Driving the bumpy road to commercialization.

Tissue engineering has always had an applied focus and there is hardly an academic publication that does not mention the applicability of its findings to the future development of a medical product. I have been involved in the industry side of tissue engineering from the start, pursuing a variety of applications, some making it to the marketplace. There have been many lessons that I have learned from direct experience (mistakes and successes), observation, through advising others, and now, in developing innovative ways to identify and eliminate the regenerative cell populations within a tumor. This brief overview of some of these lessons is written with the next generation of pioneering product developers in mind: the biologists, biochemists, and engineers who will dedicate their careers to driving medical and commercial progress in tissue engineering.

Meeting the need for regenerative therapies: translation-focused analysis of U.S. regenerative medicine opportunities in cardiovascular and peripheral vascular medicine using detailed incidence data.

Cardiac and vascular diseases represent one of the most substantial medical areas for the applications of regenerative medicine. Despite advances in endovascular repair, surgical intervention, and disease management, atherosclerosis and heart failure continue to be prominent health problems. This report analyzes the regenerative medicine treatment opportunities in both cardiovascular and peripheral vascular repair, examining the treatment opportunities for tissue-engineered vascular grafts as well as cell-based therapies. U.S. hospital discharge data were used to generate a detailed estimate of the relative target populations for cardiac and vascular disease. Gap analyses were performed for vascular access, small caliber vascular grafts, and cell-based therapies for revascularization and heart failure. The analysis compared current alternatives, gaps in medical need, and what a tissue-engineered or regenerative alternative should achieve for optimum medical and commercial feasibility. Although the number of coronary bypass grafts vastly outnumbered peripheral grafts, a detailed consideration of re-grafts and the success of first grafts combined with gap analysis (GAP) leads us to conclude that peripheral vascular disease is the more commercially feasible and attractive target opportunity for engineered small caliber grafts for the foreseeable future. Cardiac bypass would need substantial long-term clinical experience, which could be a significant hurdle. Vascular access, often regarded as a first-in-man indication, is an excellent opportunity for an engineered graft as an alternative to arteriovenous fistula that could overcome complications associated with a prosthetic graft. The GAP also suggests that for heart failure, cellular therapies should link near-term changes in repair, such as improvement in cardiac output and reduced scarring with limiting progression of the disease, reducing the need for complex pharmacologic management, and reducing rates of hospitalization. Naturally, researchers must determine where their technology and know-how can be applied most effectively, but it is clear from our analysis that an astute strategy in the use of science and technology will be important to successful translation in this space.

Commercial development of cell-based therapeutics: strategic considerations along the drug to tissue spectrum.

In cell-based therapy, the process defines the product and the biological interaction between implant and host determines the outcome. Developing the optimum combination of process, product and a clinically relevant effect has been a challenge, leaving many potential therapies stalled in early clinical studies. This special report discusses pivotal factors in the development of cell-based technologies, irrespective of where they fit on the spectrum from cell-based drug to tissue construct, and how we can ensure delivery of an effective product to the clinic and the marketplace. Epidermal cell-based therapies serve as an historical lesson.

De novo synthesis of human dermis in vitro in the absence of a three-dimensional scaffold.

Neonatal human dermal fibroblasts cultured in vitro synthesize an organized and physically substantial three-dimensional extracellular matrix, without the addition of exogenous matrix components or synthetic scaffolds. De novo matrix synthesis proceeds in an orderly manner over a 21-d culture period and beyond. Analysis of the fibroblast phenotype, i.e., matrix synthesis by the fibroblasts, suggests that both serum and serum-free conditions are conducive to the production of a human tissue-engineered "dermal equivalent". We report that given the appropriate permissive environment, the fibroblasts establish and grow a tissue in vitro, which bears striking biochemical and physical resemblance to normal human dermis.

The Biological Mechanisms Behind Injury and Inflammation: How They Can Affect Treatment Strategy, Product Performance, and Healing.

