Research Progress on Biocompatibility Evaluation of Biomedical Degradable Zinc Alloys

doi:10.11900/0412.1961.2022.00471

Acta Metall Sin

2023, Vol. 59

Issue (3): 319-334 DOI: 10.11900/0412.1961.2022.00471

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Research Progress on Biocompatibility Evaluation of Biomedical Degradable Zinc Alloys

WANG Luning¹^,²(

), YIN Yuxia¹, SHI Zhangzhi¹, HAN Qianqian³

1 School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing 100083, China
2 Beijing Advanced Innovation Center for Materials Genome Engineering, Beijing 100083, China
3 National Institutes for Food and Drug Control, Beijing 102629, China

Cite this article:

WANG Luning, YIN Yuxia, SHI Zhangzhi, HAN Qianqian. Research Progress on Biocompatibility Evaluation of Biomedical Degradable Zinc Alloys. Acta Metall Sin, 2023, 59(3): 319-334.

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Abstract

Zn and its alloys have recently been used as a new class of biodegradable biomedical metals besides magnesium and iron alloys, owing to their moderate corrosion rate and good mechanical properties. In recent years, researchers have rigorously studied the design, processing, and degradation mechanism of Zn alloys, but their biocompatibility has not been well explored. Past research on the biocompatibility of Zn alloys focused on in vitro cytotoxicity, hemolysis, and coagulation, and only a few materials were implanted into animals for characterizing the histocompatibility. Biocompatibility involves complex local and systemic reactions, such as cells, tissues, blood, and immunity. In addition to the physical and chemical properties of the material, the biocompatibility is also affected by interactions between the material and body. In this paper, the chemical and phase compositions of degradable zinc alloys were analyzed, and the biological evaluation methods were clarified. In view of the recent studies on zinc alloy biocompatibility, future research directions were proposed.

Key words: zinc alloy biocompatibility cytotoxicity blood compatibility

Received: 23 September 2022

ZTFLH:

TG146

Fund: National Natural Science Foundation of China(51871020);National Key Research and Development Program of China(2016YFC1102500)

About author: WANG Luning, professor, Tel: (010)62332184, E-mail: luning.wang@ustb.edu.cn

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https://www.ams.org.cn/EN/10.11900/0412.1961.2022.00471 OR https://www.ams.org.cn/EN/Y2023/V59/I3/319

Table 1 Properities of biodegradable metals^[11-15]

Table 2 Properties of the main degradation products of Zn alloys

Fig.1 Body response to material implantation and body-material interactions^[37,38]

Test item

Current standard

Purpose and method

Judgement criterion

Cellular response

Cell

toxicity

GB/

T16886.5—2017

The device/extract was cultured with cells, its potential cytotoxicity was evaluated by morphology and metabolic activity, such as MTT method

Cell viability > 70% was considered non-cytotoxic. For Zn-based materials, it is generally necessary to dilute the extract over a range of concentrations. Evaluate the result in vitro and in vivo comprehensively

Tissue response

Intradermal reaction

GB/T16886.10—2017

Intradermal injection of devices/materials extracts on the back skin of rabbits, to evaluate the non-specific percutaneous acute irritant effects of leachables

Erythema, edema, eschar, etc., were observed and scored according to the standard. The difference between the average scores of the test sample and the control should not be greater than 1.0

Implantation & degradation

GB/

T16886.6—2015

Final devices/materials are implanted by surgical or interventional operation, and the target tissues are collected and observed at different time points to evaluate the local toxic effect of the sample on the living tissue and the degradation process (product)

Different degrees of tissue reactions (aseptic inflammation, fibrous cysts around the implant, etc.) will appear after implantion. With the influence of degradation, the reaction is higher and longer relatively. It's best to set a similar marketed product control

Immune response

Delayed type hypersensitivity

GB/T16886.10—2017

The immunity is usually induced by injecting the extract of the device/material plus protein to guinea pigs, and stimulated again after 2 weeks. Then the skin reaction is observed to evaluate the potential contact sensitization of the sample

No local skin erythema, edema and other inflammatory manifestations was considered to be no delayed type hypersensitivity reaction. Allergic reactions do not limit its use necessarily

Systemic response

Acute systemic toxicity

GB/T16886.11—2011

Mouse is used routinely. Intravenous and intraperitoneal injection of the device/material extract is contacted with animals. The systemic response is observed to evaluate whether the sample releases toxic substances and produces acute systemic toxicity. The maximum exposure dose is 50 mL·kg^-1 body weight

Clinical performance (coat, skin, mucous membranes, respiration, muscles, behavior, etc.) should be observed and no indications. Gross pathological evaluation should be considered if clinically indicated

(Sub)chronic systemic toxicity

Rat is used routinely. The devices/materials or extracts are (repeatedly) contacted with animals by appropriate routes such as implantation, intravenous or intraperitoneal injection. The dose range is determined according to human safety limits. Clinical manifestations, body weight changes, hematological and clinical biochemical indicators, clinical pathological, gross pathological and histopathological analysis, etc., to evaluate whether the long-term exposure of sample to the human body will release toxic substances and produce (sub)chronic systemic toxicity

Compared with the control group, no significant difference should be observed in each index

