Diabetic ulcers are one of the common complications in diabetic patients. Delayed wound healing is associated with persistent pro-inflammatory M1 polarization, reduced angiogenesis and increased reactive oxygen species (ROS) in the microenvironment. Wound healing consists of multiple phases and therefore requires treatment tailored to each phase. In this study, a biphasic drug-releasing microneedle (MN) was fabricated to achieve early ROS scavenging and late accelerated angiogenesis to promote wound healing. Vascular endothelial growth factor (VEGF) was first encapsulated in methacryloylated sulfonated chitosan (SCSMA) microspheres (V@MP), and then V@MP was loaded into hyaluronic acid (HA) microneedles along with cerium dioxide nanoparticles (CONPs). Rapid dissolution of HA rapidly releases the CONPs to clear ROS, whereas the V@MP stays in the wound. SCSMA slow degradation prolongs the release of VEGF, thereby promoting angiogenesis. In vitro and in vivo studies have shown that this biphasic drug-releasing smart microneedle improves cell proliferation and migration, effectively scavenges ROS, promotes angiogenesis and tissue regeneration, and synergistically promotes M2 macrophage polarization. It provides a new delivery mode for nano-enzymes and growth factors that could be multifunctional and synergistic in the treatment of diabetic ulcers. STATEMENT OF SIGNIFICANCE: In our study, we present a microneedle (V@MP/C@MN) that can release drugs biphasically, which showed good repair ability in diabetic ulcer model. Large amounts of CONPs were rapidly released to alleviate oxidative stress during the inflammation of the wound, and V@MP stayed in the wound for a long period of time to release VEGF and promote angiogenesis in the late stage of wound healing. The results indicated that V@MP/C@MN could promote cell proliferation and migration, effectively scavenge ROS, promote angiogenesis and tissue regeneration, and synergistically promote M2 macrophage polarization, which could play a multifunctional and synergistic role in the treatment of diabetic ulcers.
{"title":"A biphasic drug-releasing microneedle with ROS scavenging and angiogenesis for the treatment of diabetic ulcers.","authors":"Xinyue He, Lianghong Peng, Liming Zhou, Huiling Liu, Yifan Hao, Yuhan Li, Zijin Lv, Baohui Zeng, Xinmin Guo, Rui Guo","doi":"10.1016/j.actbio.2024.09.045","DOIUrl":"https://doi.org/10.1016/j.actbio.2024.09.045","url":null,"abstract":"<p><p>Diabetic ulcers are one of the common complications in diabetic patients. Delayed wound healing is associated with persistent pro-inflammatory M1 polarization, reduced angiogenesis and increased reactive oxygen species (ROS) in the microenvironment. Wound healing consists of multiple phases and therefore requires treatment tailored to each phase. In this study, a biphasic drug-releasing microneedle (MN) was fabricated to achieve early ROS scavenging and late accelerated angiogenesis to promote wound healing. Vascular endothelial growth factor (VEGF) was first encapsulated in methacryloylated sulfonated chitosan (SCSMA) microspheres (V@MP), and then V@MP was loaded into hyaluronic acid (HA) microneedles along with cerium dioxide nanoparticles (CONPs). Rapid dissolution of HA rapidly releases the CONPs to clear ROS, whereas the V@MP stays in the wound. SCSMA slow degradation prolongs the release of VEGF, thereby promoting angiogenesis. In vitro and in vivo studies have shown that this biphasic drug-releasing smart microneedle improves cell proliferation and migration, effectively scavenges ROS, promotes angiogenesis and tissue regeneration, and synergistically promotes M2 macrophage polarization. It provides a new delivery mode for nano-enzymes and growth factors that could be multifunctional and synergistic in the treatment of diabetic ulcers. STATEMENT OF SIGNIFICANCE: In our study, we present a microneedle (V@MP/C@MN) that can release drugs biphasically, which showed good repair ability in diabetic ulcer model. Large amounts of CONPs were rapidly released to alleviate oxidative stress during the inflammation of the wound, and V@MP stayed in the wound for a long period of time to release VEGF and promote angiogenesis in the late stage of wound healing. The results indicated that V@MP/C@MN could promote cell proliferation and migration, effectively scavenge ROS, promote angiogenesis and tissue regeneration, and synergistically promote M2 macrophage polarization, which could play a multifunctional and synergistic role in the treatment of diabetic ulcers.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.actbio.2024.09.049
Mohammad Mehri, Hossein Sharifi, Charles K Mann, Alexus L Rockward, Kenneth S Campbell, Lik Chuan Lee, Jonathan F Wenk
The organization of myofibers and extra cellular matrix within the myocardium plays a significant role in defining cardiac function. When pathological events occur, such as myocardial infarction (MI), this organization can become disrupted, leading to degraded pumping performance. The current study proposes a multiscale finite element (FE) framework to determine realistic fiber distributions in the left ventricle (LV). This is achieved by implementing a stress-based fiber reorientation law, which seeks to align the fibers with local traction vectors, such that contractile force and load bearing capabilities are maximized. By utilizing the total stress (passive and active), both myofibers and collagen fibers are reoriented. Simulations are conducted to predict the baseline fiber configuration in a normal LV as well as the adverse fiber reorientation that occurs due to different size MIs. The baseline model successfully captures the transmural variation of helical fiber angles within the LV wall, as well as the transverse fiber angle variation from base to apex. In the models of MI, the patterns of fiber reorientation in the infarct, border zone, and remote regions closely align with previous experimental findings, with a significant increase in fibers oriented in a left-handed helical configuration and increased dispersion in the infarct region. Furthermore, the severity of fiber reorientation and impairment of pumping performance both showed a correlation with the size of the infarct. The proposed multiscale modeling framework allows for the effective prediction of adverse remodeling and offers the potential for assessing the effectiveness of therapeutic interventions in the future. STATEMENT OF SIGNIFICANCE: The organization of muscle and collagen fibers within the heart plays a significant role in defining cardiac function. This organization can become disrupted after a heart attack, leading to degraded pumping performance. In the current study, we implemented a stress-based fiber reorientation law into a computer model of the heart, which seeks to realign the fibers such that contractile force and load bearing capabilities are maximized. The primary goal was to evaluate the effects of different sized heart attacks. We observed substantial fiber remodeling in the heart, which matched experimental observations. The proposed computational framework allows for the effective prediction of adverse remodeling and offers the potential for assessing the effectiveness of therapeutic interventions in the future.
