Biomaterials for fetal membrane repair in preterm premature rupture of membranes: advances in tissue engineering strategies

Abstract

Preterm premature rupture of membranes (PPROM) remains a leading cause of spontaneous preterm birth and neonatal morbidity, yet current clinical management strategies are limited. The fetal membranes, composed of the amnion and chorion, possess limited regenerative capacity once ruptured. Recent advances in biomaterials and tissue engineering have introduced promising therapeutic platforms capable of sealing membrane defects and promoting biological healing. These approaches offer significant advantages over traditional methods by providing dynamic, customizable, and biologically integrated solutions that better mimic the native extracellular matrix (ECM) and enhance tissue regeneration. This review summarizes biomaterial-based strategies, including collagen-based and natural ECM-derived materials, growth factor and drug delivery platforms, bioadhesives, membrane patch systems, and 3D bioprinting and in situ biofabrication. These materials are increasingly engineered to mimic native extracellular matrix properties, support cell migration, modulate local inflammation, and conform to the dynamic intrauterine environment. Preclinical studies in small and large animal models have demonstrated the feasibility of these systems in achieving defect closure, reducing inflammation, and prolonging gestation. Despite encouraging results, challenges remain related to biocompatibility, degradation kinetics, intrauterine delivery, and regulatory approval. This review underscores the potential of biomaterial strategies to transform the management of PPROM and outlines future directions for translating these technologies into clinical practice.

Impact statement

Preterm premature rupture of membranes (PPROM) represents a major unsolved clinical challenge with significant implications for neonatal morbidity and mortality. Current management strategies remain palliative, lacking effective means to restore the physical integrity of fetal membranes. This review provides a comprehensive synthesis of emerging biomaterial-based strategies for fetal membrane sealing and regeneration, including collagen scaffolds, injectable hydrogels, bioadhesives, drug delivery systems, and in situ bioprinting technologies. The review offers a timely and authoritative perspective on a rapidly evolving field with the potential to transform fetal surgery and preterm birth prevention.

Introduction

Preterm premature rupture of membranes (PPROM) refers to the spontaneous rupture of fetal membranes before 37 weeks of gestation and prior to the onset of labor [1]. PPROM complicates approximately 2–4% of pregnancies and accounts for up to 40% of preterm births. PPROM is associated with significant perinatal morbidity and mortality, primarily due to risks of ascending infection, umbilical cord compression, and preterm delivery [2]. Current clinical management largely relies on antibiotics, corticosteroids, and hospitalization to prolong latency and reduce infection risk [3–5]. However, the physical rupture of the fetal membranes as the core issue has not been addressed, lack of capacity for actual tissue repair or restoration of membrane integrity [6]. Fetal membranes, comprising the amnion and chorion, function as a critical barrier to mechanical stress and microbial invasion [7, 8]. Once ruptured, these tissues have limited regenerative capacity, particularly in the late second and third trimesters [9]. This underscores a compelling unmet need for innovative therapeutic strategies capable of sealing the defect, restoring tensile integrity, and promoting regenerative healing in a biologically compatible and minimally invasive manner [10]. In this context, tissue engineering approaches have emerged as promising alternatives. Recent advances have demonstrated that injectable hydrogels such as hyaluronic acid-based hydrogels (with degradation times ranging from 2 to 4 weeks) can successfully promote tissue regeneration in fetal membrane defects. Additionally, bioadhesives based on gelatin methacryloyl (GelMA) have shown significant improvement in adhesion strength under simulated intrauterine conditions, with reported bonding strengths of up to 150 kPa. Composite patches, such as collagen-chitosan composites, have also been developed, showing promising in vivo results with enhanced cellular infiltration and tensile strength recovery. Furthermore, drug delivery systems incorporating growth factors like TGF-β have been shown to enhance cellular migration and ECM remodeling, further facilitating membrane healing. These biomaterials are increasingly engineered to mimic the extracellular matrix (ECM), support cell attachment and migration, modulate inflammation, and ultimately facilitate functional membrane repair. Moreover, preclinical studies in small and large animal models have begun to validate their feasibility and translational potential. This review aims to provide a comprehensive overview of current biomaterial-based strategies for fetal membrane repair in the setting of PPROM, with an emphasis on design principles, material classes, functional outcomes, and future directions within the field of tissue engineering (Fig. 1).

Fig. 1.

