Evaluation of Mesenchymal Stem Cell-Derived Exosomes Versus Platelet-Rich Fibrin (PRF) in Post-Extraction Socket Healing: A Randomized Controlled Clinical Trial.
Phase: PHASE1
Conditions: Alveolar Bone Loss, Tooth Extraction, Bone Regeneration
Sponsor: Al Salam University

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Al Salam University
Faculty of Dentistry
Department of Oral and Maxillofacial Surgery
Evaluation of Mesenchymal Stem Cell–Derived Exosomes Versus
Platelet-Rich Fibrin (PRF) in Post-Extraction Socket Healing: A
Randomized Controlled Clinical Trial
Research Proposal Prepared by:
Omaima Mahmoud Sakr, BDS, MSc, PhD
Ahmed Khalil Fawzi, BDS, MSc, PhD
Document Date: January 4, 2026

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Evaluation of Mesenchymal Stem Cell–Derived Exosomes
versus Platelet-Rich Fibrin (PRF) in Post-Extraction Socket
Healing: A Randomized Controlled Clinical Trial
Abstract
Background: Post-extraction alveolar bone resorption remains a major challenge affecting
implant placement and prosthetic outcomes. Platelet-rich fibrin (PRF) is widely used to enhance
healing; however, its biological activity is variable and patient-dependent.Mesenchymal stem
cell (MSC)–derived exosomes are cell-free nanovesicles rich in growth factors, cytokines, and
microRNAs that promote angiogenesis, osteogenesis, and immunomodulation.
Study objective: To compare the effectiveness of MSC-derived exosomes versus platelet-rich
fibrin (PRF) in enhancing soft tissue and bone healing of post-extraction sockets.
Methods: The study population will include 40 patients (20 per group), the sample will be
selected conveniently to fulfil the inclusion criteria. Group A – MSC-Derived Exosome.
Commercial or GMP-grade MSC-derived exosomes Group B – PRF Autologous PRF prepared
using standard centrifugation protocol. Surgical Procedure (Standardized for All Patients) This
study may establish exosome therapy as a superior regenerative alternative to PRF in oral surgery,
contributing to safer, standardized, and more effective socket preservation techniques.
Introduction
The healing course after extraction is a complex biologic phenomenon, encompassing
inflammation, angiogenesis, bone production, or rather bone generation, and tissue
condensation.(1,2)Uncontrolled bone resorption makes it necessary for the maintaining or rather
preserve alveolar bone bulk.(3)Platelet-rich fibrin (PRF) is a second-generation platelet
concentrate, which is increasingly acknowledged as a regenerative biomaterial in the
management of post-extraction sockets. (4,5)PRF contains high platelet counts along with high
levels of leucocytes and fibrin.(6) Moreover, it provides a fibrin matrix to facilitate the release of
growth factors, namely platelet-derived growth factor (PDGF), transforming growth factor-β
(TGF-β), and Vascular Endothelial Growth Factor (VEGF), to a greater extent. (4)Several studies
have provided evidence of its effectiveness in stimulating the healing of soft tissue, alleviating
postoperative pain, and promoting early bone formation within the extraction socket.
More recently, a promising cell-free approach using mesenchymal stem cell (MSC) exosomes
has appeared on the horizon. (7)Exosomes are nanovesicles secreted by MSCs that are filled with
bioactive cargo such as protein, cytokines, lipids, and micro-RNA.(8) These structures are
essential for cell-to-cell communication and can induce angiogenesis, modulate inflammation,
and accelerate osteogenic differentiation and tissue regeneration. (9)Exosomes isolated from
dental and non-dental-derived MSCs showed encouraging preclinical regenerative outcomes for

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bone and periodontal tissue regeneration, indicating their perceived usefulness in socket
restoration following tooth extraction.(10)Currently, limited randomized clinical trials compare
exosomes and PRF in oral surgery, making this study novel and clinically relevant.
Aim of the Study
To compare the effectiveness of MSC-derived exosomes versus platelet-rich fibrin (PRF) in
enhancing soft tissue and bone healing of post-extraction sockets.
Objectives
Primary Objective

To compare bone density and bone volume preservation at extraction sites treated with
MSC-derived exosomes versus PRF.
Secondary Objectives

To evaluate soft tissue healing quality

To compare postoperative pain and swelling

To assess complication rates (infection, dry socket)

To evaluate patient satisfaction
Hypothesis

Null hypothesis (H₀): There is no significant difference between MSC-derived exosomes
and PRF in post-extraction socket healing.

