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  • AKT activation by SC79 to transiently re-open pathological blood brain barrier for improved functionalized nanoparticles therapy of glioblastoma
    Biomaterials (IF 10.273) Pub Date : 2020-01-20
    Lijuan Wen; Kai Wang; Fengtian Zhang; Yanan Tan; Xuwei Shang; Yun Zhu; Xueqing Zhou; Hong Yuan; Fuqiang Hu

    Glioblastoma (GBM) is one of the malignant tumors with high mortality, and the presence of the blood brain barrier (BBB) severely limits the penetration and tissue accumulation of therapeutic agents in the lesion of GBM. Active targeting nanotechnologies can achieve efficient drug delivery in the brain, while still have a very low success rate. Here we revealed a previously unexplored phenomenon that chemotherapy with active targeting nanotechnologies causes pathological BBB functional recovery through VEGF-PI3K-AKT signaling pathway inhibition, accompanied with up-regulated expression of Claudin-5 and Occludin. Seriously, pathological BBB functional recovery induces a significant decrease of intracerebral active targeting nanotechnologies transport during GBM multiple administration, leading to chemotherapy failure in GBM therapeutics. To address this issue, we chose AKT agonist SC79 to transiently re-open functional recovering pathological BBB for continuously intracerebral delivery of brain targeted nanotherapeutics, finally producing an observable anti-GBM effect in vivo, which may offer new sight for other CNS disease treatment.

    更新日期:2020-01-21
  • Targeted camptothecin delivery via silicon nanoparticles reduces breast cancer metastasis
    Biomaterials (IF 10.273) Pub Date : 2020-01-17
    Marietta Landgraf; Christoph A. Lahr; Ishdeep Kaur; Abbas Shafiee; Alvaro Sanchez-Herrero; Phillip W. Janowicz; Akhilandeshwari Ravichandran; Christopher B. Howard; Anna Cifuentes-Rius; Jacqui A. McGovern; Nicolas H. Voelcker; Dietmar W. Hutmacher
    更新日期:2020-01-17
  • Nano-puerarin regulates tumor microenvironment and facilitates chemo- and immunotherapy in murine triple negative breast cancer model
    Biomaterials (IF 10.273) Pub Date : 2020-01-17
    Huan Xu; Mengying Hu; Mengrui Liu; Sai An; Kaiyun Guan; Menglin Wang; Lei Li; Jing Zhang; Jun Li; Leaf Huang

    Tumor associated fibroblasts (TAFs) are key stromal cells mediating the desmoplastic reaction and being partially responsible for the drug-resistance and immunosuppressive microenvironment formation in solid tumors. Delivery of genotoxic drugs off-targetedly to kill TAFs results in production of Wnt16 which renders the neighboring tumor cells drug resistant as shown in our previous study (PMC4623876). Our current approach looks for means to deactivate, rather than kill, TAFs. Reactive oxygen species (ROS) are the central hub of multiple profibrogenic pathways and indispensable for TAFs activation. Herein, puerarin was identified to effectively downregulate ROS production in the activated myofibroblast. In this study, a novel puerarin nanoemulsion (nanoPue) was developed to improve the solubility and bioavailability of puerarin. NanoPue significantly deactivated the stromal microenvironment (e.g., ∼6-fold reduction of TAFs in nanoPue treated mice compared with the PBS control, p < 0.0001) and facilitated chemotherapy effect of nano-paclitaxel in the desmoplastic triple-negative breast cancer (TNBC) model. Moreover, the removal of the physical barrier increased intra-tumoral infiltration of cytotoxic T cell by 2-fold. This activated immune microenvironment allowed nanoPue to synergize PD-L1 blockade therapy in TNBC model.

    更新日期:2020-01-17
  • Engineering ApoE3-incorporated biomimetic nanoparticle for efficient vaccine delivery to dendritic cells via macropinocytosis to enhance cancer immunotherapy
    Biomaterials (IF 10.273) Pub Date : 2020-01-16
    Songlei Zhou; Yukun Huang; Yu Chen; Shanshan Liu; Minjun Xu; Tianze Jiang; Qingxiang Song; Gan Jiang; Xiao Gu; Xiaoling Gao; Jun Chen
    更新日期:2020-01-17
  • Injectable hydrogel enables local and sustained co-delivery to the brain: Two clinically approved biomolecules, cyclosporine and erythropoietin, accelerate functional recovery in rat model of stroke
    Biomaterials (IF 10.273) Pub Date : 2020-01-16
    Anup Tuladhar; Jaclyn M. Obermeyer; Samantha L. Payne; Ricky C.W. Siu; Sohrab Zand; Cindi M. Morshead; Molly S. Shoichet

    Therapeutic delivery to the brain is limited by the blood-brain barrier and is exacerbated by off-target effects associated with systemic delivery, thereby precluding many potential therapies from even being tested. Given the systemic side effects of cyclosporine and erythropoietin, systemic administration would be precluded in the context of stroke, leaving only the possibility of local delivery. We wondered if direct delivery to the brain would allow new reparative therapeutics, such as these, to be identified for stroke. Using a rodent model of stroke, we employed an injectable drug delivery hydrogel strategy to circumvent the blood-brain barrier and thereby achieved, for the first time, local and sustained co-release to the brain of cyclosporine and erythropoietin. Both drugs diffused to the sub-cortical neural stem and progenitor cell (NSPC) niche and were present in the brain for at least 32 days post-stroke. Each drug had a different outcome on brain tissue: cyclosporine increased plasticity in the striatum while erythropoietin stimulated endogenous NSPCs. Only their co-delivery, but not either drug alone, accelerated functional recovery and improved tissue repair. This platform opens avenues for hitherto untested therapeutic combinations to promote regeneration and repair after stroke.

    更新日期:2020-01-16
  • Integration of metal-organic framework with a photoactive porous-organic polymer for interface enhanced phototherapy
    Biomaterials (IF 10.273) Pub Date : 2020-01-15
    Xiaohua Zheng; Lei Wang; Yuyao Guan; Qing Pei; Jian Jiang; Zhigang Xie

    Porphyrin-based porous organic polymers are highly potential candidates for cancer theranostics. However, un-controllable particle size and unclear photoactive mechanisms have been deemed to be “Achilles’ heels” for their biomedical application. Herein, a facile self-template strategy has been applied to integrate two types of porous materials to build the [email protected] nanocomposite (named HUC-PEG). As-synthesized HUC-PEG exhibited controllable particle shape and size, good biocompatibility, and better colloidal stability. Importantly, synergy “0 + 1 > 1” interface effects have been demonstrated to simultaneously enhance both the generation of more singlet oxygen (1O2) for photodynamic therapy (PDT) and local hyperthermia for photothermal therapy (PTT), thus to achieve favorable proliferation inhibition of tumor cell both in vitro and in vivo. Moreover, the strong X-ray attenuating ability of Hf element and excellent photothermal conversion efficacy endow this nanocomposite with computed tomography (CT)/photothermal imaging functions. We believe that our ingenious design may open a new horizon for the preparation of nanoscale POP-based therapeutic agents and also realize a paradigm shift in the understanding of photoactive mechanism in porous materials.

    更新日期:2020-01-15
  • Hierarchical assembly of nanostructured coating for siRNA-Based dual therapy of bone regeneration and revascularization
    Biomaterials (IF 10.273) Pub Date : 2020-01-14
    Helin Xing; Xing Wang; Gao Xiao; Zongmin Zhao; Shiquan Zou; Man Li; Joseph J. Richardson; Blaise L. Tardy; Liangxia Xie; Satoshi Komasa; Joji Okazaki; Qingsong Jiang; Guodong Yang; Junling Guo
    更新日期:2020-01-14
  • Transdermal colorimetric patch for hyperglycemia sensing in diabetic mice
    Biomaterials (IF 10.273) Pub Date : 2020-01-13
    Zejun Wang; Hongjun Li; Jinqiang Wang; Zhaowei Chen; Guojun Chen; Di Wen; Amanda Chan; Zhen Gu

    The integration of sampling and instant metabolite readout can fundamentally elevate patient compliance. To circumvent the need for complex in-lab apparatus, here, an all-in-one sampling and display transdermal colorimetric microneedle patch was developed for sensing hyperglycemia in mice. The coloration of 3,3′,5,5′-tetramethylbenzidine (TMB) is triggered by the cascade enzymatic reactions of glucose oxidase (GOx) and horseradish peroxidase (HRP) at abnormally high glucose levels. The HRP in the upper layer is biomineralized with calcium phosphate (CaP) shell to add a pH responsive feature for increased sensitivity as well as protection from nonspecific reactions. This colorimetric sensor achieved minimally invasive extraction of the interstitial fluid from mice and converted glucose level to a visible color change promptly. Quantitative red green and blue (RGB) information could be obtained through a scanned image of the microneedle. This costless, portable colorimetric sensor could potentially detect daily glucose levels without blood drawing procedures.

