@article{yu_wang_zhang_chen_mao_ye_kahkoska_buse_langer_gu_2020, title={Glucose-responsive insulin patch for the regulation of blood glucose in mice and minipigs}, volume={4}, ISSN={["2157-846X"]}, DOI={10.1038/s41551-019-0508-y}, abstractNote={Glucose-responsive insulin delivery systems that mimic pancreatic endocrine function could enhance health and improve quality of life for people with type 1 and type 2 diabetes with reduced β-cell function. However, insulin delivery systems with rapid in vivo glucose-responsive behaviour typically have limited insulin-loading capacities and cannot be manufactured easily. Here, we show that a single removable transdermal patch, bearing microneedles loaded with insulin and a non-degradable glucose-responsive polymeric matrix, and fabricated via in situ photopolymerization, regulated blood glucose in insulin-deficient diabetic mice and minipigs (for minipigs >25 kg, glucose regulation lasted >20 h with patches of ~5 cm2). Under hyperglycaemic conditions, phenylboronic acid units within the polymeric matrix reversibly form glucose–boronate complexes that—owing to their increased negative charge—induce the swelling of the polymeric matrix and weaken the electrostatic interactions between the negatively charged insulin and polymers, promoting the rapid release of insulin. This proof-of-concept demonstration may aid the development of other translational stimuli-responsive microneedle patches for drug delivery. A single removable transdermal patch bearing microneedles loaded with insulin and a non-degradable glucose-responsive polymeric matrix regulates blood glucose in insulin-deficient diabetic mice and minipigs.}, number={5}, journal={NATURE BIOMEDICAL ENGINEERING}, author={Yu, Jicheng and Wang, Jinqiang and Zhang, Yuqi and Chen, Guojun and Mao, Weiwei and Ye, Yanqi and Kahkoska, Anna R. and Buse, John B. and Langer, Robert and Gu, Zhen}, year={2020}, month={May}, pages={499–506} }
 @article{wang_wang_yu_zhang_zeng_gu_2019, title={A forskolin-conjugated insulin analog targeting endogenous glucose-transporter for glucose-responsive insulin delivery}, volume={7}, ISSN={["2047-4849"]}, DOI={10.1039/c9bm01283d}, abstractNote={A new insulin analog has been obtained by modifying insulin with forskolin (designated as insulin-F), a glucose transporter (Glut) inhibitor. Insulin-F is capable of binding to Glut on the plasma membrane in a glucose-dependent manner.}, number={11}, journal={BIOMATERIALS SCIENCE}, author={Wang, Jinqiang and Wang, Zejun and Yu, Jicheng and Zhang, Yuqi and Zeng, Yi and Gu, Zhen}, year={2019}, month={Nov}, pages={4508–4513} }
 @misc{zhang_yu_kahkoska_wang_buse_gu_2019, title={Advances in transdermal insulin delivery}, volume={139}, ISSN={["1872-8294"]}, DOI={10.1016/j.addr.2018.12.006}, abstractNote={Insulin therapy is necessary to regulate blood glucose levels for people with type 1 diabetes and commonly used in advanced type 2 diabetes. Although subcutaneous insulin administration via hypodermic injection or pump-mediated infusion is the standard route of insulin delivery, it may be associated with pain, needle phobia, and decreased adherence, as well as the risk of infection. Therefore, transdermal insulin delivery has been widely investigated as an attractive alternative to subcutaneous approaches for diabetes management in recent years. Transdermal systems designed to prevent insulin degradation and offer controlled, sustained release of insulin may be desirable for patients and lead to increased adherence and glycemic outcomes. A challenge for transdermal insulin delivery is the inefficient passive insulin absorption through the skin due to the large molecular weight of the protein drug. In this review, we focus on the different transdermal insulin delivery techniques and their respective advantages and limitations, including chemical enhancers-promoted, electrically enhanced, mechanical force-triggered, and microneedle-assisted methods.}, journal={ADVANCED DRUG DELIVERY REVIEWS}, author={Zhang, Yuqi and Yu, Jicheng and Kahkoska, Anna R. and Wang, Jinqiang and Buse, John B. and Gu, Zhen}, year={2019}, month={Jan}, pages={51–70} }
 @article{wang_yu_zhang_zhang_kahkoska_chen_wang_sun_cai_chen_et al._2019, title={Charge-switchable polymeric complex for glucose-responsive insulin delivery in mice and pigs}, volume={5}, ISSN={["2375-2548"]}, DOI={10.1126/sciadv.aaw4357}, abstractNote={A glucose-responsive insulin-polymer complex for self-regulated insulin release has been verified in diabetic mice and minipigs.}, number={7}, journal={SCIENCE ADVANCES}, author={Wang, Jinqiang and Yu, Jicheng and Zhang, Yuqi and Zhang, Xudong and Kahkoska, Anna R. and Chen, Guojun and Wang, Zejun and Sun, Wujin and Cai, Lulu and Chen, Zhaowei and et al.}, year={2019}, month={Jul} }
 @article{wang_yu_zhang_kahkoska_wang_fang_whitelegge_li_buse_gu_2019, title={Glucose transporter inhibitor-conjugated insulin mitigates hypoglycemia}, volume={116}, ISSN={["0027-8424"]}, DOI={10.1073/pnas.1901967116}, abstractNote={Significance}, number={22}, journal={PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, author={Wang, Jinqiang and Yu, Jicheng and Zhang, Yuqi and Kahkoska, Anna R. and Wang, Zejun and Fang, Jun and Whitelegge, Julian P. and Li, Song and Buse, John B. and Gu, Zhen}, year={2019}, month={May}, pages={10744–10748} }
