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Objectives: To conduct a secondary data analysis of how changes in smoking and drinking during pregnancy impact status of any breastfeeding and breastfeeding duration in a national cohort. Materials and Methods: A cross-sectional study was conducted using Pregnancy Risk Assessment Monitoring System (PRAMS) data between 2009 and 2017 ( n  = 334,203). Univariate and multivariate analyses were conducted on the status of any breastfeeding and breastfeeding duration. Results: A dose-dependent inverse relationship was found in which women who smoked the same or more or resumed smoking during pregnancy showed the lowest likelihood and shortest duration of breastfeeding, followed by reduced smokers, quitters, and nonsmokers. Women with a history of alcohol use were significantly more likely to breastfeed compared with women without a history of alcohol use. Conclusions: The profile of smoking change during pregnancy impacts the likelihood and duration of breastfeeding in a dose-dependent and inverse manner. No such relationship was found with drinking change during pregnancy. Public Health Implications: Significant public health efforts should focus on implementing and sustaining evidence-based interventions for prenatal smoking cessation and educating providers and maternal populations on the adverse effect of postpartum alcohol exposure.

Cellular attachment and response to biomaterials are mediated by integrin receptor binding to extracellular matrix proteins adsorbed onto the material surface. Osteoblasts interact with their substrates via several integrin complexes including fibronectin-binding α5β1 and collagen-binding α1β1 and α2β1. Knockdown of α2 or β1 integrin subunits inhibits the production of factors that promote an osteogenic microenvironment, including osteocalcin, osteoprotegerin, and TGFβ1. Osteoblasts also secrete several angiogenic growth factors such as VEGF-A (VEGF 165 ), FGF-2, and angiopoietin 1, which are regulated by titanium surface topography and surface energy. Here, we examined whether signaling through integrin receptor complexes regulates production and secretion of angiogenic factors during osteoblast differentiation on microtextured Ti surfaces. To do this, integrin subunits α1, α2, α5, and β1 were stably silenced in MG63 osteoblast-like cells cultured on grit-blasted/acid-etched hydrophobic Ti (SLA) or on hydrophilic SLA (modSLA). VEGF-A production increased in response to Ti surface topography and energy in integrin α2, α5, and β1 silenced cells but decreased in α1-silenced cells. FGF-2 decreased on modSLA substrates in both α1 and α2-silenced cells but was unchanged in response to silencing of either α5 or β1. In integrin α1, α2, and β1-silenced cells, Ang-1 increased on modSLA but α5-silencing did not affect Ang-1 production during surface mediated differentiation. These results suggest that signaling through specific integrin receptor complexes during osteoblast differentiation on microstructured Ti substrates, regulates the production of angiogenic factors by those cells, and this is differentially regulated by surface hydrophilicity. STATEMENT OF SIGNIFICANCE: Successful implantation of synthetic biomaterials into bone depends on the biological process known as osseointegration. Osseointegration is a highly regulated communication of cells that orchestrates the migration of progenitor cells towards the implant site and promotes the deposition and mineralization of extracellular matrix proteins within the implant microenvironment, to tightly join the implant to native bone. In this process, angiogenesis functions as the initiation site of progenitor cell migration and is necessary for matrix deposition by providing the necessary nutrients for bone formation. In the present study, we show a novel regulation of specific angiogenic growth factors by integrin receptor complexes. This research is important to develop biomaterials that promote and maintain osseointegration through proper vascularization and prevent implant failure in patients lacking sufficient angiogenesis., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Establishment of a patent vasculature at the bone-implant interface plays a significant role in determining overall success of orthopedic and dental implants. Osteoblasts produce vascular endothelial growth factor-A (VEGF-A), an important regulator of angiogenesis during bone formation and healing, and the amount secreted is sensitive to titanium (Ti) surface microtopography and surface energy. The purpose of this study was to determine if surface properties modulate cellular response to VEGF-A. MG63 osteoblast-like cells were transfected with shRNA targeting VEGF-A at >80% knockdown. Cells stably silenced for VEGF-A secreted reduced levels of osteocalcin, osteoprotegerin, FGF-2, and angiopoietin-1 when cultured on grit-blasted/acid-etched (SLA) and hydrophilic SLA (modSLA) Ti surfaces and conditioned media from these cultures caused reduced angiogenesis in an endothelial tubule formation assay. Treatment of MG63 cells with 20 ng/mL rhVEGF-A 165 rescued production in silenced cells and increased production of osteocalcin, osteoprotegerin, FGF-2, and angiopoietin-1, with greatest effects on control cells cultured on modSLA. Addition of a neutralization antibody against VEGF receptor 2 (VEGFR2; Flk-1) resulted in a significant increase in VEGF-A production. Overall, this study indicates that VEGF-A has two roles in osseointegration: enhanced angiogenesis and an autocrine/paracrine role in maturation of osteoblast-like cells in response to Ti surface properties. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 423-433, 2019., (© 2018 Wiley Periodicals, Inc.)

