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A Unique Mouse Model for Quantitative Assessment of Biofilm Formation on Surgical Implants in Subcutaneous Abscess

To develop a novel biomaterial with antibacterial properties for orthopedic surgical procedures, establishing an experimental animal model of ...

University of California, San Francisco (UCSF)

Spinal cord injury (SCI) is a multifaceted phenomenon associated with alterations in both motor function and sensory function. A majority of patients with SCI report sensory disturbances, including not only loss of sensation, but in many cases enhanced abnormal sensation, dysesthesia and pain. Development of therapeutics to treat these abnormal sensory changes require common measurement tools that can enable cross-species translation from animal models to human patients. We review the current literature on translational nociception/pain measurement in SCI and discuss areas for further development. Although a number of tools exist for measuring both segmental and affective sensory changes, we conclude that there is a pressing need for better, integrative measurement of nociception/pain outcomes across species to enhance precise therapeutic innovation for sensory dysfunction in SCI.

Assessments of sensory plasticity after spinal cord injury across species.

Polytraumatic injuries, specifically long bone fracture and traumatic brain injury (TBI), frequently occur together. Clinical observation has long held that TBI can accelerate fracture healing, yet the complexity and heterogeneity of these injuries has produced conflicting data with limited information on underlying mechanisms. We developed a murine polytrauma model with TBI and fracture to evaluate healing in a controlled system. Fractures were created both contralateral and ipsilateral to the TBI to test whether differential responses of humoral and/or neuronal systems drove altered healing patterns. Our results show increased bone formation after TBI when injuries occur contralateral to each other, rather than ipsilateral, suggesting a role of the nervous system based on the crossed neuroanatomy of motor and sensory systems. Analysis of the humoral system shows that blood cell counts and inflammatory markers are differentially modulated by polytrauma. A data-driven multivariate analysis integrating all outcome measures showed a distinct pathological state of polytrauma and co-variations between fracture, TBI and systemic markers. Taken together, our results suggest that a contralateral bone fracture and TBI alter the local neuroinflammatory state to accelerate early fracture healing. We believe applying a similar data-driven approach to clinical polytrauma may help to better understand the complicated pathophysiological mechanisms of healing.

Differential fracture response to traumatic brain injury suggests dominance of neuroinflammatory response in polytrauma.

Postoperative cognitive decline (PCD) requires microglial activation. Voltage-gated Kv1.3 potassium channels are involved in microglial activation. We determined the role of Kv1.3 in PCD and the efficacy and safety of inhibiting Kv1.3 with phenoxyalkoxypsoralen-1 (PAP-1) in preventing PCD in a mouse model.

Blocking Kv1.3 potassium channels prevents postoperative neuroinflammation and cognitive decline without impairing wound healing in mice.

Spinal cord injuries (SCIs) frequently occur in combination with other major organ injuries, such as traumatic brain injury (TBI) and injuries to the chest, abdomen, and musculoskeletal system (e.g., extremity, pelvic, and spine fractures). However, the effects of appendicular fractures on SCI recovery are poorly understood. We investigated whether the presence of SCI-concurrent appendicular fractures is predictive of a less robust SCI recovery. Patients enrolled in the Transforming Research and Clinical Knowledge in SCI (TRACK-SCI) prospective cohort study were identified and included in this secondary analysis study. Inclusion criteria resulted in 147 patients, consisting of 120 with isolated SCIs and 27 with concomitant appendicular fracture. The primary outcome was American Spinal Injury Association (ASIA) Impairment Scale (AIS) neurological grades at hospital discharge. Secondary outcomes included hospital length of stay, intensive care unit (ICU) length of stay, and AIS grade improvement during hospitalization. Multivariable binomial logistical regression analyses assessed whether SCI-concomitant appendicular fractures associate with SCI function and secondary outcomes. These analyses were adjusted for age, gender, injury severity, and non-fracture polytrauma. Appendicular fractures were associated with more severe AIS grades at hospital discharge, though covariate adjustments diminished statistical significance of this effect. Notably, non-fracture injuries to the chest and abdomen were influential covariates. Secondary analyses suggested that appendicular fractures also increased hospital length of stay. Our study indicated that SCI-associated polytrauma is important for predicting SCI functional outcomes. Further statistical evaluation is required to disentangle the effects of appendicular fractures, non-fracture solid organ injury, and SCI physiology to improve health outcomes among SCI patients.

