Controlled Release of Epigenetically-Enhanced Extracellular Vesicles from a GelMA/Nanoclay Composite Hydrogel to Promote Bone Repair.
Controlled Release of Epigenetically-Enhanced Extracellular Vesicles from a GelMA/Nanoclay Composite Hydrogel to Promote Bone Repair.
复制标题
DOI：
10.3390/ijms23020832
复制
发表时间：
2022-01-13
影响因子：
5.6
通讯作者：
Cox SC
中科院分区：
文献类型：
--
作者：
Man K;Barroso IA;Brunet MY;Peacock B;Federici AS;Hoey DA;Cox SC
细胞外小泡(EVS)作为一种很有前途的无细胞骨修复工具，已受到越来越多的关注。尽管EVS的骨再生潜力已经被证明，但与其治疗效力和体内较短的半衰期相关的问题阻碍了它们的临床应用。有报道称，用组蛋白脱乙酰酶抑制剂曲古抑素A(TSA)进行表观遗传重编程可以促进成骨细胞来源的EV的成骨诱导能力。合成纳米粘土膨润土(LAP)功能化的明胶甲基丙烯酰基(GelMA)水凝胶已被证明能有效地结合、稳定和改善生物活性因子的保留。这项研究探讨了利用GelMA-LAP水凝胶作为一种新的骨修复策略来改善表观遗传学增强型成骨细胞来源的EVS的局部保留率和控制递送的潜力。LAP可引起GelMA压缩弹性和剪切稀化性能随剂量的增加而增加。研究还发现，与无褶皱的凝胶相比，加入纳米粘土可以提高3D打印时的形状保真度。有趣的是，含有LAP的GelMA水凝胶在14天内显示出矿化容量增加(1.41倍)(p≤0.01)。这些纳米复合体系的EV释放动力学也受到LAP浓度的强烈影响，CD63ELISA检测到，从GelMA构建的体系中释放出明显更多的囊泡(p≤0.001)。与未经处理的EV凝胶相比，经TSA处理的成骨细胞(TSA-EVS)来源的EV可促进人骨髓基质细胞(HBMSCs)的增殖(1.09倍)、迁移(1.83倍)、组蛋白乙酰化(1.32倍)和矿化(1.87倍)(p≤0.01)。重要的是，与未经处理的EV构建物相比，TSA-EV功能化的GelMA-LAP水凝胶显著促进了包裹的hBMSCs细胞外基质胶原的产生(≥1.3倍)和矿化(≥1.78倍)，且呈剂量依赖关系(p≤0.001)。综上所述，这些发现证明了将表观遗传学增强的成骨细胞来源的EVS与纳米复合光固化水凝胶相结合，以促进无细胞囊泡方法用于骨再生的治疗效果的潜力。
Extracellular vesicles (EVs) have garnered growing attention as promising acellular tools for bone repair. Although EVs’ potential for bone regeneration has been shown, issues associated with their therapeutic potency and short half-life in vivo hinders their clinical utility. Epigenetic reprogramming with the histone deacetylase inhibitor Trichostatin A (TSA) has been reported to promote the osteoinductive potency of osteoblast-derived EVs. Gelatin methacryloyl (GelMA) hydrogels functionalised with the synthetic nanoclay laponite (LAP) have been shown to effectively bind, stabilise, and improve the retention of bioactive factors. This study investigated the potential of utilising a GelMA-LAP hydrogel to improve local retention and control delivery of epigenetically enhanced osteoblast-derived EVs as a novel bone repair strategy. LAP was found to elicit a dose-dependent increase in GelMA compressive modulus and shear-thinning properties. Incorporation of the nanoclay was also found to enhance shape fidelity when 3D printed compared to LAP-free gels. Interestingly, GelMA hydrogels containing LAP displayed increased mineralisation capacity (1.41-fold) (p ≤ 0.01) over 14 days. EV release kinetics from these nanocomposite systems were also strongly influenced by LAP concentration with significantly more vesicles being released from GelMA constructs as detected by a CD63 ELISA (p ≤ 0.001). EVs derived from TSA-treated osteoblasts (TSA-EVs) enhanced proliferation (1.09-fold), migration (1.83-fold), histone acetylation (1.32-fold) and mineralisation (1.87-fold) of human bone marrow stromal cells (hBMSCs) when released from the GelMA-LAP hydrogel compared to the untreated EV gels (p ≤ 0.01). Importantly, the TSA-EV functionalised GelMA-LAP hydrogel significantly promoted encapsulated hBMSCs extracellular matrix collagen production (≥1.3-fold) and mineralisation (≥1.78-fold) in a dose-dependent manner compared to untreated EV constructs (p ≤ 0.001). Taken together, these findings demonstrate the potential of combining epigenetically enhanced osteoblast-derived EVs with a nanocomposite photocurable hydrogel to promote the therapeutic efficacy of acellular vesicle approaches for bone regeneration.
登录
查看更多内容
影响因子：
5.6
作者：
Goto R;Nishida E;Kobayashi S;Aino M;Ohno T;Iwamura Y;Kikuchi T;Hayashi JI;Yamamoto G;Asakura M;Mitani A
通讯作者：
Mitani A
影响因子：
29.4
作者：
Gaharwar, Akhilesh K.;Mihaila, Silvia M.;Khademhosseini, Ali
通讯作者：
Khademhosseini, Ali
影响因子：
13.6
作者：
Freeman, Fiona E.;Pitacco, Pierluca;Kelly, Daniel J.
通讯作者：
Kelly, Daniel J.
影响因子：
18.9
作者：
Gresham RCH;Bahney CS;Leach JK
通讯作者：
Leach JK
影响因子：
29.4
作者：
Dawson, Jonathan I.;Kanczler, Janos M.;Oreffo, Richard O. C.
通讯作者：
Oreffo, Richard O. C.