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Abstract

Transplantation of mesenchymal stem cells (MSCs) is one of the hopeful treatments for spinal cord injury (SCI). Most current studies are in animals, and less in humans, and the optimal transplantation strategy for MSCs is still controversial. In this article, we explore the optimal transplantation strategy of MSCs through a network meta-analysis of the effects of MSCs on SCI in animal models. PubMed, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Database, China Science and Technology Journal Database (VIP), and Chinese Biomedical Literature Service System (SinoMed) databases were searched by computer for randomized controlled studies on MSCs for SCI. Two investigators independently completed the literature screening and data extraction based on the inclusion and exclusion criteria. RevMan 5.4 software was used to assess the quality of the included literature. Stata 16.0 software was used for standard meta-analysis and network meta-analysis. Standardized mean difference (SMD) was used for continuous variables to combine the statistics and calculate 95% confidence interval (95% CI). P < 0.05 was considered a statistically significant difference. Cochrane’s Q test and the I² value were used to indicate the magnitude of heterogeneity. A random-effects model was used if I² > 50% and P < 0.10 indicated significant heterogeneity between studies, and conversely, a fixed-effects model was used. Evidence network diagrams were drawn based on direct comparisons between various interventions. The surface under the cumulative ranking curve area (SUCRA) was used to predict the ranking of the treatment effects of each intervention. A total of 32 animal studies were included in this article for analysis. The results of the standard meta-analysis showed that MSCs improved motor ability after SCI. The network meta-analysis showed that the best treatment effect was achieved for adipose tissue–derived mesenchymal stromal cells (ADMSCs) in terms of cell source and intrathecal (IT) in terms of transplantation modality. For transplantation timing, the best treatment effect was achieved when transplantation was performed in the subacute phase. The available literature suggests that IT transplantation using ADMSCs in the subacute phase may be the best transplantation strategy to improve functional impairment after SCI. Future high-quality studies are still needed to further validate the results of this study to ensure the reliability of the results.

Keywords

mesenchymal stem cells spinal cord injury systematic review network meta-analysis

Introduction

Spinal cord injury (SCI) is a severe injury disorder of the central nervous system. The global incidence of SCI has been reported to range from 12 to over 65 cases per million per year¹. SCI may be caused by traffic accidents, falls, violence, and others². SCI mainly manifests as sensory, motor, and autonomic dysfunction varying degrees below the plane of injury, seriously affecting patients’ quality of life^3,4. The pathological mechanism of SCI is divided into two main stages: primary injury and secondary injury. Primary injury refers to direct damage to the spinal cord tissue by external mechanical forces, accompanied by nerve cell death, vascular damage, oxidative stress, inflammation, and excitotoxicity of nerve cells^5,6. Secondary injury occurs hours to weeks after the primary injury. It consists mainly of pathological reactions such as massive neuronal apoptosis, residual nerve fiber demyelination, gilial scar formation, and spinal cord cavitation⁷. Surgery, drugs, hyperbaric oxygen therapy, and physical therapy have been widely used in the clinical treatment of SCI, but with modest efficacy. Therefore, finding effective treatments for SCI has become an urgent problem to be solved.

Mesenchymal stem cells (MSCs) are multifunctional progenitor cells found in tissues such as bone marrow, adipose, and umbilical cord that can self-renew, proliferate, and differentiate into multiple cell lines⁸. MSCs can secrete bioactive molecules such as growth factors and cytokines, inhibit inflammation, reduce glial scarring, and resist apoptosis, thus promoting axonal regeneration, which has essential potential and broad application prospects in SCI treatment⁹. MSCs transplanted into the area of SCI can release trophic factors at the site of injury to maintain the activity of cells in the injured area and release anti-inflammatory factors to further promote vascular regeneration, blood–spinal cord barrier repair, and nerve regeneration^10,11. MSCs can also tilt the balance of inflammatory cytokines in an anti-inflammatory direction by regulating the status of macrophages astrocytes and T cells^12,13. A study showed that adipose tissue–derived mesenchymal stromal cells (ADMSCs) could activate the transforming growth factor (TGF)-β1/Smad3/procollagenlysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) pathway in spinal cord neurons and promote axonal regeneration, enhancing functional recovery after SCI¹⁴. Zhao et al.¹⁵ found that neural regeneration scaffolds of umbilical cord mesenchymal stem cells (UCMSCs) inhibited glial scar formation, promoted axonal growth, and improved motor and sensory function after SCI. Gu et al.¹⁶ reported that bone marrow mesenchymal stem cells (BMSCs) improve motor function and reduce the expression of the pro-apoptotic transcription factor C/EBP homologous protein (CHOP) and apoptosis after SCI. Although the preliminary results are hopeful, various transplantation strategies exist for MSCs. There is no uniform conclusion on the advantages and disadvantages of different transplantation strategies for SCI treatment.