{"title":"Multiscale Fiber Remodeling in the Infarcted Left Ventricle using a Stress-Based Reorientation Law.","authors":"Mohammad Mehri, Hossein Sharifi, Charles K Mann, Alexus L Rockward, Kenneth S Campbell, Lik Chuan Lee, Jonathan F Wenk","doi":"10.1016/j.actbio.2024.09.049","DOIUrl":"10.1016/j.actbio.2024.09.049","url":null,"abstract":"<p><p>The organization of myofibers and extra cellular matrix within the myocardium plays a significant role in defining cardiac function. When pathological events occur, such as myocardial infarction (MI), this organization can become disrupted, leading to degraded pumping performance. The current study proposes a multiscale finite element (FE) framework to determine realistic fiber distributions in the left ventricle (LV). This is achieved by implementing a stress-based fiber reorientation law, which seeks to align the fibers with local traction vectors, such that contractile force and load bearing capabilities are maximized. By utilizing the total stress (passive and active), both myofibers and collagen fibers are reoriented. Simulations are conducted to predict the baseline fiber configuration in a normal LV as well as the adverse fiber reorientation that occurs due to different size MIs. The baseline model successfully captures the transmural variation of helical fiber angles within the LV wall, as well as the transverse fiber angle variation from base to apex. In the models of MI, the patterns of fiber reorientation in the infarct, border zone, and remote regions closely align with previous experimental findings, with a significant increase in fibers oriented in a left-handed helical configuration and increased dispersion in the infarct region. Furthermore, the severity of fiber reorientation and impairment of pumping performance both showed a correlation with the size of the infarct. The proposed multiscale modeling framework allows for the effective prediction of adverse remodeling and offers the potential for assessing the effectiveness of therapeutic interventions in the future. STATEMENT OF SIGNIFICANCE: The organization of muscle and collagen fibers within the heart plays a significant role in defining cardiac function. This organization can become disrupted after a heart attack, leading to degraded pumping performance. In the current study, we implemented a stress-based fiber reorientation law into a computer model of the heart, which seeks to realign the fibers such that contractile force and load bearing capabilities are maximized. The primary goal was to evaluate the effects of different sized heart attacks. We observed substantial fiber remodeling in the heart, which matched experimental observations. The proposed computational framework allows for the effective prediction of adverse remodeling and offers the potential for assessing the effectiveness of therapeutic interventions in the future.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.actbio.2024.09.043
Giuseppe Sciume, Karine Guevorkian, Pierre Nassoy
The micro-pipette aspiration technique is a classical experiment used to characterize the physical properties of inert fluids and biological soft materials such as cellular aggregates. The physical parameters of the fluid, as viscosity and interfacial tension, are obtained by studying how the fluid enters the pipette when the suction pressure is increased and how it relaxes when the suction pressure is put to zero. A mathematical model representative of the experiment is needed to extrapolate the physical parameters of the fluid-like matter; however, for biological materials as cells or cell aggregates these models are always based on strong starting hypotheses that impact the significance of the identified parameters. In this article, starting from the bi-constituent nature of the cell aggregate, we derive a general mathematical model based of a Cahn-Hilliard-Navier-Stokes set of equations. The model is applied to describe quantitatively the aspiration-retraction dynamics of a cell-aggregate into and out of a pipette. We demonstrate the predictive capability of the model and highlight the impact of the assumptions made on the identified parameters by studying two cases: one with a non-wetting condition between the cells and the wall of the pipette (classical assumption in the literature) and the second one, which is more realistic, with a partial wetting condition (contact angle θs = 150°). Furthermore, our results provide a purely physical explanation to the asymmetry between the aspiration and retraction responses which is alternative to the proposed hypothesis of an mechano-responsive alteration of the surface tension of the cell aggregate. STATEMENT OF SIGNIFICANCE: Our study introduces a general mathematical model, based on the Cahn-Hilliard-Navier-Stokes equations, tailored to model micro-pipette aspiration of cell aggregates. The model accounts for the multi-component structure of the cell aggregate and its intrinsic viscoelastic rheology. By challenging prevailing assumptions, particularly regarding perfect non-wetting conditions and the mechano-responsive alteration of cell surface tension, we demonstrate the reliability of the mathematical model and elucidate the mechanisms at play, offering a purely physical explanation for observed asymmetries between the aspiration and retraction stages of the experiment.
{"title":"A bi-component model to assess the rheology of soft cellular aggregates probed using the micropipette aspiration technique.","authors":"Giuseppe Sciume, Karine Guevorkian, Pierre Nassoy","doi":"10.1016/j.actbio.2024.09.043","DOIUrl":"https://doi.org/10.1016/j.actbio.2024.09.043","url":null,"abstract":"<p><p>The micro-pipette aspiration technique is a classical experiment used to characterize the physical properties of inert fluids and biological soft materials such as cellular aggregates. The physical parameters of the fluid, as viscosity and interfacial tension, are obtained by studying how the fluid enters the pipette when the suction pressure is increased and how it relaxes when the suction pressure is put to zero. A mathematical model representative of the experiment is needed to extrapolate the physical parameters of the fluid-like matter; however, for biological materials as cells or cell aggregates these models are always based on strong starting hypotheses that impact the significance of the identified parameters. In this article, starting from the bi-constituent nature of the cell aggregate, we derive a general mathematical model based of a Cahn-Hilliard-Navier-Stokes set of equations. The model is applied to describe quantitatively the aspiration-retraction dynamics of a cell-aggregate into and out of a pipette. We demonstrate the predictive capability of the model and highlight the impact of the assumptions made on the identified parameters by studying two cases: one with a non-wetting condition between the cells and the wall of the