1. Introduction

Tissue engineering aims to address the critical shortage of transplantable organs and the limitations of autografts, driving demand for advanced regenerative solutions. Constructing three-dimensional tissue or organ structures with biological activity and function requires suitable biomaterials as scaffolds for cell growth, proliferation, and differentiation. These scaffolds not only provide physical support for cells, but also simulate the microenvironment of natural tissues to regulate cell behavior and tissue regeneration processes. Hydrogels, three-dimensional hydrophilic polymer networks, have emerged as foundational materials in bioprinting due to their exceptional biomimicry of the native extracellular matrix (ECM). Their high water content (50–99%) creates an aqueous microenvironment essential for cell encapsulation, proliferation, and differentiation. Moreover, hydrogels exhibit tunable mechanical properties (e.g., elastic modulus) via crosslinking density adjustments, enabling customization for target tissues like cartilage or skin. Biocompatibility and degradability (enzymatic for natural variants, hydrolytic for synthetics) further position hydrogels as ideal bioink substrates for constructing functional tissue constructs. Internationally, for the printability of water gel in 3D biological printing, there have been studies to explore the influence of parameters such as air pressure, feeding speed and printing distance on printing quality, and successfully prepare 3D scaffolds with a high cell survival rate [1]. In the field of bone/cartilage repair, research on photo crosslinked hydrogel focuses on its mechanism of action, the application of nano materials, cells, drugs and other additives, as well as its practical value in tissue engineering [2]. In other studies, when reviewing the progress of 3D printing of hydrogels, the rheological properties of materials were related to printing behavior, and the importance of standardized characterization of printing quality was emphasized [3]. In domestic research, the flame-retardant hydrogel prepared by using visible light curing 3D printing technology and modified itaconic acid and hydroxypropyl cellulose as raw materials shows excellent thermal stability and flame retardancy [4]. Applying DLP 3D printing technology to teaching practice, the GelMA PEGDA scaffold with a pore size of 500 μ m has been proven to have good mechanical properties and stability [5].

The clinical translation of bioprinted tissues confronts significant scientific and technological barriers. Conventional hydrogel materials fail to adequately replicate the dynamic functionality of native tissues, such as adaptive extracellular matrix remodeling. Technical compromises persist in bioprinting processes, where achieving high resolution often sacrifices cellular viability through mechanisms like shear stress in extrusion-based methods or phototoxicity in light-based polymerization. Translational roadblocks further impede progress, including the absence of standardized bioink evaluation protocols, scalable manufacturing workflows, and cost-effective production strategies. Critically, contemporary hydrogels function as passive scaffolds, lacking the autonomous responsiveness inherent to biological systems. These multifaceted challenges necessitate coordinated innovations spanning material science, process engineering, and computational methodologies.

As the core material for simulating natural extracellular matrix and constructing functional tissue engineering scaffold, bioprinting hydrogel shows irreplaceable application potential in regenerative medicine, organ replacement and other fields. However, in the process of transitioning from laboratory research to clinical application, it faces multiple challenges such as material performance matching, insufficient process accuracy, limited functional biomimicry, and clinical application obstacles. These challenges are intertwined and urgently require a systematic and multidimensional comprehensive framework for a collaborative response. This paper aims to elaborate on the construction logic and core content of this comprehensive framework, emphasizing the key significance of breaking through existing bottlenecks through multi-dimensional collaborative innovation to promote bioprinting hydrogels from structural bionics to functional bionics and accelerate the process of clinical transformation.

2. Analysis of hydrogel materials for bioprinting

2.1. Characterization and classification of bioprinting hydrogel materials

Hydrogel materials represent a cornerstone of bioprinting technology due to their unique physicochemical properties that closely approximate the natural cellular environment. These hydrophilic polymer networks, crosslinked through physical or chemical bonds, possess a defining characteristic of high water content, typically ranging from 50% to 99%. This inherent hydration creates an aqueous microenvironment essential for cell viability, effectively mimicking the extracellular matrix and providing the necessary moist conditions for encapsulated cells. Furthermore, hydrogels generally exhibit excellent biocompatibility, minimizing cytotoxic effects and reducing potential immune rejection responses while actively supporting critical cellular processes such as adhesion, proliferation, and differentiation. One of its major advantages is that by precisely adjusting parameters such as crosslinking density and molecular weight, the elastic modulus can be adjusted to meet the mechanical requirements of different target tissues such as cartilage or skin. Natural hydrogels are usually degraded by enzymes, while synthetic hydrogels are mainly degraded by hydrolysis, and the degradation rate can be precisely adjusted by chemical modification to match the specific timeline of tissue regeneration.

