Foundations of Regenerative Medicine

Clinical and Therapeutic Applications

Anthony Atala

• Publisher: Academic Press
• Year: 2009
• Print ISBN: 9780123750853
• eBook ISBN: 9780123785626
• Topic: Biological Sciences
• Subtopic: Biology
• Index: Biological Sciences

The interdisciplinary field of regenerative medicine holds the promise of repairing and replacing tissues and organs damaged by disease and of developing therapies for previously untreatable conditions, such as diabetes, heart disease, liver disease, and renal failure. Derived from the fields of tissue engineering, cell and developmental biology, biomaterials science, nanotechnology, physics, chemistry, physiology, molecular biology, biochemistry, bioengineering, and surgery, regenerative medicine is one of the most influential topics of biological research today.Derived from the successful Principles of Regenerative Medicine, this volume brings together the latest information on the advances in technology and medicine and the replacement of tissues and organs damaged by disease. Chapters focus on the fundamental principles of regenerative therapies that have crossover with a broad range of disciplines. From the molecular basis to therapeutic applications, this volume is an essential source for students, researchers, and technicians in tissue engineering, stem cells, nuclear transfer (therapeutic cloning), cell, tissue, and organ transplantation, nanotechnology, bioengineering, and medicine to gain a comprehensive understanding of the nature and prospects for this important field.- Highlights the fundamentals of regenerative medicine to relate to a variety of related science and technology fields- Introductory chapter directly addresses why regenerative medicine is important to a variety of researchers by providing practical examples and references to primary literature- Includes new discoveries from leading researchers on restoration of diseased tissues and organs

Chapter 1 Current and Future Perspectives of Regenerative Medicine

Mark E. Furth and Anthony Atala

Regenerative Medicine: Current and Future Perspectives

Progress and Challenges for Cell-Based Regenerative Medicine

Regenerative medicine seeks to devise new therapies for patients with severe injuries or chronic diseases in which the body's own responses do not suffice to restore functional tissue. A recent publication from the US National Academy of Sciences, Stem Cells and the Future of Regenerative Medicine (Committee 2002), identified a wide array of major unmet medical needs which might be addressed by regenerative technologies. These include congestive heart failure (approximately 5 million patients in the United States) (Murray-Thomas and Cowie, 2003), osteoporosis (10 million US patients), Alzheimer's and Parkinson's diseases (5.5 million patients each), severe burns (0.3 million), spinal cord injuries (0.25 million), and birth defects (0.15 million). Another area of critical need is diabetes mellitus (16 million US patients and more than 217 million worldwide) (Smyth and Heron, 2006). Patients with type 1 diabetes lack pancreatic beta-cells, essential for the production of insulin, because of autoimmune destruction and represent from 10% to 20% of the total. Many patients with type 2 diabetes also show insufficient pancreatic beta-cell mass. Thus, patients in both groups potentially might be treated if methods could be developed to promote endogenous regeneration of beta-cells or to provide enough surrogate beta-cells and pancreatic islets for transplantation (Weir, 2004).

The therapeutic use of growth factors and cytokines to stimulate the production and/or function of endogenous cells represents the area of regenerative medicine that, arguably, has shown the greatest clinical impact to date (Ioannidou, 2006). Regenerative therapies comprising living cells also have entered into practice, initially through the widespread adoption of both allogeneic and autologous bone marrow transplantation (Thomas, 1999). The presence of hematopoietic progenitor and stem cells with great replicative capacity in vivo, and their ability to reenter the bone marrow niche from the circulation, enabled this major medical advance. Subsequently, the development of methods to expand ex vivo and deliver such cell types as keratinocytes and chondrocytes, through advances in cell culture and scaffold technologies, led to successful tissue engineering for wound repair (Johnson, 2000; Lavik and Langer, 2004). Despite significant challenges in development and manufacturing, several bioartificial skin graft and cartilage replacement products have achieved regulatory approval (Lysaght and Reyes, 2001; Naughton, 2002; Lysaght and Hazlehurst, 2004). These therapies validate the potential of cell-based regenerative approaches.

