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Research progress of biopolymers combined with stem cells in the repair of intrauterine adhesions

  • Zhujie Wang , Juanjuan Jiang , Xingmiao Li , Mo Chen , Mengjia Yu , Meijun Guo , Ning Wang , Yangyang Li EMAIL logo and Xiuxiu Jiang EMAIL logo
Published/Copyright: April 12, 2023
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Nanotechnology Reviews
From the journal Nanotechnology Reviews Volume 12 Issue 1

Abstract

Asherman syndrome (AS) refers to the loss of endometrial stem cells and matrix hyperplasia caused by endometrial basal layer injury. Its common clinical manifestations include narrowing of the uterine cavity, reduction in menstrual volume, abdominal pain, amenorrhea, and infertility. According to the cause of AS, treatment includes a mechanical barrier and functional recovery. Because the functional recovery of the endometrium depends on the regeneration of endometrial epithelial cells, in the absence of cell involvement, the effect of repair by mechanical removal of adhesions is limited. Recently, tissue engineering and stem cell therapy have achieved promising progress in the recovery of organ function. Biological scaffolds have been applied to encapsulated stem cells as a therapeutic strategy for repairing endometrial damage. This review explains the progress of intrauterine materials and stem cell combined biopolymers in the study of AS and emphasizes the evidence from animal and clinical trials.

Graphical abstract

Keywords: endometrial stem cell; biopolymer; endometrium regeneration

1 Introduction

Intrauterine adhesion (IUA), commonly known as Asherman syndrome (AS), refers to partial or complete occlusion and adhesion of the uterine cavity or cervical canal. Depending on the severity, it can lead to abnormal menstruation, oligomenorrhea, amenorrhea, infertility, and repeated miscarriage. Severe endometrial damage in women of childbearing age is usually characterized by uterine scar formation and functional endometrial deficiency. The treatment option for AS is hysteroscopic adhesion lysis, followed by insertion of an intrauterine device, Foley balloon catheter, and treatment with hyaluronic acid (HA) or estrogen to prevent the recurrence of AS [1] (Figure 1). However, the recurrence rate in patients with severe adhesions varies from 20 to 62.5% depending on the geographic location [2,3].

Figure 1 The recent development of agents available for the primary prevention of AS [1]; Copyright 2021, INT J MOL SCI.
Figure 1

The recent development of agents available for the primary prevention of AS [1]; Copyright 2021, INT J MOL SCI.

The basalis of the endometrium is a stable layer that is not shed during the menstrual cycle and is the layer from which regeneration and formation of the endometrium function occurs. Endometrial epithelial stem cells are present in the glands of the basal layer. Basal cells that are not shed during menstruation can produce glandular and luminal epithelia. AS form secondary injury to the basalis layer, and can occur in any uterine surgery [4]. Under the influence of elevated estrogen levels, epithelial cells regenerate the epithelium on exposed surfaces and proliferate and regenerate new functions [2]. During the immediate postpartum period, the endometrium is thought to be more susceptible to atrophy due to the decreased estrogen levels from loss of placental estrogen as well as the antagonistic effects of elevated prolactin levels from breast feeding [5]. AS formation has also been recognized in cases of uterine infection (e.g., endometritis or infection with Mycobacterium tuberculosis) without preceding uterine instrumentation [6]. The uterus is a mixture of endometrium, muscle, and connective tissue. Histologically, the myometrium in uterine cavity adhesion is similar to the normal myometrium, but the thickness is usually increased. The connective tissue formed by thin collagen bundles usually comes from dense porous strips. Endometrial fibrosis is a common pathological manifestation of AS, in which fiber is the main factor to form tissue bridge between uterine cavity walls [7]. Due to injury of the endometrial basal layer, the surface connective tissue lacks the endometrial lining and forms a dense adhesion with the adjacent endometrium in the AS uterus. Fibrous adhesions show dense connective tissue with no lining compared with the surrounding endometrium [8]. AS itself is characterized by endometrial fibrosis, in which most of the matrix has been replaced by fibrous tissue and the glands are replaced by inactivated cubic columnar endometrial epithelium [9].

Surgical management with hysteroscopic lysis of adhesions is the gold standard for treatment and adopting an office-based approach offers several advantages. Prevention of reformation of adhesions remains challenging and no single method for preventing recurrence has shown superiority.

Compared to mechanical methods, biomaterials have become significant in scientific research and are widely used in the treatment of AS endometrial tissue after hysteroscopic adhesiolysis. A variety of composite materials, including HA gel, have been utilized to avoid adhesion after hysteroscopic adhesion separation [3,10]. These gels can cover the wound in the endometrium and temporarily obstruct adhesion of adjacent wounds. However, because the glue is absorbed relatively quickly, there is a lack of new endometrium to cover the damaged endometrial wound, and adhesion will occur again. Tissue engineering is an interdisciplinary area that aims to fabricate new tissues for replacement and total regeneration [11]. Some biopolymers can quickly form three-dimensional gels in the uterus to avoid wound contact with each other. Some biopolymers can be made into a powder to facilitate spraying into the uterine cavity. Certain biomaterials are used as drugs or for cell delivery to promote endometrial repair. In addition to hysteroscopic treatment, HA gel, hormone therapy, uterine perfusion [12,13,14], and amniotic membrane transplantation have also been used to treat AS [15]. Amniotic membrane first covers the damaged tissue and is used as a biological scaffold to regulate epithelial morphology and function. The biostimulatory action of the amniotic membrane enables endometrial cells to migrate from healthy tissue to the amniotic graft covering the injured area [15,16]. However, the use of amnion membranes as medical products in preclinical and clinical trials is quite limited. Novel modified scaffold material may be used instead of the amnion membrane in the future. According to a subsequent hysteroscopic evaluation, the use of platelet-rich plasma did not change the menstrual pattern or the development of postoperative AS [17]. Therefore, to develop new methods to prevent endometrial injury and manage AS has become a major demand.

AS refers to endometrial repair disorders. For severe endometrial damage, severe trauma to the basal layer may damage resident adult stem cells (ASCs) and may lead to refractory endometrium. This damage is irreversible. These patients may not respond to typical treatment because the basal layer of endometrium remains constant throughout the menstrual cycle and is not sensitive to hormones. At present, due to the lack of effective methods to promote regeneration after severe endometrial injury, the treatment of endometrial adhesions is limited. Therefore, it is urgent to develop new methods to prevent endometrial damage and IUAs. Some researchers hypothesized that endometrial repair disorder may be related to local stem cell damage and loss, because endometrial regeneration and repair are closely related to stem cells in endometrium. Thereby, the application of stem cell therapy to endometrial damage may be an effective strategy to restore endometrial receptivity. Evidence indicated the presence of endometrial stem/progenitor cells in the endometrium in 2004 [18]. Transplantation of stromal cells derived from autologous menstrual blood [34] and stem cells derived from autologous peripheral blood and bone marrow [131] has been used as cell therapy to stimulate the growth of endometrial lining. This idea is superior to the traditional therapy and opens up a new way for the treatment of AS.

Considering the self-renewal capacity of the endometrium, it is natural to look for endometrial stem cells in the basal layer of the mature endometrium. Colony-forming units were identified from purified populations of human endometrial epithelial and stromal cells separated from tissue obtained after hysterectomy [18,19], and SSEA-1+ [20], SOX9+ [18], LGR5 [21,22,23,24], and CDH2 (N-cadherin gene)+ [25] populations from endometrial stem cells have been proven to have clonogenic ability. After decades of animal modeling and clinical trials, cell replacement strategies have been studied in some endometrial pathological models [26,27,28,29,30,31,32,33,34]. The most popular stem cells are mesenchymal-derived cells, including bone marrow-derived mesenchymal stromal cells (BMSCs) and umbilical cord Wharton’s jelly-derived mesenchymal stromal cells. Organoids from mature endometrial epithelial cells (EECs) from mouse and human endometrium have been developed, suggesting endometrial epithelium functionality and passage ability [35]. Since the survival of stem cells in vitro remains a challenge, tissue regeneration engineering combines biomaterials with stem cells, which is conducive to the long-term culture of cells in vitro and provides a new means for the treatment of AS. From microscale cell sheet engineering and cell seed bioscaffolds to nanocellular vesicles and bioactive molecular delivery, the bionic endometrial interface not only reconstructs the physiological multilayer structure of the endometrium but also restores the appropriate nutritional microenvironment by increasing vascularization and decreasing the immune response [36]. In this review, we discuss biopolymers, stem cells, and cell-loaded biomaterials that are likely to change AS treatment modalities to achieve better clinical outcomes.

2 Using biopolymer as a mechanical barrier in the treatment of AS

Different forms of biopolymers are available, including three-dimensional porous matrices, hydrogels, and nanofibrous matrices. At present, there is little consensus on the structure and design of biopolymers for topical endometrial use. However, the following aspects should be considered: (1) the engineered biopolymers should be easy to insert into the uterus and suitable for the structure of the uterus and (2) the biopolymer composition should be biocompatible to avoid secondary damage [37]. The mechanical barrier biopolymers used are listed in Table 1.

Table 1

Biomaterials used as scaffold for uterine adhesion barrier

Scaffold type Characteristics Model Ref.
HA gel High compatibility, but limited half-life Clinic [72]
CH gel A combination of CMC and HA Rat [77]
ACH Combination of CH and alginate carboxymethylcellulose hyaluronic acid Clinic [86]
ACP Formed by cross-linking hyaluronan Clinic [85]
Thermo-responsive hyaluronic acid sol–gel Made from non-animal derived HA and synthetic poloxamers Rat [87]
Oxiplex/AP gel A viscoelastic gel composed of PEO and CMC stabilized by calcium chloride Clinic [46]
CS Excellent biodegradability, biocompatibility, antimicrobial activity, non-toxicity, and versatile chemical and physical properties Organ-on-a chip [96]
E2@uECMNPs/AP hydrogel A nanocomposite aloe/poloxamer hydrogel for β-E2 intrauterine delivery to exert multi-therapeutic effects Rat [54]
Interceed A sheet-type adhesion barrier Rabbit [106]
Silicone sheet Made from medical grade silicone (cross-linked polydimethylsiloxane polymer) and reinforced with a silicone membrane backing Clinic [109]
Pluronics F-127 Composed of PPO and PEO Clinic [53]

2.1 HA and its derivatives

Hydrogels can be roughly divided into natural hydrogens (alginate [38], fibrin [39], collagen [40], gelatin [41], agarose [42], and HA [43]) and synthetic hydrogens (polyethylene glycol [44], polyethylene oxide-sodium carboxymethylcellulose (CMC) [45,46,47], chitosan (CS) hydrogel [48], polyethylene terephthalate [49,50], and noncellular tissue matrices [51]). The above hydrogels can be applied in combination [25,26,27,28] with growth factors [51,52,53,54,55,56,57]. Meanwhile, hydrogels can also be cocultured with feeder cells. Biocompatibility, degradation, and mechanical properties are important factors for uterine cavity materials [58].

HA is a kind of water-soluble polysaccharide that has become an important constituent of the extracellular matrix (ECM). The HA molecule contains multiple disaccharide units of glucuronic acid and N-acetylglucosamine, which are bound by β1-3-type glucoside bonds [59]. HA has been a major component in biomedical applications [60]. Due to its good biocompatibility, moisture capacity, and viscoelasticity, HA has been used as a drug delivery system and tissue restoration material [58]. HA-based derivatives can provide mechanical support and biological effects for peripheral cells. HA exerts an anti-inflammatory effect via the inhibition of proinflammatory cytokines and chemokines, thereby reducing the incidence of adhesions [61]. It has been demonstrated to regulate through specific HA receptors, cell migration, inflammation, and angiogenesis, which become major stages of wound healing. Previous works have proven that most properties of HA molecules rely on the molecular size. That is, high-molecular-weight HA molecules possess anti-inflammatory and immunosuppressive properties, while low-molecular-weight HA molecules are effective proinflammatory molecules. Small HA fragments can increase the expression of several cytokines and protein production in macrophages [62,63,64,65,66,67,68,69,70,71].

HA has the advantages of high compatibility and natural composition and has been applied in clinical practice as barrier agents to prevent adhesion formation [37]. HA gels can reduce AS incidence and increase pregnancy rate after intrauterine surgery [72]. For AS, the scaffold should be retained and functional throughout the menstrual cycle. The turnover of HA molecules is a rapid process, and the half-life in the blood is only approximately 2–5 min [73]. Because of the limited half-life of HA, it is easily degraded in the body, thus limiting its effectiveness. Some modified HA-based derivatives have been developed to overcome these limitations. Cross-linked alginate saline gels decompose rapidly when reacted with calcium chelators or monovalent ions. Another type of hydrogel, temperature-sensitive heparin-modified poloxamer (HP) hydrogel with affinity to KGF, facilitate the morphologic and functional recovery of the injured rat uterus [56].

