We have introduced a new nanoparticle composition and concept to the drug delivery area with resulting successful performance in lung, ovarian, breast, and pancreatic cancers as well as mesothelioma animal models (Biomaterials, 2011, 2013, 2016; Nanomedicine, 2016). Specifically, we designed a nanoparticle that localizes to tumor after intrapertoneal (IP) injection and, once at the low pH site of the tumor, undergoes a hydrophobic to hydrophilic transition resulting in swelling and rapid release of the drug (J. Am. Chem. Soc., 2009; Nanoscale, 2013). As the drug is maintained in the carrier until it reaches the target site, high local intratumoral and intracellular concentrations are achieved with low systemic exposure. The hydrophobic to hydrophilic transition arises in the crosslinked polymeric nanoparticle from the deprotection of the acid-labile protecting group on the hydroxyl. Once expanded, the polymer network acts as a hydrogel depot to concentrate the drug and allows a prolonged exposure at the desired site. Discovery of this concentrating effect enabled an unprecedented experiment whereby empty nanoparticles are first IP injected into a tumor-bearing animal and then subsequent injection of drug, 24 h later, results in high drug levels in the tissue as compared to a drug-alone treatment (Sci. Rep., 2016). This result paves the way for a new paradigm where medical devices can be repeatedly loaded after implantation to afford a superior outcome.

The closure and repair of wounds after traumatic or surgical injury is of significant clinical and research importance. While sutures remain the common wound closure technique, they possess many disadvantages. Consequently, polymeric hydrogel sealants and adhesives are emerging as essential biomaterials for wound management and repair. Building off our successful syntheses of biodegradable polyester, polyamide, and polyether-ester dendritic polymers based on biocompatible building blocks, we crosslinked these polymers to afford new hydrogels with targeted biodegradation, mechanical, adhesive, and swelling properties (J. Am. Chem. Soc., 2002, 2004; Bioconjug. Chem., 2006). This seminal discovery of unique hydrogels catalyzed the development of corneal sealants, which are changing the standard of care for wound management (J. Cataract Refract. Surg., 2005; Invest. Ophthalmol. Vis. Sci., 2007; Arch. Ophthalmol., 2009). The discovery also led to the formation of Hyperbranch Medical Technology and commercialization of ocular (CE), dural (CE/FDA), spine (CE) and hernia patch (CE) sealants which have been used to treated thousands of patients (OcuSeal® and Adherus Surgical Sealants,® respectively).

We next developed a library of hydrogel sealants and dressings, which possess the favorable properties of tissue adhesion and swelling, and act as a preventive barrier to bacterial infection along with the unique feature of dissolution on-demand with a biocompatible aqueous solution. The mechanism of hydrogel dissolution relies on the thiol-thioester exchange reaction. These new sealants perform successfully in ex vivo and in vivo models of hemorrhage (Angew. Chem., Int. Ed., 2013), and are of interest for providing immediate treatment of severe hepatic and aortic trauma with a dissolution feature for post-emergent care at the hospital. Similarly, these hydrogels are succssful in treating second-degree burn wounds (Angew. Chem., Int. Ed., 2016), and, thus, these dressing may provide a means to repeatably change dressings in a minimally or pain-free manner.

Polysaccharides play key roles in biology, including in energy storage, as structural materials, and as modulators of protein interactions and activity. However, polysaccharides are remarkably diverse in molecular configuration, functionalization, linkage types, and degree of branching, and thus, are challenging synthetic targets. To address this fundamental problem, we reported a new method of synthesizing polysaccharide analogs. Specifically, enantiopure poly-amido-saccharides (PASs) with defined molecular weights and narrow dispersities are synthesized using an anionic ring-opening polymerization of a β-lactam sugar monomer with degrees of polymerization ranging from 25 to >120 in high yields (J. Am. Chem. Soc., 2012; ACS Macro Lett., 2013; ACS Macro Lett., 2014; Chem. Sci., 2014). The PASs have a previously unreported main chain structure that is composed of pyranose rings linked through the 1- and 2-positions by an amide bond with β-configuration. PASs offer the advantages associated with synthetic polymers, such as greater control over structure and derivitization. At the same time, they preserve many of the structural features of natural polysaccharides, such as a stereochemical regularity and rigid pyranose backbone, that make natural carbohydrate polymers important materials both for their unique properties and useful applications (J. Am. Chem. Soc., 2016).

