Pub Date : 2026-10-01Epub Date: 2026-08-14DOI: 10.1016/j.actbio.2026.08.026
Artis Brasovs, M.A. Nozzari Varkani, Jinbo Song, Yang Wang, Haobo Jiang, Konstantin G. Kornev
<div><div>Hemolymph coagulation is a vital component of insect immunity, rapidly reducing fluid loss and limiting pathogen spread after injury. In <em>Manduca sexta</em> larvae, paralytic peptide (PP) is a fast-acting cytokine activated by an unknown serine protease, and its influence on hemolymph mechanics remains largely unexplored. Here, we examine how PP exposure alters the extensional and surface rheological properties of larval hemolymph, providing insight into the physical manifestation of the immune activation. Hemolymph collected from fifth-instar larvae exhibited weak viscoelastic behavior in 84% of extensional rheology experiments, with a mean characteristic relaxation time of <span><math><mrow><mn>1.9</mn><mspace></mspace><mo>±</mo><mspace></mspace><mn>1.5</mn><mspace></mspace><mi>m</mi><mi>s</mi></mrow></math></span>. Treatment with 10 μM PP resulted in a pronounced shift toward a more Newtonian-like behavior: only 63% of samples remained viscoelastic, and the mean relaxation time (<span><math><mrow><mn>0.7</mn><mo>±</mo><mspace></mspace><mn>0.6</mn><mspace></mspace><mi>m</mi><mi>s</mi></mrow></math></span>) (<span><math><mrow><mi>p</mi><mo><</mo><mn>0.001</mn></mrow></math></span>) was reduced by >2-fold. In samples subjected to repeated measurements, PP exposure caused a rapid loss of viscoelasticity on the timescale of seconds. Surface rheology was probed using magnetic rotational spectroscopy with magnetic microrods. In hemolymphs aged for > 10 min, the surface layer of untreated and PP-treated hemolymphs behaved as a Maxwellian viscoelastic fluid. The relaxation time of the viscoelastic reaction is measured in seconds, i.e., it is three orders of magnitude larger than that in the bulk. The surface drag coefficients of the microrods on PP-treated hemolymph are about twofold smaller than those of untreated ones. As the hemocyte aggregation ceased in <span><math><mrow><mo>∼</mo><mn>10</mn></mrow></math></span> min after hemolymph extraction, these rheological signatures suggest that PP-stimulated coagulation initiates within the bulk hemolymph.</div></div><div><h3>Statement of significance</h3><div>Hemolymph coagulation is essential for insect survival, preventing fluid loss, pathogen invasion, and loss of mechanical support following injury. While molecular components of insect immune responses have been extensively studied, physical transformations of hemolymph during early wound responses remain poorly understood. Using extensional rheology and magnetic rotational spectroscopy, we show that a cytokine named paralytic peptide (PP), which is proteolytically activated after wounding, rapidly alters the viscoelastic properties of the hornworm <em>Manduca sexta</em> hemolymph. PP reduces bulk viscoelasticity within seconds and modifies interfacial rheological behavior, revealing a direct link between immune signaling and hemolymph mechanics. These findings provide new insight into how proteolytic enzyme(s) convert hemolymph
{"title":"Paralytic peptide reduces hemolymph viscoelasticity and promotes bulk-initiated coagulation in hornworm Manduca sexta","authors":"Artis Brasovs, M.A. Nozzari Varkani, Jinbo Song, Yang Wang, Haobo Jiang, Konstantin G. Kornev","doi":"10.1016/j.actbio.2026.08.026","DOIUrl":"10.1016/j.actbio.2026.08.026","url":null,"abstract":"<div><div>Hemolymph coagulation is a vital component of insect immunity, rapidly reducing fluid loss and limiting pathogen spread after injury. In <em>Manduca sexta</em> larvae, paralytic peptide (PP) is a fast-acting cytokine activated by an unknown serine protease, and its influence on hemolymph mechanics remains largely unexplored. Here, we examine how PP exposure alters the extensional and surface rheological properties of larval hemolymph, providing insight into the physical manifestation of the immune activation. Hemolymph collected from fifth-instar larvae exhibited weak viscoelastic behavior in 84% of extensional rheology experiments, with a mean characteristic relaxation time of <span><math><mrow><mn>1.9</mn><mspace></mspace><mo>±</mo><mspace></mspace><mn>1.5</mn><mspace></mspace><mi>m</mi><mi>s</mi></mrow></math></span>. Treatment with 10 μM PP resulted in a pronounced shift toward a more Newtonian-like behavior: only 63% of samples remained viscoelastic, and the mean relaxation time (<span><math><mrow><mn>0.7</mn><mo>±</mo><mspace></mspace><mn>0.6</mn><mspace></mspace><mi>m</mi><mi>s</mi></mrow></math></span>) (<span><math><mrow><mi>p</mi><mo><</mo><mn>0.001</mn></mrow></math></span>) was reduced by >2-fold. In samples subjected to repeated measurements, PP exposure caused a rapid loss of viscoelasticity on the timescale of seconds. Surface rheology was probed using magnetic rotational spectroscopy with magnetic microrods. In hemolymphs aged for > 10 min, the surface layer of untreated and PP-treated hemolymphs behaved as a Maxwellian viscoelastic fluid. The relaxation time of the viscoelastic reaction is measured in seconds, i.e., it is three orders of magnitude larger than that in the bulk. The surface drag coefficients of the microrods on PP-treated hemolymph are about twofold smaller than those of untreated ones. As the hemocyte aggregation ceased in <span><math><mrow><mo>∼</mo><mn>10</mn></mrow></math></span> min after hemolymph extraction, these rheological signatures suggest that PP-stimulated coagulation initiates within the bulk hemolymph.</div></div><div><h3>Statement of significance</h3><div>Hemolymph coagulation is essential for insect survival, preventing fluid loss, pathogen invasion, and loss of mechanical support following injury. While molecular components of insect immune responses have been extensively studied, physical transformations of hemolymph during early wound responses remain poorly understood. Using extensional rheology and magnetic rotational spectroscopy, we show that a cytokine named paralytic peptide (PP), which is proteolytically activated after wounding, rapidly alters the viscoelastic properties of the hornworm <em>Manduca sexta</em> hemolymph. PP reduces bulk viscoelasticity within seconds and modifies interfacial rheological behavior, revealing a direct link between immune signaling and hemolymph mechanics. These findings provide new insight into how proteolytic enzyme(s) convert hemolymph ","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"223 ","pages":"Pages 408-420"},"PeriodicalIF":10.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148763053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-01Epub Date: 2026-09-03DOI: 10.1016/j.actbio.2026.09.004
Xiaolong Yang, Lin Yang, Shiji Gao, Yi Zhou, Zhe Xu, Junqiao Li, Jiehua Li, Hong Tan, Feng Luo, Weili Fu
Meniscus repair is often limited by poor intrinsic healing, an adverse oxidative-inflammatory microenvironment, and insufficient mechanical continuity across the tear interface. Here, we engineered a solvent-free injectable polyurethane adhesive (PUA) loaded with connective tissue growth factor (PUA@CTGF) for meniscus tear repair that combines rapid wet interfacial stabilization, compliant defect filling, and prolonged CTGF release. The adhesive showed rapid in situ curing, high apparent initial wet lap-shear strength, and stable short-cycle compressive behavior in a 100-cycle loading–unloading test. In vitro, PUA@CTGF reduced oxidative stress-associated mitochondrial injury, modulated macrophage-associated inflammatory markers toward a more repair-supportive profile, promoted meniscal cell migration, and enhanced fibrochondrogenic matrix synthesis when combined with cyclic tensile stimulation. In a rabbit outer-vascular-zone meniscus tear model, PUA@CTGF improved repair-region continuity, matrix deposition, and tensile properties and attenuated early joint degenerative changes relative to untreated, suture, fibrin, and PUA controls, although native meniscal tensile properties were not fully restored during the 12-week observation period. Transcriptomic profiling identified mechanotransduction-related signatures, while inhibitor-supported in vitro analyses showed that GsMTx4 attenuated dynamic-loading-induced Ca2+ and YAP responses, supporting a GsMTx4-sensitive mechanotransduction response. These findings support PUA@CTGF as a bioactive polyurethane adhesive platform for wet, mechanically active meniscal repair interfaces.