Biological printing water gels are mainly classified into natural hydrogels, synthetic hydrogels and composite hydrogels. Natural hydrogels, derived from biological sources such as collagen, gelatin, alginate, and hyaluronic acid, offer superior bioactivity and inherent cellular recognition cues, facilitating favorable cell-material interactions. In contrast, synthetic hydrogels (including polyethylene glycol (PEG) and polyacrylamide and other materials) are prepared by controlled chemical synthesis, which makes them have stable mechanical properties, high design flexibility and stronger stability, but usually lack inherent biological activity and cell interaction ability. To bridge this gap, composite hydrogels have emerged as a sophisticated solution. These materials strategically combine natural and synthetic polymers, such as gelatin-PEG hybrids, or incorporate reinforcing nanofillers like nano-hydroxyapatite. This approach aims to synergistically integrate the biocompatibility and bioactivity of natural components with the enhanced mechanical robustness and tunability offered by synthetic elements or nanoparticles, creating materials better suited for the structural demands of bioprinting.

2.2. Commonly used hydrogel materials and applications for bioprinting

Selecting appropriate hydrogel materials for bioprinting necessitates careful consideration of both printability and post-printing structural stability. Among natural options, gelatin and its derivatives hold significant prominence. Gelatin's intrinsic thermo-reversible behavior, transitioning from a solution state at higher temperatures to a gel state upon cooling, makes it particularly suitable for extrusion-based printing techniques. Further enhancement comes from chemical modifications like methacrylation, yielding Gelatin Methacryloyl (GelMA), which enables photocrosslinking for shape fixation after deposition. GelMA finds extensive application in printing constructs for cartilage and skin regeneration, consistently demonstrating high post-printing cell viability often exceeding 85%. Alginate is another widely utilized natural polymer, prized for its rapid ionic crosslinking capability upon exposure to divalent cations like calcium ions, achieving gelation within seconds. This swift solidification makes alginate ideal for extrusion printing, especially for constructing vascular-like structures. Its primary drawback is the inherently low mechanical strength of pure alginate gels, typically exhibiting elastic moduli below 10 kPa, necessitating frequent combination with reinforcing agents like gelatin. Hyaluronic Acid (HA), particularly when modified with methacrylic anhydride to form Methacrylated Hyaluronic Acid (HAMA), gains photosensitivity. This allows high-resolution photopolymerization-based printing, enabling the fabrication of intricate architectures crucial for applications like articular cartilage repair, where HAMA has shown commendable cell compatibility.

Synthetic and composite hydrogels offer distinct advantages for specific bioprinting challenges. Polyethylene Glycol Diacrylate (PEGDA) is a prominent synthetic choice, valued for its extremely rapid photocrosslinking kinetics, often solidifying in less than one second, and its capacity to achieve high printing resolutions down to 50 micrometers. These properties make PEGDA exceptionally suitable for generating complex vascular networks. A notable limitation, however, is its inherent resistance to cell adhesion, often requiring surface functionalization strategies, such as grafting cell-adhesive peptide sequences like RGD (Arg-Gly-Asp), to improve cellular integration. Composite hydrogels, exemplified by blends like GelMA/alginate, represent a powerful strategy to overcome individual material limitations. Such composites retain the favorable bioactivity and cellular support of GelMA while leveraging the rapid ionic crosslinking of alginate to significantly enhance the immediate structural stability and shape fidelity of the printed construct post-deposition. This combined functionality has proven effective in demanding applications like the bioprinting of integrated osteochondral (bone-cartilage) tissues.

The preparation of hydrogel-based bioinks is a critical step, demanding a delicate balance between rheological properties essential for printing and the preservation of biological functionality for encapsulated cells or bioactive molecules. Common preparation methods include physical mixing, where cells or growth factors are directly dispersed into the hydrogel precursor solution. This straightforward approach is typically feasible for lower viscosity systems but may pose challenges for maintaining homogeneous cell distribution in more viscous inks. Chemical modification offers greater sophistication, involving the introduction of specific functional groups, like photosensitive moieties into alginate chains, to endow the hydrogel with desired responsive behaviors and compatibility with multiple printing modalities. Nano-reinforcement presents another advanced strategy, where the incorporation of nanoscale fillers such as nanocellulose or carbon nanotubes can dramatically enhance the mechanical strength of hydrogels, potentially by factors of three to five. This reinforcement often concurrently improves the shear-thinning behavior, a vital rheological property where viscosity decreases under shear stress during extrusion (facilitating flow through the nozzle) and subsequently recovers once deposited, aiding shape retention.

