Evaluating the effectiveness of online Continuing medical education during the COVID-19 pandemic.

OBJECTIVES: The study determined the effects of online continuing medical education (CME) on the clinical competency, performance, and patient outcomes of physicians and other healthcare professionals during the COVID-19 pandemic regarding the topics of COVID-19 and back pain. METHODS: Survey studies on six online CME activities were conducted from April 2020 to February 2021 at a South Korean hospital. Surveys were conducted immediately after and three months after the CME activity to measure the effectiveness of the CME activity regarding professional competence and performance, as well as patient outcomes. RESULTS: A total of 624 individuals participated in the six CME activities. Of the 2007 post-activity responses, a total of 1135 out of 1332 (85.21%) participants indicated that they were satisfied with the online education activities, and a total of 1752 out of 2007 (87.29%) participants responded that the content would influence their clinical practice. Upon a three-month follow-up, 477 out of 611 (78.07%) respondents indicated that they had made actual changes to their clinical practice. CONCLUSIONS: The online delivery method is effective for delivering CME. The results suggest that online CME ultimately influences physicians' clinical competency and performance, which leads to enforcing change in clinical practice.

Nonclinical Efficacy and Safety of CX-2029, an Anti-CD71 Probody-Drug Conjugate.

Probody therapeutics (Pb-Txs) are conditionally activated antibody-drug conjugates (ADCs) designed to remain inactive until proteolytically activated in the tumor microenvironment, enabling safer targeting of antigens expressed in both tumor and normal tissue. Previous attempts to target CD71, a highly expressed tumor antigen, have failed to establish an acceptable therapeutic window due to widespread normal tissue expression. This study evaluated whether a probody-drug conjugate targeting CD71 can demonstrate a favorable efficacy and tolerability profile in preclinical studies for the treatment of cancer. CX-2029, a Pb-Tx conjugated to maleimido-caproyl-valine-citrulline-p-aminobenzyloxycarbonyl-monomethyl auristatin E, was developed as a novel cancer therapeutic targeting CD71. Preclinical studies were performed to evaluate the efficacy and safety of this anti-CD71 PDC in patient-derived xenograft (PDX) mouse models and cynomolgus monkeys, respectively. CD71 expression was detected at high levels by IHC across a broad range of tumor and normal tissues. In vitro, the masked Pb-Tx form of the anti-CD71 PDC displayed a >50-fold reduced affinity for binding to CD71 on cells compared with protease-activated, unmasked anti-CD71 PDC. Potent in vivo tumor growth inhibition (stasis or regression) was observed in >80% of PDX models (28/34) at 3 or 6 mg/kg. Anti-CD71 PDC remained mostly masked (>80%) in circulation throughout dosing in cynomolgus monkeys at 2, 6, and 12 mg/kg and displayed a 10-fold improvement in tolerability compared with an anti-CD71 ADC, which was lethal. Preclinically, anti-CD71 PDC exhibits a highly efficacious and acceptable safety profile that demonstrates the utility of the Pb-Tx platform to target CD71, an otherwise undruggable target. These data support further clinical development of the anti-CD71 PDC CX-2029 as a novel cancer therapeutic.

Conditional PD-1/PD-L1 Probody Therapeutics Induce Comparable Antitumor Immunity but Reduced Systemic Toxicity Compared with Traditional Anti-PD-1/PD-L1 Agents.