Statement of significance
Meniscus tears are difficult to heal because the injured interface is wet, mechanically active, and biologically hostile. This study introduces a solvent-free injectable polyurethane adhesive that rapidly stabilizes wet meniscal tears while providing localized delivery of connective tissue growth factor. By combining catechol-assisted wet adhesion, compliant defect filling, short-cycle energy dissipation, reactive oxygen species buffering, and prolonged CTGF release, the adhesive provides interfacial stabilization and microenvironmental regulation. In vitro and rabbit studies showed enhanced cell migration and matrix-associated responses, improved repair-region continuity and tensile properties, and attenuation of early joint degenerative changes. This work advances biomaterial design by integrating wet interfacial stabilization with localized biochemical delivery for the repair of mechanically active, load-bearing soft-tissue interfaces.
{"title":"A bioactive polyurethane adhesive delivers interfacial mechano-biochemical cues for meniscus tear repair","authors":"Xiaolong Yang, Lin Yang, Shiji Gao, Yi Zhou, Zhe Xu, Junqiao Li, Jiehua Li, Hong Tan, Feng Luo, Weili Fu","doi":"10.1016/j.actbio.2026.09.004","DOIUrl":"10.1016/j.actbio.2026.09.004","url":null,"abstract":"<div><div>Meniscus repair is often limited by poor intrinsic healing, an adverse oxidative-inflammatory microenvironment, and insufficient mechanical continuity across the tear interface. Here, we engineered a solvent-free injectable polyurethane adhesive (PUA) loaded with connective tissue growth factor (PUA@CTGF) for meniscus tear repair that combines rapid wet interfacial stabilization, compliant defect filling, and prolonged CTGF release. The adhesive showed rapid <em>in situ</em> curing, high apparent initial wet lap-shear strength, and stable short-cycle compressive behavior in a 100-cycle loading–unloading test. <em>In vitro</em>, PUA@CTGF reduced oxidative stress-associated mitochondrial injury, modulated macrophage-associated inflammatory markers toward a more repair-supportive profile, promoted meniscal cell migration, and enhanced fibrochondrogenic matrix synthesis when combined with cyclic tensile stimulation. In a rabbit outer-vascular-zone meniscus tear model, PUA@CTGF improved repair-region continuity, matrix deposition, and tensile properties and attenuated early joint degenerative changes relative to untreated, suture, fibrin, and PUA controls, although native meniscal tensile properties were not fully restored during the 12-week observation period. Transcriptomic profiling identified mechanotransduction-related signatures, while inhibitor-supported <em>in vitro</em> analyses showed that GsMTx4 attenuated dynamic-loading-induced Ca<sup>2+</sup> and YAP responses, supporting a GsMTx4-sensitive mechanotransduction response. These findings support PUA@CTGF as a bioactive polyurethane adhesive platform for wet, mechanically active meniscal repair interfaces.</div></div><div><h3>Statement of significance</h3><div>Meniscus tears are difficult to heal because the injured interface is wet, mechanically active, and biologically hostile. This study introduces a solvent-free injectable polyurethane adhesive that rapidly stabilizes wet meniscal tears while providing localized delivery of connective tissue growth factor. By combining catechol-assisted wet adhesion, compliant defect filling, short-cycle energy dissipation, reactive oxygen species buffering, and prolonged CTGF release, the adhesive provides interfacial stabilization and microenvironmental regulation. <em>In vitro</em> and rabbit studies showed enhanced cell migration and matrix-associated responses, improved repair-region continuity and tensile properties, and attenuation of early joint degenerative changes. This work advances biomaterial design by integrating wet interfacial stabilization with localized biochemical delivery for the repair of mechanically active, load-bearing soft-tissue interfaces.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"223 ","pages":"Pages 236-258"},"PeriodicalIF":10.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-01Epub Date: 2026-01-09DOI: 10.1016/j.actbio.2026.01.019
Friederike Kaiser, Lena Schröter, Anita Ignatius, Uwe Gbureck
When bone defects surpass a critical threshold in size, they typically necessitate intervention through either autologous bone grafting or the use of synthetic substitutes to maintain structural support and prevent unwanted soft tissue infiltration. Most synthetic bone graft materials currently in use are composed of calcium phosphate compounds, such as hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP). Despite their widespread clinical adoption and long-standing research, these materials still face important limitations, including suboptimal mechanical strength and slow resorption, particularly in the case of HA. Magnesium phosphate (MgP) compounds have emerged as promising alternatives in this context. Their higher solubility compared to calcium phosphates and their encouraging performance in promoting bone regeneration, demonstrated even in large animal studies, suggest their potential as next-generation bone substitutes. This review focuses on the current state of research regarding MgP-based materials for bone repair. It explores fundamental aspects of MgP chemistry, how these materials can be processed into clinically applicable forms such as injectable cements, granules, or porous scaffolds, and examines their effects on bone healing in various preclinical animal models.
