Engineering lactate-modulating nanomedicines for cancer therapy.

Lactate in tumors has long been considered "metabolic junk" derived from the glycolysis of cancer cells and utilized only as a biomarker of malignancy, but is presently believed to be a pivotal regulator of tumor development, maintenance and metastasis. Indeed, tumor lactate can be a "fuel" for energy supply and functions as a signaling molecule, which actively contributes to tumor progression, angiogenesis, immunosuppression, therapeutic resistance, etc., thus providing promising opportunities for cancer treatment. However, the current approaches for regulating lactate homeostasis with available agents are still challenging, which is mainly due to the short half-life, low bioavailability and poor specificity of these agents and their unsatisfactory therapeutic outcomes. In recent years, lactate modulation nanomedicines have emerged as a charming and efficient strategy for fighting cancer, which play important roles in optimizing the delivery of lactate-modulating agents for more precise and effective modulation and treatment. Integrating specific lactate-modulating functions in diverse therapeutic nanomedicines may overcome the intrinsic restrictions of different therapeutic modalities by remodeling the pathological microenvironment for achieving enhanced cancer therapy. In this review, the most recent advances in the engineering of functional nanomedicines that can modulate tumor lactate for cancer therapy are summarized and discussed, and the fundamental mechanisms by which lactate modulation benefits various therapeutics are elucidated. Finally, the challenges and perspectives of this emerging strategy in the anti-tumor field are highlighted.

Xonotlite Nanowire-Containing Bioactive Scaffolds for the Therapy of Defective Adipose Tissue in Breast Cancer.

Considering the challenge in the treatment of severe breast tumor patients, xonotlite nanowire-containing bioactive scaffolds (Fe3O4-CS-GelMA) were fabricated by the 3D-printing technique for the therapy of injured adipose tissue after surgery. Importantly, benefiting from the excellent magnetothermal performance of Fe3O4 microspheres, Fe3O4-CS-GelMA scaffolds could effectively kill tumor cells in vitro and suppress breast cancer in vivo under an alternating magnetic field, and the tumor did not recur in 2 weeks. In addition, attributed to the released bioactive inorganic ions, Fe3O4-CS-GelMA composite scaffolds could effectively promote the expression of adipogenesis-related genes and proteins of adipose-derived stem cells (ADSCs) via the PI3K-AKT signaling pathway in vitro. Furthermore, Fe3O4-CS-GelMA scaffolds with ADSCs could obviously stimulate the formation of adipose in vivo, compared with that of pure GelMA without inorganic components. Therefore, this study offers a promising strategy for the therapy of breast tumors after the surgical excision of breast carcinoma.

A Universal Chelation-Induced Selective Demetallization Strategy for Bioceramic Nanosheets (BCene).

The emergence of nanosheet materials like graphene and phosphorene, which are created by breaking the interlayer van der Waals force, has revolutionized multiple fields. Layered inorganic materials are ubiquitous in materials like bioceramics, semiconductors, superconductors, etc. However, the strong interlayer covalent or ionic bonding in these crystals makes it difficult to fabricate nanosheets from them. In this study, we present a simple technique to produce nanosheets from layered crystals by selectively exfoliating their interlayer metal atoms using the metal-chelation reaction. As a proof of concept, we successfully produced bioceramic nanosheets (BCene) by extracting Ca layers from Akermanite (AKT). The 3D-printed BCene scaffolds exhibited superior mechanical strength and in vitro bioactivity compared to the scaffolds made from AKT nanopowders. Our findings demonstrate the outstanding potential of BCene nanosheets in tissue engineering. Additionally, the selective demetallization technique for nanosheet production could be applied to other inorganic layered crystals to optimize their performance.

Ion incorporation into bone grafting materials.

The use of biomaterials in regenerative medicine has expanded to treat various disorders caused by trauma or disease in orthopedics and dentistry. However, the treatment of large and complex bone defects presents a challenge, leading to a pressing need for optimized biomaterials for bone repair. Recent advances in chemical sciences have enabled the incorporation of therapeutic ions into bone grafts to enhance their performance. These ions, such as strontium (for bone regeneration/osteoporosis), copper (for angiogenesis), boron (for bone growth), iron (for chemotaxis), cobalt (for B12 synthesis), lithium (for osteogenesis/cementogenesis), silver (for antibacterial resistance), and magnesium (for bone and cartilage regeneration), among others (e.g., zinc, sodium, and silica), have been studied extensively. This review aims to provide a comprehensive overview of current knowledge and recent developments in ion incorporation into biomaterials for bone and periodontal tissue repair. It also discusses recently developed biomaterials from a basic design and clinical application perspective. Additionally, the review highlights the importance of precise ion introduction into biomaterials to address existing limitations and challenges in combination therapies. Future prospects and opportunities for the development and optimization of biomaterials for bone tissue engineering are emphasized.

