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  • Q1:WEEK 4 ASSIGHMENT Physician practices are a key component of the U.S. health care system. As a future health care administrator, it is important for you to demonstrate an understanding of the challenges and opportunities that today's physicians face in providing quality health care services. Scenario You are a newly licensed physician and have been hired to lead a small group practice. This is a new role for you, and you have decided to do some research and develop an operations plan to guide you in managing the practice and leading the staff. Instructions Part 1: Develop Part 1 of 4 for an operations plan, Parts 2–4 will be completed in Weeks 6, 8, and 10 assignments. Part 1 of the operations plan should be 3–4 pages and include at least three quality academic resources in which you: Assess a minimum of two organizational forms in a medical group practice and summarize your findings. Select the organizational form will you use for this practice and justify your selection. Explain how you will transition from the existing practice form to the form you have selected. Develop three organizational goals as the new leader of the practice, including constraints you may experience working towards those goals. Explain the role human resources management (HRM) will play in the physician practice, including attracting employees, employee retention, labor and employment laws, and compensation plans. Examine the role nursing will have in the restructuring of the practice. Develop a marketing strategy that includes three aspects of consumer behavior that should be considered and support your response. Note: Include a cover page and reference page as required in the SWS Writing Standards. Note: Incorporate the instructor feedback once you receive it to improve Part 1 of your operations plan, to be used in the Week 9 activity and Week 10 assignment. This course requires the use of Strayer Writing Standards (SWS). The library is your home for SWS assistance, including citations and formatting. Please refer to the Library site for all support. Check with your professor for any additional instructions. The specific course learning outcome associated with this assignment is: Determine an organizational form, physician and physician practice competencies, HRM functions, and marketing strategies a group practice must assume to ensure the practice's long-term success. View RubricSee Answer
  • Q2:NEED TO DO Q5-Q10. Provide required screen captures and explanations organized appropriately Instructions: Plagiarism free Solutions generated from any AI platform is strictly Prohibited Referencing and formatting Style APA Need Typed Solutions only./nBE 312 - Lab #8 Lab 8: ECG Noise and Filtering I. Background The Electrocardiogram (ECG/EKG) is an electrical signal produced by the heart muscle. It has an amplitude of about 1mV, so a good amplifier is necessary. Electrical noise or electromagnetic interference (EMI), is generated by many common appliances, such as: power lines, lights, computers, cell phones, etc. When the ECG signal is amplified the noise is amplified as well and often swamps the ECG signal. Signal conditioning the ECG signal is necessary to acquire a good quiet ECG. The IX-TA-220 Recorder has the ability to output through the Stimulator any signal that is being recorded on its input, including the iWire ports. In this lab, we are going to perform two experiments. Experiment 1 focuses on using software filters to remove noise from the ECG signal. Experiment 2 uses a hardware filter that you assemble on the breadboards to remove noise from the ECG signal. Experiment 1 1) Record the ECG from the subject using the iWire-B3G. 2) Introduce some 60Hz noise into the ECG recording, by spreading the electrode cables. 3) Identify the frequency of the noise using the spectrum analyzer. 4) Filter the signal using various software filters. 5) Compare the ECG recorded by the iWire-B3G with the filtered ECG. Experiment 2 1) Record the ECG from the subject using the iWire-B3G. 2) Output the signal recorded by the iWire-B3G using the S1 Stimulator. 3) Send the ECG signal to the breadboard, using the C-BNC-BB cable. 4) Filter the signal on the breadboard. 5) Send the filtered signal back to the IX-TA-220, using the C-DIN-BB cable. a. The C-DIN-BB cable also provides +5V and -5V power to power the circuit. 6) Compare the ECG recorded by the iWire-B3G with the filtered ECG II. Setup Equipment Required . PC or Mac Computer · IX-TA data acquisition unit and power supply · USB cable · ROAM Wireless ECG · Labscribe: Settings>BioInstrumentation>ECGFilter-ROAM . C-DIN-BB: Din to Breadboard cable · C-BNC-BB: BNC to Breadboard cable • A-BREADBOARD: Breadboard . Alcohol swabs · Disposable ECG electrodes 1 BE 312 - Lab #8 Build the Filter Circuit The first step is to construct a filter on the breadboard. The "breadboard" is a board that is used to create simple prototype electrical circuits without circuit boards or soldering to connect the components. An example is shown in Figure 1. GLOBAL SPECIALTIES Va Vb Vc ! ABCDE - FONIJ ABODE FGHI .. 5 35 40 ABCD Figure 1. Example breadboard. The one you use may look slightly different. Breadboards have internal electrical connections that are common for all breadboards. Some holes are are electrically connected to each other inside the breadboard, while others are not. As shown in Figure 2, the long rows or columns of holes (usually indicated with a blue line, or black line, or red line along them) are all electrically connected inside the board. Thus a wire plugged into one of these holes will be electrically connected to all the others in that long row or column. The central array of holes are connected differently. These are shown with the letters (A B C D E), (F G HIJ), and numbered rows (1,2,3,4 ... ). In each row A-E are all electrically connected. And F-J are electrically connected. But, (A-E) are not connected to (F-J). Rows are not connected either. Also note that if there are multiple (A-E) or (F-J) columns, they are all separate and not connected. 2 BE 312 - Lab #8 SPECIALTTES + ABCDE FGHIJ + 5 5 All the holes in this row are electrically connected in the breadboard All the holes in this row are electrically connected in the breadboard (5 holes) All the holes in this row are electrically connected in the breadboard (5 holes) 10 10m KEL 15 KER A 20 25 All the holes in this column are electrically connected in the breadboard. A and B are separate, and are not electrically connected (although the holes in A are connected to each other and the holes in B are connected to each other). Figure 2. Close-up of the breadboard explaining the internal connectivity. For this lab, you will use a second order (2-pole) low pass filter as the hardware filter. The schematic is shown in Figure 3. C2 0.22µF R2 R1 U1 + S1_Input + Output_A5 V1 V2 30.1k 30.1k C1 TL062 + 0.22JF 5v -5v Figure 3. Schematic of the low pass filter you will build and use. This filter is a Sallen Key 2-pole low pass filter. Its job is to remove 60Hz electrical noise picked up from fluorescent lights, computers, and AC power lines. Figure 4 shows this circuit as a "Fritzing diagram" which is a picture representation of what your circuit on the breadboard should look like 3 BE 312 - Lab #8 when completed. 1 in 10 FGHIJ TL062 ABCDE Figure 4. Fritzing diagram of the low pass filter. Construct the circuit as shown and double check that the wires and components are all connected correctly. Once this is done, go to the breadboard setup and connect to the iWorx. Breadboard Setup 1. Insert the BNC connector on the end of the C-BNC-BB cable into the S1 stimulator port of the TA. 2. Connect the other end of the C-BNC-BB cable to the breadboard. 3. Insert the DIN8 connector of the C-DIN-BB cable into the A5 port of the TA. 4. Connect the other end of the C-DIN-BB cable to the breadboard. See Figure 5 and Figure 6 for pictures of these connections. Do these after the circuit has been assembled. Once everything is connected, continue to the next step and place the ECG electrodes. 4 BE 312 - Lab #8 C-DIN-BB +5 V C-DIN-BB -5 V C-DIN-BB + Input C-DIN-BB - Input C-DIN-BB Ground C-BNC-BB Signal C-BNC-BB Ground 25 25 20 25 Vb abcde - + Figure 5. Photo of the breadboard with circuit. Note the wires to be connected to the iWorx box. iWorx TA-ROAM hij a REKAM ROAM Wireless HV Stimulator O A2 A4 iWire LV Stim A3 A5 A6 A7 PT 1 .2 S1 S2 BREADBOARD WB-104-1 Va C-BNC-BB Figure 6. Breadboard connection to the iWorx box. ECG Setup 5 BE 312 - Lab #8 1. Disconnect the ROAM from the dock and place the electrodes as shown in Figure 7. REKAM Figure 7. Electrode placement for ECG signal acquisition. 2. Instruct the subject to sit quietly with their hands in their lap. If the subject moves, the ECG trace will move off the top or bottom of the screen. If the subject moves any muscles in the arms or upper body, electromyograms (EMGs) from the muscles will appear on the ECG recording as noise. 6 BE 312 - Lab #8 III. Experiments Aim: To record an ECG and identify the noise and use software filters. Procedure 1. The provided ECGFilter LabScribe setting file has been preset with the following settings. The instructions in the Appendix are for your information and to help you modify other iWorx lab experiments to add the option for additional signal conditioning. 2. If you set everything up and connected the breadboard correctly, you should be able to see the hardware filtered data in Labscribe during/after the ECG data collection (Channel A5) 3. Introduce noise into the ECG signal, by spreading out the ECG leads. Separate the black cable (negative) from the red (positive) cable so environmental noise is picked up by the amplifier. 4. Click on the Record button, located on the upper right corner of the LabScribe Main window. The signal should begin scrolling across the screen. Note: If the user clicks the Record button and there is no communication between the iWorx unit and computer, an error window will appear in the center of the Main window. Make sure the iWorx unit is turned on and connected to the USB port of the computer. Click OK and select the Find Hardware function from the LabScribe Tools menu. 5. Click on the AutoScale All button on the LabScribe toolbar, to Autoscale all the channels. Half Display Double Display New File Save File Analysis XY Plot Journal Marks Time Time Two Cursors Preview View Menu Macro 1.23 Default View IXTA View Off M review Open File Main/Home FFT Find/Found Hardware Meters Stimulator Zoom Between Cursors Auto One Cursors Rec/Stop Scale Figure 8. Labscribe toolbar. 6. Record for two minutes. 7. Click Stop to halt the recording and click File -> Save As to save your data file. . Channel A12: Raw ECG is the Raw ECG signal recorded by the iWire-B3G. · Channel S1: Stim 1 is the output of the Stimulator that is sent to the breadboard · Channel A5: Filtered ECG is the Filtered output of the ECG signal, after signal conditioning on the Breadboard. 8. The signals on A12 and S1 are the same, and should be noisy. Experiment 1: ECG and 60 Hz Noise - Software Filters The first analyses will be performed using software filters. 7 BE 312 - Lab #8 Identifying the frequency of the noise. Click on the FFT icon to switch to FFT window (see Figure 9). SnapToGrid < FFT > V2-V1 T2-T1 Mea Add Function Raw ECG 28.430 18.000 6220.88€ 4 5% -5.5K- -6K-J -6.5K- -7K- -7.5Kč 0 msec 4.855 sec 9.710 sec 14.565 sec 19.415 sec < * Power Spectrum of Raw ECG Q Q Q AQ & # Freq. Resolution = 1 Hz Normalize Power1 Power2 Frea1 Frea2 Add Function 0.000 4.000 75.000 1 0.95ª 0.9 0.85 0.75- 07 0.65 06 Power 0.55 0.5- 0.45- 0.4 0.35- 0.3- 0.25 02 0.15- 0.1 0 € 20 40 60 80 Figure 9. Raw signal and FFT of the signal. · Choose the Raw ECG channel (highlighted in the image above). . Make sure you have enough data in the window, You may need to click on the double display time to increase the displayed data. · Place the cursors in the Raw ECG channel to select the region to perform the FFT. . Click the AutoScale All button above the FFT graph. You will then see the FFT of the selected signal in the bottom graph. · The signal strength near DC is too high in this case to see the noise components. · Place the Cursors in the FFT window around 4 Hz and around 75Hz, Then click on the Zoom Between Cursors icon above the FFT graph. · The FFT graph will now show data between 4 Hz and 75 Hz. . Click on the Autoscale All button for the FFT graph to autoscale the data. · Place the second cursor on the peak, you will see that it is at 60Hz. We have thus determined that the main source of our noise is at 60 Hz. 8 BE 312 - Lab #8 Snap ToGrid < > V2-V1 T2-T1 Mean Add Function Raw ECG 640.890 16.795 6248.905 NUL 0 msec 4.855 sec 9.710 sec 14.565 sec 19.415 sec < * Power Spectrum of Raw ECG & #* Freq. Resolution = 1 Hz ] Normalize Frea Frea2 Power1 Power2 Add Function 6.000 50.000 1365.067 4245.915 4 6K- 4.4K- 4.2K- 4K 3 8K- 3.6K 3.4K 3.2K 3K 2.BK 2.6 Power 2.4K 22K 2K 1.8K 1.6K- 1.4K- 1.2K 1000 800 600 400 200- . . . 10 15 . 20 25 30 . . . . . 35 40 50 . . . . . 55 60 65 70 7 Figure 10. FFT power spectrum zoomed. Software Filters for reducing the noise: Option1: Notch Filter: The notch filter can be used to remove 60Hz noise. To create a channel with the notch filter. . Click on the fx on the Raw ECG channel bar. · Choose 60 Hz notch filter. You may select to filter out the harmonics as well. . . . . Notch Filter Dialog X 50 Hz Notch Filter 60 Hz Notch Filter filter 3rd harmonic filter 2nd harmonic OK Cancel . Click OK. A notch filter channel is now created. Option2: FIR Filter: A FIR (finite impulse response) filter can be used to reduce the noise in the signal. To create a channel with an FIR filter: . Click on the Raw ECG channel bar. · Set the Low and High cutoff. For human ECG, a low cutoff of 0.1Hz and a High Cutoff of 35Hz works well. · Choose the filter type and the order of the filter. 9 BE 312 - Lab #8 Filter Setup Dialog X Filter Type : Hamming Window(default) V Low Cutoff 0.1 Filter Order ( odd number) 2001 High Cutoff 35 0 50 100 Frequency Frequences in Color are passed while those in white are blocked OK Cancel Figure 11. FIR filter setup window. Labscribe window with the two filter options is shown below. Speed: 200 s/sec Display Time: 7.110 sec Mark ALL T2-T1( 10.930 sec - 8.560 sec)= 2.370 sec - A1:Raw ECG Spirometer Q Q Q fx V2-V1= 107.050 mV -4.5K- -5.5K- -6K- É -6.5K- -7K -7.5K- C1:Comp Ch 1 Notch Filter(Raw ECG) @ @ @ fx V2-V1= 83.387 mV -5.25K- -5.75K- >-6.25K- É -6.75K-playerml -7.25K- -7.75K C2:Comp Ch 2 FIR Filter(Raw ECG) @ @ @ fx V2-V1= - 11.419 mV 1.25K 750- 250 mV -250 -750 -1.25K_ 6.190 sec 7.965 sec 9.745 sec 11.520 sec 13.295 sec Figure 12. Signals compared. Experiment 2: ECG and noise - Hardware Filter Refer to the channels S1 and A5 in Labscribe for these analyses. Compare peak values of the signal before and after filtering. Try to use the FFT analysis on the filtered signal. IV. Wrap Up When you are done with the lab, carefully remove all components and wires from the breadboard and return all to the case. Please be neat and careful! 10 BE 312 - Lab #8 V. Report Questions 1. Include screen captures/pictures of all channels recorded. 2. Provide a screen capture of the FFT the raw signal. What is the frequency of the noise? Does this match what the lab says it should be? 3. Provide a screen capture image of the filtered signal using the Notch Filter. Does this remove the noise? 4. Provide a screen capture image of the filtered signal using the FIR Filter. Does this remove the noise? 5. Which software filter was better? Why do you think this was the case? 6. (a) What is the TL062? (b) Provide a pin label diagram for the TL062. What pins did you use? 7. Assuming all electronic components in your hardware filter are "ideal," derive the H(jw) transfer function for the low pass filter. Use Matlab or Excel to create a Bode plot showing |H| in dB vs frequency. Frequency plot should start at 0.1 Hz and go up to 10,000 Hz (log scale, of course). Indicate the "cut-off frequency" on the plot. 8. Does the hardware filter remove the noise from the raw signal? 9. Can you apply the FFT analysis to the hardware filtered signal? If so, what does it show about the noise? Can you compare this to the software filtered noise? 10. Which of the three filters seemed to work best removing noise? 11 BE 312 - Lab #8 VI. Appendix A: Labscribe Setup information Open the Preferences dialog, by choosing Edit->Preferences from the Main Menu. . Channels Tab. · Enable the Channels to be recorded and Label them. These channels will be used: - A5 (Filtered ECG): This is the output of the Filter - il 2 (Raw ECG): This is the ECG measured by the iWire-B3G - S1 (Stimulator): This is what the Stimulator is outputing, which is same as the Raw ECG Channel. You do not have to enable this channel. Preferences Dialog X Channel Stimulator Views Sequences Options Events Acquisition Mode Start Stop Chart V User Speed 1000 V Samples/Sec v v User 2 Display Time 12.184000 sec Title Mode/Function Y Max Y Min Add Function Units Color A A1 Raw Ch 1 Off 5.000000 -5.000000 Add Function Units A2 Raw Ch 2 Off 5.000000 -5.000000 Add Function Units A3 Raw Ch 3 Off 5.000000 -5.000000 Add Function Units A4 Raw Ch 4 Off 5.000000 -5.000000 Add Function Units A5 Filtered ECG DIN8 0.334837 -0.202036 Add Function Units A6 Raw Ch 6 Off 5.000000 -5.000000 Add Function Units DO2 DO2 Off 5.000000 -5.000000 Add Function Units A8 Raw Ch 8 Off 5.000000 -5.000000 Add Function Units EM1 EM1 Off 5.000000 -5.000000 Add Function Units EM2 EM2 Off 5.000000 -5.000000 Add Function Units i1 1 i1 1 Off 5844.3311 -1897.861 Add Function Units i1 2 Raw ECG DC-10kHz 50mV -0.962093 -2.382150 Add Function Units i13 i1 3 Off 1.944953 -1.486055 Add Function Units i1 4 i14 Off 0.380391 -0.202361 Add Function Units SpO2 Sp02 Off 5.000000 -5.000000 Add Function Units HR HR Off 5.000000 -5.000000 Add Function Units S1 Stim 1 Record 0.628298 -0.461561 Add Function Units S2 S2 Off 5.000000 -5.000000 Add Function Units > OK Cancel · Stimulator Tab · Choose S1 stimulator · Set the mode to Analog Channel · Choose A12: Raw ECG as the analog channel to be send to the Stimulator output 12 BE 312 - Lab #8 Enable Start Stimulator with Recording. Channel Stimulator Views Sequences Options Events S1 v Import Settings Analog Channel A12:Raw ECG v Analog Channel > Start Stimulator with Recording Time Resolution 0.05 msec v Toolbar Steps Frequency 1 Amplitude (V) 0.1 Time 0.1 A 13See Answer
  • Q3:Q1} We often use laser diodes to excite biological samples and observe their fluorescence emission. Figure 1 shows a transfer function (the laser output power P vs the driving current I) of a laser diode, where you can see that a typical laser has three different operation regions (taking the transfer curve at 0oC as an example): i) Sub-threshold: the laser operates below the threshold current, Ith, emitting minimal light. ii) Linear region (this is where the laser usually operates): the driving current is higher than the threshold, the laser shows the best efficiency. iii) Saturation: the driving current is too large, and the efficiency drops again (note the behaviour in this region is not linear, but let’s approximate it with a straight line for simplicity). We also notice that the transfer function is sensitive to the temperature. The threshold current Ith is also a function of the temperature. 1.1 What are the threshold currents of the laser for 25 and 100 oC? (2, 2 marks) 1.2 What are the transfer gains (we also name the transfer gain as ‘sensitivity’ DP/DI) of the laser operating at the linear region, for 0, 25, and 100 oC, respectively? What is your observation (2, 2, 2, 3 marks) 1.3 From Question 1.2, what are the laser diode’s linear dynamic ranges (both I and P) for 0, 25, and 100 oC, respectively? (6 marks) 1.4 Suppose the fluorescence experiments require the laser diode to deliver a modulated laser power between Pmin = 1 mW and Pmax = 6 mW. What is the driving current range for 0, 25, and 100 oC, respectively? (6 marks) Instructions: Plagiarism free Solutions generated from any AI platform is strictly Prohibited Referencing and formatting Style APA Need Typed Solutions only.See Answer