Immune-checkpoint blockade has revolutionized cancer treatment. However, most patients do not respond to single-agent therapy. Combining checkpoint inhibitors with other immune-stimulating agents increases both efficacy and toxicity due to systemic T-cell activation. Protease-activatable antibody prodrugs, known as Probody therapeutics (Pb-Tx), localize antibody activity by attenuating capacity to bind antigen until protease activation in the tumor microenvironment. Herein, we show that systemic administration of anti-programmed cell death ligand 1 (anti-PD-L1) and anti-programmed cell death protein 1 (anti-PD-1) Pb-Tx to tumor-bearing mice elicited antitumor activity similar to that of traditional PD-1/PD-L1-targeted antibodies. Pb-Tx exhibited reduced systemic activity and an improved nonclinical safety profile, with markedly reduced target occupancy on peripheral T cells and reduced incidence of early-onset autoimmune diabetes in nonobese diabetic mice. Our results confirm that localized PD-1/PD-L1 inhibition by Pb-Tx can elicit robust antitumor immunity and minimize systemic immune-mediated toxicity. These data provide further preclinical rationale to support the ongoing development of the anti-PD-L1 Pb-Tx CX-072, which is currently in clinical trials.

Functional adaptation of interradicular alveolar bone to reduced chewing loads on dentoalveolar joints in rats.

OBJECTIVES: The effects of reduced chewing loads on load bearing integrity of interradicular bone (IB) within dentoalveolar joints (DAJ) in rats were investigated. METHODS: Four-week-old Sprague Dawley rats (N = 60) were divided into two groups; rats were either fed normal food, which is hard-pellet food (HF) (N = 30), or soft-powdered chow (SF) (N = 30). Biomechanical testing of intact DAJs and mapping of the resulting mechanical strains within IBs from 8- through 24-week-old rats fed HF or SF were performed. Tension- and compression-based mechanical strain profiles were mapped by correlating digital volumes of IBs at no load with the same IBs under load. Heterogeneity within IB was identified by mapping cement lines and TRAP-positive multinucleated cells using histology, and mechanical properties using nanoindentation technique. RESULTS: Significantly decreased interradicular functional space, IB volume fraction, and elastic modulus of IB in the SF group compared with the HF group were observed, and these trends varied with an increase in age. The elastic modulus values illustrated significant heterogeneity within IB from HF or SF groups. Both compression- and tension-based strains were localized at the coronal portion of the IB and the variation in strain profiles complemented the observed material heterogeneity using histology and nanoindentation. SIGNIFICANCE: Interradicular space and IB material-related mechanoadaptations in a DAJ are optimized to meet soft food related chewing demands. Results provided insights into age-specific regulation of chewing loads as a plausible "therapeutic dose" to reverse adaptations within the periodontal complex as an attempt to regain functional competence of a dynamic DAJ.

PPARγ increases HUWE1 to attenuate NF-κB/p65 and sickle cell disease with pulmonary hypertension.

Sickle cell disease (SCD)-associated pulmonary hypertension (PH) causes significant morbidity and mortality. Here, we defined the role of endothelial specific peroxisome proliferator-activated receptor γ (PPARγ) function and novel PPARγ/HUWE1/miR-98 signaling pathways in the pathogenesis of SCD-PH. PH and right ventricular hypertrophy (RVH) were increased in chimeric Townes humanized sickle cell (SS) mice with endothelial-targeted PPARγ knockout (SSePPARγKO) compared with chimeric littermate control (SSLitCon). Lung levels of PPARγ, HUWE1, and miR-98 were reduced in SSePPARγKO mice compared with SSLitCon mice, whereas SSePPARγKO lungs were characterized by increased levels of p65, ET-1, and VCAM1. Collectively, these findings indicate that loss of endothelial PPARγ is sufficient to increase ET-1 and VCAM1 that contribute to endothelial dysfunction and SCD-PH pathogenesis. Levels of HUWE1 and miR-98 were decreased, and p65 levels were increased in the lungs of SS mice in vivo and in hemin-treated human pulmonary artery endothelial cells (HPAECs) in vitro. Although silencing of p65 does not regulate HUWE1 levels, the loss of HUWE1 increased p65 levels in HPAECs. Overexpression of PPARγ attenuated hemin-induced reductions of HUWE1 and miR-98 and increases in p65 and endothelial dysfunction. Similarly, PPARγ activation attenuated baseline PH and RVH and increased HUWE1 and miR-98 in SS lungs. In vitro, hemin treatment reduced PPARγ, HUWE1, and miR-98 levels and increased p65 expression, HPAEC monocyte adhesion, and proliferation. These derangements were attenuated by pharmacological PPARγ activation. Targeting these signaling pathways can favorably modulate a spectrum of pathobiological responses in SCD-PH pathogenesis, highlighting novel therapeutic targets in SCD pulmonary vascular dysfunction and PH.

