Efficacy of adipose-derived stem cells combined with different scaffolds to repair bone defects: a systematic review and Meta-analysis

doi:10.21203/rs.3.rs-2481182/v1

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Systematic Review

Efficacy of adipose-derived stem cells combined with different scaffolds to repair bone defects: a systematic review and Meta-analysis

https://doi.org/10.21203/rs.3.rs-2481182/v1

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At the present stage, the most traditional techniques for the treatment of bone defects often fail to achieve the desired results. The tissue engineering technology about bone regeneration emerged as a new method for treating bone defects. Cells and scaffolds are the two most important key factors in tissue engineering, and there are many types of scaffolds are already in use in experiments. And there are so many studies are now on different Cellular scaffolds filled with ADSCs (adipose-derived stem cells). But these researches are still in the animal experimental stage. This study informed the clinical application of ADSCs through an evidence-based medicine analysis to evaluate the efficacy of ADSCs in repairing the bone defect. We systematically searched databases, collected relevant studies, and screened them, then analyzed the data using specialized tool and rated the credibility of the results at the end. The final results concluded that the efficiency of treatment of ADSCs combined with scaffold treatment group was superior to the control group. Quality of evidence (GRADE): high. The combination of ADSCs with cellular scaffolds may be effective in promoting repair of bone defects. However, additional, more demanding experiments are still needed to test the effect of ADSCs on bone regeneration.

Adipose-derived stem cell

Bone defect

Cell scaffold

Meta-analysis

Bone Tissue Engineering

The defect of bones is a common problem in orthopedics, with approximately 10% of such patients healing poorly(Mizrahi et al. 2013), the healing rate depends mainly on the magnitude of the flaw, the larger the flaw is, the lower rate of repair will be(SCHMITZ and HOLLINGER 1986). Usually, the bone defects caused by infection, trauma, compression fractures, joint replacement revisions and bone tumor removal(Herve Petite et al. 2000). As we all known, the tissue grafting is the gold standard of clinical treatment for large bone defects(Matsumura et al. 2019; Cabbad et al. 2019). Unfortunately, the number of grafts needed far exceeds the supply(Hurd et al. 2015). Comfortingly, the bone tissue engineering, which intends to use seed cells to promote regeneration of bone tissue, is rapid developing as a subject of tissue engineering(Zhang et al. 2017). Bone tissue engineering uses seed cells to populate the scaffold and then induce the osteogenic differentiation of it to promote the repair of defects in the surrounding bone tissue(Shadjou et al. 2018). At present, bone tissue engineering is a good alternative treatment option and experimental studies using stem cells as filler cells are ongoing(Iijima and Otsuka 2020).

Mesenchymal stem cells (MSCs) are a general term for cells that have the ability to differentiate into tissues such as cartilage, fat and bone and can renew and differentiate themselves(Dazzi et al. 2006). Although there are many sources that human MSCs can be derived from, like adult blood (PB),bone marrow (BM), adipose tissue (AT), muscle, cord blood (CB) and neonatal umbilical cord (UC), and the MSCs has been shown to promote bone healing(Wright et al. 2002; Peng et al. 2002; Meng et al. 2012, 2013), However, due to the source of acquisition and ethical and other implications, MSCs from adipose and bone marrow are currently mainly used for bone tissue engineering(Hass et al. 2011). ADSCs have such advantages that BMCs do not have(Lan et al. 2020), including small trauma, wide source, easy access and strong immune ability. Therefore, adipose stem cells had become the cells of choice for bone tissue engineering, treatment of bone defects(Zuk et al. 2001; Lan et al. 2020).