  • Q4:1. Write one paragraph describing the function of a replacement stent for an aortic aneurysm. Include in your answer details of the materials commonly used in the fabrication or the preparation of these stents. (7 marks) 2. Write one paragraph (approx 100 words) to define each of the following concepts related to medical devices in general and replacement heart valves in particular (7marks for each): • SAFETY • EFFICACY • QUALITY 3. Using the ISO 10993 Guidelines for biocompatibility testing as a reference, determine the tests required to demonstrate the biocompatibility of Vascular stents. (6 marks) Instructions: Word requirement – min 500 words Plagiarism free Solutions generated from any AI platform is strictly Prohibited Referencing and formatting Style APA Need Typed Solutions only.See Answer
  • Q5: Review Films for Wound Healing Fabricated Using a Solvent Casting Technique pharmaceutics Fabiola V. Borbolla-Jiménez ¹,2D, Sheila I. Peña-Corona Emiliano Pineda-Pérez ¹,2D, Alejandra Romero-Montero María Luisa Del Prado-Audelo ², Sergio Alberto Bernal-Chávez 4, Jonathan J. Magaña ¹,²,* and Gerardo Leyva-Gómez ³,*D I Citation: Borbolla-Jiménez, F.V.; Peña-Corona, S.I.; Farah, S.J.; Jiménez-Valdés, M.T.; Pineda-Pérez, E.; Romero-Montero, A.; Del Prado-Audelo, M.L.; Bernal-Chávez, S.A.; Magaña, J.J.; Leyva-Gómez, G. Films for Wound Healing Fabricated Using a Solvent Casting Technique. Pharmaceutics 2023, 15, 1914. https://doi.org/10.3390/ pharmaceutics15071914 check for updates Academic Editors: Giyoong Tae, Martin Federico Desimone and Gorka Orive CC Received: 18 May 2023 Revised: 10 June 2023 Accepted: 27 June 2023 Published: 9 July 2023 4.0/). BY Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 1 2 3 4 * 3 D, Sonia J. Farah ¹,2, María Teresa Jiménez-Valdés ¹,2, 3 Laboratorio de Medicina Genómica, Departamento de Genómica, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Ciudad de México 14389, Mexico; fvbj@hotmail.com (F.V.B.-J.); soniafarah1d@gmail.com (S.J.F.); teresajimenez00@gmail.com (M.T.J.-V.); emilianopineda_perez@hotmail.com (E.P.-P.) Tecnologico de Monterrey, Campus Ciudad de México, Ciudad de México 14380, Mexico; luisa.delprado@tec.mx Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico; sheilairaispc@gmail.com (S.I.P.-C.); alejandra.romero.montero@outlook.com (A.R.-M.) MDPI Departamento de Ciencias Químico-Biológicas, Universidad de las Américas Puebla, Ex-Hda. de Sta. Catarina Mártir, Cholula 72820, Puebla, Mexico; q901108@hotmail.com Correspondence: magana.jj@tec.mx (J.J.M.); leyva@quimica.unam.mx (G.L.-G.) Abstract: Wound healing is a complex process that involves restoring the structure of damaged tissues through four phases: hemostasis, inflammation, proliferation, and remodeling. Wound dressings are the most common treatment used to cover wounds, reduce infection risk and the loss of physiological fluids, and enhance wound healing. Despite there being several types of wound dressings based on different materials and fabricated through various techniques, polymeric films have been widely employed due to their biocompatibility and low immunogenicity. Furthermore, they are non-invasive, easy to apply, allow gas exchange, and can be transparent. Among different methods for designing polymeric films, solvent casting represents a reliable, preferable, and highly used technique due to its easygoing and relatively low-cost procedure compared to sophisticated methods such as spin coating, microfluidic spinning, or 3D printing. Therefore, this review focuses on the polymeric dressings obtained using this technique, emphasizing the critical manufacturing factors related to pharmaceuticals, specifically discussing the formulation variables necessary to create wound dressings that demonstrate effective performance. Keywords: skin; wound; wound healing; wound dressings; polymers; films; solvent casting 1. Introduction A wound is a disruption of the continuity of body tissue caused by physical or chemical damage. Usually, a wound is disinfected using a typical medical procedure, and antibiotic treatment is initiated to start the healing process [1]. However, a possible lack of response to antibiotics or an uncontrolled inflammatory phase can trigger the generation of chronic or infected wounds, which represents a clinical challenge [2]. In this sense, developing minimally-invasive smart dressings that integrate drug release with different therapeutic targets (such as antibiotics, anti-inflammatory agents, and analgesics) represents a desirable alternative [3,4]. Based on understanding the physiological process of wound healing, the ideal dress- ing should be biocompatible, acting as a physical barrier against microorganisms while allowing gas permeation to keep the wound hydrated and remove excess exudate [5,6]. Additionally, desirable properties include good mechanical strength and flexibility. Non- toxicity, biocompatibility, and biodegradability are also important criteria for materials used Pharmaceutics 2023, 15, 1914. https://doi.org/10.3390/pharmaceutics15071914 https://www.mdpi.com/journal/pharmaceutics Pharmaceutics 2023, 15, 1914 in dressings [7]. Hydrogels, polymer films, foams, gauzes, and hydrocolloids are among the most extensively studied dressings, depending on the wound type and therapeutic needs [8,9]. Films serve as convenient physical barriers to bacteria, maintain gas permeability, and enable in situ drug release. Furthermore, their flexibility can be tailored to accommodate individual morphology [10]. Consequently, research focuses on utilizing film dressings as drug carriers to control infections and inflammatory processes [11]. By providing a moist environment, removing wound exudates, and accelerating cellular and tissue regeneration, dressings can maintain optimal conditions for wound repair [12]. However, it is important to acknowledge the limitations of these products. For example, they encounter difficulties in simultaneous application to both external and internal wounds. Additionally, their application can exert external pressure, leading to secondary injuries [13]. This study aims to analyze the solvent casting procedure, the most widely used method for film production. Solvent casting is preferred over other methods, such as salt leaching, spin coating, microfluidic spinning, and 3D printing, due to its cost-effectiveness, simplicity, practicality, and ability to generate robust films with appropriate mechanical properties and homogeneity. However, the properties of materials obtained through solvent casting can vary significantly between production batches, influenced by environmental conditions, which can also slow the production process. Moreover, maintaining sterility throughout all manufacturing steps poses a challenge and can result in batch contamination. Thus, this study comprehensively reviews the objectives of developing polymer films and highlights the key considerations to ensure optimal final properties during the solvent casting process. Despite the method's considerable potential for industrial scaling and clinical application, there is a noticeable lack of standardized commercial products [7]. Therefore, this review identifies areas for improvement and underscores the main advan- tages of utilizing this type of dressing in wound treatment. 2. Wound Healing The wound healing process is a natural physiological reaction to tissue injury that consists of four highly integrated phases: hemostasis, inflammation, proliferation, and remodeling (Figure 1). These phases must occur in a specific sequence, at a specific time, and for a particular duration, in order that the physiologically involved functions fulfill their expected role [14]. Otherwise, this leads to improper or impaired tissue repair [15]. Epidermis Dermis Fibrin clot Erythrocyte- Blood_ vessel 1) Hemostasis Proliferating fibroblasts Epithelial cells monolayer New blood vessels -Injury 3) Proliferation Dobago -Platelet -Eschar Type III Collagen fibers Granulation tissue (2) Inflammation Necrotic tissue or bacterias Macrophage- Neutrophil- Monocyte 2 of 27 4) Remodeling Scar tissue Fibroblast. Type I Collagen fibers Figure 1. Four significant phases represent the wound healing process: (1) hemostasis, the formation of a platelet seal that prevents blood loss and a fibrin clot; (2) inflammation, where neutrophils and macrophages remove debris and prevent infection; (3) proliferation, where blood vessels reform Pharmaceutics 2023, 15, 1914 3 of 27 through angiogenesis, and fibroblasts replace the fibrin clot with granulation tissue; (4) remodeling, where the matrix is remodeled replacing type III collagen with type I, maturing to a scar. 2.1. Hemostasis The hemostasis phase begins minutes to hours after an injury through a cascade of serine protease activation, resulting in platelet activation. This activation also facili- tates the release of growth factors, such as PDGF (platelet-derived growth factor), VEGF (vascular endothelial growth factor), and TGF-α (transforming growth factor x), as well as immune mediators, contributing to the transition into the inflammatory phase [16]. PDGF and TGF-ß (transforming growth factor ß) recruit neutrophils and monocytes to initiate the inflammatory response [17]. Furthermore, this leads to the formation of a fibrin clot, referred to as an eschar, which acts as a plug for the wound, preventing blood loss, providing a scaffold for incoming immune cells, serving as a reservoir for cytokines and growth factors during the early stages of repair, and offering protection against bacterial invasion [15,16,18]. The extrinsic clotting cascade is initiated upon tissue damage and blood leakage, releasing molecules such as serotonin that induce localized vasoconstriction [19]. Sub- sequently, platelets aggregate and become activated upon contact with subendothelial collagen, forming a hemostatic plug. This plug mitigates hemorrhage and serves as a provisional matrix for cell migration by releasing scaffold proteins such as fibronectin, vitronectin, and thrombospondins, facilitating the migration of keratinocytes, immune cells, and fibroblasts [16,20]. Once a fibrin clot is formed, the coagulation process is switched off to prevent excessive thrombosis [17]. 2.2. Inflammation The inflammatory phase, which overlaps with hemostasis, occurs during the first 72 h [16]. During this phase, both humoral and cellular inflammatory responses are activated to establish an immune barrier against invading microorganisms [21]. Neu- trophils and monocytes infiltrate the wound bed to prevent further damage and eliminate pathogenic organisms and foreign debris [16,22]. The inflammation phase can be divided into early and late inflammatory phases. In the early phase, the complement cascade is activated, leading to the infiltration of neutrophils into the wound. Their primary role is to phagocytose bacteria, foreign particles, and damaged tissue [21,23]. Various chemoattractive agents attract neutrophils to the wound site, including TGF-ß, complement components such as C3a and C5a, and formyl- methionyl peptides produced by bacteria and platelet products [16,19]. During their activity, neutrophils release proteolytic enzymes, oxygen-derived free radical species, and inflammatory mediators such as TNF-α and interleukin (IL)-1 [17,21]. Once their role is fulfilled, neutrophils undergo apoptosis and are cleared from the wound typically within 2-3 days, making way for the influx of monocytes [18]. Monocytes, stimulated by cytokines, chemokines, growth factors, and soluble frag- ments of the extracellular matrix (ECM), differentiate into activated macrophages. These macrophages patrol the wound area, ingesting and killing bacteria and removing devi- talized tissue through the action of secreted matrix metalloproteinase and elastase [15]. Additionally, macrophages play a crucial role in transitioning to the proliferative phase by releasing various growth factors and cytokines, including PDGF, TGF-α, TGF-ß, insulin-like growth factor-1 (IGF-1), fibroblast growth factor (FGF), tumor necrosis factor-a (TNF-α), IL-1, and IL-6. These soluble mediators promote cell proliferation and the synthesis of ECM molecules, and activate fibroblasts for subsequent phases [19,24]. A decrease in macrophage presence within the wound indicates the inflammatory phase's conclusion and the proliferative phase's initiation [15]. Pharmaceutics 2023, 15, 1914 4 of 27 2.3. Proliferation The proliferative phase of wound healing involves several interconnected processes that restore tissue structure and function. It begins on the third day after the injury and lasts approximately two weeks [21]. One of the critical aspects of this phase is the replacement of the provisional fibrin matrix with a new matrix composed of collagen fibers, fibronectins, and proteoglycans, which are synthesized by fibroblasts. During this phase, angiogenesis, the generation of granulation tissue, collagen deposi- tion, re-epithelialization, and wound contraction occur [16,25]. Angiogenesis is stimulated by local conditions such as low oxygen tension, low pH, and high lactate levels. It involves the migration and proliferation of endothelial cells to form new blood vessels, which is cru- cial for tissue viability [17]. Macrophages are vital in promoting angiogenesis by producing VEGF [16]. Granulation tissue formation occurs concurrently with angiogenesis and primarily comprises type III collagen, fibroblasts, and new vessels. Fibroblasts are the main cells involved in granulation tissue formation. Their proliferation, and synthesis of extracellular matrix components, contributes to tissue restoration [21]. Additionally, the interaction between fibroblasts and keratinocytes plays a significant role in re-epithelialization. Factors like EGF, KGF, and TGF-α, produced by platelets, keratinocytes, and anti-inflammatory macrophages, promote keratinocyte migration and proliferation [25-27]. The process is further facilitated by the production of fibronectin, tenascin C, and laminin 332 by keratinocytes [16]. As re-epithelialization progresses, the stratified layers of the epidermis are re-established, and the maturation of the epidermis begins to restore its barrier function. TGF-ß can accelerate this maturation process [17]. The proliferation and differentiation of keratinocytes are essential for the reestablishment of a functional epidermis [25,27]. 2.4. Remodeling The remodeling phase, which occurs several weeks after the initial wound, marks the transition from granulation tissue to scar formation. This phase may last up to 1-2 years [21]. During this phase, angiogenesis slows down, and type III collagen in the granulation tissue is replaced by stronger type I collagen [16]. Myofibroblasts play a crucial role in driving the remodeling phase. They originate from fibroblasts and develop in response to mechanical tension and TGF-ß signaling. Myofibroblasts are responsible for wound contraction, and their expression of smooth muscle actin (SMA) generates the contractile force exhibited by these cells [28,29]. It is worth noting that myofibroblasts are considered terminally differentiated and undergo apoptosis once the remodeling process is complete [16]. During the remodeling phase, the granulation tissue matures into a scar, and the tensile strength of the tissue increases. This maturation is characterized by a reduction in the number of capillaries, an aggregation into larger vessels, and a decrease in the number of glycosaminoglycans. The cell density and metabolic activity in the granulation tissue also increase during this maturation process. The collagen type and organization changes further enhance the tissue's tensile strength [17]. However, the tensile strength of the healed tissue never fully reaches its original strength. A newly epithelialized wound typically has approximately 25% of the tensile strength of normal tissue, and it may take several months for the tensile strength to increase to a maximum of 80% of normal tissue [30]. The enhancement of tissue tensile strength primarily occurs through reorganizing collagen fibers, initially deposited randomly during the granulation phase. After, the enzyme lysyl oxidase, secreted by fibroblasts into the extracellular matrix (ECM), facilitates the increased covalent cross-linking of collagen molecules [17]. Pharmaceutics 2023, 15, 1914 Type of Polymer Natural Synthetic 3. Polymeric Films for Wound Healing Polymeric films (PFs) as dressings for wound healing were first vastly introduced dur- ing the Second World War as a response to the demand for advancements in medicine [31]. Bloom et al. [17] were the first to document semipermeable films in 1945 using cellophane to treat burnt prisoners of war in Italy; they reported “gratifying results” with complete healing nine days after dressing application [32]. Nowadays, PFs are commonly utilized in the medical field for healing as physical barriers for wounds which help to prevent inflammation, control the environment of the wound, and accelerate healing [33]. PFs have gained popularity due to their non-invasive nature, ease of application, biocompatibility, and the potential inclusion of antimicrobial treatments. Moreover, PFs offer flexibility, adherence, gas exchange capabilities, and trans- parency [34]. The material's flexibility enables the film to conform to complex shapes while facilitating gas exchange, which has been proven to promote healing [34]. Additionally, its transparency allows for the close monitoring of the wounded area without removing the film, thereby reducing trauma during dressing changes, minimizing exposure to bacteria, and lowering the risk of infection by up to one week [34,35]. PFs are recommended for treating partial-thickness wounds, minor burns, lacerations, and certain low-exudate ulcers such as ischemic ulcers, diabetic ulcers, venous ulcers, and pressure ulcers [34]. However, it is important to note that due to the occlusive nature of the material, films should not be used on wounds that require significant fluid absorption, as excess exudate can potentially lead to peri-wound maceration. Nevertheless, maintaining a certain level of moisture can be beneficial for the healing process by promoting keratinocyte migration to the affected area [34,36]. The performance of PFs depends on the chemical composition and the type of wound. Polymers used to formulate PFs can be divided into natural, synthetic, and blended. Therefore, the PFs will possess different qualities depending on the type of polymers employed to form the film dressing. 3.1. Natural Polymeric Films Natural polymers, also called biopolymers, offer advantages such as biocompatibility, biodegradability—at present a sought-after quality-healing properties, inertness, and adhesiveness [37]. For this reason, generally, natural polymers are preferred over synthetic ones [37]. However, they are prone to microorganism contamination and lack quality mechanical properties to form an optimal polymeric film. Some examples of natural polymers used for elaborating PFs are chitosan, hyaluronic acid, starch, silk fibroin, sericin, keratin, sodium alginate, gelatin, collagen, zein, and konjac glucomannan, among others (Table 1) [36]. Chitosan is one of the most exploited and abundant natural polymers in wound dressings, with antimicrobial and film-forming properties [38,39]. Moreover, due to their innocuousness, polymers like chitosan, cellulose, gellan gum, alginates, and starches can be used for oral cavity films [40] (Figure 2). Table 1. Types of polymers used in polymeric film casting. Examples Chitosan, hyaluronic acid, starch, silk fibroin, sericin, keratin, sodium alginate, gelatin, collagen, zein, cellulose, and konjac glucomannan Polyvinyl alcohol, polyacrylic acid, polycaprolactone, polyethylene glycol, polyvinylpyrrolidone, polylactic acid, and polydimethylsiloxane. 5 of 27 Properties Biocompatibility, biodegradability, high disponibility, healing properties, permeability, inertness, and bioadhesiveness Resistance, flexibility, structure, high degree of polymerization, thermo-responsiveness, hydrophilicity, and occlusivity Ref. [36,37] [36]See Answer