    更新日期:2020-01-14
  • Small-sized gadolinium oxide based nanoparticles for high-efficiency theranostics of orthotopic glioblastoma
    Biomaterials (IF 10.273) Pub Date : 2020-01-13
    Zheyu Shen; Ting Liu; Zhen Yang; Zijian Zhou; Wei Tang; Wenpei Fan; Yijing Liu; Jing Mu; Ling Li; Vladimir I. Bregadze; Swadhin K. Mandal; Anna A. Druzina; Zhenni Wei; Xiaozhong Qiu; Aiguo Wu; Xiaoyuan Chen

    Glioblastoma (GBM) is one of the most malignant tumors with poor prognosis and outcomes. Although smaller particle size can lead to higher blood-brain barrier (BBB)-permeability of the nanomaterials, most of the reported BBB-crossable nanomaterials for targeted GBM therapy are larger than 24 nm. To realize theranostics of GBM, co-loading of therapeutic and diagnostic agents on the same nanomaterials further results in larger particle size. In this study, we developed a kind of novel BBB-transportable nanomaterials smaller than 14 nm for high-efficiency theranostics of GBM (i.e., high contrast magnetic resonance imaging (MRI) and radiosensitization of GBM). Typically, poly(acrylic acid) (PAA) stabilized extremely small gadolinium oxide nanoparticles with modification of reductive bovine serum albumin (ES-GON-rBSA) was synthezed in water phase, resulting in excellent water-dispersibility. RGD dimer (RGD2, Glu-{Cyclo[Arg-Gly-Asp-(D-Phe)-Lys]}2) and lactoferrin (LF) were then conjugated to the ES-GON-rBSA to obtain composite nanoparticle ES-GON-rBSA-LF-RGD2 with extraordinary relaxivities (r1 = 60.8 mM−1 s−1, r2/r1 = 1.1). The maximum signal enhancement (ΔSNR) for T1-weighted MRI of tumors reached up to 423 ± 42% at 12 h post-injection of ES-GON-rBSA-LF-RGD2, which is much higher than commercial Gd-chelates (<80%). ES-GON-rBSA-LF-RGD2 exhibited high biocompatibility and can transport across the in vitro BBB model and the in vivo BBB of mice due to its small particle size (dh = 13.4 nm) and LF receptor mediated transcytosis. Orthotopic GBM studies reinforce that ES-GON-rBSA3-LF-RGD2 can accumulate in the orthotopic GBM and enhance the radiation therapy of GBM as an effective radiosensitizing agent.

    更新日期:2020-01-13
  • Reduced nucleotomy-induced intervertebral disc disruption through spontaneous spheroid formation by the Low Adhesive Scaffold Collagen (LASCol)
    Biomaterials (IF 10.273) Pub Date : 2020-01-11
    Yoshiki Takeoka; Takashi Yurube; Koichi Morimoto; Saori Kunii; Yutaro Kanda; Ryu Tsujimoto; Yohei Kawakami; Naomasa Fukase; Toshiyuki Takemori; Kaoru Omae; Yuji Kakiuchi; Shingo Miyazaki; Kenichiro Kakutani; Toru Takada; Kotaro Nishida; Masanori Fukushima; Ryosuke Kuroda

    Back pain is a global health problem with a high morbidity and socioeconomic burden. Intervertebral disc herniation and degeneration are its primary cause, further associated with neurological radiculopathy, myelopathy, and paralysis. The current surgical treatment is principally discectomy, resulting in the loss of spinal movement and shock absorption. Therefore, the development of disc regenerative therapies is essential. Here we show reduced disc damage by a new collagen type I-based scaffold through actinidain hydrolysis—Low Adhesive Scaffold Collagen (LASCol)—with a high 3D spheroid-forming capability, water-solubility, and biodegradability and low antigenicity. In human disc nucleus pulposus and annulus fibrosus cells surgically obtained, time-dependent spheroid formation with increased expression of phenotypic markers and matrix components was observed on LASCol but not atelocollagen (AC). In a rat tail nucleotomy model, LASCol-injected and AC-injected discs presented relatively similar radiographic and MRI damage control; however, LASCol, distinct from AC, decelerated histological disc disruption, showing collagen type I-comprising LASCol degradation, aggrecan-positive and collagen type II-positive endogenous cell migration, and M1-polarized and also M2-polarized macrophage infiltration. Reduced nucleotomy-induced disc disruption through spontaneous spheroid formation by LASCol warrants further investigations of whether it may be an effective treatment without stem cells and/or growth factors for intervertebral disc disease.

    更新日期:2020-01-13
  • MOF-derived nano-popcorns synthesized by sonochemistry as efficient sensitizers for tumor microwave thermal therapy
    Biomaterials (IF 10.273) Pub Date : 2020-01-11
    Ting Li; Qiong Wu; Wei Wang; Zengzhen Chen; Longfei Tan; Jie Yu; Changhui Fu; Xiangling Ren; Ping Liang; Jun Ren; Limin Ma; Xianwei Meng

    Microwave (MW) thermal therapy has been vigorously developed in recent years because of its better therapeutic efficiency and smaller side effects compared with traditional tumor treatment methods. In order to promote the tumor cell apoptosis under MW irradiation and achieve better therapeutic effect and prognosis, various microwave sensitizers have been developed. Metal organic frameworks (MOFs) have become one of the most popular materials for microwave sensitization due to their diverse morphology, porous surface and good biodegradability. However, the harsh preparation conditions and long growth time are insurmountable shortcomings of MOFs. Besides, the spongy porous structure of MOFs is not conducive to the retention of ions, leading to insufficient friction and collision between ions under MW radiation. Herein, we synthesized a kind of open-mouthed Zr MOF-derived nano-popcorns (ZDNPs) with the size of about 250 nm by a rapid sonochemical aerosol flow strategy. Compared with UIO-66, the open-mouthed ZDNPs have a better ability to entrap more ions due to their big cracks on the surface, thus improving their MW sensitization performance. The MW heating experiments in vitro present that the net temperature change value of ZDNP was 120% higher than UIO-66 at the same concentration, proving that ZDNP had a higher MW-thermo conversion efficiency than UIO-66, which provided an unprecedented direction for the exploration of more diversified MW sensitizers.

    更新日期:2020-01-13
  • Ex vivo cell-based CRISPR/Cas9 genome editing for therapeutic applications
    Biomaterials (IF 10.273) Pub Date : 2020-01-10
    Yamin Li; Zachary Glass; Mingqian Huang; Zheng-Yi Chen; Qiaobing Xu

    The recently developed CRISPR/Cas9 technology has revolutionized the genome engineering field. Since 2016, increasing number of studies regarding CRISPR therapeutics have entered clinical trials, most of which are focusing on the ex vivo genome editing. In this review, we highlight the ex vivo cell-based CRISPR/Cas9 genome editing for therapeutic applications. In these studies, CRISPR/Cas9 tools were used to edit cells in vitro and the successfully edited cells were considered as therapeutics, which can be introduced into patients to treat diseases. Considering a large number of previous reviews have been focused on the CRISPR/Cas9 delivery methods and materials, this review provides a different perspective, by mainly introducing the targeted conditions and design strategies for ex vivo CRISPR/Cas9 therapeutics. Brief descriptions of the history, functionality and applications of CRISPR/Cas9 systems will be introduced first, followed by the design strategies and most significant results from previous research that used ex vivo CRISPR/Cas9 genome editing for the treatment of conditions or diseases. The last part of this review includes general information about the status of CRISPR/Cas9 therapeutics in clinical trials. We also discuss some of the challenges as well as the opportunities in this research area.

    更新日期:2020-01-11
  • Multifunctional mesoporous black phosphorus-based nanosheet for enhanced tumor-targeted combined therapy with biodegradation-mediated metastasis inhibition
    Biomaterials (IF 10.273) Pub Date : 2020-01-10
    Leilei Chen; Min Qian; Huiling Jiang; Yiwei Zhou; Yilin Du; Yafeng Yang; Taotao Huo; Rongqin Huang; Yi Wang

    Functionalizing black phosphorus nanosheet (BP) with efficient drug loading and endowing mesoporous silica nanomaterials with appropriate biodegradation for controllable tumor-targeted chemo-photothermal therapy are still urgent challenges. Herein, an ordered mesoporous silica-sandwiched black phosphorus nanosheet ([email protected]) with the vertical pore coating was prepared. The strategy could not only enhance the BP's dispersity and improve its doxorubicin (DOX)-loading efficiency, but also facilitate post-modification such as PEGylation and conjugation of targeting ligand, TKD peptide, yielding BSPT. A DOX-loaded BSPT-based system (BSPTD) showed heat-stimulative, pH-responsive, and sustained release manners. In vitro and in vivo results demonstrated that BSPTD had a delayed but finally complete degradation in physiological medium, contributing to an optimal therapeutic window and good biosafety. As a result, BSPTD can achieve an effective chemo-photothermal synergistic targeted therapy of tumor. Moreover, treating by BSPTD was found to be capable of remarkably inhibiting the lung metastasis of tumor, attributing to the photothermal degradation-facilitated secondary drug delivery. Our study provided a robust strategy to functionalize BP nanosheet and biodegrade the mesoporous silica for extended biomedical applications.

    更新日期:2020-01-11
  • Light-activated oxygen self-supplied starving therapy in near-infrared (NIR) window and adjuvant hyperthermia-induced tumor ablation with an augmented sensitivity
    Biomaterials (IF 10.273) Pub Date : 2020-01-09
    Junjie Ren; Lei Zhang; Jiayi Zhang; Wei Zhang; Yang Cao; Zhigang Xu; Hongjuan Cui; Yuejun Kang; Peng Xue

    Glucose oxidase (GOx)-mediated starvation circumvents the energy supply for tumor growth, which has been proved as a potent tumor treatment modality. However, tumor hypoxia negatively affects the efficacy of oxygen-involved glucose decomposition reaction. Moreover, curative effect via glucose depletion is not usually satisfactory enough and adjuvant remedies are always required for a promoted tumor ablation. Herein, a multifunctional nanoreactor based on hollow Bi2Se3 nanoparticles was developed by loading oxygenated perfluorocarbon (PFC) and surface modification with GOx, which was exploited for an enhanced tumor starvation and highly sensitive photothermal therapy (PTT). GOx-mediated tumor starvation could impede the adenosine triphosphate (ATP) generation and further downregulate the expression of heat shock protein (HSP) to decrease the thermoresistance of cells. Afterwards, near infrared (NIR) laser irradiation was performed not only to trigger sensitized PTT but also to initiate the release of encapsulated oxygen to relieve local hypoxia. Then, such GOx-mediated tumor starvation would be further amplified, accompanying with secondary enhanced suppression of HSP. Both in vitro and in vivo investigations demonstrated that such nanoreactor can realize a fascinating therapeutic outcome with minimal adverse effects in virtue of the improved synergistic starvation therapy and PTT. Taken together, the proposed treatment paradigm may inspire the future development of more intelligent nanoplatforms toward high efficient cancer therapy.

