MD+DI: Could you give us an overview of biomaterials’ current and likely future role in tissue engineering?

Hendriks: The field of tissue engineering and regenerative medicine (TERM) has emerged as the result of reaching boundaries of what can be achieved within contemporary medicine. Surgical techniques moving tissue from one position to another have produced biological changes because of the abnormal interaction of the tissue at its new location. Techniques using implantable foreign body materials are associated with adverse events such as dislodgement, infection at the implant/tissue interface, fracture and migration over time. Transplantation from one individual into another has severe constraints, related to having access to enough donor tissue and organs, but also immunological problems that can produce chronic rejection and destruction over time.

TERM involves the fabrication of new and functional living tissue - either in vitro or in vivo (incl., in situ) - using biologically active cues (e.g., cells, growth factors, polynucleotides), which are usually associated with a matrix or scaffolding to guide tissue development.As a field, TERM has been defined only since the mid-1980s. TERM draws heavily on new knowledge from several interrelated, well-established disciplines, including cell and stem cell biology, biochemistry, and molecular biology, that individually and combined feed the understanding of complex living systems. Likewise, advances in materials science, chemical engineering and bioengineering allow the rational application of engineering principles to living systems. TERM literally is at the life science-materials science interface.

Significant progress has been realized since TERM’s principles were defined and its broad medical and socioeconomic promise was recognized. However, to date only relatively few TERM products have gained regulatory approval, and even less have achieved market penetration of any significance. Technical and economic hurdles must be overcome before TERM therapies will be able to reach the millions of patients who might benefit from them.

As said before, essentially there are no purpose-designed materials for tissue engineering and regenerative medicine. The promise of regenerative medicine will only be brought about when effort is put in design and development of biomaterials that are fit for that purpose.

There are multiple biomaterial forms that can be used for TERM purposes and the choice of these forms is dependent on the indication-for-use, with prime attention to challenges during surgery or for tissue development. I typically identify four primary materials-based product-categories for TERM:

1. Biomaterials for cell delivery. Cell therapy concerns the prevention or treatment of human disease by the administration of cells that have been selected, multiplied and pharmacologically treated or altered outside the body. Poor retention and integration of transplanted cells at the site of administration is a major challenge. It is thought that therapy improvement can be brought about by the use of polymer hydrogels that allow the injection or minimally invasive insertion of a combination of cells and polymer in a minimally invasive manner or surgically facile way. To do so effectively, hydrogels must meet a number of design criteria to function appropriately and promote new tissue formation. These criteria include both physical parameters (e.g., degradation and mechanical properties) as well as biological performance parameters (e.g., biocompatibility and cell adhesion). Inappropriately meeting these design criteria could cause undesirable tissue formation. Thus key to development of such biomaterials is a firm understanding of surgical procedures proposed and manipulations prior to surgery.

2. Materials for controlled delivery of growth factors. Contrary to cell therapy, use of growth factors (proteins or hormones) focuses on harnessing the regenerative potential of the endogenous tissues. These substances are aimed at regulating a variety of cellular processes at the site of administration: recruitment, growth, proliferation and differentiation.

Their first use entailed bolus injections – effective to some extent in animal studies – however, generally not confirmed in large controlled human clinical studies. Direct delivery of growth factors has the potential to stimulate tissue healing and growth, but is often associated with an initial burst of growth factors and a short half-life in vivo. The uncontrolled diffusion of growth factors may also cause undesirable side effects. Better-controlled spatial and temporal delivery that are enabled by novel materials-based technologies are required.

3. Tissue engineering scaffold materials. The most "simple" product category in TERM involves scaffold materials, typically processed into porous structures capable of supporting three-dimensional tissue formation. TERM scaffolds usually serve at least one of the following purposes:

The materials that have received most attention for use in fabrication of TERM products are aliphatic polyesters such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(ε-caprolactone) (PCL), and polycarbonates like poly(trimethylene carbonate) (PTMC), as well as their copolymers. These materials generally have shown to support cell adhesion and growth. Nonetheless, interaction between cells and synthetic polymers is not very strong. While cell adhesion can be facilitated by adsorption of proteins on the scaffold surfaces or by inclusion of bioactive compounds, in general these polymers are rather hydrophobic, do lack surface recognition sites and except for PTMC, upon degradation they form acidic products. All in all, these factors are severely limiting their further application.

Apart from these synthetic materials, natural biomaterials such as collagen or fibrin, polysaccharides, like chitosan and hyaluronic acid, but also calcium phosphate-based ceramics and decellularized tissues have found utilization as scaffold materials in TERM. The use of decellularized matrices is likely to expand, because they retain the complex set of molecules and three-dimensional structure of authentic tissues. Yet, decellularized matrices come with concerns of potential immunogenicity, presence of infectious agents, product variability, and the inability to completely specify and characterize the bioactive components of the material.

Apart from materials chemistry it should be noted that novel materials processing techniques comprise a prominent capability necessary to successfully develop TERM scaffolds. Fabrication methods like micro-extrusion and -injection moulding, electro-spinning and photolithographic techniques provide most powerful routes to fabricate scaffolds and 3D constructs with superb dimensional resolution, with some techniques moreover providing the ability to generate scaffolds with gradient properties (e.g., porosity and composition) in a directional manner.

4. Biomimetic materials. The fourth category of biomaterials involves so-called biomimetic materials. New regenerative strategies are developed through the application of bionanotechnology. Materials designed with specific structure and function mimicking complex biological molecules provide for structural and functional infrastructure serving as matrix for (endogenous) cells, participate in biological signaling, and – optionally – to efficiently deliver proteins and drugs. Different materials have been explored pre-clinically. This technological approach holds high promise, but still is in embryonic stage-of-development, and is yet to be proven beyond early pre-clinical stage. Biomimetic materials are the quintessential third generation bio-interactive biomaterials, where biological principles have been incorporated in biomaterials design.