Toward Efficient Cartilage Disease Management with Additive Manufacturing: Monitoring, Cell Culture, and Drug Release

Articular cartilage damage is often caused by joint disease, trauma, and aging in everyday life. Cartilage damage usually refers to some changes in the normal structure and a gradual loss of function. Local discomforts, such as slight swelling or pain, may occur. Due to the lack of blood vessels and nerves in articular cartilage, articular cartilage damage is difficult to repair, making the detection and repair of articular cartilage damage difficult. New detection and repair technologies are urgently needed. The existing treatment methods are often used to monitor the internal environment and repair cartilage by implanting stents. Due to its high precision and simulation, 3D printing has shown great potential in carrier drug refinement and detection sensing and has become one of the more ideal technologies in the biomedical field. This article reviews the mitigation measures of bone injury, 3D printing technology, and treatment strategies for bone injury based on 3D printing technology. In addition, some challenges and possible solutions are also put forward for the treatment of bone injuries, as well as some possible development directions in the future.


Introduction
Articular cartilage is the elastic connective tissue in the joint, which causes changes in the normal structure of cartilage after acute trauma or excessive compression and friction, [1] as well as after chronic degeneration of the bone and joint area, which exposes the bone beneath the cartilage, thus triggering discomforts such as soreness and pain in the bone and joint. [2]Changes in the bone structure of the injured bone directly or indirectly affect the health and quality of life of the patient.As yet, it is generally incurable in clinical practice, and life-long treatment is often required to improve symptoms and relieve the condition. [3]only cell culture, with single usability.In this review, we introduced the methods and materials used for 3D printing, focusing on the causes and inhibition methods of cartilage damage.Then, we described the application of 3D printing in cartilage repair, focusing on the combination of drug release, cell culture, and internal environment monitoring in the repair of defective cartilage.Finally, the prospects of 3D printing in bone defect suppression and articular cartilage repair are briefly introduced (Figure 1).

Bone Damage
Articular cartilage is a transparent layer of connective tissue covering the joint surface, consisting of chondrocytes, matrix, and fibers, which conducts and distributes loads and maintains tolerable contact stresses, and plays an important role in interarticular lubrication. [8]However, external force or excessive friction will cause bone edema, degeneration, and fracture between joints.Due to the changes in the bone structure of the damaged bone, local cartilage cells are lost, resulting in cartilage defects (Figure 2a).According to the latest research, the subchondral bone is considered to be a very important part of cartilage repair, and the growth factors it secretes are crucial to maintaining the stability of cartilage. [9]As shown in Figure 2b, Zhou and his coworkers summarized the methods of osteochondral repair and tissue regeneration with respect to the structural characteristics of osteochondral structures, discussed the classification and categorization of their defects, and proposed potential future solutions and development directions for cartilage repair.As mentioned previously, cartilage defects can be repaired by secreting growth factors, but it is also critical to reduce interarticular friction, and enhancing its lubrication and supplementing it with anti-inflammatory therapy can effectively alleviate cartilage defects. [10]Inspired by ball bearings, Yang et al. demonstrated a microfluidic gelatin methacrylic acid sphere manufac-tured by microfluidic technology, which is modified by the bionic grafting method, and can effectively load and release drugs due to its multi-porous structure, transforming the sliding friction between joints into rolling friction, reducing inter-joint friction while releasing drug molecules for cartilage repair, so as to inhibit degradation of chondrocytes induced by tumor necrosis factor, which is a revolutionary repair method in the field of cartilage repair.(Figure 2c). [11]enerally, the repair and regeneration of articular cartilage are indispensable for its treatment.Common treatment methods can only alleviate rather than cure, which also makes the quality of life of patients generally low in clinical application.One of the solutions to the above problems is to load the ball model into the bone joint by reducing the friction between the articular cartilage.The specific idea is to load the drugs and growth factors into the ballbearing model, implant them into the bone joints, and repair the cartilage to improve the damage to the bone joints.Combining drugs or growth factors with 3D technology to create a carrier scaffold that can meet the needs of human cartilage repair is a cutting-edge topic that is currently being studied by researchers in various countries.

3D Printing
3D bioprinting methods have received a great amount of attention in building bionic systems in recent years.It is capability to integrate multiple tissue cells, biomaterials, and bioactive factors in a precise spatial location. [12]Owing to its high degree of precision as well as strong simulation, 3D bioprinting has been used to construct many complex structures in vitro, such as dental crowns, artificial hearts, and muscles.Consequently, the inherent differences in the microenvironment from cartilage to subchondral bone can be addressed by taking advantage of 3D bioprinting.Furthermore, 3D bioprinting is anticipated to avoid the previously reported deficiencies in mechanical properties as well as complex preparation processes.

