Journal of Functional Biomaterials Review Bioactive Glasses: From Parent 45S5 Composition to Scaffold-Assisted Tissue-Healing Therapies Elisa Fiume, Jacopo Barberi, Enrica Verné * and Francesco Baino * ID Institute of Materials Physics and Engineering, Department of Applied Science and Technology, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Torino, Italy; elisa.fi[email protected] (E.F.); [email protected] (J.B.) * Correspondence: [email protected] (E.V.); [email protected] (F.B.); Tel.: +39-011-090-4717 (E.V.); +39-011-090-4668 (F.B.) Received: 19 February 2018; Accepted: 13 March 2018; Published: 16 March 2018 Abstract: Nowadays, bioactive glasses (BGs) are mainly used to improve and support the healing process of osseous defects deriving from traumatic events, tumor removal, congenital pathologies, implant revisions, or infections. In the past, several approaches have been proposed in the replacement of extensive bone defects, each one with its own advantages and drawbacks. As a result, the need for synthetic bone grafts is still a remarkable clinical challenge since more than 1 million bone-graft surgical operations are annually performed worldwide. Moreover, recent studies show the effectiveness of BGs in the regeneration of soft tissues, too. Often, surgical criteria do not match the engineering ones and, thus, a compromise is required for getting closer to an ideal outcome in terms of good regeneration, mechanical support, and biocompatibility in contact with living tissues. The aim of the present review is providing a general overview of BGs, with particular reference to their use in clinics over the last decades and the latest synthesis/processing methods. Recent advances in the use of BGs in tissue engineering are outlined, where the use of porous scaffolds is gaining growing importance thanks to the new possibilities given by technological progress extended to both manufacturing processes and functionalization techniques. Keywords: Bioglass; scaffold; tissue engineering; glass-ceramic; silicate glass; borate glass; phosphate glass; mesoporous bioactive glass; sol–gel; drug release 1. Introduction The need for replacing damaged parts of the body in order to restore their physiological functionality has always been the driving force which has supported research into the discovery and the design of new materials able to perform this task as efficiently as possible. After a preliminary definition of biomaterial in the 1950s, mainly based on the criterion of maximum biochemical and biological inertness in contact with body fluids (first-generation materials) [1], the discovery of Bioglass® by Larry L. Hench in 1969 [2] constituted—for the first time in the story of biomaterials—an alternative, extending the concept of biocompatibility to all those materials which were able to promote a positive response of the living system through the formation of a strong tissue–implant bond (second-generation materials) and the genetic activation of specific cell pathways (third-generation smart materials) [3]. Actually, Bioglass® represents the first example of a biomaterial belonging to the third generation, because of the biological role played by its ionic dissolution products, directly released in the physiological environment [4], as well as its capability to strongly bond the host tissue (primarily bone) with the formation of an interfacial calcium phosphate layer [5,6]. Over the last 50 years, numerous studies have been conducted [7,8] to optimize the response of the body to BGs and extend their use to a wider range of specific clinical applications. J. Funct. Biomater. 2018, 9, 24; doi:10.3390/jfb9010024 www.mdpi.com/journal/jfb J. Funct. Biomater. 2018, 9, x FOR PEER REVIEW 2 of 33 J. Funct. Biomater. 2018, 9, 24 2 of 33 Most of this research aimed to define in an exhaustive and satisfactory manner the peculiar featuresMost of ofthe this material research and, aimed in particular, to define its in ability an exhaustive to create and a strong satisfactory bond at manner the interface the peculiar with physiologicalfeatures of the tissues material as well and, as into particular,stimulate tissue its ability healing to createand regeneration. a strong bond at the interface with physiologicalBGs offer tissuesthe possibility as well as of to adjusting stimulate their tissue composition healing and in regeneration. a very flexible manner, conferring specificBGs properties offer the to possibility the material, of adjustingwhich consequent their compositionly becomes in able a very to satisfy flexible requirements manner, conferring both in hardspecific and properties soft-tissue tohealing the material, applications which [9]. consequently becomes able to satisfy requirements both in hardThe and most