  • Q6: BE 312 Lab #3 LAB 3: Stretch Receptors and Reflexes I. Background Studying the vertebrate stretch reflex is a good way to introduce students to the topics of stretch receptors, nerve conduction velocity, electromyograms (EMG), and motor control. Specialized receptors in the muscle respond to the stretching of the tendon attached to the muscle, and then send signals to motorneurons through a single synapse. The muscle fibers depolarize and twitch (contract) in response to the incoming impulse from the motorneuron. The Stretch Receptor Skeletal muscles have specialized receptors which convey information about muscle length, tension, and pressure to the central nervous system. The sensory receptors responsible for providing information about the length, or the rate of change of the length, of a muscle are called muscle spindles. Arranged in parallel with muscle fibers, the spindles are stretched when the muscle is stretched by an external force. Therefore, these receptors play a significant role in developing antigravity reflexes and maintaining muscle tone. Muscle spindles contain a small bundle of intrafusal fibers which do not contribute to the overall tension of the muscle, but regulate the excitability of the sensory afferent spindle nerves by mechanically deforming the receptors. These fibers are innervated by gamma motor neurons. Much of a muscle consists of extrafusal fibers, which are innervated by alpha motor neurons and are responsible for developing muscle tension. Motor Fibers Sensory Fiber Intrafusal Fibers Fluid Cavity Extrafusal Fibers Muscle Muscle Spindle Sensory Neuron Motor Endplates Motor Neuron Spinal Cord Figure HN-2-B1: A monosynaptic stretch reflex arc. The Stretch Reflex When a muscle is stretched, excitation of its muscle spindles causes a reflex contraction of the muscle. This reflex response is known as a stretch (myotatic) reflex. The minimal delay between the muscle stretching and the reflex contraction is due to its monosynaptic pathway. The sensory afferent nerves from the spindles synapse directly with motor neurons; there are no interneurons. This pathway constitutes the shortest possible reflex arc. 1 BE 312 Lab #3 Rectus Femoris Vastus Lateralis Patellar Ligament Tibialis anterior Tibia -Biceps Femoris Femur -Soleus -Gastrocnemius (Lateral Head) - Fibula Achilles Tendon HN-2-1 Figure HN-2-B2: The major extensors and flexors of the human knee and ankle joints. The stretch reflexes used in this exercise are elicited by striking the patellar tendon or the Achilles tendon. As an example of the stretch reflex, consider the reflex response that occurs when a person jumps from a low stool to the floor. The extensor muscles of the legs are stretched on landing, lengthening all their muscle spindles. The discharge of the muscle spindles is conveyed to the central nervous system through the fast-conducting afferent axons. These sensory axons enter the spinal cord through the dorsal root and synapse with the motor neurons of the same extensor muscle. In turn, the motor neurons trigger the contraction of the extensor muscle to oppose the stretch produced by landing, completing the reflex arc. This reflex is one of the main reasons you keep your balance and do not fall when changing certain body positions. In this lab, students will record electromyograms (EMGs), the summation of asynchronous electrical activity (muscle action potentials) in the multiple fibers in the muscle, and use them to determine the time between the stretch of the tendon and the arrival of the motor impulse at the muscle. Two reflexes in a human subject will be studied: the Achilles tendon reflex, and the patellar tendon (knee-jerk) reflex. Conduction times and nerve velocities for each reflex arc will be determined and compared. The effect of pre-existing tension in the effector muscle, or motor activity in other muscle groups, upon reflex responses will be measured. The coordination of motor activity in antagonistic muscles will also be studied. 2 BE 312 Lab #3 II. Setup Equipment Required ● ● ● PC or Mac Computer IXTA, USB cable, IXTA power supply ROAM EMG Alcohol swabs Disposable EMG electrodes PRH-100/PRH-200 Patellar reflex hammer Settings -> Human Nerve-> StretchReceptorReflex-ROAM EMG Cable and Reflex Hammer Setup 1. Locate Patellar Reflex Hammer and plug the BNC connector into Channel A3. 3. 2. Disconnect the ROAM EMG from the dock and place the electrodes as shown in Figure 1. Use an alcohol swab to clean and abrade two regions on the calf of the left leg for electrode attachment. One area is in the middle of the calf muscle, and the second area is about 3 inches below the back of the knee (see Figure 2). Let the areas dry. 4. Remove the plastic disk from a disposable electrode and apply it to one of the abraded areas. Repeat for the other area. Worx TA-ROAM Figure 2. Electrode placement on leg. A4 AS AB REKAM (a) (b) Figure 1. (a) The PRH-200 Reflex Hammer to be plugged into Channel A3. (b) The ROAM device for wireless measurements. 3 BE 312 Lab #3 5. Attach the two color-coded electrode leads as shown in Figure 2 for the Achilles Reflex. III. Experiments Exercise 1: Achilles Tendon Reflex Aim: To determine conduction time from tendon tap to response of the gastrocnemius muscle in the Achilles tendon reflex arc. Approximate Time: 20 minutes Procedure 1. Instruct the subject to sit on a lab bench so that the subject's thighs are supported by the top of the bench and his or her calves hang freely. 2. The Achilles tendon is located above the heel and connects the gastrocnemius muscle to the tarsal bone of the foot. Tap the tendon with the wide end of the reflex hammer a few times to locate a point on the tendon which produces a consistent contraction of the gastrocnemius muscle and a downward movement of the foot (plantar flexion). The opposite, upward movement is known as dorsiflexion. 3. Click Record and then instruct the subject to move his or her foot up and down to demonstrate the type of EMG that occurs during plantar flexion and dorsiflexion. Click AutoScale All. 4. Type Achilles in the Mark box. Click the mark button to mark the recording. Continue recording. 5. Tap the subject's Achilles tendon to elicit the stretch reflex. Record a total of five trials using the same tapping force. 6. After the fifth trial, click Stop to halt recording. 7. Select Save As in the File menu, type a name for the file. 8. Repeat this exercise on the same subject using three different amounts of force. Exercise 2: Patellar Tendon (Knee Jerk) Reflex Aim: To determine conduction time from tendon tap to response of the quadriceps muscle in the patellar tendon reflex arc. Approximate Time: 40 minutes Software Changes Click on the Settings menu and select the PatellarStretchReflex settings file. Procedure 1. Instruct the subject to sit on a lab bench so that the subject's thighs are supported by the top of the bench and his or her calves hang freely. 2. Remove the lead wires of the EMG recording cable from the electrodes over the subject's calf muscle. Keep these electrodes on the subject's calf muscle. 3. Place a new set of recording electrodes on the quadriceps muscle of the subject on the medial side of the thigh, so that: the black (-1) lead wire is attached to an electrode which is about 12 cm from the knee. 4 BE 312 Lab #3 the red (+1) lead wire is attached to an electrode which is about 10 cm above the negative electrode (see Figure 3). RAM Figure 3. Circuit diagram for recording EMGs from the thigh muscles. Using the iWireB3G on the left and the wireless ROAM on the right. Note: Ignore the green wire 4. Feel the position of the patellar tendon just below the kneecap. Place one hand on the patella (kneecap), and use the other hand to tap the patellar tendon with the reflex hammer. Find the point on the patellar tendon that causes the greatest response from the quadriceps muscle. 5. Click Record and then instruct the subject to raise and lower his or her lower leg to demonstrate the type of EMG that occurs during quadriceps contraction and relaxation. Click AutoScale All. Click Stop to halt the recording. 6. Type Patellar in the Mark box. 7. Click Record and then click the mark button to mark the recording. 8. Instruct the subject to relax his or her quadriceps muscle and that the exercise has begun. 9. Tap the subject's patellar tendon to elicit the stretch reflex. Record a total of five trials using the same tapping force. 10. After the fifth trial, click Stop to halt recording. 11. Select Save in the File menu. 12. Repeat this exercise on the same subject while the subject is voluntarily contracting his or her quadriceps. 5See Answer
  • Q7: Downloaded via UNIV OF SHARJAH on February 25, 2024 at 21:05:23 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. ACS! Biomaterials SCIENCE & ENGINEERING pubs.acs.org/journal/abseba Engineering a Cortisol Sensing Enteric Probiotic Vaughn Litteral,* Rebecca Migliozzi, David Metzger, Craig McPherson, and Roland Saldanha Cite This: ACS Biomater. Sci. Eng. 2023, 9, 5163-5175 Metrics & More ACCESSI ABSTRACT: Chronic stress can lead to prolonged adrenal gland secretion of cortisol, resulting in human ailments such as anxiety, post-traumatic stress disorder, metabolic syndrome, diabetes, immunosuppression, and cardiomyopathy. Real time monitoring of chronic increases in cortisol and intervening therapies to minimize the physiological effects of stress would be beneficial to prevent these endocrine related illnesses. Gut microbiota have shown the ability to secrete, respond, and even regulate endocrine hormones. One such microbe, Clostridium scindens, responds transcriptionally to cortisol. We engineered these cortisol responsive genetic elements from C. scindens into an enteric probiotic, E. coli Nissle 1917, to drive the expression of a fluorescent reporter allowing for the designing, testing, and building of a robust and physiologically relevant novel cortisol probiotic sensor. This smart probiotic was further engineered to be more sensitive and to respond to elevated cortisol by expressing tryptophan decarboxylase, thereby bestowing the ability to generate tryptamine and serotonin. Here we show that upon cortisol treatment the smart probiotic produces measurable amounts of tryptamine. Accumulated levels of these neuromodulators should improve mood, anxiety, and depression and drive down cortisol levels. Importantly, this work can serve as a model for the engineering of a sense-and-respond probiotic to modulate the gut-brain axis. KEYWORDS: engineered probiotic, probiotics, smart probiotic, gut brain axis, Escherichia coli Nissle 1917, EcN, cortisol, glucocorticoid, 5-alpha-tetrahydrocortisol, adrenal, chronic stress, tryptophan, tryptophan decarboxylase, 5-HT, serotonin, trypta lysR transcription factor, bacterial sensor, Clostridium scindens, bacterial targeted gene integration, biosensor, sense and respond circuit INTRODUCTION The prevalence of anxiety, stress, and depression is ever increasing in modern societies. Mitigating the endocrine response in times of chronic anxiety, stress, and depression has historically been a challenge due to the endocrine system's intimate role in physiological homeostasis. Neuman et al.² demonstrated that endogenous microbial sentinels have been shown to both monitor and influence the endocrine system and ultimately human physiology. Probiotics show promise in restoring homeostasis in endocrine and immunological dysregulation. More recently, engineering probiotics as living diagnostics and therapeutics has allowed for a whole cell therapeutic approach with a beneficial metabolic potential that seems unlimited. Decades of research into the interplay between the gastrointestinal tract and the nervous system referred to as the gut brain axis (GBA) has revealed an intricate communication network shown to have a great impact in human health, development, and physiology. The GBA is a bidirectional communication system between the nervous system (central nervous system, autonomic nervous system, and enteric nervous system), and hypothalamus pituitary adrenal (HPA) axis with gut microbiota symbionts. Sudo et al. demonstrated that microbiota were essential for HPA develop- ACS Publications © 2023 The Authors. Published by American Chemical Society Read Online Article Recommendations 5163 T SI Supporting Information E. coli Nissle 1917 Ato/C:lysRtdc Chromosomal DNA lysR tryptophan tdc Received: November 1, 2022 Accepted: April 17, 2023 Published: August 30, 2023 LysR tryptophan decarboxylase (TDC) Article an tryptamine. Special Issue: Design and Evaluation of Engineered Probiotics Cortisol ment in germ free mice. Stressors, such as from the host inflammatory response and environmental factors, activate the HPA through the hippocampus release of CRF (corticotropin releasing factor), which in turn stimulates the pituitary to release ACTH (adrenal corticotropic hormone). ACTH stimulates specific cellular receptors, resulting in adrenal secretion of the stress hormone cortisol. While acute stress can be beneficial, chronic stress stimuli can lead to chronic cortisol secretion with detriments to human health and performance (i.e., anxiety, stress, post-traumatic stress disorder, diabetes, immunosuppression, cardiomyopathy, weight gain, and alcoholism). About 10% of cortisol is in active form and present in the blood circulation, whereas the remainder is bound to albumin or cortisol binding globulin protein. Cortisol and associated glucocorticoid metabolites regulate nearly every cell type in the body through the glucocorticoid 15 TOIC SACS materials https://doi.org/10.1021/acsbiomaterials.2c01300 ACS Biomater. Sci. Eng. 2023, 9, 5163-5175 ACS Biomaterials Science & Engineering 16 and mineralocorticoid receptors acting as seemingly global transcription factors in gene expression. Traditional ther- apeutic interventions into ameliorating the endocrine response is met with many adverse events in off target tissues as cortisol exerts this global but tissue specific gene expression response. ¹7 18-20 Noninvasive monitoring of free cortisol in sweat and saliva has evolved in recent years as an interest in the human performance and health monitoring industry as well as the United States Department of Defense. Cortisol in saliva, sweat and tears is indicative of blood levels and is a predictive biomarker in determining real time psychological stress.ª Gastro-intestinal glucocorticoid levels have been difficult to ascertain, wherein bacterial secondary metabolism of cortisol and resultant desmolysis occurs beginning in the large intestine. Ridlon et al. employed RNA-seq to investigate cortisol metabolism and its regulated gene expression in one such gut bacterium, Clostridium scindens. C. scindens demon- strated robust response in gene expression to the stress hormone, cortisol, and observed side chain cleavage of cortisol resulting in androgen gut metabolites. These studies showed further evidence that the gut microbiota have the innate ability to monitor the host endocrine stress molecule, cortisol, and influence the metabolic fate of these endocrine hormones. 21 23-25 26,27 In addition, it has been increasingly demonstrated that gut microbiota have additional and significant neuroendocrine roles in the GBA through secondary metabolism.²2 For example, the metabolic fate in the gut of ingested tryptophan, Trp, an essential amino acid, results in indoles, serotonin (5- hydroxytryptamine, 5-HT), tryptamines, melatonin, and kynurenine. All of these metabolites have a profound effect on host mood, anxiety, sleep, and/or stress. Trp metabolism is accomplished primarily through the kynurenine pathway (95%) resulting in nicotinamide dinucleotide (NAD +) production, while only minor amounts (1%) are converted to 5-HT. Dysregulation of the kynurenine pathway can lead to aging, various mental and neurodegenerative disorders, and chronic fatigue syndrome." Whereas 5-HT has been researched for more the 70 years, its intimate role in gut physiology is just recently being understood. 28 Cortisol stimulates 5-HT reuptake in peripheral circulation through Serotonin-selective Re-uptake Transporters (SERT) further affecting 5-HT levels.30 Ninety percent of 5-HT production occurs in intestinal enterochromaffin cells (EC), and 5-HT synthesis can be stimulated through 5-HTR4 activation by the trace amine tryptamine, wherein the gut-produced 5-HT is absorbed, stored, and distributed by platelets.³ Five of the seven known classes of serotonergic receptors (5-HT1 thru 5- HT7) are expressed throughout the gut. Activation of 5-HT2a receptor by intestinal 5-HT results in a block of TNFa and subsequent increase in SERT.³ The 5-HT is distributed by platelets throughout the circulation and plays an important role in hemostasis, peristaltic reflex, and gut physiology.³5 While 5- HT does not have the ability to cross the blood brain barrier, Trp does have the ability to cross and therefore directly contributes to central and peripheral 5-HT and melatonin levels. 35,36 Sequestering of Trp through microbial secondary metabolism in the gut leads to decreased Trp in the brain and can greatly affect its bioavailability for neuroendocrine roles. Corynebacterium spp., Streptococcus spp., and Escherichia coli have been shown to synthesize 5-HT in culture. Williams et al. evaluated bacterial tryptophan decarboxylase activity (a rare functionality for gut bacteria). In fact, there is an approximately 10% prevalence in the population as discovered by Fishbach in 31,32 33,34 35 37 29 5164 Article pubs.acs.org/journal/abseba 38 39 analyzing Human Microbiome Project data. Allowing for the tryptophan decarboxylase activity in the gut would result in an increase in tryptamine and subsequent stimulation of 5-HT production from EC cells, as well as biotransformations of 5- hydroxytryptophan directly to 5-HT. In the case of chronic stress, both in animal models and human studies, subjects greatly benefited through decreasing circulating cortisol levels by increasing 5-HT levels with SRIs (Serotonin Reuptake Inhibitors).36,40 41 42 In order to mitigate the debilitating effects of chronic stress, a promising transient strategy herein was conceived to restore normal physiology and function in the gut with a whole cell engineering approach. This study utilizes a well-characterized probiotic chassis that is able to withstand and colonize the harsh gastric intestinal environment. The only commercially available Gram-negative probiotic to date, E. coli Nissle 1917, EcN, was originally isolated from a World War I soldier that was able to surprisingly survive with dysentery.4¹ The EcN strain was also recently shown to increase 5-HT extracellular concentrations in an in vitro gut tissue model." An EcN smart probiotic with elements of Clostridium scindens to sense active glucocorticoids and respond by contributing the rare Trp decarboxylase activity (similar to Clostridium sporogenes) resulted in decarboxylase activity with some substrate promiscuity toward 5-hydroxytryptophan that would result in 5-HT metabolites as well as dietary tryptophan biotransforma- tion to tryptamine. In periods of chronic stress and elevated cortisol production, we predict the engineered probiotic in the gut would increase tryptamine and ultimately intestinal 5-HT production and distribution via induced promiscuous tryptophan decarboxylase activity. The intestinal and periph- erally distributed 5-HT would drive down circulating cortisol levels and likely would improve mood, anxiety, and depression. 