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Electrostatic Flocking of Insulative and Biodegradable Polymer Microfibers for Biomedical Applications (Adv. Healthcare Mater. 19/2021)
Alec McCarthy,Johnson V. John,Lorenzo Saldana,Hongjun Wang,Matthew Lagerstrom,Shixuan Chen,Yajuan Su,Mitchell Kuss,Bin Duan,Mark A. Carlson,Jingwei Xie
doi : 10.1002/adhm.202170085
Volume 10, Issue 19 2170085
Core Cross-Linked Polymeric Micelles for Specific Iron Delivery: Inducing Sterile Inflammation in Macrophages (Adv. Healthcare Mater. 19/2021)
Tobias A. Bauer,Natalie K. Horvat,Oriana Marques,Sara Chocarro,Christina Mertens,Silvia Colucci,Sascha Schmitt,Luca M. Carrella,Svenja Morsbach,Kaloian Koynov,Federico Fenaroli,Peter Blümler,Michaela Jung,Rocio Sotillo,Matthias W. Hentze,Martina U. Muckenthaler,Matthias Barz
doi : 10.1002/adhm.202170086
Volume 10, Issue 19 2170086
Flexible Ultrasonic Patch for Accelerating Chronic Wound Healing (Adv. Healthcare Mater. 19/2021)
Wenhan Lyu,Yinji Ma,Siyu Chen,Haibo Li,Peng Wang,Ying Chen,Xue Feng
doi : 10.1002/adhm.202170092
Volume 10, Issue 19 2170092
Liquid Copolymers as Biodegradable Surgical Sealant (Adv. Healthcare Mater. 19/2021)
Neta Shimony,Alona Shagan,Bat-hen Eylon,Abraham Nyska,Adi Gross,Boaz Mizrahi
doi : 10.1002/adhm.202170093
Volume 10, Issue 19 2170093
The Delivery Challenge of Genome Editing in Human Epithelia
Marcelo Calderón,Sarah Hedtrich
doi : 10.1002/adhm.202100847
Volume 10, Issue 19 2100847
Despite exciting advances in gene editing, their clinical translation is still hampered by the lack of delivery systems that can encapsulate and deliver gene editing tools like CRISPR-Cas9 or prime editors to the target side. This is particularly challenging in human epithelia, such as the skin and the lung; the latter of which being a mucosal surface that is covered by a mucus layer. In this perspective, the design and biological assessment of delivery systems for gene editing tools like CRISPR in skin and mucosal surfaces are discussed. The current state-of-the-art, current knowledge, and translational gaps, and guide toward improved translation are highlighted.
Neuromechanobiology: An Expanding Field Driven by the Force of Greater Focus
Cara T. Motz,Victoria Kabat,Tarun Saxena,Ravi V. Bellamkonda,Cheng Zhu
doi : 10.1002/adhm.202100102
Volume 10, Issue 19 2100102
The brain processes information by transmitting signals through highly connected and dynamic networks of neurons. Neurons use specific cellular structures, including axons, dendrites and synapses, and specific molecules, including cell adhesion molecules, ion channels and chemical receptors to form, maintain and communicate among cells in the networks. These cellular and molecular processes take place in environments rich of mechanical cues, thus offering ample opportunities for mechanical regulation of neural development and function. Recent studies have suggested the importance of mechanical cues and their potential regulatory roles in the development and maintenance of these neuronal structures. Also suggested are the importance of mechanical cues and their potential regulatory roles in the interaction and function of molecules mediating the interneuronal communications. In this review, the current understanding is integrated and promising future directions of neuromechanobiology are suggested at the cellular and molecular levels. Several neuronal processes where mechanics likely plays a role are examined and how forces affect ligand binding, conformational change, and signal induction of molecules key to these neuronal processes are indicated, especially at the synapse. The disease relevance of neuromechanobiology as well as therapies and engineering solutions to neurological disorders stemmed from this emergent field of study are also discussed.
Current-Driven Organic Electrochemical Transistors for Monitoring Cell Layer Integrity with Enhanced Sensitivity
Katharina Lieberth,Paolo Romele,Fabrizio Torricelli,Dimitrios A. Koutsouras,Maximilian Brückner,Volker Mailänder,Paschalis Gkoupidenis,Paul W. M. Blom
doi : 10.1002/adhm.202100845
Volume 10, Issue 19 2100845
In this progress report an overview is given on the use of the organic electrochemical transistor (OECT) as a biosensor for impedance sensing of cell layers. The transient OECT current can be used to detect changes in the impedance of the cell layer, as shown by Jimison et al. To circumvent the application of a high gate bias and preventing electrolysis of the electrolyte, in case of small impedance variations, an alternative measuring technique based on an OECT in a current-driven configuration is developed. The ion-sensitivity is larger than 1200 mV V-1dec-1 at low operating voltage. It can be even further enhanced using an OECT based complementary amplifier, which consists of a p-type and an n-type OECT connected in series, as known from digital electronics. The monitoring of cell layer integrity and irreversible disruption of barrier function with the current-driven OECT is demonstrated for an epithelial Caco-2 cell layer, showing the enhanced ion-sensitivity as compared to the standard OECT configuration. As a state-of-the-art application of the current-driven OECT, the in situ monitoring of reversible tight junction modulation under the effect of drug additives, like poly-l-lysine, is discussed. This shows its potential for in vitro and even in vivo toxicological and drug delivery studies.
Electrostatic Flocking of Insulative and Biodegradable Polymer Microfibers for Biomedical Applications
Alec McCarthy,Johnson V. John,Lorenzo Saldana,Hongjun Wang,Matthew Lagerstrom,Shixuan Chen,Yajuan Su,Mitchell Kuss,Bin Duan,Mark A. Carlson,Jingwei Xie
doi : 10.1002/adhm.202100766
Volume 10, Issue 19 2100766
Electrostatic flocking, a textile engineering technique, uses Coulombic driving forces to propel conductive microfibers toward an adhesive-coated substrate, leaving a forest of aligned fibers. Though an easy way to induce anisotropy along a surface, this technique is limited to microfibers capable of accumulating charge. This study reports a novel method, utilizing principles from the percolation theory to make electrically insulative polymeric microfibers flockable. A variety of well-mixed, conductive materials are added to multiple insulative and biodegradable polymer microfibers during wet spinning, which enables nearly all types of polymer microfibers to accumulate sufficient charges required for flocking. Biphasic, biodegradable scaffolds are fabricated by flocking silver nanoparticle (AgNP)-filled poly(?-caprolactone) (PCL) microfibers onto substrates made from 3D printing, electrospinning, and thin-film casting. The incorporation of AgNP into PCL fibers and use of chitosan-based adhesive enables antimicrobial activity against methicillin-resistant Staphylococcus aureus. The fabricated scaffolds demonstrate both favorable in vitro cell response and new tissue formation after subcutaneous implantation in rats, as evident by newly formed blood vessels and infiltrated cells. This technology opens the door for using previously unflockable polymer microfibers as surface modifiers or standalone structures in various engineering fields.
