1. Introduction

2. Vascular Organoids

3. Vessel-on-Chip

3.2. Main materials for fabricating VoC

3.2.1. Elatiomers and thermoplastics

Elastomers and thermoplastics constitute two fundamental classes of materials that have revolutionized the field of VoC platforms, offering distinct advantages and applications. Therefore, understanding the unique properties and applications of elastomers and thermoplastics is essential for optimizing VoC platforms for diverse biomedical research purposes.

3.2.1.1. Elatiomers

PDMS, as an elastomer with excellent optical, electrical and mechanical properties, has emerged as a cornerstone material in biomedical and microfluidic research, owing to its diverse applications and favorable physical properties. Widely utilized in fabricating biomedical devices, microfluidic systems, and biomodels, PDMS offers an array of advantages for such applications. Its chemical inertness, optical transparency, gas permeability, and thermal stability make it particularly attractive for use in microfluidic platforms and OoC devices [58]. Additionally, PDMS exhibits low interfacial free energy, high physical toughness, and biocompatibility, rendering it suitable for cell culture and biomedical applications [59]. In the context of microfluidics, PDMS enables the fabrication of intricate microstructures with high precision and cost-effectiveness through soft lithography techniques. Replica molding, microcontact printing, and micro-molding in microcapillaries are among the soft lithography methods commonly employed, with replica molding being the most prevalent [60]. This method involves creating a master mold, usually from silicon, followed by replicating the desired structure in PDMS. PDMS's versatility extends to OoC devices, where it serves as a substrate for creating microenvironments that mimic physiological conditions of human organs [61].

PDMS stands out as the most widely used elastomer in VoC applications [58]. Its exceptional elasticity, transparency, and biocompatibility make it an ideal material for mimicking the mechanical properties of blood vessels. PDMS enables the fabrication of microfluidic devices with intricate geometries and precise control over channel dimensions, facilitating the replication of physiological flow conditions. Soft lithography techniques have revolutionized the rapid prototyping of PDMS-based microfluidic devices, allowing researchers to create customized vascular models with high fidelity [62]. PDMS membranes serve as cell culture interfaces within these devices, supporting the adhesion, proliferation, and migration of ECs and other relevant cell types. However, despite its numerous advantages, PDMS has limitations, particularly in terms of small hydrophobic molecule absorption, leaching of uncrosslinked oligomers, and mechanical stiffness which can impact cellular behavior and experimental outcomes [63]. The hydrophobic nature of PDMS can lead to the nonspecific adsorption of hydrophobic molecules, affecting drug screening assays and pharmacokinetic studies. Additionally, PDMS's relatively low Young's modulus may not accurately replicate the mechanical properties of native blood vessels, potentially influencing cellular responses and tissue development. To address these limitations, researchers are exploring alternative elastomers with enhanced mechanical properties and reduced small molecule absorption. Researchers are also actively exploring other strategies including surface modifications and the incorporation of alternative materials in combination with PDMS to mitigate these drawbacks. For instance, polyurethane-based elastomers and UV-curable polymers offer promising alternatives, providing greater control over material stiffness and surface properties [64].

Overall, PDMS remains a material of choice in biomedical and microfluidic research, playing a pivotal role in advancing OoC technology and facilitating drug development studies through its unique combination of properties and ease of fabrication. By leveraging these novel elastomers, researchers aim to develop VoC platforms that better mimic the complex mechanical and biochemical cues present in native vascular environments.

3.2.1.2. Thermoplastics

Apart from elastomers, thermoplastic polymers, such as polycarbonate (PC) and cyclic olefin copolymers (COCs), have emerged as viable alternatives to elastomers in VoC applications [65]. These materials offer structural stability, compatibility with high-throughput manufacturing processes, and reduced small molecule absorption, making them attractive for microfluidic platforms. Thermoplastics enable the fabrication of robust microfluidic systems with precise control over channel dimensions and geometries. They exhibit excellent biocompatibility and chemical inertness, minimizing the risk of adverse reactions with cultured cells or biological samples [65]. Moreover, thermoplastics can withstand a wide range of temperatures and mechanical forces, making them suitable for long-term cell culture experiments. However, thermoplastics lack the elasticity of elastomers, which is essential for replicating dynamic vascular environments accurately. The significant difference in Young's modulus between thermoplastics and native ECM materials can affect cell adhesion, migration, and mechanotransduction processes [59]. To address this limitation, researchers are exploring composite approaches that combine thermoplastics with hydrogels or elastomers to create hybrid devices with improved mechanical properties and cellular compatibility. By incorporating elastomeric components into thermoplastic-based microfluidic platforms, researchers aim to enhance the physiological relevance and functionality of VoC systems [59].