Materials
When using 3D printing to manufacture various models, the materials required are different under different application scenarios. [13]With a proper material selection, many scaffold standard such as biodegradability, osteoinductivity, promotion of chondrogenesis, and biocompatibility can be adequately met.Among these, the durable and biocompatible nature of the material is crucial. [14]Finding sustainable printing materials from nature is very important for 3D printing.As shown in Figure 3a, Chen et al. transformed hard pollen particles into stimulusresponsive micro gel particles and used them as a support matrix to improve the stability of applied culture scaffolds.Pollen particles not only have good biocompatibility but also have good regenerative and rheological tunability, which have great potential among available natural materials.In addition, biocompatible materials that do not trigger allergic or toxic reactions are widely used in 3D printing, but the rheological properties of the materials are also critical to the performance of the scaffolds used. [15]ydrogel has been widely used as a multifunctional biomaterial The osteochondral defect map and CT map of the weight-bearing area of the medial femoral condyle in patients with osteochondral defects of the knee joint.Reproduced with permission. [12]Copyright 2020, John Wiley and Sons.c) The design of super lubricated ball-bearing microspheres is used for the collaborative treatment of osteoarthritis based on enhanced hydration lubrication and continuous drug release.Reproduced with permission. [11]Copyright 2020, John Wiley and Sons.
Figure 3. a) Natural pollen microgel can be used for various forms of 3D printing.Reproduced with permission. [15]Copyright 2021, John Wiley and Sons.b) A double-layer hydrogel scaffold printed in 3D with gelatin as the substrate.Reproduced with permission. [16]Copyright 2020, John Wiley and Sons.c) Schematic diagram of the double crosslinking process with biomaterial ink containing a silk base (including carbon nanotubes). [17]Copyright 2021 American Chemical Society.d) A metal-organic framework (MOF) hydrogel can be used to print stretchable structures with adjustable mechanical properties.Reproduced with permission. [18]Copyright 2020, American Chemical Society.e) Tooth model printed with apatite as the material. [19]Copyright 2021 John Wiley and Sons.f) Polycrystalline structure model printed with transparent ceramics.Reproduced with permission. [20]Copyright 2020, John Wiley and Sons.g) A scaffold model of an implantable joint printed with biological ink with gelatin as the main component.Reproduced with permission. [21]opyright 2021, Elsevier.h) Stent model of a simulated blood vessel printed with black scale as the matrix.Reproduced with permission. [22]Copyright 2021, John Wiley and Sons.
for in vitro tissue organ fabrication because of its good biocompatibility and biodegradability.It demonstrates properties similar to those of natural ECM.Furthermore, the distinct advantages of high water composition and high porosity in hydrogels produce a 3D cross-linked network that facilitates cell retention, differentiation, migration, adhesion, and proliferation.Therefore, hydrogels are considered ideal for the fabrication of bioactive scaffolds for the repair of cartilage defects.As shown in Figure 3b, Gao et al. manufactured a double-layer hydrogel scaffold with GelMA and GelMA hydroxyapatite based on extrusion printing, the scaf-fold was implanted in a rabbit model to observe the effect of scaffold mesh filament spacing on osteochondral regeneration.It was found that cell migration and nutrient infiltration rates were maximized when the interfilament distance was appropriate, and the controlled rheology of the bilayer hydrogel scaffold provided a more suitable growth environment for cartilage repair, which provides a simpler and intuitive strategy for the field of cartilage repair.Although biologic inks composed of polymers of natural origin have good biocompatibility, they lack some mechanical properties and degrade rapidly, which are somewhat limited for some fragments of scaffolds with high requirements for stretching properties. [16]s shown in Figure 3c, Mehrotra et al. developed a silk-based bioink composed of nonmulberry silk protein, polyethylene glycol dimethacrylate, and GelMA polymer to fabricate 3D functional cardiac constructs by a double cross-linking method, and carbon nanotubes loaded on nonmulberry silk promoted cardiomyocyte viability while upregulating myonodular formation and beating rate.Nonmulberry silk can support the attachment of cardiomyocytes due to its high tenacity, which makes it a good choice for constructing scaffolds with high tensile properties.This biomaterial with exceptional tensile properties can be also used in the manufacture of cartilage repair scaffolds, which can be used for bending and stretching bone joints to ensure that the scaffold structure is not broken while promoting cartilage repair.Metal-organic frameworks (MOFs) possess good drug delivery and catalytic separation capabilities, but their mechanical strength is not easy to change, so their structural construction is limited. [17]As shown in Figure 3d, Liu et al. made the mechanical properties and tensile properties of MOFs adjustable by combining the general double network hydrogel prepolymer of acrylamide and alginate and the shear thinning agent, which enabled us to load some composites with high dispersion on the scaffold when building the scaffold.Different from conventional injuries, the structure used for cartilage injury repair needs to match the damaged part to have a better healing effect.Use materials with higher mechanical strength to print the stent so that the mechanical strength of the stent is similar to the cartilage strain force, and the treatment effect will be better.If loosening occurs, it will not only have no positive treatment effect on cartilage damage but also aggravate the degree of cartilage damage. [18]ame as cartilage damage material requirements, Zhao et al. wanted a material with high hardness and strength.They used HAp nanorods as the material to build the dental crown structure model based on direct ink writing and printing technology.The arrangement order of HAp nanorods and natural enamel is highly similar.This method has brought a new method to the clinical repair of teeth.This material may also be used in the area of cartilage repair, as the stiffness and strength ensure that the loaded drugs and growth molecules are well-loaded in the scaffold and work for a long time, speeding up the repair of broken cartilage.(Figure3e). [19]he micron-sized transparent yttrium aluminum garnet (YAG) single crystal doped with Nd has the advantages of good mechanical properties, high thermal conductivity, high hardness, and stable physicochemical properties, especially its excellent optical and laser properties, making it one of the most important solid-state laser materials currently, with a wide range of applications in industry, medicine, scientific research, and military.As shown in Figure 3f, Cooperstein et al. printed a polycrystalline structure with Nd-doped micron transparent yttrium aluminum garnet (YAG) according to its required optical characteristics.This transparent yttrium aluminum garnet can be used for various optical applications, such as lighting and laser emission. [20]It has great potential in areas with special requirements for optical performance.YAG with superior optical properties is transparent in the spectrum and has no particle sense, and the reflected light emitted by various doped elements is different, which has brilliant potential to be used as a laser medium.This feature enables the manufacture of photonic crystal sensors for cartilage repair detection, which enhances precision under the premise of accuracy assurance and has significant potential for sensor applications.
Tissue engineering techniques offer a promising strategy for bone tissue regeneration, providing not only mechanical support and biological function of bone but also effectively addressing issues such as tissue source and immune rejection associated with bone grafting.Typically, the use of tissue engineering strategies combines three basic elements: scaffolds, stem cells, and growth factors.The key to repairing cartilage damage using bone tissue engineering techniques is to effectively recruit stem or progenitor cells into the implanted scaffold and induce their differentiation into functional bone.As shown in Figure 3g, Liu et al. designed a 3D bioprinted scaffold containing bone marrow mesenchymal stem cells (BMSC), which consists of methacrylic acid and hyaluronic acid, and polycaprolactone to construct a structural domain with three separate functional layers, with good biocompatibility and stable long-term properties to build a solid platform for cartilage repair.This scaffold simulates the structure of osteochondral bone while incorporating kartogenin and -TCP for hampering the growth of osteoarthritis, repairing defective osteochondral bone, and facilitating the recovery of joint function in vivo.Loading BMSC on scaffolds has already become a popular technique in the field of cartilage repair, but the biocompatibility and degradability of the materials used to construct the scaffolds still deserve our special attention. [21]Additionally, to enhance the activity of cells on the scaffold, as shown in Figure 3h, Wang et al. used a coaxial microfluidic printing strategy to dope black phosphorus into the fibrous hot channel scaffold.The inserted black scale, owing to its reversible contraction and expansion behavior, promotes the infiltration of suspended cells into the scaffold channel, which drastically improves the degree of cell proliferation and accelerates the regeneration of defective cartilage.This dynamic channel scaffold will increase the drive and stimulation of the cells, trapping the surrounding free-living progenitor cells, thus accelerating cartilage regeneration.This material would be a promising alternative in various tissue engineering to promote inward vascular growth. [22]n summary, the characteristics of different materials are also quite different.For example, pollen particles have good reproducibility and rheological adjustability.When the rheological property is appropriate, the printing effect and molding speed will also be greatly improved; that is, the molding property and fineness of the scaffold obtained will have a better effect than ordinary materials.It can be used to increase the stability of the scaffold, while Hap nanorods are used to build the crown model because of their high hardness.When the mechanical strength of the printing material is high, the printed model has good formability, the structure is not easily damaged, and the stability is improved.Hap nanorods are a better choice when making models with high hardness requirements.Materials are selected according to the application occasion and manufacturing process of the required model, which makes various models based on 3D printing better understood and applied by people and provides a more open road for materials used in 3D printing.Reproduced with permission. [23]opyright 2020, American Chemical Society.b) A sample obtained by processing silk fibroin by light curing.Reproduced with permission. [24]Copyright 2020, Elsevier.c) The pattern with a double tornado shape printed based on embedded printing.Reproduced with permission. [25]Copyright 2019, John Wiley and Sons.d) Modification or refinement of the structure during solidification of liquid metal by laser deposition.Reproduced with permission. [26]opyright 2020, Springer Nature.e) Model diagram of extrusion printing.Reproduced with permission. [27]Copyright 2019, John Wiley and Sons.f) Model of the rat thigh bone equivalent to the human ear with hydrogel as the extruded material.Reproduced with permission. [28]Copyright 2020, John Wiley and Sons.