pipette (classical assumption in the literature) and the second one, which is more realistic, with a partial wetting condition (contact angle θ<sub>s</sub> = 150°). Furthermore, our results provide a purely physical explanation to the asymmetry between the aspiration and retraction responses which is alternative to the proposed hypothesis of an mechano-responsive alteration of the surface tension of the cell aggregate. STATEMENT OF SIGNIFICANCE: Our study introduces a general mathematical model, based on the Cahn-Hilliard-Navier-Stokes equations, tailored to model micro-pipette aspiration of cell aggregates. The model accounts for the multi-component structure of the cell aggregate and its intrinsic viscoelastic rheology. By challenging prevailing assumptions, particularly regarding perfect non-wetting conditions and the mechano-responsive alteration of cell surface tension, we demonstrate the reliability of the mathematical model and elucidate the mechanisms at play, offering a purely physical explanation for observed asymmetries between the aspiration and retraction stages of the experiment.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.actbio.2024.09.038
Yan Ju, Shiyuan Ma, Meimei Fu, Min Wu, Yue Li, Yue Wang, Meihan Tao, Zhihui Lu, Jinshan Guo
Discectomy is the surgical standard of care to relieve low back pain caused by intervertebral disc (IVD) herniation. However, there remains annulus fibrosus (AF) defect and nucleus pulposus (NP) degeneration, which often result in recurrent herniation (re-herniation). Herein, we develop a polyphenol-modified waterborne polyurethane bioadhesives (PPU-glues) to promote therapy prognosis after discectomy. Being composed of tannic acid (TA) mixed cationic waterborne polyurethane nanodispersions (TA/WPU+) and curcumin (Cur) embedded anionic waterborne polyurethane nanodispersions (Cur-WPU-), PPU-glue gels rapidly (<10 s) and exhibits low swelling ratios, tunable degradation rates and good biocompatibility. Due to the application of an adhesion strategy combing English ivy mechanism and particle packing theory, PPU-glue also shows considerable lap shear strength against wet porcine skin (≈58 kPa) and burst pressure (≈26 kPa). The mismatched particle sizes and the opposite charges of TA/WPU+ and Cur-WPU- in PPU-glue bring electrostatic interaction and enhance particle packing density. PPU-glue possesses superior reactive oxygen species (ROS)-scavenging capacity derived from polyphenols. PPU-glue can regulate extracellular matrix (ECM) metabolism in degenerated NP cells, and it can promote therapy biologically and mechanically in degenerated rat caudal discs. In summary, this study highlights the therapeutic approach that combines AF seal and NP augmentation, and PPU-glue holds great application potentials for post discectomy therapy. STATEMENT OF SIGNIFICANCE: Currently, there is no established method for the therapy of annulus fibrosus (AF) defect and nucleus pulposus (NP) degeneration after discectomy. Herein, we developed a polyphenol-modified biomimetic polyurethane bioadhesives (PPU-glue) with strong adhesive strength and superior bioactive property. The adhesion strategy that combined a particle packing theory and an English ivy mechanism was firstly applied to the intervertebral disc repair field, which benefited AF seal. The modified method of incorporating polyphenols was utilized to confer with ROS-scavenging capacity, ECM metabolism regulation ability and anti-inflammatory property, which promoted NP augmentation. Thus, PPU-glue attained the synergy effect for post discectomy therapy, and the design principle could be universally expanded to the bioadhesives for other surgical uses.
椎间盘切除术是缓解椎间盘(IVD)突出引起的腰痛的外科标准疗法。然而,椎间盘纤维环(AF)缺损和髓核(NP)变性仍然存在,这往往会导致椎间盘突出症复发(再疝)。在此,我们开发了一种多酚改性水性聚氨酯生物粘合剂(PPU-胶),以促进椎间盘切除术后的治疗预后。PPU 胶水由单宁酸(TA)混合阳离子水性聚氨酯纳米分散体(TA/WPU+)和姜黄素(Cur)嵌入阴离子水性聚氨酯纳米分散体(Cur-WPU-)组成,能迅速凝胶(PPU-胶水中的+和Cur-WPU-会产生静电作用并提高粒子的堆积密度)。PPU 胶具有源自多酚的卓越的活性氧(ROS)清除能力。PPU-胶能调节变性NP细胞中细胞外基质(ECM)的新陈代谢,并能从生物学和机械学角度促进变性大鼠椎间盘的治疗。总之,本研究强调了将 AF 封闭和 NP 增强相结合的治疗方法,PPU 胶在椎间盘切除术后治疗中具有巨大的应用潜力。意义说明:目前,还没有成熟的方法来治疗椎间盘切除术后纤维环(AF)缺损和髓核(NP)变性。在此,我们开发了一种多酚改性仿生物聚氨酯生物粘合剂(PPU-胶),它具有很强的粘合强度和优异的生物活性。这种结合了颗粒填料理论和英国常春藤机制的粘附策略首先被应用于椎间盘修复领域,使 AF 密封性受益匪浅。改良后的多酚类物质加入方法赋予了 PPU 胶清除 ROS 的能力、调节 ECM 代谢的能力和抗炎特性,从而促进了 NP 的增强。因此,PPU-胶水在椎间盘切除术后治疗中取得了协同效应,其设计原理可普遍推广到其他外科用途的生物粘合剂中。
{"title":"Polyphenol-modified biomimetic bioadhesives for the therapy of annulus fibrosus defect and nucleus pulposus degeneration after discectomy.","authors":"Yan Ju, Shiyuan Ma, Meimei Fu, Min Wu, Yue Li, Yue Wang, Meihan Tao, Zhihui Lu, Jinshan Guo","doi":"10.1016/j.actbio.2024.09.038","DOIUrl":"https://doi.org/10.1016/j.actbio.2024.09.038","url":null,"abstract":"<p><p>Discectomy is the surgical standard of care to relieve low back pain caused by intervertebral disc (IVD) herniation. However, there remains annulus fibrosus (AF) defect and nucleus pulposus (NP) degeneration, which often result in recurrent herniation (re-herniation). Herein, we develop a polyphenol-modified waterborne polyurethane bioadhesives (PPU-glues) to promote therapy prognosis after discectomy. Being composed of tannic acid (TA) mixed cationic waterborne polyurethane nanodispersions (TA/WPU<sup>+</sup>) and curcumin (Cur) embedded anionic waterborne polyurethane nanodispersions (Cur-WPU<sup>-</sup>), PPU-glue gels rapidly (<10 s) and exhibits low swelling ratios, tunable degradation rates and good biocompatibility. Due to the application of an adhesion strategy combing English ivy mechanism and particle packing theory, PPU-glue also shows considerable lap shear strength against wet porcine skin (≈58 kPa) and burst pressure (≈26 kPa). The mismatched particle sizes and the opposite charges of TA/WPU<sup>+</sup> and Cur-WPU<sup>-</sup> in PPU-glue bring electrostatic interaction and enhance particle packing density. PPU-glue possesses superior reactive oxygen species (ROS)-scavenging capacity derived from polyphenols. PPU-glue can regulate extracellular matrix (ECM) metabolism in degenerated NP cells, and it can promote therapy biologically and mechanically in degenerated rat caudal discs. In summary, this study highlights the therapeutic approach that combines AF seal and NP augmentation, and PPU-glue holds great application potentials for post discectomy therapy. STATEMENT OF SIGNIFICANCE: Currently, there is no established method for the therapy of annulus fibrosus (AF) defect and nucleus pulposus (NP) degeneration after discectomy. Herein, we developed a polyphenol-modified biomimetic polyurethane bioadhesives (PPU-glue) with strong adhesive strength and superior bioactive property. The adhesion strategy that combined a particle packing theory and an English ivy mechanism was firstly applied to the intervertebral disc repair field, which benefited AF seal. The modified method of incorporating polyphenols was utilized to confer with ROS-scavenging capacity, ECM metabolism regulation ability and anti-inflammatory property, which promoted NP augmentation. Thus, PPU-glue attained the synergy effect for post discectomy therapy, and the design principle could be universally expanded to the bioadhesives for other surgical uses.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.actbio.2024.09.040
