Acta Biomaterialia最新文献_第8页

Zonal Characteristics of Collagen Ultrastructure and Responses to Mechanical Loading in Articular Cartilage

IF 9.4 1区医学 Q1 ENGINEERING, BIOMEDICAL

Acta Biomaterialia

Pub Date : 2025-03-15 DOI: 10.1016/j.actbio.2025.01.047

Jingrui Hu , Keke Zheng , Benjamin E. Sherlock , Jingxiao Zhong , Jessica Mansfield , Ellen Green , Andrew D. Toms , C. Peter Winlove , Junning Chen

The biomechanical properties of articular cartilage arise from a complex bioenvironment comprising hierarchically organised collagen networks within the extracellular matrix (ECM) that interact with the proteoglycan-rich interstitial fluid. This network features a depth-dependent fibril organisation across different zones. Understanding how collagen fibrils respond to external loading is key to elucidating the mechanisms behind lesion formation and managing degenerative conditions like osteoarthritis. This study employs polarisation-resolved second harmonic generation (pSHG) microscopy to quantify the ultrastructural organisation of collagen fibrils and their spatial gradient along the depth of bone-cartilage explants under a close-to-in vivo condition. By combining with in-situ loading, we examined the responses of collagen fibrils by quantifying changes in their principal orientation and degree of alignment. The spatial gradient and heterogeneity of collagen organisation were captured at high resolution (1 μm) along the longitudinal plane of explants (0.5 mm by 2 mm). Zone-specific ultrastructural characteristics were quantified to aid in defining zonal borders, revealing consistent zonal proportions with varying overall thicknesses. Under compression, the transitional zone exhibited the most significant re-organisation of collagen fibrils. It initially allowed large deformation through the re-orientation of fibrils, which then tightened fibril alignment to prevent excessive deformation, indicating a dynamic adaptation mechanism in response to increasing strain levels. Our results provide comprehensive, zone-specific baselines of cartilage ultrastructure and micromechanics, crucial for investigating the onset and progression of degenerative conditions, setting therapeutic intervention targets, and guiding cartilage repair and regeneration efforts.

Statement of significance

Achieved unprecedented quantification of the spatial gradient and heterogeneity of collagen ultrastructural organisation at a high resolution (1 μm) along the full depth of the longitudinal plane of osteochondral explants (0.5 mm by 2 mm) under close-to-in vivo condition.

Suggested new anatomical landmarks based on ultrastructural features for determining zonal borders and found consistent zonal proportions in explants with different overall thicknesses.

Demonstrated that collagen fibrils initially respond by reorienting themselves at low strain levels, playing a significant role in cartilage deformation, particularly within the transitional zone. At higher strain levels, more collagen fibrils re-aligned, indicating a dynamic shift in the response mechanism at varying strain levels.

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引用次数: 0

Injectable skeletal muscle constructs overexpressing GLUT4 for type 2 diabetes intervention

IF 9.4 1区医学 Q1 ENGINEERING, BIOMEDICAL

Acta Biomaterialia

Pub Date : 2025-03-15 DOI: 10.1016/j.actbio.2025.03.029

Hagit Shoyhet , Yifat Herman Bachinsky , Margarita Bekerman , Lior Debbi , Gali Guterman Ram , Dina Safina , Eddy Karnieli , Shulamit Levenberg

Skeletal muscle tissue engineering aims to repair tissue defects caused by injury, cancer, metabolic or neuromuscular disease. The need for invasive implantation techniques often limits the implantation of large tissue constructs or repeated treatments. Recent studies have reported on the development of injectable scaffolds for tissue engineering; however, fabrication of skeletal muscle tissue is particularly challenging due to the large size of human myotubes and the required mechanical properties. This work developed a collagen-based shape-memory scaffold supportive of skeletal muscle tissue growth and differentiation in vitro and maintained shape post-injection in vivo. The injectable engineered muscle construct was intramuscularly delivered via a syringe needle and integrated successfully with the native muscle tissue. We demonstrated the system's potential on a Type 2 diabetes mouse model. A prominent early sign of type 2 diabetes is the reduction in GLUT4 expression and translocation in skeletal muscle; therefore, based on a previous work published by our group, we created injectable GLUT4-overexpressing muscle constructs. Following injection, GLUT4 overexpressing skeletal muscle tissue retained its shape-memory properties and viability and improved glucose homeostasis in the diabetic mice. This work demonstrated successful minimally invasive delivery of engineered muscle tissue and potential treatment for chronic muscle-related conditions.

