Correlation of Growth Factors in Platelet-Rich Plasma with Clinical Outcomes and Hematological Parameters in Regenerative Dentistry: A Systematic Review and Meta-Analysis

Correlation of Growth Factors in Platelet-Rich Plasma with Clinical Outcomes and Hematological Parameters in Regenerative Dentistry: A Systematic Review and Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Correlation of Growth Factors in Platelet-Rich Plasma with Clinical Outcomes and Hematological Parameters in Regenerative Dentistry: A Systematic Review and Meta-Analysis Monal Yuwanati, Adetola Emmanuel Babalola, Ana Carolina Morais Apolônio, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8408844/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) have shown inconsistent clinical responses in dental conditions. Variations in platelet counts and growth factor are likely factors influence it. Systematic evaluation of relationships between them is needed to optimized outcomes. Objective To assess correlation of growth factors in PRP/PRF with clinical outcomes and hematological parameters in regenerative dentistry. Methods A search was performed in Pub-Med, Scopus, and Web of Science. Studies those reported growth factor quantity in PRP/PRF and their association with hematological or clinical outcomes were included. PRP/PRF yield and growth factor levels and its correlation with platelet count and blood volume was analyzed. Results 64 randomized controlled trials involving 2477 patients were included. The pooled PRP/PRF yield was 0.115 mL/mL of whole blood, strongly correlated with blood volume (r = 0.99, p 60,000 ng/mL, VEGF from 0.23 to 60 ng/mL, and PDGF from 0.1 to 176 ng/mL. PRP/PRF yield is dependent on the quantity of blood volume rather than baseline platelet counts. Discussion Growth factor levels show substantial variation suggesting influence of biological and methodological methods. These findings clearly indicate need for standardized preparation protocols. Conclusion There is evidence of correlation of PRP/PRF, growth factor, and blood volume. Therefore, clinician must take these factors in account while preparation of PRP/PRF for regenerative procedure in dental application. Dentistry Growth factors Platelet-rich plasma Platelet-rich fibrin Platelet concentrates Regenerative dentistry Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction Autologous platelet concentrates such as platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) have become integral adjuncts in regenerative dentistry because they deliver concentrated, endogenous growth factors that direct angiogenesis, cell migration, matrix synthesis and osteogenesis. Key mediators present in these preparations - PDGF (PDGF-AA/-BB/-AB), TGF-β1, VEGF, FGF-b and EGF-are biologically plausible effectors of clinical outcomes in periodontal, endodontic and implant therapies [ 1 , 2 ]. However, clinical responses after PRP/PRF application are inconsistent across trials and indications, limiting predictability and wider adoption [ 3 , 4 ]. A major source of this heterogeneity is compositional variability: preparation protocol (centrifugation force/time), product format (liquid PRP, solid PRF, i-PRF, A-PRF), and donor hematological factors (baseline platelet and leukocyte counts) all alter growth factor yield and release kinetics [ 5 – 7 ]. Recent primary studies that directly measured individual growth factors support this mechanistic link. For example, a controlled pilot study quantified VEGF, IGF-1, TGF-β1, PDGF-BB and EGF in injectable PRF and explored their relationship with donors’ blood counts [ 8 ]. Work on advanced PRF (A-PRF) has characterized PDGF, TGF-β1 and VEGF release under clinically relevant conditions and demonstrated time-dependent availability that may favor sustained tissue repair [ 9 ]. Comparative analyses likewise show that some low-speed PRF protocols yield prolonged growth factor release compared with classical PRP, suggesting formulation-dependent biological effects [ 6 , 10 ]. Recent ex vivo studies have demonstrated that growth factor concentrations in PRP/PRF significantly influence osteoblast proliferation and angiogenic activity, providing a biological foundation for their observed clinical effects [ 12 ]. Furthermore, translational studies in dental implantology link higher PDGF and VEGF levels to better bone-to-implant contact and enhanced osseointegration quality [ 13 ]. Clinically, randomized trials and meta-analyses document benefits of platelet concentrates in intra-bony periodontal defects, implant site regeneration and regenerative endodontics, yet few studies quantitatively link measured growth factor concentrations to standardized clinical endpoints (e.g., probing depth reduction, radiographic bone fill, implant stability) [ 3 , 11 ]. Without a rigorous synthesis of evidence tying growth factor dose and donor hematology to outcomes, attempts to optimize PRP/PRF protocols remain empirical. A targeted systematic review and meta-analysis integrating studies that quantify growth factors in PRP/PRF (PDGF, TGF-β1, VEGF, FGF-b, EGF) and correlate them with hematological parameters and clinical outcomes is required. Elucidating these dose–response dynamics will strengthen the biological rationale for PRP/PRF use, guide stratification of patient subgroups, and refine regenerative treatment strategies. Methods Search Protocol This systematic review was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist [ 14 ]. This systematic review was registered with PROSPERO (International Prospective Register of Systematic Reviews) under the number CRD42024575572. Search Strategy and Information Source Search was performed in Pub-Med, Scopus, and Web of Science database using search strategy prepared based in following keywords "Platelet Rich Plasma, Plasma Platelet-Rich, Platelet-rich Plasma Gel, PRP, Growth Factors, Cytokines, Interleukins, IL-6, VEGF, Vascular Endothelial Growth Factor, Platelet-derived Growth Factor, Wound Healing, Wound, Surgery, Bone Regeneration, Periodontal Pocket, Tooth Extraction, and Osseointegration." No filter was used while searching the studies. The search results were exported as bibliometric reference file. Inclusion criteria for studies Studies estimating the growth factors in PRP and/or PRF and complete hemogram for any dental procedure in human subjects. Studies correlating growth factors in PRP and/or PRF with hematological parameters. Studies providing the growth factor levels in PRP and/or PRF and complete hemogram Case control studies/clinical trials/cross-sectional/observational studies. Studies reporting the number of samples, mean, and standard deviation for growth factors and clinicopathological parameters, including hematological parameters, effect size (coefficient r). Exclusion criteria for studies Studies with secondary data, including reviews, systematic reviews, meta-analyses, case reports, theses, and case series. Experimental studies on animal models. Studies that included patients with comorbidity. Screening and Selection Retrieved articles with abstracts were exported, managed, and uploaded to the Web application Rayyan (for screening and study selection) [ 15 ]. Using Rayyan, the titles and abstracts of each identified study were independently assessed and examined by two authors for compliance with the eligibility criteria. Following this initial evaluation, the full text of all potentially relevant publications was retrieved and further examined for inclusion. Any disagreement regarding the eligibility of studies was to be resolved by consulting a third author. Data Extraction Data from all relevant studies were extracted by two reviewers using a customized data extraction sheet via Excel (version 2401). Information recorded included: Study details: Author, date, country of origin; Participants: Population/ethnicity/race, number of participants, gender, age; Methods: Study design, method used for PRP/PRF preparation and hematology investigation, technique used for growth type estimations, total study duration, treatment, and follow-up. Outcomes: quantity of blood used for PRP, quantity of PRP/PRF obtained, type of growth factors, levels of growth factors, complete hemogram values, correlation coefficient (r), and treatment outcome. Any disagreements regarding the extraction of quantitative data were resolved by consulting a third author. Statistical analysis Descriptive analysis was carried out for the study characteristics, platelet count, PRP yield, and growth factors. Correlation analysis was performed for growth factor, platelet count, and whole blood. Meta-analysis was performed for growth factor and PRP yield with platelet count. Analysis was performed using RStudio software. Figure 1 - This is a figure. Schemes follow the same formatting and should be numbered with roman numbers. Results Eligible studies Of 2413 articles retrieved from databases and screened, 64 articles used the PRP/PRF in the treatment of oral diseases and compared the effect of PRP/PRF on outcomes in several oral diseases ( Fig. 1 - PRISMA Flow Chart) . These reported the data from 2477 patients treated with PRP/PRF alone or in combination. In addition, only a few studies reported the growth factor levels in PRP/PRF. Characteristics of included studies The included sixty-four articles were published between 2004 and 2024 [ 16 – 79 ]. Most of these studies were randomized controlled trials (RCTs- split-mouth, prospective, and double-blind). Only few studies were retrospective, comparative, or observational study designs. Out of these 64 studies, 9 studies were formally documented through registration identifiers, including NCT numbers [ 16 – 20 ], CTRI numbers [ 16 ], or adherence to institutional protocols [ 21 – 26 ]. The duration of study and patient follow-up in these studies was ranging from one week [ 27 ] to eight years [ 28 ] showing significantly variation between studies. All studies were focused on use of PRP or PRF in dental and oral surgical interventions (Supplementary file 1: Table S1) . These studies involved a heterogeneous patient demographic characteristics from different age groups, genders, and health statuses, including smokers, those with periodontal or systemic diseases, and healthy participants. Cohort sizes in these studies also varied substantially, from small groups of five participants [ 29 ] to larger assemblies of nearly five hundred [ 30 ]. The studies addressed a spectrum of clinical needs, including routine tooth extractions, complex bone grafting procedures, and the management