Blood system

Hemolysis

GB/

T16886.4—2003

Direct contact of blood with the device/material or its extract, measuring the amount of hemoglobin released by erythrocytes to evaluate the degree of erythrocytelysis and hemoglobin release caused by the device/material

Hemolysis rate should be < 5%

Genetic system

Genotoxicity

GB/

T16886.3—2019

Mammalian or non-mammalian cells, bacteria, yeast or fungi are used to determine whether a device/material or extract causes genetic mutations, changes in chromosome structure and number, or other changes in DNA or genes. Bacterial gene mutation, chromosomal aberration and mouse lymphoma test are the most used in vitro tests

There should be no significant difference compared to the negative control. If the in vitro test cannot be carried out or the results are confusing, further in vivo chromosome analysis and micronucleus test of mammalian bone marrow cells should be used

Table 3 Necessary biological test items for Zn alloy implantable devices

Test item

Current standard

Purpose and method

Judgement criterion

Blood system

Coagulation

GB/

T16886.4—2003

The devices/materials are directly contacted with venous blood and poor platelet plasma (usually rabbits), respectively, and the clotting time is measured to evaluate whether the sample contains endogenous coagulation system activators

Specify the acceptable criteria of the device/material on a verifiable basis (eg, compared to an approved device of the same type)

Platelet adhesion

The device/material is co-cultured with fresh sodium citrate anticoagulated whole blood (human, sheep or rabbit, etc.). The platelet adhesion on the surface of sample is observed to evaluate the effect of the sample on platelet performance

Thrombosis

The device/material is implanted into the vein. Thrombus formation on the surface of the sample and the intima surface of the blood vessel are observed and scored to evaluate the potential of forming thrombosis

Complement system

The device/material is contacted with human serum, and the concentration of C3a fragment formed during complement system activation is assessed by enzyme-linked immunosorbent assay to evaluate the effect of the sample on complement activation

Reproductive system

Reproductive toxicity

GB/

T16886.3—2019

8-10 weeks before mating, male and female animals (mouse) are continuously exposed to device/material or extracts until 21 d after the birth of F1 generation. The sexual function, estrus cycle, mating behavior, conception, parturition, lactation, and weaning of animals as well as the growth, development, deformity, morbidity and mortality of offspring are observed and recorded, to evaluate the influence of the sample on the reproductive function and embryonic development

There should be no significant difference compared to the negative control

Metabolic system

Toxicokinetics

GB/T16886.16—2021

To study the quantitative changes in the process of absorption, distribution, metabolism and excretion of the test substance in the body, degradation products, leachables, and metabolites of device/material should be qualitatively detected and quantitatively analyzed. Rodent models (rats, mice) are generally used. Blood, urine, feces and bile are collected regularly after exposure, and the heart, liver, spleen, stomach, kidney, gastrointestinal tract, gonads, brain, body fat, skeletal muscle and other tissues are collected, respectively, to determine the distribution of the test substance. Bioavailability, toxicity-time curve, apparent volume of distribution, clearance rate, half-life, average residence time, maximum and maximum concentration (time) of the test substance were measured through the toxicokinetic model

The mathematical model expression of metabolic process, combing with the physical and chemical shape, administration route, dose and method of the test substance is evaluated comprehensively

Table 4 Supplementary biological test items for Zn alloy implantable devices

Item	Traditional metal implant devices/materials	Degradable metal implant devices/materials
Material type	Stainless steel, nickel-titanium alloy, cobalt-chromium alloy, titanium alloy, etc.	Zn alloy, Mg alloy, Fe alloy, etc.
Property	Inert	Bioactive
Principle	Support, occupy space, etc., by physical properties to achieve clinical therapeutic effects	Physical properties function in the early stage, then the materials degrade and the target lesion tissue remodels gradually
Potential source of cytotoxicity	Processing aids, leachables	Processing aids, leachables, degradation products (ions), pH, osmotic pressure, surface energy, etc.
Sterilization method	Not limited to ethylene oxide (EO), irradiation sterilization, etc.	Methods with minimal impact on material properties
Evaluation endpoint	Morphological evaluation, cell growth ability, and metabolic characteristics (microscopic observation + MTT method, etc.)
Contact way	Extraction method, direct or indirect contact method can be selected according to the principle of "closest to the application situation". Generally, the extraction method is recommended	Extraction method, direct or indirect contact method can be selected according to the principle of "closest to the application situation"
Extraction medium	The ability to support cell growth and to extract both polar and non-polar substances	Cell culture medium with serum, generally. The ratio of serum can be adjusted according to the effect of serum on the material
Extraction condition	Generally (37 ± 1)^oC, (24 ± 2) h	The appropriate extraction time can be selected according to the implantation time, degradation rate and degradation products in vivo. Evaluation of multiple extraction times are also necessary to fully understand and assess biological risks
Extraction ratio	(Surface area or mass / volume) ± 10%
Extraction	Dilution is not recommended generally	Multiple dilutions may be necessary
Extraction treatment	Adjustment is not recommended generally	Filtration, centrifugation, pH adjustment, etc., can be used, but treatment should be recorded and evaluated
Cell line	Suitable cell lines recognized by ISO experts, such as mouse fibroblast CCL1 (L929), mouse embryonic fibroblast CCL163 (Balb/3T3 clone A31), etc. L929 cells are generally used in China	Depending on the application site, sensitivity- or site-specific cells may be required to evaluate their cellular responses more objectively

Table 5 Similarities and differences between degradable and traditional metal implanted devices/materials in cytotoxicity tests

Material

Shape

Disinfection/sterilization

Animal

Implant site

Implant period

month

Performance

Ref.

