Healing Events Research Articles

Assessing Risks of Impaired Healing and Osteomyelitis Associated with Bisphosphonates Using FDA Adverse Event Reporting System (FAERS)

Objective: Bisphosphonates are the leading class of drugs to prevent and treat osteoporosis. Numerous cases of bisphosphonates related to bone necrosis and bone fractures have been reported. In this study the risks of impaired healing and osteomyelitis associated with bisphosphonates were assessed using case reports submitted to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Methods: Using FAERS the adverse events reports from the first quarter of 2004 to the second quarter of 2012 associated with bisphosphonates and non-bisphosphonates anti-osteoporosis drugs were generated and evaluated. Standardized pharmacovigilance tools were applied to detect the signal of impaired healing and osteoporosis. Results: Among 14493 total reported events of impaired healing in FAERS, 49% of the cases were associated with use of bisphophonates. Substantial and pharmacovigilantly significant signals of impaired healing (PRR=13.39) and osteomyelitis (PRR=7.06) were detected. There was less risk of impaired healing (PRR=4.8) and osteomyelitis (PRR=1.61) associated with ibandronate (PRR=4.80) compared to other bisphosphonates. Interestingly weak but significant signals of impaired healing (PRR=3.40) and osteomyelitis (PRR=2.38) were also detected for denosumab. There were no significant risks of impaired healing (PRR=1.85) and osteomyelitis (PRR=0.25) associated with teriparatide. Conclusion: This study for the first time signals an increasing risk of impaired healing and osteomyelitis associated with bisphosphonates using FAERS. It has significant implication for patient safety in pharmacy practice. Considering the limitation of FAERS, such as under reporting, reporting bias and Weber-effect, this study provides goal for future large pharmacoepidemiologic studies.

Role of dermatopontin in re-epithelialization: implications on keratinocyte migration and proliferation.

Re-epithelialization is a key event in wound healing and any impairment in that process is associated with various pathological conditions. Epidermal keratinocyte migration and proliferation during re-epithelialization is largely regulated by the cytokines and growth factors from the provisional matrix and dermis. Extracellular matrix consists of numerous growth factors which mediate cell migration via cell membrane receptors. Dermatopontin (DPT), a non-collagenous matrix protein highly expressed in dermis is known for its striking ability to promote cell adhesion. DPT also enhances the biological activity of transforming growth factor beta 1 which plays a central role in the process of wound healing. This study was designed to envisage the role of DPT in keratinocyte migration and proliferation along with its mRNA and protein expression pattern in epidermis. The results showed that DPT promotes keratinocyte migration in a dose dependant fashion but fail to induce proliferation. Further, PCR and immunodetection studies revealed that the mRNA and protein expression of DPT is considerably negligible in the epidermis in contrast to the dermis. To conclude, DPT has a profound role in wound healing specifically during re-epithelialization by promoting keratinocyte migration via paracrine action from the underlying dermis.

Direct and indirect observation of multiple local healing events in successively loaded fibre reinforced polymer model composites using healing agent-filled compartmented fibres

Abstract Compartmented fibres containing liquid healing agents have been proposed as a new method to provide local healing in fibre reinforced polymer composites. The compartmented fibres do not contribute to the mechanical properties of the composite but only serve to locally distribute the sources of healing agent and to overcome the intrinsic problems associated with hollow fibres and spherical capsules as containers for the healing agent. In this work the intended multiple local release and healing functionality in a thermoplastic matrix is successfully demonstrated using X-ray micro-tomography and a modified three-point bending test. The results here presented further support the potential of this new concept for the development of self-healing composites.

A multiscale theory of self-crack-healing with solid healing agent assisted by shape memory effect

Solid healing agents, such as thermoplastic particles, have been widely used in molecular healing of thermosetting polymers, including conventional thermosetting polymers such as epoxy and thermosetting shape memory polymers (SMPs) such as polystyrene. Despite extensive experimental developments in this field, there is an urgent need for healing theories with the ability to correlate molecular level healing events to the bulk scale recovered material properties. A multiscale healing constitutive theory is developed in this manuscript for self-crack-healing composites with embedded solid healing agents. It is assumed that the matrix is made of SMP; and the model accounts for several microscopic healing processes including: (a) rearrangement of free crack surfaces, (b) surface approaching due to shape memory effect, (c) wetting the free surfaces by the molten solid healing agent, (d) diffusion of the solid healing agent, which has been molten upon heating, into the crack surfaces, and (e) randomization. The Continuum Damage Healing Mechanics (CDHM) is utilized to bridge the microscopic and bulk scales. The healing parameters correlate the microscopic level descriptions of the healing to the recovery of bulk material properties. The model is then introduced into the ABAQUS, through user-defined coding, and it is shown that it correlates well with the experimental observations. The developed physically consistent multiscale theory provides material designers with the ability to optimize their self-healing systems via computer aided simulations.