of various oral defects. Some trials incorporated control groups [ 26 , 31 – 35 ] receiving conventional procedures without PRP [ 16 , 17 , 22 , 23 , 35 – 40 ], while others compared the outcomes of distinct graft materials [ 21 , 29 , 33 , 34 , 41 – 45 ] or surgical methodologies [ 17 , 46 – 48 ]. The demographic data consistently showed an equitable distribution of male and female participants across a broad age range, with specific exclusion criteria often based on systemic health conditions or other risk factors. The primary objective of these studies was to evaluate treatment outcomes concerning healing processes and the incidence of complications within surgical environments, with a particular emphasis on bone repair and regeneration in the dental context. The included papers provide an overview of the methodologies employed for preparing and applying PRP and PRF in several dental and oral surgical procedures (Supplementary file 1) . Key parameters scrutinized across these investigations include baseline platelet concentrations, the specific protocols utilized for PRP/PRF preparation, and application sites. Preparation methods were having variations, from single-step [ 30 ] to two-step centrifugation methods [ 32 ]. Several studies notably reported achieving substantial platelet concentrations [ 21 , 32 – 34 , 37 , 39 , 46 , 47 , 49 , 50 ], frequently several times higher than baseline levels [ 21 , 33 , 46 , 51 ]. Platelet activation often involved agents like calcium chloride or thrombin [ 21 , 41 , 44 , 49 , 51 – 58 ]. While few studies endeavoured to quantify specific growth factors [ 34 , 39 , 43 , 44 , 48 , 53 , 54 , 56 ], other studies did not provide detailed descriptions of the analytical methods employed for their assessment. PRP and PRF was used for healing of extraction sockets, maxillary sinus floor augmentation procedures, and a bony defect, suggesting utilization of PRP and PRF in different dental treatment. Finally, the comprehensive data illuminates the diverse quantities of blood utilized for PRP and PRF preparation across numerous studies. The studies have estimated volume of PRP/PRF obtained and the types and measured levels of associated growth factors. Blood volumes ranged 8 mL [ 38 ] to 500 mL [ 57 ], with the consequent quantity of derived PRP/PRF showing wide variation, often unstated or only implicitly referenced. Growth factors frequently identified in conjunction with PRP/PRF included Platelet-Derived Growth Factor (PDGF), Transforming Growth Factor (TGF), Vascular Endothelial Growth Factor (VEGF), and Insulin-like Growth Factor (IGF), among others [ 21 , 25 , 34 , 39 , 44 , 45 , 48 , 50 , 53 – 57 , 59 , 60 ]. It's important to note that while some studies offered precise quantitative measurements for these growth factors, others merely indicated their presence without direct quantification. The limited number of studies that provided correlation coefficients suggested potential relationships between growth factor levels and clinical healing outcomes, underscoring the considerable methodological and reporting inconsistencies within the analyzed literature. 3.3 PRP quantity from Blood According to Pooled analysis of data from eight published studies from 2004 to 2020, the average yield of PRP/PRF was estimated at approximately 0.115 mL per mL of whole blood processed (Fig. 2 ). The average was derived from 82.38 mL of PRP/PRF obtained from 719 mL of blood, indicating a consistent yet variable efficiency across centrifugation method and devices. The comparison of PRP/PRF yield per ml of blood, indicates substantial variation in centrifugation methods (Fig. 3 ). PRP/PRF yields ranged from 0.012 mL/mL[ 59 ] to 0.20 mL/mL [ 51 ], with 0.115 mL/mL pooled mean. Variation in PRP/PRF yield reflects methodological variation in centrifugation process, machine configurations, and amount of blood volume used. Interestingly, Current centrifuge methods are optimized to produced yields exceeding 0.10 mL/mL from limited blood volumes. Moreover, there a significant linear relationship between blood volume and PRP/PRF yield (Pearson correlation coefficient of 0.99 (p = 7.78 × 10⁻⁷) (Fig. 3 ). This mean PRP/PFR yield can act as a reference for evaluating the volumetric efficiency of platelet concentrate preparation methods as well as can help in creating standardized protocols for clinical application. Further, findings indicate that blood volume is a primary determinant of platelet concentrate yield. This relationship may serve as a benchmark parameter for yield normalization in future studies or device comparison. The forest plot summarizes the pooled estimates of PRP volume per millilitre of blood across eight studies using a fixed-effect meta-analysis model. The overall pooled yield is 0.084 mL/mL, with a 95% confidence interval of [0.037; 0.131], when blood volume is standardized (Fig. 4 ). Overall result is significant suggesting a consistent positive yield of PRP across different methods of PRP/PRF preparations (p < 0.05). However, high heterogeneity (I² = 89.3%, p < 0.001) suggests effect of methodology, instruments, and centrifugation methods on yield. Table I Different growth factor concentrations in PRP/PRF preparations Growth Factor Author Year Level (ng/mL) Reference VEGF Fang D 2020 1.39 [ 31 ] Marukawa E 2011 20 to 60 [ 36 ] Passaretti F 2014 1.3763 ± 0.129 [ 50 ] Qiao J 2016 0.23136 ± 0.04401 [ 40 ] TGF-β / TGF-β1 / TGF-B Fang D 2020 93.4 [ 31 ] Marukawa E 2011 40 to 120 [ 36 ] Passaretti F 2014 265.6675 ± 39.8516 [ 50 ] Qiao J 2016 703.02 ± 86.77 [ 40 ] Ouyang Xiang-ying 2006 650.5 ± 82.0 [ 41 ] Lee C 2009 170.9 ± 42.2 [ 53 ] Raghoebar GM 2005 60600 ± 23600 [ 64 ] PDGF Marukawa E 2011 0.1 to 0.4 [ 36 ] Passaretti F 2014 2.18909 ± 0.225 [ 50 ] Verma R 2019 31.92 ± 10.47 [ 51 ] Qiao J 2016 176.88 ± 52.32 [ 40 ] Ouyang Xiang-ying 2006 110.2 ± 55.2 [ 41 ] bFGF Passaretti F 2014 0.00766 ± 0.00065 [ 50 ] IGF-1 Qiao J 2016 533.69 ± 67.35 [ 40 ] Within the included studies, growth factor concentrations in PRP/PRF exhibit significant variation, mostly attributed to assay methods, donor profiles, and preparation protocols (Table I). Mean Vascular endothelial growth factor (VEGF) levels ranged from 1.3–1.4 ng/mL from low of 0.23 ng/mL [ 40 ] to high of 60 ng/mL [ 36 ]. TGF-β/TGF-β1) showed a markedly variation ranging from 40 ng/mL [ 36 ] to 60,600 ng/mL [ 64 ]. Similarly, Platelet-derived growth factor (PDGF) concentrations range from as low as 0.1 ng/mL to r 176 ng/mL, with Verma R et al [ 51 ] reporting a relatively highre mean of 31.92 ng/mL. Basic fibroblast growth factor (bFGF) level was 0.0077 ng/mL [ 50 ] which was very low in quantity in PRP/PRF. Contrary, Insulin-like growth factor-1 (IGF-1) found in a high concentration of 533.69 ng/mL [ 40 ]. 3.4 Correlation of Platelet count and Obtained PRP quantity The summarized data from seven studies reveal that baseline platelet counts ranged from a lower threshold of ≥ 150 ×10⁹/L [ 59 ] to upper values of 300–450 ×10⁹/L [ 47 ], with most studies reporting means between 216 and 315 ×10⁹/L (Table II) . The data shows considerable variation in PRP quantity ranging from 0.48 mL to 10 mL. Mazor Z et al. [ 48 ] obtained the highest PRP volume (10 mL) despite a moderate platelet count of 216 ± 68 ×10⁹/L, while Cieslik-Bielecka A et al. [ 60 ] reported 6 mL with a comparable baseline. In contrast, studies such as Refahee SM et al. [ 18 ] and Célio-Mariano R et al . [ 47 ] could obtained only 1 mL of PRP despite higher platelet counts. Table II Correlation of Platelet Count and Obtained PRP Quantity Author Year Platelet Count (×10⁹/L) PRP Obtained (mL) Célio-Mariano R et al 2012 300–450* 1 Lindeboom JA et al 2007 248.5 ± 13.5 0.8–1.0 Cieslik-Bielecka A et al 2008 244 ± 68 6 Mazor Z et al 2004 216 ± 68 10 Refahee SM et al 2020 315.33 ± 26.12 1 Sammartino G et al 2005 ≥ 150** 0.48 Lee C et al 2009 273 ± 63 3 * (converted from /µL) **(estimated lower bound) Further, this is supported correlation analysis between baseline platelet count and PRP volume (Fig. 5 ). there was a weak negative correlation between these variables (–0.3757; r² = 0.0865). Thus, higher baseline platelet counts are not reliably associated with increased PRP yield, and may be inversely related. Further, analysis reflects limited use of platelet count in predicting PRP quantity, indicating that additional methodological or biological variables likely influence PRP yield. Thus, it can suggests that platelet count alone may be insufficient as a predictive marker for yield optimization. The highest baseline platelet concentration, exceeding 400 ×10⁹/L [ 47 ] reports, while records the lowest at approximately 150 ×10⁹/L [ 59 ] ( Fig. 6 ) . Further, the highest yield ratio per platelet is 0.0463 mL/×10¹² platelets [ 48 ], whereas lowest was 0.0032 or below [ 18 , 59 ] ( Fig. 7 ) . This variation could be attributed to within and between study heterogeneity in participant selection criteria, measurement methods, and platelet isolation protocols. A meta-analysis was conducted to evaluate the standardized mean differences (SMD) in growth factor (GF) yield per 10^9 platelets for PDGF and TGF-β1. For the PDGF subgroup [ 41 , 50 , 51 ], the pooled effect was SMD = 0.01307; 95% CI: 0.01072–0.01542; p < 0.0001, with extreme heterogeneity (I² = 98.9%, τ² = 0.0485). This indicates a small but statistically significant standardized effect, although study-level variability was high. For the TGF-β1 subgroup [ 41 , 50 , 53 ], the pooled effect was markedly greater, with SMD = 0.84031; 95% CI: 0.72985–0.95078; p < 0.0001, and again high heterogeneity (I² = 97.4%, τ² = 1.0359). This reflects a large and consistent effect size across studies. The overall pooled analysis yielded an effect of SMD = 0.01344; 95% CI: 0.01110–0.01579; p < 0.0001, which was heavily weighted by PDGF estimates. Importantly, the test for subgroup differences was highly significant (χ² = 215.33, df = 1, p < 0.0001), confirming that the effect of TGF-β1 on GF yield per 10^9 platelets was significantly greater than that of PDGF. Discussion The increased use of platelet concentrates in tissue regenerative dentistry in last few decades has prompted growing interest in their biological composition and clinical impact. This systematic review meta-analysis study offers a novel contribution by consolidating evidence on the correlation between growth factor concentrations in PRP/PRF and haematological parameters, with a particular emphasis on preparation efficiency and biological variability. There was substantial heterogeneity in