Pub Date : 2026-01-01DOI: 10.1016/j.actbio.2025.11.047
Ron Shahar , Senthil Thangadurai , Alexander Rack , Martha Majkut , Paul Zaslansky
The Atlantic wolffish (Anarhichas lupus) is a teleost with prominent teeth highly adapted for crushing hard-shelled prey. The dentin type of wolffish teeth is osteodentin, which differs markedly in structure from the dentin of most vertebrates. This study aimed to investigate the three-dimensional (3D) deformation and strain fields that develop in intact wolffish teeth under load. Eight wolffish teeth (three caniniform and five molariform) were studied using low- and high-energy phase-contrast-enhanced x-ray tomography, imaged both statically and during in situ compression loading. Digital volume correlation was applied to sets of unloaded and loaded scans. Unexpectedly, 3D deformations and strains showed that all teeth exhibited auxeticity (negative Poisson’s ratios), such that when a tooth is compressed longitudinally, it also contracts laterally. Strain fields were used to calculate effective Poisson’s ratios in the x–z and y–z orientations (with z as the loading direction), and yielded negative values, mostly between –1 and –2. Auxeticity is rare in mineralized biomaterials and has previously been reported only in two invertebrates (limpet teeth and nacre). Nanoindentation showed that the solid osteodentinal components have bone-like mechanical properties. Microstructural analysis of osteodentin revealed a mineralized matrix with a vast array of canals that mostly run straight up from the base, and curve outward as they approach the tooth tip. We suggest that the internal architecture of osteodentin may explain its auxeticity through a mechanism similar to that of re-entrant auxetic metamaterials. Specifically, the externally curved canals and the mineralized columns between them bend inward under compression.
Statement of significance
Here we report the surprising findings of negative Poisson’s ratios (auxeticity) in osteodentin of wolffish (Anarhichas lupus) teeth. This means that when these teeth are compressed along their length, their width also contracts. This is a rare phenomenon which has not been reported so far in mineralized tissues of vertebrates. We propose that the cause of this unusual property is the internal micro-architecture of osteodentin, particularly its vast array of canals. Since materials with this property exhibit superior mechanical properties, such as resistance to wear and impact, this finding may lead to the development of new synthetic biomaterials with desirable features.
{"title":"Axially loaded whole teeth of Atlantic wolffish exhibit negative Poisson’s ratios due to their osteodentin microarchitecture","authors":"Ron Shahar , Senthil Thangadurai , Alexander Rack , Martha Majkut , Paul Zaslansky","doi":"10.1016/j.actbio.2025.11.047","DOIUrl":"10.1016/j.actbio.2025.11.047","url":null,"abstract":"<div><div>The Atlantic wolffish (<em>Anarhichas lupus</em>) is a teleost with prominent teeth highly adapted for crushing hard-shelled prey. The dentin type of wolffish teeth is osteodentin, which differs markedly in structure from the dentin of most vertebrates. This study aimed to investigate the three-dimensional (3D) deformation and strain fields that develop in intact wolffish teeth under load. Eight wolffish teeth (three caniniform and five molariform) were studied using low- and high-energy phase-contrast-enhanced x-ray tomography, imaged both statically and during <em>in situ</em> compression loading. Digital volume correlation was applied to sets of unloaded and loaded scans. Unexpectedly, 3D deformations and strains showed that all teeth exhibited auxeticity (negative Poisson’s ratios), such that when a tooth is compressed longitudinally, it also contracts laterally. Strain fields were used to calculate effective Poisson’s ratios in the x–z and y–z orientations (with z as the loading direction), and yielded negative values, mostly between –1 and –2. Auxeticity is rare in mineralized biomaterials and has previously been reported only in two invertebrates (limpet teeth and nacre). Nanoindentation showed that the solid osteodentinal components have bone-like mechanical properties. Microstructural analysis of osteodentin revealed a mineralized matrix with a vast array of canals that mostly run straight up from the base, and curve outward as they approach the tooth tip. We suggest that the internal architecture of osteodentin may explain its auxeticity through a mechanism similar to that of re-entrant auxetic metamaterials. Specifically, the externally curved canals and the mineralized columns between them bend inward under compression.</div></div><div><h3>Statement of significance</h3><div>Here we report the surprising findings of negative Poisson’s ratios (auxeticity) in osteodentin of wolffish (<em>Anarhichas lupus)</em> teeth. This means that when these teeth are compressed along their length, their width also contracts. This is a rare phenomenon which has not been reported so far in mineralized tissues of vertebrates. We propose that the cause of this unusual property is the internal micro-architecture of osteodentin, particularly its vast array of canals. Since materials with this property exhibit superior mechanical properties, such as resistance to wear and impact, this finding may lead to the development of new synthetic biomaterials with desirable features.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"210 ","pages":"Pages 95-109"},"PeriodicalIF":9.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145643614","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 : 2026-01-01DOI: 10.1016/j.actbio.2025.12.002
Wenjie Feng , Chang Weng , Chen Li , Rui Yang , Wanrui Shi , Yi Liu , Pengfei Ge , Hao Zhang
<div><div>Cuproptosis, a recently identified copper-dependent cell death modality, has opened a new territory in tumor therapy, which is promising to reverse the problem of chemoradiotherapy resistance due to its independence on the apoptotic mechanism. However, the inefficient promotion of copper influx and the intrinsic mechanism of copper efflux due to intracellular copper homeostasis significantly limit the efficacy of cuproptosis. Herein, we propose a strategy to disrupt copper homeostasis by designing copper-omeprazole supramolecular nanodrugs (Cu-OME SNDs), which simultaneously promote copper influx and inhibit efflux, thereby leading to intense cuproptosis. On the one aspect, OME coordinates with copper ions to form self-delivery SNDs, facilitating the influx of copper ions. Under the glutathione stimulation of tumor microenvironment (TME), Cu-OME SNDs disassemble and release cuprous ions, which bind with mitochondrial acyltransferases to initiate cuproptosis. On the other aspect, the released OME inhibits copper efflux by suppressing ATPase copper transporting alpha expression, further enhancing copper dyshomeostasis and potentiating cuproptosis. A glioblastoma model is adopted to verify the cuproptosis efficacy of Cu-OME SNDs. To improve the permeability across blood-brain tumor barrier (BTB), minoxidil sulfate (MS) and T7 peptide are modified on Cu-OME SNDs to produce Cu-OME/MS@T7 SNDs. T7 peptide actively targets the transferrin receptor, facilitating the accumulation of SNDs in glioblastoma sites. MS, serving as a molecularly targeted ATP-sensitive potassium (K<sub>ATP</sub>) modulator, selectively boosts BTB permeability. Upon entering glioblastoma cells, the released MS further activates K<sub>ATP</sub> channels, promoting SNDs accumulation and establishing a positive feedback loop. Additionally, the cuproptosis induced by SNDs triggers immunogenic cell death in tumor cells, amplifying specific antitumor immunity and mitigating the immunosuppressive TME. Collectively, our findings demonstrate the effectiveness of OME-mediated nanodelivery of copper in inducing copper dyshomeostasis and triggering cuproptosis, highlighting their considerable therapeutic promise through synchronous remodeling of copper influx and efflux.