99.99%

pure

Wire,

Φ0.25 mm × 15 mm

irradiation

SD rats

Abdominal aorta

1.5, 3, 4.5, 6;

2.5, 4,

6.5

At 2.5 months of implantation, neoendothelialization was completed. The neointima contains a thin layer of SMCs and an area of low-density inflammatory cells adjacent to the zinc metal layer and within the corrosion layer, with no signs of necrosis. Despite rapid corrosion after 4 months implantation, the thickness of the neointimal layer did not increase over time. Migration and matrix formation of nucleated cells in the corroded area were observed. No inflammatory response, local necrosis, and progressive intimal hyperplasia were observed

[75,76]

99.99%

pure

Long wire,

Φ0.25 mm

70% ethanol disinfection

SD rats

Abdominal aorta

1~12,

14, 20

At 5, 6, and 8 months of implantation, there was higher cell density and chronic inflammation possibly related to stable corrosive activity. Chronic inflammation subsided between 10 and 20 months. No clear evidence of large-scale cytotoxicity was detected at any time point

[86]

99.995%

pure Zn

Stents,

Φ3.0 mm ×

10 mm, strut thickness:

165 μm

Japanese rabbits

Abdominal aorta

1, 3, 6,

No significant platelet adhesion or membranous thrombosis was observed after 3 d implantation. Neointimal coverage was observed at 1 month, indicating rapid endothelialization. No significant intimal hyperplasia or lumen loss was found at any time point, and no severe inflammation, platelet aggregation, or thrombosis was observed

[78]

Zn-0.1Li

Wire,

Φ0.25 mm × 10 mm

SD rats

Abdominal aorta

2, 4, 6.5, 9, 12

At 11 months postimplantation, moderate chronic inflammation with non-obstructive neointima was still observed in the Zn-Li alloy group. Biocompatibility is slightly worse than pure Zn

[79]

Material

Shape

Disinfection/

Animal

Implant site

Implant

Performance

Ref.

sterilization

period

month

Zn,

Zn-xMg

(x = 0.2, 0.5, 8)

Wire,

15 mm

segment

Disinfection

SD rats

Abdominal aorta

1.5, 3, 4.5, 6,

Compared with pure Zn, the biocompatibility of Zn-xMg alloy showed a slight deterioration trend with the increase of Mg content. The inflammatory cell infiltration and neointima activation increased slightly. At 6 months, Zn-8Mg did not show significant intimal thickening, but exhibited moderate chronic inflammation and a reduction in the cross-sectional area of the lumen. At 11 months, inflammation had some resolution, but intimal thickening with discontinuous endothelial cells was appeared. It is speculated that Mg₂Zn₁₁ particles may induce deleterious macrophage responses thus disrupting the positive remodeling effect of Zn

[80]

Zn-xAl

(x = 1, 3, 5)

Strip,

12 mm ×

300 μm ×

300 μm

70% ethanol disinfection

SD rats

Abdominal aorta

1.5, 3,

4.5,

At 3 months of implantation, acute local inflammation with neutrophilic and eosinophilic infiltration was still observed. At 6 months, dense fibrotic deposits around the implant were observed, no necrotic tissue was detected. Zn-xAl had acceptable compatibility with surrounding arterial tissue

[81]

Zn-0.8Cu

Stent,

Φ3.0 mm ×

20 mm, wall thickness:

~127 μm

EO sterilization

White pigs

Coronary artery

1, 3, 6, 9,

12,

18, 24

Vascular endothelialization was completed within 1 months after stent implantation. ZnCu stent provided adequate structural support and exhibited an appropriate rate of degradation within 24 months, with no accumulation of degradation products, thrombosis or inflammatory responses

[84]

Zn-4Ag,

Zn-4Ag-0.6Mn,

Zn-4Ag-

0.8Cu-0.6Mn-0.15Zr

Wire,

Φ0.25 mm ×

15 mm

Disinfection

SD rats

Abdominal aorta

3, 6

At 6 months of implantation, a significant reduction of inflammatory activities was found in the quinary alloy relative to the other Zn-based materials. And inflammation, but not smooth muscle cell hyperplasia, is correlated with neointimal growth for the Zn-Ag-based alloys

[85]

Table 6 Summary of the in vivo tests for Zn alloys in blood vessels^{[75,76,78-81,84-86]}

Material

Shape

Disinfection/Sterilization

Animal

Implant

site

Implant

period

Performance

Ref.

