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Photocurable bioresorbable adhesives as functional interfaces between flexible bioelectronic devices and soft biological tissues

Abstract

Flexible electronic/optoelectronic systems that can intimately integrate onto the surfaces of vital organ systems have the potential to offer revolutionary diagnostic and therapeutic capabilities relevant to a wide spectrum of diseases and disorders. The critical interfaces between such technologies and living tissues must provide soft mechanical coupling and efficient optical/electrical/chemical exchange. Here, we introduce a functional adhesive bioelectronic–tissue interface material, in the forms of mechanically compliant, electrically conductive, and optically transparent encapsulating coatings, interfacial layers or supporting matrices. These materials strongly bond both to the surfaces of the devices and to those of different internal organs, with stable adhesion for several days to months, in chemistries that can be tailored to bioresorb at controlled rates. Experimental demonstrations in live animal models include device applications that range from battery-free optoelectronic systems for deep-brain optogenetics and subdermal phototherapy to wireless millimetre-scale pacemakers and flexible multielectrode epicardial arrays. These advances have immediate applicability across nearly all types of bioelectronic/optoelectronic system currently used in animal model studies, and they also have the potential for future treatment of life-threatening diseases and disorders in humans.

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Data availability

Source data are provided with this paper. All other data that support the results in this study are available from the corresponding author upon reasonable request.

Code availability

Software for the analysis of optical mapping data, RHYTHM, is openly available for free download at https://github.com/optocardiography. Other custom codes used in this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was generously funded by the Leducq Foundation project RHYTHM and the National Institutes of Health (R01-HL141470 to I.R.E. and J.A.R.). This work made use of the NUFAB facility of Northwestern University’s NUANCE Center, which received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633); the MRSEC programme (NSF DMR-1720139) at the Materials Research Center; the International Institute for Nanotechnology (IIN); the Keck Foundation; the Querrey Simpson Institute for Bioelectronics; the Keck Biophysics Facility, a shared resource of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, which received support in part by the NCI Cancer Center Support (P30 CA060553); the Center for Advanced Molecular Imaging (RRID:SCR_021192); Northwestern University; and the State of Illinois, through the IIN. R.T.Y. acknowledges support from the American Heart Association (19PRE34380781). M.W. acknowledges support from the National Institutes of Health (T32 AG20506). Z.X. acknowledges support from the National Natural Science Foundation of China (12072057), LiaoNing Revitalization Talents Program (XLYC2007196) and Fundamental Research Funds for the Central Universities (DUT20RC(3)032). K.A. acknowledges support from the National Institutes of Health (5K99-HL148523-02). Y.H. acknowledges support from the National Foundation of Science (CMMI1635443). Y.K. acknowledges support from the National Institutes of Health (R01NS107539 and R01MH117111), Beckman Young Investigator Award, Rita Allen Foundation Scholar Award and Searle Scholar Award. The diagrams of the mouse body with organs in Fig. 1f were created with BioRender.com.

Author information

Author notes
  1. These authors contributed equally: Quansan Yang, Tong Wei, Rose T. Yin, Mingzheng Wu, Yameng Xu.

Affiliations

  1. Center for Bio-Integrated Electronics, Northwestern University, Evanston, IL, USA

    Quansan Yang, Yeon Sik Choi, Wubin Bai, Yiyuan Yang, Mengdi Han, Min-Ho Seo, Haiwen Luan, Anthony Banks, Yonggang Huang & John A. Rogers

  2. Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA

    Quansan Yang, Yeon Sik Choi, Wubin Bai, Yiyuan Yang, Mengdi Han, Min-Ho Seo, Haiwen Luan, Anthony Banks & John A. Rogers

  3. Department of Mechanical Engineering, Northwestern University, Evanston, IL, USA

    Quansan Yang, Yujun Deng, Raudel Avila, Tzu-Li Liu, Yiyuan Yang, Haiwen Luan, Yonggang Huang & John A. Rogers

  4. Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL, USA

    Tong Wei, Tong Wang & John M. Torkelson

  5. Department of Biomedical Engineering, The George Washington University, Washington, DC, USA

    Rose T. Yin, Kedar Aras, Gregory D. Trachiotis & Igor R. Efimov

  6. Department of Neurobiology, Northwestern University, Evanston, IL, USA

    Mingzheng Wu & Yevgenia Kozorovitskiy

  7. Department of Materials Science and Engineering, Northwestern Adobe XD CC Patch, Evanston, IL, USA

    Yameng Xu, Yeon Sik Choi, Wubin Bai, Qihui Zhang, Min-Ho Seo, Seung Min Lee, John M. Torkelson, Yonggang Huang & John A. Rogers