43 Importantly, this effort models a stress-sensing and potentially neuro-modulating probiotic in in vitro systems that prove to mimic human physiology. 44 MATERIALS AND METHODS Materials. Restriction, DNA modifying enzymes, and polymerases were from New England Biolabs (Ipswich, MA, United States). Plasmid miniprep and PCR purification kits were from QIAGEN (Germantown, MD, United States). Synthetic DNA and oligonucleo- tides were obtained from Integrated DNA Technologies (IDT; Coralville, IA, United States). Unless otherwise indicated, all other chemicals and reagents were from Sigma (St. Louis, MO, United States) or Thermo Fisher Scientific (Waltham, MA, United States). 52 Bacterial Strains and Culture Conditions. Table S1 lists the E. coli strains used in this study. Figures S9-S11 display the workflow utilized for recombinant strain construction as further detailed by Yang et al. The wild type E. coli strain Nissle 1917, referenced herein as EcN (Mutaflor, DSM 6601, and serotype 06:K5:H1), was kindly supplied by Dr. A. Breedon. BW2511, JW0451-2, and JW5503-1 were obtained from the CGSC (Yale University, Dept. of MCB), E. coli NEBSalpha (cat# C2987H) strains were obtained from NEB. The E. coli strains were routinely maintained in Luria-Bertani (LB) or M9 minimal salts medium with or without 1.5% Bacto Agar (Difco Laboratories, Detroit, Mich., United States). Electrocompetent cells were prepared using Biorad's MicroPulser (BIORAD Hercules, CA) protocol for the preparation of E. coli electrocompetent cells; see Aususbel et al. and Miller and Nickoloff. 56,57 Ampicillin (50 ug/mL), apramycin (50-100 ug/uL), chloramphenicol (30 ug/mL), and kanamycin 25-50 ug/mL) were used for antibiotic selection in this study. Biotek Plate Assay. Mid log E. coli strains were used to inoculate a fresh culture in early log (OD 600 = 0.02). Glucocorticoids https://doi.org/10.1021/acsbiomaterials.2c01300 ACS Biomater. Sci. Eng. 2023, 9, 5163-5175 ACS Biomaterials Science & Engineering dissolved in culture media in 14 mm Falcon tubes (cat# 14-959-11B) with normalized DMSO 0.02-0.2% as a cosolvent and samples exposed to serially diluted glucocorticoid doses or DMSO and respective antibiotic selection. A kinetic plate assay was carried out with black/clear bottom Costar plates (cat# 3601) on a Biotek Neo2 multimodal plate reader. Both the OD 600 and the fluorescent wavelength(s) were monitored. The glucocorticoid dose response was normalized by OD600 and the EC50 was calculated with a nonlinear regression model. Data analysis was performed in Graphpad Prism 9.0. Tryptophan and Tryptamine Extraction. Following induction of tryptamine production, the culture samples were centrifuged at 16 000g for 1 min and then filtered through a 0.2 um filter, then the filtrate was treated with a 2x volume of 4N sodium hydroxide at pH 11. Next, phase extraction was performed with 1:1 with ethyl acetate, followed by mixing and centrifugation at 16 000g for 1 min to allow for phase separation. The resulting aqueous phase contained tryptophan and the organic phase captured tryptamine. Samples were subsequently prepared for HPLC analysis. Cloning and Construct Assembly. The overall cloning strategy used 2-5 DNA fragments produced from either DNA synthesis (gblocks), oligos or high-fidelity polymerase generated amplicons purified though Qiagen PCR or Qiaex gel extraction protocols. Following purification, fragments were assembled with NEB Builder HiFi Gibson Assembly using a total reaction volume of 5-10 µL. 10% of the HiFi reaction was transformed into NEB5a chemical competent cells and plated on selective media. After the plates were incubated for 18-24 h at 37 °C, individual colonies were selected for evaluation Bacterial Plasmid Construction. pLysE2Cr. The E2 crimson fluorescent reporter was designed to be under the control of LysR using the synthesized lysR with its bidirectional promoter (Genbank WP_004606447.1) included in the 250 bp upstream sequence (Figure S1) all cloned into the supplied pIDT bacterial expression vector, pIDT (kan¹), resulting in plasmid pLysRE2Cr. The lysR open reading frame (ORF) was codon optimized for E. coli expression using online in silico analysis tools provided by Integrated DNA Technologies (IDT, Coralville, IA). pLysRsfGFP. This plasmid was a gift from the U.S. Army Lab (Dr. Steve Blum) and was created by swapping the ORF of the sfGFP reporter for that of the E2 crimson reporter in plasmid pLysRE2Cr. pLysRTDC. The pLysRE2Cr plasmid was used as a PCR template for a 900bp fragment of the lysR gene (C. scindens), primed with lysR- F and lysR-R and amplified with Q5 high fidelity polymerase (NEB #M0491S). The tdc-1 (Tryptophan decarboxylase-1 from Oryza sativa) gene was synthesized by IDT as a 1.5kb fragment (see the supplemental sequence list for details) and was likewise used as a PCR template and amplified with Q5 high fidelity polymerase. The lysR and tdc-1 containing fragments were assembled via an NEB Builder HiFi Assembly kit into the XhoI/NotI sites of pAME200 (this plasmid was a gift from Dr. A. Breedon, USAF RHB) resulting in plasmid pLysTDC. PUC19lysRsfGFP-Plasmid. pLysRsfGFP was used as template with oligos to generate a linear fragment both assembled with either 200 bp or 1000bp of flanking tolC homology gblocks (See the supplemental sequence information for gblocks from IDT) assembled into the pUC19 BamH1/EcoR1 vector. PUC19lysRE2Crimson Plasmid. pLysRE2Crimson was used as templates with oligos to generate a linear fragment both assembled with either 200bp or 1000bp of flanking tolC homology gblocks (see supplemental sequence information for gblocks from IDT) assembled into the pUC19 BamH1/EcoR1 vector. PUC19lysRTDC Plasmids. pLysRE2Crimson was used as templates with oligos to generate a linear fragment both assembled with either 200 bp or 1000bp of flanking tolC homology gblocks (See Supplemental Sequence information for gblocks from IDT) assembled into the pUC19 BamH1/EcoR1 vector. Colony PCR. Colony PCR was performed by touching a standard 10 ul pipet tip into the center of the bacteria colony and transferred to the bottom of a 96-well PCR plate well. NEB Quick load 2X Taq PCR 5165 Article pubs.acs.org/journal/abseba master mix was added to each well on a cooling block and once the denaturation temperature of 95 °C was reached the samples were added to the thermocycler. The initial denaturation of the PCR was conducted for 2 min. NEB Quick load 2X Taq polymerase manufacture recommendations were followed. Standard PCR. Standard PCR employed either the NEB Quick load 2X Taq polymerase protocol for routine usage or the NEB HiFi Q5 polymerase protocol for cloning and assembly efforts in this study. Flow Cytometry Analysis. Following growth and glucocorticoid treatment, E. coli strains were diluted 1:40 in phosphate buffered saline (pH 7.4) with 20mM Hoechst 33342 DNA stain (Fisher Cat. No. H21492) and incubated at 37 °C for 10 min. Following Hoechst DNA staining, all cells were stored on ice until flow cytometry data acquisition. Samples were analyzed on a 5-laser BD FACSAria II cell sorter (BD Biosciences, San Jose, CA) with instrument setup performed using Cytometer Setup and Tracking Software (BD Biosciences). Hoechst was excited with a 355 nm laser and detected with a 450/50 filter. GFP was excited with a 488 nm laser and detected with a 525/50 nm filter. E2 crimson was excited with 561 nM laser and detected with a 670/30 nm filter. During acquisition, all parameters were collected in log mode. Data were collected and analyzed using FACSDiva 8.0 software (BD Biosciences). To reduce noise, the bacteria were cultured in sterile-filtered media and diluted in sterile-filtered PBS. Prior to acquisition, the background noise of the instrument was evaluated by analyzing water-only, sheath fluid-only, and PBS-only blank samples. Forward and side scatter gates were set to exclude noise and debris; the bacterial population, identified as Hoechst- positive cells, was further analyzed to identify single cells (FSC-height vs FSC-width, followed by SSC-height vs SSC-width). Positivity gates for the different fluorescent parameters were set after analyzing multiple controls (unstained/untreated culture, unstained/treated culture, stained/ untreated culture). Flow cytometry analyses are in the supplementary. 53 Gene Knockout Generation. Ato/C:CAT Knockout in E. coli Nissle 1917. A knockout strain was constructed using a traditional Red Recombination protocol by Datsenko and Wanner. The chloramphenicol acetyltransferase, CAT, gene in pKD3 was utilized as template to generate a CAT flanking 50 bp tolC homology PCR cassette (See Figure 4) using oligos C1 and C2. Electrocompetent EN1917 cells expressing the red recombinase helper plasmid, pKD46, were transformed with the resultant PCR product targeting the tolC gene. Cells recovered for 1 h and selection was performed on LB chloramphenicol plates (15 ug/mL). AtolC:Ap' Knockout in E. coli Nissle 1917. The apramycin resistance gene, Ap', in pMDIAI was utilized as a PCR template primed with oligos A1 and A2 to generate an Ap¹ PCR fragment with flanking 50 bp homology to tolC. According to a published protocol by Yang et al.,52 electrocompetent EcN cells expressing the pREDTKI plasmid were transformed with the PCR product targeting the tolC gene. Cells were recovered in 1 h and plated on LB apramycin selection plates (50 ug/mL) and individual colonies were selected for further analysis. 52 Targeted Gene Integration. Integration of donor cassettes from lysRsf GFP, lysRE2Crimson, and lysRtdc-1 into the tolC locus was accomplished according to published protocols by Yang et al.5² The intermediate strain AtolC:Ap¹ EcN was used as a recipient strain for targeted integration into the tolC locus. See Figures S11, S12, and S13 for workflow and an example of the screening and validation. Tryptamine Production. Early log (OD600 = 0.02) strains were grown in M9 media with 1% LB media and 2% glucose with 6 mM L- tryptophan and were maintained under selection of chloramphenicol 30ug/mL. Following an OD600 = 0.2, cultures were induced with the stated quantities of cortisol. Cultured samples were collected at the stated times and centrifuged at 16 0000g for 1 min to remove biomass and were subsequently prepared for chemical analysis. 1. RESULTS AND DISCUSSION 2.1. Designing a Novel Cortisol Biosensor. To design a real-time probiotic stress sensor, the bacterial chassis, E. coli https://doi.org/10.1021/acsbiomaterials.2c01300 ACS Biomater. Sci. Eng. 2023, 9, 5163-5175 ACS Biomaterials Science & Engineering 45-47 Nissle 1917 was employed, due to the probiotic's ability to survive the challenging gastrointestinal environment and its reported use as a framework for synthetic biology. The use of a whole cell approach affords the ability to utilize a transcription factor responsive to cortisol that can activate a downstream transcriptional response (i.e., reporter gene or stress-reducing factor). Published RNA-seq data for C. scindens ATCC 35704 demonstrated an effect for its neighboring regulon upon exposure to cortisol (Figure S1).³ LysR-type transcriptional regulators (LTTRs) are the largest prokaryotic class of transcription regulators. In C. scindens, LysR regulates its own transcription as well as its native divergently transcribed gene product. When LysR disassociates from its own promoter, lysR transcription is active, whereas when bound to the coinducer (i.e., cortisol), promoter activation results in transcription of the divergently located gene (Figure 1). Based on this design, the lysR nucleotide sequence was LysR lysR LysR LysR I Co LysR Co lysR Figure 1. Schematic of the LysR regulation of transcription in Clostridium sp. placed under native control elements for expression in E. coli K-12 and EcN strains and evaluated activation of various LysR responsive reporter genes upon cortisol induction. 2.2. Employing a Novel Cortisol Biological Recog- nition Element, BRE. In Clostridium sp. Ridlon et al. demonstrated that the lysR and its divergently transcribed gene product is transcriptionally active in the presence of cortisol, based on RNA-seq data analysis.³ Preliminary analysis was performed in order to determine if the lysR operon had the ability to function as a glucocorticoid transcriptional driven sensor, by employing the Clostridium scindens lysR native control elements driving the bidirectional expression of the E2 Crimson fluorescent reporter protein. The E2 Crimson fluorescent protein has an excitation maximum at 611 nm and emission maximum at 646 nm, is nontoxic to bacteria and performs well with live animal imaging.* The pLysE2Cr plasmid bears the kanamycin resistance gene and the pMB1 origin of replication. Chemical transformed E. coli K-12 and EcN bearing the plasmid pLysE2Cr following mid log growth were evaluated for their dose response to cortisol by measuring fluorescence with a plate reader and flow cytometry. In Figure 2, the schematic demonstrates that the LysR negatively regulates its own transcription (gold) and positively regulates the divergent reporter gene (green) with putative LysR responsive promoters (blue). Exposing the EcN probiotic bearing the pLysE2Cr to varying doses of cortisol (coinducer in Figure 2) at mid log demonstrated a definitive dose response 48 5166 pubs.acs.org/journal/abseba curve with an EC50 of 158 µM and is supra-physiological, whereas the normal human physiological cortisol concen- trations in plasma observe a diurnal variation and range between 80 and 700 nM, and the water solubility of cortisol is 772 μM. Multiparametric flow cytometry analysis was used in this study, since it affords reproducible and accurate functioning at the single cell level and fluorescent reporter proteins afford accurate representations of isogenic cultures. In the EcN wild type strain bearing the pLysE2Cr plasmid, E2 Crimson fluorescent protein expression was evaluated via flow cytometry following incubation with varying concentrations of cortisol. In Figure 2, the top panel/density plots, show a dose- dependent shift of the cell population into the E2 Crimson positive gate, indicating an increased percentage of cells expressing E2 Crimson in response to cortisol. In Figure 2, the bottom panel histograms show a dose-dependent increase in the population's median fluorescence intensity with increasing cortisol concentration. Evaluation of additional reporters such as sfGFP and iLuX (Figure S3) gave similar results. 2.3. Cortisol BRE Selectivity for a-THF, an Active Cortisol Metabolite. In an effort to determine the glucocorticoid specificity of the sensor, varying concentrations of cortisol and its associated metabolites were evaluated on early growth phase EcN bearing the engineered pLysE2Cr plasmid. Both cortisol and its active metabolite 5-alpha- tetrahydrocortisol (THF) were able to transactivate LysR and drive E2Cr reporter expression in similar percentage of the cell population (73% and 59%, respectively) as demonstrated in the density and histogram plot in Figure 3B. Furthermore, cortisol and THF demonstrated robust dose responses with similar EC50 values (213 µM and 150 μM respectively, Figure 3C). The inactive cortisol metabolite of cortisone, 5-beta- tetrahydrocortisone (THE), was unable to initiate the E2Cr reporter in a dose dependent fashion (Figure S4), further indicating the selectivity of the pLysE2Cr sensor for active glucocorticoids. Article 49 The lumen of the gut is a harsh environment with additional cortisol analogs present, such as bile salts. Bile salts are amphipathic steroid molecules found exclusively in the G.I. tract and bile salts are critical for the absorption of dietary lipophilic foodstuffs in the lumen of the small intestine because of their capacity to form micelles spontaneously in a concentration dependent manner. Deoxycholate (DOC), a secondary bile salt (typically present at 20 µM to 100 µM in the small intestines) was investigated to see if DOC would elicit a response with the LysR sensor. DOC afforded a dose response (Figure S5) with an EC50 of 1.5 mM, although these supra-physiological (>1 mM) quantities of DOC proved deleterious to ECN growth (Figure S5).5⁰ 2.4. Targeted Ablation of Glucocorticoid Efflux in E. coli Nissle 1917 to Improve Glucocorticoid Sensor Sensitivity. Although the LysR sensor is able to selectively recognize cortisol (Figure 3), the limit of cortisol detection by the LysR sensor in the wild type EcN host is not physiological relevant (EC50 = 158 µM) and requires further improvements. Available acrAB and tolC mutants (Keio collection mutants JW0451 and JW5503) generated in the wild type parental strain E. coli BW25113 were tested for cortisol sensitivity. Both acrAB and tolC mutants demonstrated a 2-log improvement in cortisol sensitivity (Figures S6 and S7). Following this, the tolC locus was ablated in EcN by directing the chloramphenicol acetyltransferase gene (CAT) gene to the tolC locus using Red homologous recombination (data not shown). PCR- https://doi.org/10.1021/acsbiomaterials.2c01300 ACS Biomater. Sci. Eng. 2023, 9, 5163-5175 ACS Biomaterials Science & Engineering A. B. C. 530/30 Blue-A 10² 10³ 104 D. LysR family TF Regulator -57 plysE2 Crimson lysR ΟμΜ Singlets 0 10 -81 %E2Cr+, Normalized Response 10 0 10 10 105 E2Crimson 670/30 YG-A Singlets 0% E2Crimson+ E2Crimson MdFI 10⁹ 10 10° E2Crimson 670/30 YG-A 100 50 10⁰ 530/30 Blue-A -65 -65 10² 62.5 μΜ Singlets 0 10² 10 Singlets pubs.acs.org/journal/abseba 10 10 E2Crimson 670/30 YG-A verified AtolC:CAT ECN mutants (data not shown) were transformed with the pLysE2Cr plasmid (Figure 4A) and 10 0.6% E2Crimson MdFI 0 10² 10ª 105 E2Crimson 670/30 YG-A E2Crimson+ 5167 reporter/response E2 Crimson 530/30 Blue-A 10² 10³ 104 105 106 Count 500 1.000 1.500 2,000 46 pMB1 ori 0 125 μM Singlets TIMME TIITING. ITIINI 10 10ª 10$ E2Crimson 670/30 YG-A 28% E2Crimson+ Singlets E2Crimson MdFI 10⁰ E2Crimson 670/30 YG-A 10² 10ª 10⁰ 158μM = EC50 104 [Cortisol nM] Figure 2. A novel cortisol responsive transcription factor drives reporter expression. (A) Schematic of the LysR operational unit, where LysR negatively regulates its own promoter and lysR (gold) and drives the expression of the reporter or response gene (green). (B) Plasmid map of pLysE2 Crimson. (C) Flow cytometric analysis of pLysE2 Crimson in EcN with 0, 62.5, and 125 uM of cortisol. Top row, density plots: the gates are indicative of positive E2 Crimson expression. Bottom row, histograms: the interval gates measure the MdFI, median fluorescence intensity. (D) Cortisol dose response curve (EC50 = 158 uM) of pLys E2Crimson in wild type EcN. Article evaluated in mid log cultures for a cortisol dose response (Figure 4C). The AtolC:CAT mutation in EcN enhanced https://doi.org/10.1021/acsbiomaterials.2c01300 ACS Biomater. Sci. Eng. 2023, 9, 5163-5175/nSee Answer
