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The ageing population, the high expectations for better quality of life and the changing lifestyle of European society call for improved, more efficient and affordable health care.
Nanotechnology can offer impressive resolutions, when applied to medical challenges like cancer, diabetes, Parkinson's or Alzheimer's disease, cardiovascular problems, inflammatory or infectious diseases.
Experts of the highest level from industry, research centers and academia convened to prepare the present vision regarding future research priorities in NanoMedicine. A key conclusion was the recommendation to set up a European Technology Platform on NanoMedicine designed to strengthen Europe's competitive position and improve the quality of life and health care of its citizens. This article has been extracted from the vision paper “European Technology Platform on NanoMedicine - Nanotechnology for Health” produced by the European Commission.
Regenerative Medicine
Introduction
In the 1960s and 1970s, the first generation of materials was developed for use inside the human body. A common feature of most of these materials was their biological inertness. The clinical success of bioinert, bioactive and resorbable implants was an important response to the medical needs of a rapidly ageing population. The field of biomaterials subsequently began to shift in emphasis from a bioinert tissue response, to instead producing bioactive components that could elicit controlled actions and reactions within the body. By the mid-1980s, bioactive materials had reached the clinic in a variety of orthopaedic and dental applications. They included various compositions of bioactive glasses, ceramics, glass-ceramics and composites, as well as a range of bioresorbable polymers. Whereas second-generation biomaterials were designed to be either resorbable or bioactive, more advanced therapeutic approaches are now being followed to combine these two properties to develop implants, which will induce a regenerative-like healing modality. In other words, help the body to heal itself.
By leveraging novel cell culture techniques and synthesis and the design of bio-resorbable polymers, tissue engineering strategies have recently emerged as the most advanced therapeutic option presently available in regenerative medicine.
Tissue engineering encompasses the use of cells and their molecules in artificial constructs that compensate for body functions that have been lost or impaired as a result of disease or accidents. It is based upon scaffold-guided tissue regeneration and involves the seeding of porous, biodegradable scaffolds with donor cells, which become differentiated and mimic naturally occurring tissues. These tissue engineered constructs are then implanted into the patient to replace diseased or damaged tissues. With time, the scaffolds are resorbed and replaced by host tissues that include viable blood supplies and nerves.
Current clinical applications of tissue-engineered constructs include engineering of skin, cartilage and bone for autologous implantation. Recent advancement in therapeutic strategies involving tissue engineering include the use of adult stem cells as a source of regenerative cells and the use of cell-signalling molecules as a source of molecular regeneration messengers.
A complex and uneven European regulatory and funding environment has limited, to date, the extensive therapeutic use of tissue-engineered treatments in addressing different clinical needs, despite the significant advancements that have been made. The high cost, together with a limited space for significant economies of scale in the mass-production of tissue engineered products, has hindered widespread clinical application. In addition, presently available tissue engineered products still share some of the concepts of substitution medicine, where a laboratory grown ‘spare part’ is implanted in the body to compensate for lost tissue. Despite these limitations, the clinical availability of therapies based on tissue engineering represents a tremendous step forward in regenerative medicine. By building on the pioneering achievements of tissue engineering, advanced therapies in regenerative medicine can therefore address even more challenging objectives - to initiate and control the regeneration of pathological tissue and to treat, modify and prevent disabling chronic disorders such as diabetes, osteoarthritis, diseases of the cardiovascular and central nervous system. Given the dynamics of Europe’s societal growth and the need to provide advanced and cost-effective therapies to an ageing population, it is a further challenge for regenerative medicine to deliver the disease modifying benefits of tissue-engineered products to a wide patient population, in a cost-effective way.
A Biomimetic Strategy
The vision for nano-assisted regenerative medicine is the development of cost-effective disease-modifying therapies that will allow for in-situ tissue regeneration.
The implementation of this approach involves not only a deeper understanding of the basic biology of tissue regeneration – wound healing, in its widest sense – but also the development of effective strategies and tools to initiate and control the regenerative process.
In the field of biomaterials and biotechnology, the term ‘biomimetics’ has been established to describe the process of simulating what occurs in nature. The biomimetic philosophy can be condensed into three basic elements: intelligent biomaterials, bioactive signalling molecules and cells.
Intelligent Biomaterials and Smart Implants
Third-generation biomaterials that involve tailoring of resorbable polymers at the molecular level to elicit specific cellular responses show great promise as scaffolds or matrices in tissue regeneration. These ‘intelligent’ biomaterials are designed to react to changes in the immediate environment and to stimulate specific cellular responses at the molecular level. Molecular modifications of resorbable polymer systems elicit specific interactions with cells and direct cell proliferation, differentiation and extracellular matrix production and organization. For example, new generations of synthetic polymers are being developed which can change their molecular conformation in response to changes in temperature, pH, electrical stimuli or energetic status.