    更新日期:2020-01-09
  • Remodeling extracellular matrix based on functional covalent organic framework to enhance tumor photodynamic therapy
    Biomaterials (IF 10.273) Pub Date : 2020-01-09
    Shi-Bo Wang; Zhao-Xia Chen; Fan Gao; Cheng Zhang; Mei-Zhen Zou; Jing-Jie Ye; Xuan Zeng; Xian-Zheng Zhang
    更新日期:2020-01-09
  • Gold–silver nanoshells promote wound healing from drug-resistant bacteria infection and enable monitoring via surface-enhanced Raman scattering imaging
    Biomaterials (IF 10.273) Pub Date : 2020-01-08
    Jian He; Yue Qiao; Hongbo Zhang; Jun Zhao; Wanli Li; Tingting Xie; Danni Zhong; Qiaolin Wei; Shiyuan Hua; Yinhui Yu; Ke Yao; Hélder A. Santos; Min Zhou
    更新日期:2020-01-09
  • Force-dependent extracellular matrix remodeling by early-stage cancer cells alters diffusion and induces carcinoma-associated fibroblasts
    Biomaterials (IF 10.273) Pub Date : 2020-01-08
    Wei-Hung Jung; Nicholas Yam; Chin-Chi Chen; Khalid Elawad; Brian Hu; Yun Chen

    It is known cancer cells secrete cytokines inducing normal fibroblasts (NFs) to become carcinoma-associated fibroblasts (CAFs). However, it is not clear how the CAF-promoting cytokines can effectively navigate the dense ECM, a diffusion barrier, in the tumor microenvironment to reach NFs during the early stages of cancer development. In this study, we devised a 3D coculture system to investigate the possible mechanism of CAF induction at early stages of breast cancer. We found that in a force-dependent manner, ECM fibrils are radially aligned relative to the tumor spheroid. The fibril alignment enhances the diffusion of exosomes containing CAF-promoting cytokines towards NFs. Suppression of force generation or ECM remodeling abolishes the enhancement of exosome diffusion and the subsequent CAF induction. In summary, our finding suggests that early-stage, pre-metastatic cancer cells can generate high forces to align the ECM fibrils, thereby enhancing the diffusion of CAF-promoting exosomes to reach the stroma and induce CAFs.

    更新日期:2020-01-09
  • X-rays-optimized delivery of radiolabeled albumin for cancer theranostics
    Biomaterials (IF 10.273) Pub Date : 2020-01-07
    Xuan Yi; Hailin Zhou; Zheng Zhang; Saisai Xiong; Kai Yang
    更新日期:2020-01-07
  • In vivo imaging of calcium and glutamate responses to intracortical microstimulation reveals distinct temporal responses of the neuropil and somatic compartments in layer II/III neurons
    Biomaterials (IF 10.273) Pub Date : 2020-01-07
    Eles Jr; Kozai Tdy

    Objective Intracortical microelectrode implants generate a tissue response hallmarked by glial scarring and neuron cell death within 100–150 μm of the biomaterial device. Many have proposed that any performance decline in intracortical microstimulation (ICMS) due to this foreign body tissue response could be offset by increasing the stimulation amplitude. The mechanisms of this approach are unclear, however, as there has not been consensus on how increasing amplitude affects the spatial and temporal recruitment patterns of ICMS. Approach We clarify these unknowns using in vivo two-photon imaging of mice transgenically expressing the calcium sensor GCaMP6s in Thy1 neurons or virally expressing the glutamate sensor iGluSnFr in neurons. Calcium and neurotransmitter activity are tracked in the neuronal somas and neuropil during long-train stimulation in Layer II/III of somatosensory cortex. Main results Neural calcium activity and glutamate release are dense and strongest within 20–40 μm around the electrode, falling off with distance from the electrode. Neuronal calcium increases with higher amplitude stimulations. During prolonged stimulation trains, a sub-population of somas fails to maintain calcium activity. Interestingly, neuropil calcium activity is 3-fold less correlated to somatic calcium activity for cells that drop-out during the long stimulation train compared to cells that sustain activity throughout the train. Glutamate release is apparent only within 20 μm of the electrode and is sustained for at least 10s after cessation of the 15 and 20 μA stimulation train, but not lower amplitudes. Significance These results demonstrate that increasing amplitude can increase the radius and intensity of neural recruitment, but it also alters the temporal response of some neurons. Further, dense glutamate release is highest within the first 20 μm of the electrodes site even at high amplitudes, suggesting that there may be spatial limitations to the amplitude parameter space. The glutamate elevation outlasts stimulation, suggesting that high-amplitude stimulation may affect neurotransmitter re-uptake. This ultimately suggests that increasing the amplitude of ICMS device stimulation may fundamentally alter the temporal neural response, which could have implications for using amplitude to improve the ICMS effect or “offset” the effects of glial scarring.

    更新日期:2020-01-07
  • ROS-augmented and tumor-microenvironment responsive biodegradable nanoplatform for enhancing chemo-sonodynamic therapy
    Biomaterials (IF 10.273) Pub Date : 2020-01-06
    Jie An; Yong-Guo Hu; Kai Cheng; Cheng Li; Xiao-Lin Hou; Gang-Lin Wang; Xiao-Shuai Zhang; Bo Liu; Yuan-Di Zhao; Ming-Zhen Zhang

    Nanocarrier for augmenting the efficacy of reactive oxygen species (ROS) by tumor microenvironment (TME) has become an emerging strategy for cancer treatment. Herein, a smart biodegradable drug delivery nanoplatform with mitochondrial-targeted ability, pH-responsive drug release and enzyme-like catalytic function is designed. This efficient ROS-generating platform uses ultrasound with deeper penetration capability as excitation source for combined chemotherapy and sonodynamic therapy (SDT) of tumor. In vitro experiments show that the nanoplatform can co-load Ce6 and DOX and be degraded in slight acid environment, and the DOX release rate is 63.91 ± 1.67%. In vivo experiments show that the nanoplatform has extremely biosafety and can be enriched in tumor site and excluded from body after 24 h. More significantly, after combined treatment, the tumors are eliminated and the mice still survive healthily without recurrence after 60 d. This is because not only it can achieve mitochondrial targeting and use platinum particle to increase oxygen content in TME to enhance the effect of SDT, but also it can use weak acidic TME to accelerate drug release to achieve the combination of chemotherapy and SDT. The probe provides a new strategy for designing ROS-based nanoplatform for the treatment of malignant tumor.

    更新日期:2020-01-06
  • Redox-responsive polyprodrug nanoparticles for targeted siRNA delivery and synergistic liver cancer therapy
    Biomaterials (IF 10.273) Pub Date : 2020-01-06
    Senlin Li; Phei Er Saw; Chunhao Lin; Yan Nie; Wei Tao; Omid C. Farokhzad; Lei Zhang; Xiaoding Xu
    更新日期:2020-01-06
  • Urea removal strategies for dialysate regeneration in a wearable artificial kidney
    Biomaterials (IF 10.273) Pub Date : 2020-01-06
    Maaike K. van Gelder; Jacobus A.W. Jong; Laura Folkertsma; Yong Guo; Christian Blüchel; Marianne C. Verhaar; Mathieu Odijk; Cornelus F. Van Nostrum; Wim E. Hennink; Karin G.F. Gerritsen

    The availability of a wearable artificial kidney (WAK) that provides dialysis outside the hospital would be an important advancement for dialysis patients. The concept of a WAK is based on regeneration of a small volume of dialysate in a closed-loop. Removal of urea, the primary waste product of nitrogen metabolism, is the major challenge for the realization of a WAK since it is a molecule with low reactivity that is difficult to adsorb while it is the waste solute with the highest daily molar production. Currently, no efficient urea removal technology is available that allows for miniaturization of the WAK to a size and weight that is acceptable for patients to carry. Several urea removal strategies have been explored, including enzymatic hydrolysis by urease, electro-oxidation and sorbent systems. However, thus far, these methods have toxic side effects, limited removal capacity or slow removal kinetics. This review discusses different urea removal strategies for application in a wearable dialysis device, from both a chemical and a medical perspective.

    更新日期:2020-01-06
  • Human lung organoids develop into adult airway-like structures directed by physico-chemical biomaterial properties
    Biomaterials (IF 10.273) Pub Date : 2020-01-06
    Briana R. Dye; Richard L. Youngblood; Robert S. Oakes; Tadas Kasputis; Daniel W. Clough; Jason R. Spence; Lonnie D. Shea

    Tissues derived from human pluripotent stem cells (hPSCs) often represent early stages of fetal development, but mature at the molecular and structural level when transplanted into immunocompromised mice. hPSC-derived lung organoids (HLOs) transplantation has been further enhanced with biomaterial scaffolds, where HLOs had improved tissue structure and cellular differentiation. Here, our goal was to define the physico-chemical biomaterial properties that maximally enhanced transplant efficiency, including features such as the polymer type, degradation, and pore interconnectivity of the scaffolds. We found that transplantation of HLOs on microporous scaffolds formed from poly (ethylene glycol) (PEG) hydrogel scaffolds inhibit growth and maturation, and the transplanted HLOs possessed mostly immature lung progenitors. On the other hand, HLOs transplanted on poly (lactide-co-glycolide) (PLG) scaffolds or polycaprolactone (PCL) led to tube-like structures that resembled both the structure and cellular diversity of an adult airway. Our data suggests that scaffold pore interconnectivity and polymer degradation contributed to the maturation, and we found that the size of the airway structures and the total size of the transplanted tissue was influenced by the material degradation rate. Collectively, these biomaterial platforms provide a set of tools to promote maturation of the tissues and to control the size and structure of the organoids.

