Preclinical evaluation of acute systemic toxicity of magnesium incorporated poly(lactic-co-glycolic acid) porous scaffolds by three-dimensional printing

doi:10.12336/biomatertransl.2021.03.009

Biomaterials Translational ›› 2021, Vol. 2 ›› Issue (3): 272-284.doi: 10.12336/biomatertransl.2021.03.009

Preclinical evaluation of acute systemic toxicity of magnesium incorporated poly(lactic-co-glycolic acid) porous scaffolds by three-dimensional printing

Jing Long¹, Bin Teng², Wei Zhang¹, Long Li¹^,³, Ming Zhang³, Yingqi Chen³, Zhenyu Yao¹, Xiangbo Meng¹, Xinluan Wang¹, Ling Qin¹^,⁴, Yuxiao Lai¹^,²^,⁵^,^*()

1 Centre for Translational Medicine and Research and Development, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong Province, China
2 Centre for Energy Metabolism and Reproduction, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong Province, China
3 Guangdong Engineering Laboratory of Biomaterials Additive Manufacturing, Guangdong, Guangdong Province, China
4 Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
5 Key Laboratory of Health Informatics, Chinese Academy of Sciences, Shenzhen, Guangdong Province, China

Received:2021-06-08 Revised:2021-07-31 Accepted:2021-08-20 Online:2021-09-28 Published:2021-09-28
Contact: Yuxiao Lai E-mail:yx.lai@siat.ac.cn
About author:Yuxiao Lai, yx.lai@siat.ac.cn.
First author contact:
†Present Addresses: Centre for Translational Medicine and Research and Development, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong Province, China.

Abstract

Abstract:

Biodegradable polymer scaffolds combined with bioactive components which accelerate osteogenesis and angiogenesis have promise for use in clinical bone defect repair. The preclinical acute toxicity evaluation is an essential assay of implantable biomaterials to assess the biosafety for accelerating clinical translation. We have successfully developed magnesium (Mg) particles and beta-tricalcium phosphate (β-TCP) for incorporation into poly(lactic-co-glycolic acid) (PLGA) porous composite scaffolds (PTM) using low-temperature rapid prototyping three-dimensional-printing technology. The PTM scaffolds have been fully evaluated and found to exhibit excellent osteogenic capacity for bone defect repair. The preclinical evaluation of acute systemic toxicities is essential and important for development of porous scaffolds to facilitate their clinical translation. In this study, acute systemic toxicity of the PTM scaffolds was evaluated in mice by intraperitoneal injection of the extract solutions of the scaffolds. PTM composite scaffolds with different Mg and β-TCP content (denoted as PT5M, PT10M, and PT15M) were extracted with different tissue culture media, including normal saline, phosphate-buffered saline, and serum-free minimum essential medium, to create the extract solutions. The evaluation was carried out following the National Standard. The acute toxicity was fully evaluated through the collection of extensive data, including serum/organs ion concentration, fluorescence staining, and in vivo median lethal dose measurement. Mg in major organs (heart, liver, and lung), and Mg ion concentrations in serum of mice, after intraperitoneal injection of the extract solutions, were measured and showed that the extract solutions of PT15M caused significant elevation of serum Mg ion concentrations, which exceeded the safety threshold and led to the death of the mice. In contrast, the extract solutions of PT5M and PT10M scaffolds did not cause the death of the injected mice. The median lethal dose of Mg ions in vivo for mice was determined for the first time in this study to be 110.66 mg/kg, and the safety level of serum magnesium toxicity in mice is 5.4 mM, while the calcium serum safety level is determined as 3.4 mM. The study was approved by the Animal Care and Use Committee of Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (approval No. SIAT-IRB-170401-YGS-LYX-A0346) on April 5, 2017. All these results showed that the Mg ion concentration of intraperitoneally-injected extract solutions was a determinant of mouse survival, and a high Mg ion concentration (more than 240 mM) was the pivotal factor contributing to the death of the mice, while changes in pH value showed a negligible effect. The comprehensive acute systemic toxicity evaluation for PTM porous composite scaffolds in this study provided a reference to guide the design and optimization of this composite scaffold and the results demonstrated the preclinical safety of the as-fabricated PTM scaffold with appropriate Mg content, strongly supporting the official registration process of the PTM scaffold as a medical device for clinical translation.

