Marketing Costs and Prices: An Expanded View

More than twenty years ago Farris and Reibstein (1979) published research that demonstrated a strong cross-sectional correlation between relative advertising expenditures and relative prices charged by manufacturers of non-durable consumer goods. Data for that research were taken from the PIMS database. The correlation was demonstrated to survive a number of controls for relative quality and market share. The correlation was also shown to be stronger for later stages in the product life-cycle and for products purchased in relatively small dollar amounts. The research made no claims about the direction of causality from advertising to prices or vice versa. Instead, the paper argued that from the management perspective “consistency” between advertising and pricing was important. In other words, businesses with high (or low) relative prices should generally also have high (or low) levels of relative advertising. The claim for the importance of consistency was buttressed by evidence in the paper that businesses with inconsistent pricing and advertising strategies earned lower ROIs. In this chapter we first review and then extend the earlier Farris and Reibstein (1979) study with new analyses based on the PIMS data. The review is placed in the context of a broader managerial (not necessarily a public policy) concern with the relationship between total marketing costs (not just advertising) and prices. The expanded view of marketing costs includes salesforce and other marketing expenses – budget items with collective dollar values that are typically three to four times advertising budgets

Development of a completely biological tissue engineered heart valve.

University of Minnesota Ph.D. dissertation. April 2009. Major: Chemical Engineering. Advisor: Robert T. Tranquillo. 1 computer file (PDF); xii, 215 pages, appendices A-C.In the United States alone, over 100,000 heart valve replacement procedures are performed each year, with approximately 45% of patients below age 65. While current mechanical and bioprosthetic heart valves are viable options, they have several limitations. The most significant limitation is for pediatric patients, since neither of these valve types grow and remodel with the patient. Tissue engineering provides a methodology to create functional heart valves that can grow and remodel similar to native tissue once implanted. Several tissue engineering approaches have been proposed using decellularized native scaffolds, synthetic biopolymers, and biological polymers seeded with cells. Fibrin provides a scaffold to create tissue-engineered heart valves (TEHV) that are completely biological with an environment permissive for extracellular matrix (ECM) deposition. Previous research in our lab has demonstrated the feasibility of creating a fibrin-based TEHV with neonatal human dermal fibroblast (nHDF) that yields valve leaflets with structural and mechanical anisotropy similar to native leaflets. However, the TEHV had sub-optimal tensile mechanical properties and was thus unable to withstand physiological forces. The development of tissue can be accelerated by both chemical and mechanical stimulus. Previously, fibrin based TEHV were cultured with chemical stimulus in the form of growth factors supplemented in the culture medium resulting in improved ECM deposition by the cells; however, no mechanical stimulation was applied. Prior research in both our lab and by other researchers has shown cyclic stretching with constant strain amplitude is a method to stimulate remodeling of biological scaffolds seeded with cells. Initial experiments were conducted to evaluate the effect of cyclic stretching on fibrin-based tubular constructs seeded with porcine valve interstitial cells (PVIC) and nHDF. Cyclic stretching with 10% constant strain amplitude applied for 3 weeks led to modest improvement in tensile properties of the tubular constructs. We hypothesized that long-term cyclic stretching, as was used in this study, could induce cellular adaptation, minimizing the benefits of cyclic stretching. This hypothesis was tested in subsequent experiments using tubular constructs cultured with incremental strain amplitude cyclic stretching, with an average strain of 10% for 3 weeks. Both PVIC and nHDF seeded constructs exhibited a 2-fold improvement in ultimate tensile strength (UTS) and collagen density over samples conditioned with constant strain amplitude strteching. To verify that this was the result of a cellular response, phosphorylation of extracellular signal-regulated kinase (ERK) was measured by western blot. At 5 weeks, the phosphorylated ERK was 255% higher in incremental cyclic strained samples compared to constant strain samples. nHDF-seeded tubular constructs were also used to optimize the use of transforming growth factor beta (TGF-β). Studies showed that under cyclic stretching conditions, TGF-β has detrimental effects on total collagen deposition and collagen maturation. Western blot analysis showed a decrease in p-ERK signaling in TGF-β treated samples. However, TGF-β use demonstrated a benefit by increasing the elastin content of the tissue constructs. In subsequent experiments, a sequence of cyclic stretching and TGF-β supplementation was used to optimize tensile mechanical properties and elastin content of the engineered tissue. Based on the results with tubular constructs, a novel bioreactor was designed to apply controlled cyclic stretching to the fibrin-based TEHV. Briefly, the valve was mounted on two plastic end-pieces with elastic latex tube placed around TEHV. Using a reciprocating syringe pump, culture medium was cyclically pumped into the bioreactor. The root distension, which was determined by the stiffer latex was used as a control parameter, and in turn stretched the leaflets. A separate flowloop (connected to the bioreactor end-pieces) was used to control nutrient transport to the TEHV. Using an incremental strain amplitude stretching regime, fibrin-based TEHV were conditioned in the bioreactor for 3 weeks. Cyclically stretched valves (CS valve) had improved tensile properties and collagen deposition compared to statically-cultured valves. The mechanical stiffness (modulus) and anisotropy (measured as ratio of leaflet modulus in circumferential to radial directions) in the leaflets was comparable to native sheep pulmonary valve leaflets. Collagen organization/ maturation also improved in CS valves over statically-cultured valves as observed by picrosirius red staining of tissue crosssections. In addition, the CS valve root could withstand pressures of up to 150 mmHg and its compliance was comparable to that of the sheep pulmonary artery at physiological pressures. To assess in vivo remodeling TEHV were implanted in the pulmonary artery of two sheep for 4.5 weeks with the pulmonary valve either left intact or rendered incompetent by leaflet excision. Echocardiography immediately after implantation showed functional coapting leaflets, with normal right heart function. It was also performed just prior to explantation, revealing functional leaflets although with moderate regurgitation in both cases and a partial detachment of one leaflet from the root in one case. The explanted leaflets had thickness and tensile properties comparable the implanted leaflets. There was endothelialization on the lumenal surface of the TEHV root. These preliminary results are unprecedented for a TEHV developed from a biological scaffold; however, many issues remain to be surmounted. In further development of the TEHV with a fibrin scaffold, photo-cross linking of the fibrin gel was utilized as a method to stiffen the matrix, thereby inhibiting excessive cell-induced compaction. Preliminary studies with tubular constructs demonstrated reduced compaction of cross-linked fibrin gel during cyclic stretching with no effect on nHDF proliferation or deposited collagen. In addition, a preliminary investigation using blood outgrowth endothelial cells (BOEC) has been conducted to assess their adhesion to the remodeled TEHV surface. Studies showed BOEC adhesion and proliferation on remodeled fibrin surface creating a confluent layer after 4 days of culture. Successful seeding of sheep BOEC on the TEHV surface prior to implantation would reduce the risk of clotting. Overall, the studies presented in this dissertation advance the development of a completely biological tissue-engineered heart valve. These studies improve our understanding of the role of cyclic stretching in tissue remodeling and have furthered the science of mechnotransduction and tissue remodeling

