The high attrition rate of drug candidates in clinical trials is often attributed to the use of conventional two-dimensional cell cultures and animal models that fail to accurately recapitulate human physiology. Three-dimensional (3D) bioprinting has emerged as a transformative technology for creating sophisticated, patient-relevant tissue models for drug screening and toxicity assessment. Concurrently, machine learning (ML) offers a powerful paradigm for extracting insights from complex, multi-modal data and optimizing intricate processes. This review presents a comprehensive and critical overview of the convergence of 3D bioprinting and ML, with a focus on their integrated applications in drug development. We critically and comprehensively analyze the various data types generated throughout the bioprinting workflow, from process parameters and material properties to biological and “omics” data. We then discuss the application of diverse ML approaches, from statistical methods to deep learning, for optimizing bioprinting processes and enhancing the predictive accuracy of drug screening. By including specific quantitative outcomes and comparative analyses from recent studies, we provide an evidence-based perspective on the state of the field and highlight its potential to accelerate the drug discovery pipeline.

Conventional tumor models have historically failed to fully recapitulate the intricate pathophysiological complexity and dynamic microenvironment of human malignancies, significantly limiting their translational potential. The recent convergence of microfluidic technology and 3D bioprinting has ushered in a paradigm shift in oncology research, enabling more physiologically relevant models. This review provides a comprehensive analysis of the limitations inherent in traditional tumor modeling platforms and elaborates on the fundamental principles underlying microfluidics and additive manufacturing. It systematically explores the integrated applications of 3D-bioprinting–microfluidics systems across three core domains: engineering pathomimetic tumor models, advancing therapeutic screening platforms, and developing high-sensitivity diagnostic tools. This interdisciplinary synergy allows for unprecedented spatiotemporal control over the tumor microenvironment, precise biochemical gradient formation, and seamless integration of functional biosensors. The review further discusses persistent challenges—such as material biocompatibility, fabrication scalability, and the need for standardized validation—and proposes future directions—including the development of multiorgan-on-chip systems, stimuli-responsive biomaterials, and artificial intelligence-enhanced analytical frameworks. The continued integration of 3D bioprinting and microfluidics holds transformative potential for accelerating precision oncology and improving clinical outcomes.  

Additive manufacturing (AM) has transformed the field of metallic bone implants by enabling the production of patient-specific, biomimetic, and high-performance devices. This review focuses on the personalized design of bone implants using AM technologies, particularly selective laser melting and electron beam melting, which allow the fabrication of complex lattice structures that replicate the trabecular architecture of native bone. These architectures enhance load transfer, reduce stress shielding, and promote osseointegration. The review also explores current strategies and digital tools for biomimetic design, as well as numerical simulation methods—including finite element analysis, computational fluid dynamics, and multi-field coupling models—used to optimize implant geometry, porosity, and mechanical performance. Furthermore, recent clinical and preclinical data on in vivo functionality and biological integration are synthesized, with emphasis on the latest advancements to enhance functional outcomes. Altogether, the work provides a comprehensive roadmap for researchers and clinicians seeking to advance implant innovation and improve skeletal tissue repair.

The complexity and variability of lung anatomy, together with the difficulty of repairing lung tissue defects, have long constrained the progress of lung surgery in the era of precision and individualized treatment. In recent years, three-dimensional (3D) printing, deeply integrated with biomedical materials, has emerged as a transformative innovation in regenerative medicine and tissue engineering, offering new strategies to overcome these technical bottlenecks. This review summarizes the current status and clinical applications of 3D printing in lung surgery. By enabling the accurate reproduction of patient-specific anatomical models and the fabrication of functional tissue substitutes in combination with bioactive materials, 3D printing provides unprecedented opportunities to address major challenges such as complex lung nodule resection and bronchial repair and reconstruction. Initially confined to the generation of static anatomical models for surgical planning, teaching, and training, the technology has now advanced, especially with the integration of artificial intelligence, toward the development of real-time intraoperative navigation guides and customized implants. Collectively, these advances have transformed 3D printing from an auxiliary adjunct into a pivotal driver of personalized approaches in lung surgery, with the potential to reshape surgical paradigms and expand future therapeutic frontiers.

