In Situ Synthesis of Liquid Metal Conductive Fibers toward Smart Cloth.

To meet the diverse needs of humans, smart cloth has become a potential research hotspot to replace traditional cloth. However, it is challenging to manufacture a flexible fabric with multiple functions. Here, we introduce a smart cloth based on liquid metal (LM) conductive fibers. Ga2O3 nanoparticles are obtained through ultrasonic pretreatment. Furthermore, a coordination bond is formed between thiol groups on the surface of protein fibers and Ga2O3 through a scraping method, allowing Ga2O3 particles to be grafted onto the surface of protein fibers in situ. Finally, LM conductive fibers are encapsulated using a photocuring adhesive. In addition, a wearable smart cloth integrated with multiple sensors has been developed based on LM conductive fibers. Users can not only monitor their movement trajectory and the surrounding environment in real time but also have their data supervised by family members through a client, achieving remote and continuous monitoring. The development of this wearable smart cloth provides strong support for future wearable, flexible electronic devices.

Bioactive fiber-reinforced hydrogel to tailor cell microenvironment for structural and functional regeneration of myotendinous junction.

Myotendinous junction (MTJ) injuries are prevalent in clinical practice, yet the treatment approaches are limited to surgical suturing and conservative therapy, exhibiting a high recurrence rate. Current research on MTJ tissue engineering is scarce and lacks in vivo evaluation of repair efficacy. Here, we developed a three-dimensional-printed bioactive fiber-reinforced hydrogel containing mesenchymal stem cells (MSCs) and Klotho for structural and functional MTJ regeneration. In a rat MTJ defect model, the bioactive fiber-reinforced hydrogel promoted the structural restoration of muscle, tendon, and muscle-tendon interface and enhanced the functional recovery of injured MTJ. In vivo proteomics and in vitro cell cultures elucidated the regenerative mechanisms of the bioactive fiber-reinforced hydrogel by modulating oxidative stress and inflammation, thus engineering an optimized microenvironment to support the survival and differentiation of transplanted MSCs and maintain the functional phenotype of resident cells within MTJ tissues, including tendon/muscle cells and macrophages. This strategy provides a promising treatment for MTJ injuries.

An injectable active hydrogel based on BMSC-derived extracellular matrix for cartilage regeneration enhancement.

Articular cartilage injury impairs joint function and necessitates orthopedic intervention to restore the structure and function of the cartilage. Extracellular matrix (ECM) scaffolds derived from bone marrow mesenchymal stem cells (BMSCs) can effectively promote cell adhesion, proliferation, and chondrogenesis. However, pre-shaped ECM scaffolds have limited applicability due to their poor fit with the irregular surface of most articular cartilage defects. In this study, we fabricated an injectable active ECM hydrogel from autologous BMSCs-derived ECM by freeze-drying, liquid nitrogen milling, and enzymatic digestion. Moreover, our in vitro and in vivo results demonstrated that the prepared hydrogel enhanced chondrocyte adhesion and proliferation, chondrogenesis, cartilage regeneration, and integration with host tissue, respectively. These findings indicate that active ECM components can provide trophic support for cell proliferation and differentiation, restoring the structure and function of damaged cartilage.

The impact and mechanism of nerve injury on bone metabolism.

With an increasing understanding of the mechanisms of fracture healing, it has been found that nerve injury plays a crucial role in the process, but the specific mechanism is yet to be completely revealed. To address this issue and provide novel insights for fracture treatment, we compiled this review. This review aims to study the impact of nerve injury on fracture healing, exploring the role of neurotrophic factors in the healing process. We first revisited the effects of the central nervous system (CNS) and the peripheral nervous system (PNS) on the skeletal system, and further explained the phenomenon of significantly accelerated fracture healing under nerve injury conditions. Then, from the perspective of neurotrophic factors, we delved into the physiological functions and mechanisms of neurotrophic factors, such as nerve growth factor (NGF), Neuropeptides (NPs), and Brain-derived neurotrophic factor (BDNF), in bone metabolism. These effects include direct actions on bone cells, improvement of local blood supply, regulation of bone growth factors, control of cellular signaling pathways, promotion of callus formation and bone regeneration, and synergistic or antagonistic effects with other endocrine factors, such as Sema3A and Transforming Growth Factor ß (TGF-ß). Finally, we discussed the treatments of fractures with nerve injuries and the future research directions in this review, suggesting that the relationship between nerve injury and fracture healing, as well as the role of nerve injury in other skeletal diseases.