Core Cross-Linked Polymeric Micelles for Specific Iron Delivery: Inducing Sterile Inflammation in Macrophages
Tobias A. Bauer,Natalie K. Horvat,Oriana Marques,Sara Chocarro,Christina Mertens,Silvia Colucci,Sascha Schmitt,Luca M. Carrella,Svenja Morsbach,Kaloian Koynov,Federico Fenaroli,Peter Blümler,Michaela Jung,Rocio Sotillo,Matthias W. Hentze,Martina U. Muckenthaler,Matthias Barz
doi : 10.1002/adhm.202100385
Volume 10, Issue 19 2100385
Iron is an essential co-factor for cellular processes. In the immune system, it can activate macrophages and represents a potential therapeutic for various diseases. To specifically deliver iron to macrophages, iron oxide nanoparticles are embedded in polymeric micelles of reactive polysarcosine-block-poly(S-ethylsulfonyl-l-cysteine). Upon surface functionalization via dihydrolipoic acid, iron oxide cores act as crosslinker themselves and undergo chemoselective disulfide bond formation with the surrounding poly(S-ethylsulfonyl-l-cysteine) block, yielding glutathione-responsive core cross-linked polymeric micelles (CCPMs). When applied to primary murine and human macrophages, these nanoparticles display preferential uptake, sustained intracellular iron release, and induce a strong inflammatory response. This response is also demonstrated in vivo when nanoparticles are intratracheally administered to wild-type C57Bl/6N mice. Most importantly, the controlled release concept to deliver iron oxide in redox-responsive CCPMs induces significantly stronger macrophage activation than any other iron source at identical iron levels (e.g., Feraheme), directing to a new class of immune therapeutics.
Flexible Ultrasonic Patch for Accelerating Chronic Wound Healing
Wenhan Lyu,Yinji Ma,Siyu Chen,Haibo Li,Peng Wang,Ying Chen,Xue Feng
doi : 10.1002/adhm.202100785
Volume 10, Issue 19 2100785
Ultrasound treatment is an effective method for accelerating chronic wound healing. However, it is not widely used because traditional ultrasonic probes cannot be conformal to the wound surface, which leads to limitations of use and unstable treatment effects. In addition, the use of liquid coupling agent increases the chance of wound infection. A strategy is proposed to design and fabricate a flexible ultrasonic patch for treating chronic wounds effectively. The piezoelectric ceramic in the patch is discretized into several linearly arranged units, which are integrated on a flexible circuit substrate. A thin hydrogel patch is used as both encapsulation and coupling layer to avoid wound infection and ensure the penetration of ultrasound. The ultrasonic patch is soft, light, and can completely conform to the treatment area. Bending of the patch focuses the sound beams on the center of the bending circle, which achieves control of the target treatment area. Ultrasound treatment experiments are carried out on some type-II diabetic rats. Immunohistochemical (IHC) results indicate that ultrasound accelerates wound healing by activating Rac1 in both dermal and epidermal layers. Treatment results show that wound treated with the ultrasound heals faster than wounds without. The healing time is shortened by ?40%.
Liquid Copolymers as Biodegradable Surgical Sealant
Neta Shimony,Alona Shagan,Bat-hen Eylon,Abraham Nyska,Adi Gross,Boaz Mizrahi
doi : 10.1002/adhm.202100803
Volume 10, Issue 19 2100803
Surgical sealants are widely used to prevent seepage of fluids and liquids, promote hemostasis, and close incisions. Despite the remarkable progress the field of biomaterials has undergone, the clinical uses of surgical sealants are limited because of their short persistence time in vivo, toxicity, and high production costs. Here, the development of two complementary neat (solvent-free) prepolymers, PEG4-PLGA-NHS and PEG4-NH2, that harden upon mixing to yield an elastic biodegradable sealant is presented. The mechanical and rheological properties and cross-linking rate can be controlled by varying the ratio between the two prepolymers. The tested sealants show a longer persistence time compared with fibrin glue, minimal cytotoxicity in vitro, and excellent biocompatibility in vivo. The neat, multiarmed approach demonstrated here improves the mechanical and biocompatibility properties and provides a promising tissue sealant solution for wound closure in future surgical procedures.
Magnetization-Switchable Implant System to Target Delivery of Stem Cell-Loaded Bioactive Polymeric Microcarriers
Gwangjun Go,Ami Yoo,Seokjae Kim,Jong Keun Seon,Chang-Sei Kim,Jong-Oh Park,Eunpyo Choi
doi : 10.1002/adhm.202100068
Volume 10, Issue 19 2100068
Various magnetic microcarrier systems capable of transporting cells to target lesions are developed for therapeutic agent-based tissue regeneration. However, the need for bioactive molecules and cells, the potential toxicity of the microcarrier, and the large volume and limited workspace of the magnetic targeting device remain challenging issues associated with microcarrier systems. Here, a multifunctional magnetic implant system is presented for targeted delivery, secure fixation, and induced differentiation of stem cells. This magnetic implant system consists of a biomaterial-based microcarrier containing bioactive molecules, a portable magnet array device, and a biocompatible paramagnetic implant. Among biomedical applications, the magnetic implant system is developed for knee cartilage repair. The various functions of these components are verified through in vitro, phantom, and ex vivo tests. As a result, a single microcarrier can load ?1.52 ng of transforming growth factor ? (TGF-?1) and 3.3 × 103 of stem cells and stimulate chondrogenic differentiation without extra bioactive molecule administration. Additionally, the implant system demonstrates high targeting efficiency (over 90%) of the microcarriers in a knee phantom and ex vivo pig knee joint. The results show that this implant system, which overcomes the limitations of the existing magnetic targeting system, represents an important advancement in the field.
