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Translational Research Success Requires Return to Contract Program at NIH
The Fiscal Year 2013 budget for Federal agencies includes $639 million for a new National Center for Advancing Translational Sciences (NCATS), with $575 million currently authorized. This is a response to a long-unmet need from the other National Institutes of Health to again deliver some practical products to the public, as they certainly did in the 1960-1980 period. In January of 1998, an article on “The Future of Biomedical Implants” (Pharmaceutical News, Vol 5, No.1, 1998, pages 25-29) reviewed the State of Science, 1997, the State of Economics, 1997, Long Term Prospects, New Frontiers, and the need for an Expanded Role of the NIH, summarized briefly here:
Expanded Role of the NIH
One of the functions of the NIH should be to promote inter-disciplinary studies and evaluation of biomaterials and biomedical implants. The problems encountered call for the collaboration of physical and biomedical scientists, without which the substantial advances of the early years (1965-1975) would not have resulted.
After a decade of individual-investigator awards, it is advisable to again promote long-term funding of at least a few national teams (or the stimulation of a limited number of program project grants), independent of their physical proximity, of a critical mass of biomaterials scientists and engineers; conversant biological and medical investigators; and suitable laboratory facilities. In addition to their own research activities, these teams should undertake comparative studies of the same materials and devices, and thus eliminate the controversies in the field. Such teams should be organized in collaboration with FDA and perhaps also with the medical device industry. The advanced transportation network of the United States, and the regular travel habits of most senior investigators, favor the organization of these teams on a critical skill rather than parish basis.
NIH also should regain its sponsorship of an annual Contractors meeting and specialized workshops, since the earlier leavening influence of these annual reunions was well recognized, and the publications that resulted served a major educational function of information and technology-transfer both nationally and internationally.
Since NIH does not have an explicit mandate to oversee technology as well as science, in a limited interpretation of its role, NIH has not proceeded with any ongoing assessments of the limiting role of biomaterials in the development of biomedical implant technology, and has not taken appropriate action when material unavailability became the bottleneck to progress. NIH must be more interested in the assessment of medical device technology in the light of medical, social, ethical, and legal values. In the distant past, NIH’s Artificial Heart Program was the primary focus of such attention, but other applications of implant technology did not equally benefit from similar scrutiny.
NIH also should encourage the generation of occasional white papers reviewing — from both an expert and critical vantage — the body of knowledge already accumulated (and mostly uncirculated) in the previous annual reports of contractor organizations/faculties.
A CURRENT VIEW
The news remains full of reports that "tissue-engineering" will advance synthetic biomedical implants and biomaterials beyond their successes in wound repair, and past their current troubles as litigation-bound hip replacements, to a better future as agents of regeneration of natural biological structure and function. This has not yet been at an acceptable risk/benefit ratio, or approvable by public regulatory agencies, since it has not been satisfactorily demonstrated that aseptic processing procedures or new sterilization modalities will protect against acquisition/transmission of vectors of disease (including prions, viruses, bacteria, and immune system adjuvants). Further, continued unavailability of suitable synthetic materials as scaffolds for "seed" cultures of cells (meant to generate new tissues) seriously impedes progress from laboratory to clinical utility. This problem is exacerbated by the departure of newly trained entrants to "tissue engineering," from the creed of the field's founders: scaffolds must be temporary at every step of placement/digestion/elimination from their human hosts. Regulation of tissue-engineered products will become even more vigilant and disallow any non-absorbable, remnant materials proposed for tissue-engineered products. This is especially true with regard to the commercial commodity polymers that have been withdrawn as privately marketed so-called "biomaterials." Practitioners must display increased professional responsibility to prevent introduction of non-sterile or persistent components of tissue-engineered products to human implantation.
The under-exploited and better near-term alternative of the 1990's was "bioprosthetic devices," part synthetic/part biological in origin and completely safe (by prior sterilization) at the time of implantation. These could still be the practical tissue-engineered prostheses needed for public health while the required basic science has been so slow to develop for live-tissue products in the past decades.
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As an example of "reverse progress" in this field, consider the recent withdrawal from manufacture of limb-saving products crafted from human umbilical cords, after 30 years of safe and effective clinical benefit from material previously cast away with other remnants of the afterbirth following delivery of normal healthy children. Human umbilical cord vein grafts have now become too expensive to fabricate because of additional regulations about harvesting and safely preserving these naturally fragile biological tissues, while guaranteeing absolute safety from risks of new diseases in spite of their history of good clinical function over the past three decades in thousands of grateful recipients. The surgical photo below shows such a graft in the process of a limb-saving vascular replacement operation, now relegated to the use of less satisfactory synthetic graft materials. The new National Center for Advancing Translational Sciences should take up the cause of making these biosynthetic implants again affordable for general clinical use!
