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Topography and Permeability Analyses of Vasculature-on-a-Chip Using Scanning Probe Microscopies (Adv. Healthcare Mater. 21/2021)
Yuji Nashimoto,Minori Abe,Ryota Fujii,Noriko Taira,Hiroki Ida,Yasufumi Takahashi,Kosuke Ino,Javier Ramon-Azcon,Hitoshi Shiku
doi : 10.1002/adhm.202170101
Volume 10, Issue 21 2170101
Both-In-One Hybrid Bacteria Suppress the Tumor Metastasis and Relapse via Tandem-Amplifying Reactive Oxygen Species-Immunity Responses (Adv. Healthcare Mater. 21/2021)
Mengchi Sun,Hao Ye,Qinghua Shi,Jun Xie,Xiang Yu,Hao Ling,Song You,Zhonggui He,Bin Qin,Jin Sun
doi : 10.1002/adhm.202170102
Volume 10, Issue 21 2170102
Multifunctional Hybrid Hydrogel Enhanced Antitumor Therapy through Multiple Destroying DNA Functions by a Triple-Combination Synergistic Therapy (Adv. Healthcare Mater. 21/2021)
Jiamin Zhang,Lijun Yang,Fan Huang,Cuicui Zhao,Jinjian Liu,Yumin Zhang,Jianfeng Liu
doi : 10.1002/adhm.202170105
Volume 10, Issue 21 2170105
Hierarchical Nanostructured Electrospun Membrane with Periosteum-Mimic Microenvironment for Enhanced Bone Regeneration (Adv. Healthcare Mater. 21/2021)
Laijun Liu,Yuna Shang,Chaojing Li,Yongjie Jiao,Yanchen Qiu,Chengyi Wang,Yuge Wu,Qiuyun Zhang,Fujun Wang,Zhimou Yang,Lu Wang
doi : 10.1002/adhm.202170106
Volume 10, Issue 21 2170106
The Importance of Interfaces in Multi-Material Biofabricated Tissue Structures
Martina Viola,Susanna Piluso,Jürgen Groll,Tina Vermonden,Jos Malda,Miguel Castilho
doi : 10.1002/adhm.202101021
Volume 10, Issue 21 2101021
Biofabrication exploits additive manufacturing techniques for creating 3D structures with a precise geometry that aim to mimic a physiological cellular environment and to develop the growth of native tissues. The most recent approaches of 3D biofabrication integrate multiple technologies into a single biofabrication platform combining different materials within different length scales to achieve improved construct functionality. However, the importance of interfaces between the different material phases, has not been adequately explored. This is known to determine material's interaction and ultimately mechanical and biological performance of biofabricated parts. In this review, this gap is bridged by critically examining the interface between different material phases in (bio)fabricated structures, with a particular focus on how interfacial interactions can compromise or define the mechanical (and biological) properties of the engineered structures. It is believed that the importance of interfacial properties between the different constituents of a composite material, deserves particular attention in its role in modulating the final characteristics of 3D tissue-like structures.
Tattoo Inks for Optical Biosensing in Interstitial Fluid
Martalu D. Pazos,Yubing Hu,Yuval Elani,Kathryn L. Browning,Nan Jiang,Ali K. Yetisen
doi : 10.1002/adhm.202101238
Volume 10, Issue 21 2101238
The persistence of traditional tattoo inks presents an advantage for continuous and long-term health monitoring in point of care devices. The replacement of tattoo pigments with optical biosensors aims a promising alternative for monitoring blood biomarkers. Tattoo inks functionalization enables the control of interstitial biomarkers with correlated concentrations in plasma, to diagnose diseases, evaluate progression, and prevent complications associated with physio pathological disorders or medication mismatches. The specific biomarkers in interstitial fluid provide a new source of information, especially for skin diseases. The study of tattoo inks displays insufficient regulation in their composition, a lack of reports of the related complications, and a need for further studies on their degradation kinetics. This review focuses on tattoo optical biosensors for monitoring dermal interstitial biomarkers and discusses the clinical advantages and main challenges for in vivo implantation. Tattoo functionalization provides a minimally invasive, reversible, biocompatible, real-time sensing with long-term permanence and multiplexing capabilities for the control, diagnosis, and prevention of illness; it enables self-controlling management by the patient, but also the possibility of sending the records to the doctor.
Topography and Permeability Analyses of Vasculature-on-a-Chip Using Scanning Probe Microscopies
Yuji Nashimoto,Minori Abe,Ryota Fujii,Noriko Taira,Hiroki Ida,Yasufumi Takahashi,Kosuke Ino,Javier Ramon-Azcon,Hitoshi Shiku
doi : 10.1002/adhm.202101186
Volume 10, Issue 21 2101186
Microphysiological systems (MPS) or organs-on-chips (OoC) can emulate the physiological functions of organs in vitro and are effective tools for determining human drug responses in preclinical studies. However, the analysis of MPS has relied heavily on optical tools, resulting in difficulties in real-time and high spatial resolution imaging of the target cell functions. In this study, the role of scanning probe microscopy (SPM) as an analytical tool for MPS is evaluated. An access hole is made in a typical MPS system with stacked microchannels to insert SPM probes into the system. For the first study, a simple vascular model composed of only endothelial cells is prepared for SPM analysis. Changes in permeability and local chemical flux are quantitatively evaluated during the construction of the vascular system. The morphological changes in the endothelial cells after flow stimulation are imaged at the single-cell level for topographical analysis. Finally, the possibility of adapting the permeability and topographical analysis using SPM for the intestinal vascular system is further evaluated. It is believed that this study will pave the way for an in situ permeability assay and structural analysis of MPS using SPM.
