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Mechanical Properties of Bioengineered Corneal Stroma (Adv. Healthcare Mater. 20/2021)
Nello Formisano,Cas van der Putten,Rhiannon Grant,Gozde Sahin,Roman K. Truckenmüller,Carlijn V. C. Bouten,Nicholas A. Kurniawan,Stefan Giselbrecht
doi : 10.1002/adhm.202170094
Volume 10, Issue 20 2170094
Conjugate Electrospun 3D Gelatin Nanofiber Sponge for Rapid Hemostasis (Adv. Healthcare Mater. 20/2021)
Xianrui Xie,Dan Li,Yujie Chen,Yihong Shen,Fan Yu,Wei Wang,Zhengchao Yuan,Yosry Morsi,Jinglei Wu,Xiumei Mo
doi : 10.1002/adhm.202170095
Volume 10, Issue 20 2170095
Microfluidic Tandem Mechanical Sorting System for Enhanced Cancer Stem Cell Isolation and Ingredient Screening (Adv. Healthcare Mater. 20/2021)
Yuanyuan Jia,Peiliang Shen,Tao Yan,Weijia Zhou,Jia Sun,Xin Han
doi : 10.1002/adhm.202170099
Volume 10, Issue 20 2170099
Protease Responsive Nanogels for Transcytosis across the Blood?Brain Barrier and Intracellular Delivery of Radiopharmaceuticals to Brain Tumor Cells (Adv. Healthcare Mater. 20/2021)
Smriti Singh,Natascha Drude,Lena Blank,Prachi Bharat Desai,Hiltrud Königs,Stephan Rütten,Karl-Josef Langen,Martin Möller,Felix M. Mottaghy,Agnieszka Morgenroth
doi : 10.1002/adhm.202170100
Volume 10, Issue 20 2170100
Multifunctional Polymeric Nanosystems for Dual-Targeted Combinatorial Chemo/Antiangiogenesis Therapy of Tumors
Fatima Zohra Dahmani,Yan Xiao,Juan Zhang,Yao Yu,Jianping Zhou,Jing Yao
doi : 10.1002/adhm.202101501
Volume 10, Issue 20 2101501
3D Printing Nanoscale Bioactive Glass Scaffolds Enhance Osteoblast Migration and Extramembranous Osteogenesis through Stimulating Immunomodulation
Fujian Zhao,Weihan Xie,Wen Zhang,Xiaoling Fu,Wendong Gao,Bo Lei,Xiaofeng Chen*
doi : 10.1002/adhm.202101840
Volume 10, Issue 20 2101840
Improved Small Extracellular Vesicle Secretion of Rat Adipose-Derived Stem Cells by Microgrooved Substrates through Upregulation of the ESCRT-III-Associated Protein Alix
Yurong Ji,Weiju Han,Xiaoling Fu,Jing Li,Qi Wu,Yingjun Wang
doi : 10.1002/adhm.202101876
Volume 10, Issue 20 2101876
Mechanical Properties of Bioengineered Corneal Stroma
Nello Formisano,Cas van der Putten,Rhiannon Grant,Gozde Sahin,Roman K. Truckenmüller,Carlijn V. C. Bouten,Nicholas A. Kurniawan,Stefan Giselbrecht
doi : 10.1002/adhm.202100972
Volume 10, Issue 20 2100972
For the majority of patients with severe corneal injury or disease, corneal transplantation is the only suitable treatment option. Unfortunately, the demand for donor corneas greatly exceeds the availability. To overcome shortage issues, a myriad of bioengineered constructs have been developed as mimetics of the corneal stroma over the last few decades. Despite the sheer number of bioengineered stromas developed , these implants fail clinical trials exhibiting poor tissue integration and adverse effects in vivo. Such shortcomings can partially be ascribed to poor biomechanical performance. In this review, existing approaches for bioengineering corneal stromal constructs and their mechanical properties are described. The information collected in this review can be used to critically analyze the biomechanical properties of future stromal constructs, which are often overlooked, but can determine the failure or success of corresponding implants.
Recapitulation of Thymic Function by Tissue Engineering Strategies
Catarina S. Silva,Rui L. Reis,Albino Martins,Nuno M. Neves
doi : 10.1002/adhm.202100773
Volume 10, Issue 20 2100773
The thymus is responsible for the development and selection of T lymphocytes, which in turn also participate in the maturation of thymic epithelial cells. These events occur through the close interactions between hematopoietic stem cells and developing thymocytes with the thymic stromal cells within an intricate 3D network. The complex thymic microenvironment and function, and the current therapies to induce thymic regeneration or to overcome the lack of a functional thymus are herein reviewed. The recapitulation of the thymic function using tissue engineering strategies has been explored as a way to control the body's tolerance to external grafts and to generate ex vivo T cells for transplantation. In this review, the main advances in the thymus tissue engineering field are disclosed, including both scaffold- and cell-based strategies. In light of the current gaps and limitations of the developed systems, the design of novel biomaterials for this purpose with unique features is also discussed.
Systematic Comparison of Biomaterials-Based Strategies for Osteochondral and Chondral Repair in Large Animal Models
Arlyng G. González Vázquez,Lia A. Blokpoel Ferreras,Kathleen E. Bennett,Sarah M. Casey,Pieter AJ Brama,Fergal J. O'Brien
doi : 10.1002/adhm.202100878
Volume 10, Issue 20 2100878
Joint repair remains a major challenge in orthopaedics. Recent progress in biomaterial design has led to the fabrication of a plethora of promising devices. Pre-clinical testing of any joint repair strategy typically requires the use of large animal models (e.g., sheep, goat, pig or horse). Despite the key role of such models in clinical translation, there is still a lack of consensus regarding optimal experimental design, making it difficult to draw conclusions on their efficacy. In this context, the authors performed a systematic literature review and a risk of bias assessment on large animal models published between 2010 and 2020, to identify key experimental parameters that significantly affect the biomaterial therapeutic outcome and clinical translation potential (including defect localization, animal age/maturity, selection of controls, cell-free versus cell-laden). They determined that mechanically strong biomaterials perform better at the femoral condyles; while highlighted the importance of including native tissue controls to better evaluate the quality of the newly formed tissue. Finally, in cell-laded biomaterials, the pre-culture conditions played a more important role in defect repair than the cell type. In summary, here they present a systematic evaluation on how the experimental design of preclinical models influences biomaterial-based therapeutic outcomes in joint repair.
