The overarching goal of our lab is to develop biomaterials that expand the accessibility and affordability of cellular, protein and gene therapeutics by overcoming economic, logistical, and regulatory barriers. We will engineer workflows and platform technologies that accelerate the discovery of polymers that fulfill myriad clinical needs. Current projects and research interests are summarized below. Please feel free to reach out to discuss potential collaborations.
In contrast to small molecule drugs that transiently target proteins rather than address the underlying cause of genetic diseases, gene therapeutics (anti-sense oligonucleotides, mRNA, pDNA, siRNA) modulate gene expression to achieve long-lived therapeutic effects. Additionally, genome editing technologies such as CRISPR/Cas9, prime editing, and base editing offer the possibility of permanent cures for genetic disorders. Therapeutic nucleic acids augment, delete or otherwise modify defective gene sequences, and are steadily winning approval for clinical use from regulatory agencies. Delivery vehicles must protect nucleic acids from degradation, minimize the risk of activating the immune system, and ultimately deliver these payloads to target cells safely and efficiently. The bulk of clinically approved gene therapeutics rely on engineered viral vectors that encode the requisite DNA sequences, but viral delivery is confronted with issues of cost, manufacturability, and safety. Lipid nanoparticles and physical methods of gene delivery have been developed but they are ill-suited for use in rugged environments where cold storage and specialized equipment may be unavailable.
In order to employ data-driven approaches to map relationships between polymer properties and biological responses, we must establish high-throughput experimental (HTE) workflows for biomaterial discovery that opens up unexplored and under-explored chemical domains to investigation. Combining chemical diversity, high discovery rates and the capacity to test multiple mechanistic hypotheses concurrently, HTE approaches will generate large experimental datasets from which structure-activity relationships can be derived via statistical learning. We will exploit synthetic workflows based on continuous flow polymerization and facilitate parallel processing from end to end, right from RDRP, to polymer purification, and finally sample preparation for physicochemical analysis and biological testing.
Genetic engineering promises to improve the therapeutic potency of mesenchymal stem cells which have emerged as versatile cell therapies in regenerative medicine, cancer treatment, and immunomodulation. However, hMSCs are highly recalcitrant to the introduction of exogenous nucleic acids (transfection), rendering it difficult to engineer large banks of cells expressing specific genetic modifications. We approach this ex vivo gene delivery problem by considering the nexus between the interfacial properties of stem cell culture substrates and the physicochemical attributes of engineered polyplexes. We will explore the interplay between surface chemical cues and polyplex properties by examining transfection outcomes on surface-engineered substrates of diverse chemical functionalities and brush architectures. These efforts will help us understand how cellular morphology, adhesion and proliferation are influenced by substrate features such as polymer brush composition, brush thickness, mechanical compliance, wettability, surface charge and interfacial roughness. Further, we will explore whether enhanced cell adhesion and proliferation will translate into improved polyplex uptake and editing efficiency. Ultimately, these results will inform the design of biomaterials that safely and efficiently induce genetic modifications that enhance the therapeutic potential of biomanufactured MSCs.