Shirley (X.Y) Wu ​Advanced Pharmaceutics & Drug Delivery Laboratory
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Featured Articles

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Multifunctional Albumin-MnO2 Nanoparticles Modulate Solid Tumor Microenvironment by Attenuating Hypoxia, Acidosis, Vascular Endothelial Growth Factor and Enhance Radiation Response.

ACS Nano 2014





A Multifunctional Polymeric Nanotheranostic System Delivers Doxorubicin and Imaging Agents across the Blood-Brain Barrier Targeting Brain Metastases of Breast Cancer.

ACS Nano 2014





Hybrid Nanoparticles: Design of Hybrid MnO2-Polymer-Lipid Nanoparticles with Tunable Oxygen Generation Rates and Tumor Accumulation for Cancer Treatment

Adv. Funct. Mater. 2015

Publications & Book Chapters

2009 - 2015

  1. R.X. Zhang, P. Cai, T. Zhang, K. Chen, J. Li, J. Cheng, K.S. Pang, A.M Rauth, X.Y. Wu, Polymer-lipid hybrid nanoparticles synchronize pharmacokinetics of co-encapsulated doxorubicin-mitomycin C and enable their spatiotemporal co-delivery and local bioavailability in breast 
    tumor
    , Nanomedicine, 2016
  2. Y. Li, N. Taulier, M.R. Abbaspour, P. Grootenrst, A.M. Rauth, X.Y. Wu, Optimization of controlled release nanoparticle formulation of 
    verapamil hydrochloride using artificial neural networks with genetic algorithm and response surface methodology
    , Eur J Pharm Biopharm. 2015, 94, 170-179
  3. J. Chen, J. Li, C. Gordijo, M. Chu, Y. Sun, X.Y. Wu, Stimuli-Responsive Drug Delivery Microchips, in Encyclopedia of Nanotechnology (2nd ed), Chapter ID 390, 2015
  4. Y-H. Ma, Q. Wang, J. Gong, X.Y. Wu, Formulation of granules for site-specific delivery of antimicrobial essential oil to the animal GI tract, J. Pharm. Sci. 2015
  5. A.Z. Abbasi, P. Prasad, P. Cai, C. He, W.D. Foltz, M.A. Amini, C.R. Gordijo, A.M. Rauth, X.Y. Wu, Manganese oxide and docetaxel co-loaded fluorescent polymer nanoparticles for dual modal imaging and chemotherapy of breast cancer, J. Control. Release 2015, 209, 186-196.
  6. J. Cheng, Q. Liu, A.J. Shuhendler, A.M. Rauth, X. Y. Wu, Optimizing the Design and In Vitro Evaluation of Bioreactive Glucose Oxidase-Microspheres for Enhanced Cytotoxicity against Multidrug Resistant Breast Cancer Cells, Colloids Surf. B Biointerfaces 2015, 1(130),164-172.
  7. C. Gordijo, X.Y. Wu, A new life to an old material, Materials Today 2015
  8. C. Gordijo*, A.Z. Abbasi*, M.A. Amini, H.Y. Lip, A. Maeda, P. Cai, P.J. O?Brien, R.S. DaCosta, A.M. Rauth , X.Y. Wu, Design of hybrid MnO2-polymer-lipid nanoparticles with tunable oxygen generation rate and tumor accumulation for cancer treatment, Adv Func Mater. 10.1002/adfm.201404511 (Frontispiece and editorial highlight)
  9. J. Li, M. K.L. Chu, C. R. Gordijo, A. Z. Abbasi, K. Chen, H. A. Adissu, A. Giacca, O. Plettenburg, M. Lohn, X.Y. Wu, Microfabricated microporous membranes reduce the host immune response and prolong the functional lifetime of a closed-loop insulin delivery implant in a type 1 diabetic rat model, Biomaterials 2015, 47, 51-61.
  10.  



