bearing skeletal sites where fractures occur most frequently.。显然，仍然迫切需要开发可生物降解的材料，用于固定骨折最频繁发生的重承重骨骼部位的骨折。
The mechanical strength of zinc (锌（Zn) alloys falls in a wide range, from the value of pure Mg to the value of commercial pure Ti and 316 stainless steel (Figure ）合金的机械强度范围很广，从纯镁的值到商业纯钛和316不锈钢的值（图1). For bone repair, it has been reported that the degradation rates of fixation implants should be between ）。对于骨修复，据报道，固定植入物的降解速率应在0.2 and 0.5 至0.5mm y−1 to match bone healing 匹配骨愈合[1].。镁基合金的降解速率范围为 Mg-based alloys have degradation rates ranging from 0.8 to0.8 至 2.7 mm y−1 [1,，15,，22,，23], which are above the desired degradation rates of bone implants. The degradation rates of Zn-based alloys are mainly between ，高于骨植入物所需的降解速率。锌基合金的降解速率主要在0.1 and 至0.3 mm y−1 [1,，24,，25]. Moderate corrosion rates and excellent mechanical properties make 。中等的腐蚀速率和优异的机械性能使Zn-based biodegradable metals potential candidates for biomaterial for internal fracture fixation, particularly at heavy load-bearing sites 基可生物降解金属成为内部骨折固定生物材料的潜在候选者，特别是在重承重部位[26,，27,，28]. In terms of biocompatibility, 。就生物相容性而言，Zn is the second most abundant transition metal in humans, serving as a structural or enzymatic cofactor for approximately 10% of the proteome 是人类中第二丰富的过渡金属，可作为约10%蛋白质组的结构或酶辅助因子[29]. Consequently, perturbations in 。因此，Zn homeostasis may lead to various disorders, including growth deficiencies, immune defects, neurological disorders, and cancers 稳态的扰动可能导致各种疾病，包括生长缺陷、免疫缺陷、神经系统疾病和癌症[30]. Studies also found that Zn ions (Zn。研究还发现，锌离子（锌2+) play an important role in promoting fracture healing ）在促进骨折愈合方面发挥重要作用[30,，31].。
JFB 13 00164 g001 550
Figure 图1. Mechanical properties of biodegradable and non-biodegradable materials for orthopaedic devices and their clinical applications 用于骨科器械的可生物降解和不可生物降解材料的力学性能及其临床应用[24].。
Zn-based alloys have shown a great potential of application in orthopaedics, particularly for internal fixation of fractures at heavy load-bearing bone 锌基合金在骨科中显示出巨大的应用潜力，特别是在重承重骨骨折的内部固定方面[24,，25,，32,33，33]. There has been a growing body of in vitro studies on the development of new Zn-based biodegradable materials and testing of their biodegradability, mechanical property and biocompatibility, with fewer in vivo animal studies and no clinical application as yet 。关于开发新的锌基可生物降解材料并测试其生物降解性，机械性能和生物相容性的体外研究越来越多，体内动物研究较少，尚未临床应用[34,35,36,37,34，35，36，37，38,39,40,，39，40，41,42,，42，43,44,45,46，44，45，46] (Figure （图2). Although there are several review articles that have elaborated on some aspects of those properties 尽管有几篇综述文章详细阐述了这些特性的某些方面[14,，22,，26,2，27，47,47], it remains unclear if current ，但目前尚不清楚目前的Zn-based biodegradable material are sufficient to meet clinical needs for orthopaedic internal fixation and what research gap needs to be filled next. In the following sections, we first point out the clinical requirements of implant biomaterials for orthopaedic internal fixation primarily at the heavy load-bearing skeletal sites in terms of their biodegradability, mechanical property and biocompatibility, and then summarize various typical Zn-based biodegradable materials (pure Zn, Zn-based alloys and composites) that have been developed so far and examined in vitro and in vivo for each of these properties. Lastly, unaddressed questions or future research directions are discussed with the aim of moving towards clinical applications of Zn-based biodegradable materials for orthopaedic internal fixation.基可生物降解材料是否足以满足骨科内固定的临床需求，以及下一步需要填补哪些研究空白。在以下章节中，我们首先指出植入物生物材料在重承重骨骼部位的骨科内固定的临床要求，包括其生物降解性、力学性能和生物相容性，然后总结了迄今为止已经开发的各种典型Zn基生物降解材料（纯Zn，Zn基合金和复合材料），并在体外和体内检查了每种性能。最后，讨论了未解决的问题或未来的研究方向，目的是转向Zn基生物降解材料在骨科内固定中的临床应用。
Table表 1. Characteristics of different typical metallic biomaterials.不同典型金属生物材料的特性。

Cast

86

140

1.2

SBF

-

MG63

Adding the alloying elements Mg, Ca and Sr into Zn can significantly increase the viability of MG63 and can promote the MG63 cell proliferation compared with the pure Zn and negative control groups.

[77]

Zn-1.0Ca-1Sr

HE

212

260

6.7

SBF

0.11

Zn-1.0Ca-1Sr

HR

144

203

8.8

SBF

-

Zn-0.8Li-0.4Mg

HE

438

646

3.68

-

-

-

-

[24]

Zn-3Ge-0.5Mg

Cast

66.9

88.3

1.4

HBSS

0.062

MG63

The extract with a concentration of 100% had obvious cytotoxicity to MG63 cells. When the concentration of the extract was diluted to 12.5% or lower, the survival rate of MG-63 cells was all above 90%.

