Efficacy of concentrated growth factor compared with other types of regenerative endodontic procedures: a systematic review

Abstract

Background

To investigate the regenerative ability of concentrated growth factor (CGF) during endodontic treatment compared with other regenerative procedures.

Methods

The PubMed, Web of Science Core Collection, Scopus, and Ovid MEDLINE databases were systematically searched to identify studies that examined the use of regenerative endodontic therapy (RET) utilizing CGF for patients, animals, or extracted human teeth. The risk of bias was assessed using the JBI tool for clinical studies, QUIN tool for in vitro studies, and SYRCLE tool for animal studies. The study results were qualitatively synthesized.

Results

A total of 311 studies were initially retrieved from the databases. Ultimately, nine studies were included (three randomized clinical trials, two retrospective studies, three in vitro studies, and one in vivo animal study). The risk of bias was low in two studies and moderate in seven studies. Compared with other types of regenerative procedures, CGF has a similar influence on root dentinal thickness and apical foramen width. The clinical success rate was also comparable among the investigated regenerative procedures. The influence of CGF on human pulpal/apical papilla stem cells was similar to that of other types of regenerative procedures. However, the effect of CGF was enhanced when it was combined with transforming growth factor beta 1. The use of CGF in animals also exerted radiographic, histological, and immunohistochemical effects similar to those of exerted by other regenerative procedures.

Conclusions

Compared with other regenerative procedures, CGF resulted in similar radiographic changes after the RET of necrotic permanent teeth. Similarly, CGF-conditioned medium enhanced stem cell viability, proliferation, and differentiation, with no apparent differences from other endodontic regenerative procedures. However, the interpretation of these findings is limited by the heterogeneity of included studies, variations in RET protocols, and the lack of long-term clinical outcome data.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12903-025-06358-8.

Introduction

Pulpitis secondary to dental caries is a common dental condition that results in tooth loss and adversely affects oral health and function [1]. Pulpotomy and pulpectomy are common approaches for managing pulpitis, but they can lead to loss of tooth structure and pulp vitality [2]. Immature teeth with pulp necrosis and apical periodontitis are commonly observed due to caries and trauma [3].

RET is an advanced technique that promotes the development and regeneration of necrotic immature permanent teeth and stimulates natural repair processes of the pulp‒dentin complex by combining stem cells, bioactive molecules, and scaffolds [4]. The process involves disinfecting the root canal and using bioactive materials such as calcium hydroxide or mineral trioxide aggregate (MTA) to create a hard tissue barrier. RET is especially useful for teeth with open apices, pulp necrosis, or apical periodontitis. This approach helps restore tooth vitality, supports natural healing, and may reduce the need for synthetic root canal fillings, thus yielding successful outcomes such as regenerated pulp tissue and improved tooth function. These interventions are safe and have no significant adverse effects [5].

CGF is a regenerative biomaterial derived from a patient’s own blood through centrifugation. CGF contains several key growth factors, including epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), bone morphogenetic protein (BMP), and vascular endothelial growth factor (VEGF) [6]. These components collectively contribute to its efficacy in tissue repair and regeneration. EGF promotes cell growth, proliferation, and differentiation, aiding in revascularization and tissue healing [7]. PDGF acts as a potent mitogen by stimulating the proliferation of fibroblasts and smooth muscle cells and thus supporting wound healing. FGF regulates cell growth and differentiation, particularly enhancing fibroblast proliferation and angiogenesis [8]. BMPs are crucial for bone formation, as they induce mesenchymal cells to differentiate into osteoblasts and support bone development [9]. VEGF is essential for angiogenesis, stimulating the growth of new blood vessels to facilitate revascularization [10].

Recently, CGF has been widely utilized in dental practices for bone tissue reconstruction because of its ability to accelerate healing processes and improve the outcomes of regenerative procedures by promoting revascularization and enhancing the proliferation, differentiation, and migration of key cell types involved in tissue repair. CGF is commonly used in oral surgery, dental implantology, orthopaedics, and aesthetic medicine to enhance recovery and repair [11]. Unlike other blood concentrates, CGF involves a specific centrifugation process that creates a rich fibrin network, potentially offering superior regenerative benefits. Its autologous nature minimizes the risks of immune reactions and disease transmission [12].

Hong et al. [3] investigated the potential application of CGF to promote pulp regeneration in immature teeth. They reported that CGF significantly enhanced stem cell proliferation, migration, and differentiation from the apical papilla. Another study revealed that CGF scaffolds significantly improved periapical healing and root lengthening in necrotic incisors compared with platelet-rich fibrin [13]. CGF has a relatively high clinical success rate (93.9%) over 12 months [13]. Another study compared RET with and without CGF in 56 nonvital, immature teeth. Both treatments resulted in similar clinical success rates (92.6%) and follow-up rates (96.4%), but CGF significantly improved the root length and radiographic root area [14].

Although RET has shown promise in treating necrotic immature teeth, it still faces challenges such as inconsistent outcomes, post-procedural discomfort, and difficulties in achieving reliable tissue regeneration—highlighting the need for more effective treatment options. CGF, derived from the patient’s own blood, has emerged as a potential solution due to its richness in growth factors and its strong fibrin matrix, which aids in healing and tissue regeneration [15]. Unlike other blood-derived materials such as platelet-rich plasma, CGF is produced through a specialized centrifugation process that enables a more stable and sustained release of bioactive factors. CGF also enhances cell migration, supports angiogenesis, and promotes the repair of both soft and hard tissues, offering promising benefits for endodontic procedures. Despite its growing clinical use, a comprehensive understanding of CGF’s effectiveness in RET is still lacking. Therefore, this systematic review aims to evaluate current evidence comparing CGF with other regenerative materials used in endodontics and provide insights to guide future research and clinical practice.

