In vivo safety assessment of a bio-inspired bone adhesive

Abstract

A new class of materials, bone adhesives, could revolutionise the treatment of highly fragmented fractures. We present the first biological safety investigation of a bio-inspired bone adhesive. The formulation was based upon a modified calcium phosphate cement that included the amino acid phosphoserine. This material has recently been described as substantially stronger than other bioresorbable calcium phosphate cements. Four adhesive groups with the active substance (phosphoserine) and two control groups without phosphoserine were selected for in vitro and in vivo biocompatibility testing. The test groups were subject for cell viability assay and subcutaneous implantation in rats that was followed by gene expression analysis and histology assessment after 6 and 12 weeks. All adhesive groups supported the same rate of cell proliferation compared to the α-TCP control and had viability between 45-64% when compared to cell control. There was no evidence of an increased immune response or ectopic bone formation in vivo. To conclude, this bio-inspired bone adhesive has been proven to be safe, in the present study, without any harmful effects on the surrounding soft tissue.

Gluing Living Bone Using a Biomimetic Bioadhesive: From Initial Cut to Final Healing

“…The former are frequently based on chemically engineered materials that have some attractive features and are tolerated by living cells ( Granskog et al, 2018 ). The latter aim to use a more “bioinspired” adhesive strategy ( Bré et al, 2013 ), and several of these have demonstrated promising preclinical evidence ( Kirillova et al, 2018 ; Hulsart-Billström et al, 2020 ; Kirillova et al, 2020 ). However, further translation of adhesive candidates to clinical use is far beyond the resources of research teams, while medical device companies, who have adequate resources, view a bone adhesive as a high-risk investment as there is no bone glue predicate in clinical use.…”

“…To evaluate the biological safety of PSer αTCP adhesive formulations, a standard subcutaneous murine model was used to evaluate these at 6 and 12 weeks ( Hulsart-Billström et al, 2020 ). The adhesive formulations evaluated proved to be safe both on histological and gene expressional levels, with no changes in the regulation of immune and bone marker genes.…”

Adhesives for treatment of bone fractures: A review of the state-of-the art

“…Bone cements were mostly phosphate [13,14,25], polyalkenoate [28,29] or acrylate-based cement [12,15,16,[30][31][32][33], either alone or with the addition of fillers, to improve their properties. Types of glues used were fibrin glue [17][18][19][20], consisted of human fibrinogen, bovine thrombin and calcium chloride, and dental adhesives of different consistencies [15,21,22,33], but also bioinspired glues [23,24,26].…”

“…Common filers were phosphoserine [13,24,25], in an attempt to manufacture a bioinspired glue, calcium [13,15,20,25,30,32] and magnesium [14], as natural elements providing stability and biocompatibility, glass [21,28,29], to provide increased compressive strength, and growth factors, such as platelet rich plasma, to improve bone regeneration [11,19,26,27].…”

“…(a) Treatment of highly fragmented fractures [13,16] (b) Fixation of long bone fractures [14,15,21,22,25,[30][31][32] (c) Filling bone voids and defects [15,19,20,[27][28][29]32] (d) Promoting bone regeneration [11,12,27] (e) Preventing non-union [30] (f) Maintaining reduction of fracture fixation [17,18,26]…”