Prof. Howard W. T. Matthew

My primary research interests fall within the areas of tissue engineering and biomaterials. Tissue engineering may be defined as the application of quantitative engineering principles and techniques to the study and manipulation of living tissues and their constituent cells with the ultimate goal of producing either tissue repair or bioartificial organ substitutes. The design, modification and evaluation of bioactive materials are an integral part of this effort.

In general terms, my work involves studying the interactions of cells, natural and artificial polymers, and environmental factors with a view towards the development of systems for tissue and organ repair or regeneration. One of the obstacles to development of engineered tissues is the fact that cells often lose their differentiated characteristics when transferred to in vitro systems. In addition, adverse tissue and immune responses to synthetic biomaterials in vivo often degrade the performance of engineered tissues. Loss of a specialized extracellular matrix (ECM) or three dimensional geometry are among the contributing factors for this failure. The existence of sub-optimal levels of important environmental factors, such as oxygen or critical stimulatory hormones and cytokines, may also play important roles. Among the ECM polymers, the ionic polysaccharides known as glycosaminoglycans (GAGs) are of particular interest in our work. Recent research has shown them to be instrumental in maintaining a variety of differentiated cell features, as well as being mediators of many cellular recognition events and modulators of numerous cytokine and growth factor signals. We have previously determined that these substances can be combined with other charged polymers to form composite, degradable materials of remarkable strength in a variety of configurations. We are currently examining their use as components of tissue scaffolds for a number of tissue repair and regeneration projects. Funded projects underway in my laboratory are described below.


Engineering Small and Large Diameter Vascular Grafts
Artificial replacements for large diameter (> 6 mm inner diameter) blood vessels have been successfully developed with synthetic materials, notably woven Dacron and expanded polytetrafluoroethylene. However, large synthetic prostheses are problematic in pediatric cases because they do not grow with the child and thus require revision surgeries for installation of larger conduits. In addition, the replacement of small diameter (< 6 mm inner diameter) vessels is still problematic. In this case, the problems appear to have two main causes. First, an uncontrolled proliferation of smooth muscle cells from the native vessel rapidly leads to obstruction of the graft lumen either by the cells themselves or by blood clots formed in the narrowed lumen. Failure to rapidly generate a contiguous covering of endothelium is believed to contribute significantly to this phenomenon, since an undisrupted covering of endothelial cells is effective in preventing both the initiation of thrombosis and excessive proliferation of the underlying smooth muscle. Secondly, structural failures appear to be related to fragility of the connections to natural vessels. In this case a mismatch between the mechanical properties of the graft and native vessel is believed to be a contributing factor.

This project is aimed at developing and evaluating materials and procedures for fabricating grafts capable of moderating the growth of smooth muscle cells while stimulating a controlled regeneration of the damaged vessel. Attention is focused primarily on composite materials incorporating glycosaminoglycans with other natural and synthetic biodegradable polymers. Current studies examine the mechanical and physical properties of these materials along with their interactions with blood and the cells which comprise normal blood vessels. Graft fabrication techniques have been developed for these new materials together with procedures for efficient seeding of the grafts with vascular cells prior to implantation. We are currently studying the colonization of these vessel protoypes in vitro in preparation for implantation studies.

Bioreactor Expansion of Hematopoietic Stem Cells
The inadequate supply of hematopoietic stem cell (HSC) enriched cell populationsseverely limits the widespread use of HSC transplantation as an effective treatment of hematologic and malignant diseases. In addition the success rate of hematopoietic transplant therapies could be significantly increased if large quantities transplantmaterial with a high incidence of HSCs could be reliably generated. Furthermore, this capability would greatly stimulate activities based on gene therapy of the hematopoietic system. The long term goal of this project is to address these deficiencies bydeveloping a perfusion culture system capable of specifically expanding a population of primitive hematopoietic progenitors enriched in HSCs while inhibiting lineage differentiation. In most hematopoietic expansion schemes, expansion and lineage differentiation proceed in parallel and HSC expansion per se is limited. Recent published studies suggest that it may be possible to exert precise control over the differentiation vs.proliferation activities of hematopoietic populations in vitro by controlling both the soluble cytokines and the ECM substances to which the cells are exposed. In my laboratory, the effects of these factors on the expansion of human CD34+ cord blood stem cells are being evaluated. Delivery of promising molecular species in soluble vs.immobilized form is being optimized. Results from these experiments are being incorporated into perfusion bioreactor systems. Optimization of the bioreactor operating parameters will be carried out with the goals of producing a cost efficient, high yield expansion of CD34+ cord blood stem cells and therapeutically valuable blood cell lineages.

Liver Regeneration via Hepatocyte Transplantation
There is a current need to expand the quantity of liver tissue available for transplantation. This need is particularly pressing for the pediatric population given the much lower availability of pediatric organs. One approach to addressing these needs involves developing effective methods for hepatocyte transplantation. The ability to reliably re-assemble isolated hepatocytes into a functional, "neo-organ" would greatly facilitate the development of such systems. Hepatocyte transplantation also has great potential for providing cures for a variety of liver-based, metabolic and enzyme deficiency diseases. However, tissue engineering of sizeable implantable liver systems is currently limited by the difficulty of assembling three dimensional hepatocyte cultures of a useful size, while maintaining full cell viability. The main limitation stems from the high metabolic rates of these cells and the associated low rates of diffusive mass tranfer in densely seeded tissue scaffolds. We are addressing these limitations by developing tissue scaffold designs which allow for superior nutrient and oxygen transport to the cell mass in the short term and enhanced angiogenesis in the long term. Thus the long term goal of this project is to design scaffold materials and procedures for assembling isolated hepatocytes into a functional, vascularized mini organ. The proposed work is based in part on the idea that improved oxygen transport and vascularization of densely seeded scaffolds will improve hepatocyte survival and metabolic performance in the long term.