Nanoplatform-based cascade engineering for cancer therapy.

Various therapeutic techniques have been studied for treating cancer precisely and effectively, such as targeted drug delivery, phototherapy, tumor-specific catalytic therapy, and synergistic therapy, which, however, evoke numerous challenges due to the inherent limitations of these therapeutic modalities and intricate biological circumstances as well. With the remarkable advances of nanotechnology, nanoplatform-based cascade engineering, as an efficient and booming strategy, has been tactfully introduced to optimize these cancer therapies. Based on the designed nanoplatforms, pre-supposed cascade processes could be triggered under specific conditions to generate/deliver more therapeutic species or produce stronger tumoricidal effects inside tumors, aiming to achieve cancer therapy with increased anti-tumor efficacy and diminished side effects. In this review, the recent advances in nanoplatform-based cascade engineering for cancer therapy are summarized and discussed, with an emphasis on the design of smart nanoplatforms with unique structures, compositions and properties, and the implementation of specific cascade processes by means of endogenous tumor microenvironment (TME) resources and/or exogenous energy inputs. This fascinating strategy presents unprecedented potential in the enhancement of cancer therapies, and offers better controllability, specificity and effectiveness of therapeutic functions compared to the corresponding single components/functions. In the end, challenges and prospects of such a burgeoning strategy in the field of cancer therapy will be discussed, hopefully to facilitate its further development to meet the personalized treatment demands.

Defective Black Nano-Titania Thermogels for Cutaneous Tumor-Induced Therapy and Healing.

Current challenges in cutaneous tumor therapy are healing the skin wounds resulting from surgical resection and eliminating possible residual tumor cells to prevent recurrence. To address this issue, bifunctional biomaterials equipped with effective tumor therapeutic capacity for skin cancers and simultaneous tissue regenerative ability for wound closure are highly recommended. Herein, we report an injectable thermosensitive hydrogel (named BT-CTS thermogel) with the integration of nanosized black titania (B-TiO2- x, ∼50 nm) nanoparticles into a chitosan (CTS) matrix. The B-TiO2- x nanocrystal exhibits a crystalline/amorphous core-shell structure with abundant oxygen vacancies, which endows the BT-CTS thermogels with simultaneous photothermal therapy (PTT) and photodynamic therapy (PDT) effects under single-wavelength near-infrared laser irradiation, leading to an excellent therapeutic effect on skin tumors in vitro and in vivo. Moreover, the BT-CTS thermogel not only supports the adhesion, proliferation, and migration of normal skin cells but also facilitates skin tissue regeneration in a murine chronic wound model. Therefore, such BT-CTS thermogels with easy injectability, excellent thermostability, and simultaneous PTT and PDT efficacy as well as tissue regenerative activity offers a promising pathway for the healing of cutaneous tumor-induced wounds.

Multilevel hierarchically ordered artificial biomineral.

Living organisms are known for creating complex organic-inorganic hybrid materials such as bone, teeth, and shells, which possess outstanding functions as compared to their simple mineral forms. This has inspired many attempts to mimic such structures, but has yielded few practical advances. In this study, a multilevel hierarchically ordered artificial biomineral (a composite of hydroxyapatite and gelatine) with favorable nanomechanical properties is reported. A typical optimized HAp/gelatin hybrid material in the perpendicular direction of the HAp c-axis has a modulus of 25.91 + 1.78 GPa and hardness of 0.90 + 0.10 GPa, which well matches that of human cortical bone (modulus 24.3 + 1.4 GPa, hardness 0.69 + 0.05 GPa). The bottom-up crystal constructions (from nano- to micro- to macroscale) of this material are achieved through a hard template approach by the phase transformation from DCP to HAp. The structural biomimetic material shows another way to mimic the complex hierarchical designs of sclerous tissues which have potential value for application in hard tissue engineering.