[78]

Zn-3Ge-0.5Mg

HR

253

208

9.2

HBSS

0.075

Zn-4Ag-0.6Mn

HE

-

302

35

HBSS

0.012

-

-

[79]

Zn-1Fe-1Mg

Cast

146

157

2.3

SBF

0.027

-

-

[80]

Classification分类 Materials材料 Biodegradability生物降解性 Mechanical Properties机械性能 Biocompatibility生物相容性 Applications or Potential Applications应用或潜在应用 Ref.裁判。
→ZnO + H2O,
Following the anode reaction, the Zn loses two electrons to generate the Zn2+. Cathode reaction is a process where the electrons of hydrogen dissolve oxygen reduction in the electrolyte to produce hydroxide (OH−). The simultaneous increases of Zn2+ and OH− in the solution facilitate the precipitation of Zn(OH)2, but the Zn(OH)2 is unstable and may subsequently transform into a thermodynamically more stable ZnO [34,49]. It is evident from these series of reactions above that Zn does not release hydrogen gas during biodegradation like Mg, indicating one of the major benefits of Zn.

2.2. Biodegradability of Zn-Based Alloys

It has been reported that the degradation rate of bone implants should be somewhere between 0.2 and 0.5 mm y−1 to match bone healing [1]. Hence, pure Zn clearly does not meet the requirements of biodegradable orthopaedic implants. Adding other alloying elements is one way to alter the corrosion rate of biodegradable metals. To establish binary Zn alloy systems, some studies added alloying elements that are beneficial for bone health (e.g., Mg, Ca, Sr, Li, Mn, Fe, Cu, and Ag) into Zn-based alloys (Table 2) [24,32,40,42,44,50,51,52,53,54]. They used the same melting and extrusion process to prepare a variety of binary Zn-based alloys. Various alloying elements affect the corrosion rate of Zn-based alloys to different degrees [24]. Alloying can lead to an accelerated degradation, and Fe, Ag and Cu had the most significant roles in accelerating corrosion, followed by Li, Sr, Ca and Mg (Table 2) [24]. Studies have shown that corrosion rates of current Zn-based alloys are mainly between 0.1 and 0.3 mm y−1 [1]. The choice of Zn-based alloys generally depends on clinical demands, considering the fracture site, and the shape and size of fixators. In general, the degradation rate of the currently developed Zn alloy system is relatively slow. More ternary and quaternary Zn alloys may need to be developed to match the rate of fracture healing.

2.3. Biodegradability of the Zn-Based Composites

Other than alloying, adding reinforcement to form Zn matrix composites is another way to regulate the degradation rate of Zn metals. Composites including pure Zn as a matrix and hydroxyapatite (HA) as reinforcements were prepared by spark plasma sintering (SPS) [55]. A wide range of degradation rates (0.3–0.85 mm y−1) can be achieved by changing the concentration of HA. In addition, the immersion experiment of another beta-tricalcium phosphate (β-TCP)/Zn-Mg composite showed that the corrosion resistance of the composite is slightly decreased with the increase in β-TCP content [56].
Table 2. In vitro experiments of binary Zn-based alloys.

Zn-0.8Mn-0.4

Cast

112

120

0.3

-

-

-

-

[68]

Zn-0.8Mn-0.4

HE

253

343

8

-

-

Zn-0.8Mn-0.4

HR

245

323

12

-

-
Composition (wt%) Mechanical Properties Corrosion Test Cytocompatibility Ref.
σYS (MPa) σUTS (MPa) ε (%) Corrosion Medium Corrosion

Rate (mm y−1)		 Cell Type Key Findings

4. Biocompatibility of Zn-Based Biodegradable Materials

Biocompatibility is the ability of a material to conform to the host response, cell response, and living systems, and it is a vital property of metallic internal fixation for bone repair [1]. The metallic fixation implants directly release ions into the human body, affecting the surrounding cells, tissues, and blood (Figure 4) and leading to either positive or negative results [47,81,82]. Additionally, biomaterial-induced infections are one of the leading causes of implant failure in orthopaedic surgery [25]. Postoperative wound infection may cause an increase in the cost of pain treatment and even sequelae such as limb malformation and dysfunction of the implants [26]. Thus, exploring the biocompatibility of Zn and its alloys is important considering their ultimate implanting in the human body.

Figure 4. (a) Biological roles of Zn. Reprinted with permission from Ref. [81], Copyright 2016 Wiley. (b) Comparison of the inflfluence of zinc excess versus defificiency [82].

