Feature Article

By: C.J. Kirkpatrick, REPAIR-Lab, Institute of Pathology, Johannes Gutenberg University, Mainz, Germany

The formation of crosslinks is an important chemical strategy for consolidating a macromolecular structure, and in my view this is an apt metaphor to describe the development of the multidisciplinary approach that has characterised the past 20 years in the medical device industry. Multidisciplinarity is one of the driving forces in executing the fundamental change expressed in the title of this article. The following short essay assesses the ongoing “revolution” that has taken place in the field of biomaterials and their application to medicine. It should of course be clearly stated that the developments described here are merely a glimpse of what has been achieved. Moreover, there is the expectation that a good percentage of what is still in the basic research and preclinical stages of development will establish itself in a sustainable fashion in the medical device marketplace.

 

Advances in stem cell biology mean that practically all adult tissues are suitable for regeneration, at least from a theoretical point of view. This knowledge has brought with it the ability to isolate and characterise a number of stem cell types such as mesenchymal stem cells (MSCs), which could be incorporated in a suitable tissue engineering construct for clinical application. MSCs hold great promise because of their ability to adopt various differentiation lineages, for example, osteoblastic or chondrogenic, which are relevant especially to the orthopaedic field.¹ For translational strategies, they also have the additional advantage of possessing immunomodulatory functionality.

 

It is interesting to observe how the life sciences have influenced the engineering and exact sciences (physics and chemistry) employed in the biomaterials field. Twenty years ago, cells in vitro tended to be used mostly in simple cytotoxicity assays. This is still an essential component of screening strategies and the guidelines are well formulated in ISO 10993 Biological Evaluation of Medical Devices. However, today, complex co-culture systems using primary human cells are being studied in a variety of scenarios, including in three-dimensional culture systems on biomaterial scaffolds or within hydrogels.² Where once simple binary end-points such as “cytotoxic/non-toxic” or “viable/non-viable” were used, modern assay models yield detailed information about cellular functionality, which is studied with the powerful toolbox of cell and molecular biology.³ It is evident that this technology is required to give a differentiated picture of cellular activity on biomaterials for tissue engineering applications. A further significant development during the past twenty years is the incorporation of engineering principles into cell assays. Advances in bioreactor systems mean that cells can now be subjected to biomechanical forces in a controlled environment in which important parameters can be measured on-line in a continuous fashion.⁴

 

Parallel to these major advances in the life sciences, the materials sciences have been undergoing their own evolutionary process, especially in the field of biodegradable polymers, natural or synthetic, which now have the ability to respond to small changes in physical, chemical or even biological microenvironments.⁵ Increasingly, molecular self-assembly processes are being employed to incorporate bioactive signal moieties into polymeric systems that not only have a structural component, but also a suitable biochemical stimulus to drive the regenerative process.⁶ These so-called responsive or interactive materials are being developed to be injectable and thus available for a minimally invasive application in clinical medicine. Cell encapsulation is also a strong focus of this research activity.⁷

 

In addition, progress in nanotechnology is influencing biomaterial development that involves not only engineered nanoparticles for drug or gene delivery, but also nanostructuring of all classes of biomaterials, whether metallic, ceramic or polymer.⁸ A considerable body of literature now exists on how surface modification can modulate biological responses. Creating a suitable nanostructure also fits well with the biomimetic approach to biomaterials, in which simulation of the extra cellular matrix is the central focus. This can take various forms, from incorporating nanofibres into a scaffold or matrix structure to modification of surface topography with subsequent alteration of protein adsorption, cell adhesion and other cellular functions, including proliferation and differentiation.

 

Biodegradability has become a focus of attention in the materials sciences, because a mass of data is available to highlight the negative aspects of host reaction to permanent implants. Despite the fact that considerable progress has been made in directing how biomaterials can degrade, there remain marked discrepancies between the controlled (mostly hydrolytic) environment in the materials science laboratory and the still poorly understood complex microenvironment in living tissues. In the latter, there are additional breakdown mechanisms, including production of oxygen radicals and other classes of molecules that can accelerate biomaterial degradation as well as inhibit it. It can be postulated that the balance of these mechanisms will be different from one implant location to another. Thus, a soft tissue site can be expected to show a different reaction from bone tissue. Because the underlying biological reactions are still largely unknown, a rational approach to tailoring the degradation properties of a biomaterial for a specific application remains an unachieved goal.

 

Despite all the exciting and innovative discoveries in the polymer sciences, there is still no competitive alternative for metals in load-bearing applications. Work is currently in progress to develop new composite materials with biodegradable components that could match their compressive strength over a sufficient time span to permit de novo bone formation.⁹

 

Parallel to the clear change of emphasis from replacement strategies to those aimed at healing mechanisms in the damaged or defective organ, there have been prolonged discussions about safety, ethical and regulatory issues governing human tissue-based products.¹⁰ These are prime concerns of the biomaterials industry of course, but they have also become relevant topics within academic institutions, especially those with larger consortia of partners, for example, in a research centre for regenerative medicine. This development is welcome and it has become apparent that the funding agencies, even for more basic aspects of research, are requiring project leaders to present viable concepts that are relevant for later clinical translation. The increasing awareness of the importance of translational issues, from intellectual property (IP) rights to good manufacturing practices (GMPs) and sterilisation concepts at all levels of biomaterial and medical device research, is also leading to a dialogue with the regulatory bodies, beginning at an early stage of implant development. This process has been greatly promoted over the years by periodicals such as Medical Device Technology (MDT), now European Medical Device Technology (EMDT), which have been instrumental in addressing issues of interest and importance to both industry and academia. Twenty years ago it was the exception to find life scientists who had an interest in, and knowledge of, IP, GMP and all the other acronyms that are an integral part of our modern vocabulary. Today this is taken as the norm, and in this transformation of attitude, MDT and EMDT have played a key role. I feel sure that this positive influence on, and support of, the various stakeholders will continue to flourish in the years to come. 

 

 

C. James Kirkpatrick, MD PhD DSc FRCPath FBSE, is Chairman of Pathology and Director of the REPAIR-Lab, Institute of Pathology, University Medical Centre, Johannes Gutenberg University, Langenbeckstrasse 1, D-55101 Mainz, Germany
tel. +49 6131 177 301
e-mail: kirkpatrick@repair-lab.org