Sensing Inflammation Biomarkers with Electrolyte-Gated Organic Electronic Transistors
Bernhard Burtscher,Pamela Allison Manco Urbina,Chiara Diacci,Simone Borghi,Marcello Pinti,Andrea Cossarizza,Carlo Salvarani,Magnus Berggren,Fabio Biscarini,Daniel T. Simon,Carlo A. Bortolotti
doi : 10.1002/adhm.202100955
Volume 10, Issue 20 2100955
An overview of cytokine biosensing is provided, with a focus on the opportunities provided by organic electronic platforms for monitoring these inflammation biomarkers which manifest at ultralow concentration levels in physiopathological conditions. Specifically, two of the field's state-of-the-art technologies—organic electrochemical transistors (OECTs) and electrolyte gated organic field effect transistors (EGOFETs)—and their use in sensing cytokines and other proteins associated with inflammation are a particular focus. The overview will include an introduction to current clinical and “gold standard” quantification techniques and their limitations in terms of cost, time, and required infrastructure. A critical review of recent progress with OECT- and EGOFET-based protein biosensors is presented, alongside a discussion onthe future of these technologies in the years and decades ahead. This is especially timely as the world grapples with limited healthcare diagnostics during the Coronavirus disease (COVID-19)pandemic where one of the worst-case scenarios for patients is the “cytokine storm.” Clearly, low-cost point-of-care technologies provided by OECTs and EGOFETs can ease the global burden on healthcare systems and support professionals by providing unprecedented wealth of data that can help to monitor disease progression in real time.
Overcoming the Dependence on Animal Models for Osteoarthritis Therapeutics – The Promises and Prospects of In Vitro Models
Yogendra Pratap Singh,Joseph Christakiran Moses,Nandana Bhardwaj,Biman B. Mandal
doi : 10.1002/adhm.202100961
Volume 10, Issue 20 2100961
Osteoarthritis (OA) is a musculoskeletal disease characterized by progressive degeneration of osteochondral tissues. Current treatment is restricted to the reduction of pain and loss of function of the joint. To better comprehend the OA pathophysiological conditions, several models are employed, however; there is no consensus on a suitable model. In this review, different in vitro models being developed for possible therapeutic intervention of OA are outlined. Herein, various in vitro OA models starting from 2D model, co-culture model, 3D models, dynamic culture model to advanced technologies-based models such as 3D bioprinting, bioassembly, organoids, and organ-on-chip-based models are discussed with their advantages and disadvantages. Besides, different growth factors, cytokines, and chemicals being utilized for induction of OA condition are reviewed in detail. Furthermore, there is focus on scrutinizing different molecular and possible therapeutic targets for better understanding the mechanisms and OA therapeutics. Finally, the underlying challenges associated with in vitro models are discussed followed by future prospective. Taken together, a comprehensive overview of in vitro OA models, factors to induce OA-like conditions, and intricate molecular targets with the potential to develop personalized osteoarthritis therapeutics in the future with clinical translation is provided.
Advances in Encapsulation and Delivery Strategies for Islet Transplantation
Siying Wu,Liying Wang,Yifen Fang,Hai Huang,Xinru You,Jun Wu
doi : 10.1002/adhm.202100965
Volume 10, Issue 20 2100965
Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease caused by the destruction of pancreatic ?-cells in response to autoimmune reactions. Shapiro et al. conducted novel islet transplantation with a glucocorticoid-free immunosuppressive agent in 2000 and achieved great success; since then, islet transplantation has been increasingly regarded as a promising strategy for the curative treatment of T1DM. However, many unavoidable challenges, such as a lack of donors, poor revascularization, blood-mediated inflammatory reactions, hypoxia, and side effects caused by immunosuppression have severely hindered the widespread application of islet transplantation in clinics. Biomaterial-based encapsulation and delivery strategies are proposed for overcoming these obstacles, and have demonstrated remarkable improvements in islet transplantation outcomes. Herein, the major problems faced by islet transplantation are summarized and updated biomaterial-based strategies for islet transplantation, including islet encapsulation across different scales, delivery of stem cell-derived beta cells, co-delivery of islets with accessory cells and immunomodulatory molecules are highlighted.
Prospects and Challenges of MXenes as Emerging Sensing Materials for Flexible and Wearable Breath-Based Biomarker Diagnosis
Angga Hermawan,Tahta Amrillah,Anung Riapanitra,Wee-Jun Ong,Shu Yin
doi : 10.1002/adhm.202100970
Volume 10, Issue 20 2100970
A fully integrated, flexible, and functional sensing device for exhaled breath analysis drastically transforms conventional medical diagnosis to non-invasive, low-cost, real-time, and personalized health care. 2D materials based on MXenes offer multiple advantages for accurately detecting various breath biomarkers compared to conventional semiconducting oxides. High surface sensitivity, large surface-to-weight ratio, room temperature detection, and easy-to-assemble structures are vital parameters for such sensing devices in which MXenes have demonstrated all these properties both experimentally and theoretically. So far, MXenes-based flexible sensor is successfully fabricated at a lab-scale and is predicted to be translated into clinical practice within the next few years. This review presents a potential application of MXenes as emerging materials for flexible and wearable sensor devices. The biomarkers from exhaled breath are described first, with emphasis on metabolic processes and diseases indicated by abnormal biomarkers. Then, biomarkers sensing performances provided by MXenes families and the enhancement strategies are discussed. The method of fabrications toward MXenes integration into various flexible substrates is summarized. Finally, the fundamental challenges and prospects, including portable integration with Internet-of-Thing (IoT) and Artificial Intelligence (AI), are addressed to realize marketization.