During the degradation process, some byproducts may be produced due to the breaking of covalent bonds. Most byproducts are absorbed by the metabolic cycle; however, some byproducts, such as reactive oxygen species, can also affect the regeneration process [74]. After modification with special reagents, the derivatives retain their own good biocompatibility, change their original rheological characteristics, and achieve a relatively long organism residence time [75]. These products have been unified with other biopolymers through esterification, cross-linking, and other chemical modifications [76].

Carboxymethylcellulose hyaluronic acid (CH) gel, a combination of CMC and HA, is a related compound. CMC is a high-molecular-weight polysaccharide and has been proven to be an effective antiadhesive agent [77,78]. CH has a preventive effect on adhesion formation in various surgical areas [38,79,80]. CH enables HA to quickly form a film to cover the surface of the wound and prevent adhesion.

Alginate, derived from brown seaweed, is a water-soluble polysaccharide. The uncross-linked alginate film has mucoadhesive properties and can stably adhere to a wound; therefore, sutures are not required to fix the wound. When it contacts the body fluid in the uterine cavity, the film slowly transforms into a smooth gel through hydration, effectively separating the wound from the surrounding tissues without adhesion [81]. Alginate has been used as a wound dressing, and its calcium or sodium form possesses hemostatic and antibacterial effects, which have been demonstrated to be useful for preventing adhesion formation [81–83]. Meanwhile, the combination of HA and alginate has been expected to be superior to individual performance as an antiadhesive agent.

Sodium alginate can be formed into a powder material and is easy to compress, which is helpful for spraying it in the uterine cavity [82]. Auto-cross-linked hyaluronic acid (ACP) is also a derivative formed by cross-linking HA through the covalent ester bonds between the hydroxyl and carboxyl groups of the HA molecules (Figure 2). ACP gel is catabolized through an unambiguous physiological pathway of HA degradation, ultimately releasing molecules [84]. ACP can form a solid three-dimensional structure in the uterine cavity. It displays the biocompatibility properties of its original polymer but has a higher viscosity, which can be used for supporting the shape of the uterine cavity and then blocking adhesion after hysteroscopic surgery. ACP and CH have been equally effective in terms of adhesion rate and severity [85]. In the absence of baseline AS, the AS rate of ACP after hysteroscopic surgery was lower than that of CH [86].

Figure 2 Formation process of ACP. (a) ACP is composed of CH and alginate. Carboxymethylcellulose and HA form CH gel. Alginate is extracted from brown seaweed. (b) A covalent ester bond is formed between hydroxyl and carboxyl groups. (c) ACP is auto-cross-linked hyaluronic acid.
Figure 2

Formation process of ACP. (a) ACP is composed of CH and alginate. Carboxymethylcellulose and HA form CH gel. Alginate is extracted from brown seaweed. (b) A covalent ester bond is formed between hydroxyl and carboxyl groups. (c) ACP is auto-cross-linked hyaluronic acid.

Thermoresponsive HA sol–gel is a new type of anti-adhesive barrier based on HA. It is made from HA of nonanimal origin and synthetic poloxamers, which have the versatile nature of liquid and the adhesion of sticky gels. Abt13107 is specifically used in body cavities, such as the intrauterine or nasal cavity. 17β-estradiol is used for endometrial regeneration of AS, and the heparin-poloxamer-thermoresponsive HA sol–gel can enhance its therapeutic effect [87]. However, a randomized clinical trial showed that the role of thermosensitive HA gel in the formation of AS after hysteroscopy is not less than that of a highly viscous HA anti-adhesion barrier [88].

2.2 Polyethylene oxide-sodium carboxymethylcellulose (PEO-NaCMC)

PEO-NaCMC gel is a hydrophilic, swellable viscoelastic gel containing PEO and CMC stabilized by sodium chloride [89]. When PEO and CMC samples are stabilized in a composite gel, the performance of protein rejection and tissue adhesion are additive in the prevention of adhesion after surgery. PEO was released faster than CMC from the gel, thus forming a shell structure in which CMC can be coated by PEO. The PEO-rich outer layer inhibits protein deposition and thrombosis. The CMC-rich layer anchors the gel to the tissue surface [90] (Figure 3). The intercoat prevents AS formation and improves the patency of the internal uterine ostium during subsequent hysteroscopy [46,91].

Figure 3 Preparation process of PEO-NaCMC gel and its general morphology in clinical application under hysteroscopy: (a) Schematic representation of PEO-NaCMC gel. (b) Phase separation of CMC/PEO. The gel consists of 6.7% (w/v) CMC and 0.74% (w/V) PEO in phosphate-buffered saline. (1) CMC solution; (2) PEO solution; (3) mechanical mixed solution of CMC and PEO; and (4) CMC/PEO mixture (blue) [90]; Copyright 2002, J Biomed Mater Res. (c) The operator gradually transferred the resectoscope from the bottom of the uterus to the external opening of the uterus and applied the gel to the (a) whole cavity and (b) the cervical canal [46]; Copyright 2011, Journal of Minimally Invasive Gynecology.
Figure 3

Preparation process of PEO-NaCMC gel and its general morphology in clinical application under hysteroscopy: (a) Schematic representation of PEO-NaCMC gel. (b) Phase separation of CMC/PEO. The gel consists of 6.7% (w/v) CMC and 0.74% (w/V) PEO in phosphate-buffered saline. (1) CMC solution; (2) PEO solution; (3) mechanical mixed solution of CMC and PEO; and (4) CMC/PEO mixture (blue) [90]; Copyright 2002, J Biomed Mater Res. (c) The operator gradually transferred the resectoscope from the bottom of the uterus to the external opening of the uterus and applied the gel to the (a) whole cavity and (b) the cervical canal [46]; Copyright 2011, Journal of Minimally Invasive Gynecology.

2.3 CS hydrogel

CS is a natural polysaccharide produced by partial deacetylation of chitin [92]. CS-based products have been extensively utilized in both medical materials and biomedicine because of their degradability, biocompatibility, nontoxicity, antimicrobial activity, and general chemical and physical properties [93,94], which results in the preparation of novel applicable derivatives [95]. CS-based hydrogels are an attractive class of biomaterials that promote cell adhesion. Using CS compatibility, mesenchymal stromal cells (MSCs) can be cultured in CS microchannels. A bonding strategy applying green hydrogel complexes as cell- and eco-friendly adhesives led to a significant effect on the manufacturing of microdevices suitable for advanced organ-on-a-chip research [96]. CS-based hydrogels release stromal cell-derived factor-1 alpha (SDF-1α) to recruit endogenous c-kit-positive stem cells to the damaged area and promote endometrial thickness and gland number recovery [97]. SDF-1α is a chemokine, and its receptor C-X-C chemokine receptor type 4 (CXCR4) is expressed on the surfaces of various cells, especially stem cells such as hematopoietic stem cells and MSCs [98]. Meanwhile, induced expression of endogenous CXCR4 improves cell migration [99,100] (Figure 4).

Figure 4 Preparation of recombinant stromal cell-derived factor-1 alpha containing a collagen-binding domain(CBD-SDF-1α) and its application in a bone graft model: (a) schematic graph of (CBD-SDF-1α), (b) pore size distribution of the collagen scaffold, (c) binding curves of NAT-SDF-1α and CBD-SDF-1α with collagen scaffolds, (d) the release rate of CBD-SDF-1α is slower than that of NAT-SDF-1α, and (e) chemical structure of collagen. (f) General and scanning electron microscopy images of freeze-dried hydrogel samples. (g) Immunofluorescence images of c-kit-positive cells in the injured endometrium (blue: nucleus, green: c-kit). (h) H&E and Masson staining of the endometrium after the operation. Immunohistochemical staining of CD31- and CK7-positive cells in damaged endometrium [97]; Copyright 2020, INT J BIOL MACROMOL. (d)–(h) Expression pattern of SDF-1 in living donor bone grafts in the acute stage of intrachondral bone healing. (i) Immunohistochemical staining of SDF-1. (j) H&E shows the area of new bone formation around the transplanted bone in tissue sections. (k) Quantitative expression of anti-SDF-1 and control IgG groups. (l) X-ray photos of the bone graft model on the 14th day after transplantation. (m) The results represent the bone area measurements of five independent samples. * = P < 0.05 [100]; Copyright 2009, Arthritis Rheum.
Figure 4

Preparation of recombinant stromal cell-derived factor-1 alpha containing a collagen-binding domain(CBD-SDF-1α) and its application in a bone graft model: (a) schematic graph of (CBD-SDF-1α), (b) pore size distribution of the collagen scaffold, (c) binding curves of NAT-SDF-1α and CBD-SDF-1α with collagen scaffolds, (d) the release rate of CBD-SDF-1α is slower than that of NAT-SDF-1α, and (e) chemical structure of collagen. (f) General and scanning electron microscopy images of freeze-dried hydrogel samples. (g) Immunofluorescence images of c-kit-positive cells in the injured endometrium (blue: nucleus, green: c-kit). (h) H&E and Masson staining of the endometrium after the operation. Immunohistochemical staining of CD31- and CK7-positive cells in damaged endometrium [97]; Copyright 2020, INT J BIOL MACROMOL. (d)–(h) Expression pattern of SDF-1 in living donor bone grafts in the acute stage of intrachondral bone healing. (i) Immunohistochemical staining of SDF-1. (j) H&E shows the area of new bone formation around the transplanted bone in tissue sections. (k) Quantitative expression of anti-SDF-1 and control IgG groups. (l) X-ray photos of the bone graft model on the 14th day after transplantation. (m) The results represent the bone area measurements of five independent samples. * = P < 0.05 [100]; Copyright 2009, Arthritis Rheum.

2.4 Poloxamer hydrogel

Poloxamers are copolymers of polypropylene oxide (PPO) and PEO. They form micellar solutions at low concentrations and transparent thermoreversible hydrogels at high concentrations [56]. Owing to their low toxicity and biocompatibility, they are commonly used in a variety of sustained-release drug delivery systems [101]. A thermosensitive hydrogel (E2-HP hydrogel) can be formed when micelles of heparin-poloxamer encapsulate 17β-estradiol. By targeting estrogen receptor (ER) stress effectively, the E2-HP hydrogel demonstrated prolonged release behavior estrogen receptor (ER)of β-estradiol (E2) at the targeted site and achieved more efficient endometrium regeneration [45]. Aloe vera, extracted from the leaves of aloe, has antibacterial, antifungal, antiviral, anti-inflammatory, and antioxidant properties. Aloe/poloxamer (AP) nanocomposite hydrogel was applied for the intrauterine delivery of β-E2, which can exert multiple therapeutic effects. In situ injection of the E2-loaded nanoparticulate uECM (E2@uECMNPs)/AP hydrogel not only efficiently promoted endometrial regeneration but also prevented re-adhesion. AP hybrid hydrogel can be used in clinical applications and is biomimetic and biodegradable. It also has a restorative effect, temperature-sensitive properties, and low immunogenicity [54] (Figure 5). The main disadvantage of this natural extract in the form of nanofiber felt is the lack of electrospinnability and appropriate mechanical properties. To ameliorate these issues, the scaffolds were prepared from Gel/AV mixture and PCL solution by double-nozzle electrospinning [102]. Natural aloe vera gel mixed with a silk fibroin membrane scaffold contributed to the regeneration of endothelial cells [103].

Figure 5 E2@uECMNPs/AP hydrogel promotes endometrial regeneration: (a) schematic diagram of E2@uECMNPs/AP hydrogel application in the rat AS model. (b) General image of rat uterus and quantitative analysis of residual DNA in rat uterus before (native) and after uterine decellularization (uECM). Particle sizes of (c) uECMNPs and (d) E2@uECMNPs. Transmission electron microscopy images of (e) uECMNPs and (f) E2@uECMNPs. Scale bar = 50 nm. (g) General and scanning electron microscopy images of AP hydrogels with concentrated aloe vera (0.5% AV-17% poloxamer). (h) Immunohistochemical images of cytokeratin, Ki67, and ER-β staining and (i) tumor necrosis factor-alpha and TGF on day 7 [54]; Copyright, 2020, EUR J PHARM SCI.
Figure 5

E2@uECMNPs/AP hydrogel promotes endometrial regeneration: (a) schematic diagram of E2@uECMNPs/AP hydrogel application in the rat AS model. (b) General image of rat uterus and quantitative analysis of residual DNA in rat uterus before (native) and after uterine decellularization (uECM). Particle sizes of (c) uECMNPs and (d) E2@uECMNPs. Transmission electron microscopy images of (e) uECMNPs and (f) E2@uECMNPs. Scale bar = 50 nm. (g) General and scanning electron microscopy images of AP hydrogels with concentrated aloe vera (0.5% AV-17% poloxamer). (h) Immunohistochemical images of cytokeratin, Ki67, and ER-β staining and (i) tumor necrosis factor-alpha and TGF on day 7 [54]; Copyright, 2020, EUR J PHARM SCI.