The processes behind tissue response to injury and innate immunity are integral parts of the acute wound response and the initiation of repair. In addition, inflammation is a key factor influencing both positive and negative aspects of healing in chronic wounds. Biological data on the signaling mechanisms behind these basic processes has increased dramatically over the last 10 years, yet the products and practice of wound healing have not benefited to the fullest extent from this new knowledge. An in-depth analysis of the biological mechanisms underpinning the processes that impact healing was undertaken to discover ways this information might be used to improve the treatment of chronic wounds. A synopsis of findings is presented regarding the biological mechanisms at work in injury and inflammation. It examines the early stages of wound healing from a mechanistic, biological perspective to gain insight into how this information might translate to the better use and development of wound healing products. These biological processes can impact the effectiveness of treatment from wound bed preparation to potentially regenerative products like growth factors and bioengineered skin constructs. The authors conclude that approaching wound healing from the perspective of biological mechanism can improve how effectively wounds are treated today. As importantly, viewing the development of wound care and wound healing products from the perspective of biological mechanism can lead to new ways of treating wounds that achieve greater clinical significance.

The engineering of tissues using progenitor cells.

The "engineering" of a tissue implies that it can be constructed by assembling the necessary components. However, tissues are formed through an evolving, interactive process, not through a collection of parts. This chapter focuses on the biology of the progenitor cell, the native precursor to new tissue, and its role in neogenesis, or the de novo generation of functional tissue. We present a working hypothesis for the generation of parenchymal cell populations and use this hypothesis as a basis for analysis of three parenchymal populations, epidermal cells, hepatocytes of the liver, and pancreatic islets, with a view toward what impact this information will have on the development of cell therapies. By comparing developmental processes, response to injury and disease, and behavior in vitro, we conclude that the adult progenitor cell retains the potential for substantial growth and organ neogenesis and that its biological properties make it the cell of first choice for the engineering of tissues.

Progenitor cell properties and the engineering of tissues.

The need for human tissue to aid in organ repair or provide a curative therapy is well known. In this review, we discuss the properties of the epidermal keratinocyte progenitor cell and the biology that underlies the methods that have helped deliver cell therapies to the clinic using this cell type. In addition, we review what the keratinocyte and the dermal fibroblast have taught us about the potential immunogenicity of allogeneic cells. The many observations made using the keratinocyte have broader biological implications and we discuss how this body of work parallels neural stem cell culture and might help us interpret cell behavior in the pancreas.

The use of cells in reparative medicine.

Cells are the functional elements of reparative medicine and tissue engineering. The use of living cells as a therapy presents several challenges. These include identification of a suitable source, development of adequate methods, and proof of safety and efficacy. We are now well aware that stem or pluripotent cells offer an exciting potential source for a host of functional cell types. Their true potential will only be realized through continued effort to increase basic scientific understanding at all levels, the development of adequate methods to achieve a functional phenotype, and attention to safety issues associated with adequate control of cell localization, proliferation, and differentiation. There is also new understanding regarding the immunology of parenchymal cells and new promising approaches to immune modulation, which will open the door to broader therapies using allogeneic cell sources without prohibitive immune suppression. Control of cell growth and phenotypic expression does not end in the culture vessel, but goes beyond to the patient. A living therapy is not static but dynamic, as is the host response. The cells or tissue construct in most cases will not behave as a whole-organ transplant. It is therefore important that we understand a cell or tissue therapy's ability to react and interact within the host since clinical effectiveness has proven to be one of the most difficult milestones to achieve. A living cell therapy offers great potential to alter the human condition, encompassing alteration of the current biological state of a targeted tissue or organ, augmentation of depleted or lost function, or absolute functional tissue replacement. The extent to which we are able to achieve effective cell therapies will depend on assimilating a rapidly developing base of scientific knowledge with the practical considerations of design, delivery, and host response.