3.2.1.3. Combining Elastomers and Thermoplastics

The integration of elastomers and thermoplastics represents a promising approach for optimizing VoC platforms. By leveraging the unique properties of both materials, researchers can overcome individual limitations and create hybrid devices with enhanced functionality and performance. For example, combining PDMS membranes with thermoplastic substrates allows researchers to capitalize on PDMS's elasticity for mimicking dynamic vascular environments while leveraging the structural stability and reduced small molecule absorption of thermoplastics [59]. This hybrid approach enables the fabrication of microfluidic devices that accurately replicate physiological flow conditions while minimizing experimental artifacts associated with small molecule adsorption. Moreover, the development of composite materials that combine elastomeric and thermoplastic properties opens up new possibilities for creating advanced VoC platforms with tailored mechanical and biochemical properties [59]. By engineering materials with controlled stiffness, porosity, and surface chemistry, researchers can design microfluidic devices that better mimic the complex microenvironment of native blood vessels, leading to more physiologically relevant experimental results.

In conclusion, elastomers and thermoplastics represent two distinct yet complementary classes of materials in VoC platforms. While elastomers offer exceptional elasticity and biocompatibility, thermoplastics provide structural stability and reduced small molecule absorption. By leveraging the unique properties of both materials and exploring hybrid approaches, researchers can optimize VoC platforms for a wide range of biomedical applications, advancing our understanding of vascular biology and disease mechanisms.

3.2.2. Hydrogels

Hydrogels are essential components in VoC technology due to their biocompatibility, tunable mechanical properties, and ability to mimic the natural ECM of blood vessels. Various hydrogels, both natural and synthetic, have been employed to replicate vascular environments accurately. Here, we explore different types of hydrogels used in VoC technology, detailing their properties and applications.

3.2.2.1. Alginate

Alginate is a naturally occurring polysaccharide derived from brown seaweed, renowned for its biocompatibility, non-toxicity, and ease of gelation. It forms hydrogels through ionic crosslinking with divalent cations like calcium. Alginate hydrogels provide a supportive 3D matrix that promotes cellular attachment and growth, making them suitable for vascular applications. However, alginate's mechanical properties and degradation rates are less than ideal. To enhance its functionality, alginate is often combined with other biopolymers such as gelatin or fibrin, which introduce cell-adhesion sites and improve biodegradability. These hybrid hydrogels have been used to create perfusable vascular channels and networks, demonstrating significant potential in replicating the complex architecture of blood vessels [66].

3.2.2.2. Collagen and Gelatin

Collagen is the most abundant protein in the mammalian ECM and a critical component for tissue engineering. Its natural presence in the human body ensures high biocompatibility and the promotion of cellular activities such as adhesion, proliferation, and differentiation. Collagen hydrogels can be easily molded into various shapes, making them ideal for VoC applications. Despite its advantageous biological properties, collagen's mechanical strength is relatively low, and it is prone to rapid degradation. Enhancing collagen hydrogels' stability often involves crosslinking with agents like glutaraldehyde or genipin, or blending with more robust materials [67]. Collagen-based VoC models have been instrumental in studying EC behavior and vascular permeability under physiological conditions [68].

Gelatin, a form of hydrolyzed collagen, retains many of collagen's favorable biological properties but is more versatile in its applications. Gelatin hydrogels are particularly valued for their biocompatibility, low immunogenicity, and ease of processing. They can form hydrogels at physiological temperatures, which is advantageous for encapsulating living cells. However, like collagen, gelatin hydrogels suffer from weak mechanical properties and rapid degradation at body temperature. These limitations can be mitigated through chemical modifications, such as methacrylation, which allow for photo-crosslinking to create more stable structures. Gelatin methacrylate (GelMA) hydrogels are widely used in VoC systems to simulate the vascular environment and study endothelialization and cell-cell interactions under dynamic flow conditions [69].

3.2.2.3. Fibrin

Fibrin, a protein involved in blood clotting, forms hydrogels through the polymerization of fibrinogen in the presence of thrombin. Fibrin hydrogels are highly biocompatible and support cell migration, proliferation, and differentiation, making them ideal for vascular tissue engineering. Their natural role in wound healing and angiogenesis further enhances their utility in VoC models. Fibrin hydrogels can mimic the dynamic ECM remodeling, providing a realistic environment for studying vascular biology [70]. However, fibrin hydrogels are relatively weak and degrade quickly. To address these challenges, researchers often combine fibrin with other hydrogels or reinforce it with synthetic polymers, creating composite materials that offer better mechanical properties and controlled degradation rates.

3.2.2.4. Synthetic Polymer

Polyethylene Glycol (PEG) is a synthetic polymer known for its hydrophilicity, biocompatibility, and resistance to protein adsorption. PEG hydrogels are widely used in biomedical applications due to their tunable mechanical properties and chemical functionality. PEG hydrogels can be engineered to mimic various aspects of ECM by incorporating bioactive molecules and cell-adhesion peptides. In VoC applications, PEG-based hydrogels provide a stable and customizable platform for creating vascular networks. They offer precise control over porosity, stiffness, and degradation, enabling the study of cellular responses to different mechanical and biochemical cues [71].