both the quantity of PRP/PRF obtained and the concentrations of growth factors such as PDGF, TGF-β, and VEGF. These variations reflect in platelet count in blood from individuals as well as methodological difference in the preparation protocols across the included studies [ 38 , 42 , 43 ]. These findings are substantiated by difference in sample sizes, geographic locations, patient demographics, and PRP/PRF preparation methods. These observations are in line observation by previous reviews [ 62 ], which emphasized that differences in centrifugation settings or sample handling often explain discrepancies in clinical outcomes. Therefore, standardization of PRP and PFR preparation protocol remains critical for reproducibility and clinical reliability. Having said that, clinician must consider the individual biological variation in blood composition to obtain desired amount of PRP/PRF to get optimum clinical success. Among the quantitative findings, a strong positive correlation was observed between the volume of blood processed and the final PRP/PRF yield, suggesting that blood volume is a more reliable predictor of output than baseline platelet count. As shown in Table 3 and Fig. 5 , the correlation between platelet count and PRP/PRF yield was weak, indicating that this parameter alone does not adequately predict protocol performance. This supports existing evidence that procedural variables such as centrifugation speed, rotor type, and anticoagulant use play a more decisive role in determining final yield [ 50 , 56 ].Beyond total yield, growth factor concentrations in PRP/PRF were highly variable. TGF-β showed large variation in quantity ranging from 40 ng/mL to over 60,000 ng/mL. Similar, large variation in yield was noted with PDGF and VEGF [ 38 , 42 , 53 , 55 ]. These variations in yield may be linked to individual person related factors, analysis methods, and mechanism involved in release of growth factors within blood samples. Further, histological studies reported that uneven platelet entrapment within the fibrin matrix, particularly when fixed-angle centrifugation is used, which tends to concentrate cells along the distal tube wall impacting the growth factor yield [ 21 ]. Moreover, In-vitro studies have shown that high platelet densities may impair cellular proliferation due to inhibitory feedback mechanisms such as local pH shifts and receptor saturation resulting in variation in growth factor yield [ 22 ]. Therefore, instead of focusing on maximizing platelet enrichment from blood, clinicians and researcher must identify an optimal growth factor concentration which may be more clinically successful in delivering the desired outcomes. Our meta-analysis showed PRP/PRF yield being directly correlated with the blood volume used for preparation and is a rich source of growth factors for regenerative treatments. Interestingly, the pooled estimate of yield per millilitre of blood have a relatively small confidence interval despite inter-individual variability, indicating that blood-volume normalization is a reliable parameter to assess protocol efficiency. Similar observations have been reported in musculoskeletal and dermatological applications [ 7 , 40 ]. While prior analyses involving platelet count demonstrated that technical factors determine final yield, the use of normalized parameters enables more standardized and comparable evaluations of efficiency across studies and devices. Comparable findings have also been reported in regenerative medicine, where efficient protocols achieved higher yields even from lower baseline values [ 21 , 42 ]. Moreover, growth factor yield varied across different preparation protocols. Growth factor yields per 10⁹ platelets showed that, even after normalization, platelets released significantly high quantities of growth factors per platelet irrespective of protocol. These results are in line with Anitua et al. observation [ 28 ], which reported the influence of platelet activation methods and fibrin architecture on growth factor release. These findings clearly support role of methodological variation not only in quantitative yield but also in the quality and bio-activity of the concentrates, outweighing the influence of baseline haematology on clinical success. Unfortunately, even though individual studies included in this review reported growth factor concentrations, none provided standardized clinical endpoints such as probing depth reduction, bone fill, or implant stability. This gap shows the limitation in dose–response modelling and highlights the need for future trials to quantify both biological and clinical outputs in an integrated manner. Clinically, these findings can help in clarifying the inconsistent outcomes observed in regenerative treatments. PRP and PRF have shown promise in improving bone regeneration, periodontal healing, implant stability, and soft tissue repair. However, differences in growth factor release may partly explain the variability in clinical success [ 25 , 40 , 39 ]. PRP/PRF have demonstrated efficacy in improving bone density, osseointegration, and reducing postoperative complications, yet in some cases, they offer minimal or no advantage over traditional grafting or surgical approaches [ 24 , 45 , 46 ]. The evidence indicates that platelet concentrates are not universally effective and may require customization according to individual biology and procedural needs. Given the biological heterogeneity among patients, it is likely that some individuals respond more favourably to platelet concentrates than others. Future studies should stratify participants accordingly to clarify which subgroups benefit most and under what conditions. Their clinical utility also appears to be indication-specific: in oral and Maxillofacial surgery, PRP/PRF is frequently used to accelerate socket healing and enhance sinus lift outcomes; in periodontology, it supports angiogenesis and soft tissue coverage [ 25 , 28 , 31 , 40 ]; and beyond dentistry, PRP is increasingly used in musculoskeletal and dermatologic procedures, though with similarly variable outcomes [ 7 ]. Across all these fields, a shared limitation remains the heterogeneity in growth factor concentrations, underscoring the urgent need for reproducible preparation techniques and clearer identification of patient subgroups most likely to benefit. Beside this common limitation, our review identified a critical gaps in the literature. First, the lack of precise reporting on growth factor concentrations and their correlation with hematological profiles. Second, many studies failed to provide precise quantitative data on growth factor concentrations, and even fewer studies correlated these with patients' hematological profiles [ 22 , 26 , 27 , 36 , 37 , 39 ]. Without transparent reporting of centrifugation parameters, platelet enrichment ratios, and storage conditions, pooling data across studies may not give actual correlation, and comparisons between devices may not be reasonable. Additionally, known confounders such as smoking, diabetes, systemic inflammation, sex hormones, and anticoagulant use were rarely analyzed, despite knowing their influence on platelet function and growth factor release. Despite these limitations in primary studies, strengths of this review are the inclusion of studies conducted over last two decades, descriptive and meta-analytic approach, and the normalization of yield to both blood volume and platelet count [ 34 , 40 ]. The random-effects meta-analysis assisted in estimation of pooled effect size despite heterogeneity within studies. Future clinical studies evaluating PRP/PRF's effectiveness in tissue regeneration should prioritize multi-center randomized clinical trials with standardized preparation and reporting protocols [ 8 , 9 , 44 ]. In addition, these clinical trial must directly correlate PRP/PRF yield with clinical outcomes rather than limiting to bone density, implant stability, or wound healing, and assess growth factor release kinetics at multiple time points. Furthermore, proteomic profiling and genomic stratification of individual may help identify biological predictors of treatment response and support the development of personalized regenerative approaches. By consolidating current evidence on growth factor in PRP/PRF, methodology impact, and limited clinical correlations, this review provide a direction toward more personalized, evidence-driven protocols for PRP/PRF use in regenerative field. Finally, even though PRP/PRF remain promising tissue derivative for accelerating, improving wound healing and tissue regeneration process, their predictable translation into clinical practice remains hindered by variation in preparation, biological heterogeneity, and inconsistent reporting. Considering need for optimized personalized treatment strategies involving PRP/PRF in tissue regenerative treatments, there is a need for standardized preparation protocols alongside rigorous methodology and transparent reporting, to bridge the gap between laboratory finding and clinical outcomes. Conclusion This systematic review provide the evidence on correlation of platelet concentrates with growth factors, however, their clinical translation is hindered by variability in growth factor levels and preparation protocols. PRP/PRF yield is strongly dependent on the volume of blood processed rather than baseline platelet count, underscoring the role of methodological factors in determining efficiency. The wide heterogeneity in growth factor concentrations, particularly TGF-β, PDGF, and VEGF, highlights the influence of both biological and technical variables. Closing the gap between laboratory findings and clinical outcomes requires standardization of PRP/PRF preparation methods along with clear reporting, and robust alignment with clinical endpoints. In addition, conducting multi-centre clinical trials involving molecular profiling could lay the groundwork for personalized use of platelet concentrates, promoting their consistent and effective application in regenerative therapies. Abbreviations PRP- Platelet-Rish Plasma PRF- Platelet-Risch Fibrin PC- Platelet Concentrates PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses PDGF- Platelet-Derived Growth Factor TGF-B- Transforming Growth Factor-Beta IL- Interleukin RCT- Randomized Controlled Trial NCT- Non Clinical Trial VEGF- Vascular Endothelial Growth Factor IGF- Insulin-like Growth Factor Declarations Conflict of Interest The authors have no conflicts of interest to declare. Contribution Contributions Conceptualization: M. Y., A. E. B., and A. C. Methodology: M. Y. and A. E. B. Software: A. E. B. Validation: B. K. U., Y. L., and M. A. T. C. Formal Analysis: M. Y. and A. E. B. Investigation: V. A. S., A. O. A., A. C. M. A., J. F., J. T. T., and A. G. Resources: V. A. S. and A. O. A. Data Curation: M. Y., A. E. B., and S. P. Writing—Original Draft Preparation (Co-First Authors): M. Y. and A. E. B. Visualization: B. K. U., Y. L., and M. A. T. C. Writing—Review & Editing: S. P., V. A. S., A. C., M. Y., A. E. B., A. O. A., A. C. M. A., B. K. U., Y. L., M. A. T. C., J. F., J. T. T., and A. G. Supervision: A. C. Project Administration: A. C. All authors reviewed and approved the final manuscript. Regulatory Statement The review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines, as recommended by the EQUATOR Network. In addition, this systematic review was registered with PROSPERO (CRD42024575572). This review was carried out using a systematic search of electronic databases. 