The extension to new therapeutic areas, especially the development of neo-organs with complex three-dimensional structure, will depend on complementary advances in biology, materials science, and engineering. A major limitation remains the ability to provide oxygen and nutrients to neo-tissues both in vitro and after implantation. Advances in scaffold composition and design, in bioreactor technology, and in the use of pro-angiogenic factors may all help to overcome this barrier and are discussed in depth in other chapters of this book.

Here we will focus mainly on sources of cells for regenerative medicines. A primary issue remains the choice between using a patient's own cells, or those of a closely matched relative, versus those from an unrelated allogeneic donor. More broadly, future developments depend heavily on increased understanding and effective utilization of multiple classes of progenitor and stem cells.

When populations that include precursor cells (i.e. cells not yet fully differentiated and capable of significant proliferation) can be obtained from a small biopsy of a patient's tissue, and these cells are able to expand and differentiate in culture and/or after implantation back into the patient, autologous therapies are feasible. These have the great advantage of avoiding the risk of immune rejection based on differences in histocompatibility antigens, so that the use of immunosuppressive drugs is not required. However, there is a substantial practical appeal to “off the shelf” products that do not require the cost and time associated with customized manufacturer of an individual product for each individual recipient (Lysaght and Hazlehurst, 2004).

Among the approved bioengineered skin products, Dermagraft (Smith & Nephew) and Apligraf (Organogenesis) utilize allogeneic cells expanded from donated human foreskins to treat many unrelated patients. Despite the genetic mismatch between donor and recipient, the skin cells in Dermagraft and Apligraf do not induce acute immune rejection, possibly because of the absence of antigen-presenting cells in the grafts (Briscoe et al., 1999; Horch et al., 2005). Thus, these products can be utilized without immunosuppressive drug therapy (Moller et al., 1999). Eventually, the donated skin cells may be rejected, but after sufficient time has passed for the patient's endogenous skin cells to recover and take their place.

Products based on autologous cells also have achieved regulatory approval and reached the market. In particular, Genzyme Biosurgery has developed Epicel, a permanent skin replacement product for patients with life-threatening burns, and Carticel, a chondrocyte-based treatment for large articular cartilage lesions. In each case seed cells are obtained from a small biopsy of the patient's tissue. These cells are expanded in culture, processed, and returned to the patient.

New Therapies Using Autologous Cells

Recent clinical studies highlight ongoing efforts to develop new autologous cell-based therapies. The recognition that, in addition to hematopoietic stem cells, bone marrow also contains mesenchymal stem cells (MSC) and endothelial progenitor cells (EPC), has spurred ongoing efforts to use autologous marrow cells for blood vessel tissue engineering and for treatment of myocardial infarction.

In the case of engineering of blood vessels, vascular grafts of autologous bone marrow cells seeded onto biodegradable synthetic conduits or patches have been implanted in children with congenital heart defects (Shin'oka et al., 2005). Safety data on 42 patients with a mean follow-up period of 490 days post-surgery appeared very encouraging, with no major adverse events reported. The grafted engineered vessels remained patent and functional. Moreover, there was evidence that the vessels increased in diameter as the patients grew, thus highlighting a critical potential advantage of regenerative therapies incorporating living cells.

Further advances in blood vessel engineering will likely arise from multidisciplinary approaches demanding advances at the interface of biology and engineering. In recent preclinical studies scaffolds for neo-vessels blending collagen type I and elastin with polylactic-co-glycolic acid (PLGA) were fabricated by electrospinning and showed compliance, burst pressure, and mechanical properties comparable to native vessels (Stitzel et al., 2006). The electrospun vessels also displayed good biocompatibility both in vitro and after implantation in vivo. When seeded with endothelial and smooth muscle cells, or progenitor MSCs and/or EPCs, these constructs may provide a basis to produce functional vascular grafts suitable for clinical applications such as cardiac bypass procedures. The seeding process itself may demand future advances, since it will be difficult for cells to penetrate a nanofibrillar structure in which pore spaces are considerably smaller than the diameter of a cell (Lutolf and Hubbell, 2005). Electrospinning actually may be used to incorporate living cells into a fibrous matrix. A recent proof of concept study documented that smooth muscle cells could be concurrently electrospun with an elastomeric poly(ester urethane)urea, leading to “microintegration” of the cells in strong, flexible fibers with mechanical properties not greatly inferior to those of the synthetic polymer alone (Stankus et al., 2006). The cell population retained high viability and, when maintained in a perfusion bioreactor, the cellular density in the electrospun fibers doubled over 4 days in culture. One can imagine that in the future, progenitors of vessel cells may be harvested from a patient, incorporated into an electrospun matrix and incubated in a bioreactor, first to drive expansion and differentiation and then, via pulsed flow, to promote vessel maturation (Niklason et al., 1999).