</div></div><div><h3>Statement of significance</h3><div>Cuproptosis has opened a promising frontier in tumor therapy. However, its efficacy is substantially hampered by the inefficient copper influx and the intrinsic copper efflux mechanism driven by intracellular copper homeostasis. To address these challenges, we propose a “two birds with one stone” strategy to disrupt copper homeostasis using copper-omeprazole supramolecular nanodrugs (Cu-OME SNDs). In this design, OME coordinates with copper ions to form self-delivery SNDs, enhancing the delivery efficiency of exogenous copper ions. Meanwhile, the released OME further blocks copper efflux by suppressing ATP7A copper efflux transporter. Collectively, this work demo
{"title":"Omeprazole-mediated nanodelivery of copper for synchronous remodeling of copper influx and efflux in cuproptotic glioblastoma therapy","authors":"Wenjie Feng , Chang Weng , Chen Li , Rui Yang , Wanrui Shi , Yi Liu , Pengfei Ge , Hao Zhang","doi":"10.1016/j.actbio.2025.12.002","DOIUrl":"10.1016/j.actbio.2025.12.002","url":null,"abstract":"<div><div>Cuproptosis, a recently identified copper-dependent cell death modality, has opened a new territory in tumor therapy, which is promising to reverse the problem of chemoradiotherapy resistance due to its independence on the apoptotic mechanism. However, the inefficient promotion of copper influx and the intrinsic mechanism of copper efflux due to intracellular copper homeostasis significantly limit the efficacy of cuproptosis. Herein, we propose a strategy to disrupt copper homeostasis by designing copper-omeprazole supramolecular nanodrugs (Cu-OME SNDs), which simultaneously promote copper influx and inhibit efflux, thereby leading to intense cuproptosis. On the one aspect, OME coordinates with copper ions to form self-delivery SNDs, facilitating the influx of copper ions. Under the glutathione stimulation of tumor microenvironment (TME), Cu-OME SNDs disassemble and release cuprous ions, which bind with mitochondrial acyltransferases to initiate cuproptosis. On the other aspect, the released OME inhibits copper efflux by suppressing ATPase copper transporting alpha expression, further enhancing copper dyshomeostasis and potentiating cuproptosis. A glioblastoma model is adopted to verify the cuproptosis efficacy of Cu-OME SNDs. To improve the permeability across blood-brain tumor barrier (BTB), minoxidil sulfate (MS) and T7 peptide are modified on Cu-OME SNDs to produce Cu-OME/MS@T7 SNDs. T7 peptide actively targets the transferrin receptor, facilitating the accumulation of SNDs in glioblastoma sites. MS, serving as a molecularly targeted ATP-sensitive potassium (K<sub>ATP</sub>) modulator, selectively boosts BTB permeability. Upon entering glioblastoma cells, the released MS further activates K<sub>ATP</sub> channels, promoting SNDs accumulation and establishing a positive feedback loop. Additionally, the cuproptosis induced by SNDs triggers immunogenic cell death in tumor cells, amplifying specific antitumor immunity and mitigating the immunosuppressive TME. Collectively, our findings demonstrate the effectiveness of OME-mediated nanodelivery of copper in inducing copper dyshomeostasis and triggering cuproptosis, highlighting their considerable therapeutic promise through synchronous remodeling of copper influx and efflux.</div></div><div><h3>Statement of significance</h3><div>Cuproptosis has opened a promising frontier in tumor therapy. However, its efficacy is substantially hampered by the inefficient copper influx and the intrinsic copper efflux mechanism driven by intracellular copper homeostasis. To address these challenges, we propose a “two birds with one stone” strategy to disrupt copper homeostasis using copper-omeprazole supramolecular nanodrugs (Cu-OME SNDs). In this design, OME coordinates with copper ions to form self-delivery SNDs, enhancing the delivery efficiency of exogenous copper ions. Meanwhile, the released OME further blocks copper efflux by suppressing ATP7A copper efflux transporter. Collectively, this work demo","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"210 ","pages":"Pages 499-515"},"PeriodicalIF":9.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145679566","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 : 2026-01-01DOI: 10.1016/j.actbio.2025.12.004
Stanislas Von Euw , Kian F. Eichholz , Olwyn R. Mahon , Tristan Georges , Aisling Teahan , Jérôme Charliac , Marion Merle , Camille Chareyron , Guillaume Laurent , Thierry Azaïs , Nadine Nassif , Daniel J. Kelly
Biomaterial-based therapies for bone regeneration have long relied on synthetic calcium phosphate particles to improve their overall performance. However, these particles often lack the compositional and structural complexity of their biogenic counterparts and fail to capture the intrinsic heterogeneity of bone mineral across spatial and temporal scales. Here, a series of organic–inorganic composites containing well-defined proxies for biogenic calcium phosphate particles at successive stages of bone biomineralization reveals that osteogenic differentiation of human mesenchymal stem cells increases significantly for partially crystalline hydroxyapatite nanoparticles coated with a hydrophilic amorphous surface layer whose proportion reaches at least 35 %. This coating occurs naturally on bone hydroxyapatite nanoparticles, with a proportion that decreases as the particles age, and may contribute to the unparalleled clinical success of autologous bone grafts. Mechanistically, a hydration shell of tightly bound water molecules on the amorphous layer is proposed to enhance binding of extracellular signaling molecules at the cell–material interface, amplifying osteogenic commitment. These findings provide a mechanistic basis for previous observations that biomimetic hydroxyapatite particles outperform their highly crystalline counterparts, underscore the critical importance of truly bone-mimetic material designs for next-generation bone-regenerative therapies, and offer an unprecedented view of how biophysical surface cues direct stem-cell function.
