Adah Almutairi, Ph.D. - US grants

DESCRIPTION (Provided by the applicant) Abstract: A new strategy, an amplified response strategy for inducing multi photon driven processes non-invasively in living systems, will be investigated. This strategy should enable optical and thus remote control or activation of materials and substances inside living systems non-invasively with depth control previously unattainable. The impact of such remote control is large and broad allowing previously invasive procedures to be performed non-invasively, and previously inaccessible target sites to be reached for both treatment and diagnosis. The multi photon phenomena allowed unparalled spatio temporal control, and where longer wavelengths were employed, deeper penetration into turbid bulk media such as tissue. Despite the revolutionary impact this phenomena has had on neuroscience, microscopy and lithography, it has been generally very difficult to apply this technique in vivo to stimulate biomaterials, diagnostics and drug delivery systems. Currently there are no reported systems for in vivo multi photon responsive materials. The dogma is that not enough photons can reach the materials to initiate a response. A strategy we aim to explore is the amplified response strategy, a strategy inspired by one that has revolutionized the electronics industry with the advent of chemically amplified photoresists for fabrication of computer chips. When a single responsive molecular unit, repetitively embedded in a material, simultaneously absorbs two photons, the changes in that molecular unit will cause a domino effect that will unravel the entire material as a whole. It is almost like a knitted jumper;pull on a bit of loose thread and the whole thing unravels. Public Health Relevance: The impact of remote control over the behavior of implanted or circulating materials inside living systems is large and broad allowing previously invasive procedures to be performed non-invasively, and previously inaccessible target tissue to be reached for both treatment and diagnosis.

TECHNICAL: Abalone shell is tough and fracture resistant. The structure has a brick-and-mortar organization with calcium carbonate (aragonite) bricks surrounded by the organic mortar. The toughness is attributed to the organized arrangement of the aragonite platelets and nanoscale features present at the mineral/organic interface. These nanoscale features include mineral bridges, nanoasperities on the surface of the aragonite tiles and the viscoelastic/adhesive properties of the organic. The main objectives of this work are to fabricate model ceramic/polymer laminates, identify and quantify the contributions of microstructural features that have been attributed to the toughening of the shell. This work is expected to lead to a new class of bioinspired composite materials that are strong, hard and fracture resistant. Students will be cross-trained in biology, materials science and nanoscience.

NON-TECHNICAL DESCRIPTION: Bioinspired materials are emerging as a new class of synthetic structures. The abalone shell is tough and fracture resistant, despite being built from weak constituents: organic matter and a soft mineral (ceramic). Under magnification, the shell has a "brick-and-mortar" structure of mineral bricks and organic mortar. Bioinspired synthetic layered materials based on this structure are expected to have exceptional toughness and fracture resistance. Fabrication and testing of layered organic (polymer) / ceramic structures that duplicate the structure of the abalone shell is the main focus of research. This work is expected to lead to a new class of composite materials that are strong, hard and fracture resistant. Graduate, undergraduate and high school students will be cross-trained in biology, materials science and nanoscience. New classes will be introduced into the curriculum and outreach to underrepresented student populations is a part of this project.

This award by the Biomaterials program in the Division of Materials Research to University of California-San Diego is to investigate magnetic remote spatio-temporal control of biomaterials and their payloads. Magnetic nanocapsules containing therapeutics could provide a viable means to remotely control the release of therapeutics to cell aggregates, through the blood vessels and blood-brain barrier. The magnetic nanocapsules respond to remotely applied magnetic fields to release drugs on-demand. To experimentally demonstrate the concept of spatio-temporal control of biomaterial response, the investigators will design and construct nanocapsules with innovative on-off switchable drug delivery approaches. The nature and dimension of these capsulated magnetic materials with therapeutics will be varied to understand the effects of these parameters on biomaterial characteristics and their drug release behavior. The anticipated impacts are expected to be significant in the drug delivery area that will benefit clinically challenging central nervous system disorders as well as cancer treatments. Graduate students will be trained with the multidisciplinary facets of this research project, and involves highly interdisciplinary fields such as materials science, biology, bioengineering, chemistry and chemical engineering. The educational outreach plan of this project will involve Annual San Diego Science Festival (Science Week San Diego) and Teacher Training and Professional Development programs that are organized by the BioBridge Science Outreach Initiative, a community based partnership among University of California, San Diego, San Diego School districts and industry.

This research project aims to investigate smart drug release systems based on magnetic nanocapsules containing therapeutic drug payloads. Such a controllable drug delivery techniques could provide viable means to treat Alzheimer's disease and other central nervous system disorders, and various types of cancers using on-demand release of drugs. To experimentally demonstrate the concept of remote spatio-temporal control of biomaterial response, the investigators will design and construct nanocapsules, and the nature and dimension of the capsule materials and magnetic materials will be varied to understand the effects of these parameters on biomaterial characteristics and efficiency of drug release behavior. The new technique can also be applied broadly to many other therapeutic areas to benefit large patient populations, and also provide opportunities for broader economic stimulus. The new approach will also stimulate many scientists and engineers in the materials science and bioengineering field for further innovations and understanding of biomaterials design, behavior and applications. This highly multidisciplinary research project will also emphasize the educational aspects for graduate, undergraduate, and high school students, including under-privileged high school students.

Biomaterial enhancement of stem cell transplant efficacy for macular degeneration No effective therapies yet exist for advanced macular degeneration. Restoring vision in severe cases requires replacing both retinal pigmented epithelium (RPE) and photoreceptors because photoreceptors require functional RPE to survive. However, no approach to replace both cell types has yet been introduced. Further, previous attempts to replace photoreceptors have met limited success in rodent models, likely because of low survival rates and restricted distribution of transplanted cells. This project integrates solutions to both of these challenges: we propose to transplant human embryonic stem (ES) cell-derived primitive retinal stem cells (hpRSCs), a cell population that is more pluripotent than cell types previously transplanted to restore vision. We have shown that hpRSCs yield both RPE and photoreceptors in vitro and in vivo; replacing both cell types in vivo would yield longer-lasting visual improvements, as transplant-derived RPE would support transplant-derived photoreceptors. In order to develop a maximally effective therapy, we will deliver hpRSCs in an injectable hydrogel whose biochemistry and mechanics closely match those of the ocular extracellular matrix, which has recently been shown to uniformly distribute transplanted cells across the retina. This project stands to position ES cell-derived RPCs for translation into the clinic. The key to this advance is the collaboration between the PIs, bringing together a leader in macular degeneration models and the differentiation of stem cells into retinal neurons (Zhang) with a biomaterials research group (Almutairi). The Zhang group's expertise will ensure that this project advances development of HAMC for ocular transplantation significantly: previous work has not employed relevant animal models, so the impact of the material on transplanted cells' differentiation and functional recovery has not yet been assessed. Further, it has relied on cells that are easiest to derive, whereas this project will employ ES cell-derived RPCs, which are the only clinically viable option. By completion of this project, we expect to: 1. Assess the effect of HAMC delivery on survival and distribution of subretinally injected retinal stem cells 2. Define the effect of HAMC on the ability of retinal stem cells to differentiate into RPE and photoreceptors in vitro and in vivo 3. Identify the delivery method that maximizes visual improvement ensuing from subretinal injection of retinal stem cells in Royal College of Surgeons (RCS) rats