Eric A. Appel's research while affiliated with Stanford Medicine and other places

Publications (148)

Preprint
Development of effective vaccines for infectious diseases has been one of the most successful global health interventions in history. Though, while ideal subunit vaccines strongly rely on antigen and adjuvant(s) selection, the mode and timescale of exposure to the immune system has often been overlooked. Unfortunately, poor control over the deliver...
Preprint
The introduction of transcutaneous and subcutaneous implants and devices into the human body instigates fouling and foreign body responses that limit their functional lifetimes. Polymer coatings are a promising solution to improve the biocompatibility of such implants, with potential to enhance in vivo device performance and prolong device lifetime...
Preprint
Most vaccines require several immunizations to induce robust immunity, and indeed, most SARS-CoV-2 vaccines require an initial two-shot regimen followed by several boosters to maintain efficacy. Such a complex series of immunizations unfortunately increases the cost and complexity of populations-scale vaccination and reduces overall compliance and...
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Full-text available
Many cell-based therapies are challenged by the poor localization of introduced cells and the use of biomaterial scaffolds with questionable biocompatibility or bio-functionality. Endothelial progenitor cells (EPCs), a popular cell type used in cell-based therapies due to their robust angiogenic potential, are limited in their therapeutic capacity...
Article
Monoclonal antibodies are a staple in modern pharmacotherapy. Unfortunately, these biopharmaceuticals are limited by their tendency to aggregate in formulation, resulting in poor stability and often requiring low concentration drug formulations. Moreover, existing excipients designed to stabilize these formulations are often limited by their toxici...
Article
Vision impairment resulting from chronic eye diseases, such as macular degeneration and glaucoma, severely impacts patients’ quality of life and poses an immense global financial burden. Current standard of care for such diseases includes daily eye drops or frequent intravitreal (ITV) injections, which are burdensome treatment modalities resulting...
Preprint
Vision impairment resulting from chronic eye diseases, such as macular degeneration and glaucoma, severely impacts patients' quality of life and poses an immense global financial burden. Current standard of care for such diseases includes daily eye drops or frequent intravitreal (ITV) injections, which are burdensome treatment modalities resulting...
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Full-text available
While excipients are often overlooked as the “inactive” ingredients in pharmaceutical formulations, they often play a critical role in protein stability and absorption kinetics. Recent work has identified an ultrafast absorbing insulin formulation that is the result of excipient modifications. Specifically, the insulin monomer can be isolated by re...
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Full-text available
When properly deployed, the immune system can eliminate deadly pathogens, eradicate metastatic cancers, and provide long‐lasting protection from diverse diseases. Unfortunately, realizing these remarkable capabilities is inherently risky as disruption to immune homeostasis can elicit dangerous complications or autoimmune disorders. While current re...
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Full-text available
Designing yield stress fluids to exhibit desired functional properties is an integral challenge in many applications such as 3D printing, drilling, food formulation, fiber spinning, adhesives, and injectable biomaterials. Extensibility in particular has been found to be a highly beneficial characteristic for materials in these applications; however...
Preprint
While excipients are often overlooked as the "inactive" ingredients in pharmaceutical formulations, they often play a critical role in protein stability and absorption kinetics. Recent work has identified an ultrafast absorbing insulin formulation that is the result of excipient modifications. Specifically, the insulin monomer can be isolated by re...
Article
Full-text available
Hydrogels that can be injected into the body using standard needles or catheters enable a minimally invasive strategy to prolong local delivery of therapeutic cargo. In particular, physically cross‐linked hydrogels exhibit shear‐thinning and self‐healing behaviors enabling facile injectability and depot formation upon administration. While prior ef...
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Full-text available
Ebola virus (EBOV), a member of the Filoviridae family of viruses and a causative agent of Ebola Virus Disease (EVD), is a highly pathogenic virus that has caused over twenty outbreaks in Central and West Africa since its formal discovery in 1976. The only FDA-licensed vaccine against Ebola virus, rVSV-ZEBOV-GP (Ervebo®), is efficacious against inf...
Article
The immune system is one of the most important, complex biological networks regulating and protecting human health. Its precise modulation can prevent deadly infections and fight cancer. Accordingly, prophylactic vaccines and cancer immunotherapies are some of the most powerful technologies to protect against potential dangers through training of t...