Light-Controlled Precise Delivery of NIR-Responsive Semiconducting Polymer Nanoparticles with Promoted Vascular Permeability
Weizhi Qi,Tingting Li,Chen Zhang,Fei Liu,Jun Wang,Dandan Chen,Xiaofeng Fang,Changfeng Wu,Kai Li,Lei Xi
doi : 10.1002/adhm.202100569
Volume 10, Issue 19 2100569
The endothelial barrier plays an essential role in health and disease by protecting organs from toxins while allowing nutrients to access the circulation. However, it is the major obstacle that limits the delivery of therapeutic drugs to the diseased tissue. Here, it is reported for the first time that near-infrared (NIR) laser pulses can transiently promote the delivery of semiconducting polymer nanoparticles passing the vascular barrier via photoacoustic-effect-induced accumulation, only by the aid of pulse laser irradiation. This strategy enables selective and substantial accumulation of the NIR-absorbing nanoparticles inside specific tissues, implying the discovery of an unprecedented approach for light-controlled nanoparticle delivery. Especially, the nanoparticle delivery in solid tumors by 10-min laser scanning is approximately six times higher than that of the enhanced permeability and retention (EPR) effect in 24 h under current experimental conditions. Further results confirm that this strategy facilitates substantial accumulation of nanoparticles in the mouse brain with intact skull. This approach thus opens a new door for tissue-specific delivery of nanomaterials with an unprecedented level of efficiency and precision.
Nanozyme with Robust Catalase Activity by Multiple Mechanisms and Its Application for Hypoxic Tumor Treatment
Chongchong Wang,Yanqing Li,Weijie Yang,Lin Zhou,Shaohua Wei
doi : 10.1002/adhm.202100601
Volume 10, Issue 19 2100601
Utilizing catalase-mimicking nanozymes to produce O2 is an effective method to overcome tumor hypoxia. However, it is challenging to fabricate nanozymes with ultrahigh catalytic activity. Palladium nanosheet (Pd NS), a photothermal agent for photothermal therapy (PTT), has superior catalase-mimicking activity. Here, titanium dioxide (TiO2) is used to modify Pd NS (denoted Pd@TiO2) by a simple one-step method to improve its catalytic activity about 8 times. The enhancement mechanism's fundamental insights are discussed through experiments and density functional theory calculations. Next, zinc phthalocyanine is loaded on Pd@TiO2 to form a nanomotor (denoted PTZCs) with the synergistic activities of photodynamic therapy and PTT. PTZCs inherit the catalase activity of Pd@TiO2 to facilitate the decomposition of endogenous H2O2 to O2, which can relieve tumor hypoxia and propel PTZC migration to expand the reach of PTZCs, further enhancing its synergistic treatment outcome both in vitro and in vivo. It is proposed that this work can provide a simple and effective strategy for catalytic activity enhancement and bring a critical new perspective to studying and guiding the nanozyme design.
Phototriggered Self-Adaptive Functionalized MOC-Based Drug Delivery Platform Promises High Antitumor Efficacy
Yifeng Shen,Congjun Xu,Jie Chen,Zilin Guan,Yanjuan Huang,Zishan Zeng,Xiaoyu Xu,Xiaomin Tan,Chunshun Zhao
doi : 10.1002/adhm.202100676
Volume 10, Issue 19 2100676
Due to their great stability and special cavities, metal-organic cages (MOCs) are increasingly considered as promising nanocarriers for drug delivery. However, the size and surface dilemmas restrict their further biomedical applications. The ultrasmall size of MOCs facilitates tumor penetration but suffers from quick clearance and poor accumulation at the tumor site. Hydrophobicity of MOC surfaces improves internalization into tumor cells while causing low blood circulation time as well as poor biocompatibility. Therefore, it remains challenging for the MOC-based drug delivery nanoplatform to realize high therapeutic efficacy because it requires different or even opposite dimensions and surface characteristics in different steps of circulation, penetration, accumulation, and internalization processes. In this study, an unprecedented phototriggered self-adaptive platform (ZnPc@polySCage) is developed by integrating functionalized MOCs and a photodynamic therapy based reactive oxygen species responsive strategy to realize high-efficiency tumor-specific therapy. ZnPc@polySCage remains hydrophilic and stealthy during circulation, and retains its small original size for tumor penetration, while transforming to a larger size for effective accumulation and hydrophobic for enhanced internalization under laser irradiation in tumor tissue. With these essential transitions, ZnPc@polySCage demonstrates prominent antitumor effects. Overall, the work provides an advantageous strategy for functional MOC-based platforms and biomedical applications.
CaCO3-Encapuslated Microspheres for Enhanced Transhepatic Arterial Embolization Treatment of Hepatocellular Carcinoma
Aimi Zhang,Zhisheng Xiao,Qiufang Liu,Panli Li,Fei Xu,Jianjun Liu,Huiquan Tao,Liangzhu Feng,Shaoli Song,Zhuang Liu,Gang Huang
doi : 10.1002/adhm.202100748
Volume 10, Issue 19 2100748
Transcatheter arterial embolization (TAE) is an extensively applied treatment method for hepatocellular carcinoma (HCC). However, the worsened tumor microenvironment (TME, e.g., reduced pH post-TAE) may result in unsatisfactory therapeutic outcome. Herein, a new kind of embolic agent, calcium carbonate encapsulated alginate microspheres (CaCO3-ALG MSs) are synthesized. Such CaCO3-ALG MSs are able to neutralize the tumor pH owing to the reaction of CaCO3 with protons, which would not affect the overall morphology of microspheres after decomposition of CaCO3. TAE treatment with CaCO3-ALG MSs is then conducted in an orthotopic rat liver cancer model. 18F-Fluorodeoxyglucose micropositron emission tomography/computed tomography imaging is conducted post-TAE and discovered that intra-arterial injection of CaCO3-ALG MSs shows obvious enhanced therapeutic outcome compared to the same treatment with bare ALG MSs or the clinically used lipiodol. Further studies including analysis of immune cells in tumors, cytokine assays, and bioinformatics analysis all verify the reverse of immunosuppressive TME toward a more immunosupportive one after TAE with CaCO3-ALG MSs. The research not only presents a new CaCO3-containing embolic agent for enhanced TAE treatment of HCC but also highlights a clinically meaningful approach to improve cancer treatment via tumor pH neutralization.