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Braz Oral Res 34(supp1 1):e026. 10.1590/1807-3107bor-2020.vol34.0026 Prati C, Zamparini F, Pirani C, Montebugnoli L, Canullo L, Gandolfi MG A Multilevel Analysis of Platform-Switching Flapless Implants Placed at Tissue Level: 4-year Prospective Cohort Study. Int J Oral Maxillofac Implants 2020 Mar/Apr ;35(2):330–341. 10.11607/jomi.7541 Assery MKA (February 2019) Efficacy of Artificial Salivary Substitutes in Treatment of Xerostomia: A Systematic Review. J Pharm Bioallied Sci 11(1):S1–S12. 10.4103/jpbs.JPBS_220_18 Additional Declarations The authors declare no competing interests. Supplementary Files Supplementeryfile1.xlsx Summary of Individual Study Characteristics PRISMA2020checklistPRP.docx PRISMA Checklist Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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2","display":"","copyAsset":false,"role":"figure","size":3061376,"visible":true,"origin":"","legend":"\u003cp\u003ePRP/PRF Yield per mL of Blood Across Studies\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8408844/v1/5f4494f56b826e03d325627d.jpg"},{"id":99190777,"identity":"f2082ed6-9137-4911-94fa-9e16382581d7","added_by":"auto","created_at":"2025-12-30 00:52:39","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3082324,"visible":true,"origin":"","legend":"\u003cp\u003eThe comparative yield analysis of PRP/PRF per millilitre of blood across studies\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8408844/v1/6510deb1098e247503095565.jpg"},{"id":99190791,"identity":"14377f9f-1c9c-40e0-be89-9ac01c2f36a5","added_by":"auto","created_at":"2025-12-30 00:52:40","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":4333972,"visible":true,"origin":"","legend":"\u003cp\u003eThe pooled estimates of PRP volume per millilitre of blood across studies\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8408844/v1/cc82e6930cec23ee2ed0156d.jpg"},{"id":99190800,"identity":"f08092b7-9172-42a4-9ece-126c35b2c54e","added_by":"auto","created_at":"2025-12-30 00:52:40","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":2890339,"visible":true,"origin":"","legend":"\u003cp\u003eScatter plot showing relationship between baseline platelet count (×10³/µL) and PRP volume (mL) across seven individual cases\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8408844/v1/97971823ddc0ef704c3f0b25.jpg"},{"id":99317201,"identity":"293cd178-414d-4651-a0dd-6bd853233444","added_by":"auto","created_at":"2025-12-31 16:29:45","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":2809003,"visible":true,"origin":"","legend":"\u003cp\u003eThe bar graph presenting a comparative overview of mean platelet counts (expressed in ×10⁹/L) across seven published studies\u003c/p\u003e","description":"","filename":"Figure6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8408844/v1/342c21e81bf8dcf6934e6dbb.jpg"},{"id":99316687,"identity":"7bbb0a08-4336-4d49-a2c9-79d1dd19b737","added_by":"auto","created_at":"2025-12-31 16:29:00","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":2879358,"visible":true,"origin":"","legend":"\u003cp\u003eThe bar graph comparing the yield of platelet-rich plasma (PRP) per unit platelet count (expressed as mL per ×10¹²/)\u003c/p\u003e","description":"","filename":"Figure7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8408844/v1/5c6b2c0d1cf10b65e2f39aec.jpg"},{"id":99190784,"identity":"adc32a08-1c86-49ec-a8ce-31f4a6acddce","added_by":"auto","created_at":"2025-12-30 00:52:40","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":4707501,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot presenting a meta-analysis comparing the yield of two growth factors—PDGF and TGF-β1—normalized per 10\u003csup\u003e9\u003c/sup\u003e platelets\u003c/p\u003e","description":"","filename":"Figure81.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8408844/v1/c68c1a9a031efbc3dd4013a5.jpg"},{"id":99791656,"identity":"5d0930b0-244d-4aa7-918d-d2a177eac10e","added_by":"auto","created_at":"2026-01-08 13:07:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":25486469,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8408844/v1/555d487a-c57b-4af5-9828-b963aed249de.pdf"},{"id":99190774,"identity":"0c900375-f748-42dd-a283-dad0089b49f1","added_by":"auto","created_at":"2025-12-30 00:52:39","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":56684,"visible":true,"origin":"","legend":"\u003cp\u003eSummary of Individual Study Characteristics\u003c/p\u003e","description":"","filename":"Supplementeryfile1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8408844/v1/56ec0cf14caa8f5390bf3f0f.xlsx"},{"id":99316221,"identity":"1c9c151f-2220-4405-90a9-2d1988e67fd4","added_by":"auto","created_at":"2025-12-31 16:27:54","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":275805,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA Checklist\u003c/p\u003e","description":"","filename":"PRISMA2020checklistPRP.docx","url":"https://assets-eu.researchsquare.com/files/rs-8408844/v1/94c6ad7bff447a46bf66ac12.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eCorrelation of Growth Factors in Platelet-Rich Plasma with Clinical Outcomes and Hematological Parameters in Regenerative Dentistry: A Systematic Review and Meta-Analysis\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAutologous platelet concentrates such as platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) have become integral adjuncts in regenerative dentistry because they deliver concentrated, endogenous growth factors that direct angiogenesis, cell migration, matrix synthesis and osteogenesis. Key mediators present in these preparations - PDGF (PDGF-AA/-BB/-AB), TGF-β1, VEGF, FGF-b and EGF-are biologically plausible effectors of clinical outcomes in periodontal, endodontic and implant therapies [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, clinical responses after PRP/PRF application are inconsistent across trials and indications, limiting predictability and wider adoption [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA major source of this heterogeneity is compositional variability: preparation protocol (centrifugation force/time), product format (liquid PRP, solid PRF, i-PRF, A-PRF), and donor hematological factors (baseline platelet and leukocyte counts) all alter growth factor yield and release kinetics [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Recent primary studies that directly measured individual growth factors support this mechanistic link. For example, a controlled pilot study quantified VEGF, IGF-1, TGF-β1, PDGF-BB and EGF in injectable PRF and explored their relationship with donors\u0026rsquo; blood counts [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Work on advanced PRF (A-PRF) has characterized PDGF, TGF-β1 and VEGF release under clinically relevant conditions and demonstrated time-dependent availability that may favor sustained tissue repair [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Comparative analyses likewise show that some low-speed PRF protocols yield prolonged growth factor release compared with classical PRP, suggesting formulation-dependent biological effects [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Recent ex vivo studies have demonstrated that growth factor concentrations in PRP/PRF significantly influence osteoblast proliferation and angiogenic activity, providing a biological foundation for their observed clinical effects [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Furthermore, translational studies in dental implantology link higher PDGF and VEGF levels to better bone-to-implant contact and enhanced osseointegration quality [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClinically, randomized trials and meta-analyses document benefits of platelet concentrates in intra-bony periodontal defects, implant site regeneration and regenerative endodontics, yet few studies quantitatively link measured growth factor concentrations to standardized clinical endpoints (e.g., probing depth reduction, radiographic bone fill, implant stability) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Without a rigorous synthesis of evidence tying growth factor dose and donor hematology to outcomes, attempts to optimize PRP/PRF protocols remain empirical.\u003c/p\u003e \u003cp\u003eA targeted systematic review and meta-analysis integrating studies that quantify growth factors in PRP/PRF (PDGF, TGF-β1, VEGF, FGF-b, EGF) and correlate them with hematological parameters and clinical outcomes is required. Elucidating these dose\u0026ndash;response dynamics will strengthen the biological rationale for PRP/PRF use, guide stratification of patient subgroups, and refine regenerative treatment strategies.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003eSearch Protocol\u003c/h2\u003e\n\u003cp\u003eThis systematic review was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]. This systematic review was registered with PROSPERO (International Prospective Register of Systematic Reviews) under the number CRD42024575572.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eSearch Strategy and Information Source\u003c/h3\u003e\n\u003cp\u003eSearch was performed in Pub-Med, Scopus, and Web of Science database using search strategy prepared based in following keywords \"Platelet Rich Plasma, Plasma Platelet-Rich, Platelet-rich Plasma Gel, PRP, Growth Factors, Cytokines, Interleukins, IL-6, VEGF, Vascular Endothelial Growth Factor, Platelet-derived Growth Factor, Wound Healing, Wound, Surgery, Bone Regeneration, Periodontal Pocket, Tooth Extraction, and Osseointegration.