Both-In-One Hybrid Bacteria Suppress the Tumor Metastasis and Relapse via Tandem-Amplifying Reactive Oxygen Species-Immunity Responses
Mengchi Sun,Hao Ye,Qinghua Shi,Jun Xie,Xiang Yu,Hao Ling,Song You,Zhonggui He,Bin Qin,Jin Sun
doi : 10.1002/adhm.202100950
Volume 10, Issue 21 2100950
Bacterial therapy, which targets the tumor site and aims at exerting an antitumor immune response, has displayed a great potential against malignant tumors. However, failure of the phase I clinical trial of Salmonella strain VNP20009 alone demonstrates that bacterial treatment alone can unsatisfy the requirements of high efficiency and biosafety. Herein, a strategy of both-in-one hybrid bacteria is proposed, wherein the chemotherapeutic drug doxorubicin (DOX) is integrated onto the surface of glucose dehydrogenase (GDH)-overexpressed non-pathogenic Escherichia coli (E. coli) strain, to potentiate the antitumor efficacy. Nicotinamide adenine dinucleotide phosphate (NADPH), which is produced by GDH from E. coli, promotes the generation of toxic reactive oxygen species (ROS) within the tumor, and ROS is then catalyzed by the DOX-activated NADPH oxidases. Importantly, the hybrid bacteria enhance stimulated systemic antitumor immune responses, thereby leading to effective tumor eradication. When this strategy is applied in four different tumor models, the hybrid bacteria significantly inhibited tumor metastasis, postsurgical regrowth, and primary/distal tumor relapse. The both-in-one ROS-immunity-boosted hybrid bacteria strategy provides knowledge for the rational design of bacteria-based synergistic cancer therapy.
Multifunctional Hybrid Hydrogel Enhanced Antitumor Therapy through Multiple Destroying DNA Functions by a Triple-Combination Synergistic Therapy
Jiamin Zhang,Lijun Yang,Fan Huang,Cuicui Zhao,Jinjian Liu,Yumin Zhang,Jianfeng Liu
doi : 10.1002/adhm.202101190
Volume 10, Issue 21 2101190
Brachytherapy, as an effective setting for precise cancer therapy in clinic, can lead to serious DNA damage. However, its therapeutic efficacy is always limited by the DNA self-repair property, tumor hypoxia-associated radiation resistance as well as inhomogeneous distribution of the radioactive material. Herein, a multifunctional hybrid hydrogel (131I-hydrogel/DOX/GNPs aggregates) is developed by loading gold nanoparticle aggregates (GNPs aggregates) and DOX into a radionuclide iodine-131 (131I) labelled polymeric hydrogels (131I-PEG-P(Tyr)8) for tumor destruction by completely damaging DNA self-repair functions. This hybrid hydrogel exhibits excellent photothermal/radiolabel stability, biocompatibility, and fluorescence/photothermal /SPECT imaging properties. After local injection, the sustained releasing DOX within tumor greatly inhibits the DNA replication. Meanwhile, GNPs aggregates as a radiosensitizer and photosensitizer show a significant improvement of brachytherapeutic efficacy and cause serious DNA damage. Simultaneously, GNPs aggregates induce mild photothermal therapy under 808 nm laser irradiation, which not only inhibits self-repair of the damaged DNA but also effectively relieves tumor hypoxic condition to enhance the therapeutic effects of brachytherapy, leading to a triple-synergistic destruction of DNA functions. Therefore, this study provides a highly efficient tumor synergistic therapy platform and insight into the synergistic antitumor mechanism in DNA level.
Hierarchical Nanostructured Electrospun Membrane with Periosteum-Mimic Microenvironment for Enhanced Bone Regeneration
Laijun Liu,Yuna Shang,Chaojing Li,Yongjie Jiao,Yanchen Qiu,Chengyi Wang,Yuge Wu,Qiuyun Zhang,Fujun Wang,Zhimou Yang,Lu Wang
doi : 10.1002/adhm.202101195
Volume 10, Issue 21 2101195
An ideal periosteum substitute should be able to mimic the periosteum microenvironment that continuously provides growth factors, recruits osteoblasts, and subsequent extracellular matrix (ECM) mineralization to accelerate bone regeneration. Here, a calcium-binding peptide-loaded poly(?-caprolactone) (PCL) electrospun membrane modified by the shish-kebab structure that can mimic the periosteum microenvironment was developed as a bionic periosteum. The calcium-binding peptide formed by the negatively charged heptaglutamate domain (E7) in the E7-BMP-2 with calcium ion in the tricalcium phosphate sol (TCP sol) through electrostatic chelation not only extended the release cycle of E7-BMP-2 but also promoted the biomineralization of the bionic periosteum. Cell experiments showed that the bionic periosteum could significantly improve the osteogenic differentiation of the rat-bone marrow-derived mesenchymal stem cells (rBMSCs) through both chemical composition and physical structure. The in vivo evaluation of the bionic periosteum confirmed the inherent osteogenesis of this periosteum microenvironment, which could promote the regeneration of vascularized bone tissue. Therefore, the hierarchical nanostructured electrospun membrane with periosteum-mimic microenvironment is a promising periosteum substitute for the treatment of bone defects.