Study Design: Prospective, randomized controlled trial., Objective: To compare pain, physical/mental functional recovery and recurrent herniation for patients following lumbar microdiscectomy with and without the use of a cryopreserved amniotic tissue graft., Summary of Background Data: Although microdiscectomy procedures are routinely successful for patients with lumbar radiculopathy due to herniated disc disease, residual low back pain, and recurrent herniation remain unsolved clinical problems., Methods: Following Investigated Review Board approval, 80 subjects were randomized in a 1:1 ratio to either receive cryopreserved amniotic (cAM) tissue or no tissue following elective lumbar microdiscectomy surgery. cAM grafts were applied to the annular defect at the conclusion of the procedure. Patients provided preoperative and postoperative clinical assessment data out to 24 months using the Oswestry Disability Index (ODI), Short Form-12 (SF-12) Health Survey, and Visual Analog Pain Scale for back and leg pain. Patients with symptomatic recurrent disc herniation were recorded., Results: In total, 48 males and 32 females with an average age of 47.2 years were included. Mean ODI scores for subjects treated with cAM graft demonstrated statistically greater improvement at 6 weeks (14.49 vs. 21.82; P=0.05) and 24 months (6.62 vs. 14.40; P=0.02) compared with controls. Similarly, SF-12 Physical Component Scores demonstrated statistically greater gains in the cAM group at both the 6 weeks and 24 months. None of the subjects in the cAM graft group sustained a recurrent herniation at the same surgical level, whereas 3 patients in the control group sustained a recurrent herniation at the same surgical level, with 2 requiring fusion to manage persistent pain., Conclusions: The data demonstrate statistically superior clinical outcomes following lumbar microdiscectomy as measured by ODI and SF-12 (physical composite scale) and a lower rate of recurrent herniation with the use of a cAM tissue graft compared with traditional microdiscectomy.

Background: We developed a DVD training tool to educate physicians evaluating emergency residents on accurate Standardized Direct Observation Assessment Tool (SDOT) application., Objective: Our goal was to assess whether this training video improved attendings' and senior residents' SDOT use., Methods: Participants voluntarily completed SDOT evaluations based on a scripted "test" video. A DVD with "positive" and "negative" scenarios of proper SDOT use was viewed. It included education on appropriate recording of 26 behaviors. The test scenario was viewed again and follow-up SDOTs submitted. Performances by attendings and residents on the pre- and post-test SDOTs were compared., Results: Twenty-six attendings and 26 senior residents participated. Prior SDOT experience was noted for 8 attendings and 11 residents. For 20 anchors, participants recorded observed behaviors with statistically significant difference on one each of the pretest (no. 20; p = 0.034) and post-test (no. 14; p = 0.041) SDOTs. On global competency assessments, pretest medical knowledge (p = 0.016) differed significantly between groups. The training intervention changed one anchor (no. 5; p = 0.035) and one global assessment (systems-based practice; p = 0.031) more negatively for residents. Recording SDOTs with exact agreement occurred 48.73% for attendings pretest and 54.41% post-test; resident scores were 45.86% and 49.55%, respectively. DVD exposure slightly raised attending scores (p = 0.289) and significantly lowered resident scores (p = 0.046)., Conclusions: Exposure to an independently developed SDOT training video tended to raise attending scores, though without significance, while at the same time lowered senior resident scores statistically significantly. Emergency attendings' and senior residents' SDOT scoring rarely differed with significance; about half of anchor behaviors were recorded with exact agreement. This suggests senior residents, with appropriate education, may participate in SDOT assessment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Osteoarthritis (OA) is a progressive degenerative joint disease, and to date, no disease-modifying OA drug exists. Amniotic membrane and umbilical cord products have been used clinically in several diseases due to their anti-inflammatory and antiscarring properties. In the present study, we sought to evaluate whether a particulate amniotic membrane and umbilical cord (AM/UC) matrix could aid in attenuating disease progression. Lewis rats underwent medial meniscus transection (MMT) to induce OA. Two weeks after surgery, animals received intra-articular injections (50 μL) of either 50 or 100 μg/μL particulate AM/UC or saline control and were subsequently euthanized 1 or 4 weeks later. Cartilage degeneration was assessed using both histological scoring methods and equilibrium partitioning of an ionic contrast agent-microcomputed tomography (EPIC-μCT). EPIC-μCT analysis demonstrated that overall cartilage destruction was attenuated, with a significant increase in both cartilage thickness and volume as well as a significant decrease in total lesion area in animals injected with either dose of particulate AM/UC at 1 week, but only a high dose at 4 weeks postinjection. Osteoarthritis Research Society International (OARSI) histology scores of tibial sections corroborated EPIC-μCT results. Overall joint destruction was attenuated in animals injected with either dose of AM/UC tissue compared with saline-injected control animals at 1 week postinjection. Only high-dose AM/UC-injected animals continued to show less overall joint destruction by 4 weeks postinjection. Intra-articular injection of particulate AM/UC tissue attenuates cartilage degradation in a rat MMT model of OA, suggesting that it may be able to slow joint destruction in patients with OA.

