nanomaterials Article Nanoscale Strontium-Substituted Hydroxyapatite Pastes and Gels for Bone Tissue Regeneration Caroline J. Harrison 1 , Paul V. Hatton 1, * , Piergiorgio Gentile 2 and Cheryl A. Miller 1   Citation: Harrison,C.J.; Hatton, P.V.; Gentile, P.; Miller, C.A. Nanoscale Strontium-Substituted Hydroxyapatite Pastes and Gels for Bone Tissue Regeneration. Nanomaterials 2021, 11, 1611. https://doi.org/10.3390/ nano11061611 Academic Editors: Nicholas Dunne, Helen McCarthy and Tanya Levingstone Received: 25 May 2021 Accepted: 14 June 2021 Published: 19 June 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 School of Clinical Dentistry, The University of Sheffield, 19 Claremont Crescent, Sheffield S10 2TA, UK; c.j.harrison@sheffield.ac.uk (C.J.H.); c.a.miller@sheffield.ac.uk (C.A.M.) 2 School of Engineering, Stephenson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, UK; piergiorgio.gentile@newcastle.ac.uk * Correspondence: paul.hatton@sheffield.ac.uk; Tel.: +44-114-215-9336 Abstract: Injectable nanoscale hydroxyapatite (nHA) systems are highly promising biomaterials to address clinical needs in bone tissue regeneration, due to their excellent biocompatibility, bioinspired nature, and ability to be delivered in a minimally invasive manner. Bulk strontium-substituted hydroxyapatite (SrHA) is reported to encourage bone tissue growth by stimulating bone deposition and reducing bone resorption, but there are no detailed reports describing the preparation of a systematic substitution up to 100% at the nanoscale. The aim of this work was therefore to fabricate systematic series (0–100 atomic% Sr) of SrHA pastes and gels using two different rapid-mixing methodological approaches, wet precipitation and sol-gel. The full range of nanoscale SrHA materials were successfully prepared using both methods, with a measured substitution very close to the calculated amounts. As anticipated, the SrHA samples showed increased radiopacity, a beneficial property to aid in vivo or clinical monitoring of the material in situ over time. For indirect methods, the greatest cell viabilities were observed for the 100% substituted SrHA paste and gel, while direct viability results were most likely influenced by material disaggregation in the tissue culture media. It was concluded that nanoscale SrHAs were superior biomaterials for applications in bone surgery, due to increased radiopacity and improved biocompatibility. Keywords: nanoscale calcium phosphate; strontium; injectable biomaterial; bone graft substitute 1. Introduction Annually, millions of patients worldwide require grafts or alloplastic biomaterials to repair bone defects caused by trauma, cancer surgery, or congenital deformities. When bone healing is compromised, there can be a great detrimental impact on a patient’s quality of life as well as increased treatment costs. The current gold standard material is an autologous bone graft typically taken from the iliac crest of the patient. However, harvesting of the bone has significant disadvantages in terms of donor-site morbidity, pain suffered by the patient, and graft availability. Bone allograft is therefore commonly employed, but this has associated risks, including viral or prion transmission and a less predictable host response due to processing [1]. Therefore, there is a great interest in improved synthetic biomaterials for effective and consistent bone tissue regeneration. The ideal bone augmentation material should be osteoconductive to aid the regrowth of bone tissue, and be available in a suitable form to allow for the surgeon to easily implant it into the defect site. Synthetic calcium phosphates, such as hydroxyapatite (HA), have been widely used in medicine and dentistry. Nanoscale hydroxyapatite (nHA) can be considered bioinspired due to its similarity to the mineral found naturally in bone and tooth enamel [2,3]. Calcium phosphates have typically been used in the form of powders, granules, or as coatings on the surface of implants. However, the development of nHA has allowed alternative forms of bone graft substitute to be investigated. One promising technology that has been developed is a paste based upon the combination of nHA with water. Clinical and animal Nanomaterials 2021, 11, 1611. https://doi.org/10.3390/nano11061611 https://www.mdpi.com/journal/nanomaterials