Materials Today Bio 25 (2024) 100932

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Materials Today Bio

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Zinc based biodegradable metals for bone repair and regeneration:

Bioactivity and molecular mechanisms
Ping Li a, b, c, 1, Jingtao Dai d, 1, Yageng Li e, Dorothea Alexander f, Jaroslav Čapek g,
Jürgen Geis-Gerstorfer h, Guojiang Wan i, Jianmin Han j, **, Zhentao Yu k, ***, An Li l, *
a
Center of Oral Implantology, Stomatological Hospital, School of Stomatology, Southern Medical University, South Jiangnan Road No. 366, Guangzhou 510280, China
b
School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Medical University, Guangzhou,
Guangdong, 510182, China
c
Department of Prosthodontics, School and Hospital of Stomatology, Guangzhou Medical University, Guangzhou, Guangdong, 510182, China
d
Department of Orthodontics, Stomatological Hospital, School of Stomatology, Southern Medical University, South Jiangnan Road No. 366, Guangzhou 510280, China
e
Beijing Advanced Innovation Center for Materials Genome Engineering, School of Materials Science and Engineering, University of Science and Technology Beijing,
Beijing 100083, China
f
Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, Osianderstrasse 2-8, Tübingen 72076, Germany
g
FZU – the Institute of Physics, Czech Academy of Sciences, Na Slovance 1999/2, Prague 8, 18200, Czech Republic
h
Section Medical Materials Science and Technology, University Hospital Tübingen, Osianderstrasse 2-8, Tübingen 72076, Germany
i
Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu
610031, China
j
National Engineering Laboratory for Digital and Material Technology of Stomatology, Department of Dental Materials, Peking University School and Hospital of
Stomatology, Beijing 100081, China
k
Institute of Advanced Wear & Corrosion Resistant and Functional Materials, Jinan University, Guangzhou 510632, China
l
Department of Periodontology, Stomatological Hospital, School of Stomatology, Southern Medical University, South Jiangnan Road 366, Guangzhou 510280, China

A R T I C L E I N F O A B S T R A C T

Keywords: Bone fractures and critical-size bone defects are significant public health issues, and clinical treatment outcomes
Biodegradable metals are closely related to the intrinsic properties of the utilized implant materials. Zinc (Zn)-based biodegradable
Zinc metals (BMs) have emerged as promising bioactive materials because of their exceptional biocompatibility,
Bone fracture healing
appropriate mechanical properties, and controllable biodegradation. This review summarizes the state of the art
Bone tissue engineering
Guided bone regeneration
in terms of Zn-based metals for bone repair and regeneration, focusing on bridging the gap between biological
Biocompatibility mechanism and required bioactivity. The molecular mechanism underlying the release of Zn ions from Zn-based
BMs in the improvement of bone repair and regeneration is elucidated. By integrating clinical considerations and
the specific bioactivity required for implant materials, this review summarizes the current research status of Zn-
based internal fixation materials for promoting fracture healing, Zn-based scaffolds for regenerating critical-size
bone defects, and Zn-based barrier membranes for reconstituting alveolar bone defects. Considering the signif­
icant progress made in the research on Zn-based BMs for potential clinical applications, the challenges and
promising research directions are proposed and discussed.

1. Introduction imposes a serious economic burden [1,2]. These serious diseases are
challenging to treat due to factors such as patient age, defect size, and
Skeletal defects—mainly caused by trauma (bone fracture), in­ the compromised self-healing abilities of bone tissue [3,4]. However, in
fections (osteomyelitis and periodontal disease), osteoporosis, tumors, response to these challenges, the field of skeletal tissue engineering has
and other skeletal disorders—represent a global public health issue that witnessed a surge in the application and development of

* Corresponding author.
** Corresponding author.
*** Corresponding author.
E-mail addresses: [email protected] (J. Han), [email protected] (Z. Yu), [email protected] (A. Li).
1
These authors contributed equally as first authors to this work.

https://doi.org/10.1016/j.mtbio.2023.100932
Received 18 September 2023; Received in revised form 12 December 2023; Accepted 25 December 2023
Available online 28 December 2023
2590-0064/© 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
P. Li et al. Materials Today Bio 25 (2024) 100932

biomaterials-based strategies tailored to accommodate the specific type bone defects.

and severity of the ailment [5,6]. Various biomaterials—ranging from Recent reviews have concentrated on aspects such as fabrication
metals, polymers, ceramics, to composites—have emerged as viable techniques [28,29], mechanical properties [29–31], surface modifica­
options for bone regeneration owing to their exceptional biocompati­ tion [32,33], and potential clinical applications of Zn-based BMs [23,
bility [7,8]. In the field of tissue engineering, there has been a notable 34–36]. However, the bioactive effects of Zn-based implants for bone
shift in the ongoing development of biomaterials, transitioning from applications remain unclear. Our review aims to focus on the state of the
bioinert to bioactive matrices [9,10]. Metallic biomaterials exhibit art in terms of Zn-based implants for bone repair and regeneration, with
remarkable advantages, including superior biocompatibility, robust a specific emphasis on bridging the gap between biological mechanisms
mechanical strength, inherent bioactivities, and cost-effective and the required bioactivity. First, this review elucidates the molecular
manufacturing processes, making them highly promising for applica­ mechanisms behind the promotion of bone regeneration by Zn ions.
tions in bone tissue engineering. While traditional metallic biomaterials Considering disease types and clinical application, the required bioac­
like stainless steel, titanium alloys, and cobalt-chromium alloys offer tivity and biofunctionality of implant materials is highlighted. As illus­
excellent wear resistance, biocompatibility, and mechanical strength, trated in Fig. 1, based on the clinical applications (i.e., internal fixation,
they also have several drawbacks, including stress shielding effects, the tissue scaffold, and barrier membrane), this review summarizes the
emergence of metal artifacts, and the need for additional surgery for bioactivity of Zn-based metals for bone repair and regeneration. Finally,
their removal [11,12]. Resorbable polymers have emerged as an alter­ the challenges and prospects are proposed to provide insights for the
native orthopedic implant material, but their inferior mechanical clinical translation of Zn-based metals.
properties can generate local acid degradation products, leading to
noninfectious inflammatory reactions [13,14]. 2. Underlying mechanisms for the improvement of bone repair
Liu and colleagues defined biodegradable metals (BMs) have been and regeneration through Zn-based metals
defined as “metals expected to corrode gradually in vivo, with an appropriate
host response elicited by released corrosion products, which can pass through Considering bone repair and regeneration, the degradation products
or be metabolized or assimilated by cells and/or tissue, and then dissolve of Zn-based implants contribute to the sophisticated bone microenvi­
completely upon fulfilling the mission to assist with tissue healing with no ronment. Over the process of bone healing, complex interactions be­
implant residues” [15]. The development of BMs has focused on the use of tween various Zn degradation products and major skeletal cell
magnesium (Mg), iron (Fe), and zinc (Zn), as well as their alloy­ populations (i.e., osteoblasts, osteoclasts, endothelial cells, and immune
s/composites. The utilization of degradable metallic implants in ortho­ cells) can occur, determining the host response to the Zn-based implant
pedic surgeries can mitigate the challenges linked to the subsequent [37,38]. To date, previous in vivo studies have demonstrated acceptable
removal of non-degradable metallic implants. The Mg-based implants in vivo biocompatibility of Zn and its alloys/composites during long-term
offer the additional benefits superior mechanical properties [16], pro­ degradation processes [39–41]. Although no systematic toxic effects
motion of bone metabolism [17], and potential treatment for were reported, it is evident that fibrous encapsulation around Zn-based
medication-related osteonecrosis of the jaw [18]. Nevertheless, the implants occurs during long-term degradation, probably attributable to
rapid degradation and release of hydrogen remain areas of concern. In the local release of degradation products [42]. As shown in Fig. 2,
contrast, Fe and its alloys exhibit relatively slow degradation with various animal bone defect models have demonstrated that Zn-based
insoluble degradation products remaining in physiological environ­ plates/screws accelerated bone fracture repair [43], Zn-based scaffolds
ments [19]. The research and development of Zn-based BMs for bone enhanced new bone formation [44], and Zn-based membranes promoted
fixation applications can be traced back to the early 2010s, proposed by bone regeneration [45]. The bioactivity and biofunctionality of
Vojtech et al. [20]. Over the last decade, pure Zn and Zn-based alloy­ Zn-based BMs are mainly based on their degradation resulting in Zn ions
s/composites have emerged as a new generation of BMs because of their release. Understanding of the temporal and spatial distribution of Zn
acceptable biocompatibility, moderate biodegradation, superior me­ ions is critical for the success prediction of clinical applications. Herein,
chanical properties, and potential bioactivity [21,22]. the impact of extracellular Zn ions on cellular function and the molec­
When assessing the primary advantages of Zn-based BMs, it is ular mechanism underlying the beneficial effects of Zn-based implants
important to note that the intrinsic corrosion profile of Zn ranges be­ are summarized systematically and in detail. In general, Zn ions have
tween those of Mg and Fe. Unlike Mg-based BMs, the degradation of Zn- multiple functions in bone repair and regeneration, including the pro­
based BMs does not involve hydrogen release, thereby avoiding poten­ motion of osteogenic differentiation of mesenchymal stem cells (MSCs),
tial adverse effects and supporting tissue healing [23]. A recent study the enhancement of osteoblastic bone formation, and the inhibition of
investigated the in vivo comparative performance of additively manu­ osteoclastic bone resorption [46,47]. Also, Zn ions may stimulate
factured Mg-based and Zn-based scaffolds during the healing process. angiogenesis and induce immunomodulation, leading to new bone for­
The main finding revealed that Mg scaffolds led to delayed yet complete mation [48].
defect healing with bone ingrowth, while Zn scaffolds facilitated early
healing and the formation of high-quality new bone, despite the 2.1. Zn-mediated osteogenic differentiation
restricted calcification of osteoid within the Zn scaffold [24]. In contrast
to Fe-based BMs, the degradation products released from Zn-based BMs A common finding shows that Zn ions promote cell proliferation,
can be safely metabolized and eliminated, at least in animal models in alkaline phosphatase (ALP) activity, osteogenic differentiation, and
vivo [21,25]. Zn-based implants for bone repair and regeneration, such calcium deposition of MSCs in both primary and established cell lines
as internal fixation materials, scaffolds, and barrier membranes, have [49–53]. In the early stage of osteogenic differentiation, extracellular Zn
been developed and examined using various fabrication techniques, ions upregulate the expression of specific genes in MSCs, such as ALP,
including casting, powder metallurgy, extrusion, and additive runt-related transcription factor 2 (RUNX2), and type 1 collagen [49,
manufacturing [26,27]. To date, numerous in vivo studies have been 54]. During middle and late differentiation stages, Zn-supplementation
conducted to evaluate the effectiveness and safety of Zn-based BMs for significantly enhances expression of late osteogenic markers by MSCs
bone repair and regeneration. Particularly noteworthy is the registration (i.e., osteocalcin and osteopontin) [55,56]. More importantly, the
of clinical trials for Zn-based implants, aimed at treating maxillofacial impact of Zn on cell function regulation is dominated by dose-dependent
bone fractures (ChiCTR2100051050) and anterior cruciate ligament effects. Extracellular Zn concentrations have double-edged effects on
reconstruction (ChiCTR2300072163). Therefore, Zn-based BMs exhibit bone marrow-derived MSCs (BMSCs). Low Zn ion concentration (2–5 μg
potential beneficial effects for bone repair and regeneration, offering mL− 1) can enhance the initial adhesion and proliferation of BMSCs and
unprecedented advantages over conventional treatment alternatives for subsequently regulate Zn transportation to induce osteogenic