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Full-text available
Biofouling on the surface of implanted medical devices and biosensors severely hinders device functionality and drastically shortens device lifetime. Poly(ethylene glycol) and zwitterionic polymers are currently considered “gold standard” device coatings to reduce biofouling. To discover novel anti‐biofouling materials, we created a combinatorial l...
Article
Directing biological functions is at the heart of next-generation biomedical initiatives in tissue and immuno-engineering. However, the ambitious goal of engineering complex biological networks requires the ability to precisely perturb specific signaling pathways at distinct times and places. Using lipid nanotechnology and the principles of supramo...
Preprint
Monoclonal antibodies are a staple in modern pharmacotherapy. Unfortunately, these biopharmaceuticals are limited by their tendency to aggregate in formulation, resulting in poor stability and often requiring low concentration drug formulations. Moreover, existing excipients designed to stabilize these formulations are often limited by their toxici...
Preprint
Prolonged maintenance of therapeutically-relevant levels of broadly neutralizing antibodies (bnAbs) is necessary to enable passive immunization against infectious disease. Unfortunately, protection only lasts for as long as these bnAbs remain present at a sufficiently high concentration in the body. Poor pharmacokinetics and burdensome administrati...
Preprint
Hydrogels that can be injected into the body using standard needles or catheters enable a minimally invasive strategy to prolong local delivery of therapeutic drug and cellular cargo. In particular, physically crosslinked hydrogels exhibit shear-thinning and self-healing behaviors enabling facile injectability and depot formation upon administratio...
Preprint
Full-text available
Designing yield stress fluids to exhibit desired functional properties is an integral challenge in many applications such as 3D printing, drilling, food formulation, fiber spinning, adhesives and injectable biomaterials. Extensibility in particular has been found to be a highly beneficial characteristic for materials in these applications; however,...
Article
Adoptive cell therapy (ACT) has proven to be highly effective in treating blood cancers, but traditional approaches to ACT are poorly effective in treating solid tumors observed clinically. Novel delivery methods for therapeutic cells have shown promise for treatment of solid tumors when compared with standard intravenous administration methods, bu...
Article
Recent far-reaching advances in synthetic biology have yielded exciting tools for the creation of new materials. Conversely, advances in the fundamental understanding of soft-condensed matter, polymers and biomaterials offer new avenues to extend the reach of synthetic biology. The broad and exciting range of possible applications have substantial...
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Full-text available
Purpose: To create an alkali injury symblephara mouse model to study conjunctival fibrosis pathophysiology and test polymer nanoparticle (PNP) hydrogel as a preventative therapeutic. Methods: Mice were injured using NaOH-soaked filter paper to determine the optimal NaOH concentration to induce the formation of symblephara. Injured mice were obse...
Preprint
Full-text available
We demonstrated that joint delivery of human-derived endothelial progenitor cell (EPC) and smooth muscle cell (SMC) sheets mimics the native architecture of structurally mature blood vessels and contributes to limiting ventricular remodeling using a confluent SMC-EPC bi-level cell sheet engineered by cell-sheet technology and transplanted into an a...
Article
Full-text available
The efficacy and safety of a chemotherapy regimen fundamentally depends on its pharmacokinetics. This is currently measured based on blood samples, but the abnormal vasculature and physiological heterogeneity of the tumor microenvironment can produce radically different drug pharmacokinetics relative to the systemic circulation. We have developed a...
Article
Full-text available
The development of effective vaccines that can be rapidly manufactured and distributed worldwide is necessary to mitigate the devastating health and economic impacts of pandemics like COVID-19. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, which mediates host cell entry of the virus, is an appealing antigen for subunit vaccines...
Preprint
Adoptive cell therapy (ACT) has proven to be highly effective in treating blood cancers such as B cell malignancies, but traditional approaches to ACT are poorly effective in treating the multifarious solid tumors observed clinically. Locoregional cell delivery methods have shown promising results in treating solid tumors compared to standard intra...
Article
Full-text available
Endogenous capability of the post-mitotic human heart holds great promise to restore the injured myocardium. Recent evidence indicates that the extracellular vesicles (EVs) regulate cardiac homeostasis and regeneration. Here, we investigated the molecular mechanism of EVs for self-repair. We isolated EVs from human iPSC-derived cardiomyocytes (iCMs...