Zn,

Zn-0.4Li

Rod,

Φ1.6 mm × 15 mm

SD rats

Femoral

2 months

Neither pure Zn nor Zn-0.4Li implanted sites showed osteolysis, deformation, dislocation, or air shadows. Compared to immediate postoperation, the adjacent cortical bone showed higher radiographic densities at 8 weeks postoperation, indicating peripheral osteogenesis. Compared with pure Zn, more collagen and new bone tissue were observed around the Zn-0.4Li implants

[87]

Zn-0.8Mn,

Zn-0.8Sr

Porous scaffold

Rats

Femoral condyle

4, 8, and 12 weeks

New bone formation was observed at 4 weeks after Zn-0.8Mn implantation, and a large amount of new bone tissue was observed around the scaffold at 8 and 12 weeks postoperation. The trabecular bone was thicker than that of pure Ti group. Zn-0.8Mn scaffold showed good osteogenic performance and biocompatibility in vivo. Zn ions were not accumulated in the organs. Zn-0.8Sr scaffold also has good bone defect repair performance and growth tendency without inflammatory reaction

[88,

89]

Zn-0.5Mn

Φ1.5 mm × 5 mm

UV disinfection

SD rats

Tibia

4 months

After 4 months implantation, healthy bone and blood vessels were observed, bone marrow hyperplasia was showed by pathological sections, liver and kidney functions were not affected

[90]

Zn-0.4Fe,

Zn-0.4Cu,

Zn-2.0Ag,

Zn-0.8Mg,

Zn-0.8Ca,

Zn-0.1Sr,

Zn-0.4Li,

Zn-0.1Mn

Rod,

Φ1.6 mm × 15 mm

SD rats

Femoral

2 months

The cortical bone surrounding the implant thickened and radiographic dense increased, indicating circumferential osteogenesis. All implants were biocompatible with no evidence of osteolysis, deformity or dislocation. At 2 months implantation, new bone was formed and contacted the implants directly

[91]

Zn, Zn-2Fe

Φ7 mm ×

2 mm

Wistar rats

Subcutaneous tissue of back

4, 8,

12, 18,

24 weeks

No tissue inflammation or necrosis was observed

[93]

Zn-0.8Li-0.1Mn

Gastroin-testinal staple

Disinfection

Mini

fragrant

pigs

Gastrointestinal

anastomosis

3 d,

8 weeks,

12 weeks

In the early stage after surgery, there were a small amount of inflammatory cells (mainly neutrophils and lymphocytes) and macrophages around the Zn-Li-Mn and Ti alloy nails. Inflammation cells around the Zn-Li-Mn alloy nails were slightly less than the Ti alloy group. At 12 weeks postoperation, new gastrointestinal tissues were found around the nails in both groups, the tissues healed well, and the number of inflammatory cells was significantly reduced

[92]

Table 7 Summary of the in vivo tests for Zn alloys in Orthopedics and other issues^[87~93]