Biomaterials for fetal membrane repair in preterm premature rupture of membranes

Structure and pathophysiology of the fetal membranes

The fetal membranes, comprising the amnion and chorion, play a pivotal role in maintaining pregnancy by providing mechanical protection, immunological defense, and biochemical signaling at the maternal-fetal interface (Fig. 2) [11]. Structurally, the amnion is a thin and avascular layer, which is composed of a single layer of epithelial cells, a basement membrane, and a compact collagen-rich extracellular matrix (ECM) [12, 13]. Fetal membranes exhibit remarkable tensile strength and elasticity, attributed to its organized collagen fibrils and high content of elastin and fibronectin [14]. Fetal membranes are functionally dynamic throughout gestation, responding to mechanical stress, hormonal signals, and microbial threats [15]. However, their structural integrity becomes increasingly vulnerable in the second and third trimesters due to progressive remodeling, oxidative stress, and senescence. Mechanical stretching from uterine distension and fetal movements contributes to cellular and matrix microfractures, while inflammatory mediators such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and prostaglandins amplify tissue degradation [16, 17]. These factors stimulate matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, which degrade collagen and weaken the ECM scaffold. Infections can further disrupt membrane integrity [18]. For example, ascending pathogens such as Ureaplasma urealyticum or Gardnerella vaginalis activate toll-like receptor (TLR) pathways and elicit neutrophilic infiltration, contributing to chorioamnionitis and premature rupture [19, 20]. Oxidative stress and mitochondrial dysfunction, often secondary to hypoxia or inflammation, impair epithelial cell viability and promote apoptotic signaling, compromising the amniotic barrier [21]. The fetal membranes possess limited innate repair capacity, mediated by resident stem-like cells and paracrine signaling [22]. However, the regenerative ability is often insufficient to restore membrane continuity once a rupture occurs [23]. Importantly, spontaneous healing of PPROM is rare and unpredictable, particularly in the absence of a protective matrix scaffold [24]. These insights highlight the need for external interventions that can provide mechanical sealing, support cellular regeneration, and modulate the pathological microenvironment to promote effective healing [25].

Fig. 2.

Schematic of the fetal membrane showing its layers, cell types, mechanical properties, and rupture-prone sites

Tissue engineering for fetal membrane repair

Given the limited intrinsic regenerative capacity of the fetal membranes and the high clinical stakes associated with PPROM, the development of biomaterial-based strategies for membrane sealing and repair has garnered increasing attention [26]. Over the past three decades, experimental techniques such as amniotic membrane patches, collagen plugs, gelatin sponges, fibrin sealants, mussel-inspired adhesives, laser welding, and polymeric films have been developed and tested in both in vitro and in vivo models [27]. The clinical rationale for these strategies is multifactorial [28]. First, restoring and maintaining adequate amniotic fluid volume is essential to prevent complications such as pulmonary hypoplasia and limb contractures, which are commonly associated with oligohydramnios. Second, sealing the rupture site helps to reduce the risk of ascending intrauterine infection, thereby lowering the incidence of chorioamnionitis, maternal sepsis, and neonatal morbidity. Finally, by reinforcing the integrity of the fetal membranes, these interventions aim to prolong gestation and improve both fetal and maternal outcomes by delaying preterm labor. While several of these approaches have shown promise in preclinical and early clinical studies, their effectiveness remains variable, and challenges related to biocompatibility, inflammation, and in utero application still hinder widespread clinical translation [29]. Many existing biomaterial systems rely primarily on mechanical occlusion, but their clinical effectiveness is also influenced by key material properties such as bioadhesiveness, swelling behavior, degradability, and resistance to uterine shear forces. A representative example is the fetoscopically deliverable sealing device developed by Devaud et al., which consists of an umbrella-shaped nitinol mesh coated with a polyester film and bioinspired mussel-derived fibrin adhesive [30]. This composite system was designed for minimally invasive application to cover fetal membrane defects, representing an early but promising direction toward functional and translational repair technologies.

Biomaterial-based strategies for fetal membrane sealing and regeneration

Recent advancements in biomaterials have enabled the development of innovative therapeutic platforms to address the multifaceted challenges of fetal membrane repair in PPROM [31]. These strategies aim not only to provide mechanical sealing of the rupture site but also to foster a regenerative microenvironment that promotes cell recruitment, modulates inflammation, and facilitates tissue integration. The recent biomaterial-based strategies for fetal membrane sealing and regeneration are listed in Table 1, and a comparative table summarizing the quantitative performance metrics of various biomaterial strategies for fetal membrane repair in PPROM was shown in Table 2.

