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.
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.
Table 1 Properities of biodegradable metals[11-15]
Degradation
Solubility, 20oC
Stability
Density
LD50, acute systemic
Equivalent to human
Toxicity
product
g·L-1
g·cm-3
toxicity, oral, rat
lethal dose
level
mg·kg-1
g
ZnO
0.0029,
Stable
5.68
> 2000
50
Low toxicity
slightly soluble
ZnCO3·3Zn(OH)2
Insoluble
Stable
-
> 10000
500
Non-toxic
Zn3(PO4)2
2.7,
Stable
-
> 5000
500
Non-toxic
slightly soluble
ZnCl2
Soluble
Stable
1.01
> 5000
500
Non-toxic
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
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
Zn
Wire,
Φ0.25 mm × 15 mm
UV
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
Zn
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,
12
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,
11
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,
6
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]
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