The body's inflammatory response is a critical step in the wound healing process, not only in preventing infection but also in providing some of the signals required for new tissue formation. However, large and severe wounds seen on the battlefield and in the burn and trauma units of hospitals often exhibit a prolonged inflammatory period and significant scar formation. The scar tissue can be so taut and thick that movement is prohibited and painful physical therapy or surgical intervention is required. There is clear evidence that inflammation plays a major role in scar formation, suggesting that control of inflammation during healing can increase the ratio of functional tissue to scar tissue. This presents an opportunity to engineer, at the molecular level, materials that actively change the inflammatory environment. Proteins called cytokines are a critical component of inflammation and they direct cellular activities. To prevent inflammation during infection, some viral and bacterial pathogens have evolved proteins that bind or degrade specific inflammatory cytokines, such as tumor necrosis factor alpha (TNF-£). The goal of this proposal is to mimic these pathogen mechanisms by engineering protein nanoparticles that scavenge cytokines to achieve control over inflammation for applications in severe wound healing.
Intellectual Merit: The proposed work will assess the ability of engineered pathogen-mimetic protein nanoparticle to modulate inflammation. Objectives are to (1) design and fabricate nanoparticles made from viral TNF-£ binding proteins, soluble receptors and bacterial TNF-£ -ndegrading proteases; (2) assess nanoparticle binding or degrading capacities for TNF-£ as a function of particle properties; (3) evaluate the in vitro cellular response to TNF-£ modulation by nanoparticles. The results of this work will establish the feasibility of using active proteins as therapeutic material building blocks which is desirable because they can be manipulated to provide both biological interactions as well as required chemical and physical properties. The particles described here do not follow a traditional drug delivery approach but instead will demonstrate the ability to exert a therapeutic effect without interacting directly with cells. This proposal introduces a new class of anti-inflammatory therapeutics, harnessing the strategies of pathogenic viruses and bacteria and re-engineering them for the ultimate goal of healing patients.
Broader impacts: Many people, with a variety of inflammatory conditions, would benefit from the novel cytokine modulating materials produced in this proposal. However, this proposal will have gains well beyond the anticipated scientific results. The PI has planned a variety of activities to recruit and retain women and under-represented minorities in chemical engineering. At the most basic level this proposal will support one graduate and undergraduate under-represented students, maintaining the diversity of her current lab. She will provide individual mentoring to encourage them to continue their careers in engineering and serve as role models for the next generation. The PI will serve in the summer STEPS program to recruit science/math majors at Historically Black Colleges for a dual degree in engineering at Georgia Tech. She will teach introductory chemical engineering to program participants and have one student perform research from this proposal in her lab. The PI is also active in the Women in Engineering (WIE) program and will participate in outreach programs to generate excitement for engineering in Atlanta-area middle and high school girls. She will also informally mentor the WIE chemical engineering graduate women's group. Finally, this work and related examples from the literature will be incorporated into core chemical engineering courses taught by the PI, relating research to fundamental engineering concepts.
The body’s inflammatory response is a critical step in the wound healing process, not only in preventing infection but also in providing some of the signals required for new tissue formation. Control of inflammation during healing can increase the body’s healing response. Proteins called cytokines are a critical component of inflammation. To prevent inflammation during infection, some viral and bacterial pathogens have evolved proteins that bind or degrade specific inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α). The general goal was to mimic these pathogen mechanisms by engineering protein materials that reduce TNF-a concentration to control inflammation for applications in wound healing. To achieve this goal, experimental work has produced three major results. First, we have produced an enzyme from bacteria and demonstrated its ability to degrade TNF-a. We modified the enzyme in order to be able to incorporate it into protein materials that can help protect and deliver the enzyme in tissue. Next, we produced a protein partner that can self-assemble in tissue to concentrate and release therapeutic proteins, like the enzyme. Finally, we produced a different protein partner that can be combined with therapeutic proteins like the enzyme, into large structures that protect the enzyme in tissue but still allow it to be active. Producing the protein partners and understanding how they can assemble into structures will be beneficial for the ultimate application in inflamed tissue but also reveals novel protein interactions that can be controlled to produce materials with desired properties. A new class of protein materials were made that could be used for a variety of applications, ranging from delivering other therapeutic proteins to protecting enzymes that can produce valuable industrial products. Many people, with a variety of inflammatory conditions, could benefit from the novel cytokine degrading materials produced with this research. However, this project had gains well beyond the scientific results. Four students were trained and mentored in the course of the experimental work. A variety of activities were implemented to recruit and retain women in chemical engineering and STEM fields in general. The PI developed two hands-on drug delivery and biomaterials module for 40 6-7th grade girls who visited the PI's lab for a week each summer. Feedback indicated the modules significantly increased the girls’ awareness and enthusiasm towards chemical engineering. The PI gave the keynote address to high school women at 'Introduce a Girl to Engineering' Day. She told the young women about how and why she became a chemical engineer, the type of research she does to help fight diseases, and what they should do to prepare themselves to go to college and become engineers themselves. In addition, the PI took two local female high school students into the lab for a 5-week internship. She worked directly with the young woman to not only teach them research skills but also mentored them towards careers in engineering.