Table 1.

Biomaterial-based strategies for fetal membrane sealing and regeneration

Author	Year	Material type	Design features	Sealing mechanism	Delivery method	In vivo model	Highlights	Reference
Meuwese et al.	2023	Collagen plug with shape memory	Expands upon hydration; minimally invasive delivery	Physical expansion	Fetoscopic (via 3 mm cannula)	Ex vivo human FM and porcine bladder	Rapid expansion and sealing	[33]
Alessandrino et al.	2019	Three-layer silk fibroin scaffold	Multi-layer mimicking vessel walls	Endothelialization support	Surgical implantation	Vascular graft in rats	Mechanical strength; possible FM application	[36]
Avilla-Royo et al.	2022	PEG-based hydrogel with amnion cells	Tailored hydrogel for ECM deposition	Cell-mediated ECM formation	In vitro application	Ex vivo culture	Regenerative tissue modeling	[37]
Famos et al.	2022	Hydrogel-based micro model	Miniaturized 3D FM healing model	Cell migration and healing simulation	In vitro lab model	None	High-throughput material testing	[38]
Avilla-Royo et al.	2023	Mussel-inspired bioadhesive	Wet adhesion and rapid gelation	Catechol adhesion chemistry	Fetoscopic	Ovine FM defect model	Strong adhesion in wet tissue	[40]
Devaud et al.	2021	Bioadhesives (e.g., Glubran2)	Catheter-based precise application	Adhesive bonding	Fetoscopic (10 F trocar)	Pregnant sheep	Precise, reproducible sealing	[41]
Devaud et al.	2022	Cyanoacrylate-based patch	Mechanical support with glue	Patch + adhesive synergy	Minimally invasive	Ovine FM	Sustained long-term sealing	[44]
Zhao et al.	2022	Photoresponsive hydrogel	7-axis robotic bioprinting	In situ rapid bioprinting	Robot-assisted MIS	Ex vivo fetal membrane model	High precision, remote surgery-ready	[48]

Table 2.

The quantitative performance metrics of various biomaterial strategies for fetal membrane repair in PPROM

Biomaterial strategy	Defect closure rate (%)	Inflammation reduction	Gestational duration prolongation (Days)	Cell migration and ECM remodeling	Reference
Collagen-based Materials	90%	Reduced IL-6 and TNF-α by 30–50%	Prolonged by 5–10 days	Enhanced amnion mesenchymal cell migration and ECM remodeling observed; collagen gel entraps M2 macrophages, promoting healing.	[56]
Natural ECM-derived Materials	70–85%	Decreased pro-inflammatory cytokines by 25–40%	Prolonged by 4–8 days	Improved fibroblast migration and collagen deposition in vivo; supports epithelial-mesenchymal transition (EMT).	[24]
Growth Factor and Drug Delivery Platforms	75–90%	Reduced IL-6 and TNF-α by 35–55%	Prolonged by 6–12 days	Increased cell proliferation and ECM deposition; PDGF-BB-loaded hydrogels promote host cell recruitment and matrix production.	[10]
Bioadhesives	60–80%	Modulated cytokine response, decreased IL-6 by 20–40%	Prolonged by 3–7 days	Moderate cell migration; ECM remodeling at defect site; tissue glue-based sealing patch demonstrated watertight sealing in ovine model.	[39]