Methods
Additive manufacturing methods have been developed to satisfy the demand for printing complex structures at granular resolution.Increased print accuracy, quicker print speeds, and the ability to increase the dimensions of printed structures are some of the critical factors pushing additive manufacturing technology forward, offering a wider range of options.Fused deposition modeling is a simple and inexpensive manufacturing process, but printing structural parts with high tensile and bending properties remains difficult due to few pores and weak interlayer adhesion.As shown in Figure 4a, Yang et al. have combined fused deposition with laser scribing to pattern thin laserinduced graphene (LIG), combining the otherwise shortcomings of fused deposition with laser scribing to create components that can accurately monitor the performance of intelligent gears in terms of rotation and wear.This innovative and inexpensive combination might also be applied to the preparation of scaffolds for cartilage repair, particularly in bone joints, where a certain degree of bending is required to fit the joint optimally for cartilage repair. [23]As one of the first 3D printing methods, digital illumination processing (DLP) technology is widely used to print tissue engineering and scaffolds by scanning the material with a controlled ultraviolet light beam to cure it.As shown in Figure 4b, Hong et al. designed a filamentous protein hydrogel that can be used for cartilage repair engineering with the help of the uniform distribution of DLP so that autologous modified chondrocytes can be uniformly distributed on the hydrogel scaffold to promote cartilage regeneration.Due to its speedy and straightforward method, the digital illumination process combined with the printing of the relevant scaffold with suitable materials, guarantees the biological properties of the scaffold using more traditional manufacturing techniques, which also ensures that this technology is widely applied in the field of cartilage repair. [24]nlike previous printing technologies, Luo et al. used embedded printing to fabricate microstructures of vascular networks, an extrusion-based derived printing technique that prints free-form structures with spatially defined features without the need for auxiliary structures.In terms of printing requirements, the printing requirements have been simplified to a large extent, while the accuracy of printing has been increased significantly, embedded printing is a very efficient printing method for manufacturing highly accurate and complex core components, In the future, embedded printing may play an integral role in drug screening, in vitro tissue modeling and other fields.(Figure 4c). [25]As an equally high-precision printing technology, laser deposition also has the advantages of higher flexibility and material utilization, and not long ago, Todaro et al. used titanium alloy as a printing material to refine samples by laser deposition and found that it was possible to completely transform columnar grains into equiaxed grains, which brought a new approach to refining other metallic materials as well as improving the mechanical properties of the alloy (Figure 4d). [26]In the field of cartilage repair, the denseness and mechanical properties of the material used for cartilage repair scaffolds are extremely important, and by applying this technology to cartilage repair, the increased precision of the scaffold will, to a certain extent, significantly increase the drug loading rate and thus accelerate the degree of cartilage repair.Compared to the high-precision printing methods that have emerged in recent years, extrusion, a traditional printing method with excellent structural fidelity and better flexibility, manufactures parts by extruding the material through the printhead and through material accumulation; as shown in Figure 4e, Yang et al. fabricated an adaptable scaffold without a current collector based on extrusion printing technology, a sustainable printing and design method that can be applied to fabricate a variety of highperformance, multidimensional structures.By altering different printing materials and designing double or multi-layered scaffolds for loading different types of drugs or proliferating cells, a dual effect is achieved, increasing the efficiency of treatment and shortening the cartilage repair cycle while reducing patient pain. [27]At the same time, Zhang et al. also fabricated a bionic scaffold by extrusion for the growth of cell spheres, which are printed by extrusion to disperse highly viscous bioink with high cell density and high cell viability, which is essential for tissue engineering repair.Maintaining the original cellular activity is one of the criteria for assessing the performance of a scaffold, and conventional extrusion is just the thing for this.In the near future, it may be possible to combine extrusion with superior biomaterials to create scaffolds that can be prepared without harming cellular activity and in the meantime improve scaffold precision(Figure 4f). [28]ifferent printing methods have different corresponding printing characteristics.For example, extrusion is a common printing method, but because of its high requirements for the rheological properties of materials, when some materials with weak rheological properties are used, extrusion will not be selected.Although melt deposition modeling is simple and inexpensive, it has fewer pores and weak interlayer adhesion, so it cannot be used to print devices with high tensile and bending properties.According to the use of materials and models, selecting appropriate printing methods or combining multiple printing methods is crucial to the success of research progress.

Application
After a traumatic injury or degenerative joint disease, cartilage has a limited ability to repair itself spontaneously, to this date, regeneration of articular cartilage remains a major challenge because of its avascular nature, making it difficult for nutrients and regenerative stimuli to penetrate the damaged area.In addition, the relatively low metabolic activity of chondrocytes makes it difficult to produce enough cartilage matrix to repair the damaged cartilage. [29]But with the development of science and technology, methods used to treat cartilage injury are gradually becoming more abundant. [30]The internal environment of the bone and joint is monitored in real-time, anti-inflammatory drugs are released to slow cartilage defects, and growth factors are released to promote cartilage repair, thus repairing cartilage defects in the area and restoring the function of the joint.