pH-Sensitive Molecular-Switch-Containing Polymer Nanoparticle for Breast Cancer Therapy with Ferritinophagy-Cascade Ferroptosis and Tumor Immune Activation
Tiantian Zuo,Tianxu Fang,Jun Zhang,Jie Yang,Rui Xu,Zhihua Wang,Huizi Deng,Qi Shen
doi : 10.1002/adhm.202100683
Volume 10, Issue 21 2100683
Ferritin internalized into tumor cells is degraded and releases iron ions via ferritinophagy. Iron ions participate in Fenton reaction to produce reactive oxygen species for lipid peroxidation and ferroptosis. Inhibition of indoleamine-2,3-dioxygenase (IDO) decreases tryptophan elimination to induce T cells activation for tumor immunosuppression relief. The active tumor targeting nanoparticles containing ferritin and a pH-sensitive molecular-switch (FPBC@SN) are developed to utilize ferritinophagy-cascade ferroptosis and tumor immunity activation for cancer therapy. FPBC@SN disintegrates in acidic cytoplasm and releases sorafenib (SRF) and IDO inhibitor (NLG919). SRF upregulates nuclear receptor coactivator 4 (NCOA4) to induce ferritin and endogenous iron pool degradation by ferritinophagy, then obtained iron ions participate in the Fenton reaction to produce lipid peroxide (LPO). Meanwhile, SRF blocks glutathione synthesis to downregulate glutathione peroxidase 4 (GPX4) which can scavenge LPO as a different pathway from ferritinophagy to promote ferroptosis in tumor cells. NLG919 inhibits IDO to reduce tryptophan metabolism, so immunity in tumors is aroused to anti-tumor. In vitro and in vivo experiments prove FPBC@SN inhibits tumor cell growth and metastasis, indicating the potential of FPBC@SN for breast cancer therapy based on the combination of ferritinophagy-cascade ferroptosis and tumor immunity activation.
Mechanical Stress Induces a Transient Suppression of Cytokine Secretion in Astrocytes Assessed at the Single-Cell Level with a High-Throughput Microfluidic Chip
Xiaowei Shao,Chunhua Wang,Chao Wang,Lei Han,Yunrui Han,Dean Nižeti?,Yu Zhang,Lin Han
doi : 10.1002/adhm.202100698
Volume 10, Issue 21 2100698
Brain cells are constantly subjected to mechanical signals. Astrocytes are the most abundant glial cells of the central nervous system (CNS), which display immunoreactivity and have been suggested as an emerging disease focus in the recent years. However, how mechanical signals regulate astrocyte immunoreactivity, and the cytokine release in particular, remains to be fully characterized. Here, human neural stem cells are used to induce astrocytes, from which the release of 15 types of cytokines are screened, and nine of them are detected using a protein microfluidic chip. When a gentle compressive force is applied, altered cell morphology and reinforced cytoskeleton are observed. The force induces a transient suppression of cytokine secretions including IL-6, MCP-1, and IL-8 in the early astrocytes. Further, using a multiplexed single-cell culture and protein detection microfluidic chip, the mechanical effects at a single-cell level are analyzed, which validates a concerted downregulation by force on IL-6 and MCP-1 secretions in the cells releasing both factors. This work demonstrates an original attempt of employing the protein detection microfluidic chips in the assessment of mechanical regulation on the brain cells at a single-cell resolution, offering novel approach and unique insights for the understanding of the CNS immune regulation.
Heat-Confined Tumor-Docking Reversible Thermogel Potentiates Systemic Antitumor Immune Response During Near-Infrared Photothermal Ablation in Triple-Negative Breast Cancer
Vishnu Revuri,Santhosh Kalash Rajendrakumar,Myong-Suk Park,Adityanarayan Mohapatra,Saji Uthaman,Jagannath Mondal,Woo Kyun Bae,In-Kyu Park,Yong-Kyu Lee
doi : 10.1002/adhm.202100907
Volume 10, Issue 21 2100907
Triple-negative breast cancer (TNBC) features immunologically “cold” tumor microenvironments with limited cytotoxic T lymphocyte (CTL) infiltration. Although ablation therapies have demonstrated modulation of “cold” TNBC tumors to inflamed “hot” tumors, recruitment of myeloid derived suppressor cells (MDSCs) at the tumors post ablation therapies prevents the infiltration of CTLs and challenge the antitumor potentials of T-cell therapies. Here, a thermal ablation immunotherapy strategy is developed to prevent the immune suppressive effects of MDSCs during photothermal ablation and induce a durable systemic antitumor immunity to eradicate TNBC tumors. An injectable pluronic F127/hyaluronic acid (HA)-based hydrogel embedded with manganese dioxide (BM) nanoparticles and TLR7 agonist resiquimod (R848) (BAGEL-R848), is synthesized to induce in situ laser-assisted gelation of the hydrogel and achieve desired ablation temperatures at a low laser-exposure time. Upon 808-nm laser irradiation, a significant reduction in the tumor burden is observed in BAGEL-R848-injected 4T1 tumor-bearing mice. The ablation induced immunogenic cell death and sustained release of R848 from BAGEL-R848 promotes dendritic cell maturation and reduced MDSCs localization in tumors. In addition, inflammatory M1 macrophages and CD8+IFN+ CTL are enriched in distant tumors in bilateral 4T1 tumor model, preventing metastatic tumor growth and signifying the potential of BAGEL-R848 to treat TNBC.