Katrina Knight, Sophya Breedlove, Temitope Obisesan, Morgan Egnot, Niusha Daneshdoost, Gabrielle King G, Leslie Meyn, Ken Gall, Pamela Moalli
Complications following surgical repair of pelvic organ prolapse (POP) with polypropylene mesh (PPM) are common. Recent data attributes complications, in part, to stiffness mismatches between the vagina and PPM. We developed a 3D printed elastomeric membrane (EM) from a softer polymer, polycarbonate urethane (PCU). EMs were manufactured with more material given the low inherent material strength of PCU. We hypothesized that the EMs would be associated with an improved host response as compared to PPM. A secondary goal was to optimize the material distribution (fiber width and device thickness) within EMs, in regards to the host response. EM constructs (2×1cm2) with varied polymer stiffness, fiber width, and device thickness were implanted onto the vagina of New Zealand white rabbits for 12 weeks and compared to similarly sized PPMs. Sham implanted animals served as controls. Mixed effects generalized linear models were used to compare the effect of construct type accounting for differences in independent variables. EMs had an overall superior host response compared to PPM as evidenced by preservation of vaginal smooth muscle morphology (p-values<0.01), decreased total cellular response to construct fibers (p-values<0.001), and a reduced percent of macrophages (p-values<0.02) independent of how the material was distributed. Both PP and EMs negatively impacted vaginal contractility and glycosaminoglycan (GAG) content relative to Sham (all p-values<0.001) with EMs having less of an impact on GAGs (p-values<0.003). The results suggest that softer PCU EMs made with more material are well tolerated by the vagina and comprises a future material for POP repair devices. STATEMENT OF SIGNIFICANCE: Prolapse is a debilitating condition in which loss of support to the vagina causes it and the organs supported by it to descend from their normal position in the pelvis. Surgical solutions to rebuild support involves the use of polypropylene mesh which is orders of magnitude stiffer than the vagina. This mismatch results in complications including exposure of the mesh into the vagina and pain. To provide an innovative solution for women, we have developed an elastomeric membrane from a soft polymer that matches the stiffness of the vagina. Here, we show in a rabbit animal model that this device incorporates better into the vagina and is associated with an overall improved host response as compared to polypropylene mesh.
使用聚丙烯网片(PPM)进行盆腔器官脱垂(POP)手术修复后,并发症很常见。最新数据显示,并发症的部分原因是阴道和聚丙烯网片之间的硬度不匹配。我们用一种较软的聚合物聚碳酸酯聚氨酯(PCU)开发了一种三维打印弹性膜(EM)。由于 PCU 的固有材料强度较低,我们在制造 EM 时使用了更多的材料。我们假设,与 PPM 相比,EM 会改善宿主反应。我们的第二个目标是优化 EM 内的材料分布(纤维宽度和器件厚度),以改善宿主反应。将具有不同聚合物硬度、纤维宽度和装置厚度的 EM 构造(2×1cm2)植入新西兰白兔的阴道 12 周,并与类似大小的 PPM 进行比较。假体植入动物作为对照组。混合效应广义线性模型用于比较结构类型对自变量差异的影响。与 PPM 相比,EMs 在总体上具有更优越的宿主反应,这体现在阴道平滑肌形态的保留上(p 值
{"title":"Vaginal host response to polycarbonate urethane, an alternative material for the repair of pelvic organ prolapse.","authors":"Katrina Knight, Sophya Breedlove, Temitope Obisesan, Morgan Egnot, Niusha Daneshdoost, Gabrielle King G, Leslie Meyn, Ken Gall, Pamela Moalli","doi":"10.1016/j.actbio.2024.09.040","DOIUrl":"https://doi.org/10.1016/j.actbio.2024.09.040","url":null,"abstract":"<p><p>Complications following surgical repair of pelvic organ prolapse (POP) with polypropylene mesh (PPM) are common. Recent data attributes complications, in part, to stiffness mismatches between the vagina and PPM. We developed a 3D printed elastomeric membrane (EM) from a softer polymer, polycarbonate urethane (PCU). EMs were manufactured with more material given the low inherent material strength of PCU. We hypothesized that the EMs would be associated with an improved host response as compared to PPM. A secondary goal was to optimize the material distribution (fiber width and device thickness) within EMs, in regards to the host response. EM constructs (2×1cm<sup>2</sup>) with varied polymer stiffness, fiber width, and device thickness were implanted onto the vagina of New Zealand white rabbits for 12 weeks and compared to similarly sized PPMs. Sham implanted animals served as controls. Mixed effects generalized linear models were used to compare the effect of construct type accounting for differences in independent variables. EMs had an overall superior host response compared to PPM as evidenced by preservation of vaginal smooth muscle morphology (p-values<0.01), decreased total cellular response to construct fibers (p-values<0.001), and a reduced percent of macrophages (p-values<0.02) independent of how the material was distributed. Both PP and EMs negatively impacted vaginal contractility and glycosaminoglycan (GAG) content relative to Sham (all p-values<0.001) with EMs having less of an impact on GAGs (p-values<0.003). The results suggest that softer PCU EMs made with more material are well tolerated by the vagina and comprises a future material for POP repair devices. STATEMENT OF SIGNIFICANCE: Prolapse is a debilitating condition in which loss of support to the vagina causes it and the organs supported by it to descend from their normal position in the pelvis. Surgical solutions to rebuild support involves the use of polypropylene mesh which is orders of magnitude stiffer than the vagina. This mismatch results in complications including exposure of the mesh into the vagina and pain. To provide an innovative solution for women, we have developed an elastomeric membrane from a soft polymer that matches the stiffness of the vagina. Here, we show in a rabbit animal model that this device incorporates better into the vagina and is associated with an overall improved host response as compared to polypropylene mesh.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1016/j.actbio.2024.09.042
Francesco Piazza, Beatrice Ravaglia, Andrea Caporale, Ana Svetić, Pietro Parisse, Fioretta Asaro, Gabriele Grassi, Luca Secco, Riccardo Sgarra, Eleonora Marsich, Ivan Donati, Pasquale Sacco
