Clinical Assessments of Fracture Healing and Basic Science Correlates: Is There Room for Convergence?

PURPOSE OF REVIEW: The purpose of this review is to summarize the clinical and basic science methods used to assess fracture healing and propose a framework to improve the translational possibilities. RECENT FINDINGS: Mainstays of fracture healing assessment include clinical examination, various imaging modalities, and assessment of function. Pre-clinical studies have yielded insight into biomechanical progression as well as the genetic, molecular, and cellular processes of fracture healing. Efforts are emerging to identify early markers to predict impaired healing and possibly early intervention to alter these processes. Despite of the differences in clinical and preclinical research, opportunities exist to unify and improve the translational efforts between these arenas to develop and optimize our ability to assess and predict fracture healing, thereby improving the clinical care of these patients.

Fractures in geriatric mice show decreased callus expansion and bone volume.

BACKGROUND: Poor fracture healing in geriatric populations is a significant source of morbidity, mortality, and cost to individuals and society; however, a fundamental biologic understanding of age-dependent healing remains elusive. The development of an aged-based fracture model system would allow for a mechanistic understanding that could guide future biologic treatments. QUESTIONS/PURPOSES: Using a small animal model of long-bone fracture healing based on chronologic age, we asked how aging affected (1) the amount, density, and proportion of bone formed during healing; (2) the amount of cartilage produced and the progression to bone during healing; (3) the callus structure and timing of the fracture healing; and (4) the behavior of progenitor cells relative to the observed deficiencies of geriatric fracture healing. METHODS: Transverse, traumatic tibial diaphyseal fractures were created in 5-month-old (n=104; young adult) and 25-month-old (n=107; which we defined as geriatric, and are approximately equivalent to 70-85 year-old humans) C57BL/6 mice. Fracture calluses were harvested at seven times from 0 to 40 days postfracture for micro-CT analysis (total volume, bone volume, bone volume fraction, connectivity density, structure model index, trabecular number, trabecular thickness, trabecular spacing, total mineral content, bone mineral content, tissue mineral density, bone mineral density, degree of anisotropy, and polar moment of inertia), histomorphometry (total callus area, cartilage area, percent of cartilage, hypertrophic cartilage area, percent of hypertrophic cartilage area, bone and osteoid area, percent of bone and osteoid area), and gene expression quantification (fold change). RESULTS: The geriatric mice produced a less robust healing response characterized by a pronounced decrease in callus amount (mean total volume at 20 days postfracture, 30.08±11.53 mm3 versus 43.19±18.39 mm3; p=0.009), density (mean bone mineral density at 20 days postfracture, 171.14±64.20 mg hydroxyapatite [HA]/cm3 versus 210.79±37.60 mg HA/cm3; p=0.016), and less total cartilage (mean cartilage area at 10 days postfracture, 101,279±46,755 square pixels versus 302,167±137,806 square pixels; p=0.013) and bone content (mean bone volume at 20 days postfracture, 11.68±3.18 mm3 versus 22.34±10.59 mm3; p<0.001) compared with the young adult mice. However, the amount of cartilage and bone relative to the total callus size was similar between the adult and geriatric mice (mean bone volume fraction at 25 days postfracture, 0.48±0.10 versus 0.50±0.13; p=0.793), and the relative expression of chondrogenic (mean fold change in SOX9 at 10 days postfracture, 135+25 versus 90±52; p=0.221) and osteogenic genes (mean fold change in osterix at 20 days postfracture, 22.2±5.3 versus 18.7±5.2; p=0.324) was similar. Analysis of mesenchymal cell proliferation in the geriatric mice relative to adult mice showed a decrease in proliferation (mean percent of undifferentiated mesenchymal cells staining proliferating cell nuclear antigen [PCNA] positive at 10 days postfracture, 25%±6.8% versus 42%±14.5%; p=0.047). CONCLUSIONS: Our findings suggest that the molecular program of fracture healing is intact in geriatric mice, as it is in geriatric humans, but callus expansion is reduced in magnitude. CLINICAL RELEVANCE: Our study showed altered healing capacity in a relevant animal model of geriatric fracture healing. The understanding that callus expansion and bone volume are decreased with aging can help guide the development of targeted therapeutics for these difficult to heal fractures.

Needle Arthroscopy as a Reduction Aid for Lower Extremity Peri-Articular Fractures: Case Series and Technical Tricks.

