Preface

Life expectancy has been continuously increasing and, consequently, human pathologies related to aging, such as musculoskeletal disorders, arthritis, nonhealing wounds, or neurodegenerative diseases, are becoming major health problems. Therefore, there is a need to identify novel strategies to improve the current therapeutic armory. This book presents a number of topics from polymer applications in the field of regenerative medicine, with a span from polymeric nanostructures to scaffolds. The full therapeutic potential of novel polymeric systems can only be developed through multidisciplinary collaborative research involving biologists, chemists, clinicians, and industries. This book tries to provide concepts and foundations to a general readership, as well as current applications and an overview of this exponentially growing field for experts.

Synthetic and natural polymers are compounds of great interest in many fields, especially in biomedical applications. In the past, they have been extensively used as excipients in traditional dosage forms, as materials for prostheses, valves, or contact lenses. More recently, their applications have been extended to sophisticated drug delivery systems and rationally designed scaffolds for cell therapy, so that interesting polymer structures for a variety of applications now cover the nanoscale in polymer therapeutics, the microscale in delivery systems, and the macroscale in hybrid cell-material constructs for tissue regeneration.

Polymeric materials are especially suited to interface with cells. Polymers are long-chain molecules that share basic features with biological macromolecules: both kinds of molecules deform with the inertial mechanism of conformational change and both are able to exhibit structure at a molecular level (the local sequence of different chemical monomers) and at a supramolecular and nano- to micrometer level (phase-separated domains, crystalline domains). More complex multimolecule arrangements leading to the macroscopic network structure of the extracellular matrix (ECM) represent a third level of structure, with typical dimensions ranging from tens to hundreds of microns.

The contributions in the first part of the book, "Methods for synthetic extracellular matrices and scaffolds," comprise those topics that are more directly related to the tissue engineering and regenerative applications of polymer structures, where their micro- and macrostructures have more importance. Key questions permitting a rational design (Chapter 1) and selection of materials (Chapters 2 and 6) for scaffolds with adequate interactions with the biological interphase (Chapters 3-5) are addressed, as well as specific techniques and applications where scaffolds drive the therapeutic output, and organ replacement is discussed in Chapter 11. A closer look is then given in Part B, "Nanostructures for tissue engineering," to the effect of modifications at the nanoscale, a hot topic in the design of nanomedicines for tissue repair, a field of exponential growth. Here the selection of polymers as active components of nanostructures together with the understanding of the solution conformation of natural and synthetic materials (Chapter 8) with self-assembled properties at the nanoscale (Chapter 7) is of crucial importance to better design therapies in regenerative medicine. These materials should be able to efficiently deliver to the targeted site the bioactive agents of different nature including small drugs, peptides, proteins (Chapters 8 and 10), or even oligonucleotide sequences (Chapter 9).

Chapter 1 addresses the performance of polymers as materials for tissue engineering scaffolds. These synthetic tridimensional structures provide grafted cells with a niche and with adequate mechanical and chemical stimuli and thus can promote the process of tissue regeneration. Various mechanical, physicochemical, biological, and structural requirements posed on these structures are discussed, and how to match them through bulk and surface chemistry and by means of different porogenic techniques are elaborated. Questions arising from the interplay between composition, function, and structure are discussed, and the most important parameters for a physical and biological characterization of scaffold performance are presented. The possibilities afforded by polymerization chemistry and/or subsequent processing or treatment make polymers such unique materials for tissue engineering scaffolds.

Many polymers from natural sources have found application in tissue engineering and regenerative medicine. Chapter 2 presents a comprehensive overview of them, as well as examples of their application and clinical use. Their origin varies from marine crustacean and algae, as well as mammalian, plants, and microorganism-processed products. These polymers have good biodegradability, usually low-inflammatory response, and reduced cytotoxicity, which make them so interesting. The properties and main uses of naturally derived polyesters, polysaccharides (chitosan, agarose, alginates, starch, hyaluronate, and others), protein-based polymers (silk, collagen, fibrin, and others) are discussed, and emphasis is given to the responsive nature of these polymers and to their modification in order to obtain sensitive biomaterial systems for tissue engineering. Stimuli-responsive or "smart" polymeric systems are polymers that undergo strong physical or chemical property changes responding to small changes in environmental conditions of a physical (e.g., temperature, light, mechanical stress, or electric field) or chemical (e.g., pH or ionic strength) nature.

Various aspects of the interaction between polymer surfaces and cells are covered in Chapters 3 and 4. This is a central problem in the understanding of the regeneration process assisted by synthetic materials. The recognition of an alien surface by a cell is mediated through its membrane receptors that interact with the adsorbed protein layer on the surface. A thorough discussion of the processes of protein adsorption, cell adhesion, and matrix remodeling phenomena at the cell-material interface is presented in Chapter 3. Cell adhesion is the first step of the regeneration process and plays a fundamental role in subsequent cell differentiation, growth, viability, and phenotype expression. The nature of the adsorbed layer of proteins on a polymer surface dictates the initial cellular response and, eventually, the fate of a synthetic material when it is placed in a biological environment. The chapters review the role of surface chemistry and patterning on the phenomenon of fibrillogenesis of adsorbed ECM proteins such as laminin and fibronectin, and the different experimental techniques to follow protein adsorption. The fundamentals of cell adhesion on synthetic polymers are also presented in these chapters. The role of the different adhesion structures is examined, especially of focal adhesions, fibrillar adhesions, and focal complexes. These are multidomain molecules that can interact with several distinct partner molecules, and they are decisive for the proliferative or migratory response of cells and for the generation of the forces governing the mechanosensory processes in cells. The influence of mechanical, topographical, and chemical properties of the synthetic surface on focal adhesion kinase, a signaling protein contributing to integrin control of cell motility, survival, and proliferation, is specifically addressed in Chapter 4.

The processes of cell-material interaction in vivo, though, are much more complex than any of the experimental situations that can be reproduced in vitro. Many cell types coexist in any tissue, and the cross-talk processes between them through different kinds of signals are to a large extent unknown. An attempt to come closer to more realistic scenarios involves the use of bioreactors, where cells and materials can be combined with different signaling molecules under culture conditions that can be controlled in ways that try to resemble aspects of the natural cell microenvironment: nutrient flow, mechanical stresses, concentration gradients, different gas diffusion, etc., including coculture systems. This problem is addressed in Chapter 5, the last of the first, "macro" part of our book, with emphasis given to the dynamic character of the processes that lead to the consideration of the bioreactor, the cells, and the soluble and synthetic materials as a hybrid system.

The second part of the book, "Nanostructures for tissue engineering," includes contributions addressing topics where the molecular and nanoscale dimensions of the materials play a dominant role, as is the case of therapeutics. Bioactive nanostructures molecularly crafted to signal cells or carry therapeutic agents to specific cells have great potential to regenerate tissues and cure disease. The chemistry of such nanostructures should allow them to interact specifically with cell receptors or intracellular structures.

The first example of the importance of nanostructures shows the application of self-curing formulations for hard as well as soft tissue regeneration (Chapter 6), which react chemically in the human body and allow targeting and controlled release of bioactive components. Self-curing systems based on macromolecular architectures can be applied locally and can act as antibacterial, antimicrobicide, or anti-inflammatory agents. Although very promising steps have been...