MicroRNA-98 reduces nerve growth factor expression in nicotine-induced airway remodeling.

Evolving evidence suggests that nicotine may contribute to impaired asthma control by stimulating expression of nerve growth factor (NGF), a neurotrophin associated with airway remodeling and airway hyperresponsiveness. We explored the hypothesis that nicotine increases NGF by reducing lung fibroblast (LF) microRNA-98 (miR-98) and PPARγ levels, thus promoting airway remodeling. Levels of NGF, miR-98, PPARγ, fibronectin 1 (FN1), endothelin-1 (EDN1, herein referred to as ET-1), and collagen (COL1A1 and COL3A1) were measured in human LFs isolated from smoking donors, in mouse primary LFs exposed to nicotine (50 µg/ml), and in whole lung homogenates from mice chronically exposed to nicotine (100 µg/ml) in the drinking water. In selected studies, these pathways were manipulated in LFs with miR-98 inhibitor (anti-miR-98), miR-98 overexpression (miR-98 mimic), or the PPARγ agonist rosiglitazone. Compared with unexposed controls, nicotine increased NGF, FN1, ET-1, COL1A1, and COL3A1 expression in human and mouse LFs and mouse lung homogenates. In contrast, nicotine reduced miR-98 levels in LFs in vitro and in lung homogenates in vivo Treatment with anti-miR-98 alone was sufficient to recapitulate increases in NGF, FN1, and ET-1, whereas treatment with a miR-98 mimic significantly suppressed luciferase expression in cells transfected with a luciferase reporter linked to the putative seed sequence in the NGF 3'UTR and also abrogated nicotine-induced increases in NGF, FN1, and ET-1 in LFs. Similarly, rosiglitazone increased miR-98 and reversed nicotine-induced increases in NGF, FN1, and ET-1. Taken together, these findings demonstrate that nicotine-induced increases in NGF and other markers of airway remodeling are negatively regulated by miR-98.

The Effects of Acupuncture on Cancer-Related Fatigue: Updated Systematic Review and Meta-Analysis.

BACKGROUND: Several studies have identified fatigue as one of the major symptoms experienced during and after cancer treatment. However, there are limited options to manage cancer related fatigue (CRF) with pharmacological interventions. Several acupuncture studies suggested that acupuncture has a positive impact on CRF. This review aims to assess the evidence of acupuncture for the treatment of CRF. METHOD: Electronic database searches were conducted on 4 English databases (Medline, PubMed, Embase, and ScienceDirect). Search keywords were; "acupuncture" and "cancer," or "cancer related fatigue." Studies published as full text randomized controlled trials (RCTs) in English were included. Estimates of change in fatigue cores were pooled using a random effects meta-analysis where randomized comparisons were available for true acupuncture versus sham acupuncture and true acupuncture versus usual care. The quality of original papers were assessed using the Cochrane Collaboration's tool for assessing risk of bias (ROB). RESULTS: Nine RCTs were selected for review with a total of 809 participants and a range of 13 to 302 participants within the studies. Six RCTs reported significant improvement of CRF for the acupuncture intervention compared to the control groups. Pooled estimates suggest Brief Fatigue Inventory scores are 0.93 points lower 95% CI (-1.65, -0.20) in true acupuncture versus sham acupuncture and 2.12 points lower 95% C (-3.21, -1.04) in true acupuncture versus usual care. Six studies had low risk of bias (ROB) and 3 studies had a moderate ROB predominantly in blinding of participants, blinding of assessors and incomplete data outcomes. Among the 9 RCTs, 2 studies have reported the occurrence of minor adverse effects (spot bleeding and bruising) related to acupuncture treatment. No serious adverse reactions related to acupuncture were reported. CONCLUSION: The current literature review suggests that acupuncture has therapeutic potential in management of CRF for cancer survivors. Promotion of acupuncture in cancer care to manage CRF may improve the quality of life of cancer survivors.