Functionalized Silk Vascular Grafts with Decellularized Human Wharton's Jelly Improves Remodeling via Immunomodulation in Rabbit Jugular Vein
Prerak Gupta,Gaurab Ranjan Chaudhuri,G. Janani,Manoj Agarwala,Debaki Ghosh,Samit K. Nandi,Biman B. Mandal
doi : 10.1002/adhm.202100750
Volume 10, Issue 19 2100750
Cell-free polymeric tissue-engineered vascular grafts (TEVGs) have shown great promise towards clinical translation; however, their limited bioactivity and remodeling ability challenge this cause. Here, a novel cell-free bioresorbable small diameter silk TEVG system functionalized with decellularized human Wharton's jelly (dWJ) matrix is developed and successfully implanted as interposition grafts into rabbit jugular vein. Implanted TEVGs remain patent for two months and integrate with host tissue, demonstrating neo-tissue formation and constructive remodeling. Mechanistic analysis reveals that dWJ matrix is a reservoir of various immunomodulatory cytokines (Interleukin-8, 6, 10, 4 and tumor necrosis factor alpha (TNF-?)), which aids in upregulating M2 macrophage-associated genes facilitating pro-remodeling behavior. Besides, dWJ treatment to human endothelial cells upregulates the expression of functional genes (cluster of differentiation 31 (CD31), endothelial nitric oxide synthase (eNOS), and vascular endothelial (VE)-cadherin), enables faster cell migration, and elevates nitric oxide (NO) production leading to the in situ development of endothelium. The dWJ functionalized silk TEVGs support increased host cell recruitment than control, including macrophages and vascular cells. It endows superior graft remodeling in terms of a dense medial layer comprising smooth muscle cells and elevates the production of extracellular matrix proteins (collagen and elastin). Altogether, these findings suggest that dWJ functionalization imitates the usefulness of cell seeding and enables graft remodeling.
Hybrid Poly(AMPS-CS)-Au Microneedle Arrays to Enrich Metabolites from Skin for Early Disease Diagnosis
Yuyin Tang,Su Li,Linyu Hu,Xuetong Sun,Bei Zhang,Wenwen Ji,Lijuan Ma,Wenhui Qian,An Kang,Dong Zhu
doi : 10.1002/adhm.202100764
Volume 10, Issue 19 2100764
Recently, some metabolites in skin interstitial fluid (SIF) have become emerging re×sources for early disease diagnosis. However, their low level in SIF and difficulty to sampling are the biggest obstacle to further potential application. Here, a swellable microneedle array patch (MNAP) with high mechanical strength is presented, and the rapid enrichment of positively charged metabolites is achieved. The MNAP is fabricated by poly (chondroitin sulfate-acrylamido-2-methylpropane sulfonic acid)-gold nanoparticles (GNPs) composites via a micro-molding. The negatively charged copolymer hydrogel not only enrich positively charged metabolites, but also provide swellable capacity. The in situ synthesis of GNPs in the process of copolymerization make the GNPs cross-link to the hydrogel, which further enhance the MNAP mechanical strength and enrichment efficiency for positively charged metabolites. By using the MNAP, around 5 mg SIF in 10 min from the high fat/cholecalciferol/methimazole-induced atherogenesis rat is extracted and 23 metabolites including 13 quaternary ammonium cationic compounds can be detected and quantified by using a LC-QTOF-MS. Dysregulated L-carnitine and choline metabolism are discovered a week earlier in the SIF than in the serum, achieving early diagnosis of the metabolism syndrome disease. This MNAP also helps users complete home sampling for early disease diagnosis and monitoring.
Versatile Nanodrugs Containing Glutathione and Heme Oxygenase 1 Inhibitors Enable Suppression of Antioxidant Defense System in a Two-Pronged Manner for Enhanced Photodynamic Therapy
Hao Zhong,Pei-Ying Huang,Ping Yan,Pei-Ling Chen,Qun-Yin Shi,Ze-An Zhao,Jing-Xuan Chen,Xian Shu,Ping Wang,Bin Yang,Zheng-Zheng Zhou,Jian-Jun Chen,Jian-Xin Pang,Ying-Feng Tu,Li-Han Liu,Xian-Zheng Zhang
doi : 10.1002/adhm.202100770
Volume 10, Issue 19 2100770
The antioxidant defense system in malignant cells, which involves antioxidant enzymes and antioxidant molecules, is an innate barrier to photodynamic therapy (PDT). Because of the complexity of the endogenous antioxidant mechanisms of these cells, simply inhibiting individual antioxidant pathways has a limited effect on improving the lethality of ROS. To enhance the efficacy of PDT for tumor treatment, a versatile nanoparticle (NP)-based drug is developed, which the authors call PZB NP, containing the glutathione inhibitor l-buthionine sulfoximine (BSO) and the heme oxygenase 1 (HO-1) inhibitor protoporphyrin zinc(II) (ZnPP) to suppress the innate antioxidant defense system of cancer cells in a two-pronged manner. BSO reduces intracellular glutathione levels to minimize ROS elimination and protein protection during PDT, and ZnPP inhibits the ROS-stimulated upregulation of the antioxidant HO-1, thus preventing ROS removal by cells after PDT. Thus, BSO and ZnPP synergistically suppress the antioxidant defense systems of cancer cells both during and after protoporphyrin-IX-mediated PDT in a two-pronged manner, resulting in tumor cell death through excess oxidative pressure. The results demonstrate that the construction of nanodrugs having dual antioxidation defense suppression properties is a promising route for the development of highly efficient ROS-based therapies.
