Abstract
Breast volume loss after cancer surgery severely affects patients’ physical and psychological well-being, while traditional reconstruction methods such as prosthetic implantation and autologous tissue transfer are limited by complications, donor-site morbidity, and poor long-term stability. To address these issues, this review summarizes recent advances in hydrogel-based 3D-printed scaffolds for breast reconstruction. The review focuses on the use of different 3D bioprinting techniques in scaffold manufacture and compares natural and synthetic hydrogels in terms of biocompatibility, mechanical properties, and biodegradability. It also involves core design principles for scaffolds to meet the unique anatomical and functional requirements of the breast, including tunable softness, promotion of vascularization, and tissue integration. Furthermore, recent applications of hydrogel-based 3D printing in adipose tissue regeneration and nipple–areola complex reconstruction are discussed in detail. The findings indicate that natural hydrogels provide advantages in cell viability and differentiation due to their biocompatibility, while synthetic hydrogels offer tunability and structural stability for long-term support. Combining the two materials can enhance reconstruction outcomes. It further addresses challenges and prospective directions in 3D printing hydrogels in breast reconstruction, paving the way for innovative research to material selection and printing strategies, enhancing patient care, and improving quality of life.
Introduction
Globally, breast cancer ranks as the most prevalent cancer affecting women.1,2 Current standardized treatment protocols for breast cancer treatment typically includes radiotherapy, chemoendocrine therapy, and surgical resection. 3 Surgical intervention is required in more than 90% of early-stage cases, 4 often resulting in a loss of breast volume. Since breasts are closely associated with feminine identity and body image, this loss can lead to profound psychological consequences, including sexual dysfunction, diminished self-esteem, and mental distress. 5
To address these challenges, plastic surgeons have developed various breast reconstruction methods. The most commonly used method is implantation, providing the benefit of reduced surgical trauma and a shorter recovery time. 6 However, complications such as contracture, 7 infection, 8 and implant rupture may occur over time. Furthermore, secondary procedures are frequently necessary to replace or revise the implants throughout a patient’s lifetime.
Autologous reconstruction offers an alternative for patients who prefer not to use implants, 8 as it demonstrates reduced immune response and lower risk of infection and deformity. However, the donor sites are limited, and there is a risk of short-term ischemic necrosis of the flap post-surgery. Another emerging technology is employing fat grafting to shape the breast contour. Fat grafting has attracted considerable attention due to its good biocompatibility and natural shaping ability, but it also has significant drawbacks. Specifically, the donor site is susceptible to bruising and swelling, 9 and the transplanted fat does not achieve complete viability. Typically, the absorption rate of transplanted fat ranges from 30% to 70% due to inadequate oxygen supply and low vascularization. 10
Given the limitations of conventional reconstruction techniques, there is a clear need to develop new and sustainable long-term solutions. Breast tissue engineering provides a promising approach dedicated to creating autologous, patient-specific constructs that accurately mimic the biophysical and biochemical characteristics of native breast tissue. The current standard strategy uses adipose tissue-derived stem cells (ADSCs) with a hydrogel-based scaffold used for breast tissue engineering. A major challenge in breast tissue engineering lies in choosing appropriate materials and processing methods for scaffold preparation that ensure ADSCs survival and development. Therefore, successful scaffold development requires materials that are both biocompatible and biodegradable. 11 The strategy concurrently allows to produce differently shaped and sized supports with a controlled microstructure. Recent studies have shown that hydrogels have garnered specific attention due to their versatility. The use of hydrogels as biomaterials in Three-Dimensional (3D) printing to create scaffolds shows great potential.
Traditional fabrication involves sanding and shearing existing materials to obtain the wanted structure and shape, but 3D printing works in the opposite direction. 12 The desired 3D model is pre-programed by computer software (i.e. CAD) and then printed layer by layer on a 3D printer to obtain the object, hence the term value-added costing.13,14 The most used techniques employed in three-dimensional printing include extrusion, ink-jet, and laser printing.
In breast reconstruction, selecting the appropriate ink is crucial for producing scaffolds with the desired mechanical strength. 15 Hydrogels have drawn considerable focus in breast tissue engineering because of their unique properties. Through careful material selection, researchers can control both the degradation rate and the mechanical strength. Natural hydrogels feature high biocompatibility, low immunogenicity, and softness, while synthetic hydrogels provide better control over material properties and display superior mechanical properties. Recently, the combined use of different types of hydrogels has been increasingly applied in breast tissue engineering. However, although previous reviews have involved breast tissue engineering, they approached the topic from different perspectives. Mayer et al. focused on the overall clinical applications of 3D printing and its practical surgical value, but providing only limited discussion of specific materials. Besides, Kiseleva et al. concentrated on disassemble and degradable 3D scaffolds, analyzing the degradation characteristics of various polymers and the role of modular structures in tissue regeneration, with particular emphasis on the balance between mechanical performance and degradation kinetics. However, these reviews did not provide a comparison of hydrogels, which represent one of the most promising material classes for breast regeneration.
By adopting a material-oriented perspective, this review not only fills the gap left by previous works but also offers researchers structured guidance for material selection and printing strategies, while providing clinicians with new insights into personalized, functional, and durable breast reconstruction.
Figure 1 illustrates the overall framework of hydrogel applications in breast tissue engineering. This review summarizes the application progress of natural and synthetic hydrogels in different 3D printing methods, combining the anatomical features of the breast with the design requirements of scaffolds. It also evaluates their advantages and limitations in breast and nipple reconstruction, aiming to provide a reference for subsequent research and clinical translation.
Overview of 3D printing-based hydrogels customized by various 3D printing techniques in breast reconstruction. The figure illustrates key material characteristics of hydrogels, including biocompatibility, flexibility, and extracellular matrix (ECM) mimicking capability, and biofunctional features. Major 3D printing technologies include inkjet printing, extrusion-based printing, laser-assisted printing, and stereolithography.
The uniqueness of breast tissue and its impact on breast tissue engineering
Breast tissue has unique anatomical characteristics that distinguish it from other soft tissues and influence scaffold design. To illustrate its relevance for breast tissue engineering, this section is divided into two parts (Figure 2). First, we explain the anatomical composition of breast tissue, including adipose, glandular, stromal, and vascular components. Second, we analyze the specific effects of these features for scaffold construction, focusing on requirements for extracellular matrix mimicry, adipogenesis, and vascularization.
