A comprehensive literature search was carried out using the PubMed and Scopus databases to identify relevant studies from January to June 2022. These databases were selected for this review because of their broad biomedical coverage, strong indexing of peer-reviewed journals, and user-friendly interfaces, ensuring efficient and high-quality literature retrieval within time and personnel constraints. However, we acknowledge that excluding additional databases such as EMBASE and Web of Science may introduce selection bias and could result in the omission of relevant studies indexed exclusively there. Future reviews may benefit from a broader database strategy to enhance comprehensiveness and reduce the risk of publication bias. Nonetheless, the search strategy used a combination of keywords related to "stem cells," "embryonic stem cells," “hematopoietic stem cells,” "induced pluripotent stem cells," “red cell substitute,” “red blood cells,” “oxygen carrier,” “blood production,” “blood substitutes,” and “artificial blood.” No other search strings beyond the determined keywords were employed.

The search aimed to identify research exploring key parameters of different stem cell sources used in stem cell-derived red blood cells.

This review included original research articles, clinical trials, in vitro studies, and animal model studies exploring stem cell-derived red blood cells as an alternative to conventionally procured blood in transfusion medicine and blood bank services. Only English-language studies were considered. Exclusion criteria included studies that did not specifically focus on blood substitutes, those unrelated to stem cell-derived red blood cells, or research centered on non-stem cell approaches. The exclusion criteria also encompassed non-scientific articles, studies published in languages other than English, and research published before 1990 or after June 2022.

In addition to exclusion based on relevance, duplicates, incomplete data, commentary pieces, conference abstracts without full manuscripts, and non-peer-reviewed sources were also excluded to maintain data quality and consistency. Some potentially relevant articles were excluded due to language barriers or lack of full-text access. Non-English studies were excluded primarily due to translation limitations and the lack of reliable linguistic resources, which could have compromised accurate data extraction and interpretation. We acknowledge that this introduces a potential language bias, possibly omitting valuable insights published in other languages. To mitigate this, we thoroughly screened the titles and abstracts across the two selected databases (PubMed and Scopus), known for indexing a broad spectrum of high-impact, peer-reviewed English-language publications. Nonetheless, future reviews could benefit from multilingual collaboration to enhance inclusivity and comprehensiveness.

Both qualitative and quantitative studies were considered. Qualitative research included experience reports, literature reviews, integrative reviews, systematic reviews, meta-analyses, and scoping reviews. For quantitative studies, case-control, prospective and retrospective cohort, and experimental studies were included. Additionally, relevant citations and references from all identified studies were reviewed to ensure comprehensive coverage.

The screening and selection process was conducted using Mendeley version 1.19.4 reference management software, following a structured three-phase approach. In Phase I, duplicate records were removed. Phase II involved screening article titles and abstracts, while Phase III entailed a comprehensive review of the full-text articles selected from the previous phase. Three independent reviewers (BHOAA, SSN, and SNFMN) assessed the titles and abstracts of all identified studies. To ensure reliability and minimize bias, they followed a standardized selection and data extraction protocol. Any discrepancies during study selection or data extraction were resolved through discussion among the reviewers. If disagreements remained unresolved, a fourth reviewer (MAZ) was consulted to facilitate consensus. In cases where consensus could not be reached immediately, the study was re-evaluated collectively before a final decision was made. This process ensured consistency, minimized bias, and maintained the integrity of the review.

For each included study, a structured data extraction process was employed to collect key information, including author, publication year, stem cell type, culture period, study purpose, and parameters of RBC maturation (such as enucleation rate and expansion yield). To ensure accuracy and consistency, the reviewers collaboratively examined the extracted data, minimizing variability in interpretation.

Additionally, to enhance transparency and reproducibility, the standardized data extraction form used in this review has been provided as supplementary material (Supplementary 1). The form includes key fields such as stem cell type, source, culture conditions, differentiation protocols, enucleation rates, hemoglobin expression, and study outcomes, which were consistently used across all included studies.

This review presents its findings using a narrative synthesis approach, adhering to the PRISMA-ScR guidelines to comprehensively identify all available evidence and highlight key characteristics. Figure 1 provides an overview of the literature search process. Initially, 11,074 articles were extracted from PubMed and Scopus. After removing duplicates, 8,854 articles remained. Sixty-five articles were included after removing titles and abstracts that did not meet the screening criteria. Next, three reviewers read these articles to confirm whether each one satisfied the research questions and eligibility criteria.

