Progress in tissue engineering and regenerative medicine.

F ascination with the ability to regenerate tissues and organs has existed since the earliest observations of Prometheus, Thevenot, and Tremblay. However, what might be called the modern era of tissue engineering and regenerative medicine began only a quarter century ago. The initial focus of a newly defined scientific discipline referred to as “tissue engineering” involved the ex vivo creation of replacement tissues intended for subsequent in vivo implantation. Skin substitutes represented the earliest attempt at engineered tissues, and by the 1990s commercial development of these products had begun. The 1980s and 1990s were the “go-go years” of tissue engineering, but by the turn of the century commercial activity had encountered a variety of problems, including challenging regulatory hurdles and almost nonexistent third-party reimbursement mechanisms needed to sustain the commercialization effort. In contrast, the science of tissue engineering has been unstoppable. By the mid1990s the emphasis on tissue replacement with ex vivo manufactured products had evolved to include broad strategies to induce both in vivo constructive remodeling of cell-based and cell-free scaffold materials and true tissue regeneration, marking the emergence of the era of regenerative medicine. The desire to construct tissues and organs more complex than partial-thickness skin substitutes made it obvious that the simple selfassembly or directed assembly of different cell types ex vivo would be inadequate to meet all the challenges. A critical issue for successful regenerative medicine applications is the source from which the cells are harvested, whether the intended use is tissue replacement, repair, or regeneration. The field of stem cell biology thus began a fullscale emergence in the 1990s and immediately became a mainstream research initiative in regenerative medicine. Human embryonic stem cells, adult stem cells, progenitor cells from a variety of tissues, and, more recently, the induced pluripotent stem cells (iPS cells) all represent potential components of a regenerative medicine strategy for tissue and organ reconstruction. iPS cells are derived from somatic cells such as fibroblasts by the transfection of selected genes, but it now appears that it may be possible to reprogram somatic cells into iPS cells without the use of transfection. Furthermore, it may not even be necessary for the reprogramming to revert cells to a state of pluripotency but rather only to a progenitor cell state from which the desired differentiated lineage can be derived. The immunogenicity of cell-based tissue replacement, the potential for teratoma or uncontrolled cell proliferation with the use of human embryonic stem cells or iPS cells, and the ethical issues and regulatory hurdles of stem cell therapy all represent significant barriers to a stem cell-based regenerative medicine approach. Clearly these are exciting times for a cell-based approach to regenerative medicine. What does the future of regenerative medicine hold, and what is the true potential of such an approach? We look forward to the development of effective therapies for degenerative diseases, traumatic injuries, and disorders for which limited therapeutic options exist such as esophageal cancer or emphysema. The derivation of blood cells from stem cells, the creation of insulin-secreting, glucoseresponsive cells for the treatment of diabetes, the constructive functional remodeling of the heart after a myocardial infarction, and the regeneration of nerves after spinal cord injury all represent realistic targets for regenerative medicine. The approaches to tissue reconstruction and regeneration have varied widely, and it is obvious that no single approach will solve all problems; rather, each tissue and each pathologic condition probably will require a different approach to obtain optimal results. It seems clear, however, that defining and controlling the microenvironmental niche within which each tissue, and even within regions of a given tissue, will be key to successful tissue regeneration. These niche conditions include such factors as oxygen concentration, cytokine gradients, pH, ionic and electrical potential, available nutrients, and mechanical forces, all of which are in a state of dynamic equilibrium in temporal and spatial patterns that are unique to each tissue and organ. Artificial bioreactors are limited in their ability to recreate these niche conditions, and the ultimate goal of true tissue regeneration almost certainly will require the use of Mother Nature’s bioreactor, the human body. The extent to which we can jump start the regenerative process and supply the appropriate ingredients will determine our success in achieving tissue and organ regeneration. The clinical translation of regenerative medicine requires more than scientific discovery. Regulatory agencies must become educated in nontraditional approaches and develop appropriate guidelines for safe and effective delivery of regenerative medicine strategies. Thirdparty payers must come on board quickly to sustain promising approaches and reward regenerative medicine strategies that have the potential to affect health care savings significantly through the discovery of true cures for conditions such as diabetes, Parkinson disease, multiple sclerosis, and organ replacement. The involvement of industry, both start-up companies and established large companies, is essential for rapid and effective delivery of regenerative medicine to physicians and patients. Finally, because of the potential for regenerative medicine to develop revolutionary clinical therapies that will address unmet patient needs, the community must be careful not to overstate what is possible and the time line necessary for these therapies to reach the patient bedside. In the past the combination of patients desperate for new treatments, scientists enthusiastic about the advances they are making, clinicians wanting to help their patients, and entrepreneurial commercial organizations has led to unrealistic expectations. This “over-hype” has not served the community well, and we must, in advocating the potential for the future, be realistic about what is doable today and what can be expected in the short and long term. This issue of PNAS has been designed to provide a view of the extremely diverse approaches to tissue engineering and regenerative medicine currently being investigated The interested reader will find articles that describe the construction of tissues as diverse as skeletal muscle, bone, heart, blood vessels, complex functional limb structures, and even the central nervous system. There are five separate articles that describe the use of stem cells as part of a regenerative strategy. This issue