The surface properties of materials contribute to host cellular response and play a significant role in determining the overall success or failure of an implanted biomaterial. Rough titanium (Ti) surface microtopography and high surface free energy have been shown to enhance osteoblast maturation in vitro and increase bone formation in vivo. Whereas the surface properties of Ti are known to affect osteoblast response, host bone quality also plays a significant role in determining successful osseointegration. One factor affecting host bone quality is patient age. We examined both in vitro and in vivo whether response to Ti surface features was affected by animal age. Calvarial osteoblasts isolated from 1-, 3-, and 11-month-old rats all displayed a reduction in cell number and increases in alkaline phosphatase-specific activity and osteocalcin in response to increasing Ti surface microtopography and surface energy. Further, osteoblasts from the three ages examined displayed increased production of osteocalcin and local factors osteoprotegerin, vascular endothelial growth factor (VEGF)-A, and active transforming growth factor (TGF)-β1 in response to increasing Ti surface roughness and surface energy. Latent TGF-β1 only increased in cultures of osteoblasts from 1- and 3-month-old rats. Treatment with the systemic osteotropic hormone 1α,25(OH)(2)D(3) further enhanced the response of osteoblasts to Ti surface features for all three age groups. However, osteoblasts derived from 11-month-old animals had a reduced response to 1α,25(OH)(2)D(3) compared to osteoblasts derived from 1- or 3-month-old animals. These results were confirmed in vivo. Ti implants placed in the femoral intramedullary canal of old (9-month-old) mice yielded lower bone-to-implant contact and neovascularization in response to Ti surface roughness and energy compared to younger (2-month-old) mice. These results show that rodent osteoblast maturation in vitro as well as new bone formation in vivo is reduced with age. Whether comparable age differences exist in humans needs to be determined., (Copyright © 2012 American Society for Bone and Mineral Research.)

Restoration of vasculature is a critical component for successful integration of implants in musculoskeletal tissue. Sodium hyaluronate (NaHY) has been used as a carrier for demineralized bone matrix (DBM). DBM is osteoinductive and osteoconductive, but whether NaHY by itself has an effect is not known. NaHY has been reported to promote neovascularization, suggesting it may increase neovasculature when used with DBM as well. To test this, we used a rat tibial marrow ablation model to assess neovascularization during bone formation and regeneration of marrow with different combinations of NaHY alone and NaHY+DBM. To assess neovascularization during normal healing, animals were euthanized at 3-, 6-, 14-, 21-, and 28-days post-ablation, and the vasculature perfused using a radio-opaque contrast agent. Vascular morphology was assessed using μCT and histology. Peak vessel volume within the marrow cavity was observed on day-14 post-ablation. Test materials were injected into the ablated marrow space as follows: (A) empty defect controls; (B) high MW (700-800 kDa) NaHY + heat inactivated DBM; (C) DBM in PBS; (D) low MW NaHY (35 kDa) + DBM; (E) high MW NaHY + DBM; (F) D:E 50:50; (G) low MW NaHY; (H) high MW NaHY; and (I) G:H 50:50. Neovascularization varied with bone substitute formulation. μCT results revealed that addition of NaHY resulted in an increase in vessel number compared to empty defects. Total blood vessel volume in all NaHY only groups were similar to DBM alone. Histomorphometry of sagittal sections showed that all three formulations of NaHY increased blood vessel number within the marrow cavity, confirming that NaHY promotes neovascularization., (Copyright © 2011 Wiley Periodicals, Inc.)