Overview of the uniqueness of breast tissue and its impact on breast tissue engineering. The diagram summarizes the major components of breast tissue, including glandular tissue, ducts, adipose tissue, and fibrous tissue, and their influence on scaffold design. These features dictate key scaffold requirements, including support for adipose tissue growth and vascularization, appropriate mechanical properties matching soft tissue, and biodegradable, biocompatible materials.
Anatomy
The breasts of adult women are two hemispherical organs located on the superficial surface of the pectoralis major muscle.16,17 The breast is characterized by a complex anatomical structure, primarily composed of glandular tissue, ducts, adipose tissue, and fibrous tissue. Breast glandular tissue (BGT) is enclosed within a delicate three-dimensional superficial system positioned anterior to the chest wall musculature. The mammary gland consists of a heterogeneous cellular ecosystem, including epithelial cells, adipocytes, fibroblasts, vascular cells, immune cells, nerves in the gland surface, and bipotent mammary stem cells (MaSCs). 18
Scaffold requirements
The unique anatomical structure of the breast leads to distinctive physical, mechanical, and biological properties, which increase the complexity of breast restoration and poses considerable challenges for the development of 3d-printed breast scaffolds. In breast tissue engineering, the primary function of the scaffold is to support adipose cells structurally, promote vascularization, and be progressively assimilated into the host tissue. 19 To meet the demands of breast reconstruction, biological scaffolds must satisfy several key requirements.
Support for adipose growth
The human breast mainly consists of adipose tissue, 20 with adipocytes comprising 90% of its volume, but the cellular contents make up less than 50%. 21 Based on this tissue composition, adipose tissue engineering and transplantation serve as essential approaches for breast tissue repair, providing the necessary environment for adipocyte survival and proliferation. 22 Ni et al. demonstrated an inductive method by using a double-layer microtissue comprising ADSCs and human umbilical vein endothelial cells (HUVECs). 23 In contrast to grafts based on single microtissues, this method significantly promotes the regeneration of adipose tissue and the vascularization process, enabling the construction of large tissue structures through the assembly of microtissues. Moreover, considering that adipose cells are highly sensitive to oxygen supply, the enhanced vascularization facilitated by this method is crucial for ensuring an adequate oxygen supply to the adipose tissue during the regeneration process. Without sufficient vascular support, transplanted fat tissue is prone to necrosis. To address this challenge, biological scaffolds must possess sufficient porosity to facilitate blood vessel ingrowth and nutrient exchange. Morrison et al. introduced techniques for addressing the challenges of angiogenesis and tissue regeneration using a tissue-engineered chamber model. 24 These methods create an environment that promotes vascular formation and supports adipose tissue growth. Incorporating angiogenic factors such as vascular endothelial growth factor (VEGF) can also accelerate angiogenesis within 3D-printed scaffolds. This increased neovascularization, in turn, enhances the supply of nutrients and oxygen to the adipocytes, thereby increasing adipocyte viability.25–27
Appropriate mechanical properties
Beyond vascular requirements, scaffolds must also match the mechanical properties of breast tissue. Breast tissue is soft with a Young’s modulus typically ranging from 0.5 to 5 kPa.28,29 Biological scaffolds should exhibit mechanical strength similar to natural breast tissue—neither too rigid to compromise the natural feel nor too weak to collapse.30,31 This is particularly important in large-volume fat grafting, such as after unilateral mastectomy for breast cancer, where a scaffold must provide adequate structural support to prevent fat resorption and deformation. For example, Rossi et al. fabricated an RGD-mimetic poly(amidoamine) oligomer macroporous foam (OPAAF) to facilitate adipose tissue regeneration. 32 They employed the gas foaming method to modulate the Young’s modulus of Poly(amidoamine) oligomer (OPAA) hydrogels that had been previously characterized.33–35 As a result, this strategy enables precise mechanical customization of pre-characterized hydrogels. In a different approach, Kracoff-Sella et al. developed a rational design approach based on structural mechanics analysis, optimizing the scaffold structure (SHAD scaffold) through analytical modeling and finite element analysis. 36 This approach allows the scaffold to maintain high porosity while achieving stiffness like that of breast adipose tissue, solving the problem of previous scaffolds being too rigid.
Biodegradable and biocompatibility
An ideal scaffold material should be biodegradable, with a degradation rate that matches the growth of newly formed adipose tissue, so that the scaffold is completely replaced by regenerated tissue over time. At the same time, the scaffold material must have low immunogenicity and excellent biocompatibility, avoiding immune rejection and preventing the formation of cytotoxic byproducts. 37 Common biodegradable polymeric materials used in breast scaffolds include Polyglycolic Acid (PGA) and Poly trimethylene carbonate (PTMC).
However, mechanical support alone is insufficient for successful reconstruction. Breast reconstruction requires not only structural support but also biochemical cues to promote cell adhesion and expansion. 38 Hydrogels, with their excellent biocompatibility and tunable physical characteristics, are considered ideal materials for breast reconstruction scaffolds. 39 For instance, alginate-gelatin hydrogels possess the capability to encapsulate adipose cells and continuously release growth factors when degrading. These growth factors play n important role in facilitating volume recovery of breast. 40
3D printing
3D printing provides precise control over scaffold geometry and structure. To clarify its role, this section is divided into two parts. First, we introduced the overall concept of 3D printing technology. The section provides a detailed introduction to the commonly used 3D printing techniques in breast tissue engineering—ink-jet printing, extrusion printing, laser-assisted printing, and stereolithography—offering a comprehensive description and comparison of their printing methods, bioinks, and their advantages and disadvantages in breast applications.
General introduction to 3D printing
Three-dimensional printing, also known as additive manufacturing (AM), is typified by the construction of three-dimensional objects through layer-by-layer accumulation. 41 The construction of 3D architecture follows specific dimensional or spatial proportions to accurately reconstruct the structure of organs and tissues. Nowadays, 3D printing is commonly used for the construction of bone, cartilage, cornea, muscle, and blood vessels. The 3D printing process includes data acquisition, 3D modeling, ink selection, and post-printing procedures. In breast tissue engineering, different kinds of bioinks are used in different 3D printed methods, including ink-jet printing, extrusion printing, laser-assisted printing, and stereolithography42,43 (Figure 3). Each method is suitable for fabricating different structures, and the selection of parameters and inks during printing directly impacts the outcome. The following discussion will focus on these specific printing methods. Table 1 provides a simple comparison of different bioprinting techniques. The following sections provide a detailed analysis based on their advantages, disadvantages and materials used in printing processes.