Statement of significance

Type 2 diabetes is a widespread metabolic disorder characterized by insulin resistance and impaired glucose regulation. This study offers a minimally invasive approach to treatment through the development of an injectable skeletal muscle construct overexpressing GLUT4 to improve glucose homeostasis. Unlike traditional surgical methods, this minimally invasive system employs a collagen-based scaffold with shape-memory properties, enabling effective tissue delivery and integration. Existing therapies are limited in addressing chronic metabolic disorders that require repeated interventions. Our work fills that gap by enhancing muscle function and glucose regulation. The scaffold's unique ability to retain its structure post-injection and support muscle differentiation presents a significant advancement with broad implications for treating metabolic diseases and advancing regenerative medicine.

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引用次数: 0

Regulation of the gelatin helix-to-coil transition through chain confinements at the polymer-protein interface and protein-protein interface

IF 9.4 1区医学 Q1 ENGINEERING, BIOMEDICAL

Acta Biomaterialia

Pub Date : 2025-03-15 DOI: 10.1016/j.actbio.2025.02.003

Woojin Choi, Jinkee Hong

Gelatin is an essential material widely used in biomedical applications due to its characteristic temperature responsivity—helix-to-coil transition. However, the current helix-to-coil transition is limited by its single-step behavior and the difficulty in designing a specific onset temperature. In this study, we investigated the fundamentals of the helix-to-coil transition with a focus on gelatin chain mobility. We observed distinctive kinetics of the helix-to-coil transition, which is resilient and can actuate in multiple steps or with a controllable onset point. This was achieved by confining the gelatin chain with a hydrophilic polymer or gelatin itself. The confinement approach serves two purposes: first, it prevents excessive mobility of the generated coils, maintaining physical resilience after the helix-to-coil transition; second, the interfacial confinement between the polymer and gelatin, referred to as polymer-protein interface confinement, restricts the helix-to-coil transition, resulting in a multistep transition process. Additionally, strong confinement at the interface between gelatins of different origins, that is protein-protein interface confinement, shifts the onset temperature to a higher point. This fundamental comprehension of helix-to-coil transition could contribute to broadening the biomedical application potential of gelatin materials.

Statement of significance

Gelatin is essential in biomedical applications due to its characteristic temperature responsivity—helix-to-coil transition. Herein, we fundamentally investigated the distinctive kinetics of the helix-to-coil transition, which is resilient and can actuate in multiple steps or with a controllable onset point. This was achieved by confining the gelatin chain with a hydrophilic polymer or gelatin itself. The gelatin chain confinement prevents excessive mobility of the generated coils, maintaining physical resilience after the helix-to-coil transition. The interfacial confinement between the polymer and gelatin restricts the helix-to-coil transition, resulting in a multistep transition process. Additionally, strong confinement at the interface between gelatins of different origins shifts the onset temperature to a higher point.

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引用次数: 0

DNA tetrahedron nanomedicine for enhanced antitumor and antimetastatic effect through the amplification of mitochondrial oxidative stress