1	Scholten K, Meng E. Materials for microfabricated implantable devices: A review [J]. Lab Chip, 2015, 15: 4256 doi: 10.1039/c5lc00809c pmid: 26400550
2	Xiao M, Chen Y M, Biao M N, et al. Bio-functionalization of biomedical metals [J]. Mater. Sci. Eng., 2017, C70: 1057
3	Pogorielov M, Husak E, Solodivnik A, et al. Magnesium-based biodegradable alloys: Degradation, application, and alloying elements [J]. Interv. Med. Appl. Sci., 2017, 9: 27
4	Sharma M P. Corrosion of bio-materials [J]. J. Metall. Mater. Eng. Res., 2020, 10: 21
5	Masiero G, Rodinò G, Matsuda J, et al. Bioresorbable coronary scaffold technologies: What's new? [J]. Cardiol. Clin., 2020, 38: 589 doi: 10.1016/j.ccl.2020.07.004 pmid: 33036720
6	Jinnouchi H, Torii S, Sakamoto A, et al. Fully bioresorbable vascular scaffolds: Lessons learned and future directions [J]. Nat. Rev. Cardiol., 2019, 16: 286 doi: 10.1038/s41569-018-0124-7 pmid: 30546115
7	Onuma Y, Muramatsu T, Kharlamov A, et al. Freeing the vessel from metallic cage: What can we achieve with bioresorbable vascular scaffolds? [J]. Cardiovasc. Interv. Ther., 2012, 27: 141 pmid: 22569783
8	de Pommereau A, de Hemptinne Q, Varenne O, et al. Bioresorbable vascular scaffolds: Time to absorb past lessons or fade away? Arch. Cardiovasc. Dis., 2018, 111: 229 doi: S1875-2136(18)30050-0 pmid: 29678390
9	Liu J Y, Wang J G, Yu Y H, et al. Advances in biodegradable vascular stent materials [J]. Mater. Sci. Forum, 2020, 987: 93 doi: 10.4028/www.scientific.net/MSF.987.93
10	Zhu D H, Cockerill I, Su Y C, et al. Mechanical strength, biodegradation, and in vitro and in vivo biocompatibility of Zn biomaterials [J]. ACS Appl. Mater. Interfaces, 2019, 11: 6809 doi: 10.1021/acsami.8b20634
11	Gąsior G, Szczepański J, Radtke A. Biodegradable iron-based materials-what was done and what more can Be done? [J]. Materials, 2021, 14: 3381 doi: 10.3390/ma14123381
12	Zhou Y Z, Wu P, Yang Y W, et al. The microstructure, mechanical properties and degradation behavior of laser-melted Mg-Sn alloys [J]. J. Alloys Compd., 2016, 687: 109 doi: 10.1016/j.jallcom.2016.06.068
13	Wen P, Voshage M, Jauer L, et al. Laser additive manufacturing of Zn metal parts for biodegradable applications: Processing, formation quality and mechanical properties [J]. Mater. Des., 2018, 155: 36 doi: 10.1016/j.matdes.2018.05.057
14	Song B, Dong S J, Liu Q, et al. Vacuum heat treatment of iron parts produced by selective laser melting: Microstructure, residual stress and tensile behavior [J]. Mater. Des., 2014, 54: 727 doi: 10.1016/j.matdes.2013.08.085
15	Jo S, Whitmore L, Woo S, et al. Excellent age hardenability with the controllable microstructure of AXW100 magnesium sheet alloy [J]. Sci. Rep., 2020, 10: 22413 doi: 10.1038/s41598-020-79390-z pmid: 33376246
16	Wang C R, Xi T F, Feng X M. The important rule of material and chemical characterization in device evaluation [J]. Chin. Med. Dev. Inf., 2007, 13(5): 4
	王春仁, 奚廷斐, 冯晓明. 医疗器械生物材料表征和化学性能检测的重要性 [J]. 中国医疗器械信息, 2007, 13(5): 4
17	Li H F, Wang P Y, Lin G C, et al. The role of rare earth elements in biodegradable metals: A review [J]. Acta Biomater., 2021, 129: 33 doi: 10.1016/j.actbio.2021.05.014
18	Liu Y, Zheng Y F, Chen X H, et al. Fundamental theory of biodegradable metals—Definition, criteria, and design [J]. Adv. Funct. Mater., 2019, 29: 1805402 doi: 10.1002/adfm.201805402
19	Wang C, Yu Z T, Cui Y J, et al. Processing of a novel Zn alloy micro-tube for biodegradable vascular stent application [J]. J. Mater. Sci. Technol., 2016, 32: 925 doi: 10.1016/j.jmst.2016.08.008
20	Zheng Y F, Xia D D, Chen Y N, et al. Additively manufactured biodegrabable metal implants [J]. Acta Metall. Sin., 2021, 57: 1499 doi: 10.11900/0412.1961.2021.00294
	郑玉峰, 夏丹丹, 谌雨农等. 增材制造可降解金属医用植入物 [J]. 金属学报, 2021, 57: 1499 doi: 10.11900/0412.1961.2021.00294
21	Hernández-Escobar D, Champagne S, Yilmazer H, et al. Current status and perspectives of zinc-based absorbable alloys for biomedical applications [J]. Acta Biomater., 2019, 97: 1 doi: S1742-7061(19)30523-9 pmid: 31351253
22	Törne K, Larsson M, Norlin A, et al. Degradation of zinc in saline solutions, plasma, and whole blood [J]. J. Biomed. Mater. Res., 2016, 104B: 1141
23	Su Y C, Cockerill I, Wang Y D, et al. Zinc-based biomaterials for regeneration and therapy [J]. Trends Biotechnol., 2019, 37: 428 doi: S0167-7799(18)30305-6 pmid: 30470548
24	Hojyo S, Fukada T. Roles of zinc signaling in the immune system [J]. J. Immunol. Res., 2016, 2016: 6762343
25	Berg J M, Shi Y G. The galvanization of biology: A growing appreciation for the roles of zinc [J]. Science, 1996, 271: 1081 doi: 10.1126/science.271.5252.1081 pmid: 8599083