2
P. Li et al. Materials Today Bio 25 (2024) 100932

Fig. 1. Schematic illustration of possible clinical applications of Zn-based biodegradable metals, including Zn-based internal fixation for bone fractures, Zn-
based scaffold for critical-sized bone defects, and Zn-based barrier membrane for alveolar bone defects.

differentiation. On the contrary, an excessively high Zn ion concentra­ causes Smad-1 activation and downregulation of RUNX2 expression
tion (5 μg mL− 1) reduces cell adhesion and proliferation and inhibits through the BMP-2 signaling pathway, suppressing osteoblast differen­
subsequent osteogenic differentiation because of the resulting Zn ho­ tiation, as shown in Fig. 3B. In contrast, with Zn level increased in
meostasis imbalance [51]. Low-concentrated Zn extracts containing media, both RUNX2 expression and Smad-1 activation can be enhanced,
degradation products of Zn-based BMs, led to enhanced osteogenic dif­ demonstrating that Zn ions promote RUNX2 via canonical BMP-2
ferentiation of periosteal stem cells, whereas high-concentrated Zn ex­ signaling [64].
tracts inhibit calcium deposition [49]. Similarly, the in vitro study by High concentrations of zinc ions have been shown to exert an
Xiong et al. [57] showed that a Zn ion concentration of 10.91–27.15 μM inhibitory effect on osteogenic differentiation, and the pivotal process
can promote the ALP activity in BMSCs and increase the expression of through which undifferentiated mesenchymal stem cells evolve into
osteogenesis-related genes, while a Zn concentration exceeding 128 μM bone-forming cells [49,57]. One molecular mechanism contributing to
significantly inhibits the ALP activity of BMSCs [57]. this inhibition entails zinc ions interfering with crucial signaling path­
The underlying molecular mechanism of Zn-mediated regulation is ways and regulatory molecules that orchestrate osteogenic differentia­
based on the activation of the mitogen-activated protein kinase (MAPK) tion. Specifically, elevated zinc concentrations can perturb the balance
pathway, the protein kinase B (AKT) pathway, the protein kinase A of intracellular signaling pathways, including those involved in pro­
(PKA) pathway, and the transforming growth factor β (TGF-β) pathway moting cell apoptosis, such as the Wnt/β-catenin pathway, which plays a
[58]. MAPK signal transduction is considered as one of the main critical role in fostering osteoblast differentiation and bone formation
signaling pathways in the osteogenic process [59]. Zhu et al. demon­ [65].
strated that implant-derived Zn ions promoted osteogenic differentia­
tion via activation of the MAPK pathway and the Gαq-PLC-AKT pathway
(Fig. 3A) [58]. In particular, Zn ions released from Zn-based BMs have 2.2. Zn-mediated inhibition of osteoclastic bone resorption
been incorporated into human MSCs through receptors/channels
GPR39/ZnR and TRPM7. As soon as they are internalized, Zn ions Zn, as an essential trace metallic element, plays a critical role in
activate the cAMP-PKA pathway and the parallel Gαq-PLC-AKT osteoclastogenesis [66]. Previous in vitro studies demonstrated that Zn
pathway, triggering intracellular calcium (Ca) ion responses. This leads ions are able to inhibit osteoclastogenesis in a dose-dependent manner
to the activation of MAPK and AKT pathways, which regulate related [67–71]. Existing literature is inconsistent in terms of the effective Zn
gene expression, resulting in MSC survival, growth, and differentiation. ion concentration. While certain studies reported inhibiting effects on
Park et al. [60] demonstrated that Zn ions promote osteogenic differ­ osteoclastogenesis by Zn ion concentrations above 1 μM [71,72], other
entiation through the activation of RUNX2 in the downstream signaling studies reported similar effects occurring at sub-nanomolar Zn concen­
pathways of the cAMP-PKA-CREB axis. Zn ions increase intracellular tration [73]. Zn substitution can modulate osteoclast activity by inhib­
cAMP levels in a dose-dependent manner. Further, PKA activity can be iting tartrate-resistant acid phosphatase activity, which represents an
enhanced following increased intracellular cAMP levels, leading to the early marker during osteoclast maturation [71,74,75]. However, Zn can
promotion of osteogenic differentiation in human BMSCs [60]. Addi­ also induce osteoclast apoptosis. Culturing of osteoclasts on
tionally, activation of the TGF-β/BMP signaling pathway has been Zn-containing tricalcium phosphate (TCP) discs has been shown to
associated with Zn-mediated osteogenic differentiation of MSCs induce osteoclast apoptosis with increasing Zn concentrations [76].
[61–63]. Gao et al. reported that Zn-containing BMs can upregulate the The underlying mechanisms for Zn-mediated inhibition of osteo­
TGF-β pathway, according to the Kyoto Encyclopedia of Genes and Ge­ clastogenesis involve the nuclear factor (NF) of activated T-cells cyto­
nomes [63]. Cho et al. [64] noted that Zn deficiency in osteoblasts plasmic 1 (NFATc1) signaling pathway and the NF-κB signaling
pathway. NFATc1 activity is considered as a master transcription

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P. Li et al. Materials Today Bio 25 (2024) 100932

Fig. 2. Various applications of Zn-based implants for bone repair and regeneration. A) Schematic illustration of internal fixation for bone fractures. B)
Representative X-ray images and histological examination showing Zn-based plate/screw accelerated bone fracture repair (reproduced with permission from
Ref. [132]). C) Schematic illustration of tissue scaffold for critical-sized bone defects. D) Representative X-ray images and histological examination showing Zn-based
scaffold enhanced new bone formation (reproduced with permission from Ref. [44]). E) Schematic illustration of barrier membrane for alveolar bone defects. F)
Representative X-ray images and histological examination showing Zn-based guided bone regeneration (GBR) membrane effectively promoting bone regeneration
(reproduced with permission from Ref. [45]).

regulator of osteoclastogenesis [77,78]. Park et al. [68] reported the downregulating receptor levels of NF-κB (RANK) by suppressing the
inhibitory effect of Zn ions during osteoclastogenesis via the production of reactive oxygen species and extracellular signal-regulated
Ca2+-calcineurin-NFATc1 signaling pathway. Their work demonstrated kinase (ERK). In addition, Zn ions can trigger crosstalk between osteo­
that Zn ions can suppress calcineurin at an early stage and inhibit cal­ blast metabolism and osteoclastic differentiation by regulating the
cium oscillations by blocking calcium influx from extracellular space RANK/RANKL/OPG pathway [79,80]. However, Zn-stimulated cross­
during the middle or late stages of osteoclast differentiation (Fig. 3C). talk between osteogenesis and osteoclastogenesis requires further
Furthermore, Zn-mediated inhibition of osteoclastogenesis was associ­ examination.
ated to the antagonism of NF-κB activation [70]. Specifically, Zn ions
can suppress the induction of receptor activator of nuclear factor κB
ligand (RANKL) of an NF-κB-luciferase reporter in osteoclast differen­ 2.3. Zn-stimulated angiogenesis contributes to the process of osteogenesis
tiation [95]. Similarly, an in vivo study by Hie and Tsukamoto [71]
showed that Zn administration can inhibit osteoclastogenesis by The mutual dependence of both processes of angiogenesis and
osteogenesis is critical considering that an impaired angiogenic ability

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P. Li et al. Materials Today Bio 25 (2024) 100932

Fig. 3. Zn-stimulated cellular reactions and underlying molecular mechanisms. A) Zn implant-mediated signaling pathway in human mesenchymal stem cells
(reproduced with permission from Ref. [58]). B) Zn contribution to the bone morphogenetic protein-2 (BMP-2) signaling pathway in osteoblasts (reproduced with
permission from Ref. [64]). C) Inhibitory effects of Zn on RANKL-induced osteoclastogenesis (reproduced with permissions from Ref. [68]). D) Effects of Zn sup­
plementation on the activation of the Smad signaling pathway in T cells (reproduced with permission from Ref. [103]).

