Acta biomaterialia最新文献

{"title":"Reciprocal folding dynamics in cellular networks at the stroma-basement membrane interface.","authors":"Youngmin Jo, Donghyun Yim, Chan E Park, Insung Yong, Jongbeom Lee, Kwang Ho Ahn, Chanhee Yang, Jae-Byum Chang, Taek-Soo Kim, Jennifer Hyunjong Shin, Taeyoon Kim, Pilnam Kim","doi":"10.1016/j.actbio.2025.05.069","DOIUrl":"10.1016/j.actbio.2025.05.069","url":null,"abstract":"<p><p>Epithelium layer stands on a membrane, called basement membrane (BM) which serves as a boundary with the underlying stroma. While most studies on morphogenesis have focused on the epithelium-BM complex, the role of the BM-stroma interface remains poorly understood. In this study, we demonstrate how forces originating from the stromal layer contribute to tissue morphogenesis. Folds focalization at the BM-stroma interface is driven by mechanical instability, which arises from the fluidity of the stroma and the polarized tractional forces acting on the rigid membrane of stromal cell condensates. Stromal cells move towards the folded region by topographic guidance, while the concentration of forces intensifies. Through this process, stromal cells and folds engage in recursive interactions, resulting in the formation of a cellular network. Our observation provides a rational mechanism for pattern formation in a multi-layered living tissue. STATEMENT OF SIGNIFICANCE: This study addresses a crucial gap in understanding how stromal cells interact with the basement membrane to lead tissue surface morphogenesis. By developing a collagen-based, nanometer-thick engineered basement membrane, we demonstrate that the stromal cells exert traction forces on the basement membrane to fold. The folding process guides stromal cell migration, which in turn induces further folding in a recursive manner. The direction of folding, invagination or evagination, is determined by the stiffness difference between the stroma and the basement membrane. This model offers better understanding about how the basement membrane interacts with stromal cells to make evaginated network structures on tissue surface.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apolipoprotein E as a potential regulator of osteoclast-osteoblast coupling in material-induced bone formation.","authors":"Yue Wang, Zhangling Nie, Huaze Liu, Joost D de Bruijn, Huipin Yuan, Chongyun Bao","doi":"10.1016/j.actbio.2025.05.070","DOIUrl":"10.1016/j.actbio.2025.05.070","url":null,"abstract":"<p><p>Osteoinductive materials which induce bone formation in non-osseous sites are promising bone substitutes to repair critical-sized bone defects. It appears that innate immune response (esp. osteoclastogenesis) to materials plays an important role in material-induced bone formation. In this study, the coupling between osteoclastogenesis and subsequent osteogenesis in material-induced bone formation was investigated. Osteoclastogenesis of mouse bone marrow-derived monocytes (BMMs) on osteoinductive tricalcium phosphate (TCPs) and non-osteoinductive tricalcium phosphate (TCPb) ceramics were evaluated with high-throughput RNA sequencing (RNA-seq) and RT-qPCR regarding secretory proteins. It turned out that osteoinductive TCPs supported osteoclastogenesis and enhanced Apolipoprotein E (ApoE) production. Meanwhile, ApoE enhanced osteogenic gene expression (Alp, Runx2, Col1a1, Osterix) and ALP staining and activity of CRL-12424 cells in vitro. Additionally, western blot assay revealed that ApoE played its role in osteogenesis of CRL-12424 by activating JAK-STAT pathway instead of PI3K-AKT pathway. The overall data indicated that ApoE was a potential coupling factor between osteoclastogenesis and osteogenesis in material-induced bone formation. By secreting ApoE, osteoclasts formed on osteoinductive materials stimulated osteogenic differentiation of osteo-progenitors via JAK-STAT pathway. STATEMENT OF SIGNIFICANCE: Osteoinductive materials can repair critical-sized bone defects, while the precise mechanism osteoinductive materials driving bone formation remains unclear. Recent research has highlighted the role of osteoclastogenesis in material-induced bone formation, how osteoclastogenesis playing its role in osteogenesis was subjected to investigation in the current study. Robust ApoE gene expression shown in osteoclastogenesis with the osteoinductive material and ApoE enhancing osteogenesis of mesenchymal stromal cells (CRL-12424) indicated ApoE as a potential regulator of osteoclast-osteoblast coupling, providing thus novel insights into the complex interplay of cellular responses and contributing to the development of more effective bone substitute materials.