• The Architectonics of Life: A Review of 3D Bioprinting for Tissue Engineering
  • Maryam Radmanfard,1,* Asal Naghipour_Kordlar,2
    1. Department of Basic Sciences, Ta.C., Islamic Azad University, Tabriz, Iran
    2. Faculty of Nursing, Tabriz University of Medical Sciences, Tabriz, Iran


  • Introduction: Tissue and organ shortages remain one of the most pressing challenges in modern healthcare (Tiwari, 2025). Organ transplantation is often the only curative therapy for patients with end-stage organ failure, yet the number of donors falls far short of demand. This discrepancy has driven the search for alternatives that can restore tissue structure and function (Shapira & Dvir, 2021). Traditional tissue engineering based on seeding cells into porous scaffolds pioneered the concept of engineered tissues. While valuable, these methods lacked architectural precision. Scaffold properties such as pore size, shape, and distribution were largely stochastic, leaving tissue formation dependent on cellular self-organization (Tan et al., 2021). The results were variable and often insufficient for functional replacement (Fang et al., 2022). 3D bioprinting represents a paradigm shift. By depositing bioinks composed of living cells, biomaterials, and bioactive molecules layer-by-layer, researchers can create constructs with defined geometries, controlled porosity, and heterogeneous cell distributions (Mirshafiei et al., 2024). Importantly, medical imaging data can be directly converted into patient-specific blueprints, aligning the technology with the goals of personalized medicine (Ren et al., 2025). Current research has branched into two synergistic directions. The first aims at in vivo tissue replacement, including constructs for bone, cartilage, skin, and vascularized tissues (Di Stefano et al., 2025; Huang et al., 2025). The second focuses on in vitro applications, such as organ-on-a-chip systems and tumor microenvironments, which provide more accurate models for disease study and drug discovery (Liao et al., 2025; Ren et al., 2025). Together, these dual tracks demonstrate the versatility and impact of 3D bioprinting in both near- and long-term horizons (Halper, 2025).
  • Methods: This review employed a narrative approach, consistent with recent works that emphasize thematic synthesis over quantitative pooling in rapidly evolving fields such as bioprinting (Halper, 2025; Tiwari, 2025). Major databases including PubMed, Scopus, Web of Science, and Google Scholar were queried for English-language literature from 2020 to present. Search terms included: 3D bioprinting, bioinks, extrusion, inkjet, laser-assisted printing, stereolithography, decellularized ECM, tissue engineering, vascularization, organ-on-a-chip, 4D bioprinting, artificial intelligence (Fang et al., 2022; Mirshafiei et al., 2024). Priority was given to peer-reviewed articles, high-quality reviews, and representative preclinical and translational studies (Tan et al., 2021; Shapira & Dvir, 2021). Data were synthesized into four thematic domains: (1) bioprinting methodologies, (2) bioink materials and biological properties, (3) functional applications in hard and soft tissue engineering, and (4) translational and future considerations (Ren et al., 2025; Gao, 2025). No quantitative meta-analysis was attempted.