Materials and methods

Protocol and registration

The current systematic review adheres to recent PRISMA guideline updates [16], and its protocol was registered in the PROSPERO database (CRD42024543225).

Information sources and search strategy

A systematic search was conducted on the 10th of February 2025 by an experienced author (N.A.) in four databases: PubMed, Web of Science Core Collection, Scopus, and Ovid MEDLINE. The search strategy was initially built for and implemented in PubMed before being adapted to other databases (Supplementary file 1). Additionally, the backwards/forwards citations of the included studies were also screened. No filters were applied during the database search.

Study eligibility criteria

The research question for this systematic review was as follows: does CGF have greater regenerative ability during endodontic treatment than do other types of regenerative procedures? The following population, intervention, comparison, and outcomes were examined in the current systematic review:

Population: Living humans with necrotic pulp teeth who underwent an endodontic regenerative procedure using CGF, human pulpal/apical papilla stem cells exposed to CGF medium in vitro, or endodontic regenerative procedures using CGF in vivo involving animals.

Intervention: CGF was used as an endodontic regenerative biomaterial.

Comparison: Different types of endodontic regeneration techniques other than CGF.

Outcome: The outcomes of the clinical studies were the clinical success rate, pain level, changes in periapical lesion size, apical foramen diameter, root length, and dentinal thickness. The outcomes of the in vitro studies were stem cell proliferation, migration, mineralization, and differentiation. The outcomes of in vivo animal studies included radiographic or histological changes in bone and cementum volume and other histological and immunohistochemical changes.

Inclusion criteria

• Any regenerative endodontic procedure utilizing CGF performed in clinical cases, on extracted human teeth (in vitro), or in vivo involving animals will be considered for inclusion.

Exclusion criteria

• Procedures using CGF for purposes other than RET.

• Other types of publications such as case reports/series, abstracts, reviews, editorials, letters to editors, and author opinion papers.

• Studies written in a language other than English.

Data extraction

Two reviewers (M.A. and N.A.) independently extracted the data from each included study using a specifically prepared Excel sheet. The extracted data for the clinical studies were as follows: (1) study design, year, and country of publication; (2) sample characteristics (size, age, and sex); (3) growth factor groups; (4) sample (number and type); (5) growth factor source; (6) RET procedure; (7) follow-up duration; (8) RET outcome(s); (9) type of radiograph(s); and (10) main study results. For in vitro studies, the extracted data were as follows: (1) study design, year, and country of publication; (2) stem cell(s) type and source; (3) growth factor(s) groups and source; (4) stem cell activity tests; (5) cell/medium incubation period; and (6) main study results. For in vivo animal studies, the extracted data were as follows: (1) study design, year, and country of publication; (2) animal sample size and age; (3) growth factor groups; (4) teeth sample (number and type); (5) growth factor source; (6) RET procedure; (7) follow-up duration; (8) RET outcome(s); (9) type of radiograph(s); and (10) main study results.

Quality assessment

The quality of the included studies was assessed on the basis of study type by the two reviewers. The Joanna Briggs Institute’s (JBI) Critical Appraisal tool were used for clinical studies [17, 18]. For in vitro studies, we used the recently published Quality Assessment Tool for In Vitro Studies (QUIN tool) [19]. For in vivo animal studies, we used the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) for animal studies [20]. For the JBI tools, there were 13 and 8 questions for randomized controlled trials and cross-sectional studies, respectively. The QUIN tool has 12 questions. The SYRCE tool has 10 questions. A scoring system was followed for each quality assessment tool for applicable questions only. For the JBI and SYRCLE tools, a positive score (score = 1) was given to each question with a ‘yes’ response, and no score (score = 0) was given to questions with ‘no’ or ‘unclear’ responses. For the QUIN tool, the original scoring was adopted based on the following question responses: adequately specified (score = 2), inadequately specified (score = 1), or not specified (score = 0). The percentage of the scores obtained for each study’s quality assessment was then divided into the total number of applicable questions/scores. Each study was classified into high (76–100%), moderate (50–75%) or low quality (less than 50%) based on the resulting percentage. Disagreements in the quality assessment stage were resolved by a mutual discussion between the two reviewers and/or by consulting the third author.

Study screening process

The study list obtained from the database search was imported into Mendeley software for deduplication using the built-in duplicate removal feature. The deduplication process was also confirmed manually for accuracy. After removing duplicates, the study list was exported to Microsoft Excel, and the titles/abstracts were screened by two independent reviewers (M.A. and B.A.) and classified as included, excluded, or undecided studies. The decision to include any study was resolved by mutual consensus of the two reviewers and/or consultation with a third reviewer (N.A.). The full texts of the potentially eligible studies were subsequently screened by the two reviewers and classified as included, excluded, or undecided. The decision to include the studies was resolved by a mutual discussion and/or consultation with the third author.

Results

Study selection

The database search resulted in 311 titles, 144 of which remained after deduplication. The title/abstract screening of the deduplicated list led to the exclusion of 110 studies. The full texts of the 34 potentially eligible studies were screened, and 25 studies were excluded. Thus, 9 studies were ultimately included in this review (Fig. 1) [6, 13, 14, 21–26]. The excluded studies and their reasons for exclusion are presented in Supplementary file 2.

Fig. 1.

PRISMA flow diagram of study screening and selection process

Study characteristics

The detailed characteristics of the included studies are presented in Tables 1, 2 and 3. The final inclusion list comprised five clinical studies (three RCTs [13, 14, 25] and two retrospective cross-sectional studies [23, 24]), three in vitro studies [6, 21, 22], and one in vivo animal study [26]. Most of the included studies were published after 2020, with the exception of one published in 2018 [22]. Regarding the country of publication, all included studies were conducted in China, with the exception of one conducted in Egypt [13] and another study that was published jointly between Saudi Arabia and Egypt [26].