\" No filter was used while searching the studies. The search results were exported as bibliometric reference file.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria for studies\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003eStudies estimating the growth factors in PRP and/or PRF and complete hemogram for any dental procedure in human subjects.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eStudies correlating growth factors in PRP and/or PRF with hematological parameters.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eStudies providing the growth factor levels in PRP and/or PRF and complete hemogram\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eCase control studies/clinical trials/cross-sectional/observational studies.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eStudies reporting the number of samples, mean, and standard deviation for growth factors and clinicopathological parameters, including hematological parameters, effect size (coefficient r).\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria for studies\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003eStudies with secondary data, including reviews, systematic reviews, meta-analyses, case reports, theses, and case series.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eExperimental studies on animal models.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eStudies that included patients with comorbidity.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003ch3\u003eScreening and Selection\u003c/h3\u003e\n\u003cp\u003eRetrieved articles with abstracts were exported, managed, and uploaded to the Web application Rayyan (for screening and study selection) [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]. Using Rayyan, the titles and abstracts of each identified study were independently assessed and examined by two authors for compliance with the eligibility criteria. Following this initial evaluation, the full text of all potentially relevant publications was retrieved and further examined for inclusion. Any disagreement regarding the eligibility of studies was to be resolved by consulting a third author.\u003c/p\u003e\n\u003ch3\u003eData Extraction\u003c/h3\u003e\n\u003cp\u003eData from all relevant studies were extracted by two reviewers using a customized data extraction sheet via Excel (version 2401). Information recorded included:\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003eStudy details: Author, date, country of origin;\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eParticipants: Population/ethnicity/race, number of participants, gender, age;\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eMethods: Study design, method used for PRP/PRF preparation and hematology investigation, technique used for growth type estimations, total study duration, treatment, and follow-up.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eOutcomes: quantity of blood used for PRP, quantity of PRP/PRF obtained, type of growth factors, levels of growth factors, complete hemogram values, correlation coefficient (r), and treatment outcome. Any disagreements regarding the extraction of quantitative data were resolved by consulting a third author.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003eStatistical analysis\u003c/h2\u003e\n\u003cp\u003eDescriptive analysis was carried out for the study characteristics, platelet count, PRP yield, and growth factors. Correlation analysis was performed for growth factor, platelet count, and whole blood. Meta-analysis was performed for growth factor and PRP yield with platelet count. Analysis was performed using RStudio software.\u003c/p\u003e\n\u003cp\u003eFigure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cstrong\u003e-\u003c/strong\u003e This is a figure. Schemes follow the same formatting and should be numbered with roman numbers.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eEligible studies\u003c/h2\u003e \u003cp\u003eOf 2413 articles retrieved from databases and screened, 64 articles used the PRP/PRF in the treatment of oral diseases and compared the effect of PRP/PRF on outcomes in several oral diseases \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e- PRISMA Flow Chart)\u003c/b\u003e. These reported the data from 2477 patients treated with PRP/PRF alone or in combination. In addition, only a few studies reported the growth factor levels in PRP/PRF.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCharacteristics of included studies\u003c/h3\u003e\n\u003cp\u003eThe included sixty-four articles were published between 2004 and 2024 [\u003cspan additionalcitationids=\"CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38 CR39 CR40 CR41 CR42 CR43 CR44 CR45 CR46 CR47 CR48 CR49 CR50 CR51 CR52 CR53 CR54 CR55 CR56 CR57 CR58 CR59 CR60 CR61 CR62 CR63 CR64 CR65 CR66 CR67 CR68 CR69 CR70 CR71 CR72 CR73 CR74 CR75 CR76 CR77 CR78\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e]. Most of these studies were randomized controlled trials (RCTs- split-mouth, prospective, and double-blind). Only few studies were retrospective, comparative, or observational study designs. Out of these 64 studies, 9 studies were formally documented through registration identifiers, including NCT numbers [\u003cspan additionalcitationids=\"CR17 CR18 CR19\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], CTRI numbers [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], or adherence to institutional protocols [\u003cspan additionalcitationids=\"CR22 CR23 CR24 CR25\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The duration of study and patient follow-up in these studies was ranging from one week [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] to eight years [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] showing significantly variation between studies. All studies were focused on use of PRP or PRF in dental and oral surgical interventions \u003cb\u003e(Supplementary file 1: Table S1)\u003c/b\u003e. These studies involved a heterogeneous patient demographic characteristics from different age groups, genders, and health statuses, including smokers, those with periodontal or systemic diseases, and healthy participants. Cohort sizes in these studies also varied substantially, from small groups of five participants [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] to larger assemblies of nearly five hundred [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. The studies addressed a spectrum of clinical needs, including routine tooth extractions, complex bone grafting procedures, and the management of various oral defects. Some trials incorporated control groups [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan additionalcitationids=\"CR32 CR33 CR34\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] receiving conventional procedures without PRP [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan additionalcitationids=\"CR36 CR37 CR38 CR39\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e], while others compared the outcomes of distinct graft materials [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan additionalcitationids=\"CR42 CR43 CR44\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e] or surgical methodologies [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan additionalcitationids=\"CR47\" citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. The demographic data consistently showed an equitable distribution of male and female participants across a broad age range, with specific exclusion criteria often based on systemic health conditions or other risk factors. The primary objective of these studies was to evaluate treatment outcomes concerning healing processes and the incidence of complications within surgical environments, with a particular emphasis on bone repair and regeneration in the dental context.\u003c/p\u003e \u003cp\u003eThe included papers provide an overview of the methodologies employed for preparing and applying PRP and PRF in several dental and oral surgical procedures \u003cb\u003e(Supplementary file 1)\u003c/b\u003e. Key parameters scrutinized across these investigations include baseline platelet concentrations, the specific protocols utilized for PRP/PRF preparation, and application sites. Preparation methods were having variations, from single-step [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] to two-step centrifugation methods [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Several studies notably reported achieving substantial platelet concentrations [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e], frequently several times higher than baseline levels [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. Platelet activation often involved agents like calcium chloride or thrombin [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan additionalcitationids=\"CR52 CR53 CR54 CR55 CR56 CR57\" citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. While few studies endeavoured to quantify specific growth factors [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e], other studies did not provide detailed descriptions of the analytical methods employed for their assessment. PRP and PRF was used for healing of extraction sockets, maxillary sinus floor augmentation procedures, and a bony defect, suggesting utilization of PRP and PRF in different dental treatment.\u003c/p\u003e \u003cp\u003eFinally, the comprehensive data illuminates the diverse quantities of blood utilized for PRP and PRF preparation across numerous studies. The studies have estimated volume of PRP/PRF obtained and the types and measured levels of associated growth factors. Blood volumes ranged 8 mL [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] to 500 mL [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e], with the consequent quantity of derived PRP/PRF showing wide variation, often unstated or only implicitly referenced. Growth factors frequently identified in conjunction with PRP/PRF included Platelet-Derived Growth Factor (PDGF), Transforming Growth Factor (TGF), Vascular Endothelial Growth Factor (VEGF), and Insulin-like Growth Factor (IGF), among others [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan additionalcitationids=\"CR54 CR55 CR56\" citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]. It's important to note that while some studies offered precise quantitative measurements for these growth factors, others merely indicated their presence without direct quantification. The limited number of studies that provided correlation coefficients suggested potential relationships between growth factor levels and clinical healing outcomes, underscoring the considerable methodological and reporting inconsistencies within the analyzed literature.