Diabetic wound healing disorder is one of the common complications in diabetic patients, characterized by chronic inflammation, impaired angiogenesis, abnormal extracellular matrix (ECM) remodeling, and markedly elevated oxidative stress. Although traditional treatment models have achieved some success, they still face challenges such as prolonged wound healing duration, increased risk of infection, and continuous formation of scar tissue, particularly in gastrointestinal surgical incisions, breast surgery incisions, orthopedic surgical incisions, and neurosurgical incisions. In recent years, the integration of biomaterials and advanced manufacturing technologies has brought new opportunities for diabetic wound healing. Hydrogels have gained increasing attention due to their excellent biocompatibility, degradability, and significant wound healing ability. As an emerging advanced manufacturing method, 3D printing technology could accurately fabricate hydrogels according to the shape and size of the wound, providing an ideal microenvironment for wound healing. This work systematically reviewed the latest research on 3D-printed hydrogels in diabetic wound healing in the past 5 years. It also thoroughly discussed the preparation methods, including physical, chemical, and biological cross-linking methods, and the specific mechanisms of promoting wound healing, such as regulating inflammatory response, promoting angiogenesis, and guiding the normal remodeling of ECM. This review aimed to provide a solid theoretical and experimental basis for the continued development and eventual clinical application of 3D-printed hydrogels for diabetic wounds.  

Bioprinting of smart skin structures is emerging as a versatile platform not only for wound coverage but also for potential sensory regeneration, real-time monitoring of structures, and tissue repair. This review presents a comprehensive roadmap to bridge the gap between biofabrication science and clinical translation. We explore investigations related to piezoelectric scaffolds, conductive polymers, and stimuli-responsive inks in preclinical environments to produce functional features such as thermal and tactile sensing. Early clinical case reports have demonstrated the feasibility of in vitro skin bioprinting strategies, such as skin patches printed for patient-specific applications using minimally manipulated autologous extracellular matrix and umbilical cord mesenchymal stem cell-laden hydrogels for the management of chronic wounds. In parallel, several preclinical in situ bioprinting studies using handheld or microfluidic-assisted devices have shown promising results in full-thickness diabetic and burn wound models in terms of enhanced re-epithelization and neovascularization. We also present inherent differences between in vitro bioprinting of autologous dermo-epithelial substitutions and in situ strategies based on artificial intelligence-guided print path generation and wound topography mapping. Although sensor-equipped bioprinted grafts have shown promising results, they are still in the early stages of development and require validation in large-scale clinical trials. Nevertheless, integration of stem cell technologies, smart biomaterials, and bio-intelligent control systems may eventually be used to support bioprinted skin constructs not only as replacement tissue, but also as potential living, sensing interfaces. This broad multidisciplinary convergence may be beneficial in redefining skin repair by enabling dynamic interactions between engineered skin grafts and host tissue physiology.  

As a frontier interdisciplinary breakthrough, magnetically controlled 4D printing integrates smart materials, additive manufacturing, and magnetic actuation, and is contributing considerably to healthcare practices. By introducing time as the fourth dimension, magnetic 4D-printed devices can dynamically transform their structure and function in response to physiological or external magnetic stimuli, enabling minimally invasive interventions with enhanced adaptability and precision. Integrating artificial intelligence (AI) into magnetically controlled 4D printing accelerates material discovery, optimizes design and manufacturing, and enables intelligent navigation and control in complex in vivo environments. Recent advances highlight promising applications in interventional therapy, targeted drug delivery, and tissue repair, yet challenges remain in achieving biocompatible multifunctional materials, scalable fabrication, and safe clinical translation. Looking ahead, synergistic integration of AI with multimodal actuation, digital twins, and biomimetic systems may unlock unprecedented opportunities for personalized, adaptive, and intelligent medical robots. This perspective outlines current progress, key challenges, and future directions of AI-enhanced magnetically controlled 4D printing, underscoring its transformative potential in redefining next-generation medical robotics.  

