Direct ink writing (DIW) has emerged as one of the most promising approaches for biomedical application, owing to its broad material compatibility, ease of operation, and high-resolution. However, the development of DIW inks with suitable rheological properties and excellent biocompatibility remains a significant challenge. Herein, an acrylate-functionalized liquid poly(4-methyl-ε-caprolactone) (PMCLDA) was synthesized as the precursor of 3D printing ink, accompanied with thiol-functionalized polyethylene glycol (PEGSH) as a rheological modifier. It was indicated from rheology study that the incorporation of PEGSH with PMCLDA precursor afforded the mixt inks shear thinning behavior. Moreover, it was verified by in situ Fourier transform infrared spectroscopy and photo-rheology that the mixed ink could rapidly cure through thiol-acrylate crosslinking under UV light. Various inks formulations were successfully utilized for printing 3D scaffolds via UV-assisted DIW, with the optimized printability for SH75 ink. Moreover, the 3D-printed scaffolds exhibited excellent elasticity and degradability. In vitro cytocompatibility assessments showed that the scaffolds exhibited good cytocompatibility and supported the proliferation of L929 mouse fibroblasts for a duration of 7 days. Therefore, it is demonstrated that the 3D-printed scaffolds crosslinked via thiol-acrylate crosslinking have great potential for applications in tissue engineering.

Stem cell therapy has demonstrated efficacy in treating bone defects. However, a critical challenge remains in effectively anchoring stem cells at the defect site and creating a conducive microenvironment that supports their proliferation and enhances bone regeneration. To address the dynamic microenvironmental changes occurring at different stages of bone defect healing, we designed a matrix metalloproteinase (MMP)-responsive biomimetic multilayer hydrogel system. The intermediate layer contains raleukin to provide targeted anti-inflammatory therapy, while the innermost layer comprises alginate/carboxymethyl cellulose microcapsules encapsulating bone marrow mesenchymal stem cells (BMSCs) to support stem cell retention, viability, and maintenance of stemness. The synergistic interaction between encapsulated BMSCs and raleukin effectively modulates the immune-inflammatory response and promotes angiogenesis, osteoblast proliferation, and differentiation. In vivo evaluation using rat skull defect model additionally demonstrates that the hydrogel system significantly enhances bone regeneration by accelerating bone metabolism and promoting osteoblast differentiation following implantation. Collectively, these findings underscore the therapeutic potential of MMP-responsive hydrogel platforms in advancing bone regeneration and related biomedical applications.

With the emergence of numerous classifications, surgical treatment for adolescent idiopathic scoliosis (AIS) can be guided more effectively. However, surgical decision-making and optimal strategies still lack standardization and personalized customization. Our study aims to devise proper deep learning (DL) models that incorporate key factors influencing surgical outcomes on the coronal plane in AIS patients to facilitate surgical decision-making and predict surgical results for AIS patients. A total of 425 AIS patients who underwent posterior spinal fixation were collected. Variables such as age, gender, preoperative and final follow-up horizontal and vertical coordinate vectors, and screw positioning data were preprocessed by parameterizing image data and transforming various data types into a unified, continuous high-dimensional feature space. Four deep learning models were designed, including Multi-Layer Perceptron model, Encoder-Decoder model, CNN-LSTM Attention model and Deep FM model. For the implementation of deep learning, 70% of the data was adopted for training and 30% for evaluation. The mean square error (MSE), mean absolute error (MAE) and curve fitting between the predicted and corresponding real postoperative spinal coordinates of the test set were adopted to validate and compare the efficacy of the DL models. A total of 425 patients with an average age of 14.60 ± 2.08 years, including 77 males and 348 females, were enrolled in this study. The Lenke type 1 and 5 AIS patients accounted for the majority of the included patients. The results showed that the Multi-Layer Perceptron model achieved the best performance among the four DL models, with a mean square error of 2.77 × 10–5 and an average absolute error of 0.00350 on the validation set. Moreover, the results predicted by the Multi-Layer Perceptron model closely matched the actual coordinate positions on the original postoperative images of patients with Lenke type 1 and AIS patients. Deep learning models can provide alternative and effective decision-making support for AIS patients undergoing surgery. Regarding the learning curve and data volume, the optimal DL models should be adjusted and refined to meet future demands.