The Development of Lung Tissue Engineering: From Biomaterials to Multicellular Systems.

The challenge of the treatment of end-stage lung disease poses an urgent clinical demand for lung tissue engineering. Over the past few years, various lung tissue-engineered constructs are developed for lung tissue regeneration and respiratory pathology study. In this review, an overview of recent achievements in the field of lung tissue engineering is proposed. The introduction of lung structure and lung injury are stated briefly at first. After that, the lung tissue-engineered constructs are categorized into three types: acellular, monocellular, and multicellular systems. The different bioengineered constructs included in each system that can be applied to the reconstruction of the trachea, airway epithelium, alveoli, and even whole lung are described in detail, followed by the highlight of relevant representative research. Finally, the challenges and future directions of biomaterials, manufacturing technologies, and cells involved in lung tissue engineering are discussed. Overall, this review can provide referable ideas for the realization of functional lung regeneration and permanent lung substitution.

Design and synthesis of bioinspired nanomaterials for biomedical application.

Natural materials and bioprocesses provide abundant inspirations for the design and synthesis of high-performance nanomaterials. In the past several decades, bioinspired nanomaterials have shown great potential in the application of biomedical fields, such as tissue engineering, drug delivery, and cancer therapy, and so on. In this review, three types of bioinspired strategies for biomedical nanomaterials, that is, inspired by the natural structures, biomolecules, and bioprocesses, are mainly introduced. We summarize and discuss the design concepts and synthesis approaches of various bioinspired nanomaterials along with their specific roles in biomedical applications. Additionally, we discuss the challenges for the development of bioinspired biomedical nanomaterials, such as mechanical failure in wet environment, limitation in scale-up fabrication, and lack of deep understanding of biological properties. It is expected that the development and clinical translation of bioinspired biomedical nanomaterials will be further promoted under the cooperation of interdisciplinary subjects in future. This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Immunomodulatory multicellular scaffolds for tendon-to-bone regeneration.

Limited motor activity due to the loss of natural structure impedes recovery in patients suffering from tendon-to-bone injury. Conventional biomaterials focus on strengthening the regenerative ability of tendons/bones to restore natural structure. However, owing to ignoring the immune environment and lack of multi-tissue regenerative function, satisfactory outcomes remain elusive. Here, combined manganese silicate (MS) nanoparticles with tendon/bone-related cells, the immunomodulatory multicellular scaffolds were fabricated for integrated regeneration of tendon-to-bone. Notably, by integrating biomimetic cellular distribution and MS nanoparticles, the multicellular scaffolds exhibited diverse bioactivities. Moreover, MS nanoparticles enhanced the specific differentiation of multicellular scaffolds via regulating macrophages, which was mainly attributed to the secretion of PGE2 in macrophages induced by Mn ions. Furthermore, three animal results indicated that the scaffolds achieved immunomodulation, integrated regeneration, and function recovery at tendon-to-bone interfaces. Thus, the multicellular scaffolds based on inorganic biomaterials offer an innovative concept for immunomodulation and integrated regeneration of soft/hard tissue interfaces.

Mesoporous Bioactive Glass-Graphene Oxide Composite Aerogel with Effective Hemostatic and Antibacterial Activities.

Hemorrhage and infection after emergency trauma are two main factors that cause deaths. It is of great importance to instantly stop bleeding and proceed with antibacterial treatment for saving lives. However, there is still a huge need and challenge to develop materials with functions of both rapid hemostasis and effective antibacterial therapy. Herein, we propose the fabrication of a composite aerogel mainly consisting of mesoporous bioactive glass (MBG) and graphene oxide (GO) through freeze-drying. This composite aerogel has a three-dimensional porous structure, high absorption, good hydrophilicity, and negative zeta potential. Moreover, it exhibits satisfactory hemostatic activities including low BCI, good hemocompatibility, and activation of intrinsic pathways. When applied to rat liver injury bleeding, it can decrease 60% hemostasis time and 75% blood loss amount compared to medical gauze. On the other hand, the composite aerogel shows excellent photothermal antibacterial capacity against Staphylococcus aureus and Escherichia coli. Animal experiments further verify that this composite aerogel can effectively kill bacteria in wound sites via photothermal treatment and promote wound healing. Hence, this MBG-GO composite aerogel makes a great choice for the therapy of emergency trauma with massive hemorrhage and bacterial infection.

