(65e) Developing Platform Biomaterials: From Messenger RNA Delivery to User-Friendly Synthetic Hydrogels

Leveraging principles from engineering and fundamental chemical synthesis, our research encompasses two primary areas: RNA delivery and user-friendly synthetic hydrogel development. Our interest in these areas is unified by a common question: how can we use rational design principles from organic chemistry to create platform biomaterials with improved function? In our talk, we will highlight both of our primary research interests, with an overarching goal of demonstrating how synthetic chemistry approaches can afford biomaterials for various applications. Below, our two primary subsections are described in brief.

RNA Delivery

Given their instability in serum and their limited ability to passively transfect cellular membranes, RNAs require delivery vectors to realize their full clinical potential.^1,2 Messenger RNAs (mRNAs), for example, could be used for biomedical applications including genomic engineering, cancer immunotherapy, and protein replacement strategies.³ But when mRNAs are administered without a delivery vector into the blood stream, the immunological response, renal clearance, and rapid degradation prevent meaningful levels of accumulation (and subsequent translation) of the mRNA within target cell populations.⁴ Lipid nanoparticles (LNPs) have emerged as an attractive non-viral delivery platform for improving the safety and potency of RNA therapeutics.^5,6 Nevertheless, their complex molecular composition makes it difficult to understand which chemical parameters ultimately impact the function of the LNP, thereby making it challenging to improve the efficacy and safety profiles of next-generation RNA delivery vectors. To address these questions, we have i. synthesized and purified rationally designed lipid materials of precise chemical structure, ii. formulated these materials into mRNA LNPs using microfluidic approaches, and iii. evaluated LNP potency and safety in vitro and in vivo as a function of the lipid’s chemical structure. Our lipids, which are actively being pursued as lead materials with pharmaceutical partners, ultimately represent robust RNA delivery vectors with high potency, low toxicity, and tunable biodistribution profiles independent of molecular targeting ligands and sequence modifications.

User-Friendly Synthetic Hydrogels

Given their tunable mechanical properties and resemblance to soft tissue, hydrogels are advantageous in a wide range of biomedical applications including 3-dimensional cell culture, controlled release, and tissue engineering.^7,8 Recent advances in chemistry and materials science have led to the proliferation of synthetic hydrogels with reproducible mechanical properties for biomaterials application.⁹ However, these systems can be difficult to implement broadly within academic and professional laboratories due to challenges associated with the synthesis, formulation, and scalability of these hydrogels and their precursors.¹⁰ Here, we aim to address some of these limitations by presenting a class of mechanically- and kinetically-tunable hydrogels whose gelation occurs at physiologically relevant temperatures without the need for initiators, specialized laboratory equipment, or complex monomer synthesis. Specifically, our hydrogel self-assembles upon bench top mixing of commercially available small molecules with a decagram-scalable polyethylene glycol derivative. The design, synthesis, and mechanical properties of our hydrogel will be discussed alongside its application for 3-dimensional cell culture for scalable biomaterials evaluation. In doing so, we not only hope to present upon an alternative hydrogel platform for biomedical application, but also to highlight the importance of rational chemical design for the development of next generation biomaterials.

References:

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2. Fenton OS, Olafson KN, Pillai PS, Mitchell MJ, Langer R Advanced Materials, Accepted.
3. Sahin U, Kariko K, Tureci, C Nat. Rev. Drug Discov. 13 (2014) 759-780
4. Kauffman KJ, Webber MJ, Anderson DG J. Control. Release (2016) 227-234
5. Fenton OS, Kauffman KJ, McClellan RL, Appel EA, Dorkin JR, Tibbitt MW, Heartlein MW, DeRosa F, Langer R, Anderson DG Advanced Materials 28 (2016) 2939-2943
6. Fenton OS, Kauffman KJ, Kaczmarek JC, McClellan RL, Jhunjhunwala S, Tibbitt MW, Zeng MD, Appel EA, Dorkin JR, Mir FF, Yang JH, Oberli MA, Heartlein MW, DeRosa F, Langer R, Anderson DG Advanced Materials 29 (2017) 1606944
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