Extrusion-based three-dimensional (3D) printing has been rapidly advancing as a key technique for fabricating tissue-engineering scaffolds. However, printing complex structures with appropriate mechanical strength and biocompatibility remains a challenge. Suspended 3D printing is an emerging fabrication strategy that enables the generation of tissues or organs within a support medium that provides a stable printing environment without the need for additional support structures. This study presents a novel strategy for fabricating intricate scaffolds using suspended 3D printing of bioinks incorporating dissolved polycaprolactone (dPCL) and hydroxyapatite (HA). The optimized dPCL/HA bioink demonstrated up to an 85% reduction in print errors compared to conventional methods, significantly enhancing 3D printability. Moreover, mechanical assessments revealed a compressive Young’s modulus approximately 50 MPa higher in dPCL/HA scaffolds compared to dPCL scaffolds. Furthermore, dPCL/HA scaffolds outperformed both PCL and dPCL scaffolds in cell proliferation tests. Complex 3D shapes, including helices, saddles, multi-curvature structures, hollow hemispheres, and zygomatic bones, were successfully fabricated, demonstrating the ability to mimic natural and intricate anatomical structures of the human body. These approaches pave the way for 3D printing patient-specific and structurally robust bone constructs with enhanced mechanical and biological properties.

Compared to conventional two-dimensional (2D) or scaffold-free three-dimensional (3D) drug screening models, biomimetic osteochondral constructs offer superior physiological relevance for studying osteoarthritis (OA) and accelerating therapeutic discovery. This study reports the development of a polymeric microarchitecture (PM)- based 3D osteochondral model for drug screening applications. Microfluidics-assisted fabrication enabled the generation of cartilage-like and osteogenic microtissues by encapsulating chondrocytes and endothelial/osteoblast cells within PMs. These multicellular aggregates were embedded in gelatin methacryloyl and assembled via 3D bioprinting into a stratified osteochondral construct. The model exhibited favorable cell viability, high proliferation, and organized microtissue formation, validating its biological functionality. An OA-like microenvironment was induced using lipopolysaccharide, significantly elevating pro-inflammatory cytokines. Treatment with diclofenac, dexamethasone, or curcumin markedly attenuated this response, reducing tumor necrosis factor-alpha, interleukin (IL)-1β, and IL-6 to 42.1, 193.5, and 193.5 pg/mL, respectively, while elevating the anti-inflammatory cytokine IL-10 to 90.2 pg/mL. Overall, this PM-based 3D osteochondral platform reproduces key features of native joint tissue and holds promise for OA research, drug screening, and regenerative medicine.  

While autologous transplants are the traditional standard intervention for non-healing bone defect regeneration, they carry many risks and limitations. Regenerative composite biomaterials are promising alternatives to conventional autograft and allograft implants. This study aimed to overcome these challenges by creating a novel biodegradable 3D biomaterial scaffold that mimics the structural and physiological properties of native bone. Scaffolds composed of magnesium phosphate (MgP) doped with copper oxide (CuO) in specific proportions (3, 5, or 7% [w/w]) were homogenously distributed in an alginate polymer matrix for the repair of calvarial bone defects in a rat model. The scaffolds were fabricated using a 3D bioprinting technique, and their physical properties were characterized through X-ray diffraction, Fourier transform infrared spectroscopy, and mechanical strength assessments. The bioactivity of the scaffolds was evaluated in vitro for biomineralization and cytotoxicity, revealing high biomineralization and cell viability. Female rats were used for the in vivo experiments, and the defects were examined using microscopic and histological analysis, computed tomography imaging, as well as serum markers including osteocalcin and procollagen III. The in vivo results demonstrated high efficacy of the scaffolds in promoting bone regeneration and enhanced healing in the calvarial defect model. The incorporation of CuO not only improved the scaffolds’ mechanical properties but also exhibited angiogenic effects, fostering an environment conducive to bone healing. Our results indicated that the Alg–MgP–CuO scaffolds have great promise for bone tissue engineering applications and repair, especially with 7% (w/w) CuO doping.  