  • Q8: Dovepress INTERNATIONAL JOURNAL OF NANOMEDICINE OPEN ACCESS International Journal of Nanomedicine Growth Factor and Its Polymer Scaffold-Based Delivery System for Cartilage Tissue Engineering a ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/dijn20 Li Chen, Jiaxin Liu, Ming Guan, Tongqing Zhou, Xin Duan & Zhou Xiang To cite this article: Li Chen, Jiaxin Liu, Ming Guan, Tongqing Zhou, Xin Duan & Zhou Xiang (2020) Growth Factor and Its Polymer Scaffold-Based Delivery System for Cartilage Tissue Engineering, International Journal of Nanomedicine,, 6097-6111, DOI: 10.2147/IJN.S249829 To link to this article: https://doi.org/10.2147/IJN.S249829 CrossMark © 2020 Chen et al. Published online: 14 Aug 2020. bmit your article to this journal Article views: 433 QView related articles View Crossmark data Citing articles: 61 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=dijn20 Taylor & Francis Taylor & Francis Group International Journal of Nanomedicine Open Access Full Text Article Growth Factor and Its Polymer Scaffold-Based Delivery System for Cartilage Tissue Engineering 1,2,* Li Chen Jiaxin Liu¹›* Ming Guan 2,3 Tongqing Zhou² Xin Duan' I Zhou Xiang 'Department of Orthopedics, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China; 2School of Dentistry, University of Michigan, Ann Arbor, MI, 48109, USA; ³Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China *These authors contributed equally to this work Correspondence: Xin Duan Tel +86-28-85422426 Email dxbaal@hotmail.com Zhou Xiang Tel +86-28-85422605 Email xiangzhou15@hotmail.com submit your manuscript | www.dovepress.com DovePress in http://doi.org/10.2147/1JN.S249829 This article was published in the following Dove Press journal: International Journal of Nanomedicine Dovepress open access to scientific and medical research REVIEW Abstract: The development of biomaterials, stem cells and bioactive factors has led to cartilage tissue engineering becoming a promising tactic to repair cartilage defects. Various polymer three-dimensional scaffolds that provide an extracellular matrix (ECM) mimicking environment play an important role in promoting cartilage regeneration. In addition, numer- ous growth factors have been found in the regenerative process. However, it has been elucidated that the uncontrolled delivery of these factors cannot fully exert regenerative potential and can also elicit undesired side effects. Considering the complexity of the ECM, neither scaffolds nor growth factors can independently obtain successful outcomes in carti- lage tissue engineering. Therefore, collectively, an appropriate combination of growth factors and scaffolds have great potential to promote cartilage repair effectively; this approach has become an area of considerable interest in recent investigations. Of late, an increasing trend was observed in cartilage tissue engineering towards this combination to develop a controlled delivery system that provides adequate physical support for neo-cartilage formation and also enables spatiotemporally delivery of growth factors to precisely and fully exert their chon- drogenic potential. This review will discuss the role of polymer scaffolds and various growth factors involved in cartilage tissue engineering. Several growth factor delivery strategies based on the polymer scaffolds will also be discussed, with examples from recent studies highlighting the importance of spatiotemporal strategies for the controlled delivery of single or multiple growth factors in cartilage tissue engineering applications. Keywords: polymer scaffold, growth factor, delivery, cartilage repair Introduction Articular cartilage is a specific type of connective tissue that covers the articular surfaces of the bone; it is mainly composed of a dense extracellular matrix (ECM) and a sparse cell population. It plays an essential role in the biomechanical functions of the joints, including shock absorption, sheer resistance and load bearing.² Once articular cartilage is damaged, it has a limited potential for sponta- neous repair due to the lack of vascularity, nerves and lymphatics. This can result in joint pain, swelling, dysfunction, and eventually lead to osteoarthritis (OA).³,4 In the past two decades, OA has been the most common form of arthritis accounting for approximately 300 million patients worldwide and undoubtedly has been considered as one of the most significant health problems that also pose a substantial financial burden on the public health system, and the patients themselves. Currently, conservative treatments, including pharmacological and non-pharmacological therapies, are commonly applied to improve joint pain, reduce stiffness and improve physical function in patients with OA. However, the therapies сс International Journal of Nanomedicine 2020:15 6097-6111 02 Ⓒ2020 Chen et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php NC and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). 6097 Chen et al 7-10 cannot prevent further joint degeneration. Surgical strate- gies are also designed to treat cartilage defects, including autologous chondrocyte implantation (ACI), microfrac- ture, osteochondral grafts and total joint arthroplasty. However, they have some inherent shortcomings such as the requirement of secondary surgery, immunogenic responses, shortage of donor tissues and pathogen trans- mission risks. Alternatively, cartilage tissue engineer- ing, which involves combining cells, scaffolds and growth factors, has emerged as a promising strategy for cartilage repair.¹¹ Meanwhile, the methods of minimally invasive surgery, including the implantation and injection, are an important component of clinical translation of tissue engi- neering techniques which have been verified in vitro. ¹2 In general, scaffolds as biologically active ECM provide mechanical support for cell growth and chondrogenic dif- ferentiation, which could be beneficial for stimulating and accelerating the cartilage regeneration process. With the development of chemistry and processing, numerous synthesized and natural materials have been applied to fabricate scaffolds that successfully promote the cartilage regeneration without noticeable signs of immune response and rejection. ¹3-15 12 16,17 While biomimetic three-dimensional scaffolds have been made, they cannot create high-quality cartilage tissue independently. Stem cells, pluripotent cells and native progenitor cells are commonly used in combination with scaffolds to accelerate and improve the regeneration process. Moreover, cell-based therapies are influenced by the cellular microenvironment to some extent. Growth factors are of high importance as they have the potency to induce and enhance cellular responses, which is beneficial for the cells as they need to differentiate into desired lineages.¹8 Although scaffolds can obtain sufficient growth factors from the culture medium under in vitro conditions, the incorporated growth factors can spread out of the scaffolds and degrade in a short time in vivo. Besides, different dosages and delivery rates are required for dif- ferent growth factors to induce the cells in in vitro or in vivo conditions. Today, a plethora of studies have been conducted to investigate the delivery of single or multiple growth factors from the scaffolds in a defined 18 19,20 manner. This review examined the delivery of growth factors for cartilage tissue engineering, with an emphasis on the polymer scaffold-based approaches. First, the aim is to enable an understanding of current applications of polymer scaffolds, following with the descriptions of different 6098 submit your manuscript | www.dovepress.com DovePress Dovepress growth factors involved in cartilage tissue engineering. A latter section will place a particular emphasis on the growth factor delivery strategies associated with polymer scaffolds. Finally, the current challenges and suggestions of polymer scaffold-based growth factor delivery for car- tilage tissue engineering are explained. Polymer Scaffolds Articular cartilage, with its unique mechanical properties pro- vides the contact surfaces for load transfer between bones, which enables the joint to withstand weight-bearing. The ability to do so is attributed to its complex structure comprised of a fluid phase and a solid matrix that is composed mainly of a depth-dependent collagen fibrous network and proteogly- cans, as well as other types of proteins, lipids, and cells. Therefore, the scaffold suitable for cartilage tissue engineering should have good biocompatibility for cell adhesion, migra- tion and proliferation, and also provide appropriate mechanical and structural support. In addition, biodegradability and being free of adverse reactions are basic properties required for a three-dimensional scaffold mimicking physiological characteristics.2¹ Currently, a wide range of natural and syn- thetic polymers play an important role in the development of scaffolds for cartilage tissue engineering. Due to superior biocompatibility and biodegradation, natural polymers like collagen, chitosan, silk fibroin, alginate, hyaluronic acid and chondroitin sulfate are suitable for initiating a fast regeneration process. However, potential pathogen transmission, immuno- genicity and poor mechanical properties limit their clinical application. On the other hand; synthesized polymers can artificially regulate the degree of polymerization, thereby con- trolling its mechanical properties, internal structure and degra- dation, which can effectively promote the regeneration process. Poly (lactic acid) (PLA), poly glycolic acid (PGA), poly lactide-co-glycolic acid (PLGA) and poly caprolactone (PCL) are the most commonly synthesized polymers in the application of three-dimensional scaffolds for cartilage tissue engineering.23 When comparing these to natural polymers, the properties of synthetic polymer-based scaffolds are consider- ably different in terms of their tunable properties, such as molecular weight, transition temperatures and crystallinity.24 Polymer nanofibers have been extensively studied due to their ability to encapsulate and deliver growth factors for different tissue regeneration purposes. Nanofiber scaf- folds with high surface to volume ratio and interconnected porous structure, seem to hold the lead position as the ideal candidate for cartilage tissue engineering. They play a role in stimulating the ECM environment, allowing 21 International Journal of Nanomedicine 2020:15 Dovepress cells to populate empty spaces and organize themselves, and mechanical stimulation can be applied to this porous structure to orient the cells and maintain a chondrocyte phenotype. As a result, scaffolds will be degraded and replaced by newly formed ECM, without producing adverse effects due to the degradation products. To date, various technologies such as electrospinning, phase separation, self-assembly, drawing and template synthesis have been applied in attempts to optimize nanofiber scaf- folds to make them more consistently bioactive and mechanically stable for effective tissue regeneration application. For example; a nanofibrous scaffold was developed that was highly porous, interconnected and degradable. It was developed using phase separation of poly l-lactic acid (PLLA) solutions combined with poro- gen leaching techniques. Through a series of characteristic tests, chondrogenic evaluations in vitro and in vivo demonstrated that this nanofibrous PLLA scaffold is an excellent candidate providing an advantageous three- dimensional microenvironment for a wide variety of car- tilage repair strategies (Figure 1).² 27-29 Growth Factors 30 Growth factors are a group of peptides that mediate cel- lular proliferation, migration and differentiation by bind- ing to transmembrane receptors located on target cells. When a sufficient number of receptors are activated, the signaling transduction process may trigger a series of specific cellular activities.³0 Concerning cartilage develop- ment, growth factors play an essential role in regulating the processes of chondrogenesis and hypertrophy, such as the members of transforming growth factor-ß (TGF-B) superfamily, insulin-like growth factor-1 (IGF-1), fibro- blast growth factor (FGF) family and platelet-derived growth factor (PDGF). In order to provide a better under- standing of their potential, descriptions of their roles involved in the regeneration and maintenance of articular cartilage will now be described (Table 1). Transforming Growth Factor-B Superfamily The TGF-ß superfamily is comprised of more than 30 closely related polypeptides, mainly including typical TGF-ßs, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and activin/inhibin, which regulate multiple cell functions from early develop- ment to regulating homeostasis throughout adult life.³1 31 International Journal of Nanomedicine 2020:15 Chen et al A large number of studies have shown that they have significant regulatory effects on the homeostasis and repair of articular cartilage. Transforming Growth Factor-B TGF-B is a dimer with a molecular weight of 25 kilo Daltons (kDa) that is composed of two identical or similar chains. There are three isoforms (1-3) that are generally considered to be potent stimulators in all stages of chon- drogenesis with a function of inducing proteoglycans and type II collagen synthesis. ³2 TGF-ß signaling transduction is based on the membrane-bound heteromeric receptors (type I and type II). Binding to type II receptors leads to the phosphorylation of type I receptors, causing the phos- phorylation of TGF-B specific Smad proteins, particularly Smad 2 and 3. In addition, some Smad-independent pathways, including p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (Erk) and stress-activated protein kinase/c-Jun NH(2)-terminal kinase (SAPK/JNK) can also be activated by TGF-B.³4 33 34 35 TGF-B is one of the main initiators of chondrogenesis of mesenchymal precursor cells, and the differentiation of mesenchymal stem cells (MSC) into chondrocytes also requires its stimulation. The expression of N-cadherin was induced by strong stimulation of TGF-ß to enhance cell adhesion and aggregation, and subsequently promote cell proliferation, differentiation and deposition of the cartilage- specific extracellular matrix.³5 Among these three isoforms, TGF-B1 was the first to be discovered, and TGF-ß1 and TGF- 33 have been used in a large number of studies to explore the effect of TGF-B on the repair of cartilage after it defects. Although some studies suggest that the ability of TGF-32 and TGF-33 to promote cartilage differentiation may be more superior to that of TGF-31, there is a consensus that there is no significant difference among the three TGF-B isoforms regarding their ability to promote cartilage differentiation. 36,37 In a Sprague-Dawley rat full-thickness cartilage defect model, Lentivirus-TGF-ß1-EGFP transduced BMSCs/calcium alginate gel significantly improved the amount of glycosaminoglycan (GAG) and type II collagen in the defect area in the early stage via activating the Smad pathway, when compared to a BMSCs/calcium alginate gel without TGF-31 transfection. Hypertrophy markers gene expression of chondrocytes were also inhibited by increasing Yes-associated protein-1 (YAP-1).38 Additionally, TGF- 31-incorporated collagen vitrigel had a better effect on mana- ging the early pain mitigation and osteochondral defect repair compared to collagen vitrigel alone.39 Moreover, BMSC submit your manuscript | www.dovepress.com DovePress 6099 Chen et al A Acc. V Magn 10.0kV 100x C 6100 E 200m were induced for the first 4 days with transient soluble TGF- B1, in which the accumulation of proteoglycans was 10-fold higher than TGF-B1-free culture after 3 weeks. These results suggest that TGF-ß promotes chondrogenic differentiation mainly depends on the extent of stimulation of the first week. 40 Nevertheless, there are still some studies that do not support the role of TGF-ß in cartilage repair in vivo. In a rabbit osteochondral defect model, oligo polyethene glycol B D submit your manuscript | www.dovepress.com DovePress F Figure I Nanofibrous PLLA scaffolds induce cartilage regeneration in vitro and in vivo. (A) SEM micrographs of nanofibrous PLLA scaffolds with macro-porous structures (Scale bar: 200 µm). (B) SEM micrographs of the nanofibrous microstructure of the pore walls at a higher magnification (Scale bar: 10 µm). (C) H&E staining showed that BMSCs grew throughout the whole scaffolds after 4 weeks in vitro chondrogenic culture on nanofibrous PLLA scaffold (Scale bar: 200um). (D) Alcian blue staining showed a dense GAG matrix deposition after 4 weeks in vitro chondrogenic culture on nanofibrous PLLA scaffold (Scale bar: 100 µm). (E) H&E staining revealed that BMSCs/ nanofibrous PLLA scaffold constructs had typical cartilage morphology after 8 weeks implanted in nude mice (Scale bar: 200 µm). (F) Safranin-O staining showed that BMSCs/nanofibrous PLLA scaffold constructs were positive for GAG-containing matrix in vivo (Scale bar: 200 µm). 10 mm. Notes: Reprinted from Gupte MJ, Swanson WB, Hu J, et al. Pore size directs bone marrow stromal cell fate and tissue regeneration in nanofibrous macroporous scaffolds by mediating vascularization. Acta Biomater. 2018;82:1-11. Copyright (2018), with permission from Elsevier.27 Dovepress (PEG) fumarate (OPF) hydrogel composites containing gela- tin microparticles (GMPs) loaded with MSCs with or without TGF-B1 did not improve cartilage morphology. Besides, undesirable side effects such as synovial fibrosis, endochon- dral ossification and hypertrophic scars were observed in vivo after a continuous stimulation by TGF-B1.4 Therefore, it is crucial to properly deliver and present TGF- ẞs in vivo for cartilage regeneration. 42-44 International Journal of Nanomedicine 2020:15See Answer