Triboelectric Nanogenerators for Self-Powered Wound Healing (Adv. Healthcare Mater. 20/2021)
Xiao Xiao,Xiao Xiao,Ardo Nashalian,Alberto Libanori,Yunsheng Fang,Xiyao Li,Jun Chen
doi : 10.1002/adhm.202170097
Volume 10, Issue 20 2170097
Triboelectric Nanogenerators for Self-Powered Wound Healing
Xiao Xiao,Xiao Xiao,Ardo Nashalian,Alberto Libanori,Yunsheng Fang,Xiyao Li,Jun Chen
doi : 10.1002/adhm.202100975
Volume 10, Issue 20 2100975
Wound healing, one of the most complex processes in the human body, involves the spatial and temporal synchronization of a variety of cell types with distinct roles. Slow or nonhealing skin wounds have potentially life-threatening consequences, ranging from infection to scar, clot, and hemorrhage. Recently, the advent of triboelectric nanogenerators (TENGs) has brought about a plethora of self-powered wound healing opportunities, owing to their pertinent features, including wide range choices of constitutive biocompatible materials, simple fabrication, portable size, high output power, and low cost. Herein, a comprehensive review of TENGs as an emerging biotechnology for wound healing applications is presented and covered from three unique aspects: electrical stimulation, antibacterial activity, and drug delivery. To provide a broader context of TENGs applicable to wound healing applications, state-of-the-art designs are presented and discussed in each section. Although some challenges remain, TENGs are proving to be a promising platform for human-centric therapeutics in the era of Internet of Things. Consequently, TENGs for wound healing are expected to provide a new solution in wound management and play an essential role in the future of point-of-care interventions.
Smart Responsive Microarray Patches for Transdermal Drug Delivery and Biological Monitoring
Li Zhao,Chunyang Zhang,Juhaina M. Abu-Ershaid,Mingshan Li,Yaocun Li,Yara Naser,Xianbing Dai,Marco T. A. Abbate,Ryan F. Donnelly
doi : 10.1002/adhm.202100996
Volume 10, Issue 20 2100996
Traditional drug delivery routes possess various disadvantages which make them unsuitable for certain population groups, or indeed unsuitable for drugs with certain physicochemical properties. As a result, a variety of alternative drug delivery routes have been explored in recent decades, including transdermal drug delivery. One of the most promising novel transdermal drug delivery technologies is a microarray patch (MAP), which can bypass the outermost skin barrier and deliver drugs directly into the viable epidermis and dermis. Unlike traditional MAPs which release loaded cargo simultaneously upon insertion into the skin, stimuli responsive MAPs based on biological stimuli are able to precisely release the drug in response to the need for additional doses. Thus, smart MAPs that are only responsive to certain external stimuli are highly desirable, as they provide safer and more efficient drug delivery. In addition to drug delivery, they can also be used for biological monitoring, which further expands their applications.
Conjugate Electrospun 3D Gelatin Nanofiber Sponge for Rapid Hemostasis
Xianrui Xie,Dan Li,Yujie Chen,Yihong Shen,Fan Yu,Wei Wang,Zhengchao Yuan,Yosry Morsi,Jinglei Wu,Xiumei Mo
doi : 10.1002/adhm.202100918
Volume 10, Issue 20 2100918
Developing an excellent hemostatic material with good biocompatibility and high blood absorption capacity for rapid hemostasis of deep non-compressible hemorrhage remains a significant challenge. Herein, a novel conjugate electrospinning strategy to prepare an ultralight 3D gelatin sponge consisting of continuous interconnected nanofibers. This unique fluffy nanofiber structure endows the sponge with low density, high surface area, compressibility, and ultrastrong liquid absorption capacity. In vitro assessments show the gelatin nanofiber sponge has good cytocompatibility, high cell permeability, and low hemolysis ratio. The rat subcutaneous implantation studies demonstrate good biocompatibility and biodegradability of gelatin nanofiber sponge. Gelatin nanofiber sponge aggregates and activates platelets in large quantities to accelerate the formation of platelet embolism, and simultaneously escalates other extrinsic and intrinsic coagulation pathways, which collectively contribute to its superior hemostatic capacity. In vivo studies on an ear artery injury model and a liver trauma model of rabbits demonstrate that the gelatin nanofiber sponge rapidly induce stable blood clots with least blood loss compared to gelatin nanofiber membrane, medical gauze, and commercial gelatin hemostatic sponge. Hence, the gelatin nanofiber sponge holds great potential as an absorbable hemostatic agent for rapid hemostasis.
Microfluidic Tandem Mechanical Sorting System for Enhanced Cancer Stem Cell Isolation and Ingredient Screening
Yuanyuan Jia,Peiliang Shen,Tao Yan,Weijia Zhou,Jia Sun,Xin Han
doi : 10.1002/adhm.202100985
Volume 10, Issue 20 2100985
Robust isolation of cancer stem cells (CSCs) in a high-throughput, label-free manner is critical for understanding tumor heterogeneity and developing therapeutic strategies targeting CSCs. Cell-mechanics-based microfluidic sorting systems provide efficient and specific platforms for investigation of stem cell-like characteristics on the basis of cell deformability and cell-substrate adhesion properties. In the present study, a microfluidic tandem mechanical sorting system is developed to enrich CSCs with high flexibility and low adhesive capacity. In the integrated microfluidic system, cancer cells are driven by hydrodynamic forces to flow continuously through two featured devices, which are functionalized with sequentially variable microbarriers and surface-coated fluid mixing microchannels, respectively. Collected deformable and low-adhesive cancer cells exhibit enhanced stem cell-like properties with higher stemness and metastasis capacity both in vitro and in vivo, compared with each single device separation. Using these devices, bioactive natural compound screening targeting CSCs is performed and a potent therapeutic compound isoliquiritigenin from licorice is identified to inhibit the lung cancer stem cell phenotype. Taken together, this microfluidic tandem mechanical sorting system can facilitate drug screening targeting CSCs and the analysis of signals regulating CSC function in drug resistance.