26	Yamaguchi M. Role of nutritional zinc in the prevention of osteoporosis [J]. Mol. Cell. Biochem., 2010, 338: 241 doi: 10.1007/s11010-009-0358-0 pmid: 20035439
27	Imbeault M, Helleboid P Y, Trono D. KRAB zinc-finger proteins contribute to the evolution of gene regulatory networks [J]. Nature, 2017, 543: 550 doi: 10.1038/nature21683
28	Hennig B, Toborek M, McClain C J, et al. Nutritional implications in vascular endothelial cell metabolism [J]. J. Am. Coll. Nutr., 1996, 15: 345 pmid: 8829090
29	Yamaguchi M. Nutritional factors and bone homeostasis: Synergistic effect with zinc and genistein in osteogenesis [J]. Mol. Cell. Biochem., 2012, 366: 201 doi: 10.1007/s11010-012-1298-7 pmid: 22476903
30	Miller L V, Krebs N F, Hambidge K M. A mathematical model of zinc absorption in humans as a function of dietary zinc and phytate [J]. J. Nutr., 2007, 137: 135 pmid: 17182814
31	Bitanihirwe B K Y, Cunningham M G. Zinc: the brain's dark horse [J]. Synapse, 2010, 63: 1029 doi: 10.1002/syn.20683
32	Kabir H, Munir K, Wen C E, et al. Recent research and progress of biodegradable zinc alloys and composites for biomedical applications: Biomechanical and biocorrosion perspectives [J]. Bioact. Mater., 2021, 6: 836 doi: 10.1016/j.bioactmat.2020.09.013 pmid: 33024903
33	Yang N, Venezuela J, Almathami S, et al. Zinc-nutrient element based alloys for absorbable wound closure devices fabrication: Current status, challenges, and future prospects [J]. Biomaterials, 2022, 280: 121301 doi: 10.1016/j.biomaterials.2021.121301
34	Su Y C, Fu J Y, Lee W, et al. Improved mechanical, degradation, and biological performances of Zn-Fe alloys as bioresorbable implants [J]. Bioact. Mater., 2022, 17: 334 doi: 10.1016/j.bioactmat.2021.12.030 pmid: 35386444
35	Xia D D, Qin Y, Guo H, et al. Additively manufactured pure zinc porous scaffolds for critical-sized bone defects of rabbit femur [J]. Bioact. Mater., 2023, 19: 12 doi: 10.1016/j.bioactmat.2022.03.010 pmid: 35415313
36	ISO. Biological evaluation of medical devices, Part 1: Evaluation and testing within a risk management process [S]. 2018
37	Anderson J M. Biological responses to materials [J]. Annu. Rev. Mater. Res., 2001, 31: 81 doi: 10.1146/annurev.matsci.31.1.81
38	Williams D F. On the mechanisms of biocompatibility [J]. Biomaterials, 2008, 29: 2941 doi: 10.1016/j.biomaterials.2008.04.023 pmid: 18440630
39	Zhao P, Xing L N, Liu W B, et al. Biocompatibility evaluation of medical devices: Status, progress and trend [J]. China Med. Dev. Inf., 2021, 27(11): 1
	赵鹏, 邢丽娜, 刘文博等. 医疗器械生物相容性评价: 现状、进展与趋势 [J]. 中国医疗器械信息, 2021, 27(11): 1
40	Williams D F. On the nature of biomaterials [J]. Biomaterials, 2009, 30: 5897 doi: 10.1016/j.biomaterials.2009.07.027 pmid: 19651435
41	Geurtsen W. Biocompatibility of dental casting alloys [J]. Crit. Rev. Oral. Biol. Med., 2002, 13: 71 pmid: 12097239
42	Salimi A, Jamali Z, Atashbar S, et al. Pathogenic mechanisms and therapeutic implication in nickel-induced cell damage [J]. Endocr. Metab. Immune., 2020, 20: 968
43	Hillen U, Haude M, Erbel R, et al. Evaluation of metal allergies in patients with coronary stents [J]. Contact Dermatitis, 2002, 47: 353 pmid: 12581282
44	Holton A D, Walsh E G, Brott B C, et al. Evaluation of in-stent stenosis by magnetic resonance phase-velocity mapping in nickel-titanium stents [J]. J. Magn. Reson. Imaging, 2005, 22: 248 pmid: 16028256
45	Liu P S, Yu B, Hu A M, et al. Development in applications of porous metals [J]. Trans. Nonferrous Met. Soc. China, 2001, 11: 629
46	Qin J H, Chen Q, Yang C Y, et al. Research process on property and application of metal porous materials [J]. J. Alloys Compd., 2016, 654: 39 doi: 10.1016/j.jallcom.2015.09.148
47	Purdue P E, Koulouvaris P, Potter H G, et al. The cellular and molecular biology of periprosthetic osteolysis [J]. Clin. Orthop. Relat. Res., 2007, 454: 251 doi: 10.1097/01.blo.0000238813.95035.1b
48	Goodman S. Wear particulate and osteolysis [J]. Orthop. Clin. North Am., 2005, 36: 41 doi: 10.1016/j.ocl.2004.06.015
49	Yang K, Shi J R, Wang L, et al. Bacterial anti-adhesion surface design: Surface patterning, roughness and wettability: A review [J]. J. Mater. Sci. Technol., 2022, 99: 82 doi: 10.1016/j.jmst.2021.05.028
50	Yao X, Peng R, Ding J D. Cell-material interactions revealed via material techniques of surface patterning [J]. Adv. Mater., 2013, 25: 5257 doi: 10.1002/adma.201301762
51	Brott T, Stump D. Overview of hemostasis and thrombosis [J]. Semin. Neurol., 1991, 11: 305 pmid: 1811287
52	Wehrmacher W H. Molecular markers of hemostasis: Introduction and overview [J]. Semin. Thromb. Hemost., 1984, 10: 215 pmid: 6515417