    更新日期:2020-01-06
  • Cell engineering: Biophysical regulation of the nucleus
    Biomaterials (IF 10.273) Pub Date : 2020-01-03
    Yang Song; Jennifer Soto; Binru Chen; Li Yang; Song Li

    Cells live in a complex and dynamic microenvironment, and a variety of microenvironmental cues can regulate cell behavior. In addition to biochemical signals, biophysical cues can induce not only immediate intracellular responses, but also long-term effects on phenotypic changes such as stem cell differentiation, immune cell activation and somatic cell reprogramming. Cells respond to mechanical stimuli via an outside-in and inside-out feedback loop, and the cell nucleus plays an important role in this process. The mechanical properties of the nucleus can directly or indirectly modulate mechanotransduction, and the physical coupling of the cell nucleus with the cytoskeleton can affect chromatin structure and regulate the epigenetic state, gene expression and cell function. In this review, we will highlight the recent progress in nuclear biomechanics and mechanobiology in the context of cell engineering, tissue remodeling and disease development.

    更新日期:2020-01-04
  • Topography elicits distinct phenotypes and functions in human primary and stem cell derived endothelial cells
    Biomaterials (IF 10.273) Pub Date : 2020-01-02
    Seep Arora; Shiming Lin; Christine Cheung; Evelyn K.F. Yim; Yi-Chin Toh

    The effective deployment of arterial (AEC), venous (VEC) and stem cell-derived endothelial cells (PSC-EC) in clinical applications requires understanding of their distinctive phenotypic and functional characteristics, including their responses to microenvironmental cues. Efforts to mimic the in-vivo vascular basement membrane milieu have led to the design and fabrication of nano- and micro-topographical substrates. Although the basement membrane architectures of arteries and veins are different, investigations into the effects of substrate topographies have so far focused on generic EC characteristics. Thus, topographical modulation of arterial- or venous-specific EC phenotype and function remains unknown. Here, we comprehensively evaluated the effects of 16 unique topographies on primary AEC, VEC and human PSC-ECs using a Multi Architectural (MARC) Chip. Gratings and micro-lenses augmented venous-specific phenotypes and depressed arterial functions in VECs; while AECs did not respond consistently to topography. PSC-ECs exhibited phenotypic and functional maturation towards an arterial subtype with increased angiogenic potential, NOTCH1 and Ac-LDL expression on gratings. Specific topographies could elicit different phenotypic and functional changes, despite similar morphological response in different ECs, demonstrating no direct correlation between the two responses.

    更新日期:2020-01-04
  • Catalase-based liposomal for reversing immunosuppressive tumor microenvironment and enhanced cancer chemo-photodynamic therapy
    Biomaterials (IF 10.273) Pub Date : 2020-01-02
    Chao Shi; Mingle Li; Zhen Zhang; Qichao Yao; Kun Shao; Feng Xu; Ning Xu; Haidong Li; Jiangli Fan; Wen Sun; Jianjun Du; Saran Long; Jingyun Wang; Xiaojun Peng

    Photodynamic therapy (PDT) and chemotherapy has been applied as a prospective approach in tumor therapeutics. However, suffering from the inherent hypoxia status in tumor microenvironment (TME), the anticancer efficiency is enormously restricted, especially PDT. Herein, we develop a unique liposomal encapsulated catalase (CAT), lyso-targeted NIR photosensitizer (MBDP) and doxorubicin (Dox), forming [email protected]@CAT, to increase tumor oxygenation by catalyzing intratumoral high-expressed H2O2 for enhancing the combination of chemo-PDT. Moreover, the enhanced tumoral oxygenation not only facilitates singlet oxygen (1O2) production but also reverses immunosuppressive TME by modulating immune cytokines to favor antitumor immunities, which significantly induce tumor death. Notably, this system also realizes specific tumor recognition to folate receptor upregulated tumors and improves intratumoral accumulation. This work provides an effective strategy to promote tumor therapeutic index, which may possess a promising future in clinical application.

    更新日期:2020-01-02
  • Actomyosin, vimentin and LINC complex pull on osteosarcoma nuclei to deform on micropillar topography
    Biomaterials (IF 10.273) Pub Date : 2020-01-02
    Nayana Tusamda Wakhloo; Sebastian Anders; Florent Badique; Melanie Eichhorn; Isabelle Brigaud; Tatiana Petithory; Maxime Vassaux; Jean-Louis Milan; Jean-Noël Freund; Jürgen Rühe; Patricia M. Davidson; Laurent Pieuchot; Karine Anselme

    Cell deformation occurs in many critical biological processes, including cell extravasation during immune response and cancer metastasis. These cells deform the nucleus, its largest and stiffest organelle, while passing through narrow constrictions in vivo and the underlying mechanisms still remain elusive. It is unclear which biochemical actors are responsible and whether the nucleus is pushed or pulled (or both) during deformation. Herein we use an easily-tunable poly-L-lactic acid micropillar topography, mimicking in vivo constrictions to determine the mechanisms responsible for nucleus deformation. Using biochemical tools, we determine that actomyosin contractility, vimentin and nucleo-cytoskeletal connections play essential roles in nuclear deformation, but not A-type lamins. We chemically tune the adhesiveness of the micropillars to show that pulling forces are predominantly responsible for the deformation of the nucleus. We confirm these results using an in silico cell model and propose a comprehensive mechanism for cellular and nuclear deformation during confinement. These results indicate that microstructured biomaterials are extremely versatile tools to understand how forces are exerted in biological systems and can be useful to dissect and mimic complex in vivo behaviour.

    更新日期:2020-01-02
  • Oxidative stress-driven DR5 upregulation restores TRAIL/Apo2L sensitivity induced by iron oxide nanoparticles in colorectal cancer
    Biomaterials (IF 10.273) Pub Date : 2019-12-31
    Yesi Shi; Junqing Wang; Jingyi Liu; Gan Lin; Fengfei Xie; Xin Pang; Yihua Pei; Yi Cheng; Yang Zhang; Zhongning Lin; Zhengyu Yin; Xiaomin Wang; Gang Niu; Xiaoyuan Chen; Gang Liu

    There exists an emergency clinical demand to overcome TRAIL/Apo2L (tumor necrosis factor-related apoptosis-inducing ligand) resistance, which is a major obstacle attributed to insufficient level or mutation of TRAIL receptors. Here, we developed an iron oxide cluster-based nanoplatforms for both sensitization and MR image-guided evaluation to improve TRAIL/Apo2L efficacy in colorectal cancer, which has an inadequate response to TRAIL/Apo2L or chemotherapy. Specifically, NanoTRAIL (TRAIL/Apo2L-iron oxide nanoparticles) generated ROS (reactive oxygen species)-triggered JNK (c-Jun N-terminal kinase) activation and induced subsequent autophagy-assisted DR5 upregulation, resulting in a significant enhanced antitumor efficacy of TRAIL/Apo2L, which confirmed in both TRAIL-resistant HT-29, intermediately resistant SW-480 and sensitive HCT-116 cells. Furthermore, in a subcutaneous colorectal cancer mouse model, the in vivo tumor retention of NanoTRAIL can be demonstrated by MR T2 weighted contrast imaging, and NanoTRAIL significantly suppressed tumor growth and prolonged the survival time without observable adverse effects compared with control and TRAIL/Apo2L monotherapy. Importantly, in the study of colorectal cancer patient-derived xenograft models, we found that the NanoTRAIL treatment could significantly improve the survival outcome with consistent ROS-dependent autophagy-assisted DR5 upregulation and tumor apoptosis. Our results describe a transformative design that can be applied clinically to sensitize Apo2L/TRAIL-resistant patients using FDA-approved iron oxide nanoparticles.