Therefore, this study used network meta-analysis to comprehensively evaluate the intervention effects of different MSCs transplantation strategies of MSCs on motor function after SCI in animals and to determine the optimal transplantation strategy for clinical decisions.

Materials and Methods

This study was conducted under the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Search Strategies

A database search of English and Chinese databases for randomized controlled trials of MSCs for SCI was performed by a computer. English language databases included PubMed, Web of Science, Cochrane Library, and Embase. Chinese databases included China National Knowledge Infrastructure (CNKI), Wanfang Database, China Science and Technology Journal Database (VIP), and Chinese Biomedical Literature Service System (SinoMed). The time frame for the search was from database creation to March 2, 2023 (please see Supplementary Material 1 for specific search strategies).

Study Selection Criteria

Inclusion criteria

Inclusion criteria included (a) randomized controlled trial of MSCs transplantation for SCI in rat models, (b) the experimental group was treated with MSCs on top of the control group, and (c) the outcome indicator was Basso–Beattie–Bresnahan (BBB).

Exclusion criteria

Exclusion criteria included (a) conference papers or duplicate published studies, (b) study data could not be extracted, (c) non-randomized controlled studies, and (d) the low-quality score of the literature.

Data Extraction

Duplicates retrieved were excluded using EndNote 20 and manually. Two investigators (Y.W. and C.G.) independently screened articles based on inclusion and exclusion criteria. When there was disagreement, it was resolved through group discussion. Two investigators (Y.W. and Y.D.) extracted the following information for each of the included animal studies: first author, year in publication, rat species, sample size, gender, age, weight, MSCs source, MSCs transplantation way, the dose of MSCs, transplantation time, final evaluation time, and outcome indicators. In studies that assess outcome indicators at multiple time points, data from the final assessment are extracted for analysis.

Quality Assessment

The risk of literature bias was assessed independently by two investigators (Y.W. and C.G.) using RevMan 5.4 software. Animal studies were assessed using SYRCLE’s risk-of-bias tool for animal studies. The evaluation included¹⁷ (a) Was the allocation sequence adequately generated and applied? (b) Were the groups similar at baseline or were they adjusted for confounders in the analysis? (c) Was the allocation adequately concealed? (d) Were the animals randomly housed during the experiment? (e) Were the caregivers and/or investigators blinded from knowledge which intervention each animal received during the experiment? (f) Were animals selected at random for outcome assessment? (g) Was the outcome assessor blinded? (h) Were incomplete outcome data adequately addressed? (i) Are reports of the study free of selective outcome reporting? (j) Was the study apparently free of other problems that could result in high risk of bias? Low risk of bias, unclear, and high risk of bias were assessed for each entry. Any disagreement in the above quality assessment process was resolved through group discussion.

Statistical Analysis

This study performed the standard meta-analysis and network meta-analysis using Stata 16.0 software (Supplementary Material 2).

Standard meta-analysis

Effect size calculation

Standardized mean difference (SMD) was used for continuous variables to combine the statistics and calculate 95% confidence interval (95% CI). P < 0.05 was considered a statistically significant difference.

Heterogeneity test

Cochrane’s Q test and the I² value were used to indicate the magnitude of heterogeneity. If I² > 50% and P < 0.10, it suggested significant heterogeneity among studies, and the random-effects model was used; if I² ≤ 50% and P ≥ 0.10, it suggested a small heterogeneity among studies, and the fixed-effects model was adopted. The combined results with more significant heterogeneity were searched for sources of heterogeneity by subgroup analysis.