Article
Full-text available
Dual‐hormone replacement therapy with insulin and amylin in patients with type 1 diabetes has the potential to improve glucose management. Unfortunately, currently available formulations require burdensome separate injections at mealtimes and have disparate pharmacokinetics that do not mimic endogenous co‐secretion. Here, amphiphilic acrylamide cop...
Article
Full-text available
Polymer–nanoparticle hydrogels are a unique class of self‐assembled, shear‐thinning, yield‐stress fluids that have demonstrated potential utility in many impactful applications. Here, we present a thorough analysis of the gelation and yielding behavior of these materials with respect to the polymer and nanoparticle component stoichiometry. Through...
Preprint
Directing and manipulating biological functions is at the heart of next-generation biomedical initiatives. However, the ambitious goal of engineering complex biological networks requires the ability to precisely perturb specific signaling pathways at distinct times and places. Biomaterials that can precisely control drug presentation are therefore...
Preprint
Full-text available
Polymer-Nanoparticle hydrogels are a unique class of self-assembled, shear-thinning, yield-stress fluids which have demonstrated potential utility in many impactful applications. Here we present a thorough analysis of the gelation and yielding behavior of these materials with respect to the polymer and nanoparticle component stoichiometry. Through...
Preprint
Polymer-Nanoparticle hydrogels are a unique class of self-assembled, shear-thinning, yield-stress fluids which have demonstrated potential utility in many impactful applications. Here we present a thorough analysis of the gelation and yielding behavior of these materials with respect to the polymer and nanoparticle component stoichiometry. Through...
Article
Vaccines are the key technology to combat existing and emerging infectious diseases. However, increasing the potency, quality and durability of the vaccine response remains a challenge. As our knowledge of the immune system deepens, it becomes clear that vaccine components must be in the right place at the right time to orchestrate a potent and dur...
Preprint
Full-text available
Polymer-Nanoparticle hydrogels are a unique class of self-assembled, shear-thinning, yield-stress fluids which haved demonstrated potential utility in many impactful applications. Here we present a thorough analysis of the gelation and yielding behavior of these materials with respect to the polymer and nanoparticle component stoichiometry. Through...
Preprint
Polymer-Nanoparticle hydrogels are a unique class of self-assembled, shear-thinning, yield-stress fluids which haved demonstrated potential utility in many impactful applications. Here we present a thorough analysis of the gelation and yielding behavior of these materials with respect to the polymer and nanoparticle component stoichiometry. Through...
Article
Full-text available
Preclinical cancer research is heavily dependent on allograft and xenograft models, but current approaches to tumor inoculation yield inconsistent tumor formation and growth, ultimately wasting valuable resources (e.g., animals, time, and money) and limiting experimental progress. Here we demonstrate a method for tumor inoculation using self-assemb...
Article
With the increasing prevalence of type 2 diabetes and fatty liver disease, there is still an unmet need to better treat hyperglycemia and hyperlipidemia. Here, we identify isthmin-1 (Ism1) as an adipokine and one that has a dual role in increasing adipose glucose uptake while suppressing hepatic lipid synthesis. Ism1 ablation results in impaired gl...
Preprint
The SARS-CoV-2 virus spike protein, specifically its receptor binding domain (RBD), has emerged as a promising target for generation of neutralizing antibodies. Although the RBD peptide subunit is easily manufactured and highly stable, RBD-based subunit vaccines have been hampered by its poor inherent immunogenicity. We hypothesize that this limita...
Preprint
Full-text available
The efficacy and safety of a chemotherapy regimen fundamentally depends on its pharmacokinetics. This is currently measured based on blood samples, but the abnormal vasculature and physiological heterogeneity of the tumor microenvironment can produce radically different drug pharmacokinetics relative to the systemic circulation. We have developed a...
Preprint
Full-text available
When properly deployed, the immune system can render deadly pathogens harmless, eradicate metastatic cancers, and provide long-lasting protection from diverse diseases. However, realizing these remarkable capabilities is inherently risky, as disruption to immune homeostasis can lead to dangerous complications and autoimmune disorders. While current...
Article
Recovery of struvite at wastewater treatment plants provides a beneficial fertilizer while preventing costly operational issues due to precipitation in pipes, pumps, and digesters. At present, however, sale of struvite as fertilizer is hampered by low revenues. A higher value proposition of struvite is its use in phosphorus-based fire retardants, i...