Protein phosphorylation plays an important role in the signal transduction and is capable of regulation of cell activity. The death-associated protein kinase 1 (DAPK1), as a Ser/Thr kinase, interacts with calmodulin (CaM) to regulate apoptotic and autophagic signaling. Autophosphorylation of DAPK1 at Ser308 located at the autoregulatory domain (ARD) blocks CaM binding and inhibits kinase catalytic activity. However, the mechanism underlying the influence of Ser308 phosphorylation (pS308) on the DAPK1 activity remains unclear. Here, we performed multiple, microsecond length molecular dynamics (MD) simulations, the molecular mechanics generalized Born/surface area (MM-GBSA) binding free energy calculations, principal component analysis, and dynamic cross-correlation analysis to unravel the conformational dynamics and allostery of the DAPK1 - CaM interaction triggered by the pS308 at the ARD. MD simulations showed that pS308 affected the conformational stability of the DAPK1 - CaM complex. Further energetic and structural exploration revealed that pS308 weakened the association of the phosphorylated DAPK1 to CaM, which lowered the susceptibility of DAPK1 to be activated by CaM. This result can provide mechanistic insights into the molecular underpinning through which the DAPK1 kinase activity is modulated by the auto-phosphorylation.

BACKGROUND:The surgical treatment of thoracic spinal tuberculosis has garnered enormous interest from researchers toward the development of posterior surgical techniques that have contributed to greater use of the 1-stage posterior approach. This study aims to demonstrate the initial clinical experience of a modified total posterior approach, in which the 1-stage posterior approach preserves the posterior spinal column structure by combining with the endoprosthetic implant fusion for thoracic spinal tuberculosis. METHODS:In this clinical study, we intended to report the initial idea of a modified total posterior approach. In detail, a 1-stage posterior approach was applied to preserve the posterior spinal column structure that could be applied to clinical practice. RESULTS:The employed practical procedure presented a reduced duration of surgical intervention and intraoperative trauma. Nevertheless, further studies with large samples and multiple centers are required to explore the idea comprehensively. CONCLUSIONS:This approach offered some advantages in terms of intraoperative exposure, blood loss volume, and length of surgery. Further, multicenter studies with large samples are needed to understand the precise effects and implications of the approach.

Bioorthogonal chemistry, recognized as a highly efficient tool in chemical biology, has shown significant value in cancer treatment. The primary objective is to develop efficient delivery strategies to achieve enhanced bioorthogonal drug treatment for tumors. Here, Janus microparticles (JMs) loaded with cyclooctene-modified doxorubicin prodrug (TCO-DOX) and tetrazine-modified indocyanine green (Tz-ICG) triggers are reported. Besides activating TCO-DOX, Tz-ICG is also a photothermal agent used in photothermal therapy (PTT), enabling the simultaneous use of biorthogonal chemotherapy and PTT. Additionally, the DOX could be significantly reduced in systemic toxicity with the modification of cyclooctene. Thus, the developed drug-carrying JMs system exhibits effective tumor cell killing in vitro and effectively inhibits tumor local progress and distant lung metastasis after postoperative treatment with good safety. These results demonstrate that the prepared JMs provide a paradigm for bioorthogonal prodrug activation and localized delivery, and hold great promise for cancer therapy as well as other related applications.