Collagen-based and natural ECM-derived materials

Collagen, the principal structural protein in the amniotic extracellular matrix (ECM), has been extensively investigated for fetal membrane repair due to its excellent biocompatibility, biodegradability, and ability to support cellular adhesion and proliferation [32]. Among the natural ECM-derived materials, type I collagen is particularly favored for its abundance and mechanical tunability. A notable example of collagen-based material application involves the development of a lyophilized type I collagen plug with shape memory properties, designed specifically for the repair of iatrogenic preterm premature rupture of membranes (iPPROM) following fetal surgery [33]. This plug is engineered to be fetoscopically applicable, with a crimped configuration that fits through a 3 mm cannula. Upon placement in physiological conditions, it rapidly expands tripling in diameter within one minute to seal the membrane defect. Ex vivo experiments using human fetal membranes and in situ evaluation in a porcine bladder model demonstrated that the plug could effectively seal defects without inducing further rupture, thereby preventing amniotic fluid leakage. These findings suggest that collagen-based plugs with responsive mechanical behavior hold significant promise as minimally invasive therapeutic devices for fetal membrane sealing. Beyond collagen, other naturally derived materials such as gelatin, fibrin, silk fibroin, and decellularized amniotic or dermal matrices have shown promise in fetal membrane repair [34]. Fibrin-based materials, in particular, have been evaluated as fetal sealants due to their inherent adhesive properties and rapid gelation. Silk fibroin, derived from silkworm cocoons, has also been investigated for its mechanical strength and biocompatibility [35]. Alessandrino et al. developed a three-layered silk fibroin tubular scaffold for vascular repair, demonstrating its potential applicability in fetal membrane repair due to its structural similarity and supportive properties [36]. Recent work has shown that human amnion-derived mesenchymal stromal cells (hAMCs) can deposit a wide array of native ECM proteins when cultured in defined 3D environments (Fig. 3) [37]. These findings emphasize the regenerative potential of amnion-derived cells and support the design of biomaterials that mimic native ECM composition for fetal membrane repair.

Fig. 3.

ECM characterization in TG-PEG hydrogels under PDGF-BB stimulation [37]. A) Protein interaction network of ECM proteins deposited by hAMCs. B) Confocal images of hAMCs and ECM deposition. C) Immunostaining of fibronectin, collagen I, laminin, and TGFβi in native amnion tissue.

(Adapted from Avilla-Royo E, Roschitzki B, Pfammatter S, et al. Amnion Cells in Tailored Hydrogels Deposit Human Amnion Native Extracellular Matrix. Advanced Functional Materials 2022;32(40):2204543)

Growth factor and drug delivery platforms

Localized delivery of pro-regenerative and anti-inflammatory molecules has the potential to shift the fetal membrane microenvironment toward healing while minimizing systemic exposure. Among the most widely studied growth factors is platelet-derived growth factor-BB (PDGF-BB), which plays a multifaceted role in fetal membrane regeneration. It enhances mesenchymal cell recruitment, angiogenesis, epithelial restitution, and modulation of local immune responses, all of which are essential processes in restoring membrane integrity. Delivery platforms range from microspheres and nanoparticles to hydrogel-based reservoirs and bioresponsive carriers. These systems enable controlled, sustained release that aligns with the biological timeline of tissue regeneration. Stimuli-responsive materials that respond to changes in pH or enzymatic activity are particularly promising for targeting inflamed or infected fetal membrane defects. A recent study developed miniaturized ex vivo models of human fetal membranes to evaluate healing dynamics after fetoscopic injury (Fig. 4) [38]. Using PDGF-BB-loaded biomaterials, researchers observed that while cell migration into the defect was limited, PDGF-BB significantly enhanced the migration of preterm amnion cells into the surrounding 3D biomaterial environment. These findings underscore the potential of growth factor delivery to promote endogenous cell recruitment and matrix interaction in fetal membrane repair, particularly when integrated into engineered scaffolds. Such approaches have shown favorable outcomes in preclinical studies, including enhanced re-epithelialization, reduced inflammatory cell infiltration, and prolonged latency periods following membrane rupture.

Fig. 4.

Ex vivo model of preterm amnion microtissue migration [38]. a) Schematic of 1-mm preterm amnion biopsies embedded in TG-PEG hydrogels ± PDGF-BB stimulation for 14 days. b) Confocal images showing enhanced cell migration under PDGF-BB stimulation. c) Quantification of migrated cells indicates increased migration with PDGF-BB. (Adapted from Famos F, Avilla-Royo E, Vonzun L, et al. Miniaturized Bioengineered Models for Preterm Fetal Membrane Healing. Fetal Diagnosis and Therapy 2022;49(5–6):235–244)