  8. The Institute of Materials Science and Engineering, Washington University in St. Louis, St. Louis, MO, USA

    Yameng Xu

  9. School of Biomedical Engineering, Korea University, Seoul, Republic of Korea

    Jahyun Koo

  10. State Key Laboratory of Structural Analysis for Industrial Equipment, Dalian University of Technology, Dalian, China

    Zhaoqian Xie

  11. Department of Engineering Mechanics, Dalian University of Technology, Dalian, China

    Zhaoqian Xie

  12. Ningbo Institute of Dalian University of Technology, Ningbo, China

    Zhaoqian Xie

  13. Department of Surgery, AnyToISO Professional 3.9.6 Build 670 Crack Product Key Free Download George Washington University, Washington, DC, USA

    Sheena W. Chen & K. Benjamin Lee

  14. Developmental Therapeutics Core, Northwestern University, Evanston, IL, USA

    Irawati Kandela, Nayereh Ghoreishi-Haack, Lori Tran & Iwona Stepien

  15. Chemistry Life Processes Institute, Northwestern University, Evanston, IL, USA

    Irawati Kandela, Chad R. Haney, Anlil Brikha, Lori Tran, Iwona Stepien, Fraser Aird, Emily A. Waters & Yevgenia Kozorovitskiy

  16. School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, China

    Shenglian Yao

  17. State Key Laboratory of Mechanical System and Vibration, Shanghai Jiao Tong University, Shanghai, China

    Yujun Deng

  18. Department of Applied Physical Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Wubin Bai

  19. Center for Advanced Molecular Imaging, Northwestern University, Evanston, IL, USA

    Chad R. Haney, Anlil Brikha & Emily A. Waters

  20. Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA

    Chad R. Haney, Emily A. Waters & John A. Rogers

  21. School of Biomedical Convergence Engineering, College of Information & Biomedical Engineering, Pusan National University, Pusan, Republic of Korea

    Min-Ho Seo

  22. Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, China

    Xinge Yu

  23. DC Veterans Affairs Medical Center, The George Washington University, Washington, DC, USA

    Gregory D. Trachiotis

  24. Departments of Civil and Wallpaper Engine 1.5.2 Crack With Serial Key [Updated] 100% Working 2021 Engineering, Northwestern University, Evanston, IL, USA

    Yonggang Huang

  25. Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    John A. Rogers

Contributions

Q.Y., T. Wei, Y.K., I.R.E. and J.A.R. conceived the ideas and designed the research. Q.Y., T. Wei, Y.X. and T.-L.L. synthesized and characterized the materials. Q.Y., Y.X., J.K., Y.S.C., W.B., Y.Y., M.H., Q.Z., T. Wang, M.-H.S., H.L., S.M.L. and A. Banks designed and fabricated the devices. R.T.Y., M.W., S.W.C., I.K., S.Y., C.R.H., K.B.L., K.A., A. Brikha, I.S., F.A., E.A.W. and G.D.T. performed the in vitro, ex vivo and in vivo studies. Q.Y., R.T.Y., Y.X., M.W., C.R.H., A. Banks and E.A.W. performed the data analysis. Z.X., R.A. and Y.D. performed the mechanical and electrical modelling. Q.Y., Y.X., R.T.Y., T.W., M.W, J.M.T., Y.H., Y.K., I.R.E. and J.A.R. wrote the manuscript with input from all authors.

Corresponding authors

Correspondence to Yevgenia Kozorovitskiy, Igor R. Efimov or John A. Rogers.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review informationNature Materials thanks John Ho, Yuhan Lee, Tsuyoshi Sekitani and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Supporting matrices for electrode-embedded 3D electronic systems.

a, Schematic illustration of procedures to integrate 3D electronics into a matrix of the BTIM. The matrix allows manual manipulation without damaging fragile features, with the ability to bond to dynamic, curved tissue surfaces. b, Image of a 3D device formed by compressive buckling on an elastomer substrate. c, Micrograph of a 3D device in a BTIM supporting matrix. d, Schematic illustrations of the 2D precursor before compressive buckling (first panel) and the 3D structure after compressive buckling (second panel), with the measuring electrode in the central area. e, Schematic illustration of the original and deformed status of the non-encapsulated (first row) and the BTIM-encapsulated (second row) 3D devices under compressive pressure. f, g, Curves for impedance and phase angle over the frequency sweep without the BTIM before and after compressive pressure. h, i, Impedance and phase angle over the frequency sweep with the BTIM under static compression fatigue tests. j, k, Impedance and phase angle over the frequency sweep with the BTIM under dynamic compression fatigue tests (pressure: 2 kPa; cycle number: 104).

Source data

Extended Data Fig. 2 Influence of APTES-functionalization on bioelectronics surfaces.

a, ToF-SIMS analysis of a representative pristine bioelectronic surface (PLA). b, Steps for selective functionalization of this surface through a patterned polyimide adhesive-coated shadow mask. c, ToF-SIMS analysis on the shadowed area of the surface shows results that are similar to those from the pristine surface. d, ToF-SIMS analysis of the exposed area of the bioelectronic surface. To normalize the intensity, the intensity I28, where the mass is 28, was set as 100 and calculate the relative intensity of each case. e, Thickness of an APTES layer formed on a silicon wafer exposed in air and submerged in water as a function of time after formation. Spectroscopic ellipsometry was used for these measurements. f, Impedance of MEA electrodes at 1 kHz in 0.1 M PBS at room temperature before APTES functionalization and immediately and 7 days after APTES functionalization (F(2,123) = 0.0201, P = 0. 9801). n = 6 independent samples in e and n = 40 independent electrodes from 10 independent devices and 3 independent batches in f. Values in e and f represent the mean ± s.d. Statistical significance and P values are determined by one-way ANOVA at a significance level of 0.05. ns indicates no statistically significant differences.

