The Emergence of Tissue Engineering as a Research Field
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4.0 Development of the Field: 1987-2002
The publication record indicates that the volume of research carried out under the rubric of tissue engineering has increased substantially since 1987, and especially since the mid-1990s, though it is difficult to determine this volume exactly because of the challenge inherent in attempting to precisely specify the scope of the field.
A convenient proxy for the scope of TE today is arguably the pair of reference volumes Principles of Tissue Engineering (first edition published in 1997, second edition in 2000) and Methods of Tissue Engineering (published in 2002), which cover an impressively broad range of research subtopics and researchers.53 The chapter-end bibliographies of Methods alone record thousands of citations to the research literature, with well over 5,000 individual researchers represented in the corpus of research thus defined.54 The scope of research referenced by these volumes overstates to some extent the reach of tissue engineering today, because many of the citations refer to prior art or to adjacent fields from which current lines of research have drawn concepts and methods. Much of the scope of knowledge represented in these volumes was created through research efforts not originally conceptualized as investigations in tissue engineering, but which have, nevertheless, contributed to the field's emergence.
Nevertheless, the growth in tissue engineering properdefined here as work perceived or designated by its participants as TEhas been substantial. This growth derives from multiple sources:
The individuals interviewed for this study found it difficult to identify seminal papers, events or specific discoveries or technical advances that could be characterized as having defined the direction or character of the field. Tissue engineering's growth and development might be better described as the result of incremental progress along several originally independent lines of work, rather than the product of a handful of major breakthroughs or discoveries. Interviews and bibliometric analysis, pointed to two early papers that have played especially important roles in shaping the overall character of the field. While the 1987 Granlibakken conference officially presented and defined the term "tissue engineering", the 1993 Langer/Vacanti review paper in Science introduced the concept of tissue engineering to a wider audience, alerted many researchers who were independently pursuing related work that others shared similar interests within a larger framework, and provided a convenient label for these activities. The Langer/Vacanti collaboration was also responsible for the paper that has probably been most influential from a substantive point of view, an article published at the beginning of 1988 describing the method of using resorbable polymer matrices as a vehicle for cell transplantation.56
On the face of it, the work presented in this paper represented a modest advance. Conceptually, it reflected a logical combination of existing approachescell-seeding of two-dimensional matrices of biological origin, as in the early work on artificial skin; three-dimensional cell culture on synthetic matrices;57 and selective cell transplantation, as in the early work on islet cell transplantation. However, the method of seeding cells on resorbable polymer scaffolds was unique and rapidly became both the most important enabling technology and the most important organizing concept in the field, serving as a common element across lines of research addressing a wide range of therapeutic challenges. As a technique for building tangible objects, it also became a vehicle for enhanced public visibilityif not enhanced public understandingof the field and its goal of "growing organs".58
The scaffolds-and-cell-seeding technique catalyzed a flurry of tinkering on a wide range of tissue and organ systems, overshadowing to some extent the more fundamental efforts proceeding in parallel to develop the underlying knowledge needed to make the products of this technique viable as therapies. Beyond the obvious need for new scaffold materials with properties optimized for specific tissue engineering applications, key knowledge gaps in the late 1980's and early 1990's included, among others:
Many researchers beganor continuedto pursue these questions in their own work, and to draw relevant insights from developments in research outside of tissue engineering.
In 2002, after 15 years since the initial NSF meetings, TE remains a mix of topical foci and research styles, reflecting in part the heterogeneous origins, intellectual traditions, and disciplinary affiliations of the mix of clinicians, engineers and scientists who work in the field.
Although recognition of the importance of gaps in the fundamental knowledge underlying tissue engineering is widespread, many of the individuals interviewed for this study referred to the persistently "Edisonian"59 character of much of the work in TE, by which they meant a sort of inspired, ad hoc tinkering focused on the solution of specific practical problems in the creation of usable products. Some considered this a positive attribute while others viewed it as a drawback, reflecting a persistent tension between two different strategies for TE. Is it best to invest in fundamental research that will lay strong theoretical and methodological foundations for the long-term productivity of TE, or are clinically-significant products sufficiently close to being within reach as to warrant an Edisonian sprint toward their creation?
