How smart do biomaterials need to be? A translational science and clinical point of view

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Abstract

Over the last 4 decades innovations in biomaterials and medical technology have had a sustainable impact on the development of biopolymers, titanium/stainless steel and ceramics utilized in medical devices and implants. This progress was primarily driven by issues of biocompatibility and demands for enhanced mechanical performance of permanent and non-permanent implants as well as medical devices and artificial organs. In the 21st century, the biomaterials community aims to develop advanced medical devices and implants, to establish techniques to meet these requirements, and to facilitate the treatment of older as well as younger patient cohorts. The major advances in the last 10 years from a cellular and molecular knowledge point of view provided the scientific foundation for the development of third-generation biomaterials. With the introduction of new concepts in molecular biology in the 2000s and specifically advances in genomics and proteomics, a differentiated understanding of biocompatibility slowly evolved. These cell biological discoveries significantly affected the way of biomaterials design and use. At the same time both clinical demands and patient expectations continued to grow. Therefore, the development of cutting-edge treatment strategies that alleviate or at least delay the need of implants could open up new vistas. This represents the main challenge for the biomaterials community in the 21st century. As a result, the present decade has seen the emergence of the fourth generation of biomaterials, the so-called smart or biomimetic materials. A key challenge in designing smart biomaterials is to capture the degree of complexity needed to mimic the extracellular matrix (ECM) of natural tissue. We are still a long way from recreating the molecular architecture of the ECM one to one and the dynamic mechanisms by which information is revealed in the ECM proteins in response to challenges within the host environment. This special issue on smart biomaterials lists a large number of excellent review articles which core is to present and discuss the basic sciences on the topic of smart biomaterials. On the other hand, the purpose of our review is to assess state of the art and future perspectives of the so called “smart biomaterials” from a translational science and specifically clinical point of view. Our aim is to filter out and discuss which biomedical advances and innovations help us to achieve the objective to translate smart biomaterials from bench to bedside. The authors predict that analyzing the field of smart biomaterials from a clinical point of view, looking back 50 years from now, it will show that this is our heritage in the 21st century.

Introduction

The development of biomaterials to improve human life, whether it would be for the replacement of dysfunctional or arthritic hips, atherosclerotic arteries and decaying teeth or for the repair of injured tissues such as cartilage and skin is ubiquitous. As a population ages, there is a growing need to replace and repair soft and hard tissues such as bones, cartilage, blood vessels or even entire organs. The biomaterials industry is currently worth ca. $28 billion with an annual growth rate of 15% expected for the next few years and the market is expected to be worth $58.1 billion (www.marketsandmarkets.com) by 2014. It is worth noting that while metals, polymers and ceramics are currently the major players on the biomaterials market, significant changes are envisioned by 2014 with tissue engineering constructs anticipated to become major contenders. Currently, orthopedic implants make up the bulk of all devices implanted (approximately 1.5 million per annum worldwide) at a cost of around $10 billion. However, it is estimated that the expenditure on biomaterials and devices for the treatment of cardiac disease will double this amount due to the increasing number of patients suffering cardiac arrests requiring treatment.

Biomaterials undoubtedly improve the quality of life for an ever-increasing number of people each year. The range of applications is vast and includes joint and limb replacements, artificial arteries and skin, contact lenses, and dentures. The implementation of these materials may be for medical reasons replacing diseased tissues and extending life expectancy or may be motivated by purely esthetic reasons (e.g. breast implants). An increasing demand for biomaterials arises from an aging population with higher expectations regarding their quality of life.

Over the past decades we have witnessed the development of various implants and medical devices to replace irreversibly damaged tissue. Over time the definition of the essential nature of a biomaterial has changed fundamentally, a process which is still ongoing [1], [2] (Fig. 1).

Materials used for biomedical applications can roughly be grouped into three main types described by the evoked tissue response. In broad terms, inert (more strictly, nearly inert as every biomaterial and even the patient's own tissue provoke an initial immune response) biomaterials elicit no or minimal tissue response, whereas bioactive materials encourage bonding to the host tissue and enhance the material's integration by stimulating new tissue growth. Biodegradable or bioresorbable materials are initially incorporated into the surrounding tissue to completely dissolve time-dependently. Classical metal implants such as cobalt–chromium alloys are typically classified as inert, ceramics may be inert, active or resorbable and polymers may be inert or resorbable.

