Among various classes of biomaterials, the majority of non-centrosymmetric crystalline materials exhibit piezoelectric properties, i.e., the accumulation of charge in response to applied mechanical stress or deformation. Due to the growing interest in nanomaterials, piezoelectric nano-biomaterials have been widely investigated, leading to remarkable advancements throughout the last two decades. Piezoelectric properties, high surface energy, targeting properties, and intricate cell-material interactions render piezoelectric nanomaterials highly attractive for application in therapeutics as well as regenerative medicine. Herein, the major focus is to highlight the wide range of applications of piezoelectric nano-biomaterials in drug delivery, theranostics, and tissue regeneration. After a brief introduction to piezoelectricity, an overview is provided on the major classes of piezoelectric biomaterials as well as a description of the origin of biopiezoelectricity in different tissues and macromolecules. Subsequently, relevant properties and postfabrication strategies of nanostructured piezoelectric biomaterials are discussed aiming to maximize piezoresponse. Finally, recent studies on nano-piezoceramics and piezopolymers are presented, with specific focus on barium titanate, zinc oxide, and polyvinylidene fluoride.

Abstract:The mechanical and biological properties of bone implants need to be optimal to form a quick and firm connection with the surrounding environment in load bearing applications. Bone is a connective tissue composed of an organic collagenous matrix, a fine dispersion of reinforcing inorganic (calcium phosphate) nanocrystals, and bone-forming and -degrading cells. These different components have a synergistic and hierarchical structure that renders bone tissue properties unique in terms of hardness, flexibility and regenerative capacity. Metallic and polymeric materials offer mechanical strength and/or resilience that are required to simulate bone tissue in load-bearing applications in terms of maximum load, bending and fatigue strength. Nevertheless, the interaction between devices and the surrounding tissue at the implant interface is essential for success or failure of implants. In that respect, coatings can be applied to facilitate the process of bone healing and obtain a continuous transition from living tissue to the synthetic implant. Compounds that are inspired by inorganic (e.g., hydroxyapatite crystals) or organic (e.g., collagen, extracellular matrix components, enzymes) components of bone tissue, are the most obvious candidates for application as implant coating to improve the performance of bone implants. This review provides an overview of recent trends and strategies in surface engineering that are currently investigated to improve the biological performance of bone implants in terms of functionality and biological efficacy. OPEN ACCESSCoatings 2012, 2 96

Each year, millions of people suffer from complex bone fractures which require proper external or internal fixation. This fixation is usually achieved by means of devices such as plates, pins, and screws. These traditional fixation strategies are associated with severe drawbacks, which have prompted research and development of a variety of bone‐adhesive biomaterials as alternative. However, a clinically applicable bone‐adhesive biomaterial—in the form of a bone‐glue or bone‐adhesive membrane—that meets all requirements has not yet been identified. This perspective article discusses the current state of the art of bone‐adhesive materials with a particular focus on their clinical requirements, mechanisms of action, and future perspective. To develop adhesive biomaterials with specific affinity to bone tissue, a more rational design should be implemented. This perspective article is intended as a starting point and inspiration for future research and development of suitable bone‐adhesive materials.

were selected "off-the-shelf" based on the ingenuity of the surgeons. [1] During the last century, significant medical and technological progress has paved the way for the field of biomaterials research and the emergence of a biomaterials industry. Various synthetic or natural biomaterials have been developed which have enabled treatment of a wide range of medical conditions. Nevertheless, biomaterials are being considered for increasingly complex indications, which has increased the requirements for biomaterials considerably during the past decades. [2] Consequently, challenging-or even contradictorycombinations of biomaterial properties are often required which cannot be met by conventional biomaterials. For instance, biomaterials are desired which combine injectability, mechanical strength, and degradability with toughness to avoid mechanical damage following crack propagation. To meet these strict requirements, biomaterials are needed which can adapt to the implantation site and are able to heal themselves upon mechanical damage. While the majority of synthetic biomaterials does not recover from mechanical damage, natural tissues display a remarkable capacity for self-healing such as the spontaneous self-repair of bone fractures or ruptured skin. This self-healing ability is the ultimate solution of nature for continued survival based Biomaterials are being applied in increasingly complex areas such as tissue engineering, bioprinting, and regenerative medicine. For these applications, challenging-or even contradictory-combinations of biomaterial properties are often required which cannot be met by conventional biomaterials. During the past decade, several new concepts have been developed to render biomaterials self-healing, thereby offering new opportunities to improve the functionality of traditional biomaterials in terms of their mechanical, handling, and biological properties. Consequently, various types of self-healing polymeric, ceramic, or composite biomaterials have been developed. Nevertheless, despite the rapid emergence of the field of self-healing biomaterials, this field of research has not been reviewed during the recent years. Therefore, this article provides a critical overview of recent progress in the field of self-healing biomaterials research by discussing both extrinsic and intrinsic self-healing systems. While the extrinsic self-healing section focuses on self-healing dental materials and orthopedic bone cements that rely on release of healing liquids from embedded microcapsules, the section on intrinsic self-healing materials mainly discusses concepts for self-healing of polymeric biomaterials that are either hydrated (hydrogels) or nonhydrated (e.g., films and coatings). Finally, benefits of the self-healing feature for biomaterials are discussed, and directions for future research and developments are outlined.