2D agarose substrates have recently been surprisingly shown to be permissive for cell adhesion, depending on their mechanics and the use of the adhesive proteins of fetal bovine serum (FBS) in the cell culture medium. Here, we elucidate how the cells exhibit two anchoring mechanisms depending on the amount of FBS. Under low FBS conditions, the cells recognize the surface-coupled adhesive sequences of fibronectin via the binding of the heterodimer α5β1 integrin. Functionality of the actomyosin axis and mechanoactivation of focal adhesion kinase (FAK) are essential for the stretching of the protein, thereby accessing the "synergy" PPSRN site and enhancing cell adhesion in combination with the downstream RGD motif. Under high FBS conditions, the specific peptide sequences are much less relevant as the adsorbed serum proteins conceal the coupled fibronectin and the cells recognize the adhesive protein vitronectin, which is constitutively present in FBS, via the binding of the heterodimer αvβ3 integrin. Similarly, the intracellular tension and FAK activity are decisive, which collectively indicate that the cells stretch the partially cryptic RGD site of vitronectin and thus make it more accessible for integrin binding. Both anchoring mechanisms only work properly if the agarose substrate is mechanically compliant in terms of linear stress-strain response, unraveling a critical balance between the mechanics of the agarose substrate and the presentation of the adhesive peptides. STATEMENT OF SIGNIFICANCE: In the context of biomaterial design, agarose hydrogels are known to lack intrinsic cell-adhesive peptide motifs and are therefore commonly used for the development of non-permissive 2D substrates. However, we unexpectedly found that agarose hydrogels can become permissive substrates for cell adhesion, depending on a compliant mechanical response of the substrate and the use of fetal bovine serum (FBS) as protein reservoir in the cell culture medium. We describe here two anchoring mechanisms that cells harness to adhere to agarose substrates, depending on the amount of FBS. Our results will have a major impact on the field of mechanobiology and shed light on the central role of FBS as a natural source of adhesive proteins that could promote cell anchoring.
{"title":"Elucidating the unexpected cell adhesive properties of agarose substrates. The effect of mechanics, fetal bovine serum and specific peptide sequences.","authors":"Francesco Piazza, Beatrice Ravaglia, Andrea Caporale, Ana Svetić, Pietro Parisse, Fioretta Asaro, Gabriele Grassi, Luca Secco, Riccardo Sgarra, Eleonora Marsich, Ivan Donati, Pasquale Sacco","doi":"10.1016/j.actbio.2024.09.042","DOIUrl":"https://doi.org/10.1016/j.actbio.2024.09.042","url":null,"abstract":"<p><p>2D agarose substrates have recently been surprisingly shown to be permissive for cell adhesion, depending on their mechanics and the use of the adhesive proteins of fetal bovine serum (FBS) in the cell culture medium. Here, we elucidate how the cells exhibit two anchoring mechanisms depending on the amount of FBS. Under low FBS conditions, the cells recognize the surface-coupled adhesive sequences of fibronectin via the binding of the heterodimer α<sub>5</sub>β<sub>1</sub> integrin. Functionality of the actomyosin axis and mechanoactivation of focal adhesion kinase (FAK) are essential for the stretching of the protein, thereby accessing the \"synergy\" PPSRN site and enhancing cell adhesion in combination with the downstream RGD motif. Under high FBS conditions, the specific peptide sequences are much less relevant as the adsorbed serum proteins conceal the coupled fibronectin and the cells recognize the adhesive protein vitronectin, which is constitutively present in FBS, via the binding of the heterodimer α<sub>v</sub>β<sub>3</sub> integrin. Similarly, the intracellular tension and FAK activity are decisive, which collectively indicate that the cells stretch the partially cryptic RGD site of vitronectin and thus make it more accessible for integrin binding. Both anchoring mechanisms only work properly if the agarose substrate is mechanically compliant in terms of linear stress-strain response, unraveling a critical balance between the mechanics of the agarose substrate and the presentation of the adhesive peptides. STATEMENT OF SIGNIFICANCE: In the context of biomaterial design, agarose hydrogels are known to lack intrinsic cell-adhesive peptide motifs and are therefore commonly used for the development of non-permissive 2D substrates. However, we unexpectedly found that agarose hydrogels can become permissive substrates for cell adhesion, depending on a compliant mechanical response of the substrate and the use of fetal bovine serum (FBS) as protein reservoir in the cell culture medium. We describe here two anchoring mechanisms that cells harness to adhere to agarose substrates, depending on the amount of FBS. Our results will have a major impact on the field of mechanobiology and shed light on the central role of FBS as a natural source of adhesive proteins that could promote cell anchoring.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-28DOI: 10.1016/j.actbio.2024.09.041
Dawn Raja Somu, Malena Fuentes, Lihua Lou, Arvind Agarwal, Marianne Porter, Vivian Merk
Shark cartilage presents a complex material composed of collagen, proteoglycans, and bioapatite. In the present study, we explored the link between microstructure, chemical composition, and biomechanical function of shark vertebral cartilage using Polarized Light Microscopy (PLM), Atomic Force Microscopy (AFM), Confocal Raman Microspectroscopy, and Nanoindentation. Our investigation focused on vertebrae from Blacktip and Shortfin Mako sharks. As typical representatives of the orders Carcharhiniformes and Lamniformes, these species differ in preferred habitat, ecological role, and swimming style. We observed structural variations in mineral organization and collagen fiber arrangement using PLM and AFM. In both sharks, the highly calcified corpus calcarea shows a ridged morphology, while a chain-like network is present in the less mineralized intermedialia. Raman spectromicroscopy demonstrates a relative increase of glucosaminocycans (GAGs) with respect to collagen and a decrease in mineral-rich zones, underlining the role of GAGs in modulating bioapatite mineralization. Region-specific testing confirmed that intravertebral variations in mineral content and arrangement result in distinct nanomechanical properties. Local Young's moduli from mineralized regions exceeded bulk values by a factor of 10. Overall, this work provides profound insights into a flexible yet strong biocomposite, which is crucial for the extraordinary speed of cartilaginous fish in the worlds' oceans. STATEMENT OF SIGNIFICANCE: Shark cartilage is a morphologically complex material composed of collagen, sulfated proteoglycans, and calcium phosphate minerals. This study explores the link between microstructure, chemical composition, and biological mechanical function of shark vertebral cartilage at the micro- and nanometer scale in typical Carcharhiniform and Lamniform shark species, which represent different vertebral mineralization morphologies, swimming styles and speeds. By studying the intricacies of shark vertebrae, we hope to lay the foundation for biomimetic composite materials that harness lamellar reinforcement and tailored stiffness gradients, capable of dynamic and localized adjustments during movement.