Poloxamers minimize toxicity concerns related to copolymer concentration [104]. Poloxamers have also been used in mammalian cell culture media for cell encapsulation and tissue engineering. Vitamin C (VitC) mitigates the cytotoxic effects of poloxamer and promotes the survival and health of poloxamer-encapsulated BMSCs in vitro. VitC is a strong reducing substance and a key regulator of pluripotency, self-renewal, and differentiation of stem cells [105]. VitC alleviates the cytotoxic effect of poloxamer, and when the poloxamer and VitC complex was transplanted in vivo, the endometrium recovered better as it thickened, with more glands and fewer fibrotic areas [53].

2.5 Interceed

The interface of interceed is made up of 100% oxidized regenerated cellulose polysaccharide and is an absorbable adhesion barrier. It contains glucuronic acid and glucose residues. The combination of preoperative gonadotropin-releasing hormone agonist [106]/estrogen [107] or an intrauterine device [108] is effective in preventing AS by increasing the number of endometrial glands and improving ER. Interceed estrogen reduced adhesions and tissue fibrosis and improved ER in a rabbit AS model [68].

2.6 Silicone sheet

Silicone sheet material is made of cross-linked polydimethylsiloxane polymer and reinforced with silicone film substrate. The application of silicone sheets seems to be effective in preventing the reformation of adhesion after hysteroscopic adhesiolysis of AS [109] (Figure 6). However, this was a retrospective, nonrandomized study, and the sample size was small.

Figure 6 (a) A silicone sheet is placed in the uterine cavity after adhesiolysis. (b) The silicone sheet is bent and improperly placed in the uterine cavity. (c) The silicone sheet is flat and properly placed in the uterine cavity [109]; Copyright 2019, Reprod Med Biol.
Figure 6

(a) A silicone sheet is placed in the uterine cavity after adhesiolysis. (b) The silicone sheet is bent and improperly placed in the uterine cavity. (c) The silicone sheet is flat and properly placed in the uterine cavity [109]; Copyright 2019, Reprod Med Biol.

Owing to their diverse sources and strong plasticity, biopolymers play a significant role in treating AS. Anti-adhesion biopolymer barriers offer structural and mechanical support for damaged tissue remodeling. They can also mimic the natural environment to a certain extent by causing physicochemical changes that mimic changes in growth factors, signaling molecules, and extracellular vesicles [110,111]. However, the use of scaffold biopolymers alone to repair large uterine defects is not sufficient [40]. Some elements need careful consideration, such as vascularization, natural cell replenishment, and scar suppression [112]. Planting cells on scaffold materials can prolong cell survival time and stimulate cell proliferation, differentiation, and vascularization, thus improving biological functions [113].

3 Use of stem cells to treat AS

Advances in stem cell research provide new opportunities for AS treatment. Stem cells are a type of undifferentiated cell with multidirectional differentiation, self-renewal potential, and paracrine functions. According to the cell source, they can be divided into embryonic stem cells (ESCs) [114], ASCs [18,115,116] and induced pluripotent stem cells (iPSCs) [117]. The main challenges in obtaining endometrial stem cells are cell isolation, differentiation, and culturing.

Relevant literature points out that endometrial stem cells include endometrial epithelial progenitor cells (EEPCs) [118], endometrial mesenchymal stromal cells (eMSCs) [119], and endometrial endothelial progenitor cells [116]. Currently, there are no specific markers for human or mouse EEPCs [120]. The eMSCs are distributed in the functionalis and basalis layers. Cytokines are commonly used for stem cell differentiation. The cytokines in differentiated or cultured endometrial stem cells are listed in Table 2.

Table 2

Glossary of stem cell types isolated or differentiated into endometrium EPC researched in IUAs

Cell types Source Factors Ref.
EPCs EPCs were predominantly in the luminal rather than glandular pitheliu Isolated from endometrium biopsy [118]
[120]
ERC Stromal cells isolated from menstrual blood that are highly proliferative and multipotent TGF-β, EGF, and PDGF-BB [125]
[34]
Bone marrow mesenchymal stem/stromal (bmMSCs) Self-renewing ASCs found in bone marrow/plastic adherent cultures/ PDGF, bFGF, TGF-b, and EGF [127]
[129]
eMSCs Adult stromal stem cells found in a perivascular location in the endometrium and distinct from endometrial stromal fibroblasts EGF, KGF, HGF, and IGF-2 [128]
UC-MSC UC-MSCs are a primitive population of MSCs between fetal and adult MSCs 17β-estradiol [135]
[136]
hESCs Pluripotent stem cells derived from the inner cell mass of a blastocyst Differentiate into three germ cell types [143]
iPSCs A pluripotent stem cell produced from an adult cell trough reprogramming by introduction of pluripotency genes or transcription factors SOX2, OCT4, KLF4, and MYC [146]
hAECs Perinatal stem cells derived from the placenta are multipotent and have immune modulatory properties similar to embryonic and adult cells Isolated from human amniotic membranes [150]
[137]
[139]
[147]
[149]
[151]
Human placenta-derived mesenchymal stem cells hAMSCs derived from the placenta Isolated from human placenta [152]
[138]
Benign uterine organoids Lgr5 high cell populations in mouse-derived endometrial organoids Following fragmentation [140]
[153]
[154]
[155]

3.1 eMSCs

eMSCs can be obtained through endometrial biopsy or menstrual blood, and eMSCs isolated from menstrual blood are called endometrial regenerative cells (ERCs) and have some advantages, including noninvasive collection, in vitro culture, and ethical problem-free usability [121,122]. Compared with BMSCs, ERCs have higher proliferation, migration, and proangiogenic abilities in vitro, especially under hypoxic conditions [123]. eMSCs can differentiate into dopaminergic neurons in vitro by inducing the expression of recombinant human fibroblast growth factor (FGF) and recombinant human epidermal growth factor (EGF) [124]. ERCs can differentiate into endometrial cells under EGF, transforming growth factor-β (TGF-β), platelet-derived growth factor B (PDGF-B), and 17β-estradiol to induce ERCs in vitro and to generate endometrial tissue in NOD-SCID mice [125]. ERC transplantation is a feasible and effective treatment for AS [34]. The possible mechanism is activation of the Akt and ERK pathways, promotion of endometrial cell proliferation and angiogenesis, and repair of damaged endometrium [126]. However, the low number of implanted menSCs in the endometrium after transplantation remains unclear.

3.2 BMSCs

BMSCs formerly called marrow stromal fibroblasts (MSFs), are ASCs that originate from the mesoderm and have the potential for self-renewal and multidirectional differentiation. In vitro MSF colony formation requires at least four growth factors: PDGF, bFGF, TGF-β, and EGF [127]. Human BMSCs can differentiate into epithelial cells in vitro when cultured in a medium containing several growth factors, including EGF, keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), and insulin-like growth factor-II (IGF-2) [128]. BMSCs derived from male mice can differentiate into EECs and improve endometrial thickness through their migration and immunomodulatory properties [129]. BMSCs overexpressing IGF-1 induce IL-10 expression and secretion by activating NF-κB signaling, thereby improving the functional regeneration of damaged rat uteri [130]. Autologous bone marrow-derived stem cells (BMDSCs) promote endometrial regeneration in patients and have been successfully conceived [26,32,131].

3.3 Umbilical cord amniotic membrane cells (UC-AMC)

The amniotic membrane lining of the umbilical cord represents a possible source of two perinatal cell types: epithelial cells from the epithelium of amniotic membrane and MSC from the stromal side blended with the Wharton’s jelly [132]. Human UC-AMC cells isolated from Wharton’s jelly display MSC characteristics [133,134]. 17β- E2 at a concentration of 1 μM was a good inducer of the differentiation of UC-AMCs into EEC-like cells in vitro. 8-Br-cAMP plus estrogen and growth factors, including EGF, TGF-β1, and PDGF-BB, can induce WJ-MSCs to differentiate into EEC-like cells by activating the PKA signaling pathway [135]. UC-AMCs improved endometrial morphology and pregnancy rates in a rat model [136].

3.4 Human amniotic membrane mesenchymal stromal cells (hAMSCs)

The concept of perinatal stem cells is still unclear [137]. The identification of stem cells from placenta needs to consider the specific tissues of cell origin, the times of passages after cell isolation and the specific markers for identifying cell types [138]. hAMSCs from placenta can induce the expression of altered cell markers with cell culture and passage of more than four times. These changes include decreased expression of CD14, CD45, and HLA-DR on hAMSCs in adhesion molecules (such as CD49b and CD49d) [139]. hAMSCs have been considered as a valuable resource for transplantation therapy and may enhance endometrial regeneration in AS disease, possibly owing to their immunomodulatory properties [140]. Transplantation of hAMSCs into a rat AS model by intraperitoneal injection resulted in improvements in endometrial thickness, gland number, and fibrotic area. hAMSCs promoted endometrial regeneration and repaired through Notch signaling [141].

3.5 Human embryonic stem cells (hESCs)

hESCs can differentiate into all three germ cell types and have an unlimited proliferation capacity [114]. Ye et al. demonstrated for the first time that neonatal mouse uterine mesenchyme can guide the differentiation of hESCs to form the female reproductive tract epithelium [142]. Our previous study successfully differentiated hESCs into endometrial progenitor cells using the endometrial progenitor markers SOX17 and FOXA2 [143]. First, ESCs were differentiated into well-defined endoderm, and subsequently, endodermal cells were induced into EPCs. Second, EPCs were induced to adopt the fate of EEPCs [144]. hESCs have a wide range of application prospects because of their diversity of differentiation; however, due to ethical disputes, there have been few clinical studies on the application of ESCs in AS treatment. A schematic of endometrial stem cell differentiation and isolation is shown in Figure 7. Cell therapy provides hope for the treatment of AS, but cell transplantation alone has great limitations in clinical application, including a persistent inflammatory response, lack of structural support, and deficiency of nutritional factors that inhibit the integration and long-term survival of stem cells.

Figure 7 Schematic of EEPCs and an endometrial organoid culture from hESCs, iPSCs, and somatic cells: (a) schematic of hESCs differentiating into EEPCs. hESCs were induced into mesendoderm germ layers and subsequently into definitive endoderm. Definitive endoderm gives rise to endometrial epithelial progenitor cells after receiving directional induction of differentiation factor treatment under a special niche condition. (b) Schematic diagram of endometrial epithelial progenitor cell differentiation from iPSCs. Somatic cells are induced into iPSCs, and iPSCs are differentiated into target progenitor cells following the procedure of hESCs differentiating into endometrial epithelial progenitor cells. (c) Schematic diagram of endometrial organoid culture.
Figure 7

Schematic of EEPCs and an endometrial organoid culture from hESCs, iPSCs, and somatic cells: (a) schematic of hESCs differentiating into EEPCs. hESCs were induced into mesendoderm germ layers and subsequently into definitive endoderm. Definitive endoderm gives rise to endometrial epithelial progenitor cells after receiving directional induction of differentiation factor treatment under a special niche condition. (b) Schematic diagram of endometrial epithelial progenitor cell differentiation from iPSCs. Somatic cells are induced into iPSCs, and iPSCs are differentiated into target progenitor cells following the procedure of hESCs differentiating into endometrial epithelial progenitor cells. (c) Schematic diagram of endometrial organoid culture.

3.6 iPSCs

iPSCs are another feasible source for reprogramming the endometrium into a pluripotent state. Park et al. reported that endometrial cells were obtained from donors in their fifth decade, and researchers used the retrovirally transduced genes SOX2, OCT4, KLF4, and MYC to reprogram the cells into iPSCs [145]. Human decidua-derived mesenchymal cells isolated from the decidua membrane were successfully induced to differentiate into iPSCs [146].