    更新日期:2020-01-01
  • Human cardiac fibrosis-on-a-chip model recapitulates disease hallmarks and can serve as a platform for drug testing
    Biomaterials (IF 10.273) Pub Date : 2019-12-31
    Olya Mastikhina; Byeong-Ui Moon; Kenneth Williams; Rupal Hatkar; Dakota Gustafson; Omar Mourad; Xuetao Sun; Margaret Koo; Alan Y.L. Lam; Yu Sun; Jason E. Fish; Edmond W.K. Young; Sara S. Nunes
    更新日期:2019-12-31
  • The novel platinum(IV) prodrug with self-assembly property and structure-transformable character against triple-negative breast cancer
    Biomaterials (IF 10.273) Pub Date : 2019-12-31
    Conglian Yang; Kun Tu; Hanlu Gao; Liao Zhang; Yu Sun; Ting Yang; Li Kong; Defang Ouyang; Zhiping Zhang
    更新日期:2019-12-31
  • Reactive oxygen species-responsive dexamethasone-loaded nanoparticles for targeted treatment of rheumatoid arthritis via suppressing the iRhom2/TNF-α/BAFF signaling pathway
    Biomaterials (IF 10.273) Pub Date : 2019-12-31
    Rongrong Ni; Guojing Song; Xiaohong Fu; Ruifeng Song; Lanlan Li; Wendan Pu; Jining Gao; Jun Hu; Qin Liu; Fengtian He; Dinglin Zhang; Gang Huang

    Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease that results in synovitis, cartilage destruction, and even loss of joint function. The frequent and long-term administration of anti-rheumatic drugs often leads to obvious adverse effects and patient non-compliance. Therefore, to specifically deliver dexamethasone (Dex) to inflamed joints and reduce the administration frequency of Dex, we developed Dex-loaded reactive oxygen species (ROS)-responsive nanoparticles (Dex/Oxi-αCD NPs) and folic acid (FA) modified Dex/Oxi-αCD NPs (Dex/FA-Oxi-αCD NPs) and validated their anti-inflammatory effect in vitro and in vivo. In vitro study demonstrated that these NPs can be effectively internalized by activated macrophages and the released Dex from NPs significantly downregulated the expression of iRhom2, TNF-α, and BAFF in activated Raw264.7. In vivo experiments revealed that Dex/Oxi-αCD NPs, especially Dex/FA-Oxi-αCD NPs significantly accumulated at inflamed joints in collagen-induced arthritis (CIA) mice and alleviated the joint swelling and cartilage destruction. Importantly, the expression of iRhom2, TNF-α, and BAFF in the joint was inhibited by intravenous injection of Dex/Oxi-αCD NPs and Dex/FA-Oxi-αCD NPs. Collectively, our data revealed that Dex-loaded ROS-responsive NPs can target inflamed joints and attenuate arthritis, and the ‘iRhom2-TNF-α-BAFF’ pathway plays an important role in the treatment of RA with the NPs, suggesting that this pathway may be a novel target for RA therapy.

    更新日期:2019-12-31
  • 更新日期:2019-12-31
  • Mitochondria-targeted TPP-MoS2 with dual enzyme activity provides efficient neuroprotection through M1/M2 microglial polarization in an Alzheimer's disease model
    Biomaterials (IF 10.273) Pub Date : 2019-12-30
    Chaoxiu Ren; Dandan Li; Qixing Zhou; Xiangang Hu

    Alzheimer's disease (AD) is one of the most common age-associated brain diseases and is induced by the accumulation of amyloid beta (Aβ) and oxidative stress. Many studies have focused on eliminating Aβ by nanoparticle affinity; however, nanoparticles are taken up mainly by microglia rather than neurons, leading poor control of AD. Herein, mitochondria-targeted nanozymes known as (3-carboxypropyl)triphenyl-phosphonium bromide-conjugated 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000]-functionalized molybdenum disulfide quantum dots (TPP-MoS2 QDs) were designed. TPP-MoS2 QDs mitigate Aβ aggregate-mediated neurotoxicity and eliminate Aβ aggregates in AD mice by switching microglia from the proinflammatory M1 phenotype to the anti-inflammatory M2 phenotype. TPP-MoS2 QDs cross the blood-brain barrier, escape from lysosomes, target mitochondria and exhibit the comprehensive activity of a bifunctional nanozyme, thus preventing spontaneous neuroinflammation by regulating the proinflammatory substances interleukin-1β, interleukin-6 and tumor necrosis factors as well as the anti-inflammatory substance transforming growth factor-β. In contrast to the low efficacy of eliminating Aβ by nanoparticle affinity, the present study provides a new pathway to mitigate AD pathology through mitochondria-targeted nanozymes and M1/M2 microglial polarization.

    更新日期:2019-12-30
  • Boosting the photodynamic therapy efficiency by using stimuli-responsive and AIE-featured nanoparticles
    Biomaterials (IF 10.273) Pub Date : 2019-12-30
    Youmei Li; Qian Wu; Miaomiao Kang; Nan Song; Dong Wang; Ben Zhong Tang
    更新日期:2019-12-30
  • Investigational new drug enabling angiotensin oral-delivery studies to attenuate pulmonary hypertension
    Biomaterials (IF 10.273) Pub Date : 2019-12-30
    Henry Daniell; Venkata Mangu; Bakhtiyor Yakubov; Jiyoung Park; Peyman Habibi; Yao Shi; Patricia A. Gonnella; Amanda Fisher; Todd Cook; Lily Zeng; Steven M. Kawut; Tim Lahm
    更新日期:2019-12-30
  • Characterization of Parylene-C degradation mechanisms: In vitro reactive accelerated aging model compared to multiyear in vivo implantation
    Biomaterials (IF 10.273) Pub Date : 2019-12-28
    Ryan Caldwell; Matthew G. Street; Rohit Sharma; Pavel Takmakov; Brian Baker; Loren Rieth

    Implantable neural microelectrodes are integral components of neuroprosthetic technologies and can transform treatments for many neural-mediated disorders. However, dielectric material degradation during long-term (>1 year) indwelling periods restricts device functional lifetimes to a few years. This comprehensive work carefully investigates in vivo material degradation and also explores the ability of in vitro Reactive Accelerated Aging (RAA) to evaluate implant stability. Parylene C-coated Utah electrode arrays (UEAs) implanted in feline peripheral nerve for 3.25 years were explanted and compared to RAA-processed devices, aged in phosphate buffered saline (PBS) + 20 mM H2O2 at either 67 or 87 °C (28 or 7 days, respectively). Electron microscopy revealed similar physical damage characteristics between explants and RAA (87 °C) devices. Parylene C degradation was overwhelmingly apparent for UEAs from both RAA cohorts. Controls aged in PBS alone displayed almost no damage. Spectroscopic characterization (EDX, XPS, FTIR) found clear indications of oxidation and chlorine abstraction for Parylene C aged in vivo. While in vitro aging was also accompanied by signs of oxidation, changes in the chemistry in vivo and in vitro were statistically different. Analysis of RAA-aged devices identified UEA fabrication approaches that may greatly improve device resistance to degradation. This work underscores the need for an improved understanding of in vivo damage mechanisms, to facilitate the critical need for representative in vitro accelerated testing paradigms for long-term implants.

    更新日期:2019-12-29
  • Ultrasound-activated particles as CRISPR/Cas9 delivery system for androgenic alopecia therapy
    Biomaterials (IF 10.273) Pub Date : 2019-12-28
    Jee-Yeon Ryu; Eun-Jeong Won; Han A Reum Lee; Jin Hyun Kim; Emmanuel Hui; Hong Pyo Kim; Tae-Jong Yoon
    更新日期:2019-12-29
  • Accepting higher morbidity in exchange for sacrificing fewer animals in studies developing novel infection-control strategies
    Biomaterials (IF 10.273) Pub Date : 2019-12-28
    Henk J. Busscher; Willem Woudstra; Theo G. van Kooten; Paul Jutte; Linqi Shi; Jianfeng Liu; Wouter L.J. Hinrichs; Hendrik W. Frijlink; Rui Shi; Jian Liu; Javad Parvizi; Stephen Kates; Vincent M. Rotello; Thomas P. Schaer; Dustin Williams; David W. Grainger; Henny C. van der Mei
    更新日期:2019-12-29
  • Porous bio-click microgel scaffolds control hMSC interactions and promote their secretory properties
    Biomaterials (IF 10.273) Pub Date : 2019-12-27
    Alexander S. Caldwell; Varsha V. Rao; Alyxandra C. Golden; Kristi S. Anseth

    Human mesenchymal stem/stromal cells (hMSCs) are known to secrete numerous cytokines that signal to endogenous cells and aid in tissue regeneration. However, the role that biomaterial scaffolds can play in controlling hMSC secretory properties has been less explored. Here, microgels were co-assembled with hMSCs using three different microgel populations, with large (190 ± 100 μm), medium (110 ± 60 μm), and small (13±6 μm) diameters, to create distinct porous environments that influenced hMSC clustering. Cells embedded in large diameter microgel networks resided in large clusters (∼40 cells), compared to small clusters (∼6 cells) observed in networks using medium diameter microgels and primarily single cells in small diameter microgel networks. Using a cytokine microarray, an overall increase in secretion was observed in scaffolds that promoted hMSC clustering, with over 60% of the measured cytokines most elevated in the large diameter microgel networks. N-cadherin interactions were identified as partially mediating these differences, so the microgel formulations were modified with an N-cadherin epitope, HAVDI, to mimic cell-cell interactions. Results revealed increased secretory properties for hMSCs in HAVDI functionalized scaffolds, even the non-clustered cells in small diameter microgel networks. Together, these results demonstrate opportunities for microgel-based scaffold systems for hMSC delivery and tailoring of porous materials properties to promote their secretory potential.

    更新日期:2019-12-29
  • Substrate curvature as a cue to guide spatiotemporal cell and tissue organization
    Biomaterials (IF 10.273) Pub Date : 2019-12-27
    Sebastien J.P. Callens; Rafael J.C. Uyttendaele; Lidy E. Fratila-Apachitei; Amir A. Zadpoor

    Recent evidence clearly shows that cells respond to various physical cues in their environments, guiding many cellular processes and tissue morphogenesis, pathology, and repair. One aspect that is gaining significant traction is the role of local geometry as an extracellular cue. Elucidating how geometry affects cell and tissue behavior is, indeed, crucial to design artificial scaffolds and understand tissue growth and remodeling. Perhaps the most fundamental descriptor of local geometry is surface curvature, and a growing body of evidence confirms that surface curvature affects the spatiotemporal organization of cells and tissues. While well-defined in differential geometry, curvature remains somewhat ambiguously treated in biological studies. Here, we provide a more formal curvature framework, based on the notions of mean and Gaussian curvature, and summarize the available evidence on curvature guidance at the cell and tissue levels. We discuss the involved mechanisms, highlighting the interplay between tensile forces and substrate curvature that forms the foundation of curvature guidance. Moreover, we show that relatively simple computational models, based on some application of curvature flow, are able to capture experimental tissue growth remarkably well. Since curvature guidance principles could be leveraged for tissue regeneration, the implications for geometrical scaffold design are also discussed. Finally, perspectives on future research opportunities are provided.

