医用可降解锌合金的生物相容性评价研究进展

doi:10.11900/0412.1961.2022.00471

金属学报

2023, Vol. 59

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

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医用可降解锌合金的生物相容性评价研究进展

王鲁宁¹^,²(

), 尹玉霞¹, 石章智¹, 韩倩倩³

1 北京科技大学材料科学与工程学院北京 100083
2 北京材料基因工程高精尖创新中心北京 100083
3 中国食品药品检定研究院北京 102629

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

引用本文:

王鲁宁, 尹玉霞, 石章智, 韩倩倩. 医用可降解锌合金的生物相容性评价研究进展[J]. 金属学报, 2023, 59(3): 319-334.
Luning WANG, Yuxia YIN, Zhangzhi SHI, Qianqian HAN. Research Progress on Biocompatibility Evaluation of Biomedical Degradable Zinc Alloys[J]. Acta Metall Sin, 2023, 59(3): 319-334.

全文: PDF(1175 KB) HTML

摘要:

锌合金由于其适宜的腐蚀速率、良好的力学性能，成为继镁合金与铁合金后的一种新型的可降解生物医用金属材料。近年来，研究者对锌合金的设计、加工制备以及降解机理进行了大量研究，但对其体内外生物相容性的研究尚不充分，仅评估了体外细胞毒性、溶血、凝血，少数材料植入动物体内进行了组织相容性的表征。然而生物相容性涉及细胞、组织、血液、免疫等复杂的局部反应和全身反应，除了材料本身的物理化学性质，还受到材料与机体相互作用的影响。本文分析了可降解医用锌合金的化学成分和物相组成，阐明了对其进行生物学评价的方法，并结合锌合金生物相容性研究现状，阐述未来的研究方向。

关键词 ：锌合金, 生物相容性, 细胞毒性, 血液相容性

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

收稿日期: 2022-09-23

ZTFLH:

TG146

基金资助:国家自然科学基金项目(51871020);国家重点研发计划项目(2016YFC1102500)

作者简介: 王鲁宁，男，1980年生，教授，博士

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表1 可降解金属的性质[11~15]

表2 锌合金主要降解产物的性质

图1 材料植入后的机体反应及机体与材料的相互作用[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

表3 锌合金植入器械必要的生物学试验项目

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

表4 锌合金植入器械补充的生物学试验项目

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

表5 可降解与传统金属植入器械/材料在细胞毒性试验中的异同

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]

表6 锌合金在血管中应用的动物试验总结[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]

表7 锌合金在骨科及其他组织应用的动物试验总结[87~93]

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