# Therapeutic effects of stem cell–derived extracellular vesicles in animal models of intervertebral disc degeneration: a systematic review and meta-analysis of species differences and delivery strategies

## TL;DR

This study reviews and analyzes how stem cell-derived extracellular vesicles can help treat disc degeneration in rats, comparing different delivery methods and cell sources.

## Contribution

The paper introduces a systematic review and meta-analysis comparing hydrogel-assisted and direct delivery of SC-sEVs for intervertebral disc degeneration.

## Key findings

- SC-sEVs significantly improved disc height, MRI, and histological scores in rat models of IVDD.
- Hydrogel-assisted delivery reduced interstudy heterogeneity without compromising efficacy.
- Human-derived EVs showed a modest advantage in MRI grading over rat-derived EVs.

## Abstract

Intervertebral disc degeneration (IVDD) is a major contributor to chronic low back pain and disability worldwide, yet current treatments remain largely palliative and do not restore disc structure or biomechanical integrity. Stem cell–derived extracellular vesicles (SC-sEVs) have emerged as promising cell-free biologics capable of modulating inflammation, apoptosis, and extracellular matrix homeostasis.

This systematic review and meta-analysis evaluated the therapeutic efficacy of SC-sEVs in rat models of puncture-induced IVDD, with a specific focus on comparing hydrogel-assisted versus direct (non-hydrogel) delivery strategies. The review was prospectively registered in PROSPERO (CRD420250654980) and conducted according to PRISMA 2020 guidelines.

Comprehensive searches of PubMed, Embase, and the Cochrane Library through August 2025 identified 19 studies enrolling 305 rats. Extracted outcomes included disc height index (DHI), MRI Pfirrmann grade, and histological score. Meta-analysis demonstrated significant improvements in DHI (mean difference [MD] = 12.8%, 95% CI 7.6–18.0), histological grade (MD = −4.1, 95% CI –5.1 to −3.2), and MRI Pfirrmann grade (MD = −1.5, 95% CI –1.8 to −1.2) at 4–8 weeks following treatment. Hydrogel-assisted delivery produced comparable overall efficacy to direct injection but contributed to reduced interstudy heterogeneity. Both human- and rat-derived EVs significantly improved all evaluated outcomes, with human-source EVs showing a modest advantage in MRI grading (P = 0.017). Risk-of-bias assessment indicated generally acceptable methodological quality, and no substantial publication bias was observed.

Overall, SC-sEV therapy demonstrates consistent regenerative benefits in preclinical IVDD models, supporting its translational promise as a minimally immunogenic, cell-free therapeutic for degenerative spine disorders. Future studies employing standardized protocols, mechanistic analyses, and long-term evaluation are needed to facilitate clinical translation.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420250654980, identifier CRD420250654980.