Inflammation can initiate osteolysis, which is the breakdown of bone by fully developed osteoclasts. The compound Oleandrin is recognized for its effects against inflammation and tumors. Our objective was to examine the effects of Oleandrin on osteoclastogenesis and osteolysis, both in vitro and in vivo. In vitro, the impact of Oleandrin on osteoclastogenesis was assessed using CCK-8 assays, TRAP staining, and bone resorption assays. Additionally, a mouse model of osteolysis caused by LPS injection into the calvaria was used to conduct an in vivo investigation, examining bone histomorphology, histology, and immunohistochemistry. In vitro, concentrations of 5 nM and 10 nM of Oleandrin were found to be non-cytotoxic based on the results obtained. In vitro, Oleandrin hindered the osteoclastogenesis and bone resorption induced by RANKL. Oleandrin successfully inhibited the phosphorylation of NF-κB p65 and PI3K p85 in osteolytic tissue, thereby suppressing LPS-induced inflammatory osteolysis in mice calvaria during the in vivo study. Furthermore, the Oleandrin-treated group exhibited a noteworthy decrease in the expression level of NFATc1, which is a crucial controller of osteoclastogenesis. To sum up, our discoveries indicate that Oleandrin could hinder osteoclastogenesis and bone resorption, thereby having the ability to suppress inflammation-induced osteolysis. The underlying mechanism involves the NF-κB/PI3K pathway and inhibition of NFATc1 activation. Therefore, the findings suggest that Oleandrin holds potential as a therapeutic remedy for osteolytic ailments.

Download This Paper Open PDF in Browser Add Paper to My Library Share: Permalink Using these links will ensure access to this page indefinitely Copy URL Copy DOI

Abstract Objective We present for the first time a novel entry point of pedicle screws (Short Rod Technique, SRT), which can avoid superior facet violation and has been verified as a safe screw placement method. The objective of this study is to report the clinical outcomes of SRT in transforaminal lumbar interbody fusion (TLIF) surgery through Wiltse approach. Methods We retrospectively analyzed the clinical outcomes of 64 patients who received SRT through Wiltse approach with a minimum of 2 years of follow-ups. Demographics, clinical outcomes and radiological parapmeters were recorded and analyzed. Results Less total postoperative drainage volume before removall (27.88 ± 10.27), shorter days of removal of drainage (1.08 ± 0.27) was observed in SRT through Wiltse approach. In addition, patients felt less wound pain after the surgery, improving their HRQOL. Upper adjacent segment degeneration (ASD) was found in 2 petients at final follow-up, and they also received revision surgery. Both back pain, leg pain and ODI improved after the surgery; however, due to the ASD patients, the mean value of leg pain and ODI were greater at final follow-up than they’re at post-operation. Less change of LL was observed at final follow-up than it at post-operation with significant difference. Compared with increase of SS at post-operation, SS decreased at final follow-up with significant difference of change of SS. PT decreased at post-operation, while it was found to be increased at final follow-up. PI remained constant before and after the surgery with no significant difference of change of PI. Sagittal alignment also tended to be imbalanced with the change of SVA signficantly greater at final follow-up than it at post-operation. In addition, due to the two cases of ASD, the loss of disc hight and change of slippage distance of upper adjacent segment were signficantly greater at final follow-up than they’re at post-operation. More degeneration of intervertebral disc was also observed at final follow-up. Conclusion Application of SRT through Wiltse approach in TLIF surgery has been validated as an effective technique with good clinical outcomes, especially for reducing the blood loss and postoperative wound pain and improving patients’ HRQOL. The present study provides spinal surgeons with a novel method for performing TLIF surgery.

Hydrogel microspheres hold great promise as scaffolds for bone repair. Their hydrated matrix, biocompatibility, and functional properties make them an attractive choice in regenerative medicine. However, the irregularity of defect requires shape adaptability of the microspheres. Additionally, there is still room for improvement regarding the component of the microspheres to achieve sufficient bioactivity. Here, we prepare multi-bioactive microspheres composed of methacrylated silk fibroin (SFMA) via microfluidic electrospray. Magnesium ascorbyl phosphate (MAP) is encapsulated within the microspheres, whose sustained release facilitates angiogenesis and osteogenic differentiation. The microspheres are further coated with a polydopamine (PDA) layer, allowing them to assemble in situ into a scaffold that conforms to the non-uniform contours of bone defects. The photothermal conversion capability of PDA also provides mild photothermal stimulation to further promote bone regeneration. Based on the synergistic effects, our in vivo experiments demonstrated that the microsphere scaffold effectively promotes bone defect healing. Thus, this multi-bioactive scaffold offers a versatile strategy for bone repair with promising clinical potential.

