{"paper_id":"1601c992-fa3c-422e-9eca-efdc4d783865","body_text":"Design, fabrication and investigation of temperature-sensitive polymer microdroplets produced by the flow-focusing microchannel under the heat produced by the flexible microheater | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Design, fabrication and investigation of temperature-sensitive polymer microdroplets produced by the flow-focusing microchannel under the heat produced by the flexible microheater Amir Mahdavi, Mohsen Nazari, Majid Salehi, Niloofar Taghipour, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6580460/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract This study aimed to produce drops that can be used in wound dressings with controlled drug release for the treatment of skin disorders and chronic wounds. The lack of precise control of drug delivery to the wound area in common approaches has prompted us to design a controllable wound dressing. The dressing was designed with three main components: the drug delivery, stimulation, and control systems. A flexible microheater was fabricated by sputtering gold and gold/titanium onto a polymer substrate, aiming to stimulate microcarriers. The electrical resistance of gold and gold/titanium microheaters was measured at about 220 and 150 ohms respectively. By using the photolithography method, a microchannel focused on the flow was designed, and subsequently, NIPAM droplets were produced as a potential drug delivery system The microchannel performance assessment demonstrated consistent droplet production, allowing for the extraction of droplets measuring 360 to 515 micrometers in diameter at the outlet by modifying the flow rate ratio within the microchannel. The temperature sensitivity of the microparticles was evaluated, and a 40% decrease in droplet diameter was observed when going from 18°C ​​to 32°C. The studied drug carriers showed positive and acceptable results for use in a smart dressing, which enables stable control over the drug release rate by the heat generated in the flexible microheater Wound dressing Microparticles Drug carriers Thermoresponsive Microdroplets flow-focusing Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 1 Introduction The skin can efficiently heal cuts and injuries, but in certain disorders, the blood vessels that supply the damaged tissue are compromised(Sanjari, Hajjar et al. 2015, Choudhary, Choudhary et al. 2024). This necessitates higher doses of drugs to be administered throughout the body to achieve adequate healing. Epidermal drug delivery is an effective solution for evades many disadvantages of the oral, inhalation, and parenteral routes(Raina, Rani et al. 2023). A typical drug delivery patch must maintain contact with the skin during movement(Galiano, Tepper et al. 2004). Currently, drug and factor release strategies include ointments, hydrogels, hydrocolloids, and polymeric dressings(Gupta, Denson et al. 2012, Saghazadeh, Rinoldi et al. 2018). The dressings used to deliver these agents to wounds include hydrogels, hydrocolloids, soft silicone gel, polyurethane foam and polymeric dressings. Although passive drug delivery systems have been developed to address this need, they often Less ability to precisely regulate the release of therapeutic agents(Li, Wang et al. 2023). as it depends such as Enhanced Permeability and Retention (EPR) diffusion(Schmaljohann 2007, Li, Wang et al. 2023) Local heating of drug carriers has emerged as a promising alternative, as it has been shown to be safe for topical application and may help optimize therapeutic efficacy and reduce the incidence of systemic and local side effects(Najafabadi, Tamayol et al. 2014, Farah, Brown et al. 2019). Microfluidic systems have various applications and advantages in targeted drug delivery(Landriscina, Rosen et al. 2015). Things including accurate dose adjustment in drug delivery, drug delivery at the exact location, stable and controlled drug release, and reduction of side effects are mentioned as advantages of these systems(Bhattacharjee, Gohil et al. 2023). Among the advantages of small-scale drug carriers compared to large-scale systems, we can mention the increase in the surface-to-volume ratio in smaller dimensions(Rawas-Qalaji, Cagliani et al. 2023). This feature puts more drug in the vicinity of the surface and can accelerate the drug release rate(Rizvi and Saleh 2018). T- and Y-shaped microchannels, coaxial microchannels, and flow focusing microchannels are common types that have been used in droplet production in microfluidic systems(Zhu and Wang 2016, Raynaldo, Whulanza et al. 2024). N-isopropyl acrylamide (NIPAM) is a unique thermosensitive material that possesses the remarkable property of being hydrophilic at lower temperatures, but becoming hydrophobic above its lower critical temperature (LCST) (T ≈32°C)(Dinari, Abdollahi et al. 2021, Throat and Bhattacharya 2024). This makes it an ideal candidate for drug delivery applications, as the polymer can be modified through co-polymerization with other monomers to adjust this critical point upwards, allowing for more precise temperature-responsive behavior and enabling more controlled drug release(Weihua, Cheng et al. 2009, Throat and Bhattacharya 2024) Due to its biocompatibility, it can be used as a carrier for medicinal purposes. To generate NIAPAM Micro-particles, we used a flow-focusing device to control and adjust the size of droplets(Jafarzadeh, Peyman et al. 2024). In figure1, a schematic representation of our proposed wound dressing in controlled drug release can be observed. The goal of a novel dermal patch design was to integrate flexible heating elements that enable on-demand drug and growth factor release(Qi, Zhang et al. 2022). The patch comprises thermosensitive drug microcarriers, which allow for precise temperature-controlled delivery of these therapeutic agents. This platform could offer a significant advancement in the field of drug delivery and open up new possibilities for personalized and targeted treatment of various skin conditions(Rezvani Ghomi, Khalili et al. 2019). 2 Material and Methods 1.2 Fabrication of the Microchannel The microchannel was made by a photolithography method. A silicon wafer disk with a 2-inch diameter was washed in distilled water/acetone several times and then kept at room temperature until it dried. Then, 1 ml of SU8 as an epoxy-based negative photoresist , was poured into the center of the silicon wafer disk and kept at ambient temperature inside a vacuum chamber(Zhu, Fan et al. 2017). The chamber pressure was set at about -0.9 bar to remove the bubbles in SU8. After the spin-coating step, the photoresist was transformed into a semi-solid state under gentle heating, and then the photomask was carefully placed on the photoresist substrate. Also, by placing a 4 mm thick glass on the photomask, any movement of the photomask on the substrate was prevented. The system is then exposed to UV radiation at a power of 8 for 200 seconds(Sarkar, Nguyen et al. 2022). The UV light passes through the clear sections of the photomask, causing the photoresist to harden in those specific areas, while the remaining regions of the photoresist remain the same. In the continuation of the manufacturing process, the glass and photomask were separated from the photoresist substrate. The system was then heated at 60 °C for 3 min and the photoresist was allowed to cool and baked again at 100 °C for 20 min(Quintana, Miró et al. 2006). In the next step, the silicon wafer was placed in a glass container filled with SU-8 solvent (developer) for 5 seconds and then thoroughly washed with isopropyl alcohol solution. This process was repeated until the additional sections of su8 were completely resolved(Yun-Ju, Tseng et al. 2003). 2.2 Microparticle generation A solution was used containing 4% to 10% w/v NIPAM, 0.3% w/v BIS as a cross-linking agent, and 4% w/v Ammonium persulfate as an initiator. This solution was used as a dispersed phase in the microchannel. Also, a 20% v/v percentage of Span80 was incorporated into liquid paraffin and used as a continuous phase in the microchannel(Ramos, Magalhães et al. 2018). The microdroplet size control was done by adjusting the flow rate ratio using syringe pumps. In this process, the particle size and distance between microparticles are checked using the image processing software of an optical microscope. The droplet size was recorded as a function of the flow ratio and its graph was drawn using Excel software(Shivakumara L R, Iliger et al. 2020). 