  • Q9: In last week's activity, you summarized health information technology (HIT) areas of concern from the Villa Health Informatics Infrastructure scenario. This week, you will select and examine a HIT device or system designed to both improve the quality of patient care and confer cost efficiencies or savings within a clinical setting. Preparation Choose and research a widely adopted HIT device or system designed to improve the quality of patient care while conferring cost efficiencies or savings within a clinical setting. Some examples include but are not limited to: ● ● ● ● Note: Choose a generic solution type, not a specific one made by a particular manufacturer. Instructions Conduct a rigorous evaluation of the HIT solution that you have selected in which you: Briefly describe the solution and summarize why it has been widely adopted. Evaluate a significant improvement to patient care that this HIT claims to confer that considers the most prominent arguments for its adoption. Provide a specific example to illustrate. Compare the cost savings or efficiencies of deploying the solution versus a commonly used alternative(s) that would effectively inform a decision to adopt it or not. ● ● Electronic medical records (EMRS). Imaging systems. Emergency room technology. Robotic surgery. Telemedicine. ● O The reason multiple alternatives might need to be considered is that some alternatives may require more than one system or "solution" to achieve similar results to the system that you have identified. Describe the resources that are required to implement, maintain, and run your chosen HIT in sufficient detail to inform a decision to adopt it. Describe the common barriers to adopting this technology. Select one and share a way(s) that providers have effectively overcome that barrier. Use at least five sources to support your writing. Choose sources that are credible, relevant, and appropriate. This course requires the use of Strayer Writing Standards (SWS). The library is your home for SWS assistance, including citations and formatting. Please refer to the Library site for all support. Check with your professor for any additional instructions. The specific course learning outcome associated with this assignment is: Evaluate health care technology, informatics, and quality assurance. View Rubric Week 10 Assignment - HIT Evaluation Week 10 Assignment - HIT Evaluation Criteria Describe a HIT solution and provide a plausible explanation of why it has been widely adopted. (20%) view longer description Ratings 40 to >36 pts Exemplary Described a HIT solution and provided a plausible explanation of why it has been widely adopted. 36 to >32 pts Competent Described a HIT solution but failed to provided a plausible explanation of why it has been widely adopted. 32 to >28 pts Needs Improvement Described a widely adopted HIT solution. 28 to >0 pts Unacceptable / 40 pts Pts Week 10 Assignment - HIT Evaluation Week 10 Assignment - HIT Evaluation Criteria Evaluate a significant improvement to patient care that a HIT claims to confer that considers the most prominent arguments for its adoption. Provide a specific example to illustrate. (20%) view longer description Ratings Did not describe a widely adopted HIT solution. 40 to >36 pts Exemplary Evaluated a significant improvement to patient care that a HIT claims to confer that considers the most prominent arguments for its adoption. Provided a specific example to illustrate. 36 to >32 pts Competent Evaluated a significant improvement to patient care that a HIT claims to confer that considers the prominent / 40 pts Pts Week 10 Assignment - HIT Evaluation Week 10 Assignment - HIT Evaluation Criteria Compare the cost savings or efficiencies of deploying the solution vs. a commonly used alternative(s) that would effectively inform a decision of whether or not to adopt it. (20%) Ratings arguments for its adoption but failed to provide a specific example to illustrate. 32 to >28 pts Needs Improvement Described an improvement to patient care that a HIT claims to confer, or provided an evaluation with significant errors or omissions. 28 to >0 pts Unacceptable Did not described an improvement to patient care that a HIT claims to confer. 40 to >36 pts Exemplary / 40 pts Pts Week 10 Assignment - HIT Evaluation Week 10 Assignment - HIT Evaluation Criteria view longer description Ratings Compared the cost savings or efficiencies of deploying the solution vs. a commonly used alternative(s) that would effectively inform a decision of whether or not to adopt it. 36 to >32 pts Competent Compared the cost savings or efficiencies of deploying the solution vs. a commonly used alternative(s) that would inform a decision of whether or not to adopt it, but with small errors or omissions. PtsSee Answer
  • Q10: Introduction "Being in a position of leadership is the most important job of any health professional anywhere along the continuum of care" (Ledlow & Coppola, 2013, p. 3). Leaders and ultimately the boards of directors of health care organizations are accountable for the safety of those they serve." National quality organizations and regulatory bodies . . . are growing in their emphasis on leadership accountabilities for safe, reliable care as well as excellence in the experience of care" (Youngberg, 2013, p. 39). With this emphasis on leadership accountability for the delivery of safe, high-quality health care services, health care leaders need to be able to drill down on what exactly safety and quality mean in the health care environment. Likewise, they also need to be able to design measures that help to ensure their organizations are able to deliver those kinds of outcomes. Read the short document Measurement Perspectives [PDF] Download Measurement Perspectives [PDF]to examine key elements related to this issue. In this final course assignment, you will have a unique opportunity to examine a health care organization's safety and quality dashboard from the perspective of four organizational leaders. You will explore each leader's specific interests regarding patient safety and quality. In particular, you will have the opportunity to perform a more in-depth analysis of the dashboard, the type of analysis a quality director might perform to further the organization's safety and quality objectives. Preparation To successfully complete this assignment: Review the Vila Health: Mercy Hospital Safety and Quality Dashboard [PDF] Download Vila Health: Mercy Hospital Safety and Quality Dashboard [PDF], which contains the data you will use for this assignment. Review the Analyze and Apply Dashboard Data Template [PPT] Download Analyze and Apply Dashboard Data Template [PPT], which you will use to create your presentation. ● • Consult the readings provided in Week 8. ● Instructions Base your assignment on the Vila Health: Mercy Hospital Safety and Quality Dashboard [PDF] Download Vila Health: Mercy Hospital Safety and Quality Dashboard [PDF]. Note: You do not need to create a dashboard for this assignment. You are simply being asked to work with the one provided here. The CEO has asked each of the organizational leaders below to prepare a joint PowerPoint presentation. In the presentation, you are to prepare a set of slides from the perspective of each of the following roles outlining their analysis of how the new numbers will inform their particular activities for the next quarter. The organizational leaders include: ● ● ● Because of the quality director's critical role in implementing the organization's safety and quality strategic objectives, this individual will open the presentation and provide additional background about how the new dashboard was developed. This individual will also close the presentation. Use the following outline to organize your presentation. Be sure to include the introduction and conclusion and address all the questions listed under these headings. Be sure to address each role and the corresponding questions. Use the Analyze and Apply Dashboard Data Template [PPT] Download Analyze and Apply Dashboard Data Template [PPT]to address the following: ● ● The quality director. The patient safety officer. The risk manager. Senior leadership. ● ● Introduction (1-2 slides) Evidence-Based Actions to Improve (2-3 slides): Recommend evidence- based actions to improve a selected measure on a health care organization's safety and quality dashboard. O O What is a safety and quality dashboard? What role do safety and quality dashboards play in helping health care organizations drive their strategic safety and quality objectives? O What measure on the health care organization's safety and quality dashboard was selected? What evidence-based actions to improve the selected measure are being recommended? Metrics Selection (3-4 slides): Describe how a health care organization chooses the metrics to include in its safety and quality dashboard. How do health care organizations determine what they want to measure? Be sure to consider: Pressures from regulators, payors, and the industry. Self-identified improvement areas. For example, one organization's safety and quality dashboard may highlight patient falls because its rate of falls is higher than the national average. This may also have resulted in increased costs to the organization. O What CQI tools did the organization use to obtain, measure, and report data? O What was the quality improvement team's role in addressing the reported measures? Quality Director (2-3 slides): Analyze areas of a safety and quality dashboard of concern to a quality director. ■ ■ ● ● ● ● O O What (if any) quality models could be used to increase the quality of patient care and outcomes for this metric? Consider PDCA, Six Sigma, Lean, Hoshin Kanri planning, et cetera. Patient Safety Officer (2–3 slides): Analyze areas of a safety and quality dashboard of concern to a patient safety officer. Which metric on the dashboard would draw the patient safety officer's attention the most? What does this dashboard metric mean and why is it important? O O Which metric on the dashboard would draw the quality director's attention the most? What does this dashboard metric mean and why is it important? What three recommendations to leadership would help to address this metric? Risk Manager (2–3 slides): Analyze areas of a safety and quality dashboard of concern to a risk manager. Which metric on the dashboard would draw the risk manager's attention the most? O O What role does the patient safety officer play in improving this metric? O What does this dashboard metric mean and why is it important? O What role does the risk manager play in improving this metric? Senior Leadership (1 slide): Assess senior leadership's role in setting a health care organization's strategic safety and quality objectives. What is the role of senior leadership (for example, CEO, COO, president, or senior VP) in driving safety and quality improvement initiatives? What next steps might senior leadership take, given the dashboard findings and the quality director's three improvement recommendations? Conclusion (2-3 slides) O Which regulatory agencies may be concerned about the findings in this dashboard? O Why would regulators be concerned about these findings? o Why are safety and quality dashboards important for monitoring key metrics in health care organizations? Your slides need to be concise and offer main ideas in bulleted format. Use the speaker notes to expand upon your findings as if they were the transcript of your presentation for the leadership team. In the health care environment, it is unlikely for a presentation and speaker notes to be in APA style. Do make sure your presentation is concise, organized, clear, and free of errors in grammar, punctuation, and spelling. Do make sure the presentation addresses all the required headings and all of the questions under each heading. Your senior leaders will want to know the sources of your information. Be sure to cite your sources in APA style in your speaker notes. Please review the Analyzing and Applying Dashboard Data Scoring Guide to ensure you understand the grading requirements for this assignment. Additional Requirements Your assignment should also meet the following requirements: ● ● ● ● Template: Use the Analyze and Apply Dashboard Data Template [PPT] Download Analyze and Apply Dashboard Data Template [PPT]to complete this assignment. Dashboard: Use the data included in the Vila Health Mercy Hospital Safety and Quality Dashboard [PDF] Download Vila Health Mercy Hospital Safety and Quality Dashboard [PDF]. References Ledlow, G. R., & Coppola, M. N. (2013). Leadership for health professionals (2nd ed.). Jones & Bartlett Learning. Youngberg, B. J. (2013). Patient safety handbook (2nd ed.). Jones & Bartlett Learning. Competencies Measured By successfully completing this assignment, you will demonstrate your proficiency in the following course competencies and scoring guide criteria: ● Length: A maximum of 20 slides, including title and reference slides. Format your title and reference slides according to current APA format. Slides should be 3-5 bullet points, 5 -7 words per bullet point, using size 24 font. Speaker notes: Be sure to include these with your slides. They provide an opportunity for you to expand on the information you are highlighting in your slides. Speaker Notes should use size 12 font, single spaced, paragraph indented. Number of references: A minimum of two references. In-text citations should be provided in the Speaker Notes section. Competency 1: Analyze the quality and performance improvement activities within the health care organization. O Recommend evidence-based actions to improve a selected measure on a health care organization's safety and quality dashboard. Competency 2: Explain the risk management function in the health care organization. o Analyze areas of a safety and quality dashboard of concern to a risk manager. Competency 3: Analyze the importance of patient safety in health care. Describe how a health care organization chooses the metrics to include in its safety and quality dashboard. O ● ● O Analyze areas of a safety and quality dashboard of concern to a quality director. o Analyze areas of a safety and quality dashboard of concern to a patient safety officer. Competency 4: Apply leadership strategies to quality improvement in a health care organization. O Assess senior leadership's role in setting a health care organization's strategic safety and quality objectives. Competency 5: Communicate in a manner that is scholarly, professional, and respectful of the diversity, dignity, and integrity of others and is consistent with the expectations for health care professionals. O Use correct grammar, punctuation, and mechanics as expected of an undergraduate learner. O Writing adheres to APA formatting rules and APA writing style with few or minor errors.See Answer
  • Q11:11:53 < CHE3008 Individual Assig... Q L 5G 62 Individual Assignment - Mini Literature Review (700-900 words) (20% of final module mark) This report will be a literature review on a research topic of interest covered in the 'Biomaterials' classes. Suomasion dreadme General guidelines: The purpose of this review is to give a brief overview of the studies performed on the selected topic and to provide a critical evaluation of the literature in a clear and concise manner. It should be an original piece of work. Only peer review journal experimental articles should be included in the review, which should be clearly cited. Students should not use other review papers to form the basis of their review. The overall objective of the assignment is to familiarise students with the scientific literature, understand these articles and critique their content. A good review identifies what information is important and condenses that information for the reader. Better understanding of the subject will make it easier to explain it thoroughly and briefly. A minimum of 8 experimental scientific papers should be used and referenced in the review (no need to submit these papers with your report). This mini-review should be between 700-900 words (excluding references). The review should: ⚫be written in your own words; ⚫be clearly structured, have an introduction and a conclusion; contain the main arguments and critical evaluation of the papers; ⚫ indicate where you agree or disagree with the authors. The review should not. ⚫use other review papers published in the literature as the basis of this report; be produced using cut-and-paste at any stage; ⚫contain any sentences (or phrases more than a few words long) occurring in the original paper (quoted or not). Provide all references used at the end of your report. Use an appropriate referencing style, for example the ACS style (link given below) or a different one: https://pubs.acs.org/doi/full/10.1021/acsguide.40303 2 35 Dashboard Calendar To-do Notifications InboxSee Answer
  • Q12:Write an argumentative essay of approximately 4-5 PAGES, 1500 words minim, which demonstrates classical argument form (introduction, arguments, opposing views, refutations, and conclusion) concerning a debatable topic relating to a bio-medical topic. The argument must relate primarily to biology/medical treatment―i.e., it should not be primarily a philosophical or ethical argument. The topic could involve any social, geographical, or historical context. Essays must utilize 5 research sources (from 5 different websites) which must be documented in MLA 8TH EDITION format (in-text citations and Works Cited page). Students must find and use 5 of their own sources-not rely only on sources listed in course materials. Sources must be underlined in essay and Works Cited to ensure they are complete (See #27 and #28 in Checklist). (See paragraph model in course materials)See Answer
  • Q13: Research Methodology Spring 2023- 2024 Assignment on "Materials and Methods" Let's examine the "Materials and Methods" sections of the published papers that you chose. How are they similar and different?? You need to select two different papers addressing similar problems. Select one common experiment that was done in both papers, and compare between the two papers on the similarities and differences of this experiment using the below form. 13 > - + ** Paper 1 Title: Link: Materials and Methods of the experiment you selected: Paper 2 Title: Link: Materials and Methods: Materials and Methods of the experiment you selected: Table 1: Differences in materials and methods of your selected experiment between Paper 1 and Paper 2. Paper 1 Paper 2 Table 2: Similarities in materials and methodology of your selected experiment between Paper 1 and Paper 2. + + Your feedback/ opinionSee Answer
  • Q14: INSTRUCTIONS: Need help writing the abstract part of the given experiment. The experiment is "Microbial Production in a Bioreactor" Experimental details along with calculations details are attache (use them) Data in excel is given as well (use if required)See Answer