4.1. Biocompatibility of Pure Zn

Zn plays a fundamental role in multiple biochemical functions of the human body, including cell division, cell growth, wound healing, and the breakdown of carbohydrates [83]. Dietary Zn2+ deficiency has been linked to impaired skeletal development and bone growth in humans and animals (Figure 5) [83]. Specifically, 85% of Zn in the human body is found in muscle and bone, 11% in the skin and liver, and the rest in other tissues [84]. Zn is located at sites of soft tissue calcification, including osteons and calcified cartilage. Zn levels in bone tissue increase as bone mineralization increases. The skeletal growth was reduced during Zn deficiency. Zn plays a key biological role in the development, differentiation and growth of various tissues in the human body [85], including nucleic acid metabolism, stimulation of new bone formation, signal transduction, protection of bone mass, regulation of apoptosis, and gene expression [14]. Zn not only inhibits related diseases such as bone loss and inflammation, but also plays an important role in cartilage matrix metabolism and cartilage II gene expression [86]. The following symptoms are associated with Zn deficiency, including impaired physical growth and development in infants and young adults, the increased risk of infection, the loss of cognitive function, the problems of memory and behavioral, and learning disability. However, excessive Zn may cause neurotoxicity problems [87]. Based on the RDI (Reference Daily Intake) values reported for mature adults, the biocompatibility of Zn (RDI: 8–20 mg/day) is not as good as that of Mg (RDI: 240–420 mg/day), but very similar to that of Fe (RDI: 8–18 mg/day) [88]. Excessive Zn can cause symptoms such as nausea, vomiting, abdominal pain, diarrhea, fatigue, and can weaken immune function and delay bone development [87]. Therefore, when Zn-based biodegradable materials are implanted into the body as bone implant materials, the toxicity of their degradation products should be considered.

Figure 5. Zn2+ deficiency has been linked to impaired skeletal development and bone growth in humans and animals [83].

4.2. Biocompatibility of Zn-Based Alloys

The results of cytotoxicity tests can reflect the biological safety of the material to some extent. Table 2 and Table 3 summarize the results of cytocompatibility testing of alloying elements. Specifically, according to the cytocompatibility testing, additions of Mg, Ca and Li do not produce cytotoxicity, but can promote cell proliferation. However, Cu, Al, and Fe show varying degrees of toxic effects on bone cells [34,37,40,42,43,73,74,89]. Regarding the effect of metal ions on antibacterial activity, Sukhodub et al. [90] systematically examined the antibacterial abilities of metal ions and reported that the sterilization rate of the metal ions from high to low was as follows: Ag, Cu+2+, Zn2+, and Mg2+. Among these metal ions, Zn ions have a good antibacterial ability when they reach a certain concentration and can kill various bacteria and fungi. Zinc is an essential element with intrinsic antibacterial and osteoinductive capacity [91]. Zn-based antimicrobial materials generally consist of zinc complexes and ZnO nano-particles. Complexes such as zinc pyrithione and its derivatives are well known antifungal compounds and have been broadly applied in medicines [92]. Lima et al. [93] prepared Zn-doped mesoporous hydroxyapatites (HAps) with various Zn contents by co-precipitation using a phosphoprotein as the porous template. They found that the antibacterial activity of the HAps samples depended strongly on their Zn2+ contents. Tong et al. [94] examined the bacterial distributions of the Zn-Cu foams pre- and post-heat treatment after co-culturing with staphylococcus aureus for 24 h, and observed good antibacterial properties of the Zn-Cu foams. Lin et al. [74] observed better antibacterial properties of Zn-1Cu-0.1Ti than pure Zn. Ren et al. [95] systematically investigated a variety of Cu-containing medical metals including stainless steels, Ti alloys, and Co-based alloys, and demonstrated good antibacterial abilities of those materials stemming from the durable and broad-spectrum antibacterial characteristics of Cu ions. Therefore, Cu-containing Zn alloys may be expected to be promising implant materials with intrinsic antibacterial ability.

4.3. Biocompatibility of Zn-Based Composites

HA is a well-known bioceramic with bioactivity that supports cell proliferation, bone ingrowth and osseointegration. HA has similar chemical and crystallographic structures to bone, which can form a chemical bond with osseous tissue, and act like nucleation for new bone [17]. Yang et al. [55] fabricated Zn-(1, 5, 10 wt%) HA composites using the SPS technique and investigated their in vitro degradation behaviors. Zn-HA composites showed significantly improved cell viability of osteoblastic MC3T3-E1 cells compared with pure Zn. An effective antibacterial property was observed as well. As a bioactive ceramic, β-TCP has good biocompatibility, osteoconductivity and biodegradability [96]. In a study by Pan et al. [56], the biocompatibility of Zn-1Mg-xβ-TCP (x = 0, 1, 3, 5 vol%) composites were investigated. When L-929 and MC3T3 cells were cultured in different concentrations for one day, the relative proliferation rate of the cells is above 80%, and the cytotoxicity is 0–1. Moreover, the addition of β-TCP makes the compatibility of the composite material to MC3T3 cells significantly higher than that of the Zn-Mg alloy.