IF 9.4 1区医学 Q1 ENGINEERING, BIOMEDICAL

Acta Biomaterialia

Pub Date : 2025-03-15 DOI: 10.1016/j.actbio.2025.02.011

Zixuan Chen , Zhaoyan Tian , Yafeng Wu , Songqin Liu

Amplifying mitochondrial oxidative stress by elevating reactive oxygen species (ROS) and reducing glutathione (GSH) levels proved highly effective in eradicating tumor cells and inhibiting metastasis. How to significantly amplify mitochondrial oxidative stress remains a challenge due to the hypoxic microenvironment and high level of GSH in the mitochondria. Herein, we smartly fabricated a multifunctional DNA tetrahedron nanomedicine (tDNA-TPP-AuNCs-BPQDs) for intracellular enzyme activated fluorescence imaging and amplified mitochondrial oxidative stress. The apurinic/apyrimidinic site (AP site) on the cantilever of DNA tetrahedron (tDNA) could be rapidly cleaved by apurinic/apyrimidinic endonuclease 1 (APE1), allowing for in situ fluorescence imaging of APE1 with high sensitivity and specificity. Gold nanoclusters (AuNCs) could continuously convert intracellular H₂O₂ to O₂ to alleviate the hypoxic conditions and adsorb intracellular GSH, thus the photodynamic therapy (PDT) effect of black phosphorus quantum dots (BPQDs) and AuNCs triggered a ∼10-fold and ∼3-fold increase in ROS generation compared to tDNA-TPP and tDNA-TPP-BPQDs, respectively. The elevated ROS and reduced GSH led to mitochondrial oxidative stress. In addition, the photothermal therapy (PTT) effect of the BPQDs and AuNCs further amplified the mitochondrial oxidative stress, which successfully induced immunogenic cell death (ICD) process and triggered a systemic antitumor immune response. The nanomedicine could render activation of fluorescence signal and anti-tumor therapeutic activity (34-fold higher than control) in tumor, thereby achieving effective tumor growth inhibition and antimetastatic effects.

Statement of significance

1. An effective mitochondrion targeting delivery system (tDNA-TPP-AuNCs-BPQDs) was developed for enhanced antitumor and antimetastatic effect through amplifying mitochondrial oxidative stress.

2. The multifunctional nanomedicine integrates tetrahedra DNA, Au NPs, TPP, and BP quantum dots to synergistically enhance cancer therapy effect through amplified mitochondrial oxidative stress. Additionally, an AP site segment was strategically incorporated into the tDNA structure for in situ fluorescence imaging of APE1 with high sensitivity and specificity in tumor cells.

3. The elevated ROS and reduced GSH amplify mitochondrial oxidative stress to induce ICD. The relieved hypoxic tumor microenvironment and induced ICD further stimulate a systemic antitumor immune response.

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引用次数: 0

Engineered macrophage membrane-coated nanoparticles attenuate calcium oxalate nephrocalcinosis-induced kidney injury by reducing oxidative stress and pyroptosis

IF 9.4 1区医学 Q1 ENGINEERING, BIOMEDICAL

Acta Biomaterialia

Pub Date : 2025-03-15 DOI: 10.1016/j.actbio.2025.02.021

Xiaozhuo Ba , Tao Ye , Yu He , Yonghua Tong , Haojie Shang , Jian Wu , Wen Deng , Zichen Zhong , Xiaoqi Yang , Kangyang Wang , Yabin Xie , Kehua Jiang , Xiaolin Guo , Kun Tang

Kidney stones are characterized by a high incidence and recurrence rate, leading to kidney injury, which in turn accelerates stone formation and deposition. Increasing evidence have demonstrated that oxidative stress and cell pyroptosis play important role in the calcium oxalate (CaOx) stones induced kidney injury. Currently, treatments related to oxidative stress and inflammation associated with kidney stones are still relatively limited. Here, we designed engineered macrophage cell membrane-coated hollow mesoporous manganese dioxide nanoparticles loaded with NLRP3 inhibitors Mcc950 (KM@M@M). KM@M@M NPs were modified with Kim-1 targeting peptides on M2-polarized macrophage membranes to achieve better targeted delivery to injured kidney tubules. Compared with traditional drugs, KM@M@M NPs reduce systemic toxicity through targeted drug delivery to the kidneys. In vivo and in vitro results demonstrate that KM@M@M NPs reduces the activation of the NLRP3 inflammasome in renal tubular epithelial cells by scavenging ROS, thereby downregulating gasdermin D cleavage and the production of inflammatory cytokines, ultimately inhibiting cell pyroptosis. In addition, bioinformatic analysis revealed that KM@M@M NPs protect against CaOx induced kidney injury via suppressing the NLRP3/GSDMD pathway. This article extending the application of engineered cell membrane-based biomimetic nanotechnology, and providing a promising strategy for dual protection in CaOx stones induced kidney injury.