3D modular bioceramic scaffolds for the investigation of the interaction between osteosarcoma cells and MSCs.

Recent advances in bone tissue engineering have shown promise for bone repair post osteosarcoma excision. However, conflicting research on mesenchymal stem cells (MSCs) has raised concerns about their potential to either promote or inhibit tumor cell proliferation. It is necessary to thoroughly understand the interactions between MSCs and tumor cells. Most previous studies only focused on the interactions between cells within the tumor tissues. It has been challenging to develop an in vitro model of osteosarcoma excision sites replicating the complexity of the bone microenvironment and cell distribution. In this work, we designed and fabricated modular bioceramic scaffolds to assemble into a co-culture model. Because of the bone-like composition and mechanical property, tricalcium phosphate bioceramic could mimic the bone microenvironment and recapitulate the cell-extracellular matrix interaction. Moreover, the properties for easy assembly enabled the modular units to mimic the spatial distribution of cells in the osteosarcoma excision site. Under this co-culture model, MSCs showed a noticeable tumor-stimulating effect with a potential risk of tumor recurrence. In addition, tumor cells also could inhibit the osteogenic ability of MSCs. To undermine the stimulating effects of MSCs on tumor cells, we present the methods of pre-differentiated MSCs, which had lower expression of IL-8 and higher expression of osteogenic proteins. Both in vitro and in vivo studies confirm that pre-differentiated MSCs could maintain high osteogenic capacity without promoting tumor growth, offering a promising approach for MSCs' application in bone regeneration. Overall, 3D modular scaffolds provide a valuable tool for constructing hard tissue in vitro models. STATEMENT OF SIGNIFICANCE: Bone tissue engineering using mesenchymal stem cells (MSCs) and biomaterials has shown promise for bone repair post osteosarcoma excision. However, conflicting researches on MSCs have raised concerns about their potential to either promote or inhibit tumor cell proliferation. It remains challenges to develop in vitro models to investigate cell interactions, especially of osteosarcoma with high hardness and special composition of bone tissue. In this work, modular bioceramic scaffolds were fabricated and assembled to co-culture models. The interactions between MSCs and MG-63 were manifested as tumor-stimulating and osteogenesis-inhibiting, which means potential risk of tumor recurrence. To undermine the stimulating effect, pre-differentiation method was proposed to maintain high osteogenic capacity without tumor-stimulating, offering a promising approach for MSCs' application in bone regeneration.

Assembled/Disassembled Modular Scaffolds for Multicellular Tissue Engineering.

The behavior of tissue resident cells can be influenced by the spatial arrangement of cellular interactions. Therefore, it is of significance to precisely control the spatial organization of various cells within multicellular constructs. It remains challenging to construct a versatile multicellular scaffold with ordered spatial organization of multiple cell types. Herein, a modular multicellular tissue engineering scaffold with ordered spatial distribution of different cell types is constructed by assembling varying cell-laden modules. Interestingly, the modular scaffolds can be disassembled into individual modules to evaluate the specific contribution of each cell type in the system. Through assembling cell-laden modules, the macrophage-mesenchymal stem cell (MSC), endothelial cell-MSC, and chondrocyte-MSC co-culture models are successfully established. The in vitro results indicate that the intercellular cross-talk can promote the proliferation and differentiation of each cell type in the system. Moreover, MSCs in the modular scaffolds may regulate the behavior of chondrocytes through the nuclear factor of activated T-Cells (NFAT) signaling pathway. Furthermore, the modular scaffolds loaded with co-cultured chondrocyte-MSC exhibit enhanced regeneration ability of osteochondral tissue, compared with other groups. Overall, this work offers a promising strategy to construct a multicellular tissue engineering scaffold for the systematic investigation of intercellular cross-talk and complex tissue engineering.

A bioactive calcium silicate nanowire-containing hydrogel for organoid formation and functionalization.