Table 1.

Detailed characteristics of the included clinical studies

Citation	Publication country, date, and type	Sample Size, age, and gender distribution	Growth factor groups	Teeth number and type	Blood-derived products preparation protocol	Endodontic procedure	Follow-up duration	Endodontic treatment outcome(s)	Radiographic assessment	Main results	Quality outcome
Elheeny et al [13]	Egypt; 2024; RCT	56 children (8.99 ± 0.76 year); 30 M: 24 F	G1: CGF (14 M: 14 F) G2: PRF (16 M: 11 F)	66 necrotic immature permanent maxillary centrals and laterals with PA lesion: 33 CGF and 33 PRF	A 10 ml venous blood sample was collected without anticoagulants and centrifuged using a specific protocol. PRF was obtained by spinning at 3000 rpm for 10 min, while CGF required a multi-speed centrifugation sequence. The fibrin-rich layer was then carefully extracted with sterile tools and cleaned of excess fluid.	At baseline: Canal access → 1.5% NaOCl, 20 ml → Saline, 20 ml → CH intracanal medicament → GCI temporary restoration. After 3 we (symptom free): Remove temporary GIC → 1.5% NaOCl, 20 ml → 0.9% Saline, 5 ml → 17% EDTA, 20 ml → CGF or PRF were inserted 3 mm below CEJ → Biodentine packing → GIC access seal → Composite restoration.	At 6 and 12 mo; two patients (4 teeth; 2 from each group) did not complete the follow-ups.	(1) Clinical success rate over 12 mo, (2) Reduction of PA lesion diameter, (3) Root dentine thickness. (4) Root length. (5) Apical foramen width, and (6) Pulp responses after 12 mo.	1) PA radiograph at baseline, 6, and 12 mo 2) CBCT at baseline and 12 mo	Success rate was 93.9% for both CGF and PRF. CGF showed more improvement of PA lesion and root length compared to PRF. Both had similar influence on root dentine thickness, apical foramen width, and pulp response. Gender, age, tooth type, and preoperative clinical status have no influence on the outcome.	High
Li et al. [23]	China; 2023; Retrospective study	13 children (CGF: 10–15 year; PRF: 7–14 year); 4 M: 9 F	G1: CGF (1 M: 5 F) G2: PRF (3 M: 4 F)	13 necrotic immature permanent teeth with PA lesion (4 maxillary centrals, 7 mandibular premolars, and 1 maxillary premolar): 7 CGF and 6 PRF	A 10 ml intravenous blood sample was collected into a non-anticoagulant tube and centrifuged using the DT-F4 device. PRF was prepared by centrifuging at 3000 rpm for 10 min, while CGF required a variable-speed 15-minute protocol. This process produced three layers: serum (top), CGF/PRF (middle), and red blood cells (bottom). The fibrin gel from the middle layer was extracted, shaped into a membrane using a specialized separator, and trimmed to fit the root canal.	At baseline: Canal access → 1–3% NaOCl, 10–20 ml → CH intracanal medicament → GCI temporary restoration. After 2 we (symptom free): Remove temporary GIC → Saline → 17% EDTA, 10–15 ml → CGF or PRF were placed to CEJ level → iRoot BP capping → Composite restoration.	3–6 mo, 7–12 mo, and 12–24 mo	(1) Apical foramen diameter, (2) root length, (3) radiographic root area, and (4) PA lesion area.	NR	No differences between CGF and PRF at 3–6 mo, 7–12 mo, and 12–24 mo. The success rate was 100% for both the two growth factors throughout the follow-up period.	Moderate
Yang et al. [24]	China; 2023; Retrospective study	107 children (9.8 ± 0.15 year); 59 M: 62 F	G1: CGF (24 M: 29 F) G2: BC (35 M: 33 F)	121 necrotic immature permanent teeth with PA lesion (53 incisors, 62 premolars, and 6 molars): 53 CGF and 68 BC.	A 9 ml intravenous blood sample was collected without anticoagulants and centrifuged using the Medifuge MF200, separating it into three layers: platelet-poor plasma (top), CGF (middle), and red blood cells (bottom). The CGF layer was then isolated and fragmented for use. For BC cases, bleeding was induced 2 mm beyond the apical foramen using a pre-curved K-file, and a clot was allowed to form 3–4 mm below CEJ.	At baseline: Canal access → 0.5–1.5% NaOCl → 0.9% saline → CH/triple antibiotic paste intracanal medicament → Caviton temporary restoration. After second visit (symptom free): Remove temporary GIC → canal system irrigation → CGF to CEJ level or BC → MTA or iRoot BP capping → GIC or flowable composite restorations.	Varies, all more than 6 mo	A combined clinical and radiographic scoring system (0–3 scores) was based on AAE Clinical Considerations for a Regenerative Procedure.	NR	No clinical or radiographic differences between CGF and BC after follow-up, with similar success rate (86.79% for CGF and 95.59% for BC)	Moderate
Zhang et al. [14]	China; 2024; RCT	56 children (10.67 ± 1.33 year); 25 M: 29 F	G1: CGF (15 M: 12 F) G2: BC (10 M: 17 F)	56 necrotic immature mandibular premolars with PA lesion: 28 CGF and 28 BC.	CGF: A 10 ml venous blood sample was collected in anticoagulant-free Vacuette tubes and centrifuged using a one-step protocol in a Medifuge machine, involving acceleration, variable speeds (2400–3000 rpm), and deceleration. This produced four layers: serum, fibrin buffy coat, a liquid growth factor phase, and red corpuscles. The CGF layer, located above the red corpuscles, was carefully extracted with some red cells retained to preserve growth factors. For BC cases, bleeding was induced using a sterile 23-G needle inserted 2 mm beyond the apical foramen, allowing blood to fill the canal up to 3–4 mm CEJ to form a BC.	One visit: Canal access → 2.5% NaOCl, 20 ml → Triple antibiotic paste intracanal medicament → CGF 3–4 mm below CEJ or BC → Resin-modified GIC	At 1 we and 6 and 12 mo; two patients (2 teeth;1 from each group) did not complete the follow-ups.	(1) Pain level at we, (2) PA lesion outcome, (3) Apical foramen diameter, (4) root length, and 4) radiographic root area.	PA radiograph at 1 we and 6 and 12 mo	No differences on pain level or success rate between CGF and BC after follow-up (92.59% success for CGF and BC). However, the increase rate of radiographic root area and root length was higher for CGF than BC at 6 and 12 mo follow-up, respectively.	High
Salah et al. [25]	Egypt; 2025; RCT	18 adults (18–30 year); Sex not mentioned	G1: CGF (Sex not mentioned) G2: PRF (Sex not mentioned)	18 mature necrotic maxillary incisors with PA with periapical index scores ≥ 3: 9 CGF and 9 PRF.	For CGF, a 10 ml venous blood sample was collected in glass tubes without anticoagulant and centrifuged using a one-step, variable-speed protocol in a Medifuge machine. This process produced three layers: serum (top), CGF (middle), and red blood cells (bottom). The CGF-containing fibrin gel was separated, squeezed, and formed into a membrane. For PRF, a 5 ml blood sample was drawn and centrifuged at 3000 rpm for 10 min using a tabletop centrifuge. The resulting layers were serum (top), PRF (middle), and red blood cells (bottom). The PRF was isolated, compressed into a membrane, fragmented, and placed into the canal up to CEJ using dental tools.	At baseline: Canal access → 1.5% NaOCl, 20 ml → Saline, 20 ml → 17% EDTA, 20 ml → CH intracanal medicament → GCI temporary restoration. After 2 we (symptom free): Remove temporary GIC → 0.9% Saline, 5 ml → 17% EDTA, 20 ml → Bleeding induced from the periapical region → CGF or PRF were inserted until CEJ → Resorbable collagen matrix → 3 mm MTA plug → Flowable composite restoration.	At 6 and 12 mo	1) Electric pulp tester and thermal test to determine pulp sensibility. 2) Reduction of PA lesion diameter, 3) Relative bone density	CBCT at baseline and 12 mo	The PA lesion size reduction and bone density were similar between CGF and PRF, while 67% of the teeth in both groups showing positive pulp sensations after follow-up.	Moderate