Source data

Extended Data Fig. 3 Analysis of the electrical distributions associated with electrical stimulation.

a, Influence of the conductivity of the interface material on electrical stimulation. b, Current density distributions in the myocardium layer and the interface material with different conductivities. c, Potential distribution in the myocardium layer and the interface material with different conductivities. d, Corresponding potential distributions on the top of the myocardium layer as a function of the interface material conductivity. e, Ratio of the potential difference on the tissues (V3 – V4) to the corresponding potential difference on the electrodes (V1Freemake music downloader - Activators Patch, 3 V) as a function of the interface material conductivity.

Source data

Extended Data Fig. 4 Analysis of the electrical distributions associated with biopotential mapping.

a, Influence of the conductivity of the BTIM on biopotential mapping. b, Biopotential distribution in the myocardium layer and the interface material layer with various conductivities. c, Calculated potential at all of the electrodes for different conductivities. d, Calculated potential on all the electrodes in the presence of the interface material layer with various conductivities (blue solid line) and in the absence of the interface material layer (red dash line).

Source data

Extended Data Fig. 5 Mechanical stability of BTIM-encapsulated wireless optoelectronics.

a, Original device position determined by photographs, and positions of BTIM-encapsulated devices (first row) and non-adhesive (second row) devices on day 1 (white), 4 (blue), and 7 (purple) post-surgery determined by MicroCT. b, c, Statistical analyses of the net translations (b) and rotations (c) of the µ-ILED in the BTIM-encapsulated (blue) and non-adhesive devices (red) on day 4 and 7 compared with those on day 1 post-surgery. n = 3 biologically independent animals. Values in b–c represent the mean ± s.d.

Source data

Extended Data Fig. 6 Applying BTIM on brain-integrated bioelectronics/optoelectronics.

a, Image of the brain areas exposed to the BTIM. b, c, Astrocyte area percentages and microglia area percentages for the sham group and the BTIM group. Black dots: animal average. Black dots: animal average, 4 animals in total. Grey dots: individual ROIs. 10–12 ROIs from 4 animals in total, 2–3 ROIs from each animal. P = 0.3546 in b and P = 0.8049 in c. d, The image of the BTIM-encapsulated b-MEA on a mouse brain ex vivo. e, Robust adhesion even when the b-MEA is lifted or shaken. n = 12 independent measurements from 4 biologically independent animals in b–c. Values in b–c represent the mean ± s.d. Statistical significance and P values are determined by two-sided Student’s Wallpaper Engine 1.5.2 Crack With Serial Key [Updated] 100% Working 2021 at a significance level of 0.05. ns indicates no statistically significant differences.

Source data

Extended Data Fig. 7 Electrogram signals of ventricular fibrillation from an MEA with BTIM encapsulation.

a, Representative electrogram signal collected from a Langendorff-perfused rabbit heart during ventricular fibrillation (VF). b, c, Phase (b) and voltage (c) map of VF over 2500 ms.

Source data

Supplementary information

Supplementary Information

Supplementary Notes 1–11, Tables 1 and 2 Wallpaper Engine 1.5.2 Crack With Serial Key [Updated] 100% Working 2021 Figs. 1–33.

Reporting Summary

Supplementary Video 1

Optoelectronic device remains in the bonded location and exhibits stable operation during natural movements of animals. The device can be wirelessly activated to emit red light (peak wavelength 630 nm), designed for its relevance in tumour irradiation.

Supplementary Video 2

BTIM firmly secures an optoelectronic device to the dorsal subcutaneous area throughout 2 months after surgery. The BTIM severs as an encapsulating coating in this situation.

Supplementary Video 3

Optoelectronic device encapsulated by the BTIM remains functional for 2 months after surgery.

Supplementary Video 4

Instability of the device coil on the mouse skull without the BTIM.

Supplementary Video 5

Stability of the device coil on the mouse skull with the BTIM encapsulating coating.

Supplementary Video 6

Battery-free devices designed for optogenetics remain functional for 2 weeks after surgery. The BTIM serves as an encapsulating coating in this situation.

Supplementary Video 7

Robust adhesion of the BTIM to a mouse cerebrum.

Supplementary Video 8

Adhesive conduit supports and protects an interconnect/cable under compression in vivo.

Supplementary Video 9

BTIM in the encapsulation strategy establishes conformal contact between electrodes of wireless cardiac pacemakers and the myocardium in vivo.

Supplementary Video 10

In vivo characterization of adhesion between electrodes and the epicardium. The heart can be dragged out of the chest due to the robust adhesion provided by the BTIM.

