The field of orthobiologics has reached its third decade and remains focused on the development of amalgamated products that combine cells, growth factors, and scaffolds into tissue engineering solutions for the treatment of musculoskeletal injury and disease. The significance of orthobiologics continues to be evident in the great demand for treatment strategies that can ameliorate illnesses that range from birth defects to degenerative changes caused by injuries and aging, for which standards of care remain unproven and offer limited benefit. Although there have been several advances in the field, transformative orthobiologic solutions for the most challenging musculoskeletal problems remain elusive because of the lack of understanding of disease pathogenesis, the absence of predictive models and translational outcome measures, the limitations of tissue engineering approaches, and the demands for regulatory approval and cost-effectiveness in the era of health. It has also been argued that the broad use of unproven orthobiologic products in clinical practice has set the field back. Thus, various subfields of orthobiologics have emerged to facilitate focus on problems specific to a particular musculoskeletal tissue or disease, which often involves novel tools of discovery.

Research studies on stem/progenitor cell therapies have been transformed by single-cell mRNA sequencing, spatial transcriptomics, and in vivo lineage tracing technologies that allow for rigorous characterization of the starting material and assessment of in vivo functional potential. The chapters in this section highlight these advances in the authors’ understanding of how stem/progenitor cells participate in autologous and paracrine roles to mediate musculoskeletal tissue development, repair, and regeneration and how their absence and dysfunction from chronic inflammation and aging lead to a lack of healing and fibrosis. Additionally, with these technologies, there may finally be a way to derive a dose for stem/progenitor cell therapy, which is critical for rigor, reproducibility, regulatory approval, and addressing the demands of evidence-based medicine.

In addition to studies with new proteins, research on growth factors for orthobiologics has markedly expanded in recent years based on the clinical success of novel delivery methods. As described in the chapters in this section, these new approaches include the same recombinant viral vectors and mRNA lipid nanoparticles used as vaccines for coronavirus disease 2019 (COVID-19). Another approach to provide signals for biologic tissue repair and regeneration that is becoming more common is the use of endosomes generated from mesenchymal stem cells (MSCs). There is also a new appreciation that tissue growth and differentiation can be stimulated by the inhibition of endogenous inhibitors (eg, sclerostin, noggin, dickkopf) with antibodies, receptor antagonists, and small interfering RNA.

Because nanotechnologies have matured, advances in orthobiologic biomaterials have extended well beyond toxicity, biocompatibility, and durability. Current research now focuses on hypotaxis, durotaxis, osteoinduction, and biointegration of various composite biomaterials. There have also been breakthroughs in personalized three-dimensional printing of metals and cells. The chapters in this section describe these current technologies as well as scaffold coatings to well-established biomaterials, to engender them with antimicrobial properties and improve biointegration.

Because in vivo proof of concept is a critical step toward clinical translation of orthobiologics, there have been major advances in animal models for specific orthopaedic indications. Indeed, the importance of this work is evidenced by the establishment of subresearch groups
within international societies (eg, the Preclinical Models Section of the Orthopaedic Research Society) and evolving requirements to comply with new regulations on the ethical use of animals for research. As such, each chapter of this text articulates the state-of-the-art in vivo model for a particular orthobiologic, and their intended purpose from initial proof of concept in small animal models (mice, rats), through Investigational New Drug/Investigational Device Exemption enabling large animal studies (dogs, sheep, horses).