Abbreviation list: AAE, American Association of Endodontics; BC, blood clot; CBCT, cone-beam computed tomography; CEJ, cementoenamel junction; CGF, concentrated growth factor; CH, calcium hydroxide; EDTA, ethylenediaminetetraacetic acid; F, females; G, group; GIC, glass ionomer cement; IL, interleukin; M, males; ml, milliliter; mm, millimeter; MMP, matrix metalloproteinase; mo, months; MTA, mineral trioxide aggregate; NaOCl, Sodium hypochlorite solution; NR, not reported; PA, periapical; PRF, platelet-rich fibrin; RCT, randomized controlled trial; SP, substance P; we, weeks; yr, years

Table 2.

Detailed characteristics of the included in vitro studies

Citation	Publication country, data, and type	Stem cell type and source	Blood-derived products preparation protocol	Stem cell activity tests	Cell/medium incubation period	Main results	Quality outcome
Li et al. [6]	China; 2021; In vitro study	hDPSCs were isolated and identified from dental pulp tissue of extracted third molars from 6 healthy human donors (12–18 year)	Venous blood samples (5 ml) were centrifuged to produce CGF and CGFe. A CGF clot was isolated, compressed, and converted into CGFe, which was then filtered and stored at ‒80 °C. CGFe was used at 100%, 50%, and 25% concentrations by dilution with α-MEM. CGF membranes used clinically were fully absorbed within 7–14 days, so these were chosen as observation time points. TGF-β1 powder (PeproTech China) was dissolved in distilled water according to the manufacturer’s instructions, and different dilutions of TGF‐β1 were stored at ‐80 °C for subsequent experiments.	hDPSCs viability (MTT assay) and osteogenic differentiation (ALP activity, western blotting, and reverse transcriptionquantitative PCR assays)	7 or 14 days	Both CGFe and TGFβ1 groups showed greater hDPSCs viability and osteogenic differentiation than controls. However, combining CGFe and TGFβ1 resulted in the highest effect.	Moderate
Dou et al. [21]	China; 2020; In vitro study	hDPSCs were isolated and identified from dental pulp tissue of extracted human third molars	Venous blood from healthy volunteers was collected in 10-ml tubes without anticoagulants. To prepare PRF, samples were centrifuged at 1,811 × g for 10 min, and the intermediate gel layer was collected. For CGF, a specific centrifuge program with varying speeds was used, and the intermediate layer was also collected. Equal volumes of PRF and CGF clots were measured using a mold, dried on gauze, frozen, ground, resuspended in α-MEM, mixed, and centrifuged to obtain PRF and CGF exudates, which were then stored at ‒80 °C.	Proliferation (Cell Counting Kit-8), viability (trypan blue dye exclusion), apoptosis (Annexin V/propidium iodide [PI] assay), cell cycle (Cell Cycle Analysis kit), and ALP activity of hDPSCs	1, 3, or 7 days	CGF and PRF were comparable in their effect on the proliferation, viability, apoptosis, cell cycle, and ALP activity of hDPSCs.	Moderate
Hong et al. [22]	China; 2018; In vitro study	SCAPs were isolated and identified from open root apices of extracted human mandibular third molars from 3 healthy donors (14–20 year)	Venous blood (10 mL) was collected from participants to prepare CGF and PRF following established protocols. The membranes were freeze-dried, ground, and incubated in DMEM at 37 °C for 24 h to extract cytokines. After centrifugation and supplementation with serum and antibiotics, the conditioned medium was obtained and prepared at three concentrations: full (1 membrane/10 mL DMEM), half, and quarter strength for both CGF and PRF.	Proliferation (Cell Counting Kit-8), migration (transwell assays), mineralization (alizarin red S staining), and real-time quantitative polymerase chain reaction analysis (ALP, bone sialoprotein, dentin matrix protein 1, and dentin sialophosphoprotein) of SCAPs	7 or 14 days	CGF and PRF had comparable effect but both significantly enhanced SCAPs proliferation, migration, and differentiation.	Moderate

