A Tunable Calcium Phosphate Coating to Drive in vivo Osseointegration of Composite Engineered Tissues.

Varying degrees of hydroxyapatite (HA) surface functionalization have been implicated as the primary driver of differential osteogenesis observed in infiltrating cells. The ability to reliably create spatially controlled areas of mineralization in composite engineered tissues is of growing interest in the field, and the use of HA-functionalized biomaterials may provide a robust solution to this challenge. In this study, we successfully fabricated polycaprolactone salt-leached scaffolds with two levels of a biomimetic calcium phosphate coating to examine their effects on MSC osteogenesis. Longer duration coating in simulated body fluid (SBF) led to increased HA crystal nucleation within scaffold interiors as well as more robust HA crystal formation on scaffold surfaces. Ultimately, the increased surface stiffness of scaffolds coated in SBF for 7 days in comparison to scaffolds coated in SBF for 1 day led to more robust osteogenesis of MSCs in vitro without the assistance of osteogenic signaling molecules. This study also demonstrated that the use of SBF-based HA coatings can promote higher levels of osteogenesis in vivo. Finally, when incorporated as the endplate region of a larger tissue-engineered intervertebral disc replacement, HA coating did not induce mineralization in or promote cell migration out of neighboring biomaterials. Overall, these results verified tunable biomimetic HA coatings as a promising biomaterial modification to promote discrete regions of mineralization within composite engineered tissues.

Degeneration alters structure-function relationships at multiple length-scales and across interfaces in human intervertebral discs.

Intervertebral disc (IVD) degeneration and associated back pain place a significant burden on the population. IVD degeneration is a progressive cascade of cellular, compositional, and structural changes, which results in a loss of disc height, disorganization of extracellular matrix architecture, tears in the annulus fibrosus which may involve herniation of the nucleus pulposus, and remodeling of the bony and cartilaginous endplates (CEP). These changes to the IVD often occur concomitantly, across the entire motion segment from the disc subcomponents to the CEP and vertebral bone, making it difficult to determine the causal initiating factor of degeneration. Furthermore, assessments of the subcomponents of the IVD have been largely qualitative, with most studies focusing on a single attribute, rather than multiple adjacent IVD substructures. The objective of this study was to perform a multiscale and multimodal analysis of human lumbar motion segments across various length scales and degrees of degeneration. We performed multiple assays on every sample and identified several correlations between structural and functional measurements of disc subcomponents. Our results demonstrate that with increasing Pfirrmann grade there is a reduction in disc height and nucleus pulposus T2 relaxation time, in addition to alterations in motion segment macromechanical function, disc matrix composition and cellular morphology. At the cartilage endplate-vertebral bone interface, substantial remodeling was observed coinciding with alterations in micromechanical properties. Finally, we report significant relationships between vertebral bone and nucleus pulposus metrics, as well as between micromechanical properties of the endplate and whole motion segment biomechanical parameters, indicating the importance of studying IVD degeneration as a whole organ.

Platelet-Rich Plasma, Bone Morphogenetic Protein, and Stem Cell Therapies.

The frequency of use of "biologics," including platelet-rich plasma (PRP), bone morphogenetic protein (BMP), and stem cell therapies in the treatment of orthopaedic conditions has significantly increased over the past few decades. The use of PRP and stem cells has been proposed for a wide variety of conditions including knee and hip osteoarthritis (OA), tendon strains and tendinopathies, muscle strains, and acute and chronic soft-tissue injuries. It has also been proposed for use in the enhancement of healing during surgical treatments. BMP has seen use in promoting fracture union and spinal fusion and has been researched as an adjunct in other procedures as well. The current state of the literature in the use and support of these biologics is outlined here.

Avoiding and Managing Complications in Routine Lumbar Spine Surgery.

Elective lumbar surgery for common degenerative lumbar spine pathology has been consistently demonstrated to have excellent outcomes by multiple validated measures and improves patient quality of life. The rate of complication is low but not unavoidable; there is an increasing recognition of risk factors that can be mitigated to decrease complication rates. When complications occur, prompt recognition and management may minimize deleterious effects on patient outcome. There are considerations for identifying risk factors and, when possible, minimizing them and general strategies for identifying and managing common complications in lumbar spine surgery.