Network meta-analysis

Evidence network diagrams were drawn based on direct comparisons between various interventions. The size of the dots in the evidence network diagram represents the sample size, and the thickness of the lines represents the number of studies¹⁸. A node-split model was used to test for local inconsistency between direct and indirect comparisons. If P > 0.05, it suggested no significant inconsistency, and the data were analyzed using the consistency model. If P ≤ 0.05, significant inconsistency was suggested, the data were analyzed using the inconsistency model, and the source of inconsistency was explored. The surface under the cumulative ranking curve area (SUCRA) was used to predict the ranking of the treatment effects of each intervention. If SUCRA is close to 1, the intervention is very effective. If SUCRA is close to 0, the intervention is probably ineffective. The symmetry of the two sides of the comparison-corrected funnel plots was used to determine whether there was a publication bias in the analysis results.

Results

Study Selection

A total of 5,605 relevant studies were retrieved. Of total, 2,868 duplicate studies were removed, and 2,563 studies were removed by reading the titles and abstracts. The full text was read carefully, and 142 studies were removed. Finally, 32 studies^19
–50 were included, including 14^{25,28,31,33
–36,40,42,43,46,48
–50} in English and 18^{19
–24,26,27,29,30,32,37
–39,41,44,45,47} in Chinese (Fig. 1).

Figure 1.

Flow chart of literature screening.

Study Characteristics

Sources of MSCs included UCMSCs (seven studies), BMSCs (24 studies), and ADMSCs (two studies). One study directly compared ADMSCs and BMSCs. MSCs transplantation route included intrathecal (IT) injection (seven studies), intralesional (IL) injection (16 studies), and intravenous (IV) injection (17 studies). Two studies directly compared IT and IL. Four studies directly compared IT and IV. Three studies directly compared IL and IV. Timing of MSCs transplantation included the acute phase (≤3 days, 19 studies), subacute phase (4–14 days, 13 studies), and chronic phase (≥15 days, 2 studies). 2 study directly compared acute phase transplantation with subacute phase transplantation. The essential characteristics of the animal studies are shown in Table 1.

Table 1.

Animal Studies of MSCs Transplantation for SCI.

