Bioactive Injectable and Self‐Healing Hydrogel Via Cell‐Free Fat Extract for Endometrial Regeneration

Abstract

The damaged endometrium and the formation of fibrosis are key barriers to pregnancy and further lead to infertility. However, how to promote endometrium repair is always a challenge. Here, a bioactive injectable and self‐healing hydrogel is developed by physically combination of thiolated polyethylene (PEG), Cu2+ and cell‐free fat extract (CEFFE, CF) for endometrial regeneration and fertility. By inheriting the advantages of various active proteins contained in CEFFE, it could induce the overall repair of endometrial microenvironment for intrauterine adhesion (IUA). In vitro, CF@Cu‐PEG reduces endometrial cell apoptosis by more than 50%, and increases angiogenesis by 92.8%. In the IUA mouse, injection of CF@Cu‐PEG significantly reduces the rate of uterine hydrometra and prevents the formation of endometrial fibrosis. Remarkably, CF@Cu‐PEG contributes to the repair of endometrial microstructure, especially increases the number of endometrial pinopodes, significantly improves endometrial receptivity, and increases the pregnancy rate of IUA mice from 7.14% to 66.67%. In summary, through the physically combination of CEFFE and Cu‐PEG, the construction of loaded bioactive injectable hydrogel not only inhibits the IUA, but also induces the self‐repair of endometrial cells in situ and improves fertility, providing a new strategy for IUA repair in clinical application.

Pro-vasculogenic Fibers by PDA-Mediated Surface Functionalization Using Cell-Free Fat Extract (CEFFE)

“…Functionalization of scaffolds with the use of pro-angiogenic biologic factors is an often-adopted strategy to stimulate vascular ingrowth into the constructs. Cell-free fat extract containing various cytokines and growth factors is a recently emerging biological substance produced from the human adipose tissue and demonstrated with powerful angiogenic effect , and therapeutic benefits (e.g., augmenting tissue expansion, attenuating inflammation, and promoting endometrial regeneration). Electrospun fibers, as a well-recognized provisional matrix for tissue scaffolding, have shown great potential for rational applications in regenerative medicine.…”

“…This benefited for not only the growth and functional expression of ECs but also modulating macrophages into the anti-inflammatory phenotype, as also confirmed in our study (Figure S5). It is likely that the presented multiple growth factors in FE may function synergistically to stimulate vascularization. − While it is the previously demonstrated pro-angiogenic effect of FE that initiated our current effort for engineering pro-vasculogenic fibers, increasing evidence suggests that our FE, derived from healthy young women of different ages (22–35 years old) , in different locations of the body (e.g., abdomen, thighs, and upper arms) with relatively stable concentrations of the major growth factors, has omnipotent biological functions in the treatment of different diseases, such as ischemic stroke, osteoporosis, osteoarthritis, spinal cord injuries, chronic wound healing, reproductive related disorders, , and so on. With the multifaceted actions identified in FE, in tandem with its cell recruitment capability observed in our current study (Figures E,F and S1) and elsewhere, the FE-PDA@PCL/GT fiber system will be well suitable for engineering 3D fibrous scaffolds , for in situ regeneration of different tissues.…”

“…From the perspective of FE as a biological therapeutic agent, the advantages of high drug-loading efficiency and prolonged FE-releasing profile in the FE-PDA@PCL/GT fibers may offer new strategies for addressing the FE delivery issues. 13,38,43 Moreover, it would also allow us to explore, in a biomimetic manner, the synergistic effects and underlying mechanism of the matrix-mimicking electrospun fibers bound with the FErelevant factors in vascularization, 60 by using the cell-forcesmatched low-density fibrous structure 61 (if being FE-functionalized) to simulate the ECs' basal lamina, the matrix of small capillaries.…”

“…With the multifaceted actions identified in FE, in tandem with its cell recruitment capability observed in our current study (Figures E,F and S1) and elsewhere, the FE-PDA@PCL/GT fiber system will be well suitable for engineering 3D fibrous scaffolds , for in situ regeneration of different tissues. From the perspective of FE as a biological therapeutic agent, the advantages of high drug-loading efficiency and prolonged FE-releasing profile in the FE-PDA@PCL/GT fibers may offer new strategies for addressing the FE delivery issues. ,, Moreover, it would also allow us to explore, in a biomimetic manner, the synergistic effects and underlying mechanism of the matrix-mimicking electrospun fibers bound with the FE-relevant factors in vascularization, by using the cell-forces-matched low-density fibrous structure (if being FE-functionalized) to simulate the ECs’ basal lamina, the matrix of small capillaries.…”

Bioengineering approaches for the endometrial research and application

“…Drug-loaded hydrogels and porous microfluidics allow for the combination of multiple therapeutics owing to their potent encapsulation capability, alleviating postoperative IUAs and improving endometrial repair [ 151 , 152 ]. Embedded active proteins and estrogen in bio-scaffolds endow them with antioxidant properties that protect against fibrosis within the uterine cavity and encourage the self-repair of the remaining endometrial cells by downregulating excessive oxidative stress and fibrosis-related mediators [ [153] , [154] , [155] , [156] , [157] ]. Administration of both SCs and their derivatives, such as human umbilical cord mesenchymal SCs (UCMSCs), mesenchymal SCs (MSCs), apoptotic bodies, and secretomes, in hydrogels and acellular scaffolds also potentially contribute to satisfactory endothelial regeneration after IUA [ [57] , [158] , [159] ].…”