Mark S. Humayun - US grants

DESCRIPTION (Adapted from applicant's abstract): By using electrical stimulation to bypass neurons which have become non-functional, implanted neural prostheses such as the cochlear implant have rehabilitated patients for whom there is no other treatment. The applicant proposes that a similar approach could benefit a subset of patients blind from retinitis pigmentosa and age-related macular degeneration, two leading causes of blindness. The results to date have supported this approach and show that vision compatible with mobility and large print reading is possible. The next critical step is to determine the maximum resolution affordable by such an approach. In this proposal, the applicant delineates key experiments necessary to achieve this goal.

DESCRIPTION (provided by applicant): Diabetic retinopathy (DR) and retinal vein occlusions (RVO) are major causes of low vision and blindness. Although DR and RVO have different underlying pathophysiology, inner retinal hypoxia secondary to ischemia is central to these diseases. Existing therapeutic approaches like pharmacological injections, pan-retinal photocoagulation, focal laser, and surgery either do not address retinal hypoxia or do so at the cost of damaging retinal tissue. Moreover, even with intravitreal injections of anti-Vascular Endothelial Growth Factors, or laser, in approximately 50% of patients, vision does not improve. Our interdisciplinary team of biologists, physicists, engineers, and physicians from seven institutions has taken a novel approach towards treating ischemic retinal disease. In this proposal, using sophisticated biological experiments, bioinformatics, biophysics and advanced bio-microelectromechanical systems (bioMEMS) engineering, we propose an OXYGENATOR system to deliver highly controlled levels of oxygen that are precisely targeted to the ischemic retina (i.e., local oxygenation within a therapeutic window). We have made significant advances towards engineering of a wireless bioelectronic implant (OXYGENATOR) that can deliver safe amounts of oxygen to the retina in a controlled manner. The OXYGENATOR consists of two units; one wearable and the other implantable. The extraocular wearable components (single ergonomic, flexible, low profile design for day and night time use) provide the inductive (RF) link for power and data. The implantable components consist of electronics to receive power and data, electronic circuitry attached to MEMS electrodes inside oxygen permeable membrane bag for electrolysis, and a refillable saline reservoir to replenish the saline inside oxygen permeable bag. The OXYGENATOR functions when the external component transmits power and data under customized software control to the implanted electronics (note software can be personalized for each patient need). The implanted electronics receive, decode and deliver controlled electrical pulses to the MEMS electrodes to result in electrolysis of the saline inside the oxygen permeable membrane bag. The oxygen then diffuses in a controlled and directional manner out the bag to the retina while shielding the anterior eye structures such as the lens. Although only nanoliters of saline are used over months of electrolysis, a refillable saline reservoir to replenish the saline inside the permeable bag has been designed to lengthen the life of the OXYGENATOR to 5+ years. In this proposal, we share our results to date on this novel approach and outline our research program in 3 specific aims. Successful completion of these 3 aims in preclinical studies will enable us to attract follow-on industrial funding to embar on clinical studies. The first aim is to use short and long term tests to quantify the retinal oxyen requirements at the cellular and tissue level. The second aim is to engineer the OXYGENATOR to demonstrate long-term efficacy and maximize efficiency. The third aim is to study the spatiotemporal dynamics of oxygen production and diffusion by controlled electrolysis in the eye.

This award provides funding for a three year standard award to support a Research Experiences for Teachers (RET) in Engineering and puter Science Site program at the University of Southern California (USC), entitled, "The Engineering Medical Therapeutic Technologies-Research Experience for Teachers (EMT2-RET)", under the direction of Dr. Mark Humayun.

The vision of the EMT2-RET program, is to leverage the considerable resources of the University of Southern California to create long-term partnerships among world-renowned biomedical engineering and computer science researchers, K-12 teachers in Los Angeles inner-city schools, and community college educators. 6-week program will support the involvement of a total of 30 (10 per year) high school and community college educators in mentored engineering and computer science research focused on medical therapeutic technologies conducted in Viterbi School of Engineering (VSoE) and the Biomimetic MicroElectronic Systems Engineering Research Center (BMES) Laboratories at USC. The coordinated efforts of multidisciplinary research groups offer RET teachers the opportunity to work in laboratories that range from basic science to systems engineering. Additionally, teachers will participate in professional development workshops in engineering and technology, aiding the teachers in the translation of the RET experience into relevant classroom activities, including discovery-based laboaratory exericses that are standards aligned.