Author	Species	Sample (E/C)	Gender	Age	Weight	Stem cell transplantation				Final evaluation time	Outcomes
Author	Species	Sample (E/C)	Gender	Age	Weight	Source	Way	Dose	Timing	Final evaluation time	Outcomes
Feng 2006	SD rat	7/7	Female	-	220-250g	Allo, BMSCs	IV	2×10⁶	1 week after SCI	6 weeks	BBB
Chen 2007	SD rat	30/30/20	Female	Adult	(240±20) g	Allo, BMSCs	IT/IV	1×10⁷	2 days after SCI	3 weeks	BBB
Cheng 2007	SD rat	12/12/12	-	7 weeks	(300±15) g	Allo, BMSCs	IL	5×10⁴	after SCI/ 1 week after SCI	6 weeks	BBB
Wu 2007	SD rat	5/5	Female	8 weeks	220-250g	Allo, BMSCs	IT	2×10⁶	1 week after SCI	3 weeks	BBB
Jing 2008	SD rat	12/12/12	Male	Adult	260-280g	Allo, BMSCs	IL/IV	1×10⁶	1 week after SCI	6 weeks	BBB
Huang 2009	SD rat	6/6	Female	Adult	250-280g	Allo, BMSCs	IV	5×10⁶	10 min after SCI	2 weeks	BBB
Khalatbary 2009	SD rat	7/7;7/7	Female	Adult	250-300g	Allo, BMSCs	IT/IV	IT: 3×10⁵; IV: 2.5×10⁶	1 week after SCI	4 weeks	BBB
Ren 2009	SD rat	10/10	-	Adult	240-260g	Allo, BMSCs	IL	3×10⁵	9 days after SCI	4 weeks	BBB
Fan 2011	Wistar rat	6/6/6	-	-	180g	Allo, BMSCs	IL/IT	5×10⁷	after SCI	3 weeks	BBB
Chen 2012	SD rat	10/10	Male	2-3 months	150-250g	Allo, BMSCs	IV	1×10⁶	3 days after SCI	5 weeks	BBB
Li 2012	SD rat	6/6	Female	Adult	200-250g	Allo, BMSCs	IV	1×10⁷	1 week after SCI	8 weeks	BBB
Wei 2012	Wistar rat	20/20	-	8 weeks	200-220g	Allo, UCMSCs	IL	-	1 week after SCI	12 weeks	BBB
Kang 2012	SD rat	12/12/12	Male	Adult	250-300g	Allo, BMSCs	IL/IV	1×10⁶	24 h after SCI	6 weeks	BBB
Huang 2013	SD rat	26/20	Male	Adult	(270±20) g	Allo, UCMSCs	IL	6×10⁷	After SCI	7 weeks	BBB
Kim 2013	SD rat	8/8/8	Male	Adult	(290-340) g	Allo, BMSCs	IL	1×10⁶	6 weeks after SCI	6 weeks	BBB
Zhou 2013	SD rat	5/5/5	Female	8 weeks	200-250g	Allo, ADMSCs/ BMSCs	IL	2×10⁵	After SCI	4 weeks	BBB
Cui 2014	Wistar rat	16/15	Female	Adult	250-280g	Allo, UCMSCs	IL	1×10⁷	After SCI	4 weeks	BBB
Song 2014	Wistar rat	20/20	Male	8-10 weeks	(160±14) g	Allo, BMSCs	IL	5×10⁴	7 days and 28 days after SCI	8 weeks	BBB
Li 2015	SD rat	6/6	Female	Adult	210-250g	Allo, BMSCs	IV	1×10⁷	1 week after SCI	8 weeks	BBB
Zhao 2015	SD rat	12/12/12/12	Female	Adult	220-250g	Allo, BMSCs	IL/IT/IV	1.5×10⁵/1×10⁶/1×10⁶	3 days after SCI	3 weeks	BBB
Jiang 2016	SD rat	8/8/8	-	Adult	200-250g	Allo, BMSCs	IV	2×10⁶	24 h/7 days after SCI	6 weeks	BBB
Kim 2016	SD rat	8/8	Male	Adult	282-322g	Allo, BMSCs	IL	1×10⁶	After SCI	6 weeks	BBB
Sun 2016	SD rat	16/16	Male	Adult	260-300g	Allo, BMSCs	IT	1×10⁶	1 week after SCI	4 weeks	BBB
Rosado 2017	Wistar rat	50/50	Male	-	300g	Allo, ADMSCs	IV	1×10⁶	3 h after SCI	3 weeks	BBB
Galhom 2018	SD rat	20/20	Male	14-16 weeks	200-250g	Allo, BMSCs	IL	1.5×10⁶	After SCI	7 weeks	BBB
Sun 2018	SD rat	10/10	Male	2-3 months	(180±5) g	Allo, BMSCs	IV	2×10⁶	After SCI	1 month	BBB
Li 2019	Wistar rat	15/15	Male	8 weeks	(112.35±5.10) g	Allo, BMSCs	IV	2×10⁶	After SCI	1 week	BBB
Moinuddin 2021	SD rat	6/6	Female	Adult	270-300g	Allo, UCMSCs	IV	2×10⁶	1 week after SCI	14 weeks	BBB
Sun 2021	SD rat	15/15	Male	8 weeks	-	Allo, BMSCs	IV	1×10⁷	After SCI	4 weeks	BBB
Yoon 2021	SD rat	7/7	Female	-	230–250g	Allo, UCMSCs	IL	1×10⁶	6 weeks after SCI	8 weeks	BBB
Cao 2022	Kunming mouse	13/13/13	Male	Adult	-	Allo, UCMSCs	IL	1×10⁷/2×10⁷	After SCI	8 weeks	BBB
Liu 2022	SD rat	10/10/10/10/10	Male	-	220g	Allo, UCMSCs	IT/IV	IT: 2.5×10⁶/5×10⁶/10×10⁶ IV: 20×10⁶	24 h after SCI	4 weeks	BBB

Study Quality and Risk of Bias

The risk-of-bias evaluation for animal studies is shown in Fig. 2. Three studies^37,41,47 described the generation of allocation sequences using the random number table method. The baseline characteristics of the groups were essentially the same for all studies. All studies did not adequately describe allocation concealment. Seven studies^{24,31,35,42,45,48,50} described the experimental procedure in which animals were randomly placed. Three studies^19,22,40 reported a random selection of animals for measurement during outcome evaluation. A total of 16 studies^{19,20,24,26,29,30,32
–34,37
–39,42,43,46,48} were blinded to outcome evaluators. All studies were free from missing study data and selective reporting. No other bias was found to exist.