Key words: acute systemic toxicity, clinical translation, magnesium, median lethal dose, porous composite scaffolds

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Figures/Tables 11

Figure 1. Macrograph image and scanning electron microscopy micrographs of 3D-printed PLGA/β-TCP/Mg composite porous scaffolds. (A) Macroscopic image of a fabricated scaffold. (B-D) Transverse section at a magnification of PT10M scaffold by SEM (original magnifications 30×, 500×, and 1000×). Scale bars: 500 μm in B, 10 μm in C, and D. 3D: three-dimensional; Mg: magnesium; PT10M: PLGA/β-TCP/10 wt% Mg porous composite scaffolds; PLGA: poly(lactic-co-glycolic acid); β-TCP: beta-tricalcium phosphate.

Figure 2. In vitro immersion degradation behaviour of scaffolds. (A) Changes in the pH value of different solutions used to soak the PT15M scaffold at 37°C for 24, 48, and 72 hours. (B, C) The concentrations of Mg ions (B) and Ca ions (C) released into serum-free MEM after incubation with PT15M at 37°C for 24, 48, and 72 hours. In the test results, MEM has a higher baseline as it contains calcium chloride. (D) The pH value, Mg, and Ca ion concentrations of MEM incubated with PT, PT5M, PT10M, and PT15M scaffolds at 37°C for 72 hours. Data are expressed as the mean ± SD. (n = 3 and experiments were repeated by twice). Ca: calcium; MEM: serum-free minimum essential medium; Mg: magnesium; PT: poly(lactic-co-glycolic acid)/beta-tricalcium phosphate porous composite scaffolds; PT5M: poly(lactic-co-glycolic acid)/beta-tricalcium phosphate/5 wt% Mg porous composite scaffolds; PT10M: poly(lactic-co-glycolic acid)/beta-tricalcium phosphate/10 wt% Mg porous composite scaffolds; PT15M: poly(lactic-co-glycolic acid)/beta-tricalcium phosphate/15 wt% Mg porous composite scaffolds.

Figure 3. In vivo acute toxicity results in mice after intraperitoneal injection of different extract solutions. Each extract solution was prepared by soaking the PT15M scaffold in the solution at 37°C for 72 hours. (A) The percentage of live and dead animals. For those mice that survived or dead, corresponding to the extract medium they were injected, we grouped them into four groups which were control/MEM/alive (Control), PT15M/saline/dead, PT15M/PBS/dead, and PT15M/MEM/dead groups. (B) Mg and Ca ion concentrations of serum in mice, 1 hour after intraperitoneal injection of extract solution. (C) H&E staining of heart, and Mg indicator fluorescent staining (green) of heart, liver, and lung. Black arrows indicate loosened cardiac tissues, and white arrows indicate enrichment sites of Mg ions in tissues. Scale bars: 200 μm. (D) The mass ratios of Mg and Ca in different organs. The control group was injected with MEM that was not incubated with any scaffolds. Data are expressed as the mean ± SD (n = 10, 5 male and 5 female). *P < 0.05, **P < 0.01, ***P < 0.001 (one-way analysis of variance followed by Tukey’s post hoc test). “A” stands for alive mice, and “D” means dead mice. Ca: calcium; H&E: haematoxylin and eosin; MEM: serum-free minimum essential medium; Mg: magnesium; PBS: phosphate-buffered saline; PT15M: poly(lactic-co-glycolic acid)/beta-tricalcium phosphate/15 wt% Mg porous composite scaffolds; Saline: normal saline.