Vertebral body fracture after TLIF: a new complication.

BACKGROUND: The transforaminal posterior approach (TLIF) procedure was first described in 1982. Current literature indicates its equality in outcomes for fusion constructs as other anterior-posterior procedures. As a procedure becomes more popular and is more frequently performed the types and number of complications that occur increase. We report on a two case series that underwent TLIF. Both patients had satisfactory postoperative imaging, but presented later with coronal plane vertebral body fractures in the caudal vertebral body of the TLIF construct. We believe the complication may be related to: (a) unrecognized fracture of the endplate during cage impaction; (b) overloading the endplates by maximizing the lordosis achieved by using the reverse jackknife position on a Jackson table; (c) underlying mineral bone disease in patients. As the TLIF procedure increases in popularity, caution should be exercised to avoid the same potential complications. PURPOSE: To describe a potential complication with the TLIF procedure. STUDY DESIGN: Case report. PATIENT SAMPLE: 2. OUTCOME MEASURE: Revision surgery. METHODS: Case series. RESULTS: Caudal vertebral body fracture is a potential complication after TLIF. CONCLUSION: TLIF procedures can result in an unstable vertebral body fracture potentially necessitating revision decompression & stabilization. We recommend extra caution in patients with mineral bone disease, as technical errors can be magnified.

Developmental morphogens direct human induced pluripotent stem cells toward an annulus fibrosus-like cell phenotype.

Introduction: Therapeutic interventions for intervertebral disc herniation remain scarce due to the inability of endogenous annulus fibrosus (AF) cells to respond to injury and drive tissue regeneration. Unlike other orthopedic tissues, such as cartilage, delivery of exogenous cells to the site of annular injury remains underdeveloped, largely due to a lack of an ideal cell source and the invasive nature of cell isolation. Human induced pluripotent stem cells (iPSCs) can be differentiated to specific cell fates using biochemical factors and are, therefore, an invaluable tool for cell therapy approaches. While differentiation protocols have been developed for cartilage and fibrous connective tissues (e.g., tendon), the signals that regulate the induction and differentiation of human iPSCs toward the AF fate remain unknown. Methods: iPSC-derived sclerotome cells were treated with various combinations of developmental signals including transforming growth factor beta 3 (TGF-ß3), connective tissue growth factor (CTGF), platelet derived growth factor BB (PDGF-BB), insulin-like growth factor 1 (IGF-1), or the Hedgehog pathway activator, Purmorphamine, and gene expression changes in major AF-associated ECM genes were assessed. The top performing combination treatments were further validated by using three distinct iPSC lines and by assessing the production of upregulated ECM proteins of interest. To conduct a broader analysis of the transcriptomic shifts elicited by each factor combination, and to compare genetic profiles of treated cells to mature human AF cells, a 96.96 Fluidigm gene expression array was applied, and principal component analysis was employed to identify the transcriptional signatures of each cell population and treatment group in comparison to native AF cells. Results: TGF-ß3, in combination with PDGF-BB, CTGF, or IGF-1, induced an upregulation of key AF ECM genes in iPSC-derived sclerotome cells. In particular, treatment with a combination of TGF-ß3 with PDGF-BB for 14 days significantly increased gene expression of collagen II and aggrecan and increased protein deposition of collagen I and elastin compared to other treatment groups. Assessment of genes uniquely highly expressed by AF cells or SCL cells, respectively, revealed a shift toward the genetic profile of AF cells with the addition of TGF-ß3 and PDGF-BB for 14 days. Discussion: These findings represent an initial approach to guide human induced pluripotent stem cells toward an AF-like fate for cellular delivery strategies.

Level dependent alterations in human facet cartilage mechanics and bone morphometry with spine degeneration.