Statement of significance
Critical-sized bone defects remain a major clinical challenge, and despite decades of research, the synthetic substitutes most widely used today are hindered by limited resorption and suboptimal mechanical performance. Magnesium phosphate based biomaterials have recently emerged as promising next-generation bone substitutes due to their favorable resorption kinetics, high initial mechanical strength, bioactivity, and potential to actively support bone regeneration. This review critically evaluates the current state of knowledge on these materials, covering their chemistry, processing into cements, granules, and scaffolds, and preclinical in vivo outcomes. By integrating findings across different magnesium-based systems, the review highlights both opportunities and remaining challenges for translation into clinical practice.
{"title":"Magnesium phosphate minerals and cements as bone substitute materials","authors":"Friederike Kaiser, Lena Schröter, Anita Ignatius, Uwe Gbureck","doi":"10.1016/j.actbio.2026.01.019","DOIUrl":"10.1016/j.actbio.2026.01.019","url":null,"abstract":"<div><div>When bone defects surpass a critical threshold in size, they typically necessitate intervention through either autologous bone grafting or the use of synthetic substitutes to maintain structural support and prevent unwanted soft tissue infiltration. Most synthetic bone graft materials currently in use are composed of calcium phosphate compounds, such as hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP). Despite their widespread clinical adoption and long-standing research, these materials still face important limitations, including suboptimal mechanical strength and slow resorption, particularly in the case of HA. Magnesium phosphate (MgP) compounds have emerged as promising alternatives in this context. Their higher solubility compared to calcium phosphates and their encouraging performance in promoting bone regeneration, demonstrated even in large animal studies, suggest their potential as next-generation bone substitutes. This review focuses on the current state of research regarding MgP-based materials for bone repair. It explores fundamental aspects of MgP chemistry, how these materials can be processed into clinically applicable forms such as injectable cements, granules, or porous scaffolds, and examines their effects on bone healing in various preclinical animal models.</div></div><div><h3>Statement of significance</h3><div>Critical-sized bone defects remain a major clinical challenge, and despite decades of research, the synthetic substitutes most widely used today are hindered by limited resorption and suboptimal mechanical performance. Magnesium phosphate based biomaterials have recently emerged as promising next-generation bone substitutes due to their favorable resorption kinetics, high initial mechanical strength, bioactivity, and potential to actively support bone regeneration. This review critically evaluates the current state of knowledge on these materials, covering their chemistry, processing into cements, granules, and scaffolds, and preclinical in vivo outcomes. By integrating findings across different magnesium-based systems, the review highlights both opportunities and remaining challenges for translation into clinical practice.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"224 ","pages":"Pages 20-38"},"PeriodicalIF":10.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145954175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-01Epub Date: 2026-01-14DOI: 10.1016/j.actbio.2026.01.026
Yueying Xiao, Janos M. Kanczler, Jonathan I. Dawson, Togay Koç
Foot and ankle arthrodesis remains a critical surgical approach for managing end-stage joint disease, yet its success is frequently hindered by the challenge of non-union. Despite advances in surgical techniques, complex cases – such as tibiotalocalcaneal fusion – still face non-union rates as high as 27 %, largely due to the region’s unique biomechanical demands and compounded by patient comorbidities and surgical variability. In recent years, orthobiologics and advanced biomaterials have demonstrated significant promise in enhancing fusion outcomes, particularly in high-risk patients with bone defects, metabolic disorders, or a history of infection. However, much of the existing clinical evidence stems from other orthopaedic contexts, with limited high-quality data specific to foot and ankle applications. To bridge this gap and support translational innovation, the development of preclinical models that accurately replicate the physiological and pathological characteristics of the human foot and ankle is essential. This review provides a comprehensive overview of the latest advancements in biologics and biomaterials for foot and ankle arthrodesis, with particular emphasis on hydrogels as next-generation platforms for bone regeneration and targeted drug delivery. Additionally, we critically examine the limitations of current preclinical models in terms of biomechanical compatibility and pathological relevance, highlighting opportunities for future refinement.
Statement of significance
Foot and ankle arthrodesis often fails due to non-union in complex, poorly vascularized regions. Emerging biomaterials, such as B2A-coated ceramics and peptide-enhanced grafts, show promise in enhancing fusion outcomes. However, a critical barrier to translation is the lack of preclinical models that reflect the foot and ankle’s pathological and mechanical complexity. This review not only surveys advanced orthobiologics but also proposes strategies for developing “negative models” and integrating high-risk conditions to better evaluate fusion efficacy. By bridging biomaterial innovation with model development, it offers a structured path for future research and clinical translation in foot and ankle fusion.