Different techniques of 3D bioprinting: (a) ink-jet printing, (b) extrusion printing, (c) laser-assisted printing, and (d) stereolithography. Figure from Yu et al. 60 under the terms of the Creative Commons Attribution International License (CC BY 4.0).
Summary of four main 3D-printing technique.
Classification of 3D printing
Ink-jet printing
Ink-jet printing, also referred to as on-demand printing or matter-jet 3D printing, is one of the pioneering techniques developed for the printing of both biological and abiotic materials. It utilizes piezoelectric or thermal-driven nozzles to dispense bioink in a series of microdroplets, 45 as shown in Figure 3. This layer-by-layer printing creates the formation of three-dimensional structures that are filled with cells. Ink-jet printing boasts high cell viability (>85%), high precision, and low cost. 46 However, due to the limited driving pressure from the nozzle and discontinuous deposition pattern, it is not feasible to print high-viscosity materials and high-concentration bioinks. 47
In breast tissue engineering, inkjet technology can generate models with complex internal structures, which helps simulate the precise location of breast tumors in relation to surrounding tissues. Inkjet bioprinting also shows promise for repairing skin lesions following breast radiotherapy by applying cell-filled bioink droplets to damaged areas.
Extrusion-based printing
Extrusion-based printing is one of the most widely used biological 3D printing techniques, developed from ink-jet printing technology to handle high-viscosity biomaterials. 48 Extrusion-based printing includes fused deposition modeling (FDM) with material melting. 49 This technology uses pneumatic pressure or mechanical drives to controllably extrude bioink, as illustrated in Figure 3. During extrusion printing, continuous extrusion force produces unbroken fibers rather than separate microdroplets. This forming method allows for using bioinks with varying viscosities and different cell concentrations. 50 Extrusion-based printing also achieves fast printing speeds and easy modification of printouts due to the lack of a need for new 3D printed models. Nonetheless, the drawbacks of this method encompass limited resolution, possible blockages in the nozzle, and cell apoptosis within the nozzle, primarily caused by the pressure applied inside. Also, as the printed filament ages, the physical stability of the printed structure changes, causing hydrogel deformations and altered mechanical properties.
Studies show that by incorporating fibroblast growth factors and various cells into these 3D structures, researchers can create vascular-like adipose tissue that remains stable for over 60 days. This extrusion 3D printing method helps restore the shape of the breast, which is of vital importance in breast reconstruction.
Laser direct writing
Laser direct writing was first used to manufacture metal templates for electronic components. In 2000, Odde and other researchers applied this technology to print live cells, leading to the development of laser direct writing bioprinting. 51 As illustrated in Figure 3, this type of 3D printing applies a laser-absorbing material to prevent direct contact between cells with the high-energy laser. Since laser-assisted bioprinting operates without the need for a nozzle, it eliminates direct physical contact between the bioink and the processing equipment. This non-contact manufacturing strategy avoids the risk of mechanical damage to the cells, maintaining high cell viability. This approach also facilitates the printing of biomaterials with high viscosity, and the spectrum of applicable materials is broader compared to ink-jet printing. Different material types can be used effectively, such as metals, ceramics, and most prominently, polymers. Polymers like polyethylene glycol (PEG), alginate, and Gelatin-methacryloyl (GelMA) are specifically employed to imitate the anatomical and mechanical features of natural organs and tissues. 52 Despite these advantages, laser direct writing remains limited by its high cost and the labor-intensive requirement of repeatedly applying biological ink to the laser-absorbing layer for each printing cycle.
Stereolithography
Like laser direct writing, stereolithography is also a light-based 3D printing model. 53 Similar to laser direct writing bioprinting, stereolithography also uses light to selectively cross-link bioinks, forming three-dimensional structures layer by layer. As illustrated in Figure 3. The photosensitive resin cured by ultraviolet light forms ultrathin layers, with the building plate beginning to shift by a value corresponding to the predetermined layer thickness. This process is repeated until the entire object is completed. The stereolithography printing employs a digital light projector to cure the bioink over its entire surface, which enhances printing efficiency and achieves high printing accuracy (up to 6 µm). The printer only necessitates a vertical mobility platform, making the apparatus easier to control. However, a major drawback is that the exposure to ultraviolet light and the compression effect can damage the cells, making it challenging to determine the balance between cellular activity and printing accuracy. Furthermore, the speed of this type of 3D printing is not rapid. In addition, the technique is relatively slow, cost-intensive, and restricted to light-curable hydrogel materials, which limits its broader application in tissue engineering.
Hydrogel
Hydrogels represent one of the most widely studied biomaterials in breast tissue engineering due to their unique features. To provide a comprehensive overview, this section is divided into two parts (Figure 4). First, we summarize the physicochemical properties of hydrogels and introduce their chemical bonds and physical structures. Second, we extend from these physicochemical features to explain why hydrogels are suitable for 3D-printed scaffolds.
The diagram links fundamental hydrogel properties, including hydrophilicity, water retention, three-dimensional network structure, and tunable mechanics, to functional characteristics required for breast reconstruction. These properties support microenvironment regulation, smart responsiveness, and adjustable scaffold design for tissue regeneration.
Fundamental physicochemical properties of hydrogels
As a class of highly hydrophilic biomaterials, hydrogels have drawn extensive interest for their ability to absorb and retain water up to 200%–300% of their own volume. 54 Even under extreme conditions, hydrogels can still maintain their shape and structural integrity. 55 This ability primarily stems from the abundant hydroxyl(-OH) groups present in their molecular structures. 56 These groups interact with water molecules, forming specific chemical bonds, which further enhance the stability of the hydrogel. This property not only imparts superior hydration capability to hydrogels but also allows them to create a microenvironment beneficial for cell growth and proliferation in biological settings, promoting tissue repair and regeneration.42,57
Hydrogels also have a three-dimensional network structure that can closely mimic the structural and functional characteristics of the natural extracellular matrix (ECM), fostering a favorable microenvironment for cellular adhesion, expansion, and specialization.58,59 Chemical modifications (e.g. PEGylation, RGD peptide modification) enhance their anti-inflammatory properties and cellular affinity of hydrogels. 60 The mechanical properties of hydrogels can also be controlled 61 ; by manipulating the extent of crosslinking, 62 molecular weight, and component ratio, their elasticity, strength, and degradation rate can be adjusted, helping them to better match different tissue environments.