    更新日期:2019-12-27
  • Recent advances in functional mesoporous silica-based nanoplatforms for combinational photo-chemotherapy of cancer
    Biomaterials (IF 10.273) Pub Date : 2019-12-27
    Ying-Jia Cheng; Jing-Jing Hu; Si-Yong Qin; Ai-Qing Zhang; Xian-Zheng Zhang
    更新日期:2019-12-27
  • Characterization of silk-hyaluronic acid composite hydrogels towards vitreous humor substitutes
    Biomaterials (IF 10.273) Pub Date : 2019-12-27
    Nicole R. Raia; Di Jia; Chiara E. Ghezzi; Murugappan Muthukumar; David L. Kaplan

    Multiple ophthalmic pathologies, such as retinal detachment and diabetic retinopathy, require the removal and replacement of the vitreous humor. Clinical tamponades such as silicone oil and fluorinated gases are utilized but limited due to complications and toxicity. Therefore, there is a need for biocompatible, stable, vitreous humor substitutes. In this study, enzymatically crosslinked silk-hyaluronic acid (HA) hydrogels formed using horseradish peroxidase and H2O2 were characterized for use as vitreous humor substitutes. The composite network structure was characterized with dynamic light scattering. In addition, the rheological, optical, and swelling properties of hydrogels with varying silk to HA ratios and crosslinking densities controlled via H2O2 were determined over time. Hydrogels had refractive indexes of 1.336 and were clear with 75–91% light transmission. Hydrogel shear storage modulus ranged between ∼6 and 240 Pa where increased H2O2 increased the modulus. After 1 month of aging, there were no changes in modulus for hydrogels with lower silk ratios, while those with higher silk ratios exhibited a significant increase in modulus. Decreasing H2O2 concentration in the reactions led to increased hydrogel volume during swelling, with higher silk ratios returning to their original size after 15 days. Dynamic light scattering results show three diffusive modes, revealing the possible structures of the hydrogel composite and are consistent with the mechanical properties and swelling results. The normalized intraocular pressure of ex vivo porcine eyes after injecting hydrogels were comparable with those treated with silicone oil showing the potential clinical utility of the hydrogels as vitreous substitutes. The versatility of the silk-HA hydrogel system, the tunable swelling properties, and the stability of hydrogels with lower silk ratios show the benefit of utilizing silk-HA hydrogels as vitreous substitutes.

    更新日期:2019-12-27
  • Microneedles for transdermal diagnostics: recent advances and new horizons
    Biomaterials (IF 10.273) Pub Date : 2019-12-26
    Gui-Shi Liu; Yifei Kong; Yensheng Wang; Yunhan Luo; Xudong Fan; Xi Xie; Bo-Ru Yang; Mei X. Wu

    Point-of-care testing (POCT), defined as the test performed at or near a patient, has been evolving into a complement to conventional laboratory diagnosis by continually providing portable, cost-effective, and easy-to-use measurement tools. Among them, microneedle-based POCT devices have gained increasing attention from researchers due to the glorious potential for detecting various analytes in a minimally invasive manner. More recently, a novel synergism between microneedle and wearable technologies is expanding their detection capabilities. Herein, we provide an overview on the progress in microneedle-based transdermal biosensors. It covers all the main aspects of the field, including design philosophy, material selection, and working mechanisms as well as the utility of the devices. We also discuss lessons from the past, challenges of the present, and visions for the future on translation of these state-of-the-art technologies from the bench to bedside.

    更新日期:2019-12-27
  • Nanoscale pathways for human tooth decay – Central planar defect, organic-rich precipitate and high-angle grain boundary
    Biomaterials (IF 10.273) Pub Date : 2019-12-26
    Fan Yun; Michael V. Swain; Hansheng Chen; Julie Cairney; Jiangtao Qu; Gang Sha; Hongwei Liu; Simon P. Ringer; Yu Han; Lingmei Liu; Xixiang Zhang; Rongkun Zheng

    Understanding the pathways and mechanisms of human tooth decay is central to the development of both prophylaxes and treatments, but only limited information is presently available about the initiation of caries at the nanoscale. By combining atom probe tomography and high-resolution electron microscopy, we have found three distinct initial sites for human dental enamel dissolution: a) along the central dark line (CDL) within carbonated apatite nanocrystals, b) at organic-rich precipitates and c) along high-angle grain boundaries. 3D maps of the atoms within hydroxyapatite nanocrystallites in sound and naturally-decayed human dental enamel reveal a higher concentration of Mg and Na in the CDL. The CDL is therefore thought to provide a pathway for the exchange of ions during demineralization and remineralization. Mg and Na enrichment of the CDL also suggests that it is associated with the ribbon-like organic-rich precursor in amelogenesis. Organic-rich precipitates and high-angle grain boundaries were also shown to be more vulnerable to corrosion while low-angle grain boundaries remained intact. This is attributed to the lower crystallinity in these regions.

    更新日期:2019-12-27
  • ROS-responsive polyurethane fibrous patches loaded with methylprednisolone (MP) for restoring structures and functions of infarcted myocardium in vivo
    Biomaterials (IF 10.273) Pub Date : 2019-12-26
    Yuejun Yao; Jie Ding; Zhaoyi Wang; Haolan Zhang; Jieqi Xie; Yingchao Wang; Liangjie Hong; Zhengwei Mao; Jianqing Gao; Changyou Gao

    Reactive oxygen species (ROS) play an important role in the pathogenesis of numerous diseases including atherosclerosis, diabetes, inflammation and myocardial infarction (MI). In this study, a ROS-responsive biodegradable elastomeric polyurethane containing thioketal (PUTK) linkages was synthesized from polycaprolactone diol, 1,6-hexamethylene diisocyanate (HDI), and ROS-cleavable chain extender. The PUTK was electrospun into fibrous patches with the option to load glucocorticoid methylprednisolone (MP), which were then used to treat MI of rats in vivo. The fibrous patches exhibited suitable mechanical properties and high elasticity. The molecular weight of PUTK was decreased significantly after incubation in 1 mM H2O2 solution for 2 weeks due to the degradation of thioketal bonds on the polymer backbone. Both the PUTK and PUTK/MP fibrous patches showed good antioxidant property in an oxidative environment in vitro. Implantation of the ROS-responsive polyurethane patches in MI of rats in vivo could better protect cardiomyocytes from death in the earlier stage (24 h) than the non ROS-responsive ones. Implantation of the PUTK/MP fibrous patches for 28 days could effectively improve the reconstruction of cardiac functions including increased ejection fraction, decreased infarction size, and enhanced revascularization of the infarct myocardium.

    更新日期:2019-12-27
  • Microphysiological systems for recapitulating physiology and function of blood-brain barrier
    Biomaterials (IF 10.273) Pub Date : 2019-12-26
    Suyeong Seo; Hwieun Kim; Jong Hwan Sung; Nakwon Choi; Kangwon Lee; Hong Nam Kim

    Central nervous system (CNS) diseases are emerging as a major issue in an aging society. Although extensive research has focused on the development of CNS drugs, the limited transport of therapeutic agents across the blood–brain barrier (BBB) remains a major challenge. Conventional two-dimensional culture dishes do not recapitulate in vivo physiology and real-time observations of molecular transport are not possible in animal models. Recent advances in engineering techniques have enabled the generation of more physiologically relevant in vitro BBB models, and their applications have expanded from fundamental biological research to practical applications in the pharmaceutical industry. In this article, we provide an overview of recent advances in the development of in vitro BBB models, with a particular focus on the recapitulation of BBB function. The development of biomimetic BBB models is postulated to revolutionize not only fundamental biological studies but also drug screening.

    更新日期:2019-12-27
  • Emerging nanomedicines for anti-stromal therapy against desmoplastic tumors
    Biomaterials (IF 10.273) Pub Date : 2019-12-26
    Xuexiang Han; Ying Xu; Marzieh Geranpayehvaghei; Gregory J. Anderson; Yiye Li; Guangjun Nie

    Solid tumors, especially desmoplastic tumors, are characterized by a dense fibrotic stroma composed of abundant cancer-associated fibroblasts and excessive extracellular matrix. These physical barriers seriously compromise drug delivery to tumor cells, leading to suboptimal treatment efficacy and resistance to current tumor-centric therapeutics. The need to overcome these problems has driven extensive investigations and sparked the flourish of anti-stromal therapy, particularly in the field of nanomedicines. In this paper, we firstly review the major components of the tumor stroma and discuss their impact on drug delivery. Then, according to the different stromal targets, we summarize the current status of anti-stromal therapy and highlight recent advances in anti-stromal nanomedicines. We further examine the potential of nano-enabled anti-stromal therapy to enhance the anti-tumor efficacy of other therapeutic modalities, including chemotherapy, immunotherapy, phototherapy and radiotherapy. Finally, the potential concerns and future developments of anti-stromal nanomedicines are discussed.

