Effects of incorporating natural substances into sodium alginate in the cultivation of human dental pulp stem cells: a systematic review with meta-analysis

ARAÚJO, Lavina Sousa; MAIA, Susana Joice Mendes; SOUZA, Nayara Oliveira de; SILVA, Paulo Goberlânio de Barros; SABOIA, Vicente de Paulo Aragão

doi:10.4322/bds.2026.e4837

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Review • Braz. Dent. Sci. 29 • 2026 • https://doi.org/10.4322/bds.2026.e4837 linkcopy

Effects of incorporating natural substances into sodium alginate in the cultivation of human dental pulp stem cells: a systematic review with meta-analysis

Efeitos da incorporação de substâncias naturais ao alginato de sódio no cultivo de células-tronco da polpa dental humana: uma revisão sistemática com meta-análise

Authorship SCIMAGO INSTITUTIONS RANKINGS

Objective This study aimed to evaluate, through a systematic review with meta-analysis, the effects of incorporating natural substances into sodium alginate scaffolds on human dental pulp stem cells (hDPSCs), considering outcomes such as adhesion, proliferation, and differentiation.

Material and Methods A comprehensive literature search was conducted in PubMed, LILACS, Scopus, Web of Science, and Embase using the MeSH descriptors “Stem Cells” and “Alginates,” combined with the Boolean operator “AND” and their respective entry terms. In vitro studies without language or date restrictions that incorporated natural substances into alginate and evaluated their effects on hDPSCs were included. Two independent reviewers performed study selection and data extraction. Risk of bias was assessed, and Cohen’s d with 95% confidence intervals (CIs) was calculated for proliferation outcomes.

Results Out of 14,290 records retrieved, five studies met the inclusion criteria, all with a low risk of bias. Three studies (n = 48 samples) were included in the meta-analysis, which revealed a significant positive effect of incorporating natural substances on hDPSC proliferation (Cohen’s d = 2.66; 95% CI = 1.27–4.05). Substances such as hydroxyapatite, gelatin, agarose, plasma rich in growth factors (PRGF), growth factors, nano-hydroxyapatite, and lactose-modified chitosan (QTL) were used to enhance alginate properties. Notably, hydroxyapatite and PRGF improved both proliferation and osteogenic differentiation.

Conclusion The incorporation of natural substances into sodium alginate scaffolds appears to enhance biological responses of hDPSCs, supporting their potential use in regenerative endodontics and tissue engineering.

KEYWORDS:
Dental pulp; Sodium alginate; Stem cell; Tissue engineering; Tissue Scaffold