Understanding the role of perfusion and chemotherapeutic response in solid tumors requires advanced in vitro models that closely recapitulate the tumor microenvironment. Addressing this need, we developed a perfusable three-dimensional (3D) gelatin methacrylate (GelMA)-based tumor model embedded with a hollow microchannel to investigate spatial variations in SKOV3 ovarian cancer cell behavior and their response to carboplatin. This study aims to overcome the limitations of conventional two-dimensional and non-perfused 3D cultures by introducing controlled perfusion and directional drug delivery, thereby providing a more physiologically relevant platform for cancer research and drug testing. Using extrusion- and inkjet-based bioprinting, SKOV3 cells were cultured within the GelMA matrix and exposed to continuous medium flow. We observed that cell behavior varied significantly with distance from the perfusion channel. Cells closer to the channel (0–300 μm) showed increased elongation (aspect ratio: 3.5), faster migration (28.98 μm/day), higher viability (96%), and elevated proliferation (index: 3.8), which progressively declined with increasing distance. Upon carboplatin exposure (0–50 μM), SKOV3 cells exhibited dose-dependent reductions in viability, proliferation, migration, and elongation, with the aspect ratio dropping to 1.17 and the viability to 5% at 50 μM. Matrix degradation analysis revealed increased pore enlargement under perfusion (87–190 μm), suggesting higher matrix metalloproteinase activity. This perfused 3D model enables precise evaluation of chemotherapeutic efficacy and tumor cell heterogeneity, offering a powerful tool for preclinical drug screening, tumor biology research, and future integration of vascular and immune components.

Diabetes is a significant global metabolic disease. Current treatments, including islet or pancreas transplantation and insulin therapy, are limited by donor shortages and suboptimal glycemic control. Islet organoids, three-dimensional (3D) cell aggregates that mimic pancreatic islets, offer a powerful tool for diabetes research, drug screening, and transplantation therapies. However, challenges remain in engineering methods for the scalable preparation of human islet organoids (hIOs) with homogeneous consistency and controllable incorporation of vascular elements. In this study, we developed a novel bioengineering approach for the stable production of human islet tissue models with vascular elements using a combination of 3D bioprinting-based organoid co-culture and cell self-assembly principles. Human adipose-derived mesenchymal stem cells were differentiated into massive and uniform human islet β-like cell aggregates (hICAs) using an off-the-shelf polydimethylsiloxane user-defined micropatterning platform system. A tri-module thermal-controlled bioprinting process employing a gelatin–alginate– Matrigel bioink was used for the 3D bioprinting of hICAs and human umbilical vein endothelial cells (HUVECs). Compared with bioprinted hICAs alone, co-bioprinted and co-cultured hICAs and HUVECs more effectively recapitulated the morphogenesis of human islet development, significantly upregulated the expression of pancreatic islet- and endothelial cell-related markers, and enhanced islet function, namely glucose-stimulated insulin secretion. Thus, the self-assembly of hICAs and HUVECs to form hIOs with vascular elements mimics natural human pancreatic islets and may promote functional maturity. Our method provides a scalable platform for generating vascularized aggregation-based tissue models, supporting studies of pancreatic development and diabetes therapy.  

In this work, we present a mobile drop-on-demand (DoD) printing system based on laser-induced side transfer (LIST). By replacing the bulky free-space optics used in previous LIST configurations with a fiber-based laser delivery system, we developed a compact printing head and integrated it as an end-effector onto a robotic arm. Using model inks with viscosities up to 165 cP and time-resolved imaging, we investigated printability, printing dynamics, and the effect of printing head-to-substrate distance on key printing quality metrics. We found that printing quality deteriorates significantly beyond a 3 mm standoff distance. To address motion-induced printing quality loss on dynamic substrates, we integrated a custom-built fiber-optic distance sensor that actively maintains a constant standoff distance in real time. This enabled high-quality printing on moving targets simulating physiological motion. Additionally, we characterized the influence of ink viscosity and laser energy on droplet formation dynamics and ejected volume. Our results demonstrate the feasibility of motion-compensated, laser-assisted DoD printing in dynamic environments, with potential applications in intraoperative tissue engineering.  