Supplementary Video 11

Characterization of adhesion between electrodes and the epicardium on day 10 after surgery. The robust adhesion remains in Movavi Slideshow Maker serial key - Crack Key For U 10 d after surgery.

Supplementary Video 12

In vivo representative ECG traces during rapid ventricular pacing at ~1,000 bpm.

Supplementary Video 13

Accurate mapping of ventricular fibrillation on a Langendorff-perfused rabbit heart. The BTIM serves as the interfacial layer in this situation to bridge the MEA and the myocardium.

Source data

Источник: https://www.nature.com/articles/s41563-021-01051-x?proof=t%29
CC BY 2.0

Rachel Abrams

Born and raised in Gainesville, Florida, Rachel Abrams studied creative writing at the University of Virginia. She Uncategorized - Activators Patch volunteering at her neighborhood community garden and growing herbs in her New York City apartment.

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    *   Changing the status Wallpaper Engine 1.5.2 Crack With Serial Key [Updated] 100% Working 2021 this option has an immediate effect (no game restart is required), however it's required to re-click the Fast-Forward button if fast-forwarding is currently active.
    *   Available speeds: 0.25 (slow), 0.5 (slow), 0.75 (slow), 1.5, 2.0, 2.5, 3.0 (default), 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 12.5, 15.0, 20.0, 22.5, 25.0, 27.5, 30.0, 45.0, 60.0.
      Added new hotkeys (they can be remapped in Settings -> Hotkeys):
    *   CTRL+W = HERC Hades: Activate Anti-Missile System.
    *   CTRL+Q = HERC Hera: Cast Shield.
      Option "Show information about unused EE2 files in the Documents folder" can now additionally be configured with the custom configuration commands in UP1.5 Settings. The alerts trigger when the number of files is greater than specified: "CustomFilesNumberCheckingPlaybacks=399", "CustomFilesNumberCheckingSaveMP=399", "CustomFilesNumberCheckingSaveSP=399".