Statement of significance
Amorphous chemical environments naturally occur around the particles of a variety of biominerals, yet they have mainly been associated with physicochemical processes such as ion exchange, crystal growth, and particle assembly. Focusing on bone bioapatite, a calcium phosphate biomineral of major clinical relevance, we show that these amorphous environments also have biological functions. Using a unique series of well-characterized proxies for biogenic calcium phosphate particles at different stages of bone biomineralization, we reveal the critical role of these amorphous chemical environments in regulating osteogenic differentiation of human mesenchymal stem cells. These results emphasize the importance of truly biomimetic designs for developing transformative biomaterials for bone repair and provide mechanistic insight into how nanoscale surface features influence stem cell behavior.
{"title":"The hydrophilic amorphous layer around bone apatite promotes osteogenesis","authors":"Stanislas Von Euw , Kian F. Eichholz , Olwyn R. Mahon , Tristan Georges , Aisling Teahan , Jérôme Charliac , Marion Merle , Camille Chareyron , Guillaume Laurent , Thierry Azaïs , Nadine Nassif , Daniel J. Kelly","doi":"10.1016/j.actbio.2025.12.004","DOIUrl":"10.1016/j.actbio.2025.12.004","url":null,"abstract":"<div><div>Biomaterial-based therapies for bone regeneration have long relied on synthetic calcium phosphate particles to improve their overall performance. However, these particles often lack the compositional and structural complexity of their biogenic counterparts and fail to capture the intrinsic heterogeneity of bone mineral across spatial and temporal scales. Here, a series of organic–inorganic composites containing well-defined proxies for biogenic calcium phosphate particles at successive stages of bone biomineralization reveals that osteogenic differentiation of human mesenchymal stem cells increases significantly for partially crystalline hydroxyapatite nanoparticles coated with a hydrophilic amorphous surface layer whose proportion reaches at least 35 %. This coating occurs naturally on bone hydroxyapatite nanoparticles, with a proportion that decreases as the particles age, and may contribute to the unparalleled clinical success of autologous bone grafts. Mechanistically, a hydration shell of tightly bound water molecules on the amorphous layer is proposed to enhance binding of extracellular signaling molecules at the cell–material interface, amplifying osteogenic commitment. These findings provide a mechanistic basis for previous observations that biomimetic hydroxyapatite particles outperform their highly crystalline counterparts, underscore the critical importance of truly bone-mimetic material designs for next-generation bone-regenerative therapies, and offer an unprecedented view of how biophysical surface cues direct stem-cell function.</div></div><div><h3>Statement of significance</h3><div>Amorphous chemical environments naturally occur around the particles of a variety of biominerals, yet they have mainly been associated with physicochemical processes such as ion exchange, crystal growth, and particle assembly. Focusing on bone bioapatite, a calcium phosphate biomineral of major clinical relevance, we show that these amorphous environments also have biological functions. Using a unique series of well-characterized proxies for biogenic calcium phosphate particles at different stages of bone biomineralization, we reveal the critical role of these amorphous chemical environments in regulating osteogenic differentiation of human mesenchymal stem cells. These results emphasize the importance of truly biomimetic designs for developing transformative biomaterials for bone repair and provide mechanistic insight into how nanoscale surface features influence stem cell behavior.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"210 ","pages":"Pages 604-616"},"PeriodicalIF":9.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145688844","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 : 2026-01-01DOI: 10.1016/j.actbio.2025.12.005
Christoph Brandt-Wunderlich , Armin Fubel , Michael Stiehm , Wolfram Schmidt , Swen Grossmann , Franziska Bonin , Florence Kosche , Christopher Lenz , Philine Baumann-Zumstein , Claus Harder , Markus Wolfer , Stefan Siewert , Klaus-Peter Schmitz
The elastic properties of coronary arteries are associated with different vascular conditions, in particular the degree of severity and pathology of coronary artery disease. In contrast to permanent stents, bioresorbable scaffolds provide temporary support to the treated lesion while allowing for restoration of the physiological vasomotion due to resorption within a certain period of time. Coronary artery distensibility may serve as a measure for vascular restoration after implantation and in vivo degradation of a bioresorbable scaffold. This study presents an investigation of the distensibility of porcine coronary arteries two and four years after implantation of a resorbable magnesium-based scaffold (RMS, FreesolveTM scaffold prototype and FreesolveTM scaffold, respectively, Teleflex) based on measurements of the pressure-dependent luminal area using an ex vivo test setup including intravascular optical coherence tomography. In case of a normotensive pressure regime, mean distensibility values were found to be 1.45 ± 0.47 × 10-3 mmHg-1 for the untreated artery regions and 1.03 × 10-3 mmHg-1 for the RMS region after two years in vivo degradation (71% distensibility recovery) as well as 1.40 ± 0.01 × 10-3 mmHg-1 after four years in vivo degradation (97% distensibility recovery), respectively. Reference measurements of a permanent drug eluting stent region revealed a distensibility of 0.80 × 10-3 mmHg-1. The findings of this study support the hypothesis that the radial elastic properties of the coronary artery can be regained following the in vivo degradation of a magnesium-based scaffold.