{"title":"Revealing chemistry-structure-function relationships in shark vertebrae across length scales.","authors":"Dawn Raja Somu, Malena Fuentes, Lihua Lou, Arvind Agarwal, Marianne Porter, Vivian Merk","doi":"10.1016/j.actbio.2024.09.041","DOIUrl":"https://doi.org/10.1016/j.actbio.2024.09.041","url":null,"abstract":"<p><p>Shark cartilage presents a complex material composed of collagen, proteoglycans, and bioapatite. In the present study, we explored the link between microstructure, chemical composition, and biomechanical function of shark vertebral cartilage using Polarized Light Microscopy (PLM), Atomic Force Microscopy (AFM), Confocal Raman Microspectroscopy, and Nanoindentation. Our investigation focused on vertebrae from Blacktip and Shortfin Mako sharks. As typical representatives of the orders Carcharhiniformes and Lamniformes, these species differ in preferred habitat, ecological role, and swimming style. We observed structural variations in mineral organization and collagen fiber arrangement using PLM and AFM. In both sharks, the highly calcified corpus calcarea shows a ridged morphology, while a chain-like network is present in the less mineralized intermedialia. Raman spectromicroscopy demonstrates a relative increase of glucosaminocycans (GAGs) with respect to collagen and a decrease in mineral-rich zones, underlining the role of GAGs in modulating bioapatite mineralization. Region-specific testing confirmed that intravertebral variations in mineral content and arrangement result in distinct nanomechanical properties. Local Young's moduli from mineralized regions exceeded bulk values by a factor of 10. Overall, this work provides profound insights into a flexible yet strong biocomposite, which is crucial for the extraordinary speed of cartilaginous fish in the worlds' oceans. STATEMENT OF SIGNIFICANCE: Shark cartilage is a morphologically complex material composed of collagen, sulfated proteoglycans, and calcium phosphate minerals. This study explores the link between microstructure, chemical composition, and biological mechanical function of shark vertebral cartilage at the micro- and nanometer scale in typical Carcharhiniform and Lamniform shark species, which represent different vertebral mineralization morphologies, swimming styles and speeds. By studying the intricacies of shark vertebrae, we hope to lay the foundation for biomimetic composite materials that harness lamellar reinforcement and tailored stiffness gradients, capable of dynamic and localized adjustments during movement.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-27DOI: 10.1016/j.actbio.2024.09.036
Changling Du, David Anthony Fikhman, Ernest Emmanuel Obeng, Sevde Nur Can, Katheryn Shi Dong, Eden Tess Leavitt, Leo Vikram Saldanha, Michaela Hall, Joshua Satalin, Michaela Kollisch-Singule, Mary Beth B Monroe
Uncontrolled bleeding is the primary cause of trauma-related death. For patients that are brought to the hospital in time to receive treatment, there is a great risk of contracting drug-resistant bacterial wound infections. Therefore, low-cost hemostatic agents with procoagulant and antibacterial properties are essential to reduce morbidity and mortality in patients with traumatic wounds. To that end, we introduced vanillic acid (VA) into shape memory polymer (SMP) foams through a dual incorporation mechanism to make dual vanillic acid (DVA) foams. The dual mechanism increases VA loading while allowing burst and sustained delivery of VA from foams. DVA foams exhibit antimicrobial and antibiofilm properties against native and drug-resistant Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis. Also, DVA foams inhibit the growth rate of both methicillin-sensitive and -resistant S. aureus colonies to limit their size and promote small colony variants. DVA SMP foams induce primary and secondary hemostasis in in vitro blood interaction studies. As a proof of concept, we demonstrated easy delivery and rapid clotting in a porcine liver injury model, indicating DVA foam feasibility for use as a hemostatic dressing. Thus, the inexpensive production of DVA SMP foams could enable a cost-effective procoagulant hemostatic dressing that is resistant to bacterial colonization to improve short- and long-term outcomes for hemorrhage control in traumatically injured patients. STATEMENT OF SIGNIFICANCE: Uncontrolled bleeding is the primary cause of preventable death on the battlefield. Of patients that survive, ∼40% develop polymicrobial infections within 5 days of injury. Drug-resistant infections are anticipated to cause more deaths than all cancers combined by 2050. Therefore, novel non-drug-based biomaterials strategies for infection control in wound care are increasingly important. To that end, we developed hemostatic polyurethane foams that include antimicrobial and pro-coagulant vanillic acid, a plant-based antimicrobial species. These foams provide excellent protection against native and drug-resistant bacteria and enhanced coagulation while remaining cytocompatible. In a pilot porcine liver injury model, vanillic acid-containing foams stabilized a bleed within <5 minutes. These biomaterials provide a promising solution for both hemorrhage and infection control in wound care.
