Abstracts

"New Developments in Biomanufacturing"

February 20, 2007

Abstracts

"Signaling pathways, experimental models and delivery strategies for tissue regeneration"

Stelios T. Andreadis, Ph.D.
Associate Professor, Department of Chemical & Biological Engineering,
State University of New York at Buffalo

Wound healing is a complicated process comprising of multiple, well-orchestrated events that are controlled by interaction of cells with other cells, soluble signals and extracellular matrix. In this presentation I will discuss two signaling pathways that may play an important role in wound healing by controlling cell-cell adhesion and migration. I will also discuss a novel strategy to deliver healing promoting factors in a cell-controlled manner.

First I will discuss a novel role of the c-jun-N-terminal protein kinase (JNK) in cell-cell adhesion by regulating adherens junction assembly and actin polymerization. Then I will discuss the mechanism through which keratinocyte growth factor (KGF) promotes cell migration by upregulating integrin alpha5. I will describe a novel hybrid model of wound healing, which is based on implantation of human bioengineered skin onto athymic mice and may facilitate studies of signaling pathways affecting reepithelialization in a realistic in vivo setting. Finally, I will describe a novel biomimetic strategy to deliver KGF in a cell-controlled manner in vivo.

"Regeneration of Functional Myocardium Using Adult Stem Cells"

Glenn R. Gaudette, Ph.D
Assistant Professor, Department of Biomedical Engineering
Worcester Polytechnic Institute

The human heart has long been considered unable to regenerate contractile cells. Recent evidence has challenged this notion, and the potential for therapeutic treatment for the millions of Americans suffering from myocardial infarctions now exist. We have recently developed a novel method to induce adult stem cells to differentiate into cardiac myocytes. These cardiogenic cells express cardiac specific proteins and have a robust calcium current equivalent to adult myocytes. When seeded onto a biological scaffold and implanted into the heart, these cells contribute to improved regional mechanical function. In addition, cardiogenic cells with clear sarcomeric bands were found in the implantation area, suggesting that cardiogenic cells differentiated into striated cardiac myocytes. These cardiogenic cells represent a potent new cellular source for mammalian myocardial regeneration and a potential therapeutic treatment for myocardial infarction.

"Dermal Collagen Matrix as a Scaffold for Tissue Regeneration"

Ronald A. Ignotz, Ph.D.
Research Scientist/Adjunct Assistant Professor, Cell Biology,
Division of Plastic and Reconstructive Surgery,
University of Massachusetts Medical School

A variety of sources of acellular dermal collagen matrices are commercially available and are being used in a number of surgical applications. Different formats of the matricies may be more suited for one application versus another application. For example, non-crosslinked dermal collagen may be readily remodeled compared to a crosslinked matrix. Conversely, a crosslinked matrix may provide more strength and durability. However, detailed comparisons have not been reported. We are comparing several commercially available dermal collagen matrices in a rat model of abdominal hernia repair. We are evaluating the collagen matricies for inflammatory reactions, cellular and vascular ingrowth, extracellular matrix deposition, length of time each material remains at the implant site and changes in strength with time.

"What to Consider When Building a Tissue Regeneration Business"

Peter C. Johnson, MD
Founder, President and CEO
Scintellix, LLC

Tissue regeneration technologies are being developed in academia for a multitude of applications worldwide. The path from the door of the University to the bedside is complex and often frustrating to the academic/inventor. However, there is perhaps no more critical step in the field than the successful commercialization of new and improved products. To stress the importance of an understanding of this pathway, this presentation outlines the process of academic-derived company formation and tissue regeneration product development. It is hoped that an awareness of the post-academic commercialization process – particularly with respect to market issues – will focus the academic/inventor on optimal areas of tissue regeneration technology creation. In this way, the eventual benefits to the patient-recipients of such technologies will be made substantially more probable.

"Oxidized low density lipoprotein induces endothelial progenitor cell apoptosis by inhibiting PI3 kinase/Akt pathway via tyrosine nitration"

Louis M Messina, MD
Division of Vascular Surgery
University of Massachusetts

The mechanisms by which risk factors such as hypercholesterolemia reduce the number of circulating endothelial progenitor cells (EPC) in patients with coronary artery disease (CAD) are incompletely understood. We tested the hypothesis that oxidized low density lipoprotein (oxLDL) induces EPC apoptosis by inactivating the PI3 kinase/Akt cell survival pathway. In cultured EPCs harvested from wild type (wt) mice, oxLDL induced apoptosis and inhibited Akt phosphorylation in a dose-dependent manner. Overexpression of constitutively active Akt rescued oxLDL induced EPC apoptosis. Immunoprecipitation demonstrated that oxLDL significantly increased tyrosine nitration on the p85 subunit of PI3 kinase, which resulted in dissociation of p85 and p110 subunits of PI3 kinase. Treatments with SOD, L-NAME, epichetechin or FETTPs, a peroxynitrite decomposition catalyst, blocked tyrosine nitration on p85 subunit of PI3 kinase, restored Akt phosphorylation and rescued apoptosis induced by oxLDL. Interestingly, oxLDL also increased p38 phosphorylation in cultured EPC in a dose-dependent manner. Treatment with pharmacologic inhibitors of p38, SB203580, further increased oxLDL induced Akt inhibition and EPC apoptosis, suggesting an interaction between Akt and p38 MAP kinase pathways.Lastly, EPCs harvested from hypercholesterolemic hypomorphic apolipoprotein E mice deficient in LDL receptor (Apoeh/hLdlr-/- mice) showed a higher rate of apoptosis than EPCs from wt mice. the signallingcultured and may explain the enhanced apopotosis displayed by EPC harvested from spontaneously hypercholesterolemice Apoeh/hLdlr-/- mice. In conclusion, oxLDL inhibits PI3 kinase pathway and induces apoptosis by causing tyrosine nitration of PI3 kinase and inhibiting Akt mediated cell survival in EPCs.

Key words: oxidized low density lipoprotein, endothelial progenitor cell, apoptosis, tyrosine nitration, PI3 kinase, Akt, p38

"A photochemical approach to tissue repair and manufacture and placement of biocompatible implants"

Robert W. Redmond, Ph.D.
Associate Professor, Department of Dermatology
Harvard Medical School

There is no single methodology that is universally appropriate for wound closure following trauma or surgical procedures. Mechanical fixation using sutures or staples is most common but can be unsuitable for delicate, friable tissues and can lead to complications due to foreign body response, inflammation and scarring and also act as a nidus for infection. In addition, the placement of sutures causes additional trauma to the tissue via needle passage. This is particularly important in peripheral nerve repair where regeneration of the nerve following injury requires structural integrity. In recent years we have developed an alternative tissue closure method based on light-activated tissue crosslinking that does not require foreign body materials and produces an immediate, water-tight closure, particularly relevant to tissues like, nerve, blood vessel and various ocular tissues. This presentation will detail some pre-clinical applications of this photochemical tissue bonding (PTB) technology and will also present second generation photochemical approaches for the production of biocompatible grafts and implants that can also be placed appropriately in tissues using PTB to solve real clinical needs, such as nerve and cartilage regeneration.

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