  • Q15: ELSEVIER Materials and Design 201 (2021) 109484 Contents lists available at ScienceDirect Materials and Design journal homepage: www.elsevier.com/locate/matdes Physical and biological engineering of polymer scaffolds to potentiate repair of spinal cord injury a,1 Yiqian Luo ª‚¹, Fei Xue 1, Kai Liud, Baoqin Li ª, Changfeng Fu ª,*, Jianxun Dingb a Department of Spine Surgery, The First Hospital of Jilin University, 1 Xinmin Street, Changchun 130021, PR China b Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, PR China c School of Chemistry and Life Science, Advanced Institute of Materials Science, Changchun University of Technology, 2055 Yan'an Street, Changchun 130021, PR China Department of Hand and Foot Surgery, The First Hospital of Jilin University, 1 Xinmin Street, Changchun 130021, PR China d Check for updates GRAPHICAL ABSTRACT • HIGHLIGHTS Polymer scaffolds possess enormous po- tential in the repair of spinal cord injury. • The optimized physical properties of scaffolds provide a favorable microenvi- ronment for spinal cord injury repair. • The biologically functionalized scaffolds reverse the adverse factors during spinal cord injury repair. FN Physical support Mechanical performance Internal structure Biodegradation Conductivity Bioelectrical signal conduction ✓ Physical functions - Polymer scaffold Biological functions- Endogenous neurogenesis NSC differentiation Axon growth Antioxidant M1| Macrophage polarization M2 MO Microenvironment regulation materials DESIGN ARTICLE INFO Article history: Received 19 November 2020 Received in revised form 2 January 2021 Accepted 12 January 2021 Available online 16 January 2021 Keywords: Polymer scaffold Spinal cord injury repair Physical support Signal transduction Microenvironment regulation Endogenous neurogenesis ABSTRACT Although the mortality rates of patients suffering from spinal cord injury (SCI) have decreased as the modalities of clinical therapy have been improved, the recovery of motor and sensory functions remains a challenge, ulti- mately leading to paraplegia or quadriplegia. Recently, neural tissue engineering scaffolds with appropriate phys- ical and biological functions have been extensively developed to promote nerve regeneration and improve motor and sensory functions during SCI therapy. In this work, we summarized the physical support and bioelectrical sig- nal conduction of polymer scaffolds for SCI repair from the aspects of biocompatibility, biodegradation, internal structure, mechanical performance, and conductivity. In addition, the biological functions of the polymer scaf- folds were reviewed for the reversal of adverse pathophysiological factors to improve the microenvironments of the injured site and promote endogenous neurogenesis during SCI therapy. Moreover, the future development of these engineered scaffolds for potential clinical applications was predicted. © 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Contents 1. Introduction. 1.1. Overview of spinal cord injury * Corresponding author. E-mail address: fucf@jlu.edu.cn (C. Fu). 1 Y. Luo and F. Xue contributed equally to this work. https://doi.org/10.1016/j.matdes.2021.109484 0264-1275/Ⓒ 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 2 2 materialstoday Y. Luo, F. Xue, K. Liu et al. 1.2. 1.3. 1.4. 2. 3. 4. 5. Microstructure of spinal cord. Pathophysiology of spinal cord injury Treatment strategies for spinal cord injury. Physical support of scaffolds for spinal cord injury repair. 2.1. Biocompatibility and biodegradability. 2.2. Internal structure. 2.3. Mechanical performance. Bioelectrical signal conduction of scaffolds for spinal cord injury repair Microenvironment regulation by scaffolds for spinal cord injury repair 4.1. Antioxidants 4.2. Regulation of macrophages. Endogenous neurogenesis induced by scaffolds for spinal cord injury repair 5.1. Promoting axon growth 5.2. Tuning endogenous neural stem cells 6. Concluding remarks and future perspectives Declaration of Competing Interest Acknowledgments References. Materials and Design 201 (2021) 109484 2 2 3 4 4 4 6 6 8 8 10 10 11 13 13 15 15 15 1. Introduction 1.1. Overview of spinal cord injury Spinal cord injury (SCI) can interrupt the connection between the brain and peripheral organs, leading to dysfunction, such as paraplegia or quadriplegia [1]. There are various causes of SCI, including traffic ac- cidents, industrial accidents, sports injuries, and so forth. Particularly, traffic accidents account for 45.4% of all SCI cases, falling accidents for 27.4%, heavy objects falling for 10.8%, and tumble for 6.5% [2]. More than 20 million patients are currently suffering from SCI worldwide, with an increase of approximately 700,000 people per year [3]. Such a difficult situation has brought considerable burden to the society, and the clinical therapeutics do not achieve satisfactory results. Currently, neural tissue engineering strategies are the most promising modality among the numerous treatment approaches being explored. In this review, we described the microstructure of the spinal cord, pathophysiology of SCI, clinical therapy strategies, and advantages of neural tissue engineering. After that, we summarized the biocompatibil- ity and biodegradability of polymer scaffolds and highlighted the signif- icance of internal structure, mechanical performance, and conductivity for SCI repair. In addition, we reviewed the past research results to show the development and advantages of neural tissue engineering scaffold-mediated SCI therapy through microenvironment regulation and promotion of endogenous neurogenesis (Fig. 1 and Table 1). This work provided a comprehensive review of the theoretical basis and ap- plication of neural tissue engineering scaffolds for SCI repair. 1.2. Microstructure of spinal cord The spinal cord is an essential part of the central nervous system. Its primary function is to conduct nerve signal transduction and process low-level non-conditioned reflexes [4]. In particular, the anatomical mi- crostructure of the spinal cord provides the basis for the orderly mainte- nance of physiological functions. From the cross-sectional view of the spinal cord, the center of the spinal cord is the longitudinal central canal that connects with the cerebral ventricle. The butterfly-shaped gray matter surrounds central canal, and the outer layer of the gray mat- ter is the white matter [5,6]. A small amount of cerebrospinal fluid in the central canal protects and supplies nutrients to the brain and spinal cord. The gray matter is composed of neurons, glial cells, and blood vessels. The aggregation of neurons forms a complex neural circuit called the processing center for low-level non-conditioned reflexes, such as myotatic, flexion, uri- nation, and defecation reflexes [7,8]. The white matter is composed of nerve fibers and fibrous astrocytes. Nerve fibers are longitudinally arranged into bundles, which are divided into ascending conduction bundles and descending conduction bundles. They transmit signals between the brain and peripheral organs. In brief, ascending conduc- tion bundles transmit the information that controls the sensation of the body, whereas descending conduction bundles mainly transmit motor information from the brain to skeletal muscles of the trunk and limbs [9,10]. 1.3. Pathophysiology of spinal cord injury The pathophysiological process of traumatic SCI can be classified into mechanical (primary) and secondary injuries [11,12]. Mechanical damages directly destroy specific structures of the spinal cord, such as gray matter, vascular system, blood-spinal cord barrier, and nerve con- duction bundles [13]. During a secondary injury, necrotic debris of the myelin sheath, aggregation of various active inflammatory cells, such Physical functions Mechanical Physical support Internal structure 2 performance Biodegradation FN NSC differentiation Endogenous neurogenesis Biological functions Axon growth M1 Polymer scaffold Conductivity Signal transduction MO M2 Antioxidant acrophage arization Microenvironment regulation Fig. 1. Physical and biological functionalities of polymer scaffolds for promotion of SCI repair. Y. Luo, F. Xue, K. Liu et al. Table 1 Preparations and functions of polymer scaffolds. Materials and Design 201 (2021) 109484 Material Carrying substance HA CNTF HA/MA NPCs CS/MA IFN-y and NSCs CS/Col Col CBD-PlexinB1-LBD Agarose Matrigel CBD-EphA4-LBD and Template method PEG Gel/PLLA Gel/MA NSLCs iNSCs PCL SCs and iNSCs PLLA/Poloxamer CAB HEMA/MA Heparin/Col PEDOT/Agarose РРУ/ТА NPCs and bFGF Electrospinning Chemical crosslinking Free radical cryopolymerization Electrodeposition Chemical crosslinking Fabrication technology Biological function Reference Mesh filtration Activate NSCs, and facilitate their migration to the lesion area and differentiation into mature neurons [37] Photocrosslinking Promot the differentiation of NPC into neurons [38] Click chemistry and UV crosslinking 3D printing Neurofilament fibers extend from the host tissue to the scaffold Decrease the formation of scar and cavity, and improve the regeneration of nerve fibers [39] [41] Chemical crosslinking Facilitate axonal regrowth and remyelination of the regenerated tissue [43] Enhance linearly organized axon regeneration, and guide the reconnection of [45] functional axons Water/oil emulsion method, free radical polymerization Inhibit the growth of glial scars, and provide an aligned structure to direct axonal regeneration [46] Co-electrospun Photocrosslinking Support the proliferation and differentiation of NSLSC into motor neurons Decrease inflammation and cavity formation, facilitate axonal and neuronal regeneration, and inhibit glial scar hyperplasia [47] [48] Increase tissue remodeling, and secrete neurotrophic factor Reduce fibrotic scarring, and boost nerve regeneration [52] [53] Promote the orientational regeneration of neurons, and bridge the spinal cord [55] stumps in the conduit Promote axonal growth [56] PANI/CS/Gel PCL/Melatonin OE-MSCs SCs Activate endogenous NSCs neurogenesis in the lesion area Promote the differentiation of OE-MSCs into motor neurons [57] [60] 3D multilayer molding Reduce post-traumatic inflammation and oxidative stress, and regulate impaired mitochondrial function [120] HA/MnO2 NP MSCs Improve the stem cell adhesive growth and nerve tissue bridging, and alleviate the oxidative microenvironments [121] Silk fibroin AECs Inhibit local inflammation, promote myelin regeneration, and enhance nerve fiber regeneration [123] PHEMA Melt casting Promote the polarization of macrophages to M2 phenotype, reduce fibrosis, and promote angiogenesis [129] PCL IL-10 Electrospinning Induce macrophage polarization toward the M2 activated state [132] PLGA Oil-in-water single emulsion solvent Induce macrophages to polarize to M2 phenotype, reduce scar formation, and [136] Fibrin HA evaporation Electrospinning and concurrent molecular self-assembling Enzyme crosslinking CS NT-3 and NSCs promote axonal regeneration Guide axon regeneration directionally, and promote directional invasion of host cells and reconstruction of vascular system [142] Promote axonal regeneration and protruding connection Support the growth and reproduction of NSCs, and promote the differentiation [162] of NSCs into neurons [144] Abbreviations: 3D, three-dimensional; AECs, amniotic epithelial cells; bFGF, basic fibroblast growth factor; CNTF, ciliary neurotrophic factor; Col, collagen; CS, chitosan; Gel, gelatin; HA, hyaluronic acid; IFN-y, interferon-y; IL-10, interleukin-10; iNSCs, induced pluripotent stem cells-derived neural stem cells; MA, methacrylic anhydride; MP, methylprednisolone; NPCs, neural precursor cells; NSCs, neural stem cells; NSLCs, neural stem-like cells; NT-3, neurotrophin-3; OE-MSCs, olfactory ecto-mesenchymal stem cells; PCL, poly(&-caprolactone); PEG, poly(ethylene glycol); PEGDA, poly(ethylene glycol) diacrylate; PHEMA, poly(2-hydroxyethylmethacrylate); PLGA, poly(lactic-co-glycolic acid); PLLA, poly(L-lactic acid); SCs, Schwann cells; TA, tannic acid; UV, ultraviolet. as granulocytes and macrophages, and active glial cell populations can be observed in the harsh local microenvironments [14]. According to the time after injury and pathological mechanism, the secondary injury can be divided into three stages: acute stage, subacute stage, and chronic stage [15]. The acute phase is defined as the 48 h period after SCI. The main pathological changes were bleeding due to vascular injury, resulting in tissue edema and ischemia. With the de- struction of microcirculation, the subsequent pathological changes, such as ion imbalance, excitatory toxins, excessive production of free radicals, and inflammatory reactions, lead to further damage of neurons and glial cells. The subacute phase is from 48 h to two weeks after in- jury. The main pathological processes include phagocytosis of the in- flammatory corpuscle and reactive proliferation of astrocytes [16]. In particular, phagocytosis is the characteristic of this stage. The reactive proliferation of astrocytes leads to glial scarring, which is a crucial barrier to axonal regeneration [17]. The definition of chronic stage is generally considered to be six months or more after SCI. The main path- ological features of chronic stage include the formation and develop- ment of scars [18,19]. The use of various therapy measures, such as regulating physical properties and endowing biological functions, to en- hance the regeneration of damaged axons and myelin sheath, is the pur- pose of treatment at this stage, while preventing the formation of scars is the current promising research direction. 1.4. Treatment strategies for spinal cord injury Clinically, SCI is usually accompanied by destruction of the vertebral column. Therefore, surgical therapy is an essential modality for SCI treatment. Surgical operations can reestablish the stability of the spine to relieve compression of the spinal cord, which creates an appropriate external microenvironment for recovery of the spinal cord. However, the approaches of surgery cannot provide further driving forces for SCI recovery [12,20]. In addition, non-surgical procedures, such as drugs, hyperbaric oxygen, and hypothermia, have shown specific efficacy in the treatment of SCI, but they have apparent shortcomings [21]. For ex- ample, the U.S. Food and Drug Administration has approved methyl- prednisolone (MP) for the treatment of SCI. MP can inhibit secondary injury by stabilizing cell membranes, inhibiting the release of endor- phins, and limiting inflammation. However, when used in high doses, it can also cause side effects, including abnormal autonomic reflexes, immunosuppression, deep vein thrombosis, and pulmonary embolism [22,23]. Furthermore, there has recently been a growing suspicion about the role of MP in promoting the recovery of nerve function during SCI therapy [24,25]. Both hypothermia and hyperbaric oxygen are aux- iliary therapy measures with limited efficacies and complicated pro- cesses [26,27]. Therefore, an effective strategy is urgently required for SCI therapy. 3 Y. Luo, F. Xue, K. Liu et al. Thus far, studies on SCI treatment have mainly focused on stem cell therapy, drug screening, gene therapy, tissue engineering, and their bi- ological mechanisms [28,29]. Particularly, tissue engineering has irre- placeable advantages in SCI therapy. The wound can be bridged, the formation of nerve scars can be inhibited, and axons at both ends of the injury can be physically guided to reconnect by tissue engineering scaffolds. Moreover, to improve the repair effect of injured spinal cord, tissue engineering scaffolds can be used as carriers of bioactive compo- nents or cells to form biofunctional scaffolds to inhibit secondary dam- age or provide the driving force for nerve regeneration [30,31]. As a result of advances in materials science and bioscience, re- searchers have developed various unique insights into the application of tissue engineering scaffolds for SCI repair and have predicted their clinical applications [32]. Several studies have confirmed the advan- tages of neural tissue engineering scaffolds for SCI therapy [33,34]. The internal structures of scaffolds not only provide adequate space for cell survival and material exchange in the nervous system, but they also offer physical guidance for axon growth to some extent. The mechanical performance of the scaffold can compensate for the lack of mechanical support caused by SCI. The conductivity of the scaffold can simulate the electrophysiological microenvironments of the nerve tissue and transmit endogenous bioelectrical signals [35]. Furthermore, the bio- logical function of the scaffold can specifically overcome adverse pathophysiological changes to regulate the microenvironments and en- dogenous neural stem cells (NSCs), promoting SCI repair. 2. Physical support of scaffolds for spinal cord injury repair Tissue engineering scaffolds provide a favorable growth microenvi- ronment and an instructional cue for nerve regeneration during SCI re- pair, which, to some extent, depends on the physical support of scaffolds [36]. Physical support suitable for SCI is a prerequisite of nerve repair, mainly depending on utilized materials and techniques during the prep- aration. Currently, various natural and synthetic polymers have been used in scaffold manufacturing. Natural polymers, including hyaluronic acid (HA) [37,38], chitosan (CS) [39-42], collagen (Col) [43,44], agarose [45], alginate [46], gelatin (Gel) [47,48], and acellular matrix [49], have been used to research nerve regeneration in SCI. Synthetic polymers in- clude poly(lactic-co-glycolic acid) (PLGA) [50,51], poly(ε-caprolactone) (PCL) [52], poly(lactic acid) (PLA) [47,53], poly(ethylene glycol) (PEG) [42,54], hydroxypropyl methacrylamide (HPMA) [55], poly(sialic acid) (PSA), methacrylate (MA) [48], poly(3,4-ethylene dioxythiophene) (PEDOT) [56], polypyrrole (PPy) [57–59], and polyaniline (PANI) [60]. The properties and applications of polymers have been discussed in de- tail in our previous review [61]. Current applications of polymers often involve combinations of mul- tiple polymers as it is challenging to provide the required physical sup- port for damaged spinal cords when using a single polymer. To prepare customized scaffolds with various forms, structures, and functions, many technologies, including electrospinning and three-dimensional (3D) printing, have been applied for the preparation [62,63]. In addition to biocompatibility and biodegradability, the internal structures, me- chanical properties, and electrical conductivities of scaffolds are also sig- nificant physical properties to ensure the best repair effect of SCI. 2.1. Biocompatibility and biodegradability Biocompatibility refers to the compatibility performance of living tissue in response to non-active materials. Implantation of foreign ma- terials into the body will affect the biological tissue microenvironments, and biological tissues will also affect the implanted materials [64]. The interaction between the implant and biological tissue will keep for a long time until a state of equilibrium is reached, or the implant is removed. Biocompatibility is necessary for the application of tissue en- gineering scaffolds in the medical field and a prerequisite for satisfac- tory repair effects because the physiological activities of cells, such as 4 Materials and Design 201 (2021) 109484 survival, proliferation, migration, and differentiation, are based on this characteristic [65,66]. Notably, during secondary injury following SCI, inflammatory cells accumulate at the site of injury and secrete large quantities of inflammatory factors, such as interleukin-1ẞ (IL-1ẞ), interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-α), thus forming an inflammatory microenvironment [1,18]. In this case, scaffolds implanted into the damaged spinal cord need to have better biocompatibility. In order to meet this condition, both natural and synthetic polymers currently used to prepare scaffolds for SCI repair need to be tested for toxicity at the cell and tissue levels. In addition to polymers, the liquid used in the preparation process is also an essential factor affecting the biocompatibility of scaffolds. Toxic organic liquids, such as methylene chloride, trichloromethane, and tetrahydrofuran, are used as solvents or crosslinking agents to prepare scaffolds through electrospinning or 3D printing [67]. Although organic solvents can be removed by natural volatilization, vacuum drying, dialysis, freeze-drying or other methods, it is still quite challenging to remove them thoroughly. Therefore, re- searchers should make a long-term effort to explore strategies that can effectively remove toxic liquids. The biodegradation of scaffolds is another crucial factor in tissue re- pair. The ideal biodegradation rate can provide adaptive growth space and mechanical support for newborn tissues. In general, the perfect biodegradation rate of scaffolds mainly depends on the growth rate of tissues [68]. Currently, there is no specific standard for the degradation rates of scaffolds for SCI repair, with degradation times ranging from weeks to years. In the future, it is of great significance to explore the ac- curate degradation times of scaffolds for the best SCI repair effect. The degradation time of a scaffold can be controlled by using composite ma- terials. To prepare scaffolds with longer degradation times, CS and HA can be mixed to create satisfactory scaffolds. Similarly, mixtures of PLGA and poly(L-lysine) [51], CS CS and Col [41], and Gel and PLA [69] have been used to prepare scaffolds with appropriate degradation rates. Li et al. designed an injectable and biodegradable hybrid hydrogel for application in SCI models. Degradation tests in vivo and in vitro showed that the degradation times of scaffolds were at least two weeks (Fig. 2A, B, and D), and no abnormal inflammatory response was found in tissues around scaffolds (Fig. 2C). Besides, the hydrogel had no significant cytotoxicity in vitro (Fig. 2E and F) [53]. 