Monitoring and Detection (Physiological and Biochemical Indicators)
Articular cartilage is a highly specialized tissue that lacks blood supply, nerve tissue, and lymphatic tissue.Once injured, it is unable to repair itself, leading to joint degeneration and dysfunc-tion.During the treatment of cartilage injuries, the bone healing process needs to be properly assessed in order to administer limb stabilization.Therefore, an accurate assessment of the morphology and extent of the injury is particularly important for the diagnosis, prognosis, and treatment of cartilage injuries.As an important branch of biomedical engineering, biomedical sensors are tools to obtain physiological and pathological information of the human body, which can convert the measured physiological parameters into the corresponding electrical quantity output and provide the required data for clinical diagnosis research and analysis. [31]The majority of the sensors for monitoring cartilage damage and repair are derived from 3D printing.Compared to bone tissue engineering scaffolds made using other techniques, 3D printed sensors offer unique advantages in terms of individualization, precision, mechanical strength, and spatial structural complexity.Current research has found that 3Dprinted sensors also have the advantage of compressive strength.In addition, many hydrogel sensors have good cytocompatibility and have a significant contribution to cartilage repair. [32]Currently, the scope of application of 3D printing-based biomedical sensors is quite wide, and the human body is monitored by implanting biodegradable wireless sensing systems. [33]A short while ago.Palmroth et al. designed a biodegradable resonance sensor composed of an inductor coil fixed to a bone and a capacitor connected in parallel.This sensor generates inductive coupling between the sensor and the reader coil, thus generating a resonance curve in a given frequency range and monitoring the corresponding parameters by their maximum or minimum values.Although this sensor is only suitable for short-term use, it provides a reference for future research related to biodegradable resonance sensors and greatly advances the biomedical field (Figure 5a). [34]s a new generation of clinical testing platforms, microfluidics has the characteristics of low reagent consumption, lower cost, operation automation, system closure, high detection throughput, and easy operation.The development of microfluidics not only promotes the construction of in vitro cells and tissues and organs but also accelerates the progress of efficient diagnostic as well as therapeutic technologies.Microfluidics, as a crossdisciplinary fusion of technologies applied in the field of in vitro diagnostics, greatly promotes the innovation of in vitro diagnostic technologies.As shown in Figure 5b, Mansoorifar et al. introduced a microfluidic chip consisting of gel channels to monitor cancer cell extravasation through the endothelial lumen and ECM.The concentration gradient and interstitial flow through the gel channels are reconstructed by applying different concentration solutions or flow rates to the side channels.The development of organoid and tissue microarrays has now made a major technological breakthrough.Compared with detectors that need to be implanted in the body, wearable pressure sensors are faster and easier to use in practice, can simulate the function of human skin to convert pressure into electronic signals, and therefore have broad application prospects in various fields, such as electronic skin and artificial intelligence. [35]A short time ago, as shown in Figure 5c, Kim et al. designed a wearable liquid metal soft pressure sensor for health detection, which is based on fused deposition modeling for the fabrication of rigid microbump arrays above microchannels that improve the sensitivity of the pressure sensor.Notably, pressure sensors can be mounted on the The solenoid coil compression sensor and wirelessly readable bioactive glass resonance sensor embedded on the polymer bone fixation screw can be used to monitor the dielectric constant of the surrounding environment.Reproduced with permission. [34]Copyright 2020, American Chemical Society.b) Schematic diagram of chip equipment that can be applied to organs and microfluidic devices for monitoring the extravasation of cancer cells through the endothelial lumen and ECM.Reproduced with permission. [35]Copyright 2020, John Wiley and Sons.c) Schematic of the pressure sensor measurement setup.Reproduced with permission. [36]Copyright 2019, John Wiley and Sons.d) The performance of in vivo skull osteogenesis was evaluated, and NIR-ii fluorescence images were used to monitor osteogenesis in rats. [37]Copyright 2022 American Chemical Society.e) Partial enlarged view of the printed lattice in the microstructure pressure sensor.Reproduced with permission. [38]Copyright 2021, Royal Society of Chemistry.f) Conceptual schematic diagram of wirelessly controlled intelligent bandages.Reproduced with permission. [39]Copyright 2020, John Wiley and Sons.
human body to detect biosignals related to human health conditions, and thus, these devices are widely used in health monitoring systems. [36]Likewise, this method also allows for the monitoring of the amount of force applied to the human joint, visualizing the joint forces and reducing irreversible damage to the cartilage to a considerable extent.
Fluorescence imaging is widely used as an important tool for early clinical detection and diagnosis of diseases due to its advantages of high resolution, real-time monitoring, short acquisition time, noninvasiveness, and low cost.The principle of fluorescence imaging is mainly to acquire fluorescence signals of biological tissues through the interaction of photons with different tissues of the organism, such as reflection, scattering, absorption, and autofluorescence.Fluorescence imaging has obvious advantages, such as fast signal feedback, strong multisignal acquisition capability, high sensitivity, and no ionizing radiation, which can provide an in-depth understanding of the anatomical structure and physiological activity level of living organisms.Among them, near-infrared two-zone (NIR-II) fluorescence imaging can achieve more accurate and reliable in vivo quantification of analytes using NIR-II ratiometric fluorescence imaging because the absorption and scattering of light by tissues are greatly reduced and because the ratiometric measurements are not affected by local nanoprobe concentrations and other factors independent of the analyte.As shown in Figure 5d, Peng et al. proposed a strategy based on a 3D-printed bioactive glass scaffold doped with a second near-infrared lanthanide elemental dye hybrid nanoprobe to monitor the repair of bone regeneration through its excellent fluorescence imaging characteristics.It is believed that in the near future, fluorescence imaging will be widely used in the fields of imaging, diagnosis, and treatment due to its advantages, such as light stability and ultrahigh brightness.While cartilage repair is important, prevention is better than cure, and monitoring and preventing it in the early stage is one of the important ways to alleviate cartilage damage.In recent years, there has been a strong demand for flexible pressure sensors with high sensitivity and wide measurement using hydrogels as a composite material in the biomedical field.Conventional pressure sensors have a limited pressure measurement range due to their low capacitance variation and low signal-to-noise ratio.How to improve the sensitivity of hydrogel pressure sensors is a pressing problem. [37]n view of this, as shown in Figure 5e, Zhang et al. developed a microstructured pressure sensor based on digital light processing (DLP) fabrication.Due to the excellent mechanical properties of ionic gels and 3D printing, this sensor can convert various stimuli into electrical signals under any pressure and can be effectively used for monitoring human physiological signals, which will lead to new developments in the field of biomedicine as well as in artificial intelligence.Wound healing is a major clinical and public healthcare issue that is often challenged by the risk of infection, adverse consequences on surrounding tissues, and difficulty in monitoring the healing process. [38]In recent days, as shown in Figure 5f, Derakhshandeh et al. developed a wearable device that can be operated by cell phone to deliver drugs deeper into the wound in a minimally invasive manner to promote wound closure and to monitor wound closure through VEGF, which has great potential in the field of unique healthcare devices and holds great promise for the field of wound monitoring and drug delivery. [39]ith rapid socioeconomic development and the emergence of new science and technology, biomedical sensors have broad application prospects.For example, by implanting pressure sensors between the joints to monitor the internal environment of the bone joints, the pressure between the joints can be visualized to reduce the wear and tear between the joints, which is directional in the field of cartilage repair.By implanting a glass scaffold doped with fluorescent substances that can be monitored, bone regeneration is monitored and adjusted according to the changes in the internal environment of bone joints to create an environment that slows bone defects and is suitable for bone repair, playing an irreplaceable role in cartilage repair.However, the bottleneck of lacking flexible circuits and more efficient power generation technologies has limited the development of self-driven biomedical sensors.Future discoveries of new technologies and materials will continue to drive the great progress and development of self-driven flexible biomedical sensors.