The majority of students in the Los Angeles Unified School District, East Los Angeles College, Pasadena City College, Los Angeles City College are from underrepresented minority groups. The RET program will train science teachers from urban schools in biomedical engineering and computer science and, in turn impact the education of their respective students. Students who traditionally have little or no direct connection with STEM will, through the RET teachers, experience the excitement of cutting edge discoveries. In addition, the professional and collegial relationships that develop between the RET teachers and their USC colleagues and the extensive academic year follow-up component of the RET will foster long-term partnerships.

Proposal: 1404089
PI: Humayun, Mark S.
Title: Retinal Nanophotoswitch

Significance
The objective of the proposed research is to develop a novel neurophotonic molecular switch for light-activation of neurons. A visual prosthesis based on this nanophotoswitch (NPS) has the potential to improve the visual acuity for the millions of patients suffering from retinal degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration. This proposal is very innovative. The biophysical mechanism is completely differentiated from electrical devices and other molecular photo-switch-based approaches. Beyond vision restoration, it is a generally useful approach for controlling excitable cells. If successful, it may have a great impact on patients who are underserved by current treatments.

The interdisciplinary research provides excellent educational opportunities for participating graduate and undergraduate students. The proposing team has an exceptional record on inclusion of women, under-represented minorities, and undergraduates in their research. They also have a good track record on outreach to the local community, and planned outreach activities include Research Experience for Teachers and activities for K-12 students.

Technical Description
Nanophotoswitch (NPS) offers a new tool to elicit electrical activity for basic science studies of neuronal function, both in vitro and also potentially in vivo. The hypothesis is based on the NPS design and results of pilot experiments, that light induces an electrical dipole in the NPS. Preliminary data indicate that an NPS based on ruthenium bipyridine (Rubpy) inserts into cell membranes and upon visible-wavelength illumination triggers action potentials in cultured excitable cells and in wholemount rat retina. When injected into the eye of blind photoceptor-degenerate rats, visual stimulation induces electrical activity in the superior colliculus. It was also demonstrated that NPS can both depolarize or hyperpolarize the membrane, depending on the environmental redox potential. This unique combination of bi-directional modulation of the membrane potential in one biophotonic switch affords the ability to both activate and inhibit the action potential firing of the illuminated cells with the same molecule, presenting largely increased flexibility in neuronal control. The NPS would be useful in studying any electrically excitable cell, including, for example, cardiomyocytes, smooth muscle cells, neuroendocrine cells, and certain glial and cancer cells. Since light-activated signaling unit is individual neurons, a visual prosthesis based on NPS system has the potential to provide higher visual acuity for the millions of patients with photoreceptor loss due to retinal degenerative diseases, such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Distinct from other nano-scale optical cellular modulating approaches using optogenetics or azobenzene-based photoswitches, this approach obviates the need for gene manipulation, toxic ultraviolet illumination or immunogenic molecules, due to the unique light-to-electrical signal transduction mechanism of the NPS.