Superhydrophobic materials are finding increased use in the biomedical area as substrates to control protein adsorption, cellular interactions, bacterial growth, and as platforms for drug delivery devices and diagnostic tools (Biomaterials, 2016). The commonality in the design of these biomaterials is to create a stable or metastable air state at the material surface, which lends itself to a number of unique properties. Via electrospinning a solution of poly(ε-caprolactone) (PCL) and a novel poly(glycerol monostearate-co-ε-caprolactone), we fabricated 3D meshes with varying surface tensions (including those exhibiting superhydrophobicity). One application for these non-woven meshes, which are flexible, easily stapled and cut, is for the controlled delivery of either hydrophobic or hydrophilic anticancer drugs for the treatment of lung cancer recurrence (J. Am. Chem. Soc., 2012; J. Control. Release, 2015; Biomaterials, 2016). The drug-loaded buttress is implanted at the resection margin to release local chemotherapeutics.

Recognizing that we can tune the surface tension of these meshes, we next designed and evaluated unique surface tension sensors. These sensors function by exploiting the transition in wetting states of liquids near the critical surface tension on each porous material. The sensor is composed of an upper, ‘responsive’ layer that wets with liquids only below a specific surface tension, after which the hydrophilic lower ‘indicator’ layer wets completely, and causes a color change due to incorporated bromocresol purple dye. Such sensors are successfully used to determine the fat content in breast milk and by doing so helps mothers feed and care for low birth weight and failure to thrive infants (Adv. Healthc. Mater., 2015).

Glycerol-based polymers are of widespread interest for industrial, cosmetic, and pharmaceutical applications (Chem. Rev., 2016). Various polymer architectures from linear to dendritic are reported for pure polyglycerol ethers and carbonates as well as copolymers with hydroxy-acids to give poly ether-esters or poly carbonate-esters. Within the biomedical arena, these polymers possess the following advantages: 1) a free hydroxyl group for functionalization with chemotherapeutic agents, antibacterial compounds, anti-inflammatory agents, fluorescent tags, or material property modifiers, 2) a defined biodegradation route to afford non-toxic and non-acidic byproducts, e.g., glycerol and carbon dioxide, 3) physical properties ranging from semi-crystalline or amorphous materials based on the polymer or co-polymer compositions, and 4) amenability to manufacturing methods such as casting or electrospinning. In many ways, these polymers provide users the capabilities of well-known polymers like PLA (polylactic acid) or PLGA (poly(lactic-co-glycolic acid)) with the additional benefits of easily modifiable structure and non-acidic products upon biodegradation. We described the first synthesis of linear polycarbonates based solely on glycerol (i.e., poly(1,3-glycerol carbonate)) using a ring opening polymerization strategy in 2003 (Macromolecules, 2003). These polymers are easily functionalized and degrade into safe, non-acidic products of glycerol and CO2. We also reported the first synthesis of atactic and isotactic linear poly(benzyl 1,2-glycerol carbonate)s via the ring-opening copolymerization of rac-/(R)-benzyl glycidyl ether with CO2 using [SalcyCoIIIX] complexes in high carbonate linkage selectivity and polymer/cyclic carbonate selectivity (J. Am. Chem. Soc., 2013). Building on these results, we next synthesized poly(glyceric acid carbonate), which is a degradable analogue of poly(acrylic acid) (J. Am. Chem. Soc., 2015).

With the ongoing global effort to reduce greenhouse gas emission and dependence on oil, electrical energy storage (EES) devices have become ubiquitous. Today, EES devices are playing key roles in energy storage, transfer, and delivery within, e.g., electric vehicles where performance at temperatures greater than 25 °C is required (Chem. Soc. Rev., 2017). Therefore, the chemical stability of the used electrolyte is crucial for broader applications. To overcome the challenge of instability at elevated temperatures, we have assembled a lithium metal battery (LMB) containing a tailored phosphonium ionic liquid / LiTFSI electrolyte that operates at 100 °C with good specific capacities and cycling stability (Chem. Sci., 2015). Substantial capacity is maintained during 70 cycles or 30 days. Instant on-off battery operation is realized via a significant temperature dependence of the electrolyte material, demonstrating the robustness and potential for use at high temperatures. Taking advantage of our synthetic route to poly(glycerol carbonate)s, we then described the synthesis of aliphatic poly(ether 1,2-glycerol carbonate)s via copolymerization of CO2 with glycidyl ethers and reported a thermally stable solid polymer electrolyte (ACS Macro Lett., 2015) which performs over a range from 25 to 100 °C.