3.7 Human amniotic epithelial cells (hAECs)

The human amniotic membrane epithelium is the cellular layer directed towards the fetus and in touch with the amniotic fluid (AF). hAECs are located in all the subregions of the hAM, and hence can be subdivided at least into human reflected amniotic membrane epithelial cells (hRAEC) and human placental amniotic membrane epithelial cells (hPAEC) [137]. hAEC shares some similarities with pluripotent ESC but are not equal. hAECs are multipotent and have immune modulatory properties similar to embryonic and adult cells.

hAEC from placenta can induce the expression of altered cell markers with cell culture and passage of more than four times. These changes include significant increase in CD13, CD44, and CD105, and expression of CD146 on hAEC culture [139,147]. The hAEC transplantation can increase endometrial thickness, promote gland and vascular hyperplasia, and reduce the area of endometrial fibrosis [148,149]. The related molecules (including vWF, VEGF, PCNA, ER, PR, LC3, and p62) associated with endometrial angiogenesis and cell proliferation increased as well [150]. Meanwhile, hAEC transplantation can lead to decreased ECM deposition and expression of PDGF-C, THBS1, and CTGF. It can be speculated that hAECs decrease collagen deposition, probably by downregulating the expression of PDGF-C, THBS1, and CTGF [151]. hAECs can also increase pregnancy outcomes and upregulate autophagy in AS mice in a paracrine manner [150]. Human placental-derived mesenchymal stem cells were encapsulated in HA hydrogels for synergistic regenerative therapy of thin endometrium [152].

3.8 Extraembryonic stem cells

Benign uterine organs vary in their proliferation and growth potential. The endometrial glands can spread out for a long time after birth (>2 generations) only in a mouse-derived lgr5high cell population in mouse-derived endometrial organoids [140]. Single orthotopic and ectopic endometrial cells can self-organize, proliferate, and expand, indicating their clonal ability. The organoids of endometriosis and proliferative endometrium show cell proliferation and a lifespan of 4–6 months [153], while leiomyoma spheres show low proliferative potential [154].

The histological type and grade of endometrial carcinoma had no effect on organoid formation. Endometrial malignant organoids were formed within 12 h–20 days, and the survival rate of malignant organoids was the highest in serous adenocarcinoma (92%) [155].

3.9 Future cell-based therapy in AS

Cell-based therapies using endometrial stem/progenitor cells hold promise for future use in regenerating inadequate endometrium. Endometrial derived tissue stem cells are the most suitable for endometrial stem cell regeneration, but the number of adult derived cells is limited. Transplantation of autologous stem cells contributes to endometrial regeneration [34,131]. However, several unsolved issues regarding cell differentiation remain and current investigations remain in the preclinical animal model phase of trials.

Allogeneic derived tissue stem cells have an individual immune response, and the materials are prone to be contaminated, the number of cells cannot meet the clinical needs. Perinatal derivatives are expected to be widely used in regenerative medicine due to their differentiation ability. In fact, many preclinical studies and preliminary clinical trials have shown that perinatal derivatives may be important tools to restore tissue damage or promote regeneration and repair of tissue microenvironment. However, there are many confusions in the identification and localization of specific perinatal tissues and cells. In the current literature, the nomenclature used does not necessarily highlight the real differences between cells. At the same time, not all cells can be simply called “stem cells from placenta” [138], regardless of the exact tissue from which they originate. Bone marrow mesenchymal stem cells have been used for research and clinical treatment of AS, but there is no evidence that bone marrow mesenchymal stem cells can differentiate or transform into EECs. iPSCs carry some unsafe factors of mother cells. Endometrial stem cells derived from ESCs are the most promising to overcome the obstacles of stem cell transplantation, such as the small number of cells and impure cells, but it is necessary to eliminate the immunogenicity of cells from foreign sources and get ethical support. At the same time, cells transplanted into the body are only temporarily used to treat uterine cavity adhesions. Finally, the patient’s own endometrium needs to grow at the adhesion site, and the transplanted cells will be metabolized or excluded from the body.

4 Bioscaffold combined with stem cells in the treatment of AS

Biopolymers provide a barrier against the recurrence of AS and support the extension of stem cells. Stem cell therapy provides a cellular basis for functional recovery of the endometrium. However, cell survival after implantation remains limited [156]. Advancements in the combination of stem cells and biopolymers have provided a new opportunity for AS treatment. The bioscaffold-combined stem cells are listed in Table 3. A schematic is shown in Figure 8 [137].

Table 3

Biomaterials used as scaffold combined with stem cells for endometrium regeneration

Scaffold type Cells Model Ref.
Collagen BMSC Rat [28]
HA hydrogel MSC-sec Rat [111]
Matrigel hESC derived EEPC Rat [143]
Decellularized uterine scaffolds BMSC Rat [168]
PSC scaffold BMSC Rat [175]
Droplet-based microfluidics HepG2 cell Rat [178]
Figure 8 Schematic illustration of the manufacturing of different biopolymer-endometrium interfaces [137]; Copyright 2020, Front Bioeng Biotechnol.
Figure 8

Schematic illustration of the manufacturing of different biopolymer-endometrium interfaces [137]; Copyright 2020, Front Bioeng Biotechnol.

4.1 Collagen combined with stem cells

Collagen, a natural biomaterial and a main component of the ECM, plays a crucial role in wound healing [157]. Collagen has been extensively used in tissue engineering scaffolds. Collagen scaffolds can offer appropriate physical support and a similar microenvironment for transplanted stem cells [158]. Song et al. planted hESCs on a collagen scaffold and added E2 and the cytokines EGF and PDGF-B. The hESC-derived cells could survive and repair the structure and function of uterine horns in a severe uterine injury rat model [159]. Further research is needed on the culture of collagen-grafted MSCs (CS/MSCs).

The local persistence and low utilization of endometrial mesenchymal stem cells limit their application in treatment. Collagen scaffolds loaded with MSCs have been used to regenerate many tissues and organs [160–162]. Collagen membranes provided a three-dimensional structure for the attachment, growth, and migration of rat BMSCs and did not impair stemness gene expression [28] (Figure 9). COL5A2, a molecular subtype of collagen V, adjusts collagen generation in fibrotic tissues. Foxf2 interacted with Smad6 and bound to the same COL5A2 promoter region; Foxf2 downregulation and Smad6 upregulation reduced fibrosis. Foxf2 interacts with Smad6 and coregulates the transcription of COL5A2 in AS pathogenesis, while they have opposite effects in fibrosis [157]. Xu et al. mixed UC-MSCs with degradable collagen fibers to form scaffolds/UC-MSCs and injected them into a uterine scar rat model. They found that the scaffold/UC-MSC system could promote the degradation of collagen in uterine scars by upregulating MMP-9, which is mainly produced by UC-MSCs, and accelerate the regeneration of the endometrium, myometrium, and blood vessels. In a prospective phase I clinical trial that enrolled 26 patients with moderate-to-severe AS, UC-MSCs containing the collagen scaffold enhanced the thickness of the endometrium, and 10 patients became pregnant [163]. CS/UC-MSCs facilitate the proliferation of human endometrial stromal cells and inhibit apoptosis. CS/UC-MSC transplantation can maintain normal luminal structure, promote endometrial regeneration and collagen remodeling, induce endometrial cell proliferation and epithelial recovery, and enhance ERα and progesterone receptor expression. It has been demonstrated that the ability of the regenerating endometrium to accept embryos improves [112]. The mechanism of hBMSCs combined with collagen-promoted endometrial generation includes the following points: CS/Exos transplantation potently induced the regeneration of endometrium and collagen remodeling, promoted the expression of estrogen receptor and endometrial genes, and restored fertility [164]. Mechanistically, CS/Exos promoted the polarization of CD163 + M2 macrophages, decreased inflammation, and increased anti-inflammatory responses in vivo and in vitro [164].

Figure 9 BMSCs loaded on collagen scaffolds promote rat endometrial regeneration: (a) Rat BMSC morphology. (b) H&E-stained BMSCs loaded on collagen scaffolds. H&E staining and scanning electron microscopy (SEM) images of collagen fibers when the collagen began to collapse at (c) 24 h, (d) 48 h, and (e) 72 h. (f) SEM images of collagen fibers. (g) SEM images of BMSCs on collagen scaffolds. (h) BMSCs were mainly located in the basement membrane of rat regenerated endometrium (red). (i) Gross image showing that the collagen/BMSC group had been integrated into adjacent tissues and had obvious neovascularization [28]; Copyright 2014, BIOMATERIALS.
Figure 9

BMSCs loaded on collagen scaffolds promote rat endometrial regeneration: (a) Rat BMSC morphology. (b) H&E-stained BMSCs loaded on collagen scaffolds. H&E staining and scanning electron microscopy (SEM) images of collagen fibers when the collagen began to collapse at (c) 24 h, (d) 48 h, and (e) 72 h. (f) SEM images of collagen fibers. (g) SEM images of BMSCs on collagen scaffolds. (h) BMSCs were mainly located in the basement membrane of rat regenerated endometrium (red). (i) Gross image showing that the collagen/BMSC group had been integrated into adjacent tissues and had obvious neovascularization [28]; Copyright 2014, BIOMATERIALS.

4.2 HA gel combined with stem cells

Another strategy focuses on the injection of hydrogels. KGF is an important epithelial tissue repair factor. A temperature-sensitive HP hydrogel with affinity for KGF (KGF-HP) was designed as a support matrix to deliver KGF and then prevent AS desorption. After treatment with the KGF-HP hydrogel for 7 days, the proliferation of endometrial glandular epithelial cells and luminal epithelial cells was observed. Meanwhile, angiogenesis of the damaged uterus was also improved [60]. It has been reported that cross-linked methacrylate-hyaluronic acid gel (MA-HA gel) loaded with the secretome from MSCs (MSC-Sec) contains cytokines and chemokines and plays a significant role in tissue repair and regeneration [165]. Synthetic MSC-Sec-loaded cross-linked HA gel is an effective intrauterine sustained-release drug delivery vector. Compared to non-cross-linked HA, cross-linked HA exhibited a more compact structure with smaller pores. The morphology of cross-linked HA becomes more stable than commercial HA gels. As a carrier, cross-linked HA can achieve sustained and long-term release of MSC-Sec (Figure 10). The MSC-Sec/HA gel created a sustained-release system to repair rat endometrial damage and promote viable pregnancy (Figure 11).

Figure 10 Preparation of MSC-Sec-HA gel. (a) Schematic diagram of the chemical synthesis of MSC-Sec-HA gel. (b) Chemical structure diagram of MSC-Sec-HA. (c) MSC-Sec-HA coated the bottle when placed upside down. SEM images of (d) Sec-non-cross-linked HA (green) and (e) Sec-cross-linked HA (red) [165]; Copyright 2019, ADV HEALTHC MATER.
Figure 10

Preparation of MSC-Sec-HA gel. (a) Schematic diagram of the chemical synthesis of MSC-Sec-HA gel. (b) Chemical structure diagram of MSC-Sec-HA. (c) MSC-Sec-HA coated the bottle when placed upside down. SEM images of (d) Sec-non-cross-linked HA (green) and (e) Sec-cross-linked HA (red) [165]; Copyright 2019, ADV HEALTHC MATER.

Figure 11 MSC-Sec-HA increased the number of glands and the endometrial thickness in a rat AS model. (a) H&E staining of the sham group, the control group, and the treatment side of the MSC-Sec-HA group. Scale bar: 70 μm. (b) Comparison of endometrial thickness and (c) the number of glands between the control and treatment groups [165]; Copyright 2019, ADV HEALTHC MATER.
Figure 11

MSC-Sec-HA increased the number of glands and the endometrial thickness in a rat AS model. (a) H&E staining of the sham group, the control group, and the treatment side of the MSC-Sec-HA group. Scale bar: 70 μm. (b) Comparison of endometrial thickness and (c) the number of glands between the control and treatment groups [165]; Copyright 2019, ADV HEALTHC MATER.

4.3 Matrigel combined with stem cells

A large number of cell types must attach to a surface to grow and multiply. Some cells, especially primary cells and stem cells, require special growth substrates and special medium conditions to maintain their undifferentiated state. The gel protein mixture has been generally utilized as a support membrane matrix for stem cells because it keeps them undifferentiated. It is derived from mouse tumor cells and is called Matrigel [93]. In our previous experiments, Matrigel was used as the basement membrane to differentiate endometrial epithelial stem cells from the hESC line (H9). Matrigel was used as a scaffold to construct endometrial organoids in vitro, and mature endometrial stromal cells were used as the niche environment. Transplanted endometrial organoids can not only facilitate endometrial repair but also promote the differentiation of neovascular endothelial cells in a mouse model of AS [143] (Figure 12).

