sakiyama_shelly

Shelly Sakiyama-Elbert, PhD

Professor of Biomedical Engineering on the Joseph and Florence Farrow Endowment

Tissue and cellular engineering approaches to neurological diseases Read More

Email: sakiyama@biomed.wustl.edu
Lab Phone: (314) 935-7556
Website: Sakiyama-Elbert Lab
Lab Location: Whitaker 350, Danforth Campus
Keywords: spinal cord injury, peripheral nerve injury, Parkinson's disease, embryonic stem cell transplantation, biomaterials, drug delivery, tissue engineering, microfluidics

Tissue and cellular engineering approaches to neurological diseases

Johnson et al. (2010) Royal Society of Chemistry

Our research program employs tissue and cellular engineering approaches to investigate biomedical problems. In particular, our lab is interested in the related areas of gene therapy, drug delivery, and stem cell biology, with applications to therapies for diseases of the nervous system.

Cell and Tissue Engineering

The need for new materials for the treatment of human disease presents many exciting research opportunities. The field of biomaterials and tissue engineering has recently experienced a paradigm shift due to a rapid increase in the understanding of the biological mechanisms underlying many diseases. My research interests focus on cellular and molecular aspects of biomaterials and tissue engineering. This research is highly interdisciplinary, combining an understand of biology, chemistry, and biomedical engineering to develop new bioactive materials, which can enhance  tissue regeneration and cell survival after transplantation. The bioactive signals that will be provided by integrated tissue engineering scaffolds include signals for cell-type specific adhesion and migration, as well as growth factors to promote cell proliferation and differentiation.

Spinal Cord Regeneration

The overall goal of this project  is to use novel biomaterials to allow controlled release of growth factors from scaffolds that facilitates regeneration in the adult  mammalian spinal cord after injury.  These “tissue engineering” scaffolds will provide two critical mechanisms for enhancing spinal cord regeneration: 1) they will provide a permissive scaffold for cellular migration and axonal outgrowth of host and/or transplanted cells into and across the lesion site (thus reducing the inhibitory environment normally found in spinal cord lesions), and 2) they will serve as a drug delivery vehicle for the controlled release of one or more neurotrophic factors to promote axonal regrowth, cellsurvival, and differentiation of transplanted neural progenitor cells after spinal cord injury.  The scaffolds are drug-delivery systems consisting of fibrin matrices containing growth factors that are released in a sustained manner during tissue regeneration.  By providing both a permissive matrix to serve as a substrate for axonal regeneration and soluble stimuli, in the form of neurotrophic factors, to enhance fiber sprouting, both the extracellular and the cellular environment within the spinal cord will be dramatically altered thereby enhancing the potential for regeneration within the central nervous system (CNS).  These scaffolds can be further modified through the addition of embryonic stem (ES) cell derived neural progenitor cells (NPCs) during polymerization.  The NPCs can serve as a source of neurotrophic factors and/or a source of cells to replace those lost due to injury.

Stem Cell Transplantation

Embryonic stem cells provide a potential source for cell replacement following injury.  In the case of spinal cord injury, stem cells can be utilized to repopulate the injured cord with neurons and glial cells that otherwise have limited self-renewal. To obtain neural cells (neurons and glial cells), stem cells are first induced to form neural progenitor cells that can differentiate following transplantation into the injured cord.  The induction and subsequent differentiation, however, leads to a heterogeneous population of cells that can be detrimental to repair.  Recent studies in my lab have shown that undifferentiated stem cells remaining after the induction can form tumors following transplantation and present significant safety concerns.  Furthermore, stem cells that were successfully induced into neural progenitor cells may differentiate into neurons, oligodendrocytes, or astrocytes, each with varying effects on spinal cord regeneration.  To account for this variability, our lab is investigating methods for isolating purified cell populations for transplantation including:  1) adding additional developmental signals during the induction process to further restrict the population of progenitor cells obtained, 2) removing undifferentiated stem cells after the induction, 3) using the fibrin matrices with incorporated growth factors to improve the survival of transplanted progenitor cells and promote differentiation into desired cell types.   By transplanting select populations of cells, we hope to understand the role of each cell type in regeneration and reduce the risks often associated with embryonic stem cells.

Drug Delivery

Growth factors are potent protein drugs that are powerful regulators of biological function. Their presence in tissues is highly regulated in both time and space. The ability to tightly regulate the release of growth factors is essential in the development of tissue engineering scaffolds. My laboratory is using combinatorial methods to design novel materials for affinity-based protein delivery. The release of proteins from affinity-base delivery systems can be optimized by changing the number of protein-binding sites in the material or by changing the affinity of the interaction between the protein and the material. The libraries of compounds developed in this project can provide a new method for the regulation of drug release profiles – regulation of the affinity of the delivery vehicle for the drug. Based on an understanding of the time course of key events required for tissue regeneration, these affinity-based protein delivery vehicles can be incorporated into tissue engineering scaffolds to provide the signals necessary to stimulate tissue regeneration on a relevant time scale.

Peripheral Nerve Injury

Our lab also develops scaffolds for drug delivery and cell transplantation for the treatment of peripheral nerve injury.  We have examined the effect of growth factor delivery from biomaterial scaffolds that serve as filler for nerve guidance conduits, as a potential alternative to nerve autografts for long gap injuries.  We have demonstrated that delivery of glial dervied neurotrophic factor (GDNF) and nerve growth factor (NGF) from fibrin scaffolds enhance functional regeneration compared to empty conduits in a 13 mm sciatic nerve injury model.  Currently we are assessing whether these delivery systems can also be used in combination with acellular nerve allografts that have recently come on the market for clinical use.

We are also studying the role of Schwann cell (SC) phenotype on motor (nerve) specific regeneration.  We hypothesis that SC provide cues that help to direct motor specific regeneration, but that they may lose expression of key signals duing expansion in cell culture (typically performed prior to transplantation.  We are evaluating environmental cues that are important for maintianing/restoring SC phenotype and the effect of phenotype of nerve regeneration through acellular allografts.


Updated February 2014

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