Bioadhesives

Bioadhesives are engineered to replicate or enhance the natural adhesion mechanisms of FM, providing strong, conformable bonding under wet, elastic, and mechanically dynamic conditions [39]. Their role is especially critical in fetoscopic procedures, where membrane punctures can precipitate amniotic fluid leakage and subsequent iatrogenic preterm premature rupture of membranes (iPPROM). To be clinically viable, bioadhesives must demonstrate rapid gelation, high tissue adhesion strength, biocompatibility, and minimal immunogenicity. A range of adhesive formulations has been explored for FM repair, including fibrin glue, chitosan-based adhesives, and mussel-inspired catechol-modified polymers. A representative example is the development of a mussel-inspired biomimetic glue (MG), engineered for application in an ovine model of iatrogenic fetal membrane (FM) defects (Fig. 5) [40]. In this study, MG was optimized for gelation kinetics compatible with fetoscopic surgery and delivered via polytetrafluoroethylene (PTFE)-coated nitinol umbrella-shaped devices to cover trocar-induced FM punctures. After in vivo implantation (N = 10), the MG-sealed sites showed 100% maternal survival and 91% fetal survival at day 10 post-surgery, with no observed amniotic fluid leakage and only mild histological tissue response. These findings suggest that MG is technically feasible, biocompatible, and effective in preventing membrane separation and iPPROM following fetal interventions. Further evidence supporting the use of tissue adhesives comes from a recent in vivo study evaluating cyanoacrylate-based glues (Histoacryl^® and Glubran2^®) used in combination with umbrella-shaped nitinol glue receptors [41]. Initially, adhesion strength was validated ex vivo on human fetal membranes using devices encapsulated in PTFE or silicone. The in vivo component involved intrauterine insertion of a 10-French trocar into pregnant sheep (N = 9), followed by deployment and fixation of the adhesive-loaded glue receptor onto the FM. Of the treated sites (n = 8), all demonstrated successful sealing, and only two showed minimal leakage at 4 h post-surgery, whereas the control site without adhesive showed significant leakage.

Fig. 5.

Sealing of fetal membrane (FM) defects in an ovine model using mussel-inspired glue (MG) [40]. a) Surgical exposure of fetal membranes via hysterotomy. b) Insertion of a catheter with tourniquet for glue application. c) Placement of MG against the amnion. d) Fixation of the umbrella-shaped receptor using sutures through the myometrium.

(Adapted from Avilla-Royo E, Seehusen F, Devaud YR, et al. In vivo Sealing of Fetoscopy-Induced Fetal Membrane Defects by Mussel Glue. Fetal Diagnosis and Therapy 2022;49(11–12):518–527)

Membrane patches

Membrane patch systems have been designed to mimic the layered architecture of the amnion and chorion, often incorporating both adhesive and mechanical support components [42]. These patches can be fabricated using electrospun fibers, hydrogels, or decellularized extracellular matrices, and are tailored to match the biomechanical properties of the surrounding fetal tissue [43]. Recent studies have demonstrated the feasibility of patch-based sealing in clinically relevant models. For example, cyanoacrylate-based sealing patches were tested in an ovine model of fetoscopy-induced fetal membrane (FM) defects, achieving robust attachment and watertight sealing (Fig. 6) [44]. At 10 days post-treatment, 100% of the patches remained attached, and more than 80% retained sealing capacity up to 24 days, despite partial detachment in CO₂ or saline-infused environments. Histological analyses revealed moderate immune responses and some epithelial disruption, but overall confirmed the sealing effectiveness of these minimally invasive implants. These findings highlight the promise of combining mechanical patch systems with bioadhesives for long-term defect closure. Integration with fetal surgery platforms, particularly fetoscopic guidance and minimally invasive delivery, is a key focus for translational application. These approaches aim to enable real-time, precise localization and deployment of patches or adhesives during intrauterine procedures, minimizing trauma to maternal and fetal tissues while restoring membrane integrity.

Fig. 6.

Minimally invasive sealing of fetal membrane (FM) defects using a cyanoacrylate-based patch [44]. a) Device for patch delivery. b–g) Stepwise deployment via fetoscopy, showing catheter insertion, receptor release, and defect sealing from external and internal views. h) Macroscopic image of uterine surface with visible implants (yellow asterisks). i) Ultrasound image showing implanted receptor (nitinol frame indicated by yellow arrows).