Figure 4. In vivo acute toxicity results of mice after intraperitoneal injection of different Mg content scaffold extract. Extract MEM solutions were prepared by soaking PT, PT5M, PT10M, and PT15M samples in MEM at 37°C for 72 hours. (A) The percentage of live and dead mice 1 hour after intraperitoneal injection of extract MEM. For those mice that survived or dead, corresponding to the scaffold extract they were injected, we grouped them into four groups which were PT/alive (PT/A), PT5M/alive (PT5M/A), PT10M/alive (PT5M/A), and PT15M/dead (PT5M/D) groups. (B) The weight change of live mice 72 hours after intraperitoneal injection of extract MEM. (C) Mg and Ca ion concentrations in serum 1 hour after intraperitoneal injection of extract MEM. Scale bars: 200 μm. (D) H&E staining of heart, and Mg indicator fluorescent staining of heart, liver, and lung. Black arrows indicate loosened cardiac tissues, and white arrows indicate enrichment sites of Mg ions in tissues. (E) The mass ratios of Mg and Ca in different organs at 1 hour after intraperitoneal injection of extract MEM. Data are expressed as the mean ± SD (n = 10-12, 5-6 male and 5-6 female). *P < 0.05, **P < 0.01, ***P < 0.001 (one-way analysis of variance followed by Tukey’s post hoc test). “A” stands for alive mice, and “D” means dead mice. Ca: calcium; H&E: haematoxylin and eosin; MEM: serum-free minimum essential medium; Mg: magnesium; PT: poly(lactic-co-glycolic acid)/beta-tricalcium phosphate porous composite scaffolds; PT5M: poly(lactic-co-glycolic acid)/beta-tricalcium phosphate/5 wt% Mg porous composite scaffolds; PT10M: poly(lactic-co-glycolic acid)/beta-tricalcium phosphate/10 wt% Mg porous composite scaffolds; PT15M: poly(lactic-co-glycolic acid)/beta-tricalcium phosphate/15 wt% Mg porous composite scaffolds.

Figure 5. In vivo acute toxicity results in mice after intraperitoneal injection of extract MEM with different pH values (7.0 and 10.0). Extract MEM was prepared by soaking PT15M at 37°C for 72 hours. For those mice that survived or dead, corresponding to the different pH values of scaffold extract they were injected, we grouped them into four groups which were MEM/pH7/alive (MEM/pH7/A), MEM/pH10/alive (MEM/pH10/A), PT15M/pH7/alive (PT15M/pH7/A), and PT15M/pH7/dead (PT15M/pH7/D) groups. (A) The percentage of live and dead animals at 1 hour after intraperitoneal injection of extract MEM. (B) The weight change of live mice at 72 hours after intraperitoneal injection of extract MEM. (C) Mg and Ca ion concentrations of serum in mice 1 hour after intraperitoneal injection of extract MEM. (D) H&E staining of heart, and Mg indicator fluorescent staining of heart, liver, and lung. Black arrows indicate loosened cardiac tissues, and white arrows indicate enrichment sites of Mg ions in tissues. Scale bars: 200 μm. (E) The mass ratios of Mg and Ca in different organs at 1 hour after intraperitoneal injection with extract MEM. Data are expressed as the mean ± SD (n = 10, 5 male and 5 female). *P < 0.05, **P < 0.01, ***P < 0.001 (one-way analysis of variance followed by Tukey’s post hoc test). “A” stands for alive mice, and “D” means dead mice. Ca: calcium; H&E: haematoxylin and eosin; MEM: serum-free minimum essential medium; Mg: magnesium; PT15M: poly(lactic-co-glycolic acid)/beta-tricalcium phosphate/15 wt% Mg porous composite scaffolds.

Figure 6. In vivo median lethal dosing results of mice after intraperitoneal injection of different concentrations of diluted extract MEM. The extract MEM was prepared by soaking the PT15M scaffold in MEM at 37 °C for 72 hours. (A) The percentage of live and dead animals. For those mice that survived or dead, corresponding to the different magnesium concentrations of MEM solutions they were injected, we grouped them into nine groups which were control group (serum-free MEM), 79 mg/kg Mg/A, 99 mg/kg Mg/A, 119 mg/kg Mg/A, 119 mg/kg Mg/D, 139 mg/kg Mg/D, and 165 mg/kg Mg/D groups. (B) The weight of the live animals. The x-axis indicates Mg content in extract solution versus the weight of the mice. (C) Mg and Ca ion concentrations in the serum of mice at 1 hour after intraperitoneal injection. (D﹣H) The mass ratios of Mg in different organs. (I-M) The mass ratios of Ca in different organs. The control group was injected with MEM with a pH value of 7.0. Data are expressed as the mean ± SD (n = 10, 5 male and 5 female). *P < 0.05, **P < 0.01, ***P < 0.001 (one-way analysis of variance followed by Tukey’s post hoc test). “A” stands for alive mice, and “D” means dead mice. Ca: calcium; MEM: serum-free minimum essential medium; Mg: magnesium.