Regeneration of articular cartilage remains a great challenge due to its poor self-healing capacity and weak stability. The microfracture surgery (MF) can provide bone marrow mesenchymal stem cells (BMSCs) and is commonly used in clinical practice, but its therapeutic effect is still limited by the lack of effective adhesion matrix and the uncontrollable tendency to develop fibrosis and even mineralization. In this study, a small molecular drug-loaded viscoelastic hydrogel-based 3D printing bilayer scaffold with a swelling-dependent gate was successfully developed to address these limitations. The scaffold consisted of a lower layer with a smaller pore size and an upper matrix with larger pore size. The former acted as a swelling-dependent gate to switch pore size, which initially was on-state allowing the infiltration of BMSCs, and eventually transformed into off-state serving as a barrier blocking excessive blood support from the bone marrow after swelling-induced closure of pores. This barrier structure cooperated with fatty acid inhibitor-suppressed hypertrophy of neo-cartilage matrix. The latter provided a biocompatible and viscoelastic matrix to guide MSCs toward stable chondrogenic commitment. By integrating structural design with the inhibitor, the bilayer scaffold provides a promising platform for future clinical applications of MF surgery in cartilage regeneration.

Tumor-associated macrophages (TAMs) play an important role in promoting tumor growth and metastasis, thus reprogramming TAMs to modulate the tumor immune microenvironment is a promising tumor treatment stratagem. Here, we present novel yeast-derived nanocarriers (YNCs) as IPI-549 delivery system for binary reprogramming of TAMs to induce anticancer immunity. The nanocarriers were fabricated from yeast cell walls with immune-oncology agent IPI-549 loading and coated with a shielding polymer for prolonged blood circulation. After intravenous injection, these YNCs could accumulate at the tumor site and be phagocytosed by TAMs via the Dectin-1 pathway to induce macrophage polarization towards M1 phenotype. In combination with IPI-549, the YNC system has efficiently inhibited tumor growth and modulated the tumor immune microenvironment through macrophage phenotypic alteration and increase of T cell-mediated antitumor immunity, which was demonstrated in a 4T1 orthotopic breast cancer mouse model. All these features indicate the promising values of our YNC delivery system in clinical antitumor applications.

Advanced bioadhesion techniques have offered unprecedented opportunities for life-saving internal surgical procedures. However, most existing bioadhesives failed to rapidly establish long-lasting reliable biointerface and effectively reconstruct normal physiological function in the body fluid-rich and inevitable dynamic internal environment. Herein, a PEGylated poly(glycerol sebacate)-based Janus adhesive patch (PEGS-based JAP) is developed by integrating physically crosslinked guanidinylated PEGS (PEGSG) and acryloylated PEGS-chemically crosslinked poly(acrylic acid)-N-hydrosuccinimide ester (PEGSA-crosslinked PAAc-NHS) with a single-sided zwitterionic polymer-interpenetrated layer. The dry JAP can rapidly absorb the unpleasant interfacial water and effectively form strong physical interactions with wet tissues. Benefiting from the amphiphilic nature of PEGSG and a simple spatial-confined drying process, the JAP is allowed to resist excessive swelling and limitedly swell along one direction to avoid deterioration of the as-established conformable patch-tissue interface. Moreover, covalent interactions formed subsequently can further improve the adhesive strength and ensure a long-lasting reliable adhesion. Meanwhile, the notch-insensitive and puncture-resistant JAP can achieve tough adhesion to adapt to the dynamic conditions owing to the highly efficient energy-dissipation mechanism of the physically cross-linked network. Combining the above ideal features with the desirable postoperative anti-adhesion ability, the PEGS-based JAP is demonstrated to be a promising candidate for internal tissue adhesion and function reconstruction.