Characteristics suitable for breast reconstruction
Improve the microenvironment
Building on these fundamental properties, hydrogels show great promise as a material for soft tissue replacement in breast reconstruction. First, hydrogels can replicate the softness and elasticity of natural breast tissue. By using 3D printing technology, hydrogels can be precisely customized to fit patient’s individual breast morphology and volume. 23 The internal structure of these hydrogels suitable for forming pores, which in turn promote cell growth and vascularization. For example, Puls et al. developed a regenerative tissue filling material for breast-conserving surgery (BCS), which promotes cellular infiltration, angiogenesis, and regeneration of breast tissue. 63 The substantial water content within hydrogels provides an ideal microenvironment that supports the viability and expansion of adipocytes. Since adipose tissue is highly sensitive to oxygen supply, the high porosity (over 80%) of hydrogels helps promote vascularization and nutrient exchange, further enhancing fat graft survival with angiogenic factors (e.g. VEGF). Beyond structural support, in post-mastectomy breast reconstruction, hydrogels can serve as both a filler and a therapeutic agent by modulating local immune responses and potentially reducing the risk of residual cancerous cells.
Smart responsive characteristics
Another important application of hydrogels is targeted drug delivery. Research demonstrates that when used as drug carriers, 3D-printed hydrogels can provide targeted delivery and sustained release, improving cancer treatment effectiveness. 64 For instance, ROS-responsive hydrogels embedded in 3D-printed scaffolds can release active substances in the tumor microenvironment, inducing ferroptosis to achieve an anti-cancer effect. The use of nanoparticle loading (such as liposomes or hydrogel nanoparticles) can further increase the drug encapsulation efficiency and prevent non-specific effects caused by drug diffusion, which offers another treatment option for breast cancer patients. 65
Hydrogels can also respond to both internal and external stimuli, allowing for the precise delivery of anti-cancer agents when triggered by corresponding signals within the tumor microenvironment.66,67 These signals include changes in pH, temperature, chemokines, and increased levels of reactive oxygen species (ROS). 68 By using these reactive behaviors, stimulus-responsive hydrogels enhance drug localization, minimize off-target effects, and improve therapeutic efficacy in cancer treatment.
Adjustability
In personalized breast reconstruction, the plasticity and adaptability of hydrogels make them an ideal choice. Combining 3D scanning and modeling technology with hydrogel printing allows personalized breast reconstruction that precisely matches the patient’s breast anatomy. Moreover, the mechanical properties of hydrogels are adjustable, and the rheological properties (such as shear-thinning behavior) allow the printed constructs to closely resemble the elasticity and softness of natural breast tissue. 52
In summary, hydrogels, with their outstanding biocompatibility, tunable mechanical properties, high water content, and smart responsive characteristics, exhibit significant potential in breast reconstruction. As smart biomaterials and 3D printing technologies continue to develop, the application of hydrogels in breast reconstruction are expected to become increasingly precise and efficient, ultimately providing higher-quality repair solution for breast cancer patients post-surgery.
Advanced 3D-printed scaffolds with enhanced performance for breast tissue engineering
In recent years, many researchers have combined 3D printing with hydrogels to generate different functional scaffolds to strive for better results (Figure 5). 69 First, we review the applications of natural hydrogels, which includes collagen, gelatin, and GelMA. Second, we examine synthetic and their composite hydrogel and show how material modifications and functionalization strategies expand their potential in breast reconstruction. This structure provides a connection from fundamental properties to clinical applications, with bioink composition, experimental validation, and translational value included.
Classification of advanced 3D-printed scaffolds for breast tissue engineering.
The figure summarizes the main scaffold types applied in breast reconstruction, including scaffold-guided breast reconstruction using natural hydrogels (gelatin, GelMA) and synthetic hydrogels (PCL, PEGDA, PLATMC, PLGA), as well as nipple–areola complex reconstruction using P4HB, MC-PEG:GelMA, and PLA.
Scaffold-guided breast reconstruction
Natural hydrogels
Natural hydrogels are known for their biocompatibility and biodegradability, and they are derived from a variety of sources, including animal, plant, algal, or human tissue specimens donated for research purposes. 70 Collagen is a crucial extracellular matrix (ECM) protein within the human breast tissue, with glandular support characteristics, and is the primary hydrogel used in human breast bioengineering and regenerative medicine research. Collagen and its derivative, gelatin, are both natural polymer materials. 71 Gelatin not only replicates the structural characteristics of breast ECM, but also actively facilitates the growth of adipocytes and supports the complex morphogenesis of human mammary epithelial cells. GelMA, a photocrosslinkable derivative of gelatin, combines biocompatibility with improved mechanical stability for breast tissue engineering. To further illustrate these features, Figure 6 summarizes gelatin- and GelMA-based composite and compares their strengths and weaknesses.
Natural biomaterials as scaffolds in breast tissue engineering. The figure illustrates various gelatin- and GelMA-based composite scaffolds and their general advantages and disadvantages.
Gelatin
Gelatin, as the primary component, not only provided excellent biocompatibility and low immunogenicity but also promoted cell adhesion through its Arg-Gly-Asp(RGD) sequences. Sutrisno et al. fabricated a composite scaffold composed of black phosphorus nanosheets (BPNSs) and gelatin, achieving dual functions of selectively targeting and killing breast cancer cells via photothermal therapy (PTT) and breast reconstruction through adipose tissue engineering. 72 In this design, BPNSs were embedded into a porous gelatin matrix, where pre-fabricated ice particles precisely regulated the scaffold’s pore structure. Under near-infrared(NIR) laser irradiation, BPNSs generated localized heat to effectively kill breast cancer cells, while the scaffold’s interconnected porous structure facilitated cell migration and distribution, thereby supporting adipose tissue regeneration. This composite system exhibited remarkable photothermal efficiency (photothermal conversion efficiency >40%) while its degradation products upregulated adipogenic-related gene expression (e.g. PPARγ and C/EBPα), synergistically enabling tumor ablation and functional breast reconstruction. The scaffold shows significant potential for integrated cancer treatment and regenerative medicine, providing a new strategy to address both tumor removal and esthetic restoration.