can increase the occurrence of nonunions and delay bone repair [81,82]. 2.4. Zn-mediated immunomodulation may couple osteogenesis
Zn ions have been shown to have in vitro pro-angiogenic effects but in a
strongly dose-dependent manner. This means that a high concentration The immune system has a significant impact on bone tissue regen­
(140 μM) of Zn ions has adverse effects on the angiogenic behavior of eration [89]. Immune cells, mainly including macrophages and T cells,
endothelial cells. In contrast, low concentrations of Zn ions (60 μM) can can indirectly promote bone repair and regeneration through cytokine
effectively promote the viability, proliferation, and migration of endo­ secretion, which interacts with various bone-related cells [90]. The
thelial cells and upregulate related gene expression [83]. In an in-ovo ability to timely resolve acute inflammation through the innate immune
chorioallantoic membrane test, endothelial cultures were exposed to Zn system is critical for normal bone healing. This is coupled with the
ion gradients, and the results showed that an appropriate Zn ion con­ transition of pro-inflammatory M1 macrophages into pro-regenerative
centration of 50 μM can promote angiogenesis and significantly increase M2 macrophages [91,92], or/and with the activation of the Th2
the levels of vascular endothelial growth factor (VEGF) and fibroblast phenotype and of regulatory T cells [93,94]. The crosstalk between
growth factor (FGF) [84]. immune cells and bone niche cells can promote the process of bone
As already mentioned for MSCs, a physiologically relevant concen­ repair and vascularization, bone deposition, and remodeling [90]. To
tration of 25 μM activates the Zn ion-sensing receptor coupled with the G date, biomaterial-based immunomodulatory strategies for tissue regen­
protein-receptor (ZnR/GPR39), triggering Gαq signaling pathways. eration have largely focused on the activation of macrophage pheno­
Subsequently, activation of PLC, AKT, MAPK, phosphoinositide 3 (PI3), types and the balance of T lymphocytes [95,96].
and extracellular signal-related kinase (ERK)1/2 signaling pathways Zn-containing biomaterials can boost the M1/M2 macrophage
follows. These pathways initiate physiological cell functions (i.e., sur­ switch and induce the secretion of anti-inflammatory and osteogenic
vival, proliferation, inflammation, and angiogenesis) in vascular endo­ cytokines, thus creating a microenvironment favorable for bone healing
thelial cells [85]. HIF-1α is a transcription factor that regulates VEGF [97–99]. Zn ions released from Zn silicate incorporated into calcium
expression via the NF-κB pathway activation [86,87]. Expression of phosphate cement were shown to downregulate inflammatory-related
hypoxia-inducible factor 1 alpha (HIF1-α) can be stabilized by hypoxic gene expression (i.e., interleukin-1, interleukin-6, and tumor necrosis
conditions and increased lactate levels [88]. High Zn ion concentrations factor) and to upregulate anti-inflammatory gene expression (inter­
can downregulate HIF-1α levels, thereby suppressing VEGF expression leukin-10) of mouse bone marrow MSCs, subsequently suppressing
under hypoxic conditions [87]. inflammation and osteoclastogenesis of RAW264.7 cells [100].
Furthermore, exosomes secreted by macrophages cultured under Zn ion

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P. Li et al. Materials Today Bio 25 (2024) 100932

supplementation (4 μM) were able to enhance the ALP activity of oste­ fracture, and craniomaxillofacial fracture. The classical principles of
oblasts, indicating that compounds of the exosomes mediate Zn-induced operative fracture fixation include: 1) restoration of the disrupted
immunomodulatory functions [101]. Nevertheless, the effect of Zn ions osseous anatomy, 2) sufficient stabilization of the fractured bone, 3)
on the potential molecular mechanisms of macrophages should be adequate blood supply to the fracture area, and 4) permission of early
investigated in future research. motion without pain, which ultimately results in an optimal functional
Zn supplementation was demonstrated to induce the polarization of recovery of the fractured bone [105,114]. The core concept of fracture
regulatory T cells (Treg). Specifically, in an experimental set-up with treatment can be summarized as ‘early functional rehabilitation’.
mixed lymphocyte cultures treated with a Zn ion concentration of 50 Thereby, stable fixation plays a critical role in eliminating motion at the
μM, the Th1-cytokine (particularly IFNγ) production was inhibited and fracture site and allowing early mobilization of the injured extremity. In
the number of Treg cells increased [102]. Regarding the potential terms of fracture fixation, stability refers to either absolute stability
mechanisms of Treg polarization, Zn ions can augment the activation of (where any micro-motion is abolished at the fracture zone under phys­
the TGFβ1-induced signaling pathway in association with an increased iological loading) or relative stability (where most motion is prevented
Smad 2/3 activation, thus increasing forkhead box P3 expression sta­ at the fracture zone, although micro-motion may still exist) [105]. The
bilization (Fig. 3D) [103]. Nevertheless, the long-term impact of simplest and most effective way to achieve absolute stability is the
Zn-based BMs on the adaptive immune response remains obscure. exertion of interfragmentary compression via plate/screw fixation. In
addition, to achieve relative stability, biological plate fixation (i.e., in­
3. Zn-based internal fixation for bone fractures direct reduction and bridge plates), external fixation, and intra­
medullary nail fixation can be used in the absence of interfragmentary
Bone fracture refers to the abrupt disruption of the continuity of bone compression [105,115].
tissue, caused by injury, trauma, stress, and bone diseases (i.e., osteo­ Based on the mechanism of bone fracture healing and relevant
porosis) [104,105]. The basic goal of fracture treatment is the restora­ clinical considerations, the required bioactivity and biofunctionality of
tion of the disrupted osseous anatomy and sufficient stabilization of the internal fixation can be summarized as follows: 1) Osteoinduction:
fractured bone [106]. Compared with non-operative treatment, the Osteoblastic differentiation and mineralization are promoted, and bone
implementation of standardized fracture fixation techniques with bone fracture healing is accelerated. 2) Osseointegration: Bone screws/nails
plates can achieve the benefits of skeletal stabilization in complex and should avoid fibrous encapsulation, as this would lead to loosening and
no-fusion fractures. This approach was proposed by the Swiss adverse effects on stability [116,117]. 3) Angiogenesis: materials should
“Arbeitsgemeinschaft für Osteosynthesefragen” group [107]. The utili­ allow and promote angiogenesis, facilitating blood supply to the fracture
zation of an appropriate biomaterial plays a critical role in the internal area. 4) Antibacterial properties: materials should prevent infection at
fixation of bone fracture. However, conventional bone plate/screws, implantation sites, especially at the initial healing stage. 5)
fabricated from non-absorbable metallic materials (i.e., stainless steel or Anti-osteoporotic properties are important for the treatment of osteo­
titanium-based alloy), still have limitations including implant fractur­ porotic bone fractures.
e/loosening, stress shielding, and the need for their removal by sec­
ondary surgeries [4,108]. Therefore, the development of novel internal 3.2. Bioactivity of Zn-based biodegradable metals for internal fixation
fixation is crucial.
In 2011, Vojtěch et al. [118] published the first study reporting on
3.1. Bone fracture healing: biological mechanism and required bioactivity the feasibility of bioabsorbable bone fixation by using Zn-based alloys.
They found that the in vitro degradation rates of Zn–Mg alloys ranged in
Bone fracture healing involves a series of complex physiological the order of tens of microns per year, and suggested that Zn doses and
processes, triggering interactions between various cellular and biome­ toxicity may be tolerated. In 2013, a landmark study by Bowen et al.
chanical factors. The whole process of bone fracture healing can be [119] demonstrated that pure Zn exhibits ideal physiological corrosion
divided into four stages: hematoma formation and inflammation, behavior in the abdominal aorta of Sprague-Dawley rats. Also, Li et al.
fibrocartilaginous callus formation, bony callus formation, and bone [120] reported good biocompatibility of Zn-1X binary alloys with
remodeling [81,109,110]. First, hematoma formation around the frac­ nutrient alloying elements in the bony environment, identifying
ture site is induced immediately following the fracture by blood vessels Zn-based alloys as promising materials for bone applications. In the
that supply the bone and periosteum. The secretion of pro-inflammatory following years, research focused on Zn-based BMs for internal fixation,
cytokines and interleukins initiates cascades of cellular events and at­ mainly including the development of novel Zn-based alloys with high
tracts monocytes, macrophages, and lymphocytes [111]. Subsequently, mechanical properties, the exploration of in vivo biocompatibility and
mesenchymal stem cells are recruited to the fracture site where they are bioactivity of Zn-based alloys, and the investigation of biodegradation in
further differentiated into fibroblasts, chondroblasts, and osteoblasts, the bony physiological environment. As summarized in Table 1,
leading to hematoma tissue replacement by cartilage callus [112]. Zn-based internal fixation applications (i.e., plates, screws, and nails)
During the stage of bony callus formation, cartilaginous callus begins to have been extensively studied in different animal models, such as the
show endochondral ossification. Also, intramembranous ossification medullary cavity model, the bone fracture model, and the
occurs, leading to the formation of a hard callus in the subperiosteal area infection-prevention model. Herein, the recent research status of
[112,113]. Specifically, osteoblasts and osteoclasts are differentiated, Zn-based internal fixations is further summarized and analyzed in terms
leading to the resorption of cartilaginous callus and the formation of of required bioactivity and biofunctionality.
new bone tissue [113]. Finally, with the balance of resorption by oste­ Zn-based internal fixation has been demonstrated to promote new
oclasts and new bone formation by osteoblasts, the hard callus un­ bone formation, which has been reported by most in vivo studies [22,
dergoes repeated remodeling, called coupled remodeling. The hard 120,122–124,127,132,134,135,145]. Compared to conventional mate­
callus is ultimately replaced by compact bone and lamellar bone, and rials (i.e., poly-l-lactic acid and Ti-based alloy), Zn-based BMs exhibit
substantial remodeling of the vasculature occurs over a period of several better osteoinduction [127,132]. Specifically, Wang et al. [127] exam­
months [109]. ined a Zn alloy osteosynthesis implant for the mandibular bone fracture
In general, the treatment principle of healing bone fractures is model. The histomorphometric results showed that in the Zn alloy
reduction and fixation, followed by rehabilitation treatment [114]. The group, new bone formation was clearly higher than in the poly-l-lactic
specific management depends on the cause, type, and location of bone acid group. In addition, a Zn-0.4Li fixation plate and screw were placed
fractures. Operative fracture fixation is an essential treatment option for in a rabbit femoral shaft fracture model. After implantation for 6
complex bone fractures, such as comminuted fracture, intra-articular months, more new cortical bone had formed at the fracture site in the