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recombinant cytokine bioconjugates with degradable nanogel substrates for macrophage immunotherapy.","authors":"Rana Ajeeb, Chloé Catelain, Harsh A Joshi, Danuta Radyna, John R Clegg","doi":"10.1016/j.actbio.2025.05.066","DOIUrl":"10.1016/j.actbio.2025.05.066","url":null,"abstract":"<p><p>Cytokines are potent endogenous modulators of innate immunity, making them key mediators of macrophage plasticity for immunotherapy. However, the clinical translation of recombinant cytokines as therapeutics is limited by systemic side effects, caused by cytokines' pleiotropy, potency, and non-specific biodistribution following systemic dosing. We developed a cytokine delivery platform utilizing poly(acrylamide-co-methacrylic acid) synthetic nanogels as a biodegradable substrate for conjugated recombinant cytokines (i.e., IFNγ, IL4, or IL10), called Synthetic Nano-CytoKines or \"SyNK\". We evaluated the phenotypic response of macrophages to these conjugates following prophylactic or therapeutic dosing, in the presence or absence of soluble inflammatory signals. Our data confirmed that SyNK is highly cytocompatible with murine macrophages, preserves the activity of conjugated recombinant cytokines to both macrophages and dendritic cells, and minimizes systemic exposure to freely soluble recombinant cytokines. Intrinsic activity of the nanomaterial was modest, acting in combination with the conjugated cytokine, and resulted in unique phenotypes with IL4-SyNK and IL10-SyNK stimulation that could potentially be leveraged for therapeutic applications. We further demonstrated that RAW264.7 macrophages adopt distinct alternative phenotypes upon IL4 or IL10 stimulation in different classically polarizing microenvironments, as measured by spectral flow cytometry and secretome multiplex, which are similar for soluble recombinant cytokine and the corresponding SyNK. These findings offer a potential mechanism through which IL4 or IL10-SyNK can redirect the classically activated macrophage antigen presentation, T cell co-stimulation, or microenvironment regulatory functions for therapeutic purposes. STATEMENT OF SIGNIFICANCE: Cytokines have been extensively investigated as immune therapies, but their clinical translation is limited by their systemic toxicity and frequent dosing regimens. Existing approaches have improved cytokine stability and local delivery but still face challenges in systemic administration and controlling immune response. We developed a cytokine delivery platform using biodegradable poly(acrylamide-co-methacrylic acid) nanogels to conjugate cytokines (e.g. IFNγ, IL4, or IL10) aimed at systemic macrophage immunotherapy. We show that our platform preserves cytokine activity and eliminates the release of free cytokine. We further explore, for the first time, how different stimuli in the macrophage environment influence their response to the cytokine bioconjugates. Our work provides thorough insights into macrophage plasticity and addresses key limitations of current strategies.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mucoadhesive micellar eyedrops for the treatment of ocular inflammation.","authors":"Yuting Zheng, Yimin Gu, Yavuz Oz, Liangju Kuang, Ann Yung, Seokjoo Lee, Reza Dana, Nasim Annabi","doi":"10.1016/j.actbio.2025.05.065","DOIUrl":"10.1016/j.actbio.2025.05.065","url":null,"abstract":"<p><p>Efficient ocular drug delivery remains a significant challenge in treating eye inflammation due to physiological barriers such as the tear film and frequent blinking, which lead to rapid drug clearance. Commercial eyedrops, like Oceanside® (0.5 % loteprednol etabonate (LE) ophthalmic suspension), suffer from low ocular bioavailability and require frequent dosing to maintain therapeutic levels. To address these limitations, we developed a mucoadhesive micellar drug delivery system to enhance the bioavailability and retention of LE on the cornea. Our system employed polymeric micelles (MCs) functionalized with phenylboronic acid (PBA), which exhibited high conjugation efficiency to enable strong binding to the mucin-rich corneal layer. These MCs were synthesized using PBA-functionalized poly (ethylene glycol)-b-poly (N-(2-hydroxypropyl) methacrylamide-oligolactate) (PBA-PEG-b-p(HPMA-Lac_m)) and subsequently dispersed into a shear-thinning matrix solution to form a micellar eyedrop formulation. The resulting eyedrop demonstrated a sustained LE release over 12 days, enabling