Research: Artificial ECM's for in situ tissue formation

Peptide modified hydrogels to induce osteoblast proliferation (Eugene Chung)

We are studying the influence of mechanical stiffness and attached peptides on cells grown on artificial extracellular matrices. We have designed a hydrogel to mimic bone extracellular matrix by incorporating a short peptide sequence from bone sialoprotein, which allows for integrin-mediated attachment to the gel. Because of a specially designed peptide crosslinker, the matrix also degrades when cells secrete a specific enzyme, MMP-13. Bone cells attach to the material, proliferate, and create their own matrix while simultaneously degrading the artificial extracellular matrix. Additionally, the hydrogel has a unique clinically-relevant property; it is injectable through small openings, allowing it to be implanted non-invasively. The synthetic hydrogel, a copolymer of N-isopropylacrylamide and acrylic acid, has been designed to be responsive to thermal stimuli. At ambient temperatures it is a liquid-like gel that can be injected and conforms to the shape of a wound. Then as it warms to body temperature, it sets and maintains its shape. Thus this bioactive hydrogel can be injected to enhance bone repair with only minor surgery. When the hydrogel is injected into the marrow space of rat femurs, new bone is formed and replaces the original hydrogel in 4 weeks. Bone formation can be further accelerated by the use of the hydrogel in conjunction with the recombinant Sonic Hedgehog protein.

Bioactive hydrogels for cardiac tissue engineering (Kimberly Kam)

After an acute myocardial infarction (AMI), or heart attack, cardiac tissue is damaged by induced cellular ischemia and in humans, does not regenerate on its own. One possible treatment is through the use of injectable bioactive materials to help mechanically strengthen the injured region and stimulate cellular ingrowth and angiogenesis. A copolymer of NIPAAm and AAc is being pursued, designed for specific mechanical properties, and modified for cellular response with peptide binding domains and solid phase Sonic Hedgehog, a potent upstream regulator of angiogenesis.

In situ forming biohybrid and composite materials for tissue regeneration (Jacob Pollock)

The micro-environment surrounding cells provides them with critical chemical and physical signals which govern cell behavior and, in turn, tissue development, maintenance, and regeneration. Natural tissues and engineered tissue constructs are typically composed of cells attached to one another and to a supporting extra-cellular matrix (ECM). These adhesive interactions are regulated by cell-surface receptors that form clusters, induce intra-cellular signaling, and link the structural components of the ECM with those of the cytoskeleton of the cell. The development and remodeling of mammalian tissue involves intimate and complex cell-cell, matrix-matrix, and cell-matrix interactions.

Our lab is currently developing novel synthetic and hybrid biomaterials for biology and regenerative medicine. Specifically, we are developing thermo-responsive polymer systems that are free-flowing liquids at room temperature and form solid artificial ECMs at physiological temperatures. These biocompatible and bioactive materials allow for cell encapsulation for three-dimensional cell culture as well as delivery through injection for medical applications. Specific and independent modulation of soluble signals, tethered attachment and signaling domains, and mechanical properties allow the study and control of cell behavior and the creation of effective, tissue-specific grafts for clinical medicine. These smart materials are also being designed for cell-mediated degradation through the incorporation of specific enzymatically cleavable domains. Finally, unique composites are being created from these materials for engineered micro-structural morphology evolution and differential release of drugs and biologics. The effect of these artificial ECMs in-vitro on bone-marrow derived mesenchymal stem cells is being studied in preparation for in-vivo evaluation. Bone regeneration can be accelerated by promoting infiltration of these cells into the materials and their differentiation into osteoblastic bone-forming cells.

Related projects involve the use of similar materials as model systems for the study of both healthy and pathological cells in three-dimensions, tools for the expansion and manipulation of undifferentiated stem cell populations, and synthetic tissue grafts, sealants, and adhesives for muscular, ophthalmologic, neural, orthopedic, and mammary tissue regeneration.

Synthetic hydrogels for the treatment of high axial myopia (James Su)

My project is an interdisciplinary effort focused on the development of synthetic biomaterials for the treatment of high axial myopia. High axial myopia (near-sightedness > -6 diopters) results from excessive elongation at the weakened posterior pole, with blinding complications such as glaucoma and retinal detachment. Presently an epidemic in parts of Asia and Europe, myopia is a significant public health problem without an effective treatment. Refractive surgery and optical appliances compensate only for the focusing error, but do not treat the excessive eye elongation. My project will explore the efficacy of implanting biocompatible hydrogel polymers into the sclera to strengthen the eye wall. With tunable elastic modulus, poly(N-isopropylacrylamide-co-acrylic acid) (p(NIPAAm-co-AAc)) exhibits a lower critical solution temperature at around 30�C, showing phase transition from a soft clear hydrogel to stiffened opaque hydrogel when implanted at 37�C. Peptide can be grafted to the hydrogel to allow for cell attachment, migration, and proliferation. The crosslinker type and amount chosen mimic the collagen cleavage sites for active MMP-2 and MMP-13 present in the sclera, providing control of degradation properties. The designed biomaterials will 1) provide mechanical support, 2) act as tissue scaffolds, and 3) act as vehicles for drug delivery in injectable form for ease of implantation. After in vitro mechanical and biological properties are defined, we will use the established chick myopia model for in vivo studies.