Statement of significance
The elastic properties of coronary arteries are associated with the pathology of coronary artery disease. Measurement of coronary artery distensibility can be used to quantitatively assess passive radial elasticity of the arterial wall. Within the current study, two porcine hearts two years and four years after implantation of a resorbable magnesium-based scaffold were investigated regarding their coronary artery distensibility. Using an ex vivo test setup based on intravascular optical coherence tomography overcomes many limitations of in vivo investigations. The results show an increasing distensibility recovery over degradation time. For the first time, the hypothesis that the elastic properties of the coronary arteries can be restored following the in vivo degradation of a magnesium-based scaffold could be verified by quantitative measurements of distensibility
{"title":"Recovery of coronary artery distensibility after two and four years in vivo degradation of a resorbable magnesium-based scaffold","authors":"Christoph Brandt-Wunderlich , Armin Fubel , Michael Stiehm , Wolfram Schmidt , Swen Grossmann , Franziska Bonin , Florence Kosche , Christopher Lenz , Philine Baumann-Zumstein , Claus Harder , Markus Wolfer , Stefan Siewert , Klaus-Peter Schmitz","doi":"10.1016/j.actbio.2025.12.005","DOIUrl":"10.1016/j.actbio.2025.12.005","url":null,"abstract":"<div><div>The elastic properties of coronary arteries are associated with different vascular conditions, in particular the degree of severity and pathology of coronary artery disease. In contrast to permanent stents, bioresorbable scaffolds provide temporary support to the treated lesion while allowing for restoration of the physiological vasomotion due to resorption within a certain period of time. Coronary artery distensibility may serve as a measure for vascular restoration after implantation and <em>in vivo</em> degradation of a bioresorbable scaffold. This study presents an investigation of the distensibility of porcine coronary arteries two and four years after implantation of a resorbable magnesium-based scaffold (RMS, Freesolve<sup>TM</sup> scaffold prototype and Freesolve<sup>TM</sup> scaffold, respectively, Teleflex) based on measurements of the pressure-dependent luminal area using an <em>ex vivo</em> test setup including intravascular optical coherence tomography. In case of a normotensive pressure regime, mean distensibility values were found to be 1.45 ± 0.47 × 10<sup>-3</sup> mmHg<sup>-1</sup> for the untreated artery regions and 1.03 × 10<sup>-3</sup> mmHg<sup>-1</sup> for the RMS region after two years <em>in vivo</em> degradation (71% distensibility recovery) as well as 1.40 ± 0.01 × 10<sup>-3</sup> mmHg<sup>-1</sup> after four years <em>in vivo</em> degradation (97% distensibility recovery), respectively. Reference measurements of a permanent drug eluting stent region revealed a distensibility of 0.80 × 10<sup>-3</sup> mmHg<sup>-1</sup>. The findings of this study support the hypothesis that the radial elastic properties of the coronary artery can be regained following the <em>in vivo</em> degradation of a magnesium-based scaffold.</div></div><div><h3>Statement of significance</h3><div>The elastic properties of coronary arteries are associated with the pathology of coronary artery disease. Measurement of coronary artery distensibility can be used to quantitatively assess passive radial elasticity of the arterial wall. Within the current study, two porcine hearts two years and four years after implantation of a resorbable magnesium-based scaffold were investigated regarding their coronary artery distensibility. Using an <em>ex vivo</em> test setup based on intravascular optical coherence tomography overcomes many limitations of <em>in vivo</em> investigations. The results show an increasing distensibility recovery over degradation time. For the first time, the hypothesis that the elastic properties of the coronary arteries can be restored following the <em>in vivo</em> degradation of a magnesium-based scaffold could be verified by quantitative measurements of distensibility</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"210 ","pages":"Pages 617-628"},"PeriodicalIF":9.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696503","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 : 2026-01-01DOI: 10.1016/j.actbio.2025.12.010
Yang Zhou , Chenglong Ge , Mengyuan Yin , Yekun Deng , Zhongmin Liu , Jingrui Shen , Renxiang Zhou , Lichen Yin
The disruption of immune homeostasis induced by cell-free DNA (cfDNA) plays a critical role in the pathogenesis of rheumatoid arthritis (RA). Intra-articular injection of cationic polymers represents a promising RA treatment modality, because they can capture cfDNA via electrostatic interaction. However, the captured cfDNA is prone to re-release upon competitive replacement by the negatively charged components in the complicated intra-articular environment. To address this critical issue, a molecular clip based on guanidine-functionalized, spiked polypeptides with orderly arranged α-helices (denoted as GP) is developed for robust intra-articular cfDNA scavenging and RA therapy. GP can bind cfDNA via electrostatic attraction and salt bridging, and more importantly, can confine cfDNA within the pockets among adjacent rod-like helices, thus forming stable complex that resists the competitive replacement by the negatively charged intra-articular components. Following intra-articular injection in collagen-induced arthritis (CIA) mice, GP efficiently scavenges cfDNA, and the GP/cfDNA complex maintains stable before being cleared from the body via biliary excretion. Consequently, GP effectively restores immune homeostasis and promotes tissue repair, thereby interrupting RA progression. This study presents an effective approach for intra-articular cfDNA scavenging, and the unique structural properties of GP underscore its therapeutic potential in targeting cfDNA-driven pathological processes in RA.
Statement of significance
Intra-articular cell-free DNA (cfDNA) scavenging using cationic polymers holds great promise for rheumatoid arthritis (RA) treatment. However, the captured cfDNA is prone to discharge upon competitive replacement by the negatively charged components in the complicated intra-articular environment. Herein, a molecular clip based on guanidine-functionalized, spiked polypeptides with orderly arranged α-helices (denoted as GP) is developed, which can capture cfDNA through electrostatic attraction and salt bridging, and confine cfDNA within the pockets among adjacent rod-like helices to avoid undesired discharge. In RA mouse model, intra-articularly injected GP effectively scavenges cfDNA and subsequently gets cleared via bile excretion, thereby restoring immune homeostasis and promoting tissue repair. This study provides an enlightened paradigm for intra-articular cfDNA scavenging and RA management.