\u003c/p\u003e \u003cp\u003e \u003cem\u003e3.3 PRP quantity from Blood\u003c/em\u003e \u003c/p\u003e \u003cp\u003eAccording to Pooled analysis of data from eight published studies from 2004 to 2020, the average yield of PRP/PRF was estimated at approximately 0.115 mL per mL of whole blood processed (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The average was derived from 82.38 mL of PRP/PRF obtained from 719 mL of blood, indicating a consistent yet variable efficiency across centrifugation method and devices.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe comparison of PRP/PRF yield per ml of blood, indicates substantial variation in centrifugation methods (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). PRP/PRF yields ranged from 0.012 mL/mL[\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e] to 0.20 mL/mL [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e], with 0.115 mL/mL pooled mean. Variation in PRP/PRF yield reflects methodological variation in centrifugation process, machine configurations, and amount of blood volume used. Interestingly, Current centrifuge methods are optimized to produced yields exceeding 0.10 mL/mL from limited blood volumes. Moreover, there a significant linear relationship between blood volume and PRP/PRF yield (Pearson correlation coefficient of 0.99 (p\u0026thinsp;=\u0026thinsp;7.78 \u0026times; 10⁻⁷) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). This mean PRP/PFR yield can act as a reference for evaluating the volumetric efficiency of platelet concentrate preparation methods as well as can help in creating standardized protocols for clinical application.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFurther, findings indicate that blood volume is a primary determinant of platelet concentrate yield. This relationship may serve as a benchmark parameter for yield normalization in future studies or device comparison.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe forest plot summarizes the pooled estimates of PRP volume per millilitre of blood across eight studies using a fixed-effect meta-analysis model. The overall pooled yield is 0.084 mL/mL, with a 95% confidence interval of [0.037; 0.131], when blood volume is standardized (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Overall result is significant suggesting a consistent positive yield of PRP across different methods of PRP/PRF preparations (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). However, high heterogeneity (I\u0026sup2; = 89.3%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) suggests effect of methodology, instruments, and centrifugation methods on yield.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eTable I\u003c/strong\u003e \u003cp\u003eDifferent growth factor concentrations in PRP/PRF preparations\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrowth Factor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAuthor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYear\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLevel (ng/mL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVEGF\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFang D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMarukawa E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 to 60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePassaretti F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.3763\u0026thinsp;\u0026plusmn;\u0026thinsp;0.129\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQiao J\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.23136\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04401\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTGF-β / TGF-β1 / TGF-B\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFang D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e93.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMarukawa E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40 to 120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePassaretti F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e265.6675\u0026thinsp;\u0026plusmn;\u0026thinsp;39.8516\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQiao J\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e703.02\u0026thinsp;\u0026plusmn;\u0026thinsp;86.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOuyang Xiang-ying\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e650.5\u0026thinsp;\u0026plusmn;\u0026thinsp;82.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLee C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e170.9\u0026thinsp;\u0026plusmn;\u0026thinsp;42.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRaghoebar GM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60600\u0026thinsp;\u0026plusmn;\u0026thinsp;23600\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePDGF\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMarukawa E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.1 to 0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePassaretti F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.18909\u0026thinsp;\u0026plusmn;\u0026thinsp;0.225\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVerma R\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31.92\u0026thinsp;\u0026plusmn;\u0026thinsp;10.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQiao J\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e176.88\u0026thinsp;\u0026plusmn;\u0026thinsp;52.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOuyang Xiang-ying\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e110.2\u0026thinsp;\u0026plusmn;\u0026thinsp;55.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ebFGF\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePassaretti F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.00766\u0026thinsp;\u0026plusmn;\u0026thinsp;0.00065\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIGF-1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQiao J\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e533.69\u0026thinsp;\u0026plusmn;\u0026thinsp;67.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWithin the included studies, growth factor concentrations in PRP/PRF exhibit significant variation, mostly attributed to assay methods, donor profiles, and preparation protocols (Table I). Mean Vascular endothelial growth factor (VEGF) levels ranged from 1.3\u0026ndash;1.4 ng/mL from low of 0.23 ng/mL [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] to high of 60 ng/mL [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. TGF-β/TGF-β1) showed a markedly variation ranging from 40 ng/mL [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] to 60,600 ng/mL [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e]. Similarly, Platelet-derived growth factor (PDGF) concentrations range from as low as 0.1 ng/mL to r 176 ng/mL, with Verma R et al [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e] reporting a relatively highre mean of 31.92 ng/mL. Basic fibroblast growth factor (bFGF) level was 0.0077 ng/mL [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e] which was very low in quantity in PRP/PRF. Contrary, Insulin-like growth factor-1 (IGF-1) found in a high concentration of 533.69 ng/mL [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cem\u003e3.4 Correlation of Platelet count and Obtained PRP quantity\u003c/em\u003e \u003c/p\u003e \u003cp\u003eThe summarized data from seven studies reveal that baseline platelet counts ranged from a lower threshold of \u0026ge;\u0026thinsp;150 \u0026times;10⁹/L [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e] to upper values of 300\u0026ndash;450 \u0026times;10⁹/L [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e], with most studies reporting means between 216 and 315 \u0026times;10⁹/L \u003cb\u003e(Table II)\u003c/b\u003e. The data shows considerable variation in PRP quantity ranging from 0.48 mL to 10 mL. Mazor Z \u003cem\u003eet al.\u003c/em\u003e [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e] obtained the highest PRP volume (10 mL) despite a moderate platelet count of 216\u0026thinsp;\u0026plusmn;\u0026thinsp;68 \u0026times;10⁹/L, while Cieslik-Bielecka A et al. [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e] reported 6 mL with a comparable baseline. In contrast, studies such as Refahee SM \u003cem\u003eet al.\u003c/em\u003e [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] and C\u0026eacute;lio-Mariano R \u003cem\u003eet al\u003c/em\u003e. [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e] could obtained only 1 mL of PRP despite higher platelet counts.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eTable II\u003c/strong\u003e \u003cp\u003eCorrelation of Platelet Count and Obtained PRP Quantity\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYear\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePlatelet Count (\u0026times;10⁹/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePRP Obtained (mL)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u0026eacute;lio-Mariano R et al\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e300\u0026ndash;450*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLindeboom JA et al\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e248.5\u0026thinsp;\u0026plusmn;\u0026thinsp;13.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.8\u0026ndash;1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCieslik-Bielecka A et al\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e244\u0026thinsp;\u0026plusmn;\u0026thinsp;68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMazor Z et al\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e216\u0026thinsp;\u0026plusmn;\u0026thinsp;68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRefahee SM et al\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e315.33\u0026thinsp;\u0026plusmn;\u0026thinsp;26.