Protease Responsive Nanogels for Transcytosis across the Blood?Brain Barrier and Intracellular Delivery of Radiopharmaceuticals to Brain Tumor Cells
Smriti Singh,Natascha Drude,Lena Blank,Prachi Bharat Desai,Hiltrud Königs,Stephan Rütten,Karl-Josef Langen,Martin Möller,Felix M. Mottaghy,Agnieszka Morgenroth
doi : 10.1002/adhm.202100812
Volume 10, Issue 20 2100812
Despite profound advances in treatment approaches, gliomas remain associated with very poor prognoses. The residual cells after incomplete resection often migrate and proliferate giving a seed for highly resistant gliomas. The efficacy of chemotherapeutic drugs is often strongly limited by their poor selectivity and the blood brain barrier (BBB). Therefore, the development of therapeutic carrier systems for efficient transport across the BBB and selective delivery to tumor cells remains one of the most complex problems facing molecular medicine and nano-biotechnology. To address this challenge, a stimuli sensitive nanogel is synthesized using pre-polymer approach for the effective delivery of nano-irradiation. The nanogels are cross-linked via matrix metalloproteinase (MMP-2,9) substrate and armed with Auger electron emitting drug 5-[125I]Iodo-4”-thio-2”-deoxyuridine ([125I]ITdU) which after release can be incorporated into the DNA of tumor cells. Functionalization with diphtheria toxin receptor ligand allows nanogel transcytosis across the BBB at tumor site. Functionalized nanogels efficiently and increasingly explore transcytosis via BBB co-cultured with glioblastoma cells. The subsequent nanogel degradation correlates with up-regulated MMP2/9. Released [125I]ITdU follows the thymidine salvage pathway ending in its incorporation into the DNA of tumor cells. With this concept, a highly efficient strategy for intracellular delivery of radiopharmaceuticals across the challenging BBB is presented.
Extrinsic Macrophages Protect While Tendon Progenitors Degrade: Insights from a Tissue Engineered Model of Tendon Compartmental Crosstalk
Tino Stauber,Maja Wolleb,Anja Duss,Patrick K. Jaeger,Irina Heggli,Amro A. Hussien,Ulrich Blache,Jess G. Snedeker
doi : 10.1002/adhm.202100741
Volume 10, Issue 20 2100741
Tendons are among the most mechanically stressed tissues of the body, with a functional core of type-I collagen fibers maintained by embedded stromal fibroblasts known as tenocytes. The intrinsic load-bearing core compartment of tendon is surrounded, nourished, and repaired by the extrinsic peritendon, a synovial-like tissue compartment with access to tendon stem/progenitor cells as well as blood monocytes. In vitro tendon model systems generally lack this important feature of tissue compartmentalization, while in vivo models are cumbersome when isolating multicellular mechanisms. To bridge this gap, an improved in vitro model of explanted tendon core stromal tissue (mouse tail tendon fascicles) surrounded by cell-laden collagen hydrogels that mimic extrinsic tissue compartments is suggested. Using this model, CD146+ tendon stem/progenitor cell and CD45+F4/80+ bone-marrow derived macrophage activity within a tendon injury-like niche are recapitulated. It is found that extrinsic stromal progenitors recruit to the damaged core, contribute to an overall increase in catabolic ECM gene expression, and accelerate the decrease in mechanical properties. Conversely, it is found that extrinsic bone-marrow derived macrophages in these conditions adopt a proresolution phenotype that mitigates rapid tissue breakdown by outwardly migrated tenocytes and F4/80+ “tenophages” from the intrinsic tissue core.
Diagnostic Radionuclides Labeled on Biomimetic Nanoparticles for Enhanced Follow-Up Photothermal Therapy of Cancer
Xuan Yi,Mengling Shen,Xinpei Liu,Jingyu Gu,Zewei Jiang,Lixing Xu,Kai Yang
doi : 10.1002/adhm.202100860
Volume 10, Issue 20 2100860
Imaging-guided local therapy is the most effective strategy to treat primary cancers in patients. However, the local therapeutic effect should be further improved under the premise of absence of induction of additional side effects. It would be meaningful to analyze the potential assistance of nuclear imaging to the follow-up treatments. In this study,cancer-targeted copper sulfide nanoparticles with 99mTc labeling (99mTc-M-CuS-PEG) are prepared using-cancer cell membranes as a synthesis reactor and applied for the potential single-photon emission computed tomography/photoacoustic imaging-guided and 99mTc-amplified photothermal therapy of cancer. Owing to the homologous targeting capability of the cancer cell membrane, M-CuS-PEG selectively accumulates in homologous tumor sites. After labeling with 99mTc, M-CuS-PEG with a high near-infrared light absorbance can realize bimodal imaging-guided photothermal therapy of cancer. Furthermore, the labeled 99mTc significantly enhances the cell uptake of M-CuS-PEG by inducing G2/M arrest of the cell cycle, further improving the photothermal antitumor effect, which is positively correlated with endocytosis of the photothermal conversion reagent. Therefore, a novel cancer-targeted theranostic nanoplatform is developed and it is revealed that the labeled 99mTc can not only guide but also amplify the subsequent therapy of cancer, providing a conceptual strategy for cancer theranostics with a high biosafety.
In–Situ-Sprayed Dual-Functional Immunotherapeutic Gel for Colorectal Cancer Postsurgical Treatment
Xinghui Si,Guofeng Ji,Sheng Ma,Yudi Xu,Jiayu Zhao,Yu Zhang,Zichao Huang,Zhaohui Tang,Wantong Song,Xuesi Chen
doi : 10.1002/adhm.202100862
Volume 10, Issue 20 2100862
Surgery remains the most preferred treatment options for colorectal cancer (CRC). Paradoxically, local recurrence and distant metastasis are usually accelerated postsurgery as a consequence of local and systemic immunosuppression caused by surgery. Therefore, modulating tumor postoperative immune microenvironment and activating systemic antitumor immunity are necessary supplementaries for CRC therapy. Here, an in-situ-sprayed immunotherapeutic gel loaded with anti-OX40 antibody (iSGels@aOX40) is reported for CRC postsurgical treatment. The iSGel is formed instantly after spraying with strong adhesion ability via crosslinking between tannic acid (TA) and poly(l-glutamic acid)-g-methoxy poly(ethylene glycol)/phenyl boronic acid (PLG-g-mPEG/PBA). TA not only serves as one component of the iSGel but also relieves the postsurgical immunosuppressive microenvironment by inhibiting the activity of cyclo-oxygenase-2 (COX-2). The aOX40 serves as an immune agonistic antibody and is released from the iSGel in a constant manner lasting for over 20 days. In a subcutaneous murine CRC model, the iSGels@aOX40 results in complete inhibition on tumor recurrence. In addition, the cured mice show resistance to tumor re-challenge, suggesting that immune memory effects are established after the iSGels@aOX40 treatment. In an orthotopic CRC peritoneal metastatic model, the iSGels@aOX40 also remarkably inhibits the growth of the abdominal metastatic tumors, suggesting great potential for clinical CRC therapy.