    更新日期:2019-12-27
  • Implantable powder-carrying microneedles for transdermal delivery of high-dose insulin with enhanced activity
    Biomaterials (IF 10.273) Pub Date : 2019-12-26
    Suyong Kim; Huisuk Yang; Jaehong Eum; Yonghao Ma; Shayan Fakhraei Lahiji; Hyungil Jung
    更新日期:2019-12-27
  • Endothelialized collagen based pseudo-islets enables tuneable subcutaneous diabetes therapy
    Biomaterials (IF 10.273) Pub Date : 2019-12-26
    Alexander E. Vlahos; Sean M. Kinney; Benjamin R. Kingston; Sara Keshavjee; So-Yoon Won; Anastasiya Martyts; Warren W.C. Chan; Michael V. Sefton

    Pancreatic islets are fragile cell clusters and many isolated islets are not suitable for transplantation. Furthermore, following transplantation, islets will experience a state of hypoxia and poor nutrient diffusion before revascularization, which is detrimental to islet survival; this is affected by islet size and health. Here we engineered tuneable size-controlled pseudo-islets created by dispersing de-aggregated islets in an endothelialized collagen scaffold. This supported subcutaneous engraftment, which returned streptozotocin-induced diabetic mice to normoglycemia. Whole-implant imaging after tissue clearing demonstrated pseudo-islets regenerated their vascular architecture and insulin-secreting β-cells were within 5 μm of a perfusable vessel – a feature unique to this approach. By using an endothelialized collagen scaffold, this work highlights a novel “bottom-up” approach to islet engineering that provides control over the size and composition of the constructs, while enabling the critical ability to revascularize and engraft when transplanted into the clinically useful subcutaneous space.

    更新日期:2019-12-27
  • Three-dimensional cell-printing of advanced renal tubular tissue analogue
    Biomaterials (IF 10.273) Pub Date : 2019-12-26
    Narendra K. Singh; Wonil Han; Sun Ah Nam; Jin Won Kim; Jae Yun Kim; Yong Kyun Kim; Dong-Woo Cho

    Despite significant progress in the development of renal tissue, recapitulation of perfusable complex renal tubular tissue with clinically relevant cellular heterogeneity is still remaining a challenge. In this study, using coaxial 3D cell-printing technique, we present microfluidic hollow tubes to realize tubular/vascular renal parenchyma composed of renal tubular epithelial and endothelial cells, respectively. We developed a functional hybrid bioink that inherits microenvironments for vascularized native kidney tissue with rapidly crosslinkable character to optimize cell functionality and retain the predefined hollow tubular structure. In addition, the novel bioink and 3D coaxial cell-printing technique provided a complex tube with tunable feature of monolayer and bilayer structure across the length of printed tube. Through prototyping a vascularized renal proximal tubule-on-a-chip, we showed its applicability to novel microfluidic renal tissue models. The renal subcapsular transplantation of the hollow tubes showed a long-term graft survival with the therapeutic capability of the tubular constructs in in vivo model of renal disease, which serves their applicability in regenerative medicine.

    更新日期:2019-12-27
  • HPMA-based star polymer biomaterials with tuneable structure and biodegradability tailored for advanced drug delivery to solid tumours
    Biomaterials (IF 10.273) Pub Date : 2019-12-26
    Libor Kostka; Lenka Kotrchová; Vladimír Šubr; Alena Libánská; Carolina A. Ferreira; Iva Malátová; Hye Jin Lee; Todd E. Barnhart; Jonathan W. Engle; Weibo Cai; Milada Šírová; Tomáš Etrych

    Design, controlled synthesis, physico-chemical and biological characteristics of novel well-defined biodegradable star-shaped copolymers intended for advanced drug delivery is described. These new biocompatible star copolymers were synthesised by grafting monodispersed semitelechelic linear (sL) N-(2-hydroxypropyl)methacrylamide copolymers onto a 2,2-bis(hydroxymethyl)propionic acid (bisMPA)-based polyester dendritic core of various structures. The hydrodynamic diameter of the star copolymer biomaterials can be tuned from 13 to 31 nm and could be adjusted to a given purpose by proper selection of the bisMPA dendritic core type and generation and by considering the sL copolymer molecular weight and polymer-to-core molar ratio. The hydrolytic degradation was proved for both the star copolymers containing either dendron or dendrimer core, showing the spontaneous hydrolysis in duration of few weeks. Finally, it was shown that the therapy with the biodegradable star conjugate with attached doxorubicin strongly suppresses the tumour growth in mice and is fully curative in most of the treated animals at dose corresponding approximately to one fourth of maximum tolerated dose (MTD) value. Both new biodegradable systems show superior efficacy and tumour accumulation over the first generation of star copolymers containing non-degradable PAMAM core.

    更新日期:2019-12-27
  • Could 3D models of cancer enhance drug screening?
    Biomaterials (IF 10.273) Pub Date : 2019-12-26
    Virginia Brancato; Joaquim Miguel Oliveira; Vitor Manuel Correlo; Rui Luis Reis; Subhas C. Kundu

    Cancer is a multifaceted pathology, where cellular and acellular players interact to drive cancer progression and, in the worst-case, metastasis. The current methods to investigate the heterogeneous nature of cancer are inadequate, since they rely on 2D cell cultures and animal models. The cell line-based drug efficacy and toxicity assays are not able to predict the tumor response to anti-cancer agents and it is already widely discussed how molecular pathway are not recapitulated in vitro so called flat biology. On the other side, animal models often fail to detect the side-effects of drugs, mimic the metastatic progression or the interaction between cancer and immune system, due to biologic difference in human and animals. Moreover, ethical and regulatory issues limit animal experimentation. Every year pharma/biotech companies lose resources in drug discovery and testing processes that are successful only in 5% of the cases. There is an urgent need to validate accurate and predictive platforms in order to enhance drug-testing process taking into account the physiopathology of the tumor microenvironment. Three dimensional in vitro tumor models could enhance drug manufactures in developing effective drugs for cancer diseases. The 3D in vitro cancer models can improve the predictability of toxicity and drug sensitivity in cancer. Despite the demonstrated advantages of 3D in vitro disease systems when compared to 2D culture and animal models, they still do not reach the standardization required for preclinical trials. This review highlights in vitro models that may be used as preclinical models, accelerating the drug development process towards more precise and personalized standard of care for cancer patients. We describe the state-of-the art of 3D in vitro culture systems, with a focus on how these different approaches could be coupled in order to achieve a compromise between standardization and reliability in recapitulating tumor microenvironment and drug response.

    更新日期:2019-12-27
  • Magnetic resonance energy transfer for in vivo glutathione susceptibility weighted imaging
    Biomaterials (IF 10.273) Pub Date : 2019-12-26
    Kun Wang; Huilin Zhang; Aijun Shen; Peiran Zhao; Xianfu Meng; Xiaoyan Chen; Yang Liu; Yanyan Liu; Teng Gong; Wanlu Wu; Xiangming Fang; Peijun Wang; Wenbo Bu
    更新日期:2019-12-27
  • Targeting downstream subcellular YAP activity as a function of matrix stiffness with Verteporfin-encapsulated chitosan microsphere attenuates osteoarthritis
    Biomaterials (IF 10.273) Pub Date : 2019-12-26
    Xianzhu Zhang; Dandan Cai; Feifei Zhou; Jie Yu; Xinyu Wu; Dongsheng Yu; Yiwei Zou; Yi Hong; Chunhui Yuan; Yishan Chen; Zongyou Pan; Varitsara Bunpetch; Heng Sun; Chengrui An; Toh Yi-Chin; Hongwei Ouyang; Shufang Zhang

    Changes in the stiffness of chondrocyte extracellular matrix (ECM) are involved in the pathological progression of osteoarthritis (OA). However, the downstream responses of cartilage ECM stiffness are still unclear. YAP (Yes-associated protein) has been extensively studied as a mechanotransducer, we thus hypothesized that by targeting the downstream molecule activity of ECM stiffness could maintain chondrocyte phenotype and prevent cartilage degeneration in OA. Here, we showed that human cartilage matrix stiffened during pathological progression of OA, and the chondrocyte YAP activity was associated with ECM stiffness. We then mimicked the physiological and pathological stiffness of human cartilage by using PDMS-based substrates, and found that YAP was activated in chondrocytes seeded on stiff substrate, gradually losing their phenotype. In addition, it was observed that YAP was also significantly activated in mice OA development, and conditional knockout (cKO) of YAP in mice preserved collagen II expression and protected cartilage from degeneration in the OA model. Furthermore, intra-articular injection of YAP-selective inhibitor, Verteporfin, significantly maintained cartilage homeostasis in mice OA model. This study indicates that the application of mechanotransducer-targeted drugs could be a potential therapeutic approach for cartilage repair in OA.

    更新日期:2019-12-27
  • Long circulating photoactivable nanomicelles with tumor localized activation and ROS triggered self-accelerating drug release for enhanced locoregional chemo-photodynamic therapy
    Biomaterials (IF 10.273) Pub Date : 2019-12-26
    Saji Uthaman; Shameer Pillarisetti; Ansuja Pulickal Mathew; Yugyeong Kim; Woo Kyun Bae; Kang Moo Huh; In-Kyu Park

    Although chemo-photodynamic therapy demonstrates promising synergetic therapeutic effect in malignant cancers, the currently available nanocarriers offer the limited capabilities for selective toxicity, drug release and tumor penetration. Herein, we developed photoactivatable nanomicelles, which are constructed by self-assembling of poly (ethylene glycol) (PEG)-stearamine (C18) conjugate (PTS) with a ROS-sensitive thioketal linker (TL) and co-loaded with doxorubicin (DOX) and photosensitizer pheophorbide A (PhA), for enhanced locoregional chemo-photodynamic therapy. Upon accumulation in tumor region, the resulting PTS nanomicelles loaded with Dox and PhA (PTS-DP) demonstrated reactive oxygen species (ROS) cascade responsive release of the DOX and PhA loaded inside. Initial intracellular release of DOX and PhA from the PTS-DP was triggered by the intrinsic presence of endogenous ROS within cancer cells. Furthermore, upon laser irradiation on the tumor region, enhanced singlet oxygen (1O2) was generated by PhA released initially in cancer cells, which in turns accelerated the cytoplasmic release of DOX through rapid dissociation of nanomicelles. The gradual elevation of local ROS level generated by light-activated PhA subsequent ROS-triggered release of DOX synergistically inhibited tumor growth and enhances the anti-tumor immunity. Findings of our study suggested that ROS-sensitive PTS nanomicelles could be a promising and innovative nanocarrier for locoregional chemo-photodynamic therapy.