The experiments so far have shown that bone tissue engineering has different effects when using different scaffolds and seed cells in the experiments(Cai et al. 2020). Although cells and scaffolds are the two most important key factors in tissue engineering, but the level of results achieved depends on the scaffold(Shadjou et al. 2018),means the choice of scaffold materi, l is crucial(Zeng et al. 2015). Scaffold materials can be natural, synthetic or decellularized tissue scaffolds, and materials can be organic or inorganic(Szpalski et al. 2012, 2013; Laronda et al. 2015). The development of suitable cell scaffolds is a critical issue(Baino and Vitale-Brovarone 2011; Costa-Pinto et al. 2011; Benders et al. 2013; Liu et al. 2013). Many types of stents have been used in experiments, such as gels, gelatin polymer stents, calcium phosphate polymer stents, platelet-rich plasma(Chang et al. 2003; Xia et al. 2004; Nöth et al. 2007; Xu et al. 2013; WU Z et al. 2015; Puvaneswary et al. 2016; Jeong et al. 2020). However, biological scaffolds must allow cells to adhere and to migrate, loading the cells, maintaining their morphology and biological function, and assisting the cells to secrete factors and excrete metabolites in the scaffold environment(Kim et al. 2015). Therefore, more research is needed to determine which scaffold is more suitable for bone tissue engineering. In our analysis, we mainly used the available experimental results to evaluate the effect of the current mainstream seed cells, i.e. ADSCs, combined with different scaffolds on the healing of bone defects.

It has been shown that the skeletal growth pattern of rabbits is similar to that of humans(Kelly 1988; Sang-Hwan Koo et al. 2001; Yasuda et al. 2003; Djasim et al. 2008). Therefore, some experiments using different scaffolds filled with ADSCs to treat bone defects in rabbits are presented in our meta-analysis, which aims to assess the efficacy of ADSCs combined with different scaffolds to repair bone defects for reference.

The meta-analysis protocol was developed and registered in the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY) (registration number: INPLASY202270031).

Search Strategy

After first customizing the relevant search strategy and then developing the relevant literature inclusion and exclusion criteria, the databases such as China Knowledge Network, Wanfang Database, Vipshop, China Biomedical Literature Database, PUBMED, EMBASE, and Cochrane Library were finally searched for a comprehensive search of follow up controlled trials (RCTs) of ADSCs for bone defects, with a search time frame of built until December 2021, with the last update in May 2022. The following are some of our search instructions: Pubmed: (("Adipose Tissue-Derived Mesenchymal Stem Cell") OR ("Adipose Tissue-Derived Mesenchymal Stem Cells") OR ("Adipose Derived Stem Cells") OR ("Adipose Derived Stem Cell")) AND (("bone repair") OR("bone repairs") OR ("bone regeneration") OR ("Fracture Healing")).

Study Selection And Data Extraction

Published experimental studies on the effectiveness of ADSCs in treating bone defects in rabbits as of May 2022, with specific and detailed raw data, were included, and the language was limited to Chinese and English. Literature with non-compliant interventions and unextractable data were excluded, as were reviews, conference proceedings and case reports. Two researchers independently performed literature screening, data extraction, extracted authors, year, sample size of the experimental and control groups, the mean and standard deviation of the experimental and control groups, the size of the defect area, the interventions for the experimental and control groups in each literature, and if there were any disagreements, they were discussed and resolved by two researchers, and finally a meta-analysis was performed using Review Manager 5.4, and the risk of bias was assessed using the Syrcle (Systematic Review Centre for Laboratory Animal Experimentation) (Hooijmans et al. 2014).

Main Outcome

Emerging bone area ratio, results expressed as mean ± standard deviation.

Quality Assessment

Two investigators assessed the study's risk of bias according to the SYRCLE independently. Judgments as 'low, high or unclear risk' were expressed as 'yes, no or unclear'(Iijima and Otsuka 2020), respectively. We defined its unclear when the stratagem of randomization was not reported, and it would be at low risk when the random consequence assessment or blinding of consequence assessor were intimated. Two scholars conducted the outcome evaluation independently, and we negotiated to deal with the differences of opinion.

Statistical analysis

Review Manager 5.4 from the Cochrane library was used to process the data. Differences between experimental and control groups were continuous variables, so expressed the results as SMD and 95% confidence intervals (CIs). Heterogeneity was expressed using the I² statistic, with 25–50%, 50–75%, and > 75% corresponding to low, moderate, and high heterogeneity, respectively(Higgins et al. 2003).

When the I2 value is beyond 50%, we will recheck whether the included original data are correct or not first to explore the source of heterogeneity. If the included data are right, we use the cut-and-fill method and the removal of a single study method then to carry out Sensitivity analysis.