Abbreviation list: ALP, Alkaline phosphatase; CGF, concentrated growth factor; CGFe, concentrated growth factor exudate; CH, calcium hydroxide; g, grams; hDPSCs, Human dental pulp stem cells; min, minutes; ml, milliliter; MTA, mineral trioxide aggregate; PCR, polymerase chain reaction; PRF, platelet-rich fibrin; RBCs, red blood cells; SCAPs, apical papilla stem cells; sec, seconds; TGF‑β1, Transforming growth factor beta 1; yr, years

Table 3.

Detailed characteristics of the included in vivo animal study

Citation	Publication country, date, and type	Animal sample size and age	Growth factor groups	Teeth number and type	Blood-derived products preparation protocol	Endodontic procedure	Follow-up duration	Endodontic Outcome(s)	Radiographic assessment	Main results	Quality outcome
Mohamed et al. [26]	Saudi Arabia and Egypt; 2023; In vivo animal study	8 mature dogs (14–16 mo)	G1: 10 -ve controls (without FP). G2: 20 + ve controls (with FP but no repair). G3: 20 MTA. G4: 20 MTA + PRF. G5: 20 MTA + CGF. Groups 2–5 were subdived into two subgroups: a) 10 4-we oral contaminated FP. b) 10 non-contaminated FP.	96 intact and mature premolars (12 teeth per dog)	Autologous venous blood was processed using specific centrifugation protocols to prepare CGF and PRF. For CGF, a one-step centrifugation program with varying speeds was used, and the intermediate layer was collected. For PRF, 10 mL of blood from a dog’s forearm was centrifuged at 3000 rpm for 12 min, producing three layers. The middle layer, the PRF clot, was extracted using tweezers.	At baseline: Oral disinfection → Canal access → Root cancal instrumentation → 2.5% NaOCl, 2 ml → 9% Saline, 3 ml → 17% EDTA, 3 ml → Single-cone obturation + AH sealer → 1.5 mm FP, 2 mm into alveolar bone → No coronal seal for subgroup a, while sterile cotton + temporary filling for subgroup b. After 4 we: Remove temporary filling → 2.5% NaOCl → 9% Saline → FP curation → 9% Saline → No FP repair for group 2. For group 3: MTA plug was placed. For groups 4–5: CGF or PRF matrix were placed in the FP until CEJ → 3 mm MTA plug → GIC.	At 3 mo	(1) FP vertical bone density, (2) Histological inflammatory cell count, epithelial proliferation, cementum and bone deposition, (3) Immunohistochemically (OPN and TRAP antibodies localisation).	PA at baseline and 3 mo	No difference between CGF and PRF groups.	Moderate

Abbreviation list: -ve, negative; +ve, positive; CEJ, cementoenamel junction; CGF, concentrated growth factor; EDTA, ethylenediaminetetraacetic acid; FP, furcation perforation; G, group; GIC, glass ionomer cement; min, minutes; ml, milliliter; mm, millimeter; mo, months; MTA, mineral trioxide aggregate; NaOCl, Sodium hypochlorite solution; OPN, osteopontin; PA, periapical; PRF, platelet-rich fibrin; rpm, revolutions per minute; sec, seconds; TRAP, tartrate-resistant acid phosphatase; we, weeks

The comparative endodontic regenerative ability of CGF and platelet-rich fibrin (PRF) was investigated in six studies [13, 24, 26–29] Moreover, two studies compared CGF and root canal blood clotting (BC) [14, 24], and another study compared CGF and transforming growth factor beta 1 (TGF‑β1) [6]. The CGF or PRF source was from the patient’s/donor’s peripheral venous blood supply [6, 13, 21–25]. Moreover, TGF‑β1 was prepared from a commercially available TGF‑β1 powder (PeproTech, China) that was dissolved in distilled water according to the manufacturer’s instructions [6]. For the root canal, BC was induced from the periapical region via a precurved K-file extruded 2 mm past the apical foramen [14, 24]. Notably, a meta-analysis was not conducted in the current study because of the high heterogeneity of the included studies.

