Intra-articular injection of platelet lysate-derived extracellular vesicles recovers from knee osteoarthritis in an in vivo rat model.

<strong>Objective:</strong> Mesenchymal stem cells (MSC) and Platelet-Rich Plasma are the main focus in the study of new regenerative treatments aimed to reverse Osteoarthritis (OA). However, extracellular vesicles (EVs) present several advantages to cell-based treatments . Thus, the aim of this study was to compare and evaluate the regenerative potential of MSC-derived EVs (cEVs) and platelet-derived EVs (pEVs) in an OA cartilage rat model.  
<strong>Design:</strong> OA in vivo model was established through injection of 6 mg MIA in the rat knee joints. After 14 and 21 days, OA knee joints were treated with 1x1010 particles of pEVs or cEVs. At day 28, the animals were sacrificed, plasma was collected to quantify CTX-II and knee joints were excised to be evaluated by CBCT. After decalcification, histology was used to determine the OARSI score and to visualize collagen and glycosaminoglycan content. 
<strong>Results:</strong> pEVs and cEVs samples did not show significant differences per se but they did in terms of regenerative effects on OA knee joints. pEVs-treated knee joints showed better subchondral bone integrity in CT-analysed parameters when compared to cEVs or OA group, showing similar values to the healthy control group. Moreover, OARSI score indicated that pEVs showed a greater OA reversion in knee joints, especially in female rats, and so indicated the analysed histological images. 
<strong>Conclusions:</strong> pEVs are proposed as a viable regeneration treatment for OA since they are not only capable of exerting their regenerative potential on osteoarthritic cartilage, but also outperform cEVs in terms of efficacy, particularly in females. 
<strong>Significance Statement</strong> 
Osteoarthritis (OA) is one of the most age-related diseases. It is estimated that 500 million people suffer from OA worldwide, representing the principal cause of chronic disability in adults. In the present study we evaluated the therapeutic effect of extracellular vesicles (EVs) from different sources (platelet lysate and human umbilical cord mesenchymal stromal cells) in an in vivo rat model. Our results demonstrate that platelet-derived EVs (pEVs) induce an OA reversion in knee joints, thus evidencing the therapeutic potential of pEVs as cell-free regenerative agents for OA treatment.

<strong>研究目的：</strong>间充质干细胞（Mesenchymal stem cells, MSC）与富血小板血浆是旨在逆转骨关节炎（Osteoarthritis, OA）的新型再生治疗研究的核心焦点。然而，细胞外囊泡（extracellular vesicles, EVs）相较于细胞疗法具备多项优势。本研究旨在对比并评估间充质干细胞来源细胞外囊泡（MSC-derived EVs, cEVs）与血小板来源细胞外囊泡（platelet-derived EVs, pEVs）在骨关节炎软骨大鼠模型中的再生潜能。
<strong>实验设计：</strong>通过向大鼠膝关节注射6mg碘乙酸钠（Monosodium iodoacetate, MIA）构建骨关节炎体内模型。造模后第14天与第21天，分别向OA模型大鼠膝关节注射1×10¹⁰个pEVs或cEVs。第28天时处死实验动物，采集血浆以定量II型胶原羧基端肽（CTX-II），并摘除膝关节通过锥形束计算机断层扫描（cone beam computed tomography, CBCT）进行评估。经脱钙处理后，采用组织学检测确定OARSI评分（OARSI score），并可视化观察胶原与糖胺聚糖的含量。
<strong>实验结果：</strong>pEVs与cEVs样本本身无显著差异，但二者对OA膝关节的再生作用存在明显差异。相较于cEVs处理组与OA模型组，pEVs处理组的膝关节在CT分析参数中表现出更优的软骨下骨完整性，其相关指标与健康对照组趋近一致。此外，OARSI评分结果显示，pEVs可更有效地逆转大鼠膝关节的骨关节炎病变，尤其在雌性大鼠中表现更为显著，组织学图像分析也印证了这一结论。
<strong>研究结论：</strong>本研究提出pEVs可作为一种可行的OA再生治疗方案，其不仅能够对骨关节炎软骨发挥再生潜能，且在疗效上优于cEVs，尤其在雌性个体中优势更为突出。
<strong>意义阐述：</strong>骨关节炎（OA）是最为常见的年龄相关性疾病之一。据估算，全球范围内有5亿人罹患OA，是成年人慢性残疾的主要诱因。本研究在大鼠体内模型中评估了不同来源（血小板裂解液与人脐带间充质基质细胞）的细胞外囊泡（EVs）的治疗效果。研究结果证实，血小板来源细胞外囊泡（pEVs）可诱导大鼠膝关节OA病变逆转，从而证明pEVs作为无细胞再生制剂用于OA治疗的治疗潜能。