Objective Improving accuracy and safety of pedicle screw placement is of great clinical importance. Electronic conductivity device (ECD) can be a promising technique with features of affordability, portability, and real‐time detection capabilities. This study aimed to validate the safety and effectiveness of a modified ECD. Methods The ECD underwent a modification where six lamps of various colors, and it was utilized in a prospectively multicenter randomized controlled clinical trial involving 96 patients across three hospitals from June 2018 to December 2018. The trial incorporated a self‐control randomization with an equal distribution of left or right side of vertebral pedicle among two groups: the free‐hand group and the ECD group. A total of 496 pedicle screws were inserted, with 248 inserted in each group. The primary outcomes focused on the accuracy of pedicle screw placement and the frequency of intraoperative X‐rays. Meanwhile, the secondary indicator measured the time required for pedicle screw placement. Results were presented as means ± SD. Paired samples t ‐test and χ 2 ‐test were used for comparison. Furthermore, an updated review was conducted, which included studies published from 2006 onwards. Results Baseline patient characteristics were recorded. The primary accuracy outcome revealed a 96.77% accuracy rate in the ECD group, compared to a 95.16% accuracy rate in the free‐hand group, with no significant differences noted. In contrast, ECD demonstrated a significant reduction in radiation exposure frequency when compared to the free‐hand group (1.11 ± 0.32 vs. 1.30 ± 0.53; p < 0.001), resulting in a 14.6% reduction. Moreover, ECD displayed a decrease of 30.38% in insertion time (70.88 ± 30.51 vs. 101.82 ± 54.00 s; p < 0.001). According to the results of the 21 studies, ECD has been utilized in various areas of the spine such as the atlas, thoracic and lumbar spine, as well as sacral 2‐alar‐iliac. The accuracy of ECD ranged from 85% to 100%. Conclusion The prospectively randomized trial and the review indicate that the use of ECD presents a secure and precise approach to the placement of pedicle screws, with the added benefit of reducing both procedure time and radiation exposure.

Aging exacerbates the dysfunction of tissue regeneration at multiple levels and gradually diminishes individual's capacity to withstand stress, damage, and disease. The excessive accumulation of reactive oxygen species (ROS) is considered a hallmark feature of senescent stem cells, which causes oxidative stress, deteriorates the host microenvironment, and eventually becomes a critical obstacle for aged bone defect repair. Till now, the strategies cannot synchronously and thoroughly regulate intracellular and extracellular ROS in senescent cells. Herein, a multihierarchy ROS scavenging system for aged bone regeneration is developed by fabricating an injectable PEGylated poly(glycerol sebacate) (PEGS-NH2 )/poly(γ-glutamic acid) (γ-PGA) hydrogel containing rapamycin-loaded poly(diselenide-carbonate) nanomicelles (PSeR). This PSeR hydrogel exhibits highly sensitive ROS responsiveness to the local aged microenvironment and dynamically releases drug-loaded nanomicelles to scavenge the intracellular ROS accumulated in senescent bone mesenchymal stem cells. The PSeR hydrogel effectively tunes the antioxidant function and delays senescence of bone mesenchymal stem cells by safeguarding DNA replication in an oxidative environment, thereby promoting the self-renewal ability and enhancing the osteogenic capacity for aged bone repair in vitro and in vivo. Thus, this multihierarchy ROS-regulated hydrogel provides a new strategy for treating degenerative diseases.

Currently, spinal interbody cages are crucial for spinal fusion surgeries. Due to the mechanical and imaging characteristics of polyetheretherketone (PEEK), it is a widely used material for cages. However, the bioinert PEEK has poor osseointegration, thereby preventing the ideal fusion of PEEK cages. Therefore, efforts have been made for improving biological activity using surface modification techniques, including physical as well as chemical modifications and surface coating. In this study, we reviewed and analyzed recent studies on PEEK surface modification techniques to enhance our understanding for future studies.