    Changes/Fixes in UP1.5 Update 8:
      Included changes from all minor updates 157000-157041.
      New version identification due to structural changes: "EE2 1.5.8", "AOS 1.5.8", "EE2 1.5.8-non1.5units", "AOS 1.5.8-non1.5units", "EE2 1.5.8 + Mod", "AOS 1.5.8 + Mod".
      Created a new DLL file: "UP15_GameHelper.dll":
    *   In modern versions of Unofficial Patch 1.5 some of the assembled game fixes and features have been migrated to the DLL and the Launcher process in order to allow multithreading and general game process offload.
      Added timestamp to filenames of screenshots taken in game (EE2: Documents\Empire Earth II\screenshots, AOS: Documents\Empire Earth II The Art of Supremacy\screenshots). It helps avoid filenames conflict during synchronization between multiple computers.
      Reworked the "Audio playback (taunts) for certain messages":
    *   Added the taunts system to in-game chat (even in Singleplayer).
    *   Added two separate checkboxes to the Maximization Helper window, "Disable Audio Taunts in Chats": "Multiplayer", "Game".
    *   Added an autoplay of the "Host is waiting to launch." taunts (when applicable).
    *   Added a sound effect, when settings change in the hosted game room (triggered by the red system message).
    *   The list of censored words (a beep sound effect) is now updated on the Launcher start.
    *   Added ignoring of the punctuation characters, e.g. taunt: "merrychristmas4" will also play when "Merry Christmas 4!" is typed.
    *   Added taunts inside the "quotation marks", e.g. audio will be played on message: I wish you a "Merry Christmas", Jenna.
    *   If the game window was minimized (iconic), the first missed taunt will still be played when the window becomes active again.
      Reworked the Game Taskbar Icon Flashing functions, when the game window is minimized (iconic):
    *   Added flashing on new messages in game chat (after game start, not only multiplayer chats).
    *   Disabled flashing when settings change in the hosted game room (triggered by the red system message).
      Game flares:
    *   Fixed a bug where in Multiplayer, players could hear the sound of invisible flares (usually sent between allies in the opposite team).
    *   Fixed an issue where the sound of an old / expired flare could play with a delay if the game window was minimized (iconic).
      Players who resign from a multiplayer game and become observers will now have the same Observers Features (ability to see/send messages/flares, etc.) as the players who were observers since the game started. It takes around 5 seconds to update by the UP1.5 Launcher's KeepAlive thread.
      Fixed a bug where the M18 Hellcat tank (American unique unit, epochs 11-15) was rotating the turret / cannon like crazy while shooting. Thanks for the report to player "Bogdan".
      The volume of sounds played by the UP1.5 Launcher (for example on special hotkeys presses) is now the same as the sound volume set in game (Settings -> Audio -> Volume -> Sound). The minimum volume is 10%. It's dynamically updated when the game process is running.
      Added new buttons to the UP1.5 Launcher / Maximization Helper windows, which allow you to quickly open folders used by game (Installation Directory, Documents, AppData).
      Integrated a new version of "Empire Earth II Playback (.e2s) to ChatLog Converter" with the UP1.5 Launcher:
    *   Registered the .e2s file format. To convert files, please simply double-click on the playback file in "Documents\Empire Earth II\playback" or "Empire Earth II The Art of Supremacy\playback" folder.
    *   Based on the old version, updated for the last time on 29.06.2013: https://forum.ee2.eu/viewtopic.php?f=54&t=1652
    *   Supports nicknames in playbacks recorded on version 157038 and newer.
    *   After a successful conversion uploads the converted file to EE2.eu for easier sharing. If fails, opens the local .txt instead.
      Included uPnP functions directly to the UP1.5 Launcher:
    *   Removed the external program "upnpc-static.exe" from the "Unofficial Patch Files" directory.
    *   Improved the uPnP effectivity when the Launcher process is behind VPN.
      Improved the UP1.5 Checksums Generator methods (for the Installation Validation reports):
    *   Included CRC32, MD5, SHA-1, SHA-256 hash functions to the Launcher.
    *   Deleted external programs from "Unofficial Patch Files" directory: "crc32sum.exe", "md5sum.exe", "sha1sum.exe".
    *   Administrative permissions are no longer needed to generate checksums.
      DirectX 9 .DLL files are no longer present in the game installation folder. The installer and the launcher use the "DXSETUP.exe" to install them to "C:\Windows\SysWOW64" (64bit Windows) or "C:\Windows\System32" (32bit Windows) directories.
      Option "Enable Anti-Aliasing in DirectX 9" is now enabled by default (fresh UP1.5 installation only).
      Fixed an issue, where UP1.5 Launcher's hotkeys didn't work in new instances (for example when the user started EE2 and AOS at the same time). The Launcher doesn't longer register hotkeys, only listens to certain keypress events. It fixes many issues where the Launcher could block PrtSc, CTRL+F7, CTRL+F8, CTRL+F9 keys from being used in other programs.
      Fixed over 200 warnings in UP1.5 Launcher's source code, and replaced deprecated or unsafe functions (as for C++20).
      Fixed "MsSpellCheckingFacility.dll_unloaded" Launcher crash, caused by the termination of the Maximization Helper thread without releasing resources.
      Improved the Full and Minor Update Installers: The status of option "Play background music during installation" is saved and respected the next time the installer is started.
      Increased the maximum number of audio instances from 30 to 50. It helps resolve an issue, where during big battles some sounds could not be played.
      Fixed an issue, where sounds of flares, audio taunts or chat messages could not be played, when the maximum number of audio instances was reached. For these sounds, we now use the 12 extra, reserved audio instances (using the similar method as Voice Over played in the Tutorial missions).
      Fixed an issue where nicknames of messages senders stored in playback files (since ver. 157038) contained a team name instead of the player name, when "Cooperative Teams" were enabled. We now use a workaround which copies a player's nickname on Multiplayer Lobby login.
      New feature: It's now possible to set the time of day in scenarios:
    *   To use it, please simply add one of the following suffixes at the end of your scenario filename: "_ToD_Dawn.scn", "_ToD_Afternoon.scn", "_ToD_Sunset.scn", "_ToD_Night.scn", "_ToD_Cycle2.scn", "_ToD_Cycle5.scn", "_ToD_Cycle10.scn", "_ToD_Cycle15.scn".
    *   This method does not work when you click "Test Mission" in the Map Editor. It's because it uses a file named "testMission.scn" and UP1.5 is unable to determine time settings from it. However, it works flawlessly when loading a scenario from the Menu.
    *   Thanks to player "Sat42" for contribution in finishing this feature.
      New feature: Discord Rich Presence (Game status in Discord user’s profile):
    *   Works in both: "Empire Earth II" and "Empire Earth II: The Art of Supremacy".