Polyvinyl Alcohol (PVA) is another synthetic polymer commonly used in hydrogel formation. PVA hydrogels are highly hydrophilic, biocompatible, and possess excellent mechanical properties. They can form stable and flexible gels through physical or chemical crosslinking. PVA hydrogels are particularly useful in VoC applications where mechanical stability and durability are crucial. Additionally, PVA can be modified with bioactive molecules to enhance cell adhesion and proliferation. PVA-based hydrogels have been employed to create robust vascular channels and networks, facilitating the study of fluid dynamics and EC behavior under physiological conditions [72].

3.2.2.5. Hybrid Hydrogels

Combining natural and synthetic hydrogels results in hybrid materials that leverage the advantages of both. Hybrid hydrogels can offer the biological functionality of natural polymers and the mechanical robustness of synthetic ones. For instance, blending alginate with GelMA or collagen with PEG can produce hydrogels that are both biocompatible and mechanically stable. These hybrid hydrogels are particularly useful in VoC technology, where mimicking the complex structure and function of blood vessels requires materials with tailored properties. By adjusting the composition and crosslinking methods, researchers can fine-tune the physical and biochemical environment to study various aspects of vascular biology and pathology [73]. In conclusion, hydrogels are integral to VoC technology, providing versatile platforms for simulating vascular environments. The ongoing development of natural, synthetic, and hybrid hydrogels continues to advance the field, enabling more accurate and functional models of blood vessels for research and therapeutic applications.

Table 1. Main materials used for fabricating VoC.

Table 1. Main materials used for fabricating VoC.

Material	Key Functional Traits	Advantages	Disadvantages	Potential Solutions
PDMS (polydimethylsiloxane)	Elasticity, Optical transparency, Gas permeability [50,59]	Biocompatible, Enables intricate microstructure, Cost-effective fabrication [50,59]	Absorbs small hydrophobic molecules, Leaching of uncrosslinked oligomers, Relatively low Young's modulus [62,63]	Surface modifications, Incorporation of alternative materials [63,73]
Thermoplastics (e.g., PC, COCs)	Structural stability, Chemical inertness [65,72]	Reduced small molecule absorption, Compatible with high-throughput manufacturing, Wide temperature tolerance [65,72]	Lack of elasticity, High Young's modulus compared to native ECM [59,65]	Combining with hydrogels or elastomers to create hybrid devices [64,73]
Alginate	Biocompatibility, Ease of gelation[66]	Non-toxic, Provides 3D matrix for cell growth [66]	Suboptimal mechanical properties, Non-ideal degradation rates [66,67]	Combining with other biopolymers (e.g., gelatin, fibrin) [66,67]
Collagen	High biocompatibility, Promotes cellular activities [67,68]	Easily moldable, Natural presence in human body [67,68]	Low mechanical strength, Rapid degradation [67,68]	Crosslinking with agents like glutaraldehyde, Blending with more robust materials [67,68]
Gelatin	Biocompatibility, Low immunogenicity [69]	Retains collagen's biological properties, Forms hydrogels at physiological temperatures [69]	Weak mechanical properties, Rapid degradation at body temperature[69]	Chemical modifications (e.g., methacrylation), Photo-crosslinking [69]
Fibrin	Supports cell migration and proliferation, Mimics dynamic ECM remodeling[67,70]	- Highly biocompatible, Natural role in angiogenesis [67,70]	Relatively weak, Degrades quickly [67,70]	Combining with other hydrogels, Reinforcing with synthetic polymers [67,70]
Polyethylene Glycol (PEG)	Hydrophilicity, Tunable mechanical properties [71]	- Resistant to protein adsorption, Customizable with bioactive molecules [71]	Lacks inherent bioactivity [71]	Incorporating cell-adhesion peptides and bioactive molecules [71]
Polyvinyl Alcohol (PVA)	Highly hydrophilic, Excellent mechanical properties [71]	Stable and flexible, Durable [71]	Limited cell adhesion properties [71]	Modification with bioactive molecules [71]
Hybrid Hydrogels	Combines properties of natural and synthetic materials [73]	Tailored mechanical and biochemical properties, Enhanced functionality [73]	Complexity in fabrication and characterization[73]	Optimizing composition and crosslinking methods [73]

3.4. Microfluidic Strategies

Microfluidics, the science of manipulating and controlling fluids at microscale, has emerged as a game-changer in various fields, including biology, energy, and materials science [85,86]. This technology offers numerous advantages, such as precise fluid control, low sample and reagent consumption, high throughput, and the potential for integration and automation [87]. Microfluidic devices, often fabricated using advanced materials and techniques [85,88], enable intricate manipulation of fluids, facilitating complex analyses, syntheses, and processes. The integration of nanomaterials into microfluidic platforms has further expanded their capabilities, enabling enhanced sensitivity, selectivity, and functionality. With continuous advancements, microfluidics holds immense potential for revolutionizing numerous applications across diverse domains [86,88].