Figure 12 The process of H9 cell differentiation into the endometrium: (a) differential microscopy of the H9 cell line. Scale bar: 500 μm. (b) Differential microscopy of EEPCs. Scale bar: 500 μm. (c) SEM image of endometrial organoids derived from H9 cells in vitro. Scale bar: 100 μm. (d) Schematic of endometrial organoid formation with endometrial stromal cells and EEPCs. (e) H&E staining of endometrial organoids in vitro. (f) H&E staining of regenerated endometrial sections from the AS rat model one month after endometrial organoid transplantation in vivo. (g) CD34, which represents neovascularization, is expressed on regenerated endometrium. Blue: DAPI. Red: CD34 [143]; Copyright 2021, Bioact Mater.
Figure 12

The process of H9 cell differentiation into the endometrium: (a) differential microscopy of the H9 cell line. Scale bar: 500 μm. (b) Differential microscopy of EEPCs. Scale bar: 500 μm. (c) SEM image of endometrial organoids derived from H9 cells in vitro. Scale bar: 100 μm. (d) Schematic of endometrial organoid formation with endometrial stromal cells and EEPCs. (e) H&E staining of endometrial organoids in vitro. (f) H&E staining of regenerated endometrial sections from the AS rat model one month after endometrial organoid transplantation in vivo. (g) CD34, which represents neovascularization, is expressed on regenerated endometrium. Blue: DAPI. Red: CD34 [143]; Copyright 2021, Bioact Mater.

4.4 Decellularized uterine scaffolds combined with stem cells

Compared with synthetic materials, decellularized scaffolds have better biocompatibility and are an alternative material for treating severe uterine injury. Vascularization in vitro is challenging. The main problem with xenogeneic animal scaffolds is the lack of safety, standardization and reproducibility [166]. Scaffolds derived from decellularized organs/tissues can be recellularized by using various types of autologous somatic cells/stem cells, especially in uterine tissue engineering [167]. The first method for vascularization relies on endothelial cells and their capacity to form new blood vessels, called neovascularization. Vascular reconstruction techniques, such as growth factors, proteins, peptides, cytokines, and cells, are used to form new blood vessels.

Another strategy emphasizes the scaffold-based method. Decellularized uterine scaffolds repair partially defective uteri by reseeding primary uterine cells to create a bioengineered uterus [168] (Figure 13) containing vessels to provide a means of creating vascularized tissue in vitro.

Figure 13 The uterine scaffold structure was preserved for tissue engineering application and 3D cell culturing: (a) immunofluorescence staining of uterine before and after decellularization. (b) [(a) Schematic graph of the experimental protocol. In the alternative experiment, the two uterine horns of rats were segmented on the anti-endometrial side. (b) The lumen side of decellularized uterine scaffold (DUS) was marked with 6-0 prolene suture. (c) The DUS patch was placed in the correct or the opposite direction (arrow). (d) Macroscopic images of uterine placement area of DUS patch after 8 weeks]. (c) H&E stained the tissue structure of regenerated uterus after correct or reverse placement of DUS. (d) [(a) The parts treated with DUS in the correct (yellow) or opposite (red) direction. (b) H&E staining of rat utero placental units untreated or treated with DUS patches in the correct or opposite direction 20 days after mating [172]]; Copyright 2019, BIOL REPROD.
Figure 13

The uterine scaffold structure was preserved for tissue engineering application and 3D cell culturing: (a) immunofluorescence staining of uterine before and after decellularization. (b) [(a) Schematic graph of the experimental protocol. In the alternative experiment, the two uterine horns of rats were segmented on the anti-endometrial side. (b) The lumen side of decellularized uterine scaffold (DUS) was marked with 6-0 prolene suture. (c) The DUS patch was placed in the correct or the opposite direction (arrow). (d) Macroscopic images of uterine placement area of DUS patch after 8 weeks]. (c) H&E stained the tissue structure of regenerated uterus after correct or reverse placement of DUS. (d) [(a) The parts treated with DUS in the correct (yellow) or opposite (red) direction. (b) H&E staining of rat utero placental units untreated or treated with DUS patches in the correct or opposite direction 20 days after mating [172]]; Copyright 2019, BIOL REPROD.

Decellularized uterine matrix scaffolds can be derived from the aortic perfusion cells of the rat uterine artery with high hydrostatic pressure or created via a uterine patch from rat uterus [169–172], porcine uterus, or ovine uterus, or whole-organ perfusion decellularization [173,174]. In a previous study, the scaffold preserved the decellularized vascular structure and initiated recellularization of the endometrium and muscularis after implantation, possibly due to circulation and homing of local stem cells [172].

4.5 Poly(glycerol sebacate) (PGS) scaffold combined with stem cells

The 3D architecture provided by a BMSC-encapsulated elastic PGS scaffold is favorable for BMSC attachment and growth [175]. In vivo bioluminescence imaging results revealed that the PGS scaffold could reliably prolong the retention time of BMSCs at the injured site of rat uterine models compared with direct intrauterine injection of BMSCS, PGS with poly (lactic-co-glycolic acid) (PLGA), and collagen scaffolds. Additionally, BMSCs can differentiate into endometrial stromal cells after the transplantation process of the PGS/BMSC scaffold but cannot differentiate into endometrial stromal cells after treatment with PLGA/BMSCs and collagen/BMSCs. Meanwhile, the levels of TGF-β1, basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and IGF were higher in endometrium treated with PGS/BMSC intrauterine transplantation. In addition, PGS/BMSC transplantation restored the morphology of the damaged uterus better than PLGA/BMSC and collagen/BMSC transplantation (Figure 14).

Figure 14 Characterization of the PGS scaffold: (a) SEM images of PGS scaffolds showing their layered porous structure, scale bar: 500 μm. (b) Differential scanning calorimetry curve of the PGS scaffold. (c) Typical compressive stress‒strain curves of three kinds of porous scaffolds and uterine tissue. Compression test for (d) PGS, (e) PLGA scaffolds, and (f) collagen scaffolds. (g) H&E staining of uterine sections after different treatments. The arrow shows the repair area (bar: 200 µm). (h) Statistical analysis of endometrial thickness and (i) the number of glands after different treatments. (j) Morphological characteristics of BMSCs observed by optical microscopy. (k) BMSCs in the PGS/BMSC group were labeled red under a confocal microscope. (l) Immunohistochemical staining of vimentin 30 days after transplantation. (Bar: 25 µm). (m) Immunohistochemical staining of CD34 in regenerated endometrium after transplantation. (n) Representative images of implanted embryos in not only normal tissues but also the regenerated area. The embryo (red) and the injured area (black) [175]; Copyright 2019, ADV HEALTHC MATER.
Figure 14

Characterization of the PGS scaffold: (a) SEM images of PGS scaffolds showing their layered porous structure, scale bar: 500 μm. (b) Differential scanning calorimetry curve of the PGS scaffold. (c) Typical compressive stress‒strain curves of three kinds of porous scaffolds and uterine tissue. Compression test for (d) PGS, (e) PLGA scaffolds, and (f) collagen scaffolds. (g) H&E staining of uterine sections after different treatments. The arrow shows the repair area (bar: 200 µm). (h) Statistical analysis of endometrial thickness and (i) the number of glands after different treatments. (j) Morphological characteristics of BMSCs observed by optical microscopy. (k) BMSCs in the PGS/BMSC group were labeled red under a confocal microscope. (l) Immunohistochemical staining of vimentin 30 days after transplantation. (Bar: 25 µm). (m) Immunohistochemical staining of CD34 in regenerated endometrium after transplantation. (n) Representative images of implanted embryos in not only normal tissues but also the regenerated area. The embryo (red) and the injured area (black) [175]; Copyright 2019, ADV HEALTHC MATER.

4.6 Droplet-based microfluidics-loaded stem cells

Droplet-based microfluidics are considered a promising technique for the construction of drug-loaded microspheres because their pore size, morphology, and microstructure can be controlled [176,177]. Cai et al. first reported a porous scaffold structure of droplet microfluidics for the treatment of AS. They proposed a feasible drug-encapsulated scaffold by the microfluidic droplet method, which combined artificial biocompatible material (GeLMA) and a natural polysaccharide material (sodium alginate). Scaffolds made from droplet-based microfluidics are not only compressible but also conducive to drug delivery and release. This scaffold can promote the formation of new blood vessels, cellularize the damaged tissue, and repair the endometrium. These merits guarantee that these drug-encapsulated porous scaffolds can be used as an alternative to improve postoperative AS [178] (Figure 15).

Figure 15 Scaffold with porous surfaces implanted into the rat uterus: (a) real-time images of droplet templates in microfluidic devices with internal and external velocities of (I) 0.5 and 2 mL/h, (II) 0.3 and 2 mL/h, and (III) 0.3 and 5 mL/h. (b) Effect of pore size on internal and external velocities. Micrographs of: (c) single-layer droplets and (d) multilayer droplets. (e) The rat uterus has good receptivity to porous scaffolds. (f) images of HepG2 cells cultured on the flat. (g) bFGF-loaded scaffold was transplanted into a rat uterus. (h) Masson staining of collagen showing large collagen remodeling at 1 week [178]; Copyright 2019, ACTA BIOMATER.
Figure 15

Scaffold with porous surfaces implanted into the rat uterus: (a) real-time images of droplet templates in microfluidic devices with internal and external velocities of (I) 0.5 and 2 mL/h, (II) 0.3 and 2 mL/h, and (III) 0.3 and 5 mL/h. (b) Effect of pore size on internal and external velocities. Micrographs of: (c) single-layer droplets and (d) multilayer droplets. (e) The rat uterus has good receptivity to porous scaffolds. (f) images of HepG2 cells cultured on the flat. (g) bFGF-loaded scaffold was transplanted into a rat uterus. (h) Masson staining of collagen showing large collagen remodeling at 1 week [178]; Copyright 2019, ACTA BIOMATER.

4.7 Convergence with organoid models

Treatment of AS is aimed at restoring endometrial structure and function. In terms of institutional reconstruction and functional recovery, 3D bioprinting and on-chip organ models represent two recent bioengineering milestones in the field of gynecological research [179] (Figure 16). 3D bioprinting also involves additional complexities, such as material selection, cell types, growth, and differentiation factors, as well as technical challenges related to living cell sensitivity and tissue reconstruction. 3D bioprinting technology has been applied in gynecological research. For example, an extrauterine mouse embryogenesis system was successfully constructed by connecting the electronic gas and pressure regulation module to the drum incubator system [180]. Through the triple inhibition of the Hippo, ERK, and TGF signaling pathways in pluripotent stem cells (naive hPSCs), human blastocysts containing only three preimplantation lineages can be constructed. These blastocysts can be attached to the receptive endometrial cell layer and can simulate implantation in vitro [181]. Organ-on-chip is an integrated method of replicating physiology in vivo through the combination of spatiotemporally controlled multicellular coculture and continuous liquid circulation stimulated by strictly controlled mechanical, electrical, and biochemical factors (CO2, O2, and growth factors). A recent investigation utilized microfluidic systems to coculture human endometrium and perivascular endothelial cells to demonstrate the steroid response [182].

Figure 16 Optimization of the culture protocol of the female reproductive tract organoid model: (a) The co-culture system includes tissue-resident cells, immune cells, the microbial population, and the vascular network, (b) customized synthetic hydrogels, (c) optimizing the integration of the microenvironment while allowing self-organization and assembly [179]; Copyright 2020, CANCER TREAT REV.
Figure 16

Optimization of the culture protocol of the female reproductive tract organoid model: (a) The co-culture system includes tissue-resident cells, immune cells, the microbial population, and the vascular network, (b) customized synthetic hydrogels, (c) optimizing the integration of the microenvironment while allowing self-organization and assembly [179]; Copyright 2020, CANCER TREAT REV.

5 Innovative medical methods using advanced biological/artificial medical equipment

Recent studies have proven that the combination or modification of cells and biomaterials (such as cell sheets and cell scaffold interfaces) demonstrates functional or structural advantages and can repair damaged uteri to varying degrees by inducing bionic variations and reconstructing the regenerative microenvironment. Cell plate engineering is a new cell transplantation technology that uses temperature-responsive Petri dishes to restore damaged organs or tissues that possess the capacity for tissue regeneration [183]. However, in practice, it is not recommended to collect endometrial cells because it is difficult to collect sufficient numbers of endometrial cells from the uterus, and the collection may be interfered with some inflammatory or infectious diseases in addition to the injury incurred by invasive surgery [184].

The natural cell sheet structure does not cause any inflammation, resulting in inconspicuous scar formation. Adipose-derived stem cells (ADSCs) are used to construct cell slices. The results demonstrated that the implantable ADSC sheet is closely attached to the damaged uterus and promotes endometrial repair by providing biomimetic nutritional support, which is essential for cell proliferation [185].