Short-Term Preclinical Application of Functional Human Induced Pluripotent Stem Cell-Derived Airway Epithelial Patches
Ratna Varma,Alba E. Marin-Araujo,Sara Rostami,Thomas K. Waddell,Golnaz Karoubi,Siba Haykal
doi : 10.1002/adhm.202100957
Volume 10, Issue 21 2100957
Airway pathologies including cancer, trauma, and stenosis lack effective treatments, meanwhile airway transplantation and available tissue engineering approaches fail due to epithelial dysfunction. Autologous progenitors do not meet the clinical need for regeneration due to their insufficient expansion and differentiation, for which human induced pluripotent stem cells (hiPSCs) are promising alternatives. Airway epithelial patches are engineered by differentiating hiPSC-derived airway progenitors into physiological proportions of ciliated (73.9 ± 5.5%) and goblet (2.1 ± 1.4%) cells on a silk fibroin–collagen vitrigel membrane (SF-CVM) composite biomaterial for transplantation in porcine tracheal defects ex vivo and in vivo. Evaluation of ex vivo tracheal repair using hiPSC-derived SF-CVM patches demonstrate native-like tracheal epithelial metabolism and maintenance of mucociliary epithelium to day 3. In vivo studies demonstrate SF-CVM integration and maintenance of airway patency, showing 80.8 ± 3.6% graft coverage with an hiPSC-derived pseudostratified epithelium and 70.7 ± 2.3% coverage with viable cells, 3 days postoperatively. The utility of bioengineered, hiPSC-derived epithelial patches for airway repair is demonstrated in a short-term preclinical survival model, providing a significant leap for airway reconstruction approaches.
A Supramolecular Nanomedicine Based on Bendamustine and MDM2-Targeted D-peptide Inhibitor for Breast Cancer Therapy
Yunjiang Zhou,Yaxin Chen,Xing Huang,Yingying Tan,Rong Hu,Chong Li,Miao-Miao Niu
doi : 10.1002/adhm.202100980
Volume 10, Issue 21 2100980
Bendamustine (BEN) is a FDA-approved bifunctional DNA-alkylating chemotherapy drug, but it suffers from short half-life, instability, and poor biocompatibility in the clinical application. Due to unique biostability of d-amino acid-containing peptides (D-peptides), constructing D-peptide-small molecule drug conjugates is emerging as a promising strategy for cancer therapy. Here, a high-affinity MDM2-targeted D-peptide (peptide 5) is discovered by applying structure-based drug design (SBDD). Taking the advantages of d-amino acids, a novel self-assembling D-peptide-small molecule drug conjugate (BEN-FF-peptide 5) is developed by simultaneously conjugating small molecule drug BEN and peptide 5 to the self-assembling peptide. In vitro results demonstrate that BEN-FF-peptide 5 exhibits superior cellular uptake ability, good biostability in human serum and strong inhibitory effect on the growth of human breast cancer (MCF-7) cells. In vivo study reveals that BEN-FF-peptide 5 significantly inhibits the growth of MCF-7 cells-derived xenograft in nude mice with no obvious side effects. This work provides a useful strategy to construct D-peptide-small molecule drug conjugates for high-efficacy and low-toxicity cancer therapy.
Spatial Stem Cell Fate Engineering via Facile Morphogen Localization
Gyuhyung Jin,Martha E. Floy,Aaron D. Simmons,Madeline M. Arthur,Sean P. Palecek
doi : 10.1002/adhm.202100995
Volume 10, Issue 21 2100995
Spatiotemporally controlled presentation of morphogens and elaborate modulation of signaling pathways elicit pattern formation during development. Though this process is critical for proper organogenesis, unraveling the mechanisms of developmental biology have been restricted by challenges associated with studying human embryos. Human pluripotent stem cells (hPSCs) have been used to model development in vitro, however difficulties in precise spatiotemporal control of the cellular microenvironment have limited the utility of this model in exploring mechanisms of pattern formation. Here, a simple and versatile method is presented to spatially pattern hPSC differentiation in 2-dimensional culture via localized morphogen adsorption on substrates. Morphogens including bone morphogenetic protein 4 (BMP4), activin A, and WNT3a are patterned to induce localized mesendoderm, endoderm, cardiomyocyte (CM), and epicardial cell (EpiC) differentiation from hPSCs and hPSC-derived progenitors. Patterned CM and EpiC co-differentiation allows investigation of intercellular interactions in a spatially controlled manner and demonstrate improved alignment of CMs in proximity to EpiCs. This approach provides a platform for the controlled and systematic study of early pattern formation. Moreover, this study provides a facile approach to generate 2D patterned hPSC-derived tissue structures for modeling disease and drug interactions.
Manganese Ferrite Nanoparticles Encapsulated into Vitamin E/Sphingomyelin Nanoemulsions as Contrast Agents for High-Sensitive Magnetic Resonance Imaging
Sandra Díez-Villares,Miguel A. Ramos-Docampo,Andrés da Silva-Candal,Pablo Hervella,Abi J. Vázquez-Ríos,Ana B. Dávila-Ibáñez,Rafael López-López,Ramón Iglesias-Rey,Verónica Salgueiriño,María de la Fuente
doi : 10.1002/adhm.202101019
Volume 10, Issue 21 2101019
Magnetic resonance imaging (MRI) is one of the most powerful non-invasive imaging modalities used in clinics due to its great spatial resolution and excellent soft-tissue contrast, though still less sensitive than other techniques such as the nuclear imaging modalities. This lack of sensitivity can be improved with the use of contrast agents based on nanomaterials. In recent years, researchers have focused on the development of magnetic nanoparticles, given their role as enhancers of the contrast signal based on the magnetic resonance. Manganese ferrite nanoparticles stand out, given their high magnetic susceptibility and magnetic soft nature. Herein, 10 nm MnFe2O4 nanoparticles, functionalized with the natural antioxidant vitamin E (VitE-MFO) are encapsulated into simple, biodegradable and non-toxic nanoemulsions (NEs), by a reproducible one-step method obtaining stable 150 nm-sized magnetic nanoemulsions (VitE-MFO-NEs). After encapsulation, the superparamagnetic properties of VitE-MFO are maintained and MR imaging studies reveal an extremely high transverse relaxivity for VitE-MFO-NEs (652.9 × 10?3 m?1 s?1), twofold higher than VitE-MFO value. Moreover, VitE-MFO-NEs show great in vivo biocompatibility and good signal in in vivo and ex vivo MRI, which indicates their great potential for biomedical imaging enhancing the negative MR contrast and significantly improving the sensitivity of MRI.