2.3. Hydrogel-based bioprinting technology

Extrusion-based bioprinting remains the most mature and widely adopted technique. It operates by depositing continuous strands of bioink, typically driven by pneumatic pressure or mechanical pistons, through a nozzle in a layer-by-layer fashion. This method is well-suited for higher viscosity hydrogels (typically within the 10-100 Pa·s range) and offers relatively fast printing speeds, potentially reaching 10 mm/s. Its primary limitation is resolution, generally falling between 50 and 500 micrometers. A core challenge in extrusion bioprinting has historically been balancing the need for high resolution and structural fidelity against the imperative to maintain high cell viability, as higher printing pressures or finer nozzles can induce damaging shear stresses. Recent material and process innovations have significantly alleviated this conflict. A novel paradigm is illustrated by particulate hydrogel assembly, exemplified by a conductive granular hydrogel system developed at the University of Pennsylvania. This approach involves first synthesizing microgel particles, approximately 90 µm in diameter from hyaluronic acid. These particles are then precisely assembled using microfluidic techniques, and conductive pathways are established through gallol-mediated in situ metal reduction. The resulting material exhibits desirable shear-thinning and self-healing properties, enabling the 3D printing of complex conductive patterns, thereby opening new avenues for engineering electroactive tissues [6].

Vat photopolymerization techniques, including stereolithography (SLA) and digital light processing (DLP), utilize light (ultraviolet or blue) to trigger the crosslinking of photosensitive hydrogels in a layer-wise manner. This approach offers superior resolution (typically 25-100 micrometers) and rapid fabrication speeds, making it ideal for generating intricate structures such as capillary networks. A significant concern, however, is potential phototoxicity to encapsulated cells from intense light exposure, particularly UV light. Key innovations addressing this include the development of visible-light curing systems. Replacing traditional UV initiators with biocompatible visible-light initiators, such as riboflavin/triethanolamine systems, substantially reduces cellular damage. An advanced example is the Silk Fibroin/Polyacrylamide (SF/PAM) triple-network hydrogel developed at Donghua University. This system employs a white-light curing strategy, achieving simultaneous crosslinking under exceptionally mild conditions, resulting in remarkably high post-printing cell viability exceeding 95% [7].

Achieving consistent high-quality bioprinted constructs requires meticulous optimization and control over numerous process parameters. These include the bioink's rheological behavior (viscosity, yield stress, shear-thinning index), crosslinking kinetics (speed, mechanism), printing speed, extrusion pressure, layer height, and environmental conditions (temperature, humidity). Advanced characterization techniques and computational algorithms are increasingly vital tools for such process control. For instance, *in situ* rheological characterization combined with structural analysis, like the Rheo-SANS/USANS (Rheology combined with Small/Ultra-Small Angle Neutron Scattering) technique employed by researchers at RMIT University, provides real-time insights into the structural evolution of complex bioinks, such as Soy Protein Isolate/Silk Fibroin (SPI/SF) blends, under shear flow. This detailed understanding offers invaluable theoretical guidance for optimizing ink formulations and printing parameters [8].

The application potential of bioprinted hydrogel constructs is vividly demonstrated in areas like bone regeneration. Studies utilizing extrusion-based printing to fabricate composite scaffolds, such as gelatin-sodium alginate hydrogels loaded with nano-hydroxyapatite and osteogenic factors like BMP-2, have shown significant promise. Implantation of such scaffolds into critical-sized calvarial defects in rat models resulted in substantially enhanced bone formation compared to controls. Micro-CT analysis after 12 weeks revealed a 38% increase in new bone volume. The success is attributed to the scaffold's designed porous architecture (pore sizes of 200-400 µm facilitating cell infiltration and vascularization) combined with the sustained release profile of BMP-2, synergistically accelerating osteoblast migration and new bone deposition [9].

2.4. Barriers to clinical translation of bioprinted hydrogel structures and strategies

Translating bioprinted hydrogel constructs from laboratory prototypes to clinical reality faces significant hurdles requiring coordinated solutions. Establishing robust standardization and clear regulatory pathways is paramount. This involves developing comprehensive standardized evaluation protocols for bioinks and printed constructs, rigorously assessing biocompatibility, printability, mechanical stability, degradation profiles, and long-term safety, especially for implantable materials. Regulatory agencies need to define clear approval frameworks tailored to these complex living products. Scaling up production while maintaining quality and consistency necessitates automation. Developing integrated automated bioreactor systems capable of handling post-printing processes – including perfusion, mechanical conditioning, environmental control, and non-destructive online monitoring of tissue maturation – is essential to minimize manual handling and enable cost-effective, reproducible manufacturing at clinically relevant scales. Finally, cost reduction is a critical factor for widespread accessibility. Strategies include sourcing materials locally, simplifying complex bioink formulations and printing processes where possible without compromising functionality, and advancing the domestic development and production of bioprinting equipment to reduce reliance on expensive imports. Innovations like low-cost visible-light curing systems replacing expensive UV photoinitiators also contribute significantly to overall cost control. Addressing these multifaceted challenges through interdisciplinary collaboration is fundamental to unlocking the full clinical potential of bioprinted hydrogel-based tissues and organs.