Acridine-Based Covalent Organic Framework Photosensitizer with Broad-Spectrum Light Absorption for Antibacterial Photocatalytic Therapy
Cuiping Zhang,Jiangna Guo,Xiuyang Zou,Siyu Guo,Yu Guo,Rongwei Shi,Feng Yan
doi : 10.1002/adhm.202100775
Volume 10, Issue 19 2100775
Antibiotic resistance is considered as one of the serious public health issues. Antibacterial photocatalytic therapy, a clinically proven antibacterial therapy, is gaining increasing attention in recent years owing to its high efficacy. Here, an acridine-based covalent organic framework (COF) photosensitizer, named TPDA, with multiple active sites is synthesized via Schiff base condensation between 2,4,6-triformylphloroglucinol (TFP) and 3,6-diaminoacridine (DAA). Owing to the increased conjugation effect of the COF skeleton and outstanding light harvesting ability of DAA, TPDA exhibits a narrow optical band gap (1.6 eV), enhancing light energy transformation and conferring a wide optical absorption spectrum (intensity arbitrary unit > 0.8) ranging from the UV to near-infrared region. Moreover, TPDA shows high antibacterial activities against both gram-negative and gram-positive bacteria within a short time (10 min) of light irradiation and is found to efficiently protect fish from skin infections. Molecular dynamics simulation data show that the introduction of DAA and TFP facilitates the interaction between TPDA and bacteria and is conducive to reactive oxygen species migration, which further improves the antimicrobial performance. These findings indicate the potential of TPDA as a novel photosensitive material for photodynamic therapy.
One-Pot Approach to Fe2+/Fe3+-Based MOFs with Enhanced Catalytic Activity for Fenton Reaction
Xin Meng,Fan Zhang,Huanling Guo,Chunyang Zhang,Hangtong Hu,Wei Wang,Jie Liu,Xintao Shuai,Zhong Cao
doi : 10.1002/adhm.202100780
Volume 10, Issue 19 2100780
Smart theragnostic nanoplatforms exhibit great promise in clinical tumor treatment. The Fe-based Fenton reaction in tumor sites may generate reactive oxygen species to kill cancer cells with negligible side effects on normal tissues. However, its efficiency and duration are limited by the low intracellular concentration of H2O2, weak acidicity of tumor tissue, and low catalytic activity of conventional Fenton reagents. Herein, a facile strategy is proposed to efficiently overcome these obstacles. An efficient enzymatic/Fenton-starvation nanoreactor PMs loaded with glucose oxidase and perfluoropentane (PGPMs) is constructed through synthesizing methoxy-PEG-carboxymethy-modified iron (Fe2+/Fe3+)-based metal–organic frameworks (PMs), followed by loading glucose oxidase (GOx) and perfluoropentane (PFP). PGPMs accumulating in the tumor tissue exhibit tumor microenvironment-responsive biodegradable behavior and unusual catalytic activity for Fenton reaction advantageous over Fe3+-based MOFs. Meanwhile, encapsulation of GOx into PGPMs further significantly increases the catalytic activity for Fenton reaction and also induces starvation therapy. PGPMs also exhibit considerable capabilities of ultrasound and tumor microenvironment-responsive T2 MR imaging applicable for contrast-enhanced diagnosis. Both in vitro and in vivo studies demonstrate the great diagnostic and therapeutic potentials of this nanoreactor in tumor.
Design of Protein-Based Liquefied Cell-Laden Capsules with Bioinspired Adhesion for Tissue Engineering
Maria C. Gomes,Dora C. S. Costa,Cláudia S. Oliveira,João F. Mano
doi : 10.1002/adhm.202100782
Volume 10, Issue 19 2100782
Platforms with liquid cores are extensively explored as cell delivery vehicles for cell-based therapies and tissue engineering. However, the recurrence of synthetic materials can impair its translation into the clinic. Inspired by the adhesive proteins secreted by mussels, liquefied capsule is developed using gelatin modified with hydroxypyridinones (Gel-HOPO), a catechol analogue with oxidant-resistant properties. The protein-based liquefied macrocapsule permitted the compartmentalization of living cells by an approachable and non-time-consuming methodology resorting to i) superhydrophobic surfaces as a processing platform of hydrogel beads, ii) gelation of gelatin at temperatures < 25 °C, iii) iron coordination of the hydroxypyridinone (HOPO) moieties at physiological pH, and iv) core liquefaction at 37 °C. With the design of a proteolytically degradable shell, the possibility of encapsulating human adipose-derived mesenchymal stem cells (hASC) with and without the presence of polycaprolactone microparticles (?PCL) is evaluated. Showing prevalence toward adhesion to the inner shell wall, hASC formed a monolayer evidencing the biocompatibility and adequate mechanical properties of these platforms for proliferation, diminishing the need for ?PCL as a supporting substrate. This new protein-based liquefied platform can provide biofactories devices of both fundamental and practical importance for tissue engineering and regenerative medicine or in other biotechnology fields.
Smart Asymmetric Hydrogel with Integrated Multi-Functions of NIR-Triggered Tunable Adhesion, Self-Deformation, and Bacterial Eradication
Lan Feng,Wenbin Shi,Qin Chen,Huitong Cheng,Jianxu Bao,Chunji Jiang,Weifeng Zhao,Changsheng Zhao
doi : 10.1002/adhm.202100784
Volume 10, Issue 19 2100784
Multifunctional hydrogels acting as wound dressing have received extensive attention in soft tissue repair; however, it is still a challenge to develop a non-antibiotic-dependent antibacterial hydrogel that has tunable adhesion and deformation to achieve on-demand removal. Herein, an asymmetric adhesive hydrogel with near-infrared (NIR)-triggered tunable adhesion, self-deformation, and bacterial eradication is designed. The hydrogel is prepared by the crosslinking polymerization of N-isopropylacrylamide and acrylic acid, during the sedimentation of conductive PPy-PDA nanoparticles based on the polymerization of pyrrole (Py) and dopamine (DA). Due to the conversion capacity from NIR light into heat for PPy-PDA NPs, the formed temperature-sensitive hydrogel exhibits tissue adhesive as well as NIR-triggered tunable adhesion and self-deformation property, which can achieve an on-demand dressing refreshing. Systematically in vitro/in vivo antibacterial experiments indicate that the hydrogel shows excellent disinfection capability to both Gram-negative and Gram-positive bacteria. The in vivo experiments in a full-layer cutaneous wound model demonstrate that the hydrogel has a good treatment effect to promote wound healing. Overall, the asymmetric hydrogel with tunable adhesion, self-deformation, conductive, and photothermal antibacterial activity may be a promising candidate to fulfill the functions of adhesion on skin tissue, easy removing on-demand, and accelerating the wound healing process.