Search and research options

We identified 1395 studies from the database（PubMed (n=482)、EMBASE (n=396)、Cochrane (n=3)、China Biomedical Literature Database (n=87)、China Knowledge Network（n=341）、Wanfang Database(n=79)、Vipshop（n=7）. After removing 330 duplicate articles, 1065 studies remained. Then we excluded 863 studies through a first screening of titles and abstracts. and additional 199 studies were excluded when we evaluated all the full-text manuscript. Finally, a total of 3 literature were entered in this meta-analysis. (Figure 1).

Study characteristics

Table 1 shows all characteristics of the 3 studies. The processing of the 3 studies was essentially similar.

We included 3 animal experiments in this meta-analysis. The years of publication were 2013 to 2019. All experiments were conducted with New Zealand rabbits. First experiment was performed with a 2-cm bone defect in the radius followed by a blank control at the control bone defect and filling the experimental group with rADSCs/β-TCP bone tissue engineering complex for 8 weeks(WU Z et al. 2015); Second experiment was performed with a 8-mm total bone defect in the cranial vault bilaterally followed by filling the control bone defect with β-TCP and the experimental group with β-TCP/Cell/Sim(Xu et al. 2013). The last experiment, after creating a 1.5 cm diameter bone defect in the rabbit skull, the control group was filled with saline as a blank control and the experimental group was filled with nPRP/ASCs complex for 16 weeks(Jeong et al. 2020).

Assessment of bias risk

Table 2 shows the results of the risk of bias assessment for the 3 studies. Both WU Z(WU Z et al. 2015) and Woonhyeok(Jeong et al. 2020) studies said randomized, but did not specifically describe the method, XU L's study did not mention randomization(Xu et al. 2013). Therefore, the risk of bias in all 3 studies was unclear in terms of sequence generation and allocation concealment. All studies documented that the experimental subjects were adult New Zealand White rabbits of similar age and weight. Therefore, the risk of bias for baseline characteristics was low. None of the three studies mentioned housing conditions at the time of feeding, nor did they report whether rats were randomly housed in the experiments. Results from all three studies were reported, without loss of experimental specimens. Although poorly described, we discussed and agreed that the risk of bias for these studies was low because the investigator's influence on the subjects was small and the outcome measures were instrumentally objective.

Three of the three included studies reported results related to the ratio of new bone area. Therefore, a quantitative analysis of these 3 studies was performed, and the results of the meta-analysis are presented in Figure 2. Compared with the control group, the treatment of bone defects with ADSC combined with different scaffolds significantly increased the ratio of new bone area (SMD6.24, 95% CI, 4.11 to 8.37). A low degree of heterogeneity was observed (I2=19%). The results showed a low degree of heterogeneity, so no heterogeneity analysis was performed. The outcome indicators were all continuous variables, so the SMD effect model was used, the IV method was used for statistics, and the 95% confidence interval was used for the overall analysis using the random effect model. And we used GRADEpro software to grade the results of the meta-analysis, and the credibility rating result is: high. (Figure 3).

According to the results of the Syrcle risk of bias assessment table, the overall risk of bias can be assessed as low or unknown risk, because there are few relevant experiments and the design of randomization of the experiments is very lacking.

The current development of bone tissue engineering brings great hope for the treatment of bone defects, and many experiments have proven that the use of adipose stem cells combined with cellular scaffolds to fill bone defects and induce differentiation can have a therapeutic effect, and what we need to do is to study in depth how to optimize the therapeutic effect once the positive effect of stem cells in treatment is fully confirmed, in order to successfully overcome the long-standing problem of bone defect treatments.

Our meta-analysis included 3 studies to compare the use of adipose-derived stem cells combined with different scaffolds for the treatment of borderline bone defects. Compared with natural healing, it has obvious promotion significance. A study(Tajima et al. 2015) used ASC/PRP mixture to treat bone defects in the lower leg of rats, and more pronounced bone growth was clearly observed in the treatment group than in the comparison group during the treatment, concluded that the combination of ASCs and PRP had significant efficacy on bone regeneration. Another study(Yoshida et al. 2019) using adipose stem cell slices to repair distal femoral bone defects also yielded positive results for better treatment outcomes compared to the control group.