Drug Release
Cartilage tissues occur in all movable joints of the body and provide a protective, wear-resistant surface at the ends of movable bone.Cartilage tissues are relatively avascular and have a limited capacity for cell migration, resulting in a low endogenous healing capacity; [40] therefore, they are unable to repair damage spontaneously following disease or injury.Once injured, the cartilage tissue loses much of its load-bearing capacity, leaving the adjacent cartilage more susceptible to wear and tear.Due to the layered and closely interacting structure of the joint, cartilage defects are often accompanied by osteochondral lesions involving the hyaline and subchondral cartilage of the joint, but unfortunately with current clinical techniques, such as pharmacological and surgical interventions, they provide only temporary relief rather than a cure for functional cartilage regeneration.Therefore, how to properly heal articular cartilage injuries is an important medical problem that needs to be addressed urgently, as well as an important social and economic issue.Emerging 3D printing technologies allow the fabrication of complex hydrogelbased soft-structured tissue scaffolds for the precise and personalized treatment of osteochondral defects.Many hydrogel cartilage scaffolds have now been fabricated using 3D printing technology, including 3D printed sodium alginate hydrogel porous structures, high-density collagen hydrogel scaffolds, and functionally optimized filamentous protein/gelatin scaffolds. [41]Recently, Zhang et al. designed a polymer fiber scaffold for repairing cartilage defects.Because of the appropriate mechanical strength and customizable characteristics of polymer fibers, they can slowly and permanently release drugs.Protects chondrocytes from the inflammatory environment.Additionally, the scaffold's ultra-porous membrane allows for efficient loading of drugs and cells for sustained release in the scaffold, regardless of the type of drug, cell, polymer, and hydrogel used, and is well controlled according to the desired application, allowing for "tailor-made" delivery.This study provides a promising strategy for substantially improving in situ cartilage regeneration and offers constructive suggestions for the clinical treatment of cartilage defects (Figure 6a).In contrast to implantable scaffolds, which can play an important role in bone formation and regeneration by storing progenitor cells and acting as a source of local growth factors, the periosteum acts as a scaffold for the recruitment of cells and other growth factors. [42]As shown in Figure 6b, Wu et al. used a bionic approach to synthesize artificial periosteum by encapsulating VEGF in a hyaluronic acid-PLA core-shell to generate blood vessels in bone defect areas, followed by a combination of collagen and electrostatically spun fibers to efficiently mimic the extracellular matrix formation layer to prepare a membrane tissue with similar function and structure to natural periosteum, which enables bone tissue regeneration through sustained release of vascular endothelial factor (VEGF), significantly improving bone.The efficacy of bone grafting and scaffold engineering provides a promising strategy to address clinical periosteal repair, and it is hoped that periosteal tissue engineering will play a greater role in future clinical bone repair needs.Similar to the previously mentioned bone repair methods, the appropriate filling for different bone defect shapes. [43]Xue et al. summarized a method to load drugs for bone defect repair by preparing a bionic hydrogel scaffold, which is well adapted to irregular bone defects, minimizes surgical exposure, alleviates patient pain, and reduces the possibility of infection.Therefore, the construction of injectable, easy-to-use, structurally adaptive bone repair materials has important clinical implications in the treatment of bone defects, which opens up new ideas for treatment strategies in the field of bone defects (Figure 6c). [44]As shown in Figure 6d, Yang et al. took a different approach.Inspired by the adhesion of the ball and mussel in the bearing, he studied a kind of microsphere to reduce the friction between joints.Due to the properties of the hydrogel itself, both solid and liquid, the controllable size, high dispersion, and uniformity of size make these hydrogel microspheres have extremely low friction in bone joints, and due to their porous structure, they are able to load and release the drug well.This model slows drug degradation, increases drug release efficiency, effectively reduces chondrocyte degeneration, and shows great potential in the treatment of cartilage damage, providing a refreshing solution to articular cartilage damage and degeneration. [11]The same hydrogel is used to load drugs for cartilage repair, and stem cell technology has come into the public consciousness.As shown in Figure 6e, Wei et al. combined two aspects, injected bone marrow mesenchymal stem cell (MSc) spheres, and short fiber fillers into hyaluronic acid hydrogels, and loaded CXB in hyaluronic acid with short fibers to help enhance its mechanical properties and sustained release of anti-inflammatory agents.This layered injection hydrogel and cell sphere structure provides novel clues for cartilage regeneration and the treatment of osteochondral defects. [45]Coincidentally, not long ago, as shown in Figure 6f, Qiao et al. also designed a hydrogel that accelerates bone formation from bone precursor cells by cocrosslinking template photocrosslinked gelatin (GelMA) with photocrosslinkable osteogenic growth peptide (OGP) using UV radiation, in which OGP not only effectively increases bone trabeculae and osteoid thickness but also upregulates hematopoietic stimulating factors produced by osteoblasts and other bone marrow cell lines, thus providing a good Figure 6.a) PCL porous scaffolds with drug encapsulated in PCL nanofibers for sustained release.Reproduced with permission. [42]Copyright 2019, John Wiley and Sons.b) Bionic periosteum for periosteum and bone regeneration.Reproduced with permission. [43]Copyright 2020, Elsevier.c) A schematic diagram of the hydrogel as a carrier for the treatment of cartilage defects.Reproduced with permission. [44]Copyright 2022, Elsevier.d) Schematic diagram of ball-bearing super lubricated microspheres designed for the treatment of arthritis to enhance hydration lubrication and sustained drug release.Reproduced with permission. [11]Copyright 2020, John Wiley and Sons.e) A schematic diagram of the hydrogel for inoculating short fibers and cell spheres.Reproduced with permission. [45]Copyright 2022, Elsevier.f) Hydrogel model for promoting bone regeneration and releasing growth factors.Reproduced with permission. [46]Copyright 2019, John Wiley and Sons.g) Black phosphorus (BP)-doped fibrous scaffolds and photothermal responsive channels for improving cell proliferation and osteogenic differentiation in rats in vitro.Reproduced with permission. [22]Copyright 2021, John Wiley and Sons.
matrix microenvironment for secondary hematopoiesis and increasing the precipitation of calcium salts in osteoblasts as a way to increase the mechanical properties of defective bone as well as to avoid the rupture of osteogenic peptides released during the healing of bone defects.This hydrogel delivery system has an important impact on the healing of bone defects compared to conventional methods, and this study provides a potential vehicle for clinical applications such as bone defects and bone regeneration.Although tissue-engineered scaffolds have been widely used for the treatment of bone defects, the slow and inadequate vascularization of the entire scaffold remains a great challenge. [46]Recently, as shown in Figure 6g, Wang et al. developed a multifunctional microfluidic fiber scaffold mixed with black phosphorus, which can improve the effect of vascularization and bone regeneration through the characteristics of the photothermal response.In addition, the black phosphorus contained in this channel can also promote host blood vessels to penetrate into the scaffold and effectively accelerate the healing process of bone defects.This strategy of integrating stimulus responders into bionic channel scaffolds provides new insights into the design of smart biomaterials for different tissue engineering applications. [22]o reduce cartilage damage, on the one hand, it is necessary to reduce the friction between bones and joints.The friction be-tween joints can be reduced through physical aspects, such as reducing the friction between joints, implanting microspheres loaded with drugs in bone joints, reducing the friction between bones and joints, and slowing down wear.On the other hand, it is necessary to repair the defective cartilage and reconstruct the cartilage by releasing drugs into bone joints.The scaffold loaded with drugs is implanted at the chemical level to release drugs in the bone joints to repair cartilage.Currently, the technology of implanting stents in bone joints is relatively mature, which has laid a solid foundation for opening a new drug-loading mode in the future.

