@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{richter_wan_wen_zhang_yu_kang_zhu_mckinnon_gu_qiang_et al._2020, title={Targeted Delivery of Notch Inhibitor Attenuates Obesity-Induced Glucose Intolerance and Liver Fibrosis}, volume={14}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.0c01007}, abstractNote={As the prevalence of obesity-induced type 2 diabetes mellitus (T2DM) and nonalcoholic steatohepatitis (NASH) continue to increase, the need for pharmacologic therapies becomes urgent. However, endeavors to identify and develop novel therapeutic strategies for these chronic conditions are balanced by the need for safety, impeding clinical translation. One shared pathology of these two diseases is a maladaptive reactivation of the Notch signaling pathway in liver. Notch antagonism with γ-secretase inhibitors effectively suppresses hepatic glucose production and reduces liver fibrosis in NASH, but its extrahepatic side effects, particularly goblet cell metaplasia, limit therapeutic utility. To overcome this barrier, we developed a nanoparticle-mediated delivery system to target γ-secretase inhibitor to liver (GSI NPs). GSI NP application reduced hepatic glucose production in diet-induced obese mice and reduced hepatic fibrosis and inflammation in mice fed a NASH-provoking diet, without apparent gastrointestinal toxicity. By changing the delivery method, these results provide proof-of-concept for the repurposing of a previously intolerable medication to address unmet needs in the clinical landscape for obesity-induced T2DM and NASH.}, number={6}, journal={ACS NANO}, author={Richter, Lauren R. and Wan, Qanfen and Wen, Di and Zhang, Yuqi and Yu, Junjie and Kang, Jin Ku and Zhu, Changyu and McKinnon, Elizabeth L. and Gu, Zhen and Qiang, Li and et al.}, year={2020}, month={Jun}, pages={6878–6886} }
 @article{yang_chen_wen_chen_wang_chen_wang_zhang_zhang_hu_et al._2019, title={A Therapeutic Microneedle Patch Made from Hair-Derived Keratin for Promoting Hair Regrowth}, volume={13}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.8b09573}, abstractNote={Activating hair follicle stem cells (HFSCs) to promote hair follicle regrowth holds promise for hair loss therapy, while challenges still remain to develop a scenario that enables enhanced therapeutic efficiency and easy administration. Here we describe a detachable microneedle patch-mediated drug delivery system, mainly made from hair-derived keratin, for sustained delivery of HFSC activators. It was demonstrated that this microneedle device integrated with mesenchymal stem cell (MSC)-derived exosomes and a small molecular drug, UK5099, could enhance the treatment efficiency at a reduced dosage, leading to promoted pigmentation and hair regrowth within 6 days through two rounds of administration in a mouse model. This microneedle-based transdermal drug delivery approach shows augmented efficacy compared to the subcutaneous injection of exosomes and topical administration of UK5099.}, number={4}, journal={ACS NANO}, author={Yang, Guang and Chen, Qian and Wen, Di and Chen, Zhaowei and Wang, Jinqiang and Chen, Guojun and Wang, Zejun and Zhang, Xudong and Zhang, Yuqi and Hu, Quanyin and et al.}, year={2019}, month={Apr}, pages={4354–4360} }
 @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} }
 @article{wen_wang_van den driessche_chen_zhang_chen_li_soto_liu_ohashi_et al._2019, title={Adipocytes as Anticancer Drug Delivery Depot}, volume={1}, ISSN={["2590-2385"]}, DOI={10.1016/j.matt.2019.08.007}, abstractNote={Tumor-associated adipocytes promote tumor growth by providing energy and causing chronic inflammation. Here, we have exploited the lipid metabolism to engineer adipocytes that serve as a depot to deliver cancer therapeutics at the tumor site. Rumenic acid (RA), as an anticancer fatty acid, and a doxorubicin prodrug (pDox) with a reactive oxygen species (ROS)-cleavable linker, are encapsulated in adipocytes to deliver therapeutics in a tumor-specific bioresponsive manner. After intratumoral or postsurgical administration, lipolysis releases the RA and pDox that is activated by intracellular ROS-responsive conversion, subsequently promoting antitumor efficacy. Furthermore, downregulation of PD-L1 expression is observed in tumor cells, favoring the emergence of CD4+ and CD8+ T cell-mediated immune responses.}, number={5}, journal={MATTER}, author={Wen, Di and Wang, Jinqiang and Van Den Driessche, George and Chen, Qian and Zhang, Yuqi and Chen, Guojun and Li, Hongjun and Soto, Jennifer and Liu, Ming and Ohashi, Masao and et al.}, year={2019}, month={Nov}, pages={1203–1214} }