Besides, gelatin and alginate have been employed for indirect 3D printing, aiming to obtain simultaneously sufficient adipose-mimicking structures and hollow channels for vascularization. Contessi Negrini et al. developed an innovative gelatin-alginate sacrificial template-based scaffold with dual-scale porosity, which offering an integrated solution for adipose tissue regeneration. 73 The study employed 3D-printed alginate filaments and microbeads as sacrificial templates embedded in a gelatin hydrogel, which were subsequently removed through crosslinking and dissolution. This process successfully constructed a three-dimensional scaffold featuring biomimetic micropores (200–400 μm) and predefined vascular channels. SEM and histomorphometric analyses confirmed that the hierarchical pore structure closely resembled native adipose tissue, in which the microporous network provided an optimal 3D microenvironment for cell infiltration. The engineered prevascular channels (≈500 μm diameter) demonstrated exceptional fluid conductivity. In vitro perfusion experiments showed that these channels achieved seamless integration with rat blood vessels and maintained stable blood flow. Mechanical testing revealed that the gelatin scaffold’s elastic modulus (3–4 kPa) precisely matched the mechanical microenvironment of natural adipose tissue, providing physical cues to guide stem cell differentiation. Human mesenchymal stem cells (hMSCs) placed on the scaffold showed 95% viability and successfully differentiated into mature adipocytes after 21-day induction. Oil Red O staining showed abundant lipid droplet accumulation, and qPCR confirmed significant upregulation of adipogenic markers including PPARγ, which evidenced the successful differentiation. The scaffold’s controlled degradation profile (≈40% degradation in 7 days with collagenase I) matched tissue regeneration timelines, maintaining structural integrity during early phases while gradually making space for new tissue formation. This study introduces a sacrificial templating approach that simultaneously achieves biomimetic microstructure construction, mechanical compatibility, and prevascularization design, establishing a novel engineering strategy for complex soft tissue regeneration.
Methacrylated gelatin (GelMA)
GelMA is widely used and known for its remarkable biocompatibility, controllable cross-linking degree and adjustable properties. The double bond (C=C) in the methacryloyl group exhibits cross-linking capability when irradiated by a photoinitiator or ultraviolet light, forming a covalently cross-linked three-dimensional network that demonstrates resistance to dissolution at physiological temperatures and enables the regulation of material mechanical properties through cross-linking density. 74 Used either alone or with other materials for breast tissue construction, 75 this polymer is particularly valuable for breast tissue regeneration.
As an example, Zhang et al. added calcium silicate (CS, CaSiO3) into a GelMA solution and used the mixture as ink for a composite hydrogel scaffold. 76 CS, among the components, serves as a bioactive ingredient to enhance adipose and blood vessel formation. In this study, three different concentrations of CS (0.2, 0.4, 0.8 wt%) were mixed with GelMA as bioink. The results showed that scaffolds with 0.8 wt% CS contained the largest quantity of CS particles. GelMA mixed with CS led to a remarkable enhancement in the adhesive, proliferative, migratory, and adipogenic potential of 3T3-L1 cells. Most importantly, these results showed that these composite scaffolds could help repair blood-vessel-rich adipose tissue in vivo (Figure 7). The introduction of CS strengthens the compressive strength and Young’s modulus of the scaffolds, thus bringing the mechanical characteristics of the engineered constructs closer to those of natural human breast tissue. Research has shown that the controlled release of bioactive ions from CS strongly supports tissue regeneration, driving lipogenesis and vascularization—key processes necessary for effective breast reconstruction.
(a) Overview of GelMA/CS composite scaffold; b)Characterization of 3D printed GelMA/CS composite scaffolds. (a) Overview of 3D-printed GelMA/CS composite scaffolds with various concentrations of CS powders. (b1–b4) SEM images of macropore structures of the 3D-printed scaffolds. (c1–c4) SEM images of surface morphologies of the 3D-printed scaffolds. (d1–d4) SEM images of cross-view of the 3D-printed scaffolds. (e) EDS mapping of 3D-printed 0.4% CS GelMA composite scaffolds. Red arrow indicates CS powder. Modified from Zhang et al. (2023) under the terms of the Creative Commons Attribution International License (CC BY 4.0).
In a different study, researchers fabricated 3D-printed scaffolds via an extrusion-based method GelMA and methacrylated κ-carrageenan (CarMA). 77 CarMA has been identified as a natural polymer that exhibits a striking structural and functional resemblance to glycosaminoglycans, which is a major component of mammalian ECM. The composite platform demonstrated tissue-like stability and mechanical strength (~2 kPa) and supported cell viability and proliferation comparable to those in GelMA scaffolds. ASCs were able to differentiate into the adipocyte lineage on the hydrogel mixed scaffold, though their differentiation potential was lower when GelMA and CarMA were used together. Despite this, the GelMA/CarMA composite scaffolds still supported adequate adipogenic differentiation of adipose-derived stem cells (ASCs). These hydrogel-based scaffolds composed of GelMA and CarMA provide a new platform for adipose tissue volume restoration in breast reconstruction, combining enhanced cell viability and adipogenic differentiation.
Synthetic hydrogels
Synthetic hydrogels are not derived from natural sources. Common types of synthetic hydrogels include polylactic acid (PLA), 78 polycaprolactone (PCL) 79 and polyacrylamide (PAM), have garnered growing interest for use in breast tissue engineering. Compared to natural polymers, these synthetic materials have obvious advantages, including tunable physicochemical properties, straightforward synthesis processes, and superior mechanical properties. Their flexible chemical structure enables precise control over key parameters such as pore architecture, surface topography, and degradation kinetics. Figure 8 provides a comparative overview of the advantages and disadvantages of different synthetic scaffolds
Synthetic biomaterials as scaffolds in breast tissue engineering. The figure compares commonly used synthetic polymers, including PCL, PLGA, and PLATMC, and summarizes their general advantages and disadvantages.