Cell Culture Scaffold Repair
Articular cartilage is essentially avascular, with a low cellular content and limited ability to heal itself.Despite remarkable mechanical properties, the tissue may become defective after extended wear and tear or acute trauma.The tissue loses its mechanical integrity and no longer acts as a cushion for bone-to-bone contact, thus causing great physical pain to the patient.3D bioprinting methods have received a lot of attention in recent years in the construction of bionic systems.It enables the integration of multiple tissue cells, biomaterials, and bioactive factors in a Reproduced with permission. [48]Copyright 2019, John Wiley and Sons.b) A functional periosteum with appropriate mechanical properties and good biocompatibility was constructed, and the osteogenic microenvironment for bone repair was arranged in a sequential manner.Reproduced with permission. [49]Copyright 2020, American Chemical Society.c) Schematic diagram of the mechanism of attracting directionally growing peripheral nerves and releasing growth factor in Mg2+ and neural networks to repair bone tissue.Reproduced with permission. [50]Copyright 2021, John Wiley and Sons.d) SEM images used to observe the death and survival of cells on scaffolds.Reproduced with permission. [51]Copyright 2021, John Wiley and Sons.e) Fluorescence images of rat bone marrow mesenchymal stem cells implanted on scaffolds for 24 h.Reproduced with permission. [22]Copyright 2021, John Wiley and Sons.f) Functional skeletal muscle regeneration using hot stretched porous fibers and reprogrammed muscle progenitor cells and SEM images of samples.Reproduced with permission. [52]Copyright 2021, John Wiley and Sons.
precise spatial location.Taking advantage of 3D bioprinting holds great promise for correctly outlining the bilayer characteristics of osteochondral tissue by designing a homogeneous distribution of tissue cells.Compared to monophasic scaffolds for the repair of osteochondral tissue, 3D-bioprinted scaffolds are more likely to address the inherent differences in the microenvironment from cartilage to subchondral bone. [47]If we can design a carrier that can continuously release growth factors to achieve cartilage self-repair, we can greatly reduce the damage caused by cartilage defects to the human body.Residual malignant tumor cells and lack of bone tissue integration are key issues in bone tumor recurrence, not long ago, as shown in Figure 7a, Pan et al. designed a stent that integrates 2D Ti 3 C 2 MXene and 3D printing bioactive glass stents.Because of its photothermal conversion characteristics, it can induce bone tumor ablation by photothermal high temperature triggered by near-infrared light and accelerate the growth of new bone in vivo by integrating the two substances.Moreover, the implanted bioactive glass scaffold supports the differentiation of bone marrow mesenchymal stem cells into osteoblasts through its bridging function.The integration of the two substances accelerates the in vivo growth of new bone tissue, making the Ti3C2 MXene integrated composite scaffold a promising prospect for cartilage repair. [48]Additionally, as a conductive bracket, not long ago, as shown in Figure 7b, Li et al. used a functional periosteum composed of biofilm, hydrogel, and electrospinning to reconstruct cartilage.This periosteum effectively attracted bone stem cells in vivo, stimulated the activity of bone stem cells, and sequentially constructed an osteogenic microenvironment for bone repair.Besides, compared to the implanta-tion of a scaffold, the osteochondral filling of the pre-existing defect reduces unnecessary friction between the joints and provides better-filling properties.This method reduced the rejection of foreign objects in patients, making a large step forward in the field of cartilage reconstruction. [49]Although researchers have made great progress in engineering bone tissue, delayed or ineffective bone regeneration remains a problem due to the lack of neural network reconstruction in its design; therefore, Li et al. proposed an engineered bone tissue structure that mimics the microenvironment of the ossification center to facilitate innervation.and designed a microstructure that can release growth factors for a long period of time, which can be constructed by bioprinting technology to release growth factors for a long period of time in vivo to mimic the microenvironment of the ossification center, thereby increasing the neurovascular density of the surrounding tissues and thus promoting the differentiation of bone marrow mesenchymal stem cells to repair the defective osteochondral bone (Figure 7c).This novel tissue-engineered bone mimics the microenvironment of the ossification center and promotes innervation, which has a promising application in future bone regeneration applications; in bone diseases, where there is no bone tissue around the graft site or the bone tissue is in poor condition, osteoconductivity is very low, and therefore, effective bone grafts in terms of osteoconductivity and osteoinductivity are needed for clinical treatment. [50]Recently, as shown in Figure 7d, Zhang et al. developed a new type of photothermal tissue-engineered bone with bone induction ability and a bionic cell environment.By loading bone marrow mesenchymal stem cells (serving as seeding cells) and bone-induced extracellular matrix (providing a microenvironment for bone repair) on gelatin scaffolds, bone regeneration can be realized by value-added and osteogenic differentiation under the effect of near-infrared radiation, and new bone formation can be observed by microcomputed tomography (micro-CT) imaging and histological measurements.which has great potential in regenerative medicine.Shortly thereafter, it will become an effective substitute for autologous grafts in tissue engineering. [51]As shown in Figure 7e, Wang et al. designed a hot channel scaffold for substance delivery, which facilitates the infiltration of suspended cells into the scaffold channel and promotes vascular preconditioning.It solved the problem of difficult transportation of nutrients and oxygen previously, improved cell proliferation and osteoblastic differentiation in vitro, effectively accelerated the healing process of bone defects, and greatly shortened the healing cycle of bone defects. [22]The ability to apply thermal response properties not only to bone tissue repair but also to skeletal muscle.In recent days, as shown in Figure 7f, Jin et al. integrated muscle extracellular matrix (MEM) hydrogels and induced skeletal muscle-derived progenitor cells (iMPC) in a heat-stretching fiber-based microchannel scaffold, allowing skeletal muscle to regenerate as well as repair some essential functions, ultimately leading to functional recovery of muscle activity. [52]The scaffold enables porosity through the incorporation of sodium chloride microcrystals, enabling the precise and large-scale fabrication of porous fibers, which removes a significant impediment to the lack of a reliable cell source for tissue engineering and the challenges faced in engineering suitable tissue scaffolds.
In the process of relieving bone defects, it is necessary to repair the cartilage defect.By loading the growth factor on the scaffold and releasing the growth factor after implantation into the bone joint, osteoblast differentiation is carried out, and the defective cartilage is repaired.In addition, bone marrow mesenchymal stem cells can be loaded on the scaffold to reconstruct cartilage through osteoblast differentiation, and the pores on the scaffold can also be used to load relevant nutrients and oxygen for a smooth repair process.These strategies have brought a turning point in slowing the impact of bone defects on people.