2008 and Before

  1. Liu, J., Scollard, D. A., Reilly, R. M., Wu, X. Y., & Johnston, M. R. (2008). Effect of particle size on the lymphatic distribution of 111Indium-aminopolystyrene through intrapleural administration. Lymphology, 41(4), 153-160. 
  2. Kim, K., Liu, X., Zhang, Y., Cheng, J., Wu, X. Y., & Sun, Y. (2008). Mechanical characterization of polymeric microcapsules using a force-feedback MEMS microgripper. Paper presented at the Proceedings of the 30th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS'08 - "Personalized Healthcare through Technology", 1845-1848.
  3. Kim, K., Liu, X., Zhang, Y., Cheng, J., Wu, X. Y., & Sun, Y. (2008). Mechanical characterization of polymeric microcapsules using a force-feedback MEMS microgripper. Conference Proceedings : ...Annual International Conference of the IEEE Engineering in Medicine and Biology Society.IEEE Engineering in Medicine and Biology Society.Conference, 2008, 1845-1848. 
  4. Chattopadhyay, N., Zastre, J., Wong, H. -., Wu, X. Y., & Bendayan, R. (2008). Solid lipid nanoparticles enhance the delivery of the HIV protease inhibitor, atazanavir, by a human brain endothelial cell line. Pharmaceutical Research, 25(10), 2262-2271. 
  5. Kim, K., Cheng, J., Liu, Q., Wu, X. Y., & Sun, Y. (2008). MEMS capacitive force sensors for micro-scale compression testing of biomaterials. Paper presented at the Proceedings of the IEEE International Conference on Micro Electro Mechanical Systems (MEMS), 888-891. 
  6. Li, Y., Wong, H. L., Shuhendler, A. J., Rauth, A. M., & Wu, X. Y. (2008). Molecular interactions, internal structure and drug release kinetics of rationally developed polymer-lipid hybrid nanoparticles. Journal of Controlled Release, 128(1), 60-70.  
  7. Huang, H. Y., Shaw, J., Yip, C., & Wu, X. Y. (2007). Microdomain pH gradient and kinetics inside composite polymeric membranes of pH and glucose sensitivity. Pharmaceutical Research, 25(5), 1150-1157. 
  8. A.J. Shuhendler, P. O’Brien, A.M. Rauth, X.Y. Wu (2008) On the synergistic effect of doxorubicin and mitomycin C against breast cancer cells, Drug Metabolism and Drug Interactions, 22 (4), 201-233.
  9. Abdekhodaie, M. J., & Wu, X. Y. (2008). Drug release from ion-exchange microspheres: Mathematical modeling and experimental verification. Biomaterials, 29(11), 1654-1663. 
  10. Moselhy, J., Sarkar, S., Chia, M. C., Mocanu, J. D., Taulier, N., Liu, F. F., et al. (2007). Evaluation of copolymers of N-isopropylacrylamide and 2-dimethyl(aminoethyl)methacrylate in nonviral and adenoviral vectors for gene delivery to nasopharyngeal carcinoma. International Journal of Nanomedicine, 2(3), 461-478. 
  11. Liu, Q., Rauth, A. M., & Wu, X. Y. (2007). Immobilization and bioactivity of glucose oxidase in hydrogel microspheres formulated by an emulsification-internal gelation-adsorption-polyelectrolyte coating method. International Journal of Pharmaceutics, 339(1-2), 148-156. 
  12. Wong, H. L., Bendayan, R., Rauth, A. M., Li, Y., & Wu, X. Y. (2007). Chemotherapy with anticancer drugs encapsulated in solid lipid nanoparticles. Advanced Drug Delivery Reviews, 59(6), 491-504. 
  13. Liu, J., Meisner, D., Kwong, E., Wu, X. Y., & Johnston, M. R. (2007). A novel trans-lymphatic drug delivery system: Implantable gelatin sponge impregnated with PLGA-paclitaxel microspheres. Biomaterials, 28(21), 3236-3244. 
  14. Wong, H. L., Rauth, A. M., Bendayan, R., & Wu, X. Y. (2007). In vivo evaluation of a new polymer-lipid hybrid nanoparticle (PLN) formulation of doxorubicin in a murine solid tumor model. European Journal of Pharmaceutics and Biopharmaceutics, 65(3), 300-308. 
  15. Wong, H. L., Bendayan, R., Rauth, A. M., & Wu, X. Y. (2006). Simultaneous delivery of doxorubicin and GG918 (elacridar) by new polymer-lipid hybrid nanoparticles (PLN) for enhanced treatment of multidrug-resistant breast cancer. Journal of Controlled Release, 116(3), 275-284.
  16. Wong H.L., Li Y., Bendayan R., Rauth A.M., Wu X.Y. (2006) Solid lipid nanoparticles for cancer chemotherapy, in: Nanotechnology for Cancer Therapy, CRC Press, pp.714-776 (on invitation).
  17. Li, Y., Taulier, N., Rauth, A. M., & Wu, X. Y. (2006). Screening of lipid carriers and characterization of drug-polymer-lipid interactions for the rational design of polymer-lipid hybrid nanoparticles (PLN). Pharmaceutical Research, 23(8), 1877-1887. 