Alternative hypothesis (H₁): MSC-derived exosomes result in superior bone and soft
tissue healing compared to PRF.
Study Design

Type: Prospective, randomized, controlled, single-blind clinical trial

Allocation: 1:1 ratio

Blinding: Outcome assessor blinded

Study duration: 6 months

Study setting: El Salam University / oral and maxillofacial surgery department
Sample Size

Total sample: 40 patients (20 per group)

(Adjustable after power analysis; expected power 80%, α = 0.05)

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Study Population
Inclusion Criteria

Patients aged 18–55 years

Indicated for single non-infected tooth extraction

Good systemic health (ASA I or II)

Intact socket walls

Willing to participate and sign informed consent
Exclusion Criteria

Smokers (>5 cigarettes/day)

Pregnancy or lactation

Uncontrolled systemic disease (e.g., diabetes)

Acute infection or abscess at extraction site

History of radiotherapy or bisphosphonate therapy

Immunosuppressive drug use
Randomization

Computer-generated random sequence

Allocation concealment using sealed opaque envelopes
Interventions
a-Group A – MSC-Derived Exosomes

Commercial or GMP-grade MSC-derived exosomes

Dosage: X μg exosomal protein suspended in sterile saline or hydrogel

Applied directly into extraction socket immediately after extraction

Socket closed with simple interrupted sutures
b- Group B – PRF

Autologous PRF prepared using standard centrifugation protocol

PRF membrane placed into extraction socket

Socket closed with simple interrupted sutures
Surgical Procedure (Standardized for All Patients)

Local anesthesia

Atraumatic tooth extraction

No flap elevation

Socket irrigation with sterile saline

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
Intervention applied according to group

Suturing with 3-0 or 4-0 resorbable sutures
Postoperative Care

Standard analgesics (paracetamol)

No prophylactic antibiotics unless clinically indicated

Chlorhexidine mouthwash (0.12%) twice daily for 7 days

Postoperative instructions standardized
Outcome Measures
Primary Outcomes

Bone density (HU) measured using CBCT at: Baseline (immediate post-extraction)
3 months

Alveolar ridge width and height changes (CBCT)
Secondary Outcomes

Soft tissue healing index (Landry score)

Pain intensity (VAS scale) at days 1, 3, 7

Facial swelling (linear measurements)

Incidence of dry socket or infection

Patient satisfaction questionnaire
Follow-Up Schedule
Time Point
Assessment

Day 1 Pain, swelling

Day 7 Soft tissue healing, complications

1 month
Clinical healing

3 months
CBCT evaluation

14. Data Collection & Statistical Analysis

Data analyzed using SPSS

Independent t-test for quantitative variables

Chi-square test for categorical variables

Repeated measures ANOVA for follow-up comparisons

Significance level set at p < 0.05
15. Ethical Considerations

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
Approval from Institutional Ethics Committee

Informed consent obtained from all participants

Confidentiality maintained

Adverse events monitored and documented
Expected Outcomes
MSC-derived exosomes will show:

Greater bone density

Improved ridge preservation

Reduced postoperative inflammation

Faster soft tissue healing
Significance of the Study
This study may establish exosome therapy as a superior regenerative alternative to PRF in oral
surgery, contributing to safer, standardized, and more effective socket preservation techniques.
Potential Limitations

Regulatory restrictions on exosome use

Cost and availability

Short follow-up period
Future Directions

Long-term implant success evaluation

Dose-response studies

Combination therapy (Exosomes + PRF)
References
1. Laforgia A., et al. (2024) — The Use of Platelet-Rich Fibrin (PRF) in the Management of
Alveolar Sockets, Dry Socket and Post-Extraction Healing: A Systematic Review. MDPI
International Journal of Molecular Sciences.
2. Alzahrani AA., et al. (2017) — Influence of platelet rich fibrin on post-extraction socket
healing. (Clinical study reporting accelerated bone fill and healing).
3. Areewong K., et al. (2019) — Platelet-rich fibrin to preserve alveolar bone sockets:
randomized clinical evaluation. Clinical Implant Dentistry and Related Research.
4. Saleh N., et al. (2021) — Clinical and radiographic evaluation of advanced platelet-rich
fibrin (A-PRF) in extraction sockets. Egyptian Dental Journal (study on A-PRF vs natural
healing).

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5. Meta-analysis / systematic reviews on PRF in extraction sockets (2022–2024) — multiple
meta-analyses and RCT syntheses showing PRF improves soft- and hard-tissue healing
and preserves ridge dimensions.
6. Ning X., et al. (2024) — Dental Stem Cell-Derived Exosomes: A Review of Their
Isolation, Classification, Functions and Mechanisms. (Comprehensive review on dental
MSC-exosomes and craniofacial bone/soft tissue regeneration).
7. Nakao Y., et al. (2021) — Exosomes from TNF-α-treated human gingiva-derived
mesenchymal stem cells: therapeutic effects in periodontal models. (Preclinical work
demonstrating bone/periodontal benefits).
8. Hilmy F., et al. (2024) — Evaluation of adipose-derived stem cell (ASC) exosomes in
bone/soft tissue healing — preclinical models and translational discussion. (Open-access
review/experimental report).
9. Villani C., et al. (2024) — Exosome-laden hydrogels as carriers for oral bone/tissue
regeneration: review and prospects. MDPI International Journal of Molecular Sciences.
10. Tajafrooz F., et al. (2025) — Exosome-based therapeutics in bone regeneration:
mechanisms, engineering, and translational hurdles.