Rough titanium (Ti) surface microarchitecture and high surface energy have been shown to increase osteoblast differentiation, and this response occurs through signaling via the alpha(2)beta(1) integrin. However, clinical success of implanted materials is dependent not only upon osseointegration but also on neovascularization in the peri-implant bone. Here we tested the hypothesis that Ti surface microtopography and energy interact via alpha(2)beta(1) signaling to regulate the expression of angiogenic growth factors. Primary human osteoblasts (HOB), MG63 cells and MG63 cells silenced for alpha(2) integrin were cultured on Ti disks with different surface microtopographies and energies. Secreted levels of vascular endothelial growth factor-A (VEGF-A), basic fibroblast growth factor (FGF-2), epidermal growth factor (EGF), and angiopoietin-1 (Ang-1) were measured. VEGF-A increased 170% and 250% in MG63 cultures, and 178% and 435% in HOB cultures on SLA and modSLA substrates, respectively. In MG63 cultures, FGF-2 levels increased 20 and 40-fold while EGF increased 4 and 6-fold on SLA and modSLA surfaces. These factors were undetectable in HOB cultures. Ang-1 levels were unchanged on all surfaces.Media from modSLA MG63 cultures induced more rapid differentiation of endothelial cells and this effect was inhibited by anti-VEGF-A antibodies. Treatment of MG63 cells with 1 alpha,25(OH)(2)D3 enhanced levels of VEGF-A on SLA and modSLA.Silencing the alpha(2) integrin subunit increased VEGF-A levels and decreased FGF-2 levels. These results show that Ti surface microtopography and energy modulate secretion of angiogenic growth factors by osteoblasts and that this regulation is mediated at least partially via alpha(2)beta(1) integrin signaling., ((c) 2010 Elsevier Ltd. All rights reserved.)

Objective: Surface roughness and surface free energy are two important factors that regulate cell responses to biomaterials. Previous studies established that titanium (Ti) substrates with micron-scale and submicron scale topographies promote osteoblast differentiation and osteogenic local factor production and that there is a synergistic response to micro-rough Ti surfaces that have retained their high surface energy via processing that limits hydrocarbon contamination. This study tested the hypothesis that the synergistic response of osteoblasts to these modified surfaces depends on both surface micro-structure and surface energy., Methods: Ti disks were manufactured to present three different surface structures: smooth pretreatment (PT) surfaces with R(a) of 0.2 microm; acid-etched surfaces (A) with a submicron roughness R(a) of 0.83 microm; and sandblasted/acid-etched surfaces (SLA) with R(a) of 3-4 microm. Modified acid-etched (modA) and modified sandblasted/acid-etched (modSLA) Ti substrates, which have low contamination and present a hydroxylated/hydrated surface layer to retain high surface energy, were compared with regular low surface energy A and SLA surfaces. Human osteoblast-like MG63 cells were cultured on these substrates and their responses, including cell shape, growth, differentiation (alkaline phosphatase, osteocalcin), and local factor production (TGF-beta1, PGE(2), osteoprotegerin (OPG)) were analyzed (N=6 per variable). Data were normalized to cell number., Results: There were no significant differences between smooth PT and A surfaces except for a small increase in OPG. Compared to A surfaces, MG63 cells produced 30% more osteocalcin on modA, and 70% more on SLA. However, growth on modSLA increased osteocalcin by more than 250%, which exceeded the sum of independent effects of surface energy and topography. Similar effects were noted when levels of latent TGF-beta1, PGE(2) and OPG were measured in the conditioned media., Conclusions: The results demonstrate a synergistic effect between high surface energy and topography of Ti substrates and show that both micron-scale and submicron scale structural features are necessary.