During the 1960s and 1970s a first generation of biomaterials was developed for routine use as medical implants and devices. The biomedical industry evolved and up to now the quality of life of millions of patients could be improved. There are a lot of examples of medical devices that have greatly improved patient care such as artificial joints, dental implants, ocular lenses or vascular stents. But a lot of these successes were accidental rather than by design and many materials were originally designed for other applications [3]. The implants often consisted of materials used for commodity products not necessarily addressing aspects related to biocompatibility. Initially, the development of implants with improved performance relied on a trial and error basis as only little was known about materials sciences and biological interactions. The goal of early biomaterials research was to accomplish an appropriate combination of chemical and physical properties to match those of the replaced tissue with a minimal foreign body response in the host [4]. Therefore, within metallic systems plain carbon and vanadium implants, which demonstrated overt corrosion, were replaced by increasingly superior stainless steels, then by strongly passivated cobalt–chromium alloys. In respect to polymers, nylons and polyesters were substituted by materials less likely to degrade such as polytetrafluorethylene (PTFE), polymethylmetacrylate (PMMA), polyethylene and silicones. In the 1980s there were more than a hundred implants and devices in clinical use made from about 30 different materials [4]. A common feature of most of the biomaterials used these days was their limited biological activity also known as “inertness”. The underlying principle of these biomaterials was to reduce the immune response to a minimum, not to cause foreign body reactions and to prevent biological rejection [4], [5]. For a lot of implants, this paradigm is still valid today.

Based on a better understanding of the foreign body response, in the 1980s and 1990s, the field of biomaterials began to shift in emphasis away from using mainly inert materials towards the development of bioactive components in order to elicit a specific biological response at the interface of the material [6], [7]. By the mid 1990s bioactive materials had reached clinical use in a variety of orthopedic, dental and cardiovascular applications including various compositions of metals (titanium alloys, etc.) and bioceramics. Henceforth, it can be argued that the field of biomaterials has developed side by side with novel strategies in surgery allowing for the creation and expansion of more effective and less invasive treatment options. Subsequently, implants with porous coatings and structures facilitating tissue ingrowth were designed to achieve a stable three-dimensional interlocking with the surrounding tissue. Consequently, the concept of bioactive implant fixation was born and the development of sophisticated multifunctional interfaces again resulted in increased implant lifetimes [7], [8], [9]. However, a counter force to the above described technological advancements was the increasing level of regulation and the threat of litigation. A large number of these materials still represent the state of the art of commercial products used clinically, e.g. in orthopedics and dentistry [10]. However, for permanent implants, resistance to abrasion or wear, durability, fatigue strength, stability and permeability to small molecules can be critical. Peri-implantitis due to bacterial infection, systemic or local reactions due to toxic or immunological processes or mechanical implant failure, inter alia, still represent challenging problems. As a consequence, materials with tunable degradation rates and resorption properties became more and more important offering the possibility to overcome the disadvantages of solid permanent implants [4].

The major advances in the last 10 years from a cellular and molecular knowledge point of view provided the scientific foundation for the development of third-generation biomaterials. With the introduction of new concepts in molecular biology in the 2000s and advances in proteomics, a differentiated understanding of biocompatibility slowly evolved [11]. These discoveries significantly affected the way of biomaterial synthesis, design and use. At the same time both clinical demands and patient expectations continued to grow. Therefore, the development of cutting-edge treatment strategies that alleviate or at least delay the need of implants could open up new vistas. This represents the main challenge for the biomaterials community in the 21st century [12]. As a result, the present decade has seen the emergence of the fourth generation of biomaterials, the so-called smart or biomimetic biomaterials. This work is based on the hypothesis that it is conceivable to construct biomimetic matrices to mimic nature's hierarchical structural assemblages and mechanisms of simplicity and elegance that are conserved throughout genera and species. There is a direct spatial and temporal relationship of morphologic and molecular events that emphasize the biomimicry of the remodeling cycles from the cell to tissue to organ. Another key challenge when designing smart biomaterials is to capture the degree of complexity needed to mimic the extracellular matrix (ECM) of natural tissue. We are still a long way from recreating the molecular architecture of the ECM one to one and the dynamic mechanism by which information is revealed in response to challenges within the host environment. However, we have made significant progress especially in the design and fabrication of scaffolds in the area of tissue engineering and regenerative medicine.