In vivo spectral guided removal of composite from tooth surfaces with a CO2 laser.

Dental composites are used as restorative materials to replace tooth structure after the removal of caries, shaping, covering teeth for esthetic purposes and as adhesives. Dentists spend more time replacing existing restorations that fail than they do placing new restorations. Tooth colored restorations are difficult to differentiate from the surrounding tooth structure making them challenging to remove completely without incidental removal of healthy tooth structure. Previous studies have demonstrated that CO2 lasers in conjunction with spectral feedback can be used to selectively remove composite from tooth surfaces. In addition, we assembled a system feasible for clinical use that incorporates a spectral feedback system, scanning system, articulating arm and a clinical handpiece and subsequently evaluated the performance of that system on extracted teeth. The purpose of this study was to test this system in vivo to demonstrate its efficacy relative to dental clinicians. Eight test subjects with premolar teeth scheduled for extraction for orthodontic reasons had bilateral premolars prepared with small occlusal cavity preparations and filled with dental composite. The laser scanning system was used to remove the composite from one of the preparations and a dental handpiece was used to remove the composite from the other. Cross polarization optical coherence tomography was used to measure the volume of the preparation before and after composite placement and removal. There was no significant difference in the loss of enamel and residual composite between the laser and the handpiece. This study demonstrated that a computer controlled spectral guided CO2 laser scanning system can be used in vivo to selectively remove composite from tooth surfaces.

A Novel Compound, "FA-1" Isolated from Prunus mume, Protects Human Bronchial Epithelial Cells and Keratinocytes from Cigarette Smoke Extract-Induced Damage.

Extract of the Japanese apricot (JAE) has biological properties as an antioxidant and anti-inflammatory agent. We hypothesized that JAE might exert therapeutic effects on cigarette smoke (CS)-induced DNA damage and cytotoxicity. In this study, we found that concentrated JAE protects against cigarette smoke extract (CSE)-induced cytotoxicity and DNA damage accompanied by increased levels of aldehyde dehydrogenase (ALDH)2, 3A1, and Werner's syndrome protein (WRN) in immortalized human bronchial epithelial cells (HBEC2) and normal human epidermal keratinocytes (NHEK). Using the centrifugal partition chromatography (CPC) method, we identified an undescribed compound, 5-hydroxymethyl-2-furaldehyde bis(5-formylfurfuryl) acetal (which we named FA-1), responsible for the protective effects against CSE. This chemical structure has not been reported from a natural source to date. Protective effects of isolated FA-1 against CSE were observed in both HBEC2 and NHEK cells. The studies described herein suggest that FA-1 isolated from JAE protects against CSE-induced DNA damage and apoptosis by augmenting multiple isozymes of ALDH and DNA repair and reducing oxidative stress.

A Chimeric Antibody against ACKR3/CXCR7 in Combination with TMZ Activates Immune Responses and Extends Survival in Mouse GBM Models.

Glioblastoma (GBM) is the least treatable type of brain tumor, afflicting over 15,000 people per year in the United States. Patients have a median survival of 16 months, and over 95% die within 5 years. The chemokine receptor ACKR3 is selectively expressed on both GBM cells and tumor-associated blood vessels. High tumor expression of ACKR3 correlates with poor prognosis and potential treatment resistance, making it an attractive therapeutic target. We engineered a single chain FV-human FC-immunoglobulin G1 (IgG1) antibody, X7Ab, to target ACKR3 in human and mouse GBM cells. We used hydrodynamic gene transfer to overexpress the antibody, with efficacy in vivo. X7Ab kills GBM tumor cells and ACKR3-expressing vascular endothelial cells by engaging the cytotoxic activity of natural killer (NK) cells and complement and the phagocytic activity of macrophages. Combining X7Ab with TMZ allows the TMZ dosage to be lowered, without compromising therapeutic efficacy. Mice treated with X7Ab and in combination with TMZ showed significant tumor reduction by MRI and longer survival overall. Brain-tumor-infiltrating leukocyte analysis revealed that X7Ab enhances the activation of M1 macrophages to support anti-tumor immune response in vivo. Targeting ACKR3 with immunotherapeutic monoclonal antibodies (mAbs) in combination with standard of care therapies may prove effective in treating GBM.