3D-printed antibiotic-loaded bone cement spacers as adjunctive therapy for hip periprosthetic infection after arthroplasty: A clinical assessment.

OBJECTIVE: To explore the effect of three-dimensional (3D) printing to create personalized antibiotic-loaded bone cement (ALBC) spacers to assist in treatment of periprosthetic infection after total hip arthroplasty (THA). METHODS: The data of 40 patients with postoperative infection after THA were analysed retrospectively. The patients were divided into two groups: the 3D-printing group (age 47-78 years, n = 20) and the conventional group (age 57-78 years, n = 20). In stage I surgery, 3D-printed silicone moulds were used to create ALBC spacers for the 3D-printing group, while traditional manual methods were used to create spacers for the conventional group. After the infection was controlled, both groups underwent conventional hip revision surgery (stage II surgery). All patients were evaluated using the Harris Hip Score (HHS) (primary outcome) for hip function. RESULTS: All 40 patients had follow-up data from 3 months after stage I surgery and 12 months after stage II surgery. The intergroup difference in HHS was 11.25 points [97.5% confidence interval (CI) 7.92-14.58; P < 0.01] at 3 months after stage I surgery, and 9.15 points (97.5% CI 4.82-13.48; P < 0.01) at 12 months after stage II surgery. The overall difference between the two groups was 9.55 points (97.5% CI 5.83-13.27; P < 0.01), which was significant (P < 0.05). CONCLUSION: During the follow-up period, the hip function of the 3D-printing group was superior to that of the conventional group following the treatment of infections after THA.

Cytotoxic Epipolythiodioxopiperazines from the Deep-Sea-Derived Fungus Exophiala mesophila MCCC 3A00939.

Four new aranotin-type epipolythiodioxopiperazines, graphiumins K-N (1-4), along with four known analogues (5-8), were isolated from the deep-sea-derived fungus Exophiala mesophila MCCC 3A00939. Their structures were elucidated by detailed interpretation of NMR and mass spectrometric data. The absolute configuration of the isolates was deduced by a single-crystal X-ray diffraction analysis and the comparisons of experimental electronic circular dichroism (ECD) data with calculated ECD spectra. Graphiumins K (1) and L (2) exhibited cytotoxic activities against the K562, H69AR, and MDA-MB-231 cancer cells with IC50 values ranging from 2.3 to 5.9 µM.

Using UPLC-LTQ-Orbitrap-MS and HPLC-CAD to Identify Impurities in Cycloastragenol, Which Is a Pre-Clinical Candidate for COPD.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease that has become the third leading cause of death worldwide. Cycloastragenol (CAG), which is the genuine sapogenin of the main active triterpene saponins in Astragali radix, is a bioavailable pre-clinical candidate for chronic obstructive pulmonary disease (COPD), and it was investigated in our previous study. In order to progress medical research, it was first efficiently produced on a 2.5-kg scale via Smith degradation from astragaloside IV (AS-IV). Simultaneously, since the impurity profiling of a drug is critical for performing CMC documentation in pre-clinical development, a study on impurities was carried out. As these structures do not contain chromophores and possess weak UV absorption characteristics, HPLC-CAD and UPLC-LTQ-Orbitrap-MS were employed to carry out the quality control of the impurities. Then, column chromatography (CC), preparative thin-layer chromatography (PTLC), and crystallization led to the identification of 15 impurities from CAG API. Among these impurities, compounds 1, 4, 9, 10, 14, and 15 were elucidated via spectroscopic analysis, and 2-3, 5-8, and 11-13 were putatively identified. Interestingly, the new compounds 9 and 14 were rare 10, 19-secocycloartane triterpenoids that displayed certain anti-inflammatory activities against LPS-induced lymphocyte cells and CSE-induced MLE-12 cells. Additionally, a plausible structural transformation pathway of the degradation compounds from CAG or AS IV was proposed. The information obtained will provide a material basis to carry out the quality control and clinical safety assurance of API and related prescriptions. Reasonable guidance will also be provided regarding the compounds with weak UV absorption characteristics.