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 Table 1

P. Li et al.
Representative in vivo studies on Zn-based biodegradable metals for internal fixations.
(1) Osteoinduction
Zn-based BMs (wt%) Working Designed Animal Implant site Control Duration Degardation rate Main key findings Ref.
history implant model

Zn–1Mg, Rolled Nail C57BL/6 Medullary cavity of Sham control 8w 0.17 mm/year The new bone thickness of the Zn–1Mg, Zn–1Ca, and Zn–1Sr pin [120]
Zn–1Ca, mice femoral shaft 0.19 mm/year groups is significantly higher than that of the sham control group.
Zn–1Sr 0.22 mm/year

Zn-0.05 Mg Extruded Pin Rabbit Femoral shaft Pure Zn 24 w N. A. The Zn and Zn-0.05 Mg alloy can promote the formation of new [121]
bone tissue at the interface between the implant material and the
bone tissue.
Zn-5HA Spark plasma Pin Sprague- Femur condyle Pure Zn 8w Volume loss: 3.2 The osteogenesis performance of the Zn-5HA composite was [122]
sintering Dawley rat % better than that of pure Zn, and the former did not lead to obvious
inflammatory reactions.
Zn–5Mg composite Spark plasma Pin Sprague Femoral condyle Pure Zn 8w Volume loss: 2.4 The Zn–5Mg composite exhibited higher osteogenesis and [123]
sintering Dawley rat % osseointegration abilities than pure Zn.
Zn Extruded Pin Sprague- Femur condyle N. A. 4w N. A. New bone formation was observed around the Zn implant, [124]
Dawley rat whereas some fibrotic and collagenous tissues could be found
between the implants and newly formed bone.
Zn N. A. Pin Sprague- Femur condyle N. A. 4w N. A. Some connective tissues can be formed at the bone [125]
Dawley rat tissue–implant interface. Moreover, the degradation products
were not uniformly distributed on the Zn surface.
Zn–2Mg Extruded Hemispherical Wistar rats Rat’s cranium Mg–4Y–3RE 12 w 0.10 mm/year Zn–2Mg had no adverse effects on the behavior or physical [126]
implant alloy condition of rats and did not cause inflammatory reactions. The
corrosion of Zn–2Mg was relatively slow and uniform.
Zn-(0.001 % < Mg < Extruded Plate and screw Beagles Mandibular fracture Poly-l-lactic 24 w 0.095 ± 0.009 The Zn alloy possesses good mechanical properties that support [127]
2.5 %, 0.01 % < Fe < acid and Ti alloy mm/year fracture healing.
2.5 %) The new bone formation around the Zn alloy was significantly
higher than that detected in the poly-l-lactic acid group.
7

Zn-0.4Cu Extruded Pin Rat Femur shaft Pure Zn 8w Ranged from 0.13 New bone tissue formed around all the Zn-based implants. Larger [22]
Zn-2.0 A g to 0.26 mm/year amounts of new bone tissue continuously formed were observed
Zn-0.4Li around the implants in the Zn-0.4Li, Zn-0.1Mn, Zn-0.8 Mg, Zn-
Zn-0.4Fe 0.8Ca, and Zn-0.1Sr alloys. Adding the Mg, Ca, Sr, and Li
Zn-0.1Sr elements to Zn could improve its osteogenic abilities and
Zn-0.8 Mg osseointegration.
Zn-0.8Ca
Zn-0.1Mn

Zn–2Cu Extruded Nail Sprague- Femur infection- Blank, 6w N. A. The Zn–2Cu alloy showed an effective antibacterial ability and [128]
Dawley rat prevention model Ti inhibited the inflammatory and toxic side effects induced by
MRSA bacteria in the rat femur.
Zn–Li ZrO2 -nanofilm Pin Sprague- Femur condyle Zn–Li alloy 12 w N. A. Thicker and denser new bone formation was found in the [129]
coated Dawley rat (without surroundings of the coated Zn-based implants. The ZrO2
(Extruded) coating) nanofilm-coated Zn effectively promotes osseointegration and
controls its biodegradation behavior.
Zn–2Ag Extruded Pin Sprague- Osteomyelitis Blank, 6w N. A. The Zn–2Ag alloy group showed significant antibacterial activity [130]
Dawley rat prevention model in Ti against MRSA.

Materials Today Bio 25 (2024) 100932

rat femur
Extract C57BL/6 Ti particle-induced Blank, 2w N. A. The Zn–2Ag alloy extract effectively inhibited osteoclast bone
mice cranial osteolysis Pure Zn resorption, showing outstanding anti-osteolytic properties.
model
Screw New Femoral condylar split Ti-based alloy 24 w N. A. The Zn–2Ag-based screws showed reliable performance in bone
Zealand fractures (Ti–6Al–4V) fracture fixation in a femoral condyle fracture rabbit model.
rabbits
Pure Zn N. A. Screw New Anterior cruciate Mg screw 12 w Volume loss: 2.0 The screw-released Zn element effectively attenuated bone [131]
Zealand ligament (ACL) Ti screw % tunnel enlargement after anterior cruciate ligament
rabbits reconstruction reconstruction in rabbits.
(continued on next page)
 Table 1 (continued )

P. Li et al.
Zn-based BMs (wt%) Working Designed Animal Implant site Control Duration Degardation rate Main key findings Ref.
history implant model

Zn-0.4Li Extruded Rod Sprague- Femurs shaft Pure Zn 8w 0.15 mm/year The volume of new bone formed around the Zn-0.4Li alloy [132]
Dawley rat implant was significantly higher than that formed around the
pure Zn implant.
Plates/screw New Shaft fracture model Ti-based alloy 24 w N. A. The Zn-0.4Li-based plates/screws exhibited a bone fracture
Zealand (Ti–6Al–4V) fixation performance comparable to that of their Ti–6Al-4 V
rabbits counterparts.
Zn-0.8Li-0.1Sr Extruded Intramedullary Sprague- Osteoporotic femur Pure Zn 24 w N. A. The Zn-0.4Li alloy implants showed significantly higher [133]
nail Dawley rat bone fracture osteogenic effects and higher performance for the treatment of
osteoporotic bone fracture than the pure Ti implants.
Zn-0.05 Mg-(0, 0.5, 1 N. A. Rod New Bilateral distal femur Pure Zn 24 w N. A. The Zn–Mg–Ag alloy showed no toxicity to visceral organs and [134]
wt%)Ag Zealand promoted new bone formation around the implant.
rabbits
Zn–0.8Mg–0.2Sr Extruded Screw New Tibia bone N. A. 120 days 13.5 μm/year The material did not induce any inflammatory reaction or [135]
Zealand systemic toxicity. Periosteal apposition and the formation of new
rabbits bone with a regular structure were frequently observed near the
implant surface.
Zn–0.8Mg–0.2Sr Extruded Screws New Tibia bone N. A. 360 days N. A. The alloy showed good biocompatibility and resulted in a low [136]
Zealand inflammatory response. The released degradation products were
rabbits fully incorporated into the new tissue.
Zn-0.5Mn Extruded Rod Sprague- Tibia bone Stainless steel 120 days N. A. The Zn-0.5Mn implant can promote the restoration of the [137]
Dawley rat (SUS304) medullary damage and causes no inflammation or damage to the
liver and kidneys.
Zn-0.5Mn Extruded Rod Sprague- The proximal end of Stainless steel 12 days N. A. The unimodal ultrafine-grained Zn-based implants could induce [138]
Dawley rat the tibia (SUS304) bone formation and revascularization in the early period.
Moreover, the implant does not cause inflammatory responses or
damage to the liver and kidneys in vivo.
Zn-0.8Li-0.5Ag Extruded Intramedullary Sprague- MRSA-induced Blank, 6w N. A. The Zn-0.8Li-0.5Ag alloy implants showed good antibacterial [139]
8

nail Dawley rat osteomyelitis model Ti and osteogenic properties. Furthermore, the alloy is biologically
safe for in vivo use.
Zn-(0.001 % < Mg < Extruded Plate and screw Beagles Mandibular fracture N. A. 12 m 0.183 mm/year Zn-based implants had good in vivo biocompatibility. The zinc [140]
2.5 %, 0.01 % < Fe < at 3 months, content of the bone significantly increased in the 3–6-month post-
2.5 %) 0.065 mm/year implantation period. A trend of replacement of degradation
at 12 months products by bone was observed.
Zn-0.7Sr Extruded Pin Sprague- Femoral tissue Pure Zn 12 w 0.028 mm/y The Zn-0.7Sr implant promoted the new bone formation and [141]
Zn–4Sr Dawley rat 0.035 mm/y increased osseointegration ability compared to that of the other
0.020 mm/y two implants.
Zn N. A. Pin Sprague- Staphylococcus aureus Ti 8w N. A. Zn is favorable for the formation of neutrophil extracellular traps [142]
Dawley rat (S. aureus)-infected rat by regulating the release of DNA fibers and granule proteins in a
model reactive oxygen species-dependent manner, thereby promoting
osseointegration in S. aureus-infected rat femurs.
Zn-0.5 V, Extruded Pin Sprague- Femoral tissue Zn 12 w Ranged from 0.03 Zn alloys induced significantly higher bone-implant contact [143]
Zn-0.5Cr, Dawley rat to 0.05 mm/year ratios, indicative of a higher osseointegration ability.
Zn-0.5Zr

Zn–La, Extruded Pin New Tibia bone Zn 12 w N. A. Three alloys, Zn–La, Zn–Ce and Zn–Nd, exhibit superior in vivo [144]

Materials Today Bio 25 (2024) 100932

Zn–Ce, Zealand biocompatibility and the improved osseointegration in the
Zn–Nd rabbits animal tibia model compared to that of the pure Zn.