  18. Abdekhodaie, M. J., & Wu, X. Y. (2006). Drug loading onto ion-exchange microspheres: Modeling study and experimental verification. Biomaterials, 27(19), 3652-3662. 
  19. Wong, H. L., Rauth, A. M., Bendayan, R., Manias, J. L., Ramaswamy, M., Liu, Z., et al. (2006). A new polymer-lipid hybrid nanoparticle system increases cytotoxicity of doxorubicin against multidrug-resistant human breast cancer cells. Pharmaceutical Research, 23(7), 1574-1585. 
  20. Cheung, R. Y., Rauth, A. M., Ronaldson, P. T., Bendayan, R., & Wu, X. Y. (2006). In vitro toxicity to breast cancer cells of microsphere-delivered mitomycin C and its combination with doxorubicin. European Journal of Pharmaceutics and Biopharmaceutics, 62(3), 321-331. 
  21. Liu, J., Wong, H. -., Moselhy, J., Bowen, B., Wu, X. Y., & Johnston, M. R. (2006). Targeting colloidal particulates to thoracic lymph nodes. Lung Cancer, 51(3), 377-386. 
  22. Cheung, R. Y., Ying, Y., Rauth, A. M., Marcon, N., & Wu, X. Y. (2005). Biodegradable dextran-based microspheres for delivery of anticancer drug mitomycin C. Biomaterials, 26(26), 5375-5385. 
  23. Abdekhodaie, M. J., & Wu, X. Y. (2005). Modeling of a cationic glucose-sensitive membrane with consideration of oxygen limitation. Journal of Membrane Science, 254(1-2), 119-127.
  24. Cheung, R. Y., Rauth, A. M., & Wu, X. Y. (2005). In vivo efficacy and toxicity of intratumorally delivered mitomycin C and its combination with doxorubicin using microsphere formulations. Anti-Cancer Drugs, 16(4), 423-433. 
  25. Li, Y., Rauth, A. M., & Wu, X. Y. (2005). Prediction of kinetics of doxorubicin release from sulfopropyl dextran ion-exchange microspheres using artificial neural networks. European Journal of Pharmaceutical Sciences, 24(5), 401-410. 
  26. Zhou, Y., Chu, J. S., Zhou, T., & Wu, X. Y. (2005). Modeling of dispersed-drug release from two-dimensional matrix tablets. Biomaterials, 26(8), 945-952.
  27. Cheung, R. Y., Kuba, R., Rauth, A. M., & Wu, X. Y. (2004). A new approach to the in vivo and in vitro investigation of drug release from locoregionally delivered microspheres. Journal of Controlled Release, 100(1), 121-133. 
  28. Zhang, K., & Wu, X. Y. (2004). Temperature and pH-responsive polymeric composite membranes for controlled delivery of proteins and peptides. Biomaterials, 25(22), 5281-5291. 
  29. Wong, H. L., Bendayan, R., Rauth, A. M., & Wu, X. Y. (2004). Development of solid lipid nanoparticles containing ionically complexed chemotherapeutic drugs and chemosensitizers. Journal of Pharmaceutical Sciences, 93(8), 1993-2008. 
  30. Wu, Z. H., Sun, M., Mei, X. Y., & Ruda, H. E. (2004). Growth and photoluminescence characteristics of AlGaAs nanowires. Applied Physics Letters, 85(4), 657-659. 
  31. ZHang, K., Huang, H., Yang, G., Shaw, J., Yip, C., & Wu, X. Y. (2004). Characterization of nanostructure of stimuli-responsive polymeric composite membranes. Biomacromolecules, 5(4), 1248-1255. 
  32. Zhou, Y., Chu, J. S., & Wu, X. Y. (2004). Theoretical analysis of drug release into a finite medium from sphere ensembles with various size and concentration distributions. European Journal of Pharmaceutical Sciences, 22(4), 251-259. 
  33. Zhang, K., Quan, C., Huang, H., Taulier, N., & Wu, X. Y. (2004). On the stability of insulin delivered through a new glucose-responsive polymeric composite membrane. Journal of Pharmacy and Pharmacology, 56(5), 611-620. 
  34. Liu, Z., Ballinger, J. R., Rauth, A. M., Bendayan, R., & Wu, X. Y. (2003). Delivery of an anticancer drug and a chemosensitizer to murine breast sarcoma by intratumoral injection of sulfoprophyl dextran microspheres. Journal of Pharmacy and Pharmacology, 55(8), 1063-1073.
  35. Wu X.Y. and Yam F., Polymer system for drug delivery and solute separation, US patent No. 6,565,872 (May 2003).
  36. Zhou, Y., & Wu, X. Y. (2003). Modeling and analysis of dispersed-drug release into a finite medium from sphere ensembles with a boundary layer. Journal of Controlled Release, 90(1), 23-36. 
  37. Wu X.Y., Zhang Q. and Arshady R. (2003) Stimuli Sensitive Hydrogels. Polymer Structure and Phase Transition (invited review chapter) in: Polymeric Biomaterials, R. Arshady (Ed.), Citus Books, London, UK, p157-194.