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSammartino G et al\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;150**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLee C et al\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e273\u0026thinsp;\u0026plusmn;\u0026thinsp;63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e*\u003cem\u003e(converted from /\u0026micro;L)\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\u003cp\u003e**(estimated lower bound)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFurther, this is supported correlation analysis between baseline platelet count and PRP volume (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). there was a weak negative correlation between these variables (\u0026ndash;0.3757; r\u0026sup2; = 0.0865). Thus, higher baseline platelet counts are not reliably associated with increased PRP yield, and may be inversely related. Further, analysis reflects limited use of platelet count in predicting PRP quantity, indicating that additional methodological or biological variables likely influence PRP yield. Thus, it can suggests that platelet count alone may be insufficient as a predictive marker for yield optimization.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe highest baseline platelet concentration, exceeding 400 \u0026times;10⁹/L [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e] reports, while records the lowest at approximately 150 \u0026times;10⁹/L [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e] \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. Further, the highest yield ratio per platelet is 0.0463 mL/\u0026times;10\u0026sup1;\u0026sup2; platelets [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e], whereas lowest was 0.0032 or below [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e] \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. This variation could be attributed to within and between study heterogeneity in participant selection criteria, measurement methods, and platelet isolation protocols.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA meta-analysis was conducted to evaluate the standardized mean differences (SMD) in growth factor (GF) yield per 10^9 platelets for PDGF and TGF-β1. For the PDGF subgroup [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e], the pooled effect was SMD\u0026thinsp;=\u0026thinsp;0.01307; 95% CI: 0.01072\u0026ndash;0.01542; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, with extreme heterogeneity (I\u0026sup2; = 98.9%, τ\u0026sup2; = 0.0485). This indicates a small but statistically significant standardized effect, although study-level variability was high. For the TGF-β1 subgroup [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e], the pooled effect was markedly greater, with SMD\u0026thinsp;=\u0026thinsp;0.84031; 95% CI: 0.72985\u0026ndash;0.95078; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, and again high heterogeneity (I\u0026sup2; \u003cb\u003e=\u003c/b\u003e 97.4%, τ\u0026sup2; = 1.0359). This reflects a large and consistent effect size across studies. The overall pooled analysis yielded an effect of SMD\u0026thinsp;=\u0026thinsp;0.01344; 95% CI: 0.01110\u0026ndash;0.01579; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, which was heavily weighted by PDGF estimates. Importantly, the test for subgroup differences was highly significant (χ\u0026sup2; = 215.33, df\u0026thinsp;=\u0026thinsp;1, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), confirming that the effect of TGF-β1 on GF yield per 10^9 platelets was significantly greater than that of PDGF.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe increased use of platelet concentrates in tissue regenerative dentistry in last few decades has prompted growing interest in their biological composition and clinical impact. This systematic review meta-analysis study offers a novel contribution by consolidating evidence on the correlation between growth factor concentrations in PRP/PRF and haematological parameters, with a particular emphasis on preparation efficiency and biological variability. There was substantial heterogeneity in both the quantity of PRP/PRF obtained and the concentrations of growth factors such as PDGF, TGF-β, and VEGF. These variations reflect in platelet count in blood from individuals as well as methodological difference in the preparation protocols across the included studies [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThese findings are substantiated by difference in sample sizes, geographic locations, patient demographics, and PRP/PRF preparation methods. These observations are in line observation by previous reviews [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e], which emphasized that differences in centrifugation settings or sample handling often explain discrepancies in clinical outcomes. Therefore, standardization of PRP and PFR preparation protocol remains critical for reproducibility and clinical reliability. Having said that, clinician must consider the individual biological variation in blood composition to obtain desired amount of PRP/PRF to get optimum clinical success.\u003c/p\u003e \u003cp\u003eAmong the quantitative findings, a strong positive correlation was observed between the volume of blood processed and the final PRP/PRF yield, suggesting that blood volume is a more reliable predictor of output than baseline platelet count. As shown in Table\u0026nbsp;3 and Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, the correlation between platelet count and PRP/PRF yield was weak, indicating that this parameter alone does not adequately predict protocol performance. This supports existing evidence that procedural variables such as centrifugation speed, rotor type, and anticoagulant use play a more decisive role in determining final yield [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e].Beyond total yield, growth factor concentrations in PRP/PRF were highly variable. TGF-β showed large variation in quantity ranging from 40 ng/mL to over 60,000 ng/mL. Similar, large variation in yield was noted with PDGF and VEGF [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. These variations in yield may be linked to individual person related factors, analysis methods, and mechanism involved in release of growth factors within blood samples. Further, histological studies reported that uneven platelet entrapment within the fibrin matrix, particularly when fixed-angle centrifugation is used, which tends to concentrate cells along the distal tube wall impacting the growth factor yield [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Moreover, In-vitro studies have shown that high platelet densities may impair cellular proliferation due to inhibitory feedback mechanisms such as local pH shifts and receptor saturation resulting in variation in growth factor yield [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Therefore, instead of focusing on maximizing platelet enrichment from blood, clinicians and researcher must identify an optimal growth factor concentration which may be more clinically successful in delivering the desired outcomes.\u003c/p\u003e \u003cp\u003eOur meta-analysis showed PRP/PRF yield being directly correlated with the blood volume used for preparation and is a rich source of growth factors for regenerative treatments. Interestingly, the pooled estimate of yield per millilitre of blood have a relatively small confidence interval despite inter-individual variability, indicating that blood-volume normalization is a reliable parameter to assess protocol efficiency. Similar observations have been reported in musculoskeletal and dermatological applications [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. While prior analyses involving platelet count demonstrated that technical factors determine final yield, the use of normalized parameters enables more standardized and comparable evaluations of efficiency across studies and devices. Comparable findings have also been reported in regenerative medicine, where efficient protocols achieved higher yields even from lower baseline values [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMoreover, growth factor yield varied across different preparation protocols. Growth factor yields per 10⁹ platelets showed that, even after normalization, platelets released significantly high quantities of growth factors per platelet irrespective of protocol. These results are in line with Anitua et al. observation [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], which reported the influence of platelet activation methods and fibrin architecture on growth factor release. These findings clearly support role of methodological variation not only in quantitative yield but also in the quality and bio-activity of the concentrates, outweighing the influence of baseline haematology on clinical success. Unfortunately, even though individual studies included in this review reported growth factor concentrations, none provided standardized clinical endpoints such as probing depth reduction, bone fill, or implant stability. This gap shows the limitation in dose\u0026ndash;response modelling and highlights the need for future trials to quantify both biological and clinical outputs in an integrated manner.\u003c/p\u003e \u003cp\u003eClinically, these findings can help in clarifying the inconsistent outcomes observed in regenerative treatments. PRP and PRF have shown promise in improving bone regeneration, periodontal healing, implant stability, and soft tissue repair. However, differences in growth factor release may partly explain the variability in clinical success [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. PRP/PRF have demonstrated efficacy in improving bone density, osseointegration, and reducing postoperative complications, yet in some cases, they offer minimal or no advantage over traditional grafting or surgical approaches [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. The evidence indicates that platelet concentrates are not universally effective and may require customization according to individual biology and procedural needs. Given the biological heterogeneity among patients, it is likely that some individuals respond more favourably to platelet concentrates than others. Future studies should stratify participants accordingly to clarify which subgroups benefit most and under what conditions. Their clinical utility also appears to be indication-specific: in oral and Maxillofacial surgery, PRP/PRF is frequently used to accelerate socket healing and enhance sinus lift outcomes; in periodontology, it supports angiogenesis and soft tissue coverage [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]; and beyond dentistry, PRP is increasingly used in musculoskeletal and dermatologic procedures, though with similarly variable outcomes [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Across all these fields, a shared limitation remains the heterogeneity in growth factor concentrations, underscoring the urgent need for reproducible preparation techniques and clearer identification of patient subgroups most likely to benefit.