Rhim Won-Kyu, Woo Jiwon, Kim Jun Yong, Lee Eun Hye, Cha Seung-Gyu, Kim Da-Seul, Baek Seung-Woon, Park Chun Gwon, Kim Bum Soo, Kwon Tae Gyun, Han Dong Keun
Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Republic of Korea.
Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Republic of Korea; Department of Biomedical Engineering and Intelligent Precision of Healthcare Convergence, SKKU Institute for Convergence, Sungkyunkwan University (SKKU) 2066 Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do 16419, Republic of Korea; Intelligent Precision of Healthcare Convergence, SKKU Institute for Convergence, Sungkyunkwan University (SKKU) 2066 Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do 16419, Republic of Korea.
J Adv Res. 2025 Mar;69:75-89. doi: 10.1016/j.jare.2024.03.018. Epub 2024 Mar 25.
With prevalence of chronic kidney disease (CKD) in worldwide, the strategies to recover renal function via tissue regeneration could provide alternatives to kidney replacement therapies. However, due to relatively low reproducibility of renal basal cells and limited bioactivities of implanted biomaterials along with the high probability of substance-inducible inflammation and immunogenicity, kidney tissue regeneration could be challenging.
To exclude various side effects from cell transplantations, in this study, we have induced extracellular vesicles (EVs) incorporated cell-free hybrid PMEZ scaffolds.
Hybrid PMEZ scaffolds incorporating essential bioactive components, such as ricinoleic acid grafted Mg(OH) (M), extracellular matrix (E), and alpha lipoic acid-conjugated ZnO (Z) based on biodegradable porous PLGA (P) platform was successfully manufactured. Consecutively, for functional improvements, melatonin-modulated extracellular vesicles (mEVs), derived from the human umbilical cord MSCs in chemically defined media without serum impurities, were also loaded onto PMEZ scaffolds to construct the multiplexed PMEZ/mEV scaffold.
With functionalities of Mg(OH) and extracellular matrix-loaded PLGA scaffolds, the continuous nitric oxide-releasing property of modified ZnO and remarkably upregulated regenerative functionalities of mEVs showed significantly enhanced kidney regenerative activities. Based on these, the structural and functional restoration has been practically achieved in 5/6 nephrectomy mouse models that mimicked severe human CKD.
Our study has proved the combinatory bioactivities of the biodegradable PLGA-based multiplexed scaffold for kidney tissue regeneration in 5/6 nephrectomy mouse representing a severe CKD model. The optimal microenvironments for the morphogenetic formations of renal tissues and functional restorations have successfully achieved the combinatory bioactivities of remarkable components for PMEZ/mEV, which could be a promising therapeutic alternative for CKD treatment.
随着全球慢性肾脏病（CKD）患病率的上升，通过组织再生恢复肾功能的策略可为肾脏替代疗法提供替代方案。然而，由于肾基底细胞的可重复性相对较低、植入生物材料的生物活性有限，以及物质诱导炎症和免疫原性的可能性较高，肾脏组织再生可能具有挑战性。
为了排除细胞移植的各种副作用，在本研究中，我们制备了包裹细胞外囊泡（EVs）的无细胞混合PMEZ支架。
基于可生物降解的多孔聚乳酸-乙醇酸共聚物（PLGA）平台，成功制备了包含重要生物活性成分的混合PMEZ支架，这些成分包括蓖麻油酸接枝的Mg(OH)（M）、细胞外基质（E）和α-硫辛酸共轭的ZnO（Z）。随后，为了改善功能，将在无血清杂质的化学限定培养基中从人脐带间充质干细胞衍生的褪黑素调节的细胞外囊泡（mEVs）也加载到PMEZ支架上，以构建多重PMEZ/mEV支架。
具有负载Mg(OH)和细胞外基质的PLGA支架的功能、修饰的ZnO的持续一氧化氮释放特性以及mEVs显著上调的再生功能，显示出显著增强的肾脏再生活性。基于这些，在模拟严重人类CKD的5/6肾切除小鼠模型中实际实现了结构和功能的恢复。
我们的研究证明了基于可生物降解PLGA的多重支架在5/6肾切除小鼠（代表严重CKD模型）中用于肾脏组织再生的组合生物活性。肾脏组织形态发生形成和功能恢复的最佳微环境已成功实现了PMEZ/mEV显著成分的组合生物活性，这可能是CKD治疗的一种有前景的治疗替代方案。
