Well-defined aminooxy terminated N-(2-hydroxypropyl) methacrylamide macromers for site specific bioconjugation of glycoproteins.

Syntheses and characterization of aminooxy terminated polymers of N-(2-hydroxyproyl) methacrylamide (HPMA) of controlled molecular weight and narrow molecular weight distribution are presented here. Design of a chain transfer agent (CTA) containing N-tert-butoxycarbonyl (t-Boc) protected aminooxy group enabled us to use reversible addition-fragmentation (RAFT) polymerization technique to polymerize the HPMA monomer. An amide bond was utilized to link the aminooxy group and the CTA through a triethylene glycol spacer. As a result, the aminooxy group is linked to the poly(HPMA) backbone through a hydrolytically stable amide bond. By varying the monomer to initiator ratios, polymers with targeted molecular weights were obtained. The molecular weights of the polymers were determined by gel permeation chromatography (GPC) and mass spectrometry (ESI and MALDI-TOF). The t-Boc protecting group was quantitatively removed to generate aminooxy terminated poly(HPMA) macromers. These macromers were converted to rhodamine B terminated poly(HPMA) by reacting N-hydroxysuccinimide (NHS) ester of the dye with the terminal aminooxy group to form a stable alkoxyamide bond. Utility of these dye-labeled polymers as molecular probes was evaluated by fluorescence microscopy by studying their intracellular uptake by renal epithelial cells. These aminooxy terminated poly(HPMA) were also tested as biocompatible carriers to prepare chemoselective bioconjugates of proteins using transferrin (Tf) as the protein. Oxidation of the sialic acid side chains of Tf generated aldehyde functionalized protein that was reacted with aminooxy terminated poly(HPMA), which resulted in protein-polymer bioconjugates carrying oxime linkages. These bioconjugates were characterized by gel electrophoresis and MALDI-TOF mass spectrometry.

Maxillofacial anatomy: the mandibular symphysis.

Placement of dental implants in the anterior mandible is considered by many clinicians to be a relatively low-risk procedure. However, hemorrhagic episodes following implant placement in the mandibular symphysis are regularly reported and can have serious consequences. The use of high-resolution focused cone beam scanners has given us the ability to visualize the intricate neurovascular network of the intraforaminal region without distortion and in greater detail. Knowledge of the arterial supply and navigated implant placement in the mandibular symphysis can help to avoid these potentially life-threatening emergencies.

The Use of a Dehydrated, Deepithelialized Amnion-Chorion Membrane in Guided Bone Regeneration Involving Staged Implant Placement: Case Series with a 5-Year Follow-up.

Barrier membranes are critical to the success of guided bone regeneration (GBR). Though not directly involved in bone regeneration, barrier membranes hold bone graft materials at the surgical site during the slow process of bone regeneration and prevent the infiltration of fibrotic gingival tissues that would compromise new bone formation. Many options are available on the market, but membranes derived from placental tissues are gaining rapid adoption due to their unique biologic and handling properties. In this case series, a dehydrated human deepithelialized amnion-chorion membrane (ddACM) was used in combination with freeze-dried bone allograft (FDBA) for two-stage GBR procedures. Data from 1-year and 5-year follow-up appointments are presented, as well as predictable indications for the use of ddACM. Using ddACM with FDBA for GBR cases led to predictable bone regeneration with osseointegrated implants at 5-year postoperative visits.

Indications for Simultaneous Implantation and Bone Augmentation Using the Allograft Bone Ring Technique.

Dental implant therapy often requires bone augmentation to facilitate stable implantation with a predictable outcome. Traditionally, this is accomplished through guided bone regeneration (GBR), which is a series of surgical procedures that use barrier membrane technology to direct the growth of new hard and soft tissues in sites with insufficient volumes for the purpose of placing dental implants. GBR and implant placement can be performed in either one or two surgeries. This article will focus on a novel simultaneous approach that utilizes a custom milled cancellous allograft bone ring that is stabilized through the graft preparation and apical threads of the dental implant. Indications include simultaneous implant placement in a deficient sinus as well as horizontal and vertical four-, three-, two-, and one-wall defects.

Clinical evaluation alveolar ridge preservation with a beta-tricalcium phosphate socket graft.