5. In Vivo Evaluation of Zn-Based Biodegradable Materials with Animal Models

In addition to in vitro testing, in vivo animal experiments are a necessary step in assessing the performances of Zn-based biodegradable materials prior to translation into clinical applications. Different from in vitro experiments where the biodegradability, mechanical property, and biocompatibility of a material are often tested separately, animal models can be used to examine all these properties together in an in vivo condition. Although the in vivo animal experiments may not be able to fully mimic the mechanical, biological and chemical environments in the human body, they are currently the best way to evaluate the interactions between Zn-based biodegradable materials and host [15,24,25,36,97]. There are far fewer in vivo studies on Zn-based biomaterials than in vitro studies. Several representative in vivo studies on Zn-based biodegradable materials were summarized in Table 4. Yang et al. [24] implanted the pure Zn into the rat femur condyle. A serious fibrous tissue encapsulation was found for pure Zn, resulting in the lack of direct bonding between bone and implant (Figure 6a). The delayed osseointegration of pure Zn is claimed to be attributed to the local high Zn ion concentration. Consistent with the observations in vitro, the in vivo results confirmed that alloying with appropriate elements such as Mg, Ca and Sr can effectively improve the biocompatibility. Yang et al. [55] implanted the pure Zn into the rat femur condyle. A serious fibrous tissue encapsulation was found for pure Zn, resulting in the lack of direct bonding between bone and implant (Figure 6b). Meanwhile, Jia et al. [70] implanted the Zn-0.8 wt.%Mn alloy into the rat femoral condyle for repairing bone defects with pure Ti as control. Their results showed that the new bone tissue at the bone defect site in both groups gradually increased with time, but a large amount of new bone tissue was observed around the Zn-0.8Mn alloy scaffold (Figure 6c). More importantly, in a heavy load-bearing rabbit shaft fracture model, the Zn-0.4Li-based bone plates and screws showed comparable performance in bone fracture fixation compared to the Ti-6Al-4 V counterpart whereas the cortical bone in the Zn-0.4Li alloy group was much thicker (Figure 6d). The results suggest the great potential of Zn-Li based alloys for degradable biomaterials in heavy load-bearing applications [25]. Figure 6. (a) Hard tissue sections of pure Zn, Zn-0.4Li, Zn-0.1Mn, Zn-0.8 Mg, Zn-0.8Ca, Zn-0.1Sr, Zn-0.4Fe, Zn-0.4Cu and Zn-2Ag in metaphysis. The magnified region is marked by red rectangle. NB, new bone; DP, degradation products; FT, fibrous tissue. Scale bar, 0.5 mm in low magnification, 500 μm in high magnification [24]. (b) Histological characterization of hard tissue sections at implant sites. Van Gieson staining of pure Zn. Reprinted with permission from Ref. [55], Copyright 2018, Elsevier. (c) The Van Gieson staining results of specimens 4 weeks, 8 weeks, and 12 weeks postoperatively. Within each row, full-view images of bone defect areas (20×), medium magnification images (50×), and higher magnification images (100×) arranged from left to right. Reprinted with permission from Ref. [70], Copyright 2020, Elsevier. (d) Van Gieson staining of representative histological images of femoral fracture healing at 6 months. The fracture healing and fixation screws are magnified and marked by red rectangles. Reprinted with permission from Ref. [25], Copyright 2021, Elsevier. It can be seen from those in vivo studies above (Table 4) that the Zn-based biodegradable materials play an important role in promoting osteogenesis. The corrosion rate of Zn-based biodegradable materials is relatively slow in vivo and can provide a long-term mechanical support in the period of fracture healing [24,25,36]. No incomplete fracture healing and structural collapse of the implant were reported during the animal experiments on load-bearing parts such as the femur [25]. However, the long-term results of the Zn-based implants remain unknown since those animal studies generally lasted for 8–24 weeks [24,25,46]. Additionally, the in vivo studies testing performances of Zn-based implants in fracture fixation are limited [24]. Currently, only small animal models, such as mice, rats and rabbits have been used to examine primarily the biodegradability and biocompatibility of Zn2+ metals on bone defect sites (Table 4) [24,25,33,36,46,51,55,56,70,97]. Although mammals have many similarities, differences across small animals, large animals and humans should be recognized [98]. For example, the difference in skeletal size across various species affects the amount of Zn materials that needs to be degraded or absorbed as well as the mechanical environment, which may lead to varied results between preclinical studies and clinical applications. Therefore, with clinical translations in mind, future studies may be warranted with large animal models. In addition, as Zn-based implants are expected to be used at heavy load-bearing sites for internal fracture fixation, proper site-specific in vivo animal models should be used to test their biodegradability, mechanical properties and biocompatibility (Figure 7).

Figure 7. Schematic representation of common animal bone defect models [98].

Table 4. Relevant animal studies of Zn-based biodegradable materials as potential orthopaedic implants.

Zn-Based Metals

Designed Implants

Control

Surgeries

Animal Species

Major Findings

Ref.

Zn-Mn

Scaffold

Pure Ti

Insertion into

femoral condyle

Rats

The new bone tissues at the bone defect sites gradually increased with time in both groups, and numerous new bone tissues were observed around the Zn-0.8Mn alloy scaffold

[70]

Zn-1Mg, Zn-1Ca, Zn-1Sr

Intramedullary

nails

NA

Insertion into

femoral marrow

medullary cavity

Mice

There was no inflammation observed around the implantation site and no mouse died after operation. The new bone thickness of Zn-1Mg, Zn-1Ca and Zn-1Sr pin groups are significantly larger than the sham control group.

[51]

Zn-HA

Pin

Pure Zn

Insertion into

femoral condyle

Rats

There was new bone formation around the Zn-HA composite, and the bone mass increased over time. With prolonged implantation time, the Zn-HA composite was more effective than pure Zn in promoting new bone formation.