53	Wu S, Applewhite A J, Niezgoda J, et al. Oxidized regenerated cellulose/collagen dressings: Review of evidence and recommendations [J]. Adv. Skin Wound Care, 2017, 30: S1 doi: 10.1097/01.ASW.0000525951.20270.6c
54	Zhang L, Wang S M, Tan M H, et al. Efficacy of oxidized regenerated cellulose/collagen dressing for management of skin wounds: A systematic review and meta-analysis [J]. Evid.-Based Complement. Alternat. Med., 2021, 2021: 1058671
55	Liu C H, Wu S F, Hou L, et al. Study on cytotoxicity tests of medical devices based on IC50 [J]. Chin. J. Med. Lnstrument., 2014, 38: 433
	刘成虎, 吴世福, 侯丽等. 基于IC50的医疗器械细胞毒性试验方法的研究 [J]. 中国医疗器械杂志, 2014, 38: 433
56	Lin W J, Zhang G, Cao P, et al. Cytotoxicity and its test methodology for a bioabsorbable nitrided iron stent [J]. J. Biomed. Mater. Res., 2015, 103B: 764
57	Dargusch M S, Balasubramani N, Venezuela J, et al. Improved biodegradable magnesium alloys through advanced solidification processing [J]. Scr. Mater., 2020, 177: 234 doi: 10.1016/j.scriptamat.2019.10.028
58	Niederlaender J, Walter M, Krajewski S, et al. Cytocompatibility evaluation of different biodegradable magnesium alloys with human mesenchymal stem cells [J]. J. Mater. Sci.: Mater. Med., 2014, 25: 835 doi: 10.1007/s10856-013-5119-7
59	Ma J, Zhao N, Zhu D H. Endothelial cellular responses to biodegradable metal zinc [J]. ACS Biomater. Sci. Eng., 2015, 1: 1174 pmid: 27689136
60	Shearier E R, Bowen P K, He W L, et al. In vitro cytotoxicity, adhesion, and proliferation of human vascular cells exposed to zinc [J]. ACS Biomater. Sci. Eng., 2016, 2: 634 pmid: 27840847
61	Kubásek J, Vojtěch D, Jablonská E, et al. Structure, mechanical characteristics and in vitro degradation, cytotoxicity, genotoxicity and mutagenicity of novel biodegradable Zn-Mg alloys [J]. Mater. Sci. Eng., 2016, C58: 24
62	Jablonská E, Vojtěch D, Fousová M, et al. Influence of surface pre-treatment on the cytocompatibility of a novel biodegradable ZnMg alloy [J]. Mater. Sci. Eng., 2016, C68: 198
63	Venezuela J, Dargusch M S. The influence of alloying and fabrication techniques on the mechanical properties, biodegradability and biocompatibility of zinc: A comprehensive review [J]. Acta Biomater., 2019, 87: 1 doi: S1742-7061(19)30055-8 pmid: 30660777
64	Shi Z Z, Yu J, Liu X F, et al. Effects of Ag, Cu or Ca addition on microstructure and comprehensive properties of biodegradable Zn-0.8Mn alloy [J]. Mater. Sci. Eng., 2019, C99: 969
65	Li P, Schille C, Schweizer E, et al. Selection of extraction medium influences cytotoxicity of zinc and its alloys [J]. Acta Biomater., 2019, 98: 235 doi: S1742-7061(19)30179-5 pmid: 30862550
66	Reference individuals for use in radiation protection-Part 5: Human body elemental composition and contents of element in main tissues and organs [S]. 2014
67	Mostaed E, Sikora-Jasinska M, Drelich J W, et al. Zinc-based alloys for degradable vascular stent applications [J]. Acta Biomater., 2018, 71: 1 doi: S1742-7061(18)30125-9 pmid: 29530821
68	Wang J L, Witte F, Xi T F, et al. Recommendation for modifying current cytotoxicity testing standards for biodegradable magnesium-based materials [J]. Acta Biomater., 2015, 21: 237 doi: 10.1016/j.actbio.2015.04.011 pmid: 25890098
69	Boon G D. An overview of hemostasis [J]. Toxicol. Pathol., 1993, 21: 170 pmid: 8210939
70	De Gaetano G. Historical overview of the role of platelets in hemostasis and thrombosis [J]. Haematologica, 2001, 86: 349 pmid: 11325638
71	Yin Y X, Zhou C, Shi Y P, et al. Hemocompatibility of biodegradable Zn-0.8 wt% (Cu, Mn, Li) alloys [J]. Mater. Sci. Eng., 2019, C104: 109896
72	Liu X W, Sun J K, Zhou F Y, et al. Micro-alloying with Mn in Zn-Mg alloy for future biodegradable metals application [J]. Mater. Des., 2016, 94: 95 doi: 10.1016/j.matdes.2015.12.128
73	Shen C, Liu X W, Fan B, et al. Mechanical properties, in vitro degradation behavior, hemocompatibility and cytotoxicity evaluation of Zn-1.2Mg alloy for biodegradable implants [J]. RSC Adv., 2016, 6: 86410 doi: 10.1039/C6RA14300H
74	Liu X W, Sun J K, Yang Y H, et al. Microstructure, mechanical properties, in vitro degradation behavior and hemocompatibility of novel Zn-Mg-Sr alloys as biodegradable metals [J]. Mater. Lett., 2016, 162: 242 doi: 10.1016/j.matlet.2015.07.151
75	Bowen P K, Drelich J, Goldman J. Zinc exhibits ideal physiological corrosion behavior for bioabsorbable stents [J]. Adv. Mater., 2013, 25: 2577 doi: 10.1002/adma.201300226
76	Bowen P K, Guillory II R J, Shearier E R, et al. Metallic zinc exhibits optimal biocompatibility for bioabsorbable endovascular stents [J]. Mater. Sci. Eng., 2015, C56: 467
77	Pierson D, Edick J, Tauscher A, et al. A simplified in vivo approach for evaluating the bioabsorbable behavior of candidate stent materials [J]. J. Biomed. Mater. Res., 2012, 100B: 58 doi: 10.1002/jbm.b.31922