\u003c/p\u003e \u003cp\u003eBeside this common limitation, our review identified a critical gaps in the literature. First, the lack of precise reporting on growth factor concentrations and their correlation with hematological profiles. Second, many studies failed to provide precise quantitative data on growth factor concentrations, and even fewer studies correlated these with patients' hematological profiles [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Without transparent reporting of centrifugation parameters, platelet enrichment ratios, and storage conditions, pooling data across studies may not give actual correlation, and comparisons between devices may not be reasonable. Additionally, known confounders such as smoking, diabetes, systemic inflammation, sex hormones, and anticoagulant use were rarely analyzed, despite knowing their influence on platelet function and growth factor release.\u003c/p\u003e \u003cp\u003eDespite these limitations in primary studies, strengths of this review are the inclusion of studies conducted over last two decades, descriptive and meta-analytic approach, and the normalization of yield to both blood volume and platelet count [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. The random-effects meta-analysis assisted in estimation of pooled effect size despite heterogeneity within studies. Future clinical studies evaluating PRP/PRF's effectiveness in tissue regeneration should prioritize multi-center randomized clinical trials with standardized preparation and reporting protocols [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. In addition, these clinical trial must directly correlate PRP/PRF yield with clinical outcomes rather than limiting to bone density, implant stability, or wound healing, and assess growth factor release kinetics at multiple time points. Furthermore, proteomic profiling and genomic stratification of individual may help identify biological predictors of treatment response and support the development of personalized regenerative approaches.\u003c/p\u003e \u003cp\u003eBy consolidating current evidence on growth factor in PRP/PRF, methodology impact, and limited clinical correlations, this review provide a direction toward more personalized, evidence-driven protocols for PRP/PRF use in regenerative field. Finally, even though PRP/PRF remain promising tissue derivative for accelerating, improving wound healing and tissue regeneration process, their predictable translation into clinical practice remains hindered by variation in preparation, biological heterogeneity, and inconsistent reporting. Considering need for optimized personalized treatment strategies involving PRP/PRF in tissue regenerative treatments, there is a need for standardized preparation protocols alongside rigorous methodology and transparent reporting, to bridge the gap between laboratory finding and clinical outcomes.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis systematic review provide the evidence on correlation of platelet concentrates with growth factors, however, their clinical translation is hindered by variability in growth factor levels and preparation protocols. PRP/PRF yield is strongly dependent on the volume of blood processed rather than baseline platelet count, underscoring the role of methodological factors in determining efficiency. The wide heterogeneity in growth factor concentrations, particularly TGF-β, PDGF, and VEGF, highlights the influence of both biological and technical variables. Closing the gap between laboratory findings and clinical outcomes requires standardization of PRP/PRF preparation methods along with clear reporting, and robust alignment with clinical endpoints. In addition, conducting multi-centre clinical trials involving molecular profiling could lay the groundwork for personalized use of platelet concentrates, promoting their consistent and effective application in regenerative therapies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cul\u003e\n\u003cli\u003ePRP- Platelet-Rish Plasma\u003c/li\u003e\n\u003cli\u003ePRF- Platelet-Risch Fibrin\u003c/li\u003e\n\u003cli\u003ePC- Platelet Concentrates\u003c/li\u003e\n\u003cli\u003ePRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses\u003c/li\u003e\n\u003cli\u003ePDGF- Platelet-Derived Growth Factor\u003c/li\u003e\n\u003cli\u003eTGF-B- Transforming Growth Factor-Beta\u003c/li\u003e\n\u003cli\u003eIL- Interleukin\u003c/li\u003e\n\u003cli\u003eRCT- Randomized Controlled Trial\u003c/li\u003e\n\u003cli\u003eNCT- Non Clinical Trial\u003c/li\u003e\n\u003cli\u003eVEGF- Vascular Endothelial Growth Factor\u003c/li\u003e\n\u003cli\u003eIGF- Insulin-like Growth Factor\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eContribution\u003c/h2\u003e \u003cp\u003eContributions Conceptualization: M. Y., A. E. B., and A. C. Methodology: M. Y. and A. E. B. Software: A. E. B. Validation: B. K. U., Y. L., and M. A. T. C. Formal Analysis: M. Y. and A. E. B. Investigation: V. A. S., A. O. A., A. C. M. A., J. F., J. T. T., and A. G. Resources: V. A. S. and A. O. A. Data Curation: M. Y., A. E. B., and S. P. Writing\u0026mdash;Original Draft Preparation (Co-First Authors): M. Y. and A. E. B. Visualization: B. K. U., Y. L., and M. A. T. C. Writing\u0026mdash;Review \u0026amp; Editing: S. P., V. A. S., A. C., M. Y., A. E. B., A. O. A., A. C. M. A., B. K. U., Y. L., M. A. T. C., J. F., J. T. T., and A. G. Supervision: A. C. Project Administration: A. C. All authors reviewed and approved the final manuscript.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eRegulatory Statement\u003c/strong\u003e \u003cp\u003eThe review adheres to the \u003cem\u003ePreferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020)\u003c/em\u003e guidelines, as recommended by the EQUATOR Network. In addition, this systematic review was registered with PROSPERO (CRD42024575572).\u003c/p\u003e \u003cp\u003eThis review was carried out using a systematic search of electronic databases. Since it is based entirely on previously published studies, no additional ethical approval was needed.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eNone\u003c/p\u003e\u003ch2\u003eData availability statement\u003c/h2\u003e \u003cp\u003eAll data generated or analysed during this study are included in this published article and its supplementary information files.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEppley BL, Woodell JE, Higgins J (2004) Platelet quantification and growth factor analysis from platelet-rich plasma: implications for wound healing. 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Int J Oral Maxillofac Implants 2020 Mar/Apr ;35(2):330\u0026ndash;341. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.11607/jomi.7541\u003c/span\u003e\u003cspan address=\"10.11607/jomi.7541\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAssery MKA (February 2019) Efficacy of Artificial Salivary Substitutes in Treatment of Xerostomia: A Systematic Review. J Pharm Bioallied Sci 11(1):S1\u0026ndash;S12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4103/jpbs.JPBS_220_18\u003c/span\u003e\u003cspan address=\"10.4103/jpbs.JPBS_220_18\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Department of Oral Medicine and Radiology King George’s Medical University, India","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Growth factors, Platelet-rich plasma, Platelet-rich fibrin, Platelet concentrates, Regenerative dentistry","lastPublishedDoi":"10.21203/rs.3.rs-8408844/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8408844/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePlatelet-rich plasma (PRP) and platelet-rich fibrin (PRF) have shown inconsistent clinical responses in dental conditions. Variations in platelet counts and growth factor are likely factors influence it. Systematic evaluation of relationships between them is needed to optimized outcomes.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo assess correlation of growth factors in PRP/PRF with clinical outcomes and hematological parameters in regenerative dentistry.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA search was performed in Pub-Med, Scopus, and Web of Science. Studies those reported growth factor quantity in PRP/PRF and their association with hematological or clinical outcomes were included. PRP/PRF yield and growth factor levels and its correlation with platelet count and blood volume was analyzed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e64 randomized controlled trials involving 2477 patients were included. The pooled PRP/PRF yield was 0.115 mL/mL of whole blood, strongly correlated with blood volume (r\u0026thinsp;=\u0026thinsp;0.99, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) but not with baseline platelet count (r = \u0026minus;\u0026thinsp;0.37). Growth factor quantity showed large variation, with TGF-β ranging from 40 ng/mL to \u0026gt;\u0026thinsp;60,000 ng/mL, VEGF from 0.23 to 60 ng/mL, and PDGF from 0.1 to 176 ng/mL. PRP/PRF yield is dependent on the quantity of blood volume rather than baseline platelet counts.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eGrowth factor levels show substantial variation suggesting influence of biological and methodological methods. These findings clearly indicate need for standardized preparation protocols.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThere is evidence of correlation of PRP/PRF, growth factor, and blood volume. Therefore, clinician must take these factors in account while preparation of PRP/PRF for regenerative procedure in dental application.\u003c/p\u003e","manuscriptTitle":"Correlation of Growth Factors in Platelet-Rich Plasma with Clinical Outcomes and Hematological Parameters in Regenerative Dentistry: A Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-30 00:52:34","doi":"10.21203/rs.3.rs-8408844/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f6c4ffeb-3941-44cf-a231-0dd6fd9c7133","owner":[],"postedDate":"December 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":60633611,"name":"Dentistry"}],"tags":[],"updatedAt":"2026-01-05T22:46:05+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-30 00:52:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8408844","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8408844","identity":"rs-8408844","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}