prolonged therapeutic exposure. In vitro, ex vivo, and in vivo studies confirmed enhanced mucoadhesion and extended corneal retention. The formulation was biocompatible with human corneal epithelial cells and demonstrated ocular safety in mice. In a murine model of electrocautery-induced corneal inflammation, a once-daily administration of LE-loaded PBA-MC eyedrops significantly reduced corneal opacity, preserved corneal structure, and lowered immune cell infiltration and cytokine levels. Notably, the therapeutic efficacy of the LE-loaded PBA-MC eyedrops matched that of commercial Oceanside®, which required four daily doses. These findings suggest that the engineered PBA-MC eyedrops could serve as a promising platform for ocular drug delivery, addressing the challenges associated with treating eye inflammation effectively. STATEMENT OF SIGNIFICANCE: Mucoadhesive nanoparticles used for ocular drug delivery often suffer from low attachment efficiency, limiting their effectiveness. Additionally, the lack of in vivo comparisons with commercial eye drops hinders evaluating their clinical benefits. To address these issues, we developed PBA-functionalized polymeric MCs to enhance the bioavailability of LE by increasing its retention on the corneal mucin layer. These MCs showed high PBA conjugation efficiency, a 12-day sustained release of LE, strong mucin adhesion, in vitro and in vivo biocompatibility. In a mouse model of corneal inflammation, a once-daily LE-loaded micellar eyedrop matched the efficacy of the commercial LE eyedrop (Oceanside®, 0.5 %), which was dosed four times daily, reducing corneal opacity, preserving corneal structure, and decreasing inflammation.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond Gadolinium: The Potential of Manganese Nanosystems in MRI and Multimodal Imaging Agents.","authors":"Lorenzo Tei, Mauro Botta, Carlos F G C Geraldes","doi":"10.1016/j.actbio.2025.05.058","DOIUrl":"https://doi.org/10.1016/j.actbio.2025.05.058","url":null,"abstract":"<p><p>Manganese-based nanoparticles (Mn-NPs) hold great promise as MRI contrast agents and components of theranostic nanoplatforms, serving as a promising alternative to the more established gadolinium(III)-based nanosystems. This potential stems from their unique physicochemical properties and improved safety profile. This review introduces the fundamental principles of relaxation to highlight the key physicochemical characteristics of Mn-based nanosystems that influence their effectiveness. We primarily examine two oxidation states of manganese, Mn(II) and Mn(III), to demonstrate the efficacy of Mn-NPs as relaxation probes, with a brief discussion of one Mn(IV) system. Subsequently, we review recent studies on Mn-NP-based MRI contrast agents, focusing on the correlation between nanoparticle structure and the oxidation state of the paramagnetic centre. For Mn(II), the most common strategy involves utilizing stable Mn-chelates anchored to or encapsulated within the nanoparticles. In contrast, for the higher oxidation state, Mn(III), Mn(III)-porphyrin and phthalocyanine NPs are the primary non-Mn oxide nanosystems of choice. Regarding nanoplatform composition, Mn(II)-based platforms utilizing lipids (micelles or liposomes), polysaccharides (nanogels), dendrimers, metal-organic frameworks, inorganic NPs, and silicas are among the most frequently investigated. While numerous in vitro and in vivo animal MRI studies of Mn nanoplatforms have been reported, none have yet received clinical approval. We describe innovative surface modification and functionalization procedures designed to improve NP characteristics (e.g., size, stability, dispersibility, relaxivity, targeting, and toxicity) and impart multifunctionality for multimodal imaging. These strategies may provide valuable guidance for the development of Mn-NPs toward future clinical applications, particularly in cancer theranostics. STATEMENT OF SIGNIFICANCE: This review provides a critical analysis of the current landscape of Mn-based nanoparticles, which are increasingly being explored as MRI contrast agents and for multimodal imaging. This growing interest is largely driven by concerns over the potential toxicity and environmental impact of traditional Gd-based systems. The review introduces the key structural and dynamic parameters that determine the effectiveness of these nanosystems, highlighting their direct relationship with molecular design. It also examines the crucial stability and kinetic inertness requirements that influence their development. By critically discussing selected recent examples across a diverse range of nanosystems, including micelles, liposomes, silica-based platforms, and MOFs, this review identifies existing challenges and provides key insights to guide their future clinical translation.