78	Yang H T, Wang C, Liu C Q, et al. Evolution of the degradation mechanism of pure zinc stent in the one-year study of rabbit abdominal aorta model [J]. Biomaterials, 2017, 145: 92 doi: S0142-9612(17)30532-X pmid: 28858721
79	Zhao S, Seitz J M, Eifler R, et al. Zn-Li alloy after extrusion and drawing: Structural, mechanical characterization, and biodegradation in abdominal aorta of rat [J]. Mater. Sci. Eng., 2017, C76: 301
80	Jin H L, Zhao S, Guillory R, et al. Novel high-strength, low-alloys Zn-Mg (< 0.1wt% Mg) and their arterial biodegradation [J]. Mater. Sci. Eng., 2018, C84: 67
81	Bowen P K, Seitz J M, Guillory II R J, et al. Evaluation of wrought Zn-Al alloys (1, 3, and 5 wt % Al) through mechanical and in vivo testing for stent applications [J]. J. Biomed. Mater. Res., 2018, 106B: 245
82	Tang L P, Eaton J W. Inflammatory responses to biomaterials [J]. Am. J. Clin. Pathol., 1995, 103: 466 doi: 10.1093/ajcp/103.4.466 pmid: 7726145
83	Lane J P, Perkins L E L, Sheehy A J, et al. Lumen gain and restoration of pulsatility after implantation of a bioresorbable vascular scaffold in porcine coronary arteries [J]. JACC: Cardiovasc. Interventions, 2014, 7: 688 doi: 10.1016/j.jcin.2013.11.024
84	Zhou C, Li H F, Yin Y X, et al. Long-term in vivo study of biodegradable Zn-Cu stent: A 2-year implantation evaluation in porcine coronary artery [J]. Acta Biomater., 2019, 97: 657 doi: S1742-7061(19)30559-8 pmid: 31401346
85	Oliver A A, Guillory II R J, Flom K L, et al. Analysis of vascular inflammation against bioresorbable Zn-Ag-based alloys [J]. ACS Appl. Bio Mater., 2020, 3: 6779 doi: 10.1021/acsabm.0c00740
86	Drelich A J, Zhao S, Guillory II R J, et al. Long-term surveillance of zinc implant in murine artery: Surprisingly steady biocorrosion rate [J]. Acta Biomater., 2017, 58: 539 doi: S1742-7061(17)30336-7 pmid: 28532901
87	Yang H T, Qu X H, Wang M Q, et al. Zn-0.4Li alloy shows great potential for the fixation and healing of bone fractures at load-bearing sites [J]. Chem. Eng. J., 2021, 417: 129317 doi: 10.1016/j.cej.2021.129317
88	Jia B, Yang H T, Han Y, et al. In vitro and in vivo studies of Zn-Mn biodegradable metals designed for orthopedic applications [J]. Acta Biomater., 2020, 108: 358 doi: S1742-7061(20)30141-0 pmid: 32165194
89	Jia B, Yang H T, Zhang Z C, et al. Biodegradable Zn-Sr alloy for bone regeneration in rat femoral condyle defect model: In vitro and in vivo studies [J]. Bioact. Mater., 2021, 6: 1588 doi: 10.1016/j.bioactmat.2020.11.007 pmid: 33294736
90	Guo P S, Zhu X L, Yang L J, et al. Ultrafine- and uniform-grained biodegradable Zn-0.5Mn alloy: Grain refinement mechanism, corrosion behavior, and biocompatibility in vivo [J]. Mater. Sci. Eng., 2021, C118: 111391
91	Yang H T, Jia B, Zhang Z C, et al. Alloying design of biodegradable zinc as promising bone implants for load-bearing applications [J]. Nat. Commun., 2020, 11: 401 doi: 10.1038/s41467-019-14153-7 pmid: 31964879
92	Guo H, Hu J L, Shen Z Q, et al. In vitro and in vivo studies of biodegradable Zn-Li-Mn alloy staples designed for gastrointestinal anastomosis [J]. Acta Biomater., 2021, 121: 713 doi: 10.1016/j.actbio.2020.12.017 pmid: 33321221
93	Kafri A, Ovadia S, Yosafovich-Doitch G, et al. In vivo performances of pure Zn and Zn-Fe alloy as biodegradable implants [J]. J. Mater. Sci.: Mater. Med., 2018, 29: 94 doi: 10.1007/s10856-018-6096-7
94	Qu X H, Yang H T, Jia B, et al. Biodegradable Zn-Cu alloys show antibacterial activity against MRSA bone infection by inhibiting pathogen adhesion and biofilm formation [J]. Acta Biomater., 2020, 117: 400 doi: 10.1016/j.actbio.2020.09.041 pmid: 33007485
95	Lin J X, Tong X, Shi Z M, et al. A biodegradable Zn-1Cu-0.1Ti alloy with antibacterial properties for orthopedic applications [J]. Acta Biomater., 2020, 106: 410 doi: S1742-7061(20)30096-9 pmid: 32068137
96	Lin S, Ran X L, Yan X H, et al. Systematical evolution on a Zn-Mg alloy potentially developed for biodegradable cardiovascular stents [J]. J. Mater. Sci.: Mater. Med., 2019, 30: 122 doi: 10.1007/s10856-019-6324-9
97	Tong X, Shi Z M, Xu L C, et al. Degradation behavior, cytotoxicity, hemolysis, and antibacterial properties of electro-deposited Zn-Cu metal foams as potential biodegradable bone implants [J]. Acta Biomater., 2020, 102: 481 doi: S1742-7061(19)30781-0 pmid: 31740321
98	Peng F, Xie J N, Liu H M, et al. Shifting focus from bacteria to host neutrophil extracellular traps of biodegradable pure Zn to combat implant centered infection [J]. Bioact. Mater., 2023, 21: 436 doi: 10.1016/j.bioactmat.2022.09.004 pmid: 36185738

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