Figure 2.

Risk assessment of bias in animal studies.

Standard Meta-Analysis

The acute phase of SCI

A total of 19 articles^{20,21,24,27,28,31,32,34,35,38
–40,42
–45,47,49,50} were transplanted with MSCs in the acute phase of SCI. Heterogeneity between studies was significant (I² = 88.1%, P < 0.1) and was analyzed using the random-effects model. Subgroup analysis according to transplantation modality showed that BBB scores were significantly higher in the MSCs group than in the control group (IT: SMD = 3.80, 95% CI = 2.81–4.80, P < 0.05; IV: SMD = 2.27, 95% CI = 1.78–2.77, P < 0.05; IL: SMD = 4.34, 95% CI = 2.87–5.80, P < 0.05) (Fig. 3).

Figure 3.

Meta-analysis of MSCs transplantation in the acute phase of SCI.

The subacute phase of SCI

A total of 13 articles^{19,21
–23,25,26,29,30,36,37,39,41,46} were transplanted with MSCs at the subacute phase of SCI, with significant heterogeneity among studies (I² = 86.8%, P < 0.1). The random-effects model was used for analysis. Subgroup analysis according to transplantation modality showed that BBB scores were significantly higher in the MSCs group than in the control group (IT: SMD = 6.02, 95% CI = 2.70–9.33, P < 0.05; IV: SMD = 3.96, 95% CI = 2.83–5.10, P < 0.05; IL: SMD = 4.96, 95% CI = 2.51–7.40, P < 0.05) (Fig. 4).

Figure 4.

Meta-analysis of MSCs transplantation in the subacute phase of SCI.

The chronic phase of SCI

Two articles^33,48 were transplanted in the chronic phase of SCI. Heterogeneity between studies was small (I² = 0%, P > 0.1) and was analyzed using the fixed-effects model. Subgroup analysis according to transplantation modality showed that BBB scores were significantly higher in the MSCs group than in the control group (IV: SMD = 3.47, 95% CI = 1.86–5.09, P < 0.05; IL: SMD = 4.42, 95% CI = 3.01–5.83, P < 0.05) (Fig. 5).

Figure 5.

Meta-analysis of MSCs transplantation in the chronic phase of SCI.

Network Meta-Analysis

Network meta-analysis was performed according to different cell sources, transplantation ways, and times using the BBB score as an outcome indicator. The network relationship diagram was sequential (Fig. 6A–C). Local inconsistency tests were performed separately for the closed loops in Fig. 6A–C. The results showed P > 0.05, so the consistency model was used. The SUCRA ranking of different cell sources was AD > BM > UC > CG (83.0% > 78.0% > 39.0% > 0.0%, Fig. 6D). The ranking of SUCRA by different transplantation ways was IT > IL > IV > CG (88.3% > 76.6% > 35.1% > 0.0%, Fig. 6E). The ranking of SUCRA by different transplantation times was subacute > chronic > acute > CG (91.6% > 65.3% > 42.8% > 0.3%, Fig. 6F). The imperfectly symmetrical comparison-corrected funnel plots suggest a possible publication bias and a small sample effect in the above results (Fig. 6G–I).

Figure 6.

Network meta-analysis of animal studies. A: Network relationship of different cell sources; (B) Network relationship of different transplantation ways; C: Network relationship of different transplantation times; D: SUCRA of different cells sources; (E) SUCRA of different transplantation ways; F: SUCRA of different transplantation times; G: Funnel plot of different cell sources; H: Funnel plot of different transplantation ways; I: Funnel plot of different transplantation times.

Discussion

The standard meta-analysis was performed on 32 animal studies in this study. The results showed that treatment with MSCs was effective in improving motor function after SCI compared with controls. A comprehensive comparison of different MSCs cell sources, transplantation modalities, and transplantation times in animal studies was performed by network meta-analysis using the BBB score as an outcome index. The results showed that ADMSCs were best treated in terms of cell source, IT was best treated in terms of transplantation modality, and transplantation was best treated in terms of transplantation timing when performed in the subacute phase. While ADMSCs demonstrated sound therapeutic effects in animal studies, clinical studies related to ADMSCs are currently less available, and the clinical efficacy in SCI patients needs to be further explored.