PURPOSE: To determine the efficacy of an alloplastic graft material, consisting of a pure-phase beta-tricalcium phosphate (beta-TCP), in the preservation of ridge volume after tooth extraction and before dental implant placement. Histomorphometric analysis was completed on a few samples to determine the percentage of vital bone over a fixed healing period. MATERIALS AND METHODS: Patients requiring tooth extraction and bone regeneration before implant placement were included in this study. Measurements of alveolar width were made at the time of extraction and the time of implant placement. The extraction sites were grafted with a pure-phase beta-TCP and covered with a barrier. Approximately 6 months after surgery, the sites were reentered for implant placement. Cores were taken of the regenerated material for histologic analysis, with a trephine used as the first bur in preparation for some of the osteotomies. Implants were placed according to the manufacturers' recommendations and loaded at the appropriate time. RESULTS: The beta-TCP placed at the time of grafting extraction sockets was well tolerated in all sites with all of the barriers used. There were no incidences of postoperative infection or graft rejection. At the time of implant placement, much of the graft material had resorbed and been converted to vital alveolar bone. The implant recipient sites were dense and supported placement of endosseous dental implants that were fully stable. The width of the extraction sockets was preserved to 91% of the preoperative width. CONCLUSIONS: Extraction socket grafting with the pure-phase beta-TCP tested in this study and covered with either a resorbable collagen or dense polytetrafluoroethylene barrier is a predictable method for preserving alveolar dimensions. The graft material resorbs to a high percentage in the timeframe desired between extraction and dental implant placement, as shown clinically, radiographically, and histologically. In addition, the regenerated material in the socket has enough density to support implant placement with subsequent loading in the 4- to 6-month period used in this study.

A One-Stage Procedure to Achieve Predictable Implant Placement and Guided Bone Regeneration.

Advancements in implant dentistry have led to increased predictability in bone augmentation procedures, resulting in fewer complications and larger bone yields. As demonstrated in this case report, one such innovation, the Straumann® AlloGraft Ring, enhances the clinician's ability to place a dental implant in a restoratively driven fashion with simultaneous guided bone regeneration.

A Prospective Clinical Study on Implant Survival at 1-Year Post-Loading of a Bone-Level Tapered Implant in Private Practice: Multicentered Study.

This non-interventional study evaluated the implant survival and success of a new bone-level tapered implant design in seven private dental practices in the United States. One hundred subjects in need of implant(s) were enrolled according to all cleared indications. After implant surgery, subjects were followed for a period of 1-year post-loading. Treatment planning, implant stability, radiographic evaluation of bone levels, soft-tissue characteristics, clinician satisfaction, and adverse events were assessed. A total of 184 implants were placed, of which 172 were evaluable at 1-year follow-up. Of the 172 evaluable implants, 169 survived and were successful at 1-year post-loading. Of 152 implants with radiographs at 1 year, 90% showed no bone remodeling or <1 mm bone loss. Overall clinician satisfaction was high across all centers. Normal soft-tissue profiles were reported around the implants with improvement in color, form, and mucosal attachment at 1 year. In a "real-world" setting this observational study demonstrated high implant survival and success, stable crestal bone levels, high clinician satisfaction, and a low incidence of adverse events.

Design, Synthesis, and in†vitro Evaluation of Multivalent Drug Linkers for High-Drug-Load Antibody-Drug Conjugates.

A series of novel multivalent drug linkers (MDLs) containing cytotoxic agents were synthesized and conjugated to antibodies to yield highly potent antibody-drug conjugates (ADCs) with drug/antibody ratios (DARs) higher than those typically reported in the literature (10 vs. ≈4). These MDLs contain two copies of a cytotoxic agent attached to biocompatible scaffolds composed of a branched peptide core and discrete polyethylene glycol (PEG) chains to enhance solubility and decrease aggregation. These drug linkers produced well-defined ADCs, whose DARs could be accurately determined by LC-MS. Using this approach, ADCs with significantly lower aggregation and higher DAR than those of conventional drug linker design were obtained with highly hydrophobic cytotoxic agents such as monomethyldolastatin 10 (MMAD). The in vitro potencies of the MDL-derived conjugates matched that of ADCs of similar DAR with conventional linkers, and the potency increased proportionally with drug loading. This approach may provide a means to prepare highly potent ADCs from a broader range of drugs, including those with lower cytotoxicity or poor solubility, which otherwise limits their use for antibody-drug conjugates. This may also provide a means to further improve the potency achievable with cytotoxins currently used in ADCs.

