A Novel Class of Injectable Bioceramics That Glue Tissues and Biomaterials

Abstract

Calcium phosphate cements (CPCs) are clinically effective void fillers that are capable of bridging calcified tissue defects and facilitating regeneration. However, CPCs are completely synthetic/inorganic, unlike the calcium phosphate that is found in calcified tissues, and they lack an architectural organization, controlled assembly mechanisms, and have moderate biomechanical strength, which limits their clinical effectiveness. Herein, we describe a new class of bioinspired CPCs that can glue tissues together and bond tissues to metallic and polymeric biomaterials. Surprisingly, alpha tricalcium phosphate cements that are modified with simple phosphorylated amino acid monomers of phosphoserine (PM-CPCs) bond tissues up to 40-fold stronger (2.5–4 MPa) than commercial cyanoacrylates (0.1 MPa), and 100-fold stronger than surgical fibrin glue (0.04 MPa), when cured in wet-field conditions. In addition to adhesion, phosphoserine creates other novel properties in bioceramics, including a nanoscale organic/inorganic composite microstructure, and templating of nanoscale amorphous calcium phosphate nucleation. PM-CPCs are made of the biocompatible precursors calcium, phosphate, and amino acid, and these represent the first amorphous nano-ceramic composites that are stable in liquids.

A biomechanical test model for evaluating osseous and osteochondral tissue adhesives

“…Tisseel fibrin adhesive was produced by Baxter (Baxter Medical AB, Kista, Sweden). OsStic was created by mixing commercially available phosphoserine (Flamma, S.p.A. Italy) and alpha tricalcium phosphate powders (Robert Mathys Stiftung foundation, > 97% pure), at a 3:7 M ratio, with a liquid to powder ratio of 0.2 ml per gram (ml g − 1 ) and deionized water as the liquid [17]. Murine femurs were isolated from sacrificed Sprague Dawley rats, wrapped in gauze, soaked in phosphate buffer saline (PBS) and stored at -20°C.…”

“…A number of adhesives have been proposed for fracture repair, including acrylate-based glue [12], collagen or fibrin glues [13], click chemistry-based glues [14], and, more recently, adhesive ceramics [15][16][17]. While naturally derived adhesives, such as fibrin glue (Tisseel), are cyto-and biocompatible and may retain biologic elements that enhance healing, their bond strengths KiloPascal (KPa) are relatively poor compared to the properties of cancellous and cortical bone [11,18].…”

“…The preclinical efficacy of calcified tissue adhesives has been evaluated using mechanical test models that include: shear force, on cubed bone tissue (i.e. cubes cut from fresh bone, and tested in shear by gluing the cube surfaces together before applying a shear force [12,17,26]; tensile loading [8,10]; or push-out, which is a commonly used test for adhesive bonding in dental applications [27]. In these studies the mechanical testing regimen did not reflect physiological loading, which is complex and may include bending, compression, shear and torsion [28,29].…”

Factors That Determine the Adhesive Strength in a Bioinspired Bone Tissue Adhesive

“…Coacervation and nanoscale electrostatic interactions are also sufficient to create relatively strong tissue adhesion [4][5][6][7]. Recently, strong adhesion has been created in biomaterials that are not adhesive (bioceramics) by incorporating a modified amino acid (phosphoserine) [8][9][10]. Phosphoserine-modified cements (PMCs) display a unique microstructure, appearing amorphous rather than crystalline [10], can stabilize bioactive phases and remodel into precursors of hydroxyapatite [11], and display significantly improved healing, compared to unmodified cements [12][13][14][15].…”

“…Recently, strong adhesion has been created in biomaterials that are not adhesive (bioceramics) by incorporating a modified amino acid (phosphoserine) [8][9][10]. Phosphoserine-modified cements (PMCs) display a unique microstructure, appearing amorphous rather than crystalline [10], can stabilize bioactive phases and remodel into precursors of hydroxyapatite [11], and display significantly improved healing, compared to unmodified cements [12][13][14][15]. PMCs are particularly suited for hard tissue applications, with a stronger compressive and (adhesive) shear strength than human On the molecular level, the bond strength of an adhesive reflects a compromise between: (a) the adhesive strength, where adhesive failure occurs via load dissipation between the adhesive and adherend surfaces (e.g., deformation of bonds between poly-methyl methacrylate (PMMA) and a metal or tissue surface (physical interlocking and van der Waals' interactions)) [34,35]; and (b) the cohesive strength of the polymeric matrix (e.g., crosslinking density), or between the matrix/binder and other phases (e.g., in asphalt) [36].…”