Ti6Al4V scaffolds demonstrate significant translational potential for bone defect reconstruction by virtue of their exceptional biocompatibility and corrosion resistance. However, achieving concurrent osseointegration enhancement and mechanical compatibility with native cancellous bone remains a critical design constraint. A trabecular bone-mimetic porous Ti6Al4V scaffold was fabricated via Voronoi-tessellated computer-aided design and selective laser melting. Precise modulation of pore architecture enabled controlled porosity. The mechanical properties of the scaffold were characterized through compression testing. Early-stage in vivo osseointegration was evaluated at weeks 4 and 12 in a rabbit femoral condyle defect model using histomorphometry and micro-computed tomography, with comparisons made against conventional strut-based and G-curved lattice structures. The Voronoi scaffold demonstrated an elastic modulus and yield strength comparable to cancellous bone, thereby mitigating stress-shielding effects. Additionally, according to the results from the biomechanics, computational fluid dynamics, and in vivo analyses, the scaffold demonstrated significantly enhanced osteogenic potential and superior bone-implant interface integration compared to the strut and triply periodic minimal surface (TPMS) designs. In conclusion, the Voronoi design provides an effective biomimetic strategy for fabricating porous titanium alloy bone scaffolds with enhanced osteogenic properties, which embody higher potential than conventional struts and TPMS structures in facilitating bone defect repair.  

An integrated framework combining finite element analysis (FEA) and artificial neural networks (ANN) is presented to enhance the prediction and design of bioprinted scaffolds. By leveraging the strengths of data-driven learning and physics-based simulations, the hybrid approach (ANN + FEA) achieved superior predictive accuracy and generalization compared to standalone approaches. Validation against experimental results demonstrated that a single ANN model yields a relative error of 5.17% when predicting the scaffold’s Young’s modulus. Incorporating FEA simulation based on ANN-predicted geometry and material properties reduced the relative error to 4.72%, representing an 8.6% improvement. The framework also enables accurate simulation of unseen combinations of printing parameters located far from the experimental data manifold, reducing prediction errors from 14.2% (ANN-only) to 5.7% (hybrid). By integrating predictive modeling, simulation, and data augmentation, this approach offers an efficient pathway for optimizing scaffold designs and accelerating the development of biomaterials with tailored mechanical performance.

Cartilage injury and degeneration are common clinical problems that severely affect joint function and quality of life. Due to the limited self-healing capacity of cartilage, there is an urgent need for advanced biomaterials and strategies to promote effective cartilage regeneration. In this study, we present a 3D-bioprinted kartogenin (KGN)-loaded hydrogel with optimized biocompatibility and biomechanical properties for cartilage regeneration. By investigating the molecular mechanisms underlying KGN-induced chondrogenic differentiation of bone marrow stromal cells (BMSCs), we identified the critical role of the Smad1/5/9 signaling pathway through transcriptomic analysis. The hydrogel scaffold demonstrated uniform microstructure, robust mechanical stability, and controlled degradation, supporting BMSC adhesion and proliferation. In vitro experiments revealed that KGN activation of Smad1/5/9 significantly enhanced chondrogenic differentiation, evidenced by upregulated cartilage-specific matrix production and morphological changes in BMSCs, while pathway inhibition diminished this effect. Animal experiments using a rat model of cartilage injury demonstrated the hydrogel’s biosafety, with no systemic toxicity or adverse inflammation, and its capacity to promote structured neocartilage formation rich in type II collagen. Histological and immunohistochemical analyses further validated the hydrogel’s superior repair efficacy compared to controls. These findings highlight the dual functionality of the 3D-printed KGN-loaded hydrogel as a mechanically stable carrier and a bioactive inducer of BMSC chondrogenesis, mediated via Smad1/5/9 signaling, offering a promising strategy for cartilage tissue engineering.