Database and trucations	Items found
PUBMED	1.857
(((((((((((((((("Stem Cells"[Mesh]) OR "Cell, Stem") OR "Cells, Stem") OR "Stem Cell") OR "Progenitor Cells") OR "Cell, Progenitor") OR "Cells, Progenitor") OR "Progenitor Cell") OR "Mother Cells") OR "Cell, Mother") OR "Cells, Mother") OR "Mother Cell") OR "Colony-Forming Unit") OR "Colony Forming Unit") OR "Colony-Forming Units") OR "Colony Forming Units") AND (((((((((((((((((((((((((((("Alginates"[Mesh]) OR "Alginate") OR "Kaltostat") OR "Vocoloid") OR "Calginat") OR "Potassium Alginate") OR "Alginate, Potassium") OR "Alginic Acid, Potassium Salt") OR "Sodium Alginate") OR "Alginate, Sodium") OR "Alginic Acid, Sodium Salt") OR "poly(Mannuronic Acid), Sodium Salt") OR "Kalrostat 2") OR "Sodium Calcium Alginate") OR "Alginate, Sodium Calcium") OR "Calcium Alginate, Sodium") OR "Barium Alginate") OR "Alginate, Barium") OR "Alginic Acid, Barium Salt") OR "Calcium Alginate") OR "Alginate, Calcium") OR "Alginic Acid, Calcium Salt") OR "Copper Alginate") OR "Alginate, Copper") OR "Alginic Acid, Copper Salt") OR "Alloid G") OR "Kalrostat") OR "Xantalgin")	1.857
LILACS	2.191
(tw:( "Stem Cells" OR "Cell, Stem" OR "Cells, Stem" OR "Stem Cell" OR "Progenitor Cells" OR "Cell, Progenitor" OR "Cells, Progenitor" OR "Progenitor Cell" OR "Mother Cells" OR "Cell, Mother" OR "Cells, Mother" OR "Mother Cell" OR "Colony-Forming Unit" OR "Colony Forming Unit" OR "Colony-Forming Units" OR "Colony Forming Units") AND (tw:( "Alginates" OR "Alginate" OR "Kaltostat" OR "Vocoloid" OR "Calginat" OR "Potassium Alginate" OR "Alginate, Potassium" OR "Alginic Acid, Potassium Salt" OR "Sodium Alginate" OR "Alginate, Sodium" OR "Alginic Acid, Sodium Salt" OR "poly(Mannuronic Acid), Sodium Salt" OR "Kalrostat 2" OR "Sodium Calcium Alginate" OR "Alginate, Sodium Calcium" OR "Calcium Alginate, Sodium" OR "Barium Alginate" OR "Alginate, Barium" OR "Alginic Acid, Barium Salt" OR "Calcium Alginate" OR "Alginate, Calcium" OR "Alginic Acid, Calcium Salt" OR "Copper Alginate" OR "Alginate, Copper" OR "Alginic Acid, Copper Salt" OR "Alloid G" OR "Kalrostat" OR "Xantalgin") )	2.191
SCOPUS	2.725
(TITLE-ABS-KEY ("Stem Cells" OR "Cell, Stem" OR "Cells, Stem" OR "Stem Cell" OR "Progenitor Cells" OR "Cell, Progenitor" OR "Cells, Progenitor" OR "Progenitor Cell" OR "Mother Cells" OR "Cell, Mother" OR "Cells, Mother" OR "Mother Cell" OR "Colony-Forming Unit" OR "Colony Forming Unit" OR "Colony-Forming Units" OR "Colony Forming Units") AND TITLE-ABS-KEY ("Alginates" OR "Alginate" OR "Kaltostat" OR "Vocoloid" OR "Calginat" OR "Potassium Alginate" OR "Alginate, Potassium" OR "Alginic Acid, Potassium Salt" OR "Sodium Alginate" OR "Alginate, Sodium" OR "Alginic Acid, Sodium Salt" OR "poly(Mannuronic Acid), Sodium Salt" OR "Kalrostat 2" OR "Sodium Calcium Alginate" OR "Alginate, Sodium Calcium" OR "Calcium Alginate, Sodium" OR "Barium Alginate" OR "Alginate, Barium" OR "Alginic Acid, Barium Salt" OR "Calcium Alginate" OR "Alginate, Calcium" OR "Alginic Acid, Calcium Salt" OR "Copper Alginate" OR "Alginate, Copper" OR "Alginic Acid, Copper Salt" OR "Alloid G" OR "Kalrostat" OR "Xantalgin") )	2.725
WEB OF SCIENCE	3.824
TOPIC: ("Stem Cells" OR "Cell, Stem" OR "Cells, Stem" OR "Stem Cell" OR "Progenitor Cells" OR "Cell, Progenitor" OR "Cells, Progenitor" OR "Progenitor Cell" OR "Mother Cells" OR "Cell, Mother" OR "Cells, Mother" OR "Mother Cell" OR "Colony-Forming Unit" OR "Colony Forming Unit" OR "Colony-Forming Units" OR "Colony Forming Units") AND TOPIC: ("Alginates" OR "Alginate" OR "Kaltostat" OR "Vocoloid" OR "Calginat" OR "Potassium Alginate" OR "Alginate, Potassium" OR "Alginic Acid, Potassium Salt" OR "Sodium Alginate" OR "Alginate, Sodium" OR "Alginic Acid, Sodium Salt" OR "poly(Mannuronic Acid, Sodium Salt" OR "Kalrostat 2" OR "Sodium Calcium Alginate" OR "Alginate, Sodium Calcium" OR "Calcium Alginate, Sodium" OR "Barium Alginate" OR "Alginate, Barium" OR "Alginic Acid, Barium Salt" OR "Calcium Alginate" OR "Alginate, Calcium" OR "Alginic Acid, Calcium Salt" OR "Copper Alginate" OR "Alginate, Copper" OR "Alginic Acid, Copper Salt" OR "Alloid G" OR "Kalrostat" OR "Xantalgin")	3.824
EMBASE	3.693
("Stem Cells" OR "Cell, Stem" OR "Cells, Stem" OR "Stem Cell" OR "Progenitor Cells" OR "Cell, Progenitor" OR "Cells, Progenitor" OR "Progenitor Cell" OR "Mother Cells" OR "Cell, Mother" OR "Cells, Mother" OR "Mother Cell" OR "Colony-Forming Unit" OR "Colony Forming Unit" OR "Colony-Forming Units" OR "Colony Forming Units") AND ("Alginates" OR "Alginate" OR "Kaltostat" OR "Vocoloid" OR "Calginat" OR "Potassium Alginate" OR "Alginate, Potassium" OR "Alginic Acid, Potassium Salt" OR "Sodium Alginate" OR "Alginate, Sodium" OR "Alginic Acid, Sodium Salt" OR "poly(Mannuronic Acid), Sodium Salt" OR "Kalrostat 2" OR "Sodium Calcium Alginate" OR "Alginate, Sodium Calcium" OR "Calcium Alginate, Sodium" OR "Barium Alginate" OR "Alginate, Barium" OR "Alginic Acid, Barium Salt" OR "Calcium Alginate" OR "Alginate, Calcium" OR "Alginic Acid, Calcium Salt" OR "Copper Alginate" OR "Alginate, Copper" OR "Alginic Acid, Copper Salt" OR "Alloid G" OR "Kalrostat" OR "Xantalgin")	3.693