Controlled compaction with ruthenium-catalyzed photochemical cross-linking of fibrin-based engineered connective tissue

Tissue engineering utilizing fibrin gel as a scaffold has the advantage of creating a completely biological replacement. Cells seeded in a fibrin gel can induce fibril alignment by traction forces when subjected to appropriate mechanical constraints. While gel compaction is key to successful tissue fabrication, excessive compaction can result due to low gel stiffness. This study investigated using ruthenium-catalyzed photo-cross-linking as a method to increase gel stiffness in order to minimize over-compaction. Cross-links between the abundant tyrosine molecules that comprise fibrin were created upon exposure to blue light. Cross-linking was effective in increasing the stiffness of the fibrin gel by 93% with no adverse effects on cell viability. Long-term culture of cross-linked tubular constructs revealed no detrimental effects on cell proliferation or collagen deposition due to cross-linking. After 4 weeks of cyclic distension, the cross-linked samples were more than twice as long as non-cross-linked controls, with similar cell and collagen contents. However, the cross-linked samples required a longer incubation period to achieve a UTS and modulus comparable to controls. This study shows that photo-cross-linking is an attractive option to stiffen the initial fibrin gel and thereby reduce cell-induced compaction, which can allow for longer incubation periods and thus more tissue growth without compaction below a useful size