    *   Shows if the user is currently in Launcher, Support Chat, Game Wallpaper Engine 1.5.2 Crack With Serial Key [Updated] 100% Working 2021, Multiplayer Lobby, or if is watching a playback, or if is playing/observing a Singleplayer Wallpaper Engine 1.5.2 Crack With Serial Key [Updated] 100% Working 2021 Multiplayer match.
    *   Shows the Multiplayer nickname, what game the user is currently in, free slots, rating type, game type, epochs, map type and climate.
    *   It's connected with the EE2.eu KeepAlive thread (so the Multiplayer status is updated based on the response from Server). It gives a possibility to improve it "live" (without installing extra updates).
    *   It can be disabled by the custom configuration command: "DisallowDiscordRichPresence=1" in UP1.5 Settings.
    *   To join the Official EE2.eu Discord Server, please visit: https://www.ee2.eu/discord/
      Option "Remove 100 FPS limit" is no longer BETA. It has been renamed to: "Remove 100 (or 64) FPS limit", so users who experience this problem can find it faster.
      Improved the Auto-Maximization:
    *   It will no longer wait for the Launcher splash image to disappear before the first attempt.
    *   After the first successful maximization, it will no longer try to maximize the window again.
    *   Fixed a bug where sometimes the keyboard did not work in-game after the auto-maximization (until the next ALT+TAB). Thanks for the report to player "IndieRock00".
      Improved the Christmas expansion: Tweaked the Christmas Tree colors and fixed a bug where colors of ornaments could become black after opening and closing the Full Screen Map (TAB key). This bug persisted until the game was restarted and didn't occur on all graphics cards.
      Fixed an issue with hotkeys / keyboard after maximizing the game. It could occur after the game was launched while minimized (e.g. on Multiplayer, minimized on the loading screen, and maximized when the screen with a city center was already displayed). The game would then think that the AltGr key was all the time pressed and it could be manually fixed by pressing the CTRL+ALT keys (or using ALT+TAB twice). UP15_GameHelper.dll now uses a new workaround to detect if the game was just maximized, and simulates the CTRL+ALT keys press to fix this problem for you.
      Included the new EE2 / EE2: AOS maps created by Loewenherz: "Loew World Map" (updated version, for 10 players), "Gulf Crisis" (for 6 players), "Congo" (for 4 players), "Highland" (for 2 players), "Mirage" (for 8 players), "Imperial Grounds" (for 8 players), "Mars" (for 4 players). Most of the new maps are a reconstruction of EE3 maps. Details: https://ee2.eu/t5304
      Integrated 6 Bogdan's scenarios: "Save Byzantium", "Korean War 1950", "The Inhabited Island", "The Inhabited Island: Bad Guys", "Cold War 1965", "North African Campaign" with the EE2 "Single Player" -> "Play Campaign" menu. Thanks to Loewenherz for preparing and improving files. Details: https://ee2.eu/t5323
      Updated the "under building" texture on Tundra climate for the snowy seasons in order to match a glitch present on all other climates, where it's possible to see enemy's buildings shape / size. Some of multiplayer users complained about this difference.
      Reduced the base health points of Tundra Bear from 150 to 50 for a better balance and lower annoyance.
      Fixed a bug (present since ver 1.0), where a multiplayer game could drastically slow down:
    *   It usually occurred when a player (who was in a slot between other players) left the hosted game room before the game started. Multiplayer users bypassed this bug by asking players to re-join, but it wasn't always working due that the EE2ENet thread has its own slots, unrelated to the slots which we see in the game room.
    *   It could occasionally occur when any player quit the active game.
    *   The fix skips checking the number of remaining players, in a function which calculates the maximum ping (because it used to ignore the other active EE2ENet slots), and verifies if the slot is correct using a different method.
    *   Additionally fixed the same problem, which could occur after the host migration.
    *   Added debug messages on the game chat, when the problem is detected and fixes activated (only visible by the host player).
    *   Detailed information about this issue and fix explanation: https://ee2.eu/t5441
      New feature: Maximization Helper has an option named: "Unlock Game Speed Change hotkeys in scenarios":
    *   Unlocks the game speed change hotkeys (by default - and +) in games where option "Lock Game Speed" was checked, or Campaign Missions / Custom Scenarios where game speed is locked by default, with no possibility to unlock.
    *   To prevent abuses, this option is grayed out when you're in a Multiplayer game.
    *   Changing the status of this option has an immediate effect (no game restart is required).
      Updated the alert bell sound, in non-modern epochs to a less annoying, single beat bell (when enemy's air units are in the range of the warehouse).
      Multiplayer Lobby improvements:
    *   Changed the automatic list of hosted games refresh time from 10 seconds to 5 seconds.
    *   Fixed an issue where clicking on the "Refresh List of Games" button was not changing the color of grayed-out games back to black when new slots became available.
      Fixed a graphics bug where Net Fire Launchers (heavy artillery in epoch 15) was changing colors (blinking to the dark one). The bug was actually caused by a different unit: Paladin Point Defense (mobile anti aircraft in epoch 15) which used the same texture as Net Fire Launchers for the wheels. It was visible on Net Wallpaper Engine 1.5.2 Crack With Serial Key [Updated] 100% Working 2021 Launchers whenever Paladin trucks were moving (reference video: https://youtu.be/TaMkxtyMor8?t=1186 ). The .nif file has been updated to use a copy of the texture.
      Fixed a bug in the "Supreme Effort" (Middle Eastern special power in epochs 1-5, "Your citizens' construction speed is increased by 100%"). The power bonus was given to ALL PLAYERS IN GAME, even those using civilizations from different regions. When Wallpaper Engine 1.5.2 Crack With Serial Key [Updated] 100% Working 2021 players clicked the same special power button, the construction speed was scaling even more!
      Improved the "Support for Tobii Eye Tracker devices". Added a detection if the game UI is currently hidden (CTRL+ALT+H hotkey) in order to use new gaze zones. It gives an amazing experience, for example when observing Multiplayer games. Details: https://www.ee2.eu/blog/018-eye-tracker
      UP1.5 executables (Launcher, DLL files, Installers) are now code-signed by the EE2.eu self-signed certificate.
      Added a new option to UP1.5 Settings: "Install EE2.eu Certificate". It installs the self-signed certificate: "EE2.eu - Dr. Mona Lisa" from file "Unofficial Patch Files\EE2.eu_Certificate.crt" as a Trusted Root Certification Authority. This helps verify the signature of executables provided by EE2.eu (e.g. Launcher, DLL files, Installer, Language Changer) and displays "EE2.eu - Dr. Mona Lisa" as the publisher name in UAC warnings. An EV Code Signing certificate from an official Certificate Authority would cost around $400 (USD) per year. Thanks to the self-signing method, the software provided by EE2.eu remains free, but secure! Unchecking this option will remove the certificate if it's already installed.
      Added a few UP1.5 sounds to Game Settings -> Audio -> Test Sound Volume box.