3.2 Investigation of the sensitivity of droplets to temperature In order to investigate the changes in the size of microparticles due to temperature changes, the microparticles were placed in contact with water under a digital light microscope and their temperature was controlled by a controllable hot-cooling plate. By fixing the particle size at each temperature, the particle size was obtained through image processing using microscope software. Droplet size recording was done in the heating process and in the cooling process and repeated several times(Mora, Bellack et al. 2014). 4.2 Microheater fabrication In order to make a flexible microheater, the Poly(methyl methacrylate) (PMMA) substrate was placed in the sputtering machine chamber and a steel mask with a thickness of one millimeter was placed on it. The intended mask included a zigzag cut pattern to create a suitable dispersion on the surface of the substrate. Then, the sputtering device was vacuumed by 10 -5 Torr.(Salim, Knj et al. 2015) In the next step, titanium sputtering was done under argon gas. By injecting gas into the chamber, the vacuum level of the chamber was fixed at the value of 10 -2 Torr. The plasma power in the titanium coating was set at 60 watts and 15 nm of titanium was deposited on the substrate(Li, Pace et al. 2018). Then, 200 nm of gold was deposited on titanium with 30 watts of plasma power. Also, silver conductive glue was used to connect the wires to the microheater. This process was used for both polydimethylsiloxane ( PDMS) & PMMA substrates. The microheaters fabrication process was done once without considering the titanium and only with the gold layer on both substrates(Tippo, Thanachayanont et al. 2013). 3 Results and discussions 1.3 Impact of Spin Coating Speed on SU8 Layer Thickness in Microfluidics In this study, a microfluidic system was used to produce polymer microparticles. The microchannel was fabricated using the photolithography method and NIPAM microdroplets were produced using it. Photolithography was done by spin-coating SU8 as a negative photoresist on the surface of the silicon wafer disk in two stages. As shown in Table 1 , increasing the speed of the spin coater results in a thinner layer of SU8 on the disc. Table 1 Velocity, acceleration, and time values in each step of photoresist spin coating on silicone disc wafer step Acceleration (rpm/s) Velocity (rpm) Duration (s) 1 100 500 20 2 300 2100 30 2.3 Microfluidics flow components: The first step in the process of producing temperature-sensitive microdrops is to create a highly purified solution of NIPAM. Recrystallization method was done to purify NIPAM by using an equal mixture of hexane and acetone. Then an aqueous mixture of NIPAM, N,N′-Methylenebisacrylamide (BIS) and ammonium persulfate was used as a dispersed flow of polymer fluid in a microchannel. In Table 2, the weight to volume percentage of the materials used in the aqueous polymer solution is specified Table 2 Weight-to-volume percentage of triple-distilled water as dispersed flow phase NO. Solution NIPAM % BIS % Ammonium persulfate % 1 4% NIPAM 4 % 0.3 % 4 % 2 10% NIPAM 10 % 0.3 % 4 % To create a uniform solution, the mixture was exposed to 75-watt ultrasonic vibrations for one minute using a probe. Great care was taken to keep the solution temperature below 4°C during this process to avoid premature activation of the initiator, which can occur at temperatures above 25°C. (In this case, an ice water bath was used). In addition to the preparation of the microfluidic solution, the dispersed flow phase was also synthesized, which is an essential component of the microchannel. To enhance the interaction between the NIPAM droplets and the continuous phase of the microchannel, 20% v/v percentage of Span-80 was incorporated into liquid paraffin. Span-80, a surfactant, modifies the surface tension of the continuous phase, allowing for improved connection of the NIPAM droplets and enabling a more efficient microfluidic system. 3.3 Microheater fabrication: To create a flexible microheater, two transparent and flexible substrates were gold-coated using a sputtering method. Substrate selection proved to be crucial in microheater fabrication, with PDMS and PMMA identified as suitable materials due to their desirable transparency and flexibility characteristics. The sputtering process on both substrates was also done once using titanium and gold and another time using only gold to check different conditions. The fabrication processes and quality control measures for substrates were thoroughly evaluated and analyzed. 4.3 PDMS substrate creation process: A mixture of 3 mL PDMS and 0.3 mL hardener was thoroughly blended within a beaker before being subjected to a vacuum chamber at 0.9 bar for 5 minutes. The solution was then poured onto the center of a well-cleaned 4x4 mm, 3 mm thick glass, previously washed with acetone and distilled water. To achieve even distribution, the glass was placed on a spin coater for 2 minutes at 800 rpm. Subsequent heating on a hot plate at 80 °C for 30 min initiated the hardening of the PDMS. The resulting substrate showed proper transparency and flexibility for use in microheater fabrication. 5.3 PMMA substrate creation process: A 10% weight-to-volume ratio of PMMA powder was dissolved in chlorobenzene, gradually polymerizing over time. The low viscosity of the solution necessitated a low-speed spin coating process to achieve a thin layer formation on the glass substrate. Consequently, the PMMA solution was left at room temperature for 6 hours, allowing viscosity to increase, followed by spin coating at 1000 rpm for 2 minutes. The glass substrate was then heated on a hot plate for 30 minutes at 80°C. Qualitative assessments indicated that the PMMA substrate exhibited higher optical transparency compared to the PDMS substrate, although its elastic properties were significantly lower. However, considering the drug delivery system's non-elasticity requirements, the PMMA low elasticity did not impose limitations on its application. The physical attributes of the PMMA substrate were also found to be suitable for use in microheater fabrication. 6.3 Microdroplet Producing Process: To generate microdroplets using the fabricated microchannel, NIPAM and oil solutions were loaded into separate 2.5 mL and 20 mL syringes, respectively. Then the syringes were placed in separate syringe pumps to control the flow of each phase separately. Upon connecting the pumps to the microchannel, NIPAM, and oil solutions were flowed at rates of 0.3 mL/h and 2.1 mL/h, respectively, successfully producing NIPAM microdroplets. Throughout the droplet production process, the flow ratio of the droplet phase fluid to the oil phase fluid varied between 14% and 84%. Considering the importance of preventing the polymerization of the polymer fluid before entering the microchannel as well as changes in viscosity, it is important to keep the syringe at a low temperature. Therefore, according to Figure 3, a chamber made with a 3D printer was used to circulate cold water around the syringe shell to ensure its low temperature. The final step in fabricating the microchannel mold involves removing any excess material using developer solvent, and allowing the photoresist to harden by placing the system on a hot plate at 150°C for 30 minutes. This process results in the creation of a relief design on the silicon wafer, finishing the fabrication of the microchannel mold. Two separate inlets on the microchannel are considered for the entry of 2 immiscible fluids. One was used for continuous flow, while the other was considered for dispersed flow. Both streams were then collected from the outlet of the microchannel and placed into a petri dish. A digital microscope image processing software was employed to ascertain the diameter of the generated droplets. Figure 4 presents images of droplets being produced at various flow rates captured by the digital microscope, While Figure 5 illustrates a diagram of droplet diameter relative to the flow rate ratio. Additionally, Figure 5 showcases the variation in the center-to-center distance between consecutive droplets at the microchannel outlet as a function of the flow rate ratio. The results indicated that increasing the flow rate ratio in both 4% and 10% NIPAM solutions led to an increase in droplet diameter. However, the diameter increase rate for a 10% NIPAM solution tended towards zero when the flow rate ratio exceeded 0.4. According to Diagrame. 