N. A.: not available, MRSA: methicillin-resistant Staphylococcus aureus.

P. Li et al. Materials Today Bio 25 (2024) 100932

Fig. 4. Possible molecular mechanisms of Zn-based internal fixation materials. A) Zn ions released from pure Zn screws induce Svct2 expression in primary
osteoblasts via the NF-κB pathway (reproduced with permission from Ref. [131]). B) Zn-0.4Li based alloy induces the PI3K-AKT signaling pathway during bone repair
(reproduced with permission from Ref. [132]). C) Suggested underlying anti-microbial mechanism of Zn–2Cu alloys against methicillin-resistant Staphylococcus
aureus (MRSA; reproduced with permission from Ref. [128]). D) Possible bactericidal mechanism of Zn–2Ag alloys (reproduced with permission from Ref. [130]). E)
Proposed underlying mechanism for the antimicrobial properties of Zn-0.8Li-0.5 A g alloys against MRSA (reproduced with permission from Ref. [139].) F)
Mechanism of gene-induction by Zn2+, Li+, and Sr2+ ions in osteoblasts, which further influences bone remodeling (reproduced with permission from Ref. [133]).

Zn-0.4Li alloy group, compared with the Ti-based alloy group [132]. vitamin C transporter 2 (Svct2) in primary osteoblasts via the NF-κB
These better osteopromotive properties of Zn-based BMs are partly the pathway; this induced the expressions of RUNX2 and osterix, which
result of the osteoinductive effects of Zn ions released from implants promote osteogenic differentiation, as illustrated in Fig. 4A [131]. Yang
during their degradation [127,132]. Notably, as shown in Table 1, et al. [132] explored the potential mechanism of Zn–Li alloy implants by
previous in vivo studies showed that Zn-based alloys or composites have bioinformatics analysis. As shown in Fig. 4B, the degradation products
better osteoinductive properties than pure Zn. Yang et al. [22] implan­ released from the Zn-0.4Li alloy could induce new bone formation
ted different Zn-based pins in rat femurs. Their histological analysis through the activation of the PI3K-AKT pathway and stimulation of
showed that addition of the elements Mg, Ca, Sr, and Li to pure Zn can metallothionein proteins (MT1 and MT2).
improve the new bone area, probably because of the release of alloy
elements. Regarding the potential mechanism of Zn-based implants, (2) Osseointegration
screw-released pure Zn ions upregulated the expression of sodium

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P. Li et al. Materials Today Bio 25 (2024) 100932

To improve osseointegration of bone screws, direct bone bonding to ions released from Zn–Cu alloys exhibit effective antibacterial activity
implants can facilitate the stabilization of the osteosynthesis system for towards Staphylococcus aureus (S. aureus) [151,152]. Notably, more than
fractured bone healing [146]. An important finding of previous in vivo half of all orthopedic implant-related infections are caused by S. aureus,
studies is that pure Zn implanted in the bony environment leads to the especially by methicillin-resistant S. aureus (MRSA) [153,154]. To
formation of fibrous connective tissue between implants and newly mimic implant-related infections, an MRSA-induce osteomyelitis model
formed bones, probably adversely affecting the stabilization of implants was established to evaluate the anti-bacterial ability of Zn–2Cu alloys
[22,123–125,129]. This phenomenon can contribute to the fact that a [128], Zn-0.8Li-0.5 A g alloys [139], and Zn–2Ag alloys [130]. Zn-based
rapid release of Zn ions leads to local mass accumulation around the alloys could effectively control MRSA-induced femoral osteomyelitis in
implant. Such an excessive release of Zn ions may interfere with the vivo. Nevertheless, the underlying antibacterial mechanisms of Zn-based
formation and remodeling of new bone [123–125,129]. Thus, to alloys are based on various molecular mechanisms. Firstly, Zn–2Cu al­
improve the osseointegration of pure Zn, Zn ion release and accumula­ loys can significantly downregulate the expression of genes related to
tion can be controlled via different approaches, such as alloying/com­ cell wall synthesis (MurC, MurE, and saeR), bacterial adhesion (clfA, and
posite treatments and surface modifications. Yang et al. [22] suggested atlE), and biofilm formation (icaA, icaB, icaC, icaD, icaR, SigB, and Spa),
that Zn-based alloys (e.g., Zn-0.8 Mg, Zn-0.8Ca, Zn-0.4Li, and Zn-0.1Sr autolysis (SarA, lytM, lytR, ArlR, and ArlS), MRSA antibiotic resistance
alloys) should have a higher bone-implant contact ratio than pure Zn. (PBP2a, MecA, FemA, FemB, and FemX), and bacterial virulence (empbp
The optimal bone-implant contact ratio is determined by the uniform and ssaA), as shown in Fig. 4C [128]. The bactericidal mechanism of the
corrosion mode with appropriate degradation rates of Zn-based alloys. Zn–2Ag alloy involves the expression of MRSA genes associated with
Similar to these results, compared to pure Zn, osseointegration can be autolysis (atlE, ArlS, lytM, lytR, and atlE), biofilm formation (icaA, icaB,
enhanced with Zn–Mg composites, which can be explained by the syn­ icaC, icaD, Luxs, and fbe), and drug resistance (FemA, FemB, and FemX),
ergic biological effect of the co-release of Zn ions and Mg ions through as shown in Fig. 4D [130]. Thirdly, Zn-0.8Li-0.5 A g alloys kill MRSA
preferential corrosion of a sacrificial Mg-rich phase. In addition, rare mainly by disturbing its cellular metabolism (by inhibiting localization,
earth elements (RE) such as lanthanum (La), cerium (Ce), and neo­ transport, and transporter activity) and inducing the production of
dymium (Nd) can serve as alloying elements for the biodegradable bi­ reactive oxygen species; this alloy could also inhibit biofilm formation
nary Zn alloys. A recent in vivo study has shown that implantation of and virulence of MRSA and alleviate drug resistance (Fig. 4E) [139].
Zn–La, Zn–Ce, and Zn–Nd alloys resulted in significantly improved
osseointegration compared to pure Zn. This observation can be attrib­ (5) Anti-osteoporotic effects
uted to the slower degradation process of the Zn-RE alloys, leading to
enhanced mechanical integrity for longer periods of implantation [144]. With the aging of the global population, osteoporotic bone fractures
In another strategy, proposed by Yuan et al. [123,129], Zn-0.1Li alloys have become a significant challenge for orthopedic surgeons [112].
were modified as a barrier layer of the ZrO2 nanofilm by the atomic layer While several internal fixation materials with anti-osteoporotic effects
deposition technique. The ZrO2 nanofilm-coated Zn-0.1Li alloy have been proposed and developed [155,156], further research on
demonstrated better in vivo osseointegration, which can be attributed to Zn-based internal fixation with anti-osteoporotic properties is still
the decreased Zn ion release, enabling the beneficial effect of efficient Zn required. Zhang et al. [133] fabricated and investigated a novel
ion doses on new bone formation. In summary, pure Zn implants showed Zn-0.8Li-0.1Sr (Zn–Li–Sr) alloy with high mechanical strength to treat
delayed osseointegration in vivo, which can be optimized in Zn com­ osteoporotic bone fractures. Zn–Li–Sr intramedullary nails were placed
posites to prevent rapid Zn ion release. in the femur bone of ovariectomized rats and their
osteoporotic-bone-fracture treatment effects were evaluated and
(3) Angiogenesis compared to Ti-based nails. The results demonstrated that the Zn–Li–Sr
implant possesses superior osteogenesis-inducing and
Adequate blood supply to the fracture area is critical for bone healing osteoporotic-bone-fracture treatment effects, compared to pure Ti im­
[105,114]. Internal fixation materials that promote local angiogenesis plants. As shown in Fig. 4F, the osteoporotic-bone-fracture treatment
facilitate the blood supply of the fracture area. To date, Zn-based BMs mechanism of the Zn–Li–Sr implant is related to the synergic effects of
have been suggested to promote angiogenesis and induce revasculari­ Zn2+, Li+, and Sr2+ ion release, stimulating the expression of four
zation [84,138,147,148]. Firstly, the release of Zn ions from pure Zn and osteogenic genes (ALP, COL-1, osteocalcin, and RUNX2) [133]. Specif­
Zn–Mg alloys has been shown to promote the proliferative and angio­ ically, Zn2+ ions can stimulate bone formation by the Wnt/β-catenin
genic properties of endothelial cells, resulting in an up-regulation of the pathway [157] and inhibit bone resorption by the NF-κB pathway [158].
expression of angiogenesis-related genes (i.e., HIF-1, VWF, VEGF, and Li+ ions can promote the proliferation of osteoblasts via the Wnt/β-ca­
CD31). However, the angiogenesis process is not influenced by Mg ions tenin pathway [158]. Sr2+ ions can stimulate bone formation by upre­
released from Zn–Mg alloys [147]. Qian et al. [148] developed an gulating the expression of osteoprotegerin and by inhibiting bone
organic-inorganic collagen entrapped Ca/Zn phosphate coating to con­ resorption by the NF-κB pathway [159,160].
trol the Zn ion release of Zn substrates within a suitable concentration
range. This hybrid coating was shown to enhance angiogenic properties 4. Zn-based bone tissue engineering scaffold for critical-sized
in terms of viability, migration, and tube formation of endothelial cells. bone defects
A short-term biocompatibility in vivo study demonstrated that unimodal
ultrafine-grained Zn-0.5Mn alloy can induce revascularization in the Large critical-sized bone defects (typically >2 cm, depending on the
early period of post-implantation, indicating its angiogenic potential anatomical site) caused by traumatic injury, congenital defects, degen­
[138]. Nevertheless, the effect of the angiogenic properties of Zn-based erative diseases, or surgical removal of tumors remain one of the pri­
internal fixation on the fractured bone site remains obscure, and the mary challenges [161]. Undoubtedly, bone autografting is the gold
underlying mechanism needs to be further examined. standard for the treatment of critical-sized bone defects, but its main
drawbacks are limited supply, requirement for additional operation, and
(4) Antibacterial properties donor site morbidity [162]. To overcome these limitations, tissue en­
gineering has been first proposed by Professor Robert Langer through
Antibacterial properties of internal fixation materials can prevent three-dimensional porous scaffolds [163,164]. After 30 years of devel­
post-operative infections. Theoretically, certain metal ions (such as Zn, opment, bone tissue engineering (BTE) strategies have been extensively
Cu, and Ag) are regarded as antibacterial agents [149,150]. Previous in investigated and are being used in clinical treatment [165,166]. Current
vitro studies demonstrated that the synergistic effects of Zn ions and Cu scaffold materials are made of ceramics, polymers, and bioinert metals.