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STATE OF THE SCIENCE, 2012
Inadequacies of prior testing and quality control of some traditionally available medical devices and biomaterials also continue to hold back progress with numerous other implants. Before the turn of the Century, devices such as pump-oxygenators, pacemakers, vascular grafts, prosthetic valves and artificial hearts all showed significant advances based on the ready availability of commercial materials which have since mostly been withdrawn from the medical marketplace. Progress in design is now contingent upon the identification of substantially equivalent materials from other sources or the synthesis of new construction materials. The service lives of most current implantable devices have reached their limits, as noted in the unacceptable deterioration under load of otherwise acceptable materials (polyethylene and cobalt-chromium alloys in acetabular cups; polytetrafluoroethylene in jaw joints) in contact with body tissues, or with the adverse longer term reactions of body tissues to the presence of breakdown products from other prosthetic devices (silicone implants). Desired closer interactions have not occurred between materials science and such basic biological sciences as molecular and cellular pathology, immunology and hematology. Post-2000 progress with biomedical devices has been limited by the absence of breakthroughs in design or de novo synthesis of new classes of materials yet to be attained. Knowledge of "biomaterials" of predictable biological response is still seriously lacking in the public domain, so pressing clinical needs for new or improved devices which could improve both the diagnosis and treatment of heart, lung and blood diseases, among others, are held hostage to the world's dependence on once-withdrawn and now slowly re-introduced commodity polymers.
Here is a continuing problem: Except for commercially pure titanium and a few other "osseointegrating" implants, all other "biomaterials" induce a "foreign body" reaction when introduced to a biological environment. They are either walled off by a reorganization of surrounding tissues, or become coated with poorly described biological materials derived from these tissues. Most often, the outcome is characterized as "inflammatory response" in the extravascular space, and as "thrombosis" in the cardiovascular system, both terms being misleading in their disguise of un-deciphered complexity. These responses engage complex biological processes involving the interactions of many different biomolecules and cells at the foreign interfaces. Still not understood are at least two main phases of response: an acute phase characterized predominantly by protein and cellular activity; and a chronic phase in which the changes are slower, leaving "passivated" surfaces. There has not been the needed widespread or deeper inquiry into the complexity of these processes by materials scientists, engineers and physicians, and there have not yet been sufficient efforts to purify and standardize biomaterials using the sophisticated physico-chemical and biological test methods necessary for characterizing these interactions. For nearly 30 years, increases in knowledge and improvements in assays have not been sufficient to support the desired pace of introduction of new clinical devices and implants. Surface properties expressed as outermost chemical arrays, polymer configurations, charges and topographic variations that trigger the biological responses, have been investigated mainly in academic labs and not well-translated to clinical benefit. A reason for this is that correlations linking surface properties and biological responses have not met general agreement. There is no consensus about which "animal model" or "test system" is best. Rheology (flow factors) influences and, in some cases, dominates the biological responses, but again the test systems applicable to discerning such effects remain elusive.
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Here is a continuing "bad example" of work yet to be accomplished:
This is a photograph of the unexpectedly "worn down" dome of a TMJ (TemporoMandibular Joint) implant, originally placed with a perfect hemispherical shape into a young woman's jaw.
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When a patient was suffering from the pain of such a no-longer-well-functioning appliance, and from her body's reaction to the wear debris then collecting behind her ear prompted additional surgery, the implanter's response was often to replace this polymer-on-metal joint with an all metal-on-metal joint, surface features of which are displayed here:
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Used only with express written permission
Used only with express written permission
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This is the type of metal-on-metal articulation that is now causing serious problems in hip resurfacing applications for orthopedic patients, and has gone mostly unreported in the TMJ population also needing removal of these pain-provoking implants.
STATE OF THE ECONOMICS, 2012
After quieting, but not really overcoming, the "Biomaterials Availability Crisis" of the 1990's, there has not been the needed support of applied as well as fundamental biomaterials research in close collaboration with clinical investigations. Advances that are critically dependent upon the availability of complex and expensive facilities were retarded by segregation of research projects into separate investigator-initiated academic units. Practical aspects of experimental procedures, and interactions among implant and biomaterials research groups were not adequately stimulated, and there was little provision for the exchange of materials between laboratories, or mutual visits by scientists and technicians. The exclusive dependence in the past 30 years on limited-focus, investigator-initiated grant-supported programs -- at the expense of the break-up of the multidisciplinary physician-engineer-scientist teams that accounted for most of the progress in biomedical implants in the decade 1965-1975 -- denied the public of new device concepts or implant materials. Rather, there has continued to be inefficiency and the re-treading of many of the well-worn paths of prior investigators. As a result, biomaterials and implant research still stagnates, not yet "rescued" by the bold plan to "leapfrog" the problems of the past by proclaiming a new era of "tissue engineering", without overcoming the obvious difficulties of having no raw materials substituted for those (many withdrawn by their commercial owners, to avoid litigation) still successfully used--with varying success-- for implantable devices.