1 , the center-to-center distance between droplets decreased with increasing flow ratio to 10% NIPAM(Mashiyama, Hemmi et al. 2024). This distance increase can be attributed to a limitation imposed by the rising droplet diameter. In essence, higher flow rates result in larger droplets, subsequently increasing the center-to-center distance. The results indicated that increasing the flow rate ratio in both 4% and 10% NIPAM solutions led to an increase in droplet diameter. However, the diameter increase rate for 10% NIPAM solution tended towards zero when the flow rate ratio exceeded 0.4. According to Diagrame.2, the center-to-center distance between droplets decreased with increasing flow ratio for 10% NIPAM. This distance increase can be attributed to a limitation imposed by the rising droplet diameter. In essence, higher flow rates resulted in larger droplets, subsequently increasing the center-to-center distance. Further experimentation and analysis revealed that the constant diameter observed at high flow rates in 10% NIPAM droplets was due to the high NIPAM concentration. The elevated NIPAM concentration decreased fluidity, causing the droplet phase to assume a quasi-solid state, leading to a distinct behavior compared to low-concentration solutions. Additional observations and studies demonstrated that since droplets produced at the microchannel outlet were not polymerized, and instead underwent polymerization after extraction into a glass container, the proximity between droplets could cause collisions. These collisions might lead to the formation of larger droplets, thus affecting droplet size uniformity. 7.3 Microdroplet Characterization: During the characterization process, it was observed that 4% NIPAM droplets did not polymerize effectively over time, retaining their initial form. In contrast, 10% NIPAM microdroplets exhibited complete polymerization at a consistent temperature of 25 degrees Celsius. As polymerization progressed which showed in Figure.8, the microdroplets transitioned to a semi-solid state, with their color evolving from an initially transparent and colorless appearance to white. Following polymerization and thorough rinsing with double distilled water, the particles were placed in a container of double-distilled water at 4 degrees Celsius for 1 hour. Diagram 3, depicts a diagram of droplet diameter as a function of temperature. According to the data, increasing temperatures led to a decrease in droplet diameter, with a higher rate of diameter change occurring at 21 degrees and subsequently decreasing at 26 degrees. The findings demonstrate that an increase in temperature can result in up to a 46% reduction in droplet diameter compared to the initial state. Additionally, a hysteresis property was observed when the temperature was lowered again, highlighting the reversible behavior of the droplets. 8.3 Flexible Microheater Characterization: Characterization of the flexible microheaters revealed that the conductivity of the microheater constructed on the PDMS substrate was nearly zero, preventing the passage of electric current. The resistance values of microheaters fabricated in PMMA were measured to be 223 and 150 Ohms for cases without a middle layer and with titanium as the middle layer, respectively. Investigations into the cause of PDMS conductivity indicated that gold pattern conductivity on PDMS could be attributed to the material's elasticity and porosity. Since thin PDMS layers exhibit high elasticity, gold particle connections may be disrupted due to surface stretching, significantly reducing conductivity. Furthermore, the potential presence of porosity on the PDMS surface may also contribute to this effect. In contrast, the PMMA substrate's low elasticity minimizes the occurrence of macroscopic stretching on its surface. In Figure.7, to evaluate the response of the gold-titanium microheater to the electric field, two wires have been connected to the microheater through conductive silver ink. In Figure.8 by applying a 5-volt electric potential difference, temperature values were recorded as a function of time, enabling the analysis of the microheater's thermal behavior and responsiveness to electrical input. To assess the temperature distribution across the microheater's surface, thermal images were captured at various time intervals using an infrared camera to illustrate the microheater's temperature distribution over time. The data show that over time, the heat generated in the conductive pattern spreads across the surface, resulting in a more uniform temperature distribution throughout the microheater To use temperature-sensitive microdroplets as a wound dressing, it is crucial to incorporate them into a suitable matrix. For this purpose, the development of a flexible hydrogel coating was considered to encapsulate the microdroplet collection while maintaining the moisture levels of the wound surface. The hydrogel's ability to retain moisture and adapt to the wound bed ensures an optimal environment for promoting wound healing while harnessing the benefits of temperature-sensitive microdroplets. 9.3 Control System Design: To manage and control the microheater's operation, an ATMEGA328_DIP microcontroller was employed. The electronic circuit was designed to facilitate connections with various components, including the power supply, NTC temperature sensor, temperature adjustment keys, a 16×2-character display, and the flexible microheater. This design enabled monitoring and regulation of the microheater's temperature, ensuring optimal performance and accurate control over drug release from the delivery system. As depicted in Figure.9, the capacitor's role in dampening voltage fluctuations contributed to stable voltage measurements. This, in turn, enabled accurate recording of temperature values, which is crucial for precise control over the microheater's operation within the drug delivery system. 4 Discussion and Conclusion The microchannel characterization demonstrated its suitability for generating uniform microdroplets using a concentrating flow technique. By employing 10% NIPAM as the dispersed phase and liquid paraffin as the continuous phase, consistent droplet sizes were achieved. As the flow rate ratio of the dispersed to continuous phase increased from 0.14 to 0.84, a corresponding rise in droplet diameter was observed, ranging from approximately 360 to 515 micrometers. The polymerized NIPAM microdroplets exhibited a notable response to temperature changes during the characterization stage. By applying controlled heat, the temperature sensitivity of the microdroplets was investigated, revealing a maximum 40% decrease in droplet diameter as the temperature increased from 18 to 32 °C. Remarkably, this diameter change proved to be reversible, with droplet size increasing upon temperature reduction when placed near water. This reversible behavior, indicative of drug diffusion and absorption, suggests that the controllable hydrophilic and hydrophobic properties of the microdroplets at varying temperatures can be effectively utilized in the proposed wound dressing application. The favorable behavior of temperature-sensitive droplets in this study can lead to facilitating the acquisition and production of innovative wound dressings with appropriate controllability of drug release. The proposed dressing's behavior aligns with the controllable nature of the microdroplets. However, the mechanical structure and inherent challenges of the assembly precluded in vitro testing of the wound dressing, necessitating further advancement to fully assess its potential. The characterization of the fabricated flexible microheater revealed that the PDMS substrate was unsuitable due to its high elasticity and surface porosity, which led to poor electrical conductivity. This challenge prevented the development of a microheater using PDMS. In contrast, the PMMA substrate demonstrated good electrical conductivity, with the addition of a 15 nm titanium middle layer further reducing electrical resistance. Consequently, the gold-titanium microheater proved to be a suitable stimulus for the drug delivery system. Characterization of the microheater showed that applying a 5-volt potential at ambient temperature resulted in a stable temperature state within 15 seconds, and the temperature distribution on its surface was appropriate. This uniform temperature distribution can facilitate a more controlled and uniform release of microdroplets. Declarations Author Contribution In a research paper submitted, the first author is a PhD student and is responsible for selecting the topic, designing the experiment, and writing the paper. His supervisor is the corresponding author, or the second author, who is the scientific supervisor and scientific and theoretical guide of the project. The third author helped in selecting materials and designing the experiment. The fourth author is responsible for conducting the experiment and writing the scientific paper. 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Fan, H. Huang and F. Duan (2017). \"Coalescence of droplets on micro-structure patterned hydrophobic planar solid surfaces.