  • Results: 1. Bioprinting modalities and trade-offs Four core modalities define the field: • Inkjet bioprinting: Employs thermal or piezoelectric forces to eject droplets. It is low-cost, high-speed, and precise but limited to low-viscosity inks (< ~15 Pa·s) and is prone to nozzle clogging. Cell viability remains moderate (≈85–90%) (Fang et al., 2022). • Extrusion bioprinting: Uses pneumatic or mechanical pressure to extrude continuous filaments. It supports viscous, cell-dense inks and yields mechanically robust structures but at lower resolution and with potential shear-induced cell damage. Viability ranges widely (40–95%) (Tan et al., 2021; Mirshafiei et al., 2024). • Laser-assisted bioprinting (LIFT): Uses laser pulses to propel droplets from a donor ribbon. This method is nozzle-free, versatile with viscosities, and provides high cell viability (>95%). However, costs and operational complexity limit widespread adoption (Ren et al., 2025). • Vat photopolymerization (SLA, DLP): Employs light-based curing to achieve high accuracy and speed. Restricted to photo-crosslinkable bioinks, and risks of phototoxicity remain, though mitigated by visible-light photoinitiators (Shapira & Dvir, 2021). Key insight: Each method reflects a process–material–viability trilemma, where improvements in structural fidelity often come at the expense of cell health (Halper, 2025). 2. Bioinks: material foundations of living constructs Bioinks are critical to bioprinting success. • Natural polymers (e.g., alginate, gelatin, collagen, hyaluronic acid) provide biocompatibility and bioactivity but have weak mechanical strength (Mathur et al., 2025). • Synthetic polymers (e.g., PEG, PCL, Pluronic) are tunable and reproducible but bio-inert, often requiring modification (Fang et al., 2022). • Hybrid inks combine properties of natural and synthetic systems to balance printability and function (Tan et al., 2021). • Decellularized ECM (dECM) bioinks provide a tissue-specific microenvironment rich in signaling cues but require reinforcement for mechanical stability (Mirshafiei et al., 2024). Rheological properties such as viscosity and shear-thinning are decisive, enabling smooth extrusion while maintaining shape fidelity (Mathur et al., 2025). 3. Functional tissue applications • Bone: Hybrid constructs (PCL frameworks filled with cell-laden hydrogels) show osteogenic potential in preclinical models. Achieving cortical bone strength remains an unmet goal (Huang et al., 2025). • Cartilage: Layered bioinks mimic zonal organization, improving histological similarity to native cartilage. Long-term integration under mechanical load remains challenging (Mirshafiei et al., 2024). • Skin: Multi-layer constructs containing fibroblasts and keratinocytes replicate dermal-epidermal organization. In situ printing directly onto wounds accelerates healing and offers potential for automation (Di Stefano et al., 2025). • In vitro models: Bioprinting enables organ-on-a-chip systems with perfusable microchannels and tumor models capturing the 3D microenvironment (Ren et al., 2025). These platforms enhance drug screening accuracy and reduce reliance on animal testing (Gao, 2025). 4. Translational constraints Despite progress, several barriers hinder clinical adoption: • Vascularization: Constructs larger than 1–2 mm require perfusable vasculature. Sacrificial inks and coaxial printing offer partial solutions but long-term integration is unresolved (Mirshafiei et al., 2024; Liao et al., 2025). • Manufacturing scale and standardization: Current methods are slow and lack GMP-grade standardization. Automated systems and standardized bioink libraries are needed (Fang et al., 2022; Mathur et al., 2025). • Regulatory pathways: Guidelines for living bioprinted products remain unclear, creating uncertainty for translation (Halper, 2025; Tiwari, 2025). • Cost: High equipment and material expenses limit access, particularly in resource-constrained settings (Shapira & Dvir, 2021). 5. Emerging frontiers • 4D bioprinting: Incorporates time-responsive bioinks that self-morph or adapt post-implantation (Mathur et al., 2025). • Artificial intelligence: Machine learning tools can optimize printing parameters, predict bioink printability, and generate scaffold designs, accelerating innovation (Ren et al., 2025; Liao et al., 2025).
  • Conclusion: 3D bioprinting represents a technological leap in tissue engineering, enabling precise, customizable, and biologically relevant constructs (Mirshafiei et al., 2024; Fang et al., 2022). Applications in bone, cartilage, skin, and in-vitro modeling highlight both immediate and long-term potential (Di Stefano et al., 2025; Huang et al., 2025). Yet, clinical translation remains dependent on solving the vascularization challenge, scaling and standardizing manufacturing, and establishing regulatory clarity (Liao et al., 2025; Tiwari, 2025). Future integration of 4D printing and AI-driven design offers pathways to intelligent, adaptive tissues (Mathur et al., 2025; Ren et al., 2025). With sustained innovation, 3D bioprinting can progress from laboratory prototypes to clinically transformative therapies, bridging today’s tissue shortages with tomorrow’s regenerative solutions (Halper, 2025; Shapira & Dvir, 2021).
  • Keywords: 3D bioprinting; tissue engineering; bioinks; regenerative medicine; additive manufacturing