Developing a combat-relevant translatable large animal model of heterotopic ossification

Abstract

Heterotopic ossification (HO) refers to ectopic bone formation, typically in residual limbs following trauma and injury. A review of injuries from Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) indicated that approximately 70% of war wounds involved the musculoskeletal system, largely in part from the use of improvised explosive devices (IED) and rocket-propelled grenades (RPG). HO is reported to occur in approximately 63%–65% of wounded warriors from OIF and OEF. Symptomatic HO may delay rehabilitation regimens since it often requires modifications to prosthetic limb componentry and socket size. There is limited evidence indicating a mechanism for preventing HO. This may be due to inadequate models, which do not produce HO bone structure that is morphologically similar to HO samples obtained from wounded warfighters injured in theatre. We hypothesized that using a high-power blast of air (shockwave) and simulated battlefield trauma (i.e. bone damage, tourniquet, bacteria, negative pressure wound therapy) in a large animal model, HO would form and have similar morphology to ectopic bone observed in clinical samples. Initial radiographic and micro-computed tomography (CT) data demonstrated ectopic bone growth in sheep 24 weeks post-procedure. Advanced histological and backscatter electron (BSE) analyses showed that 5 out of 8 (63%) sheep produced HO with similar morphology to clinical samples. We conclude that not all ectopic bone observed by radiograph or micro-CT in animal models is HO. Advanced histological and BSE analyses may improve confirmation of HO presence and morphology, which we demonstrated can be produced in a large animal model.

Biofilm Growth on Simulated Fracture Fixation Plates Using a Customized CDC Biofilm Reactor for a Sheep Model of Biofilm-Related Infection

“…We have developed multiple reactor systems that address this limitation. For example, we developed a reactor to grow biofilms on PEEK membranes for inoculation into the proximal medial aspect of sheep tibiae [10,28], another to grow biofilms on collagen coupons for inoculation into excision wounds of a pig back model [11], and another (developing) to grow biofilms on the surface of silica beads that model sand particles that contaminate blast-related injuries [12].…”

“…Orthopedic surgeons continue to seek solutions to manage and treat these infections in both military and civilian sectors. Animal models that more closely replicate contamination events at the point of injury, or that replicate the presence of mature biofilms in an infected site are pivotal to improving the development of therapeutics that can specifically target the biofilm phenotype and accompanying infections [9][10][11][12][13].…”

“…We have shown that biofilm inocula develop low-grade, chronic infection in sheep models [10,12,28]. This work also involved a modified CDC biofilm reactor in which biofilms were grown on polyetheretherketone (PEEK) membranes [29].…”

Articular fragment restoration is critical to mitigate post-traumatic osteoarthritis in a porcine pilon fracture model

“…Post-image processing was done using Microsoft Research Image Composite Editor to mosaic/stitch the BSE images together, resulting in a high-resolution map of the entire ankle ( Fig. 4 ) [ 14 ]. The SEM images were quantitatively measured for the percentage of bone in the subchondral region directly below the damaged cartilage and in the contralateral control ankle for host bone comparison.…”

Contemporary perspectives on heterotopic ossification

“…Furthermore, injections of local irritants like ethanol or hydrochloric alcohol produce unreliable phenotypes (154). More clinically translatable models include hip arthroplasty, which has been validated in rabbits (155); rat extremity blast injury (156); simulated combat trauma by shockwave in sheep (157); and Achilles tenotomy with or without (158) concomitant burn (a reproducible, controlled polytrauma model) (159).…”