Sulfated Alginate Hydrogels Prolong the Therapeutic Potential of MSC Spheroids by Sequestering the Secretome (Adv. Healthcare Mater. 21/2021)
Marissa Gionet-Gonzales,Alena Casella,Daphne Diloretto,Clara Ginnell,Katherine H. Griffin,Anne Bigot,J. Kent Leach
doi : 10.1002/adhm.202170104
Volume 10, Issue 21 2170104
Sulfated Alginate Hydrogels Prolong the Therapeutic Potential of MSC Spheroids by Sequestering the Secretome
Marissa Gionet-Gonzales,Alena Casella,Daphne Diloretto,Clara Ginnell,Katherine H. Griffin,Anne Bigot,J. Kent Leach
doi : 10.1002/adhm.202101048
Volume 10, Issue 21 2101048
Cell-based approaches to tissue repair suffer from rapid cell death upon implantation, limiting the window for therapeutic intervention. Despite robust lineage-specific differentiation potential in vitro, the function of transplanted mesenchymal stromal cells (MSCs) in vivo is largely attributed to their potent secretome comprising a variety of growth factors (GFs). Furthermore, GF secretion is markedly increased when MSCs are formed into spheroids. Native GFs are sequestered within the extracellular matrix (ECM) via sulfated glycosaminoglycans, increasing the potency of GF signaling compared to their unbound form. To address the critical need to prolong the efficacy of transplanted cells, alginate hydrogels are modified with sulfate groups to sequester endogenous heparin-binding GFs secreted by MSC spheroids. The influence of crosslinking method and alginate modification is assessed on mechanical properties, degradation rate, and degree of sulfate modification. Sulfated alginate hydrogels sequester a mixture of MSC-secreted endogenous biomolecules, thereby prolonging the therapeutic effect of MSC spheroids for tissue regeneration. GFs are sequestered for longer durations within sulfated hydrogels and retain their bioactivity to regulate endothelial cell tubulogenesis and myoblast infiltration. This platform has the potential to prolong the therapeutic benefit of the MSC secretome and serve as a valuable tool for investigating GF sequestration.
A Dual-Nanozyme-Catalyzed Cascade Reactor for Enhanced Photodynamic Oncotherapy against Tumor Hypoxia
Miaomiao Chen,Jitao Song,Jialong Zhu,Gaobo Hong,Jing An,Erting Feng,Xiaojun Peng,Fengling Song
doi : 10.1002/adhm.202101049
Volume 10, Issue 21 2101049
Tumor hypoxia is a typical characteristic of tumor microenvironment (TME), which seriously compromises the therapeutic effect of photodynamic therapy (PDT). The development of nanozymes with oxygen-generation ability is a promising strategy to overcome the oxygen-dependent of PDT but remained a great challenge. Herein, a dual-nanozymes based cascade reactor HAMF is proposed to alleviate tumor hypoxia for enhanced PDT. The hollow mesoporous silica nanoparticles (HMSNs) are constructed as an excellent nanocarrier to load ultra-small gold nanoparticles (Au NPs) and manganese dioxide (MnO2) shell via in situ reduction method, and further coordination with an efficient photosensitizer 4-DCF-MPYM (4-FM), a thermally activated delayed fluorescence (TADF) fluorescein derivative. With the response to TME, MnO2 can catalyze endogenous H2O2 into O2 and subsequently accelerating glucose oxidation by Au NPs to produce additional H2O2, which is reversely used as the substrate for MnO2-catalyzed reaction, thereby constantly producing singlet oxygen (1O2) for enhanced PDT upon light irradiation. This work proposed a cascade reactor based on dual-nanozyme to relieve tumor hypoxia for effective tumor suppression, which may enrich the application of multi-nanozymes in biomedicine.
3D-Printed Regenerative Magnesium Phosphate Implant Ensures Stability and Restoration of Hip Dysplasia
Nasim Golafshan,Koen Willemsen,Firoz Babu Kadumudi,Elke Vorndran,Alireza Dolatshahi-Pirouz,Harrie Weinans,Bart C. H. van der Wal,Jos Malda,Miguel Castilho
doi : 10.1002/adhm.202101051
Volume 10, Issue 21 2101051
Osteoarthritis of the hip is a painful and debilitating condition commonly occurring in humans and dogs. One of the main causes that leads to hip osteoarthritis is hip dysplasia. Although the current surgical methods to correct dysplasia work satisfactorily in many circumstances, these are associated with serious complications, tissue resorption, and degeneration. In this study, a one-step fabrication of a regenerative hip implant with a patient-specific design and load-bearing properties is reported. The regenerative hip implant is fabricated based on patient imaging files and by an extrusion assisted 3D printing process using a flexible, bone-inducing biomaterial. The novel implant can be fixed with metallic screws to host bone and can be loaded up to physiological loads without signs of critical permanent deformation or failure. Moreover, after exposing the hip implant to accelerated in vitro degradation, it is confirmed that it is still able to support physiological loads even after losing ?40% of its initial mass. In addition, the osteopromotive properties of the novel hip implant is demonstrated as shown by an increased expression of osteonectin and osteocalcin by cultured human mesenchymal stem cells after 21 days. Overall, the proposed hip implant provides an innovative regenerative and mechanically stable solution for hip dysplasia treatment.