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydrogel system with growth cone-targeted hydroxyapatite nanorods: Regulating calcium signals for peripheral nerve injury repair.","authors":"Zhenghang Li, Xiaoduo Tang, Hongmeng Yang, Laijin Lu, Junhu Zhang, Yang Liu","doi":"10.1016/j.actbio.2025.05.060","DOIUrl":"10.1016/j.actbio.2025.05.060","url":null,"abstract":"<p><p>Calcium (Ca²⁺) regulation assumes a critical role in the repair course of peripheral nerve injury (PNI). However, effective calcium sources capable of providing sustained Ca²⁺ signals to promote growth cone extension remain limited. Herein, the coupling of biotinylated dextran amine (BDA) to amine-functionalized hydroxyapatite nanorods (nHAP-NH₂) remarkably promoted and maintained the extension of growth cones throughout nerve regeneration. Therefore, a newly developed therapeutic system for PNI was constructed based on a hydrogel (Gel) loaded with BDA-nHAP (nHAP-NH₂ with surface modification of BDA) and vascular endothelial growth factor (VEGF). The sustained-release BDA-nHAP has the potential to continuously and targetedly increase the Ca²⁺ levels within the growth cone, and further boost neurite outgrowth by modulating the PI3K-PAK and MAPK signalling pathways. Moreover, VEGF can significantly promote angiogenesis in the early stage of nerve repair, which is critical for optimizing the functional efficacy of BDA-nHAP in enhancing neurogenesis. Thus, this innovative integrated therapeutic system with neurogenesis and angiogenesis capabilities may offer a new solution for achieving high-quality functional recovery from PNI. STATEMENT OF SIGNIFICANCE: For PNI, there remains a scarcity of effective calcium sources capable of providing sustained Ca²⁺ signals within the growth cone to enhance its extension. Herein, a newly developed therapeutic system for PNI was constructed based on a Gel loaded with BDA-nHAP and VEGF. The sustained-release BDA-nHAP has the potential to continuously and targetedly increase the Ca²⁺ levels within the growth cone, and further boost neurite outgrowth throughout the whole process of nerve regeneration. Moreover, VEGF can significantly promote angiogenesis in the early stage of nerve repair, which is critical for optimizing the functional efficacy of BDA-nHAP in enhancing neurogenesis. Thus, this innovative therapeutic system may offer a new solution for achieving high-quality functional recovery from PNI.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Poly(vinyl alcohol) reduced and capped gold nanoparticles as contrast enhancers to target and improve detection of medial calcification.","authors":"Tao Song, Kyoungmi Bak, Dahyun Kyung, Monzur Murshed, Marta Cerruti","doi":"10.1016/j.actbio.2025.05.059","DOIUrl":"10.1016/j.actbio.2025.05.059","url":null,"abstract":"<p><p>Medial calcification is the pathological deposition of calcium phosphate (CaP) minerals in the elastin-rich medial layers of arteries, leading to vessel stiffening and increased risk of heart failure. There are no drugs to treat medial calcification, and thus it would be important to detect the disease as early as possible to enable adequate prevention. In the clinic, X-ray based computed tomography (CT) is used to diagnose medial calcification, but the few and small CaP minerals present in early stages of medial calcification do not provide enough X-ray contrast to be detectable by CT. Herein, we propose poly(vinyl alcohol) (PVA) reduced and capped gold nanoparticles (PVA@AuNPs) to target medial calcification and improve its detection in early stages. AuNPs can greatly absorb X-rays and thus work as contrast enhancers for CT. Results show that PVA@AuNPs can bind to CaP minerals containing hydroxyl ions on their surface, most likely via hydrogen-bond interactions with PVA capping polymers; indeed, mineral binding efficiency depends on the hydrolysis degree of PVA. AuNPs prepared from 99 %+ hydrolyzed PVA (PVA99@AuNPs) bind selectively to calcified vs. non-calcified elastin in vitro, and in vivo they improve the contrast of medial calcification in 4-week-old matrix Gla-protein deficient mice imaged through micro-CT. STATEMENT OF SIGNIFICANCE: The few and small calcium phosphate (CaP) minerals present in early stages of medial calcification do not provide enough contrast for clinical detection via