3.4.1. Wall Trapping Method

Recreating vasculature in an OoC device is a crucial step towards developing physiologically relevant models for studying various biological processes and disease mechanisms. One promising approach to achieve this is the wall-trapping method, which involves seeding ECs onto the sidewalls of microfluidic channels to form an endothelial barrier [82,89].

The wall-trapping method can be realized using either a porous membrane or a hydrogel matrix. Porous membranes, often fabricated from PDMS, allow for co-culture of multiple cell types, enabling the study of cell-cell interactions [89,90,91,92]. However, the membrane's planar structure differs from the hollowed nature of in vivo vasculature, posing a limitation. Alternatively, hydrogels, such as collagen or fibrin, can be utilized to create lumenized channels [92]. This approach allows for full interaction between the trapped ECs and the surrounding cells without the need for an intermediate membrane.

One notable advantage of the hydrogel-based wall-trapping method is the ability to create hollowed structures, mimicking the tubular architecture of blood vessels. This can be achieved by utilizing a sacrificial material, such as a needle or a bioprinted structure, to generate a lumen within the hydrogel. Subsequently, the sacrificial material is removed, leaving behind a hollow channel lined with ECs. This approach has been successfully employed in angiogenesis models, enabling the study of vascular sprouting and the evaluation of antiangiogenic drugs [92].

While the wall-trapping method offers several advantages, it is not without challenges. The fabrication of precise, hollowed structures within hydrogels can be technically demanding, often requiring specialized equipment or techniques [92]. Additionally, the cell seeding process may subject the trapped cells to high shear stress, potentially compromising their viability and function. To overcome these limitations, ongoing research efforts are focused on refining the fabrication methods and exploring alternative materials and techniques. For instance, the integration of advanced bioprinting technologies holds promise for creating intricate, patient-specific vascular networks within hydrogel matrices [93]. Moreover, the development of biocompatible and biomimetic materials that can better recapitulate the native ECM environment is an active area of research [94].

Overall, the wall-trapping method represents a valuable tool in the field of VoC technology, enabling the recreation of physiologically relevant vasculature in vitro. By addressing the current limitations through innovative materials and fabrication strategies, this approach has the potential to unlock new avenues for studying vascular biology, disease modeling, and drug screening, ultimately contributing to the advancement of personalized medicine and regenerative therapies.

3.4.2. Microencapsulation Method

The microencapsulation method, also known as the self-assembling or self-morphogenesis method, has emerged as a promising approach for recreating vasculature in VoC technology. This method involves encapsulating ECs within microfluidic chambers or microchannels under precisely controlled microenvironmental conditions, allowing the spontaneous formation of vascular structures [95].

A key advantage of the microencapsulation method is its ability to induce vasculogenesis and angiogenesis processes without subjecting the cells to high shear stress, which can compromise their viability and function. The encapsulated ECs self-organize and form vascular networks in response to specific morphogenetic cues, such as growth factors and ECM components. Vascular endothelial growth factor (VEGF) plays a pivotal role in promoting vascular sprouting and formation within these microencapsulated systems [96]. Additionally, other factors like fibroblast growth factor (FGF) and angiopoietin (ANG) have been explored to modulate the formation and stabilization of the vascular structures [97].

For instance, Campisi et al. successfully created a vascularized network by culturing hiPSC-derived ECs (hiPSC-ECs) in a microfluidic device supplemented with VEGF, enabling the tri-culture of iPSC-ECs, pericytes, and astrocytes to mimic the complex blood-brain barrier microenvironment [98].

While the microencapsulation method enables the generation of intricate vascular networks, one limitation is the unpredictable sprouting patterns, which can be challenging when aiming to recapitulate precise tissue structures and functions. To address this issue, researchers have explored the application of microfluidic forces, such as shear stress, circumferential stress, and axial stress, to guide and shape the newly formed vasculature [99]. These biomechanical forces, combined with other undefined factors influencing vasculogenesis and angiogenesis, offer the potential to exert greater control over the morphogenesis process.

However, further research is needed to fully understand and harness these factors for recreating accurate vascular architectures within VoC platforms. Overall, the microencapsulation method represents a valuable tool for studying vascular biology and developing physiologically relevant vascular models. By leveraging the self-organizing capabilities of ECs and the precise control of microenvironmental cues, this approach holds promise for advancing VoC technology and enabling applications in disease modeling, drug screening, and regenerative medicine [94].