 @article{yan_zhang_liu_ye_yu_chen_wang_zhang_hu_kang_et al._2019, title={Shape-controlled synthesis of liquid metal nanodroplets for photothermal therapy}, volume={12}, ISSN={["1998-0000"]}, DOI={10.1007/s12274-018-2262-y}, number={6}, journal={NANO RESEARCH}, author={Yan, Junjie and Zhang, Xudong and Liu, Yang and Ye, Yanqi and Yu, Jicheng and Chen, Qian and Wang, Jinqiang and Zhang, Yuqi and Hu, Quanyin and Kang, Yang and et al.}, year={2019}, month={Jun}, pages={1313–1320} }
 @article{zhang_yu_wen_chen_gu_2018, title={The potential of a microneedle patch for reducing obesity}, volume={15}, ISSN={["1744-7593"]}, DOI={10.1080/17425247.2018.1449831}, abstractNote={Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, USA; Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA}, number={5}, journal={EXPERT OPINION ON DRUG DELIVERY}, author={Zhang, Yuqi and Yu, Jicheng and Wen, Di and Chen, Guojun and Gu, Zhen}, year={2018}, pages={431–433} }
 @article{qian_feng_yu_chen_hu_sun_xiao_hu_bellotti_shen_et al._2017, title={Anaerobe-Inspired Anticancer Nanovesicles}, volume={56}, ISSN={["1521-3773"]}, DOI={10.1002/anie.201611783}, abstractNote={Abstract}, number={10}, journal={ANGEWANDTE CHEMIE-INTERNATIONAL EDITION}, author={Qian, Chenggen and Feng, Peijian and Yu, Jicheng and Chen, Yulei and Hu, Quanyin and Sun, Wujin and Xiao, Xuanzhong and Hu, Xiuli and Bellotti, Adriano and Shen, Qun-Dong and et al.}, year={2017}, month={Mar}, pages={2588–2593} }
 @misc{yu_zhang_kahkoska_gu_2017, title={Bioresponsive transcutaneous patches}, volume={48}, ISSN={["1879-0429"]}, DOI={10.1016/j.copbio.2017.03.001}, abstractNote={Transdermal drug delivery systems that utilize transcutaneous patches of arrayed microneedles have attracted increasing interest in medical practice as an alternative method to hypodermic injection. Over the past ten years, research has focused on leveraging physiological signals associated with diseases or skin-specific tissues to create bioresponsive patches that release drug directly in response to an internally-generated stimulus. This review surveys the recent advances in the development and use of bioresponsive transcutaneous patches for on-demand smart and precise drug delivery, exploiting different physiological signals including pH, serum glucose levels, and enzyme activity. The clinical potential of these devices, including challenges and opportunities, is also discussed.}, journal={CURRENT OPINION IN BIOTECHNOLOGY}, author={Yu, Jicheng and Zhang, Yuqi and Kahkoska, Anna R. and Gu, Zhen}, year={2017}, month={Dec}, pages={28–32} }
 @misc{cheng-gen_chen_feng_xiao_dong_yu_hu_shen_gu_2017, title={Conjugated polymer nanomaterials for theranostics}, volume={38}, ISSN={["1745-7254"]}, DOI={10.1038/aps.2017.42}, abstractNote={Conjugated polymer nanomaterials (CPNs), as optically and electronically active materials, hold promise for biomedical imaging and drug delivery applications. This review highlights the recent advances in the utilization of CPNs in theranostics. Specifically, CPN-based in vivo imaging techniques, including near-infrared (NIR) imaging, two-photon (TP) imaging, photoacoustic (PA) imaging, and multimodal (MM) imaging, are introduced. Then, CPN-based photodynamic therapy (PDT) and photothermal therapy (PTT) are surveyed. A variety of stimuli-responsive CPN systems for drug delivery are also summarized, and the promising trends and translational challenges are discussed.}, number={6}, journal={ACTA PHARMACOLOGICA SINICA}, author={Cheng-gen, Qian and Chen, Yu-lei and Feng, Pei-jian and Xiao, Xuan-zhong and Dong, Mei and Yu, Ji-cheng and Hu, Quan-yin and Shen, Qun-dong and Gu, Zhen}, year={2017}, month={Jun}, pages={764–781} }
 @article{hu_yu_qian_lu_kahkoska_xie_jing_buse_gu_2017, title={H2O2-Responsive Vesicles Integrated with Transcutaneous Patches for Glucose-Mediated Insulin Delivery}, volume={11}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.6b06892}, abstractNote={A self-regulated "smart" insulin administration system would be highly desirable for diabetes management. Here, a glucose-responsive insulin delivery device, which integrates H2O2-responsive polymeric vesicles (PVs) with a transcutaneous microneedle-array patch was prepared to achieve a fast response, excellent biocompatibility, and painless administration. The PVs are self-assembled from block copolymer incorporated with polyethylene glycol (PEG) and phenylboronic ester (PBE)-conjugated polyserine (designated mPEG-b-P(Ser-PBE)) and loaded with glucose oxidase (GOx) and insulin. The polymeric vesicles function as both moieties of the glucose sensing element (GOx) and the insulin release actuator to provide basal insulin release as well as promote insulin release in response to hyperglycemic states. In the current study, insulin release responds quickly to elevated glucose and its kinetics can be modulated by adjusting the concentration of GOx loaded into the microneedles. In vivo testing indicates that a single patch can regulate glucose levels effectively with reduced risk of hypoglycemia.}, number={1}, journal={ACS NANO}, author={Hu, Xiuli and Yu, Jicheng and Qian, Chenggen and Lu, Yue and Kahkoska, Anna R. and Xie, Zhigang and Jing, Xiabin and Buse, John B. and Gu, Zhen}, year={2017}, month={Jan}, pages={613–620} }