Image-Guided TME-Improving Nano-Platform for Ca2+ Signal Disturbance and Enhanced Tumor PDT (Adv. Healthcare Mater. 19/2021)
Yuping Jiang,Wei Meng,Lijuan Wu,Kai Shao,Lili Wang,Mengchao Ding,Jinsheng Shi,Xiaoying Kong
doi : 10.1002/adhm.202170088
Volume 10, Issue 19 2170088
Image-Guided TME-Improving Nano-Platform for Ca2+ Signal Disturbance and Enhanced Tumor PDT
Yuping Jiang,Wei Meng,Lijuan Wu,Kai Shao,Lili Wang,Mengchao Ding,Jinsheng Shi,Xiaoying Kong
doi : 10.1002/adhm.202100789
Volume 10, Issue 19 2100789
Dysfunction of the calcium balancing system and disruption of calcium distribution can induce abnormal intracellular calcium overload, further causing serious damage and even cell death, which provides a potential therapeutic approach for tumor treatment. Herein, a nano-platform, which includes UCNPs-Ce6@RuR@mSiO2@PL-HA NPs (UCRSPH) and SA-CaO2 nanoparticles, is prepared for improving the tumor micro-environment (TME), Ca2+ signal disturbance as well as enhanced photodynamic tumor therapy (PDT). UCRSPH combined with SA-CaO2 can alter TME and relieve hypoxia of the tumor to realize self-reinforcing PDT under near-IR irradiation (980 nm). The ruthenium red (RuR) in the UCRSPH NPs can be released to the cytoplasm after endocytosis of the nanoparticles, target Ca2+ channel proteins on the endoplasmic reticulum and mitochondria, sarcoplasmic reticulum Ca2+-ATPase (SERCA), and mitochondrial calcium uniporter (MCU). The combined participation of nanoparticles and RuR promotes Ca2+ imbalance and cytoplasmic calcium overload with the assistance of CaO2, and provides tumor cells higher sensitivity to PDT. Furthermore, the nano-platform also provides fluorescence imaging and calcification computed tomography imaging for in vivo treatment guidance. In conclusion, this image-guided nano-platform show potential for highly specific, efficient combined therapy against tumor cells with minimal side-effects to normal cells by integrating TME improvement, self-reinforcing PDT, and Ca2+ signal disturbance.
Facile Polyphenol–Europium Assembly Enabled Functional Poly(l-Lactic Acid) Nanofiber Mats with Enhanced Antioxidation and Angiogenesis for Accelerated Wound Healing
Keke Wu,Xiaoxian Wu,Jinshan Guo,Yanpeng Jiao,Changren Zhou
doi : 10.1002/adhm.202100793
Volume 10, Issue 19 2100793
Burns, trauma, surgery and chronic diabetic ulcers are the most common reasons causing skin wounds in clinic. Thus, developing a functional wound dressing has been an imperative issue. Herein, functional wound dressing (poly(l-lactic acid) PLLA-((tanic acid (TA)/europium (Eu))n) is fabricated through a facile polyphenol–europium ion assembly to ameliorate wound microenvironment via scavenging excessive reactive oxygen species (ROS) and promoting angiogenesis. The physicochemical characterization indicates that the multicycle assembled TA/Eu is uniformly deposited on PLLA-(TA/Eu)n nanofiber mats surface. In vitro 2,2-diphenyl-1-picrylhydrazyl (DPPH) antioxidant tests display good antioxidant ability by scavenging more than 75% ROS, and significantly increasing the antioxidant enzyme levels in vivo. Cytocompatibility experiments illustrate that PLLA-(TA/Eu)n nanofiber mats can promote the adhesion and proliferation of human umbilical vein endothelial cells (HUVECs) and L929 cells. Meanwhile, real-time quantitative polymerase chain reaction (PCR) (RT-qPCR) and western blot assays illustrate that it can stimulate proangiogenesis by elevating the expression of angiogenesis-related genes and proteins. In vivo Sprague–Dawley (SD) rats experiments indicate that PLLA-(TA/Eu)n nanofiber mats can significantly promote wound healing by improving both angiogenesis and antioxidant activity. Taken together, the functional PLLA-(TA/Eu)n nanofiber mats can offer significant promise as wound dressing for accelerated wound healing.
Biomimetic Liposome with Surface-Bound Elastase for Enhanced Tumor Penetration and Chemo-Immumotherapy
Yong-Jiang Li,Jun-Yong Wu,Xiong-Bin Hu,Tianjinhao Ding,Tiantian Tang,Da-Xiong Xiang
doi : 10.1002/adhm.202100794
Volume 10, Issue 19 2100794
Dense extracellular matrix (ECM) in the tumor stroma has been a challenge for drug penetration and cytotoxic T lymphocyte (CTL) infiltration. Neutrophil elastase (NE), in surface-bound form, can destruct ECM rapidly, may be used for remodeling tumor ECM, and overcoming tumor stromal barrier. Focusing on elastosis in triple-negative breast tumor, biomimetic liposomes with chimeric cell membrane proteins (LMP) are developed and for the first time, it is demonstrated that LMP with surface-bound elastase (NE-LMP) can target and degrade ECM effectively in tumor stroma, with minimal toxicity to normal tissues. The pretreatment of NE-LMP increases the accumulation of chemotherapeutics at the tumor site and enhances antitumor effects. Also, NE-LMP facilitates CTL infiltration in tumors and exhibits enhanced chemo-immunotherapy in combination of PD-1 immune checkpoint blockade treatment in orthotopic 4T1 tumor-bearing mice, with significantly prolonged survival. Moreover, the remodeling of the tumor ECM by NE-LMP shows inhibiting effects on metastasis in the lung. Findings from this study suggest that NE-LMP holds promise for enhancing deep penetration of drug and infiltration of CTL in desmoplastic tumor by effective degrading ECM in the tumor stroma.