Access to nanotechnology has offered a completely new perspective to the material scientist to mimic the different types of extra-cellular matrices present in tissues. Techniques are now available which can produce macromolecular structures of nanometre size, with finely controlled composition and architecture.
Conventional polymer chemistry, combined with novel methodologies such as electrospinning, phase separation, direct patterning and self-assembly, have been used to manufacture a range of structures, such as nanofibres of different and well defined diameters and surface morphologies, nanofibrous and porous scaffolds, nanowires and nanoguides, nanospheres, nano ‘trees’ (e.g. dendrimers), nano-composites and other macromolecular structures.
Nanotechnology also improves non-resorbable biomaterials and effective manipulation of biological interactions at the nanometre level, which will dramatically improve the functionality and longevity of implanted materials. By applying bioactive nanoparticle coatings on the surface of implants, it will be possible to bond the implant more naturally to the adjoining tissue and significantly prolong the implant lifetime. Similarly, it may be possible to surround implanted tissue with a nanofabricated barrier that would prevent activation of the rejection mechanisms of the host, allowing a wider utilization of donated organs. Nanomaterials and/or nanocomposites with enhanced mechanical properties could replace the materials that fatigue-fail due to crack initiation and propagation during physiological loading conditions. Nanomaterials with enhanced elec trical properties that remain functional for the duration of implantation could replace the conventional materials utilised for neural prostheses, whose performance deteriorates over time. Third-generation bioactive glasses and macroporous foams can be designed to activate genes that stimulate regeneration of living tissues.
By understanding the fundamental contractile and propulsive properties of tissues, biomaterials can be fabricated that will have nanometre-scale features representing the imprinted features of specific proteins.
In conclusion, nanotechnology can assist in the development of biomimetic, intelligent biomaterials, which are designed to positively react to changes in their immediate environment and stimulate specific regenerative events at the molecular level in order to generate healthy tissues.
Bioactive Signalling Molecules
Bioactive signalling molecules are defined as those molecules which are naturally present in cells (cytokines, growth factors, receptors, second messengers) and trigger regenerative events at the cellular level. Recently available therapies based on signalling molecules involve the uncontrolled delivery of a single growth factor - which is an obvious oversimplification, in light of the complexities associated with the healing cascades of living tissues, especially in chronic pathologies. Sequential signalling is obligatory in the fabrication and repair of tissues; therefore the development of technologies for the sequential delivery of proteins, peptides and genes is critical.
The provision of the correct bioactive signalling molecules to initiate and direct the regenerative process is being pursued by designing bioactive materials and encoding biological signals able to trigger biological events. The primary goal is to develop extracellular, matrix-like materials, by either combining natural polymers or developing structures starting from synthetic molecules combined with matricellular cues. By immobilizing specific proteins, peptides and other biomolecules onto a material, it is possible to mimic the extracellular matrix (ECM) environment and provide a multifunctional cell adhesive surface. Cell-specific recognition factors can be incorporated into the resorbable polymer surface, including the adhesive proteins, fibronectin or functional domains of ECM components. Polymer surfaces can be tailored with proteins that influence interactions with endothelium, synaptic development and neurite stimulation.
To achieve any advancement it is essential to understand those molecular interactions that lead to regenerative pathways, and the development of technologies for the sequential delivery of proteins, peptides and genes to mimic the signalling cascade. The use of nanotechnologies is advocated in assisting in the development of therapies involving the activation and spatio-temporal control of in-vivo tissue regeneration.
In conclusion, nano-assisted technologies will enable the development of bioactive materials which release signalling molecules at controlled rates by diffusion or network breakdown that in turn activate the cells in contact with the stimuli. The cells then produce additional growth factors that will stimulate multiple generations of growing cells to self-assemble into the required tissues in-situ.
Cell Based Therapies
Cellular differentiation occurs in mammals as part of the embryological development and continues in adult life as part of the normal cell turnover or repair following injury. Growth, from the cellular aspect, means a continuous process of cellular turnover that is dependent on the presence of self-renewing tissue stem cells that give rise to progenitor and mature cells. Cellular turnover is known to be fast in certain tissues, such as intestinal epithelium, blood and epidermis, and slow in others, such as bone and cartilage, while it has been considered limited or nonexistent in tissues such as the brain and the heart.
