FUNDAMENTALS of MOLECULAR RECOGNITION
Supramolecular interactions take advantage of many weak intermolecular forces simultaneously yielding selective complexes exhibiting extremely high binding affinities that are ideally suited for the systematic study and quantitative determination of the thermodynamic and kinetic properties of non-covalent interactions ubiquitous in nature. To understand chemical complexity and emergent behavior in hierarchically assembled materials, model supramolecular moieties are being developed and characterized to derive principles of bottom-up control of macroscopic properties in dynamically crosslinked materials. We seek to build prescriptive models for understanding the role of kinetics and thermodynamics in dynamically crosslinked polymeric materials and to use these models to synthesize new materials with emergent properties.
HYDROGELS for THERAPEUTIC CELL and DRUG DELIVERY
Hydrogels are an important class of biomaterial that have received much attention for controlled drug-delivery applications on account of their similarity to soft biological tissue and highly variable mechanical properties. Many hydrogel systems utilizing covalent crosslinking approaches, including various radical processes using light, temperature, and pH, have been reported, yet these have several limitations on account of the irreversibility of their crosslinks. Shear-thinning hydrogels are water-swollen dynamically crosslinked polymer networks that exhibit viscous flow under shear stress (shear-thinning) and rapid recovery when the applied stress is relaxed (self-healing). These properties afford minimally invasive implantation in vivo though direct injection or catheter delivery to tissues, contributing to a rapid gain in interest in their application for drug delivery and tissue regeneration. A crucial challenge in these materials is facile and mild formation, modular modification and finely tunable control over mechanical properties, as well as rapid self-healing after flow.
By exploiting dynamic, multivalent interactions between biodegradable nanoparticles and biopolymer chains, we have developed shear-thinning injectable hydrogels where the delivery of therapeutics can be precisely controlled, enabling months-long release of entrapped cargo. Indeed, we have shown that multiple therapeutics that are dramatically physicochemically distinct can be delivered with similar release profiles over user-defined timeframes extending from days to months. These materials are readily processed and synthesized in a facile, inexpensive, and scalable manner, which are distinguishing features for many important biomedical applications. We have shown, for example, that physicochemically-distinct cargo that would normally exhibit a 10-fold difference in diffusivity (and therefore release) can be co-delivered over user-defined timeframes extending from days to months. We have shown that when we engineer our hydrogels to have a very small, dynamic hydrogel network that constrains the diffusion of both cargo at the same time, the self-diffusion of the dynamic hydrogel matrix becomes the rate limiting step for diffusion of both cargo. This unique feature allows for sustained co-delivery of multifarious cargo, despite the fact that they may be wildly different in size and chemistry.
BIOPHARMACEUTICAL FORMULATION ENGINEERING
With the shift from small molecule drugs to biopharmaceuticals have come formulation challenges inherent to proteins (e.g., insulin) that range from poor stability, protein aggregation, poor drug absorption, and often undesirable pharmacokinetics. Excipients are the non-medicinal components of drug formulations that facilitate effective drug delivery, drug solubility, solution viscosity, and formulation stability. Yet, current excipients were developed for small molecule drugs and are not optimized for protein formulations. We seek to address biopharmaceutical formulation challenges by specifically designing polymeric excipients with protein therapeutics in mind. We have recently developed polymers to facilitate stable protein formulation, to modulate absorption kinetics, and to enable co-formulation of otherwise incompatible proteins.
One primary area we have applied these formulation advances is in the development of improved insulin formulations for the treatment of diabetes. While insulin has been used to treat diabetes for almost 100 years, current clinical formulations have severe challenges with appropriately recapitulating endogenous hormone function and exceptionally prone to non-reversible aggregation when exposed to heat and agitation and therefore require costly cold chain storage and transport. To address these challenges we have developed an approach to supramolecular PEGylation of proteins. Our “designer” supramolecular excipient binds non-covalently to insulin with micromolar affinities such that over 99% of complexes are bound at typical formulation concentrations, yet less than 1% are bound upon dilution in the body. Accordingly, this designer excipient imparts unprecedented formulation stability and automatic release of authentic therapeutic proteins upon administration in the body. We have also developed simple “drop-in” copolymer excipients capable of dramatically enhancing insulin formulation stability by blocking protein adsorption to interfaces. These copolymers have enabled the development of new ultrafast insulin formulations. We continue to explore new approaches to addressing critical biopharmaceutical formulation challenges.
HYDROGELS for INDUSTRIAL APPLICATIONS
We have recently developed a hydrogel platform comprising inexpensive, renewable, and environmentally-benign starting materials that are simple to manufacture on scale and exhibit a number of unique mechanical behaviors. These hydrogels demonstrate the potential to be transformational in the way complicated engineering challenges are addressed in a number of large-scale industrial processes. Many industrial applications often require, or would benefit greatly from, the use of hydrogels instead of water alone. Previously reported materials, however, are too expensive, poorly scalable, or toxic to people or the environment to be used widely. In contrast, our materials are extremely inexpensive and simple to manufacture on scale and comprise starting materials widely used in food and drug formulations. Furthermore, our materials exhibit a number of highly useful properties that are impossible with traditional hydrogels, allowing them to be deployed in processes that require flow, injection, or spraying, and as such can enable greener and more water-wise processes.
New materials can enable unique solutions to existing challenges in industrial processes ranging from pipeline maintenance in food and beverage manufacturing to fire retardant application in wildland fire prevention. A central feature of these two particular applications is the gross over-consumption of water on account of inherent inefficiencies in the use of water in these processes. Water is an invaluable natural resource and total industrial freshwater use in the United States has reached an astonishing 16 million gallons per day (not including usage for thermoelectric power, irrigation, livestock, or mining). Recent water conservation efforts on account of long-standing droughts in California and elsewhere highlight the great need to develop novel approaches to complex engineering challenges in these applications and others. In a recent article, we demonstrated that our hydrogels can significantly reduce water usage in pipeline maintenance operations in commercial food and beverage manufacturing, while also dramatically reducing the loss of product confronting many batch processes. We also reported gel-based fire retardant formulations that can enable more effective tactical approaches to fighting wildland fires that are impossible with current formulations. This work represents a new paradigm for the fabrication of self-assembled moldable hydrogels from renewable and environmentally-benign starting materials that meet the critical need for technological advancements in a number of industrial applications.