[55]

Zn-0.05Mg

Pin

Pure Zn

Insertion into

femoral condyle

Rabbits

No inflammatory cells were found at the fracture site, and new bone tissue formation was confirmed at the bone/implant interface, proving that the Zn-0.05Mg alloy promoted the formation of new bone tissue.
Non-biodegradable metallicmaterials不可生物降解的金属材料 316L SS不锈钢 Non-biodegradable不可生物降解 High elastic modulus, low wear and corrosion resistance, high tensile strength高弹性模量，低磨损和耐腐蚀性，高拉伸强度 High biocompatibility高生物相容性 Acetabular cup, bone screws, bone plates, pins, etc.髋臼杯、骨螺钉、骨板、销钉等 [
Zn-0.8Mg 203 301 13 MEM 0.07111]
U-2OS,

L-929 Zn is less biocompatible than magnesium and the maximum safe concentrations of Zn2+ for the U-2OS and L929 cells are 120 μM and 80 μM. [50] Co–Cr alloys钴铬合金 Non-biodegradable不可生物降解 High elastic modulus, high wear and corrosion resistance高弹性模量，高耐磨性和耐腐蚀性 Low biocompatibility低生物相容性 Bone screws, bone plates, femoral stems, total hip replacements, etc.骨螺钉、骨板、股骨干、全髋关节置换术等。 [12]
Zn-1.0Ca 206 252 12.7 HBSS 0.09 MG63 Adding the alloying elements Ca into Zn can significantly increase the viability of MG63 and can promote the MG63 cell proliferation compared with the pure Zn and negative control groups. [51] Ti alloys钛合金 Non-biodegradable不可生物降解 Poor fatigue strength, light weight疲劳强度差，重量轻 High biocompatibility高生物相容性
Zn-1.1Sr 220 250Dental implants, bone screws, bone plates, etc.种植牙、骨螺钉、骨板等 22[11 SBF,13]11，13 ]
0.4 Biodegradable metallic materials可生物降解的金属材料 Mg-based alloys镁基合金 Biodegradable, high degradation rate可生物降解，降解率高 Poor mechanical properties, elastic modulus are close to cortical bone力学性能差，弹性模量接近皮质骨 高生物相容性，High biocompatibility, H2 evolution演化 Bone screws, bone plates (non-load bearing parts), etc.接骨螺钉、接骨板（非承重部件）等 [2,，9]
Fe-based alloys铁基合金 Biodegradable, low degradation rate可生物降解，降解率低 High elastic modulus, poor mechanical properties弹性模量高，机械性能差 Low biocompatibility低生物相容性 Bone screws, bone plates, etc.骨螺钉、骨板等 [9]
Zn-based alloys锌基合金 Biodegradable, moderate corrosion rate可生物降解，腐蚀速度适中 High elastic modulus, high mechanical properties, low creep resistance高弹性模量、高机械性能、低抗蠕变性 Cytotoxicity, no gas production, high biocompatibility细胞毒性大，不产气，生物相容性高 Bone screws, bone plates (load-bearing parts (potential applications)), etc.接骨螺钉、接骨板（承重部件（潜在应用））等 [3,，9,，10]
JFB 13 00164 g002 550
Figure 图2. A schematic indicating the state of the art of research on 指示用于骨科内固定的Zn-based biodegradable materials for orthopaedic internal fixation.基可生物降解材料研究现状的示意图。

2. Biodegradability of Zn-Based Biodegradable Materials锌基生物降解材料的生物降解性

It is well known that human bodies are full of fluid solutions and bear mechanical loading, generating corrosive and mechanical environments for biodegradable materials. It is expected that after biodegradable metals are implanted in the human body, they can gradually degrade at a suitable rate that matches the healing rate of bone tissues (Figure 众所周知，人体充满了流体溶液并承受机械负荷，对可生物降解的材料产生腐蚀性和机械性环境。预计可生物降解的金属植入人体内后，可以以与骨组织愈合速度相匹配的合适速度逐渐降解（图3). However, different types of fractures at different skeletal sites require different fixation implants (as well as the amounts of degradable materials). Therefore, considering designs of suitable ）。然而，不同骨骼部位的不同类型的骨折需要不同的固定植入物（以及可降解材料的量）。因此，考虑设计合适的具有适当降解速率的Zn-based devices with a proper degradation rate to meet clinical fixation requirements of different fractures, it is necessary to understand the degradation mechanisms, regulation of the degradation rate, and mechanical factors influencing the degradation of biodegradable metals. It is evident that pure Zn has a relatively low degradation rate. Adding alloy elements or reinforcement materials is commonly used to tune the biodegradability of Zn.基器件以满足不同骨折的临床固定要求，有必要了解降解机理、降解速率的调控以及影响可生物降解金属降解的力学因素。很明显，纯锌具有相对较低的降解率。添加合金元素或增强材料通常用于调节锌的生物降解性。
Jfb 13 00164 g003 550
Figure 3. Schematics illustrating the processes of bone healing and implant degradation under a perfect matching scene.