{"title":"Innovations in foot and ankle arthrodesis: Biological and biomaterial approaches to reducing non-union and the challenge of preclinical models","authors":"Yueying Xiao, Janos M. Kanczler, Jonathan I. Dawson, Togay Koç","doi":"10.1016/j.actbio.2026.01.026","DOIUrl":"10.1016/j.actbio.2026.01.026","url":null,"abstract":"<div><div>Foot and ankle arthrodesis remains a critical surgical approach for managing end-stage joint disease, yet its success is frequently hindered by the challenge of non-union. Despite advances in surgical techniques, complex cases – such as tibiotalocalcaneal fusion – still face non-union rates as high as 27 %, largely due to the region’s unique biomechanical demands and compounded by patient comorbidities and surgical variability. In recent years, orthobiologics and advanced biomaterials have demonstrated significant promise in enhancing fusion outcomes, particularly in high-risk patients with bone defects, metabolic disorders, or a history of infection. However, much of the existing clinical evidence stems from other orthopaedic contexts, with limited high-quality data specific to foot and ankle applications. To bridge this gap and support translational innovation, the development of preclinical models that accurately replicate the physiological and pathological characteristics of the human foot and ankle is essential. This review provides a comprehensive overview of the latest advancements in biologics and biomaterials for foot and ankle arthrodesis, with particular emphasis on hydrogels as next-generation platforms for bone regeneration and targeted drug delivery. Additionally, we critically examine the limitations of current preclinical models in terms of biomechanical compatibility and pathological relevance, highlighting opportunities for future refinement.</div></div><div><h3>Statement of significance</h3><div>Foot and ankle arthrodesis often fails due to non-union in complex, poorly vascularized regions. Emerging biomaterials, such as B2A-coated ceramics and peptide-enhanced grafts, show promise in enhancing fusion outcomes. However, a critical barrier to translation is the lack of preclinical models that reflect the foot and ankle’s pathological and mechanical complexity. This review not only surveys advanced orthobiologics but also proposes strategies for developing “negative models” and integrating high-risk conditions to better evaluate fusion efficacy. By bridging biomaterial innovation with model development, it offers a structured path for future research and clinical translation in foot and ankle fusion.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"224 ","pages":"Pages 256-271"},"PeriodicalIF":10.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145992274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Intervertebral disc (IVD) degeneration is the most common musculoskeletal disorder worldwide. Yet, the underlying pathological processes remain largely unclear, primarily due to the lack of suitable in vitro models that accurately replicate the complex interactions of vascular and neural growth, inflammatory cytokine secretion, and immune cell infiltration that contribute to disc degeneration. To address this gap, we developed an affordable microfluidic IVD model using a 5-axis computer numerical control (CNC) micromilling machine with a multi-chamber culture design featuring a central disc zone divided by micropillars to accommodate nucleus pulposus (NP) and annulus fibrosus (AF). The design also incorporates two peripheral zones for co-culturing neurovascular units, separated by radial microgratings to maintain the avascular and aneural milieu of healthy discs. Under healthy conditions, our microfluidic device effectively restricted the migration of neural and endothelial cells when co-cultured with NP cells. Conversely, upon IL-1β-induced inflammation, we observed significant neural (325 ± 209 µm) and endothelial (884 ± 214 µm) cell migration towards the NP cells. Beyond neurovascular invasion, our IVD-on-a-chip provided valuable insights into immune cell dynamics, revealing that M1 macrophage infiltration, not just neovascularization, plays a key role in the progression of disc degeneration. Strikingly, our findings revealed that therapeutic interventions using glycosaminoglycan supplementation and celecoxib treatment resulted in a fourfold reduction in macrophage infiltration and over a twentyfold decrease in neural invasion compared to the inflamed control group. This highlights the potential of our system for drug testing aimed at preventing neovascularization and innervation, which are typically associated with discogenic pain.
Statement of significance
Most spine abnormalities are directly linked to intervertebral disc (IVD) degeneration, accounting for 40–50% of chronic lower back pain cases, often leading to lumbar disc prolapse, radiculopathy, spinal stenosis, and myelopathy. In fact, many aspects of the mechanisms behind disc degeneration remain elusive due to the lack of in vitro models replicating the complex inflammatory and catabolic processes involved. Hence, this study presents an improved micro-physiological IVD-on-a-chip platform that captures key characteristics of symptomatic disc degeneration, starting with inflammatory cytokine-induced nucleus pulposus dysregulation, neovascularization, macrophage infiltration, and sensory neuron ingrowth. The developed IVD-on-a-chip system offers new capabilities for investigating local degenerative responses that drive disc-related pain, serving as a high-throughput platform for testing potential drugs inhibiting complex neuro-immuno-vascular interactions.
{"title":"Modelling disc degeneration-induced neurovascular invasion on a chip for chronic low back pain therapeutic testing","authors":"Sandhya Natesan, Tarun Shyam Mohan, Mayank Singh, Pavan Pandit, G.L. Samuel, Greeshma Thrivikraman","doi":"10.1016/j.actbio.2026.05.037","DOIUrl":"10.1016/j.actbio.2026.05.037","url":null,"abstract":"<div><div>Intervertebral disc (IVD) degeneration is the most common musculoskeletal disorder worldwide. Yet, the underlying pathological processes remain largely unclear, primarily due to the lack of suitable in vitro models that accurately replicate the complex interactions of vascular and neural growth, inflammatory cytokine secretion, and immune cell infiltration that contribute to disc degeneration. To address this gap, we developed an affordable microfluidic IVD model using a 5-axis computer numerical control (CNC) micromilling machine with a multi-chamber culture design featuring a central disc zone divided by micropillars to accommodate nucleus pulposus (NP) and annulus fibrosus (AF). The design also incorporates two peripheral zones for co-culturing neurovascular units, separated by radial microgratings to maintain the avascular and aneural milieu of healthy discs. Under healthy conditions, our microfluidic device effectively restricted the migration of neural and endothelial cells when co-cultured with NP cells. Conversely, upon IL-1β-induced inflammation, we observed significant neural (325 ± 209 µm) and endothelial (884 ± 214 µm) cell migration towards the NP cells. Beyond neurovascular invasion, our IVD-on-a-chip provided valuable insights into immune cell dynamics, revealing that M1 macrophage infiltration, not just neovascularization, plays a key role in the progression of disc degeneration. Strikingly, our findings revealed that therapeutic interventions using glycosaminoglycan supplementation and celecoxib treatment resulted in a fourfold reduction in macrophage infiltration and over a twentyfold decrease in neural invasion compared to the inflamed control group. This highlights the potential of our system for drug testing aimed at preventing neovascularization and innervation, which are typically associated with discogenic pain.</div></div><div><h3>Statement of significance</h3><div>Most spine abnormalities are directly linked to intervertebral disc (IVD) degeneration, accounting for 40–50% of chronic lower back pain cases, often leading to lumbar disc prolapse, radiculopathy, spinal stenosis, and myelopathy. In fact, many aspects of the mechanisms behind disc degeneration remain elusive due to the lack of in vitro models replicating the complex inflammatory and catabolic processes involved. Hence, this study presents an improved micro-physiological IVD-on-a-chip platform that captures key characteristics of symptomatic disc degeneration, starting with inflammatory cytokine-induced nucleus pulposus dysregulation, neovascularization, macrophage infiltration, and sensory neuron ingrowth. The developed IVD-on-a-chip system offers new capabilities for investigating local degenerative responses that drive disc-related pain, serving as a high-throughput platform for testing potential drugs inhibiting complex neuro-immuno-vascular interactions.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"224 ","pages":"Pages 239-255"},"PeriodicalIF":10.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148019211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-01Epub Date: 2026-08-19DOI: 10.1016/j.actbio.2026.08.032