Near-infrared imaging of enamel hypomineralization due to developmental defects.

The increasing prevalence of mild hypomineralization due to developmental defects on tooth surfaces poses a challenge for caries detection and caries risk assessment and reliable methods need to be developed to discriminate such lesions from active caries lesions that need intervention. Previous studies have demonstrated that areas of hypomineralization are typically covered with a relatively thick surface layer of highly mineralized and transparent enamel similar to arrested lesions. Seventy-six extracted human teeth with mild to moderate degrees of suspicious fluorosis were imaged using near-infrared reflectance and transillumination. Enamel hypomineralization was clearly visible in both modalities. However, it was difficult to distinguish hypomineralization due to developmental defects from caries lesions with contrast measurements alone. The location of the lesion on tooth coronal surface (i.e. generalized vs. localized) seems to be the most important indicator for the presence of enamel hypomineralization due to developmental defects.

Automated ablation of dental composite using an IR pulsed laser coupled to a plume emission spectral feedback system.

OBJECTIVE: The purpose of this study is to assemble a laser system for the selective removal of dental composite from tooth surfaces, that is feasible for clinical use incorporating a spectral feedback system, a scanning system, articulating arm and a clinical hand-piece, and evaluate the performance of that system on extracted teeth. METHODS: Ten extracted teeth were collected and small fillings were placed on the occlusal surface of each tooth. A clinical system featuring a CO2 laser operating at 50 Hz and spectral optical feedback was used to remove the composite. Removal was confirmed using a cross polarized optical coherence tomography (CP-OCT) system designed for clinical use. RESULTS: The system was capable of rapidly removing composite from small preparations on tooth occlusal surfaces with a mean loss of enamel of less than 20 µm. CONCLUSION: We have demonstrated that spectral feedback can be successfully employed in an automated system for composite removal by incorporating dual photodiodes and a galvanometer controlled CO2 laser. Additionally, the use of registered OCT images presents as a viable method for volumetric benchmarking. Overall, this study represents the first implementation of spectral feedback into a clinical hand-piece and serves as a benchmark for a future clinical study. Lasers Surg. Med. 49:658-665, 2017. © 2017 Wiley Periodicals, Inc.

Automated ablation of dental composite using an IR pulsed laser coupled to a plume emission spectral feedback system.

Dental composites are used as restorative materials for filling cavities, shaping, and covering teeth for esthetic purposes, and as adhesives. Dentists spend more time replacing existing restorations that fail than they do placing new restorations. Tooth colored restorations are difficult to differentiate from the surrounding tooth structure making them challenging to remove without damaging healthy tooth structure. Previous studies have demonstrated that CO2 lasers in conjunction with spectral feedback can be used to selectively remove composite from tooth surfaces. The purpose of this study is to assemble a system that is feasible for clinical use incorporating a spectral feedback system, a scanning system, articulating arm and a clinical handpiece and then evaluate the performance of that system on extracted teeth. In addition, the selectivity of composite removal was analyzed using a high-speed optical coherence tomography system that is suitable for clinical use. The system was capable of rapidly removing composite from small preparations on tooth occlusal surfaces with a mean loss of enamel of less than 20-µm.

Periodontal ligament entheses and their adaptive role in the context of dentoalveolar joint function.