Hyaluronic acid (HA)-based hydrogels have gained significant interest for many biomedical applications because of their biocompatibility and degradability as glycosaminoglycans. However, it is challenging to control their mechanical properties and degradation rates. In this study, we investigated the potential of carbodihydrazide-modified HA (HA-CDH) and oxidized diol-modified HA (odHA) to form hydrogels. We modulated the mechanical stiffness of the HA-CDH/odHA hydrogels by adjusting the degree of CDH substitution and polymer composition in the gels. These hydrogels exhibited improved hydrolytic stability under physiological conditions, which was attributed to the presence of multiple delocalized electron arrangements within the hydrazone bonds. Notably, the enzymatic degradability of these hydrogels was unaffected by the hydrazone bonds. We developed self-healing HA-CDH/odHA hydrogels using free adipic acid dihydrazide and utilized them to fabricate various three-dimensional (3D) structures via 3D printing. We integrated resonance-stabilized hydrazone chemistry with self-healing behavior in HA-based hydrogels, enabling both slow degradation and direct extrusion-based 3D bioprinting of cell-laden constructs without secondary networks or post-crosslinking treatments. Furthermore, we investigated the effect of enhanced mechanical stiffness on in vitro cell differentiation and observed significant gene expression levels that were indicative of chondrogenic and osteogenic differentiation within hydrogels with increased stiffness. These findings could help elucidate the effect of the physical properties of natural polysaccharide-based hydrogels on cell phenotype modulation and expand their applications in tissue engineering.  

The regeneration of large-segmental bone defects remains a significant clinical challenge due to their complex microenvironments. Three-dimensional (3D)-printed polycaprolactone (PCL) scaffolds offer a potential solution but exhibit limited osteoinductive capacity. In this study, 3D-printed PCL/β-tricalcium phosphate (TCP) composite scaffolds were pretreated with NaOH, followed by functionalization with bioactive collagen and β‑TCP. These modifications markedly improved the scaffolds’ hydrophilicity without compromising mechanical integrity. In vitro studies with MC3T3-E1 cells demonstrated that the CS@TCP scaffolds significantly enhanced early osteogenic differentiation compared to C, CS, and CS@COL scaffolds, as indicated by the alkaline phosphatase activity assay. In vivo evaluation using three different rabbit cranial defect models revealed superior new bone formation in the partial-thickness cranial defect (PTD) groups compared to the full-thickness cranial defect (FTD) and intact cranial bone onlay (Onlay) groups, potentially due to the increased vascularization and abundant endogenous stem cells in the PTD groups. Despite reduced new bone formation in the Onlay group, its bone integration advantages may be advantageous for cosmetic surgery applications. This study investigated how β‑TCP surface modification interacts with clinical application-specific microenvironments to maximize the regenerative potential of 3D-printed scaffolds, providing crucial guidance for scaffold design in effective bone defect repair across various clinical scenarios.

When limbal stem cell deficiency (LSCD) is partial, the standard treatment involves covering the corneal surface with amniotic membrane (AM), which supports the proliferation of the remaining limbal stem cells (LSCs). In cases of complete LSCD, the most common treatment is cultured limbal epithelial transplantation (CLET), although there is a risk of rejection. Studies have shown that mesenchymal stem cell transplantation is equally safe and effective as CLET. Recent research has demonstrated successful differentiation of adipose-derived adult mesenchymal stem cells (ADSCs) into LSCs. Combining AM transplantation with LSCs improves treatment efficacy. However, a limitation of AM use is donor variability and the associated risk of immune rejection. We propose the use of 3D-printed collagen as a scaffold seeded with LSCs derived from ADSCs for the treatment of LSCD in a rat model. The 3D-printed collagen scaffolds exhibited good transparency. In vitro differentiation of ADSCs into LSCs showed morphological changes that were more pronounced and occurred more rapidly on 3D-printed collagen. Among the tested substrates, 3D-printed collagen was the most efficient for differentiation, yielding the highest expression of LSC-specific markers (p63α and BMI-1) and the corneal epithelial marker (SSEA-4). LSCs differentiated in either AM or 3D-printed collagen I scaffolds were transplanted into a rat model of LSCD and compared with the standard, cell-free AM treatment. In all treatment groups, the induced epithelial wound was closed; however, integration of the 3D-printed collagen scaffold was statistically superior to that of AM. However, markers for different corneal structures (PAS, BMI-1, p63α, and cytokeratins 12 and 13) indicated that the generated epithelium was conjunctival rather than corneal, suggesting that the contribution of ADSC-derived LSCs was insufficient for complete corneal re-epithelization.  