Inclusion criteria	Exclusion criteria
In vitro laboratory assays	Literature reviews
Research using natural substances incorporated into sodium alginate	Research with synthetic substances
Research evaluating the effect on the cultivation of human dental pulp stem cells
No time period limitation
No language limitation

Study	Substance incorporated into alginate	Alginate concentration	Format	Type of preparation	Outcomes
Anitua et al. [ ¹⁹ ]	Gelatin, hydroxyapatite and PRGF	2%	Cylindrical	Extrusion bioprinting	Increased cell adhesion and chemotaxis. The addition of HAp and PGRF caused a higher cell proliferation and differentiation rate in osteogenic medium
Oliver-Ferrándiz et al. [ ²⁰ ]	Agarose	3%	Disc	Solution cross-linked with CaCl2	Significant increase in the expression of aggrecan and type II collagen in differentiation medium
Alipour et al. [ ²¹ ]	Gelatin and nanohydroxyapatite	1%	Microcapsule	Needle extrusion	Mitochondrial activity increased 1.26 times after 3 weeks. Increased levels of osteogenic genes (BMP-2, osteocalcin, osteonectin and RUNX-2) and enhanced hDPSCs differentiation in the presence of HAp.
Bhoj et al. [ ²² ]	Growth factors (VEGF and FGF-2)	Not reported	Conical plug	Not reported	Increase in the number of viable cells. The presence of growth factors induced cell proliferation in the first 7 days of culture.
Porrelli et al. [ ²³ ]	Hydroxyapatite and lactose-modified chitosan	2%	Cylindrical	Solution cross-linked with CaCl2	Lactose-modified chitosan did not show a significant effect on cell proliferation, even though a slight positive effect was observed. There was an increase in alkaline phosphatase and extracellular matrix deposition. Cell adhesion was improved and osteogenic differentiation increased.

Certainty assessment
Participants (studies)	Risk of bias	Inconsistency	Indirect evidence	Inaccuracy	Publication bias	Certainty of evidence
Cell proliferation assays
48 (3 ECRs)	Not serious	Not serious	Not serious	Not serious	Highly suspicious publication biasa	⨁⨁⨁◯ Moderate

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E-mail: bds.ict@unesp.br

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[TFN1] ^a
Asymmetrical distribution of points in the funnel plot.