Antibacterial Dual Network Hydrogels for Sensing and Human Health Monitoring
Huan Lei,Jing Zhao,Xiaoxuan Ma,Hang Li,Daidi Fan
doi : 10.1002/adhm.202101089
Volume 10, Issue 21 2101089
Polymer-based conductive hydrogels have the synergistic advantages of high conductivity and tissue-like properties, making them promising candidates for the construction of flexible electronic devices. However, conductive hydrogel materials can easily absorb microorganisms due to their high water content. To address the problem that conductive hydrogels are susceptible to infection by external pathogens when monitoring wounds and when used in implanted organs, tannic acid-borax (TA-B) complexes are introduced into classical dual network polyacrylamide/agarose (PAM/Agar) hydrogels to form PAM/Agar/TA-B hydrogel conductors. These hydrogels are antibacterial and have good mechanical properties, light transmission, electrical conductivity, and adhesion. TA-B increases the compressive stress of the PAM/Agar/TA-B hydrogel by 58.14% compared to a PAM/Agar hydrogel. The PAM/Agar/TA-B hydrogel can be used as an electronic conductor for electronic skin and wearable sensors. Outstanding biocompatibility allows the hydrogel to be used as a monitoring device at wounds to monitor heartbeat, skin wounds, and internal tissue status in real time. In summary, an antibacterial strain sensing matrix that is safe for human health monitoring is developed.
Distinct Effects of Heparin and Interleukin-4 Functionalization on Macrophage Polarization and In Situ Arterial Tissue Regeneration Using Resorbable Supramolecular Vascular Grafts in Rats
Valentina Bonito,Suzanne E. Koch,Merle M. Krebber,Daniel A. Carvajal-Berrio,Julia Marzi,Renee Duijvelshoff,Emily B. Lurier,Serena Buscone,Sylvia Dekker,Simone M. J. de Jong,Tristan Mes,Koen R. D. Vaessen,Eva M. Brauchle,Anton W. Bosman,Katja Schenke-Layland,Marianne C. Verhaar,Patricia Y. W. Dankers,Anthal I. P. M. Smits,Carlijn V. C. Bouten
doi : 10.1002/adhm.202101103
Volume 10, Issue 21 2101103
Two of the greatest challenges for successful application of small-diameter in situ tissue-engineered vascular grafts are 1) preventing thrombus formation and 2) harnessing the inflammatory response to the graft to guide functional tissue regeneration. This study evaluates the in vivo performance of electrospun resorbable elastomeric vascular grafts, dual-functionalized with anti-thrombogenic heparin (hep) and anti-inflammatory interleukin 4 (IL-4) using a supramolecular approach. The regenerative capacity of IL-4/hep, hep-only, and bare grafts is investigated as interposition graft in the rat abdominal aorta, with follow-up at key timepoints in the healing cascade (1, 3, 7 days, and 3 months). Routine analyses are augmented with Raman microspectroscopy, in order to acquire the local molecular fingerprints of the resorbing scaffold and developing tissue. Thrombosis is found not to be a confounding factor in any of the groups. Hep-only-functionalized grafts resulted in adverse tissue remodeling, with cases of local intimal hyperplasia. This is negated with the addition of IL-4, which promoted M2 macrophage polarization and more mature neotissue formation. This study shows that with bioactive functionalization, the early inflammatory response can be modulated and affect the composition of neotissue. Nevertheless, variability between graft outcomes is observed within each group, warranting further evaluation in light of clinical translation.
Mechanotopography-Driven Design of Dispersible Nanofiber-Laden Hydrogel as a 3D Cell Culture Platform for Investigating Tissue Fibrosis
Suntae Kim,Cholong Choi,Chaenyung Cha
doi : 10.1002/adhm.202101109
Volume 10, Issue 21 2101109
Fibrosis is one of the most frequent occurrences during one's lifetime, identified by various physiological changes including, most notably, excessive deposition of extracellular matrix (ECM). Despite its physiological importance, it is still a significant challenge to conduct a systematic investigation of tissue fibrosis, mainly due to the lack of in vitro 3D tissue model that can accurately portray the characteristic features of fibrotic events. Herein, a hybrid hydrogel system incorporating dispersible nanofibers is developed to emulate highly collagenous deposits formed within a fibrotic tissue leading to altered mechanotopographical properties. Micrometer-length, aqueous-stable nanofibers consisting of crosslinked gelatin network embedded with graphene oxide (GO) or reduced graphene (rGO) are infused into hydrogel, resulting in controllable mechanotopographical properties while maintaining permeability sufficiently enough for various cellular activities. Ultimately, the ability to induce fibrotic behavior of fibroblasts cultured in these mechanotopography-controlled, nanofiber-laden hydrogels is investigated in detail.
DNA Logic Circuits for Multiple Tumor Cells Identification Using Intracellular MicroRNA Molecular Bispecific Recognition
Qiqi Yang,Fan Yang,Wenhao Dai,Xiangdan Meng,Wei Wei,Yaru Cheng,Jinhong Dong,Huiting Lu,Haifeng Dong
doi : 10.1002/adhm.202101130
Volume 10, Issue 21 2101130
The aberrant expression level of intracellular microRNAs (miRNAs) holds great promise for differentiating cell types at the molecular level. However, cell subtype discrimination based on a single miRNA molecular level is not sufficient and reliable. Herein, multiple identifiable and reporting modules are integrated into a single DNA circuit for multiple cancer cell subtypes identification based on miRNAs bispecific recognition. The DNA three-dimensional (3D) logic gate nano-hexahedron framework extends three recognition modules and three reporting modules to form three “AND” logic gates. Each Boolean operator “AND” returns an “ON” signal in the presence of bispecific miRNAs, simultaneously enabling three types of cell subtype identification. It not only enables the discrimination of cancer cells A549 and MCF-7 from normal cells NHDF but also successfully distinguishes different types of cancer cells. The bispecific intracellular miRNA controllable DNA circuit, with low signal-to-noise ratio, easily extends to various cell type discrimination by adjusting the miRNA species, provides huge opportunities for accurately differentiating multiple cell types at the molecular level.