Finally, 15 full-text articles were included and subsequently subclassified based on stem cell type: six studies on ESCs, five on HSCs, and four on iPSCs. ESC-related studies predominated in this scoping review, whereas HSCs and iPSCs had an equal number of studies examining the most suitable stem cell-derived RBCs.

Figure 1

Table 1

Author (Year)	Type of stem cell & Culture time	Aim	RBCs maturation		Yield/expansion (RBCs per stem cell blood unit)
			Enucleation rate (%)	Hb ration (Hb expression)
Chang et al., (2006)	hESCs 15 to 56 days	To study the expressed Hb in RBCs-like cells from hESCs	Not quantified	Embryonic Hb Gower I (ζ2ε2) HbF (γ2) Rare HbA (α and β globins)	Not quantified
Lu et al., (2008) (Lanza group)	hESCs 19-21 days	To study the biological properties of in lab enucleated RBCs from hESCs.	> 60%	Embryonic Hb Gower I (ζ2ε2) HbF (α2γ2) HbA, only some α chains	3.86 x 1010
Hiroyama et al., (2008) (Nakamura group)	murine ESCs 120 days	To develop functional RBCs from murine ESCs	Not quantified	Only HbA (α and β globins)	Visible, improved RBC counts in vivo
Ma et al., (2008)	hESCs 18 days	To develop functional erythrocytes from hESCs in vitro	> 60 to 82%	γ and β globins	2 × 104 - 106
Honig et al., (2010) (Lanza team)	hESCs 21 days	To investigate the Hb subunits of erythroid cells derived from hESCs	NA	Hb Gower I>Hb Barts (γ4)	Not quantified
Dias et al., (2011)	hESCs 90 days	To generate RBCs from hiPSCs	12%	ε - and γ- globins	2.5 x 105
Malik et al., (1998)	HSCs 21 days	To produce human RBCs model form HSCs	10 to 42%	β globins with insignificant fetal globin	Not quantified
Neildez-Nguyen et al., (2002) (Douay group)	HSCs 18 - 21 days	To produce a large-scale ex-vivo hRBCs	60 to 95%	more HbF (in vitro) HbA (> 95% in vivo)	5 x 109-2.8 x 1011
Giarratana et al., (2005) (Douay group)	HSCs 15 to 18 days	To generate a full mature human RBCs from HSCs	98% ±1	HbA > HbF (peripheral blood & adult bone marrow) HbF> HbA (cord blood)	up to 1.95 x 106
Shah et al., (2016)	HSCs 18 days	To generate and evaluate stem-derived RBCs from HSCs	53.4%	γ > α globins	4 x 109
Zhang et al., (2017)	HSCs 21 days	To generate large scale RBCs from HSCs	50% ± 5.7	HbF and β globins	2.9 ~5 ×1011
Lapillone et al., (2010) (Douay group)	hiPSCs 25 days	To generate and differentiate hiPSCs into definitive RBCs	4 to 10%	ε - and γ- globins	up to 4.4 x 108
Dias et al., (2011)	hiPSCs 90 days	To generate RBCs from hiPSCs	2 to 10%	ε - and γ- globins	6 x 108
Kobari et al., (2012) (Douay group)	hiPSCs 52 days	To generate a terminal matured RBC from iPSCs	20 to 26%	ε - and γ globins	1.5 - 2.8 x 109
Park et al., (2020)	hiPSCs 31 days	To develop a bankable hiPSCs	Not quantified	Undetectable amount of HbA	8 x 106-1.8 x 107

Abbreviations: Adult hemoglobin (HbA); Fetal hemoglobin (HbF); Hemoglobin (Hb); Human embryonic stem cells (hESCs); Human induced pluripotent stem cells (hiPSCs); Hematopoietic stem cells (HSCs); Reb blood cells (RBCs)

Table 2

Parameter	hESCs	HSCs	iPSCs
Culture Time (day)	15 - 90 days (for murine ESCs up to 120 days)	15 - 21 days	25 - 90 days
RBCs Yield (per stem cell blood unit)	105 - 1010	106 - 1011	105 - 109
Enucleation Rate (%)	>60%	10 - 98%	2 - 26%
Hb Expression	Mainly embryonic/HbF	Mostly HbA	Primarily HbF with some HbA