We could know after a thorough search that this is the first systematic review and meta-analysis to evaluate the effectiveness of ADSCs in combination with different scaffolds for the treatment of bone defects. We evaluated homogeneous stem cell sources and rabbit models. And the results showed the same low heterogeneity. However, randomization was found to be important in clinical trials during the bias evaluation to offset the effects of other factors. And compared to human clinical trials, randomized designs have less impact on the results of animal experiments because in animal studies, the study subjects are usually the same animals of essentially the same age and weight. However, Jeong et al.(Jeong et al. 2013) have mentioned that the results obtained in experiments where blinding was not maintained during treatment may be possible after overestimation. Housing conditions can have a significant impact on experimental animals and thus affect the results of experiments(van de Weerd et al. 2002). We found that all three studies we included were poorly designed in terms of randomization, so the experimental results were likely overestimated.

The results of this analysis have limitations. Due to the small number of studies, the evaluation of the efficacy of ADSCs derived from this meta-analysis remains to be validated at a later stage. Quality assessment of the studies was generally low due to the lack of description of randomization methods, allocation concealment, and blinding. However, Conradi et al.(Conradi and Joffe 2017) reported that about animal studies, published studies are more informative than unpublished ones. Therefore, the results of this analysis can provide some reference value.

Our meta-analysis showed that ADSCs combined with cell scaffolds can effectively promote the healing of bone defects. However, results from an unblinded design may lead to overestimation of the efficacy of ADSCs. And there are still few such experiments, so to avoid bias, we must evaluate the efficacy of adipose stem cells by increasing the experimental size and designing the study more rigorously.

Funding Statements

This work was funded by the Qinghai Provincial Science and Technology Program， Project No. 2019-ZJ-7067

Author Contributions

Conceptualization, Draft the manuscript, XIONG YB; Process the data, XIONG YB and LIU JH; Writing—review & editing, XIONG YB, LI CL, LIU JH and HE YH; XIONG YB, LI CL, LIU JH and HE YH all authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

Ethics approval and consent to participate

Not applicable.

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Table 1. Characteristics of the included studies

Characteristics of the included studies
Study	Year	Tsample	Csample	Tmean	Cmean	Tsd	Csd	Defect area	Experimental intervention	Control intervention	Outcomes
WU Z	2015	8	8	54.79	19.25	4.9	3.09	0.5*2	rADSCs/β-TCP	Blank	Bone regeneration area ratio
Woonhyeok Jeong	2019	8	6	80.16	56.19	2.834	6.101	1.5*1.5	nPRP/ASCS	Normal saline	Bone regeneration area ratio
XV L	2013	6	6	29.07	8.38	4.15	1.26	3.140.40.4	β-TCP/Cell/Sim	β-TCP	Bone regeneration area ratio

Table 2. Results of SYRCLE (Systematic Review Center for Experimental Animal Experiments) assessment

Individual risk of bias and quality assessment using SYRCLE (Systematic Review Centre for Laboratory Animal Experimentation)

Study	Selection			Performance		Detection		Attrition	Reporting	Others
Study	Sequence generation	Baseline characteristics	Allocation concealment	Random housing	Performance blinding	Random outcome assessment	Blinding of outcome assessment	Incomplete outcome data	Selective outcome reporting	Other bias
Woonhyeok Jeong 2019	Unclear	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Yes	Yes	Yes
WU Z 2015	Unclear	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Yes	Yes	Unclear
XV L 2013	Unclear	Yes	Unclear	Unclear	Unclear	Unclear	Unclear	Yes	Yes	Yes

Notes: A “yes” judgement indicates a low risk of bias; a “no” judgment indicates high risk of bias; the judgment will be “unclear” if insufficient details have been reported to assess the risk of bias properly.

No competing interests reported.

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Efficacy of adipose-derived stem cells combined with different scaffolds to repair bone defects: a systematic review and Meta-analysis

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Abstract

Figures

Introduction

Materials And Methods

Search Strategy

Study Selection And Data Extraction

Main Outcome

Quality Assessment

Statistical analysis

Results

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

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