 @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{chen_wang_zhang_chen_hu_li_wang_wen_zhang_lu_et al._2019, title={In situ sprayed bioresponsive immunotherapeutic gel for post-surgical cancer treatment}, volume={14}, ISSN={["1748-3395"]}, DOI={10.1038/s41565-018-0319-4}, abstractNote={Cancer recurrence after surgical resection remains a significant cause of treatment failure. Here, we have developed an in situ formed immunotherapeutic bioresponsive gel that controls both local tumour recurrence after surgery and development of distant tumours. Briefly, calcium carbonate nanoparticles pre-loaded with the anti-CD47 antibody are encapsulated in the fibrin gel and scavenge H+ in the surgical wound, allowing polarization of tumour-associated macrophages to the M1-like phenotype. The released anti-CD47 antibody blocks the 'don't eat me' signal in cancer cells, thereby increasing phagocytosis of cancer cells by macrophages. Macrophages can promote effective antigen presentation and initiate T cell mediated immune responses that control tumour growth. Our findings indicate that the immunotherapeutic fibrin gel 'awakens' the host innate and adaptive immune systems to inhibit both local tumour recurrence post surgery and potential metastatic spread.}, number={1}, journal={NATURE NANOTECHNOLOGY}, author={Chen, Qian and Wang, Chao and Zhang, Xudong and Chen, Guojun and Hu, Quanyin and Li, Hongjun and Wang, Jinqiang and Wen, Di and Zhang, Yuqi and Lu, Yifei and et al.}, year={2019}, month={Jan}, pages={89-+} }
 @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{yu_zhang_yan_kahkoska_gu_2018, title={Advances in bioresponsive closed-loop drug delivery systems}, volume={544}, ISSN={["1873-3476"]}, DOI={10.1016/j.ijpharm.2017.11.064}, abstractNote={Controlled drug delivery systems are able to improve efficacy and safety of therapeutics by optimizing the duration and kinetics of release. Among them, closed-loop delivery strategies, also known as self-regulated administration, have proven to be a practical tool for homeostatic regulation, by tuning drug release as a function of biosignals relevant to physiological and pathological processes. A typical example is glucose-responsive insulin delivery system, which can mimic the pancreatic beta cells to release insulin with a proper dose at a proper time point by responding to plasma glucose levels. Similar self-regulated systems are also important in the treatment of other diseases including thrombosis and bacterial infection. In this review, we survey the recent advances in bioresponsive closed-loop drug delivery systems, including glucose-responsive, enzyme-activated, and other biosignal-mediated delivery systems. We also discuss the future opportunities and challenges in this field.}, number={2}, journal={INTERNATIONAL JOURNAL OF PHARMACEUTICS}, author={Yu, Jicheng and Zhang, Yuqi and Yan, Junjie and Kahkoska, Anna R. and Gu, Zhen}, year={2018}, month={Jun}, pages={350–357} }
 @article{zhang_wang_yu_wen_kahkoska_lu_zhang_buse_gu_2018, title={Bioresponsive Microneedles with a Sheath Structure for H2O2 and pH Cascade-Triggered Insulin Delivery}, volume={14}, ISSN={["1613-6829"]}, DOI={10.1002/smll.201704181}, abstractNote={Abstract}, number={14}, journal={SMALL}, author={Zhang, Yuqi and Wang, Jinqiang and Yu, Jicheng and Wen, Di and Kahkoska, Anna R. and Lu, Yue and Zhang, Xudong and Buse, John B. and Gu, Zhen}, year={2018}, month={Apr} }
 @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{ye_wang_zhang_hu_zhang_liu_wen_milligan_bellotti_huang_et al._2017, title={A melanin-mediated cancer immunotherapy patch}, volume={2}, ISSN={["2470-9468"]}, DOI={10.1126/sciimmunol.aan5692}, abstractNote={Transdermal microneedle patch integrated with whole tumor lysate containing melanin facilitates cancer immunotherapy upon near-infrared light irradiation.}, number={17}, journal={SCIENCE IMMUNOLOGY}, author={Ye, Yanqi and Wang, Chao and Zhang, Xudong and Hu, Quanyin and Zhang, Yuqi and Liu, Qi and Wen, Di and Milligan, Joshua and Bellotti, Adriano and Huang, Leaf and et al.}, year={2017}, month={Nov} }
 @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} }
 @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{zhang_wang_yu_gu_2017, title={Smart materials and systems as artificial pancreas for diabetes treatment}, volume={25}, journal={Smart materials for tissue engineering: applications}, author={Zhang, Y. Q. and Wang, M. Z. and Yu, J. C. and Gu, Z.}, year={2017}, pages={358–381} }
 @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{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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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} }
 @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} }
 @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} }