It might be expected that Edisonian approaches would be most strongly associated with TE research and development efforts in the corporate sector, while the academic sector would be more strongly focused on fundamentals. The former is certainly true, and because the corporate sector has accounted for the great majority of the funds invested in TE,60 it necessarily follows that the character of corporate R&D has had a substantial impact on the character of the TE enterprise overall.
Many of our informants observed that corporate R&D efforts in tissue engineering have had a modest effect on the progress of the field. Corporate R&D has focused on the creation of proprietary intellectual content centered on the challenges of bringing products to market, and less on the solution of broader challenges in science or engineering. Knowledge transfer from industry back to academia has been limited.
However, many respondents suggest that the Edisonian approach remains a powerful force within the academic sector as well. In part, this reflects the natural inclination of some workers in the field, many but not all of these clinicians who bring to their work a strong practical bent. Some observers believe that another influencea deleterious onehas been the combined effect of a shortage of funding from traditional sources of support for academic research together with the incentives created by the venture-capital-funded boom in biotechnology startup companies during select periods in the 1980s and 1990s, that has induced some researchers to attempt prematurely to "productize" their ideas or research findings.
Given the eclectic nature of the field, it is difficult to make judgments as to the level of progress that has been made in the years since 1987. One way of interpreting the significance of the events of 1987 is that they marked the beginning of an attempt by engineers to systematize and formalize the field of tissue engineering. The principle of rational design is central to the engineering approach. In turn, rational design is made possible by the elucidation of theoretical principles of broad generalizability and by the systematic characterization of available materials and methods in terms of the parameters that comprise these theoretical models. In the tissue engineering context, some of these principles would need to come from engineeringfor example, those related to mechanical aspects of tissues, the behavior of biomaterials, and processes for producing, preserving and distributing TE products. Others would need to come from biologyfor example, the behavior of cells and of growth factors. Still others would need to come from clinical medicinefor example, principles of physiology and pathophysiology. No matter whether their disciplinary roots have been in medicine, in engineering or in biology, TE researchers have from the earliest days of their involvement recognized that the future success of the field depends heavily on strengthening the base of systematic knowledge underlying TE applications. Yet it was engineers who first sought to articulate this point clearly and make it the foundation for a formalization of the field.61
While this principle is sound, however, the development of the field since 1987 reflects little progress toward a systematization of TE through the creation of a foundation of broadly applicable theory or even a well-structured phenomenology. Although a great deal of new knowledge has been accumulated, deficits in fundamental understanding cataloged in recent reviews62 are similar in general outline to those recognized in the late 1980s and early 1990s. Researchers today have gained a much more detailed and sophisticated understanding of the specific challenges that must be addressed, however, and some progress has been made in framing research challenges in particular areas of TE in a more systematic way.63
Perhaps the most important explanation for this slow progress is simply that the rationalization of TE represents an intellectual challenge of enormous magnitude. Construction of replacement tissues and organs, or controlled induction of endogenous reparative capacities to restore tissue structure and function, represent extraordinarily difficult systems engineering problems, and knowledge both of the behavior of the system components and of the necessary principles of systems integration remains primitive in relation to what is required.
Another factor affecting the rate of progress may be important gaps in the intellectual resources that have been brought to bear on the challenges of tissue engineering, and in the degree of cross-disciplinary integration that has been achieved. In her plenary address at the 2001 BECON symposium, Nancy Parenteau articulated these concerns:
With respect to its headline goal as wellto create living replacement parts for the human bodythe progress of TE has been slow. As with the underlying scientific challenges, the work of the past fifteen years in tissue engineering has served above all to clarify our understanding of how difficult it will be to achieve the full extent of TE's therapeutic vision.
In his 1987 draft concept memo, NSF's Allan Zelman identified a list of "types of tissues most likely to bring early success". In Zelman's words, these were:
Preliminary progress has been made in the development of many of these tissues, though it is understood that much more work is required before "off-the-shelf" products will be available:
Skin. Skin is perhaps the most successful of the tissue engineered therapies, with several products having completed clinical trials, met with FDA approval, and made the transition to market. In 1997, the FDA approved TransCyte66, a skin replacement tissue made by Advanced Tissue Sciences, which consists of dermal keratinocytes grown on a biodegradable polymer. TransCyte serves as a temporary wound cover for burns as new tissue forms. Apligraf67, manufactured by Organogenesis, utilizes live human skin cells to form a dual layer skin equivalent approved by the FDA to treat diabetic leg and foot ulcers.