2.1. Biodegradability of Pure Zn

Zn is a relatively low active metal. The standard electrode potential of Zn is −0.76 V, which lies between those of Mg (−2.37 V) and Fe (−0.44 V) [14]. It is prone to corrode in various fluid environments within the human body [22]. Studies have been extensively focused on the in vitro corrosion behavior of pure Zn in different corrosion media, such as Hank’s balanced salt solution (HBSS), phosphate buffer saline (PBS), and stimulated body fluid (SBF) [16,28,48]. The medium electrode potential of Zn is associated with a moderate corrosion rate of approximately 0.1 mm y−1 [28]. The corrosion mechanism of Zn is regulated by the following reactions:
Zn→Zn2+ + 2e−,
2H2O + O2 + 4e−→4OH−,
2Zn + 2H2O + O2→2Zn(OH)2,
Zn(OH)2
HOBs, hMSCs
The proliferation ability of the two kinds of cells did not decrease in the zinc alloy leaching solution. When the concentration of the leaching solution was low, the growth of the two kinds of cells was promoted.
[32]
Zn-0.4Li 387 520 5.0 SBF 0.019 MC3T3-E1 Zn-0.4Li alloy extract can significantly promote the proliferation of MC3T3-E1 cells. [24]
Zn-5.0Ge 175 237 22 HBSS 0.051 MC3T3-E1 The diluted extracts at a concentration 12.5% of both the as-cast Zn-5Ge alloy and pure Zn showed grade 0 cytotoxicity; the diluted extracts at the concentrations of 50% and 25% of Zn-5Ge alloy showed a significantly higher cell viability than those of pure Zn. [52]
Zn-6.0Ag - 290 - SBF 0.114 - - [44]
Zn-0.8Fe 127 163 28.1 SBF 0.022 MC3T3-E1 MC3T3-E1 cells had unhealthy morphology and low cell viability. [24]
Zn-4Cu 327 393 44.6 HBSS 0.13 L-929, TAG,

SAOS-2		 Zn-4Cu alloy had no obvious cytotoxic effect on L929, TAG and Saos-2 cells. [53]
Zn-0.8Mn 98.4 104.7 1.0 - - L-929 Zn-0.8Mn alloy showed 29% to 44% cell viability in 100% extract, indicating moderate cytotoxicity. [40]
Zn-2Al 142 192 12 SBF 0.13 MG63 Cell viability decreased to 67.5 ± 5.3% in 100% extract cultured for one day, indicating that high concentrations of ions have a negative effect on cell growth. With the extension of culture time, the number of cells increased significantly. [42]
Zn-0.0.5Zr 104 157 22 - - - - [54]
YS: yield Strength; UTS: ultimate tensile strength; SBF: stimulated body fluid; MEM: minimum essential medium; HBSS: Hank’s balanced salt solution; L-929: mouse fibroblasts; MG63: human osteosarcoma cells; HOBs: human osteoblasts; MSCs: human bone marrow mesenchymal stem cells; MC3T3-E1: mouse preosteoblasts; TAG: human immortalized periosteal cells; SAOS-2: human osteosarcoma cells; U-2OS: human osteosarcoma cells.

2.4. Biodegradability of Zn-Based Biomaterials under Mechanical Loading

The response of biodegradable materials to the combined effect of physiological loading and corrosion environment is an important issue in vivo since stress-induced degradation and cracking are common [57]. Particularly, for load-bearing fracture fixation where biodegradable implant undertakes loading, it is critical to understand how mechanical stress affects the biodegradation behavior of the implant.
The combination of mechanical loading and a specific corrosive medium environment can lead to sudden cracking and failure of degradable metals. This phenomenon is called stress corrosion cracking [57]. In vivo animal experiments and clinical studies have indicated the role of mechanical stress in the early failure of biodegradable implants [19,57,58,59]. Li et al. conducted slow-strain rate testing (SSRT) and constant-load immersion tests on a promising Zn-0.8 wt%Li alloy [60]. They investigated its stress corrosion cracking susceptibility and examined its feasibility as biodegradable metals with pure Zn serving as a control group. They observed that the Zn-0.8 wt%Li alloy exhibited a low stress corrosion cracking susceptibility. This was attributed to variations in microstructure and deformation mechanism after alloying with Li. In addition, compared to the “no stress” condition (0.124 mm y−1), the corrosion rate of the Zn-Li alloy only increased slightly under tensile stress of 11.1 MPa (0.129 mm y−1) and compressive stress of 17.7 MPa (0.125 mm y−1). Both pure Zn and Zn-0.8 wt%Li alloy did not fracture over a period of 28 days during the constant-load immersion test. The magnitude of the applied stress was close to the physiological loading condition and thus the authors proved the feasibility of both materials as biodegradable metals. So far, there are only a few experimental studies on the stress corrosion of Zn-based biodegradable materials. Since previous experimental studies have shown in degradable polymers or Mg-based alloys that the corrosion rate is affected by the loading mode (tension or compression) and magnitude [18,61,62,63,64], it is assumed that these effects also exist in Zn-based biodegradable materials. Identification of the quantitative relationships between various forms of applied loading and degradation behaviors of Zn-based materials is important for the design of load-bearing fixation implants. However, the corrosion behaviors of Zn-based biomaterials under different loading conditions need to be further explored.
Cyclic loading-induced fatigue fractures are very common in engineered metals, where the fatigue strength is further reduced in a corrosive environment [65]. It was reported that under the combined effects of stress and corrosive media, fatigue cracks propagate faster [57]. Corrosion fatigue is of primary concern for metallic internal fixation which commonly bear cyclic dynamic loads in vivo. The corrosion pit propagation rate is influenced by the magnitude of stress, frequency, and cycle number [66,67]. Previous studies have compared the compression-induced fatigue behavior of additively manufactured porous Zn in air and in revised simulated body fluid (r-SBF) [68]. The fatigue strength of the additively-manufactured porous Zn was high in air (i.e., 70% of its yield strength) and even higher in r-SBF (i.e., 80% of its yield strength). The high value of the relative fatigue strength in air could be attributed to the high ductility of pure Zn itself. The formation of corrosion products around the strut junctions might explain the higher fatigue strength of additive manufacturing Zn in r-SBF. The favorable fatigue behavior of additive manufacturing porous Zn further highlights its potential as a promising bone-substituting biomaterial. Another study found in their fatigue testing of Zn-0.5Mg-WC nanocomposites that the material survived after 10 million cycles of tensile loading when the maximum stress was 80% of the yield stress [69]. These results suggest that the Zn-0.5Mg-WC nanocomposite is a promising candidate for biodegradable materials. So far, there has been no report on the fatigue corrosion behavior of Zn-based alloys in vivo. Since the resistance of a material to fatigue and corrosion is an important consideration for designing implants, future relevant studies on Zn-based biomaterials may be required.