Organoids, which are 3D multicellular constructs, have garnered significant attention in recent years. Existing organoid culture methods predominantly utilize natural and synthetic polymeric hydrogels. This study explored the potential of a composite hydrogel mainly consisting of calcium silicate (CS) nanowires and methacrylated gelatin (GelMA) as a substrate for organoid formation and functionalization, specifically for intestinal and liver organoids. Furthermore, the research delved into the mechanisms by which CS nanowires promote the structure formation and development of organoids. It was discovered that CS nanowires can influence the stiffness of the hydrogel, thereby regulating the expression of the mechanosensory factor yes-associated protein (YAP). Additionally, the bioactive ions released by CS nanowires in the culture medium could accelerate Wnt/ß-catenin signaling, further stimulating organoid development. Moreover, bioactive ions were found to enhance the nutrient absorption and ATP metabolic activity of intestinal organoids. Overall, the CS/GelMA composite hydrogel proves to be a promising substrate for organoid formation and development. This research suggested that inorganic biomaterials hold significant potential in organoid research, offering bioactivities, biosafety, and cost-effectiveness.

A Multifunctional Hydrogel for Simultaneous Visible H2 O2 Monitoring And Accelerating Diabetic Wound Healing.

Diabetic wound is one of the chronic wounds that is difficult to heal, and effective treatment of it still confronts a great challenge. Monitoring the variation of diabetic wound microenvironment (such as hydrogen peroxide (H2 O2 )) can understand the wound state and guide the wound management. Herein, a multifunctional hydrogel with the abilities of monitoring the H2 O2 concentration, alleviating oxidative stress and promoting wound healing is developed, which is prepared by encapsulating manganese-containing bioactive glass (MnBG) and CePO4 :Tb in biocompatible gelatin methacryloyl (GelMA) hydrogel (CPT-MnBG-Gel). On the one hand, the H2 O2 -dependent fluorescence quenching effect of the CePO4 :Tb contributes to visible monitoring of the H2 O2 concentration of wounds via smartphone imaging, and the CPT-MnBG-Gel hydrogel can effectively monitor the H2 O2 level of 10.35-200 µmol L-1 . On the other hand, MnBG can alleviate oxidative stress and promote the proliferation, migration and differentiation of fibroblasts and endothelial cells in vitro owing to the bioactive Mn and Si ions, and in vivo evaluation also demonstrates that the CPT-MnBG-Gel hydrogels can effectively accelerate wound healing. Hence, such multifunctional hydrogel is promising for diabetic wound management and accelerating wound healing.

Diatomite-incorporated hierarchical scaffolds for osteochondral regeneration.

Osteochondral regeneration involves the highly challenging and complex reconstruction of cartilage and subchondral bone. Silicon (Si) ions play a crucial role in bone development. Current research on Si ions mainly focuses on bone repair, by using silicate bioceramics with complex ion compositions. However, it is unclear whether the Si ions have important effect on cartilage regeneration. Developing a scaffold that solely releases Si ions to simultaneously promote subchondral bone repair and stimulate cartilage regeneration is critically important. Diatomite (DE) is a natural diatomaceous sediment that can stably release Si ions, known for its abundant availability, low cost, and environmental friendliness. Herein, a hierarchical osteochondral repair scaffold is uniquely designed by incorporating gradient DE into GelMA hydrogel. The adding DE microparticles provides a specific Si source for controlled Si ions release, which not only promotes osteogenic differentiation of rBMSCs (rabbit bone marrow mesenchymal stem cells) but also enhances proliferation and maturation of chondrocytes. Moreover, DE-incorporated hierarchical scaffolds significantly promoted the regeneration of cartilage and subchondral bone. The study suggests the significant role of Si ions in promoting cartilage regeneration and solidifies their foundational role in enhancing bone repair. Furthermore, it offers an economic and eco-friendly strategy for developing high value-added osteochondral regenerative bioscaffolds from low-value ocean natural materials.

Bioprinting of inorganic-biomaterial/neural-stem-cell constructs for multiple tissue regeneration and functional recovery.

Tissue regeneration is a complicated process that relies on the coordinated effort of the nervous, vascular and immune systems. While the nervous system plays a crucial role in tissue regeneration, current tissue engineering approaches mainly focus on restoring the function of injury-related cells, neglecting the guidance provided by nerves. This has led to unsatisfactory therapeutic outcomes. Herein, we propose a new generation of engineered neural constructs from the perspective of neural induction, which offers a versatile platform for promoting multiple tissue regeneration. Specifically, neural constructs consist of inorganic biomaterials and neural stem cells (NSCs), where the inorganic biomaterials endows NSCs with enhanced biological activities including proliferation and neural differentiation. Through animal experiments, we show the effectiveness of neural constructs in repairing central nervous system injuries with function recovery. More importantly, neural constructs also stimulate osteogenesis, angiogenesis and neuromuscular junction formation, thus promoting the regeneration of bone and skeletal muscle, exhibiting its versatile therapeutic performance. These findings suggest that the inorganic-biomaterial/NSC-based neural platform represents a promising avenue for inducing the regeneration and function recovery of varying tissues and organs.