Similar strategies may be attempted to treat patients with congestive heart failure (Krupnick et al., 2004). Already, a number of clinical studies have been carried out on the injection of autologous bone marrow cells, sometimes unfractionated sometimes enriched for stem/progenitor cells, into the heart after myocardial infarction (Stamm et al., 2006). The initial rationale for this approach came from experiments in rodents interpreted as demonstrating the production of new cardiomyocytes through the transdifferentiation of hematopoietic stem cells. Evidence for myogenesis of grafted cells, whether from the hematopoietic lineage or, as seems much more plausible, from mesenchymal progenitors, remains sparse. However, some controlled studies do indicate potential clinical benefits from the autologous cell therapy. This may result from the production of angiogenic factors by the injected cells rather than from integration of donor cells into either muscle or new blood vessels. Nonetheless, although still a daunting challenge, the application of regenerative medicine principles to repair damaged cardiac muscle now seems within the possible realm (Dimmeler et al., 2005). The correct choice of cell source, the d...

Table of contents

• Cover
• Title Page
• Copyright
• Dedication
• Table of Contents
• Preface
• List of Contributors
• Chapter 1: Current and Future Perspectives of Regenerative Medicine
• Chapter 2: Fundamentals of Cell-Based Therapies
• Chapter 3: Stem Cell Research
• Chapter 4: Molecular Organization of Cells
• Chapter 5: Cell–ECM Interactions in Repair and Regeneration
• Chapter 6: Developmental Mechanisms of Regeneration
• Chapter 7: The Molecular Basis of Pluripotency in Principles of Regenerative Medicine
• Chapter 8: Embryonic Stem Cells
• Chapter 9: Stem Cells Derived from Amniotic Fluid and Placenta
• Chapter 10: Bone Marrow Stem Cells
• Chapter 11: Mesenchymal Stem Cells
• Chapter 12: Islet Cell Therapy and Pancreatic Stem Cells
• Chapter 13: Mechanical Determinants of Tissue Development
• Chapter 14: Morphogenesis and Morphogenetic Proteins
• Chapter 15: Physical Stress as a Factor in Tissue Growth and Remodeling
• Chapter 16: Engineering Cellular Microenvironments
• Chapter 17: Applications of Nanotechnology
• Chapter 18: Design Principles in Biomaterials and Scaffolds
• Chapter 19: Naturally Occurring Scaffold Materials
• Chapter 20: Synthetic Polymers
• Chapter 21: Surface Modification of Biomaterials
• Chapter 22: Biocompatibility and Bioresponse to Biomaterials
• Chapter 23: Islet Cell Transplantation
• Chapter 24: Cell-Based Repair for Cardiovascular Regeneration and Neovascularization
• Chapter 25: Cell Therapies for Bone Regeneration
• Chapter 26: Cell-Based Therapies for Musculoskeletal Repair
• Chapter 27: Hepatocyte Transplantation
• Chapter 28: Cell-Based Drug Delivery
• Chapter 29: Engineering of Large Diameter Vessels
• Chapter 30: Cardiac Tissue
• Chapter 31: Intracorporeal Kidney Support
• Chapter 32: Genitourinary System
• Chapter 33: Tissue Engineering of the Reproductive System
• Chapter 34: Phalanges and Small Joints
• Chapter 35: Functional Tissue Engineering of Ligament and Tendon Injuries
• Chapter 36: Tissue Therapy
• Chapter 37: Peripheral Nerve Regeneration
• Chapter 38: Innovative Regenerative Medicine Approaches to Skin Cell-Based Therapy for Patients with Burn Injuries
• Chapter 39: Ethical Considerations
• Chapter 40: To Make is to Know
• Chapter 41: Overview of FDA Regulatory Process
• Chapter 42: Current Issues in US Patent Law
• Index