Clinical studies

For the clinical studies [13, 23, 24], the patient sample size ranged from 13 to 107 patients (250 in total). The endodontic regenerative procedure was conducted in four studies in necrotic immature permanent teeth, ranging from 13 to 121 teeth (274 in total) [23, 24]. One study examined mature necrotic teeth in adults [14]. The tooth type was also variable, where maxillary central and lateral incisors were examined in two studies [13, 25]; two studies examined incisors, premolars, and/or molars [23, 24]; and one study examined mandibular premolars [14]. RET was conducted in the included clinical studies at two visits, with the exception of one where it was conducted at a single visit [14]. At the baseline visit, the pulp canal(s) were accessed and irrigated, followed by the placement of calcium hydroxide intracanal medicaments and temporary restoration. Two studies also used triple antibiotic paste as an intracanal medicament [14, 24]. The interval between the baseline visit and the second visit was three weeks for one study [13] and two weeks for two studies [23, 25]; one study did not report the interval between visits [24]. At the second visit, the teeth were confirmed to be symptom-free. The temporary restoration was removed, followed by canal irrigation and the insertion of CGF or other growth factors into the canals at or 3 mm below the level of the cementoenamel junction. Pulp capping agents (MTA, Biodentine, or iROOT) were added, followed by a final restoration. Treatment follow-up duration was variable across the studies, with a minimum of 1 week, 3–6 months, and up to 48 months. Combined clinical and radiographic outcomes were assessed at each follow-up visit to verify endodontic regeneration success (Table 1). The type of radiograph was not reported in two studies [23, 24]; however, one study used periapical X-rays [14], one used cone beam computed tomography (CBCT) [25], and the other used periapical X-rays and CBCT [13].

In vitro studies

For in vitro studies, human dental pulp stem cells (hDPSCs) were isolated and identified from dental pulp tissues obtained from extracted human third molars [6, 21]. In contrast, apical papilla stem cells (SCAPs) were isolated and identified from the open root apices of extracted human mandibular third molars [23]. The age and number of donors were not reported in one study [21], but there were six healthy donors (12–18 years) in one study [6] and three healthy donors (14–20 years) in another [22]. The stem cell/growth factor medium was incubated for 1, 3, 7, and/or 14 days. Stem cell activity in terms of proliferation, migration, mineralization, and differentiation was analysed using various methods (Table 2).

In vivo animal studies

For the in vivo animal study [26], about 90 mature premolars from eight 14–16-month-old dogs were divided into five groups: (1) 10 negative controls with no furcation involvement; (2) 20 positive controls with unrepaired furcation; (3) 20 with MTA packing; (4) 20 with PRF + MTA; and (5) 20 with CGF + MTA. Groups 2–5 were split into two subgroups: one with no coronal seal and exposed to 4-week oral contamination, and another with a seal and no contamination. At baseline, pulp canals were disinfected, instrumented, irrigated, and filled with gutta-percha and AH sealer. A 1.5-mm hole was drilled into the furcation area, 2 mm into the bone. Calcium hydroxide and temporary restorations were applied (except in contaminated subgroups). After four weeks, restorations were removed from uncontaminated teeth, canals irrigated, and furcations treated accordingly: left unrepaired (group 2), sealed with MTA (group 3), PRF + MTA (group 4), or CGF + MTA (group 5). Antibiotics were given for pain management. The final restoration (GIC) was placed for groups 2–5 (Table 3). After 3 months of follow-up, the dogs were sacrificed. Radiographic (periapical X-ray), histological, and immunohistochemical outcomes were assessed.

Quality of the included studies

Supplementary file 3 presents the quality assessment of the included studies using the JBI, QUIN, and SYRCLE tools. The results revealed that two studies had a low risk of bias [13, 14], whereas the other seven studies had a moderate risk of bias [6, 21–26].

Results of the included studies

A summary of the included studies’ results is presented in Table 4. Below is a detailed description of the results obtained from individual studies according to their methodology.

Table 4.

Shows a results summary of the comparative efficacy of CGF in relation to other endodontic regenerative methods obtained from the included studies

Citation	Study Type	Compared To	Summary of CGF Efficacy
Elheeny et al. [13] Li et al. [23] Yang et al. [24] Zhang et al. [14] Salah et al. [25]	Clinical	PRF, BC	CGF demonstrated comparable or superior outcomes to PRF in angiogenesis, osteogenesis, root development, and healing. It outperformed BC specifically in root development and periapical healing.
Li et al. [6] Dou et al. [21] Hong et al. [22]	In-vitro	PRF, CGFe, MTA, Ca(OH)₂	CGF enhanced cell viability, osteogenesis, and ALP activity. PRF promoted greater proliferation and earlier cell migration. CGFe combined with TGF-β1 showed the most potent effects overall.
Mohamed et al. [26]	In-vivo animal	PRF, MTA, Controls	CGF increased epithelial proliferation compared to the negative control and was similar to PRF. No significant difference was found between CGF and PRF. Both CGF and PRF were effective when combined with MTA.

Abbreviation list: ALP, alkaline phosphatase; BC, blood clot; Ca(OH)₂, calcium hydroxide; CGF, concentrated growth factor; CGFe, concentrated growth factor exudate; MTA, mineral trioxide aggregate; PRF, platelet-rich fibrin; TGF-β1, transforming growth factor beta 1

Clinical studies

With respect to the radiographic differences between CGF and PRG or BC, the included studies revealed that all investigated growth factors had a similar influence on root dentinal thickness and apical foramen width after follow-up [13, 14, 23, 24]. However, Elheeny et al. [13] showed that CGF improved the periapical lesion size and root length more than did PRF after 12 months of follow-up. Li et al. [23] showed that PRF increased the periapical root area (root outline under the CEJ minus the root canal space) more than CGF at 12 to 24 months of follow-up, but there were no differences in periapical lesion size.

Salah et al. [25] reported that bone density and periapical lesion size were similar for CGF and PRF, which resulted in 67% of the teeth showing positive sensation. Concerning the clinical success of endodontic regenerative therapy, two studies reported that the use of CGFs resulted in a similar rate to that of PRF after follow-up (pooled rate 96.95%) [13, 23]. While the success rate for BC was lower than that for CGF in one study (86.79% and 95.59%, respectively) [24], another study reported very similar success rates (92.59% success rates for CGF and BC) [14]. Factors such as tooth type, preoperative clinical status, patient age, and sex did not influence the outcome [13].