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P. Li et al. Materials Today Bio 25 (2024) 100932

The main shortcoming of ceramic-based scaffolds is their brittleness, the BTE scaffold before implantation [177]. Osteoinductivity is the
while polymer-based scaffolds have relatively unfavorable mechanical presence of growth factors (signaling molecules) that attract
properties [167]. Additionally, bioinert metallic biomaterials (i.e., Ti bone-forming stem cells and encourage their differentiation into osteo­
and its alloys) have also been used for BTE scaffolds. However, bioinert blasts [178]. Regulatory signals, such as biological, biochemical, and
BTE scaffolds may cause long-term endothelial dysfunction, permanent biophysical factors within the ECM, can directly influence cellular ac­
physical irritation, and chronic inflammatory local reactions [168]. tivities and the fates of cells surrounding the ECM, eventually promoting
Therefore, a novel bioactive material for BTE scaffolds needs to be bone regeneration [179]. Osteogenicity is determined by the presence of
developed. viable osteogenic cells that can promote bone formation [169,180]. The
strategy of cell-based BTE combines living osteogenic cells with BTE
scaffolds ex vivo to enable the development of a cell-seeded scaffold, that
4.1. Bone tissue engineering: biological mechanism and required can be transferred to the bone defect site to stimulate new bone for­
bioactivity mation [181,182].
BTE strategies are considered by disease-related and patient-related
In principle, the goal of bone tissue engineering is to produce arti­ factors. First, high vascular density in certain bone regions (i.e., meta­
ficial bone constructs and micro-environments that mimic both the physis) makes them prone to osteomyelitis infection, thereby potentially
structural characteristics and physiological behavior of autogenous bone requiring antibacterial properties [183]. Additionally, bone defects can
to facilitate the regeneration and re-growth of bone tissue [169,170]. be caused by the surgical removal of tumors, such as osteosarcoma. A
Bone tissue consists of characteristic cell types, an extracellular matrix new multifunctional scaffold with anti-tumor effects has been proposed
(ECM), and biologically active molecules that are produced by cells and and developed [184,185]. BTE treatments for use in pediatric patients
integrated into the ECM [171,172]. The extracellular bone matrix is a must consider biodegradation properties or dynamic structural proper­
natural nanocomposite of inorganic Ca phosphate minerals and organic ties that facilitate their tissue remodeling to aid the ongoing growth of
collagenous components (mainly type I collagen), and noncollagenous the skeleton [186,187]. Conversely, regarding elderly individuals, the
matrix components [173,174]. Inspired by the hierarchical structure of effects of natural aging on the bone microstructure should be integrated,
bone and its natural formation processes, tissue engineering strategies such as anti-osteoporotic effects [188,189].
should meet three principles: make scaffolds osteoconductive, achieve Considering the BTE mechanism and its clinical considerations, the
osteoinduction through growth factors, and equip cells with osteogenic required bioactivity and biofunctionality of BTE scaffolds can be sum­
capability [175,176] (Fig. 5). marized as follows: 1) Osteoconduction is defined as the ability of a
The three-tiered approach, i.e., osteoconductivity, osteoinductivity, scaffold to support tissue ingrowth, osteoprogenitor cell growth, and
and osteogenicity, are proposed and introduced to the BTE treatment. further development for bone formation [190,191]. 2) Osteoinduction is
Specifically, osteoconductivity is defined as the ability to serve as a defined as the induction of osteoblastic differentiation and mineraliza­
scaffold for new bone formation and vascular ingrowth [43]. The BTE tion, which promotes new bone formation [192]. 3) Materials should
scaffold typically serves as a mimicking ECM, as it provides mechanical promote angiogenesis, thus ensuring sufficient blood supply [193]. 4)
support and a suitable environment for the attachment, proliferation, Scaffolds should have antibacterial properties and should prevent
and differentiation of cells. Bone-related cells can be either recruited infection during tissue healing [194,195]. 5) For anti-osteoporotic
from surrounding native bone tissue after implantation or seeded onto

Fig. 5. Bone physiology and the principle of bone tissue engineering. Scheme for integrating biomaterials development, bone biology, and computational
modeling towards bone tissue engineering (reproduced with permission from Ref. [176]).

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P. Li et al. Materials Today Bio 25 (2024) 100932

Table 2
Representative in vivo studies on the use of Zn-based BMs as BTE scaffolds.
(1) Osteoconduction
Zn-based BMs Working history Pore size Porosity Animal Implant site Control Duration Main key findings Ref.
(wt%) (mm) (%) modes

Zn-0.8Mn Extrusion and 0.5 30.85 Rat Femoral Pure Ti 12 w The formation of abundant new bone tissue [44]
laser condyle was observed around the Zn-0.8Mn alloy
cauterization defect repair scaffold, indicating its superior osteogenic
model properties.
CaP coated Hot press 0.2–0.35 65–75 Rabbit Cranial bone Pure Ti 6m New bone formation in the coated Zn group [206]
Zn–3Cu–1Mg sintering defect model Pure Zn was significantly higher than that in other
alloy Zn groups, indicating that the Ca–P coating
alloy could effectively promote
osseointegration.
Zn-0.8Li-0.1Ca Extrusion and 0.5 23.27 New Radial bone Pure Ti 24 w The new bone tissue integration and [207]
laser Zealand defect model growth were significantly better on the
cauterization rabbits Zn0⋅8Li0⋅1Ca alloy scaffold than on pure
Ti.
Zn-0.8Sr Extrusion and 0.5 30.83 Rat Femoral Pure Ti 12 w The in vivo test confirmed the biosafety and [208]
laser condyle considerable osteogenic properties of the
cauterization defect repair Zn-0.8Sr alloy scaffold, which significantly
model promoted bone defect repair.
Zn Additive 0.6 67 % New Femurs Pure Zn 12 w The newly formed bone was in better [209]
Zn–1Mg manufacturing (L- Zealand contact with the Zn–1Mg scaffold than
PBF) rabbit with pure Zn, demonstrating its better
biocompatibility and osteogenic effects.
Zn–2Ag–0.04 Air pressure 0.5–0.6 80 New Trochlea of Pure Zn 6m The newly formed bone grew in the pores [210,
Mg infiltration Zealand femur bone Zn–2Ag and was in direct contact with the surface 211]
method rabbit defect of the Zn–2Ag-0.04 Mg scaffold, indicating
good biocompatibility and bone
regeneration ability.
Zn–2Cu Air pressure 0.275 68.7 Sprague- Femur bone Pure Zn 6m Pure zinc and Zn–2Cu porous scaffolds [212]
infiltration Dawley defect showed excellent biocompatibility and
method rat normal inflammatory responses.
Pure Zn Additive 0.6 N. A. New Femur N. A. 24 w The pure Zn porous scaffold showed good [213]
manufacturing (L- Zealand condyle biocompatibility and osteogenic promotion
PBF) rabbit critical size ability in vivo.
bone defec

L-PBF: laser powder bed fusion, N. A.: not available.

effects, agents should be used that are capable to promote bone regen­ products of Zn–1Mg scaffolds were composed of Zn, O, C, Ca, and P, plus
eration in osteoporotic skeletal defect sites [189,196]. 6) For anti-tumor the addition of Mg. The better osteoconductive capacity of Zn–1Mg
effects, scaffolds should kill or inhibit residual tumor cells to achieve scaffolds may be attributed to the released Mg ions, which facilitate
bone tumor therapy [197,198]. bone regeneration [209]. As depicted in Fig. 6A, a recent study revealed
that additively manufactured Zn-based scaffolds were implanted in a
4.2. Bioactivity of Zn-based biodegradable metals for scaffolds bone defect, while being compared to Ti-based and Mg-based scaffolds.
In the case of Zn scaffolds, the anterior region was already enveloped by
Compared to bulk Zn-based BMs, porous Zn-based scaffolds have a porous, mineralized bone layer by week 5. Furthermore, by week 25,
been proposed and examined for bone tissue regeneration over the years the overall bone mass surrounding the Zn scaffold surpassed that sur­
[199]. Porous Zn scaffolds can be fabricated through various techniques, rounding the Mg scaffold (Fig. 6B). The in-vivo comparative study of
including air pressure infiltration [199,200], powder metallurgy with bioresorbable Mg and Zn scaffolds demonstrated that Mg scaffolds
spark plasma sintering [201,202], infiltration casting [203,204], resulted in delayed but complete defect healing with bone ingrowth,
hot-pressing sintering [204], and additive manufacturing [205]. Addi­ while Zn scaffolds promoted early healing and the formation of
tionally, novel Zn-based scaffolds have been developed and explored in high-quality newly-formed bone, notwithstanding limited calcification
vivo, as summarized in Table 2. The current status of Zn-based scaffolds of osteoid inside the scaffold, as illustrated in Fig. 6C [24].
is further summarized based on the required bioactivity and bio­
functionality for bone tissue regeneration. (2) Osteoinduction and angiogenesis
The osteoconduction capacity of the scaffold can promote the growth
of bone cells on its surface, which is an essential prerequisite for bone Compared with Ti-based scaffolds, Zn-based BTE scaffolds have been
tissue engineering. Zn-based alloy BTE scaffolds have good osteo­ identified as excellent osteoinductive materials for new bone formation
conductive capacity (osseointegration), as reported by most in vivo [44,206–208]. Jia et al. [44] have shown that the implantation of a
studies [44,206–209,213]. Alloying can optimize this capacity. Specif­ Zn-0.8Mn alloy scaffold in a bone defect achieved increased new bone
ically, Xia et al. assessed the in vivo biocompatibility of a porous scaffold formation and thickness of trabecular bones, compared to Ti-based
consisting of pure Zn [213]. After week 4 of implantation, a fibrous scaffolds at the same time points after implantation. The superior oste­
tissue layer had emerged between the bone tissue and the Zn scaffold, ogenic properties of the Zn-0.8Mn alloy in vivo can be contributed to
indicating that the relatively high concentrations of degradation prod­ appropriate mechanical support and slow co-release of Zn and Mn ions
ucts exceeded the tolerance level of the body at this early stage. In a [44]. Additionally, Zhang et al. also examined Zn-0.8Li-0.1Ca alloy
study by Qin et al. [209] Zn–1Mg porous scaffolds were implanted in scaffolds for critical-sized bone defect regeneration at load-bearing sites.
rabbit femurs. After 12 weeks, the Zn–1Mg porous scaffolds were in Better integration and growth conditions of new bone tissue were
direct contact with the surrounding bone while pure Zn porous scaffolds observed around the Zn–Li–Ca scaffold, compared to pure Ti scaffold.
were still surrounded by fibrous connective tissue. The degradation This result can be explained by the physiological functions of Zn, Li, and