(Adapted from Devaud YR, Avilla-Royo E, Lionetti L, et al. Tissue Glue-Based Sealing Patch for the in vivo Prevention of Iatrogenic Prelabor Preterm Rupture of Fetal Membranes. Fetal Diagnosis and Therapy 2023;50(5):332–343)

3D bioprinting and in situ biofabrication

Three-dimensional (3D) bioprinting holds considerable potential for fabricating fetal membrane analogs with high spatial resolution and tissue specificity [45]. Bioinks composed of gelatin methacrylate (GelMA), hyaluronic acid derivatives, or decellularized ECM (dECM) enable the printing of scaffold structures that mimic the physical and biochemical features of native amnion [46]. In situ bioprinting, or direct deposition of bioinks onto the membrane defect under imaging or fetoscopic guidance, is being explored for personalized, defect-conforming repair [47]. Although still in the early stages, this approach may eventually enable point-of-care fabrication of membrane patches with integrated cells, growth factors, or bioactive cues. A recent study introduced a novel subaqueous bioprinting platform combining an ultrafast photoresponsive hydrogel (gelation within 1.5 s) with a 7-axis robotic system to enable minimally invasive in situ fabrication (Fig. 7) [48]. This system was used to print hydrogel patches with customized “gel rivets” designed to enhance adhesion and mechanical integration within the fluid-filled intrauterine environment. In both an in vitro uterine model and a mid-gestational rabbit model of PROM, the printed patch demonstrated strong tissue adherence, favorable biocompatibility, mechanical compatibility with native membranes, and an effective sealing duration sufficient to support gestational prolongation. These findings highlight the translational potential of subaqueous bioprinting for fetal membrane repair and pave the way for broader applications in intrauterine tissue regeneration. The major challenges include achieving adequate adhesion in a fluid-filled environment, ensuring sterility during intrauterine delivery, and developing compact, precise printing devices compatible with fetal surgery platforms.

Fig. 7.

Sealing evaluation of subaqueous bioprinting in a rabbit PROM model [48]. a) Schematic of the in vivo sealing procedure. b) Bioprinting of an I-shaped hydrogel patch at gestational day 22 and assessment at day 31. c) H&E staining of sealing sites versus control groups. d) Quantitative comparison of sealing effectiveness. e) Masson’s trichrome staining showing collagen capsule formation. f) H&E staining confirming hydrogel–tissue integration. g) Immunofluorescence staining (CD68, DAPI) indicating macrophage response. (Adapted from Zhao W, Hu C, Xu T, et al. Subaqueous Bioprinting: A Novel Strategy for Fetal Membrane Repair with 7-Axis Robot-Assisted Minimally Invasive Surgery. Advanced Functional Materials 2022;32(51):2207496)

Hydrogel systems

Hydrogels have emerged as highly versatile materials for fetal membrane repair due to their injectability, hydration capacity, and tunable mechanical and biochemical properties (Table 3) [49]. Shear-thinning hydrogels can be delivered through minimally invasive routes and rapidly recover their structure post-injection [50, 51]. Self-healing hydrogels further enhance the sealing effect by dynamically repairing minor disruptions over time [52, 53]. Functional hydrogels can be engineered to incorporate therapeutic agents such as anti-inflammatory drugs, antibiotics, or growth factors, enabling sustained release at the repair site [54]. Injectable collagen hydrogels have been developed to conform to irregular rupture sites, providing a bioactive matrix that promotes cell adhesion, proliferation, and matrix remodeling [55]. Mogami et al. demonstrated that injection of type I collagen gel into mechanically ruptured fetal membranes in a murine model significantly accelerated amnion healing, increasing closure rates from 40% to 90% within 72 hours [56]. The collagen gel formed a supportive matrix beneath the ruptured site, facilitating tissue regeneration. Other commonly used hydrogel platforms include polyethylene glycol (PEG), hyaluronic acid (HA), and alginate, each offering distinct advantages in terms of gelation kinetics, biocompatibility, and ECM mimicry [57, 58]. Ochsenbein-Kölble et al. evaluated injectable PEG-based hydrogels for fetal membrane repair [59]. They found that a mussel-mimetic PEG hydrogel effectively sealed iatrogenic membrane defects in an in vitro model, demonstrating efficient, nondisruptive, and nontoxic bonding to fetal membranes. More recently, Avilla-Royo et al. developed a modular transglutaminase-crosslinked PEG (TG-PEG) hydrogel loaded with platelet-derived growth factor-BB (PDGF-BB) to address fetoscopy-induced membrane defects (Fig. 8) [60]. TG-PEG hydrogels demonstrated excellent in vitro bioactivity, promoting amniotic cell proliferation and migration. When applied in vivo to seal fetoscopic defects in the fetal membrane and uterus, these hydrogels adhered tightly and remained stable for at least 10 days. Preclinical evidence suggests that these hydrogels can seal membrane defects, reduce inflammation, and support tissue integration. Moreover, responsive hydrogel systems such as temperature-sensitive or enzymatically degradable gels are under development to improve site-specific activation and degradation [61].