In addition to loading cells directly into scaffolds, many methods also focus on surface or structural modification for better biocompatibility, stronger cell adsorption and uptake, and delivery of bioactive growth factors [186,187]. Bacterial cellulose (BC) is a biocompatible and absorbent bacterium. Silk fibrin (SF) and SDF-1α were added to enhance the porosity of BC [188]. There are many methods to modify scaffolds, such as bFGF modification in the collagen binding domain (CBD) [189], collagen loading of CBD/VEGF [190], regulation of bFGF release in porous collagen [178] temperature-sensitive hydrogel-loaded KGF [56], release of 17β-E2 heparin poloxamer hydrogel [87], and stem cell secretory modification of hydrogels containing a variety of growth factors [126,165,171,191]. These modifications induced uterine cell migration in vitro and increased endometrial thickness and the number of fetuses produced.

6 Clinical perspective and current application status of cell-combined polymers in AS

Research on engineered uterine tissues is still in its infancy. The production of bioengineered scaffolds requires more research and a better understanding of the microenvironment to simulate the dynamic changes of the endometrium. To date, most of cell therapy trials are in the recruitment phase, which limits the assessment of long-term safety. The evidence from some existing clinical trials of biopolymers combined with cell therapy has shown positive results. The expansion of preclinical studies to large animals should continue to develop scaffolds that can be applied to humans. Transplanting clinical-grade UC-MSCs containing degradable collagen scaffolds into the uterine cavity of patients with recurrent AS is a safe and effective therapeutic method that can improve endometrial proliferation, differentiation, and neovascularization [163,192]. Collagen scaffolds can be loaded with autologous bone marrow mononuclear cells [33] and collagen-binding bFGF [193] in patients with AS. In the future, safety problems related to biocompatibility and immunogenicity must be considered before the use of these technologies in humans. In addition to tissue transplantation, research into whole-organ transplantation of the uterus must continue [194]. Engineered biopolymers will continue to be used for research in a variety of fields, such as new drug development, toxicity analysis and transplantation [195]. Therefore, engineered endometrial tissue technology is expected to be continued, and patients with refractory reproductive diseases may be helped [58].

Meanwhile, the establishment of a more compatible animal model is an important part of the research on the repair and transformation of endometrial injury using biopolymer tissue engineering technology [196]. Recently, Feng et al. [197] reported an AS animal model using pregnant rats. In this study, the timing of endometrial injury associated with the puerperium was considered to be one of the most important factors and was associated with endometrial recovery within 3 days after curettage in nonpregnant rats. Pregnancy-related hormonal changes inhibit epithelial cell regeneration and promote interstitial tissue fibrosis. Hence, the animal model simulating human AS using pregnant rats possesses great advantages in the actual pathophysiology of AS as clinically observed [198].

7 Concluding remarks

A large body of scientific literature shows that physical barriers and treatment are conducive to the prevention of postoperative complications. However, adhesion is inevitable due to the lack of functional recovery of the endometrium. Researchers have attempted to reconstruct the damaged uterus through cell therapy to restore endometrial function. Tissue engineering aims to develop functional substitutes for repairing damaged tissues by combining cells, biological cues, and biomaterial scaffolds [199]. The reconstruction of the repair microenvironment after endometrial damage requires the synergistic action of treatment elements and functional stem cells. Further research may focus on using a new formulation approach to develop therapeutic factors combined with stem cells, such as the combination method of granular systems loaded with therapeutic factors and bioactive scaffolds bound with functional stem cells. The use of sustained and controlled release technology, local targeted drug delivery technology or tissue engineering technology may be expected to resolve the bottlenecks in the clinical treatment of AS (Figure 17) [200].

Figure 17 Biopolymer-based endometrial regeneration methods: loading cytokines on scaffolds (a) direct loading or adsorption, (b) fixation by forming ionic complexes, (c) fixation by specific heparin-mediated interactions, (d) granular system. Delivery to therapeutic targets by encapsulating stem cells with biomaterials [200]; Copyright 2021, Mater Today, Bio.
Figure 17

Biopolymer-based endometrial regeneration methods: loading cytokines on scaffolds (a) direct loading or adsorption, (b) fixation by forming ionic complexes, (c) fixation by specific heparin-mediated interactions, (d) granular system. Delivery to therapeutic targets by encapsulating stem cells with biomaterials [200]; Copyright 2021, Mater Today, Bio.

# These authors contributed equally to this work and should be considered first co-authors.

Acknowledgments

The authors would like to thank Yangyang Li for advising the article.

  1. Funding information: This study was supported by the National Natural Science Foundation of China (81401179).

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Conflict of interest: The authors state no conflict of interest.

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Received: 2022-04-12
Revised: 2023-01-18
Accepted: 2023-02-26
Published Online: 2023-04-12