Recent advances in skin tissue engineering have resulted in the following examples of products in the last 5 or so years:
Companies have approached the development of skin equivalents from different perspectives: autologous cellular replacements (Genzyme Biosurgery), allogeneic cellular replacements (Advanced Tissue Sciences and Organogenesis), and completely acellular replacements (Integra). Each of these appear to achieve success as wound coverings. However, scar tissue formation and wound contraction issues remain problematic. Available products also fail in several ways to mimic the structure and function of native skin. Substitutes have long acted as passive wound covers, lacking certain essential functions/components-including hair follicles, and glands72. Development of such enhancements are the focus of current research in living skin equivalents and suggests the use of stem cells as a basis for development of fully differentiated skin equivalents. Choice of matrix support to maintain fibroblasts and keratinocytes is also still being investigated.
Vascular grafting. Progress to date in the development of tissue engineered vascular grafts has focused on mimicking the three layers of the normal muscular artery, using combinations of live cells, bioresorbable and non-bioresorbable scaffolding constructs. At present, there are no FDA approved live vascular replacement therapies. Several techniques are in pre-clinical trial but face challenges that may prevent their widespread use/application in the near future."73
Huynh and colleagues at Organogenesis and Duke University, for example have used porcine intestine as a graft base for seeding of endothelial cells, which will grow and develop into vessel like structures74. The use of porcine cells, while important for clinical research, have unknown effects if transplanted into humans. Other sources for graft bases are also being explored, including fibrillar collagen and bovine collagen gels. However, none of these have produced a vascular substitute with the mechanical properties and strength of native blood vessels. Traditional problems plaguing the field, including clotting and scar tissue formation also persist in cellular replacements and prevent laboratory products from making it to the clinical trial stage. To combat such problems, researchers have attempted to embed the graft materials with antibiotics and antithrombotic coatings with limited success. There is also the need to create a functional nerve supply and capillary network in vitro to support live vascular tissues. Until such challenges are remedied, prosthetic grafts, made of substances like Dacron and polytetrafluoroethylene, will continue to serve as the major therapy.
Kidney. As a highly complex organ, whole kidney replacement organs are far from being a reality. However, progress has been made in development of temporary replacement devices, such as extracorporeal kidney assist devices. Dr. David Humes, Chairman of The Department of Internal Medicine at The University of Michigan, Ann Arbor, has successfully completed in vivo testing of a Renal Tubule Assist Device (RAD) for treating acute renal failure75. The only other treatments currently available for acute renal failure are hemofiltration and dialysis. Extracorporeal devices may improve the outcomes of these patients while making treatment much less costly.
Pancreas/Islet cells. Islet cell transplantation techniques have consisted of two major approaches: perfusion devices and microencapsulation. Perfusion devices, though developed as early as 1970, have failed to make it to the clinical trial stage to due long-term biocompatibility issues, membrane breakage, and size limitations (a problem which plagues bioartificial implantable livers as well). Microencapsulation, has also been in existence for several decades. Refinements to this technique over time involved improving the biocompatibility of the encapsulating materials. Some researchers suggest that widespread clinical application of microencapsulation techniques is just around the corner.76
Several commercial tissue engineering approaches to repair/replace pancreatic function describe the current state of the field:
Liver. Several bioartificial liver (BAL) bioreactor designs have been developed in the laboratory to replace liver function. The basic design of a BAL device consists of circulating patient plasma extracoporeally through a bioreactor that houses/maintains liver cells (hepatocytes) sandwiched between artificial plates or capillaries.78 Bioreactor materials have either a spherical shape, large surface area, large pores or high porosity, or are hydrophilic and biocompatible.79 These features can help to achieve the high density cultures of hepatocytes required. However, there is no one material that possess all of these desired properties. Researchers are actively seeking a support matrix that could provide all these properties in order to have a BAL with improved efficiency and effectiveness. Clinical trials of some BAL devices are already underway in the United States and the UK. Circe Biomedical currently has the HepatAssist liver device in clinical trial, which is a extracorporeal device consisting of a hollow-fiber bioreactor lined with porcine cells.80
Numerous other challenges plague the development of tissue engineered livers:
Bone, cartilage. Like skin, tissue engineering of bone and cartilage has experienced relative success as compared to other tissue engineered products. Current strategies consist of two major approaches: transplantation of osteochondral grafts and transplantation of chondrocytes81. Cell populations from cultured periosteum have the ability to form new bone and cartilage under the appropriate conditions and with the addition of the appropriate growth factors.82 Transplantation of osteochondral grafts, however, runs a possible risk of rejection in the recipient.