Statement of significance

Currently, apart from invasive surgery, there are few pharmacological therapies for CaOx-induced renal injury. This study presents a new strategy using engineered macrophage cell membrane-coated hollow mesoporous manganese dioxide nanoparticles (KM@M@M) to target and treat calcium oxalate (CaOx)-induced kidney injury. The nanoparticles effectively scavenge reactive oxygen species (ROS) and inhibit NLRP3 inflammasome activation, preventing pyroptosis and kidney damage. By delivering NLRP3 inhibitors directly to injured renal tubules, KM@M@M NPs reduce inflammation and stone deposition. This work demonstrates the potential of biomimetic nanotechnology for targeted treatment, offering a promising approach to prevent CaOx-induced renal injury and enhance therapeutic outcomes in kidney stone disease.

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引用次数: 0

Rapid synthesis of degradable ester/thioether monomers and their incorporation into thermoset polyurethane foams for traumatic wound healing

IF 9.4 1区医学 Q1 ENGINEERING, BIOMEDICAL

Acta Biomaterialia

Pub Date : 2025-03-15 DOI: 10.1016/j.actbio.2025.02.027

Natalie Marie Petryk, Leo Saldanha, Shawn Sutherland, Mary Beth B. Monroe

Polyurethane (PUr) foam hemostatic dressings are highly effective at controlling bleeding in traumatic wounds, but their traditionally slow degradation rate requires dressing removal, which could result in wound rebleeding. Incorporating degradable linkages into the PUr network can provide a biodegradable dressing that could be left in place during healing, eliminating rebleeding upon removal and providing scaffolding for new tissue ingrowth with no remains of the applied dressing after healing. In this work, a library of degradable PUr foams was synthesized from degradable monomers based on hydrolytically labile esters and oxidatively labile thioethers using rapid click-chemistry reactions. In a twelve-week in vitro degradation study in 3% hydrogen peroxide and 0.1 M sodium hydroxide, incorporation of degradable monomers resulted in significantly increased PUr foam mass loss, offering biodegradable foam dressings that could better match the rate of traumatic wound healing. Changes to foam chemical, mechanical, thermal, and physical properties throughout degradation were also analyzed. Furthermore, the degradable PUr foams had increased platelet interactions, which could improve foam-induced clotting for a more effective hemostatic dressing. Overall, a biodegradable PUr foam hemostatic dressing could significantly improve healing outcomes in traumatic wounds.

Statement of significance

A simple, solvent-free, rapid synthesis technique was developed to provide degradable polythiol monomers for use in polyurethane synthesis. The degradable monomers were incorporated into hemostatic polyurethane foams to provide materials with tunable degradation rates within clinically-relevant time frames. The resulting foams and their degradation byproducts were cytocompatible and hemocompatible, and foams made with the new degradable monomers had enhanced blood clotting, enabling their future use as hemostatic dressings.