ADMSCs can be obtained from fat aspirates obtained by liposuction, are widely available, enable autologous transplantation, reduce immune rejection caused by allografts, have a high ability to differentiate into neurons, and have a few ethical issues⁵¹. An animal study showed that ADMSCs can reduce Janus family of cytoplasmic tyrosine kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) phosphorylation in astrocytes by inhibiting the Jagged1/Notch signaling pathway to treat SCI rats, which may be a potential mechanism for their improved motor function⁵². UCMSCs can be obtained from waste tissue such as umbilical cord blood and perivascular and subendothelial umbilical veins, and there are no medical ethical issues⁵³. UCMSCs are mostly allogeneic and have been gradually applied in basic and clinical research because of their easy access, high value-added rate, low immunogenicity, and non-tumorigenicity⁵⁴. It was shown that pro-inflammatory factors interleukin (IL)-1β, interferon-gamma (IFN-γ), IL-6, and tumor necrosis factor (TNF)-α were elevated in the serum of SCI rats, and there was a tendency to reduce the elevation of IFN-γ, IL-6, and TNF-α after treatment with UCMSCs⁵⁰. BMSCs are stem cells in the bone marrow that have the potential for multidirectional differentiation and contribute to hematopoiesis and bone regeneration⁵⁵. Li et al.⁴⁵ found that TLR4 expression was significantly reduced in SCI rats after BMSCs transplantation, suggesting that BMSCs transplantation could significantly inhibit TLR4 expression after SCI, thus reducing the inflammatory response. BMSCs are easy to obtain by autologous isolation and have less immune rejection in SCI patients, so they are primarily used in clinical studies for cell transplantation⁵⁶.

There are some limitations to this study: (a) the included clinical literature was small, and the sample size of individual literature was small; (b) the language type of the included literature includes only English and Chinese, which may have regional and ethnic limitations and is not comprehensive; (c) most of the studies were not allocation concealed, which may produce bias; and (d) the bias analyses both suggested that there may be a small difference and bias.

Conclusion

In conclusion, the currently available evidence in the literature suggests that IT transplantation using ADMSCs in the subacute phase in SCI may be the best transplantation strategy to improve functional impairment after SCI. MSCs transplantation using this strategy could be performed in SCI patients in clinical trials to verify the validity of the findings. Considering the limitations of this study, more large sample sizes, and multicenter, high-quality animal studies are needed in the future to further validate the results of this study to ensure the reliability of the findings. The biological therapeutic mechanisms of MSCs for SCI should also be explored in depth.

Supplemental Material

sj-docx-1-cll-10.1177_09636897241262992 – Supplemental material for Mesenchymal Stem Cells for the Treatment of Spinal Cord Injury in Rat Models: A Systematic Review and Network Meta-Analysis

Supplemental material, sj-docx-1-cll-10.1177_09636897241262992 for Mesenchymal Stem Cells for the Treatment of Spinal Cord Injury in Rat Models: A Systematic Review and Network Meta-Analysis by Yueying Wang, Yi Ding and Chenchen Guo in Cell Transplantation

Footnotes

Author Contributions

Y.W. conceived the theme of the study. Y.W. and C.G. performed the systematic search, reviewed the literature, and extracted the data. Y.W. and Y.D. analyzed data and wrote the first draft of the paper. Y.W. and C.G. checked and modified the manuscript. All authors read and approved the final manuscript.

Availability of Data and Material

The data used to support the findings of this study are available from the corresponding author upon request.

Ethical Approval

Ethical approval is not applicable to this study.

Statement of Human and Animal Rights

This article does not contain any studies with human or animal subjects.

Statement of Informed Consent

There are no human subjects in this article and informed consent is not applicable.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by the National Natural Science Foundation of China (82374556) and the Shandong Traditional Chinese Medicine Science and Technology Development Programs (Q-2023067 and Q-2023069).

ORCID iD

Yi Ding

Supplemental Material

Supplemental material for this article is available online.

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