3. Mechanical Properties of Zn-Based Biodegradable Materials

In addition to the biodegradable properties, the mechanical properties of the biodegradable metals are also important considerations for designing orthopaedic implants for internal fixation. Yield strength (YS), ultimate tensile strength (UTS), elongation (ε) and elastic modulus (E) are common parameters which are used to indicate the mechanical properties of biomedical materials [11,37,70,71,72,73]. Extensive studies have determined those mechanical parameters of Zn-based biodegradable materials. The reported mechanical criteria for degradable metals (e.g., Mg-based) are UTS 300 MPa and ε 20% [22]. On the other hand, the current gold standard for medical metal materials, such as Ti and its alloys, has a tensile strength of over 600 MPa [13]. To certain extent, these criteria could provide guides of mechanical properties for development of Zn-based degradable materials. However, the requirement may vary with different load-bearing sites.

3.1. Mechanical Properties of Pure Zn

Pure Zn has extremely low yield strength (29.3 MPa) and elongation (1.2%) in its as-cast condition [74]. The Young’s modulus of pure Zn is around 94 GPa [16]. Obviously, it is difficult to meet the mechanical criteria as biodegradable metals [22]. On the other hand, owing to the low melting point of Zn, several additional uncertainties exist with regard to the mechanical properties of biodegradable Zn and Zn-based alloys. Low creep resistance, high susceptibility due to natural aging, and static recrystallization may lead to the failure of Zn-based biodegradable materials during storage at a room temperature and usage at a body temperature [26]. Studies showed that Zn-based alloys underwent appreciable creep deformation under human body temperature (37°) [75]. In addition, recrystallization of Zn-based alloys under stress can reduce their resistance to creep [42]. Thus, creep deformation is an important factor that should be considered in the studies of pure Zn.

3.2. Mechanical Properties of Zn-Based Alloys

Alloying is a common approach to change the mechanical properties of metals, where alloy ratio is essential for studies of Zn-based alloys. Attempts have been made to optimizing the Zn-based alloys by changing the alloy ratio, in order to obtain better mechanical performance in vitro and then move to in vivo conditions [24,32,40,42,44,50,51,52,53,54]. Zn-based alloys have Young’s modulus values ranging from 100 to 110 GPa depending on alloying conditions [16]. As summarized in Table 2, the Zn-based alloys with improved mechanical properties to various degrees are generated by adding elements of Mg [50], Ca [51], Sr [32], Li [24], Ge [52], Ag [44], Fe [24], Cu [53], Mn [40], Al [42], Zr [54]. The improvement of adding Li elements is particularly obvious, but the elongation of Zn-Li is only 5%. Following addition of the Cu element, the elongation of the Zn-based alloys reaches 44.6%. Binary Zn-based alloys have poor mechanical properties and may not be applicable in load-bearing sites of the skeleton. Table 3 summarizes the mechanical properties of ternary Zn-based alloys on the basis of binary Zn-based alloys. Different mechanical processing methods have great influences on the mechanical properties of the same Zn-based alloys. Among the three common mechanical processing operations (hot extrusion, hot rolling, and casting), the hot extrusion can produce the greatest improvement in mechanical properties of Zn-based alloys. Compared with binary Zn-based alloys, ternary Zn-based alloys have largely improved mechanical properties. For example, the tensile strength of Zn-0.8Li-0.4Mg is 646 MPa, which is greater than those of pure titanium or 316L SS (Figure 1) [24]. In addition, reasonable mechanical integrity of Zn-0.8Li-0.4Mg was maintained in vitro, and is expected to be used for bone repair at load-bearing sites.

3.3. Mechanical Properties of Zn-Based Composites

Apart from the addition of alloying elements, adding reinforcement matrix as composite could also regulate the mechanical properties of Zn metals. The biocompatibility and the mechanical properties were improved by controlling the type and content of the second phase to form a composite material. In a previous study, Zn-HA composites were prepared with pure Zn as matrix and hydroxyapatite (HA) as reinforcement by spark plasma sintering [55]. In vivo tests showed that the addition of HA resulted in a better performance in osteogenesis with prolonged fixation time. In another study, Zn-Mg-β-TCP composites were prepared with Zn-Mg as matrix and β-TCP as enhancer by the mechanical stirring combined with ultrasonic assisted casting and hot extrusion technology [56]. This material had an ultimate tensile strength of 330.5 MPa and showed better biocompatibility than Zn-Mg alloys in cellular experiments. A barrier layer of ZrO2 nanofilm was constructed on the surface of Zn-0.1 wt%Li alloy via atomic layer deposition (ALD) [76]. Their results indicated that the addition of ZrO2 could effectively improve cell adhesion and vitality, and promote osseointegration, but the non-degradation of ZrO2 brought new challenges. Composites often have advantages over alloys due to the addition of second-phase enhancers. Compared with pure Zn, the addition of a second-phase material largely enhances its mechanical strength and biocompatibility. However, it was reported that the ductility of Zn-based composite materials is only 10% or even lower, with a greater brittleness [22], bringing difficulties to the processing of orthopaedic devices (such as bone screws and bone plates). In addition, the complex manufacturing process, high cost of composite materials, and a lack of sufficient basic theoretical supports in the field of preparation and processing still limit their developments. Table 3. In vitro experiments of ternary Zn-based alloys.