Lactate Consumption via Cascaded Enzymes Combined VEGF siRNA for Synergistic Anti-Proliferation and Anti-Angiogenesis Therapy of Tumors
Yan Tang,Changhao Jia,Yu Wang,Wenjun Wan,Hui Li,Gui Huang,Xuenong Zhang
doi : 10.1002/adhm.202100799
Volume 10, Issue 19 2100799
Lactate, as the most abundant component with concentrations of 4–40 mm in tumors, contributes to the regulation of metabolic pathways, angiogenesis, and immunosuppression, exhibiting remarkable potential in cancer treatment. Therefore, a codelivery strategy that combined the cascaded enzymes Lactate oxidase/Catalase (LOx/CAT) and vascular endothelial growth factor (VEGF) siRNA (siVEGF) to suppress tumor proliferation and angiogenesis synergistically is creatively proposed. In brief, the cationic liposomes (LIP) encapsulated with LOx/CAT and siVEGF via hydrophilic interaction and electrostatic adsorption followed by coating with PEGylated phenylboronic acid (PP) is established (PPL@[LOX+CAT]). Moreover, a simple 3-aminophenylboronic acid (PBA)-shielded strategy via fructose (Fru) is applied to further enhance the targeting efficiency in the tumor site. The obtained co-encapsulated nanoparticles (NPs) can simultaneous intracellular release of LOx/CAT and siVEGF, and the collaborative use of LOx and CAT can promote lactate consumption even under a hypoxic tumor microenvironment (TME) without producing systemic toxicity. The combined application of lactate depletion and VEGF silencing demonstrated the efficient migration suppression of 4T1 cells in vitro and superior antitumor and antimetastatic properties in vivo. This work offers a promising tumor treatment strategy via integrating cascaded enzymes and gene therapy, and explores a promising therapy regimen for 4T1 triple-negative breast cancer.
A Magnetically Powered Stem Cell-Based Microrobot for Minimally Invasive Stem Cell Delivery via the Intranasal Pathway in a Mouse Brain (Adv. Healthcare Mater. 19/2021)
Sungwoong Jeon,Sun Hwa Park,Eunhee Kim,Jin-young Kim,Sung Won Kim,Hongsoo Choi
doi : 10.1002/adhm.202170089
Volume 10, Issue 19 2170089
Targeted stem cell delivery with microrobots has emerged as a potential alternative therapeutic strategy in regenerative medicine, and intranasal administration is an effective approach for minimally invasive delivery of therapeutic agents into the brain. In this study, a magnetically powered stem cell-based microrobot (“Cellbot”) is used for minimally invasive targeted stem cell delivery to the brain through the intranasal passage. The Cellbot is developed by internalizing superparamagnetic iron oxide nanoparticles (SPIONs) into human nasal turbinate stem cells. The SPIONs have no influence on hNTSC characteristics, including morphology, cell viability, and neuronal differentiation. The Cellbots are capable of proliferation and differentiation into neurons, neural precursor cells, and neurogliocytes. The Cellbots in the microfluidic channel can be reliably manipulated by an external magnetic field for orientation and position control. Using an ex vivo model based on brain organoids, it is determined that the Cellbots can be transplanted into brain tissue. Using a murine model, it is demonstrated that the Cellbots can be intranasally administered and magnetically guided to the target tissue in vivo. This approach has the potential to effectively treat central nervous system disorders in a minimally invasive manner.
A Magnetically Powered Stem Cell-Based Microrobot for Minimally Invasive Stem Cell Delivery via the Intranasal Pathway in a Mouse Brain
Sungwoong Jeon,Sun Hwa Park,Eunhee Kim,Jin-young Kim,Sung Won Kim,Hongsoo Choi
doi : 10.1002/adhm.202100801
Volume 10, Issue 19 2100801
Targeted stem cell delivery with microrobots has emerged as a potential alternative therapeutic strategy in regenerative medicine, and intranasal administration is an effective approach for minimally invasive delivery of therapeutic agents into the brain. In this study, a magnetically powered stem cell-based microrobot (“Cellbot”) is used for minimally invasive targeted stem cell delivery to the brain through the intranasal passage. The Cellbot is developed by internalizing superparamagnetic iron oxide nanoparticles (SPIONs) into human nasal turbinate stem cells. The SPIONs have no influence on hNTSC characteristics, including morphology, cell viability, and neuronal differentiation. The Cellbots are capable of proliferation and differentiation into neurons, neural precursor cells, and neurogliocytes. The Cellbots in the microfluidic channel can be reliably manipulated by an external magnetic field for orientation and position control. Using an ex vivo model based on brain organoids, it is determined that the Cellbots can be transplanted into brain tissue. Using a murine model, it is demonstrated that the Cellbots can be intranasally administered and magnetically guided to the target tissue in vivo. This approach has the potential to effectively treat central nervous system disorders in a minimally invasive manner.
Formation of 3D Self-Organized Neuron-Glial Interface Derived from Neural Stem Cells via Mechano-Electrical Stimulation
Youyi Tai,Gerardo Ico,Karen Low,Junze Liu,Tanvi Jariwala,David Garcia-Viramontes,Kyu Hwan Lee,Nosang V. Myung,B. Hyle Park,Jin Nam
doi : 10.1002/adhm.202100806
Volume 10, Issue 19 2100806
Due to dissimilarities in genetics and metabolism, current animal models cannot accurately depict human neurological diseases. To develop patient-specific in vitro neural models, a functional material-based technology that offers multi-potent stimuli for enhanced neural tissue development is devised. An electrospun piezoelectric poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)) nanofibrous scaffold is systematically optimized to maximize its piezoelectric properties while accommodating the cellular behaviors of neural stem cells. Hydro-acoustic actuation is elegantly utilized to remotely activate the piezoelectric effect of P(VDF-TrFE) scaffolds in a physiologically-safe manner for the generation of cell-relevant electric potentials. This mechano-electrical stimulation, which arose from the deflection of the scaffold and its consequent generation of electric charges on the scaffold surface under hydro-acoustic actuation, induces the multi-phenotypic differentiation of neural stem cells simultaneously toward neuronal, oligodendrocytic, and astrocytic phenotypes. As compared to the traditional biochemically-mediated differentiation, the 3D neuron-glial interface induced by the mechano-electrical stimulation results in enhanced interactions among cellular components, leading to superior neural connectivity and functionality. These results demonstrate the potential of piezoelectric material-based technology for developing functional neural tissues in vitro via effective neural stem cell modulation with multi-faceted regenerative stimuli.
Localized Chemotherapy Based on Injectable Hydrogel Boosts the Antitumor Activity of Adoptively Transferred T Lymphocytes In Vivo
Yue Cao,Yuhao Zhou,Zhixiong Chen,Zhen Zhang,Xuesi Chen,Chaoliang He
doi : 10.1002/adhm.202100814
Volume 10, Issue 19 2100814
The adoptive transfer of antigen-specific T cells has been successfully applied in the treatment of hematological malignancies. However, its application in the treatment of solid tumors has been overshadowed by the immunosuppressive tumor microenvironment. In this context, a preprocessing strategy is developed to reprogram the immunosuppressive tumor microenvironment using a thermoresponsive hydrogel loaded with doxorubicin (DOX@Gel). Compared with hydrogel-based chemotherapy alone or adoptive T cell therapy alone, this combination exhibits enhanced anti-tumor efficacy. In addition to the direct killing of tumor cells, the local chemotherapy releases tumor-associated antigens which enhance the proliferation and effector function of endogenous and adoptively transferred T cells. Moreover, DOX@Gel significantly reduces the numbers of both myeloid derived suppressor cells and Tregs in tumor microenvironment. It is suggested that DOX@Gel promotes the efficacy of adoptively transferred T cells against solid tumors, overcoming the key limitations of adoptive T cell therapy.