OBJECTIVE: The dynamic bone-periodontal ligament (PDL)-tooth fibrous joint consists of two adaptive functionally graded interfaces (FGI), the PDL-bone and PDL-cementum that respond to mechanical strain transmitted during mastication. In general, from a materials and mechanics perspective, FGI prevent catastrophic failure during prolonged cyclic loading. This review is a discourse of results gathered from literature to illustrate the dynamic adaptive nature of the fibrous joint in response to physiologic and pathologic simulated functions, and experimental tooth movement. METHODS: Historically, studies have investigated soft to hard tissue transitions through analytical techniques that provided insights into structural, biochemical, and mechanical characterization methods. Experimental approaches included two dimensional to three dimensional advanced in situ imaging and analytical techniques. These techniques allowed mapping and correlation of deformations to physicochemical and mechanobiological changes within volumes of the complex subjected to concentric and eccentric loading regimes respectively. RESULTS: Tooth movement is facilitated by mechanobiological activity at the interfaces of the fibrous joint and generates elastic discontinuities at these interfaces in response to eccentric loading. Both concentric and eccentric loads mediated cellular responses to strains, and prompted self-regulating mineral forming and resorbing zones that in turn altered the functional space of the joint. SIGNIFICANCE: A multiscale biomechanics and mechanobiology approach is important for correlating joint function to tissue-level strain-adaptive properties with overall effects on joint form as related to physiologic and pathologic functions. Elucidating the shift in localization of biomolecules specifically at interfaces during development, function, and therapeutic loading of the joint is critical for developing "functional regeneration and adaptation" strategies with an emphasis on restoring physiologic joint function.

Near-IR and CP-OCT imaging of suspected occlusal caries lesions.

INTRODUCTION: Radiographic methods have poor sensitivity for occlusal lesions and by the time the lesions are radiolucent they have typically progressed deep into the dentin. New more sensitive imaging methods are needed to detect occlusal lesions. In this study, cross-polarization optical coherence tomography (CP-OCT) and near-IR imaging were used to image questionable occlusal lesions (QOC's) that were not visible on radiographs but had been scheduled for restoration on 30 test subjects. METHODS: Near-IR reflectance and transillumination probes incorporating a high definition InGaAs camera and near-IR broadband light sources were used to acquire images of the lesions before restoration. The reflectance probe utilized cross-polarization and operated at wavelengths from 1,500 to 1,700 nm where there is an increase in water absorption for higher contrast. The transillumination probe was operated at 1,300 nm where the transparency of enamel is highest. Tomographic images (6 × 6 × 7 mm3 ) of the lesions were acquired using a high-speed swept-source CP-OCT system operating at 1,300 nm before and after removal of the suspected lesion. RESULTS: Near-IR reflectance imaging at 1,500-1,700 nm yielded significantly higher contrast (P < 0.05) of the demineralization in the occlusal grooves compared with visible reflectance imaging. Stains in the occlusal grooves greatly reduced the lesion contrast in the visible range yielding negative values. Only half of the 26 lesions analyzed showed the characteristic surface demineralization and increased reflectivity below the dentinal-enamel junction (DEJ) in 3D OCT images indicative of penetration of the lesion into the dentin. CONCLUSION: This study demonstrates that near-IR imaging methods have great potential for improving the early diagnosis of occlusal lesions. Lasers Surg. Med. 49:215-224, 2017. © 2017 Wiley Periodicals, Inc.

Strain mapping and correlative microscopy of the alveolar bone in a bone-periodontal ligament-tooth fibrous joint.