soft-tissue common healing medical applications products [based9]. on Bioglass® which are available in clinical practice deal withThe mostthe regeneration common medical of calcified products tissues based (e.g on., bone, Bioglass enamel)® which in orthopedics are available and in dentistry clinical practice [10]. dealIn with addition, the regeneration technological of calcified advances tissues in biomaterials (e.g., bone, enamel)production inorthopedics processes made and dentistryit possible, [10 ].in recentIn years, addition, to fabricate technological mechanically advances better-performing in biomaterials 3D production structures processes(scaffolds) made[11,12], it opening possible, upin new recent possibilities years, toin fabricatethe replacement mechanically of bone better-performingtissue also in load-bearing 3D structures sites [13,14]. (scaffolds) [11,12], openingRecent up studies new possibilities have also in highlighted the replacement the ofenormo boneus tissue potential also in load-bearingof BGs in soft sites tissue [13,14 repair]. applicationsRecent [15,16]. studies Promising have also results highlighted were obtained the enormous with regard potential to the ofvascularization BGs in soft tissueprocess repair [17] andapplications nerve regeneration [15,16]. Promising [18], as well results as in were the obtainedformation with of neo-cartilage regard to the [19]. vascularization process [17] andAll nerve these regeneration aspects make [18 ],BGs as wellvery asattractive in the formation in the development of neo-cartilage of TE [ 19and]. regenerative medicine approaches,All these where aspects the makeavailability BGs very of attractivefunctional in arti theficial development in vitro-vascularized of TE and regenerative tissue substitutes medicine is particularlyapproaches, important where the in availability order to guarantee of functional the necessary artificial in nutrients vitro-vascularized and oxygen tissue supply substitutes from the is earliestparticularly days after important the device in order implantation to guarantee [20]. the necessary nutrients and oxygen supply from the earliestGiven days the after extension the device of implantation the topic proposed [20]. in the present review, we have analyzed comprehensivelyGiven the the extension most significant of the topic literature proposed available in in the thepresent field. A Search review, was we conducted have analyzed in the databasecomprehensively SCOPUS theby using most the significant following literature terms as available major keywords: in the field. bioglass, A Search bioactive was conducted glass, scaffold, in the tissuedatabase engineering, SCOPUS bysol–gel, using themesoporous following bioactive terms as majorglass, keywords:composite. bioglass, The present bioactive work glass, provides scaffold, a widetissue overview engineering, on BGs sol–gel, and BG-based mesoporous scaffolds bioactive for TE glass,, thus representing composite. Thea valid present source work of information provides a forwide researchers overview interested on BGs and in BG-based a complete scaffolds and organi for TE,zed thus presentation representing from a valid the sourceearlier ofstages information to the latestfor researchers developments. interested in a complete and organized presentation from the earlier stages to the latest developments. 2. BGs: A Historical Overview 2. BGs: A Historical Overview The discovery of BGs in 1969 is attributed to Larry L. Hench, a Graduate Research Professor in the DepartmentThe discovery of Material of BGs inScience 1969 isand attributed Engineering to Larry at the L. University Hench, a Graduate of Florida Research [21]. Professor in the DepartmentIn order to obtain of Material a material Science able and to Engineeringsurvive exposure at the to University the human of body Florida with [21 ].no formation of a scarIn tissue order around to obtain the aimplanted material abledevice, to survive from 19 exposure69 to 1971, to three the human different body glass with compositions no formation were of a tested,scar tissue on the around basis of the the implanted Na2O–CaO–SiO device,2 fromternary 1969 state to 1971,diagram three shown different in Figure glass compositions1 [2]. were tested, on the basis of the Na2O–CaO–SiO2 ternary state diagram shown in Figure1[2]. FigureFigure 1. 1. CompositionalCompositional diagram diagram for for bone-b bone-bonding.onding. Note Note regions regions A, A, B, B, C, C, D. D. Region Region S Sis is a aregion region of of classclass A A bioactivity bioactivity where where bioactive bioactive glasses glasses (BGs) (BGs) bond bond to to bone bone and and soft soft tissues tissues and and are are gene gene activating. activating. ReproducedReproduced with with permission