Multiplexed PLGA scaffolds with nitric oxide-releasing zinc oxide and melatonin-modulated extracellular vesicles for severe chronic kidney disease

Won Kyu Rhim; Jiwon Woo; Jun Yong Kim; Eun Hye Lee; Seung Gyu Cha; Da Seul Kim; Seung Woon Baek; Chun Gwon Park; Bum Soo Kim; Tae Gyun Kwon; Dong Keun Han

doi:10.1016/j.jare.2024.03.018

Multiplexed PLGA scaffolds with nitric oxide-releasing zinc oxide and melatonin-modulated extracellular vesicles for severe chronic kidney disease

Won Kyu Rhim, Jiwon Woo, Jun Yong Kim, Eun Hye Lee, Seung Gyu Cha, Da Seul Kim, Seung Woon Baek, Chun Gwon Park, Bum Soo Kim, Tae Gyun Kwon, Dong Keun Han

Department of Medicine

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Introduction: 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. Objectives: To exclude various side effects from cell transplantations, in this study, we have induced extracellular vesicles (EVs) incorporated cell-free hybrid PMEZ scaffolds. Methods: Hybrid PMEZ scaffolds incorporating essential bioactive components, such as ricinoleic acid grafted Mg(OH)₂ (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. Results: With functionalities of Mg(OH)₂ 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. Conclusion: 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.

Original language	English
Pages (from-to)	75-89
Number of pages	15
Journal	Journal of Advanced Research
Volume	69
DOIs	https://doi.org/10.1016/j.jare.2024.03.018
State	Published - Mar 2025

Keywords

Kidney regeneration
Melatonin-modulated extracellular vesicles (mEVs)
Nitric oxide (NO)
PMEZ scaffold
ZnO

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.jare.2024.03.018

Cite this

Rhim, W. K., Woo, J., Kim, J. Y., Lee, E. H., Cha, S. G., Kim, D. S., Baek, S. W., Park, C. G., Kim, B. S., Kwon, T. G., & Han, D. K. (2025). Multiplexed PLGA scaffolds with nitric oxide-releasing zinc oxide and melatonin-modulated extracellular vesicles for severe chronic kidney disease. Journal of Advanced Research, 69, 75-89. https://doi.org/10.1016/j.jare.2024.03.018

@article{d23d8c3dec8a47c6b69e738dedd40078,

title = "Multiplexed PLGA scaffolds with nitric oxide-releasing zinc oxide and melatonin-modulated extracellular vesicles for severe chronic kidney disease",

abstract = "Introduction: 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. Objectives: To exclude various side effects from cell transplantations, in this study, we have induced extracellular vesicles (EVs) incorporated cell-free hybrid PMEZ scaffolds. Methods: Hybrid PMEZ scaffolds incorporating essential bioactive components, such as ricinoleic acid grafted Mg(OH)2 (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. Results: With functionalities of Mg(OH)2 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. Conclusion: 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.",

keywords = "Kidney regeneration, Melatonin-modulated extracellular vesicles (mEVs), Nitric oxide (NO), PMEZ scaffold, ZnO",

author = "Rhim, {Won Kyu} and Jiwon Woo and Kim, {Jun Yong} and Lee, {Eun Hye} and Cha, {Seung Gyu} and Kim, {Da Seul} and Baek, {Seung Woon} and Park, {Chun Gwon} and Kim, {Bum Soo} and Kwon, {Tae Gyun} and Han, {Dong Keun}",

note = "Publisher Copyright: {\textcopyright} 2023",

year = "2025",

month = mar,

doi = "10.1016/j.jare.2024.03.018",

language = "English",

volume = "69",

pages = "75--89",

journal = "Journal of Advanced Research",

issn = "2090-1232",

publisher = "Elsevier B.V.",

}

TY - JOUR

T1 - Multiplexed PLGA scaffolds with nitric oxide-releasing zinc oxide and melatonin-modulated extracellular vesicles for severe chronic kidney disease

AU - Rhim, Won Kyu

AU - Woo, Jiwon

AU - Kim, Jun Yong

AU - Lee, Eun Hye

AU - Cha, Seung Gyu

AU - Kim, Da Seul

AU - Baek, Seung Woon

AU - Park, Chun Gwon

AU - Kim, Bum Soo

AU - Kwon, Tae Gyun

AU - Han, Dong Keun

PY - 2025/3

Y1 - 2025/3

N2 - Introduction: 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. Objectives: To exclude various side effects from cell transplantations, in this study, we have induced extracellular vesicles (EVs) incorporated cell-free hybrid PMEZ scaffolds. Methods: Hybrid PMEZ scaffolds incorporating essential bioactive components, such as ricinoleic acid grafted Mg(OH)2 (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. Results: With functionalities of Mg(OH)2 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. Conclusion: 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.

AB - Introduction: 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. Objectives: To exclude various side effects from cell transplantations, in this study, we have induced extracellular vesicles (EVs) incorporated cell-free hybrid PMEZ scaffolds. Methods: Hybrid PMEZ scaffolds incorporating essential bioactive components, such as ricinoleic acid grafted Mg(OH)2 (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. Results: With functionalities of Mg(OH)2 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. Conclusion: 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.

KW - Kidney regeneration

KW - Melatonin-modulated extracellular vesicles (mEVs)

KW - Nitric oxide (NO)

KW - PMEZ scaffold

KW - ZnO

UR - http://www.scopus.com/inward/record.url?scp=85189676448&partnerID=8YFLogxK

U2 - 10.1016/j.jare.2024.03.018

DO - 10.1016/j.jare.2024.03.018

M3 - Article

C2 - 38537702

AN - SCOPUS:85189676448

SN - 2090-1232

VL - 69

SP - 75

EP - 89

JO - Journal of Advanced Research

JF - Journal of Advanced Research

ER -

Multiplexed PLGA scaffolds with nitric oxide-releasing zinc oxide and melatonin-modulated extracellular vesicles for severe chronic kidney disease

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this