无法控制的出血是创伤导致死亡的主要原因。对于及时送往医院接受治疗的患者来说,伤口感染耐药细菌的风险很大。因此,具有促凝和抗菌特性的低成本止血剂对于降低创伤伤口患者的发病率和死亡率至关重要。为此,我们通过双重加入机制将香草酸(VA)引入形状记忆聚合物(SMP)泡沫中,制成了双香草酸(DVA)泡沫。这种双重机制增加了香草酸的负载量,同时允许从泡沫中迸发和持续输送香草酸。DVA 泡沫对金黄色葡萄球菌(S. aureus)和表皮葡萄球菌(Staphylococcus epidermidis)具有抗菌和抗生物膜特性。此外,DVA 泡沫还能抑制对甲氧西林敏感和耐药的金黄色葡萄球菌菌落的生长速度,从而限制其大小并促进小菌落的变异。在体外血液相互作用研究中,DVA SMP 泡沫可诱导原发性和继发性止血。作为概念验证,我们在猪肝损伤模型中证明了 DVA 泡沫易于输送和快速凝结的特性,这表明 DVA 泡沫用作止血敷料是可行的。因此,DVA SMP 泡沫的生产成本低廉,可以生产出具有成本效益、抗细菌定植的促凝止血敷料,从而改善外伤患者短期和长期的出血控制效果。意义说明:无法控制的出血是战场上可预防死亡的主要原因。在存活的患者中,有 40% 会在受伤后 5 天内发生多微生物感染。预计到 2050 年,耐药性感染造成的死亡人数将超过所有癌症造成的死亡人数总和。因此,在伤口护理中采用新型非药物生物材料策略来控制感染变得越来越重要。为此,我们开发了止血聚氨酯泡沫,其中包括抗菌剂和促凝血剂香草酸(一种植物性抗菌剂)。这些泡沫能很好地防止本地细菌和耐药细菌的感染,增强凝血功能,同时保持细胞相容性。在猪肝脏损伤试验模型中,含香草酸的泡沫能稳定猪肝脏内的出血。
{"title":"Vanillic Acid-based Pro-coagulant Hemostatic Shape Memory Polymer Foams with Antimicrobial Properties against Drug-resistant Bacteria.","authors":"Changling Du, David Anthony Fikhman, Ernest Emmanuel Obeng, Sevde Nur Can, Katheryn Shi Dong, Eden Tess Leavitt, Leo Vikram Saldanha, Michaela Hall, Joshua Satalin, Michaela Kollisch-Singule, Mary Beth B Monroe","doi":"10.1016/j.actbio.2024.09.036","DOIUrl":"https://doi.org/10.1016/j.actbio.2024.09.036","url":null,"abstract":"<p><p>Uncontrolled bleeding is the primary cause of trauma-related death. For patients that are brought to the hospital in time to receive treatment, there is a great risk of contracting drug-resistant bacterial wound infections. Therefore, low-cost hemostatic agents with procoagulant and antibacterial properties are essential to reduce morbidity and mortality in patients with traumatic wounds. To that end, we introduced vanillic acid (VA) into shape memory polymer (SMP) foams through a dual incorporation mechanism to make dual vanillic acid (DVA) foams. The dual mechanism increases VA loading while allowing burst and sustained delivery of VA from foams. DVA foams exhibit antimicrobial and antibiofilm properties against native and drug-resistant Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis. Also, DVA foams inhibit the growth rate of both methicillin-sensitive and -resistant S. aureus colonies to limit their size and promote small colony variants. DVA SMP foams induce primary and secondary hemostasis in in vitro blood interaction studies. As a proof of concept, we demonstrated easy delivery and rapid clotting in a porcine liver injury model, indicating DVA foam feasibility for use as a hemostatic dressing. Thus, the inexpensive production of DVA SMP foams could enable a cost-effective procoagulant hemostatic dressing that is resistant to bacterial colonization to improve short- and long-term outcomes for hemorrhage control in traumatically injured patients. STATEMENT OF SIGNIFICANCE: Uncontrolled bleeding is the primary cause of preventable death on the battlefield. Of patients that survive, ∼40% develop polymicrobial infections within 5 days of injury. Drug-resistant infections are anticipated to cause more deaths than all cancers combined by 2050. Therefore, novel non-drug-based biomaterials strategies for infection control in wound care are increasingly important. To that end, we developed hemostatic polyurethane foams that include antimicrobial and pro-coagulant vanillic acid, a plant-based antimicrobial species. These foams provide excellent protection against native and drug-resistant bacteria and enhanced coagulation while remaining cytocompatible. In a pilot porcine liver injury model, vanillic acid-containing foams stabilized a bleed within <5 minutes. These biomaterials provide a promising solution for both hemorrhage and infection control in wound care.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-27DOI: 10.1016/j.actbio.2024.09.039
Juncen Zhou, Hanbo Wang, Sannakaisa Virtanen, Lukasz Witek, Hongzhou Dong, David Thanassi, Jie Shen, Yunzhi Peter Yang, Cunjiang Yu, Donghui Zhu
Implant-associated bacterial infections are a primary cause of complications in orthopedic implants, and localized drug delivery represents an effective mitigation strategy. Drawing inspiration from the morphology of desiccated soil, our group has developed an advanced drug-delivery system augmented onto titanium (Ti) plates. This system integrates zinc oxide (ZnO) nanorod arrays with a vancomycin drug layer along with a protective Poly(lactic-co-glycolic acid) (PLGA) coating. The binding between the ZnO nanorods and the drug results in attached drug blocks, isolated by desiccation-like cracks, which are then encapsulated by PLGA to enable sustained drug release. Additionally, the release of zinc ions and the generation of reactive oxygen species (ROS) from the ZnO nanorods enhance the antibacterial efficacy. The antibacterial properties of ZnO nanorod-drug-PLGA system have been validated through both in vitro and in vivo studies. Comprehensive investigations were conducted on the impact of bacterial infections on bone defect regeneration and the role of this drug-delivery system in the healing process. Furthermore, the local immune response was analyzed and the immunomodulatory function of the system was demonstrated. Overall, the findings underscore the superior performance of the ZnO nanorod-drug-PLGA system as an efficient and safe approach to combat implant-associated bacterial infections. STATEMENT OF SIGNIFICANCE: Implant-associated bacterial infections pose a significant clinical challenge, particularly in orthopedic procedures. To address this, we developed an innovative ZnO nanorod-drug-PLGA system for local antibiotic delivery on conventional titanium implants. This system is biodegradable and features a unique desiccation-like structure that enables sustained drug release, along with the active substances released from the ZnO nanorods. In a rat calvarial defect model challenged with S. aureus, our system demonstrated remarkable antibacterial efficacy, significantly enhanced bone defect regeneration, and exhibited local immunomodulatory effects that support both infection control and osteogenesis. These breakthrough findings highlight the substantial clinical potential of this novel drug delivery system and introduce a transformative coating strategy to enhance the functionality of traditional metallic biomaterials.