However, scientific results in recent years have radically changed the view of the ability of even these tissues to regenerate after ischaemic injury. This paradigm shift will refocus research into the understanding of mechanisms for stem cell recruitment, activation, control and homing.
The major focus of ongoing and future efforts in regenerative medicine will be to effectively exploit the enormous self-repair potential that has been observed in adult stem cells. Given the logistical complexities and the costs associated with today’s tissue engineering therapies, which are based on the autologous reimplantation of culture-expanded differentiated cells, next generation therapies will need to build on the progress made with tissue engineering in understanding the huge potential for cell based therapies which involve undifferentiated cells. Nanotechnology will help in pursuing two main objectives – identifying signalling systems in order to leverage the self-healing potential of endogenous adult stem cells, and developing efficient targeting systems for adult stem cell therapies.
In conclusion, cell-based therapies should be aimed at the efficient harvesting of adult stem cells, to allow for a brief pre-implantation, cultivation stage, or, preferably, for immediate intra-operative administration using an intelligent biomaterial as a biointeractive delivery vehicle. Of huge impact would also be the ability to implant cell-free, intelligent, bioactive materials that would effectively provide signalling to leverage the self-healing potential of the patients own stem cells.
Basis For A Strategic Research Agenda
Careful consideration of the high-potential for regenerative medicine leads to the conclusion that much basic and applied research must be undertaken, not only in developmental biology and stem cell research, but also in the field of biomaterials. As numerous European groups are amongst the world leaders in biomaterials and cell therapies, there are great opportunities here for European small and medium enterprises.
This is a niche where the European Research Area can gain prestige and a corresponding share of the world market in the development, production and marketing of such ‘intelligent’ biomaterials.
These complex challenges can be addressed only by an interdisciplinary approach using international specialists, with both academic and industrial backgrounds.
This will require enlarging the number, facilities and staffing of the relevant laboratories within Europe, with an emphasis on nanotechnology expertise and capability. It will be essential to set up multidisciplinary research groups which bring together chemistry and biochemistry, molecular and cell biology, materials science and engineering, as well as ensuring an adequate balance of academic and industrial researchers.
Thanks to nanotechnology, a cellular and molecular basis has been established for the development of third-generation biomaterials that will provide the scientific foundation for the design of scaffolds for tissue engineering, and for in-situ tissue regeneration and repair, needing only minimally-invasive surgery.
It is strongly recommended that in future planning policy, attention and resources be focused on developing these biomaterials.
Projects will also need to be highly focused towards a clearly identified clinical application, not being limited to basic research on the optimisation of ‘generic’ cell/artificial matrix constructs. They must be rooted in the specific characteristics of the tissue to be regenerated, and in the economic advantage of one approach over another.
It should be feasible to design a new generation of gene-activating biomaterials tailored for specific patients and disease states. Emphasis should be given to projects designed with the objective of developing disease-modifying, cost-effective treatments for chronic disabilities that mostly affect the elderly, such as diabetes, osteoarthritis, cardiovascular and central nervous system degenerative disorders.
To this end, the following research activities will need to be promoted:
• The development of ‘intelligent’, multi-functional biomaterials
• Control of the structure of materials at the micro and nanoscale - mandatory in the design of intelligent scaffolds. This will also require research in the fields of micro- and nanofabrication for the creation of structures that differentially control cell adhesion, proliferation and function
• Technologies for the development of new generations of synthetic polymers that can change their molecular conformation in response to changes in external stimuli (temperature, pH, electric field or energetic status)
• Technologies for the development of bioactive nanocoatings
• Projects which include electronic and/or communication components in forms of nanowires and nanopores (or their equivalents) for the stimulation and biosensing of cells within an artificial matrix
• Sensor technology for the assessment of the interface activity and the progress of implant integration
• Novel technologies that enable the development of biomaterials for the sequential delivery of actives and/or chemo-attractants for the triggering of endogenous self-repair mechanisms
• Stem cell research, aimed at understanding mainly the potential and plasticity of adult stem cells
• The development of technologies for minimally invasive site-specific cell therapy
• Research aiming to generate knowledge and products centred on the nanoscale interactions between different types of cells and their immediate environment
• Monitoring tissue regeneration
• Sensors for precise gene activation and control during cell and tissue growth
• In-vitro and in-vivo toxicity testing of engineered nanoparticles
Finally, a future goal for regenerative medicine is the possibility of using bioactive stimuli to activate genes as a preventative treatment; maintaining the health of tissues as they age. Only a few years ago this concept would have seemed unimaginable. But we need to remember that only 30 years ago the concept of a material that would not be rejected by living tissues also seemed unimaginable!
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