\" RSC Adv. 7: 23954-23960. Zhu, P. and L. Wang (2016). \"Passive and active droplet generation with microfluidics: a review.\" Lab Chip 17: 34-75. Additional Declarations No competing interests reported. Supplementary Files Diagrams.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-6580460\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":473302950,\"identity\":\"7e52751d-f68d-49e4-813e-c3a3831aeaa9\",\"order_by\":0,\"name\":\"Amir Mahdavi\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Shahrood University of Technology\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Amir\",\"middleName\":\"\",\"lastName\":\"Mahdavi\",\"suffix\":\"\"},{\"id\":473302951,\"identity\":\"775379ce-d498-433c-807e-c6c5fa2df6a2\",\"order_by\":1,\"name\":\"Mohsen Nazari\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIiWNgGAWjYPACCTkGCQY2EIuxASpCUIsxQgsbcVoYEhvQtOAGurObH3/4ucciff7s5mePKypsZDfcb2D88IPBIh+XFrM7xwwMe55J5G64c8zc8MyZNOMNxxiYJXsYJCwbcGm5kWCQwHMAqEUiwUyyse1wIlALgzTQLwY4bbmR/uHgnwMS6fIz0r/BtDD/xq8lx7AZaEsCw40cuC1sBGzJKWaWOSBhuOFGTplkA9AvM48ltln2GOB12OaPbw7UyQMdtk2yARhifYcPH77xo6IOpxZsAJQASNIwCkbBKBgFowAdAAAAS1bSnQ/RGAAAAABJRU5ErkJggg==\",\"orcid\":\"\",\"institution\":\"Shahrood University of Technology\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Mohsen\",\"middleName\":\"\",\"lastName\":\"Nazari\",\"suffix\":\"\"},{\"id\":473302952,\"identity\":\"03bc135f-d134-430e-b25d-e8547450bd8b\",\"order_by\":2,\"name\":\"Majid Salehi\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Shahrood University of Medical Sciences\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Majid\",\"middleName\":\"\",\"lastName\":\"Salehi\",\"suffix\":\"\"},{\"id\":473302953,\"identity\":\"f91b8479-4d8a-4d85-9fa5-1c51638f8cca\",\"order_by\":3,\"name\":\"Niloofar Taghipour\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Shahid Beheshti University of Medical Sciences\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Niloofar\",\"middleName\":\"\",\"lastName\":\"Taghipour\",\"suffix\":\"\"},{\"id\":473302954,\"identity\":\"e6fb8156-5a89-4b15-afca-f38ac34fc3d8\",\"order_by\":4,\"name\":\"zahra mohammadi\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Bojnord University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"zahra\",\"middleName\":\"\",\"lastName\":\"mohammadi\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2025-05-02 18:53:14\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-6580460/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-6580460/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":85077580,\"identity\":\"f791ac17-2b38-4a01-b440-5604845ed22c\",\"added_by\":\"auto\",\"created_at\":\"2025-06-20 16:58:20\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":263673,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eSchematic of the proposed wound dressing\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6580460/v1/f18fc83bb3857bb446109401.png\"},{\"id\":85077587,\"identity\":\"adb41777-acf3-4483-81db-ddda68fadf1d\",\"added_by\":\"auto\",\"created_at\":\"2025-06-20 16:58:20\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":480030,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eThe fabricated flow-focusing microchannel\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6580460/v1/66c6017afb92a2b223628963.png\"},{\"id\":85078111,\"identity\":\"7cc3716c-1394-40d4-acd1-caeaedd9b90f\",\"added_by\":\"auto\",\"created_at\":\"2025-06-20 17:06:20\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":209243,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eThe chamber made by 3D printing method to keep the polymer fluid temperature low inside the syringe\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6580460/v1/7bf93ab1460128da36767af4.png\"},{\"id\":85078969,\"identity\":\"54354b2b-d49b-490e-aa84-c2e7537e5c53\",\"added_by\":\"auto\",\"created_at\":\"2025-06-20 17:14:20\",\"extension\":\"png\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":327757,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eOnline checking the droplet size using a digital optical microscope\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"4.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6580460/v1/04feff747d0a7cfa3dc64706.png\"},{\"id\":85077584,\"identity\":\"4c38edec-c3a2-4881-8708-962d96cb73a7\",\"added_by\":\"auto\",\"created_at\":\"2025-06-20 16:58:20\",\"extension\":\"png\",\"order_by\":5,\"title\":\"Figure 5\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":588304,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eMicroscopic images of microdroplets producing 4% NIPAM in the outlet of the microchannel (the flow rate specified by the Qr parameter. Also, the parameters D and S are the diameter of the produced drops)\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"5.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6580460/v1/a3429a26041aa80b0de06a46.png\"},{\"id\":85078115,\"identity\":\"7db32515-b3cb-411b-bba5-73901b4376b6\",\"added_by\":\"auto\",\"created_at\":\"2025-06-20 17:06:20\",\"extension\":\"png\",\"order_by\":6,\"title\":\"Figure 6\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":614831,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eOptical microscope image of the produced microdroplets before and after polymerization\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"6.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6580460/v1/677bb1c57a13e2428a44befd.png\"},{\"id\":85077592,\"identity\":\"0151a959-1437-48c7-9747-dd548eab86b0\",\"added_by\":\"auto\",\"created_at\":\"2025-06-20 16:58:20\",\"extension\":\"png\",\"order_by\":7,\"title\":\"Figure 7\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":211702,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eThe completed flexible microheater\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"7.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6580460/v1/7a6b901194e4a6536662f0ab.png\"},{\"id\":85077595,\"identity\":\"d49cd500-06f1-4fd9-b4a7-786804f071cb\",\"added_by\":\"auto\",\"created_at\":\"2025-06-20 16:58:20\",\"extension\":\"png\",\"order_by\":8,\"title\":\"Figure 8\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":844312,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eThermal images of titanium gold microheater by applying 5 V electric potential\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"8.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6580460/v1/27abafb0d0dd3679e2fbd9c2.png\"},{\"id\":85078970,\"identity\":\"eae24bd4-818d-4616-84e2-3763e56968c3\",\"added_by\":\"auto\",\"created_at\":\"2025-06-20 17:14:20\",\"extension\":\"png\",\"order_by\":9,\"title\":\"Figure 9\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":60883,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eThe schematic of the circuit that enables the connection of the NTC temperature sensor to the microcontroller\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"9.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6580460/v1/46a3a19a06ef3eedd6932cb3.png\"},{\"id\":86615354,\"identity\":\"f66df18f-5346-4be9-95e8-92cca76dff1e\",\"added_by\":\"auto\",\"created_at\":\"2025-07-14 00:16:30\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":4940788,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6580460/v1/e541e32f-91a2-4996-9de5-f830f99934a5.pdf\"},{\"id\":85077581,\"identity\":\"d8d17d59-2ec4-4d2d-b5ef-00932035f7f6\",\"added_by\":\"auto\",\"created_at\":\"2025-06-20 16:58:20\",\"extension\":\"docx\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":145108,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Diagrams.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6580460/v1/0e57986c46d7f407f3e0b4fe.docx\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Design, fabrication and investigation of temperature-sensitive polymer microdroplets produced by the flow-focusing microchannel under the heat produced by the flexible microheater\",\"fulltext\":[{\"header\":\"1 Introduction\",\"content\":\"\\u003cp\\u003eThe skin can efficiently heal cuts and injuries, but in certain disorders, the blood vessels that supply the damaged tissue are compromised(Sanjari, Hajjar et al. 2015, Choudhary, Choudhary et al. 2024). This necessitates higher doses of drugs to be administered throughout the body to achieve adequate healing. Epidermal drug delivery is an effective solution for evades many disadvantages of the oral, inhalation, and parenteral routes(Raina, Rani et al. 2023). A typical drug delivery patch must maintain contact with the skin during movement(Galiano, Tepper et al. 2004). Currently, drug and factor release strategies include ointments, hydrogels, hydrocolloids, and polymeric dressings(Gupta, Denson et al. 2012, Saghazadeh, Rinoldi et al. 2018).