In vitro studies

The viability of hDPSCs cultured in CGF- or PRF-conditioned medium was not different and was similar to that of control hDPSCs21. Compared with the other CGF concentrations (0%, 25%, or 50%), the combination of one ng/ml TGF‑β1 with 100% CGF resulted in the highest hDPSC proliferation after seven days of incubation [6]. Compared with the controls, CGF- and PRF-conditioned media significantly promoted hDPSC proliferation after 3 days of incubation [21]. Moreover, the apoptotic rates of hDPSCs did not differ between the CGF- or PRF-conditioned medium groups after 1, 3, and 7 days of incubation [21]. On the other hand, the proliferation of SACPs cultured with different concentrations of CGF- or PRF-conditioned media (25%, 50%, or 100%) did not differ at 1, 3, 5, and 7 days of follow-up. However, all the values were greater than those of the controls [22].

In contrast to CGF, PRF-conditioned medium enhanced the migration capacity of SACPs compared with that of the controls after 12 h of incubation [22]. After 24 h of incubation, the number of migratory cells in both CGF-conditioned medium and PRF-conditioned medium did not differ but was significantly greater than that in the controls [22].

Li et al. [6] reported that 100% CGF resulted in similar expression levels of hDPSC osteogenic genes, such as alkaline phosphatase (ALP), runt‑related transcription factor 2, and bone sialoprotein, compared with 1 ng/ml TGF‑β1 at 7 or 14 days of incubation, but both were greater than those in the controls. However, osteocalcin expression levels did not differ from those of the control at 7 or 14 days of hDPSC incubation in 100% CGF or one ng/ml TGF‑β1-conditioned media [6].Compared with the other groups, the combination of one ng/ml TGF‑β1 with 100% CGF resulted in the highest expression of ALP, runt‑related transcription factor 2, bone sialoprotein, and osteocalcin in hDPSCs after 7 or 14 days of incubation [6]. Moreover, Duo et al. [21] reported similar ALP activity in hDPSCs cultured in CGF- or PRF-conditioned media after 1, 3, and 7 days of culture. On the other hand, the expression levels of the SACPs ALP, bone sialoprotein, dentin matrix protein 1, and dentin sialophosphoprotein were downregulated after a 7-day incubation period in PRF or CGF media compared with those in the controls [22]. After 14 days of incubation, compared with the control medium, the PRF- or CGF-conditioned media significantly increased the expression of SACP osteogenic genes, but the expression in the PRF-conditioned medium was significantly greater than that in the CGF22-conditioned medium [22].

In vivo animal studies

The included animal study [26] revealed that teeth with furcation involvement, which were repaired with MTA + CGF or MTA + PRF, presented a similar but significant increase in radiographic interradicular bone density compared with that of unrepaired teeth. However, the difference was not significant compared with that of teeth repaired with MTA alone. Histologically, the number of inflammatory cells in the furcation area was also similar between the CGF and PRF groups but was significantly lower than that in the unrepaired teeth and MTA alone groups. On the other hand, cementum deposition in the furcation area was similar among the MTA + CGF, MTA + PRF, and MTA alone groups. However, all of these values were significantly greater than those in the unrepaired furcation group. Similarly, epithelial proliferation at the furcation area was similar among the MTA + CGF, MTA + PRF, and MTA alone groups, but the proliferation was significantly lower than that in the unrepaired furcation group. Immunohistochemically, the level of osteopontin antibody in the MTA + CGF or MTA + PRF groups was significantly greater than that in the unrepaired furcation group, whereas the level of tartrate-resistant acid phosphatase was significantly lower.

Discussion

This systematic review synthesized evidence from clinical trials, in vitro experiments, and animal studies to assess the potential of CGF in RET. Analysis of clinical studies showed that CGF had similar success rates and radiographic outcomes to techniques like PRF, promoting root development and periapical healing. In vitro studies demonstrated that CGF-conditioned media support dental stem cell growth, while animal studies confirmed comparable radiographic, histological, and immunohistochemical results. Our findings further suggest that CGF is a promising option for RET, offering regenerative effects on par with other techniques like PRF.

Five clinical studies investigated the use of CGF and PRF in necrotic permanent teeth [13, 14, 23–25]. These studies generally report high success rates (often ≥ 90%) for both scaffolds. For instance, one trial in children found a 93.9% success rate in both CGF and PRF groups, with CGF showing greater average improvement in root length and lesion healing [13]. This finding may be attributed to CGF’s enhanced growth factor load and its stable fibrin architecture [27, 28], which can improve material handling and the targeted release of biomolecules [28]. In contrast, a smaller study reported 100% success in both CGF and PRF arms, finding no difference between the two [23]. The lack of detectable differences in such studies is often explained by small sample size or short follow-up periods. Other factors—such as baseline lesion size, tooth type, or patient age—could also mask small treatment effects if not controlled.

The comparative work involving the BC technique indicates that it can perform similarly to CGF in some clinical settings [14, 24]. For example, one retrospective study in children found CGF and BC equally effective [24], reflecting children’s strong natural healing potential [29], where the induced bleeding from the BC technique can provide an adequate source of signalling molecules to stimulate regeneration [30]. This suggests that in straightforward pediatric cases with good natural healing capacity, simple blood clot scaffolds may suffice. However, CGF’s advantages become more apparent in challenging scenarios. Studies by Zhang et al. and Elheeny et al. reported enhanced root maturation and lesion repair with CGF compared to PRF or BC [13, 14]. These improvements are thought to arise from CGF’s high platelet and growth factor content and its sustained release profile [27]. In sum, clinical evidence suggests that CGF and PRF yield comparable outcomes in routine regenerative cases, but CGF’s biological characteristics may offer added benefit in complex or compromised cases (e.g., large lesions or older patients).