Anisometric Microstructures to Determine Minimal Critical Physical Cues Required for Neurite Alignment
Sitara Vedaraman,Amaury Perez-Tirado,Tamas Haraszti,Jose Gerardo-Nava,Akihiro Nishiguchi,Laura De Laporte
doi : 10.1002/adhm.202100874
Volume 10, Issue 20 2100874
In nerve regeneration, scaffolds play an important role in providing an artificial extracellular matrix with architectural, mechanical, and biochemical cues to bridge the site of injury. Directed nerve growth is a crucial aspect of nerve repair, often introduced by engineered scaffolds imparting linear tracks. The influence of physical cues, determined by well-defined architectures, has been mainly studied for implantable scaffolds and is usually limited to continuous guiding features. In this report, the potential of short anisometric microelements in inducing aligned neurite extension, their dimensions, and the role of vertical and horizontal distances between them, is investigated. This provides crucial information to create efficient injectable 3D materials with discontinuous, in situ magnetically oriented microstructures, like the Anisogel. By designing and fabricating periodic, anisometric, discreet guidance cues in a high-throughput 2D in vitro platform using two-photon lithography techniques, the authors are able to decipher the minimal guidance cues required for directed nerve growth along the major axis of the microelements. These features determine whether axons grow unidirectionally or cross paths via the open spaces between the elements, which is vital for the design of injectable Anisogels for enhanced nerve repair.
ROS-Responsive Boronate-Stabilized Polyphenol–Poloxamer 188 Assembled Dexamethasone Nanodrug for Macrophage Repolarization in Osteoarthritis Treatment
Xinxin Li,Xinyu Wang,Qingfeng Liu,Junjie Yan,Donghui Pan,Lizhen Wang,Yuping Xu,Fang Wang,Yuhang Liu,Xiaotian Li,Min Yang
doi : 10.1002/adhm.202100883
Volume 10, Issue 20 2100883
Osteoarthritis (OA) is a disabling joint disease associated with chronic inflammation. The polarization of macrophages plays the key role in inflammatory microenvironment of joint which is a therapeutic target for OA treatment. Herein, a boronate-stabilized polyphenol–poloxamer assembled dexamethasone nanodrug with reactive oxygen species (ROS)-responsive drug release behavior and ROS scavenging ability is prepared. Thanks to that, the nanodrug can efficiently inhibit the ROS and nitric oxide production in lipopolysaccharide-activated RAW264.7 macrophages and modulate macrophages M2 polarization at a much lower concentration than free drug dexamethasone. Furthermore, the monosodium iodoacetate-induced OA mice treated with this nanodrug is very similar with the normal mice with the evaluation of body weight and scores including clinical arthritis scores, claw circumference, and kinematics score. The inflammation associated angiogenesis is also reduced which revealed by 68Ga-labeled arginine-glycine-aspartic acid peptide micro-positron emission tomography imaging. Cartilage degradation and bone erosion in the joints are also inhibited by the nanodrug, along with the inhibition of proinflammatory cytokines. In addition, the biosafety of this nanodrug is also verified. This nanodrug with excellent immunomodulation properties can be used not only for OA therapy but also for other inflammatory diseases associated with excess oxidative stress and macrophage polarization.
Inkjet Printed Textile Force Sensitive Resistors for Wearable and Healthcare Devices
Beomjun Ju,Inhwan Kim,Braden M. Li,Caitlin G. Knowles,Amanda Mills,Landon Grace,Jesse S. Jur
doi : 10.1002/adhm.202100893
Volume 10, Issue 20 2100893
Pressure sensors for wearable healthcare devices, particularly force sensitive resistors (FSRs) are widely used to monitor physiological signals and human motions. However, current FSRs are not suitable for integration into wearable platforms. This work presents a novel technique for developing textile FSRs (TFSRs) using a combination of inkjet printing of metal-organic decomposition silver inks and heat pressing for facile integration into textiles. The insulating void by a thermoplastic polyurethane (TPU) membrane between the top and bottom textile electrodes creates an architectured piezoresistive structure. The structure functions as a simple logic switch where under a threshold pressure the electrodes make contact to create conductive paths (on-state) and without pressure return to the prior insulated condition (off-state). The TFSR can be controlled by arranging the number of layers and hole diameters of the TPU spacer to specify a wide range of activation pressures from 4.9 kPa to 7.1 MPa. For a use-case scenario in wearable healthcare technologies, the TFSR connected with a readout circuit and a mobile app shows highly stable signal acquisition from finger movement. According to the on/off state of the TFSR with LED bulbs by different weights, it can be utilized as a textile switch showing tactile feedback.
Biocompatible Micron-Scale Silk Fibers Fabricated by Microfluidic Wet Spinning
Arne Lüken,Matthias Geiger,Lea Steinbeck,Anna-Christin Joel,Angelika Lampert,John Linkhorst,Matthias Wessling
doi : 10.1002/adhm.202100898
Volume 10, Issue 20 2100898
For successful material deployment in tissue engineering, the material itself, its mechanical properties, and the microscopic geometry of the product are of particular interest. While silk is a widely applied protein-based tissue engineering material with strong mechanical properties, the size and shape of artificially spun silk fibers are limited by existing processes. This study adjusts a microfluidic spinneret to manufacture micron-sized wet-spun fibers with three different materials enabling diverse geometries for tissue engineering applications. The spinneret is direct laser written (DLW) inside a microfluidic polydimethylsiloxane (PDMS) chip using two-photon lithography, applying a novel surface treatment that enables a tight print-channel sealing. Alginate, polyacrylonitrile, and silk fibers with diameters down to 1 µm are spun, while the spinneret geometry controls the shape of the silk fiber, and the spinning process tailors the mechanical property. Cell-cultivation experiments affirm bio-compatibility and showcase an interplay between the cell-sized fibers and cells. The presented spinning process pushes the boundaries of fiber fabrication toward smaller diameters and more complex shapes with increased surface-to-volume ratio and will substantially contribute to future tailored tissue engineering materials for healthcare applications.