This study details a method to calculate strains within interradicular alveolar bone using digital volume correlation on X-ray tomograms of intact bone-periodontal ligament-tooth fibrous joints. The effects of loading schemes (concentric and eccentric) and optical magnification on the resulting strain in alveolar bone will be investigated with an intent to correlate deformation gradients with data sets from other complementary techniques. Strain maps will be correlated with structural and site-specific mechanical properties obtained on the same specimen using atomic force microscopy and atomic force microscopy-based nanoindentation technique. Specimens include polydimethylsiloxane as a standard material and intact hemi-mandibles harvested from rats. X-ray tomograms were taken at no-load and loaded conditions using an in situ load cell coupled to a micro X-ray computed tomography unit. Digital volume correlation was used to calculate deformations within alveolar bone. Comparison of strain maps was made as a result of different loading schemes (concentric vs eccentric) and at different magnifications (4× vs 10×). Virtual sections and strain maps from digital volume correlation solutions were aligned with structure and reduced elastic modulus to correlate datasets of the same region within a specimen. Strain distribution between concentrically and eccentrically loaded complexes was different but illustrated a similar range. Strain maps of homogeneous materials (polydimethylsiloxane) resulting from digital volume correlation at different magnifications were similar. However, strain maps of heterogeneous materials at lower and higher magnification differed. The digital volume correlation technique illustrated a dependence on optical magnification specifically for heterogeneous materials such as bone. The results at a higher optical magnification highlight the potential for extracting deformation at higher resolutions. Correlation of data spaces from different complementary techniques is plausible and could provide insights into biological and physicochemical processes that lead to functional adaptation of tissues and joints.

Multiscale biomechanical responses of adapted bone-periodontal ligament-tooth fibrous joints.

Reduced functional loads cause adaptations in organs. In this study, temporal adaptations of bone-ligament-tooth fibrous joints to reduced functional loads were mapped using a holistic approach. Systematic studies were performed to evaluate organ-level and tissue-level adaptations in specimens harvested periodically from rats (N=60) given powder food for 6 months over 8,12,16,20, and 24 weeks. Bone-periodontal ligament (PDL)-tooth fibrous joint adaptation was evaluated by comparing changes in joint stiffness with changes in functional space between the tooth and alveolar bony socket. Adaptations in tissues included mapping changes in the PDL and bone architecture as observed from collagen birefringence, bone hardness and volume fraction in rats fed soft foods (soft diet, SD) compared to those fed hard pellets as a routine diet (hard diet, HD). In situ biomechanical testing on harvested fibrous joints revealed increased stiffness in SD groups (SD:239-605 N/mm) (p<0.05) at 8 and 12 weeks. Increased joint stiffness in early development phase was due to decreased functional space (at 8 weeks change in functional space was -33 µm, at 12 weeks change in functional space was -30 µm) and shifts in tissue quality as highlighted by birefringence, architecture and hardness. These physical changes were not observed in joints that were well into function, that is, in rodents older than 12 weeks of age. Significant adaptations in older groups were highlighted by shifts in bone growth (bone volume fraction 24 weeks: Δ-0.06) and bone hardness (8 weeks: Δ-0.04 GPa, 16 weeks: Δ-0.07 GPa, 24 weeks: Δ-0.06 GPa). The response rate (N/s) of joints to mechanical loads decreased in SD groups. Results from the study showed that joint adaptation depended on age. The initial form-related adaptation (observed change in functional space) can challenge strain-adaptive nature of tissues to meet functional demands with increasing age into adulthood. The coupled effect between functional space in the bone-PDL-tooth complex and strain-adaptive nature of tissues is necessary to accommodate functional demands, and is temporally sensitive despite joint malfunction. From an applied science perspective, we propose that adaptations are registered as functional history in tissues and joints.

Biomechanics and strain mapping in bone as related to immediately-loaded dental implants.

The effects of alveolar bone socket geometry and bone-implant contact on implant biomechanics, and resulting strain distributions in bone were investigated. Following extraction of lateral incisors on a cadaver mandible, implants were placed immediately and bone-implant contact area, stability implant biomechanics and bone strain were measured. In situ biomechanical testing coupled with micro X-ray microscopy (µ-XRM) illustrated less stiff bone-implant complexes (701-822 N/mm) compared with bone-periodontal ligament (PDL)-tooth complexes (791-913 N/mm). X-ray tomograms illustrated that the cause of reduced stiffness was due to limited bone-implant contact. Heterogeneous elemental composition of bone was identified by using energy dispersive X-ray spectroscopy (EDS). The novel aspect of this study was the application of a new experimental mechanics method, that is, digital volume correlation, which allowed mapping of strains in volumes of alveolar bone in contact with a loaded implant. The identified surface and subsurface strain concentrations were a manifestation of load transferred to bone through bone-implant contact based on bone-implant geometry, quality of bone, implant placement, and implant design. 3D strain mapping indicated that strain concentrations are not exclusive to the bone-implant contact regions, but also extend into bone not directly in contact with the implant. The implications of the observed strain concentrations are discussed in the context of mechanobiology. Although a plausible explanation of surgical complications for immediate implant treatment is provided, extrapolation of results is only warranted by future systematic studies on more cadaver specimens and/or in vivo models.