PCL
PCL is one of the most widely used synthetic scaffold materials. Pati et al. developed a 3D bioprinting technology based on decellularized extracellular matrix (dECM) bioinks and used dECM to fabricate open-porous, cubic PCL frameworks, achieving precise reconstruction of tissue-specific microenvironments. 80 In vitro studies showed that the expression of adipogenic regulatory factors and the early marker lipoprotein lipase (LPL) was significantly upregulated, confirming the bioink’s ability to promote adipogenesis. In vivo, four types of implants were transplanted into nude mice: (1) pure PCL scaffolds, (2) PCL-dECM mixtures (acellular), (3) cell-loaded PCL-dECM constructs, and (4) injectable cell-loaded dECM. The results indicated that PCL scaffolds showed minimal tissue interaction, while injectable dECM was completely absorbed at 12 weeks. However, both cell-loaded and acellular PCL-dECM constructs showed strong adipogenic capabilities, with type IV collagen deposition at 2 weeks indicating early signs of vascularization and complete integration with the host at 12 weeks. Additionally, dECM constructs exhibited low immunogenicity and long-term stability in in vivo, providing new strategies for tissue engineering, drug screening, and disease model construction.
For example, Jwa et al. used a 3D printing technique to fabricate polycaprolactone (PCL) scaffolds designed to restore breast tissue after partial mastectomy. 81 To evaluate the regenerative effects of different PCL-based scaffolds, three variants were implanted into mouse models: (1) pure PCL, (2) PCL blended with collagen, and (3) PCL incorporating autologous breast tissue fragments. After 6 months, the scaffolds successfully repaired breast tissue. MicroCT imaging and histological analysis confirmed soft tissue restoration, with the PCL group showing the greatest volume of adipose tissue. However, the PCL scaffold alone showed increased expression of TNF-α and microcalcification, indicating an inflammatory response, which was mitigated in the PCL-collagen and PCL-tissue groups. These results suggest that PCL scaffolds, particularly when combined with collagen or tissue fragments, have potential for breast tissue restoration after partial mastectomy, though further optimization is needed to reduce inflammation and improve mechanical properties for clinical applications.
In another study, researchers explored the use of multi-functional polycaprolactone/cobalt orthosilicate (CoSi/PCL) composite scaffolds for breast reconstruction. 82 These scaffolds feature a macroporous structure, and the addition of CoSi does not affect the porosity. The researchers implanted scaffolds into mice and divided them into four groups: PCL scaffold alone (PCL), 0.25%CoSi composite scaffold alone (0.25%CoSi), PCL scaffold loaded with 3T3-L1 cells (PCL + Cell), and 0.25%CoSi scaffold loaded with 3T3-L1 cells (0.25%CoSi + Cell). After 4 weeks, the scaffolds were analyzed, and the results showed that the 3D-printed 0.25%CoSi composite scaffold holds great potential as a graft for vascularized adipose tissue regeneration. Cell viability and live/dead cell staining results under NIR II light further confirmed the anti-tumor effects of CoSi/PCL. Further analysis revealed that the synthesized CoSi endowed the CoSi/PCL composite scaffold with excellent photothermal conversion efficiency in the NIR II region, giving the CoSi/PCL composite scaffold outstanding in vivo and in vitro anti-tumor functionality under NIR II light exposure.
Poly (ethylene glycol) diacrylate (PEGDA)
PEGDA is often used in breast tissue engineering because of their good formability and biocompatibility. Melchels et al. validated that variations in scaffold structures can lead to different mechanical properties. 83 Building on this concept, Zhu et al. developed a Gyroid scaffold with a triply periodic minimal surface (TPMS) which exhibits a similar elastic modulus to native breast tissue 84 (Figure 9). The TPMS scaffold was fabricated with channel diameters ranging from 2.0 to 3.0 mm, ensuring structural integrity in local areas while maintaining favorable pore sizes. A poly(ethylene glycol) diacrylate/gelatin methacrylate (PEGDA/GelMA) hydrogel was utilized to create a cell-loaded breast scaffold. This TPMS scaffold architecture ensures structural stability and features multiple parallel channels that can be adjusted to modulate elastic modulus. This scaffold’s low elastic modulus aligns well with breast tissue, thus offering a stable and secure growth environment for adipose cell transplantation. This approach offers a practical method for replicating the characteristics of native breast tissue through structural modifications alone.
(a) Schematic diagram depicting the design and fabrication of breast scaffold consisting of polycaprolactone triply periodic minimal surface scaffold, poly (ethylene glycol) diacrylate/gelatin methacrylate hydrogel, and hydrogel loaded with human adipose-derived stem cells; (b) The fabrication and characterization of triply periodic minimal surface scaffold: (A) Triply periodic minimal surface scaffold printed by fused deposition modeling; and (B) the porosity and channel diameter of printed scaffolds. Modified from Zhu et al. 84 under the terms of the Creative Commons Attribution International License (CC BY 4.0).
PLATMC
PLATMC is a copolymer of lactide and trimethylene carbonate (TMC). Jain et al. pioneered the use of extrusion-based 3D printing technology to create degradable and pliable 3D scaffolds from medical-grade poly(L-lactide-co-trimethylene carbonate) (PLATMC), targeting large-volume adipose tissue defects (Figure 10). 85 The scaffolds were optimized for printability by minimizing polymer degradation during the printing process. In vitro research findings revealed significant improvements in cell attachment, proliferation, and adipogenic differentiation on PDA-coated scaffolds, as evidenced by upregulated adipogenic genes (PPARG, ADIPOQ) and increased lipid droplet accumulation. This approach highlights the potential of combining degradable polymers with surface functionalization for soft tissue engineering. In addition, surface modification with polydopamine (PDA) significantly enhanced hydrophilicity.
(a) Fabrication process of PLATMC_PDA based scaffolds; (b) Confocal microscopy examination of initial cell attachment and spreading after 4h on 3D printed scaffolds, Green = actin, and Blue = nucleus. (Scale bar- 50 μm); (c) ASC response on the 3D printed scaffolds in growth medium. (a) DNA measurement employing picogreen assay on the days 7 and 11. (**p < 0.01) (b) Confocal images (day 7) revealing cell distribution and proliferation on the scaffolds: actin (green), nucleus (blue), scale bar 50 μm. (c) SEM images of cell-material interaction on 3D printed scaffolds were taken at 7 day: Illustration of cellular protrusion and the scaffold covered with cell sheet. Modified from Jain et al. (2020) under the terms of the Creative Commons Attribution International License (CC BY 4.0).