Hanwen Fan, Preston Nguyen, Zerrin Uzum, Julia Kehl, Xiaqiu Xiao, Julia Bell, Veda Manikonda, Jacob Zachary Chen, Van Anh Nguyen, Srikanth Sampathkumar, Noah Dover, Andrei Demkov, Morgan Lilly, Lindsay A. Dawson, Connor P. Dolan, Yuxiao Zhou
<div><div>Mouse digit tip regeneration offers a model for mammalian epimorphic regeneration, yet the spatiotemporal evolution between emerging tissue architecture and its mechanical environments remain poorly understood. In this study, we employed a multiscale approach, integrating <em>in vivo</em> micro-CT imaging, atomic force microscopy (AFM) nanomechanical mapping, and finite element modeling (FEM), to quantitatively characterize the temporal evolution of structural organization, local nanomechanical properties, and tissue-scale mechanical environments throughout mouse digit tip regeneration following amputation. AFM measurements revealed distinct patterns of structural reconstruction during regeneration: while the proximal stump underwent rapid repair-associated ossification, the distal tip underwent blastema-driven regeneration characterized by the formation and progressive coalescence of discrete mineralized regions within a highly compliant extracellular matrix. Comparison of the multiscale measurements showed that structural reconstruction and local mechanical maturation progressed along distinct temporal trajectories, with gross anatomical continuity restored by 21 days post-amputation (DPA), whereas native-like local nanomechanical properties continued to mature through 28–31 DPA. FEM analyses further showed progressive restoration of dorsal–ventral stress symmetry during regeneration, with the ventral-to-dorsal mechanical stress and strain ratio approaching the near-unity value observed in unamputated digits, while evolving distal geometry progressively altered stress distributions within the regenerated bone. Together, these findings establish a quantitative multiscale dataset for comparing structural reconstruction, local mechanical maturation, and the evolution of tissue-scale mechanical environments throughout digit regeneration. This multiscale perspective provides a quantitative reference for evaluating functional recovery and may inform the development of bio-inspired strategies for enhancing musculoskeletal regeneration in non-regenerative contexts.</div></div><div><h3>Statement of significance</h3><div>Mammalian digit tip regeneration is a model of complex tissue regrowth, yet how structural organization, local mechanical properties, and tissue-scale mechanical environments evolve during regeneration remains poorly understood. Here, we integrate <em>in vivo</em> micro-CT imaging, atomic force microscopy, and finite element modeling to quantitatively characterize the multiscale structural and mechanical evolution of regenerating mouse digits. Our findings show that structural reconstruction, local matrix maturation, and tissue-scale mechanical environments evolve over distinct spatial and temporal patterns throughout regeneration, providing quantitative insight into the progression of matrix organization and mechanical function. This multiscale framework establishes a quantitative basis for investigating mechanobiological regu
{"title":"Multiscale analysis reveals distinct temporal trajectories of morphological reconstruction and mechanical maturation during mouse digit tip regeneration","authors":"Hanwen Fan, Preston Nguyen, Zerrin Uzum, Julia Kehl, Xiaqiu Xiao, Julia Bell, Veda Manikonda, Jacob Zachary Chen, Van Anh Nguyen, Srikanth Sampathkumar, Noah Dover, Andrei Demkov, Morgan Lilly, Lindsay A. Dawson, Connor P. Dolan, Yuxiao Zhou","doi":"10.1016/j.actbio.2026.08.032","DOIUrl":"10.1016/j.actbio.2026.08.032","url":null,"abstract":"<div><div>Mouse digit tip regeneration offers a model for mammalian epimorphic regeneration, yet the spatiotemporal evolution between emerging tissue architecture and its mechanical environments remain poorly understood. In this study, we employed a multiscale approach, integrating <em>in vivo</em> micro-CT imaging, atomic force microscopy (AFM) nanomechanical mapping, and finite element modeling (FEM), to quantitatively characterize the temporal evolution of structural organization, local nanomechanical properties, and tissue-scale mechanical environments throughout mouse digit tip regeneration following amputation. AFM measurements revealed distinct patterns of structural reconstruction during regeneration: while the proximal stump underwent rapid repair-associated ossification, the distal tip underwent blastema-driven regeneration characterized by the formation and progressive coalescence of discrete mineralized regions within a highly compliant extracellular matrix. Comparison of the multiscale measurements showed that structural reconstruction and local mechanical maturation progressed along distinct temporal trajectories, with gross anatomical continuity restored by 21 days post-amputation (DPA), whereas native-like local nanomechanical properties continued to mature through 28–31 DPA. FEM analyses further showed progressive restoration of dorsal–ventral stress symmetry during regeneration, with the ventral-to-dorsal mechanical stress and strain ratio approaching the near-unity value observed in unamputated digits, while evolving distal geometry progressively altered stress distributions within the regenerated bone. Together, these findings establish a quantitative multiscale dataset for comparing structural reconstruction, local mechanical maturation, and the evolution of tissue-scale mechanical environments throughout digit regeneration. This multiscale perspective provides a quantitative reference for evaluating functional recovery and may inform the development of bio-inspired strategies for enhancing musculoskeletal regeneration in non-regenerative contexts.</div></div><div><h3>Statement of significance</h3><div>Mammalian digit tip regeneration is a model of complex tissue regrowth, yet how structural organization, local mechanical properties, and tissue-scale mechanical environments evolve during regeneration remains poorly understood. Here, we integrate <em>in vivo</em> micro-CT imaging, atomic force microscopy, and finite element modeling to quantitatively characterize the multiscale structural and mechanical evolution of regenerating mouse digits. Our findings show that structural reconstruction, local matrix maturation, and tissue-scale mechanical environments evolve over distinct spatial and temporal patterns throughout regeneration, providing quantitative insight into the progression of matrix organization and mechanical function. This multiscale framework establishes a quantitative basis for investigating mechanobiological regu","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"223 ","pages":"Pages 341-353"},"PeriodicalIF":10.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148802923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-01Epub Date: 2026-09-08DOI: 10.1016/j.actbio.2026.08.044
Stefana A. Costan, Kira M. Hallerbach, Samuel Y. Kim, Chris Camp, Minkyu Kim, Ingmar H. Riedel-Kruse
Engineered living materials (ELMs) at the multicelluar level represent an innovation that promises programmable properties for various applications. However, the rational tuning of the mechanical properties of such ELMs from first principles remains a challenge. Here we use synthetic cell–cell adhesins to systematically characterize how rheological and viscoelastic properties of multicellular materials made from living bacteria can be tuned through adhesion strength, cell size, cell shape, and adhesion logic. We find that many of the previous results obtained for non-living materials also apply to bacterial ELMs. Additionally, the incorporation of synthetic adhesins, combined with the adaptability of bacterial cells in modifying various cellular parameters, constitutes a new approach for the precise control over material properties. Furthermore, we demonstrate that rheology is a powerful tool for actively shaping the microscopic structure of ELMs, enabling control over cell aggregation and particle rearrangement, a key feature for complex material design. These results deepen our understanding of tuning the viscoelastic properties and fine structure of ELMs for bioprinting, microbial consortia design, and biomedical applications.
