BACKGROUND
The establishment and maintenance of pregnancy depend on endometrial competence. Asherman syndrome (AS) and intrauterine adhesions (IUA), or endometrial atrophy (EA) and thin endometrium (TE), can either originate autonomously or arise as a result from conditions (i.e. endometritis or congenital hypoplasia), or medical interventions (e.g. surgeries, hormonal therapies, uterine curettage or radiotherapy). Affected patients may present an altered or inadequate endometrial lining that hinders embryo implantation and increases the risk of poor pregnancy outcomes and miscarriage. In humans, AS/IUA and EA/TE are mainly treated with surgeries or pharmacotherapy, however the reported efficacy of these therapeutic approaches remains unclear. Thus, novel regenerative techniques utilizing stem cells, growth factors, or tissue engineering have emerged to improve reproductive outcomes.


OBJECTIVE AND RATIONALE
This review comprehensively summarizes the methodologies and outcomes of emerging biotechnologies (cellular, acellular, and bioengineering approaches) to treat human endometrial pathologies. Regenerative therapies derived from human tissues or blood which were studied in preclinical models (in vitro and in vivo) and clinical trials are discussed.


SEARCH METHODS
A systematic search of full-text articles available in PubMed and Embase was conducted to identify original peer-reviewed studies published in English between January 2000 and September 2023. The search terms included: human, uterus, endometrium, Asherman syndrome, intrauterine adhesions, endometrial atrophy, thin endometrium, endometritis, congenital hypoplasia, curettage, radiotherapy, regenerative therapy, bioengineering, stem cells, vesicles, platelet-rich plasma, biomaterials, microfluidic, bioprinting, organoids, hydrogel, scaffold, sheet, miRNA, sildenafil, nitroglycerine, aspirin, growth hormone, progesterone, and estrogen. Preclinical and clinical studies on cellular, acellular, and bioengineering strategies to repair or regenerate the human endometrium were included. Additional studies were identified through manual searches.


OUTCOMES
From a total of 4366 records identified, 164 studies (3.8%) were included for systematic review. Due to heterogeneity in the study design and measured outcome parameters in both preclinical and clinical studies, the findings were evaluated qualitatively and quantitatively without meta-analysis. Groups using stem cell-based treatments for endometrial pathologies commonly employed mesenchymal stem cells (MSCs) derived from the human bone marrow or umbilical cord. Alternatively, acellular therapies based on platelet-rich plasma (PRP) or extracellular vesicles are gaining popularity. These are accompanied by the emergence of bioengineering strategies based on extracellular matrix (ECM)-derived hydrogels or synthetic biosimilars that sustain local delivery of cells and growth factors, reporting promising results. Combined therapies that target multiple aspects of tissue repair and regeneration remain in preclinical testing but have shown translational value. This review highlights the myriad of therapeutic material sources, administration methods, and carriers that have been tested.


WIDER IMPLICATIONS
Therapies that promote endometrial proliferation, vascular development, and tissue repair may help restore endometrial function and, ultimately, fertility. Based on the existing evidence, cost, accessibility, and availability of the therapies, we propose the development of triple-hit regenerative strategies, potentially combining high-yield MSCs (e.g. from bone marrow or umbilical cord) with acellular treatments (PRP), possibly integrated in ECM hydrogels. Advances in biotechnologies together with insights from preclinical models will pave the way for developing personalized treatment regimens for patients with infertility-causing endometrial disorders such as AS/IUA, EA/TE, and endometritis.


REGISTRATION NUMBER
https://osf.io/th8yf/.

Evolution of biotechnological advances and regenerative therapies for endometrial disorders: a systematic review.


 Recombinant collagen is a pivotal topic in foundational biological research and epitomizes the application of critical bioengineering technologies. These technological advancements have profound implications across diverse areas such as regenerative medicine, organ replacement, tissue engineering, cosmetics, and more. Thus, recombinant collagen and its preparation methodologies rooted in genetically engineered cells mark pivotal milestones in medical product research. This article provides a comprehensive overview of the current genetic engineering technologies and methods used in the production of recombinant collagen, as well as the conventional production process and quality control detection methods for this material. Furthermore, the discussion extends to foresee the strides in physical transfection and magnetic control sorting studies, envisioning an enhanced preparation of recombinant collagen-seeded cells to further fuel recombinant collagen production.