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Full-text available
Advances in hydrogel technology have unlocked unique and valuable capabilities that are being applied to a diverse set of translational applications. Hydrogels perform functions relevant to a range of biomedical purposes—they can deliver drugs or cells, regenerate hard and soft tissues, adhere to wet tissues, prevent bleeding, provide contrast duri...
Article
Full-text available
Vaccines are critical for combating infectious diseases across the globe. Influenza, for example, kills roughly 500,000 people annually worldwide, despite annual vaccination campaigns. Efficacious vaccines must elicit a robust and durable antibody response, and poor efficacy often arises from inappropriate temporal control over antigen and adjuvant...
Preprint
Full-text available
Preclinical cancer research is heavily dependent on allograft and xenograft models, but current approaches to tumor inoculation yield inconsistent tumor formation and growth, ultimately wasting valuable resources (e.g., animals, time, and money) and limiting experimental progress. Here we demonstrate a method for tumor inoculation using self-assemb...
Preprint
Full-text available
There are 150 million people with diabetes worldwide who require insulin replacement therapy and the prevalence of diabetes is rising fastest in middle and low-income countries. Current formulations require costly refrigerated transport and storage to prevent loss of insulin integrity. This study shows the development of simple "drop-in" amphiphili...
Preprint
Dual-hormone replacement therapy with insulin and amylin in patients with type 1 diabetes has the potential to improve glucose management. Unfortunately, currently available formulations require burdensome separate injections at mealtimes and have disparate pharmacokinetics that do not mimic endogenous co-secretion. Here, we use amphiphilic acrylam...
Article
Full-text available
Understanding how automated insulin delivery (AID) algorithm features impact glucose control under full closed loop delivery represents a critical step toward reducing patient burden by eliminating the need for carbohydrate entries at mealtimes. Here, we use a pig model of diabetes to compare AndroidAPS and Loop open-source AID systems without meal...
Preprint
The development of an effective vaccine that can be rapidly manufactured and distributed worldwide is necessary to mitigate the devastating health and economic impacts of pandemics like COVID-19. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, which mediates host cell entry of the virus, is an appealing antigen for subunit vaccin...
Article
These methods describe how to formulate injectable, supramolecular polymer-nanoparticle (PNP) hydrogels for use as biomaterials. PNP hydrogels are composed of two components: hydrophobically modified cellulose as the network polymer and self-assembled core-shell nanoparticles that act as non-covalent cross linkers through dynamic, multivalent inter...
Article
A preventative treatment of fire retardants at high-risk locales can potentially stop a majority of wildfires. For example, over 80% of wildfire ignitions in California occur at high-risk locales such as adjacent to roadsides and utility infrastructure. Recently a new class of ammonium polyphosphate retardants was developed with enhanced adherence...
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Full-text available
Physical networks typically employ enthalpy-dominated crosslinking interactions that become more dynamic at elevated temperatures, leading to network softening. Moreover, standard mathematical frameworks such as time-temperature superposition assume network softening and faster dynamics at elevated temperatures. Yet, deriving a mathematical framewo...
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Full-text available
Prophylactic vaccines often exploit adjuvants to drive potent and directed immune responses. Small‐molecule toll‐like receptor (TLR) agonists are promising adjuvant candidates; however, the poor pharmacokinetics and rapid distribution of these relatively hydrophilic small molecules results in systemic side effects that have limited their usage to t...
Article
Insulin was first isolated almost a century ago, yet commercial formulations of insulin and its analogs for hormone replacement therapy still fall short of appropriately mimicking endogenous glycemic control. Moreover, the controlled delivery of complementary hormones (such as amylin or glucagon) is complicated by instability of the pharmacologic a...
Article
Post‐operative adhesions are fibrous bands of scar tissue formed between internal tissues and organs causing clinical morbidity and their prevention represents a critical unmet need. Over 20 million Americans undergo invasive surgery each year and 95% of those patients develop post‐operative adhesions. More specifically, peritoneal adhesions formin...
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Full-text available
The sustained release of vaccine cargo has been shown to improve humoral immune responses to challenging pathogens such as influenza. Extended codelivery of antigen and adjuvant prolongs germinal center reactions, thus improving antibody affinity maturation and the ability to neutralize the target pathogen. Here, we develop an injectable, physicall...
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Full-text available
Thermogelling tri-block terpolymers were made from a bifunctional PEG RAFT agent. The critical solution behavior was tunable by alteration of the terpolymer composition, enabling modulation of gelation temperatures and hydrogel viscoelasticity.