Statement of significance: The fields of Engineered Living Materials (ELMs) and Synthetic biology undergo rapid synergistic advancements, with bacterial and eukaryotic cells serving as modular building blocks for programmable materials. A critical challenge lies in the precise control and tunability over the mechanical and structural properties of ELMs. This paper demonstrates (1) the tunability of material viscoelasticity through key cellular parameters, i.e., adhesin strength, adhesion logic, cell shape, and multi-component mixing ratios; and (2) the generation of spatially defined colloidal consortia, mesoscopic structuring, pore formation and defect minimization through rheological manipulations. This paper bridges gaps between synthetic biology and materials science by providing a quantitative basis for ELM design and characterization, and by extending results from non-living particle suspensions to ELMs.
{"title":"Controlling viscoelastic behavior and microstructural organization in engineered living materials using synthetic adhesins and rheometry","authors":"Stefana A. Costan, Kira M. Hallerbach, Samuel Y. Kim, Chris Camp, Minkyu Kim, Ingmar H. Riedel-Kruse","doi":"10.1016/j.actbio.2026.08.044","DOIUrl":"10.1016/j.actbio.2026.08.044","url":null,"abstract":"<div><div>Engineered living materials (ELMs) at the multicelluar level represent an innovation that promises programmable properties for various applications. However, the rational tuning of the mechanical properties of such ELMs from first principles remains a challenge. Here we use synthetic cell–cell adhesins to systematically characterize how rheological and viscoelastic properties of multicellular materials made from living bacteria can be tuned through adhesion strength, cell size, cell shape, and adhesion logic. We find that many of the previous results obtained for non-living materials also apply to bacterial ELMs. Additionally, the incorporation of synthetic adhesins, combined with the adaptability of bacterial cells in modifying various cellular parameters, constitutes a new approach for the precise control over material properties. Furthermore, we demonstrate that rheology is a powerful tool for actively shaping the microscopic structure of ELMs, enabling control over cell aggregation and particle rearrangement, a key feature for complex material design. These results deepen our understanding of tuning the viscoelastic properties and fine structure of ELMs for bioprinting, microbial consortia design, and biomedical applications.</div><div><em>Statement of significance:</em> The fields of Engineered Living Materials (ELMs) and Synthetic biology undergo rapid synergistic advancements, with bacterial and eukaryotic cells serving as modular building blocks for programmable materials. A critical challenge lies in the precise control and tunability over the mechanical and structural properties of ELMs. This paper demonstrates (1) the tunability of material viscoelasticity through key cellular parameters, i.e., adhesin strength, adhesion logic, cell shape, and multi-component mixing ratios; and (2) the generation of spatially defined colloidal consortia, mesoscopic structuring, pore formation and defect minimization through rheological manipulations. This paper bridges gaps between synthetic biology and materials science by providing a quantitative basis for ELM design and characterization, and by extending results from non-living particle suspensions to ELMs.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"223 ","pages":"Pages 376-386"},"PeriodicalIF":10.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148914700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Injury to articular cartilage remains a major clinical challenge owing to its limited self-healing capacity. Current cell-based therapies are limited by issues such as dedifferentiation and regulatory hurdles, whereas existing scaffold systems often lack the essential biochemical signals necessary for effective tissue regeneration. Consequently, biomimetic acellular strategies capable of recruiting endogenous stem cells while establishing a conducive biochemical microenvironment to direct their chondrogenic differentiation are needed. In this study, we developed a bioactive, hierarchical porous extracellular matrix (ECM) scaffold fabricated via low-temperature deposition manufacturing (LDM) and functionalized with the bone marrow-homing peptide PFS (amino acid sequence PFSSTKT) to increase in situ cartilage regeneration. The scaffold preserves the native biochemical characteristics of ECM while enabling stable functionalization with the chemoattractant peptide PFS. In vitro studies demonstrated that the PFS-functionalized ECM scaffold exhibited favorable biocompatibility and supported cell adhesion, migration, and proliferation. In vivo studies using a rabbit full-thickness cartilage defect model further showed enhanced endogenous stem cell recruitment and hyaline-like cartilage regeneration in the PFS-ECM group compared with the ECM and control groups. The regenerated tissue exhibited improved matrix composition, biomechanical properties, and histological scores. Collectively, this work presents a cell-free, biofunctional ECM-based scaffold strategy that promotes endogenous repair of articular cartilage, providing a promising approach for cartilage regeneration without exogenous cell transplantation.
Statement of Significance
Articular cartilage repair remains a significant clinical challenge. While current cell-based therapies face limitations such as dedifferentiation, conventional scaffolds often lack essential bioinductive signals. To address this challenge, we have developed a bioactive extracellular matrix scaffold functionalized with the chemotactic peptide PFS. In this design, the PFS peptide enhances endogenous stem cell recruitment, while the ECM provides a chondrogenic microenvironment. Experimental results confirmed that this scaffold significantly promotes stem cell migration and chondrogenic differentiation. Animal studies demonstrated that the PFS-ECM group outperformed control groups in cell recruitment, hyaline cartilage regeneration, and mechanical properties, offering a promising cell-free solution with translational potential for clinical cartilage repair.