Status and Developmental Trends in Recombinant Collagen Preparation Technology

Endometrial injury poses a significant challenge in tissue regeneration, with type III collagen (COL III) playing a pivotal role in maintaining endometrial integrity and facilitating repair. Our study explored the utility of recombinant human type III collagen (RHC) as an intervention for endometrial damage. To address the challenges associated with the inherent instability and rapid degradation of COL III in vivo, we developed an RHC-HA hydrogel by conjugating RHC with hyaluronic acid (HA), thus ensuring a more stable and sustained delivery. Our findings suggested that the RHC-HA hydrogel significantly promoted endometrial regeneration and restored fertility. The hydrogel facilitated prolonged retention of RHC in the uterus, leading to a substantial improvement in the repair process. The synergistic interaction between RHC and HA greatly enhances cell proliferation and adhesion, surpassing the efficacy of HA or RHC alone. Additionally, the RHC-HA hydrogel demonstrated notable anti-fibrotic effects, which are crucial for preventing abnormalities during endometrial healing. These findings suggested that the RHC-HA hydrogel presented a therapeutic strategy in the treatment of uterine endometrial injuries, which may improve female reproductive health. 

An endometrial biomimetic extracellular matrix (ECM) for enhanced endometrial regeneration using hyaluronic acid hydrogel containing recombinant human type III collagen.

The skin, being the body's primary defense mechanism, is susceptible to various injuries such as epidermal wounds, natural aging, and ultraviolet-induced damage. As a result, there is growing interest in researching skin repair methods. Traditional animal-derived collagen, widely available on the market, poses risks due to its immunogenicity and potential for viral contamination. In contrast, recombinant collagen sourced from human genes offers a safer alternative. To investigate the potential of human recombinant collagen in skin repair, our research team applied two types, type I human collagen (Col I) and CF-1552(I), to two different skin injury models: a wound-healing model and a photo-aging model. Our findings indicate that both Col I and CF-1552(I) effectively enhance wound healing and repair skin damaged by ultraviolet exposure. Notably, CF-1552(I) showed effects comparable to Col I in promoting cell proliferation in the wound-healing model and increasing malondialdehyde content in the photo-aging model, suggesting that CF-1552(I) may offer greater potential for skin repair compared to the larger Col I molecule. 

Recombinant collagen for the repair of skin wounds and photo-aging damage


 Recombinant humanized collagen was an extracellular matrix (ECM)-inspired biomimetic biomaterial and prepared by biosynthesis technology, which was considered as non-allergenic and could possibly activate tissue regeneration. The influence of tag sequence on both structures and performances of recombinant humanized collagen type III (rhCol III) was investigated, and the effect of rhCol III on cell behaviors was evaluated and discussed using Schwann cells (SCs) as in vitro model which was critical in the repair process after peripheral nerve injury. The results demonstrated the introduction of tag sequence would influence both advanced structures and properties of rhCol III, while rhCol III regulated SCs adhesion, spreading, migration and proliferation. Also, both nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) increased when exposed to rhCol III. As the downstream proteins of integrin-mediated cell adhesions, phosphorylation of focal adhesion kinase (FAK) and expression of vinculin was up-regulated along with the promotion of SCs adhesion and migration. The current findings contributed to a better knowledge of the interactions between rhCol III and SCs, and further offered a theoretical and experimental foundation for the development of rhCol III based medical devices and clinical management of peripheral nerve injury.