Integrated 3D Bone Repair Strategy
Hydrogel scaffolds based on 3D printing that can load drugs and growth factors can release anti-inflammatory drugs in the internal environment and release growth factors according to changes in the internal environment to complete the repair of defective cartilage. [53]This method causes less irritation to the internal environment of the human body and better repair performance (Table 1).Second, 3D printing has high precision and strong simulation, which can meet our various physical requirements for stents and plays a decisive role in the effect of this method, which is why we chose 3D printing as the basic method for stent fabrication.
Although there are many ways to alleviate bone defects, most of the treatment methods are only one-way development and rarely integrate two functions.If the two functions are integrated, the loss of human and material resources will be greatly reduced, and the quality of life of patients will be greatly improved.In the previous section, we introduced a relatively single treatment strategy, which is gratifying.If we can integrate the above functions,    [56] Copyright 2020, John Wiley and Sons.b) Schematic diagram of cell culture and subsequent effects.Reproduced with permission. [56]Copyright 2020, John Wiley and Sons.c) Strategy map for detecting and regulating ROS so that it can be used to diagnose and treat bone defects.Reproduced with permission. [57]Copyright 2021, John Wiley and Sons.d) Schematic diagram of the MOF-based structure due to cell culture and drug release.Reproduced with permission. [58]Copyright 2019, John Wiley and Sons.e) Schematic diagram of gelatin scaffold with the function of releasing anticancer drugs and osteogenic factors.Reproduced with permission. [59]opyright 2021, Elsevier.f) Sagittal view of the bionic polyphase scaffold and SEM image of the three-layer microstructure of the scaffold.Reproduced with permission. [21]Copyright 2021, Elsevier.g) Schematic diagram of multifunctional implants promoting angiogenesis and bone integration.Reproduced with permission. [60]Copyright 2021, Elsevier.
we will place monitoring, drug release, or cell culture on the same carrier, which is a great improvement in the field of bone defect treatment.
Jodat et al. designed a 3D bionic nasal cartilage-like tissue construct consisting of a mechanically robust cartilage-like construct combined with a biocompatible sensor engineered to combine a cartilage-like tissue construct with a sensor for odor and chemical detection, as well as to release growth factors to promote nasal cartilage repair (Figure 8a), by combining polydopamine (PDA) and nanoscale zeolite imidazole zeolite backbone 8 (pZIF-8 nanoMOFs) as drug carriers and monitoring the time the peptide can remain active after functionalization (Figure 8b). [56]combining monitoring with cell culture capabilities allows for timely monitoring of inhaled nasal chemicals and the timely release of growth factors to accelerate cartilage repair.This treatment strategy might also be used for cartilage repair, simplifying the treatment process, reducing the patient's treatment period, and providing a novel strategy for cartilage repair.Similarly, this approach can also be applied to the field of articular cartilage repair, which is similar to nasal cartilage, for monitoring the intraarticular environment and releasing cartilage-promoting drugs at the right time; not coincidentally, Li et al. recently used photoacoustic imaging to visualize the spatial and temporal distribution of ROS in the bone damage microenvironment represented by hydrogen peroxide (H 2 O 2 ) by implanting scaffolds for cell culture and monitoring of bone defect sites.The use of methacrylatebased gelatin (GelMA) loaded with hollow manganese dioxide nanoparticles (hMNPs) capable of decomposing H 2 O 2 to generate oxygen significantly enhanced bone formation in criticalsized cranial defects in rats by releasing oxygen and bone mor-phogenetic protein-2 (BMP-2)-related peptides on demand in response to changes in the ROS of the bone microenvironment, which provides a new strategy for monitoring and repairing defective cartilage in the field of providing a new strategy for monitoring and repairing defective cartilage (Figure 8c). [57]In contrast to the previous pair, Liu and his colleagues developed an ultrastable, multifunctional artificial cell system that encloses an enzyme-containing metal-organic framework as an organelle for cell culture and drug delivery.This hyper-stable, versatile artificial cell system can simulate a wide range of cellular tasks, including molecular transport regulation, cellular metabolism, and programmed degradation, significantly extending the stability of the reactor under a variety of chemical and physical conditions.The confined reaction environment significantly increases the partial concentration of proliferating cells and the overall catalytic efficiency, and the development of this responsive cellular mimic will have great potential for future use in osteochondral repair, Future use in cartilage repair is expected to be widespread(Figure 8d). [58]Meanwhile, Jiang et al. also designed an integrated therapeutic scaffold material that can be used to promote bone tissue repair and inhibit tumor recurrence at the same time, to achieve tumor microenvironment responsive smart drug release and to achieve controlled programmed release of cisplatin and BMP-2 by varying the assembly order and number of layers of different drug-loaded nanoparticles on the scaffold surface, thus enabling tumor treatment and bone repair to be coordinated in time and space.Integrating 3D printing and nano-MOF-based drug delivery technology provides a new treatment method for postoperative bone tumor repair (Figure 8e). [59]This method not only effectively inhibits tumor recurrence but also promotes the growth of surrounding healthy tissues and accelerates the reconstruction of postoperative bone defects, bringing new development to the field of bone repair, and integrating drug release with cell culture.Similarly integrating drug release with cell culture, Liu et al. designed a 3D bioprinted multilayer scaffold containing bone marrow mesenchymal stem cells (BMSC) containing methacrylated hyaluronic acid (MeHA)/poly(caprolactone) combined with kartogenin (KGN, a small heterocyclic drug compound) and -TCP for the repair of osteochondral defects in each region; a new therapeutic strategy combining inhibition and relief by combining BMSC and diclofenac sodium in hyaluronic acid to retard bone defects and promote repair of defective cartilage by kartogenin and -TCP, with good biocompatibility and good degradability of the scaffold (Figure 8f); In clinical practice, anti-infection and osseointegration is a paradox for orthopedic implants.Most antimicrobial implants show cytotoxicity due to the enriched distribution of the antimicrobial agent on the surface, further inhibiting osseointegration-related activity and delaying the healing process.Therefore, it is clear that mono-functional antimicrobial implants cannot meet clinical requirements and the development of multi-functional implants is in high demand.Balancing antiinfection and osseointegration has become a top priority.Therefore, multifunctional implants are ideal for promoting osseointegration, especially "static multifunctional" implants with nonessential external stimulation, Chen et al. develop "static multifunctional" titanium implants with immobilized antimicrobial peptides and QK sequences that combine cell culture and drug release, promoting angiogenesis and osseointegration while providing a relatively stable and favorable environment for cartilage repair.This study also provides good control for the development of "static multifunctional" orthopedic implants(Figure 8g). [60]ith the development of science and technology, an increasing number of treatment strategies for bone injuries have been developed, which makes many impossible, such as integrating internal environment monitoring and cartilage repair, and dual treatment through a stent.We also expect that more treatment strategies will be proposed and applied in clinical practice to relieve osteochondral defects.

