Cellular Engineering 537 plicated protein kinase C(PKC)as part of the signaling pathway which links a shear- stress-related mechanical signal to the intracellular events underlying alterations in cell morphology(22).This second messenger may also be involved in the control of the endothelial cell's growth program. It should be emphasized that in vivo endothelial cells reside in a flow environment, and thus to study vascular endothelial biology in static culture is at best a simulation of a region of flow stasis and at worst artifactual.Furthermore,endothelial cells re- spond differently to differing flow environments,and one should never collectively talk of flow as a single stimulus.Just as there are different chemical agonists,each with their own separate effect,there also are different types of flow agonists,i.e.,a variety of types of flow environments,each of which will have their own agonist ef- fect(23).Thus,as important as cell culture studies have been to the study of vascu- lar biology,it is clear that there is much more which needs to be done if we are to engineer the cell culture environment so as to make it truly simulate physiologic con- ditions.This includes the use of realistic flow environments,but other factors,e.g., the medium,extracellular matrix components,and the presence of neighboring cells, will also need to be included. TISSUE ENGINEERING Tissue engineering,still in its infancy,is an activity within the field of medical and biological engineering which predates its name.The term originated in 1987 at a bi- oengineering panel meeting held at the National Science Foundation.In early 1988 the first tissue engineering meeting was held at Lake Tahoe,California.At this meet- ing a working definition was formulated (39): Tissue engineering is the application of the principles and methods of engineering and the life sciences toward the fundamental understanding of structure-function relationships in normal and pathological mammalian tissues and the development of biological substitutes to restore,maintain,or improve functions. Contained in the above is the essence of tissue engineering,i.e.,the use of living cells, together with extracellular components,either natural or synthetic,in the develop- ment of implantable parts or devices for the restoration or replacement of function. An excellent example of tissue engineering,one which demonstrates the importance of cell culture,is the development of artificial skin (32,40).The use of the term ar- tificial here must be qualified since many of the approaches,in using living cells and matrix molecules,are quite natural.In at least one case,dermal and epidermal cells, together with extracellular matrix and nutrients,are grown in culture to produce a skin which in effect is a living equivalent of that found normally on the body(6,7). Another type of artificial skin graft involves a highly porous collagen matrix which serves as a template for the graft(44).When the graft is attached to a wound,fibro- blasts migrate to it from surrounding tissue and permeate the collagen sponge.These fibroblast cells produce new collagen,the original matrix is slowly degraded,and epi- dermal cells from the edges of the wound grow inwards and cover the graft area. There are still other entries into this market.Currently there are four different companies working to develop a tissue-engineered artificial skin.This skin,as the first product developed with the technology of tissue engineering,is an important develop- ment.However,there are a number of other applications of this emerging technology.Cellular Engineering 53 7 plicated protein kinase C (PKC) as part of the signaling pathway which links a shear￾stress-related mechanical signal to the intracellular events underlying alterations in cell morphology (22). This second messenger may also be involved in the control of the endothelial cell's growth program. It should be emphasized that in vivo endothelial cells reside in a flow environment, and thus to study vascular endothelial biology in static culture is at best a simulation of a region of flow stasis and at worst artifactual. Furthermore, endothelial cells re￾spond differently to differing flow environments, and one should never collectively talk of flow as a single stimulus. Just as there are different chemical agonists, each with their own separate effect, there also are different types of flow agonists, i.e., a variety of types of flow environments, each of which will have their own agonist ef￾fect (23). Thus, as important as cell culture studies have been to the study of vascu￾lar biology, it is clear that there is much more which needs to be done if we are to engineer the cell culture environment so as to make it truly simulate physiologic con￾ditions. This includes the use of realistic flow environments, but other factors, e.g., the medium, extracellular matrix components, and the presence of neighboring cells, will also need to be included. TISSUE ENGINEERING Tissue engineering, still in its infancy, is an activity within the field of medical and biological engineering which predates its name. The term originated in 1987 at a bi￾oengineering panel meeting held at the National Science Foundation. In early 1988 the first tissue engineering meeting was held at Lake Tahoe, California. At this meet￾ing a working definition was formulated (39): Tissue engineering is theapplication of the principles and methods of engineering and the life sciences toward the fundamental understanding of structure-function relationships in normal and pathological mammalian tissues and the development of biological substitutes to restore, maintain, or improve functions. Contained in the above is the essence of tissue engineering, i.e., the use of living cells, together with extracellular components, either natural or synthetic, in the develop￾ment of implantable parts or devices for the restoration or replacement of function. An excellent example of tissue engineering, one which demonstrates the importance of cell culture, is the development of artificial skin (32,40). The use of the term ar￾tificial here must be qualified since many of the approaches, in using living cells and matrix molecules, are quite natural. In at least one case, dermal and epidermal cells, together with extracellular matrix and nutrients, are grown in culture to produce a skin which in effect is a living equivalent of that found normally on the body (6,7). Another type of artificial skin graft involves a highly porous collagen matrix which serves as a template for the graft (44). When the graft is attached to a wound, fibro￾blasts migrate to it from surrounding tissue and permeate the collagen sponge. These fibroblast cells produce new collagen, the original matrix is slowly degraded, and epi￾dermal cells from the edges of the wound grow inwards and cover the graft area. There are still other entries into this market. Currently there are four different companies working to develop a tissue-engineered artificial skin. This skin, as the first product developed with the technology of tissue engineering, is an important develop￾ment. However, there are a number of other applications of this emerging technology