{"title":"Helix-guarded molecular clips confer robust scavenging of intra-articular cell-free DNA for the treatment of rheumatoid arthritis","authors":"Yang Zhou , Chenglong Ge , Mengyuan Yin , Yekun Deng , Zhongmin Liu , Jingrui Shen , Renxiang Zhou , Lichen Yin","doi":"10.1016/j.actbio.2025.12.010","DOIUrl":"10.1016/j.actbio.2025.12.010","url":null,"abstract":"<div><div>The disruption of immune homeostasis induced by cell-free DNA (cfDNA) plays a critical role in the pathogenesis of rheumatoid arthritis (RA). Intra-articular injection of cationic polymers represents a promising RA treatment modality, because they can capture cfDNA <em>via</em> electrostatic interaction. However, the captured cfDNA is prone to re-release upon competitive replacement by the negatively charged components in the complicated intra-articular environment. To address this critical issue, a molecular clip based on guanidine-functionalized, spiked polypeptides with orderly arranged α-helices (denoted as GP) is developed for robust intra-articular cfDNA scavenging and RA therapy. GP can bind cfDNA <em>via</em> electrostatic attraction and salt bridging, and more importantly, can confine cfDNA within the pockets among adjacent rod-like helices, thus forming stable complex that resists the competitive replacement by the negatively charged intra-articular components. Following intra-articular injection in collagen-induced arthritis (CIA) mice, GP efficiently scavenges cfDNA, and the GP/cfDNA complex maintains stable before being cleared from the body <em>via</em> biliary excretion. Consequently, GP effectively restores immune homeostasis and promotes tissue repair, thereby interrupting RA progression. This study presents an effective approach for intra-articular cfDNA scavenging, and the unique structural properties of GP underscore its therapeutic potential in targeting cfDNA-driven pathological processes in RA.</div></div><div><h3>Statement of significance</h3><div>Intra-articular cell-free DNA (cfDNA) scavenging using cationic polymers holds great promise for rheumatoid arthritis (RA) treatment. However, the captured cfDNA is prone to discharge upon competitive replacement by the negatively charged components in the complicated intra-articular environment. Herein, a molecular clip based on guanidine-functionalized, spiked polypeptides with orderly arranged α-helices (denoted as GP) is developed, which can capture cfDNA through electrostatic attraction and salt bridging, and confine cfDNA within the pockets among adjacent rod-like helices to avoid undesired discharge. In RA mouse model, intra-articularly injected GP effectively scavenges cfDNA and subsequently gets cleared <em>via</em> bile excretion, thereby restoring immune homeostasis and promoting tissue repair. This study provides an enlightened paradigm for intra-articular cfDNA scavenging and RA management.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"210 ","pages":"Pages 535-548"},"PeriodicalIF":9.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145703101","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 : 2026-01-01DOI: 10.1016/j.actbio.2025.12.001
Wenjin Dai , Mengjun Zeng , Lu Zhang , Guangwei Shi , Hong Wang , Chengyi Xu , Riguang Zhao , Cong Zhang , Jiu Wang , Liqun Jiang
An intelligent hydrogel system that can rapidly release local anesthetics in response to simple mechanical kneading offers a patient-friendly solution for managing osteoarthritis (OA) pain during acute flare-ups. Conventional stimuli-responsive hydrogels often require specialized devices (e.g., near-infrared emitters and ultrasound generators), limiting their accessibility in real-world settings. A kneading-responsive hydrogel composed of oxidized hyaluronic acid (OHA) and carboxymethyl chitosan, incorporating pressure-sensitive multivesicular liposomes (pMVLs) loaded with phosphoric acid and benzocaine covalently linked to OHA, was developed in this study. Mechanical kneading (0.25 ± 0.03 kg/cm²) ruptured the pMVLs, releasing acid to lower the gel pH from 7.4 to 6.7, thereby cleaving Schiff base bonds and accelerating benzocaine release by 2.26-fold in vitro. In OA-rat models, periarticular injection of the hydrogel significantly increased pain thresholds, and kneading raised benzocaine accumulation in the synovial fluid by 3.88-fold, improving locomotor activity and joint function. The release was gated by a predefined pressure threshold: the hydrogel remained quiescent under physiological interstitial pressures but was activated by conscious kneading (0.25 ± 0.03 kg/cm²), allowing for patient-controlled, on-demand analgesia. This kneading-responsive hydrogel enables self-controlled, on-demand analgesia without the need for specialized equipment, providing a convenient strategy for precision pain management in OA.
Statement of Significance
Many pain-relief options rely on clinic devices or fixed depots that patients cannot control. We report an equipment-free, kneading-responsive hyaluronic-acid hydrogel that converts gentle finger pressure (0.25 kg·cm⁻², measured) into on-demand local anesthesia for osteoarthritis flares. The reservoir combines a pH-sensitive OHA/CMS network with pressure-sensitive multivesicular liposomes that release phosphoric acid, transiently lowering the pH to cleave imine (Schiff-base) bonds and accelerate benzocaine release. In OA rats, a single kneading produced ∼48 h of drug elevation, while the depot persisted for up to 14 days; once-daily kneading maintained effective analgesia for up to 6 days, improving pain, mobility, and cartilage preservation. Benchmarking versus NIR/ultrasound highlights the trade-off between remote triggering and simple, patient-directed use. This self-managed platform enables localized, repeat-dosing pain control.
{"title":"A kneading-responsive hyaluronic acid-based hydrogel for on-demand local anesthesia in osteoarthritis","authors":"Wenjin Dai , Mengjun Zeng , Lu Zhang , Guangwei Shi , Hong Wang , Chengyi Xu , Riguang Zhao , Cong Zhang , Jiu Wang , Liqun Jiang","doi":"10.1016/j.actbio.2025.12.001","DOIUrl":"10.1016/j.actbio.2025.12.001","url":null,"abstract":"<div><div>An intelligent hydrogel system that can rapidly release local anesthetics in response to simple mechanical kneading offers a patient-friendly solution for managing osteoarthritis (OA) pain during acute flare-ups. Conventional stimuli-responsive hydrogels often require specialized devices (e.g., near-infrared emitters and ultrasound generators), limiting their accessibility in real-world settings. A kneading-responsive hydrogel composed of oxidized hyaluronic acid (OHA) and carboxymethyl chitosan, incorporating pressure-sensitive multivesicular liposomes (pMVLs) loaded with phosphoric acid and benzocaine covalently linked to OHA, was developed in this study. Mechanical kneading (0.25 ± 0.03 kg/cm²) ruptured the pMVLs, releasing acid to lower the gel pH from 7.4 to 6.7, thereby cleaving Schiff base bonds and accelerating benzocaine release by 2.26-fold <em>in vitro</em>. In OA-rat models, periarticular injection of the hydrogel significantly increased pain thresholds, and kneading raised benzocaine accumulation in the synovial fluid by 3.88-fold, improving locomotor activity and joint function. The release was gated by a predefined pressure threshold<strong>:</strong> the hydrogel remained quiescent under physiological interstitial pressures but was activated by conscious kneading (0.25 ± 0.03 kg/cm²), allowing for patient-controlled, on-demand analgesia. This kneading-responsive hydrogel enables self-controlled, on-demand analgesia without the need for specialized equipment, providing a convenient strategy for precision pain management in OA.</div></div><div><h3>Statement of Significance</h3><div>Many pain-relief options rely on clinic devices or fixed depots that patients cannot control. We report an equipment-free, kneading-responsive hyaluronic-acid hydrogel that converts gentle finger pressure (0.25 kg·cm⁻², measured) into on-demand local anesthesia for osteoarthritis flares. The reservoir combines a pH-sensitive OHA/CMS network with pressure-sensitive multivesicular liposomes that release phosphoric acid, transiently lowering the pH to cleave imine (Schiff-base) bonds and accelerate benzocaine release. In OA rats, a single kneading produced ∼48 h of drug elevation, while the depot persisted for up to 14 days; once-daily kneading maintained effective analgesia for up to 6 days, improving pain, mobility, and cartilage preservation. Benchmarking versus NIR/ultrasound highlights the trade-off between remote triggering and simple, patient-directed use. This self-managed platform enables localized, repeat-dosing pain control.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"210 ","pages":"Pages 160-175"},"PeriodicalIF":9.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145679526","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 : 2026-01-01DOI: 10.1016/j.actbio.2025.12.025