{"title":"PFSSTKT(PFS)-functionalized Hierarchical Porous ECM Scaffolds Facilitate Articular Cartilage Regeneration through the Recruitment of Endogenous Stem Cells and Chondrogenic Induction","authors":"Mingxue Chen, Jiang Wu, Hao Wang, Yongkang Yang, Xiang Sui, Liwei Fu, Quanyi Guo","doi":"10.1016/j.actbio.2026.02.026","DOIUrl":"10.1016/j.actbio.2026.02.026","url":null,"abstract":"<div><div>Injury to articular cartilage remains a major clinical challenge owing to its limited self-healing capacity. Current cell-based therapies are limited by issues such as dedifferentiation and regulatory hurdles, whereas existing scaffold systems often lack the essential biochemical signals necessary for effective tissue regeneration. Consequently, biomimetic acellular strategies capable of recruiting endogenous stem cells while establishing a conducive biochemical microenvironment to direct their chondrogenic differentiation are needed. In this study, we developed a bioactive, hierarchical porous extracellular matrix (ECM) scaffold fabricated via low-temperature deposition manufacturing (LDM) and functionalized with the bone marrow-homing peptide PFS (amino acid sequence PFSSTKT) to increase <em>in situ</em> cartilage regeneration. The scaffold preserves the native biochemical characteristics of ECM while enabling stable functionalization with the chemoattractant peptide PFS. In vitro studies demonstrated that the PFS-functionalized ECM scaffold exhibited favorable biocompatibility and supported cell adhesion, migration, and proliferation. In vivo studies using a rabbit full-thickness cartilage defect model further showed enhanced endogenous stem cell recruitment and hyaline-like cartilage regeneration in the PFS-ECM group compared with the ECM and control groups. The regenerated tissue exhibited improved matrix composition, biomechanical properties, and histological scores. Collectively, this work presents a cell-free, biofunctional ECM-based scaffold strategy that promotes endogenous repair of articular cartilage, providing a promising approach for cartilage regeneration without exogenous cell transplantation.</div></div><div><h3>Statement of Significance</h3><div>Articular cartilage repair remains a significant clinical challenge. While current cell-based therapies face limitations such as dedifferentiation, conventional scaffolds often lack essential bioinductive signals. To address this challenge, we have developed a bioactive extracellular matrix scaffold functionalized with the chemotactic peptide PFS. In this design, the PFS peptide enhances endogenous stem cell recruitment, while the ECM provides a chondrogenic microenvironment. Experimental results confirmed that this scaffold significantly promotes stem cell migration and chondrogenic differentiation. Animal studies demonstrated that the PFS-ECM group outperformed control groups in cell recruitment, hyaline cartilage regeneration, and mechanical properties, offering a promising cell-free solution with translational potential for clinical cartilage repair.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"224 ","pages":"Pages 207-222"},"PeriodicalIF":10.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146203583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
After joint cartilage injury, due to abnormal vascular invasion, the repaired tissue often forms fibrous cartilage with poor mechanical properties, not matching normal articular hyaline cartilage. The overexpression of vascular endothelial growth factor (VEGF) is considered a significant cause of hyaline cartilage repair failure, while bevacizumab, a commonly used clinical VEGF inhibitor, exhibits a potent anti-angiogenic effect. Therefore, this study combines bevacizumab-loaded nanoparticles with host-guest macromer dynamic hydrogels (HBN hydrogel) to form a composite system, delivering bevacizumab through sustained release to inhibit angiogenesis, improve the cartilage regeneration microenvironment, and thus promote in situ hyaline cartilage repair. The dynamic structure of the host-guest macromer hydrogel supports cell adhesion, aggregation, and spreading within a three-dimensional network, promoting stem cell chondrogenic differentiation under three-dimensional culture conditions. The HBN hydrogel effectively inhibits vascular ingrowth and promotes hyaline cartilage formation when implanted subcutaneously in nude mice. In the orthotopic rat knee defect model, the HBN hydrogel significantly enhanced the quality of in situ repair by promoting anti-inflammatory M2 macrophage polarization and suppressing catabolic enzymes, thereby regenerating hyaline cartilage that closely mirrors native tissue. Ultimately, by synergistically coupling an adaptive three-dimensional mechanical network with the sustained anti-angiogenic and immunomodulatory release of bevacizumab, this composite system provides a highly translational platform for joint repair.
Statement of significance
Cartilage repair remains challenging because regenerating neotissue often turns into fibrocartilage due to abnormal blood vessel invasion. We introduce a dynamic host–guest macromer (HGM) hydrogel loaded with bevacizumab nanoparticles to block vascular invasion and promote true hyaline cartilage regeneration. Unlike traditional static hydrogels, this dynamic system supports cell adhesion and spreading in 3D, providing a more favorable environment for tissue formation. In vivo studies show that the HGM hydrogel induces smooth, cartilage-like tissue with minimal vascularization. This work offers a supramolecular materials-based strategy to regulate angiogenesis and inspire therapeutic approaches for hyaline cartilage repair.
{"title":"Supramolecular dynamic hydrogels loaded with bevacizumab nanoparticles promote hyaline cartilage regeneration by inhibiting angiogenesis","authors":"Aikang Li, Zilu Jiao, Peng Liu, Mingxin Lin, Jiayou Chen, Rongji Liang, Jingtao Huang, Yaohang Yue, Fuyang Cao, Hongbo You, Hui Zeng, Kunyu Zhang, Jianjing Lin","doi":"10.1016/j.actbio.2026.04.028","DOIUrl":"10.1016/j.actbio.2026.04.028","url":null,"abstract":"<div><div>After joint cartilage injury, due to abnormal vascular invasion, the repaired tissue often forms fibrous cartilage with poor mechanical properties, not matching normal articular hyaline cartilage. The overexpression of vascular endothelial growth factor (VEGF) is considered a significant cause of hyaline cartilage repair failure, while bevacizumab, a commonly used clinical VEGF inhibitor, exhibits a potent anti-angiogenic effect. Therefore, this study combines bevacizumab-loaded nanoparticles with host-guest macromer dynamic hydrogels (HBN hydrogel) to form a composite system, delivering bevacizumab through sustained release to inhibit angiogenesis, improve the cartilage regeneration microenvironment, and thus promote <em>in situ</em> hyaline cartilage repair. The dynamic structure of the host-guest macromer hydrogel supports cell adhesion, aggregation, and spreading within a three-dimensional network, promoting stem cell chondrogenic differentiation under three-dimensional culture conditions. The HBN hydrogel effectively inhibits vascular ingrowth and promotes hyaline cartilage formation when implanted subcutaneously in nude mice. In the orthotopic rat knee defect model, the HBN hydrogel significantly enhanced the quality of <em>in situ</em> repair by promoting anti-inflammatory M2 macrophage polarization and suppressing catabolic enzymes, thereby regenerating hyaline cartilage that closely mirrors native tissue. Ultimately, by synergistically coupling an adaptive three-dimensional mechanical network with the sustained anti-angiogenic and immunomodulatory release of bevacizumab, this composite system provides a highly translational platform for joint repair.</div></div><div><h3>Statement of significance</h3><div>Cartilage repair remains challenging because regenerating neotissue often turns into fibrocartilage due to abnormal blood vessel invasion. We introduce a dynamic host–guest macromer (HGM) hydrogel loaded with bevacizumab nanoparticles to block vascular invasion and promote true hyaline cartilage regeneration. Unlike traditional static hydrogels, this dynamic system supports cell adhesion and spreading in 3D, providing a more favorable environment for tissue formation. <em>In vivo</em> studies show that the HGM hydrogel induces smooth, cartilage-like tissue with minimal vascularization. This work offers a supramolecular materials-based strategy to regulate angiogenesis and inspire therapeutic approaches for hyaline cartilage repair.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"224 ","pages":"Pages 223-238"},"PeriodicalIF":10.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147791734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-01Epub Date: 2026-09-01DOI: 10.1016/j.actbio.2026.08.055