The zygapophyseal joints of the spine, also known as the facet joints, are paired diarthrodial joints posterior to the intervertebral disc and neural elements. The pathophysiology of facet osteoarthritis (OA), as well as crosstalk between the disc and facets, remains largely understudied compared to disc degeneration. The purpose of this study was to characterize alterations to human facet cartilage and subchondral bone across a spectrum of degeneration and to investigate correlations between disc and facet degeneration. Human lumbar facet articular surfaces from six independent donors were subject to creep indentation mechanical testing to quantify cartilage mechanical properties, followed by microcomputed tomography (µCT) analyses for subchondral bone morphometry. The degenerative state of each articular surface was assessed via macroscopic scoring and via Osteoarthritis Research Society International histopathology scoring. Our data suggest reduced facet cartilage compressive and tensile moduli and increased permeability with increasing degenerative grade, particularly at the lower levels of the spine. µCT analyses revealed spinal level-dependent alterations to the subchondral bone, with an increase in trabecular bone at the L4-L5 level, but a decrease at the upper levels of the lumbar spine with increasing degenerative grade. Cortical bone volume fraction was generally decreased with increasing degenerative grade across spinal levels. Correlation analysis revealed several associations between quantitative measures of disc degeneration and facet OA. This study showed that alterations in the mechanical properties of facet cartilage and in the structural properties of facet subchondral bone correlated with aspects of disc degeneration and were highly dependent on spinal level.

Do Prophylactic Inferior Vena Cava Filters Affect the Rates of Venous Thromboembolism and Pulmonary Embolism in Patients Undergoing Major Spine Surgery?

STUDY DESIGN: Retrospective Analysis. BACKGROUND: Venous thromboembolism (VTE) represents a significant cause of morbidity and mortality in major spine surgery. Placement of prophylactic inferior vena cava filters (IVCF) in patients undergoing major spine surgery was previously adopted at our institution. This study reports our experience and compares VTE rates between patients with and without preoperative IVCF placement. METHODS: A Retrospective comparative study was conducted on adult patients who underwent IVCF placement and those who did not prior to their spinal fusion procedure, between 2013 and 2016. Thoracolumbar fusions (anterior and/or posterior) of 7 or more levels, spinal osteotomies, and a minimum of a 3-month follow-up were included. Traumatic, oncologic, and cervical pathology were excluded. Primary outcomes measured included the incidence of overall VTE (DVT/PE), death, IVCF related complications, and IVCF retrieval. RESULTS: 386 patients who underwent major spine surgery, 258 met the eligibility criteria. Of those patients, 105 patients (40.7%) had prophylactic IVCF placement. All patients had postoperative SCDs and chemoprophylaxis. The presence of an IVCF was associated with an increased rate of overall VTE (14.3% vs 6.5%, P ≤ .05) and DVT episodes (8.6% vs 2.6%, P = .04). The rate of PE for the IVCF group and non-IVCF group was 8.6% and 4.6%, respectively, which was not statistically significant (P = .32). The all-cause mortality rate overall of 2.3% was statistically similar between both groups (P = 1.0). The IVCF group had higher rates of hematoma/seroma vs the non-IVCF group (12.4% vs 3.9%, P ≤ .05). 99 IVCFs were retrievable designs, and 85% were successfully retrieved. Overall IVCF-related complication rate was 11%. CONCLUSIONS: No statistical difference in PE or mortality rates existed between the IVCF and the control group. Patients with IVCF placement experienced approximately twice the rate of VTE and three times the rate of DVT compared to those without IVCF. The IVCF-related complication rate was 11%. Based on the results of this study, the authors recommend against the routine use of prophylactic IVCFs in adults undergoing major spine surgery. LEVEL OF EVIDENCE: III.

Mechanical crosstalk between the intervertebral disc, facet joints, and vertebral endplate following acute disc injury in a rabbit model.