The evolution of bioprinting from an empirically driven, trial-and-error process towards a computationally driven paradigm demands deep integration with computational science. Machine learning algorithms, particularly deep learning, hold immense potential for analyzing vast datasets generated from printing experiments. These models can predict optimal combinations of critical parameters (e.g., bioink concentration, crosslinking intensity, printing speed, temperature) to achieve desired outcomes, drastically reducing development time and cost. Multi-scale computational modeling provides another powerful framework. This involves integrating molecular dynamics simulations to understand crosslinking mechanisms at the molecular level, finite element analysis (FEA) to predict mechanical behavior and scaffold deformation under load, and computational fluid dynamics (CFD) to model and optimize the ink flow during deposition. Such integrated simulations enable virtual screening and optimization of the entire bioprinting workflow. The concept of digital twins – creating a real-time digital replica of the physical printing process – further enhances control. By incorporating online monitoring (e.g., via cameras, sensors) and closed-loop feedback control systems, digital twins can ensure consistent print quality and structural fidelity, providing crucial quality assurance for future clinical translation [10].

2.5. Challenges and future research directions for bioprinted hydrogel materials

Despite significant progress, several formidable challenges persist, guiding the trajectory of future research towards greater biomimicry and intelligence. Current hydrogels excel in compositional and structural biomimicry but fall short in replicating the dynamic, responsive functions of native tissues. Future advancements necessitate a deeper exploration of natural tissue's adaptive regulatory mechanisms to engineer next-generation smart hydrogels. A critical frontier is achieving multi-signal responsiveness, designing hydrogels capable of simultaneously sensing and responding to mechanical, electrochemical, and thermal stimuli. Examples include photothermal responsive materials where near-infrared light exposure triggers concurrent structural remodeling and controlled release of bioactive factors like growth factors. Another revolutionary concept involves embedding engineered genetic circuits within cells encapsulated in hydrogels, creating "living hydrogels." These systems would enable cells to autonomously sense local environmental changes and execute programmed feedback responses, significantly enhancing the autonomy and functionality of engineered tissues. Simulating metabolic functions is paramount for complex organs like the liver or kidney. Hydrogels designed for such applications require sophisticated selective permeability and molecular transport capabilities akin to biological barriers (e.g., the blood-brain barrier). Achieving this may involve precise micro- and nano-porous structure design coupled with advanced surface functionalization strategies.

3. Conclusion

Hydrogel materials stand as an indispensable cornerstone of bioprinting technology, offering unparalleled biocompatibility, tunable physicochemical properties, and critical structural support for cellular growth and tissue regeneration. This paper systematically establishes that natural hydrogels (e.g., GelMA, alginate, HAMA) excel in bioactivity and cell interaction, synthetic variants (e.g., PEGDA) provide superior mechanical control and print resolution, while composite hydrogels strategically merge these advantages to overcome individual limitations, enabling the fabrication of complex constructs like osteochondral tissues. Extrusion-based bioprinting remains dominant for its versatility with high-viscosity bioinks, whereas vat photopolymerization techniques achieve exceptional resolution for capillary-scale architectures, both enhanced by innovations such as visible-light curing systems and granular hydrogels to mitigate cell damage and improve functionality. Computational integration—via machine learning, multi-scale modeling, and digital twins—is revolutionizing process optimization, enabling predictive control over bioink rheology, crosslinking kinetics, and structural fidelity. Despite promising *in vivo* outcomes, such as hydrogel-nHA/BMP-2 scaffolds driving a 38% increase in bone volume, clinical translation faces significant barriers including regulatory ambiguity, manufacturing scalability, and cost constraints. Current hydrogels primarily mimic static tissue composition and structure, lacking the dynamic, multi-signal responsiveness inherent to native tissues. Future research must prioritize the development of "smart" hydrogels capable of real-time adaptation to mechanical, electrochemical, and thermal cues—potentially via photothermal systems or engineered genetic circuits within "living hydrogels." Additionally, replicating metabolic functions (e.g., selective permeability for liver/kidney models) demands advanced micro/nano-porous designs. Addressing scalability through automation, cost-effective materials, and standardized regulatory frameworks will be pivotal to transitioning laboratory innovations into clinically viable therapies, ultimately unlocking the full potential of bioprinted organs.