      "Middle Mouse Button Actions" improvements:
    *   Added a new option: "Flare Hotkey" to the Maximization Helper window.
    *   To activate, click the Middle Mouse Button and the Left or the Right Mouse Button at the same time.
    *   It simulates the flare hotkey press (ALT+Y, or ALT+SHIFT+T if you're currently observing a Multiplayer game).
      Improved displaying of the number of idle citizens in the citizen manager cursor:
    *   Changed the text alignment to the right.
    *   If option "Automatic Font Size for Screen Resolutions" is enabled in UP1.5 Settings, and the screen resolution height is 1440 or greater, the Launcher will apply a memory-fix to use the smaller font.
      Added support for the new Windows 10 "Segoe UI Variable" fonts. UP1.5 Launcher will use the new fonts as a replacement of the current "Segoe UI", if they're available on Wallpaper Engine 1.5.2 Crack With Serial Key [Updated] 100% Working 2021 system (in the future releases of Windows 10, around year 2022).
      Improved the "Random Seed" generation using UP15_GameHelper.dll:
    *   Fixed a bug where sometimes, the default random seed value was "1".
    *   Fixed a bug where the random seed value was set to "1" after using the "Load Settings" button (to load the .fav file).
    *   When manually typing "0" or "1", a random number will be generated in memory, however the sparkocam 2.6 8 crack - Free Activators seed box will still show the typed value.
    *   Sometimes on multiplayer, the node players might see a different random seed value than the host player. This is not important as the correct seed is sent to all connected nodes on game start.
      Fixed a bug where Ambulance (1.5) could heal itself and the other ambulances.
      Increased the healing ratio of Sister (1.5), produced in the Hospital (1.5).
      Added the missing Cycle Production button to Hospital (1.5).
      Fixed a bug where Hospital (1.5) could only set the rally point to the sea.
      Integrated calsch03's "The Roman Expedition" (Quest based scenario), with the EE2 AOS "Single Player" -> "Play Campaign" menu. Thanks for the map creation and scenario integration to Loewenherz. More information: https://forum.ee2.eu/viewtopic.php?f=54&t=5483
      Included the new EE2 World map: "Made by Victor - Earth.map", created by "VictorZas". Details: EdrawSoft Edraw Max Serial key quality of vanilla EE2 music files, from MP3 128kbps to 320kbps:
    *   Thanks to Michael Gordon Shapiro (EE2 music composer) for providing uncompressed .wav files, specially for Unofficial Patch 1.5. Check out Michael's music at: https://mikemusic.com/
    *   Significantly improved volume levels of the Ambient music in order to remove the "buzz" and align with tracks for all regions. Every track has been deeply checked for the best possible improvements, without affecting the composer's quality. Changes made by EE2 developers have also been applied.
    *   Unfortunately, the improved Empire Earth II: The Art of Supremacy music is not available for the time being (different music producer).
    *   After installing this update, the UP1.5 Launcher will automatically enable music in-game and adjust volumes for the best user experience. This will happen only 1 time (a cookie file is used).
      Updated ambient & weather sounds for all climates:
    *   Added the ultra-high quality land, forest and weather (rain, snow, wind, dust storm) sounds, ensuring that they sound as similar to the original ones as possible.
    *   The new sounds have been purchased by Dr.MonaLisa for ~$100 USD. They're fully licensed for Empire Earth II Unofficial Patch 1.5 usage only. Please consider donating for more features of this type: https://ee2.eu/donate
    *   Due to the license limitation, the new sounds are encrypted and it's impossible to mod them nor import to the other game mods (with the exception of Developers Version of UP1.5).
    *   Updated the Uranium Mine, Oil Rig and Boat Move sounds with higher quality versions (88kbps vs 32kbps), which were available in EE2 Single Player Demo files.
    *   The old ambient sounds were available in 32kbps .wav format, that's why quality was so poor.
    *   Fixed a bug where the last "loopingSounds” and "sounds" entry in DbAmbientSoundSet (dbambientaudio.ddf / dbambientaudi5.ddf) was ignored.
    *   The updated ambient sounds can be disabled by changing "Unlock UP1.5 units, buildings, models, sounds." to "No" in UP1.5 Settings.
    *   Thanks to user "Fortuking" from EE1 Reborn for the idea and generic help.
      Fixed a bug (present since ver 1.0), where projectiles (guided missiles, torpedoes and bombs) were exploding way too high above ships. Reference addresses: 007F7B1C (EE2), 0088E8CC (AOS):
    *   It was happening, because the game uses the unit size X (width) as their top impact border. It was not that noticeable for the smaller, rounded ground units as much as for the big, elliptical ships.
    *   The fix detects if the target unit "moveType" is "kUnitMoveType_NavalShallow" or "kUnitMoveType_NavalDeep" and if the source projectile is a bomb, torpedo or a guided missile. It then simulates the same behaviour as when attacking buildings. Following with the guided missiles is not negatively affected (works in the unchanged form).
    *   It improves explosion visuals during sea battles. Missiles, bombs and torpedoes now explode right next to the hull instead of somewhere far beside. It does not affect arrows and cannon balls in lower epochs. Discussion and before/after screenshots are available in this forum topic: https://forum.ee2.eu/viewtopic.php?p=26690#p26690
      Increased the "Maximum Sound Memory" to 200MB (from 100MB in versions 157024+, originally 5MB).
      Option "Reduce visual weather effects for Blizzard, Sandstorm" is now enabled by default for users who have never changed the status of this option. This doesn't affect Developers Version of UP1.5. It's to give the best experience to new players who have no time to check for all available UP1.5 options, and might get annoyed by the game after seeing these bad weather effects.
      Included the official EE2 / EE2: AOS maps from the Empire Earth® II Pre-Order Bonus Disc: "Desert World_bonus.map", "Even Steven_bonus.map", "Iron Cross_bonus.map", "Oldie Island_bonus.map", "Bayside_Bonus.map".
      INFORMATION: Unofficial Patch 1.5 is compatible with Windows 11, since version 1.5.7.0 (October 2018).
      Added Seasonal Textures, created by Loewenherz:
    *   Winter textures for Unofficial Patch 1.5 buildings.
    *   All seasons textures for trees in "Loew's Ambient Pack".
      Added a workaround for a bug that causes messages in game disappearing too quickly:
    *   The workaround is performed by the (separate) watchdog thread in UP15_GameHelper.dll.
    *   The bug is occurring when more than 5 messages are shown on chat, so the oldest message is sent to the history. However, a game function is still trying to hide these messages after their timeout, causing wrong messages to be removed from visible chat. The workaround is too advanced to explain in the changelog. In short, it copies further timeouts of messages to the first auto-disappearing slots, and then uses other fixes in order to prevent a bug where messages stay on screen endlessly.
      More improvements and features will be added with time by 158000s Minor Updates.