Various Tip Applications and Temperature Changes of Er,Cr:YSGG-Laser Irradiated Implants In Vitro.

The impact of the laser tip on implant temperature when irradiating implants with lasers to treat peri-implantitis has received little attention. The present study was designed to assess the influence of two laser tips (sapphire chisel [MC3] and radial firing perio [RFP]) on temperature change of an implant irradiated with an Er,Cr:YSGG laser in vitro under various operational conditions. The results suggest that Er,Cr:YSGG irradiation using either tip with supplemental cooling can be a thermally safe approach to implant decontamination. However, use of the RFP tip consistently resulted in a greater temperature rise. The MC3 tip thus may be preferable to the RFP tip for open-flap implant debridement.

The Use of Enamel Matrix Derivative in Two-Stage Guided Bone Regeneration Procedures.

INTRODUCTION: Frequently, clinicians are confronted with situations that require the regeneration of a deficient alveolar ridge before implant placement. This is often the result of the extraction of hopelessly compromised teeth. Enamel matrix derivative (EMD) has been used successfully in the treatment of periodontal disease, including guided tissue regeneration, and the treatment of mucogingival defects. Although the exact mechanism of action is not clearly understood, there may in fact be more uses for this product. This case series reviews a proposed mechanism of action of EMD and depicts its effective use in guided bone regeneration (GBR). CASE SERIES: Three cases requiring GBR were treated with a mixture of human freeze-dried bone and EMD. The teeth were extracted, sockets were thoroughly debrided, and the defects were filled with the EMD-saturated allograft. Dental implants were placed after 10 to 16 weeks of hard and soft tissue maturation. CONCLUSIONS: The use of a freeze-dried bone allograft saturated with EMD can be used successfully in GBR. Three cases demonstrate both horizontal and vertical bone regeneration with successful implant placement.

Hyaluronic acid-based drug conjugates: state-of-the-art and perspectives.

Hyaluronan (HA) is biodegradable, highly biocompatible, and contains derivatizable functional groups along its backbone. This relatively simple, non-branched polysaccharide can target specific cell surface receptors making it an attractive polymeric carrier for targeted delivery of therapeutic agents. This article provides an overview of recent developments involving small molecule and bio-macromolecule conjugates of HA as new generation of human therapeutic agents. Several approaches have been developed to prepare conjugates of HA with small molecule drugs, therapeutic peptides, antibodies, and nucleotides. This article discusses such approaches that can modulate the pharmacokinetic and biodistribution of these therapeutic agents so as to appreciate the design criteria for HA based (bio)conjugates or nanoparticles based on their in vitro assay and in vivo pharmacokinetic study.

Toxicity of nano-zero valent iron to freshwater and marine organisms.

We tested whether three commercial forms (uncoated, organic coating, and iron oxide coating) of nano zero-valent iron (nZVI) are toxic to freshwater and marine organisms, specifically three species of marine phytoplankton, one species of freshwater phytoplankton, and a freshwater zooplankton species (Daphnia magna), because these organisms may be exposed downstream of where nZVI is applied to remediate polluted soil. The aggregation and reactivity of the three types of nZVI varied considerably, which was reflected in their toxicity. Since levels of Fe(2+) and Fe(3+) increase as the nZVI react, we also evaluated their toxicity independently. All four phytoplankton species displayed decreasing population growth rates, and Daphnia magna showed increasing mortality, in response to increasing levels of nZVI, and to a lesser degree with increasing Fe(2+) and Fe(3+). All forms of nZVI aggregated in soil and water, especially in the presence of a high concentration of calcium ions in groundwater, thus reducing their transports through the environment. However, uncoated nZVI aggregated extremely rapidly, thus vastly reducing the probability of environmental transport and potential for toxicity. This information can be used to design a risk management strategy to arrest the transport of injected nZVI beyond the intended remediation area, by injecting inert calcium salts as a barrier to transport.

Early bone healing around different implant bulk designs and surgical techniques: A study in dogs.