Abbreviations: Adult hemoglobin (HbA); Fetal hemoglobin (HbF); Hemoglobin (Hb); Embryonic stem cells (ESCs); Induced pluripotent stem cells (iPSCs); Hematopoietic stem cells (HSCs); Reb blood cells (RBCs)

The final 15 full-text articles included in the final analysis were further subclassified based on the type of stem cells studied. This included six studies focused on embryonic stem cells (ESCs), five on hematopoietic stem cells (HSCs), and four on induced pluripotent stem cells (iPSCs). Studies on ESCs were the most predominant in this scoping review, while HSCs and iPSCs had an equal number of studies, reflecting ongoing efforts to identify the most suitable stem cell-derived substitutes for red blood cells. Table 1 outlines the characteristics of the 15 studies finalized and included in this review. For clearer comparison, a consolidated overview of the three stem cell types across consistent parameters is presented in Table 2. Additionally, the most commonly used culture medium is Iscove's Modified Dulbecco's Medium (IMDM) supplemented with cytokines, while the differentiation protocols employed include a stepwise induction using erythropoietin (EPO), stem cell factor (SCF), interleukin-3 (IL-3), and dexamethasone.

Most of the articles identified and included in this review utilized human ESCs for culturing, with culture durations ranging from 15 to 28 days on average. However, outlier studies for human ESCs by Dias et al. (2011) and Chang et al. (2006) reported a much longer culture period of up to 56 and 90 days, respectively, while Hiroyama et al. (2008) reported 90 days for murine ESCs42, 43, 44. Some studies such as Chang et al. (2006), Hiroyama et al. (2008), and Honig et al. (2010) lacked key information, such as RBC yield and enucleation rates43, 44, 45. Such key data were either not reported or only partially described, resulting in NA (not available) entries in Table 1. This lack of uniform reporting limits direct comparison across studies in Table 2 and may affect the strength of our conclusions regarding the relative efficiency of different stem cell sources. The absence of such critical metrics highlights the need for standardized reporting practices in future research to enable more robust meta-analyses and to facilitate translational comparisons.

Among the remaining studies, Lu et al. (2008)24 and Ma et al. (2008)46 reported enucleation rates exceeding 60%, with Lu et al. (2008)24 also achieving the highest yield, followed by Dias et al. (2011)42. All studies demonstrated that progenitor cells expressed embryonic and fetal hemoglobin subunits during the differentiation process. Notably, Nakamura et al. uniquely detected adult hemoglobin (HbA) in their cultured cells.

The study by Malik et al. (1998) successfully established an in vitro human RBC model23. However, the enucleation rate was ≤ 42%, and yield data were not provided. The RBCs produced primarily expressed adult β-globin hemoglobin. Subsequent studies reported more promising results, with Neildez-Nguyen et al. (2002)47 and Giarratana et al. (2005)21 achieving enucleation rates exceeding 95%. More recent studies, including those by Shah et al. (2016)48 and Zhang et al. (2017)49, reported enucleation rates of 53.4% and 50%, respectively. Zhang et al. (2017)49 also achieved the highest cell expansion rate, reaching 4.8–5 × 10¹⁹ RBCs per stem cell blood unit. While most studies reported fetal hemoglobin (HbF) as the predominant expressed form, studies utilizing peripheral blood or adult bone marrow sources21 and in vivo approaches47 demonstrated higher expression of HbA.

Notably, the outcomes of HSC-derived red blood cell production show variability across studies. For example, Malik et al. (1998) reported enucleation rates ranging from 10–40%, whereas Giarratana et al. (2005) achieved up to 98% enucleation. This discrepancy may be attributed to several factors, including differences in HSC sources (e.g., cord blood vs. peripheral blood), culture duration, cytokine cocktails, and stage-specific supplementation with factors such as erythropoietin (EPO), stem cell factor (SCF), or glucocorticoids. Furthermore, advances in protocol optimization and improvements in cell sorting or feeder layer techniques over time may also explain such enhanced outcomes in later studies. This underscores the importance of standardized methodologies and comprehensive reporting to ensure reproducibility and comparability across research efforts.

Lastly, among the four studies that used iPSCs, Kobari et al. (2012)50 achieved the highest cell expansion rate, ranging from 1.5 to 2.8 × 10⁹ RBCs per stem cell blood unit. However, enucleation rates across all studies were low, not exceeding 26%. Dias et al. (2011)42 and Hiroyama et al. (2008) reported a significantly longer culture period compared to other studies, including Lapillonne et al. (2010), Kobari et al. (2012), and Park et al. (2020)34, 44, 50, 51. While all studies documented the expression of embryonic and fetal hemoglobin subunits, Park et al. (2020), despite being the most recent, did not report the enucleation rate51.