Team & Usage Terms



Patch Creator:
Dr Mona Lisa (Leader)
Special thanks for help to:
Iwanicki, Loewenherz, TheGrouchDE, Vetinte, Laetitian, RGV1, Calsch03, Gonzalo (Michael34), Fireheart2, Townsendigital, FireKing, Jodocus, CompagniaDellaMorte, IndieRock00, Maurits.

By installing Unofficial Version 1.5 you agree on the Unofficial Patch 1.5 Act:http://forum.ee2.eu/t1716-up15-act
(including anonymous usage statistic system, multiplayer banning-system and fair play rules in the public MP games)

If you like the patch, please consider donating. The money are very important to keep everything up. I would very appreciate any help.

Software used during development & credits:

IndigoRose's Setup Factory has been choosen by me as the Installer Builder program for Unofficial Patch 1.5. I tested many free and paid installer builders, but none of them had the features we needed. Thanks to Setup Factory Unofficial Patch 1.5 and Minor Update installers have features like: EE2-a-like skin, automatic detection of current game version, checking if update of configuration files is required, automatic detection of the installation folder, downloading most recent files from EE2.eu Server, and much more! You can read a separate article about the new installer at EE2.eu BLOG (click).

d3d8to9 by Patrick Mours is a pseudo-driver module that intends to improve compatibility and stability in games using Direct3D 8 for rendering by converting all API calls and lowlevel shaders to equivalent Direct3D 9 ones. By that it also opens those games to the new possibilities from proven tools and wrappers written for Direct3D 9. The version of d3d8to9 available in Unofficial Patch 1.5 has been modified by Dr.MonaLisa to add additional fixes prepared for Empire Earth II and Empire Earth II the Art of Supremacy (for example a fix for missing fire/explosion effects) and is configurable Wallpaper Engine 1.5.2 Crack With Serial Key [Updated] 100% Working 2021 the "UP1.5 Settings". d3d8to9 license.

freesfx.co.uk is used for some of the new sound effects, for example air raid siren.

IMPORTANT copyrights notice:
The creator of Unofficial Patch 1.5 does not allow you to re-upload UP1.5 installation files to any other server / website. If you want to share UP1.5 with your friends - please send them the link to the Official Download Page: https://ee2.eu/patch
For breaking this rule, we will be forced to send DMCA Takedown Requests.
Источник: https://www.ee2.eu/patch/

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