2.2. Internal structure The internal structure of the scaffold can provide channels for the ex- change of metabolic substances. Additionally, it can guide the regenera- tion of nerve tissue through physical contact [70]. Researchers have attempted to create a scaffold with an internal structure similar to that of the spinal cord to provide a natural path for tissue growth [71,72]. Previously, the acellular matrix of neural tissue was considered as one of the most promising scaffolds because it can retain the major internal structure of nerve tissue. However, its application was signifi- cantly limited, owing to limited supply and immune rejection [73,74]. Many studies consider porosity, aperture, and specific morphology, such as orientation arrangement, to be the most essential factors of the internal structures for SCI repair. Particularly, scaffolds with a poros- ity of 90% and aperture of 10-100 μm are the most suitable scaffolds for cell growth, and the directional arrangement structure can guide the or- derly growth of nerve fiber to the maximum extent [75,76]. Currently, technologies, including freeze-drying, electrospinning [77], and 3D printing [62], are used to fabricate scaffolds with suitable internal struc- tures. Although freeze-drying can control the porosity and aperture of scaffolds, the prepared scaffolds usually have the disadvantages of in- sufficient mechanical integrity and non-orientation. Electrospinning is widely used to prepare oriented scaffolds by forming oriented fibers. However, electrospun scaffolds are mainly used to treat peripheral nerve injury and are rarely used for SCI repair. This may be due to the Y. Luo, F. Xue, K. Liu et al. A Day 1 Day 3 Day 7 Day 14 C Day 1 Materials and Design 201 (2021) 109484 Day 3 0.2 0.4 0.6 0.8 B Day 7 Day 14 Day 1 D 40 Weight loss (%) Day 3 Day 35 55 30 25 25 4°C 37 °C 20 20 15 ヨ Cell viability (%) Day 14 100 80 60 60 40 40 20 NIH-3T3 F Astrocyte Cell viability (%) 50 50 40 40 30 50 20 20 10 10 50 μm 10 2 3 4 Degradation time (week) 0 25 50 100 200 400 600 800 1000 Copolymer concentration (μg mL-1) 0 0 1 2 4 6 8 10 Concentration of CAB (nM) Fig. 2. Biodegradation and biocompatibility of cabazitaxel (CAB)-encapsulated hybrid hydrogel. (A) Representative fluorescence imaging of mice after subcutaneous injection of hydrogel. (B) A representative optical image of in vivo degradation time of mixed hydrogel. (C) Hematoxylin and eosin (H&E) staining was performed on the tissue around the injected hydrogel at a predetermined time point, and results demonstrated that the hydrogel had good biocompatibility. (D) Degradation rate of hydrogels at different temperatures. The degradation rate was faster at 37 °C compared to that at 4 °C. (E) and (F) The cytotoxicity of the polymer and CAB were tested. Reproduced with permission from [53]. A Lesion site Grey matter White matter B Cooing unit Heating unit C Rat spinal cord Top view Side view Growth Scaffold Cells A+B Cells B Cells A Fig. 3. Preparation of 3D printed scaffold with similar structure of spinal cord. (A) Schematic illustration of spinal cord illustrating grey matter and white matter boundaries and a design for a 3D bioprinted multichannel scaffold for modelingspinal cord. (B) Schematic diagram of 3D printing. (C) Exhibition of a transected rat spinal cord and design principle for scaffolds consisting of multiple and continuous channels. Top view and side view image of scaffold. Reproduced with permission from [81]. 5See Answer
  • Q16: Individual Assignment – Mini Literature Review (700-900 words) (20% of final module mark) This report will be a literature review on a research topic of interest covered in the 'Biomaterials' classes. General guidelines: The purpose of this review is to give a brief overview of the studies performed on the selected topic and to provide a critical evaluation of the literature in a clear and concise manner. It should be an original piece of work. Only peer review journal experimental articles should be included in the review, which should be clearly cited. Students should not use other review papers to form the basis of their review. The overall objective of the assignment is to familiarise students with the scientific literature, understand these articles and critique their content. A good review identifies what information is important and condenses that information for the reader. Better understanding of the subject will make it easier to explain it thoroughly and briefly. A minimum of 8 experimental scientific papers should be used and referenced in the review (no need to submit these papers with your report). This mini-review should be between 700-900 words (excluding references). The review should: be written in your own words; contain the main arguments and critical evaluation of the papers; • be clearly structured, have an introduction and a conclusion; • • indicate where you agree or disagree with the authors. The review should not: use other review papers published in the literature as the basis of this report; • • be produced using cut-and-paste at any stage; . contain any sentences (or phrases more than a few words long) occurring in the original paper (quoted or not). Provide all references used at the end of your report. Use an appropriate referencing style, for example the ACS style (link given below) or a different one: https://pubs.acs.org/doi/full/10.1021/acsguide.40303See Answer
  • Q17: PHA223 Rapid Review 2023-2024 Guidance Notes & Generic Marking Scheme Topic:-Development of Nanomedicine Strategies to Target Coronavirus Article link :- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457919/ Requirements - 3000 words (without reference) - you can use a maximum of 6 references - make sure that u including every single point - highlighting the small topic that in each section Structure of your assignment The required length of this assignment is 3000 words (+/- 10%), excluding references. A penalty will be applied if the word count falls below or exceeds this limit in accordance with standard university procedures. No special adjustments on words counts will be made for figures, tables, or flow charts. The word count will be adjudicated using Microsoft Word. Guidance on Assignment Structure 1. INTRODUCTION You must outline your question and the aims of your literature search. This section needs to set the scene of your topic by including relevant background information surrounding key concepts of your topic. In your introduction, you will give definitions and provide sufficient information for the reader to understand your topic and what you will be searching for in the literature. Your introduction should be structured in a way so that a reader understands exactly what your literature search will focus on. 2. METHODOLOGY In this section, you need to clearly explain your search strategy. Everything you do to identify selected articles for discussion must be clearly stated in this section. This includes outlining which key words were used, which databases were searched, when the databases were searched and any search criteria/filters that were applied. If a reader was to screen your methodology, they should arrive at the same articles as you did if you outlined your processes effectively. You must also include details of your inclusion/exclusion criteria that you apply when screening each article. You must also include a PRISMA flow diagram outlining your process of selecting articles and at what stages you applied your inclusion/exclusion criteria. To support you with your methodology and identification of suitable articles, please refer to the Rapid Review lecture and the online recording provided by the library services team. 3. RESULTS & CRITICAL APPRAISAL You must present your literature findings to the reader and therefore, the evidence for the proposition or therapeutic intervention you have outlined in your topic. This must include an effective critique of the identified literature with associated interpretation and link back to your topic. You will be expected to analyse your selected articles for the strengths and weaknesses of their conclusions based upon the quality and appropriateness of their studies. It will be beneficial to create a “summary table" of your literature findings which outlines some key information relating to each article included. 4. DISCUSSION & CONCLUSION You will need to finish your report by summarizing your findings and explaining relevance into practice/science. You will need to make clear concluding statements as to whether your literature findings have a clear outcome and ensure that your conclusion directly relates back to your topic. 5. REFERENCES Full in text citations are essential in addition to a full, accompanying bibliography. Either Harvard or Vancouver referencing style will be permitted. This will not form aprt of your word count. Oral Viva In addition addition to the written work you will submit, you will be asked to present yourself for an oral discussion with your tutor, probably after the Easter break. The conversation will be related to the dissertation that you have submitted and can be expected to last approximately 20 minutes. The exact dates and times that you must attend this meeting will be announced later in the term. The assignment comprises 30% of the available marks for PHA223. Within this 30%, 90% of the marks are attributed to the written work and 10% of the available marks are available via the oral defence. As the member of staff you will be holding your discussion with will want to read your written report before talking to you, it is imperative that you hand in your work by the deadline as stated above. Failure to hand in your work on time will therefore also have a negative impact on your ability to perform well in the oral discussion component of this assignment as well as the written component. Any problems or questions, please contact Alex To support you in the development of your review, I have created a very brief checklist of the key components I expect your review to contain (please see next page). 3 Appendix 1 – PRISMA Guides - he following link will support you in writing your report. This is a direct link to the PRISMA diagram which must be included within your methodology section. PRISMA 2020 flow diagram new SRS v1.docx (live.com) The following link directs you to the PRISMA checklist. This will support you in developing your own reviews. A checklist for use in your report has also been produced for you which links to the PRIMSA checklist. Microsoft Word - PRISMA 2009 Checklist.doc (prisma-statement.org) Biology of the virus Surface proteine Structure of proteine SRNA,DNA, transmetion (incoded genes) why we don't use the proteine it self in the body? Bread about the vaccien, applications ☹important of nanomedicien esearch for other therapates drugs for (could) example => clorophein - not very effectiev) Eviruse behaffier inside the body (particelse) ∞other uses of nanomedicen Res peratory system Title Spike Serves protein Included Appendix 2 - Checklist Section Introduction Background Aim Methodology Search terms and database Eligibility Criteria Search Strategy Data Collection Article Information Bias Assessment Synthesis methods Study selection Results & Discussion Summary table Synthesis of results Summary of findings Conclusion Conclusion Sumerias Checklist item Title clearly stated. Outline definitions and key concepts relating to your topic. State the aim of the review (chart) Draw Specify all databases, search engines (and all other sources) used to identify your articles. Date ranges of searches should be included. Clearly state the inclusion and exclusion criteria used to select your articles State all filters applied during your literature searches State how you decided whether a study met inclusion criteria and how you screened each article to determine this. Provide details of outcomes for which data was sought (for example: article types, participant characteristics, intended outcomes) Provide details on how you reduced risk of bias within your own searches Outline how you will document your findings Include the PRISMA flow diagram Brief summary of each article identified for inclusion (optional) Critically appraise the findings from each article and integrate findings into core themes. Ensure that all interpretations are linked and discussed in relation to your research topic. Strengths and weaknesses of the articles should be highlighted and discussed to provide context into your discussion. Assessment of bias within your articles should also be included. Where necessary, discussions of statistical significance should also be made. Discuss the findings in relation to what is already known about your topic. Do they support what is already known, do they add new information, or do they disagree with previously outlined facts? General overview of findings and implications linked to your topic. Ensure this is clear, concise, and not a repetition of previously discussed findings. Outline whether any future research is required as a result of your findings or if there is a clear conclusion from your gathered information. References References Full list of bibliography references linked to in text citations. Use Harvard or Vancouver referencing style Draft 22/2 Ginars onmeron marchSee Answer
  • Q18: BE 312 Lab #8 Lab 8: ECG Noise and Filtering I. Background The Electrocardiogram (ECG/EKG) is an electrical signal produced by the heart muscle. It has an amplitude of about 1mV, so a good amplifier is necessary. Electrical noise or electromagnetic interference (EMI), is generated by many common appliances, such as: power lines, lights, computers, cell phones, etc. When the ECG signal is amplified the noise is amplified as well and often swamps the ECG signal. Signal conditioning the ECG signal is necessary to acquire a good quiet ECG. The IX-TA-220 Recorder has the ability to output through the Stimulator any signal that is being recorded on its input, including the iWire ports. In this lab, we are going to perform two experiments. Experiment 1 focuses on using software filters to remove noise from the ECG signal. Experiment 2 uses a hardware filter that you assemble on the breadboards to remove noise from the ECG signal. Experiment 1 1) Record the ECG from the subject using the iWire-B3G. 2) Introduce some 60Hz noise into the ECG recording, by spreading the electrode cables. 3) Identify the frequency of the noise using the spectrum analyzer. 4) Filter the signal using various software filters. 5) Compare the ECG recorded by the iWire-B3G with the filtered ECG. Experiment 2 1) Record the ECG from the subject using the iWire-B3G. 2) Output the signal recorded by the iWire-B3G using the S1 Stimulator. 3) Send the ECG signal to the breadboard, using the C-BNC-BB cable. 4) Filter the signal on the breadboard. 5) Send the filtered signal back to the IX-TA-220, using the C-DIN-BB cable. a. The C-DIN-BB cable also provides +5V and -5V power to power the circuit. 6) Compare the ECG recorded by the iWire-B3G with the filtered ECG II. Setup Equipment Required • PC or Mac Computer • IX-TA data acquisition unit and power supply • USB cable • ROAM Wireless ECG • Labscribe: Settings>BioInstrumentation>ECGFilter-ROAM • C-DIN-BB: Din to Breadboard cable • C-BNC-BB: BNC to Breadboard cable A-BREADBOARD: Breadboard • • Alcohol swabs • Disposable ECG electrodes 1 BE 312 Lab #8 Build the Filter Circuit The first step is to construct a filter on the breadboard. The “breadboard” is a board that is used to create simple prototype electrical circuits without circuit boards or soldering to connect the components. An example is shown in Figure 1. GLOBAL SPECIALTIES alalalala Va Vb Ve Figure 1. Example breadboard. The one you use may look slightly different. Breadboards have internal electrical connections that are common for all breadboards. Some holes are are electrically connected to each other inside the breadboard, while others are not. As shown in Figure 2, the long rows or columns of holes (usually indicated with a blue line, or black line, or red line along them) are all electrically connected inside the board. Thus a wire plugged into one of these holes will be electrically connected to all the others in that long row or column. The central array of holes are connected differently. These are shown with the letters (A B C D E), (F G HIJ), and numbered rows (1,2,3,4...). In each row A-E are all electrically connected. And F-J are electrically connected. But, (A-E) are not connected to (F-J). Rows are not connected either. Also note that if there are multiple (A-E) or (F-J) columns, they are all separate and not connected. 2 BE 312 Lab #8 SPECIALITES 5 ABCD FGH 5 10 10 All the holes in this row are electrically connected in the breadboard All the holes in this row are electrically connected in the breadboard (5 holes) All the holes in this row are electrically connected in the breadboard (5 holes) All the holes in this column are in the breadboard. electrically connected A and B are separate, and are not electrically connected (although the holes in A are connected to each other and the holes in B are connected to each other). Figure 2. Close-up of the breadboard explaining the internal connectivity. For this lab, you will use a second order (2-pole) low pass filter as the hardware filter. The schematic is shown in Figure 3. C2 0.22μF U1 R2 + R1 Output_A5 S1_Input V1 TL062 V2 30.1k 30.1k C1 0.22µF 5v -5v Figure 3. Schematic of the low pass filter you will build and use. This filter is a Sallen Key 2-pole low pass filter. Its job is to remove 60Hz electrical noise picked up from fluorescent lights, computers, and AC power lines. Figure 4 shows this circuit as a “Fritzing diagram” which is a picture representation of what your circuit on the breadboard should look like 3 BE 312 Lab #8 when completed. 0000000 Figure 4. Fritzing diagram of the low pass filter. TL062 Construct the circuit as shown and double check that the wires and components are all connected correctly. Once this is done, go to the breadboard setup and connect to the iWorx. Breadboard Setup 1. Insert the BNC connector on the end of the C-BNC-BB cable into the S1 stimulator port of the TA. 2. Connect the other end of the C-BNC-BB cable to the breadboard. 3. Insert the DIN8 connector of the C-DIN-BB cable into the A5 port of the TA. 4. Connect the other end of the C-DIN-BB cable to the breadboard. See Figure 5 and Figure 6 for pictures of these connections. Do these after the circuit has been assembled. Once everything is connected, continue to the next step and place the ECG electrodes. 4 BE 312 Lab #8 C-DIN-BB Ground C-BNC-BB Ground C-BNC-BB Signal C-DIN-BB +5 V C-DIN-BB-5 V C-DIN-BB+ Input C-DIN-BB- Input HI Vb a abcde TO 220 25 Figure 5. Photo of the breadboard with circuit. Note the wires to be connected to the iWorx box. ECG Setup BREADBOARD iWorx TA-ROAM RAM A1 ROAM Wireless A2 iWire A3 A4 A5 A6 A7 PT 2 C-BNC-BB LV Stim $1 $2 Figure 6. Breadboard connection to the iWorx box. 15See Answer

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Biomedical Engineering is a field that combines principles of engineering and biology to design and develop innovative solutions for healthcare and medical challenges.


Can I pay someone to do my Biomedical Engineering homework for me?

Yes, at TutorBin, you can pay our qualified tutors to handle your Biomedical Engineering homework, which can help you better understand and improve your knowledge of the subject.


Which is the best website for Biomedical Engineering homework help?

As per student ratings, TutorBin is regarded as the best website for Biomedical Engineering assignment help.


Can I get instant Biomedical homework help in the USA?

You can access instant Biomedical assignment help in the USA through our 24/7 online platform to promptly address your needs.


Where can I get the best Biomedical Engineering homework help?

You can receive the best Biomedical Engineering assignment help from us, as we have Biomedical tutors with years of experience and expertise to guide you through tasks or topics step by step.

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