Pre-Clinical Evaluation of Biological Bone Substitute Materials for Application in Highly Loaded Skeletal Sites

Abstract

The development of bone substitute materials (BSMs) intended for load-bearing bone defects is highly complicated, as biological and mechanical requirements are often contradictory. In recent years, biological BSMs have been developed which allow for a more efficient integration of the material with the surrounding osseous environment and, hence, a higher mechanical stability of the treated defect. However, while these materials are promising, they are still far from ideal. Consequently, extensive preclinical experimentation is still required. The current review provides a comprehensive overview of biomechanical considerations relevant for the design of biological BSMs. Further, the preclinical evaluation of biological BSMs intended for application in highly loaded skeletal sites is discussed. The selected animal models and implantation site should mimic the pathophysiology and biomechanical loading patterns of human bone as closely as possible. In general, sheep are among the most frequently selected animal models for the evaluation of biomaterials intended for highly loaded skeletal sites. Regarding the anatomical sites, segmental bone defects created in the limbs and spinal column are suggested as the most suitable. Furthermore, the outcome measurements used to assess biological BSMs for regeneration of defects in heavily loaded bone should be relevant and straightforward. The quantitative evaluation of bone defect healing through ex vivo biomechanical tests is a valuable addition to conventional in vivo tests, as it determines the functional efficacy of BSM-induced bone healing. Finally, we conclude that further standardization of preclinical studies is essential for reliable evaluation of biological BSMs in highly loaded skeletal sites.

Influence of bisphosphonate treatment on bone substitute performance in osteoporotic conditions

“…The choice for a suitable bone defect model should rely on approximation of the aimed clinical application to maximize predictive value of the outcome; however, a true extrapolation of in vivo animal experimental data to clinical settings is merely impossible. [57][58][59][60] In view of these considerations, we have opted for a standardized bone defect model in the femoral condyle of rats owing to possibilities to compare systemic bone disease conditions, standardized qualitative/quantitative evaluation options, and ethical aspects. Given the dissimilarities with clinical settings, it remains evident that our results should be considered with caution regarding clinical translation.…”

“…Overall, one needs to realize that experimental animal bone defect models provide a simplistic representation of clinical conditions to evaluate specific aspects of bone regeneration, but apparent differences in bone physiology, “freshness” of bone defects, temporal differences in evaluation periods and drug administration, and bone architecture. The choice for a suitable bone defect model should rely on approximation of the aimed clinical application to maximize predictive value of the outcome; however, a true extrapolation of in vivo animal experimental data to clinical settings is merely impossible 57–60 . In view of these considerations, we have opted for a standardized bone defect model in the femoral condyle of rats owing to possibilities to compare systemic bone disease conditions, standardized qualitative/quantitative evaluation options, and ethical aspects.…”

A review of bioceramics scaffolds for bone defects in different types of animal models: HA and β -TCP

“…In the last decades, the use of small ruminant (sheep and goats) models have been acknowledged as animal models in orthopedic research [112,113], as tabulated in table 10. Sheep and goats have been used as a model to repair long bones (femur and tibia), fracture restoration devices, bone filler constituents in cranial bones, tissue response to wear byproducts, extraoral surgical, and intervertebral disk substitutes The long bones found in sheep limbs(tibia) are considered ideal as they are comparable in shape and size to the human tibia and are easily accessible for surgery [114], as shown in figure 4. According to the International Standard Organization (ISO) 10993 for Biocompatibility Evaluation of Medical Devices, there is 6 implants material that can be implanted in the long bones of each sheep for up to 12 samples [48].…”

“…Small ruminant bones are similar to human bones in terms of weight, size of bone, bone composition, bone healing, and remodeling [106,114]. However, there is a difference between human and sheep bones, for example, sheep's cortical bone remains principally plexiform until the age of 7 to 9 years [51,110].…”

A Preclinical Trial Protocol Using an Ovine Model to Assess Scaffold Implant Biomaterials for Repair of Critical-Sized Mandibular Defects

“…These defects can either be segmental or partial. 15 In clinical practice, a partial defect is called a marginal mandibulectomy, where a full thickness defect of the mandible is called a segmental mandibulectomy (Figure 1). A segmental defect results in loss of continuity of the host bone and therefore affects the native occlusion, which is not the case for a partial defect.…”