  38. Wu X.Y., Zhang Q. and Arshady R. (2003) Stimuli Sensitive Hydrogels. Response and Release Modulation (invited review chapter) in: Polymeric Biomaterials, R. Arshady (Ed.), Citus Books, London, UK, p195-231.
  39. Zhou, Y., & Wu, X. Y. (2002). Theoretical analyses of dispersed-drug release from planar matrices with a boundary layer in a finite medium. Journal of Controlled Release, 84(1-2), 1-13. 
  40. Zhang, K., & Wu, X. Y. (2002). Modulated insulin permeation across a glucose-sensitive polymeric composite membrane. Journal of Controlled Release, 80(1-3), 169-178. 
  41. Liu, Z., Cheung, R., Wu, X. Y., Ballinger, J. R., Bendayan, R., & Rauth, A. M. (2001). A study of doxorubicin loading onto and release from sulfopropyl dextran ion-exchange microspheres. Journal of Controlled Release, 77(3), 213-224. 
  42. Liu, Z., Bendayan, R., & Wu, X. Y. (2001). Triton-X-100-modified polymer and microspheres for reversal of multidrug resistance. Journal of Pharmacy and Pharmacology, 53(6), 779-787. 
  43. Yam, F., Wu, X. Y., & Zhang, Q. (2000). A novel composite membrane for temperature-and pH-responsive permeation 
  44. Lenet, B. J., Komorowski, R., Wu, X. Y., Huang, J., Grad, H., Lawrence, H. P., et al. (2000). Antimicrobial substantivity of bovine root dentin exposed to different chlorhexidine delivery vehicles. Journal of Endodontics, 26(11), 652-655. 
  45. Liu, Z., Wu, X. Y., Ballinger, J. R., & Bendayan, R. (2000). Synthesis and characterization of surface-hydrophobic ion-exchange microspheres and the effect of coating on drug release rate. Journal of Pharmaceutical Sciences, 89(6), 807-817.
  46. Huang, J., Wong, H. -., Zhou, Y., Wu, X. Y., Grad, H., Komorowski, R., et al. (2000). In vitro studies and modeling of a controlled-release device for root canal therapy. Journal of Controlled Release, 67(2-3), 293-307. 
  47. Huang, J., Kao, H., & Wu, X. Y. (2000). The pH-dependent biphasic release of azidothymidine from a layered composite of PVA disks and P(MMA/MAA) spheres. Journal of Controlled Release, 67(1), 45-54. 
  48. Komorowski, R., Grad, H., Wu, X. Y., & Friedman, S. (2000). Antimicrobial substantivity of chlorhexidine-treated bovine root dentin. Journal of Endodontics, 26(6), 315-317. 
  49. Moselhy, J., Wu, X. Y., Nicholov, R., & Kodaria, K. (2000). In vitro studies of the interaction of poly(NIPAm/MAA) nanoparticles with proteins and cells. Journal of Biomaterials Science, Polymer Edition, 11(2), 123-147. 
  50. Li, J. -., Zhou, Y., Wu, X. Y., Odidi, I., & Odidi, A. (2000). Characterization of wet masses of pharmaceutical powders by triaxial compression test. Journal of Pharmaceutical Sciences, 89(2), 178-190. 
  51. Wu, X. Y., & Lee, P. I. (2000). Preparation and characterization of inulin ester microspheres as drug carriers. Journal of Applied Polymer Science, 77(4), 833-840. 
  52. Q. Zhang, L. Liu, X.Y. Wu, K. Yao (2000) pH-responsive swelling behavior of collagen complex materials, Art. Cells Blood Subs. Immob. Biotech. 28, 255-262.
  53. F. Yam, X.Y. Wu and Q. Zhang (2000) A novel composite membrane for temperature and pH responsive permeation, in: Controlled Drug Delivery: Designing Technology for the Future, Ed. K. Park, ACS, Washington, DC, pp. 263-272.
  54. Y. Sun, H. Zhou, Q. Zhang, X.Y. Wu (2000) Improved controlled release study of lomustine, Art. Cell, Blood Subs. Immob. Biotech. 28, 173-180.
  55. Wu, X. Y., & Zhou, Y. (1999). Studies of diffusional release of a dispersed solute from polymeric matrixes by finite element method. Journal of Pharmaceutical Sciences, 88(10), 1050-1057. 
  56. Huang, J., & Wu, X. Y. (1999). Effects of pH, salt, surfactant and composition on phase transition of poly(NIPAm/MAA) nanoparticles. Journal of Polymer Science, Part A: Polymer Chemistry, 37(14), 2667-2676. 
  57. Ly, J., & Wu, X. Y. (1999). Bimodal release of theophylline from 'seed-matrix' beads made of acrylic polymers. Pharmaceutical Development and Technology, 4(2), 257-267. 
  58. Liu, Z., Wu, X. Y., & Bendayan, R. (1999). In vitro investigation of ionic polysaccharide microspheres for simultaneous delivery of chemosensitizer and antineoplastic agent to multidrug-resistant cells. Journal of Pharmaceutical Sciences, 88(4), 412-418. 