Injectable composite colloidal gels are developed for regeneration of osteoporotic bone defects through a bottom-up assembly from bisphosphonatefunctionalized gelatin and bioactive glass particles. Upon bisphosphonate functionalization, gelatin nanoparticles show superior adhesion toward bioactive glass particles, resulting in elastic composite gels. By tuning their composition, these composite colloidal gels combine mechanical robustness with self-healing ability. The composite colloidal gels support cell proliferation and differentiation in vitro without requiring any osteogenic supplement. In vivo evaluation of the composite colloidal gels reveals their capacity to support the regeneration of osteoporotic bone defects. Furthermore, the bisphosphonate modification of gelatin induces a therapeutic effect on the peri-implantation region by enhancing the bone density of the osteoporotic bone tissue. Consequently, these composite colloidal gels offer new therapeutic opportunities for treatment of osteoporotic bone defects.

The ultimate goal of this work was to develop a biocompatible and biomimetic in situ crosslinkable hydrogel scaffold with an instructive capacity for bone regenerative treatment. To this end, synthetic hydrogels were functionalized with two key components of the extracellular matrix of native bone tissue, i.e. the three-amino acid peptide sequence RGD (which is the principal integrin-binding domain responsible for cell adhesion and survival of anchorage-dependent cells) and calcium phosphate (CaP) nanoparticles in the form of hydroxyapatite (which are similar to the inorganic phase of bone tissue). Rat bone marrow osteoblast-like cells (OBLCs) were encapsulated in four different biomaterials (plain oligo(poly(ethylene glycol) fumarate) (OPF), RGDmodifi ed OPF, OPF enriched with CaP nanoparticles and RGD-modifi ed OPF enriched with CaP nanoparticles) and cell survival, cell spreading, proliferation and mineralized matrix formation were determined via cell viability assay, histology and biochemical analysis for alkaline phosphatase activity and calcium. This study showed that RGD peptide sequences promoted cell spreading in OPF hydrogels and hence play a crucial role in cell survival during the early stage of culture, whereas CaP nanoparticles signifi cantly enhanced cell-mediated hydrogel mineralization. Although cell spreading and proliferation activity were inhibited, the combined effect of RGD peptide sequences and CaP nanoparticles within OPF hydrogel systems elicited a better biological response than that of the individual components. Specifi cally, both a sustained cell viability and mineralized matrix production mediated by encapsulated OBLCs were observed within these novel biomimetic composite systems.

Preprosthetic surgery has become a routine procedure to obtain sufficient bone quantity and quality for dental implant installation in patients with an initial inadequate bone volume. Although autologous bone onlay or inlay grafting is still the preferred bone augmentation technique, a broad range of synthetic bone substitutes have been developed, for example, calcium phosphate cement (CPC). The introduction of porosity within CPC can be used to increase CPC degradation and bone ingrowth. Therefore, three different strategies to obtain porous CPCs were evaluated in this preclinical study. Instantaneously porous CPC (CPC-IP) was compared with delayed porous CPC in vitro and in vivo. CPC-IP was obtained by the creation of CO₂ bubbles during setting, whereas delayed porous CPC was obtained after the degradation of incorporated poly(lactic-co-glycolic acid) (PLGA) microspheres. As an additional aspect, delayed porous CPC was created by the incorporation of either hollow or dense degradable PLGA microspheres (CPC-hPLGA and CPC-dPLGA). All CPC compositions showed appropriate clinical handling properties and an interconnected porous structure with a final porosity above 70% (v/v). In vitro degradation studies showed the gradual formation of pores and further CPC-matrix dissolution for CPCs containing PLGA microspheres (dPLGA microspheres > hPLGA microspheres). For in vivo evaluation of the CPCs, an augmentation model was used, allowing a CPC injection into a rigidly immobilized Teflon ring on the rat skull. Histological evaluation after 12 weeks of implantation showed bone formation using all three CPCs. Bone apposition reached volumetric amounts of up to 10% of the augmentation area and a maximum augmentation height of ∼1 mm. CPC-IP showed significantly more bone formation and resulted in a superior bone apposition height compared with both CPCs containing PLGA microspheres. No differences in biological performance were observed between the CPCs containing hPLGA and those containing dPLGA microspheres. Further research is necessary to enhance the bone appositional speed and amount of CPCs for bone augmentation procedures before them being used in a potential clinical setting.

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