Enhanced Cartilage and Subchondral Bone Repair Using Carbon Nanotube-Doped Peptide Hydrogel-Polycaprolactone Composite Scaffolds.

A carbon nanotube-doped octapeptide self-assembled hydrogel (FEK/C) and a hydrogel-based polycaprolactone PCL composite scaffold (FEK/C3-S) were developed for cartilage and subchondral bone repair. The composite scaffold demonstrated modulated microstructure, mechanical properties, and conductivity by adjusting CNT concentration. In vitro evaluations showed enhanced cell proliferation, adhesion, and migration of articular cartilage cells, osteoblasts, and bone marrow mesenchymal stem cells. The composite scaffold exhibited good biocompatibility, low haemolysis rate, and high protein absorption capacity. It also promoted osteogenesis and chondrogenesis, with increased mineralization, alkaline phosphatase (ALP) activity, and glycosaminoglycan (GAG) secretion. The composite scaffold facilitated accelerated cartilage and subchondral bone regeneration in a rabbit knee joint defect model. Histological analysis revealed improved cartilage tissue formation and increased subchondral bone density. Notably, the FEK/C3-S composite scaffold exhibited the most significant cartilage and subchondral bone formation. The FEK/C3-S composite scaffold holds great promise for cartilage and subchondral bone repair. It offers enhanced mechanical support, conductivity, and bioactivity, leading to improved tissue regeneration. These findings contribute to the advancement of regenerative strategies for challenging musculoskeletal tissue defects.

Evaluation of outcomes of discectomy with a dynamic neutralization system in treatment of lumbar disk herniation / Evaluación de los resultados de la discectomía con un sistema de neutralización dinámica en el tratamiento de la hernia de disco lumbar

Objective The study aimed to explore the clinical outcomes of discectomy with dynamic neutralization system (Dynesys) for single-segmental lumbar disk herniation (LDH) versus simple discectomy. Methods The eligible patients with single-segmental LDH were randomly divided into the discectomy with Dynesys group (group A) and the simple discectomy group (group B). The Oswestry disability index (ODI), visual analog score (VAS), radiological results of intervertebral height and range of motion (ROM) of the treated segment were evaluated pre- and post-operatively in both groups. Operation duration and blood loss were recorded. Complications, reoperation, and mortality were also assessed. All patients received a 2-year follow-up. Results 123 (96.1%) participants completed the follow-up. The operation duration and blood loss of group B were significantly lower than those of group A (p<0.05). After operation, ODI and VAS were improved significantly in both groups, and there was no significant difference between the two groups immediately after surgery. But a rising trend was found in ODI and VAS of group B, especially after the 1-year follow-up (p<0.05). X-rays showed a continuing loss of intervertebral height of the treated segment in group B, while it was preserved in group A (p<0.05). ROM of the treated segment was also maintained stable in group A. Conclusion Discectomy with Dynesys is safe and effective for LDH treatment (AU)