 @article{yu_qian_zhang_cui_zhu_shen_ligler_buse_gu_2017, title={Hypoxia and H2O2 Dual-Sensitive Vesicles for Enhanced Glucose-Responsive Insulin Delivery}, volume={17}, ISSN={["1530-6992"]}, DOI={10.1021/acs.nanolett.6b03848}, abstractNote={A glucose-responsive closed-loop insulin delivery system mimicking pancreas activity without long-term side effect has the potential to improve diabetic patients' health and quality of life. Here, we developed a novel glucose-responsive insulin delivery device using a painless microneedle-array patch containing insulin-loaded vesicles. Formed by self-assembly of hypoxia and H2O2 dual-sensitive diblock copolymer, the glucose-responsive polymersome-based vesicles (d-GRPs) can disassociate and subsequently release insulin triggered by H2O2 and hypoxia generated during glucose oxidation catalyzed by glucose specific enzyme. Moreover, the d-GRPs were able to eliminate the excess H2O2, which may lead to free radical-induced damage to skin tissue during the long-term usage and reduce the activity of GOx. In vivo experiments indicated that this smart insulin patch could efficiently regulate the blood glucose in the chemically induced type 1 diabetic mice for 10 h.}, number={2}, journal={NANO LETTERS}, author={Yu, Jicheng and Qian, Chenggen and Zhang, Yuqi and Cui, Zheng and Zhu, Yong and Shen, Qundong and Ligler, Frances S. and Buse, John B. and Gu, Zhen}, year={2017}, month={Feb}, pages={733–739} }
 @article{yu_zhang_sun_kahkoska_wang_buse_gu_2017, title={Insulin-responsive glucagon delivery for prevention of hypoglycemia}, volume={13}, DOI={10.1002/smll.201770108}, abstractNote={In article number 1603028, by Zhen Gu and co-workers, an insulin-responsive glucagon delivery device based on a microneedle (MN)-array patch is developed. Utilizing hyperinsulinemia as a dangerous signal, this “smart glucagon patch” can release glucagon to reduce the risk of hypoglycemia during diabetes management.}, number={19}, journal={Small (Weinheim An Der Bergstrasse, Germany)}, author={Yu, J. C. and Zhang, Y. Q. and Sun, W. J. and Kahkoska, A. R. and Wang, J. Q. and Buse, J. B. and Gu, Z.}, year={2017} }
 @article{zhang_liu_yu_yu_wang_qiang_gu_2017, title={Locally Induced Adipose Tissue Browning by Microneedle Patch for Obesity Treatment}, volume={11}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.7b04348}, abstractNote={Obesity is one of the most serious public health problems in the 21st century that may lead to many comorbidities such as type-2 diabetes, cardiovascular diseases, and cancer. Current treatments toward obesity including diet, physical exercise, pharmacological therapy, as well as surgeries are always associated with low effectiveness or undesired systematical side effects. In order to enhance treatment efficiency with minimized side effects, we developed a transcutaneous browning agent patch to locally induce adipose tissue transformation. This microneedle-based patch can effectively deliver browning agents to the subcutaneous adipocytes in a sustained manner and switch on the "browning" at the targeted region. It is demonstrated that this patch reduces treated fat pad size, increases whole body energy expenditure, and improves type-2 diabetes in vivo in a diet-induced obesity mouse model.}, number={9}, journal={ACS NANO}, author={Zhang, Yuqi and Liu, Qiongming and Yu, Jicheng and Yu, Shuangjiang and Wang, Jinqiang and Qiang, Li and Gu, Zhen}, year={2017}, month={Sep}, pages={9223–9230} }
 @misc{zhang_yu_kahkoska_gu_2017, title={Photoacoustic Drug Delivery}, volume={17}, ISSN={["1424-8220"]}, DOI={10.3390/s17061400}, abstractNote={Photoacoustic (PA) technology holds great potential in clinical translation as a new non-invasive bioimaging modality. In contrast to conventional optical imaging, PA imaging (PAI) enables higher resolution imaging with deeper imaging depth. Besides applications for diagnosis, PA has also been extended to theranostic applications. The guidance of PAI facilitates remotely controlled drug delivery. This review focuses on the recent development of PAI-mediated drug delivery systems. We provide an overview of the design of different PAI agents for drug delivery. The challenges and further opportunities regarding PA therapy are also discussed.}, number={6}, journal={SENSORS}, author={Zhang, Yuqi and Yu, Jicheng and Kahkoska, Anna R. and Gu, Zhen}, year={2017}, month={Jun} }
 @article{wang_ye_sun_yu_wang_lawrence_buse_gu_2017, title={Red Blood Cells for Glucose-Responsive Insulin Delivery}, volume={29}, ISSN={["1521-4095"]}, DOI={10.1002/adma.201606617}, abstractNote={Glucose‐responsive delivery of insulin mimicking the function of pancreatic β‐cells to achieve meticulous control of blood glucose (BG) would revolutionize diabetes care. Here the authors report the development of a new glucose‐responsive insulin delivery system based on the potential interaction between the glucose derivative‐modified insulin (Glc‐Insulin) and glucose transporters on erythrocytes (or red blood cells, RBCs) membrane. After being conjugated with the glucosamine, insulin can efficiently bind to RBC membranes. The binding is reversible in the setting of hyperglycemia, resulting in fast release of insulin and subsequent drop of BG level in vivo. The delivery vehicle can be further simplified utilizing injectable polymeric nanocarriers coated with RBC membrane and loaded with Glc‐Insulin. The described work is the first demonstration of utilizing RBC membrane to achieve smart insulin delivery with fast responsiveness.}, number={18}, journal={ADVANCED MATERIALS}, author={Wang, Chao and Ye, Yanqi and Sun, Wujin and Yu, Jicheng and Wang, Jingqiang and Lawrence, David S. and Buse, John B. and Gu, Zhen}, year={2017}, month={May} }