  59. Wu, X. Y., & Zhou, Y. (1999). Simulation of diffusional release of a dispersed solute from polymeric matrices into a finite volume. Proceedings of the Controlled Release Society, (26), 1016-1017. 
  60. Yam F. and Wu X.Y. (1999) A novel composite membrane for temperature responsive permeation, Polymer Preprint, 40, 312-313.
  61. Wu, X. Y., Eshun, G., & Zhou, Y. (1998). Effect of interparticulate interaction on release kinetics of microsphere ensembles. Journal of Pharmaceutical Sciences, 87(5), 586-593. 
  62. Wu, X. Y., & Zhou, Y. (1998). Finite element analysis of diffusional drug release from complex matrix systems. II. factors influencing release kinetics. Journal of Controlled Release, 51(1), 57-71.
  63. Wu, X. Y., & Zhou, Y. (1998). Numerical analysis of drug release from matrix tablets with moving boundaries. Proceedings of the Controlled Release Society, (25), 451-452. 
  64. Wu, X. Y., Zhou, Y., & Eshun, G. (1998). Influence of drug accumulation and particle separation on release kinetics of multiparticulate systems. Proceedings of the Controlled Release Society, (25), 449-450. 
  65. Wu, X. Y., Ly, J., & Zhou, Y. (1998). Modeling of bimodal release from composite polymeric beads. Proceedings of the Controlled Release Society, (25), 447-448. 
  66. Huang, J., Wong, H. L., Wu, X. Y., Grad, H. A., Komorowski, R., & Friedman, S. (1998). A device for controlled release of antibacterial drugs for dental root canal therapy. Proceedings of the Controlled Release Society, (25), 778-779. 
  67. Zhou, Y., & Wu, X. Y. (1997). Finite element analysis of diffusional drug release from complex matrix systems. I. complex geometries and composite structures. Journal of Controlled Release, 49(2-3), 277-288.
  68. Subotic, D. V., & Wu, X. Y. (1997). Interactions of poly(N-isopropylacrylamide-co-methacrylic acid) with poly(N-vinylpyrrolidone). Industrial and Engineering Chemistry Research, 36(4), 1302-1309. 
  69. Pelton R.H., Wu X.Y., McPhee W., and Tam K.C., The preparation and characterization of polyNIPAM latexes, in: Colloidal polymer particles, Ed. J.W. Goodwin and R. Buscall, Academic Press, pp.81-99 (1995).
  70. Wu X.Y., Pelton R.H., Hamielec A.E., Woods D.R., and McPhee W., The kinetics of poly(N-isopropylacrylamide) microgel latex formation,  Colloid Polym. Sci. 272, 467-477 (1994).
  71. Hunkeler D., Wu X.Y. and Hamielec A.E., Pelton R.H., and Woods D.R., Characterization of polyacrylamide-co-sodium acrylate, in: Macro-Ion Characterization, From Dilute Solutions to Complex Fluids, Ed. K.S. Schmitz, pp.162-177 (1994).
  72. Wu, X. Y., & Lee, P. I. (1993). Preparation and characterization of thermal- and pH-sensitive nanospheres. Pharmaceutical Research, 10(10), 1544-1547. 
  73. Wu X.Y., Pelton R.H., Tam K.C., Woods D.R., and Hamielec A.E. Poly(N-isopropylacrylamide). I. Interactions with sodium dodecyl sulphate measured by conductivity, J. Polym. Sci.: Part A: Polym. Chem. 31, 957-962 (1993). 
  74. Tam K.C., Wu X.Y., and Pelton R.H., Poly(N-isopropylacrylamide). II. Effect of polymer concentration, temperature, and surfactant on the viscosity of aqueous solutions, J. Polym. Sci.: Part A: Polym. Chem., 31, 963-969 (1993). 
  75. Hunkeler D., Wu X.Y. and Hamielec A.E., Molecular weight characterization of poly(acrylamide-co-sodium acrylate) II. Light scattering, J. Appl. Polym. Sci. 46, 649-657 (1992). 
  76. Tam K.C., Wu X.Y. and Pelton R.H., Viscometry - A useful tool for studying conformational changes of poly(N-isopropylacrylamide) in solutions, Polymer Communications, 33, 436-438 (1992). 
  77. Hunkeler D., Wu X.Y. and Hamielec A.E., Characterization of polyelectrolytes, in: Polyelectrolyte Gels, Properties, Preparation, and Applications, Ed. R.S. Harland and R.K. Prud'homme, pp.53-79 (1992).
  78. Wu X.Y., Hunkeler D., Hamielec A.E., Pelton R.H. and Woods D.R., Molecular weight characterization of poly(acrylamide-co-sodium acrylate)  I. Viscometry, J. Appl. Polym. Sci. 42, 2081-2093 (1991). 
  79. Wu X.Y., Hunkeler D., Hamielec A.E. and Pelton R., Molecular weight characterization of polyelectrolytes, Polymer Materials Sci. Eng. 58, 792-794 (1988).