Morgan L. Egnot , Katrina M. Knight , Leslie A. Meyn , Nisha A. Shetty , Steven D. Abramowitch , Pamela A. Moalli
Pelvic regenerative medicine lags behind other fields in availability of regenerative bioscaffolds derived from decellularized vagina, resulting in fewer platforms for investigating pelvic pathology in vitro and an absence of regenerative grafts mimicking unique vaginal properties. Utilizing nulliparous porcine vagina obtained from an abattoir, the goal of this study was to 1) evaluate the efficacy of different modalities of decellularization (freeze-thaw, detergent, and a combined hybrid method) on reducing cellularity, the primary outcome of decellularization, and 2) characterize in-depth the impact of these modalities on the structural properties and composition of the remaining matrix using mechanical and biochemical analyses. While all methods tested showed roughly equivalent performance in reducing cellularity, success diverged regarding preservation of matrix properties. Freeze-thaw decellularization reduced cellular components the least but preserved fiber architecture and gross mechanics. Detergent decellularization achieved moderate cellular component reduction and preserved glycosaminoglycan content but distorted fiber architecture. Overall, hybrid decellularization resulted in maximum antigenic cellular component reduction but poorly retained gross mechanics and glycosaminoglycan content. Additionally, heterogeneity in composition and mechanics between vaginal regions was observed between the proximal-distal orientations, mirroring observations in other animal models. Like other tissues, there is no one-size-fits-all approach to decellularizing the vagina, and selection of the decellularization method should be concordant with the most desired properties of the resultant matrix product. This study suggests that freeze-thaw methods are ideal for investigation of native biomechanical properties, detergent methods for generating raw materials for further manufacturing, and hybrid methods are best suited for generating whole-tissue acellular matrices.
Statement of significance
Vaginal tissue engineering is understudied, hampering investigations into clinical regenerative potential and informed choice of decellularization method. We selected three decellularization methods and evaluated their efficacy and off-target effects on full thickness adult nulliparous porcine vagina isolated from six distinct vaginal regions. We found that while all methods similarly reduced cellular contents, each altered the resulting vaginal extracellular matrix structure and composition in a region-specific manner, which may have implications for generation of regenerative bioscaffolds or mechanistic studies of matrix mechanics. Data generated from this study will shape guidelines for vaginal decellularization based on scientific or clinical need, establish a link between changes in matrix properties and decellularization method, and further define regional complexity within the adult porcine vagina
{"title":"Decellularization method and tissue region impact the structural properties and composition of porcine vaginal extracellular matrix","authors":"Morgan L. Egnot , Katrina M. Knight , Leslie A. Meyn , Nisha A. Shetty , Steven D. Abramowitch , Pamela A. Moalli","doi":"10.1016/j.actbio.2025.12.025","DOIUrl":"10.1016/j.actbio.2025.12.025","url":null,"abstract":"<div><div>Pelvic regenerative medicine lags behind other fields in availability of regenerative bioscaffolds derived from decellularized vagina, resulting in fewer platforms for investigating pelvic pathology in vitro and an absence of regenerative grafts mimicking unique vaginal properties. Utilizing nulliparous porcine vagina obtained from an abattoir, the goal of this study was to 1) evaluate the efficacy of different modalities of decellularization (freeze-thaw, detergent, and a combined hybrid method) on reducing cellularity, the primary outcome of decellularization, and 2) characterize in-depth the impact of these modalities on the structural properties and composition of the remaining matrix using mechanical and biochemical analyses. While all methods tested showed roughly equivalent performance in reducing cellularity, success diverged regarding preservation of matrix properties. Freeze-thaw decellularization reduced cellular components the least but preserved fiber architecture and gross mechanics. Detergent decellularization achieved moderate cellular component reduction and preserved glycosaminoglycan content but distorted fiber architecture. Overall, hybrid decellularization resulted in maximum antigenic cellular component reduction but poorly retained gross mechanics and glycosaminoglycan content. Additionally, heterogeneity in composition and mechanics between vaginal regions was observed between the proximal-distal orientations, mirroring observations in other animal models. Like other tissues, there is no one-size-fits-all approach to decellularizing the vagina, and selection of the decellularization method should be concordant with the most desired properties of the resultant matrix product. This study suggests that freeze-thaw methods are ideal for investigation of native biomechanical properties, detergent methods for generating raw materials for further manufacturing, and hybrid methods are best suited for generating whole-tissue acellular matrices.</div></div><div><h3>Statement of significance</h3><div>Vaginal tissue engineering is understudied, hampering investigations into clinical regenerative potential and informed choice of decellularization method. We selected three decellularization methods and evaluated their efficacy and off-target effects on full thickness adult nulliparous porcine vagina isolated from six distinct vaginal regions. We found that while all methods similarly reduced cellular contents, each altered the resulting vaginal extracellular matrix structure and composition in a region-specific manner, which may have implications for generation of regenerative bioscaffolds or mechanistic studies of matrix mechanics. Data generated from this study will shape guidelines for vaginal decellularization based on scientific or clinical need, establish a link between changes in matrix properties and decellularization method, and further define regional complexity within the adult porcine vagina</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"210 ","pages":"Pages 206-220"},"PeriodicalIF":9.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145764050","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 : 2026-01-01DOI: 10.1016/j.actbio.2025.12.008
Ayda Pourmostafa , Gabrielle Uskach , Mohammad Jafari , Elvan Dogan , Swaprakash Yogeshwaran , Teresa L. Wood , Sobhan Ghaeini-Hesaroueiye , Lin Han , Farid Alisafaei , Amir K. Miri
Solid tumor cells can adopt a range of morphological states linked to distinct functional behaviors during tumor progression. Some remain in a proliferative state, forming tight clusters, others detach and elongate into an invasive state, and some retain a rounded amoeboid form with minimal matrix adhesion. However, factors determining which morphological state a cell adopts remain poorly understood. We used a combined theoretical and experimental framework to study how extracellular matrix (ECM) mechanics regulate solid tumor cell morphology in three-dimensional (3D) environments. We developed a theoretical mechanical energy model based on the minimum energy principle, which suggests that a cell will adopt the morphological state (rounded, elongated, or clustered) that minimizes the total energy of the cell-ECM system. Using MDA-MB-231 breast cancer cells, we established a reliable protocol for encapsulating cells into 3D naturally-derived hydrogels with controlled stiffness. We confirmed the model’s results in vitro over an extended culture period. In soft ECMs, cells transitioned over time to an elongated morphology, while in stiff ECMs, cells favored clustered configurations. These transitions were governed by the hydrogel-based ECM’s physical, not chemical, properties, as confirmed using chemically distinct yet mechanically matched composite matrices. These new insights have implications for solid tumor cell invasion modeling in vitro.
