Dysfunctional stem and progenitor cells impair fracture healing with age

Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature; mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form the new vasculature that supplies blood to the fracture site. In the elderly, the healing process is slowed, partly due to decreased regenerative function of these stem and progenitor cells. MSCs from older individuals are impaired with regard to cell number, proliferative capacity, ability to migrate, and osteochondrogenic differentiation potential. The proliferation, migration and function of EPCs are also compromised with advanced age. Although the reasons for cellular dysfunction with age are complex and multidimensional, reduced expression of growth factors, accumulation of oxidative damage from reactive oxygen species, and altered signaling of the Sirtuin-1 pathway are contributing factors to aging at the cellular level of both MSCs and EPCs. Because of these geriatric-specific issues, effective treatment for fracture repair may require new therapeutic techniques to restore cellular function. Some suggested directions for potential treatments include cellular therapies, pharmacological agents, treatments targeting age-related molecular mechanisms, and physical therapeutics. Advanced age is the primary risk factor for a fracture, due to the low bone mass and inferior bone quality associated with aging; a better understanding of the dysfunctional behavior of the aging cell will provide a foundation for new treatments to decrease healing time and reduce the development of complications during the extended recovery from fracture healing in the elderly

A Comprehensive Review of Mouse Diaphyseal Femur Fracture Models

Complications related to treatment of long bone fractures still stand as a major challenge for orthopaedic surgeons. Elucidation of the mechanisms of bone healing and development, and the subsequent alteration of these mechanisms to improve outcomes, typically requires animal models as an intermediary between in vitro and human clinical studies. Murine models are some of the most commonly used in translational research, and mouse fracture models are particularly diverse, offering a wide variety of customization with distinct benefits and limitations depending on the study. This review critically examines three common femur fracture models in the mouse, namely cortical hole, 3-point fracture (Einhorn), and segmental bone defect. We lay out the general procedure for execution of each model, evaluate the practical implications and important advantages/disadvantages of each and describe recent innovations. Furthermore, we explore the applications that each model is best adapted for in the context of the current state of murine orthopaedic research

No pain, no gain? The effects of pain-promoting neuropeptides and neurotrophins on fracture healing

Neuropeptides and neurotrophins are key regulators of peripheral nociceptive nerves and contribute to the induction, sensitization, and maintenance of pain. It is now known that these peptides also regulate non-neuronal tissues, including bone. Here, we review the effects of numerous neuropeptides and neurotrophins on fracture healing. The neuropeptides calcitonin-gene related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) have varying effects on osteoclastic and osteoblastic activity. Ultimately, CGRP and SP both accelerate fracture healing, while VIP and PACAP seem to negatively impact healing. Unlike the aforementioned neuropeptides, the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have more uniform effects. Both factors upregulate osteoblastic activity, osteoclastic activity, and, in vivo, stimulate osteogenesis to promote fracture healing. Future research will need to clarify the exact mechanism by which the neuropeptides and neurotrophins influence fracture healing. Specifically, understanding the optimal expression patterns for these proteins in the fracture healing process may lead to therapies that can maximize their bone-healing capabilities and minimize their pain-promoting effects. Finally, further examination of protein-sequestering antibodies and/or small molecule agonists and antagonists may lead to new therapies that can decrease the rate of delayed union/nonunion outcomes and fracture-associated pain

Comparative analysis of authorship trends in the Journal of Hand Surgery European and American volumes: A bibliometric analysis

Background The purpose of this study was to better understand the authorship publishing trends in the field of hand surgery. To accomplish this, a comparative analysis was completed between the European and American volumes of the Journal of Hand Surgery (JHSE and JHSA) over the past three decades. Well-established bibliometric methods were used to examine one representative year from each of the past three decades. The focus of the study was to examine changes in author gender over time as well as to compare authorship trends across the two volumes. Materials and methods All JHSA and JHSE publications from 1985, 1995, 2005, and 2015 were placed into a Microsoft Excel spreadsheet. Data was collected for each publication including the gender of first and corresponding authors, corresponding author position, corresponding author country of origin, number of credited institutions, authors, printed pages, and references. Countries were grouped by regions. Results A total of 450 and 763 manuscripts from JHSE and JHSA, respectively, met inclusion criteria. JHSE and JHSA both showed increases in most variables analyzed over time. Both journals showed an increase in female first and corresponding authors. JHSE and JHSA displayed a rise in collaboration between institutions and countries. Conclusions Both JHSE and JHSA display increasing female inclusion in the hand surgery literature, which has traditionally been a male dominated field. The observed increase in collaboration between institutions and countries is likely linked to advances in technology that allow sharing of information more conveniently and reliably than was previously possible. As further advances are made socially and technologically, hopefully these trends will continue, leading to faster and higher quality research being generated in the field of hand surgery