\\u0026nbsp;The dressings used to deliver these agents to wounds include hydrogels, hydrocolloids, soft silicone gel, polyurethane foam and polymeric dressings.\\u0026nbsp;Although passive drug delivery systems have been developed to address this need, they often Less ability to precisely regulate the release of therapeutic agents(Li, Wang et al. 2023). as it depends \\u0026nbsp; such as \\u0026nbsp;Enhanced Permeability and Retention (EPR) \\u0026nbsp;diffusion(Schmaljohann 2007, Li, Wang et al. 2023)\\u0026nbsp;Local heating of drug carriers has emerged as a promising alternative, as it has been shown to be safe for topical application and may help optimize therapeutic efficacy and reduce the incidence of systemic and local side effects(Najafabadi, Tamayol et al. 2014, Farah, Brown et al. 2019).\\u0026nbsp;Microfluidic systems have various applications and advantages in targeted drug delivery(Landriscina, Rosen et al. 2015). Things including accurate dose adjustment in drug delivery, drug delivery at the exact location, stable and controlled drug release, and reduction of side effects are mentioned as advantages of these systems(Bhattacharjee, Gohil et al. 2023). \\u0026nbsp;Among the advantages of small-scale drug carriers compared to large-scale systems, we can mention the increase in the surface-to-volume ratio in smaller dimensions(Rawas-Qalaji, Cagliani et al. 2023). This feature puts more drug in the vicinity of the surface and can accelerate the drug release rate(Rizvi and Saleh 2018). T- and Y-shaped microchannels, coaxial microchannels, and flow focusing microchannels are common types that have been used in droplet production in microfluidic systems(Zhu and Wang 2016, Raynaldo, Whulanza et al. 2024).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eN-isopropyl acrylamide (NIPAM) is a unique thermosensitive material that possesses the remarkable property of being hydrophilic at lower temperatures, but becoming hydrophobic above its\\u0026nbsp;\\u003cem\\u003elower critical temperature\\u003c/em\\u003e (LCST)\\u0026nbsp;(T ≈32°C)(Dinari, Abdollahi et al. 2021, Throat and Bhattacharya 2024).\\u0026nbsp;This makes it an ideal candidate for drug delivery applications, as the polymer can be modified through co-polymerization with other monomers to adjust this critical point upwards, allowing for more precise temperature-responsive behavior and enabling more controlled drug release(Weihua, Cheng et al. 2009, Throat and Bhattacharya 2024)\\u0026nbsp;Due to its biocompatibility, it can be used as a carrier for medicinal purposes. To generate NIAPAM Micro-particles, we used a flow-focusing device to control and adjust the size of droplets(Jafarzadeh, Peyman et al. 2024). In figure1, a schematic representation of our proposed wound\\u0026nbsp;dressing in\\u0026nbsp;controlled drug release can be observed. The goal of a novel dermal patch design was to integrate flexible heating elements that enable on-demand drug and growth factor release(Qi, Zhang et al. 2022). The patch comprises thermosensitive drug microcarriers, which allow for precise temperature-controlled delivery of these therapeutic agents. This platform could offer a significant advancement in the field of drug delivery and open up new possibilities for personalized and targeted treatment of various skin conditions(Rezvani Ghomi, Khalili et al. 2019).\\u003c/p\\u003e\"},{\"header\":\"2 Material and Methods\",\"content\":\"\\u003cp\\u003e1.2\\u0026nbsp; Fabrication of the Microchannel\\u003c/p\\u003e\\n\\u003cp\\u003eThe microchannel was made by a photolithography method. A silicon wafer disk with a 2-inch diameter was washed in\\u0026nbsp;distilled\\u0026nbsp;water/acetone several times and then kept at room temperature until it dried. Then, 1 ml of SU8 as\\u0026nbsp;an epoxy-based \\u003cem\\u003enegative photoresist\\u003c/em\\u003e, was poured into the center of the silicon wafer disk and kept at ambient temperature inside a vacuum chamber(Zhu, Fan et al. 2017). The chamber pressure was set at about -0.9 bar to remove the bubbles in SU8. After the spin-coating step, the photoresist was transformed into a semi-solid state under gentle heating, and then the photomask was carefully placed on the photoresist substrate. Also, by placing a 4 mm thick glass on the photomask, any movement of the photomask on the substrate was prevented. The system is then exposed to UV radiation at a power of 8\\u0026nbsp;\\u003cimg src=\\\"data:image/png;base64,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\\\" style=\\\"width: 63px; height: 28.4268px;\\\" width=\\\"63\\\" height=\\\"28.4268\\\"\\u003e\\u0026nbsp;for 200 seconds(Sarkar, Nguyen et al. 2022). The UV light passes through the clear sections of the photomask, causing the photoresist to harden in those specific areas, while the remaining regions of the photoresist remain the same. In the continuation of the manufacturing process, the glass and photomask were separated from the photoresist substrate. The system was then heated at 60 \\u0026deg;C for 3 min and the photoresist was allowed to cool and baked again at 100 \\u0026deg;C for 20 min(Quintana, Mir\\u0026oacute; et al. 2006). In the next step, the silicon wafer was placed in a glass container filled with SU-8 solvent (developer) for 5 seconds and then thoroughly washed with isopropyl alcohol solution. This process was repeated until the additional sections of su8 were completely resolved(Yun-Ju, Tseng et al. 2003).\\u003c/p\\u003e\\n\\u003cp\\u003e2.2\\u0026nbsp;Microparticle generation\\u003c/p\\u003e\\n\\u003cp\\u003eA solution was used containing 4% to 10% w/v NIPAM, 0.3% w/v BIS as a cross-linking agent, and 4% w/v Ammonium persulfate as an initiator. This solution was used as a dispersed phase in the microchannel. Also, a 20% v/v percentage of Span80 was incorporated into liquid paraffin and used as a continuous phase in the microchannel(Ramos, Magalh\\u0026atilde;es et al. 2018). The microdroplet size control was done by adjusting the flow rate ratio using syringe pumps. In this process, the particle size and distance between microparticles are checked using the image processing software of an optical microscope. The droplet size was recorded as a function of the flow ratio and its graph was drawn using Excel software(Shivakumara L R, Iliger et al. 2020).\\u003c/p\\u003e\\n\\u003cp\\u003e3.2\\u0026nbsp;Investigation of the sensitivity of droplets to temperature\\u003c/p\\u003e\\n\\u003cp\\u003eIn order to investigate the changes in the size of microparticles due to temperature changes, the microparticles were placed in contact with water under a digital light microscope and their temperature was controlled by a controllable hot-cooling plate. By fixing the particle size at each temperature, the particle size was obtained through image processing using microscope software. Droplet size recording was done in the heating process and in the cooling process and repeated several times(Mora, Bellack et al. 2014).\\u003c/p\\u003e\\n\\u003cp\\u003e4.2\\u0026nbsp;Microheater fabrication\\u003c/p\\u003e\\n\\u003cp\\u003eIn order to make a flexible microheater, the Poly(methyl methacrylate) (PMMA) substrate was placed in the sputtering machine chamber and a steel mask with a thickness of one millimeter was placed on it. The intended mask included a zigzag cut pattern to create a suitable dispersion on the surface of the substrate. Then, the sputtering device was vacuumed by 10\\u003csup\\u003e-5\\u003c/sup\\u003e Torr.(Salim, Knj et al. 2015) In the next step, titanium sputtering was done under argon gas. By injecting gas\\u0026nbsp;into\\u0026nbsp;the chamber, the vacuum level of the chamber was fixed at the value of 10\\u003csup\\u003e-2\\u003c/sup\\u003e Torr. The plasma power in the titanium coating was set at 60 watts and 15 nm of titanium was deposited on the substrate(Li, Pace et al. 2018). Then, 200 nm of gold was deposited on titanium with 30 watts of plasma power. Also,\\u0026nbsp;silver conductive glue was used to connect the wires to the microheater. This process was used for both\\u0026nbsp;polydimethylsiloxane (\\u003cem\\u003ePDMS)\\u003c/em\\u003e \\u0026amp; PMMA substrates. The microheaters fabrication process was done once without considering the titanium and only with the gold layer on both substrates(Tippo, Thanachayanont et al. 2013).\\u003c/p\\u003e\"},{\"header\":\"3 Results and discussions \",\"content\":\"\\u003cp\\u003e1.3\\u0026nbsp;Impact of Spin Coating Speed on SU8 Layer Thickness in Microfluidics\\u003c/p\\u003e\\n\\u003cp\\u003eIn this study, a microfluidic system was used to produce polymer microparticles. The microchannel was fabricated using the photolithography method and NIPAM microdroplets\\u0026nbsp;were produced using\\u0026nbsp;it. Photolithography was done by spin-coating SU8 as a negative photoresist on the surface of the silicon wafer disk in two stages. As shown in Table 1 , increasing the speed of the spin coater results in a thinner layer of SU8 on the disc.