Download PDF Winter Bridge on Frontiers of Engineering December 15, 2022 Volume 52 Issue 4 From novel applications of microbes to DEI in engineering to the potential for hydrogen energy, Frontiers of Engineering participants tackle today’s challenging world issues. The winter issue of The Bridge showcases research by early-career engineers as shared at the 2022 US FOE symposium. Bioinspired Materials—based Approaches to Address Antimicrobial Resistance Thursday, December 15, 2022 Author: Caitlin Howell Nature is inspiring the development of living and synthetic materials that can adapt to discourage microbial growth. The rise of antimicrobial resistance is one of the greatest global public health challenges; the World Health Organization (WHO 2021) places it in the top 10 concerns facing humanity. It causes nearly 5 million deaths globally each year (Antimicrobial Resistance Collaborators 2022), and in the United States alone, more than 2.8 million antimicrobial-resistant infections occur each year, leading to more than 35,000 deaths.[1] The Postantimicrobial Age Alarmingly, infections and deaths due to resistant organisms rose at least 15 percent in the first year of the Covid-19 pandemic (CDC 2022), painting a grim picture for future pandemics and other disease outbreaks expected to arise as climate change exacerbates cross-species viral transmission (Carlson et al. 2022). Although new antimicrobial compounds continue to be discovered, the pace is slowing—while the appearance of new antimicrobial-resistant organisms increases at a rapid rate (WHO 2021). The increase in resistance is further accelerated by the widespread presence of antimicrobials not only in healthcare facilities but in the environment, often due to overuse in agriculture. Antimicrobials are commonly fed to cattle, pigs, and poultry to boost their weight—a practice that is estimated to expand by 11.5 percent across all continents by 2030 (Tiseo et al. 2020). Addressing the burgeoning crisis of antimicrobial resistance requires a coordinated and multifaceted effort that brings together communities, healthcare facilities, industry, and agricultural partners as well as other stakeholders. The development and implementation of new technologies and materials will also be important to provide the necessary tools and devices, which must not unintentionally serve as colonization, growth, and proliferation sites for microorganisms. Although a significant amount of excellent research has focused on this goal (Truong et al. 2022), there remains a critical and persistent need for innovation as the antimicrobial crisis worsens. Nature’s Approaches to Controlling Microbes Over millions of years, nature has developed multiple ways to direct or stop microbial growth on surfaces (figure 1), leading to microbial control mechanisms that are elegant and effective and that discourage the development of resistance. For example, cicada (Ivanova et al. 2012) and dragonfly (Bandara et al. 2017) wings are covered with nanopillar arrays that rupture the membranes of microbial cells. Lotus plants have hierarchically structured, wax-covered bumps on the surfaces of their leaves, which water droplets simply roll off, cleaning away adherent microorganisms in the process (figure 1B) (Barthlott and Neinhuis 1997). The scales of the mako shark are patterned in such a way that water flowing over them creates vortices, making it more difficult for micro-organisms to adhere (Choi et al. 2020). Pilot whale skin has a nanopatterned surface that is perfused with an enzyme-laden gel that breaks the chemical bonds of organisms attempting to colonize the surface (Baum et al. 2001). These are only a few of the myriad ways that nature controls, reduces, or eliminates the adhesion of microbes on surfaces. Bioinspired Liquid Layers Interest in another bioinspired antimicrobial solution is growing: liquid coatings. Inspired by the way mucosal tissue controls large bacterial cohorts in humans, this approach involves the use of a mobile, dynamic, and sacrificial liquid barrier between microorganisms and the surface they may contaminate (figure 1C). Critically, the aim with liquid coatings, like human mucosal tissue, is not to kill microbes but to change their environment to discourage activity that is harmful. In one example, liquid coatings can stop microbes from forming irreversibly adhered slimy coverings around themselves, known as biofilms. When a surface is coated in a water-immiscible liquid, biofilms and the bacteria in them have been shown to simply slide off (Regan et al. 2019). The fact that liquid coatings can be applied on a broad range of medically and industrially relevant materials—from glass to metals, rubbers (Howell et al. 2018), and filtration membranes (Shah et al. 2022)—has unlocked new tools in the fight against antimicrobial resistance. Studies of the performance of liquid coatings in complex environments (e.g., in living systems) have further demonstrated their potential to maintain effectiveness against the challenges of difficult and dynamic conditions. In proof-of-concept experiments in vivo using urinary catheters, one of the most common and infection-prone medical devices (Tambyah and Oon 2012), liquid coatings performed beyond expectations, reducing not only surface adhesion by some of the most aggressive infectious microbes but also overall surface protein contamination (Andersen et al. 