The potential role of mechanotransduction in the management of pediatric calvarial bone flap repair.

Pediatric patients suffering traumatic brain injuries may require a decompressive craniectomy to accommodate brain swelling by removing a portion of the skull. Once the brain swelling subsides, the preserved calvarial bone flap is ideally replaced as an autograft during a cranioplasty to restore protection of the brain, as it can reintegrate and grow with the patient during immature skeletal development. However, pediatric patients exhibit a high prevalence of calvarial bone flap resorption post-cranioplasty, causing functional and cosmetic morbidity. This review examines possible solutions for mitigating pediatric calvarial bone flap resorption by delineating methods of stimulating mechanosensitive cell populations with mechanical forces. Mechanotransduction plays a critical role in three main cell types involved with calvarial bone repair, including mesenchymal stem cells, osteoblasts, and dural cells, through mechanisms that could be exploited to promote osteogenesis. In particular, physiologically relevant mechanical forces, including substrate deformation, external forces, and ultrasound, can be used as tools to stimulate bone repair in both in vitro and in vivo systems. Ultimately, combating pediatric calvarial flap resorption may require a combinatorial approach using both cell therapy and bioengineering strategies.

Ultrasound-derived mechanical stimulation of cell-laden collagen hydrogels for bone repair.

Cell therapy is emerging as an effective treatment strategy for many diseases. Here we describe a novel approach to bone tissue repair that combines hydrogel-based cell therapy with low intensity pulsed ultrasound (LIPUS), an FDA approved treatment for fracture repair. Bone marrow-derived stromal cells (BMSCs) have been encapsulated in type I collagen hydrogels and mechanically stimulated using LIPUS-derived acoustic radiation force (ARF). We observed the expression and upward trend of load-sensitive, osteoblast-specific markers and determined that the extent of cell response is dependent on an optimal combination of both hydrogel stiffness and ARF intensity. Specifically, cells encapsulated in hydrogels of optimal stiffness respond at the onset of ultrasound by upregulating early bone-sensitive markers such as calcium, cyclooxygenase-2, and prostaglandin E2 , and later by supporting mineralized tissue formation after 21 days of culture. In vivo evaluation of a critical size calvarial defect in NOD scid gamma (NSG) mice indicated that the implantation of BMSC-laden hydrogels of optimal stiffness improved healing of calvarial defects after daily administration of ARF over 4 weeks. Collectively, these findings validate the efficacy of our system of localized cell delivery for treating bone defects where undifferentiated BMSCs are induced to the osteoblastic lineage. Further, in vivo healing may be enhanced via non-invasive transdermal mechanical stimulation of implanted cells using ARF.

Vertical Transmission at the Pathogen-Symbiont Interface: Serratia symbiotica and Aphids.

Many insects possess beneficial bacterial symbionts that occupy specialized host cells and are maternally transmitted. As a consequence of their host-restricted lifestyle, these symbionts often possess reduced genomes and cannot be cultured outside hosts, limiting their study. The bacterial species Serratia symbiotica was originally characterized as noncultured strains that live as mutualistic symbionts of aphids and are vertically transmitted through transovarial endocytosis within the mother's body. More recently, culturable strains of S. symbiotica were discovered that retain a larger set of ancestral Serratia genes, are gut pathogens in aphid hosts, and are principally transmitted via a fecal-oral route. We find that these culturable strains, when injected into pea aphids, replicate in the hemolymph and are pathogenic. Unexpectedly, they are also capable of maternal transmission via transovarial endocytosis: using green fluorescent protein (GFP)-tagged strains, we observe that pathogenic S. symbiotica strains, but not Escherichia coli, are endocytosed into early embryos. Furthermore, pathogenic S. symbiotica strains are compartmentalized into specialized aphid cells in a fashion similar to that of mutualistic S. symbiotica strains during later stages of embryonic development. However, infected embryos do not appear to develop properly, and offspring infected by a transovarial route are not observed. Thus, cultured pathogenic strains of S. symbiotica have the latent capacity to transition to lifestyles as mutualistic symbionts of aphid hosts, but persistent vertical transmission is blocked by their pathogenicity. To transition into stably inherited symbionts, culturable S. symbiotica strains may need to adapt to regulate their titer, limit their pathogenicity, and/or provide benefits to aphids that outweigh their cost.IMPORTANCE Insects have evolved various mechanisms to reliably transmit their beneficial bacterial symbionts to the next generation. Sap-sucking insects, including aphids, transmit symbionts by endocytosis of the symbiont into cells of the early embryo within the mother's body. Experimental studies of this process are hampered by the inability to culture or genetically manipulate host-restricted, symbiotic bacteria. Serratia symbiotica is a bacterial species that includes strains ranging from obligate, heritable symbionts to gut pathogens. We demonstrate that culturable S. symbiotica strains, which are aphid gut pathogens, can be maternally transmitted. Cultured S. symbiotica therefore possesses a latent capacity for evolving a host-restricted lifestyle and can be used to understand the transition from pathogenicity to beneficial symbiosis.

Bone Flap Resorption in Pediatric Patients Following Autologous Cranioplasty.

Following a decompressive craniectomy, the autologous bone flap is generally considered the reconstructive material of choice in pediatric patients. Replacement of the original bone flap takes advantage of its natural biocompatibility and the associated low risk of rejection, as well as the potential to reintegrate with the adjacent bone and subsequently grow with the patient. However, despite these advantages and unlike adult patients, the replaced calvarial bone is more likely to undergo delayed bone resorption in pediatric patients, ultimately requiring revision surgery. In this review, we describe the materials that are currently available for pediatric cranioplasty, the advantages and disadvantages of autologous calvarial replacement, the incidence and classification of bone resorption, and the clinical risk factors for bone flap resorption that have been identified to date.

Precision, Sensitivity and Patient Preference of Non-Invasive Thermometers in a Pediatric Surgical Acute Care Setting.

PURPOSE: The purpose of the project was to compare the temporal artery thermometer (TAT) to the digital probe thermometer readings at axillary or oral sites, to determine the relative precision and sensitivity of the three methods of thermometry, to compare their readings to core temperature when feasible, and to survey patient and family thermometer preferences. DESIGN & METHODS: A randomized crossover design in a 70-bed surgical unit over eight months. Two sets of temperature measurements were obtained for each patient: TAT, axillary, oral (depending on patient ability) and a bladder temperature representing core body temperature (when available). Each method was used twice on each patient, to examine within-method precision. Following measurement, patients or caregivers provided their thermometer preference. For younger/nonverbal patients, a professional observer recorded a disruption score. N=298 patients were enrolled RESULTS: TAT was more precise than oral and axillary thermometers (p<0.001 vs. axillary, p=0.001 vs. oral). TAT measurements were higher on average than axillary and oral, by 0.7°C and 0.6°C respectively (p<0.001). TAT's disruption score for younger patients was 0.6 points lower on average than axillary (p<0.001). 84% of patients and families who indicated a clear thermometry preference chose TAT. Only 3 patients had bladder-temperature devices, and therefore accuracy could not be analyzed. CONCLUSIONS: TAT is more precise, more fever sensitive, less disruptive to younger children, and more preferred by patients and families. PRACTICE IMPLICATIONS: TAT is an acceptable temperature measure that could be substituted for oral or axillary temperature in acute care pediatric settings.