\\u003c/p\\u003e\\n\\u003cp\\u003eTable 1 Velocity, acceleration, and time values in each step of photoresist spin coating on silicone disc wafer\\u003c/p\\u003e\\n\\u003ctable border=\\\"0\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 8.44444%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003estep\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 38.2222%;\\\"\\u003e\\n \\u003cp\\u003eAcceleration (rpm/s)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 22.6667%;\\\"\\u003e\\n \\u003cp\\u003eVelocity (rpm)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 30.6667%;\\\"\\u003e\\n \\u003cp\\u003eDuration (s)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 8.44444%;\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 38.2222%;\\\"\\u003e\\n \\u003cp\\u003e100\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 22.6667%;\\\"\\u003e\\n \\u003cp\\u003e500\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 30.6667%;\\\"\\u003e\\n \\u003cp\\u003e20\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 8.44444%;\\\"\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 38.2222%;\\\"\\u003e\\n \\u003cp\\u003e300\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 22.6667%;\\\"\\u003e\\n \\u003cp\\u003e2100\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 30.6667%;\\\"\\u003e\\n \\u003cp\\u003e30\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003e2.3\\u0026nbsp;Microfluidics flow components:\\u003c/p\\u003e\\n\\u003cp\\u003eThe first step in the process of producing temperature-sensitive microdrops is to create a highly purified solution of NIPAM. Recrystallization method was done to purify NIPAM by using an equal mixture of hexane and acetone. Then an aqueous mixture of NIPAM, N,N\\u0026prime;-Methylenebisacrylamide (BIS) and ammonium persulfate was used as a dispersed flow of polymer fluid in a microchannel. In Table 2, the weight to volume percentage of the materials used in the aqueous polymer solution is specified\\u003c/p\\u003e\\n\\u003cp\\u003eTable 2 Weight-to-volume percentage of triple-distilled water as dispersed flow phase\\u003c/p\\u003e\\n\\u003ctable border=\\\"0\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"666\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15.3153%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eNO.\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 24.3243%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eSolution\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17.1171%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eNIPAM %\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 13.5135%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eBIS %\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 29.7297%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003eAmmonium persulfate %\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15.3153%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003e1\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 24.3243%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003e4% NIPAM\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17.1171%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003e4 %\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 13.5135%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003e0.3 \\u0026nbsp; \\u0026nbsp;%\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 29.7297%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003e4 %\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 15.3153%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003e2\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 24.3243%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003e10% NIPAM\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 17.1171%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003e10 %\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 13.5135%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003e0.3 \\u0026nbsp; \\u0026nbsp;%\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 29.7297%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003e4 %\\u003c/em\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003eTo create a uniform solution, the mixture was exposed to 75-watt ultrasonic vibrations for one minute using a probe. Great care was taken to keep the solution temperature below 4\\u0026deg;C during this process to avoid premature activation of the initiator, which can occur at temperatures above 25\\u0026deg;C. (In this case, an ice water bath was used). In addition to the preparation of the microfluidic solution, the dispersed flow phase was also synthesized, which is an essential component of the microchannel. To enhance the interaction between the NIPAM droplets and the continuous phase of the microchannel, 20% v/v percentage of Span-80 was incorporated into liquid paraffin. Span-80, a surfactant, modifies the surface tension of the continuous phase, allowing for improved connection of the NIPAM droplets and enabling a more efficient microfluidic system.\\u003c/p\\u003e\\n\\u003cp\\u003e3.3\\u0026nbsp;Microheater fabrication:\\u003c/p\\u003e\\n\\u003cp\\u003eTo create a flexible microheater, two transparent and flexible substrates were gold-coated using a sputtering method. Substrate selection proved to be crucial in microheater fabrication, with PDMS and PMMA identified as suitable materials due to their desirable transparency and flexibility characteristics. The sputtering process on both substrates was also done once using titanium and gold and another time using only gold to check different conditions. The fabrication processes and quality control measures for substrates were thoroughly evaluated and analyzed.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e4.3\\u0026nbsp;PDMS substrate creation process:\\u003c/p\\u003e\\n\\u003cp\\u003eA mixture of 3 mL PDMS and 0.3 mL hardener was thoroughly blended within a beaker before being subjected to a vacuum chamber at 0.9 bar for 5 minutes. The solution was then poured onto the center of a well-cleaned 4x4 mm, 3 mm thick glass, previously washed with acetone and distilled water. To achieve even distribution, the glass was placed on a spin coater for 2 minutes at 800 rpm. Subsequent heating on a hot plate at 80 \\u0026deg;C for 30 min initiated the hardening of the PDMS.\\u003cspan dir=\\\"RTL\\\"\\u003e\\u0026nbsp;\\u003c/span\\u003eThe resulting substrate showed proper transparency and flexibility for use in microheater fabrication.\\u003c/p\\u003e\\n\\u003cp\\u003e5.3\\u0026nbsp;PMMA substrate creation process:\\u003c/p\\u003e\\n\\u003cp\\u003eA 10% weight-to-volume ratio of PMMA powder was dissolved in chlorobenzene, gradually polymerizing over time. The low viscosity of the solution necessitated a low-speed spin coating process to achieve a thin layer formation on the glass substrate. Consequently, the PMMA solution was left at room temperature for 6 hours, allowing viscosity to increase, followed by spin coating at 1000 rpm for 2 minutes. The glass substrate was then heated on a hot plate for 30 minutes at 80\\u0026deg;C.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eQualitative assessments indicated that the PMMA substrate exhibited higher optical transparency compared to the PDMS substrate, although its elastic properties were significantly lower. However, considering the drug delivery system\\u0026apos;s non-elasticity requirements, the PMMA low elasticity did not impose limitations on its application. The physical attributes of the PMMA substrate were also found to be suitable for use in microheater fabrication.\\u003c/p\\u003e\\n\\u003cp\\u003e6.3\\u0026nbsp;Microdroplet Producing Process:\\u003c/p\\u003e\\n\\u003cp\\u003eTo generate microdroplets using the fabricated microchannel, NIPAM and oil solutions were loaded into separate 2.5 mL and 20 mL syringes, respectively. Then the syringes were placed in separate syringe pumps to control the flow of each phase separately. Upon connecting the pumps to the microchannel, NIPAM, and oil solutions were flowed at rates of 0.3 mL/h and 2.1 mL/h, respectively, successfully producing NIPAM microdroplets. Throughout the droplet production process, the flow ratio of the droplet phase fluid to the oil phase fluid varied between 14% and 84%. Considering the importance of preventing the polymerization of the polymer fluid before entering the microchannel as well as changes in viscosity, it is important to keep the syringe at a low temperature. Therefore, according to Figure 3, a chamber made with a 3D printer was used to circulate cold water around the syringe shell to ensure its low temperature.