Background: Intra-articular fractures represent a challenging group of injuries that can occur in many different locations. In addition to restoring the mechanical alignment and stability of the extremity, accurate reduction of the articular surface is a primary goal for the treatment of peri-articular fractures. A variety of methods have been deployed to assist in the visualization and subsequent reduction of the articular surface, each with a unique set of pros and cons. The ability to visualize the articular reduction must be balanced against the soft tissue trauma required for extensile exposures. Arthroscopic assisted reduction has gained popularity for the treatment of a variety of articular injuries. Recently, needle based arthroscopy has been developed, predominantly as an outpatient tool for the diagnosis of intra-articular pathology. We present an initial experience with and technical tricks for the use of a needle based arthroscopic camera in the treatment of lower extremity peri-articular fractures. Methods: A retrospective review of all cases where needle arthroscopy was used as a reduction adjunct in lower extremity peri-articular fractures at a single, academic, level one trauma center was performed. Results: Five patients with six injuries were treated with open reduction internal fixation with adjunctive needle based arthroscopy. Early experience and tips and tricks for successful utilization of this technique are presented. Conclusion: Needle based arthroscopy may represent a valuable adjunct in the treatment of peri-articular fractures and warrants further investigation. Level of Evidence: IV.

Outcomes of Various Antibiotic Cement-Coated Intramedullary Implants on the Treatment of Long Bone Septic Nonunion.

OBJECTIVE: To determine the effectiveness of various types of antibiotic-coated intramedullary implants in the treatment of septic long bone nonunion. DESIGN: Retrospective chart review. SETTING: Level 1 trauma center. PARTICIPANTS: Forty-one patients with septic long bone nonunion treated with an antibiotic cement-coated intramedullary implant. INTERVENTION: Surgical debridement and placement of a type of antibiotic-coated intramedullary implant. MAIN OUTCOME MEASUREMENTS: Union and need for reoperation. RESULTS: At an average 27-month follow-up (6-104), 27 patients (66%) had a modified radiographic union score of the tibia of 11.5 or greater, 12 patients (29%) a score lower than 11.5, and 2 patients (5%) underwent subsequent amputation. Six patients underwent no further surgical procedures after the index operation. Patients treated with a rigid, locked antibiotic nail achieved earlier weight-bearing (P = 0.001), less frequently required autograft (P = 0.005), and underwent fewer subsequent procedures (average 0.38 vs. 3.60, P = 0.004) than those treated with flexible core antibiotic rods. CONCLUSIONS: Antibiotic-coated intramedullary implants are successful in the treatment of septic nonunions in long bones. In our cohort, rigid, statically locked nails allowed faster rehabilitation, decreased the need for autograft, and decreased the number of additional surgical procedures. Further study is needed to confirm these findings. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Bone healing in an aged murine fracture model is characterized by sustained callus inflammation and decreased cell proliferation.

Geriatric fractures take longer to heal and heal with more complications than those of younger patients; however, the mechanistic basis for this difference in healing is not well understood. To improve this understanding, we investigated cell and molecular differences in fracture healing between 5-month-old (young adult) and 25-month-old (geriatric) mice healing utilizing high-throughput analysis of gene expression. Mice underwent bilateral tibial fractures and fracture calluses were harvested at 5, 10, and 20 days post-fracture (DPF) for analysis. Global gene expression analysis was performed using Affymetrix MoGene 1.0 ST microarrays. After normalization, data were compared using ANOVA and evaluated using Principal Component Analysis (PCA), CTen, heatmap, and Incromaps analysis. PCA and cross-sectional heatmap analysis demonstrated that DPF followed by age had pronounced effects on changes in gene expression. Both un-fractured and 20 DPF aged mice showed increased expression of immune-associated genes (CXCL8, CCL8, and CCL5) and at 10 DPF, aged mice showed increased expression of matrix-associated genes, (Matn1, Ucma, Scube1, Col9a1, and Col9a3). Cten analysis suggested an enrichment of CD8+ cells and macrophages in old mice relative to young adult mice and, conversely, a greater prevalence of mast cells in young adult mice relative to old. Finally, consistent with the PCA data, the classic bone healing pathways of BMP, Indian Hedgehog, Notch and Wnt clustered according to the time post-fracture first and age second. CLINICAL SIGNIFICANCE: Greater understanding of age-dependent molecular changes with healing will help form a mechanistic basis for therapies to improve patient outcomes. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:149-158, 2018.