Qingche Pan, Xinwei Tao, Jianliang Li, Tianle Zhou, Huaping Tan
<div><div>Polyacrylic acid-based composites hold substantial promise for intelligent wound dressing applications, owing to their intrinsic hydrophilicity and pH responsiveness. Nevertheless, their clinical translation is hindered by insufficient mechanical properties and excessive adhesion, which are directly induced by high hydrophilicity. Herein, a dual-network Janus hydrogel based on polyacrylic acid (PAA) and sodium alginate (SA), denoted as tannic acid–iron nanoparticles@polyacrylic acid/sodium alginate (TA-Fe NPs@PS Janus), was rationally fabricated. This hydrogel incorporates self-assembled TA-Fe nanoparticles (TA-Fe NPs) with inherent antibacterial activity and magnetic responsiveness. Magnetic enrichment of nanoparticles at the bottom side of the hydrogel not only significantly enhances mechanical toughness via metal–phenolic network (MPN) but also renders the top and bottom layers with distinct intelligent responses to heterogeneous pH microenvironments, thus enabling effective antibiotic-free treatment of infected wounds. TA-Fe NPs@PS Janus integrates high mechanical toughness, sensing performance, and pH responsiveness, enabling monitoring of wound microenvironmental changes through combined responses to pH and ionic variations throughout the recovery process. The physicochemical, mechanical, and rheological properties of the hydrogel were systematically characterized, and <em>in vitro</em> antibacterial assessments were conducted. Results demonstrate that TA-Fe NPs significantly enhance hydrogel toughness: compared with the pristine PAA/SA hydrogel (PS), the composite hydrogel incorporating 0.3% (w/v) TA-Fe NPs exhibits a 1200% increase in tensile toughness (from 0.06 MJ m⁻³ to 0.78 MJ m⁻³). The hydrogel displays high sensitivity and undergoes reversible deformation and intelligent responsive behavior under cyclic pH changes. It not only exhibits high antibacterial efficacy but also demonstrates favorable cytocompatibility. Therefore, this study proposes a smart, stimuli-responsive multifunctional hydrogel dressing for treating chronic wound inflammation and monitoring the healing process, highlighting its potential for clinical applications.</div></div><div><h3>Statement of significance</h3><div>Chronic infected wounds severely threaten human health, yet clinically viable smart wound dressings are lacking. Polyacrylic acid (PAA) hydrogels are attractive for wound management but suffer from poor mechanical toughness and over-adhesion. We fabricate a dual-network Janus hydrogel (TA-Fe NPs@PS Janus) incorporating PAA, sodium alginate and tannic acid-iron nanoparticles. Magnetically concentrated TA-Fe NPs form metal-phenolic networks, boosting toughness by 1044.2% and creating asymmetric pH responsiveness. This cytocompatible hydrogel achieves antibiotic-free antibacterial function and real-time infection monitoring via pH changes. It overcomes key drawbacks of PAA hydrogels, integrates diagnosis and therapy, and offers a translatable s
{"title":"pH-Responsive double-network Janus hydrogel incorporates tannic acid–iron nanoparticles for chronic wound healing and monitoring","authors":"Qingche Pan, Xinwei Tao, Jianliang Li, Tianle Zhou, Huaping Tan","doi":"10.1016/j.actbio.2026.08.055","DOIUrl":"10.1016/j.actbio.2026.08.055","url":null,"abstract":"<div><div>Polyacrylic acid-based composites hold substantial promise for intelligent wound dressing applications, owing to their intrinsic hydrophilicity and pH responsiveness. Nevertheless, their clinical translation is hindered by insufficient mechanical properties and excessive adhesion, which are directly induced by high hydrophilicity. Herein, a dual-network Janus hydrogel based on polyacrylic acid (PAA) and sodium alginate (SA), denoted as tannic acid–iron nanoparticles@polyacrylic acid/sodium alginate (TA-Fe NPs@PS Janus), was rationally fabricated. This hydrogel incorporates self-assembled TA-Fe nanoparticles (TA-Fe NPs) with inherent antibacterial activity and magnetic responsiveness. Magnetic enrichment of nanoparticles at the bottom side of the hydrogel not only significantly enhances mechanical toughness via metal–phenolic network (MPN) but also renders the top and bottom layers with distinct intelligent responses to heterogeneous pH microenvironments, thus enabling effective antibiotic-free treatment of infected wounds. TA-Fe NPs@PS Janus integrates high mechanical toughness, sensing performance, and pH responsiveness, enabling monitoring of wound microenvironmental changes through combined responses to pH and ionic variations throughout the recovery process. The physicochemical, mechanical, and rheological properties of the hydrogel were systematically characterized, and <em>in vitro</em> antibacterial assessments were conducted. Results demonstrate that TA-Fe NPs significantly enhance hydrogel toughness: compared with the pristine PAA/SA hydrogel (PS), the composite hydrogel incorporating 0.3% (w/v) TA-Fe NPs exhibits a 1200% increase in tensile toughness (from 0.06 MJ m⁻³ to 0.78 MJ m⁻³). The hydrogel displays high sensitivity and undergoes reversible deformation and intelligent responsive behavior under cyclic pH changes. It not only exhibits high antibacterial efficacy but also demonstrates favorable cytocompatibility. Therefore, this study proposes a smart, stimuli-responsive multifunctional hydrogel dressing for treating chronic wound inflammation and monitoring the healing process, highlighting its potential for clinical applications.</div></div><div><h3>Statement of significance</h3><div>Chronic infected wounds severely threaten human health, yet clinically viable smart wound dressings are lacking. Polyacrylic acid (PAA) hydrogels are attractive for wound management but suffer from poor mechanical toughness and over-adhesion. We fabricate a dual-network Janus hydrogel (TA-Fe NPs@PS Janus) incorporating PAA, sodium alginate and tannic acid-iron nanoparticles. Magnetically concentrated TA-Fe NPs form metal-phenolic networks, boosting toughness by 1044.2% and creating asymmetric pH responsiveness. This cytocompatible hydrogel achieves antibiotic-free antibacterial function and real-time infection monitoring via pH changes. It overcomes key drawbacks of PAA hydrogels, integrates diagnosis and therapy, and offers a translatable s","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"223 ","pages":"Pages 520-540"},"PeriodicalIF":10.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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