Current products and strategies include:
To our knowledge, no other allogeneic, cell-based organ- or tissue-replacement product is close to market. Autologous efforts remain dominant. Efforts to bring to market tissue-engineered products that address defects in complex metabolic functions or replace vital organs will require more time and effort before reaching success. Research and development programs on various approaches to the bioartificial pancreas are said to have consumed over $200 million of private sector funds to date, but designs capable of routine success in large animal models are yet unavailable, while encapsulated cell therapy has failed to demonstrate efficacy in phase III clinical trials.86 Extracorporeal replacement of critical metabolic functions of the kidney and liver has reached the stage of small clinical trials&$151;Phase I (safety) for the former and Phase II (preliminary safety and efficacy) for the latter.87 In both cases, the devices' mode of operation involves extracorporeal blood circulation comparable to that of a dialysis machine, and both are initially targeted toward treatment of acute, life-threatening metabolic failure. The tissue-engineered replacement heart remains a distant vision.88
As noted previously, from the beginning, more subtle conceptions of TE have extended its scope to encompass not only the production of replacement parts that embody the necessary structure and function, but the possibility of induction of endogenous reparative capabilities as well. In principle, such induction may be achieved via a variety of approaches, including implantation of cells that express growth factor molecules, implantation of non-living materials (for example, a collagen sponge) containing growth factor molecules, delivery of genes that encode the required growth factor, or by local or systemic infusion of growth factor molecules. The observed physiologic effects of the "skin replacement" products in promoting wound healing suggest that they might also be described as the first "induced repair" products rather than as replacement organs. Acellular "skin replacement" products on the market, such as the INTEGRA® dermal regeneration template derived from the work of Yannas,89 are designed to function in this way. After more than 30 years of research on bone morphogenetic proteins, a BMP product has also recently reached the market - Medtronic's INFUSETM bone graft product, incorporating recombinant human bone morphogenetic protein rhBMP-2.90 Several companies market acellular matrix materials for bulk applications in orthopedic and reconstructive surgery.
In bringing therapeutic products to market, tissue engineers must surmount not only daunting technical challenges, but regulatory and business obstacles as well. The regulatory environment for cell-containing products is complex and still at an early stage in its evolution; it imposes a substantial financial burden on the product development process, directly through the efficacy standards the product must meet and through the cost of funding the trials needed to demonstrate that efficacy, and indirectly through the financial effects of delay in bringing products to market. Finally, for a product to be viable, it must be possible to develop it, achieve regulatory approval, manufacture it, distribute it and market it at a price adequate to yield a positive economic return.
The difficulty of companies like Organogenesis and Advanced Tissue Sciences in recent times also raises concerns around the financial viability of some tissue engineered products. As of this writing, both Organogenesis and Advanced Tissue Sciences are undergoing reorganization under Chapter 11 bankruptcy protection, and on trends to date it appears unlikely that revenues from their artificial skin products will ever cover the cost of the capital invested in their development. At the aggregate level, cumulative investment in tissue engineering research has been estimated to exceed $3.5 billion, of which well over 90% has been provided by private sources, with negligible financial return.91 Such concerns are well known by individuals in the public and private sectors and will be important considerations in strategy development for building not only clinically viable, but commercially viable products.
It is clear from these examples that despite notable contributions and advancements, tissue engineering is still a field in its infancy. Whether tissue engineering as we know it today will prove to be a powerful general strategy for developing therapeutic products and methods that can meet the dual hurdles of therapeutic efficacy and commercial viability remains to be seen. A strong research effort is underway, however, and advances in other emerging areas of science, such as stem cell research, are likely to make significant contributions toward helping tissue engineering to become a viable field.
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