 @article{zhang_yu_wang_hanne_cui_qian_wang_xin_cole_gallippi_et al._2017, title={Thrombin-responsive transcutaneous patch for auto-anticoagulant regulation}, volume={29}, DOI={10.1002/adma.201770028}, abstractNote={A thrombin-responsive microneedle-based transcutaneous patch is developed by C. M. Gallippi, Y. Zhu, Z. Gu, and co-workers, as demonstrated in article 1604043. The anticoagulant drug heparin is loaded into the hyaluronic acid needles through a thrombin cleavable peptide linker. This heparin patch can sense the thrombin level in blood vessels and autoregulate blood coagulation in a long-term manner. Cover design credit: Yuqi Zhang.}, number={4}, journal={Advanced Materials}, author={Zhang, Y. Q. and Yu, J. C. and Wang, J. Q. and Hanne, N. J. and Cui, Z. and Qian, C. G. and Wang, C. and Xin, H. L. and Cole, Jacqueline and Gallippi, C. M. and et al.}, year={2017} }
 @article{di_yu_wang_yao_suo_ye_pless_zhu_jing_gu_2017, title={Ultrasound-triggered noninvasive regulation of blood glucose levels using microgels integrated with insulin nanocapsules}, volume={10}, ISSN={1998-0124 1998-0000}, url={http://dx.doi.org/10.1007/S12274-017-1500-Z}, DOI={10.1007/s12274-017-1500-z}, number={4}, journal={Nano Research}, publisher={Springer Nature}, author={Di, Jin and Yu, Jicheng and Wang, Qun and Yao, Shanshan and Suo, Dingjie and Ye, Yanqi and Pless, Matthew and Zhu, Yong and Jing, Yun and Gu, Zhen}, year={2017}, month={Mar}, pages={1393–1402} }
 @article{qian_chen_zhu_yu_zhang_feng_tang_hu_sun_lu_et al._2016, title={ATP-Responsive and Near-Infrared-Emissive Nanocarriers for Anticancer Drug Delivery and Real-Time Imaging}, volume={6}, ISSN={["1838-7640"]}, DOI={10.7150/thno.14843}, abstractNote={Stimuli-responsive and imaging-guided drug delivery systems hold vast promise for enhancement of therapeutic efficacy. Here we report an adenosine-5'-triphosphate (ATP)-responsive and near-infrared (NIR)-emissive conjugated polymer-based nanocarrier for the controlled release of anticancer drugs and real-time imaging. We demonstrate that the conjugated polymeric nanocarriers functionalized with phenylboronic acid tags on surface as binding sites for ATP could be converted to the water-soluble conjugated polyelectrolytes in an ATP-rich environment, which promotes the disassembly of the drug carrier and subsequent release of the cargo. In vivo studies validate that this formulation exhibits promising capability for inhibition of tumor growth. We also evaluate the metabolism process by monitoring the fluorescence signal of the conjugated polymer through the in vivo NIR imaging.}, number={7}, journal={THERANOSTICS}, author={Qian, Chenggen and Chen, Yulei and Zhu, Sha and Yu, Jicheng and Zhang, Lei and Feng, Peijian and Tang, Xin and Hu, Quanyin and Sun, Wujin and Lu, Yue and et al.}, year={2016}, pages={1053–1064} }
 @article{zhang_yu_zhu_gu_2016, title={Elastic drug delivery: could treatments be triggered by patient movement?}, volume={11}, ISSN={["1748-6963"]}, DOI={10.2217/nnm.15.197}, abstractNote={NanomedicineVol. 11, No. 4 EditorialFree AccessElastic drug delivery: could treatments be triggered by patient movement?Yuqi Zhang, Jicheng Yu, Yong Zhu & Zhen GuYuqi Zhang Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill & North Carolina State University, Raleigh, NC 27695, USASearch for more papers by this author, Jicheng Yu Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill & North Carolina State University, Raleigh, NC 27695, USASearch for more papers by this author, Yong Zhu Department of Mechanical & Aerospace Engineering, North Carolina State University, Raleigh, NC 27695, USASearch for more papers by this author & Zhen Gu*Author for correspondence: E-mail Address: zgu@email.unc.edu Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill & North Carolina State University, Raleigh, NC 27695, USASearch for more papers by this authorPublished Online:19 Jan 2016https://doi.org/10.2217/nnm.15.197AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: drug deliverymechanical-responsivenanoparticlewearable devicesFirst draft submitted: 22 October 2015; Accepted for publication: 12 November 2015; Published online: 19 January 2016Nanoparticle-based drug delivery systems have drawn extensive attention for treating a broad range of diseases during the last few decades [1,2]. In order to enhance therapeutic efficacy, reduce side effects and prolong action time, vast efforts have been dedicated to the development of on-demand, precise drug release. In light of this, numerous stimuli-responsive designs have been exploited, including external triggers like mechanical force, temperature, light, ultrasound, electric current and magnetic field as well as internal factors like pH, redox, enzymes, ATP and hypoxia [3–8]. Compared with other stimuli-responsive designs, the macroscopic mechanical force-mediated approach, as one of the most promising strategies, possesses several advantages. It can be generated on-demand during the patients’ daily movement, such as tension in bone joints, tendons and muscles, or compression in cartilage and bones. Therefore, a self-administrated therapy can be readily achieved without requirement of additional instrumentations. In addition, in contrast to the inaccurate internal