Spinal Cord Neuronal Network Formation in a 3D Printed Reinforced Matrix—A Model System to Study Disease Mechanisms (Adv. Healthcare Mater. 19/2021)
Natalie Fischhaber,Jessica Faber,Ezgi Bakirci,Paul D. Dalton,Silvia Budday,Carmen Villmann,Natascha Schaefer
doi : 10.1002/adhm.202170090
Volume 10, Issue 19 2170090
Spinal Cord Neuronal Network Formation in a 3D Printed Reinforced Matrix—A Model System to Study Disease Mechanisms
Natalie Fischhaber,Jessica Faber,Ezgi Bakirci,Paul D. Dalton,Silvia Budday,Carmen Villmann,Natascha Schaefer
doi : 10.1002/adhm.202100830
Volume 10, Issue 19 2100830
3D cell cultures allow a better mimicry of the biological and mechanical environment of cells in vivo compared to 2D cultures. However, 3D cell cultures have been challenging for ultrasoft tissues such as the brain. The present study uses a microfiber reinforcement approach combining mouse primary spinal cord neurons in Matrigel with melt electrowritten (MEW) frames. Within these 3D constructs, neuronal network development is followed for 21 days in vitro. To evaluate neuronal development in 3D constructs, the maturation of inhibitory glycinergic synapses is analyzed using protein expression, the complex mechanical properties by assessing nonlinearity, conditioning, and stress relaxation, and calcium imaging as readouts. Following adaptation to the 3D matrix-frame, mature inhibitory synapse formation is faster than in 2D demonstrated by a steep increase in glycine receptor expression between days 3 and 10. The 3D expression pattern of marker proteins at the inhibitory synapse and the mechanical properties resemble the situation in native spinal cord tissue. Moreover, 3D spinal cord neuronal networks exhibit intensive neuronal activity after 14 days in culture. The spinal cord cell culture model using ultrasoft matrix reinforced by MEW fibers provides a promising tool to study and understand biomechanical mechanisms in health and disease.
Overcoming T Cell Exhaustion via Immune Checkpoint Modulation with a Dendrimer-Based Hybrid Nanocomplex
Yue Gao,Zhijun Ouyang,Chao Yang,Cong Song,Chunjuan Jiang,Shaoli Song,Mingwu Shen,Xiangyang Shi
doi : 10.1002/adhm.202100833
Volume 10, Issue 19 2100833
T cell exhaustion, in which dysfunctional T cells are limited in cytokine release and constrained in immune response, leads to immune escape of cancer cells and decreased efficiency of cancer immunotherapy. Direct regulation or blocking of programmed death 1 (PD-1) represents a promising strategy to overcome T cell exhaustion for reinvigorating anticancer immunity. Here, the construction of a 1,3-propanesultone (1,3-PS)-grafted zwitterionic dendrimer-entrapped gold nanoparticle platform chelated with Gd(III) (Gd-Au DENP-PS) for immune checkpoint modulation is reported. The developed Gd-Au DENP-PS possesses good stability, antifouling property, biocompatibility, and dual-mode computed tomography (CT)/magnetic resonance (MR) imaging functions, and allows for efficient packaging and serum-enhanced delivery of PD-1 siRNA to mediate PD-1 gene silencing in T cells in vitro, and also in vivo in a melanoma-bearing mouse model and in healthy aging mice. The dendrimer nanocomplexes or T cell-laden nanocomplexes enable suppression of tumor growth through the generation of significant effector CD8+ and CD4+ T cells, and the tumor immunotherapeutic potency can be further improved by combination with an indoleamine 2,3-dioxygenase inhibitor. This study identifies a new possibility with a functional dendrimer-based nanohybrid platform for dual-mode CT/MR imaging-guided cancer immunotherapy via the regulation of T cell exhaustion.
Anticoagulant Hydrogel Tubes with Poly(?-Caprolactone) Sheaths for Small-Diameter Vascular Grafts
Chunliang Zhang,Qian Xie,Ruitao Cha,Li Ding,Liujun Jia,Lei Mou,Shiyu Cheng,Nuoxin Wang,Zulan Li,Yang Sun,Chuanjue Cui,Yu Zhang,Yan Zhang,Fengshan Zhou,Xingyu Jiang
doi : 10.1002/adhm.202100839
Volume 10, Issue 19 2100839
Small-diameter vascular grafts (inner diameter < 6 mm) are useful in treating cardiovascular diseases. The off-the-shelf small-diameter vascular grafts for clinical applications remain a great limitation owing to their thrombogenicity or intimal hyperplasia. Herein, bilayer anticoagulant hydrogel tubes with poly(?-caprolactone) (PCL) sheaths are prepared by freeze-thawing and electrospinning, which contain nanofibrillated cellulose (NFC)/poly(vinyl alcohol) (PVA)-heparin/poly-L-lysine nanoparticles tube as an inner layer and PCL sheath as an outer layer. The structure, anticoagulant property, and biocompatibility of the inner layer are studied. The effects of thickness of the outer layer on perfusion performance and mechanical property of hydrogel tubes with PCL sheaths (PCL-NFC/PVA-NPs tubes) are investigated. The effect of compliance of PCL-NFC/PVA-NPs tubes on their blood flow is studied by numerical simulation. The tissue compatibility and the patency of PCL-NFC/PVA-NPs tubes are evaluated by implantation in subcutaneous tissue of rats and carotid artery of rabbits. PCL-NFC/PVA-NPs tubes have prominent anticoagulation, sufficient burst pressure and good compliance similar to native arteries. PCL-NFC/PVA-NPs tubes facilitate infiltration of host cells and achieve active proliferation of recruited cells, which will be a promising candidate for small-diameter vascular grafts.