PROJECT SUMMARY/ABSTRACT The USC Roski Eye K12 program will provide mentored research training along with didactic and practical training to Scholars who demonstrate a commitment to a career as a clinician-scientist in vision research. USC Roski Eye K12 Scholars will benefit from a constellation of assets: 1) immersion in the intensely academic, highly innovative research environment at the USC Roski Eye Institute, ranked #2 in NEI funding; 2) research training by a productive, well-established group of 32 Preceptors with successful mentorship track-records who collectively hold 56 active NIH grants (including 30 R01s, 2 P01s, 5 U54, U01 or U10 awards, 5 P30 or P50 awards, and 2 T32s); 3) an experienced, capable and committed leadership team; and 4) a carefully designed individualized curriculum that will equip Scholars with the research skills needed to become independent clinician-scientists. Scholars will have the opportunity for research immersion in the following ophthalmologic themes: Imaging, Bioengineering and Nanotechnology, Epidemiology, Inflammation and Regeneration, and Neurodegeneration. The USC Roski Eye K12 proposes four aims: 1) Equip Scholars with skills to conduct vision research by individualized, didactic research training; 2) Mentor Scholars to articulate incisive, important research ideas, design scientifically rigorous approaches, critically analyze results and communicate research findings; 3) Train Scholars to proactively foster a collaborative and multidisciplinary team approach to advance vision research; and 4) Transition Scholars to develop independent and productive research programs. In terms of deliverables, all Scholars will be expected to publish and present their research findings, and develop and submit strong, scientifically rigorous, competitive individual mentored career development (K series) or research (R series) grant applications. The USC Roski Eye K12 program, Scholars, and Preceptors will be critically and regularly evaluated to ensure the program?s effectiveness in achieving the aims. The USC Roski Eye K12 will thus produce talented, promising new ophthalmologist-scientists dedicated to becoming outstanding, innovative, independent investigators who will address visual impairment and lead vision research into the 21st century.

Retinal blindness, such as retinitis pigmentosa (RP), age-related macular degeneration (AMD), and glaucoma (POAG), is characterized by unrelenting neuronal death (photoreceptor loss in RP and AMD and ganglion cell loss in POAG). These prevalent blinding conditions account for a significant part of the estimated US$139 billion annual economic burden of vision disorders in the U.S. This group has, for the first time, shown that controlled microscale electromagnetic (EM) stimulation can lead to neuroprotective changes in the retina. The transformational vision of this project is to use non-invasive controlled electrical stimulation to induce genetic changes in the mammalian retina to slow down the progression of retinal blindness and perhaps even restore some level of the lost vision. The success of such an approach would spawn a whole new area in basic science, engineering, and medicine and in doing so develop new, innovative, cross-disciplinary educational programs critical to foster the next-generation of researchers of bioelectronic devices to affect protective genetic changes.


A number of mechanisms have been identified as to why neuronal death occurs in different retinal blinding disorders (e.g., genetic mutations in RP, lipid metabolism abnormalities and inflammation in AMD, and elevated intraocular pressure in POAG to name a few). This group has shown that controlled microscale electromagnetic (EM) stimulation can lead to epigenetic retinal changes with implications for neuroprotective changes. The hypothesis of this proposal is that neuroepigenetic and chromatin remodeling of the retina induced through controlled electrical stimulation is a key molecular determinant of neuroprotection and could prove to be pivotal for the treatment of certain retinal blindness conditions. The vision of this proposal is that the findings will demonstrate how stimulation using electromagnetic (EM) fields can be effectively adopted to slow or halt the progression of prevalent retinal diseases.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

This project proposes to use in silico simulations to engineer nanoscale, biocompatible, protective barrier that will enhance our first line of defenses - prevention of pathogenic infection from entering and infecting the host. The principal investigator aims to develop a topical method that will enhance protection against virus attachment onto the nasal and oral as well as conjunctival epithelial cells, while preserving normal physiology and biochemistry. The project team will use computer models to engineer delivery devices to produce the optimal particle characteristics to maximally prevent microbial infection. If successful, this project can lead to paradigm changing alternatives to reducing public health risk to air borne infections like COVID-19 and seasonal flu which may be associated with devastating effects on the United States and World economy. The proposed approach will be swiftly conducted to present realistic solutions that may be useable in the face of this COVID-19 pandemic as well as future flu viruses of similar magnitude.