3.4.3. 3D Bioprinting

3D bioprinting has emerged as a promising technique for creating complex biomimetic structures, including blood vessels and vascular networks. This technology combines biomaterials, cells, and computer-aided design to fabricate 3D constructs with high precision and intricate geometries. The ability to engineer vascularized tissues has significant implications for regenerative medicine, drug testing, and disease modeling [85,100]

In this section, we will discuss the various approaches and advancements in 3D bioprinting for modeling vasculature. One of the key strategies employed in 3D bioprinting of vasculature involves the use of microfluidic chips. Salmon et al. [87] demonstrated the engineering of neurovascular organoids using 3D printed microfluidic chips. They incorporated ECs and pericytes within a hydrogel matrix, enabling the formation of a perfusable vascular network. This approach allowed for the study of blood-brain barrier function and the interaction between neural and vascular components.

Another innovative approach is the development of continuously perfusable and customizable VoC platforms. This platform allows for real-time monitoring and manipulation of the vascular network, making it a valuable tool for studying vascular biology and disease modeling.

In addition to microfluidic systems, direct 3D bioprinting of vessel-like structures has also been explored. Gao et al. [101] developed a method for 3D bioprinting of vessel-like structures with multilevel fluidic channels. By employing a coaxial nozzle system and a sacrificial material, they were able to create hierarchical vascular networks with interconnected channels. This approach holds promise for engineering complex vascularized tissues.

Xu et al. [102] proposed a novel strategy for creating biomimetic blood vessels using 3D bioprinting technology. They employed a coaxial nozzle system to print a multi-layered construct, mimicking the structure of a blood vessel. The inner layer consisted of ECs, while the outer layer comprised SMCs, replicating the native architecture of blood vessels.

In addition to these approaches, researchers have explored various bioprinting methods for fabricating in vitro tubular blood vessel models. Sasmal et al. [85] provided a comprehensive review of 3D bioprinting techniques for modeling vasculature, including extrusion-based, inkjet-based, and laser-assisted bioprinting. They highlighted the advantages and limitations of each method and discussed the potential applications of these vascular models in drug testing and disease modeling. Kim et al. [100] also reviewed bioprinting methods for fabricating in vitro tubular blood vessel models. They discussed the importance of considering factors such as cell types, biomaterials, and printing parameters to achieve physiologically relevant and functional vascular constructs.

In summary, 3D bioprinting offers a versatile and powerful platform for engineering vascularized tissues and modeling vasculature. Researchers have developed various strategies, including microfluidic chips, continuously perfusable platforms, and direct bioprinting of vessel-like structures. These approaches have leveraged techniques such as coaxial nozzle systems, sacrificial materials, and multi-layered printing to create biomimetic vascular networks. The ability to precisely control the architecture, composition, and perfusion of these vascular constructs holds great potential for advancing regenerative medicine, drug testing, and disease modeling studies. Bioprinting has emerged as a promising technology for recreating vasculature in VoC models. This advanced fabrication technique allows for the precise deposition of biomaterials and living cells in a layer-by-layer manner, enabling the creation of intricate 3D structures that mimic the complexity of native vascular networks [93,103]. By leveraging different bioprinting strategies as discussed below, researchers can overcome the limitations of traditional microfabrication methods and achieve greater control over the architectural features, cell distribution, and biomimetic properties of the engineered vasculature [98,104]. However, challenges related to material selection, resolution, and scalability remain, and further developments are needed to fully realize the potential of bioprinting for VoC applications [105].

3.4.3.1. Injection Molding

Injection molding has emerged as a significant fabrication technique for producing VoC devices, offering unparalleled precision, repeatability, and scalability [94,106]. This method involves injecting molten polymer into a meticulously designed mold cavity, where it cools and solidifies into intricate microvascular networks that mimic the complex physiology of blood vessels [57,69]. The injection molding process begins with the selection of an appropriate thermoplastic polymer, chosen for its ease of molding and stable properties upon cooling [94]. The selected polymer is heated until it reaches a fluid state and then injected under high pressure into the mold cavity, which is designed to incorporate detailed features such as varying diameters and intricate geometries that accurately replicate natural blood vessels [69,93]. Once the polymer fills the mold, a carefully controlled cooling process takes place to prevent warping or deformation, which could compromise the functionality of the microchannels. After solidification, the molded part is ejected, revealing the desired vascular structures required for VoC applications [85,93].

One of the primary advantages of injection molding is the high precision and consistency it offers [94]. The process can repeatedly produce microchannels with exact dimensions, ensuring the reliability and functionality of the VoC devices. This precision is particularly crucial when creating microvascular networks that need to closely mimic the natural physiological conditions of human blood vessels [85]. Additionally, injection molding is highly efficient for mass production [94]. Once the mold is created, it can produce a large number of identical devices with minimal variation, making it an attractive option for VoC technology, where multiple devices may be required for extensive testing and research [85,107]. This scalability can accelerate the development and application of VoC technologies in biomedical research and drug development.