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

  1. Research Articles
  2. Preparation of CdS–Ag2S nanocomposites by ultrasound-assisted UV photolysis treatment and its visible light photocatalysis activity
  3. Significance of nanoparticle radius and inter-particle spacing toward the radiative water-based alumina nanofluid flow over a rotating disk
  4. Aptamer-based detection of serotonin based on the rapid in situ synthesis of colorimetric gold nanoparticles
  5. Investigation of the nucleation and growth behavior of Ti2AlC and Ti3AlC nano-precipitates in TiAl alloys
  6. Dynamic recrystallization behavior and nucleation mechanism of dual-scale SiCp/A356 composites processed by P/M method
  7. High mechanical performance of 3-aminopropyl triethoxy silane/epoxy cured in a sandwich construction of 3D carbon felts foam and woven basalt fibers
  8. Applying solution of spray polyurea elastomer in asphalt binder: Feasibility analysis and DSR study based on the MSCR and LAS tests
  9. Study on the chronic toxicity and carcinogenicity of iron-based bioabsorbable stents
  10. Influence of microalloying with B on the microstructure and properties of brazed joints with Ag–Cu–Zn–Sn filler metal
  11. Thermohydraulic performance of thermal system integrated with twisted turbulator inserts using ternary hybrid nanofluids
  12. Study of mechanical properties of epoxy/graphene and epoxy/halloysite nanocomposites
  13. Effects of CaO addition on the CuW composite containing micro- and nano-sized tungsten particles synthesized via aluminothermic coupling with silicothermic reduction
  14. Cu and Al2O3-based hybrid nanofluid flow through a porous cavity
  15. Design of functional vancomycin-embedded bio-derived extracellular matrix hydrogels for repairing infectious bone defects
  16. Study on nanocrystalline coating prepared by electro-spraying 316L metal wire and its corrosion performance
  17. Axial compression performance of CFST columns reinforced by ultra-high-performance nano-concrete under long-term loading
  18. Tungsten trioxide nanocomposite for conventional soliton and noise-like pulse generation in anomalous dispersion laser cavity
  19. Microstructure and electrical contact behavior of the nano-yttria-modified Cu-Al2O3/30Mo/3SiC composite
  20. Melting rheology in thermally stratified graphene-mineral oil reservoir (third-grade nanofluid) with slip condition
  21. Re-examination of nonlinear vibration and nonlinear bending of porous sandwich cylindrical panels reinforced by graphene platelets
  22. Parametric simulation of hybrid nanofluid flow consisting of cobalt ferrite nanoparticles with second-order slip and variable viscosity over an extending surface
  23. Chitosan-capped silver nanoparticles with potent and selective intrinsic activity against the breast cancer cells
  24. Multi-core/shell SiO2@Al2O3 nanostructures deposited on Ti3AlC2 to enhance high-temperature stability and microwave absorption properties
  25. Solution-processed Bi2S3/BiVO4/TiO2 ternary heterojunction photoanode with enhanced photoelectrochemical performance
  26. Electroporation effect of ZnO nanoarrays under low voltage for water disinfection
  27. NIR-II window absorbing graphene oxide-coated gold nanorods and graphene quantum dot-coupled gold nanorods for photothermal cancer therapy
  28. Nonlinear three-dimensional stability characteristics of geometrically imperfect nanoshells under axial compression and surface residual stress
  29. Investigation of different nanoparticles properties on the thermal conductivity and viscosity of nanofluids by molecular dynamics simulation
  30. Optimized Cu2O-{100} facet for generation of different reactive oxidative species via peroxymonosulfate activation at specific pH values to efficient acetaminophen removal
  31. Brownian and thermal diffusivity impact due to the Maxwell nanofluid (graphene/engine oil) flow with motile microorganisms and Joule heating
  32. Appraising the dielectric properties and the effectiveness of electromagnetic shielding of graphene reinforced silicone rubber nanocomposite
  33. Synthesis of Ag and Cu nanoparticles by plasma discharge in inorganic salt solutions
  34. Low-cost and large-scale preparation of ultrafine TiO2@C hybrids for high-performance degradation of methyl orange and formaldehyde under visible light
  35. Utilization of waste glass with natural pozzolan in the production of self-glazed glass-ceramic materials
  36. Mechanical performance of date palm fiber-reinforced concrete modified with nano-activated carbon
  37. Melting point of dried gold nanoparticles prepared with ultrasonic spray pyrolysis and lyophilisation
  38. Graphene nanofibers: A modern approach towards tailored gypsum composites
  39. Role of localized magnetic field in vortex generation in tri-hybrid nanofluid flow: A numerical approach
  40. Intelligent computing for the double-diffusive peristaltic rheology of magneto couple stress nanomaterials
  41. Bioconvection transport of upper convected Maxwell nanoliquid with gyrotactic microorganism, nonlinear thermal radiation, and chemical reaction
  42. 3D printing of porous Ti6Al4V bone tissue engineering scaffold and surface anodization preparation of nanotubes to enhance its biological property
  43. Bioinspired ferromagnetic CoFe2O4 nanoparticles: Potential pharmaceutical and medical applications
  44. Significance of gyrotactic microorganisms on the MHD tangent hyperbolic nanofluid flow across an elastic slender surface: Numerical analysis
  45. Performance of polycarboxylate superplasticisers in seawater-blended cement: Effect from chemical structure and nano modification
  46. Entropy minimization of GO–Ag/KO cross-hybrid nanofluid over a convectively heated surface
  47. Oxygen plasma assisted room temperature bonding for manufacturing SU-8 polymer micro/nanoscale nozzle
  48. Performance and mechanism of CO2 reduction by DBD-coupled mesoporous SiO2
  49. Polyarylene ether nitrile dielectric films modified by HNTs@PDA hybrids for high-temperature resistant organic electronics field
  50. Exploration of generalized two-phase free convection magnetohydrodynamic flow of dusty tetra-hybrid Casson nanofluid between parallel microplates
  51. Hygrothermal bending analysis of sandwich nanoplates with FG porous core and piezomagnetic faces via nonlocal strain gradient theory
  52. Design and optimization of a TiO2/RGO-supported epoxy multilayer microwave absorber by the modified local best particle swarm optimization algorithm
  53. Mechanical properties and frost resistance of recycled brick aggregate concrete modified by nano-SiO2
  54. Self-template synthesis of hollow flower-like NiCo2O4 nanoparticles as an efficient bifunctional catalyst for oxygen reduction and oxygen evolution in alkaline media
  55. High-performance wearable flexible strain sensors based on an AgNWs/rGO/TPU electrospun nanofiber film for monitoring human activities
  56. High-performance lithium–selenium batteries enabled by nitrogen-doped porous carbon from peanut meal
  57. Investigating effects of Lorentz forces and convective heating on ternary hybrid nanofluid flow over a curved surface using homotopy analysis method
  58. Exploring the potential of biogenic magnesium oxide nanoparticles for cytotoxicity: In vitro and in silico studies on HCT116 and HT29 cells and DPPH radical scavenging
  59. Enhanced visible-light-driven photocatalytic degradation of azo dyes by heteroatom-doped nickel tungstate nanoparticles
  60. A facile method to synthesize nZVI-doped polypyrrole-based carbon nanotube for Ag(i) removal
  61. Improved osseointegration of dental titanium implants by TiO2 nanotube arrays with self-assembled recombinant IGF-1 in type 2 diabetes mellitus rat model
  62. Functionalized SWCNTs@Ag–TiO2 nanocomposites induce ROS-mediated apoptosis and autophagy in liver cancer cells
  63. Triboelectric nanogenerator based on a water droplet spring with a concave spherical surface for harvesting wave energy and detecting pressure
  64. A mathematical approach for modeling the blood flow containing nanoparticles by employing the Buongiorno’s model
  65. Molecular dynamics study on dynamic interlayer friction of graphene and its strain effect
  66. Induction of apoptosis and autophagy via regulation of AKT and JNK mitogen-activated protein kinase pathways in breast cancer cell lines exposed to gold nanoparticles loaded with TNF-α and combined with doxorubicin
  67. Effect of PVA fibers on durability of nano-SiO2-reinforced cement-based composites subjected to wet-thermal and chloride salt-coupled environment
  68. Effect of polyvinyl alcohol fibers on mechanical properties of nano-SiO2-reinforced geopolymer composites under a complex environment
  69. In vitro studies of titanium dioxide nanoparticles modified with glutathione as a potential drug delivery system
  70. Comparative investigations of Ag/H2O nanofluid and Ag-CuO/H2O hybrid nanofluid with Darcy-Forchheimer flow over a curved surface
  71. Study on deformation characteristics of multi-pass continuous drawing of micro copper wire based on crystal plasticity finite element method
  72. Properties of ultra-high-performance self-compacting fiber-reinforced concrete modified with nanomaterials
  73. Prediction of lap shear strength of GNP and TiO2/epoxy nanocomposite adhesives
  74. A novel exploration of how localized magnetic field affects vortex generation of trihybrid nanofluids
  75. Fabrication and physicochemical characterization of copper oxide–pyrrhotite nanocomposites for the cytotoxic effects on HepG2 cells and the mechanism
  76. Thermal radiative flow of cross nanofluid due to a stretched cylinder containing microorganisms
  77. In vitro study of the biphasic calcium phosphate/chitosan hybrid biomaterial scaffold fabricated via solvent casting and evaporation technique for bone regeneration
  78. Insights into the thermal characteristics and dynamics of stagnant blood conveying titanium oxide, alumina, and silver nanoparticles subject to Lorentz force and internal heating over a curved surface
  79. Effects of nano-SiO2 additives on carbon fiber-reinforced fly ash–slag geopolymer composites performance: Workability, mechanical properties, and microstructure
  80. Energy bandgap and thermal characteristics of non-Darcian MHD rotating hybridity nanofluid thin film flow: Nanotechnology application
  81. Green synthesis and characterization of ginger-extract-based oxali-palladium nanoparticles for colorectal cancer: Downregulation of REG4 and apoptosis induction
  82. Abnormal evolution of resistivity and microstructure of annealed Ag nanoparticles/Ag–Mo films
  83. Preparation of water-based dextran-coated Fe3O4 magnetic fluid for magnetic hyperthermia
  84. Statistical investigations and morphological aspects of cross-rheological material suspended in transportation of alumina, silica, titanium, and ethylene glycol via the Galerkin algorithm
  85. Effect of CNT film interleaves on the flexural properties and strength after impact of CFRP composites
  86. Self-assembled nanoscale entities: Preparative process optimization, payload release, and enhanced bioavailability of thymoquinone natural product
  87. Structure–mechanical property relationships of 3D-printed porous polydimethylsiloxane films
  88. Nonlinear thermal radiation and the slip effect on a 3D bioconvection flow of the Casson nanofluid in a rotating frame via a homotopy analysis mechanism
  89. Residual mechanical properties of concrete incorporated with nano supplementary cementitious materials exposed to elevated temperature
  90. Time-independent three-dimensional flow of a water-based hybrid nanofluid past a Riga plate with slips and convective conditions: A homotopic solution
  91. Lightweight and high-strength polyarylene ether nitrile-based composites for efficient electromagnetic interference shielding
  92. Review Articles
  93. Recycling waste sources into nanocomposites of graphene materials: Overview from an energy-focused perspective
  94. Hybrid nanofiller reinforcement in thermoset and biothermoset applications: A review
  95. Current state-of-the-art review of nanotechnology-based therapeutics for viral pandemics: Special attention to COVID-19
  96. Solid lipid nanoparticles for targeted natural and synthetic drugs delivery in high-incidence cancers, and other diseases: Roles of preparation methods, lipid composition, transitional stability, and release profiles in nanocarriers’ development
  97. Critical review on experimental and theoretical studies of elastic properties of wurtzite-structured ZnO nanowires
  98. Polyurea micro-/nano-capsule applications in construction industry: A review
  99. A comprehensive review and clinical guide to molecular and serological diagnostic tests and future development: In vitro diagnostic testing for COVID-19
  100. Recent advances in electrocatalytic oxidation of 5-hydroxymethylfurfural to 2,5-furandicarboxylic acid: Mechanism, catalyst, coupling system
  101. Research progress and prospect of silica-based polymer nanofluids in enhanced oil recovery
  102. Review of the pharmacokinetics of nanodrugs
  103. Engineered nanoflowers, nanotrees, nanostars, nanodendrites, and nanoleaves for biomedical applications
  104. Research progress of biopolymers combined with stem cells in the repair of intrauterine adhesions
  105. Progress in FEM modeling on mechanical and electromechanical properties of carbon nanotube cement-based composites
  106. Antifouling induced by surface wettability of poly(dimethyl siloxane) and its nanocomposites
  107. TiO2 aerogel composite high-efficiency photocatalysts for environmental treatment and hydrogen energy production
  108. Structural properties of alumina surfaces and their roles in the synthesis of environmentally persistent free radicals (EPFRs)
  109. Nanoparticles for the potential treatment of Alzheimer’s disease: A physiopathological approach
  110. Current status of synthesis and consolidation strategies for thermo-resistant nanoalloys and their general applications
  111. Recent research progress on the stimuli-responsive smart membrane: A review
  112. Dispersion of carbon nanotubes in aqueous cementitious materials: A review
  113. Applications of DNA tetrahedron nanostructure in cancer diagnosis and anticancer drugs delivery
  114. Magnetic nanoparticles in 3D-printed scaffolds for biomedical applications
  115. An overview of the synthesis of silicon carbide–boron carbide composite powders
  116. Organolead halide perovskites: Synthetic routes, structural features, and their potential in the development of photovoltaic
  117. Recent advancements in nanotechnology application on wood and bamboo materials: A review
  118. Application of aptamer-functionalized nanomaterials in molecular imaging of tumors
  119. Recent progress on corrosion mechanisms of graphene-reinforced metal matrix composites
  120. Research progress on preparation, modification, and application of phenolic aerogel
  121. Application of nanomaterials in early diagnosis of cancer
  122. Plant mediated-green synthesis of zinc oxide nanoparticles: An insight into biomedical applications
  123. Recent developments in terahertz quantum cascade lasers for practical applications
  124. Recent progress in dielectric/metal/dielectric electrodes for foldable light-emitting devices
  125. Nanocoatings for ballistic applications: A review
  126. A mini-review on MoS2 membrane for water desalination: Recent development and challenges
  127. Recent updates in nanotechnological advances for wound healing: A narrative review
  128. Recent advances in DNA nanomaterials for cancer diagnosis and treatment
  129. Electrochemical micro- and nanobiosensors for in vivo reactive oxygen/nitrogen species measurement in the brain
  130. Advances in organic–inorganic nanocomposites for cancer imaging and therapy
  131. Advancements in aluminum matrix composites reinforced with carbides and graphene: A comprehensive review
  132. Modification effects of nanosilica on asphalt binders: A review
  133. Decellularized extracellular matrix as a promising biomaterial for musculoskeletal tissue regeneration
  134. Review of the sol–gel method in preparing nano TiO2 for advanced oxidation process
  135. Micro/nano manufacturing aircraft surface with anti-icing and deicing performances: An overview
  136. Cell type-targeting nanoparticles in treating central nervous system diseases: Challenges and hopes
  137. An overview of hydrogen production from Al-based materials
  138. A review of application, modification, and prospect of melamine foam
  139. A review of the performance of fibre-reinforced composite laminates with carbon nanotubes
  140. Research on AFM tip-related nanofabrication of two-dimensional materials
  141. Advances in phase change building materials: An overview
  142. Development of graphene and graphene quantum dots toward biomedical engineering applications: A review
  143. Nanoremediation approaches for the mitigation of heavy metal contamination in vegetables: An overview
  144. Photodynamic therapy empowered by nanotechnology for oral and dental science: Progress and perspectives
  145. Biosynthesis of metal nanoparticles: Bioreduction and biomineralization
  146. Current diagnostic and therapeutic approaches for severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) and the role of nanomaterial-based theragnosis in combating the pandemic
  147. Application of two-dimensional black phosphorus material in wound healing
  148. Special Issue on Advanced Nanomaterials and Composites for Energy Conversion and Storage - Part I
  149. Helical fluorinated carbon nanotubes/iron(iii) fluoride hybrid with multilevel transportation channels and rich active sites for lithium/fluorinated carbon primary battery
  150. The progress of cathode materials in aqueous zinc-ion batteries
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https://doi.org/10.1515/ntrev-2022-0529
Keywords for this article
endometrial stem cell; biopolymer; endometrium regeneration
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. Preparation of CdS–Ag2S nanocomposites by ultrasound-assisted UV photolysis treatment and its visible light photocatalysis activity