3D Bioprinted Multicellular Vascular Models
Karli A. Gold,Biswajit Saha,Navaneeth Krishna Rajeeva Pandian,Brandon K. Walther,Jorge A. Palma,Javier Jo,John P. Cooke,Abhishek Jain,Akhilesh K. Gaharwar
doi : 10.1002/adhm.202101141
Volume 10, Issue 21 2101141
3D bioprinting is an emerging additive manufacturing technique to fabricate constructs for human disease modeling. However, current cell-laden bioinks lack sufficient biocompatibility, printability, and structural stability needed to translate this technology to preclinical and clinical trials. Here, a new class of nanoengineered hydrogel-based cell-laden bioinks is introduced, that can be printed into 3D, anatomically accurate, multicellular blood vessels to recapitulate both the physical and chemical microenvironments of native human vasculature. A remarkably unique characteristic of this bioink is that regardless of cell density, it demonstrates a high printability and ability to protect encapsulated cells against high shear forces in the bioprinting process. 3D bioprinted cells maintain a healthy phenotype and remain viable for nearly one-month post-fabrication. Leveraging these properties, the nanoengineered bioink is printed into 3D cylindrical blood vessels, consisting of living co-culture of endothelial cells and vascular smooth muscle cells, providing the opportunity to model vascular function and pathophysiology. Upon cytokine stimulation and blood perfusion, this 3D bioprinted vessel is able to recapitulate thromboinflammatory responses observed only in advanced in vitro preclinical models or in vivo. Therefore, this 3D bioprinted vessel provides a potential tool to understand vascular disease pathophysiology and assess therapeutics, toxins, or other chemicals.
Theranostic Heterodimeric Prodrug with Dual-Channel Fluorescence Turn-On and Dual-Prodrug Activation for Synergistic Cancer Therapy
Maolin Jiang,Kewei Wang,Xuan Xiao,Qingyu Zong,Rui Zheng,Youyong Yuan
doi : 10.1002/adhm.202101144
Volume 10, Issue 21 2101144
Theranostic prodrugs that can precisely monitor drug activation with synergistic therapeutic effects are highly desirable for personalized medicine. In this study, a theranostic heterodimeric prodrug, CyNH-SS-DOX, with synchronous and independent dual-channel fluorescence turn-on and dual-prodrug activation for synergistic cancer therapy is developed. A hemicyanine fluorescent drug, CyNH2, with good therapeutic effects found in this work, is conjugated to doxorubicin (DOX) through a disulfide linker to form CyNH-SS-DOX. Before activation, both the fluorescence of DOX and CyNH2 are in the off state and the toxicity is low. In the presence of intracellular glutathione, both the fluorescence of DOX and CyNH2 at different channels are turned on. Meanwhile, DOX and CyNH2 are activated in a synergistic anticancer effect. It is believed that CyNH-SS-DOX is promising for monitoring prodrug activation in dual-fluorescence channels and for enhancing therapeutic efficacy with few side effects.
A Highly Ordered, Nanostructured Fluorinated CaP-Coated Melt Electrowritten Scaffold for Periodontal Tissue Regeneration
Arwa Daghrery,Jessica A. Ferreira,Isaac J. de Souza Araújo,Brian H. Clarkson,George J. Eckert,Sarit B. Bhaduri,Jos Malda,Marco C. Bottino
doi : 10.1002/adhm.202101152
Volume 10, Issue 21 2101152
Periodontitis is a chronic inflammatory, bacteria-triggered disorder affecting nearly half of American adults. Although some level of tissue regeneration is realized, its low success in complex cases demands superior strategies to amplify regenerative capacity. Herein, highly ordered scaffolds are engineered via Melt ElectroWriting (MEW), and the effects of strand spacing, as well as the presence of a nanostructured fluorinated calcium phosphate (F/CaP) coating on the adhesion/proliferation, and osteogenic differentiation of human-derived periodontal ligament stem cells, are investigated. Upon initial cell-scaffold interaction screening aimed at defining the most suitable design, MEW poly(?-caprolactone) scaffolds with 500 µm strand spacing are chosen. Following an alkali treatment, scaffolds are immersed in a pre-established solution to allow for coating formation. The presence of a nanostructured F/CaP coating leads to a marked upregulation of osteogenic genes and attenuated bacterial growth. In vivo findings confirm that the F/CaP-coated scaffolds are biocompatible and lead to periodontal regeneration when implanted in a rat mandibular periodontal fenestration defect model. In aggregate, it is considered that this work can contribute to the development of personalized scaffolds capable of enabling tissue-specific differentiation of progenitor cells, and thus guide simultaneous and coordinated regeneration of soft and hard periodontal tissues, while providing antimicrobial protection.