The choice of polymer is critical in injection molding for VoC devices [94]. PDMS is commonly used due to its biocompatibility, optical transparency, and flexibility, making it an excellent material for replicating the soft, elastic nature of blood vessels. However, PDMS can absorb small molecules, which may interfere with certain applications. In such cases, alternative materials like cyclic olefin copolymer or polystyrene may be used to provide chemical resistance or reduced absorption [108].

Despite its numerous advantages, injection molding also presents some challenges. The initial cost of creating a mold can be high, requiring precise machining and robust materials to withstand the injection pressure and thermal cycling [107]. While this investment is justified for large-scale production, it may pose a barrier for smaller research labs or early-stage development projects. Another challenge is the shrinkage and potential deformation of the polymer during cooling [94]. Mold designers must account for these factors to ensure that the final product maintains the necessary dimensions and functionality. Additionally, while thermoplastics are versatile, not all polymers suitable for biological applications can be used in injection molding, potentially limiting material choices.

Despite these challenges, injection molding remains a powerful and versatile technique for fabricating VoC devices, providing the precision and scalability needed to replicate complex microvascular networks [85,93]. By carefully selecting appropriate materials and optimizing the molding process, researchers and manufacturers can produce high-quality, reliable devices that advance the capabilities of VoC technology in biomedical research.

3.4.3.2. Laser-Assisted Bioprinting

Laser-assisted bioprinting has emerged as a promising technique for creating intricate vascular structures within VoC platforms. This approach leverages the precision and versatility of laser technology to deposit biomaterials and living cells in predetermined patterns, enabling the fabrication of complex and biomimetic microvascular networks [69,85].

One of the key advantages of laser-assisted bioprinting is its ability to create on-demand patterns of various cell types and biomaterials with high spatial resolution [108,109]. This flexibility allows researchers to recreate the intricate architecture of blood vessels, including varying diameters, branching patterns, and the incorporation of supporting cell types, such as pericytes and SMCs [110]. Moreover, laser-assisted bioprinting facilitates the integration of inorganic materials, such as hydroxyapatite, into the printed constructs, which can enhance the biomimetic properties and functionality of the engineered vasculature [108]. This capability is particularly valuable for the development of bone-mimetic VoC models, enabling the study of vascular-bone interactions and the evaluation of bone regeneration strategies[111] .

The bioprinting process can be performed with a wide range of biomaterials, including hydrogels, which provide a supportive and biomimetic environment for the encapsulated cells [109,110]. Alginate, a natural polysaccharide, has been successfully employed in laser-assisted bioprinting, allowing for the fabrication of intricate 3D cellular constructs with high viability and structural integrity [109]. Despite its advantages, laser-assisted bioprinting also faces challenges that require further research and optimization. One crucial aspect is the selection of appropriate laser parameters, such as wavelength, pulse duration, and energy density, to ensure minimal damage to the deposited biomaterials and cells [110,112]. Additionally, the integration of vascularization strategies with other OoC components, such as microfluidic channels and porous membranes, remains an area that requires further exploration [111].

Ongoing research efforts are focused on advancing the capabilities of laser-assisted bioprinting for VoC applications. This includes the development of novel bioinks with enhanced printability and biocompatibility, as well as the exploration of multi-material printing strategies to create heterogeneous and biomimetic vascular structures [110,112]. Furthermore, the integration of advanced imaging and feedback systems can facilitate real-time monitoring and optimization of the bioprinting process, ensuring accurate and reproducible results [112].

Overall, laser-assisted bioprinting offers a powerful tool for recreating the intricate and biomimetic vasculature within VoC platforms, enabling the development of physiologically relevant models for various biomedical applications, including disease modeling, drug screening, and regenerative medicine [69,93,112].

3.4.3.3. Micro-Extrusion Bioprinting

Micro-extrusion bioprinting has emerged as a versatile and promising technique for creating biomimetic vascular structures within VoC platforms. This technology involves the extrusion of bioinks, which are biomaterial-cell suspensions, through microscale nozzles to generate intricate 3D constructs [113,114]. One of the key advantages of micro-extrusion bioprinting is its ability to create complex and heterogeneous structures with high spatial control [115]. This precision enables the fabrication of vascular networks with varying diameters, branching patterns, and the incorporation of different cell types, such as ECs, pericytes, and SMCs, to mimic the native architecture of blood vessels [57,116].