computed tomography (CT). Herein, we show that 99 %+ hydrolyzed poly(vinyl alcohol) reduced and capped gold nanoparticles (PVA99@AuNPs) selectively bind CaP minerals in medial calcification, thus improving their contrast and (micro)CT detection. Unlike previously proposed targeting agents, PVA99@AuNPs bind to CaP mineral phases present in early-stage medial calcification but not to the extracellular matrix onto which minerals are deposited, thus enabling accurate and specific targeting. Their straightforward synthesis and biocompatibility significantly enhance their potential for clinical translation. Earlier detection of medial calcification would greatly improve disease management, particularly important since no treatments are available for the disease.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Degeneration mechanisms and advancements in optimization for preparation and crosslinking strategy of pericardium-based bioprosthetic heart valves.","authors":"Xueyu Huang, Bangquan Wei, Lepeng Chen, Li Yang, Cheng Zheng, Yunbing Wang","doi":"10.1016/j.actbio.2025.05.062","DOIUrl":"10.1016/j.actbio.2025.05.062","url":null,"abstract":"<p><p>Valvular heart disease (VHD), clinically manifested as the malfunction of heart valves, greatly threatens public health worldwide. The morbidity and mortality of VHD increase significantly with age, and the high prevalence of VHD in aging society has prompted the urgency for effective treatment. Prosthetic heart valve replacement is currently recognized as the gold standard for VHD treatment. Bioprosthetic heart valves (BHVs), generally manufactured from glutaraldehyde crosslinked xenogeneic tissue, exhibited better hemodynamics and lower thrombogenicity than mechanical heart valves (MHVs) and could be implanted by transcatheter valve replacement systems, which markedly improved the efficiency of VHD therapy, especially for the elderly patients. However, BHVs degenerate within 10-15 years after implantation, which is greatly associated with their defects including cytotoxicity, calcification, immune response, matrix degradation, mechanical damage, and thrombosis. To prolong the service life of BHVs, recent studies have developed a series of innovative modification strategies to improve the biocompatibility, mechanical performance, matrix components stability, anticalcification, and antithrombotic properties of conventional glutaraldehyde crosslinked BHVs. Moreover, a series of new crosslinking and modification strategies have been proposed and developed to fabricate non-glutaraldehyde crosslinked BHVs with good stability, biocompatibility, hemocompatibility, anticalcification property, durability, and hydrodynamics. In this review, we first summarized the defects of BHVs and the related reasons from the perspective of biomaterials, and then comprehensively detailed the functional modification strategies for BHVs based on glutaraldehyde crosslinking. We provided detailed insights into novel non-glutaraldehyde crosslinking and modification strategies for BHVs. Finally, the current challenges and prospects of BHVs were also discussed. STATEMENT OF SIGNIFICANCE: Bioprosthetic heart valves (BHVs) currently face challenges such as cytotoxicity, thrombosis, calcification, and immunoinflammatory responses, which contribute to structural valve degeneration and reduce the longevity of BHVs. This review provides a comprehensive introduction to the detailed defects associated with glutaraldehyde crosslinked BHVs from the perspective of biomaterials. It then thoroughly elaborates on the modification strategies based on glutaraldehyde crosslinking, as well as detailed insights into novel non-glutaraldehyde crosslinking strategies for BHVs. Finally, the challenges and prospects facing BHVs are discussed.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polyanhydride nanoparticles encapsulating innate sensor agonists activate epithelial and airway cells and reduce Respiratory Syncytial Virus infection in mice.","authors":"Fabián E Díaz, Elizabeth A Grego, Ali Uslu, Balaji Narasimhan, Jodi L McGill","doi":"10.1016/j.actbio.2025.05.061","DOIUrl":"10.1016/j.actbio.2025.05.061","url":null,"abstract":"<p><p>Acute respiratory tract infections (ARTI) are a leading cause of morbidity and mortality in infants worldwide. Considering the emergence of antimicrobial resistance as a global threat, there is increasing interest in immunomodulatory strategies to prevent respiratory infections. Since ARTIs are caused by several pathogens, immunomodulatory strategies aiming to engage innate responses