CHIR99021 Promotes hiPSC-Derived Cardiomyocyte Proliferation in Engineered 3D Microtissues
Ramona Hesselbarth,Tilman U. Esser,Kaveh Roshanbinfar,Stefan Schrüfer,Dirk W. Schubert,Felix B. Engel
doi : 10.1002/adhm.202100926
Volume 10, Issue 20 2100926
Cardiac tissue engineering is a promising strategy to generate human cardiac tissues for modeling cardiac diseases, screening for therapeutic drugs, and repairing the injured heart. Yet, several issues remain to be resolved including the generation of tissues with high cardiomyocyte density. Here, it is shown that the integration of the glycogen synthase kinase-3? inhibitor CHIR99021 in collagen I hydrogels promotes proliferation of human-induced pluripotent stem cell-derived (hiPSC) cardiomyocytes post-fabrication improving contractility of and calcium flow in engineered 3D cardiac microtissues. CHIR99021 has no effect on the gelation kinetics or the mechanical properties of collagen I hydrogels. Analysis of cell density and proliferation based on Ki-67 staining indicates that integration of CHIR99021 together with external CHIR99021 stimulation increases hiPSC-cardiomyocyte number by ?2-fold within 7 d post-fabrication. Analysis of the contractility of engineered cardiac tissues after another 3 d in the absence of external CHIR99021 shows that CHIR99021-induced hiPSC-cardiomyocyte proliferation results in synchronized calcium flow, rhythmic beating, increased speed of contraction and contraction amplitude, and reduced peak-to-peak time. The CHIR99021-stimulated engineered cardiac microtissues exhibit spontaneous rhythmic contractions for at least 35 d. Collectively, the data demonstrate the potential of induced cardiomyocyte proliferation to enhance engineered cardiac microtissues by increasing cardiomyocyte density.
Near-Infrared Light-Triggered Polyprodrug/siRNA Loaded Upconversion Nanoparticles for Multi-Modality Imaging and Synergistic Cancer Therapy
Gaizhen Kuang,Hongtong Lu,Shasha He,Hejian Xiong,Jie Yu,Qingfei Zhang,Yubin Huang
doi : 10.1002/adhm.202100938
Volume 10, Issue 20 2100938
Stimuli-responsive nanosystems have been widely applied as effective modalities for drug/gene co-delivery in cancer treatment. However, precise spatiotemporal manipulations of drug/gene co-delivery, as well as multi-modality imaging-guided cancer therapy, still remain a daunting challenge. Here, multifunctional polyprodrug/siRNA loaded upconversion nanoparticles (UCNPs) are reported that combine computed tomography (CT), magnetic resonance (MR), and upconversion luminescence (UCL) tri-modality imaging and near-infrared (NIR) light-activated drug/gene on-demand delivery. The photoactivatable platinum(IV) (Pt(IV))-backbone polymers (PPt) and the siRNA targeting polo-like kinase 1 (Plk1) are loaded on the surface of polyethyleneimine (PEI)-coated UCNPs (PUCNP) to obtain the multifunctional polyprodrug/siRNA loaded UCNPs (PUCNP@Pt@siPlk1). The PUCNP@Pt@siPlk1 can be served as a “nanotransducer” to convert NIR light (980 nm) into local ultraviolet (UV) to visible light for the cleavage of photosensitive PPt, resulting in the simultaneous on-demand release of high toxic platinum(II) (Pt(II)) and siPlk1. Meanwhile, the PUCNP@Pt@siPlk1 has CT, T1-weighted MR, and UCL tri-modality imaging abilities. Based on these merits, PUCNP@Pt@siPlk1 displayed excellent synergistic therapeutic efficacy via image-guided and NIR light-activated platinum-based chemotherapy and RNA interfering in vitro and in vivo. Thus, this developed nanosystem with NIR light-controlled drug/gene delivery and multi-modality imaging abilities, will display great potential in combining chemotherapy and gene therapy.
Plasmonically Enhanced CRISPR/Cas13a-Based Bioassay for Amplification-Free Detection of Cancer-Associated RNA
Lin Liu,Zheyu Wang,Yixuan Wang,Jingyi Luan,Jeremiah J. Morrissey,Rajesh R. Naik,Srikanth Singamaneni
doi : 10.1002/adhm.202100956
Volume 10, Issue 20 2100956
Novel methods that enable sensitive, accurate and rapid detection of RNA would not only benefit fundamental biological studies but also serve as diagnostic tools for various pathological conditions, including bacterial and viral infections and cancer. Although highly sensitive, existing methods for RNA detection involve long turn-around time and extensive capital equipment. Here, an ultrasensitive and amplification-free RNA quantification method is demonstrated by integrating CRISPR-Cas13a system with an ultrabright fluorescent nanolabel, plasmonic fluor. This plasmonically enhanced CRISPR-powered assay exhibits nearly 1000-fold lower limit-of-detection compared to conventional assay relying on enzymatic reporters. Using a xenograft tumor mouse model, it is demonstrated that this novel bioassay can be used for ultrasensitive and quantitative monitoring of cancer biomarker (lncRNA H19). The novel biodetection approach described here provides a rapid, ultrasensitive, and amplification-free strategy that can be broadly employed for detection of various RNA biomarkers, even in resource-limited settings.
Precise Targeting Therapy of Orthotopic Gastric Carcinoma by siRNA and Chemotherapeutic Drug Codelivered in pH-Sensitive Nano Platform
Quan Wang,Yu Tian,Lei Liu,Chuanrong Chen,Wei Zhang,Liting Wang,Qianqian Guo,Li Ding,Hao Fu,Hongjiang Song,Junyu Shi,Yourong Duan
doi : 10.1002/adhm.202100966
Volume 10, Issue 20 2100966
Gastric cancer is one of the most common malignant tumors, which remains as an obstacle to human health. Nowadays, targeted nanoparticles to gastric tumor tissues, provide new strategy for improved therapy but still remain challenging. The major hurdle of targeted therapeutic nanoparticles comes from the limited enrichment and poor selectivity of therapeutic agents in in situ tumor. Herein, a pH-sensitive targeted nano platform coloaded As2O3 and human epidermal growth factor receptor-2 (HER2)-siRNA (AH RNPs) is developed to achieve targeting therapy in orthotopic gastric carcinoma. AH RNPs can effectively prevent the degradation of siRNA and overcome the poor solubility of As2O3. In vitro studies show that AH RNPs could achieve synergistic inhibition of growth and metastasis on SGC7901 cells. Surprisingly, AH RNPs not only target gastric subcutaneous tumor, but also target in situ tumor, and express loaded genes in in situ tumor. Moreover, AH RNPs show excellent antitumor effect in orthotopic gastric tumor model and the anticancer mechanism is related about inhibiting the activation of ERK signal and downregulating the expression of cxc chemokine receptor 4 (CXCR4), HER2, MMP2, and MMP9 protein. This study provides a multi-functional vector for precise targeting therapy of gastric cancer, which may serve as a potential clinical application for future gastric cancer.