Adaptive properties of human cementum and cementum dentin junction with age.

OBJECTIVES: The objective of this study was to evaluate age related changes in physical (structure/mechanical properties) and chemical (elemental/inorganic mineral content) properties of cementum layers interfacing dentin. METHODS: Human mandibular molars (N=43) were collected and sorted by age (younger=19-39, middle=40-60, older=61-81 years). The structures of primary and secondary cementum (PC, SC) types were evaluated using light and atomic force microscopy (AFM) techniques. Chemical composition of cementum layers were characterized through gravimetric analysis by estimating ash weight and concentrations of Ca, Mn, and Zn trace elements in the analytes through inductively coupled plasma mass spectroscopy. The hardness of PC and SC was determined using microindentation and site-specific reduced elastic modulus properties were determined using nanoindentation techniques. RESULTS: PC contained fibrous 1-3 µm wide hygroscopic radial PDL-inserts. SC illustrated PC-like structure adjacent to a multilayered architecture composing of regions that contained mineral dominant lamellae. The width of the cementum dentin junction (CDJ) decreased as measured from the cementum enamel junction (CEJ) to the tooth apex (49-21 µm), and significantly decreased with age (44-23 µm; p<0.05). The inorganic ratio defined as the ratio of post-burn to pre-burn weight increased with age within primary cementum (PC) and secondary cementum (SC). Cementum showed an increase in hardness with age (PC (0.40-0.46 GPa), SC (0.37-0.43 GPa)), while dentin showed a decreasing trend (coronal dentin (0.70-0.72 GPa); apical dentin (0.63-0.73 GPa)). SIGNIFICANCE: The observed physicochemical changes are indicative of increased mineralization of cementum and CDJ over time. Changes in tissue properties of teeth can alter overall tooth biomechanics and in turn the entire bone-tooth complex including the periodontal ligament. This study provides baseline information about the changes in physicochemical properties of cementum with age, which can be identified as adaptive in nature.

In situ compressive loading and correlative noninvasive imaging of the bone-periodontal ligament-tooth fibrous joint.

This study demonstrates a novel biomechanics testing protocol. The advantage of this protocol includes the use of an in situ loading device coupled to a high resolution X-ray microscope, thus enabling visualization of internal structural elements under simulated physiological loads and wet conditions. Experimental specimens will include intact bone-periodontal ligament (PDL)-tooth fibrous joints. Results will illustrate three important features of the protocol as they can be applied to organ level biomechanics: 1) reactionary force vs. displacement: tooth displacement within the alveolar socket and its reactionary response to loading, 2) three-dimensional (3D) spatial configuration and morphometrics: geometric relationship of the tooth with the alveolar socket, and 3) changes in readouts 1 and 2 due to a change in loading axis, i.e. from concentric to eccentric loads. Efficacy of the proposed protocol will be evaluated by coupling mechanical testing readouts to 3D morphometrics and overall biomechanics of the joint. In addition, this technique will emphasize on the need to equilibrate experimental conditions, specifically reactionary loads prior to acquiring tomograms of fibrous joints. It should be noted that the proposed protocol is limited to testing specimens under ex vivo conditions, and that use of contrast agents to visualize soft tissue mechanical response could lead to erroneous conclusions about tissue and organ-level biomechanics.