Introduction The use of biologic adjuvants (orthobiologics) is becoming commonplace in orthopaedic surgery. Amongst other applications, biologics are often added to enhance fusion rates in spinal surgery and to promote bone healing in complex fracture patterns. Generally, orthopaedic surgeons use only one biomolecular agent (ie allograft with embedded bone morphogenic protein-2) rather than several agents acting in concert. Bone fusion, however, is a highly multifactorial process and it likely could be more effectively enhanced using biologic factors in combination, acting synergistically. We used artificial neural networks to identify combinations of orthobiologic factors that potentially would be more effective than single agents.

Methods Available data on the outcomes associated with various orthopaedic biologic agents, electrical stimulation, and pulsed ultrasound were curated from the literature and assembled into a form suitable for machine learning. The best among many different types of neural networks was chosen for its ability to generalize over this dataset, and that network was used to make predictions concerning the expected efficacy of 2400 medically feasible combinations of 9 different agents and treatments.

Results The most effective combinations were high in the bone-morphogenic proteins (BMP) 2 and 7 (BMP2, 15mg; BMP7, 5mg), and in osteogenin (150ug). In some of the most effective combinations, electrical stimulation could substitute for osteogenin. Some other effective combinations also included bone marrow aspirate concentrate. BMP2 and BMP7 appear to have the strongest pairwise linkage of the factors analyzed in this study.

Conclusions Artificial neural networks are powerful forms of artificial intelligence that can be applied readily in the orthopaedic domain, but neural network predictions improve along with the amount of data available to train them. This study provides a starting point from which networks trained on future, expanded datasets can be developed. Yet even this initial model makes specific predictions concerning potentially effective combinatorial therapeutics that should be verified experimentally. Furthermore, our analysis provides an avenue for further research into the basic science of bone healing by demonstrating agents that appear to be linked in function.

CLINICAL RELEVANCE Bone healing is a highly multifactorial process, and it likely could be more effectively enhanced using combinations of factors rather than single factors in isolation. This study provides a starting point for an integration of biomedical experimentation and computational AI that ultimately could lead to highly sophisticated combinatorial treatments for bone repair and other applications in orthopaedic medicine.

The authors have declared no competing interest.

This study did not receive any funding.

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The study used ONLY human data that were openly available in the biomedical literature, as cited in the manuscript and its supplement.

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