represent a promising strategy to prevent ARTIs. Here, innate-stimulating nanoparticles (NPs) synthesized from combinations of polyanhydride copolymers and pattern recognition receptor (PRR) agonists were developed to increase disease resistance by activating innate mechanisms at the mucosal level. In vitro analysis on human and bovine respiratory epithelial cells showed that innate-sensor agonist-loaded NPs triggered transcription of inflammatory, antiviral, and antimicrobial mediators. Moreover, pre-treatment with NPs reduced human and bovine orthopneumovirus (RSV) infectious titers in vitro. Intranasal administration of PRR-containing polyanhydride NPs to mice led to transient production of cytokines and chemokines in lungs, suggesting immune activation. The immunogenicity and antiviral properties of NPs were dependent on both polyanhydride copolymer chemistry and the innate agonist encapsulated within the NPs. Prophylactic administration of NPs containing either TLR2/1, TLR4, or TLR2/7 agonists resulted in reduced RSV morbidity and viral lung loads. Selected NPs also showed protective effects when administered 14 days before infection. These results indicate that NPs efficiently prime human and bovine respiratory tract epithelial cells and trigger antiviral defenses in vitro and reduce RSV disease in mice. STATEMENT OF SIGNIFICANCE: Our research focuses on the use of polyanhydride nanoparticles (NPs) encapsulating innate sensor agonists to activate epithelial and airway cells. This innovative approach leverages the unique properties of nanotechnology to harness the innate immune system's potential, providing broad resistance against multiple pathogens. We designed a panel of PRR agonist-loaded polyanhydride NPs with varying chemistries and investigated their effectiveness as innate immunomodulators in the respiratory tract. We demonstrate that NPs activate protective innate immune responses in airway epithelial cells and reduce RSV infectious titers in vitro. NP-treated mice showed protection against RSV-induced morbidity and had reduced viral loads. These findings highlight the potential of polyanhydride NPs as a versatile platform for prophylactic intervention against respiratory viruses in both humans and livestock.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Strength, deformability, damage and fracture toughness of fibrous material networks: Application to fibrin clots.","authors":"Evgenii Kliuchnikov, Angelos Gkarsen Dagklis, Rustem I Litvinov, Kenneth A Marx, John W Weisel, John L Bassani, Prashant K Purohit, Valeri Barsegov","doi":"10.1016/j.actbio.2025.05.057","DOIUrl":"10.1016/j.actbio.2025.05.057","url":null,"abstract":"<p><p>A multiscale approach to mechanical testing in silico, which combines discrete particle-based simulations and large-deformation continuum mechanics, is developed to explore the mechanobiology, damage and fracture of fibrous materials. Combined with tensile testing in vitro of fibrin networks, the mechanical scaffold of blood clots, mechanisms of fibrin rupture are investigated that underlie embolization of intravascular blood clots (thrombi), a major cause of ischemic stroke and pulmonary embolism. At moderate strains (<50%), no network damage is observed. At larger strains, damage evolves and the network ruptures when only ∼5% of fibers and branch points break, opening a ∼150 µm rupture zone in silico. A continuum model that predicts macroscopic behavior for arbitrary states of deformation, including damage evolution, is constructed from the mesoscopic simulations with direct correlation of the damage parameter and the number of broken bonds in contrast to phenomenological damage laws. The continuum model can access length- and time-scales that are inaccessible in discrete simulations, which allows prediction of fracture toughness, the material property that determines rupture resistance in the presence of defects. This critical property for a fibrin network at physiological solid volume fraction and accounting for the dramatic decrease in volume (∼90%) under uniform tensile stressing is predicted to be 2.5-7.7 J/m², in good agreement with experiment. These insights into mechanisms of blood clot fracture can lead to the development of new approaches to predict and prevent embolization of intravascular thrombi. The multiscale approach developed is applicable to a wide range of fibrous network-based biomaterials. STATEMENT OF SIGNIFICANCE: Dummy.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144144920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}