Appendicular Fracture and Polytrauma Correlate with Outcome of Spinal Cord Injury: A Transforming Research and Clinical Knowledge in Spinal Cord Injury Study.

Clinical and preclinical data suggest accelerated bone fracture healing in subjects with an additional traumatic brain injury (TBI). Mechanistically, altered metabolism and neuro-endocrine regulations have been shown to influence bone formation after combined fracture and TBI, thereby increasing the bone content in the fracture callus. However, the early inflammatory response towards fracture and TBI has not been investigated in detail so far. This is of great importance, since the early inflammatory phase of fracture healing is known to be essential for the initiation of downstream regenerative processes for adequate fracture repair.

Altered early immune response after fracture and traumatic brain injury.

Western blot is a popular biomolecular analysis method for measuring the relative quantities of independent proteins in complex biological samples. However, variability in quantitative western blot data analysis poses a challenge in designing reproducible experiments. The lack of rigorous quantitative approaches in current western blot statistical methodology may result in irreproducible inferences. Here we describe best practices for the design and analysis of western blot experiments, with examples and demonstrations of how different analytical approaches can lead to widely varying outcomes. To facilitate best practices, we have developed the blotRig tool for designing and analyzing western blot experiments to improve their rigor and reproducibility. The blotRig application includes functions for counterbalancing experimental design by lane position, batch management across gels, and analytics with covariates and random effects.

Improving rigor and reproducibility in western blot experiments with the blotRig analysis.

Use-dependent plasticity after spinal cord injury (SCI) enhances neuromotor function, however, the optimal timing to initiate rehabilitation remains controversial. To test impacts of early disuse, we established a rodent model of transient hindlimb suspension in acute phase SCI. Early disuse in the first 2-week after SCI undermined recovery on open-field locomotion, kinematics, and swim tests even after 6-week of normal gravity reloading. Early disuse produced chronic spinal circuit hyper-excitability in H-reflex and interlimb reflex tests. Quantitative synaptoneurosome analysis of lumboventral spinal cords revealed shifts in AMPA receptor (AMPAR) subunit GluA1 localization and serine 881 phosphorylation, reflecting enduring synaptic memories of early disuse stored in the spinal cord. Automated confocal analysis of motoneurons revealed persistent shifts toward GluA2-lacking, calcium-permeable AMPARs in disuse subjects. Unsupervised machine learning associated multidimensional synaptic changes with persistent recovery deficits in SCI. The results argue for early aggressive rehabilitation to prevent disuse plasticity that limits SCI recovery.

Disuse plasticity limits spinal cord injury recovery.

Pain is one of the primary indicators of a bone fracture and serves both a functional and practical role in guiding recovery. However, fracture pain can persist long after the fracture itself has clinically healed. The neural and molecular mechanisms that drive acute pain postfracture, and how these mechanisms are pathologically usurped to trap patients into persistent, debilitating, and often difficult to treat, chronic pain, are not well understood. The aim of this review is to provide insight into the risk factors for pain persistence after fracture, review the physiological and pathophysiological mechanisms of fracture pain, and critically evaluate the literature around fracture pain assessment techniques/models. Taken together, the concepts covered herein will provide a strong foundation to support the development of more effective treatments to better alleviate postfracture pain.

Article	Year
Assessments of sensory plasticity after spinal cord injury across species. Neuroscience letters\| PubMed ID: 28007646	2017
Differential fracture response to traumatic brain injury suggests dominance of neuroinflammatory response in polytrauma. Scientific reports\| PubMed ID: 31434912	2019
Blocking Kv1.3 potassium channels prevents postoperative neuroinflammation and cognitive decline without impairing wound healing in mice. British journal of anaesthesia\| PubMed ID: 32624183	2020
Appendicular Fracture and Polytrauma Correlate with Outcome of Spinal Cord Injury: A Transforming Research and Clinical Knowledge in Spinal Cord Injury Study. Journal of neurotrauma\| PubMed ID: 35255740	2022
Altered early immune response after fracture and traumatic brain injury. Frontiers in immunology\| PubMed ID: 36761764	2023
Improving rigor and reproducibility in western blot experiments with the blotRig analysis. Scientific reports\| PubMed ID: 39284854	2024
Disuse plasticity limits spinal cord injury recovery. iScience\| PubMed ID: 40224010	2025
A bad break: mechanisms and assessment of acute and chronic pain after bone fracture. Pain\| PubMed ID: 40408239	2025

Kazuhito Morioka

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