3D printing of biomaterials for vascularized and innervated tissue regeneration.

Neurovascular networks play significant roles in the metabolism and regeneration of many tissues and organs in the human body. Blood vessels can transport sufficient oxygen, nutrients, and biological factors, while nerve fibers transmit excitation signals to targeted cells. However, traditional scaffolds cannot satisfy the requirement of stimulating angiogenesis and innervation in a timely manner due to the complexity of host neurovascular networks. Three-dimensional (3D) printing, as a versatile and favorable technique, provides an effective approach to fabricating biological scaffolds with biomimetic architectures and multimaterial compositions, which are capable of regulating multiple cell behaviors. This review paper presents a summary of the current progress in 3D-printed biomaterials for vascularized and innervated tissue regeneration by presenting skin, bone, and skeletal muscle tissues as an example. In addition, we highlight the crucial roles of blood vessels and nerve fibers in the process of tissue regeneration and discuss the future perspectives for engineering novel biomaterials. It is expected that 3D-printed biomaterials with angiogenesis and innervation properties can not only recapitulate the physiological microenvironment of damaged tissues but also rapidly integrate with host neurovascular networks, resulting in accelerated functional tissue regeneration.

3D printing of cell-delivery scaffolds for tissue regeneration.

Tissue engineering strategy that combine biomaterials with living cells has shown special advantages in tissue regeneration and promoted the development of regenerative medicine. In particular, the rising of 3D printing technology further enriched the structural design and composition of tissue engineering scaffolds, which also provided convenience for cell loading and cell delivery of living cells. In this review, two types of cell-delivery scaffolds for tissue regeneration, including 3D printed scaffolds with subsequent cell-seeding and 3D cells bioprinted scaffolds, are mainly reviewed. We devote a major part to present and discuss the recent advances of two 3D printed cell-delivery scaffolds in regeneration of various tissues, involving bone, cartilage, skin tissues etc. Although two types of 3D printed cell-delivery scaffolds have some shortcomings, they do have generally facilitated the exploration of tissue engineering scaffolds in multiple tissue regeneration. It is expected that 3D printed cell-delivery scaffolds will be further explored in function mechanism of seeding cells in vivo, precise mimicking of complex tissues and even organ reconstruction under the cooperation of multiple fields in future.

Lithium-Containing Biomaterials Stimulate Cartilage Repair through Bone Marrow Stromal Cells-Derived Exosomal miR-455-3p and Histone H3 Acetylation.

The repair of damaged cartilage still remains a great challenge in clinic. It is demonstrated that bone marrow stromal cells (BMSCs)-chondrocytes communication is of great significance for cartilage repair. Moreover, BMSCs have been confirmed to enhance biological function of chondrocytes via exosome-mediated paracrine pathway. Lithium-containing scaffolds have been reported to effectively promote cartilage regeneration; however, whether lithium-containing biomaterial could facilitate cartilage regeneration through regulating BMSCs-derived exosomes has not been illustrated. In the study, the model lithium-substituted bioglass ceramic (Li-BGC) is selected and regulatory effects of BMSCs-derived exosomes after Li-BGC treatment (Li-BGC-Exo) are systemically evaluated. The data reveal that Li-BGC-Exo notably promotes chondrogenesis, which attributes to the upregulated exosomal miR-455-3p transfer, consequently leads to suppression of histone deacetylase 2 (HDAC2) and enhanced histone H3 acetylation in chondrocytes. Notably, BMSCs-derived exosomes after LiCl treatment (LiCl-Exo) exhibits the similar regulatory effect with Li-BGC-Exo, indicating that the pro-chondrogenesis capability of them is mainly owing to the lithium ions. Furthermore, the in vivo study proves that LiCl-Exo remarkably facilitates cartilage regeneration. The research may provide novel possibility for the intrinsic mechanism of chondrogenesis trigged by lithium-containing biomaterials, and suggests that application of lithium-containing scaffolds may be a promising strategy for cartilage regeneration.