Objetivo El objetivo de este estudio es explorar los resultados clínicos de la discectomía con sistema de neutralización dinámica (Dynesys) para la hernia de disco lumbar (LDH) de un solo segmento vs. la discectomía simple. Métodos Los pacientes elegibles con LDH de un solo segmento se dividieron aleatoriamente en el grupo de discectomía con Dynesys (grupo A) y el grupo de discectomía simple (grupo B). El índice de discapacidad de Oswestry (ODI), la puntuación analógica visual (VAS), los resultados radiológicos de la altura intervertebral y el rango de movimiento (ROM) del segmento tratado se evaluaron antes y después de la operación en ambos grupos. Se registraron la duración de la operación y la pérdida de sangre. También se evaluaron las complicaciones, la reintervención y la mortalidad. Todos los pacientes recibieron un seguimiento de dos años. Resultados Completaron el seguimiento 123 (96,1%) participantes. La duración de la operación y la pérdida de sangre del grupo B fueron significativamente menores que las del grupo A (p < 0,05). Después de la operación, ODI y VAS mejoraron significativamente en ambos grupos y no hubo diferencias significativas entre los dos grupos inmediatamente después de la cirugía. Pero se encontró una tendencia ascendente en ODI y EVA del grupo B, especialmente después del seguimiento de un año (p < 0,05). Las radiografías mostraron una pérdida continua de la altura intervertebral del segmento tratado en el grupo B, mientras que se conservó en el grupo A (p < 0,05). El ROM del segmento tratado también se mantuvo estable en el grupo A. Conclusión La discectomía con Dynesys es segura y efectiva para el tratamiento de LDH (AU)

Advances in PD-1 signaling inhibition-based nano-delivery systems for tumor therapy.

In recent years, cancer immunotherapy has emerged as an exciting cancer treatment. Immune checkpoint blockade brings new opportunities for more researchers and clinicians. Programmed cell death receptor-1 (PD-1) is a widely studied immune checkpoint, and PD-1 blockade therapy has shown promising results in a variety of tumors, including melanoma, non-small cell lung cancer and renal cell carcinoma, which greatly improves patient overall survival and becomes a promising tool for the eradication of metastatic or inoperable tumors. However, low responsiveness and immune-related adverse effects currently limit its clinical application. Overcoming these difficulties is a major challenge to improve PD-1 blockade therapies. Nanomaterials have unique properties that enable targeted drug delivery, combination therapy through multidrug co-delivery strategies, and controlled drug release through sensitive bonds construction. In recent years, combining nanomaterials with PD-1 blockade therapy to construct novel single-drug-based or combination therapy-based nano-delivery systems has become an effective mean to address the limitations of PD-1 blockade therapy. In this study, the application of nanomaterial carriers in individual delivery of PD-1 inhibitors, combined delivery of PD-1 inhibitors and other immunomodulators, chemotherapeutic drugs, photothermal reagents were reviewed, which provides effective references for designing new PD-1 blockade therapeutic strategies.

Tough Gelatin Hydrogel for Tissue Engineering.

Tough hydrogel has attracted considerable interest in various fields, however, due to poor biocompatibility, nondegradation, and pronounced compositional differences from natural tissues, it is difficult to be used for tissue regeneration. Here, a gelatin-based tough hydrogel (GBTH) is proposed to fill this gap. Inspired by human exercise to improve muscle strength, the synergistic effect is utilized to generate highly functional crystalline domains for resisting crack propagation. The GBTH exhibits excellent tensile strength of 6.67 MPa (145-fold that after untreated gelation). Furthermore, it is directly sutured to a ruptured tendon of adult rabbits due to its pronounced toughness and biocompatibility, self-degradability in vivo, and similarity to natural tissue components. Ruptured tendons can compensate for mechanotransduction by GBTH and stimulate tendon differentiation to quickly return to the initial state, that is, within eight weeks. This strategy provides a new avenue for preparation of highly biocompatible tough hydrogel for tissue regeneration.

Fabrication and Properties of the Multifunctional Rapid Wound Healing Panax notoginseng@Ag Electrospun Fiber Membrane.