factors due to the complicated physiological environment, the degree of stretch or compression is more conveniently controlled by the patient themselves, leading to a precise dosage-, spatial- and temporal-controllable administration of drug release.Physical deformation of drug carriers supported on an elastomer substrate caused by stretch or compression is one of the most important strategies for mechanical force-triggered release. Mooney group designed a compression-responsive system for controlled release of growth factor [9]. Inspired by the natural extracellular matrices, they developed a hydrogel with reversible binding of drug as synthetic extracelluar matrices. The physical-loaded hydrogel could respond to repeated compression stimulus and as a result released free drug. Afterward, the matrices could be refilled by free drug during relaxation via dissociation of previously bound drug. Using VEGF as a model drug in in vivo studies, they demonstrated that the implanted hydrogels allowed an increase in VEGF concentration near implantation site as applying mechanical signals, subsequently leading to a local enhanced vascularization. In another case, Jeong group developed a strain-sensitive patch consisting of arrays of microcapsules onto a rubbery substrate for drug release [10]. When stretch was applied to the elastomer substrate, the volume of the stretchable microcapsules encapsulating cargoes decreased accordingly with the substrate, then pumping out the preloaded molecules. Under different degrees of mechanical stretching, the release rate and amount of cargoes could be adjusted. This patch has the potential to respond to body motions, even to the mechanical stretching of organs, muscles and tendons when it is implanted into body.We have recently developed a multipurpose wearable, tensile strain-triggered drug delivery device, which comprised of a stretchable elastomer and microgel depots containing drug-loaded nanoparticles [11]. The drugs can be continuously released from the nanoparticles and temporarily stored in the microgels. When applying a tensile strain, the drugs were released from micro-depots due to the enlarged surface area for diffusion and Poisson's ratio-induced compression toward the microgels. Therefore, a sustained drug release can be conveniently achieved by daily body motion, while a pulsatile release is able to be controlled through intentional administration. We demonstrated that this device could be simply attached to a finger joint, and stretched to trigger the drug release when the finger is flexed for multiple cycles, which allowed patients to control the dose and release timing of antibacterial drug on their own.Furthermore, we integrated this stretch-sensitive device with a microneedle array patch for on-demand transcutaneous insulin delivery [3], which allowed the blood glucose level of mice to decline quickly to a normoglycemic range within 0.5 h. Meanwhile, the obvious pulsatile and continuous reduction in blood glucose level were observed when applying a strain with an interval of 4 h. Based on this technology, the diabetic patients can easily maintain normoglycemia through simple joint movement instead of a traditional painful insulin injection. This skin-mountable device can be further extended for anti-inflammatory, anti-infective drug or painkiller delivery. More importantly, this facile strategy allows immediate medical treatment in emergency situation by patient's simple body movement.Besides the direct drug release via changing diffusion area or pumping out caused by physical deformation, tension or compression can also generate energy to change the physical properties of drug carriers. For example, Pioletti group exploited dissipation properties of hydrogel as an internal heat source to trigger the thermal-sensitive drug release instead of additional external heat source [12]. Self heating was quickly produced after 5 min cyclic mechanical loading. The increased temperature further caused the shrinkage of thermal-responsive nanoparticles entrapped in the hydrogel and subsequent drug release.In addition, mechanical stretch or compression is able to tune the molecular conformation and intermolecular interaction between host molecule and guest molecule, resulting in a force-triggered drug release [13,14]. Based on this phenomenon, Ariga group reported a mechanically controlled monolayer formed by a steroid cyclophane molecule with a cyclic core linked to four steroid moieties via the flexible L-lysine spacer [13]. The applied compression could lead to a cavity-forming conformation of the cyclophane. Therefore, the hydrophobic model drug was easily trapped in this hydrophobic cavity. In contrast, expansion of the monolayer could release the encapsulated drug through the molecular transformation from cavity to planarity. Similarly, they developed a mechanical stimulus-activated β-cyclodextrin (CyD)-crosslinked alginate gel [15]. As applying mild mechanical compression, the model drug ondansetron, the entrapped guest, could be released from the host CyD moieties, due to the change in inclusion ability of CyD. The host–guest interactions dominated by van der Waals interactions and hydrogen bonds in a gel matrix can be more easily broken than covalent bonds, which provide a convenient on-demand administration of medicines operated intentionally by the patient.The research and development of