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引用次数: 0

Machine learning insights into calcium phosphate nucleation and aggregation

IF 9.4 1区医学 Q1 ENGINEERING, BIOMEDICAL

Acta Biomaterialia

Pub Date : 2025-03-15 DOI: 10.1016/j.actbio.2025.02.036

Jing Wang , Xin Wang , Dingguo Xu

In this study, we utilized machine learning interatomic potentials (MLIPs) to investigate the nucleation mechanisms of calcium phosphate, a critical component of bone and teeth. Our analysis encompassed the process from pre-nucleation stage to the growth of amorphous calcium phosphate (ACP) in solution. We observed fluctuations in free calcium ion concentration and tracked the formation of uniform clusters in the early nucleation phases, confirming the existence of pre-nucleation clusters (PNCs). The PNCs are characterized by the composition Ca₂[(PO₄)_1.6(HPO₄)(H₂PO₄)_0.4] and predominantly exhibit a triangular structure formed by phosphate groups. This structure is not only the core of the short-range ordered units in ACP but also exhibits the structural characteristics of the fundamental building blocks of HAP. Importantly, these clusters interact dynamically with water molecules through hydrogen bonding and proton exchange, which is essential for their stability and growth. The gradual growth of these clusters occurs via ion attachment and cluster adsorption. This work provides insights into calcium phosphate mineralization, with implications for materials science and biomedical engineering, particularly in biomaterial synthesis. The application of MLIPs demonstrates a high-accuracy, efficient approach for simulating complex systems may advance our understanding of crystallization and biomineralization processes.

Statement of significance

Calcium phosphate nucleation is crucial in biological mineralization and the synthesis of biomaterials, serving as a key aspect in the design of hydroxyapatite (HAP)-based biomaterials. However, the mechanisms of early nucleation remain unclear due to the complex ion-water interactions, which lead to rapid nucleation rates and small cluster sizes. This study combines MLIP with MD simulations to explore the nucleation process of calcium phosphate, revealing the transition from pre-nucleation to the formation of ACP. It clarifies the relationship between PNCs and the crystalline structure of HAP. This work addresses the knowledge gap regarding early-stage calcium phosphate nucleation and highlights the potential of MLIP in simulating complex ionic solutions, laying a solid foundation for AI-guided research in biological and biomedical materials.

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引用次数: 0

A waviness-centered damage model for collagenous soft tissues 以波状为中心的胶原软组织损伤模型。

IF 9.4 1区医学 Q1 ENGINEERING, BIOMEDICAL

Acta Biomaterialia

Pub Date : 2025-03-15 DOI: 10.1016/j.actbio.2025.01.031

Jia Lu , Xuehuan He , Ferdinando Auricchio

This article presents a damage model for collagenous tissue under monotonic loading. Given that the true stretch of collagen fibers is not uniform and is regulated by fiber waviness, we postulate that damage commences from more stretched (i.e. straighter) fibers and progresses to less stretched (i.e. wavier) ones. The complicated nonlinear response is regarded as the outcome of two competing mechanisms: the recruitment of wavy intact fibers and the loss of taut functioning fibers. The progression of damage is modeled by an evolving damage front in the waviness domain. A power law is proposed for the evolution of damage front. The model was fitted to four groups of published uniaxial and biaxial tests data of vascular tissues. Spot-on fits were observed in all groups.

引用次数: 0

Bidirectional amplification of oxidative stress through the mitochondria-targeted Co-Delivery of nanogolds and chlorin e6 Using ROS-responsive organosilica nanocarriers

IF 9.4 1区医学 Q1 ENGINEERING, BIOMEDICAL

Acta Biomaterialia

Pub Date : 2025-03-15 DOI: 10.1016/j.actbio.2025.01.051

Dongsheng Yu , Jianming Yuan , Chiyi Ou , Qinghua Chen , Haowen Li , Chenhui Hao , Jiaojiao Zheng , Shuang Liu , Mingqiang Li , Du Cheng

Bidirectional amplification of oxidative stress within the mitochondria is essential to enhance photodynamic therapy (PDT), and efficient co-delivery of reducing agents and reactive oxygen species (ROS)-generating agents is critical for achieving this with minimal side effects. However, the absence of an effective platform for mitochondria-targeted co-delivery and spatially controlled tumor-specific therapy limits the potential applicability of this strategy. In this study, we developed an ROS-sensitive organosilica nanocarrier, encapsulating nanogold and introducing chlorin e6 (Ce6) and triphenylphosphine (TPP) through a one-pot sol-gel process. Following TPP-mediated mitochondria-targeted delivery, ROS generated by Ce6 under near-infrared (NIR) irradiation not only damaged the mitochondria but also disrupted the nanoparticles within the tumor, leading to the release of nanogold. These ultra-small nanogolds, due to their high surface area, exhibited enhanced glutathione scavenging capacity, which, in combination with ROS, synergistically amplified oxidative stress to overcome the high resistance of tumor cells. Both in vitro and in vivo experiments confirmed the effectiveness of this strategy, demonstrating efficient co-delivery, controlled drug release, spatially targeted oxidative stress amplification, and synergistic antitumor effects. Thus, we present a facile platform for the spatially controlled bidirectional amplification of oxidative stress with minimal side effects.