The Panax notoginseng@Ag core/shell electrospun fiber membrane was prepared by coaxial electrospinning combined with the UV reduction method (254 nm). The prepared Panax notoginseng@Ag core/shell nanofiber membrane has a three-dimensional structure, and its swelling ratio could reach as high as 199.87%. Traditional Chinese medicine Panax notoginseng can reduce inflammation, and the silver nanoparticles have antibacterial effects, which synergistically promote rapid wound healing. The developed Panax notoginseng@Ag core/shell nanofiber membrane can effectively inhibit the growth of the Gram-negative bacteria Escherichia coli and the Gram-positive bacteria Staphylococcus aureus. The wound healing experiments in Sprague Dawley mice showed that the wound residual area rate of the Panax notoginseng@Ag core/shell electrospun nanofiber membrane group was only 1.52% on day 9, and the wound of this group basically healed on day 12, while the wound residual area rate of the gauze treatment group (control group) was 16.3% and 10.80% on day 9 and day 12, respectively. The wound of the Panax notoginseng@Ag core/shell electrospun nanofiber membrane group healed faster, which contributed to the application of the nanofiber as Chinese medicine rapid wound healing dressings.

Nanoparticle-Based Combination Therapy for Ovarian Cancer.

Ovarian cancer is one of the most common malignant tumors in gynecology with a high incidence. Combination therapy, eg, administration of paclitaxel followed by a platinum anticancer drug is recommended to treat ovarian cancer due to its advantages in, eg, reducing side effects and reversing (multi)drug-resistance compared to single treatment. However, the benefits of combination therapy are often compromised. In chemo and chemo/gene combinations, co-deposition of the combined therapeutics in the tumor cells is required, which is difficult to achieve due to dramatic pharmacokinetic differences between combinational agents in free forms. Moreover, some undesired properties such as the low-water solubility of chemodrugs and the difficulty of cellular internalization of gene therapeutics also hinder the therapeutic potential. Delivery of dual or multiple agents by nanoparticles provides opportunities to tackle these limits. Nanoparticles encapsulate hydrophobic drug(s) to yield aqueous dispersions facilitating its administration and/or to accommodate hydrophilic genes facilitating its access to cells. Moreover, nanoparticle-based therapeutics can not only improve drug properties (eg, in vivo stability) and ensure the same drug disposition behavior with controlled drug ratios but also can minimize drug exposure of the normal tissues and increase drug co-accumulation at targeted tissues via passive and/or active targeting strategies. Herein, this work summarizes nanoparticle-based combination therapies, mainly including anticancer drug-based combinations and chemo/gene combinations, and emphasizes the advantageous outcomes of nanocarriers in the combination treatment of ovarian cancer. In addition, we also review mechanisms of synergetic effects resulting from different combinations.

Reversible Recognition-Based Boronic Acid Probes for Glucose Detection in Live Cells and Zebrafish.

Glucose, a critical source of energy, directly determines the homeostasis of the human body. However, due to the lack of robust imaging probes, the mechanism underlying the changes of glucose homeostasis in the human body remains unclear. Herein, diboronic acid probes with good biocompatibility and high sensitivity were synthesized based on an ortho-aminomethylphenylboronic acid probe, phenyl(di)boronic acid (PDBA). Significantly, by introducing the water-solubilizing group -CN directly opposite the boronic acid group and -COOCH3 or -COOH groups to the ß site of the anthracene in PDBA, we obtained the water-soluble probe Mc-CDBA with sensitive response (F/F0 = 47.8, detection limit (LOD) = 1.37 µM) and Ca-CDBA with the highest affinity for glucose (Ka = 4.5 × 103 M-1). On this basis, Mc-CDBA was used to identify glucose heterogeneity between normal and tumor cells. Finally, Mc-CDBA and Ca-CDBA were used for imaging glucose in zebrafish. Our research provides a new strategy for designing efficient boronic acid glucose probes and powerful new tools for the evaluation of glucose-related diseases.

Comparative pharmacokinetics of four major compounds after oral administration of Mori Cortex total flavonoid extract in normal and diabetic rats.