A 3D Bioprinted In Vitro Model of Pulmonary Artery Atresia to Evaluate Endothelial Cell Response to Microenvironment
Martin L. Tomov,Lilanni Perez,Liqun Ning,Huang Chen,Bowen Jing,Andrew Mingee,Sahar Ibrahim,Andrea S. Theus,Gabriella Kabboul,Katherine Do,Sai Raviteja Bhamidipati,Jordan Fischbach,Kevin McCoy,Byron A. Zambrano,Jianyi Zhang,Reza Avazmohammadi,Athanasios Mantalaris,Brooks D. Lindsey,David Frakes,Lakshmi Prasad Dasi,Vahid Serpooshan,Holly Bauser-Heaton
doi : 10.1002/adhm.202100968
Volume 10, Issue 20 2100968
Vascular atresia are often treated via transcatheter recanalization or surgical vascular anastomosis due to congenital malformations or coronary occlusions. The cellular response to vascular anastomosis or recanalization is, however, largely unknown and current techniques rely on restoration rather than optimization of flow into the atretic arteries. An improved understanding of cellular response post anastomosis may result in reduced restenosis. Here, an in vitro platform is used to model anastomosis in pulmonary arteries (PAs) and for procedural planning to reduce vascular restenosis. Bifurcated PAs are bioprinted within 3D hydrogel constructs to simulate a reestablished intervascular connection. The PA models are seeded with human endothelial cells and perfused at physiological flow rate to form endothelium. Particle image velocimetry and computational fluid dynamics modeling show close agreement in quantifying flow velocity and wall shear stress within the bioprinted arteries. These data are used to identify regions with greatest levels of shear stress alterations, prone to stenosis. Vascular geometry and flow hemodynamics significantly affect endothelial cell viability, proliferation, alignment, microcapillary formation, and metabolic bioprofiles. These integrated in vitro–in silico methods establish a unique platform to study complex cardiovascular diseases and can lead to direct clinical improvements in surgical planning for diseases of disturbed flow.
Mitochondrial Metabolism Targeted Nanoplatform for Efficient Triple-Negative Breast Cancer Combination Therapy
Lu Lu,Genhua Liu,Chuanchuan Lin,Ke Li,Tingting He,Jixi Zhang,Zhong Luo,Kaiyong Cai
doi : 10.1002/adhm.202100978
Volume 10, Issue 20 2100978
Tumor reprogram pathway of mitochondrial metabolism is an emerging approach for malignant tumor treatment, such as triple-negative breast cancer. In this study, a tumor/mitochondria cascaded targeting, adenosine-triphosphate (ATP) responsive nanocarrier of zeolitic imidazolate framework-90 (ZIF-90) for breast cancer combination therapy is reported. Atovaquone (AVO) and hemin are loaded into ZIF-90, then a peptide iRGD with tumor-targeting ability is modified on the ZIF-90 nanoplatform. Hemin can specifically degrade BTB and CNC homology1 (BACH1), resulting in the changes of mitochondrial metabolism, and AVO acts as the inhibitor of the electron transport chain (ETC). The degradation of BACH1 using hemin can effectively improve the anti-tumor efficiency of mitochondrial metabolism inhibitor AVO, by increasing dependency on mitochondrial respiration. This nanoplatform displays both tumor-targeting and mitochondria-targeting capacity with high level of ATP responsive drug release behavior. The specific characteristic of mitochondria-targeting ability of this nanoplatform can increase the accumulation of AVO in the mitochondria, and in turn, can effectively improve the inhibition of the ETC. Both in vitro and in vivo results reveal that this composite nanocarrier has excellent tumor inhibition ability with limited side effects. Accordingly, this study provides an attractive strategy in the mitochondrial metabolism for cancer targeted therapy.
K2Mn3[FeII(CN)6]2 NPs with High T1-Relaxivity Attributable to Water Coordination on the Mn(II) Center for Gastrointestinal Tract MR Imaging
Murthi S. Kandanapitiye,Thiloka M. Dassanayake,Arosha C. Dassanayake,John Shelestak,Robert J. Clements,Can Fernando,Songping D. Huang
doi : 10.1002/adhm.202100987
Volume 10, Issue 20 2100987
The lack of acid stability in the stomach and of temporal stability when moving through the gastrointestinal (GI) tract has made the development of oral magnetic resonance imaging (MRI) contrast agents based on the platform of Gd3+–complexes problematic.On the other hand, the negative contrast enhancement produced by the T2-weighted magnetic metal oxide nanoparticles (NPs) often renders the image readout difficult. Biocompatible NPs of the manganese Prussian blue analog K2Mn3[FeII(CN)6]2 exhibit extremely high stability under the acidic conditions of the gastric juice. Additionally, the high r1 relaxivity, low toxicity, and high temporal stability of such NPs offer great potential for the development of a true T1-weighted oral contrast agent for MRI of the entire GI tract.