patients’ movement-controlled drug delivery systems hold promise in improving patients’ compliance by providing a self-directed and on-demand treatment. Nonetheless, there are still many remaining challenges for clinical development. For example, the current systems cannot precisely control the release dose of therapeutics. A fundamental study on the dynamic relationships between the phase transitions of materials and the relevant release profile should be closely investigated. Moreover, regarding the different movement extent and ability for different individuals, how to generate a personalized platform and consistently apply the mechanical trigger signal are difficult tasks ahead that need to be addressed. Integration of this device with other wearable modalities to monitor the real-time physiological signals (e.g., electrocardiograph, blood glucose levels or body temperature [16,17]) and motion signals [18,19] might be able to provide feedback to guide the precise, personalized drug delivery. Last but not least, good biocompatibility and biodegradability for materials is extremely important for further translation of the elastic drug delivery system. Tailoring materials mimicking the structures and composites of natural systems offer a promising strategy [5,20].Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 Jiang T, Mo R, Bellotti A, Zhou J, Gu Z. Gel–liposome‐mediated co‐delivery of anticancer membrane‐associated proteins and small‐molecule drugs for enhanced therapeutic efficacy. Adv. Funct. Mater. 24(16), 2295–2304 (2014).Crossref, CAS, Google Scholar2 Sun W, Jiang T, Lu Y, Reiff M, Mo R, Gu Z. Cocoon-like self-degradable dna nanoclew for anticancer drug delivery. J. Am. Chem. 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ACS Nano 9(7), 6644–6654 (2015).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByExternal stimuli-responsive drug delivery systemsMechanical on-off gates for regulation of drug release in cutaneous or musculoskeletal tissue repairsMaterials Science and Engineering: C, Vol. 115Biomechano-Interactive Materials and Interfaces7 June 2018 | Advanced Materials, Vol. 30, No. 31Nanomaterial‐Enabled Wearable Sensors for Healthcare30 November 2017 | Advanced Healthcare Materials, Vol. 7, No. 1 Vol. 11, No. 4 Follow us on social media for the latest updates Metrics History Published online 19 January 2016 Published in print February 2016 Information© Future Medicine LtdKeywordsdrug deliverymechanical-responsivenanoparticlewearable devicesFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download}, number={4}, journal={NANOMEDICINE}, author={Zhang, Yuqi and Yu, Jicheng and Zhu, Yong and Gu, Zhen}, year={2016}, pages={323–325} }
 @article{yu_zhang_hu_wright_gu_2016, title={Hypoxia-Sensitive Materials for Biomedical Applications}, volume={44}, ISSN={["1573-9686"]}, DOI={10.1007/s10439-016-1578-6}, abstractNote={Hypoxia is a typical hallmark of various diseases, including cancer, ischemic diseases, and stroke. It is also associated with the disease progression. Therefore, it is critical to develop an effective strategy to target the hypoxic region for diagnosis and treatment. In this review, we summarize recent progress in the development of hypoxia-responsive systems for imaging, sensing and therapy. Two types of hypoxia-sensitive systems, the hypoxia inducible factor-1 based systems and bioreductive molecule based systems, were reviewed with comments on their advantages and limitations. Future opportunities and challenges are also discussed in the end.}, number={6}, journal={ANNALS OF BIOMEDICAL ENGINEERING}, author={Yu, Jicheng and Zhang, Yuqi and Hu, Xiuli and Wright, Grace and Gu, Zhen}, year={2016}, month={Jun}, pages={1931–1945} }
 @article{yu_zhang_sun_wang_ranson_ye_weng_gu_2016, title={Internalized compartments encapsulated nanogels for targeted drug delivery}, volume={8}, ISSN={["2040-3372"]}, DOI={10.1039/c5nr08895j}, abstractNote={Drug delivery systems inspired by natural particulates hold great promise for targeted cancer therapy. An endosome formed by internalization of plasma membrane has a massive amount of membrane proteins and receptors on the surface, which is able to specifically target the homotypic cells. Herein, we describe a simple method to fabricate an internalized compartments encapsulated nanogel with endosome membrane components (EM-NG) from source cancer cells. Following intracellular uptake of methacrylated hyaluronic acid (m-HA) adsorbed SiO2/Fe3O4 nanoparticles encapsulating a crosslinker and a photoinitiator, EM-NG was readily prepared through in situ crosslinking initiated under UV irradiation after internalization. The resulting nanogels loaded with doxorubicin (DOX) displayed enhanced internalization efficiency to the source cells through a specific homotypic affinity in vitro. However, when treated with the non-source cells, the EM-NGs exhibited insignificant difference in therapeutic efficiency compared to a bare HA nanogel with DOX. This study illustrates the potential of utilizing an internalized compartments encapsulated formulation for targeted cancer therapy, and offers guidelines for developing a natural particulate-inspired drug delivery system.}, number={17}, journal={NANOSCALE}, author={Yu, Jicheng and Zhang, Yuqi and Sun, Wujin and Wang, Chao and Ranson, Davis and Ye, Yanqi and Weng, Yuyan and Gu, Zhen}, year={2016}, pages={9178–9184} }