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Full-text available
Biosensors that continuously measure circulating biomolecules in real time could provide insights into the health status of patients and their response to therapeutics. But biosensors for the continuous real-time monitoring of analytes in vivo have only reached nanomolar sensitivity and can measure only a handful of molecules, such as glucose and b...
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Full-text available
Many biomaterials have been developed which aim to match the elastic modulus of the brain for improved interfacing. However, other properties such as ultimate toughness, tensile strength, poroviscoelastic responses, energy dissipation, conductivity, and mass diffusivity also need to be considered.
Article
Ischemic heart disease is the most common type of heart disease, responsible for roughly 10 million deaths worldwide annually. While standard clinical interventions have resulted in improved patient outcomes, access to small diameter vessels required for cardiovascular interventions, and long-term patient mortality rates associated with eventual he...
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Full-text available
The widespread adoption of bead-based multiplexed bioassays requires the ability to easily synthesize encoded microspheres and conjugate analytes of interest to their surface. Here, we present a simple method (MRBLEs 2.0) for the efficient high-throughput generation of microspheres with ratiometric barcode lanthanide encoding (MRBLEs) that bear fun...
Article
Full-text available
Biotherapeutics currently dominate the landscape of new drugs because of their exceptional potency and selectivity. Yet, the intricate molecular structures that give rise to these beneficial qualities also render them unstable in formulation. Hydrogels have shown potential as stabilizing excipients for biotherapeutic drugs, providing protection aga...
Article
Full-text available
Physically associated hydrogels (PHs) capable of reversible transitions between solid and liquid‐like states have enabled novel strategies for 3D printing, therapeutic drug and cell delivery, and regenerative medicine. Among the many design criteria (e.g., viscoelasticity, cargo diffusivity, biocompatibility) for these applications, engineering PHs...
Article
Full-text available
Vaccines aim to elicit a robust, yet targeted, immune response. Failure of a vaccine to elicit such a response arises in part from inappropriate temporal control over antigen and adjuvant presentation to the immune system. In this work, we sought to exploit the immune system's natural response to extended pathogen exposure during infection by desig...
Article
Amphiphilic copolymers capable of extracting membrane proteins directly from lipid bilayers into “native nanodiscs” promise a simpler membrane protein sample preparation procedure for structural and functional studies. Unfortunately, the selection of nanodisc-forming copolymers is currently limited to molecules that are heterogeneous in terms of mo...
Article
Cancer immunotherapy can be augmented with toll-like receptor agonist (TLRa) adjuvants, which interact with immune cells to elicit potent immune activation. Despite their potential, use of many TLRa compounds has been limited clinically due to their extreme potency and lack of pharmacokinetic control, causing systemic toxicity from unregulated syst...
Article
Full-text available
Controlled radical polymerization of vinyl monomers with multivinyl cross-linkers leads to the synthesis of highly branched polymers with controlled spatial density of functional chain ends. The resulting polymers synthesized in this manner have large dispersities resulting from a mixture of unreacted primary chains, low molecular weight branched s...
Article
Full-text available
Restrictions to reduce human interaction have helped to avoid greater suffering and death from the COVID-19 pandemic, but have also created socioeconomic hardship. This disruption is unprecedented in the modern era of global observing networks, pervasive sensing and large-scale tracking of human mobility and behaviour, creating a unique test bed fo...
Article
Insulin has been used to treat diabetes for almost 100 years; yet, current rapid-acting insulin formulations do not have sufficiently fast pharmacokinetics to maintain tight glycemic control at mealtimes. Dissociation of the insulin hexamer, the primary association state of insulin in rapid-acting formulations, is the rate-limiting step that leads...
Preprint
Full-text available
Widespread adoption of bead-based multiplexed bioassays requires the ability to easily synthesize encoded microspheres and conjugate analytes of interest to their surface. Here, we present a simple method (MRBLEs 2.0) for efficient high-throughput generation of microspheres with ratiometric barcode lanthanide encoding (MRBLEs) bearing functional gr...
Preprint
Full-text available
Vaccines aim to elicit a robust, yet targeted, immune response. Failure of a vaccine to elicit such a response arises in part from inappropriate temporal control over antigen and adjuvant presentation to the immune system. In this work, we sought to exploit the immune response to extended pathogen exposure during infection by designing an easily ad...