The influence of tag-sequence on recombinant humanized collagen (rhCol) and the evaluation of rhCol on schwann cell behaviors

Abstract Recently, evidence has suggested that chronic endometritis (CE) is a crucial factor associated with infertility and failure of assisted reproductive techniques, prompting concern in the reproductive field. Studies have shown that persistent infiltered immune cells stimulation result in the disturbance of endometrial immune microenvironment could lead to the infertility of CE patients finally. Conventional treatments are limited because they lack immune regulation, so it is urgent to develop a novel approach to treat CE and promote embryo implantation in patients with CE. Herein, we prepared recombinant humanized type III collagen (rhCol III) with high cell adhesion activity to regulate macrophages and repair the endometrium. In this study, M1 macrophages and M1 macrophages cultured medium and lipopolysaccharide (LPS) co-stimulated inflammatory endometrium stromal cells (ESCs) were established in vitro to mimic CE condition. rhCol III promoted M1 macrophages toward M2 phenotype, improved cell migration, viability and collagen components of inflammatory ESCs. Also, the inflammatory response of inflammatory ESCs was downregulated after rhCol III treatment. Subsequently, LPS was used for CE rat model and a 28-day observation was performed; inflammatory cells’ infiltration, endometrium repair, extracellular matrix (ECM) remodeling and pregnancy outcomes were promoted after rhCol III endometrial infusion. In conclusion, rhCol III promoted (i) macrophage polarization toward M2 macrophages, (ii) pro-inflammatory cytokine production and anti-inflammatory cytokine reduction, (iii) ECM remodeling and (iv) fertility restoration. Meanwhile, rhCol III enhanced cell biological functions by interacting with discoidin domain receptors, regulated cell metabolism and reduced the inflammatory response through the inhibition of the NF-κB/YAP signaling pathway. Overall, the results illustrated the potential therapeutic prospects of rhCol III for CE treatment.

/pdf/recombinant-humanized-collagen-remodels-endometrial-immune-2gtm3qt0.pdf

Recombinant humanized collagen remodels endometrial immune microenvironment of chronic endometritis through macrophage immunomodulation

Aim: To evaluate the protective effect of axillary channel-assisted (ACA) transoral endoscopic thyroidectomy vestibular approach on mental nerve. Materials and Methods: From August 2018 to December 2020, 126 cases of thyroid micro-carcinoma patients who underwent endoscopic thyroidectomy were recruited retrospectively. Of those, 74 cases were performed with ACA trans-oral endoscopic thyroidectomy vestibular approach (ACA_TOETVA) (V and A group), 52 cases received standard TOETVA (V group). On postoperative day 1 (POD1), nylon monofilament test and numbness visual analogue scale score were conducted to evaluate the severity of numbness within the mental area, facial expression was tested to determine the motor function of lower mandible and the thickness of cutaneous and subcutaneous layers was measured with ultrasound. The other observation parameters including the time for operation and intraoperative blood loss were carefully collected. Results: On POD1, nylon monofilament test showed that scores in the V and A group (2.9 ± 0.3) were significantly higher than V group (1.7 ± 0.5), P < 0.01, u = 254. The completion percentage of facial expression in the V and A group was 90.5% (67/74) and significantly higher than in V group (21.2%, 11/52), P < 0.01, χ2 = 62.35. The thickness increment of cutaneous and subcutaneous layer was 2.2 ± 1.2 mm in the V and A group, which was significantly less than in the V group (4.0 ± 1.2 mm), P < 0.01, u = 605. Compared with V group, the operation time (113.4 ± 22.3 min vs. 127.7 ± 25.6 min, u = 1262) and intraoperative blood loss (43.5 ± 13.4 ml vs. 51.0 ± 14.1 ml, u = 1355) were also significantly less in the V and A group. Conclusions: The ACA transoral endoscopic thyroidectomy possesses the protective effect on mental nerve and motor function of lower mandible and facilitates the operative procedures of TOETVA.

Axillary channel-assisted TOETVA: An effective way to prevent mental nerve from iatrogenic injury?

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Recombinant humanized collagen remodels endometrial immune microenvironment of chronic endometritis through macrophage immunomodulation

Axillary channel-assisted TOETVA: An effective way to prevent mental nerve from iatrogenic injury?

Axillary channel-assisted TOETVA: An effective way to prevent mental nerve from iatrogenic injury?