The purpose of this article is to assess state of the art and future perspectives of the so called “smart biomaterials” from a translational science and specifically clinical point of view, hence viewed through the eyes of a clinician scientist. The following review is intended as a guiding overview of the topic and focuses on the disciplines of musculoskeletal, dental and plastic surgery as it is beyond the scope of this article to cover all surgical disciplines; in addition these fields represent – based on our literature search – the main areas of application of smart biomaterials.

Section snippets

Need for smart biomaterials

To satisfy the need for long-term repair and good clinical outcome, a paradigm shift is needed from methods to replace tissues with permanent implants to more biological approaches that focus on repair and reconstitution of tissue structure and function [12]. Despite considerable advantages in the understanding of physical and chemical material properties, only few so-called smart biomaterials have found their way into clinical application so far. Nevertheless, according to the EU-Report on

Classical biomaterials

The following section describes conventional biomaterials currently used in clinical practice and how their limitations have led to new technological developments in order to improve their in vivo performance. A lot of these basic principles have likewise influenced the development of smart biomaterials in tissue engineering applications.

Smart biomaterials for tissue engineering applications

The application of the principles of biology and engineering to the development of functional substitutes for damaged tissue has seen laboratories worldwide forging impressive multidisciplinary teams to focus on restoring, maintaining or improving the function of a wide range of human tissues. While progress has been made to deliver bench to bedside solutions, the rate at which tissue engineering has seen innovations translated to the clinic has been slower than originally expected and the

Articular cartilage

Nearly twenty years ago, Brittberg and colleagues pioneered in applying culture expanded autologous chondrocytes under a periosteal flap to treat focal cartilage lesions of the knee establishing the first generation of autologous chondrocyte implantation (ACI) [219]. However, first generation ACI revealed several disadvantages, such as transplant hypertrophy, delamination and graft failure [220], [221]. Within the past two decades we have witnessed tremendous experimental and clinical research

Mesenchymal stem cells, materials and regeneration

Multipotent mesenchymal stem cells (MSC) are the principal source driving the regeneration of mesenchymal tissues. Multipotent MSC populations can be obtained from various sites such as bone marrow (as a gold standard), bone trabeculae, adipose tissue, and ligaments and show great promise for regenerative strategies [20], [286], [287]. Supportive MSC populations with less pronounced multipotent characteristics can be distinguished as shown for pancreatic islet associated populations [288]. This

Smart biomaterial technologies from a health care point of view

To understand the differences between the present health care environment for biomedical innovations and the trend in the 21st century to move towards new treatment concepts based on the fact of value-consciousness, one has to keep in mind three effects of every innovation: a) the effect on the quality of treatment relative to the quality of established treatment options (e.g. increase in implant survival, reduction of morbidity and mortality, pain relief, etc.); b) the effect on the costs of

Conclusion

More than fifty years of research and development of new biomaterials did result in extending the lifetime of a large number of the currently used medical devices, implants and prostheses. However, from a helicopter view, modern medicine overall did result in the extension of patients' lifetime which in a matter of fact increased faster than the lifetime extension of the numerous medical devices, implants and prostheses. Thus, in the 21st century an alternative approach to the replacement of

Acknowledgments

This work is supported, in part, by the “Deutsche Forschungsgemeinschaft” (DFG RA1820/2-1, LR and UN), the “Interdisziplinäres Zentrum für Klinische Forschung” (IZKF Z-3/8, LR; IZKF D-137, UN and LR), the 7th Framework Programme (FP-7) of the European Community (ADIPOA and VascuBone, LR and UN) and the Australian Research Council (Future Fellowship Programme).

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    This review is part of the Advanced Drug Delivery Reviews theme issue on “Bionics — biologically inspired smart materials”.

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