Soft X-Ray Stimulated Lanthanide@MOF Nanoprobe for Amplifying Deep Tissue Synergistic Photodynamic and Antitumor Immunotherapy
Xiaoting Zhao,Youbin Li,Linman Du,Zhiming Deng,Mingyang Jiang,Songjun Zeng
doi : 10.1002/adhm.202101174
Volume 10, Issue 21 2101174
Combining photodynamic therapy (PDT) and immunotherapy has shown profound impact for synergistic treatment of malignant tumors. However, the shallow penetration depth of the traditional visible light activated PDT, immunosuppressive tumor microenvironment (TME), and poor immunogenicity of deep-seated solid tumors have significantly impeded the therapeutic efficiency. Herein, a soft X-ray activated nanoprobe is rationally engineered via integrating porphyrin Zr-based metal–organic framework with lanthanide NaYF4:Gd,Tb@NaYF4 scintillator nanoparticles (SNPs) by a new in situ growth strategy for synergistic PDT and immunotherapy of tumor. The nanoprobe possesses remarkably enhanced reactive oxygen species (ROS) generation triggered by soft X-ray via further covalently grafting rose bengal on the nanoprobe, even at tissue depths of 3 cm. Moreover, the soft X-ray induced ROS can act as potential immunogenic cell death (ICD) trigger, subsequently leading to the activation of the adaptive antitumor immune-response. Significantly, the boosted ROS generation can further modulate the immunosuppressive TME. This work provides new strategy of designing antitumor nanoprobes for soft X-ray triggered deep-tissue PDT and immune response, breaking the depth barriers suffered by the traditional photoactivated PDT or ICD using visible and near infrared light.
3D Printing of Black Bioceramic Scaffolds with Micro/Nanostructure for Bone Tumor-Induced Tissue Therapy
Xin Wang,Yin Liu,Meng Zhang,Dong Zhai,Yufeng Wang,Hui Zhuang,Bing Ma,Yu Qu,Xiaopeng Yu,Jingge Ma,Hongshi Ma,Qingqiang Yao,Chengtie Wu
doi : 10.1002/adhm.202101181
Volume 10, Issue 21 2101181
It is common to improve the relevant performance in the field of energy storage materials or catalytic materials by regulating the number of defects. However, there are few studies on the biomaterials containing defects for tissue engineering. Herein, a new type of defect-rich scaffolds, black akermanite (B-AKT) bioceramic scaffolds with micro/nanostructure, the thickness of which is from 0.14 to 1.94 µm, is fabricated through introducing defects on the surface of bioceramic scaffolds. The B-AKT scaffolds have advantages on the degradation rate and the osteogenic capacity over the AKT (Ca2MgSi2O7) scaffolds due to the surface defects which stimulate the osteogenic differentiation of rabbit bone mesenchymal stem cells via activating bone morphogenetic protein 2 ?BMP2? signaling pathway and further promote bone formation in vivo. In addition, the prepared B-AKT scaffolds, the temperature of which can be over 100 °C under the near infrared ?NIR? irradiation (0.66 W cm?2), possess excellent performance on photothermal and antitumor effects. The work develops an introducing-defect strategy for regulating the biological performance of bioceramic scaffolds, which is expected to be applied in the next generation of bioceramic scaffolds for regenerative medicine.
Multistage Cooperative Nanodrug Combined with PD-L1 for Enhancing Antitumor Chemoimmunotherapy
Haihui Wang,Yongfei Liu,Xiaohui Zhu,Chengyun Chen,Zhangcheng Fu,Min Wang,Danying Lin,Zhaowei Chen,Chunhua Lu,Huanghao Yang
doi : 10.1002/adhm.202101199
Volume 10, Issue 21 2101199
Combinatorial CpG oligonucleotide (CPG) and chemotherapy drug represent a promising approach to reactivate immune system. However, these two agents possess different physicochemical properties, hindering the application of direct self-assembly of these two cargos into a single nanostructure. Here, a multistage cooperative nanodrug is developed by the direct self-assembly of cis-platinum (CDDP, Pt), l-arginine (l-Arg, R), and CPG (defined as PtR/CPG) for antitumor chemoimmunotherapy. First, the CDDP can induce cell apoptosis. Meanwhile, CDDP also promotes the production of H2O2, catalyzing the conversion of l-Arg into nitric oxide (NO). The generated NO decreases the multidrug resistance of cells toward CDDP. Thus, the synergistic effects of CDDP and NO can trigger immunogenic cell death to produce tumor-associated antigens (TAAs). The TAAs and CPG will induce the maturation of dendritic cells (DCs) and enhance antigen presentation ability of DCs. In this way, the PtR/CPG can reverse the immunosuppressive microenvironment, sensitizing tumors to immune checkpoint inhibitors mediated by the programmed death-ligand 1 (PD-L1) antibody. Furthermore, the PtR/CPG combined with the PD-L1 antibody decreases the exhaustion and dysfunction of cytotoxic T lymphocytes to elicit durable systemic immune response. As a result, the prepared PtR/CPG nanodrug in combination with PD-L1 may be highly significant for cancer immunotherapy.
A Redox-Responsive Nanovaccine Combined with A2A Receptor Antagonist for Cancer Immunotherapy
Peng Yan,Yang Luo,Xinyang Li,Yingmin Li,Yi Wang,Jian Wu,Shaobing Zhou
doi : 10.1002/adhm.202101222
Volume 10, Issue 21 2101222
In situ vaccination can trigger an antitumor immune response. However, the therapeutic effect is still limited since the high expression of adenosine binding to G protein-coupled receptor A2AR induces an immunosuppressive effect. In this work, a new formulation is presented with the combination of a nanovaccine based on redox-responsive polymer micelles and A2AR antagonist SCH58261. The micelles simultaneously encapsulate immunogenic cell death (ICD) inducer doxorubicin (DOX) and adjuvant toll-like receptor 7 and 8 (TLR7/8) agonist R848, acting as the potent in situ vaccines. A high concentration of glutathione in tumor cells leads to the disintegration of these micelles, releasing DOX and R848 to mediate ICD, inducing the activation of dendritic cells and initiating an immune response. Meanwhile, A2AR antagonist SCH58261, a generation immune checkpoint blocker, inhibits the immunosuppressive adenosinergic pathway in the tumor microenvironment, activating natural killer (NK) cells and CD8+ T cells, and inhibiting the proliferation of regulatory T cells. Therefore, this formulation can trigger a robust systemic antitumor immune response.