A malignant tumor is more than a single mutated cell population replicating without regard to the otherwise healthy tissue, within which it resides. Rather it is characterized by changes in the microenvironment resulting from the interplay between the extracellular matrix, the malignant cells, and their assorted support of endothelial, tumor associated macrophages, cancer associated fibroblasts, pericytes, and immune cells. However, artificially polarized cells, adhered to treated polystyrene, are used as our first round of testing for research in cancer biology, cancer immunology, drug delivery, and novel drug discovery. In order to develop a model that better mimics a tumor, we are preparing, characterizing, and evaluating spheroids, or multicellular aggregates, embedded in a 3D collagen matrix as an in vitro cancer model (Biomaterials 2014). The advantages of this system are a more physiological environment for cellular interactions, metabolism, growth, and invasion. Importantly, the technique is scalable for high throughput applications and the combination of whole spheroid techniques with single cell analysis allows in-depth investigations into basic cancer cell behavior from the macroscopic to single molecule scales. We are exploring the: 1) interplay between tumor associated macrophages and cancer cells, 2) effect of chemotherapeutic response based on cell type and embedded multicellular architecture, 3) efficacy of drug delivery systems for deep tumor penetration, and 4) role of the microenvironmental on cancer stem cell presence.

Today, there are no quantitative clinical techniques for imaging healthy or diseased articular cartilage. Articular cartilage is the smooth, hydrated tissue that lines the ends of long bones in load bearing joints. As a first step to address this unmet clinical need, we are designing new contrast agents for computed tomography (CT) (Chem. Rev., 2013) and magnetic resonance imaging (MRI). Specifically, we have developed a unique family of CT (J. Am. Chem. Soc., 2009; Angew. Chem., Int. Ed., 2014) and MRI (Chem. Commun., 2015) contrast agents based on electrostatic interactions between the agents and the negatively charged glycosaminoglycans present in articular cartilage. These contrast agents (e.g., CA4+) enable sensitive, non-destructive contrast enhanced imaging to assess the biochemical and biomechanical properties of articular cartilage with 3D visual maps of cartilage glycosaminoglycan content, equilibrium modulus, and coefficient of friction in multiple animal and human cadaveric models (J. Orthop. Res., 2011; Osteoarthr. Cartil., 2011; Osteoarthr. Cartil., 2013; Radiology, 2013; Cartilage, 2016; J. Orthop. Res., 2016). These agents and methods are empowering researchers to study diseases like osteoarthritis (OA) and to evaluate new OA therapies in both small (mice, rats, and rabbits) and large (horse) animal models.

Synovial fluid is the clear, viscous liquid that efficiently lubricates the articular cartilage lining the ends of bones in synovial joints such as the knee. Healthy synovial fluid contains hyaluronic acid (HA), which affords optimal lubrication, shock absorption, and viscoelastic properties for sustained joint function. Given that injury or life-long continued use results in lower concentrations of produced HA and induces mechanical wear at the cartilage surface (i.e., osteoarthritis), we are designing, synthesizing, and evaluating an anionic polymer as a novel biolubricant. By reducing the coefficient of friction and minimizing wear, the time until a total knee surgery is required could be delayed. There are no such concepts reported or treatments available today. Using ring-open polymerization, anionic polymers with large molecular weights (1 to 10M g/mol) are synthesized which lubricate articular cartilage surfaces (J. Am. Chem. Soc., 2013). Their performance is similar to that of healthy synovial fluid and superior to those of saline and Synvisc in an ex vivo human cartilage plug-on-plug model. In addition, the polymers are not readily degraded by hyaluronidase and are not cytotoxic to human chondrocytes in vitro. The rheological and lubricating properties are dependent on the polymer chemical structure. For example, olefin hydrogenation reduces polymer viscosity by several orders of magnitude (J. Am. Chem. Soc., 2010). Large animal model studies are ongoing to evaluate polymer efficacy in osteoarthritis trauma models.