Introduction: Mori Cortex has been used in traditional Chinese Medicine as an antidiabetic agent. The aim of this study was to establish a UPLC-MS/MS method for simultaneous determination of morin, morusin, umbelliferone and mulberroside A in rat plasma and investigate the pharmacokinetics differences between normal and diabetic rats following oral administration of Mori Cortex total flavonoid extract. Methods: Samples were pre-treated by protein precipitation and genkwanin was used as internal standard. Chromatographic separation was performed using a Hypersil GOLD C18 column (50 mm × 2.1 mm, 3 µm). The mobile phase consisted of acetonitrile and water (containing 0.1% formic acid) in gradient mode at a flow rate of 0.5 ml/min. The transitions of m/z 300.9→107.1, m/z 419.3→297.1, m/z 160.9→77.0, m/z 567.1→243.2 and m/z 283.1→268.2 were selected for morin, morusin, umbelliferone, mulberroside A and internal standard, respectively. Results: The intra- and inter-day precision for analytes were less than 12.5% and the accuracy ranged from -8.1% to 3.5%. The extraction recovery was >88.5% and no obvious matrix effect was observed. The AUC (0-t) and C max of morin were 501.3 ± 115.5 ng/mL*h and 127.8 ± 56.0 ng/mL in normal rats and 717.3 ± 117.4 ng/ml*h and 218.6 ± 33.5 ng/ml in diabetic rats. Meanwhile, the AUC (0-t) and C max of morusin were 116.4 ± 38.2 ng/ml*h and 16.8 ± 10.1 ng/mL in normal rats and 325.0 ± 87.6 ng/mL*h and 39.2 ± 5.9 ng/ml in diabetic rats. For umbelliferone and mulberroside A, the AUC (0-t) and C max also increased significantly in diabetic rats (p < 0.05). Discussion: The validated method was successfully applied to the pharmacokinetic study in normal and diabetic rats.

Silk Fibroin and Sericin Differentially Potentiate the Paracrine and Regenerative Functions of Stem Cells Through Multiomics Analysis.

Silk fibroin (SF) and sericin (SS), the two major proteins of silk, are attractive biomaterials with great potential in tissue engineering and regenerative medicine. However, their biochemical interactions with stem cells remain unclear. In this study, multiomics are employed to obtain a global view of the cellular processes and pathways of mesenchymal stem cells (MSCs) triggered by SF and SS to discern cell-biomaterial interactions at an in-depth, high-throughput molecular level. Integrated RNA sequencing and proteomic analysis confirm that SF and SS initiate widespread but distinct cellular responses and potentiate the paracrine functions of MSCs that regulate extracellular matrix deposition, angiogenesis, and immunomodulation through differentially activating the integrin/PI3K/Akt and glycolysis signaling pathways. These paracrine signals of MSCs stimulated by SF and SS effectively improve skin regeneration by regulating the behavior of multiple resident cells (fibroblasts, endothelial cells, and macrophages) in the skin wound microenvironment. Compared to SS, SF exhibits better immunomodulatory effects in vitro and in vivo, indicating its greater potential as a carrier material of MSCs for skin regeneration. This study provides comprehensive and reliable insights into the cellular interactions with SF and SS, enabling the future development of silk-based therapeutics for tissue engineering and stem cell therapy.

3D-Printing of succulent plant-like scaffolds with beneficial cell microenvironments for bone regeneration.

Biomimetic materials with complicated structures inspired by natural plants play a critical role in tissue engineering. The succulent plants, with complicated morphologies, show tenacious vitality in extreme conditions due to the physiological functions endowed by their unique anatomical structures. Herein, inspired by the macroscopic structure of succulent plants, succulent plant-like bioceramic scaffolds were fabricated via digital laser processing 3D printing of MgSiO3. Compared with conventional scaffolds with interlaced columns, the structures could prevent cells from leaking from the scaffolds and enhance cell adhesion. The scaffold morphology could be well regulated by changing leaf sizes, shapes, and interlacing methods. The succulent plant-like scaffolds show excellent properties for cell loading as well as cell distribution, promoting cellular interplay, and further enhancing the osteogenic differentiation of bone marrow stem cells. The in vivo study further illustrated that the succulent plant-like scaffolds could accelerate bone regeneration by inducing the formation of new bone tissues. The study suggests that the obtained succulent plant-like scaffold featuring the plant macroscopic structure is a promising biomaterial for regulating cell distribution, enhancing cellular interactions, and further improving bone regeneration.