Table 1 The clinical signs and observed symptoms for mice after intraperitoneal injection of different ratio diluted extract MEM.

Dose (mg/kg)	Time	Dyspnea	Prostration	Convulsion	Ptosis	Salivation	Piloerection	Diuresis	Edema	Erythema
0	1 day	﹣	﹣	﹣	﹣	﹣	﹣	﹣	﹣	﹣
0	3 day	﹣	﹣	﹣	﹣	﹣	﹣	﹣	﹣	﹣
79	1 day	﹣	﹣	﹣	﹣	﹣	﹣	﹣	﹣	﹣
79	3 day	﹣	﹣	﹣	﹣	﹣	﹣	﹣	﹣	﹣
99	1 day	﹣	+	﹣	﹣	﹣	﹣	﹣	﹣	﹣
99	3 day	﹣	﹣	﹣	﹣	﹣	﹣	+	﹣	﹣
119	1 day	﹣	+	﹣	﹣	﹣	﹣	﹣	﹣	﹣
119	3 day	﹣	﹣	﹣	﹣	﹣	﹣	+	﹣	﹣
139	1 day	+	+	+	﹣	﹣	﹣	﹣	﹣	﹣
139	3 day	﹣	﹣	﹣	﹣	﹣	﹣	+	﹣	﹣
165	1 day	+	+	+	﹣	﹣	﹣	﹣	﹣	﹣
165	3 day	NA	NA	NA	NA	NA	NA	NA	NA	NA

Additional Table 1 Verified the difference between different extract solutions effect on acute systemic toxicity in vivo.

Group	Reagent	Male mice (n)	Female mice (n)	Death rate (%)
Control	MEM	5	5	0
PT15M	MEM	5	5	100
PT15M	PBS	5	5	100
PT15M	Saline	5	5	100

Additional Table 2 Determined Mg effect of in vivo acute toxicity based on various Mg content scaffolds.

Group	Reagent	Male mice (n)	Female mice (n)	Death rate (%)
PT	MEM	5	5	0
PT5M	MEM	5	5	0
PT10M	MEM	5	5	0
PT15M	MEM	6	6	100

Additional Table 3 Effect of pH value on in vivo acute systemic toxicity.

Group	Reagent	Male mice (n)	Female mice (n)	Death rate (%)
MEM (pH 7.0)	MEM	5	5	0
MEM (pH 10.0)	MEM	5	5	0
PT15M (pH 7.0)	MEM	5	5	67
PT15M (pH 10.0)	MEM	5	5	100

Additional Figure 1. Haematoxylin and eosin staining of heart, liver, lung, spleen, and kidney 1 hour after intraperitoneal injection of extract MEM. The extract MEM was incubated with scaffolds at 37°C for 72 hours. The results showed that the wavy appearance of the myocardium was only apparent in PT15M/pH7/D extract-treated dead mice, while the myocardium in the MEM, PT5M/A, PT10M/A, and PT15M/pH7/A groups remained normal. There were no abnormalities in the liver, lung, spleen, or kidney in any groups. Black arrows indicate loosened cardiac tissues. Scale bars: 200 μm. “A” stands for alive mice, and “D” means dead mice. MEM: serum-free minimum essential medium; Mg: magnesium; PT5M: poly(lactic-co-glycolic acid)/beta-tricalcium phosphate/5 wt% Mg porous composite scaffolds; PT10M: poly(lactic-co-glycolic acid)/beta-tricalcium phosphate/10 wt% Mg porous composite scaffolds; PT15M: poly(lactic-co-glycolic acid)/beta-tricalcium phosphate/15 wt% Mg porous composite scaffolds.

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Preclinical evaluation of acute systemic toxicity of magnesium incorporated poly(lactic-co-glycolic acid) porous scaffolds by three-dimensional printing

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