目的 评估CT导航系统在重度僵硬性脊柱畸形矫形术中的置钉准确性及临床疗效.方法 回顾性纳入2017年1月至2022年12月我院收治的43例重度僵硬性脊柱畸形病人,其中21例采用术中CT导航系统辅助置钉(421枚螺钉)的病人纳入导航组,22例采用传统徒手置钉(386枚螺钉)的病人纳入徒手组.收集两组病人的一般资料、手术前后主弯Cobb角、矫正率、置钉数量以及顶椎区域置钉数量.采用Gertzbein和Robbins分级分析两组病人术后CT图像,以评估置钉准确性.结果 两组病人手术前后主弯Cobb角及矫正率比较,差异无统计学意义(P>0.05).较之徒手组,导航组置入于顶椎区域的螺钉数量更多[(7.37±1.12)个vs.(6.45±0.96)个],手术时间更长[(376.19±56.26)min vs.(331.36±50.92)min],差异均有统计学意义(P<0.05);但出血量无明显差异(P>0.05).两组病人总体置钉准确率比较,差异无统计学意义(P=0.586);但在顶椎区域,导航组置钉准确率显著高于徒手组(96.1％vs.89.4％,χ2=5.051,P=0.025).此外,术中CT导航系统明显降低了椎弓根内侧穿孔率(χ2=5.122,P=0.024).结论 CT导航系统可有效提高重度僵硬性脊柱畸形顶椎区域的置钉准确性.

The aim of this study was to explore whether a robot-assisted (RA) technique has advantages over the conventional fluoroscopy-assisted (FA) technique in clinical and radiological outcomes and whether it could decrease the incidence of mis-implantations of pedicle screws in adolescent idiopathic scoliosis (AIS) correction surgery. A total of 101 patients with AIS were recruited (RA group: 45 patients underwent RA screw insertion; FA group: 56 patients underwent FA screw insertion). When comparing the radiological data between the two groups, the major and secondary curves were both corrected proficiently with no difference in Cobb angle comparison at the last follow-up, suggesting that both the RA technique and the FA technique could lead to efficient radiographic correction and similar clinical outcomes (all, p > 0.05). In the RA group, operation time, blood loss, and transfusion volume were significantly greater than those in the FA group, while the accuracy of screw implantations in patients with AIS with a thoracic scoliotic curve in the RA group was higher than that in the FA group. In conclusion, both the RA and FA techniques could approach proficient radiographic correction and similar clinical outcomes in AIS surgery. Compared with the conventional fluoroscopy technique, the RA technique might improve the accuracy of screw implantations in patients with AIS with a thoracic scoliotic curve, while the increased operation time, blood loss, and transfusion volume might be the disadvantages due to the preliminary stage of the learning curve.

Many hydrogel patches are developed to solve the pervasive and severe challenge of complex wound healing, while most of them still lack satisfactory controllability and comprehensive functionality. Herein, inspired by multiple creatures, including octopuses and snails, a novel muti-functional hydrogel patch is presented with controlled adhesion, antibacterial, drug release features, and multiple monitoring functions for intelligent wound healing management. The patch with micro suction-cup actuator array and a tensile backing layer is composed of tannin grafted gelatin, Ag-tannin nanoparticles, polyacrylamide (PAAm) and poly(N-isopropylacrylamide) (PNIPAm). In virtue of the photothermal gel-sol transition of tannin grafted gelatin and Ag-tannin nanoparticles, the patches exert a dual anti-microbial effect and temperature-sensitive snail mucus-like features. In addition, as the "suction-cups" consisting of thermal responsive PNIPAm can undergo a contract-relax transformation, the medical patches can adhere to the objects reversibly and responsively, and release their loaded vascular endothelial growth factor (VEGF) controllably for wound healing. More attractively, benefiting from their fatigue resistance, self-healing ability of the tensile double network hydrogel, and electrical conductivity of Ag-tannin nanoparticles, the proposed patches can report multiple wound physiology parameters sensitively and continuously. Thus, it is believed that this multi-bioinspired patch has immense potential for future wound healing management.