PLGA
Recently, researchers used extrusion 3D printing technology to fabricate biocompatible filaments to construct the lactide-co-glycolide-co-trimethylene carbonatecarbonate (PLGA-oTMC) scaffold, providing a favorable environment for the growth of ADSC. In the experiment, the survival and colonization of ADSCs in linear, lamella geometry and hexagonal geometry were compared. Results showed that ADSCs in the lamella geometry scaffold showed a high colonization depth after 2 days of culture. ADSCs had good viability and proliferative capacity in the whole observation period. The lamellar geometry scaffold provided the ADSCs with a larger contact surface area, thus creating more anchorage points for the cells. These findings show that scaffold structure affects ADSC survival, indicating promising potential for tissue engineering. 86
Nipple-areola complex reconstruction
Moving beyond breast volume restoration, nipple reconstruction presents additional challenges that tissue engineering approaches aim to address. 87 Compared to traditional flap techniques, nipple reconstruction without flaps better preserves the underlying blood vessels, promoting improved vascularization of skin grafts and superior maintenance of long-term nipple projection. 88 This approach also reduces complex incisions and flap manipulation, significantly decreasing the incidence of nipple atrophy, local tissue-related complications, and morbidity incurred at the donor site. Cao et al. employed autologous auricular cartilage cell injections and thermosensitive polymer gel scaffolds to reconstruct nipples in a pig model. 89 They applied intradermal purse-string sutures, a technique based on the principle of gathering and approximating tissue edges to create a conical or rounded shape, thereby facilitating the formation of a well-defined and symmetrical shape and contour for the reconstructed nipples. A method was developed by Pashos et al., which involved the excision of the nipple-areola complex(NAC) from rhesus macaques followed by decellularization to generate scaffolds. 90 Their aim was to seed these natural scaffolds with bone marrow-derived stem cells (BMSCs) and subsequently reimplant them into primate subjects.
Due to limitations with natural materials, researchers have turned to synthetic materials for scaffolds. For example, Samadi et al. employed PLA to create cylindrical scaffolds and incorporated autologous rib cartilage tissue into them. 91 Even though positive findings were observed in mice, the authors also identified certain constraints, which were primarily associated with the degradation duration and the rigidity of the scaffold matrix. To address these issues, recent studies utilized more rapidly degrading printable materials to further conduct in vivo experiments.
Recently, Van Belleghem et al. developed a mixed scaffold composed of biodegradable gelatin methacrylate (GelMA) and non-resorbable methylcellulose-polyethylene glycol (MC-PEG) using dual-extrusion bioprinting technology for regenerating the nipple-areola complex after mastectomy. 92 The scaffold was printed in alternating layers of GelMA (containing human skin fibroblasts) and MC-PEG bioink, forming a double-network structure. GelMA provides cell adhesion sites and supports host tissue integration, while MC-PEG maintains structural stability through hydrophobic interactions and covalent cross-linking. In vitro experiments showed that scaffold combinations with MC-PEG:GelMA ratios of 1:2 and 1:3 had the highest fibroblast survival rates (74.98% and 78.35%, respectively, after 14 days), with compressive moduli (101.4–111.4 kPa) close to the mechanical properties of porcine nipple tissue. In a 3-week culture simulating fibroblast contraction, scaffolds with a higher MC-PEG ratio (1:1) exhibited only a 10.3% contraction in nipple protrusion height, significantly better than the 16.8% contraction in pure GelMA scaffolds. After 4 weeks of subcutaneous implantation in rats, the mixed scaffolds displayed mild inflammation, neovascularization (approximately 5–8 vessels per field), and thin fibrous encapsulation (average thickness 50–100 μm). The 1:3 ratio scaffold achieved the best balance between degradation and host cell infiltration. This scaffold resists deformation caused by scar contraction and can maintain the shape of the reconstructed nipple over time, offering a new tissue engineering solution for long-term stability and esthetic adaptation in nipple reconstruction. This approach could also reduce secondary surgeries and support psychological recovery in patients.
In another study, using 3D printing techniques, Dong et al. created bioabsorbable scaffolds from poly-4-hydroxybutyrate (P4HB), offering a promising solution for nipple reconstruction. 93 The study used mechanically processed autologous rib cartilage (CC) and filled it within 3D-printed P4HB scaffolds to promote new tissue growth and protect the reconstructed nipple from contraction forces. After 6 months of in vivo experiments, it was observed that rib cartilage-laden scaffolds achieved a markedly greater degree of projection relative to scaffold-free reconstructed nipples. P4HB scaffolds with inherent internal 3D lattice topographies (excluding the rib cartilage) exhibited the most rapid rate of material resorption. SEM and histological analyses not only substantiated the successful achievement of vascularization but also revealed the concurrent formation of fat-fibrous tissue. Furthermore, in experiments with rib cartilage-filled and empty scaffolds, the rib cartilage-filled group showed a significantly higher volume increase and tissue growth compared to the empty scaffold group, with volume increasing by 102.5% after 3 months. This indicates that 3D-printed P4HB scaffolds in nipple reconstruction effectively promote tissue growth while maintaining the structure and function of the nipple, particularly in preventing nipple contraction and maintaining its biomechanical properties. The use of 3D-printed bioabsorbable P4HB scaffolds, combined with autologous cells, holds significant clinical potential.
To reduce reliance on rib cartilage, Dong et al. later optimized the printing parameters for P4HB lattice scaffolds and developed rolled P4HB braided mesh scaffolds. 94 The final experimental results indicated that the P4HB lattice scaffold—with a 20%–25% infill density and a filament diameter of 0.2 mm—along with a mechanically thermoformed mesh scaffold, represents the current optimal solution for nipple reconstruction. Although promising, robust validation in large preclinical animal models with long-term follow-up is still required to confirm durability and translational relevance.
Translational readiness level (TRL) framework
The Technology Readiness Level (TRL) system, originally developed by the National Aeronautics and Space Administration (NASA), has become a widely accepted framework for assessing technological maturity across multiple industries, particularly with regard to market and clinical readiness. 95 Naveau et al. proposed an initial TRL framework for the bioprinting process 96 ; however, this model provided only a brief outline of nine stages and lacked the level of detail required for a rational and operational assessment of technological maturity. Subsequently, O’Connell et al. introduced a comprehensive nine-level TRL framework for bioprinting in regenerative medicine. 97
Under this definition, TRL 1–2 encompass concept development and project planning. TRL 3 reflects laboratory concept evaluation, typically including in vitro biocompatibility, bioink formulation, and printability optimization, and may also involve an initial proof-of-concept demonstrated in vitro and/or in an early small-animal setting. TRL 4 corresponds to a robust proof-of-concept achieved in a relevant environment, typically through in vivo implantation in an animal model. TRL 5 requires high-fidelity validation in well-characterized large-animal models with clinically relevant follow-up and early regulatory readiness (e.g. GLP-aligned testing and quality/regulatory planning), while TRL 6 represents first-in-human Phase 1 safety evaluation. Using this stringent biomedical TRL framework, we classified each scaffold category discussed in this review according to the highest level of evidence currently documented in the literature. A summary of the assigned TRL levels for each material system is provided in Table 2.
