CAREER: Designing Hybrid Metal-Organic Framework–Hydrogel Biomaterials for Bio-instructive Chemokine Gradients

About This Grant

PART 1: NON-TECHNICAL SUMMARY Cells in the body use chemical signals, called chemokines, to guide immune cells to specific locations. This guidance is essential to influence their behavior and help fight infections or maintain normal health processes. These chemical signals often take the form of gradients, meaning the concentration of the chemical signal changes across a region. Immune cells sense these gradients and follow them like a map. Thus, the ability to precisely program these gradients would enable a powerful means to instruct cell behavior. Hydrogels - soft, stretchable materials used in medical products like contact lenses - are currently the standard tool that serves as a passive reservoir of these chemical signals, releasing them over time. However, these simple release mechanisms do not match complex biological timing. Moreover, they cannot schedule release of multiple signals unless leveraging differences in signal size or solubility, and fail to protect the signals against biological stresses that can degrade them. This underscores the need for innovative hybrid biomaterials that can mimic the body's natural way of forming these signaling gradients, and advances the field of biotechnology. This research develops platforms that can release these chemical signals to guide immune cells in predictable ways in three-dimensional environments. It leverages computational modeling-informed design and rationally structured combinations of porous nanoparticles (that can encapsulate and protect chemokines) with hydrogel chemistry. Design features such as nanoparticle pore size, nanoparticle degradation rate, and chemical interactions linking nanoparticles to the hydrogel, can control chemokine protection and release, and shape resulting gradient formation. By uncovering these foundational structure-function relationships, this research will define design principles that map how cells move, forming the basis for future innovations across biotechnology sectors in immune therapies and regenerative medicine. This project also integrates a significant educational component to broaden engagement and participation in STEM. Local high school students will learn about biotechnology and nanomaterials through hands-on activities, veterans will participate in facilitated two-way discussions to strengthen the research-community nexus, and curriculum development will train students for biotechnology-based STEM careers. PART 2: TECHNICAL SUMMARY This CAREER project will rationally design hybrid materials comprising metal-organic framework (MOF) nanoparticles embedded in hydrogels to program chemokine gradients and resulting immune cell chemotaxis. Chemical signaling gradients are crucial for guiding cell behavior; chemokine spatial distribution influences and biases cell movement. Thus, precisely programming these gradients can instruct cell behavior. Hydrogels have served as passive cargo reservoirs to release these types of cues, but they traditionally exhibit release dictated by a single degradation process, which may not match complex biological timing. Moreover, they cannot schedule multi-cargo release unless leveraging differences in cargo size or solubility - insufficient to program complex responses - and these systems cannot protect chemokines against biological stresses and achieve precise spatiotemporal tuning without cargo conjugation to the network, which risks altering function or structure. Holistically, this underscores the need for innovative biomaterials. By leveraging the tunable degradation, pore size, protective stability, and connective chemical interactions of MOF integrated into hydrogels, this project will program chemokine release and instruct immune activity through 4 research objectives: (i): determine how MOF nanostructure encodes chemokine release; (ii) alter hybrid interactions between MOF nanostructure and hydrogel chemistry; (iii) evaluate how the interplay of local MOF chemokine release and global hydrogel environment affects chemokine gradient formation; and (iv) define biointerface dynamics by employing cell migration and activation as readouts. Collectively, this will deepen understanding of design principles that govern hybrid materials tailored for dynamic and precise chemical signaling. Insights gained can inform biotechnological interventions to program cell movement and interactions, and enable therapeutic breakthroughs in immunotherapy and regenerative medicine that depend on immune activity. The broader impacts of this work integrate with educational objectives: (i) increase participation in biotechnology and hydrogel materials for young trainees; (ii) increase biomaterials exposure and communication with veterans; and (iii) curriculum development to bridge biomaterials design with immunology and enhance critical analysis skills to prepare students for biotechnologically-focused STEM careers. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.