NEEDED TRANSLATIONAL KNOWLEDGE FOR PRACTICAL IMPLANTABLE DEVICES
Most published information regarding tissue-material and blood-material interactions has been obtained invasively, intermittently, and very early in the processes. Knowledge of these phenomena is fragmented rather than coherent, descriptive rather than analytical, and only relevant to the initial aspects of the interactions.
Progress in the synthesis of new polymers, copolymers, blends and composites has not led, over the past many years, to the formulation of any new FDA-approved materials designed to meet the exacting structural requirements of flexing parts in orthopedic or cardiovascular prostheses. The effects of cyclic loads and stresses on surface structure and thus on biological oucomes, remain to be investigated. With a longer time perspective, reliability testing under the cycling conditions of actual use has been slow in leading to decisions in the screening process. There is a need to validate techniques for accelerated testing of the mechanical properties of new polymers to be used in implant devices. A special effort must be made to assure that the materials' surface properties are preserved in clinically relevant states during such testing, avoiding the now-common use of ink markings and deliberate cuts that court "stress corrosion cracking", in non-physiological ways. The illustration below is of a Finite Element Analysis , computer-based method for quickly predicting and designing around excess stresses that might be encountered in structural ceramics now proposed for substitution of the failing polymeric and metallic TMJ prostheses.
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Another limiting aspect is the required comparative testing of large numbers of candidate implant materials. Since the degree of confidence which can be placed in assays described in the literature is low; few have been standardized. Simple, reproducible, quantitative assays for testing of tissue-material and blood-material interactions remain to be developed. The chemical and materials-products industries will not screen or provide candidate materials and make them available for device development, in light of the extremely negative consequences for those companies caught up in "class-action" implant-related legal proceedings.
The predictive significance of bulk and surface properties of biomaterials has not been high enough to guide materials scientists in the formulation and synthesis of new implantable compounds. Variable bulk molecular composition and structures, uncontrolled surface configurations and topographies, extractable contaminants in "medical grade" materials, and neglect of surface characteristics and local flow effects have been noted in prior years. Correction will require a broader availability of expensive analytical equipment (e.g. for various modes of spectroscopy) which is not commonly installed in academic biomedical or even materials science laboratories.
There also is a need to provide investigators with "primary reference materials" having well-characterized and reproducible properties; indeed for "families" of primary reference materials, such as segmented polyurethanes and acrylic copolymers.
As implantable devices are now expected to perform safely and effectively for progressively longer periods of use, it has become critical to better assess the degradation and corrosion of materials exposed to biological environments. In bioresorbable polymer scaffolds for tissue engineering, for instance, average chain length or molecular weight may actually increase in the first stage of degradation because of the preferential hydrolysis of smaller chains. Leaching of polymer additives or finishing agents, or conversely absorption or adsorption of chemicals present in a biological environment by an implanted polymer, also present problems for devices installed in the body for longer periods. Silicone rubber prostheses that "take up" birth control pill ingredients, and store them for years, are an unhappy example.
LONGER TERM PROSPECTS FOR IMPROVED TISSUE-MATERIAL AND BLOOD-MATERIAL INTERACTIONS
More information is needed about the time course of formation, stabilization, modification, decay and replacement of tissue-material and blood-material interfaces. The general chemical history of the material may be well known, and the fabrication, sterilization and storage history of the device may be similarly documented. Details must be gathered concerning transition from storage to implantation, the initial events at the tissue-material or blood-material interface, and the time course of interactions as new interfaces are formed, stabilized and then undergo "reconstructions" which lead to tolerance or rejection of the devices. In comparison with other systems where synthetic or engineering materials confront biological phases, such as in dental or oceanic environments, considerations of the "climax communities" of adherent cells/organisms must be addressed.