 @article{qian_yu_chen_hu_xiao_sun_wang_feng_shen_gu_2016, title={Light-Activated Hypoxia-Responsive Nanocarriers for Enhanced Anticancer Therapy}, volume={28}, ISSN={["1521-4095"]}, DOI={10.1002/adma.201505869}, abstractNote={A light-activated hypoxia-responsive conjugated polymer-based nanocarrier is developed for efficiently producing singlet oxygen ((1) O2 ) and inducing hypoxia to promote release of its cargoes in tumor cells, leading to enhanced antitumor efficacy. This dual-responsive nanocarrier provides an innovative design guideline for enhancing traditional photodynamic therapeutic efficacy integrated with a controlled drug-release modality.}, number={17}, journal={ADVANCED MATERIALS}, author={Qian, Chenggen and Yu, Jicheng and Chen, Yulei and Hu, Quanyin and Xiao, Xuanzhong and Sun, Wujin and Wang, Chao and Feng, Peijian and Shen, Qun-Dong and Gu, Zhen}, year={2016}, month={May}, pages={3313–3320} }
 @misc{zhang_yu_bomba_zhu_gu_2016, title={Mechanical Force-Triggered Drug Delivery}, volume={116}, ISSN={["1520-6890"]}, DOI={10.1021/acs.chemrev.6b00369}, abstractNote={Advanced drug delivery systems (DDS) enhance treatment efficacy of different therapeutics in a dosage, spatial, and/or temporal controlled manner. To date, numerous chemical- or physical-based stimuli-responsive formulations or devices for controlled drug release have been developed. Among them, the emerging mechanical force-based stimulus offers a convenient and robust controlled drug release platform and has attracted increasing attention. The relevant DDS can be activated to promote drug release by different types of mechanical stimuli, including compressive force, tensile force, and shear force as well as indirect formats, remotely triggered by ultrasound and magnetic field. In this review, we provide an overview of recent advances in mechanically activated DDS. The opportunities and challenges regarding clinical translations are also discussed.}, number={19}, journal={CHEMICAL REVIEWS}, author={Zhang, Yuqi and Yu, Jicheng and Bomba, Hunter N. and Zhu, Yong and Gu, Zhen}, year={2016}, month={Oct}, pages={12536–12563} }
 @article{ye_yu_wang_nguyen_walker_buse_gu_2016, title={Microneedles Integrated with Pancreatic Cells and Synthetic Glucose-Signal Amplifiers for Smart Insulin Delivery}, volume={28}, ISSN={0935-9648}, url={http://dx.doi.org/10.1002/ADMA.201506025}, DOI={10.1002/adma.201506025}, abstractNote={An innovative microneedle (MN)-based cell therapy is developed for glucose-responsive regulation of the insulin secretion from exogenous pancreatic β-cells without implantation. One MN patch can quickly reduce the blood-sugar levels (BGLs) of chemically induced type-1 diabetic mice and stabilize BGLs at a reduced level for over 10 h.}, number={16}, journal={Advanced Materials}, publisher={Wiley}, author={Ye, Yanqi and Yu, Jicheng and Wang, Chao and Nguyen, Nhu-Y and Walker, Glenn M. and Buse, John B. and Gu, Zhen}, year={2016}, month={Mar}, pages={3115–3121} }
 @article{sun_ji_hu_yu_wang_qian_hochu_gu_2016, title={Transformable DNA nanocarriers for plasma membrane targeted delivery of cytokine}, volume={96}, ISSN={["1878-5905"]}, DOI={10.1016/j.biomaterials.2016.04.011}, abstractNote={Direct delivery of cytokines using nanocarriers holds great promise for cancer therapy. However, the nanometric scale of the vehicles made them susceptible to size-dependent endocytosis, reducing the plasma membrane-associated apoptosis signaling. Herein, we report a tumor microenvironment-responsive and transformable nanocarrier for cell membrane targeted delivery of cytokine. This formulation is comprised of a phospholipase A2 (PLA2) degradable liposome as a shell, and complementary DNA nanostructures (designated as nanoclews) decorated with cytokines as the cores. Utilizing the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a model cytokine, we demonstrate that the TRAIL loaded DNA nanoclews are capable of transforming into nanofibers after PLA2 activation. The nanofibers with micro-scaled lengths efficiently present the loaded TRAIL to death receptors on the cancer cell membrane and amplified the apoptotic signaling with reduced TRAIL internalization.}, journal={BIOMATERIALS}, author={Sun, Wujin and Ji, Wenyan and Hu, Quanyin and Yu, Jicheng and Wang, Chao and Qian, Chenggen and Hochu, Gabrielle and Gu, Zhen}, year={2016}, month={Jul}, pages={1–10} }
 @article{ye_yu_gu_2016, title={Versatile Protein Nanogels Prepared by In Situ Polymerization}, volume={217}, ISSN={["1521-3935"]}, DOI={10.1002/macp.201500296}, abstractNote={Proteins with unique structure and function have tremendous applications for cancer treatment, vaccination, diagnosis, regenerative medicine, and therapies for loss‐of‐function genetic diseases. A general method of loading and delivering active forms of proteins toward cells and tissues is highly desirable for remaining activity, enhancing stability, and avoiding potential immunogenicity of proteins. Nanogels with cross‐linked structure provide a versatile platform for storage and release of proteins. Herein, the recent advances in protein nanogels made by the in situ polymerization method, from preparation to application are summarized. A range of stimuli‐responsive formulations for on‐demand release, in a spatial, temporal, and dosage‐controlled manner, is highlighted. Future opportunities as well as challenges of protein nanogels are also discussed.