The selection of bioinks plays a crucial role in the success of micro-extrusion bioprinting for VoC applications. Various natural and synthetic biomaterials, including collagen, alginate, and hydrogels, have been explored as bioink components [113,117]. These materials provide a supportive and biocompatible environment for the encapsulated cells, facilitating their proliferation, differentiation, and organized assembly into vascular structures [114,118]. Micro-extrusion bioprinting also offers the ability to create multi-material constructs, enabling the integration of different cell types and biomaterials within a single printed structure [119]. This capability is particularly valuable for recapitulating the heterogeneity and complexity of native vasculature, which often involves the interaction of multiple cell types and ECM components [116,117]. Despite its advantages, micro-extrusion bioprinting faces several challenges that require further research and optimization. One significant challenge is maintaining cell viability and function during the printing process, as the shear forces and extrusion pressures can potentially damage the cells [114,115]. Additionally, achieving precise control over the deposition and fusion of bioinks is crucial for creating seamless and continuous vascular structures [115,117].

Ongoing research efforts are focused on developing advanced bioinks with improved printability, biocompatibility, and mechanical properties [113,115]. Furthermore, the integration of micro-extrusion bioprinting with other fabrication techniques, such as sacrificial templating or stereolithography, holds promise for creating more complex and biomimetic vascular architectures within VoC platforms [116,120].

Overall, micro-extrusion bioprinting offers a powerful tool for recreating the intricate and heterogeneous vasculature within VoC models. By leveraging the versatility of bioink formulations and the precise deposition capabilities of this technology, researchers can develop physiologically relevant vascular models for studying various biological processes, disease mechanisms, and evaluating therapeutic interventions [114,117,118].

3.4.3.4. Stereolithography Bioprinting

Stereolithography, a pioneering additive manufacturing technique, has revolutionized the field of 3D printing since its inception in the 1980s. Introduced by Chuck Hull through his groundbreaking patent [121], this technology utilizes a photopolymerization process to selectively cure a liquid photopolymer resin, layer by layer, creating intricate 3D objects. The advent of stereolithography paved the way for numerous applications, including the fabrication of prototypes, molds, and end-use products across various industries. However, its true potential has been realized in the realm of biomedical engineering, where it has enabled the creation of complex biological constructs and OoC systems [58].

Stereolithographic 3D bioprinting has emerged as a powerful tool for manufacturing intricate biomimetic structures with exceptional precision and resolution. By leveraging the principles of photopolymerization, researchers have been able to create highly detailed and biofunctionalized hydrogel constructs, capable of mimicking the intricate microarchitecture of native tissues [122]. One notable application of this technology is the development of 3D culture chips with integrated perfusion networks, which provide a more physiologically relevant environment for cell culture studies. These advanced in vitro models have the potential to improve our understanding of biological processes, disease mechanisms, and drug screening, reducing the need for animal testing [123].

Moreover, the ability to fabricate multivascular networks and functional intravascular topologies within biocompatible hydrogels has opened up new avenues for tissue engineering and regenerative medicine. These vascularized constructs can facilitate the integration and survival of implanted cells or tissues, overcoming the longstanding challenge of maintaining adequate nutrient and oxygen supply [118]. As the field of OoC technology continues to evolve, stereolithographic 3D bioprinting has emerged as a crucial manufacturing technique [120]. By enabling the precise construction of microfluidic devices and biomimetic structures, researchers can create more sophisticated OoC systems that better recapitulate the complexity of human physiology. Furthermore, recent advancements in 3D bioprinting have facilitated the development of vascularized tumor-on-a-chip models, providing valuable insights into cancer biology and potentially accelerating the discovery of novel therapeutic strategies.

While stereolithography has already made significant contributions to the biomedical field, ongoing research and technological advancements promise to unlock even greater possibilities. With continued interdisciplinary collaboration among engineers, biologists, and clinicians, stereolithographic 3D bioprinting holds the potential to revolutionize personalized medicine, drug discovery, and tissue engineering, ultimately improving patient outcomes and advancing human health.

3.4.3.5. Sacrificial Bio-Printing

Sacrificial bioprinting has emerged as a powerful technique for creating intricate vascular networks within hydrogel constructs, enabling the development of advanced VoC systems. This approach involves the fabrication of sacrificial structures that are subsequently removed, leaving behind perfusable channels that mimic the intricate vasculature found in living tissues. One of the pioneering studies in this field [114] demonstrated the feasibility of creating perfused functional vascular channels within 3D hydrogel constructs using a sacrificial bioprinting process. By printing a sacrificial material and encapsulating it within a cell-laden hydrogel, researchers were able to generate intricate vascular networks that could be perfused with desired fluids.

Building on this foundation, subsequent research [116] has expanded the capabilities of sacrificial bioprinting to generate multi-scale vascular networks within 3D hydrogels. These hierarchical vascular architectures, consisting of interconnected channels of varying diameters, more accurately recapitulate the complexity of native vasculature, enabling the development of more physiologically relevant VoC models. To further enhance the biomimicry of these vascular constructs, researchers have explored the integration of complex channel geometries [117,118] and the incorporation of multiple fluidic channels within a single construct [122]. These advancements have enabled the creation of more sophisticated VoC systems that better recapitulate the intricate branching patterns and hierarchical organization of native vasculature.