\\u003c/p\\u003e\\n\\u003cp\\u003eThe final step in fabricating the microchannel mold involves removing any excess material using developer solvent, and allowing the photoresist to harden by placing the system on a hot plate at 150\\u0026deg;C for 30 minutes. This process results in the creation of a relief design on the silicon wafer, finishing the fabrication of the microchannel mold. Two separate inlets on the microchannel are considered for the entry of 2 immiscible fluids. One was used for continuous flow, while the other was considered for dispersed flow. Both streams were then collected from the outlet of the microchannel and placed into a petri dish.\\u003c/p\\u003e\\n\\u003cp\\u003eA digital microscope image processing software was employed to ascertain the diameter of the generated droplets. Figure 4\\u003cspan dir=\\\"RTL\\\"\\u003e\\u0026nbsp;\\u003c/span\\u003epresents images of droplets being produced at various flow rates captured by the digital microscope, While Figure 5 illustrates a diagram of droplet diameter relative to the flow rate ratio. Additionally, Figure 5 showcases the variation in the center-to-center distance between consecutive droplets at the microchannel outlet as a function of the flow rate ratio.\\u003c/p\\u003e\\n\\u003cp\\u003eThe results indicated that increasing the flow rate ratio in both 4% and 10% NIPAM solutions led to an increase in droplet diameter. However, the diameter increase rate for a 10% NIPAM solution tended towards zero when the flow rate ratio exceeded 0.4. According to Diagrame.\\u003cspan dir=\\\"RTL\\\"\\u003e1\\u003c/span\\u003e, the center-to-center distance between droplets decreased with increasing flow ratio to 10% NIPAM(Mashiyama, Hemmi et al. 2024). This distance increase can be attributed to a limitation imposed by the rising droplet diameter. In essence, higher flow rates result in larger droplets, subsequently increasing the center-to-center distance.\\u003c/p\\u003e\\n\\u003cp\\u003eThe results indicated that increasing the flow rate ratio in both 4% and 10% NIPAM solutions led to an increase in droplet diameter. However, the diameter increase rate for 10% NIPAM solution tended towards zero when the flow rate ratio exceeded 0.4. According to Diagrame.2, the center-to-center distance between droplets decreased with increasing flow ratio for 10% NIPAM. This distance increase can be attributed to a limitation imposed by the rising droplet diameter. In essence, higher flow rates resulted in larger droplets, subsequently increasing the center-to-center distance. Further experimentation and analysis revealed that the constant diameter observed at high flow rates in 10% NIPAM droplets was due to the high NIPAM concentration. The elevated NIPAM concentration decreased fluidity, causing the droplet phase to assume a quasi-solid state, leading to a distinct behavior compared to low-concentration solutions. Additional observations and studies demonstrated that since droplets produced at the microchannel outlet were not polymerized, and instead underwent polymerization after extraction into a glass container, the proximity between droplets could cause collisions. These collisions might lead to the formation of larger droplets, thus affecting droplet size uniformity.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e7.3\\u0026nbsp;Microdroplet Characterization:\\u003c/p\\u003e\\n\\u003cp\\u003eDuring the characterization process, it was observed that 4% NIPAM droplets did not polymerize effectively over time, retaining their initial form. In contrast, 10% NIPAM microdroplets exhibited complete polymerization at a consistent temperature of 25 degrees Celsius. As polymerization progressed which showed in Figure.8, the microdroplets transitioned to a semi-solid state, with their color evolving from an initially transparent and colorless appearance to white. Following polymerization and thorough rinsing with double distilled water, the particles were placed in a container of double-distilled water at 4 degrees Celsius for 1 hour.\\u003c/p\\u003e\\n\\u003cp\\u003eDiagram 3, depicts a diagram of droplet diameter as a function of temperature. According to the data, increasing temperatures led to a decrease in droplet diameter, with a higher rate of diameter change occurring at 21 degrees and subsequently decreasing at 26 degrees. The findings demonstrate that an increase in temperature can result in up to a 46% reduction in droplet diameter compared to the initial state. Additionally, a hysteresis property was observed when the temperature was lowered again, highlighting the reversible behavior of the droplets.\\u003c/p\\u003e\\n\\u003cp\\u003e8.3\\u0026nbsp;Flexible Microheater Characterization:\\u003c/p\\u003e\\n\\u003cp\\u003eCharacterization of the flexible microheaters revealed that the conductivity of the microheater constructed on the PDMS substrate was nearly zero, preventing the passage of electric current. The resistance values of microheaters fabricated in PMMA were measured to be 223 and 150 Ohms for cases without a middle layer and with titanium as the middle layer, respectively. Investigations into the cause of PDMS conductivity indicated that gold pattern conductivity on PDMS could be attributed to the material\\u0026apos;s elasticity and porosity. Since thin PDMS layers exhibit high elasticity, gold particle connections may be disrupted due to surface stretching, significantly reducing conductivity. Furthermore, the potential presence of porosity on the PDMS surface may also contribute to this effect. In contrast, the PMMA substrate\\u0026apos;s low elasticity minimizes the occurrence of macroscopic stretching on its surface. In Figure.7, to evaluate the response of the gold-titanium microheater to the electric field, two wires have been connected to the microheater through conductive silver ink.\\u003c/p\\u003e\\n\\u003cp\\u003eIn Figure.8 by applying a 5-volt electric potential difference, temperature values were recorded as a function of time, enabling the analysis of the microheater\\u0026apos;s thermal behavior and responsiveness to electrical input. To assess the temperature distribution across the microheater\\u0026apos;s surface, thermal images were captured at various time intervals using an infrared camera to illustrate the microheater\\u0026apos;s temperature distribution over time. The data show that over time, the heat generated in the conductive pattern spreads across the surface, resulting in a more uniform temperature distribution throughout the microheater\\u003c/p\\u003e\\n\\u003cp\\u003eTo use temperature-sensitive microdroplets as a wound dressing, it is crucial to incorporate them into a suitable matrix. For this purpose, the development of a flexible hydrogel coating was considered to encapsulate the microdroplet collection while maintaining the moisture levels of the wound surface. The hydrogel\\u0026apos;s ability to retain moisture and adapt to the wound bed ensures an optimal environment for promoting wound healing while harnessing the benefits of temperature-sensitive microdroplets.\\u003c/p\\u003e\\n\\u003cp\\u003e9.3\\u0026nbsp;Control System Design:\\u003c/p\\u003e\\n\\u003cp\\u003eTo manage and control the microheater\\u0026apos;s operation, an ATMEGA328_DIP microcontroller was employed. The electronic circuit was designed to facilitate connections with various components, including the power supply, NTC temperature sensor, temperature adjustment keys, a 16\\u0026times;2-character display, and the flexible microheater. This design enabled monitoring and regulation of the microheater\\u0026apos;s temperature, ensuring optimal performance and accurate control over drug release from the delivery system. As depicted in Figure.9, the capacitor\\u0026apos;s role in dampening voltage fluctuations contributed to stable voltage measurements. This, in turn, enabled accurate recording of temperature values, which is crucial for precise control over the microheater\\u0026apos;s operation within the drug delivery system.\\u003c/p\\u003e\"},{\"header\":\"4 \\tDiscussion and Conclusion\",\"content\":\"\\u003cp\\u003eThe microchannel characterization demonstrated its suitability for generating uniform microdroplets using a concentrating flow technique. By employing 10% NIPAM as the dispersed phase and liquid paraffin as the continuous phase, consistent droplet sizes were achieved. As the flow rate ratio of the dispersed to continuous phase increased from 0.14 to 0.84, a corresponding rise in droplet diameter was observed, ranging from approximately 360 to 515 micrometers.