Background: Vertebral endplate sclerosis and facet osteoarthritis have been documented in animals and humans. However, it is unclear how these adjacent pathologies engage in crosstalk with the intervertebral disc. This study sought to elucidate this crosstalk by assessing each compartment individually in response to acute disc injury. Methods: Eleven New Zealand White rabbits underwent annular disc puncture using a 16G or 21G needle. At 4 and 10 weeks, individual compartments of the motion segment were analyzed. Discs underwent T 1 relaxation mapping with MRI contrast agent gadodiamide as well T 2 mapping. Both discs and facets underwent mechanical testing via vertebra-disc-vertebra tension-compression creep testing and indentation testing, respectively. Endplate bone density was quantified via µCT. Discs and facets were sectioned and stained for histology scoring. Results: Intervertebral discs became more degenerative with increasing needle diameter and time post-puncture. Bone density also increased in endplates adjacent to both 21G and 16G punctured discs leading to reduced gadodiamide transport at 10 weeks. The facet joints, however, did not follow this same trend. Facets adjacent to 16G punctured discs were less degenerative than facets adjacent to 21G punctured discs at 10 weeks. 16G facets were more degenerative at 4 weeks than at 10, suggesting the cartilage had recovered. The formation of severe disc osteophytes in 16G punctured discs between 4 and 10 weeks likely offloaded the facet cartilage, leading to the recovery observed. Conclusions: Overall, this study supports that degeneration spans the whole spinal motion segment following disc injury. Vertebral endplate thickening occurred in response to disc injury, which limited the diffusion of small molecules into the disc. This work also suggests that altered disc mechanics can induce facet degeneration, and that extreme bony remodeling adjacent to the disc may promote facet cartilage recovery through offloading of the articular cartilage.

Injectable Radiopaque Hyaluronic Acid Granular Hydrogels for Intervertebral Disc Repair.

Injectable hydrogels offer minimally-invasive treatment options for degenerative disc disease, a prevalent condition affecting millions annually. Many hydrogels explored for intervertebral disc (IVD) repair suffer from weak mechanical integrity, migration issues, and expulsion. To overcome these limitations, an injectable and radiopaque hyaluronic acid granular hydrogel is developed. The granular structure provides easy injectability and low extrusion forces, while the radiopacity enables direct visualization during injection into the disc and non-invasive monitoring after injection. The radiopaque granular hydrogel is injected into rabbit disc explants to investigate restoration of healthy disc mechanics following needle puncture injury ex vivo and then delivered in a minimally-invasive manner into the intradiscal space in a clinically-relevant in vivo large animal goat model of IVD degeneration initiated through degradation by chondroitinase. The radiopaque granular hydrogel successfully halted loss of disc height due to degeneration. Further, the hydrogel not only enhanced proteoglycan content and reduced collagen content in the nucleus pulposus (NP) region compared to degenerative discs, but also helped to maintain the structural integrity of the disc and promote healthy segregation of the NP and annulus fibrosus regions. Overall, this study demonstrates the great potential of an injectable radiopaque granular hydrogel for treatment of degenerative disc disease.

Tension-activated nanofiber patches delivering an anti-inflammatory drug improve repair in a goat intervertebral disc herniation model.

Conventional microdiscectomy treatment for intervertebral disc herniation alleviates pain but does not repair the annulus fibrosus, resulting in a high incidence of recurrent herniation and persistent dysfunction. The lack of repair and the acute inflammation that arise after injury can further compromise the disc and result in disc-wide degeneration in the long term. To address this clinical need, we developed tension-activated repair patches (TARPs) for annulus fibrosus repair and local delivery of the anti-inflammatory factor anakinra (a recombinant interleukin-1 receptor antagonist). TARPs transmit physiologic strain to mechanically activated microcapsules embedded within the patch, which release encapsulated bioactive molecules in direct response to spinal loading. Mechanically activated microcapsules carrying anakinra were loaded into TARPs, and the effects of TARP-mediated annular repair and anakinra delivery were evaluated in a goat model of annular injury in the cervical spine. TARPs integrated with native tissue and provided structural reinforcement at the injury site that prevented aberrant disc-wide remodeling resulting from detensioning of the annular fibrosus. The delivery of anakinra by TARP implantation increased matrix deposition and retention at the injury site and improved maintenance of disc extracellular matrix. Anakinra delivery additionally attenuated the inflammatory response associated with TARP implantation, decreasing osteolysis in adjacent vertebrae and preserving disc cellularity and matrix organization throughout the annulus fibrosus. These results demonstrate the therapeutic potential of TARPs for the treatment of intervertebral disc herniation.

Transforming growth factor ß controls CCN3 expression in nucleus pulposus cells of the intervertebral disc.