Polytraumatized patient lower extremity nonunion development: Raw data

In this article we report data collected to evaluate the pathomechanistic effect of acute anaerobic metabolism in the polytraumatized patient and its subsequent effect on fracture nonunion; see "Base Deficit ≥6 within 24 Hours of Injury is a Risk Factor for Fracture Nonunion in the Polytraumatized Patient" (Sardesai et al., 2021) [1]. Data was collected on patients age ≥16 with an Injury Severity Score (ISS) >16 that presented between 2013-2018 who sustained a fracture of the tibia or femur distal to the femoral neck. Patients presenting to our institution greater than 24 hours post-injury and those with less than three months follow-up were excluded. Medical charts were reviewed to collect patient demographic information and known nonunion risk-factors, including smoking, alcohol use, and diabetes. In addition, detailed injury characteristics to quantify injury magnitude including ISS, Glasgow Coma Scale (GCS) at admission, and ICU length of stay were recorded. ISS values were obtained from our institutional trauma database where they are entered by individuals trained in ISS calculations. Associated fracture-related features including fracture location, soft-tissue injury (open vs. closed fracture), vascular injury, and compartment syndrome were recorded. Finally, vital signs, base deficit (BD), and blood transfusions over 24 hours from admission were recorded. We routinely measure BD and less consistently measure serum lactate in trauma patients at the time of presentation or during resuscitation. BD values are automatically produced by our laboratory with any arterial blood gas order, and we recorded BD values from the medical record. Clinical notes and radiographs were reviewed to confirm fracture union versus nonunion and assess for deep infection at the fracture site. Patients were categorized as having a deep infection if they were treated operatively for the infection prior to fracture healing or classification as a nonunion. Nonunion was defined by failure of progressive healing on sequential radiographs and/or surgical treatment for nonunion repair at least six months post-injury

Fracture Healing and Pain Tolerance in Aging Populations

Introduction: Delayed fracture healing is associated with increased morbidity and mortality, and patients with fractures suffer from injury-associated pain as well as post- operative surgical pain. Age is associated with an increased risk of fracture and delayed/impaired fracture healing. Opioids are commonly prescribed for post-orthopedic pain mitigation. Opioids, beyond eliciting cognitive impairment, are commonly associated with tolerance and addiction. This class of drugs, including buprenorphine, may also be associated with a slower resolution of pain and functional status. Objective: Here we used a mouse femoral segmental bone defect (SBD) bone repair model to examine the impact of opioids and fracture/fracture healing on pain behaviors in old and young mice. Methods: Young (3-4-month-old) and old (22-24-month-old) C57BL/6 male mice underwent a SBD surgery (8-10 mice/group). Animals were treated with either bone morphogenetic protein 2 (BMP-2) or vehicle (saline). Bone healing was examined via longitudinal x-rays and terminal micro-computed tomography (μCT). All mice were subjected to a three-day course of buprenorphine. Stimulus dependent mechanical and thermal pain thresholds as well as stimulus independent locomotion activity and exploration behavior were determined before and after SBD surgery/opioid exposure. Addition-ally, asymmetric directed pain behaviors including flinching, licking, lifting, shaking of the ipsilateral hindlimb were assayed in both treatment groups at post-injury timepoints using 20- minute-long video sessions by blinded observers. All animal procedures were approved by the Indiana University IACUC. Results: The ability of BMP-2 to enhance SBD bone union was evident by 2 weeks post-surgery (x-ray) and the return to pre-injury levels of ambulation/locomotion activity was observed by week 4. Vehicle-treated SBD mice did not meet these milestones even at 8 weeks post-surgery. The relative change in tactile allodynia was determined between baseline and 2 weeks post-surgery for young and old mice treated with saline or BMP-2. Contrary to what would be expected, all 4 groups: old, young, healed and unhealed had a reduction of their pain threshold by ~70% at 2 weeks post-surgery (p\u3e0.05). Stimulus- independent pain behavior was also evident in both vehicle and BMP-2 treated CSD animals as defined by asymmetric directed behaviors including flinching, licking, lifting, and shaking of the ipsilateral hindlimb. Conclusion: The data indicates that post-fracture pain thresholds are similar between both healed and unhealed, young and old mice. Therefore, the effect of musculoskele-tal injury and/or buprenorphine may be responsible for the pain experienced following trauma. Distinguishing between these will be critical for further understanding how to best treat acute and chronic pain associated with musculoskeletal injury, particularly for geriatric patients