In vitro studies using human dental stem cells consistently show that both CGF and PRF favour cell proliferation, differentiation, and mineralization [6, 21, 22]. These effects are driven by the abundance of growth factors (e.g., TGF-β1, VEGF, PDGF) released from the fibrin scaffolds. One study reported that supplementing CGF with TGF-β1 further enhanced stem cell viability and osteogenic differentiation [23]. This implies that CGF provides a supportive three-dimensional scaffold while exogenous factors can fine-tune cell behaviour. In general, isolated comparisons find no substantial differences between CGF and PRF in their ability to induce cellular responses [21]. This equivalence is expected given their similar preparation from blood and overlapping biochemical contents [21, 22, 31]. However, CGF’s tighter fibrin network may create a slightly more favourable microenvironment for sustained growth factor delivery [32]. Overall, these laboratory findings reinforce that CGF is at least as effective as PRF in driving stem-cell mediated regeneration, and they hint that CGF’s characteristics (like sustained release) could further support complex tissue formation when needed.

Only one animal study has directly addressed CGF in endodontic contexts [26]. In a dog model of furcation perforation, addition of CGF or PRF to MTA cement significantly improved repair compared to MTA alone [26]. Both CGF + MTA and PRF + MTA groups showed more complete healing, suggesting that the embedded growth factors accelerate tissue regeneration in perforation sites. These findings imply that combining CGF with standard endodontic materials could be beneficial, especially in scenarios like root perforations or incomplete apex formation. Nonetheless, these results must be interpreted with caution since animal physiology and healing differ from humans.

This review suggests that CGF is a viable regenerative scaffold with strengths including its autologous nature, rich growth factor content, and ease of preparation. Like PRF and BC, CGF is obtained from the patient’s own blood (minimizing immune reactions) and poses low risk of complications. Its denser fibrin architecture provides mechanical stability and may ensure a more uniform delivery of signalling molecules over time [32]. These properties make CGF especially attractive in cases requiring robust regeneration, such as large necrotic lesions or teeth with open apices. Compared to the unpredictable nature of an induced blood clot, CGF can offer consistency, since the concentration of platelets and cytokines in CGF can be quantifiable and reproducible across patients, whereas a blood clot’s content varies with individual bleeding. In practice, the decision might also consider patient factors, for example, inducing a blood clot is very simple and cost-free, which may be sufficient in healthy young patients, while CGF requires centrifugation but could be justified in difficult cases. Importantly, all these scaffolds appear safe and autologous, meaning no significant adverse reactions have been reported.

This review adhered to the PRISMA guidelines and includes clinical, in vitro, and in vivo animal studies to comprehensively evaluate CGF efficacy in RET. However, it has several limitations that need to be highlighted. The number of high-quality studies is still small, and most trials have relatively short follow-ups. The included clinical studies showed moderate heterogeneity in design, patient age, lesion size, and outcome measures. Further, several studies had small sample sizes and methodological inconsistencies. These factors reduce confidence in pooled results and highlight the need for standardized protocols. Additionally, few studies reported long-term functional outcomes (such as continued root maturation years after treatment), so the sustained effects of CGF remain uncertain. Future research should aim to strengthen the evidence base by conducting larger, multicenter randomized trials with standardized protocols [31, 32]. Studies with longer follow-up (beyond two years) are needed to determine if the modest early advantages of CGF translate into lasting benefits. It would also be valuable to investigate CGF’s performance in diverse patient populations, including adults and teeth with unusual anatomy or chronic infection.

Conclusions

The present systematic review is the first to investigate the comparative efficacy of CGF and other RET procedures in human clinical, in vitro, and in vivo animal settings. Compared with other regenerative procedures, CGF resulted in similar radiographic changes after the RET of necrotic immature permanent teeth. Similarly, compared with other regenerative procedures, CGF-conditioned media increased hDPSC/SCAPs viability, proliferation, and differentiation with no apparent differences. Additionally, animal research has shown similar radiographic, histological, and immunohistochemical efficacy between CGF and other endodontic regenerative procedures. Overall, these results indicate that CGF may be superior to other regenerative procedures as a biomaterial for use in complex cases in RET. It has a higher concentration and consistent release of growth factors and cytokines over a longer period, potentially enhancing tissue healing and root development. It also has better handling properties that enable more efficient and accurate placement in pulp revitalization cases. However, these findings should be interpreted cautiously due to the limited number and heterogeneity of the included studies. While CGF appears to be a promising biomaterial in RET, further studies are necessary to explore its long-term outcome in diverse patient populations.

Electronic supplementary material

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Author contributions

M.A., N.A., and B.A. conceptualized and designed the study; M.A. and B.A. collected the data; M.A., N.A., and B.A. analyzed and interpreted the data; N.A. made the figures and tables; N.A. and B.A. drafted the manuscript, M.A., N.A., and B.A. critically revised the manuscript. All authors contributed equally and approved the final draft of the manuscript.

Funding

The Researchers would like to thank the Deanship of Graduate Studies and Scientific Research at Qassim University for financial support (QU-APC-2025).

Data availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Declarations

Competing interests

The authors declare no competing interests.

Ethical approval

No ethical approval was required for this study as neither human participants nor animals were utilized.

Informed consent

No informed consent was required for this study as neither human participants nor animals were utilized.

Consent for publication

Not applicable.