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P. Li et al. Materials Today Bio 25 (2024) 100932

Fig. 6. Osteoconductive and osteoinductive effects of Zn-based scaffolds. A) Scheme for Mg and Zn scaffolds implanted into the distal femur of New Zealand
white rabbits. B) Histological analysis of Mg scaffold, Zn scaffold, Ti scaffold, and sham control after 5 and 25 weeks of implantation, determined by Von Kossa/
Macneal’s staining and Masson-Goldner staining. C) The schematic diagram of the interaction between scaffolds and bone regeneration (reproduced with permission
from Ref. [24]).

Ca ions, which are favorable for bone formation and inhibit bone and Zn–Cu alloys have been shown to possess good antibacterial effects
resorption [207]. Jia et al. [208] examined the in vivo repair properties [153,154,215,216]. Similarly, porous Zn–Cu based scaffolds showed
of Zn–Sr alloy scaffolds and explored the underlying cellular mecha­ effective antibacterial properties against S. aureus and Escherichia coli,
nism. The Zn-0.8Sr alloy was confirmed to promote bone regeneration and the antibacterial effects was higher with higher Cu content [212].
and bone ingrowth. RNA-sequencing results associated with the osteo­ However, the in vivo antibacterial ability and the underlying mechanism
genic activity showed that the expression of genes involved in the pro­ in porous Zn-based scaffolds remain obscure.
cesses of bone mineralization, bone morphogenesis, ossification, and Anti-osteoporotic effects facilitate bone regeneration at osteoporotic
bone remodeling were significantly upregulated in the Zn–Sr alloy skeletal defect sites. As discussed in Section 3.2., Zn-based internal fix­
group. Because the expression of key proteins (Wnt3a, β-catenin, Akt, ation materials with anti-osteoporotic effects have been fabricated and
p-Akt, and Erk) of signaling pathways was significantly elevated in the their feasibility validated [133,157]. However, further study and un­
Zn-0.8Sr alloy group, induction of the downstream osteogenic proteins derstanding of the anti-osteoporotic effects of porous Zn-based scaffolds
(osteocalcin and RUNX2) promotes osteogenesis and angiogenesis are still lacking.
[208]. Apart from the released degradation products, a recent study In osteosarcoma patients post clinical resection, efforts have been
showed that additively manufactured Zn-0.8Li-0.1 Mg alloy scaffolds directed towards creating porous scaffolds with inherent anti-tumor
with varying porosities significantly influenced biocompatibility and properties aimed at eradicating recurrent tumors [217,218]. However,
osteogenic ability. These findings reveal the critical role of alloying as of now, only a limited number of in vitro studies have presented
design and porosity in shaping the biocompatibility and osteogenic findings on biodegradable Zn-based alloys with antitumor capabilities,
potential of Zn-based scaffolds [214]. illustrating their high toxicity towards osteosarcoma cells and low
toxicity towards human dental pulp stem cells [219]. As such, further
(3) Antibacterial properties, anti-osteoporotic effects, and anti-tumor research is warranted to substantiate the presence of anti-tumor effects
effects and elucidate the biological mechanisms underlying the use of Zn-based
alloys for porous scaffolds.
Antibacterial properties of BTE scaffolds can avoid post-operative
infection during tissue healing. Bulk Zn-based metals, Zn–Ag, Zn–Mg,

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P. Li et al. Materials Today Bio 25 (2024) 100932

Fig. 7. Schematic overview of the GBR treatment. A) The supposed position of a GBR membrane as physical barrier. B) The GBR membrane promotes the structural
reconstitution of the defect with newly formed bone tissue compared with the untreated sham defect where soft tissue infiltrates the defect site. C) Supposed un­
derlying cellular and molecular mechanisms during GBR treatment (reproduced with permission from Ref. [222]).

5. Zn-based barrier membrane for alveolar bone defects However, instead of merely being a physical passive barrier, the GBR
barrier membrane (porcine collagen) promotes regenerative processes
To address alveolar bone defects, guided bone regeneration treat­ within the underlying defect by activating host cells, and allow them to
ment has been introduced. These techniques involve the application of communicate which each other to promote undisturbed new bone for­
barrier membranes to prevent the infiltration of non-osteogenic cells mation, as shown in Fig. 7B [222,225,226]. The schematic images
from surrounding soft tissues [220]. However, the currently available provide an overview of the position of the GBR membrane and the un­
GBR membranes cannot meet clinical requirements mainly because of derlying cellular and molecular mechanisms involved (Fig. 7A–C).
their low mechanical strength [221,222]; thus, novel barrier membrane Firstly, monocytes, macrophages, and osteoprogenitors can migrate
materials must be developed. from surrounding tissue into the membrane. Cells migrate into the
membrane to express and secrete factors for bone formation and bone
5.1. Guided bone regeneration: biological mechanism and required remodeling (i.e., BMP-2, TGF-β, VEGF, and FGF-2). Both cellular and
bioactivity molecular activities inside the GBR membrane can regulate the
pro-osteogenic (i.e., RANKL) and osteoclastic (i.e., cathepsin K and
The basic mechanism of GBR is to prevent undesirable cells from calcitonin receptor) molecular patterns at the defect site [222].
non-osteogenic tissues to interfere with bone regeneration [222,223]. Considering the GBR mechanism and associated clinical consider­
To achieve this, a physical barrier membrane is placed between the bone ations, the required bioactivity and biofunctionality of the barrier
defect and surrounding soft tissue (Fig. 7A). Compared to bone tissue, membrane is summarized as follows: 1) The barrier membrane should
soft tissue (such as fibroblasts and epithelial cells) grows relatively fast, feature occlusivity (occlusiveness and cell occlusion), where the mate­
occupies available space, and builds up soft connective tissue [224]. For rial should act as a barrier to exclude undesirable cell types from
GBR treatment, the barrier membrane creates a shielded space for bone entering the secluded space adjacent to the bone defect. 2) The top side
formation and natural healing in an undisturbed or protected manner. (soft tissue) of the barrier membrane should feature soft tissue

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P. Li et al. Materials Today Bio 25 (2024) 100932

integration to promote the rapid growth of epithelial cells on the ma­ GBR membrane application. To date, most previous studies on Zn-based
terial surface and facilitate primary wound closure. 3) The back side GBR membranes used in vitro tests, including alloy fabrication, and
(bone tissue) of the barrier membrane should feature osteoinduction, evaluations of mechanical properties, degradation behavior, cyto­
induce osteoblastic differentiation and mineralization, and accelerate compatibility, and antibacterial properties [228–232]. Only a few
new bone formation. 4) The materials of the barrier membrane should studies have been focused on the bioactivity of Zn-based GBR mem­
promote angiogenesis, thus facilitating blood supply of the bone brane. The research status of Zn-based barrier membranes is summa­
regeneration area. 5) The barrier membrane should feature antibacterial rized and illustrated in Table 3.
properties, and materials should prevent infection during the healing Occlusiveness, osteoinduction, soft tissue integration, angiogenesis,
stage. and antibacterial properties are optimal bioactive and biofunctional
effects of barrier membranes. Previous in vivo studies demonstrated that
a Zn membrane with 300 μm pores can promote bone formation and
5.2. Bioactivity of Zn-based biodegradable metals for use as barrier prevent soft tissue infiltration. This is comparable to Ti-based mem­
membrane branes, indicating prominent osteogenic capability and occlusivity [45].
In addition, considering clinical applications, the antibacterial effects of
Recently, Zn-based barrier membranes have gained increasing implants must be effective against infection-related microorganisms.
attention for GBR [35,227]. In 2020, Guo et al. [45] were the first to Regarding GBR treatment, postoperative oral infections involve multiple
examine the in vitro and in vivo performances of pure Zn for potential

Table 3
Summary of the mechanical properties, biodegradation, and biocompatibility of the reported Zn-based GBR membranes.
Mateirals Mechanical properties Biodegradation Biocompatibility and bioactive effects Ref.