\\u003c/p\\u003e\\n\\u003cp\\u003eThe polymerized NIPAM microdroplets exhibited a notable response to temperature changes during the characterization stage. By applying controlled heat, the temperature sensitivity of the microdroplets was investigated, revealing a maximum 40% decrease in droplet diameter as the temperature increased from 18 to 32 °C. Remarkably, this diameter change proved to be reversible, with droplet size increasing upon temperature reduction when placed near water. This reversible behavior, indicative of drug diffusion and absorption, suggests that the controllable hydrophilic and hydrophobic properties of the microdroplets at varying temperatures can be effectively utilized in the proposed wound dressing application.\\u003c/p\\u003e\\n\\u003cp\\u003eThe favorable behavior of temperature-sensitive droplets in this study can lead to facilitating the acquisition and production of innovative wound dressings with appropriate controllability of drug release. The proposed dressing's behavior aligns with the controllable nature of the microdroplets. However, the mechanical structure and inherent challenges of the assembly precluded in vitro testing of the wound dressing, necessitating further advancement to fully assess its potential.\\u003c/p\\u003e\\n\\u003cp\\u003eThe characterization of the fabricated flexible microheater revealed that the PDMS substrate was unsuitable due to its high elasticity and surface porosity, which led to poor electrical conductivity. This challenge prevented the development of a microheater using PDMS. In contrast, the PMMA substrate demonstrated good electrical conductivity, with the addition of a 15 nm titanium middle layer further reducing electrical resistance. Consequently, the gold-titanium microheater proved to be a suitable stimulus for the drug delivery system. Characterization of the microheater showed that applying a 5-volt potential at ambient temperature resulted in a stable temperature state within 15 seconds, and the temperature distribution on its surface was appropriate. This uniform temperature distribution can facilitate a more controlled and uniform release of microdroplets.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003ch2\\u003eAuthor Contribution\\u003c/h2\\u003e\\u003cp\\u003eIn a research paper submitted, the first author is a PhD student and is responsible for selecting the topic, designing the experiment, and writing the paper. His supervisor is the corresponding author, or the second author, who is the scientific supervisor and scientific and theoretical guide of the project. The third author helped in selecting materials and designing the experiment. The fourth author is responsible for conducting the experiment and writing the scientific paper. The last or fifth author is responsible for conducting the aforementioned experiments and writing the initial paper.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eBhattacharjee, G., N. Gohil, M. Shukla, S. Sharma, I. Mani, A. Pandya, D.-T. Chu, N. L. Bui, Y.-V. N. Thi, K. Khambhati, R. Maurya, S. Ramakrishna and V. Singh (2023). \\u0026quot;Exploring the potential of microfluidics for next-generation drug delivery systems.\\u0026quot; \\u003cu\\u003eOpenNano\\u003c/u\\u003e 12: 100150.\\u003c/li\\u003e\\n\\u003cli\\u003eChoudhary, V., M. Choudhary and W. B. Bollag (2024). \\u0026quot;Exploring Skin Wound Healing Models and the Impact of Natural Lipids on the Healing Process.\\u0026quot; \\u003cu\\u003eInternational Journal of Molecular Sciences\\u003c/u\\u003e 25(7): 3790.\\u003c/li\\u003e\\n\\u003cli\\u003eDinari, A., M. Abdollahi and M. Sadeghizadeh (2021). \\u0026quot;Design and fabrication of dual responsive lignin-based nanogel via \\u0026quot;grafting from\\u0026quot; atom transfer radical polymerization for curcumin loading and release.\\u0026quot; \\u003cu\\u003eSci Rep\\u003c/u\\u003e 11(1): 1962.\\u003c/li\\u003e\\n\\u003cli\\u003eFarah, H. A., M. B. Brown and W. J. McAuley (2019). \\u0026quot;Heat Enhanced Follicular Delivery of Isotretinoin to the Skin.\\u0026quot; \\u003cu\\u003ePharm Res\\u003c/u\\u003e 36(8): 124.\\u003c/li\\u003e\\n\\u003cli\\u003eGaliano, R. D., O. M. Tepper, C. R. Pelo, K. A. Bhatt, M. Callaghan, N. Bastidas, S. Bunting, H. G. Steinmetz and G. C. Gurtner (2004). \\u0026quot;Topical vascular endothelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow-derived cells.\\u0026quot; \\u003cu\\u003eThe American journal of pathology\\u003c/u\\u003e 164(6): 1935-1947.\\u003c/li\\u003e\\n\\u003cli\\u003eGupta, J., D. D. Denson, E. I. Felner and M. R. Prausnitz (2012). \\u0026quot;Rapid local anesthesia in humans using minimally invasive microneedles.\\u0026quot; \\u003cu\\u003eClin J Pain\\u003c/u\\u003e 28(2): 129-135.\\u003c/li\\u003e\\n\\u003cli\\u003eJafarzadeh, F., H. Peyman, H. Roshanfekr, S. Azizi, A. O. Idris and M. 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Macka (2018). \\u0026quot;Miniaturised electrically actuated high pressure injection valve for portable capillary liquid chromatography.\\u0026quot; \\u003cu\\u003eTalanta\\u003c/u\\u003e 180: 32-35.\\u003c/li\\u003e\\n\\u003cli\\u003eMashiyama, S., R. Hemmi, T. Sato, A. Kato, T. Taniguchi and M. Yamada (2024). \\u0026quot;Pushing the limits of microfluidic droplet production efficiency: engineering microchannels with seamlessly implemented 3D inverse colloidal crystals.\\u0026quot; \\u003cu\\u003eLab on a Chip\\u003c/u\\u003e 24(2): 171-181.\\u003c/li\\u003e\\n\\u003cli\\u003eMora, M., A. Bellack, M. Ugele, J. Hopf and R. Wirth (2014). \\u0026quot;The temperature gradient-forming device, an accessory unit for normal light microscopes to study the biology of hyperthermophilic microorganisms.\\u0026quot; \\u003cu\\u003eAppl Environ Microbiol\\u003c/u\\u003e 80(15): 4764-4770.\\u003c/li\\u003e\\n\\u003cli\\u003eNajafabadi, A. H., A. Tamayol, N. Annabi, M. Ochoa, P. Mostafalu, M. 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Wang (2016). \\u0026quot;Passive and active droplet generation with microfluidics: a review.\\u0026quot; \\u003cu\\u003eLab Chip\\u003c/u\\u003e 17: 34-75.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Wound dressing, Microparticles, Drug carriers, Thermoresponsive, Microdroplets, flow-focusing\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-6580460/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-6580460/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003eThis study aimed to produce drops that can be used in wound dressings with controlled drug release for the treatment of skin disorders and chronic wounds. The lack of precise control of drug delivery to the wound area in common approaches has prompted us to design a controllable wound dressing. The dressing was designed with three main components: the drug delivery, stimulation, and control systems. A flexible microheater was fabricated by sputtering gold and gold/titanium onto a polymer substrate, aiming to stimulate microcarriers. The electrical resistance of gold and gold/titanium microheaters was measured at about 220 and 150 ohms respectively. By using the photolithography method, a microchannel focused on the flow was designed, and subsequently, NIPAM droplets were produced as a potential drug delivery system The microchannel performance assessment demonstrated consistent droplet production, allowing for the extraction of droplets measuring 360 to 515 micrometers in diameter at the outlet by modifying the flow rate ratio within the microchannel. The temperature sensitivity of the microparticles was evaluated, and a 40% decrease in droplet diameter was observed when going from 18\\u0026deg;C ​​to 32\\u0026deg;C. The studied drug carriers showed positive and acceptable results for use in a smart dressing, which enables stable control over the drug release rate by the heat generated in the flexible microheater\\u003c/p\\u003e\",\"manuscriptTitle\":\"Design, fabrication and investigation of temperature-sensitive polymer microdroplets produced by the flow-focusing microchannel under the heat produced by the flexible microheater\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-06-20 16:58:15\",\"doi\":\"10.21203/rs.3.rs-6580460/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"ca520211-ae79-4500-aee1-1d896d787867\",\"owner\":[],\"postedDate\":\"June 20th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-07-14T00:08:21+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-06-20 16:58:15\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-6580460\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-6580460\",\"identity\":\"rs-6580460\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}