  3. Significance of nanoparticle radius and inter-particle spacing toward the radiative water-based alumina nanofluid flow over a rotating disk
  4. Aptamer-based detection of serotonin based on the rapid in situ synthesis of colorimetric gold nanoparticles
  5. Investigation of the nucleation and growth behavior of Ti2AlC and Ti3AlC nano-precipitates in TiAl alloys
  6. Dynamic recrystallization behavior and nucleation mechanism of dual-scale SiCp/A356 composites processed by P/M method
  7. High mechanical performance of 3-aminopropyl triethoxy silane/epoxy cured in a sandwich construction of 3D carbon felts foam and woven basalt fibers
  8. Applying solution of spray polyurea elastomer in asphalt binder: Feasibility analysis and DSR study based on the MSCR and LAS tests
  9. Study on the chronic toxicity and carcinogenicity of iron-based bioabsorbable stents
  10. Influence of microalloying with B on the microstructure and properties of brazed joints with Ag–Cu–Zn–Sn filler metal
  11. Thermohydraulic performance of thermal system integrated with twisted turbulator inserts using ternary hybrid nanofluids
  12. Study of mechanical properties of epoxy/graphene and epoxy/halloysite nanocomposites
  13. Effects of CaO addition on the CuW composite containing micro- and nano-sized tungsten particles synthesized via aluminothermic coupling with silicothermic reduction
  14. Cu and Al2O3-based hybrid nanofluid flow through a porous cavity
  15. Design of functional vancomycin-embedded bio-derived extracellular matrix hydrogels for repairing infectious bone defects
  16. Study on nanocrystalline coating prepared by electro-spraying 316L metal wire and its corrosion performance
  17. Axial compression performance of CFST columns reinforced by ultra-high-performance nano-concrete under long-term loading
  18. Tungsten trioxide nanocomposite for conventional soliton and noise-like pulse generation in anomalous dispersion laser cavity
  19. Microstructure and electrical contact behavior of the nano-yttria-modified Cu-Al2O3/30Mo/3SiC composite
  20. Melting rheology in thermally stratified graphene-mineral oil reservoir (third-grade nanofluid) with slip condition
  21. Re-examination of nonlinear vibration and nonlinear bending of porous sandwich cylindrical panels reinforced by graphene platelets
  22. Parametric simulation of hybrid nanofluid flow consisting of cobalt ferrite nanoparticles with second-order slip and variable viscosity over an extending surface
  23. Chitosan-capped silver nanoparticles with potent and selective intrinsic activity against the breast cancer cells
  24. Multi-core/shell SiO2@Al2O3 nanostructures deposited on Ti3AlC2 to enhance high-temperature stability and microwave absorption properties
  25. Solution-processed Bi2S3/BiVO4/TiO2 ternary heterojunction photoanode with enhanced photoelectrochemical performance
  26. Electroporation effect of ZnO nanoarrays under low voltage for water disinfection
  27. NIR-II window absorbing graphene oxide-coated gold nanorods and graphene quantum dot-coupled gold nanorods for photothermal cancer therapy
  28. Nonlinear three-dimensional stability characteristics of geometrically imperfect nanoshells under axial compression and surface residual stress
  29. Investigation of different nanoparticles properties on the thermal conductivity and viscosity of nanofluids by molecular dynamics simulation
  30. Optimized Cu2O-{100} facet for generation of different reactive oxidative species via peroxymonosulfate activation at specific pH values to efficient acetaminophen removal
  31. Brownian and thermal diffusivity impact due to the Maxwell nanofluid (graphene/engine oil) flow with motile microorganisms and Joule heating
  32. Appraising the dielectric properties and the effectiveness of electromagnetic shielding of graphene reinforced silicone rubber nanocomposite
  33. Synthesis of Ag and Cu nanoparticles by plasma discharge in inorganic salt solutions
  34. Low-cost and large-scale preparation of ultrafine TiO2@C hybrids for high-performance degradation of methyl orange and formaldehyde under visible light
  35. Utilization of waste glass with natural pozzolan in the production of self-glazed glass-ceramic materials
  36. Mechanical performance of date palm fiber-reinforced concrete modified with nano-activated carbon
  37. Melting point of dried gold nanoparticles prepared with ultrasonic spray pyrolysis and lyophilisation
  38. Graphene nanofibers: A modern approach towards tailored gypsum composites
  39. Role of localized magnetic field in vortex generation in tri-hybrid nanofluid flow: A numerical approach
  40. Intelligent computing for the double-diffusive peristaltic rheology of magneto couple stress nanomaterials
  41. Bioconvection transport of upper convected Maxwell nanoliquid with gyrotactic microorganism, nonlinear thermal radiation, and chemical reaction
  42. 3D printing of porous Ti6Al4V bone tissue engineering scaffold and surface anodization preparation of nanotubes to enhance its biological property
  43. Bioinspired ferromagnetic CoFe2O4 nanoparticles: Potential pharmaceutical and medical applications
  44. Significance of gyrotactic microorganisms on the MHD tangent hyperbolic nanofluid flow across an elastic slender surface: Numerical analysis
  45. Performance of polycarboxylate superplasticisers in seawater-blended cement: Effect from chemical structure and nano modification
  46. Entropy minimization of GO–Ag/KO cross-hybrid nanofluid over a convectively heated surface
  47. Oxygen plasma assisted room temperature bonding for manufacturing SU-8 polymer micro/nanoscale nozzle
  48. Performance and mechanism of CO2 reduction by DBD-coupled mesoporous SiO2
  49. Polyarylene ether nitrile dielectric films modified by HNTs@PDA hybrids for high-temperature resistant organic electronics field
  50. Exploration of generalized two-phase free convection magnetohydrodynamic flow of dusty tetra-hybrid Casson nanofluid between parallel microplates
  51. Hygrothermal bending analysis of sandwich nanoplates with FG porous core and piezomagnetic faces via nonlocal strain gradient theory
  52. Design and optimization of a TiO2/RGO-supported epoxy multilayer microwave absorber by the modified local best particle swarm optimization algorithm
  53. Mechanical properties and frost resistance of recycled brick aggregate concrete modified by nano-SiO2
  54. Self-template synthesis of hollow flower-like NiCo2O4 nanoparticles as an efficient bifunctional catalyst for oxygen reduction and oxygen evolution in alkaline media
  55. High-performance wearable flexible strain sensors based on an AgNWs/rGO/TPU electrospun nanofiber film for monitoring human activities
  56. High-performance lithium–selenium batteries enabled by nitrogen-doped porous carbon from peanut meal
  57. Investigating effects of Lorentz forces and convective heating on ternary hybrid nanofluid flow over a curved surface using homotopy analysis method
  58. Exploring the potential of biogenic magnesium oxide nanoparticles for cytotoxicity: In vitro and in silico studies on HCT116 and HT29 cells and DPPH radical scavenging
  59. Enhanced visible-light-driven photocatalytic degradation of azo dyes by heteroatom-doped nickel tungstate nanoparticles
  60. A facile method to synthesize nZVI-doped polypyrrole-based carbon nanotube for Ag(i) removal
  61. Improved osseointegration of dental titanium implants by TiO2 nanotube arrays with self-assembled recombinant IGF-1 in type 2 diabetes mellitus rat model
  62. Functionalized SWCNTs@Ag–TiO2 nanocomposites induce ROS-mediated apoptosis and autophagy in liver cancer cells
  63. Triboelectric nanogenerator based on a water droplet spring with a concave spherical surface for harvesting wave energy and detecting pressure
  64. A mathematical approach for modeling the blood flow containing nanoparticles by employing the Buongiorno’s model
  65. Molecular dynamics study on dynamic interlayer friction of graphene and its strain effect
  66. Induction of apoptosis and autophagy via regulation of AKT and JNK mitogen-activated protein kinase pathways in breast cancer cell lines exposed to gold nanoparticles loaded with TNF-α and combined with doxorubicin
  67. Effect of PVA fibers on durability of nano-SiO2-reinforced cement-based composites subjected to wet-thermal and chloride salt-coupled environment
  68. Effect of polyvinyl alcohol fibers on mechanical properties of nano-SiO2-reinforced geopolymer composites under a complex environment
  69. In vitro studies of titanium dioxide nanoparticles modified with glutathione as a potential drug delivery system
  70. Comparative investigations of Ag/H2O nanofluid and Ag-CuO/H2O hybrid nanofluid with Darcy-Forchheimer flow over a curved surface
  71. Study on deformation characteristics of multi-pass continuous drawing of micro copper wire based on crystal plasticity finite element method
  72. Properties of ultra-high-performance self-compacting fiber-reinforced concrete modified with nanomaterials
  73. Prediction of lap shear strength of GNP and TiO2/epoxy nanocomposite adhesives
  74. A novel exploration of how localized magnetic field affects vortex generation of trihybrid nanofluids
  75. Fabrication and physicochemical characterization of copper oxide–pyrrhotite nanocomposites for the cytotoxic effects on HepG2 cells and the mechanism
  76. Thermal radiative flow of cross nanofluid due to a stretched cylinder containing microorganisms
  77. In vitro study of the biphasic calcium phosphate/chitosan hybrid biomaterial scaffold fabricated via solvent casting and evaporation technique for bone regeneration
  78. Insights into the thermal characteristics and dynamics of stagnant blood conveying titanium oxide, alumina, and silver nanoparticles subject to Lorentz force and internal heating over a curved surface
  79. Effects of nano-SiO2 additives on carbon fiber-reinforced fly ash–slag geopolymer composites performance: Workability, mechanical properties, and microstructure
  80. Energy bandgap and thermal characteristics of non-Darcian MHD rotating hybridity nanofluid thin film flow: Nanotechnology application
  81. Green synthesis and characterization of ginger-extract-based oxali-palladium nanoparticles for colorectal cancer: Downregulation of REG4 and apoptosis induction
  82. Abnormal evolution of resistivity and microstructure of annealed Ag nanoparticles/Ag–Mo films
  83. Preparation of water-based dextran-coated Fe3O4 magnetic fluid for magnetic hyperthermia
  84. Statistical investigations and morphological aspects of cross-rheological material suspended in transportation of alumina, silica, titanium, and ethylene glycol via the Galerkin algorithm
  85. Effect of CNT film interleaves on the flexural properties and strength after impact of CFRP composites
  86. Self-assembled nanoscale entities: Preparative process optimization, payload release, and enhanced bioavailability of thymoquinone natural product
  87. Structure–mechanical property relationships of 3D-printed porous polydimethylsiloxane films
  88. Nonlinear thermal radiation and the slip effect on a 3D bioconvection flow of the Casson nanofluid in a rotating frame via a homotopy analysis mechanism
  89. Residual mechanical properties of concrete incorporated with nano supplementary cementitious materials exposed to elevated temperature
  90. Time-independent three-dimensional flow of a water-based hybrid nanofluid past a Riga plate with slips and convective conditions: A homotopic solution
  91. Lightweight and high-strength polyarylene ether nitrile-based composites for efficient electromagnetic interference shielding
  92. Review Articles
  93. Recycling waste sources into nanocomposites of graphene materials: Overview from an energy-focused perspective
  94. Hybrid nanofiller reinforcement in thermoset and biothermoset applications: A review
  95. Current state-of-the-art review of nanotechnology-based therapeutics for viral pandemics: Special attention to COVID-19
  96. Solid lipid nanoparticles for targeted natural and synthetic drugs delivery in high-incidence cancers, and other diseases: Roles of preparation methods, lipid composition, transitional stability, and release profiles in nanocarriers’ development
  97. Critical review on experimental and theoretical studies of elastic properties of wurtzite-structured ZnO nanowires
  98. Polyurea micro-/nano-capsule applications in construction industry: A review
  99. A comprehensive review and clinical guide to molecular and serological diagnostic tests and future development: In vitro diagnostic testing for COVID-19
  100. Recent advances in electrocatalytic oxidation of 5-hydroxymethylfurfural to 2,5-furandicarboxylic acid: Mechanism, catalyst, coupling system
  101. Research progress and prospect of silica-based polymer nanofluids in enhanced oil recovery
  102. Review of the pharmacokinetics of nanodrugs
  103. Engineered nanoflowers, nanotrees, nanostars, nanodendrites, and nanoleaves for biomedical applications
  104. Research progress of biopolymers combined with stem cells in the repair of intrauterine adhesions
  105. Progress in FEM modeling on mechanical and electromechanical properties of carbon nanotube cement-based composites
  106. Antifouling induced by surface wettability of poly(dimethyl siloxane) and its nanocomposites
  107. TiO2 aerogel composite high-efficiency photocatalysts for environmental treatment and hydrogen energy production
  108. Structural properties of alumina surfaces and their roles in the synthesis of environmentally persistent free radicals (EPFRs)
  109. Nanoparticles for the potential treatment of Alzheimer’s disease: A physiopathological approach
  110. Current status of synthesis and consolidation strategies for thermo-resistant nanoalloys and their general applications
  111. Recent research progress on the stimuli-responsive smart membrane: A review
  112. Dispersion of carbon nanotubes in aqueous cementitious materials: A review
  113. Applications of DNA tetrahedron nanostructure in cancer diagnosis and anticancer drugs delivery
  114. Magnetic nanoparticles in 3D-printed scaffolds for biomedical applications
  115. An overview of the synthesis of silicon carbide–boron carbide composite powders
  116. Organolead halide perovskites: Synthetic routes, structural features, and their potential in the development of photovoltaic
  117. Recent advancements in nanotechnology application on wood and bamboo materials: A review
  118. Application of aptamer-functionalized nanomaterials in molecular imaging of tumors
  119. Recent progress on corrosion mechanisms of graphene-reinforced metal matrix composites
  120. Research progress on preparation, modification, and application of phenolic aerogel
  121. Application of nanomaterials in early diagnosis of cancer
  122. Plant mediated-green synthesis of zinc oxide nanoparticles: An insight into biomedical applications
  123. Recent developments in terahertz quantum cascade lasers for practical applications
  124. Recent progress in dielectric/metal/dielectric electrodes for foldable light-emitting devices
  125. Nanocoatings for ballistic applications: A review
  126. A mini-review on MoS2 membrane for water desalination: Recent development and challenges
  127. Recent updates in nanotechnological advances for wound healing: A narrative review
  128. Recent advances in DNA nanomaterials for cancer diagnosis and treatment
  129. Electrochemical micro- and nanobiosensors for in vivo reactive oxygen/nitrogen species measurement in the brain
  130. Advances in organic–inorganic nanocomposites for cancer imaging and therapy
  131. Advancements in aluminum matrix composites reinforced with carbides and graphene: A comprehensive review
  132. Modification effects of nanosilica on asphalt binders: A review
  133. Decellularized extracellular matrix as a promising biomaterial for musculoskeletal tissue regeneration
  134. Review of the sol–gel method in preparing nano TiO2 for advanced oxidation process
  135. Micro/nano manufacturing aircraft surface with anti-icing and deicing performances: An overview
  136. Cell type-targeting nanoparticles in treating central nervous system diseases: Challenges and hopes
  137. An overview of hydrogen production from Al-based materials
  138. A review of application, modification, and prospect of melamine foam
  139. A review of the performance of fibre-reinforced composite laminates with carbon nanotubes
  140. Research on AFM tip-related nanofabrication of two-dimensional materials
  141. Advances in phase change building materials: An overview
  142. Development of graphene and graphene quantum dots toward biomedical engineering applications: A review
  143. Nanoremediation approaches for the mitigation of heavy metal contamination in vegetables: An overview
  144. Photodynamic therapy empowered by nanotechnology for oral and dental science: Progress and perspectives
  145. Biosynthesis of metal nanoparticles: Bioreduction and biomineralization
  146. Current diagnostic and therapeutic approaches for severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) and the role of nanomaterial-based theragnosis in combating the pandemic
  147. Application of two-dimensional black phosphorus material in wound healing
  148. Special Issue on Advanced Nanomaterials and Composites for Energy Conversion and Storage - Part I
  149. Helical fluorinated carbon nanotubes/iron(iii) fluoride hybrid with multilevel transportation channels and rich active sites for lithium/fluorinated carbon primary battery
  150. The progress of cathode materials in aqueous zinc-ion batteries
  151. Special Issue on Advanced Nanomaterials for Carbon Capture, Environment and Utilization for Energy Sustainability - Part I
  152. Effect of polypropylene fiber and nano-silica on the compressive strength and frost resistance of recycled brick aggregate concrete
  153. Mechanochemical design of nanomaterials for catalytic applications with a benign-by-design focus
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