Tensile Ultimate Elongation Methods (solution) Main findings Models (cell/ Main findings
yield tensile (%) animial)
strength strength
(MPa) (MPa)

Pure Zn As rolled 92.2 ± 108.0 ± 42.8 ± 2.7 Immersion test The DR of the Zn Extract test Undiluted extracts had [45]
membranes 8.8 4.9 (Hank’s solution) membrane with (MC3T3-E1) noticeable toxicity,
300 μm pores was whereas cell viability
0.046 ± 0.004 mm/ was improved when cells
year, whereas the were cultured in the
Zn membrane with diluted extracts.
1000 μm pores Rat calvarial The Zn membrane with
degraded quickly. bone defect 300 μm pores displayed
model favorable osteogenic
ability in vivo.
Pure Zn As N. A. N. A. N. A. Immersion test The DR of the pure Extract test The 50 % Zn extracts and [228]
extruded (artificial saliva) Zn reached 31.42 and direct test pre-treated Zn surface
μm/year after 28 (HGF) presented acceptable in
days of immersion. vitro HGF
cytocompatibility.
Electrochemical test DR was 3.96 μm/ Antibacterial Zn shows high
year on day 28. tests antibacterial activity
against Porphyromonas
gingivalis.
Zn As 67.1 127.3 27.2 Immersion test and The addition of Fe Extract test The extracts of the Zn- [233]
Zn-0.5Cu extruded 113.1 164.2 35.5 electrochemical test accelerated the (L929, Saos-2, 0.5Cu-0.2Fe alloy had no
Zn-0.5Cu- 115.7 176.0 43.9 (α-MEM medium degradation of the TAg) apparent cytotoxic
0.1Fe 152.3 202.3 41.2 and artificial saliva) Zn-0.5Cu-xFe effects.
Zn-0.5Cu- 182.1 240.1 20.5 alloys, which were Antibacterial The Zn-0.5Cu-0.2Fe
0.2Fe corroded relatively tests surfaces could inhibit the
Zn-0.5Cu- uniformly. initial adhesion of
0.4Fe Streptococcus gordonii
and oral mixed bacteria.
Zn-0.8Li As rolled 183.5 238.1 75.0 Immersion test and The DRs in Ringer’s Extract test Sample extracts had [234]
Zn-0.8Li-0.2 253.7 341.3 30.6 electrochemical test solution for 35 days (L929, BMSCs) good cytocompatibility,
Mg 196.2 254.7 97.9 (Ringer’s solution) were ranked as and the Zn–Li–Ag alloy
Zn-0.8Li-0.2 Zn–Li–Mg (0.17 was of Grade 0–1.
Ag mm/year) > Zn–Li
(0.12 mm/year) >
Zn–Li–Ag (0.11
mm/year).
Zn-0.5Fe As- NA 100.53 0.51 Electrochemical The DRs of the as- Extract test Diluted extracts (12.5 % [235]
membrane sintered 101.31 150.92 19.93 tests (Ringer’s sintered, as- (MC3T3-E1) and 25 %) showed no
As 110.20 168.8 16.25 solution) extruded, and as- apparent cytotoxic
extruded rolled Zn-0.5Fe effects.
Membrane alloys were 0.146
mm/year, 0.125
mm/year, and
0.115 mm/year,
respectively.
Zn–Ti–Cu–Ca–P Sintering Compressive strength: 214 MPa Electrochemical test The DR was 0.18 Extract test The alloy had no [232]
Micro-hardness: 79.34 HV (Hank’s solution mm/year. (Vero cells) cytotoxic effects.

N. A.: not available, DR: degradation rate, MC3T3-E1: mouse osteoblastic cell line, HGF: human gingival fibroblast, L929: mouse fibroblasts, Saos-2: human osteo­
sarcoma cells, TAg: human immortalized cranial periosteal cells, BMSCs; bone marrow mesenchymal stem cells: BMSCs.

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P. Li et al. Materials Today Bio 25 (2024) 100932

species of bacteria, such as Streptococci, anaerobic Gram-negative rods, CO2− 2−

3 , and HPO4 ), organic components (e.g., proteins, glucose, and
and anaerobic Gram-positive cocci [236,237]. Previous studies investi­ amino acids), and buffering agents. Zn degradation is associated with
gated the antibacterial properties of Zn-based membranes using Por­ oxygen consumption, and with less than 5 %; in the bony environment,
phyromonas gingivalis, Streptococcus gordonii, and a mix of oral bacteria physiological oxygen levels are relatively low. Undoubtedly, it would be
[228,229]. Compared to a Ti-based samples and pure Zn, the surfaces of a substantial advance to clarify how these physiological elements in­
Zn–Cu–Fe alloys show higher antibacterial effects towards S. gordonii fluence the degradation process of Zn-based implants. Additionally, the
and mixed oral bacteria, which is probably due to the increased release in vivo long-term degradation of Zn-based bone implants is also worth
of Zn ions and a shift towards alkaline pH levels [229]. Additionally, studying. Passivation layers can retard the degradation kinetics of Zn-
pure Zn exhibited high antibacterial activity against P. gingivalis, which based implants during the degradation process. To the best of our
can be attributed to the release of Zn ions [228]. The angiogenic ca­ knowledge, there are currently no reports showing that Zn-based bone-
pacity of the GBR barrier membrane can facilitate bone regeneration related implants can be fully degraded and absorbed during the limited
[238,239]. However, the effect of Zn-based barrier membranes on observation period.
angiogenesis remains unknown. Additionally, considering primary The problem that the resistance of Zn-based implants to internal
wound closure, a fast soft tissue integration by migration of gingival fixation in human-body-fluid-assisted fractures (e.g., stress corrosion
fibroblasts can prevent exposure and infection of the barrier membrane cracking) may adversely affect the mechanical integrity of implants
[240–242]. Nevertheless, it is still not clear how Zn-based surfaces in­ must be overcome. Further, the mechanical integrity of the BTE scaffold
fluence wound closure. is mainly determined by the corrosion fatigue of the porous Zn-based
scaffold during the long-term degradation. Another important issue is
6. Challenges and perspectives crevice-induced corrosion which can occur in Zn-based implants,
probably causing failure of their mechanical integrity [243]. Therefore,
Recent studies have investigated and demonstrated the bioactivity a deeper understanding of corrosion-induced mechanical integrity has to
and biofunctionality of Zn-based BMs for the repair and regeneration of be reached.
bone tissue. Nevertheless, the existing knowledge concerning Zn-based
BMs remains inadequate, leading to obstacles in the commercial avail­
ability of Zn-based implants. Previous studies have primarily concen­ 6.2. Host response: new insights into the biological mechanisms behind
trated on the biocompatibility, mechanical properties, biodegradation, Zn-based BMs
and bioactivity of Zn-based BMs for internal fixation, tissue scaffolding,
and barrier membranes. In consideration of bioactivity related to clinical According to the current in vivo animal tests, Zn-based BMs have not
aspects, significant challenges and future research endeavors in this field exhibited systemic toxic effects. However, it is crucial to further inves­
revolve around the intricate interplay between long-term biodegrada­ tigate the long-term biosafety of the resulting degradation products,
tion, host response, and material optimization”, as illustrated in Fig. 8. particularly pertaining to their absorption, distribution, metabolism,
and excretion, as well as the implications of Zn ion release from the
6.1. Long-term biodegradation: corrosion mechanism of Zn-based BMs in orthopedic implant during prolonged degradation. This detailed exam­
physiological environments ination is essential for a comprehensive understanding of the potential
long-term impacts on human health and safety arising from the break­
Considerable efforts have been directed to examine the corrosion down of these Zn-based implants.
mechanisms of Zn-based BMs in vivo; however, several important aspects Regarding the degradation products, previous studies focused on the
are not yet completely understood. After implantation, the main body effects of initial degradation products (i.e., Zn ions and hydroxide ions)
fluid is human interstitial fluid, which includes inorganic ions (e.g., Cl− , on biological functions. Theoretically, Zn-based bone implants degrade
gradually into different degradation products within the physiological
environment [244]. The intermediate products on the surface of
Zn-based implants, mainly zincite, Zn hydroxide, and Zn phosphate, can
also participate in physiological activities and functions. Released sol­
uble or insoluble degradation products can trigger the host innate
and/or adaptive immune responses [245].
Bone formation represents a complex, multifaceted process involving
the interplay of various factors and cellular interactions. It encompasses
the orchestrated involvement of signaling molecules, cellular differen­
tiation, extracellular matrix deposition, and the regulation of minerali­
zation. Importantly, research has demonstrated the critical influence of
the nervous system, particularly peripheral and central nerves, on bone
formation [246,247]. Understanding this neural involvement is essential
not only for comprehending the mechanisms behind divalent metal
cations (Mg2+, Zn2+, and Cu2+)-induced bone formation by sensory
nerves but also for recognizing the intricate and interconnected nature
of bone physiology [248]. In future research, exploring the intricate role
of the nervous system in bone formation induced by Zn-based implants
can provide valuable insights into the broader understanding of bone
remodeling and regeneration processes.
Based on the recent advancements in evidence-based biomaterials/
medicine research, standardized tests for the biosafety of Zn-based BMs
should be further established and verified [249]. These should include
Fig. 8. Schematic illustration of challenges and perspectives of Zn-based the optimization of biological evaluation, the selection of animal
biodegradable metals for bone repair and regeneration, showcasing the cyclic models, and the standardization of pre-clinical protocols. Overall, an
interrelation between long-term biodegradation, host response, and material in-depth and mechanistic understanding of the host response to
optimization. Zn-based implants has not been reached.

16
P. Li et al. Materials Today Bio 25 (2024) 100932

6.3. Material optimization: controllable Zn ion release synergistically Czech Science Foundation (project no. 23-05592 S), Open Foundation of
mediates bioactivity Shandong Key Laboratory of Oral Tissue Regeneration (No.
SDKQ202302), and Medical Scientific Research Foundation of Guang­
The bioactivity and biofunctionality of Zn-based implants with re­ dong Province (No. A2023108, A2023369)
gard to the process of osteogenesis, angiogenesis, immunomodulation,
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