The treatment of infectious bone defects is a major challenge in orthopedics, with infection control and defect repair as the two primary treatment goals. The development of 3D-printed bone scaffolds capable of sustained and stable antibiotic release is an effective strategy for treating such defects. Specifically, the antibiotic loading method and the concentration of released antibiotics significantly affect infection control and bone repair outcomes. In this study, double antibiotic microspheres were prepared via the double emulsion-solvent evaporation method. Moxifloxacin and rifampicin (RM) were encapsulated by poly(lactic-co-glycolic acid) (PLGA), forming RM–PLGA. Subsequently, different concentrations of RM–PLGA and basic fibroblast growth factor (bFGF) were loaded onto a 3D-printed triply periodic minimal surface (TPMS) titanium scaffold (TiS) with a graded porosity design, enabling stable dual-controlled antibiotic release and enhanced release stability. In vitro results revealed that RM–PLGA/bFGFgelatin methacrylate [GelMA])@TiS exhibited strong antimicrobial properties, cytocompatibility, and the capacity for osteoblast differentiation and extracellular mineralization. In vivo, RM–PLGA/bFGF(GelMA)@ TiS was effective in inhibiting infections induced by Staphylococcus aureus while promoting osteogenesis and angiogenesis. These results suggest that RM–PLGA-2/ bFGF(GelMA)@TiS can stably release antibiotics to achieve the therapeutic goals of infection control and induction of both osteogenesis and angiogenesis.  

The repair of large segmental bone defects has always been a significant challenge in clinical practice, with stress shielding being one of the key issues. Here, tree-like fractal biomimetic scaffolds were created based on the morphological similarity between natural trees and bone trabeculae. To optimize the balance between high yield strength and low elastic modulus of the scaffold, an integrated particle swarm optimization-backpropagation-non-dominated sorting genetic algorithm III (PSO-BP-NSGA III) was employed. The scaffolds were fabricated using selective laser melting three-dimensional printing with Ti6Al4V, and their mechanical performance was experimentally evaluated and compared with the algorithm’s predictions. The tree-like fractal scaffold exhibited a radial gradient in porosity, similar to that of natural bone. The second-order fractal scaffold achieved an effective synergy between yield strength and Young’s modulus, demonstrating high yield strength and low Young’s modulus. Additionally, it showed a favorable fluid flow gradient and permeability, with a comprehensive permeability of 3.13 × 10−8 m². The relative errors between the test and predicted values of yield strength and Young’s modulus were 0.83% and 7.93% respectively, indicating that the PSO-BP-NSGA III integrated algorithm has good predictive ability. These findings establish a validated bionic design framework that integrates advanced optimization algorithms to guide the development of bone tissue engineering scaffolds.  

Concerns related to the trachea frequently arise from obstructive conditions and occlusions, such as tracheal stenosis, tracheomalacia, traumatic disruptions, and papillary thyroid carcinoma. These medical challenges underscore the need for new biomaterials to support tissue engineering for tissue regeneration. The advent of three-dimensional (3D) bioprinting technology has emerged as a pivotal advancement, facilitating the fabrication of patient-specific, biocompatible, cell-laden constructs. This technological advancement enables the controlled promotion of cell growth and tissue development, thereby offering a promising avenue for tissue regeneration. In this study, we developed mixed ultrashort peptide bioinks for the 3D bioprinting of a trachea-like construct that exhibits self-healing and elastic properties. We employed a stiffness prediction map (SPM) as an empirical tool to predict the physical characteristics and stiffness behavior of the mixed bioinks, thereby facilitating the optimization of the 3D bioprinting process. The SPM enabled the fine-tuning of these bioinks by identifying peptide mixtures that successfully mimic the natural stiffness of the perichondral niche microenvironment. These mixed bioinks successfully promoted mesenchymal stromal cell differentiation towards chondrocyte formation, thereby facilitating the biofabrication of elastic 3D-printed structures for trachea regeneration. Our bioinks exhibited remarkable printing resolution and mechanical properties while supporting cell growth and chondrogenesis. The bioprinted trachea-like model, cultured for up to 100 days, showed excellent mechanical properties, resulting a stable elastic biomaterial. This study is the first to combine SPM with 3D bioprinting for the fabrication of a trachea-like model, supporting the development of advanced self-healing biomaterials for trachea tissue regeneration.