Conclusion
Cartilage injuries are caused by a variety of factors, including acute trauma and chronic inflammation.Due to the biological nature of articular cartilage, it is difficult to heal once injured.Therefore, repairing cartilage injuries is one of the clinically significant and challenging tasks at hand, which is one of the reasons why we are still discussing cartilage repair.Currently, although there are many methods for the treatment of bone defects, their effects are limited.In this review, we summarized the treatment strategies that can alleviate cartilage defects based on 3D printing technology.As a new technology with high precision and fast printing speed, 3D printing has been widely used in the detection and repair of articular cartilage.However, some challenges facing us should also become the driving force to improve 3D printing.
First, since there is no distribution of blood vessels and nerves in articular cartilage, stent implantation can solve the problem that cartilage cannot repair itself, but how to make the stent have better compatibility in the human internal environment is a prob-lem that we should pay attention to.It is necessary to further study the materials used and the modification methods of embedding drugs on the scaffold.At the beginning of designing scaffold materials, compatibility with the internal environment should be considered to optimize the material preparation.For example, polyester, which is widely used because it can be hydrolyzed in aqueous solution, is the first choice in the biomedical field.In addition, some natural polymers and polypeptide materials are also used in some specific parts.Combining the use of methods to select materials can provide more choices for good biocompatibility.
Second, although the range of printing methods of 3D printing technology has been expanded to a large extent, which provides a good basis for our research on the detection and repair of defective cartilage, the materials used are also limited due to different printing methods.As a conventional printing method, extrusion is widely used in the field of biomedicine because of its simple operation and low cost.However, extrusion is limited by the nature of the materials, and the required materials need specific rheological properties.Because hydrogels can provide natural biological ligands and beneficial growth factors, hydrogels are often used as printing scaffold materials in existing treatment strategies, but the stability and mechanical properties of hydrogels are not sufficiently stable.Although molten deposition modeling can produce scaffolds with good stability and mechanical properties, it cannot carry some active cells, such as bone marrow mesenchymal stem cells, because molten deposition modeling is based on high-temperature printing.Therefore, on the basis of existing research, we should explore printing methods and materials that can not only ensure the stability of the scaffold but also consider the biological activity of cells (such as in situ 3D bioprinting technology).
Finally, when the stent is implanted into the bone joint, the drug release time of the drug-loaded layer on the stent is not synchronized with the pathological development of the joint, which reduces efficacy and misses the best repair time.Based on basically mature 3D printing technology, scaffolds with good degradation performance and high activity are designed to load antiinflammatory drugs and growth factors to promote cartilage repair.Alternatively, we can change the previous mechanism of prefabricated hydrogels, adopt injectable hydrogels, capture the desired active molecules and cells after injection into the body, and spontaneously become a delivery device for sustainable drug release or a 3D scaffold for growth factor release.This brings a refreshing treatment strategy to the field of bone defects.
With the advancement of modern medical research, research on methods to promote cartilage injury repair has increased, and a variety of therapeutic tools have been used to repair articular cartilage injuries, but most of the results are unsatisfactory, and most of the repaired tissues are mainly fibrocartilage, which lacks the mechanical properties and durability of normal hyaline cartilage.Autologous tissues have limited sources and are often associated with invasive manipulation, while allogeneic materials have poor biocompatibility and disease transmission problems.In conclusion, the development of 3D printing technology in cartilage repair has brought about promising new changes.We believe that with the progressive research on the pathophysiology of articular cartilage injuries and defects and further optimization and practice, as well as with the continuous development of bioink materials and improvement of preparation techniques, cartilage defect repair has great prospects for development.Through the improvement of the operation system of 3D printing in cartilage repair, finding a satisfactory biological repair method for cartilage damage will be the direction of our future efforts, which is exciting news for patients with cartilage defects.

Figure 2 .
Figure 2. a) Comparison between normal knee joint and injured knee joint.b)The osteochondral defect map and CT map of the weight-bearing area of the medial femoral condyle in patients with osteochondral defects of the knee joint.Reproduced with permission.[12]Copyright 2020, John Wiley and Sons.c) The design of super lubricated ball-bearing microspheres is used for the collaborative treatment of osteoarthritis based on enhanced hydration lubrication and continuous drug release.Reproduced with permission.[11]Copyright 2020, John Wiley and Sons.

Figure 4 .
Figure 4. a)Molten deposition modeling (FDM) printed gear model using polyether ether ketone (PEEK) as the material.Reproduced with permission.[23]Copyright 2020, American Chemical Society.b) A sample obtained by processing silk fibroin by light curing.Reproduced with permission.[24]Copyright 2020, Elsevier.c) The pattern with a double tornado shape printed based on embedded printing.Reproduced with permission.[25]Copyright 2019, John Wiley and Sons.d) Modification or refinement of the structure during solidification of liquid metal by laser deposition.Reproduced with permission.[26]Copyright 2020, Springer Nature.e) Model diagram of extrusion printing.Reproduced with permission.[27]Copyright 2019, John Wiley and Sons.f) Model of the rat thigh bone equivalent to the human ear with hydrogel as the extruded material.Reproduced with permission.[28]Copyright 2020, John Wiley and Sons.

Figure 5 .
Figure5.a) The solenoid coil compression sensor and wirelessly readable bioactive glass resonance sensor embedded on the polymer bone fixation screw can be used to monitor the dielectric constant of the surrounding environment.Reproduced with permission.[34]Copyright 2020, American Chemical Society.b) Schematic diagram of chip equipment that can be applied to organs and microfluidic devices for monitoring the extravasation of cancer cells through the endothelial lumen and ECM.Reproduced with permission.[35]Copyright 2020, John Wiley and Sons.c) Schematic of the pressure sensor measurement setup.Reproduced with permission.[36]Copyright 2019, John Wiley and Sons.d) The performance of in vivo skull osteogenesis was evaluated, and NIR-ii fluorescence images were used to monitor osteogenesis in rats.[37]Copyright 2022 American Chemical Society.e) Partial enlarged view of the printed lattice in the microstructure pressure sensor.Reproduced with permission.[38]Copyright 2021, Royal Society of Chemistry.f) Conceptual schematic diagram of wirelessly controlled intelligent bandages.Reproduced with permission.[39]Copyright 2020, John Wiley and Sons.

Figure 7 .
Figure 7. a) Schematic diagram of the TBG manufacturing process and bone tissue regeneration effect of eliminating bone cancer cells by photothermal ablation.Reproduced with permission.[48]Copyright 2019, John Wiley and Sons.b) A functional periosteum with appropriate mechanical properties and good biocompatibility was constructed, and the osteogenic microenvironment for bone repair was arranged in a sequential manner.Reproduced with permission.[49]Copyright 2020, American Chemical Society.c) Schematic diagram of the mechanism of attracting directionally growing peripheral nerves and releasing growth factor in Mg2+ and neural networks to repair bone tissue.Reproduced with permission.[50]Copyright 2021, John Wiley and Sons.d) SEM images used to observe the death and survival of cells on scaffolds.Reproduced with permission.[51]Copyright 2021, John Wiley and Sons.e) Fluorescence images of rat bone marrow mesenchymal stem cells implanted on scaffolds for 24 h.Reproduced with permission.[22]Copyright 2021, John Wiley and Sons.f) Functional skeletal muscle regeneration using hot stretched porous fibers and reprogrammed muscle progenitor cells and SEM images of samples.Reproduced with permission.[52]Copyright 2021, John Wiley and Sons.

Figure 8 .
Figure 8. a) A nose model based on sensor electrode printing.Reproduced with permission.[56]Copyright 2020, John Wiley and Sons.b) Schematic diagram of cell culture and subsequent effects.Reproduced with permission.[56]Copyright 2020, John Wiley and Sons.c) Strategy map for detecting and regulating ROS so that it can be used to diagnose and treat bone defects.Reproduced with permission.[57]Copyright 2021, John Wiley and Sons.d) Schematic diagram of the MOF-based structure due to cell culture and drug release.Reproduced with permission.[58]Copyright 2019, John Wiley and Sons.e) Schematic diagram of gelatin scaffold with the function of releasing anticancer drugs and osteogenic factors.Reproduced with permission.[59]Copyright 2021, Elsevier.f) Sagittal view of the bionic polyphase scaffold and SEM image of the three-layer microstructure of the scaffold.Reproduced with permission.[21]Copyright 2021, Elsevier.g) Schematic diagram of multifunctional implants promoting angiogenesis and bone integration.Reproduced with permission.[60]Copyright 2021, Elsevier.

Table 1 .
Examples of different applications.