Patents & Copyrights

  • X.Y. Wu and F. Yam, CA patent No. 2,262,073 (issued in March 2009) Polymeric System for Drug Delivery and Solute Separation.
  • J. Liu, M. Johnston, X.Y. Wu, PCT/CA2006/001321 Methods and devices for lymphatic targeting (PCT Application).
  • J. Liu, M. Johnston, X.Y. Wu, US 12/063,614. Methods and devices for lymphatic targeting (USA).
  • J. Liu, M. Johnston, X.Y. Wu, CA 2,618,807 Methods and devices for lymphatic targeting (Canada).
  • J. Liu, M. Johnston, X.Y. Wu, EP2006000775100 (Publication# EP1922094A1) Methods and devices for lymphatic targeting (Europe).
  • J. Liu, M. Johnston, X.Y. Wu, CN200680038249.5 Methods and devices for lymphatic targeting (China).
  • J. Liu, M. Johnston, X.Y. Wu, IN 2108/DELNP/2008 Methods and devices for lymphatic targeting (India).
  • J. Liu, M. Johnston, X.Y. Wu, 200680038249.5 Methods and devices for lymphatic targeting (Hong Kong).
  • J. Liu, M. Johnston, X.Y. Wu, US60/707,534 Lymphatic Targeting (US Provisional Application).
  • X.Y. Wu, C. Gordijo, K. Zhang, H. Huang, US 61/331,690 Insulin delivery device (US Provisional Application).

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