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}, number={3}, journal={MACROMOLECULAR CHEMISTRY AND PHYSICS}, author={Ye, Yanqi and Yu, Jicheng and Gu, Zhen}, year={2016}, month={Feb}, pages={333–343} }
 @article{xiao-hui_ji-cheng_nai-yan_wei-dong_yu-yan_zhen_2015, title={Confinement-induced nanocrystal alignment of conjugated polymer by the soft-stamped nanoimprint lithography}, volume={24}, ISSN={["1741-4199"]}, DOI={10.1088/1674-1056/24/10/104215}, abstractNote={Soft-stamped nanoimprint lithography (NIL) is considered as one of the most effective processes of nanoscale patterning because of its low cost and high throughput. In this work, this method is used to emboss the poly (9, 9-dioctylfluorene) film. By reducing the linewidth of the nanogratings on the stamp, the orientations of nanocrystals are confined along the grating vector in the nanoimprint process, where the confinement linewidth is comparable to the geometrical size of the nanocrystal. When the linewidth is about 400 nm, the poly (9, 9-dioctylfluorene) (PFO) nanocrystals could be orderly arranged in the nanogratings, so that both pattern transfer and well-aligned nanocrystal arrangement could be achieved in a single step by the soft-stamped NIL. The relevant mechanism of the nanocrystalline alignment in these nanogratings is fully discussed. The modulation of nanocrystal alignment is of benefit to the charge mobilities and other performances of PFO-based devices for the future applications.}, number={10}, journal={CHINESE PHYSICS B}, author={Xiao-Hui, Li and Ji-Cheng, Yu and Nai-Yan, Lu and Wei-Dong, Zhang and Yu-Yan, Weng and Zhen, Gu}, year={2015}, month={Oct} }
 @article{di_yu_ye_ranson_jindal_gu_2015, title={Engineering Synthetic Insulin-Secreting Cells Using Hyaluronic Acid Microgels Integrated with Glucose-Responsive Nanoparticles}, volume={8}, ISSN={["1865-5033"]}, DOI={10.1007/s12195-015-0390-y}, number={3}, journal={CELLULAR AND MOLECULAR BIOENGINEERING}, author={Di, Jin and Yu, Jicheng and Ye, Yanqi and Ranson, Davis and Jindal, Abhilasha and Gu, Zhen}, year={2015}, month={Sep}, pages={445–454} }
 @misc{zhang_yu_shen_gu_2015, title={Glucose-responsive synthetic closed-loop insulin delivery systems}, volume={27}, number={1}, journal={Progress in Chemistry}, author={Zhang, Y. Q. and Yu, J. C. and Shen, Q. D. and Gu, Z.}, year={2015}, pages={11–26} }
 @article{yu_zhang_ye_disanto_sun_ranson_ligler_buse_gu_2015, title={Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery}, volume={112}, ISSN={["0027-8424"]}, DOI={10.1073/pnas.1505405112}, abstractNote={Significance}, number={27}, journal={PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, author={Yu, Jicheng and Zhang, Yuqi and Ye, Yanqi and DiSanto, Rocco and Sun, Wujin and Ranson, Davis and Ligler, Frances S. and Buse, John B. and Gu, Zhen}, year={2015}, month={Jul}, pages={8260–8265} }
 @article{di_yao_ye_cui_yu_ghosh_zhu_gu_2015, title={Stretch-Triggered Drug Delivery from Wearable Elastomer Films Containing Therapeutic Depots}, volume={9}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.5b03975}, abstractNote={Mechanical force-based stimulus provides a simple and easily accessible manner for spatiotemporally controlled drug delivery. Here we describe a wearable, tensile strain-triggered drug delivery device consisting of a stretchable elastomer and microgel depots containing drug loaded nanoparticles. By applying a tensile strain to the elastomer film, the release of drug from the microdepot is promoted due to the enlarged surface area for diffusion and Poisson's ratio-induced compression on the microdepot. Correspondingly, both sustained drug release by daily body motions and pulsatile release by intentional administration can be conveniently achieved. Our work demonstrated that the tensile strain, applied to the stretchable device, facilitated release of therapeutics from microdepots for anticancer and antibacterial treatments. Moreover, polymeric microneedles were further integrated with the stretch-responsive device for transcutaneous delivery of insulin and regulation of blood glucose levels of chemically induced type 1 diabetic mice.}, number={9}, journal={ACS NANO}, author={Di, Jin and Yao, Shanshan and Ye, Yanqi and Cui, Zheng and Yu, Jicheng and Ghosh, Tushar K. and Zhu, Yong and Gu, Zhen}, year={2015}, month={Sep}, pages={9407–9415} }