Statement of significance
We study the fundamental question of how solid tumor cells adapt their morphology in response to the physical characteristics of the extracellular matrix. This work establishes a robust experimental platform for studying cellular markers in triple-negative breast cancer (TNBC) cells, followed by a biophysical modeling of the cell invasion. Cell clustering was observed in stiffe ECMs, while an elongated morphology was observed in soft ECMs. Our theoretical modeling revealed how the biophysical properties of the matrix can impact cell morphology and invasion behavior. This work can contribute to personalized medicine by making more effective, tailored cancer models.
{"title":"Extracellular matrix physical properties regulate cancer cell morphological transitions in 3D hydrogel microtissues","authors":"Ayda Pourmostafa , Gabrielle Uskach , Mohammad Jafari , Elvan Dogan , Swaprakash Yogeshwaran , Teresa L. Wood , Sobhan Ghaeini-Hesaroueiye , Lin Han , Farid Alisafaei , Amir K. Miri","doi":"10.1016/j.actbio.2025.12.008","DOIUrl":"10.1016/j.actbio.2025.12.008","url":null,"abstract":"<div><div>Solid tumor cells can adopt a range of morphological states linked to distinct functional behaviors during tumor progression. Some remain in a proliferative state, forming tight clusters, others detach and elongate into an invasive state, and some retain a rounded amoeboid form with minimal matrix adhesion. However, factors determining which morphological state a cell adopts remain poorly understood. We used a combined theoretical and experimental framework to study how extracellular matrix (ECM) mechanics regulate solid tumor cell morphology in three-dimensional (3D) environments. We developed a theoretical mechanical energy model based on the minimum energy principle, which suggests that a cell will adopt the morphological state (rounded, elongated, or clustered) that minimizes the total energy of the cell-ECM system. Using MDA-MB-231 breast cancer cells, we established a reliable protocol for encapsulating cells into 3D naturally-derived hydrogels with controlled stiffness. We confirmed the model’s results <em>in vitro</em> over an extended culture period. In soft ECMs, cells transitioned over time to an elongated morphology, while in stiff ECMs, cells favored clustered configurations. These transitions were governed by the hydrogel-based ECM’s physical, not chemical, properties, as confirmed using chemically distinct yet mechanically matched composite matrices. These new insights have implications for solid tumor cell invasion modeling <em>in vitro</em>.</div></div><div><h3>Statement of significance</h3><div>We study the fundamental question of how solid tumor cells adapt their morphology in response to the physical characteristics of the extracellular matrix. This work establishes a robust experimental platform for studying cellular markers in triple-negative breast cancer (TNBC) cells, followed by a biophysical modeling of the cell invasion. Cell clustering was observed in stiffe ECMs, while an elongated morphology was observed in soft ECMs. Our theoretical modeling revealed how the biophysical properties of the matrix can impact cell morphology and invasion behavior. This work can contribute to personalized medicine by making more effective, tailored cancer models.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"210 ","pages":"Pages 17-26"},"PeriodicalIF":9.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696453","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 : 2026-01-01DOI: 10.1016/j.actbio.2025.12.015
Hanne Criel, Charlotte Grootaert, John Van Camp
The liver’s complex microenvironment and spatially zonated functions present major challenges for in vitro modeling, particularly in drug development and disease research. While oxygen and nutrient gradients have been used to create zonation, the potential of the surrounding biomaterial, i.e. the extracellular matrix (ECM), remains relatively underexplored. Recently, native ECM components and/or binding motifs, such as decellularized ECM (dECM) or arginine–glycine–aspartate (RGD) peptides, are increasingly integrated to improve in vitro hepatocyte functionality. However, the biological underpinning of ECM-cell interactions and resulting hepatocyte behavior are often poorly understood, which hampers to exploit the full potential of biomaterial-based strategies for relevant liver tissue modeling. Within this context, the spatial ECM characteristics within the Space of Disse are of critical importance. In this review, we therefore first outline how ECM–receptor interactions influence hepatocyte function and then review how biomaterial composition and mechanics steer zone-specific cell functionality. We propose six practical design principles to guide biomaterial engineering for future applications, including mechanical tuning, affinity-guided selection, zone-specific ligand selection, enhanced ligand diversity, binding site accessibility, and native molecular environment preservation. These strategies will not necessarily increase model complexity, but may support intentional biology-driven biomaterial design beyond conventional scaffold macro-engineering, and enhance the physiological relevance of 3D liver models without sacrificing scalability, simplicity, or reproducibility.