Complex bone defects continue to pose significant challenges in the field of orthopedics, where restoring structural integrity and promoting osteointegration are essential for successful repair outcomes. Three-dimensional (3D) printing offers a robust approach for fabricating patient-specific scaffolds with precise architectural and functional control. In this study, we designed and fabricated porous scaffolds composed of tantalum and titanium alloys, both with identical porosity, utilizing 3D printing technology. We systematically compared their mechanical properties, in vitro osteogenic potential, and in vivo bone integration within a defect model. The porous tantalum (PTa) scaffolds demonstrated exceptional biocompatibility, enhanced cell adhesion, and significantly promoted the osteogenic differentiation of mesenchymal stem cells, as well as extracellular matrix mineralization. In vivo, the PTa scaffolds not only expedited bone repair but also improved osteoconductive ingrowth compared to their titanium counterparts. Multi-omics analyses further elucidated potential biological mechanisms underlying the superior performance of PTa. These findings underscore the potential of 3D-printed PTa as a promising scaffold material for the clinical repair of bone defects.  

The rising prevalence of orthopedic conditions in aging populations has created a growing demand for advanced implants with enhanced biocompatibility, mechanical performance, and tissue integration. To meet these demands, it is necessary to investigate the metamaterial properties of cross-scale porous structures, including both macroscale architecture and microscale texture. Accordingly, we employed parametric modeling to design porous structures; analyzed blood flow distribution through various multi-level porous designs using mold flow simulation; evaluated their compressive properties through finite element analysis; assessed biocompatibility via animal experiments; and obtained tissue ingrowth data using micro-computed tomography. The results indicated that when fluid flowed through cross-scale porous structures, the overall pressure was low, and the Kelvin cell structure exhibited favorable flow field characteristics under low pressure. When the structures were pressurized, texturization methods involving material removal resulted in larger displacements, while those involving material addition led to smaller displacements. The Kelvin cell structure exhibited extensive tissue ingrowth with a dense tissue pattern internally, and the amount of ingrowth decreased from the inside to the outside. Increasing the roughness of porous structures via material removal increased the surface-to-volume ratio to a certain extent but did not promote tissue ingrowth. In contrast, increasing roughness by material addition favored tissue ingrowth, laying a foundation for the design of cross-scale metamaterial implants.

Osteochondral defects resulting from trauma or degenerative diseases are challenging to treat due to the complex hierarchical structure and limited self-healing capacity of articular cartilage. Recent advancements have identified SOX9-positive (SOX9+) sclerotomal progenitors (scl-progenitors), derived from human pluripotent stem cells, as a promising cell source capable of mimicking endochondral ossification and promoting osteochondral regeneration. A personalized three-dimensional (3D)-bioprinted scaffold was developed using treated dentin matrix (TDM)—a decellularized matrix rich in low-crystallinity hydroxyapatite, type I collagen, and osteoinductive factors—as the core bioactive material. To enhance mechanical strength and printability, the TDM was combined with methacrylated gelatin and zirconia nanoparticles. SOX9+ scl-progenitors were encapsulated within the hydrogel matrix and printed using extrusion-based 3D bioprinting to fabricate cell-laden scaffolds with tunable biomechanical and biological properties. The engineered constructs supported robust cell viability, proliferation, and differentiation toward osteochondral lineages in vitro. In vivo implantation in a nude rat knee osteochondral defect model demonstrated excellent biocompatibility and significant regeneration of both cartilage and subchondral bone tissue. This study presents a translatable and customizable platform integrating stem cell technology, natural biomaterials, and 3D bioprinting for osteochondral tissue engineering. The bioengineered construct offers substantial advantages for personalized osteochondral defect repair over conventional approaches.