OBJECTIVE: To investigate transforming growth factor ß (TGFß) regulation of CCN3 expression in cells of the nucleus pulposus. METHODS: Real-time reverse transcription-polymerase chain reaction and Western blot analyses were used to measure CCN3 expression in the nucleus pulposus. Transfections were used to measure the effect of Smad3, MAPKs, and activator protein 1 (AP-1) on TGFß-mediated CCN3 promoter activity. Lentiviral knockdown of Smad3 was performed to assess the role of Smad3 in CCN3 expression. RESULTS: CCN3 was expressed in embryonic and adult intervertebral discs. TGFß decreased the expression of CCN3 and suppressed its promoter activity in nucleus pulposus cells. DN-Smad3, Smad3 small interfering RNA, or DN-AP-1 had little effect on TGFß suppression of CCN3 promoter activity. However, p38 and ERK inhibitors blocked suppression of CCN3 by TGFß, suggesting involvement of these signaling pathways in the regulation of CCN3. Interestingly, overexpression of Smad3 in the absence of TGFß increased CCN3 promoter activity. We validated the role of Smad3 in controlling CCN3 expression in Smad3-null mice and in nucleus pulposus cells transduced with lentiviral short hairpin Smad3. In terms of function, treatment with recombinant CCN3 showed a dose-dependent decrease in the proliferation of nucleus pulposus cells. Moreover, CCN3-treated cells showed a decrease in aggrecan, versican, CCN2, and type I collagen expression. CONCLUSION: The opposing effect of TGFß on CCN2 and CCN3 expression and the suppression of CCN2 by CCN3 in nucleus pulposus cells further the paradigm that these CCN proteins form an interacting triad, which is possibly important in maintaining extracellular matrix homeostasis and cell numbers.

Odontoid fractures with neurologic deficit have higher mortality and morbidity.

BACKGROUND: Type II odontoid fractures are reportedly increasing in incidence and occur primarily in the elderly. Neurologic deficits (ND) at presentation add to the morbidity of these fractures; however, reports are limited as a result of small case series. It is unclear what specific complications are associated with ND and whether these result in increased incidence of mortality. QUESTIONS/PURPOSES: We established the incidence of ND with Type II odontoid fractures and determined if ND are associated with increased inpatient mortality and morbidity during hospitalization. METHODS: Twenty patients with acute Type II odontoid fracture and ND were identified from our institutional database. Baseline presenting characteristics and hospital course data were collected. The cohort was compared with a previously published cohort of 188 patients without ND by age, mechanism of injury, displacement, associated spinal injuries, comorbidities, treatment, mortality, and complications. Patients were only followed during acute-care hospitalization (mean, 11.9 days; range, 0-41 days). RESULTS: The incidence of ND among all Type II odontoid fractures was 9.6%. Ten of 20 patients with Type II odontoid fractures and ND died during hospitalization, and patients with complete cord injuries were 9.33 (95% confidence interval, 1.19-73.0) times more likely to die. Patients with ND experienced more complications and more respiratory complications than those without ND. CONCLUSIONS: ND after Type II odontoid fractures is a rare event associated with a high risk of early and rapid clinical decline. LEVEL OF EVIDENCE: Level III, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

Regulation of CCN2/connective tissue growth factor expression in the nucleus pulposus of the intervertebral disc: role of Smad and activator protein 1 signaling.

OBJECTIVE: To investigate transforming growth factor beta (TGFbeta) regulation of connective tissue growth factor (CTGF) expression in cells of the nucleus pulposus of rats, mice, and humans. METHODS: Real-time reverse transcription-polymerase chain reaction and Western blot analyses were used to measure CTGF expression in the nucleus pulposus. Transfections were used to measure the effects of Smads 2, 3, and 7 and activator protein 1 (AP-1) on TGFbeta-mediated CTGF promoter activity. RESULTS: CTGF expression was lower in neonatal rat discs than in skeletally mature rat discs. An increase in CTGF expression and promoter activity was observed in rat nucleus pulposus cells after TGFbeta treatment. Deletion analysis indicated that promoter constructs lacking Smad and AP-1 motifs were unresponsive to treatment. Analysis showed that full-length Smad3 and the Smad3 MH-2 domain alone increased CTGF activity. Further evidence of Smad3 and AP-1 involvement was seen when DN-Smad3, SiRNA-Smad3, Smad7, and DN-AP-1 suppressed TGFbeta-mediated activation of the CTGF promoter. When either Smad3 or AP-1 sites were mutated, CTGF promoter induction by TGFbeta was suppressed. We also observed a decrease in the expression of CTGF in discs from Smad3-null mice as compared with those from wild-type mice. Analysis of human nucleus pulposus samples indicated a trend toward increasing CTGF and TGFbeta expression in the degenerated state. CONCLUSION: TGFbeta, through Smad3 and AP-1, serves as a positive regulator of CTGF expression in the nucleus pulposus. We propose that CTGF is a part of the limited reparative response of the degenerated disc.