Statement of significance
There is an urgent demand for in vitro liver models that accurately reflect human biology for drug testing, disease modeling, and regenerative medicine. Existing systems rarely capture the liver’s complexity, while animal models face ethical and translational constraints. A crucial but largely neglected feature is liver zonation, the region-specific variation in hepatocyte function. While oxygen and nutrient gradients are known to influence zonation, the role of extracellular matrix (ECM) cues remains underexplored. This review integrates evidence from hepatology, ECM–receptor biology, and biomaterials to propose an evidence-based, zonation-aware design framework. By translating biological principles into actionable material guidelines, it offers researchers the tools to develop next-generation liver models that better predict human outcomes and accelerate progress across the whole field.
{"title":"Extracellular matrix cues as drivers of liver zonation: A framework for in vitro biomaterial design","authors":"Hanne Criel, Charlotte Grootaert, John Van Camp","doi":"10.1016/j.actbio.2025.12.015","DOIUrl":"10.1016/j.actbio.2025.12.015","url":null,"abstract":"<div><div>The liver’s complex microenvironment and spatially zonated functions present major challenges for <em>in vitro</em> modeling, particularly in drug development and disease research. While oxygen and nutrient gradients have been used to create zonation, the potential of the surrounding biomaterial, i.e. the extracellular matrix (ECM), remains relatively underexplored. Recently, native ECM components and/or binding motifs, such as decellularized ECM (dECM) or arginine–glycine–aspartate (RGD) peptides, are increasingly integrated to improve <em>in vitro</em> hepatocyte functionality. However, the biological underpinning of ECM-cell interactions and resulting hepatocyte behavior are often poorly understood, which hampers to exploit the full potential of biomaterial-based strategies for relevant liver tissue modeling. Within this context, the spatial ECM characteristics within the Space of Disse are of critical importance. In this review, we therefore first outline how ECM–receptor interactions influence hepatocyte function and then review how biomaterial composition and mechanics steer zone-specific cell functionality. We propose six practical design principles to guide biomaterial engineering for future applications, including mechanical tuning, affinity-guided selection, zone-specific ligand selection, enhanced ligand diversity, binding site accessibility, and native molecular environment preservation. These strategies will not necessarily increase model complexity, but may support intentional biology-driven biomaterial design beyond conventional scaffold macro-engineering, and enhance the physiological relevance of 3D liver models without sacrificing scalability, simplicity, or reproducibility.</div></div><div><h3>Statement of significance</h3><div>There is an urgent demand for <em>in vitro</em> liver models that accurately reflect human biology for drug testing, disease modeling, and regenerative medicine. Existing systems rarely capture the liver’s complexity, while animal models face ethical and translational constraints. A crucial but largely neglected feature is liver zonation, the region-specific variation in hepatocyte function. While oxygen and nutrient gradients are known to influence zonation, the role of extracellular matrix (ECM) cues remains underexplored. This review integrates evidence from hepatology, ECM–receptor biology, and biomaterials to propose an evidence-based, zonation-aware design framework. By translating biological principles into actionable material guidelines, it offers researchers the tools to develop next-generation liver models that better predict human outcomes and accelerate progress across the whole field.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"210 ","pages":"Pages 192-205"},"PeriodicalIF":9.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145710333","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}
The rising global incidence of cartilage-related diseases, such as osteoarthritis, has intensified interest in regenerative strategies using human mesenchymal stromal cells (hMSCs). Mechanical cues are pivotal for hMSC chondrogenesis, and bioreactor systems, ranging from single-stimulus designs to advanced multiaxial platforms, provide controlled environments to study these effects. hMSC chondrogenic responses under mechanical loading are promising but highly variable, depending on factors such as TGF-β priming, scaffold stiffness, oxygen tension, and timing of stimulation. This review critically examines bioreactor design strategies for hMSC chondrogenesis, outlining technical advantages and limitations. The impact of physiological forces, including hydrostatic pressure, dynamic compression, and combined shear–compression loading, is analyzed alongside differences in study design and their relevance to replicating native cartilage architecture, where chondrons and their pericellular matrix govern load transmission. Comparisons with studies using native cartilage structures are included. The role of in silico models as complementary tools to reduce experimental time is highlighted. Finally, integrated approaches combining bioreactor design, experimental mechanobiology, and computational modeling are proposed to advance functional cartilage regeneration and accelerate clinical translation.
Statement of significance
Classical testing protocols for novel biomaterials intended for cartilage repair and regeneration are typically performed statically, while the articulating joint is subject to complex load. Within this review we highlight the role of mechanics, a key biological driver, in chondrogenesis to provide an informative background to inform future biomaterials testing.
{"title":"The impact of mechanical bioreactors on human mesenchymal stromal cells utilized for articular cartilage repair","authors":"L. Mecchi , M.M.J. Caron , T.J.M. Welting , M.J. Stoddart","doi":"10.1016/j.actbio.2025.12.029","DOIUrl":"10.1016/j.actbio.2025.12.029","url":null,"abstract":"<div><div>The rising global incidence of cartilage-related diseases, such as osteoarthritis, has intensified interest in regenerative strategies using human mesenchymal stromal cells (hMSCs). Mechanical cues are pivotal for hMSC chondrogenesis, and bioreactor systems, ranging from single-stimulus designs to advanced multiaxial platforms, provide controlled environments to study these effects. hMSC chondrogenic responses under mechanical loading are promising but highly variable, depending on factors such as TGF-β priming, scaffold stiffness, oxygen tension, and timing of stimulation. This review critically examines bioreactor design strategies for hMSC chondrogenesis, outlining technical advantages and limitations. The impact of physiological forces, including hydrostatic pressure, dynamic compression, and combined shear–compression loading, is analyzed alongside differences in study design and their relevance to replicating native cartilage architecture, where chondrons and their pericellular matrix govern load transmission. Comparisons with studies using native cartilage structures are included. The role of in silico models as complementary tools to reduce experimental time is highlighted. Finally, integrated approaches combining bioreactor design, experimental mechanobiology, and computational modeling are proposed to advance functional cartilage regeneration and accelerate clinical translation.</div></div><div><h3>Statement of significance</h3><div>Classical testing protocols for novel biomaterials intended for cartilage repair and regeneration are typically performed statically, while the articulating joint is subject to complex load. Within this review we highlight the role of mechanics, a key biological driver, in chondrogenesis to provide an informative background to inform future biomaterials testing.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"210 ","pages":"Pages 40-56"},"PeriodicalIF":9.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145783870","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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