PURPOSE: To evaluate the bone healing response to different implant root shape designs in a dog model. MATERIALS AND METHODS: Three by eight millimeter screw-type short-pitch (SP) and large-pitch (LP) implants (Intra-Lock International, Boca Raton, FL, USA), and 4.5 x 6 mm plateau (P) implants (Bicon LLC, Boston, MA, USA) were placed along the proximal tibia of six dogs for 2 and 4 weeks. The combination of implant design and final osteotomy drilling resulted in healing chambers for the LP and P implants. The implants were nondecalcified processed to plates of approximately 30-microm thickness and were evaluated by optical microscopy for healing patterns and bone-to-implant contact (BIC). One-way analysis of variance at 95% level of significance and Tukey's test were utilized for multiple comparisons among the groups' BIC. RESULTS: Microscopy showed a approximately 150-microm region of newly deposited bone along the whole perimeter of SP implants, near the edge of the LP implant threads, and plateau tips for P implants. Rapid woven bone formation and filling was observed in regions where surgery and implant design resulted in healing chambers. No significant differences in BIC were observed (p > .75). CONCLUSIONS: Different implant design/surgical protocol resulted in varied bone healing patterns. However, the BIC and bone morphology evolution between implant designs were comparable. Regardless of the combination between implant design and final osteotomy drilling, bone morphology evolution from 2 to 4 weeks was comparable.

Functional polymers as therapeutic agents: concept to market place.

Biologically active synthetic polymers have received considerable scientific interest and attention in recent years for their potential as promising novel therapeutic agents to treat human diseases. Although a significant amount of research has been carried out involving polymer-linked drugs as targeted and sustained release drug delivery systems and prodrugs, examples on bioactive polymers that exhibit intrinsic therapeutic properties are relatively less. Several appealing characteristics of synthetic polymers including high molecular weight, molecular architecture, and controlled polydispersity can all be utilized to discover a new generation of therapies. For example, high molecular weight bioactive polymers can be restricted to gastrointestinal tract, where they can selectively recognize, bind, and remove target disease causing substances from the body. The appealing features of GI tract restriction and stability in biological environment render these polymeric drugs to be devoid of systemic toxicity that are generally associated with small molecule systemic drugs. The present article highlights recent developments in the rational design and synthesis of appropriate functional polymers that have resulted in a number of promising polymer based therapies and biomaterials, including some marketed products.

Surgical navigation in oral implantology.

The ability to generate 3-dimensional volumetric images of the maxillofacial area has allowed surgeons to evaluate anatomy before surgery and plan for the placement of implants in ideal positions. However, the ability to transfer that information to surgical reality has been the most challenging part of implant dentistry. With the advent of computer-assisted surgery, the surgeon may now navigate through the entire implant procedure with extremely high accuracy. A new portable laptop navigated system for oral implantology is discussed as an adjunct for complex implant cases.

Treatment of the contaminated implant surface using the Er,Cr:YSGG laser.

Treatment of the contaminated implant surface by mechanical and chemotherapeutic means has met with mixed success. Incomplete surface debridement or alteration of the implant surface could compromise attempts at grafting and reintegration of the implant body. Development of a laser system operating at 2780 nm and using an ablative hydrokinetic process offers the possibility for more efficient decontamination and debridement. The Er,Cr: YSGG laser is evaluated and compared with the most commonly used chemotherapeutic modality for treatment of the implant surface. A scanning electron microscope study is presented comparing YSGG ablation to citric acid treatment of the titanium plasma sprayed and HA-coated implant surface. We can conclude that laser ablation using the YSGG laser is highly efficient at removing potential contaminants on the roughened implant surface while demonstrating no effects on the titanium substrate.

Evaluation of hyaluronan from different sources: Streptococcus zooepidemicus, rooster comb, bovine vitreous, and human umbilical cord.

Sodium hyaluronate (HA) is widely distributed in extracellular matrixes and can play a role in orchestrating cell function. Consequently, many investigators have looked at the effect of exogenous HA on cell behavior in vitro. HA can be isolated from several sources (e.g., bacterial, rooster comb, umbilical cord) and therefore can possess diverse impurities. This current study compares the measured impurities and the differences in biological activity between HA preparations from these sources. It was demonstrated that nucleic acid and protein content was highest in human umbilical cord and bovine vitreous HA and was low in bacterial and rooster comb HA. Macrophages exposed to human umbilical cord HA produced significantly higher amounts of TNF-alpha relative to control or bacterial-derived HA. These results indicate that the source of HA should be considered due to differences in the amounts and types of contaminants that could lead to widely different behaviors in vitro and in vivo.