The application of sacrificial bioprinting in cancer research [117] has also gained significant attention. By creating vascularized tumor-on-chip models, researchers can investigate the interplay between cancer cells and the vascular microenvironment, potentially leading to insights that could inform the development of novel therapeutic strategies. Furthermore, the integration of advanced fabrication techniques, such as two-photon 3D printing and scaffold molding [121], has been explored to improve the fidelity and resolution of sacrificial bioprinting processes. These approaches have the potential to enhance the precision and complexity of the vascular networks created, further bridging the gap between engineered constructs and native tissues.

While sacrificial bioprinting has already made significant contributions to the field of VoC technology, ongoing research and technological advancements promise to unlock even greater possibilities. With continued interdisciplinary collaboration and the integration of complementary fabrication techniques, sacrificial bioprinting holds the potential to revolutionize the development of physiologically relevant VoC models, ultimately advancing our understanding of vascular biology and facilitating the translation of these technologies to clinical applications.

Table 2. Key strategies for creating VoC.

Table 2. Key strategies for creating VoC.

Fabrication Technique	Key Advantages	Disadvantages	Potential Solutions to Limitations
Soft-lithography	Precise control over microstructures, Biocompatible (PDMS), Gas permeable, Enables multilayered devices [75]	PDMS absorbs small hydrophobic molecules, PDMS may swell or degrade with organic solvents [75]	Surface modifications, Use of alternative materials, Careful selection of experimental conditions [75]
3D bioprinting	Creates complex 3D structures, Enables vascularized tissues, High precision and customization [85,87,100,101]	Technical complexity, Limited by printable materials, Challenges in maintaining cell viability [85,100]	Development of advanced bioinks, Optimization of printing parameters, Integration with other fabrication methods [85,87,100,101]
Photolithography	High precision for microfluidic structures, Compatible with various materials, Enables complex channel designs [77,78,79,80]	Requires cleanroom facilities, Limited feature resolution, Material compatibility issues [77,78,79,80]	Development of single-step processes [77], Exploration of alternative photo-sensitive materials [78], Integration with other fabrication techniques [80]
Non-lithographic methods (e.g., SMART)	Creates rounded cross-sections, Simplifies biomimetic scaffold creation [89]	Limited demonstration for multiscale structures, Less established than other methods [89]	Further research and development, Integration with existing fabrication strategies [89]
Wall trapping method	Enables co-culture of multiple cell types, Creates lumenized channels [95,96]	Planar membrane structure (for porous membranes), High shear stress during cell seeding [95,96]	Use of hydrogels instead of membranes, Optimization of cell seeding techniques, Integration with advanced bioprinting [95,96]
Microencapsulation method	Induces spontaneous vascular formation, Low shear stress on cells, Mimics natural vasculogenesis [98,99,103]	Unpredictable sprouting patterns, Challenges in controlling precise structures [98,99,103]	Application of microfluidic forces to guide growth, Optimization of growth factor combinations, Integration with other fabrication methods [98,99,103]
Injection molding	High precision and repeatability, Scalable for mass production, Efficient for complex microchannels [116]	High initial mold cost, Polymer shrinkage and deformation, Limited material choices [116]	Careful mold design to account for shrinkage, Development of new moldable biomaterials, Optimization of cooling processes [116]
Laser-assisted bioprinting	High spatial resolution, On-demand patterning, Enables multi-material constructs [122,123]	Potential cell damage from laser, Challenges in integrating with other components [122,123]	Optimization of laser parameters, Development of protective bioinks, Integration of real-time monitoring systems [122,123]
Micro-extrusion bioprinting	Creates complex, heterogeneous structures, Enables multi-material constructs, Wide range of printable materials [116,117]	Shear stress may damage cells, Challenges in precise bioink deposition [116,117]	Development of shear-thinning bioinks, Optimization of extrusion parameters, Integration with other fabrication techniques [116,117]
Stereolithography bioprinting	High resolution and precision, Enables complex 3D structures, Rapid fabrication [119,120,121]	Limited by photo-crosslinkable materials, Potential cytotoxicity of photoinitiators [120,121]	Development of biocompatible photopolymers, Optimization of light exposure parameters, Integration with other bioprinting techniques [120,121]
Sacrificial bioprinting	Creates perfusable channels, Enables complex vascular networks, Suitable for multi-scale structures	Challenges in removing sacrificial material, Limited by properties of sacrificial materials	Development of easily removable sacrificial materials, Integration with other fabrication techniques, Optimization of removal processes

4. Vascularized Organoids

5. Future Prospects and Innovations as Well as Potential Challenges

6. Conclusion

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