{"title":"Hybrid Zinc Oxide Nanocoating on Titanium Implants: Controlled Drug Release for Enhanced Antibacterial and Osteogenic Performance in Infectious Conditions.","authors":"Juncen Zhou, Hanbo Wang, Sannakaisa Virtanen, Lukasz Witek, Hongzhou Dong, David Thanassi, Jie Shen, Yunzhi Peter Yang, Cunjiang Yu, Donghui Zhu","doi":"10.1016/j.actbio.2024.09.039","DOIUrl":"https://doi.org/10.1016/j.actbio.2024.09.039","url":null,"abstract":"<p><p>Implant-associated bacterial infections are a primary cause of complications in orthopedic implants, and localized drug delivery represents an effective mitigation strategy. Drawing inspiration from the morphology of desiccated soil, our group has developed an advanced drug-delivery system augmented onto titanium (Ti) plates. This system integrates zinc oxide (ZnO) nanorod arrays with a vancomycin drug layer along with a protective Poly(lactic-co-glycolic acid) (PLGA) coating. The binding between the ZnO nanorods and the drug results in attached drug blocks, isolated by desiccation-like cracks, which are then encapsulated by PLGA to enable sustained drug release. Additionally, the release of zinc ions and the generation of reactive oxygen species (ROS) from the ZnO nanorods enhance the antibacterial efficacy. The antibacterial properties of ZnO nanorod-drug-PLGA system have been validated through both in vitro and in vivo studies. Comprehensive investigations were conducted on the impact of bacterial infections on bone defect regeneration and the role of this drug-delivery system in the healing process. Furthermore, the local immune response was analyzed and the immunomodulatory function of the system was demonstrated. Overall, the findings underscore the superior performance of the ZnO nanorod-drug-PLGA system as an efficient and safe approach to combat implant-associated bacterial infections. STATEMENT OF SIGNIFICANCE: Implant-associated bacterial infections pose a significant clinical challenge, particularly in orthopedic procedures. To address this, we developed an innovative ZnO nanorod-drug-PLGA system for local antibiotic delivery on conventional titanium implants. This system is biodegradable and features a unique desiccation-like structure that enables sustained drug release, along with the active substances released from the ZnO nanorods. In a rat calvarial defect model challenged with S. aureus, our system demonstrated remarkable antibacterial efficacy, significantly enhanced bone defect regeneration, and exhibited local immunomodulatory effects that support both infection control and osteogenesis. These breakthrough findings highlight the substantial clinical potential of this novel drug delivery system and introduce a transformative coating strategy to enhance the functionality of traditional metallic biomaterials.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Endometriosis seriously affects 6-10% of reproductive women globally and poses significant clinical challenges. The process of ectopic endometrial cell colonization shares similarities with cancer, and a dysfunctional immune microenvironment, characterized by non-classically polarized macrophages, plays a critical role in the progression of endometriosis. In this study, a targeted nano delivery system (BSA@Mif NPs) was developed using bovine serum albumin (BSA) as the carrier of mifepristone. The BSA@Mif NPs were utilized to selectively target M2 macrophages highly enriched in ectopic endometrial tissue via the SPARC receptor. This targeting strategy increases drug concentration at ectopic lesions while minimizing its distribution to normal tissue, thereby reducing side effects. In vitro studies demonstrated that BSA@Mif NPs not only enhanced the cellular uptake of M2-type macrophages and ectopic endometrial cells but also improved the cytotoxic effect of mifepristone on ectopic endometrial cells. Furthermore, the BSA@Mif NPs effectively induced immunogenic cell death (ICD) in ectopic endometrial cells and repolarized M2-type macrophages toward the M1 phenotype, resulting in a synergistic inhibition of ectopic endometrial cell growth. In vivo experiments revealed that BSA@Mif NPs exhibited significant therapeutic efficacy in endometriosis-bearing mice by increasing drug accumulation in the endometriotic tissues and modulating the immune microenvironment. This targeted biomimetic delivery strategy presents a promising approach for the development of endometriosis-specific therapies based on existing drugs. STATEMENT OF SIGNIFICANCE: Macrophages play an essential role in immune dysfunctional microenvironment promoting the occurrence and progression of endometriosis and can be a crucial target for developing immune microenvironment regulation strategies for the unmet long-term management of endometriosis. The albumin nanoparticles constructed based on SPARC overexpression in macrophages and endometrial cells and albumin biosafety can achieve the targeted therapy of endometriosis by increasing the passive- and active-mediated drug accumulation in ectopic endometrium and remodeling the immune microenvironment based on macrophage regulation. This study has the following implications: i) overcoming the inherent shortcomings of clinical drugs by nanotechnology is an alternative way of developing medication; ii) developing microenvironment modulation strategies based on macrophage regulation for endometriosis management is feasible.
{"title":"Targeting Delivery of Mifepristone to Endometrial Dysfunctional Macrophages for Endometriosis Therapy.","authors":"Meng Zhang, Yiqing Ye, Zhengyun Chen, Xiaodong Wu, Yue Chen, Pengfei Zhao, Mengdan Zhao, Caihong Zheng","doi":"10.1016/j.actbio.2024.09.037","DOIUrl":"https://doi.org/10.1016/j.actbio.2024.09.037","url":null,"abstract":"<p><p>Endometriosis seriously affects 6-10% of reproductive women globally and poses significant clinical challenges. The process of ectopic endometrial cell colonization shares similarities with cancer, and a dysfunctional immune microenvironment, characterized by non-classically polarized macrophages, plays a critical role in the progression of endometriosis. In this study, a targeted nano delivery system (BSA@Mif NPs) was developed using bovine serum albumin (BSA) as the carrier of mifepristone. The BSA@Mif NPs were utilized to selectively target M2 macrophages highly enriched in ectopic endometrial tissue via the SPARC receptor. This targeting strategy increases drug concentration at ectopic lesions while minimizing its distribution to normal tissue, thereby reducing side effects. In vitro studies demonstrated that BSA@Mif NPs not only enhanced the cellular uptake of M2-type macrophages and ectopic endometrial cells but also improved the cytotoxic effect of mifepristone on ectopic endometrial cells. Furthermore, the BSA@Mif NPs effectively induced immunogenic cell death (ICD) in ectopic endometrial cells and repolarized M2-type macrophages toward the M1 phenotype, resulting in a synergistic inhibition of ectopic endometrial cell growth. In vivo experiments revealed that BSA@Mif NPs exhibited significant therapeutic efficacy in endometriosis-bearing mice by increasing drug accumulation in the endometriotic tissues and modulating the immune microenvironment. This targeted biomimetic delivery strategy presents a promising approach for the development of endometriosis-specific therapies based on existing drugs. STATEMENT OF SIGNIFICANCE: Macrophages play an essential role in immune dysfunctional microenvironment promoting the occurrence and progression of endometriosis and can be a crucial target for developing immune microenvironment regulation strategies for the unmet long-term management of endometriosis. The albumin nanoparticles constructed based on SPARC overexpression in macrophages and endometrial cells and albumin biosafety can achieve the targeted therapy of endometriosis by increasing the passive- and active-mediated drug accumulation in ectopic endometrium and remodeling the immune microenvironment based on macrophage regulation. This study has the following implications: i) overcoming the inherent shortcomings of clinical drugs by nanotechnology is an alternative way of developing medication; ii) developing microenvironment modulation strategies based on macrophage regulation for endometriosis management is feasible.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}