TRL-based Classification of scaffold systems and supporting evidence.
Among the materials discussed in this review, most natural hydrogels and composite formulations remain at early translational stages. Scaffolds such as GelMA-based composites primarily demonstrate laboratory-level proof-of-concept or short-term in vivo feasibility in small-animal models. Within the TRL framework, non-implantation studies correspond to TRL 3, whereas implantation studies correspond to TRL 4. These scaffolds generally lack the regulatory alignment, quality management systems (QMS), and long-term in vivo validation required to progress beyond this stage.
Synthetic polymers, including PCL, PLGA, and PLATMC, benefit from established regulatory histories and widespread medical use. However, under the TRL evaluation framework, the studies discussed above largely remain at TRL 3 or TRL 4, with none validated in well-characterized large-animal models under clinically relevant conditions.
Scaffolds developed for nipple–areola complex (NAC) reconstruction represent the most advanced application scenarios among the scaffolds discussed in this review. In particular, the tissue-engineered nipple construct reported by Cao et al., which was evaluated in a porcine model, may be considered approaching TRL 5 due to its validation in a large-animal environment. However, the absence of regulatory readiness and human safety evaluation precludes formal classification at TRL 5. In contrast, more recent NAC scaffold systems, including P4HB-based constructs and hydrogel-based approaches (e.g. MC-PEG:GelMA or PLA-based systems), remain at TRL 4, as their validation is confined to small-animal models.
Overall, current research in breast tissue engineering remains largely focused on scaffold design and small-animal validation, with innovation in material printing approaches as the primary focus, while clinical applicability and translational considerations remain insufficiently addressed. Therefore, the majority of 3D-printed breast scaffold strategies reported to date remain confined to early translational development.
Current challenges and future directions
The future of 3D printing–assisted breast reconstruction is promising, though still in its early stages. Significant progress has been achieved with multifunctional composite scaffolds, which have shown potential in both breast cancer treatment and breast tissue regeneration. Nonetheless, high manufacturing costs and the absence of large-scale clinical data remain major barriers to clinical translation. In this context, several promising lines of future research could improve the efficiancy of these scaffolds, solidifying their role in breast engerineering.
Requirement for validation in large preclinical animal models
Validation in large preclinical animal models represents a critical requirement for translating hydrogel-based scaffolds into clinical breast reconstruction following mastectomy. Small animal models are insufficient to reproduce the large-volume soft tissue replacement, biomechanical loading, and surgical conditions encountered in clinical practice. Anatomical and physiological similarities between pigs and humans support the use of pigs as a relevant animal model. 98 Compared with other large animals such as sheep or non-human primates, pigs offer practical advantages, including lower housing and maintenance costs, easier handling, and broader regulatory acceptance.
Early large-animal feasibility was exemplified by the work of Cao et al., who demonstrated the maintenance of nipple projection and structural stability using a tissue-engineered construct implanted in a porcine model, providing one of the first proofs of concept for scaffold-assisted soft-tissue reconstruction in a clinically relevant environment. More recent representative work by Cheng et al. demonstrated long-term soft tissue regeneration within 3D-printed breast scaffolds implanted in pigs, with follow-up periods of up to 12 months. 99 These studies confirmed the feasibility of scaffold-guided regeneration and volume maintenance in a large animal setting, supporting early translational progress. However, the scaffolds used were primarily relatively simple synthetic structures, such as medical-grade polycaprolactone (PCL), with limited incorporation of composite or multifunctional designs. In addition, the reconstructed volumes typically ranged from 100 to 150 mL, corresponding approximately to small-to-moderate breast sizes. Future studies should evaluate larger reconstructive volumes and more complex scaffold systems. At the same time, multicenter studies using porcine models are needed to confirm the oncological safety of breast scaffolds before routine clinical application.
Developments of 4D printing (4DP)
One of the most promising areas of research is the development of 4DP technology. The introduction of 4DP technology enables hydrogel scaffolds to respond controllably to external stimuli such as time, temperature, pH, and mechanical forces. This will allow dynamic adjustments of breast tissue morphology and mechanical environment, enabling the scaffold to autonomously adjust its structure and curvature based on changes in the internal microenvironment (such as fluid permeation and tissue contraction) after implantation, thereby achieving a more precise match with the individual’s anatomical structure.
Integration of artificial intelligence (AI)
AI can dynamically optimize the formulation of bio-inks in real-time to improve characteristics such as hardness, viscosity, and crosslinking behavior. AI can also optimize the design and composition of breast scaffold biomaterials through machine learning algorithms. These algorithms can analyze large datasets to predict the performance of various bio-inks and materials under conditions such as mechanical stress, contact with residual breast tissue, and temperature fluctuations. Furthermore, the open-source nature of AI data lowers the cost of data analysis, making 3D-assisted breast reconstruction treatments accessible to more patients in the future.
Conclusion
The use of 3D-printed hydrogel scaffolds holds tremendous promise for advancing breast reconstruction because they can meet the structural requirements of the breast, ensure safety for patients, and allow localized radiotherapy and chemotherapy. This review has explored that natural and synthetic hydrogels provide complementary advantages in supporting adipogenesis, vascularization, and structural integrity. Despite their numerous advantages, the application of hydrogles in breast tissue engineering presents several challenges, such as mechanical strength mismatch, ensuring long-term stability, addressing the issue of bilateral breast symmetry. Future research endeavors should prioritize the development of smart hydrogel scaffolds enabled by 4DP and AI-assisted design and clinical translation supported by long-term validation studies. Continued research efforts and new technologies, will be instrumental in overcoming current challenges and translating these advancements into clinical practice, ultimately offering a valuable option for patients.
Footnotes
Acknowledgements
The authors would like to thank all the study participants for their time and insights into their experiences.
Author contributions
Zhuoyue Li: Writing – review & editing, Writing – original draft, Visualization. Shuqin Wang: Writing – review & editing, Methodology, Investigation. Qian Tan: Writing – review & editing, Project administration.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data availability statement
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.