Return to Play for Cervical and Lumbar Spine Conditions.

Although the safety of contact sports has improved over the years, participation in any sport always carries a risk of injury. When cervical or lumbar spine injuries do occur, prompt diagnosis is essential, and athletes must be held out of the sport if indicated to prevent further harm and allow for recovery. This article highlights some of the most common cervical spine pathologies (stinger/burners, strain, stenosis/cord neuropraxia, disc herniation, and fracture/instability) and lumbar spine pathologies (strain, disc degeneration, disc herniation, fracture, spondylolysis/spondylolisthesis, and scoliosis) encountered in sports and reviews the associated return to play guidelines and expectations for each condition.

A challenging playing field: Identifying the endogenous impediments to annulus fibrosus repair.

Intervertebral disc (IVD) herniations, caused by annulus fibrosus (AF) tears that enable disc tissue extrusion beyond the disc space, are very prevalent, especially among adults in the third to fifth decade of life. Symptomatic herniations, in which the extruded tissue compresses surrounding nerves, are characterized by back pain, numbness, and tingling and can cause extreme physical disability. Patients whose symptoms persist after nonoperative intervention may undergo surgical removal of the herniated tissue via microdiscectomy surgery. The AF, however, which has a poor endogenous healing ability, is left unrepaired increasing the risk for re-herniation and pre-disposing the IVD to degenerative disc disease. The lack of understanding of the mechanisms involved in native AF repair limits the design of repair systems that overcome the impediments to successful AF restoration. Moreover, the complexity of the AF structure and the challenging anatomy of the repair environment represents a significant challenge for the design of new repair devices. While progress has been made towards the development of an effective AF repair technique, these methods have yet to demonstrate long-term repair and recovery of IVD biomechanics. In this review, the limitations of endogenous AF healing are discussed and key cellular events and factors involved are highlighted to identify potential therapeutic targets that can be integrated into AF repair methods. Clinical repair strategies and their limitations are described to further guide the design of repair approaches that effectively restore native tissue structure and function.

Putting the Pieces in Place: Mobilizing Cellular Players to Improve Annulus Fibrosus Repair.

The intervertebral disc (IVD) is an integral load-bearing tissue that derives its function from its composite structure and extracellular matrix composition. IVD herniations involve the failure of the annulus fibrosus (AF) and the extrusion of the nucleus pulposus beyond the disc boundary. Disc herniations can impinge the neural elements and cause debilitating pain and loss of function, posing a significant burden on individual patients and society as a whole. Patients with persistent symptoms may require surgery; however, surgical intervention fails to repair the ruptured AF and is associated with the risk for reherniation and further disc degeneration. Given the limitations of AF endogenous repair, many attempts have been made toward the development of effective repair approaches that reestablish IVD function. These methods, however, fail to recapitulate the composition and organization of the native AF, ultimately resulting in inferior tissue mechanics and function over time and high rates of reherniation. Harnessing the cellular function of cells (endogenous or exogenous) at the repair site through the provision of cell-instructive cues could enhance AF tissue regeneration and, ultimately, improve healing outcomes. In this study, we review the diverse approaches that have been developed for AF repair and emphasize the potential for mobilizing the appropriate cellular players at the site of injury to improve AF healing. Impact statement Conventional treatments for intervertebral disc herniation fail to repair the annulus fibrosus (AF), increasing the risk for recurrent herniation. The lack of repair devices in the market has spurred the development of regenerative approaches, yet most of these rely on a scarce endogenous cell population to repair large injuries, resulting in inadequate regeneration. This review identifies current and developing strategies for AF repair and highlights the potential for harnessing cellular function to improve AF regeneration. Ideal cell sources, differentiation strategies, and delivery methods are discussed to guide the design of repair systems that leverage specialized cells to achieve superior outcomes.