Biomaterial Wettability Affects Fibrin Clot Structure and Fibrinolysis (Adv. Healthcare Mater. 20/2021)
Alexander M. Ruhoff,Jun Ki Hong,Lingzi Gao,Jasneil Singh,Clara Tran,Grace Mackie,Anna Waterhouse
doi : 10.1002/adhm.202170098
Volume 10, Issue 20 2170098
Biomaterial Wettability Affects Fibrin Clot Structure and Fibrinolysis
Alexander M. Ruhoff,Jun Ki Hong,Lingzi Gao,Jasneil Singh,Clara Tran,Grace Mackie,Anna Waterhouse
doi : 10.1002/adhm.202100988
Volume 10, Issue 20 2100988
Thrombosis on blood-contacting medical devices can cause patient fatalities through device failure and unstable thrombi causing embolism. The effect of material wettability on fibrin network formation, structure, and stability is poorly understood. Under static conditions, fibrin fiber network volume and density increase in clots formed on hydrophilic compared to hydrophobic polystyrene surfaces. This correlates with reduced plasma clotting time and increased factor XIIa (FXIIa) activity. These structural differences are consistent up to 50 µm away from the material surface and are FXIIa dependent. Fibrin forms fibers immediately at the material interface on hydrophilic surfaces but are incompletely formed in the first 5 µm above hydrophobic surfaces. Additionally, fibrin clots on hydrophobic surfaces have increased susceptibility to fibrinolysis compared to clots formed on hydrophilic surfaces. Under low-flow conditions, clots are still denser on hydrophilic surfaces, but only 5 µm above the surface, showing the combined effect of the surface wettability and coagulation factor dilution with low flow. Overall, wettability affects fibrin fiber formation at material interfaces, which leads to differences in bulk fibrin clot density and susceptibility to fibrinolysis. These findings have implications for thrombus formed in stagnant or low-flow regions of medical devices and the design of nonthrombogenic materials.
Size-Confined Effects of Nanostructures on Fibronectin-Induced Macrophage Inflammation on Titanium Implants
Haoning Qi,Miusi Shi,Yueqi Ni,Wenting Mo,Peng Zhang,Shuting Jiang,Yufeng Zhang,Xuliang Deng
doi : 10.1002/adhm.202100994
Volume 10, Issue 20 2100994
Macrophage activation determines the fate of biomaterials implantation. Though researches have shown that fibronectin (FN) is highly involved in integrin-induced macrophage activation on biomaterials, the mechanism of how nanosized structure affects macrophage behavior is still unknown. Here, titanium dioxide nanotube structures with different sizes are fabricated to investigate the effects of nanostructure on macrophage activation. Compared with larger sized nanotubes and smooth surface, 30 nm nanotubes exhibit considerable lesser pro-inflammatory properties on macrophage differentiation. Confocal protein observation and molecular dynamics simulation show that FN displays conformation changes on different nanotubes in a feature of “size-confined,” which causes the hiding of Arg-Gly-Asp (RGD) domain on other surfaces. The matching size of nanotube with FN allows the maximum exposure of RGD on 30 nm nanotubes, activating integrin-mediated focal adhesion kinase (FAK)-phosphatidylinositol-3 kinase ? (PI3K?) pathway to inhibit nuclear factor kappa B (NF-?B) signaling. In conclusion, this study explains the mechanism of nanostructural-biological signaling transduction in protein and molecular levels, as well as proposes a promising strategy for surface modification to regulate immune responses on bioimplants.
Rigidity Bridging Flexibility to Harmonize Three Excited-State Deactivation Pathways for NIR-II-Fluorescent-Imaging-Guided Phototherapy
Weijing Huang,Huocheng Yang,Zongxing Hu,Yifan Fan,Xiaofang Guan,Wenqi Feng,Zhihong Liu,Yao Sun
doi : 10.1002/adhm.202101003
Volume 10, Issue 20 2101003
Small organic phototherapeutic molecules of the second near-infrared (NIR-II) window (1000–1700 nm) serve as promising candidates for theranostics. However, developing such versatile agents for fluorescence-guided photodynamic/photothermal therapy remains a demanding task stirred by competitive energy dissipation pathways, including radiative decay, internal conversion, and intersystem crossing. To the best of current knowledge, the current paradigm for addressing the issue has deliberately approached the optimum balance among three deactivation processes through offsetting from each other, possibly leading to a comprehensively compromised theranostic efficacy. Few reports aim to modulate the three deactivation pathways excluding sacrificing any one of them. Herein, a molecular design strategy to construct a phototherapeutic organic fluorophore CCNU-1060, armed with NIR-II luorescence-guided phototherapeutic properties, is rationally developed. With a flexible motor, tetraphenylethene, bridged to the rigidified coplanar core boron-azadipyrromethene, the desired CCNU-1060 is subsequently encapsulated into an amphiphilic matrix to form CCNU-1060 nanoparticles (NPs), which match or transcend its precursor NJ-1060 NPs in the three energy dissipation processes. CCNU-1060 NPs are utilized to realize high-spatial vessel imaging and effective NIR-II fluorescence-guided phototherapeutic tumor ablation. This study unlocks a viewpoint of molecular engineering that simultaneously regulates multiple energy dissipation pathways for the construction of versatile phototherapy agents.
An Organic Nanotherapeutic Agent Self-Assembled from Cyanine and Cu (II) for Combined Photothermal and Chemodynamic Therapy
Xiaojing Li,Dongmei Xi,Mingwang Yang,Wen Sun,Xiaojun Peng,Jiangli Fan
doi : 10.1002/adhm.202101008
Volume 10, Issue 20 2101008
Although the combination of photothermal/chemodynamic therapy (PTT/CDT) based on various inorganic nanomaterials has promising anticancer effects, poor biocompatibility and biodegradability of inorganic nanoplatforms pose obstacles to their use in clinic. On the contrary, nanoscale metal?organic particles are considered to be a promising platform because of their biocompatibility and efficient metabolism. Herein, HA@Cy-Cu NPs are prepared using the coordination-driven assembly of cyanine dyes with Cu2+ ions. HA@Cy-Cu NPs demonstrate excellent synergistic PTT/CDT, a high photothermal conversion efficiency (43%), and enhanced photostability. Moreover, Cu2+ in the NPs can be reduced to Cu+ by glutathione (GSH) and can transform H2O2 to •OH, which down-regulates intracellular GSH levels and up-regulates significant oxidative damage. Therefore, promising in vivo tumor ablation is observed at a low dose of HA@Cy-Cu, suggesting that the combination of PTT/CDT greatly improved the antitumor performance. HA@Cy-Cu can further improve organic nano-systems for anti-tumor therapy by integrating PTT and CDT.
