Female reproductive system is anatomically divided into vagina, cervix, fallopian tubes, uterus and ovaries. Platelet-rich plasma (PRP) as a rich source of plasma proteins and platelets, has become an attractive therapeutic approach for reproductive tissue regeneration [1]. Despite of all unique features of PRP using in reproductive system related diseases, the rapid release of activation factors from PRP and limited lifespan have acted as limitations for this method [2, 3]. In recent years, researchers have used PRP encapsulation in biomaterials and hydrogels to address these challenges. PRP loaded hydrogels by gradually biodegradation in body environment allow for sustain release of PRP. This systematic review highlighted the use of PRP loaded hydrogels in reproductive system tissues regeneration. This study investigated the role of hydrogels and biomaterials in improving the effectiveness PRP therapy for reproductive system related diseases and finally, generation of this method for vagina repair in Mullerian anomalies.

This systematic review and meta-analysis followed the PRISMA guidelines and searched multiple databases, including PubMed, Scopus, Web of Science, and Cochrane until January 2025. To evaluate the studies, the review used the SYRCLE’s tool to assess risk of bias, and the GRADE method to determine the certainty of evidence for each outcome. A random-effects meta-analysis was performed, and heterogeneity was evaluated.

Overall, 7 studies included in this systematic review and meta-analysis. The meta-analysis demonstrated that combining platelet-rich plasma (PRP) with hydrogel scaffolds significantly enhanced endometrial regeneration compared to untreated intrauterine adhesions (IUAs).

PRP/hydrogel combinations markedly improved endometrial thickness (SMD: 2.85, 95% CI: 1.59–4.12, p < 0.001), glandular density (SMD: 4.12, CI: 1.90–6.33, p < 0.001), and angiogenesis (SMD: 6.13, CI: 2.77–9.49, p < 0.001), while reducing fibrosis (SMD: -5.21, CI: -7.35–-3.06, p < 0.001). These effects were attributed to the sustained release of growth factors (e.g., VEGF, PDGF) from hydrogels, which prolonged therapeutic activity compared to PRP alone. PRP/hydrogel combinations showed marginal superiority over PRP monotherapy in improving endometrial thickness (SMD: 1.44, CI: 0.34–2.54, p = 0.01) and angiogenesis (SMD: 1.99, CI: 0.71–3.27, p = 0.002), but no significant advantage in glandular density restoration. Hydrogel scaffolds alone were inferior to PRP in enhancing glandular density (SMD: -2.66, CI: -5.06–-2.26, p = 0.03) and fibrosis reduction, underscoring the critical role of PRP’s bioactive components. Mechanistically, PRP/hydrogel therapies downregulated fibrotic markers (Collagen-I, α-SMA, TGF-β) and inhibited TGF-β1-SMAD2/3 signaling, while promoting anti-inflammatory M2 macrophage polarization. Functional outcomes, such as embryo implantation rates, were significantly improved with PRP/hydrogel (SMD: 4.04, CI: 1.44–5.64, p = 0.002), though heterogeneity (I² = 93%) highlighted variability in scaffold materials and PRP protocols. Sensitivity analyses confirmed the robustness of these findings after excluding high-bias studies. According to reported results, it seems that this method has ability to regenerate any part of reproductive system tissues and could be a promising treatment method for patients with Mullerian anomaly.

In conclusion, PRP/hydrogel synergistically enhances endometrial tissue regeneration by combining sustained growth factor delivery with scaffold-mediated structural support, offering a promising therapeutic strategy for reproductive system tissues regeneration, especially in patients with Mullerian anomalies. Standardization of protocols is needed to optimize clinical translation.

Injectable, stable, and biodegradable hydrogel with platelet-rich plasma induced by l-serine and sodium alginate for effective treatment of intrauterine adhesions
Locationally activated PRP via an injectable dual-network hydrogel for endometrial regeneration.
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