    更新日期:2019-12-27
  • Dual-stimuli responsive nanotheranostics for mild hyperthermia enhanced inhibition of Wnt/β-catenin signaling
    Biomaterials (IF 10.273) Pub Date : 2019-12-24
    Tao Feng; Liang Zhou; Zhongyuan Wang; Chunxiao Li; Yifan Zhang; Jing Lin; Desheng Lu; Peng Huang

    Wnt/β-catenin signaling cascade is highly associated with tumorigenesis and progression of various cancers. Targeting Wnt/β-catenin signaling exhibits a promising way for cancer treatment. Herein, dual-stimuli responsive nanotheranostics was synthesized, which was composed of melanin coated magnetic nanoparticles (MMNs) and Wnt signaling inhibitor obatoclax (OBX) for multimodality imaging guided mild hyperthermia-enhanced chemotherapy. The MMNs could be used as contrast agents for magnetic resonance imaging (MRI) and photoacoustic imaging (PAI) guided photothermal therapy. In addition, OBX-loaded MMNs (OBX-MMNs) were specific response to both pH changes and near-infrared (NIR) light illumination, which could trigger OBX release. Most intriguingly, tumor tissue accumulation and cellular internalization of this nanotheranostics could be dramatically enhanced through mild hyperthermia generated by laser-irradiated MMNs. Laser irradiation exhibited efficient chemotherapeutic outcome through enhancing OBX-mediated inhibition of the Wnt/β-catenin signaling. Our results indicated the as-prepared OBX-MMNs hold great potential for MR/PA dual-modal imaging guided mild hyperthermia-enhanced chemotherapy.

    更新日期:2019-12-25
  • In situ gas foaming based on magnesium particle degradation: A novel approach to fabricate injectable macroporous hydrogels
    Biomaterials (IF 10.273) Pub Date : 2019-12-24
    Yanmei Tang; Sihan Lin; Shi Yin; Fei Jiang; Mingliang Zhou; Guangzheng Yang; Ningjia Sun; Wenjie Zhang; Xinquan Jiang

    Injectable hydrogels are attractive biomaterials for cell delivery in tissue engineering. However, the in vivo viability of transplanted cells remains limited. Typically, macroporous structures constructed in hydrogels are utilized to enhance oxygen and nutrients diffusion for cell survival and to promote integration between the material and host tissue. A new gas-foaming method to generate pores was proposed by directly adding Mg particles into cell-laden hydrogel solutions, taking advantage of the H2 gas formed during the degradation of Mg. The optimization design of the size and amount of Mg particles added into the hydrogels was investigated. Improved cell viability and proliferation were demonstrated in the group with Mg particles. Additionally, Mg2+ ions generated during Mg degradation facilitated the osteogenic differentiation of stem cells encapsulated in hydrogels. Extensive vascularized bone regeneration in the femoral defects of rats revealed that the use of Mg particles as the foaming agent is feasible, endowing injectable hydrogels with optimized porosity and enhanced bioactivity, and providing a new strategy for future designs of porous hydrogels in tissue engineering.

    更新日期:2019-12-25
  • Patient-derived scaffolds uncover breast cancer promoting properties of the microenvironment
    Biomaterials (IF 10.273) Pub Date : 2019-12-23
    Göran Landberg; Paul Fitzpatrick; Pauline Isakson; Emma Jonasson; Joakim Karlsson; Erik Larsson; Andreas Svanström; Svanheidur Rafnsdottir; Emma Persson; Anna Gustafsson; Daniel Andersson; Jennifer Rosendahl; Sarunas Petronis; Parmida Ranji; Pernilla Gregersson; Ylva Magnusson; Joakim Håkansson; Anders Ståhlberg

    Tumor cells interact with the microenvironment that specifically supports and promotes tumor development. Key components in the tumor environment have been linked to various aggressive cancer features and can further influence the presence of subpopulations of cancer cells with specific functions, including cancer stem cells and migratory cells. To model and further understand the influence of a specific microenvironments we have developed an experimental platform using cell-free patient-derived scaffolds (PDSs) from primary breast cancers infiltrated with standardized breast cancer cell lines. This PDS culture system induced a series of orchestrated changes in differentiation, epithelial-mesenchymal transition, stemness and proliferation of the cancer cell population, where an increased cancer stem cell pool was confirmed using functional assays. Furthermore, global gene expression profiling showed that PDS cultures were similar to xenograft cultures. Mass spectrometry analyses of cell-free PDS identified subgroups based on their protein composition that were linked to clinical properties, including tumor grade. Finally, we observed that an induction of epithelial-mesenchymal transition-related genes in cancer cells growing on the PDSs were significantly associated with clinical disease recurrences in breast cancer patients. Patient-derived scaffolds thus mimics in vivo-like growth conditions and uncovers unique information about the malignancy-inducing properties of tumor microenvironment.

    更新日期:2019-12-25
  • Lipid-based nanodelivery approaches for dopamine-replacement therapies in Parkinson’s disease: from preclinical to translational studies
    Biomaterials (IF 10.273) Pub Date : 2019-12-23
    Govindarajan Karthivashan; Palanivel Ganesan; Shin-Young Park; Ho-Won Lee; Dong-Kug Choi

    The incidence of Parkinson's disease (PD), the second most common neurodegenerative disorder, has increased exponentially as the global population continues to age. Although the etiological factors contributing to PD remain uncertain, its average incidence rate is reported to be 1% of the global population older than 60 years. PD is primarily characterized by the progressive loss of dopaminergic (DAergic) neurons and/or associated neuronal networks and the subsequent depletion of dopamine (DA) levels in the brain. Thus, DA or levodopa (L-dopa), a precursor of DA, represent cardinal targets for both idiopathic and symptomatic PD therapeutics. While several therapeutic strategies have been investigated over the past decade for their abilities to curb the progression of PD, an effective cure for PD is currently unavailable. Even DA replacement therapy, an effective PD therapeutic strategy that provides an exogenous supply of DA or L-dopa, has been hindered by severe challenges, such as a poor capacity to bypass the blood–brain barrier and inadequate bioavailability. Nevertheless, with recent advances in nanotechnology, several drug delivery systems have been developed to bypass the barriers associated with central nervous system therapeutics. In here, we sought to describe the adapted lipid-based nanodrug delivery systems used in the field of PD therapeutics and their recent advances, with a particular focus placed on DA replacement therapies. This work initially explores the background of PD; offers descriptions of the most recent molecular targets; currently available clinical medications/limitations; an overview of several lipid-based PD nanotherapeutics, functionalized nanoparticles, and technical aspects in brain delivery; and, finally, presents future perspectives to enhance the use of nanotherapeutics in PD treatment.

    更新日期:2019-12-23
  • Orbital floor repair using patient specific osteoinductive implant made by stereolithography
    Biomaterials (IF 10.273) Pub Date : 2019-12-23
    Olivier Guillaume; Mike A. Geven; Viktor Varjas; Peter Varga; Dominic Gehweiler; Vincent A. Stadelmann; Tanja Smidt; Stephan Zeiter; Christoph Sprecher; Ruud R.M. Bos; Dirk W. Grijpma; Mauro Alini; Huipin Yuan; Geoff R. Richards; Tingting Tang; Ling Qin; Lai Yuxiao; Peng Jiang; David Eglin

    The orbital floor (OF) is an anatomical location in the craniomaxillofacial (CMF) region known to be highly variable in shape and size. When fractured, implants commonly consisting of titanium meshes are customized by plying and crude hand-shaping. Nevertheless, more precise customized synthetic grafts are needed to meticulously reconstruct the patients’ OF anatomy with better fidelity. As alternative to titanium mesh implants dedicated to OF repair, we propose a flexible patient-specific implant (PSI) made by stereolithography (SLA), offering a high degree of control over its geometry and architecture. The PSI is made of biodegradable poly(trimethylene carbonate) (PTMC) loaded with 40 wt % of hydroxyapatite (called Osteo-PTMC). In this work, we developed a complete work-flow for the additive manufacturing of PSIs to be used to repair the fractured OF, which is clinically relevant for individualized medicine. This work-flow consists of (i) the surgical planning, (ii) the design of virtual PSIs and (iii) their fabrication by SLA, (iv) the monitoring and (v) the biological evaluation in a preclinical large-animal model. We have found that once implanted, titanium meshes resulted in fibrous tissue encapsulation, whereas Osteo-PMTC resulted in rapid neovascularization and bone morphogenesis, both ectopically and in the OF region, and without the need of additional biotherapeutics such as bone morphogenic proteins. Our study supports the hypothesis that the composite osteoinductive Osteo-PTMC brings advantages compared to standard titanium mesh, by stimulating bone neoformation in the OF defects. PSIs made of Osteo-PTMC represent a significant advancement for patients whereby the anatomical characteristics of the OF defect restrict the utilization of traditional hand-shaped titanium mesh.

    更新日期:2019-12-23
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