Multi-objective property optimisation of a phosphoserine-modified calcium phosphate cement for orthopaedic and dental applications using design of experiments methodology
Antzela Tzagiollari, John Redmond, Helen O. McCarthy, Tanya J. Levingstone, Nicholas J. Dunne
Acta Biomaterialia
School of Mechanical and Manufacturing Engineering

Phosphoserine is a ubiquitous molecule found in numerous proteins and, when combined with alpha-tricalcium phosphate (α-TCP) powder, demonstrates the ability to generate an adhesive biomaterial capable of stabilising and repairing bone fractures. Design of Experiments (DoE) approach was able to optimise the composition of phosphoserine-modified calcium phosphate cement (PM-CPC) demonstrating that the liquid:powder ratio (LPR) and quantity of phosphoserine (wt%) significantly influenced the handling, mechanical, and adhesion properties. Subsequently, the DoE optimisation process identified the optimal PM-CPC formulation, exhibiting a compressive strength of 29.2 ± 4.9 MPa and bond/shear strength of 3.6 ± 0.9 MPa after a 24 h setting reaction. Moreover, the optimal PM-CPC composition necessitated a mixing time of 20 s and displayed an initial setting time between 3 and 4 min, thus enabling homogenous mixing and precise delivery within a surgical environment. Notably, the PM-CPC demonstrated a bone-to-bone bond strength of 1.05 ± 0.3 MPa under wet conditions, coupled with a slow degradation rate during the first five days. These findings highlight the ability of PM-CPC to effectively support and stabilise bone fragments during the initial stages of natural bone healing. The developed PM-CPC formulations fulfil the clinical requirements for working and setting times, static mechanical, degradation properties, and injectability, enabling surgeons to stabilise complex bone fractures. This innovative bioinspired adhesive represents a significant advancement in the treatment of challenging bone injuries, offering precise delivery within a surgical environment and the potential to enhance patient outcomes.

Complex bone fractures present significant challenges in healthcare, often requiring complex surgical intervention and leading to poor clinical outcomes. The Global Burden of Diseases report in 2019 highlighted a substantial increase of approximately 70 % in new bone fracture cases since 1990, with 145 million new cases reported [1]. While the natural healing process of bone fracture is generally effective [2,3], the use of metal hardware is a common approach in the treatment of post-traumatic injuries. However, metal hardware [4] has limitations and often results in poor healing and a lack of mechanical integrity, particularly in fractures occurring in patients with osteoporosis [5]. Bone plates, screws and pins tend to loosen over time, necessitating their removal, which can lead to cortical bone loss [6,7]. Additionally, there is currently no convenient method to stabilise small bone fragments and prevent micromotion in cases involving multiple bone fragments resulting from multiple breaks.

This manuscript presents a noteworthy contribution to the field of bone fracture healing and fixation by introducing a novel phosphoserine-modified calcium phosphate cement (PM-CPC) adhesive by incorporating phosphoserine and alpha-TCP. This study demonstrates the fabrication and extensive characterisation of this adhesive biomaterial that holds great promise for stabilising and repairing complex bone fractures. Design of Experiment (DoE) software was used to investigate the correlations between process, property, and structure of the adhesive, resulting in a cost-effective formulation with desirable physical and handling properties. The PM-CPC adhesive exhibited excellent adhesion and cohesion properties in wet-field conditions. This research offers significant potential for clinical translation and contributes to the ongoing advancements in bone tissue engineering.