Application of Hydrogel-Based Delivery System in Endometrial Repair

Lin, Yifeng; Dong, Shunni; Zhao, Wei; Hu, Kai-Lun; Liu, Juan; Wang, Siwen; Tu, Mixue; Du, Binyang; Zhang, Dan

doi:10.1021/acsabm.0c00971

Cited by 16 publications

(12 citation statements)

References 95 publications

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“…Moreover, HA hydrogel has a three-dimensional cross-linked network and shows low interfacial tension and adhesion characteristics, which can provide structural and mechanical support for adjacent cells. As a result, HP-MSCs can be gradually released from the hydrogel to achieve the optimal therapeutic effect [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Synergistic regenerative therapy of thin endometrium by human placenta-derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogels

Lin

Dong

et al. 2022

Stem Cell Res Ther

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Background Thin endometrium is a primary cause of defective endometrial receptivity, resulting in infertility or recurrent miscarriage. Much effort has been devoted toward regenerating thin endometrium by stem cell-based therapies. The human placenta-derived mesenchymal stem cells (HP-MSCs) are emerging alternative sources of MSCs with various advantages. To maximize their retention inside the uterus, we loaded HP-MSCs with cross-linked hyaluronic acid hydrogel (HA hydrogel) to investigate their therapeutic efficacy and possible underlying mechanisms. Methods Ethanol was injected into the mice uterus to establish the endometrium-injured model. The retention time of HP-MSCs and HA hydrogel was detected by in vivo imaging, while the distribution of HP-MSCs was detected by immunofluorescence staining. Functional restoration of the uterus was assessed by testing embryo implantation rates. The endometrial morphological alteration was observed by H&E staining, Masson staining, and immunohistochemistry. In vitro studies were further conducted using EdU, transwell, tube formation, and western blot assays. Results Instilled HP-MSCs with HA hydrogel (HP-MSCs-HA) exhibited a prolonged retention time in mouse uteri than normal HP-MSCs. In vivo studies showed that the HP-MSCs-HA could significantly increase the gland number and endometrial thickness (P < 0.001, P < 0.05), decrease fibrous area (P < 0.0001), and promote the proliferation and angiogenesis of endometrial cells (as indicated by Ki67 and VEGF, P < 0.05, P < 0.05, respectively) in mice injured endometrium. HP-MSCs-HA could also significantly improve the embryo implantation rate (P < 0.01) compared with the ethanol group. Further mechanistic study showed the paracrine effects of HP-MSCs. They could not only promote the proliferation and migration of human endometrial stromal cells via the JNK/Erk1/2-Stat3-VEGF pathway but also facilitate the proliferation of glandular cells via Jak2-Stat5 and c-Fos-VEGF pathway. In turn, the increased VEGF in the endometrium promoted the angiogenesis of endothelial cells. Conclusion Our study suggested the potential therapeutic effects and the underlying mechanisms of HP-MSCs-HA on treating thin endometrium. HA hydrogel could be a preferable delivery method for HP-MSCs, and the strategy represents a promising therapeutic approach against endometrial injury in clinical settings. Graphical abstract

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Section: Introductionmentioning

confidence: 99%

Synergistic regenerative therapy of thin endometrium by human placenta-derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogels

Lin

Dong

et al. 2022

Stem Cell Res Ther

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“…Proteins were extracted from the treated human endometrial stromal cells and glandular cells and then lysed by RIPA lysis buffer (Cell Signaling Technology, Boston, MA, USA) as previously described [24]. The concentration of protein was detected using a bicinchoninic acid protein assay kit (Thermo Scienti c, Waltham, MA, USA).…”

Section: Protein Isolation and Western Blot Analysismentioning

confidence: 99%

“…Thus, the traditional in situ instillation of HP-MSCs tends to cause part of the cell suspension to slip out of the uterus via the vagina, which limits the maximal e cacy of stem cells retention. Several novel strategies have been adopted for enhancing the retention time of stem cells, including hyaluronic acid (HA) and Pluronic F-127 [21][22][23][24][25][26]. Among those, HA hydrogel is a promising candidate for the encapsulation and release of HP-MSCs for endometrial therapy.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synergistic regenerative therapy of thin endometrium by human placenta-derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogels

Lin

Dong²,

et al. 2021

Preprint

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Background: Endometrial injury is one of the major causes of thin endometrium and subfertility. Stem cell-based therapies have made strides towards further efficacious treatment of injured endometrium. However, reported therapeutic stem cells that can be used for thin endometrium are difficult to acquire for large-scale clinical application. The human placenta-derived mesenchymal stem cells (HP-MSCs) are emerging alternative sources of MSCs for their robuster expansion ability, lower immunogenicity as well as extensive sources. To maximize their retention inside the uterus, we loaded HP-MSCs with cross-linked hyaluronic acid hydrogel (HA hydrogel) to investigate their therapeutic efficacy and possible underlying mechanisms.Methods: The murine endometrial injury model was established by ethanol (95%) perfusion, with further intrauterine instillation of treating materials. The retention time of HP-MSCs was detected by in vivo imaging and ex vivo frozen section. Functional restoration of the uterus was assessed by testing embryo implantation rates. The endometrial morphological alteration was observed by H&E staining, Masson staining, and immunohistochemistry (Ki67). The stromal and glandular cells were isolated from the human endometrium to determine proliferation, migration, signaling pathway changes via EdU assay, transwell migration assay, and western blot respectively. Results: Instilled HP-MSCs with HA hydrogel (HP-MSCs-HA) exhibited a prolonged retention time in mouse uteri compared with normal HP-MSCs. In vitro data showed that the HP-MSCs-HA could significantly increase the gland number and endometrial thickness, decrease fibrous area, promote the proliferation of endometrial cells, and improve the embryo implantation rate. In vitro assays indicated that HP-MSCs-HA could not only promote the proliferation and migration of human endometrial stromal via the JNK/Erk1/2-Stat3-VEGF pathway but also promote the proliferation of glandular cells via Jak2-Stat5 and c-Fos-VEGF pathway. Conclusion: Our study suggested the potential therapeutic effects and the underlying mechanisms of HP-MSCs-HA on treating thin endometrium. HA hydrogel could be a preferable delivery method for HP-MSCs and the strategy represents a promising therapeutic approach against endometrial injury in clinical settings.

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“…Hydrogels with self-healing property, good mechanical property, and stretchability are of enormous importance in the field of biology. − Hydrogels are used in tissue engineering, − cell delivery, − drug delivery, − and wound healing process. , Amine–acrylate, − thiol–acrylate, − thiol–ene, azide–alkyne click cycloaddition, ,, and nucleophilic substitution ,,, reactions are well-established methodologies to construct purely covalent hydrogels. Injectable hydrogels are also formed by temperature-induced gelation and covalent/ionic (metal ion) bond formation .…”

Section: Introductionmentioning

confidence: 99%

Modulation of Properties through Covalent Bond Induced Formation of Strong Ion Pairing between Polyelectrolytes in Injectable Conetwork Hydrogels

Kumar

Nutan

Jewrajka

2021

ACS Appl. Bio Mater.

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In situ simultaneous formation of both covalent linkages and ion pair is challenging yet necessary to control the biological properties of a hydrogel. We report that the generation of covalent linkages (+N–C) facilitates the simultaneous formation of ion pairs between polyelectrolytes (PEs) in a hydrogel network. Co-injection of tertiary amine functional macromolecules and reactive poly(ethylene glycol) (PEG) containing negatively charged PE leads to the formation of hydrogel conetworks consisting of covalent junctions and ion pairs. Our design is based on the gradual appearance of +N–C junctions followed by formation of ion pairs. This strategy provides an easy access to hydrogel networks bearing a predetermined proportion of ion pair and covalent cross-linking junction. The proportion of ion pair could be varied by introducing a precalculated proportion of mono- and difunctional reactive PEG in the hydrogel system. The topology of the prepolymer and the hydrogel could be modulated (graft) during hydrogel formation. This approach is applicable to obtain covalent/ionic, covalent bond induced purely ionic, and purely covalent hydrogels of several macromolecular entities. The effect of ion pairing in the hydrogels is strongly reflected in the modulus, strain bearing, degradation, free volume, swelling, and drug release properties. The hydrogels exhibit microscopic recovery of modulus after application of high amplitude strain depending on the prepolymer concentration (chain entanglement) and nature of hydrogel network. The hydrogels are hemocompatible, and the covalent/ionic hydrogels show a slower release of methotrexate than that of the purely covalent hydrogel. This work provides an understanding for the in situ construction and manipulation of biological properties of hydrogels through the covalent bond induced formation of a strong ion pair.

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Application of Hydrogel-Based Delivery System in Endometrial Repair

Cited by 16 publications

References 95 publications

Synergistic regenerative therapy of thin endometrium by human placenta-derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogels

Synergistic regenerative therapy of thin endometrium by human placenta-derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogels

Synergistic regenerative therapy of thin endometrium by human placenta-derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogels

Modulation of Properties through Covalent Bond Induced Formation of Strong Ion Pairing between Polyelectrolytes in Injectable Conetwork Hydrogels

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