Table 3.

Hydrogel for fetal membrane sealing and regeneration

Study	Material type	Key features	Application to FM repair	In vivo model	Reference
Avilla-Royo et al., 2023	TG-PEG hydrogel releasing PDGF-BB	Bioactive, promotes FM healing, stable for 10 days	Sealing FM defects post-fetoscopy	Pregnant sheep model	[60]
Tsai et al., 2021	Nanocomposite double-network hydrogel	Shear-thinning, self-healing, injectable	Potential for FM repair	Ex vivo human FM model	[51]
Sakamoto et al., 2022	Supramolecular glycopeptide hydrogel	Shear-thinning, injectable, enzyme delivery	Potential for FM repair	/	[50]
Kaur et al., 2021	Chitosan/collagen hydrogel with SWCNTs	Enhanced mechanical strength, osteogenic properties	Potential for FM repair	/	[55]
He et al., 2019	Thermoresponsive hydrogel + growth factor nanoparticles	Injectable, angiogenic, supports cell proliferation	Indirect application to FM regeneration potential	Rat subcutaneous model	[61]

Fig. 8.

Structural and functional characterization of TG-PEG hydrogels for fetal membrane repair [60]. (A) SEM imaging of fetal membranes; (B) schematic of hydrogel crosslinking and cell encapsulation; (C) mechanical properties and (D) swelling behavior of soft and stiff hydrogels; (G–H) cytoskeletal staining and spheroid culture of hAMCs with or without PDGF-BB; (I) quantification of cell migration from spheroids; (J) side views of cell migration on hydrogel gradients; (K) invasion index across PDGF-BB concentrations; (L) proliferation of encapsulated hAMCs in response to PDGF-BB. (Adapted from Avilla-Royo E, Vonzun L, Seehusen F, et al. Engineered Platelet-Derived Growth Factor-Releasing Hydrogels Promote Fetal Membrane Healing In Vivo. Advanced Functional Materials 2023;33(9):2208910)

Challenges and future perspectives

Despite the promising advances in biomaterials for fetal membrane (FM) repair, several key challenges remain that limit their clinical translation. Foremost among these are concerns regarding safety, immunogenicity, and the long-term degradation profile of implanted materials [62]. Any biomaterial used in the intrauterine environment must be biocompatible, non-teratogenic, and fully resorbable or removable, with degradation products that do not elicit inflammatory or cytotoxic responses [63]. Standardization is another critical need. Current preclinical studies vary widely in their methods for assessing sealing efficacy, mechanical durability, and tissue integration. Establishing consensus on mechanical testing protocols will be essential for meaningful comparison between platforms and for meeting regulatory benchmarks [64]. Ethical and regulatory considerations also pose unique barriers. Interventions on the fetal membranes inherently involve two patients, mother and fetus, requiring strict safety thresholds and ethical oversight [65]. Patient-specific factors, such as maternal age, hormonal history, and the unique circumstances of pregnancy in transgender and nonbinary individuals, may significantly influence the choice and performance of biomaterials used for fetal membrane repair. These factors can have a direct impact on ECM quality, inflammation, and the regenerative capacity of the fetal membranes. Older maternal age has been associated with altered collagen synthesis, reduced ECM remodeling, and increased inflammation. In older individuals, the regenerative capacity of the fetal membranes may be diminished due to age-related changes in cellular function. Hormonal fluctuations during pregnancy significantly influence ECM composition and inflammatory responses. In patients with endocrine disorders or hormonal imbalances, the ability of the fetal membranes to repair and remodel effectively may be impaired, potentially altering the performance of biomaterial interventions, especially those that require optimal ECM integration or regulation of local inflammation. Hormone therapy may alter the inflammatory response, potentially requiring biomaterials that modulate inflammation more effectively. It is crucial to consider these factors when selecting biomaterials to ensure compatibility and optimal healing in this diverse patient group. The implications of these patient-specific factors suggest that a personalized approach to biomaterial selection may be necessary. Personalized biomaterial strategies could enhance the clinical translation of these technologies by ensuring better outcomes for individuals with diverse biological and hormonal profiles.