Protein adsorption studies, already widely performed, should continue with major new goals focused on "processing" of the initially deposited films by arriving and attaching cells. A frustrating problem encountered in animal studies and human implants is calcification of portions of devices which are subject to a significant degree of flexing. The mechanisms of calcification in cardiovascular devices, such as bioprosthetic heart valves, must be elucidated if progress is to be made in these implants. This problem may be resolved by design or material modifications, or by pharmacologic treatment of the subject bearing the device (or some combination). The phenomenon seems to be more pronounced in growing hosts than in adults. Clear differentiation of surface calcification (scale formation) versus tissue mineralization (as in neointima embrittlement) must be attempted.
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Prior decades of macroscopic and microscopic observations have not successfully demonstrated roles of surface geometry, texture, or local fluid dynamics in material-blood or material-tissue compatibility. Surface roughness and topography, the presence of particulate matter or trapped air bubbles, the local changes in fluid dynamics and cell-material interactions due to defects, cracks and devices, and conversely the beneficial effects of some surface coatings, all have been found to be important determinants of device acceptance and functional survival in certain circumstances. One can minimize problems by appropriate fabrication, processing and implantation techniques, but the real challenge is to document the contribution of rheology to the long-term performance of implant-medical devices.
Animal models should give way almost entirely to in vitro assays in the coming years. Various animal species, test systems, device designs, implant and contact sites, and resultant acute vs chronic responses all have been tested sufficiently to show there is no single ideal animal model for all clinical devices and implants. Increased efforts should be made to acquire and analyze the 40-year human, ongoing in vivo experience with current implants, and develop an outcome database from this retrospective information as the devices are retrieved from diverse human hosts who may bequeath these to science.
Pump-oxygenators, cardiac pacemakers, vascular grafts, dental implants, intra-ocular lenses, prosthetic valves, circulatory assist devices and artificial hearts have not seen significant development in the past twenty years, and major advances have not occurred. Small vascular prostheses for peripheral and coronary vessels still present a major challenge, and the widespread acceptance of aorta-coronary bypass surgery now demands a substitute for saphenous veins in cases where these vessels are not available, or have already been used in previous operations.
Since vascular grafts typically fail at the ends and not in the middle, materials and designs for small vascular prostheses must include systems for safe, effective anastomotic junctions between vessels and prostheses. Adhesives, bioresorbable clips and other junction systems do offer alternatives to suturing and stapling techniques. Evidence for stress-cracking and/or chemical etching of some of the current materials must be organized and assessed, and countermeasures sought.
Percutaneous coronary angioplasty, once considered established as a therapeutic modality, has an unacceptable recurrence of arterial stenosis following the intervention. Implantable angioplasty stabilizers or stents may extend the benefit of invasive procedures, but still lack appropriate materials and implantation techniques.
Development of percutaneous leads for substance or energy transmission remains a serious need, as well. Material-tissue interactions have not yet been well matched to the biological characteristics of the cell systems the materials contact. The clinical need is acute in relation to cardiovascular devices, but developing long-term stability for percutaneous leads also will benefit other fields of medicine, including nephrology, neurology and rehabilitation. Neuro-modulatory devices for pain or tremor control are especially in need of more safe and effective electrodes that do not become surrounded with a salty "moat" within a "foreign body scar" capsule, the currently most frequent outcome.
NEW FRONTIERS
Fewer than 20 -- and all of these commercial, proprietary -- polymers, metals and ceramics have been successfully incorporated in biomedical devices and implants. Experience suggests that the standard polymers should be replaced by blends, composites and laminates which more nearly achieve desired properties (e.g. water vapor permeability resistance for the flexing parts of ventricular assist devices).
Pharmacologically active biomaterials, originally as heparinized surfaces for long-term contact with blood, have been expanded to include bound antithrombins, antiplatelet aggregation agents and fibrinolytic enzymes. Implantable drug delivery systems contain drugs, and in addition to enzymes, can accommodate organelles or live cells in the future.
"Tissue engineering" requires synthetic or modified biological bioresorbable materials to be used as transient scaffolds and inducers of tissue growth or regeneration in various prosthetic replacements. Progress in cross-linking of collagen and fabrication of synthetic polyesters, well established for surgical sutures, is ready for expansion to more complex implants.
There is a long-unfulfilled need for instrumentation which allows continuous or even intermittent monitoring of the biotransformation of implants. Fiber-optic catheters remain to be developed for remote, transvascular monitoring of blood-material or tissue-material interfaces in vivo by appropriate spectroscopic techniques. Strain gauges or acoustic sensors linked to the outside by telemetry have provided some information on implanted heart valves and arterial grafts, and the piezoelectric and pyroelectric properties of some polymers have been used to monitor changes in the mechanical properties of some implanted materials. These efforts should be extended.
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