Cell morphology and mechanosensing can be decoupled in fibrous microenvironments and identified using artificial neural networks.

Cells interpret cues from and interact with fibrous microenvironments through the body based on the mechanics and organization of these environments and the phenotypic state of the cell. This in turn regulates mechanoactive pathways, such as the localization of mechanosensitive factors. Here, we leverage the microscale heterogeneity inherent to engineered fiber microenvironments to produce a large morphologic data set, across multiple cells types, while simultaneously measuring mechanobiological response (YAP/TAZ nuclear localization) at the single cell level. This dataset describing a large dynamic range of cell morphologies and responses was coupled with a machine learning approach to predict the mechanobiological state of individual cells from multiple lineages. We also noted that certain cells (e.g., invasive cancer cells) or biochemical perturbations (e.g., modulating contractility) can limit the predictability of cells in a universal context. Leveraging this finding, we developed further models that incorporate biochemical cues for single cell prediction or identify individual cells that do not follow the established rules. The models developed here provide a tool for connecting cell morphology and signaling, incorporating biochemical cues in predictive models, and identifying aberrant cell behavior at the single cell level.

Trends in epidemiology and management of type II odontoid fractures: 20-year experience at a model system spine injury tertiary referral center.

STUDY DESIGN: A retrospective cohort study of consecutive type II Odontoid fractures presenting to a Level 1 Regional Model Systems Spinal Cord Injury Center between June 1985 and July 2006. OBJECTIVE: To assess trends in management of type II Odontoid fractures presenting to a Level 1 Model Systems Regional Spinal Cord Injury Center over a 20-year period. SUMMARY OF BACKGROUND DATA: Type II Odontoid fracture management is controversial, and a majority of studies have had relatively small cohorts. There is no consensus regarding definitive treatment, particularly in older patients. METHODS: Medical records of 263 consecutive type II Odontoid fractures from June 1985 to July 2006 were retrospectively reviewed. Patients were excluded if they had neurologic deficits, nonacute fracture, or ambiguous fracture classification. A cohort of 192 neurologically intact, acute type II odontoid fractures were identified. Admission records were reviewed for age, date of injury, date of admission, date of discharge, mechanism of injury, associated injuries, medical comorbidities, and radiologic findings. RESULTS: There was a statistically significant increase in the rate of presentation of type II odontoid fractures with time. The average age and medical comorbidities of the patient did not change over time. The probability of operative management markedly increased over time, corresponding to a statistically significant increase in length of hospital stay for patients undergoing surgery. The discharge disposition correlated significantly to both age of the patient and associated injuries. CONCLUSIONS: The number and frequency of type II odontoid fractures compared with other spine injuries seems to be increasing over the last 2 decades, which may be correlated with the increasing number of elderly persons in the population, given that referral patterns have been unchanged at our institution. Prospective outcomes data are needed to better elucidate optimal treatment algorithms from both, an outcomes and cost-efficacy perspective.

Restoration of physiologic loading modulates engineered intervertebral disc structure and function in an in vivo model.

Tissue-engineered whole disc replacements are an emerging treatment strategy for advanced intervertebral disc degeneration. A challenge facing the translation of tissue-engineered disc replacement to clinical use are the opposing needs of initial immobilization to advantage integration contrasted with physiologic loading and its anabolic effects. Here, we utilize our established rat tail model of tissue engineered disc replacement with external fixation to study the effects of remobilization at two time points postimplantation on engineered disc structure, composition, and function. Our results suggest that the restoration of mechanical loading following immobilization enhanced collagen and proteoglycan content within the nucleus pulposus and annulus fibrosus of the engineered discs, in addition to improving the integration of the endplate region of the construct with native bone. Despite these benefits, angulation of the vertebral bodies at the implanted level occurred following remobilization at both early and late time points, reducing tensile failure properties in the remobilized groups compared to the fixed group. These results demonstrate the necessity of restoring physiologic mechanical loading to engineered disc implants in vivo, and the need to transition toward their evaluation in larger animal models with more human-like anatomy and motion compared to the rat tail.