Common engineering failure modes, such as adhesion loss, cyclic loading tolerance, and degradation mismatch, must be addressed to improve the performance and clinical applicability of biomaterials for fetal membrane repair. Adhesion loss occurs when biomaterials fail to integrate properly with the surrounding tissue, leading to detachment or insufficient sealing at the defect site. To overcome this, future designs could incorporate bioadhesive materials with cell-adhesive peptides or integrin-binding ligands to promote stronger tissue interactions, along with surface modification techniquesto enhance adhesion. Cyclic loading tolerance is another challenge, as the fetal membrane is exposed to mechanical stress from uterine expansion and fetal movements. To improve this, reinforced composite materials with fibrous networks or nanomaterials like carbon nanotubes could enhance strength and flexibility, while self-healing materials could autonomously repair minor cracks. Controlled degradation is crucial for ensuring biomaterials degrade at a rate that matches tissue healing. Mismatch in degradation rates can result in either insufficient support or chronic inflammation. To address this, tailored polymer networks or biodegradable cross-linkers could be used to regulate degradation rates, with smart materials that respond to specific tissue cues to ensure synchronization with the natural healing process. Addressing these failure modes through innovative design solutions will enhance the durability, functionality, and clinical translation of biomaterials for fetal membrane repair, ensuring better outcomes for PPROM patients.

Future directions will focus on the development of multifunctional biomaterials capable of sensing the local microenvironment and responding to inflammation, infection, or mechanical stress [66]. Such systems may include responsive hydrogels, bioadhesives that adjust to shear or pH, or integrated platforms combining drug delivery, cell support, and mechanical sealing in a single construct [67]. From a manufacturing and delivery perspective, the clinical translation of these advanced biomaterials will require consideration of scalability, reproducibility, and cost-effectiveness. These materials can be produced in bulk, sterilized, and packaged for clinical use with fewer logistical challenges compared to more complex integrated platforms. In terms of delivery, minimally invasive methods, such as injectable hydrogels or bioadhesives, are the most feasible in the short term, as they can be administered via catheter-based systems or topical applications, offering precise and localized delivery to the fetal membrane defect site. The ease of delivery and controlled degradation of these materials also make them ideal candidates for clinical trials, as they can be adapted to match the rate of tissue healing. Successful translation will depend on the integration of biomaterial systems with minimally invasive fetal surgery platforms, particularly fetoscopy-compatible delivery devices [68]. Innovations in catheter-based application, flexible printing systems, or image-guided deployment tools will play a pivotal role in enabling precise and atraumatic intrauterine application of sealing materials [69]. Together, these challenges define a dynamic and multidisciplinary frontier at the intersection of biomaterials science, fetal surgery, and regenerative medicine [70]. Continued collaboration between engineers, clinicians, and regulatory experts will be essential to bring next-generation fetal membrane repair strategies into clinical practice.

Conclusion

PPROM continues to be a major contributor to preterm birth, neonatal morbidity, and mortality. The lack of effective clinical strategies to repair fetal membrane (FM) defects following spontaneous or iatrogenic rupture highlights the critical need for innovative, biomaterial-based interventions. Over the past decade, considerable advances have been made in the development and evaluation of bioengineered platforms, including hydrogels, bioadhesives, growth factor delivery systems, and 3D-printed scaffolds, which have shown promise in preclinical studies by promoting cellular migration, modulating inflammation, and sealing membrane defects. Emerging technologies such as in situ bioprinting and stimuli-responsive delivery systems offer exciting new possibilities for personalized, minimally invasive fetal therapy. Despite these advancements, several significant challenges remain in translating these biomaterials into clinical practice. Key issues include ensuring material safety, immunocompatibility, and long-term degradation profiles, as well as standardizing mechanical performance benchmarks for intrauterine conditions. Additionally, navigating the ethical and regulatory hurdles associated with fetal interventions presents further complexities. Ultimately, the clinical translation of biomaterial-based strategies offers a promising pathway for revolutionizing the management of PPROM, enhancing outcomes for both mothers and neonates.

Author contributions

LF: Methodology, Software, Writing- Original draft preparation; ZL: Data curation; XL: Visualization, YJ: Validation; HL: Conceptualization, Supervision, Writing- Reviewing and Editing.

Funding

This review was funded by Jilin University 2024 Bethune Project (2024B34) and the Natural Science Foundation of Jilin Province (YDZJ202501ZYTS003).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.