This research will fundamentally contribute to modeling the interactions between viral membranes and nanoscale barriers. The production of an innovative nanoscale biodegradable barrier may reduce the socioeconomic and public health burden significantly by lowering the risk of viral infection during the flu season or pandemics. The project team comprise of an interdisciplinary team that include engineers, ophthalmologists, molecular biologist, virologist and pharmacologist to explore a problem that could have a tremendous impact on the way we respond to seasonal flu or pandemics. Besides the potential benefits to reduce COVID-19 and influenza related deaths in the US and worldwide, the proposed work will afford us the opportunity to train engineering and biomedical students in a highly interdisciplinary research activity.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Despite enormous advances in recent years to develop neuroprosthetics to bypass damaged areas of the Central Nervous System (CNS), these devices fail to halt the progression of the underlying degenerative diseases for which they were designed. Moreover, there are no effective therapies for many of the neurodegenerative conditions that affect, for example, the eye or the brain, and the humanitarian and economic impact of blinding diseases and dementia are enormous, with underrepresented groups particularly impacted by these conditions. The goal of this project is to enable restoration of function to the CNS by therapies that promote the repair and regeneration of damaged neurons and neural networks instead of bypassing damaged areas. To achieve this goal of delaying vision loss and neural degeneration in dementia through devices this team brings together engineers, surgeons, neuroscientists and big data/imaging scientists.

This research team will devise and optimize, experimentally and computationally, the electrical stimulation waveform characteristics needed to reprogram damaged neural network morphologies; create, “first of its kind” complete mesoscale connectivity atlases of the global neural networks exposed to electric fields and field gradients; develop predictive multiscale computational models of neural activity in healthy, degenerated and electrically stimulated neural networks; and design and engineer programmable implantable electronic systems for the acute neurostimulation of the neural tissue. The utility of the tools developed in the proposed effort will be enhanced by end-users providing design input, thus facilitating fully integrated, mutually beneficial, sustained convergent collaborations that are needed to develop the therapeutic opportunities of the next generation.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

The Coronavirus Disease 2019 (COVID-19) pandemic has dramatically impacted the way humans live and has resulted in more than 6 million deaths worldwide. This project uses a topical barrier to enhance the defense capabilities of the lining found in the nose, which is a highly novel method to prevent Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2) infections. The aim of this EArly-concept Grant for Exploratory Research (EAGER) project is to engineer a nasal spray and new type of applicator that can deliver a special coating that prevents viral and microbial infection. This user-friendly approach, if further developed, has the potential to be effective in preventing SAR-CoV-2 variants from infecting humans. Moreover, the innovative barrier could reduce the risk of other airborne threats, e.g., could be rapidly employed during the flu seasons or new emerging pandemics. The in silico computational models developed can also be used to expedite the development of accurate and precise countermeasures. The planned studies will provide opportunities to train engineering and biomedical science students who work collaboratively through highly interdisciplinary (engineering, molecular biology, virology and pharmacology) research studies and will enhance ongoing education and outreach activities focused on attracting underrepresented minority groups into these areas of research.

The overall goal of this project is to engineer an innovative, biodegradable, nanobarrier (anti viral coating) that is safe and can be widely deployed to protect the public from SARS-CoV-2 infections. Although traditional approaches like vaccines, mask mandates, and social distancing are being used to prevent or reduce the spread of COVID-19, long-term compliance is a challenge. Therefore, a novel approach to infection prevention is urgently needed. This project proposes a user-friendly nanobarrier designed to prevent viral and microbial attachment and infection of epithelial cells by enhancing the defense capabilities of the mucocutaneous lining found in nasopharyngeal passages. The nanobarrier inactivates enveloped viruses by sequestering essential cholesterols required for viral attachment, infection, and transmission. This project has two major objectives: (1) to use 3D-simulation of the nasopharyngeal cavity to optimize the parameters (droplet and delivery product characteristics) to guide the engineering of an applicator for accurate deposition of the nanobarrier to areas most susceptible to COVID-19 infection, facilitating translation into preclinical models, and (2) evaluate the efficacy of the nanobarrier in a validated coronavirus mouse model. The final nanobarrier will be agnostic to SARS-CoV-2 variants and can be quickly rolled-out to effectively prevent infection. The simulation approach used in this project will serve as a platform to develop targeted interventions with optimized delivery into the nasopharyngeal cavity. Additionally, this project will expand knowledge and understanding of how SARS-CoV-2 variants infect as well as their susceptibility.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.