Composition (wt%) and Manufacturing Process

Mechanical Properties

Corrosion Test

Cytocompatibility

Ref.

σYS (MPa)

σUTS (MPa)

ε (%)

Corrosion Medium

Corrosion

Rate (mm/y)

Cell Type

Key Findings

Zn-1.5Mg-0.5Zr

HE

350

425

12

-

-

L-929

Overall, the L-929 cells exhibit polygonal or spindle shape, and well spread and proliferated in the extracts of pure Zn and Zn alloys.

[39]

Zn-1.0Ca-1Sr

[46]

Zn-(0.001% < Mg < 2.5%,

0.01% < Fe < 2.5%)

Screw and plate

PLLA, Ti-based alloys

Mandible fracture

Beagles

The new bone formation in the Zn alloy group and the titanium alloy group was significantly higher than that in the PLLA group. In addition, the new bone formation in the Zn-based alloys group was slightly higher than that in the Ti-based alloys group. The degradation of Zn implants in vivo would not increase the concentration of Zn2+.

[96]

Zn-X (Fe, Cu, Ag, Mg, Ca, Sr, Mn, Li)

Intramedullary

nails

Pure Zn

Insertion into

femoral marrow

medullary cavity

Rats

Pure Zn, Zn-0.4Fe, Zn-0.4Cu and Zn-2.0Ag alloy implants showed localized degradation patterns with local accumulation of products. In contrast, the degradation of Zn-0.8Mg, Zn-0.8Ca, Zn-0.1Sr, Zn-0.4Li and Zn-0.1Mn was more uniform on the macroscopic scale.

[24]

Zn-0.8Sr

Scaffold

Pure Ti

Insertion into

femoral condyle

Rats

Zn-based alloys promote bone regeneration by promoting the proliferation and differentiation of MC3T3-E1 cells, upregulating the expression of osteogenesis-related genes and proteins, and stimulating angiogenesis.

[36]

Zn-0.8Li-0.1Ca

Scaffold

Pure Ti

Insertion into radial defect

Rabbits

The Zn-0.8Li-0.1Ca alloy has a similar level of biocompatibility to pure titanium, but it promotes regeneration significantly faster than pure Ti.

[33]

Zn-0.4Li

Screw and plate

Ti-6Al-4V

Femoral shaft fracture

Rabbits

Plates and screws made of Zn-0.4Li alloy showed comparable performance to Ti-6Al-4V in fracture fixation, and the fractured bone healed completely six months after surgery.

[25]

Zn-1Mg-nvol%β-TCP (n  =  0, 1)

Columnar samples

Zn-1Mg

Specimens in lateral thighs.

Rats

Zn-1Mg alloy and Zn-1Mg-β-TCP composites had no significant tissue inflammation and showed good biocompatibility.

[56]

 

6. Summary and Future Directions

A growing number of new Zn-based biodegradable materials have been developed and their biodegradability, mechanical properties, and biocompatibility were tested mostly in vitro and partially in vivo. An ideal biodegradable material for orthopaedic internal fixation should have a suitable combination of biocompatibility, biodegradability, and mechanical properties (YS, UTS, and ε). Although the mechanical properties of pure Zn are difficult to meet the requirements of orthopaedic fixation, Zn-based alloys can achieve the mechanical properties of traditional implants used in internal fixation at load-bearing sites. Zn-based materials have a moderate corrosion rate and good biocompatibility. Their degradation by-product Zn2+ can promote bone growth and mineralization. These properties support Zn-based biodegradable materials as an alternative for internal fixation implants at heavy load-bearing skeletal sites. However, many questions still need to be addressed before Zn-based biodegradable materials can be used for fracture fixation in clinics (Figure 8).

图8.Zn基生物降解材料的未来发展方向。

在生物降解性方面，（1）目前Zn基生物降解材料的降解速度仍然相对较慢，需要根据目标骨骼部位进一步调整以匹配其愈合速度;（2）由于骨架上存在静载荷和动载荷，需要更好地了解材料的应力腐蚀和疲劳腐蚀。在力学性能方面，（1）目前Zn基生物降解材料的弹性模量（94–110 GPa）高于骨，在用于内固定时应降低弹性模量以避免应力屏蔽;（2）Zn基合金在人体生理温度下对内固定植入物失效的蠕变效应应进一步探讨。在生物相容性方面，（1）由于锌含量高2+对细胞有毒性作用，应尽量调节内固定的降解速率，确保降解产物的浓度不超过植入部位的安全浓度范围;（2）抗菌特性可进一步探索。此外，体内实验应从小动物模型转向大型动物模型，以进行重载骨折固定。

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