2022). Similarly, tests using liquid-coated vs. uncoated hernia meshes in a device-associated infection model showed a significant reduction in the amount of adherent bacteria as well as a decrease in harmful inflammatory markers (Chen et al. 2017). While the results from liquid coatings are promising, they—like most approaches to address the problem of microbial growth on surfaces in this age of antimicrobial resistance—are based in the concept that a simple, nonadaptive surface can resist colonization in a complex, microbe-containing environment. That may be true in some circumstances, but in others it can be a very challenging goal because part of what makes these environments so complex is their tendency to change with time. On static surfaces, changes often result in either a depletion of the functional component of the material (e.g., antimicrobial compound, liquid coating) or a covering of the functional surface by proteins or other compounds produced by the growing microorganisms. In nature, the most successful examples of materials that remain effective at reducing or eliminating microbial colonization long-term are living materials, which can change and adapt to maintain their functionality amid changes to their surroundings. As mentioned above, lotus leaves, shark scales, pilot whale skin, and human mucosal tissue all possess the ability to either heal when damaged or be replaced as needed, in addition to being able to signal to the overall organism when more drastic measures (e.g., movement away from or out of a particular environment) are required. In extreme environments with very high microbial densities, such as mucosal tissue, “good” microbes are recruited to participate in maintaining a healthy dynamic equilibrium in a variety of ways (Lynch and Pedersen 2016). A New Way to Think about the Problem: Working with Bacteria Researchers are just beginning to uncover the depth of complexity of “good” microbes in the human microbiomes and the extent to which they affect overall health (Schmidt et al. 2018). The human body, particularly the gut, is home to 1013–1014 bacteria, fungi, viruses, and archae (Gill et al. 2006) whose metabolic and trophic activities protect and contribute to the body’s normal functioning (Fan and Pedersen 2021). Healthy gut ecosystems help reduce multiple metabolic diseases (Fan and Pedersen 2021) as well as anxiety, depression, and other brain and psychiatric disorders (Morais et al. 2021). Research has also uncovered how systems seemingly unrelated to the gut, such as the lung, respond to the microbial community through pulmonary-intestinal cross-talk (Dumas et al. 2018). Living materials can change and adapt to maintain their functionality amid changes to their surroundings. As understanding of how the microbiome affects overall health continues to grow, new approaches will be needed to translate this knowledge into therapeutic applications. One method of applying microbiome knowledge to the creation of therapeutics is the development of a synthetic microbiome, or an engineered system of “good” microbes. Although many promising approaches are in active development, several challenges remain, including maintaining the right balance of organisms and composition of the surrounding environment (Mabwi et al. 2021). Inspired by the observation that natural microbiomes are constantly in a state of dynamic change mediated by feedback loops, liquid coatings are being used in hybrid living-nonliving materials systems that can both sense microorganisms (Dixon et al. 2022) and enable a -targeted response such as delivery of compounds to either stop or encourage growth (Marquis et al. 2020). The system makes use of an embedded vascular network filled with a functional fluid, much as the vascular systems of living organisms are filled with blood or other transport fluids. When a water-soluble nonliving material substrate is used, compounds produced by the microbes at the interface can diffuse into the fluid in the channels below and be collected for analysis (figure 2). Likewise, active compounds can be introduced into the channel network and diffuse up to the surface to affect the microbes growing there. Recent work has shown how this approach can be used to sense the development of a group of microbes over time (Dixon et al. 2022) and then tightly control the location of those microbes, resulting in a defined pattern (Marquis et al. 2020). Hope for the Postantimicrobial Future Looking to nature to inform the development of effective, nonchemical materials strategies to control microorganisms on surfaces is already opening new doors in the race against antimicrobial resistance. The identification of novel natural strategies is ongoing, while the application of such strategies is becoming more and more sophisticated with advances in materials science. The further development of nature-inspired approaches, particularly those that seek to work with microbes rather than against them wherever possible, will play a critical role in helping the global community continue to adapt to life in the postantimicrobial age. References Andersen MJ, Fong CK, La Bella AA, Molina JJ, Molesan A, Champion MM, Howell C, Flores-Mireles AL. 2022. Inhibiting host-protein deposition on urinary catheters reduces associated urinary tract infections. eLife 11. Antimicrobial Resistance Collaborators. 2022. 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