Analyses of the findings demonstrate the development of reticulocytes from embryonic stem cells (ESCs), hematopoietic stem cells (HSCs), and induced pluripotent stem cells (iPSCs) in laboratory settings. These studies also reported relevant process parameters. This scoping review identified key benchmarks and insights into the field. Among the stem cell types analyzed, ESCs, HSCs, and iPSCs were chosen as they are the most sourced in generating stem cell-derived red blood cells (RBCs). Other approaches, such as immortalized stem cell lineages, represent newer methods in this area but were less represented in the screened literature. For example, a research group led by Trakarnsanga at the University of Bristol is working on immortalized stem cell lineages as potential oxygen carriers30. Since 2017, this team has been conducting clinical trials in the United Kingdom with 20 to 25 human subjects under a consortium that includes the National Health Service (NHS), universities, blood service centers, and corporations. Although the type of stem cells used in these trials has not been disclosed, their work underscores the potential of alternative stem cell sources for RBC production52.

While several reviews have explored the generation of red blood cells (RBCs) from various stem cell sources, most focus either on a single cell type or broadly summarize outcomes without consolidating critical biological parameters. This scoping review addresses that gap by uniquely synthesizing and directly comparing key functional metrics across embryonic stem cells (ESCs), hematopoietic stem cells (HSCs), and induced pluripotent stem cells (iPSCs). Specifically, we analyze and map enucleation rates, hemoglobin subtype expression (HbA, HbF), culture duration, and RBC yield—four parameters that are essential for assessing the translational potential of stem cell-derived RBCs. This comparative approach not only highlights the relative advantages and limitations of each stem cell type but also serves as a foundational reference to guide optimization efforts and standardization in future research and clinical translation.

Among the three stem cell types reviewed, ESCs were the most represented in the final articles and initial screenings. This prominence is likely due to the earlier discovery of ESCs in 1981, which made them the first isolated stem cell type. Their pluripotent nature, which allows differentiation into all tissue types, and their relative ease of genetic manipulation for developing animal models have established ESCs as a key component of stem cell research. In contrast, iPSCs, discovered in 2006 by Takahashi and Yamanaka14, represent a breakthrough that was built upon insights from ESC research. HSCs, as the natural progenitors of all blood cells, offer distinct advantages due to their self-renewal capabilities and fewer ethical concerns compared to ESCs.

The use of ESCs remains ethically contentious in many jurisdictions due to their embryonic origin, leading to stricter regulatory oversight and limited public acceptance. In contrast, iPSCs and adult-derived HSCs offer more ethically acceptable and practically feasible alternatives. iPSCs provide the advantage of patient-specific compatibility and circumvent immune rejection, although their genomic stability and safety still require careful validation. Meanwhile, HSCs sourced from bone marrow, cord blood, or mobilized peripheral blood are already well-established in clinical practice, making them attractive candidates despite their lower expansion capacity.

The culture duration for transforming stem cells into enucleated RBCs is consistently reported to range between 20 and 28 days, aligning with established timelines in prior research. However, exceptions were noted, such as the work by Dias et al. (2011)42, which required a longer culture period due to insufficient enucleation rates after RBC expansion. This review also identified a correlation between enucleation rate and yield, wherein a low or absent enucleation rate led to limited or unreported yields. Factors contributing to this limitation may include intrinsic properties of the stem cell lines, such as genetic mutations, signaling pathways, and cell membrane receptor profiles, as well as external environmental conditions, including chemical concentrations and treatment protocols. Dias et al. (2011) highlighted the need for further investigation into these factors42. While earlier studies, such as Malik et al. (1998), focused primarily on demonstrating in vitro RBC production from HSCs, they did not address large-scale production or yield but successfully reported adult β-globin expression in enucleated RBCs23.

Regarding hemoglobin expression, early studies predominantly identified embryonic and fetal hemoglobin (HbF) chains in stem cell-derived RBCs. However, Giarratana et al. demonstrated that HSCs derived from peripheral blood and bone marrow expressed predominantly adult hemoglobin (HbA), whereas cord blood-derived RBCs exhibited higher fetal hemoglobin (HbF) levels, consistent with their natural composition21. Similarly, Neildez-Nguyen et al. observed increased HbA expression when laboratory-derived RBCs were introduced into a physiological environment, suggesting that biophysical factors and chemical interactions in vivo can influence hemoglobin expression profiles47.