Statement of Significance

Mitochondrial oxidative stress involves both ROS generation and GSH depletion, indicating that bidirectional amplification is required for mitochondria-targeted antitumor therapy. However, most of existing strategies just focus on ROS generation, which limits the amplification level of oxidative stress. Thus, the mitochondria-targeted co-delivery of photodynamic agent and GSH scavenging agent is an effective approach to address this limitation. Besides, the lack of facile nanoplatform also hinders the application of strategies aimed at bidirectionally amplifying oxidative stress. In this study, we developed a facile nanoplatform for mitochondria-targeted co-delivery of the photodynamic agent Chlorin e6 and GSH scavenging agent nanogold using a ROS-responsive organosilica nanocarrier. This approach successfully achieved bidirectional amplification of oxidative stress, resulting in a synergistic antitumor effect with minimal side effects.

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引用次数: 0

Dual-targeting Aggregation-induced emission polymer micelles mediate immunogenic sonodynamic therapy for Tumor cell growth inhibition and macrophage reprogramming

IF 9.4 1区医学 Q1 ENGINEERING, BIOMEDICAL

Acta Biomaterialia

Pub Date : 2025-03-15 DOI: 10.1016/j.actbio.2025.01.065

Haiheng Peng , Dandan Wang , Shiwen Huang , Aixi Yu

Sonodynamic therapy (SDT) is a promising cancer treatment known for its deep tumor penetration and high efficacy. However, developing highly efficient sonosensitizers remains a significant challenge. Reports on SDT using aggregation-induced emission luminogens (AIEgens) are rare, highlighting the urgent need for novel AIE-active sonosensitizers. For the first time, we have developed tumor- and macrophage-targeting nano micelles, AIE/Biotin/Mannose-M (ABM-M), utilizing aggregation-induced emission polymers. The ABM-M mediate immunogenic cell death through SDT. By reprogramming tumor-associated macrophages (TAMs), they promote the conversion of M2 macrophages into M1 macrophages, reversing the tumor's immunosuppressive environment. We optimized the ratio of functional molecules to achieve maximum fluorescence intensity and reactive oxygen species (ROS) generation. The multi-targeting nature of ABM-M enables them to bind to relevant antibodies or other molecules, enhancing the capture and presentation of tumor antigens. This, in turn, activates the immune responses of dendritic cells and T cells while inhibiting angiogenesis, creating a more favorable microenvironment for antitumor therapy. Furthermore, ABM-M can be combined with immune checkpoint inhibitors, such as anti-PD-L1 antibodies, to achieve promising outcomes in cancer immunotherapy. The ABM-M nanomaterials offer multi-layered and multi-targeting immune regulation. This study provides a blueprint for developing next-generation cancer diagnostic and therapeutic strategies.

Statement of significance

Our research pioneers the use of nanomicelles to simultaneously target both tumor cells and tumor-associated macrophages (TAMs), integrated with sonodynamic therapy. Through precise ratio adjustments, we engineered nanomicelles capable of multi-target regulation. These micelles uniquely induce immunogenic cell death (ICD) and repolarize macrophages from an immunosuppressive M2 phenotype to an immunostimulatory M1 phenotype, reversing the tumor's immunosuppressive microenvironment. This dual mechanism can be enhanced by combining with immune checkpoint inhibitors, such as anti-PD-L1 antibodies, offering a promising strategy to treat refractory cancers. Extensive in vitro and in vivo validation confirms their therapeutic potential, providing a solid foundation for clinical application. This innovative approach shows significant promise for revolutionizing cancer treatment and improving patient outcomes.

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引用次数: 0