Evaluation of outcomes of discectomy with a dynamic neutralization system in treatment of lumbar disk herniation.

OBJECTIVE: The study aimed to explore the clinical outcomes of discectomy with dynamic neutralization system (Dynesys) for single-segmental lumbar disk herniation (LDH) versus simple discectomy. METHODS: The eligible patients with single-segmental LDH were randomly divided into the discectomy with Dynesys group (group A) and the simple discectomy group (group B). The Oswestry disability index (ODI), visual analog score (VAS), radiological results of intervertebral height and range of motion (ROM) of the treated segment were evaluated pre- and post-operatively in both groups. Operation duration and blood loss were recorded. Complications, reoperation, and mortality were also assessed. All patients received a 2-year follow-up. RESULTS: 123 (96.1%) participants completed the follow-up. The operation duration and blood loss of group B were significantly lower than those of group A (p<0.05). After operation, ODI and VAS were improved significantly in both groups, and there was no significant difference between the two groups immediately after surgery. But a rising trend was found in ODI and VAS of group B, especially after the 1-year follow-up (p<0.05). X-rays showed a continuing loss of intervertebral height of the treated segment in group B, while it was preserved in group A (p<0.05). ROM of the treated segment was also maintained stable in group A. CONCLUSION: Discectomy with Dynesys is safe and effective for LDH treatment.

Advancing Strategies for Proteolysis-Targeting Chimera Design.

Proteolysis-targeting chimeras (PROTACs) have shown great therapeutic potential by degrading various disease-causing proteins, particularly those related to tumors. Therefore, the introduction of PROTACs has ushered in a new chapter of antitumor drug development, marked by significant advances over recent years. Herein, we describe recent developments in PROTAC technology, focusing on design strategy, development workflow, and future outlooks. We also discuss potential opportunities and challenges for PROTAC research.

A 3D multifunctional bi-layer scaffold to regulate stem cell behaviors and promote osteochondral regeneration.

Osteochondral defect (OCD) regeneration remains a great challenge. Recently, multilayer scaffold simulating native osteochondral structures have aroused broad interest in osteochondral tissue engineering. Here, we developed a 3D multifunctional bi-layer scaffold composed of a kartogenin (KGN)-loaded GelMA hydrogel (GelMA/KGN) as an upper layer mimicking a cartilage-specific extracellular matrix and a hydroxyapatite (HA)-coated 3D printed polycaprolactone porous scaffold (PCL/HA) as a lower layer simulating subchondral bone. The bi-layer scaffolds were subsequently modified with tannic acid (TA) prime-coating and E7 peptide conjugation (PCL/HA-GelMA/KGN@TA/E7) to regulate endogenous stem cell behaviors and exert antioxidant activity for enhanced osteochondral regeneration. In vitro, the scaffolds could support cell attachment and proliferation, and enhance the chondrogenic and osteogenic differentiation capacity of bone marrow-derived mesenchymal stem cells (BMSCs) in a specific layer. Besides, the incorporation of TA/E7 significantly increased the biological activity of the bi-layer scaffolds including the pro-migratory effect, antioxidant activity, and the maintenance of cell viability against oxidative stress. In vivo, the developed bi-layer scaffolds enhanced the simultaneous regeneration of cartilage and subchondral bone when implanted into a rabbit OCD model through macroscopic, micro-CT, and histological evaluation. Taken together, these investigations demonstrated that the 3D multifunctional bi-layer scaffolds could provide a suitable microenvironment for endogenous stem cells, and promote in situ osteochondral regeneration, showing great potential for the clinical treatment of OCD.