In addition to these parameters, researchers should consider reporting other critical characteristics, including biochemical and membrane properties (e.g., 2,3-diphosphoglycerate and ATP levels), O2-Hb dissociation curves, cell size (compared to the normal RBC diameter of 6–8 µm), hemoglobin content, estimated transfusion units relative to therapeutic RBC requirements (approximately 2 × 10¹² RBCs per stem cell blood unit), and whether laboratory-derived RBCs express specific blood group antigens or resemble universal O Rh-negative RBCs.

Based on the results analyzed earlier, HSCs appear to be the most promising source for generating RBC substitutes. They demonstrate robust erythroid maturation within a consistent culture period of 21 days, achieving high yields with favorable enucleation rates. Additionally, HSCs are associated with fewer ethical concerns compared to ESCs and are less costly than iPSCs. Among HSC sources, discarded cord blood units, which often fail to meet volume thresholds for transplantation, represent an underutilized resource for in vitro RBC expansion. Unfortunately, these units are not usually stored for this purpose.

Some HSC-related studies demonstrate suboptimal outcomes in terms of red blood cell yield, enucleation rates, or hemoglobin expression. This underperformance can be attributed primarily to source heterogeneity and protocol variability. HSCs can be derived from various sources such as bone marrow, peripheral blood, or umbilical cord blood, each with distinct biological characteristics and proliferative capacities. For instance, cord blood-derived HSCs may exhibit higher proliferation but lower enucleation efficiency compared to adult sources. Additionally, differences in isolation techniques, such as CD34⁺ selection purity, as well as variability in cytokine combinations, serum supplementation, and oxygen tension during culture, significantly impact differentiation outcomes. Early-phase studies may also lack stage-specific optimization of differentiation protocols or use outdated culture systems, leading to inconsistent or inefficient RBC production. These disparities highlight the urgent need for harmonized protocols and more precise characterization of starting HSC populations to improve reproducibility and clinical translation.

Finally, future research should focus on addressing the key bottlenecks in scaling up stem cell-derived RBC production, including cost-effectiveness, manufacturing efficiency, and batch-to-batch reproducibility. A major hurdle in clinical translation is the low RBC yield per stem cell unit relative to transfusion needs. Current protocols often generate insufficient quantities, far below the ~2×10¹² RBCs required for a single unit of transfusable blood. Achieving such volumes would require substantial upscaling, optimized bioreactor systems, and cost-effective, serum-free media, all of which remain ongoing challenges in the field.

Moreover, current differentiation protocols often involve costly cytokines and prolonged culture times, which limit clinical and commercial viability. Developing serum-free, chemically defined media and integrating bioreactor-based expansion systems could help streamline production. Furthermore, advances in gene editing and synthetic biology may enhance enucleation efficiency and hemoglobin switching to adult forms, further improving the functionality of lab-generated RBCs.

Although notable protocol differences across studies were identified, we did not conduct a meta-regression analysis due to the substantial heterogeneity in study designs, outcome reporting, and the small number of eligible studies. As a scoping review, our primary objective was to map existing evidence and summarize key parameters, rather than statistically pool outcomes. Given these limitations, a qualitative synthesis was deemed more appropriate. However, future systematic reviews with a larger, more standardized dataset could explore quantitative approaches such as meta-regression to better assess the impact of protocol variability on outcomes like enucleation rate, yield, and hemoglobin expression.

In summary, this review provides strong evidence supporting the feasibility of generating RBCs from various stem cell sources, with HSCs emerging as the most viable option for future applications. However, the review also highlights a lack of comprehensive studies that address all critical parameters for stem cell-derived RBC production. This gap is partly due to variations in protocols and methodologies, as well as challenges during the initial screening process, which yielded unrelated results due to shared keywords with other biomedical fields. Despite these limitations, the findings underscore the significant potential of stem cell-derived RBCs as substitutes for transfusion purposes, while also identifying areas that require further research and standardization.

In conclusion, significant and rapid progress has been made in the development of blood transfusion alternatives. This scoping review highlights that ESCs are the most widely used stem cell source for generating RBC substitutes, followed by HSCs and iPSCs. These three stem cell types have emerged as the primary candidates for artificial blood production. The review aims to assist researchers by providing essential insights into key parameters that should be considered when reporting and publishing experimental findings on artificial blood, including enucleation rate, hemoglobin composition, and cell expansion.

Based on the findings, HSCs appear to be the most promising source for blood cell substitutes, demonstrating superior culture efficiency, enucleation rates, and expansion potential compared to other stem cell types. While HSCs demonstrate favorable outcomes in terms of culture duration and enucleation efficiency, it is important to note that they represent a heterogeneous population derived from various sources, including cord blood, bone marrow, and mobilized peripheral blood. These sources differ in proliferation capacity, differentiation potential, and accessibility, which may significantly influence the reported outcomes. Therefore, while HSCs appear promising, their performance cannot be universally generalized without accounting for source-specific variations. Future studies should stratify findings based on HSC origin to enable more precise comparisons and optimize protocols accordingly. Nonetheless, this review serves as a valuable resource for scientists by summarizing previous studies and their key findings, offering a comprehensive and concise reference to support future research. Additionally, it encompasses studies focusing on RBC substitutes derived from ESCs, HSCs, and iPSCs.

Emerging approaches such as immortalized erythroid progenitor cell lines offer a promising avenue for consistent, large-scale production of red blood cells with higher yields and improved reproducibility. These cell lines bypass donor variability and enable standardized, controlled erythropoiesis under GMP conditions. While not the primary focus of this review, such technologies could complement stem cell-based methods by providing stable platforms for preclinical testing and transfusion applications.

Looking forward, future studies should aim to adopt standardized reporting frameworks that include details on cell source, passage number, culture conditions, enucleation efficiency, hemoglobin subtype expression, and yield per input cell. Transparent, harmonized reporting will facilitate cross-study comparison, replication, and eventual clinical translation of stem cell-derived RBC technologies.

However, the final number of included articles was limited due to restrictions in full-text availability and language barriers. The scope of databases used in this review may also have led to the unintentional omission of relevant studies on stem cell-derived blood substitutes. Furthermore, as this review did not include a formal quality appraisal assessment, some lower-quality studies may have been included.

While this review aimed to comprehensively capture relevant studies on stem cell-derived red blood cells, some publications were excluded due to full-text unavailability or language constraints. This may introduce a degree of selection bias, as potentially valuable data particularly from non-English-speaking regions could not be assessed. Acknowledging this, future reviews could benefit from multilingual collaboration or expanded database access to enhance global representation and comprehensiveness of the evidence base. Despite these limitations, this study provides a valuable foundation for advancing research in artificial blood substitutes and highlights key areas for further investigation.

ATP: Adenosine Triphosphate, CD34+: Cluster of Differentiation 34, EMA: European Medicines Agency, EPO: Erythropoietin, ESC / ESCs: Embryonic Stem Cell(s), FDA: Food and Drug Administration, GMP: Good Manufacturing Practice, HBOCs: Hemoglobin-Based Oxygen Carriers, HbA: Adult Hemoglobin, HbF: Fetal Hemoglobin, HSC / HSCs: Hematopoietic Stem Cell(s), IL-3: Interleukin-3, IMDM: Iscove’s Modified Dulbecco’s Medium, iPSC / iPSCs: Induced Pluripotent Stem Cell(s), NHS: National Health Service, PFC: Perfluorocarbon, PRISMA-ScR: Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement for Scoping Reviews, RBC / RBCs: Red Blood Cell(s), RESTORE (trial name, not spelled out in the text), SCF: Stem Cell Factor.

We sincerely thank the Ministry of Higher Education, Malaysia, for supporting this research through the Fundamental Research Grant Scheme (FRGS), which facilitated the work presented in this scoping review.

(I) Conceptualization, methodology development, data curation, formal analysis, and drafting of the original manuscript: MAZ, SSN (II) Administrative support, critical review, and manuscript editing: BHOAA, SSN, SNFMN, MYA, RM (III) Data acquisition, validation, and analysis: MAZ, BHOAA, SSN (IV) Experimental execution and dataset compilation: BHOAA, MYA, RM (V) Data analysis, interpretation, and result evaluation: MAZ, BHOAA, SSN, SNFMN (VI) Final approval of the manuscript and accountability for the integrity of the work: All authors.

This review is a part of research funded by the Fundamental Research Grant Scheme (FRGS), Malaysia [Grant number: FRGS/1/2019/STG07/USM/02/13].

Data and materials used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Not applicable.

Not applicable.

The authors declare that they have no competing interests.