Ustekinumab for the Treatment of Crohn’s Disease

Introduction: Ustekinumab is a humanized immunoglobulin G monoclonal antibody that targets the shared p40 subunit of interleukin IL-12 and IL-23. It demonstrated promises in phase 2 trials for induction and maintenance therapy of anti-TNF resistant Crohn’s Disease (CD). In this study we sought to present our experience with subcutaneous ustekinumab in anti TNF resistant CD patients in a tertiary referral center. Methods: We performed a retrospective chart review of patients who were prescribed ustekinumab for treatment of CD between January 2010 and May 2014. Demographic, clinical, and treatment data were obtained. Primary end points were clinical response and remission which were defined as 3 points decline in Harvey-Bradshaw score from baseline and HBI less than 5 at week 8 respectively. Secondary outcomes were clinical response and maintenance of remission at 6 months. We also reviewed ancillary outcome such as modified short inflammatory bowel disease questionnaire (SIBDQ), mucosal healing, and serious adverse events. Results: The demographic characteristics of the patients were as follows: 14 (74%) female; 17 (90%) white; 2 (10%) Hispanic; mean age 36±16.7; and BMI 24±6.2. The disease characteristics based on Montreal classification were as follows: location 100% ileocolonic; disease phenotype: penetrating (B3)-90%; stricturing (B2)-10%. Twelve patients (63%) had perianal involvement, 4 (21%) had ileostomy, and 18 (94%) were steroid refractory. Previous treatment included one anti TNF failure in 5 patients (26%) and >1 anti TNF failure in 14 (74%). Three (15%), 9 (47%) and 5 (26.3%) failed concomitant methotrexate, 6 MP and imuran therapy respectively. Three patients were excluded as they just started therapy. All patients received ustekinumab 90 mg subcutaneous at week 0, 2, 8 as induction therapy. The maintenance dose was 90 mg subcutaneous every 8 weeks. Follow-up data was available for 16 and 11 patients at week 8 and 6 months respectively. Conclusion: Clinical response and remission were achieved in 13 out of 16 (81%) and 9 out of 16 (56%) patients at 8 weeks. In 6 months 7 out of 11 (63%) patients maintained their clinical response and 5 (45%) remained in clinical remission. Eleven out of 16 (69%) patients had SIBDQ improvement at week 8. Of 11 patients who had data available at 6 months, 8 (72%) had SIBDQ>35. Two out of 5 patients achieved mucosal healing at either 8 week or 6 months. Of 10 patients who had repeat imaging either at 8 weeks or 6 months, 4 showed improvement and 6 remained unchanged. None of our patients developed serious adverse events. In this cohort of patients with anti-TNF resistant CD, ustekinumab use resulted in clinical response in 81% and remission in 56% of patients with majority maintaining clinical response and remission up to 6 months of follow-up. Disclosure - Dr. Sarah Glover - Advisory Committee: Abbvie, Grant/Research Support: Biogen, Bristol Myers Squibb, Celgene, Elan, Janssen, Pfizer and UCB.

Foxo1 inhibits diabetic mucosal wound healing but enhances healing of normoglycemic wounds.

Re-epithelialization is an important part in mucosal wound healing. Surprisingly little is known about the impact of diabetes on the molecular events of mucosal healing. We examined the role of the transcription factor forkhead box O1 (Foxo1) in oral wounds of diabetic and normoglycemic mice with keratinocyte-specific Foxo1 deletion. Diabetic mucosal wounds had significantly delayed healing with reduced cell migration and proliferation. Foxo1 deletion rescued the negative impact of diabetes on healing but had the opposite effect in normoglycemic mice. Diabetes in vivo and in high glucose conditions in vitro enhanced expression of chemokine (C-C motif) ligand 20 (CCL20) and interleukin-36γ (IL-36γ) in a Foxo1-dependent manner. High glucose–stimulated Foxo1 binding to CCL20 and IL-36γ promoters and CCL20 and IL-36γ significantly inhibited migration of these cells in high glucose conditions. In normal healing, Foxo1 was needed for transforming growth factor-β1 (TGF-β1) expression, and in standard glucose conditions, TGF-β1 rescued the negative effect of Foxo1 silencing on migration in vitro. We propose that Foxo1 under diabetic or high glucose conditions impairs healing by promoting high levels of CCL20 and IL-36γ expression but under normal conditions, enhances it by inducing TGF-β1. This finding provides mechanistic insight into how Foxo1 mediates the impact of diabetes on mucosal wound healing.

Effect of molecular weight of PEG soft segments on photo-stimulated self-healing performance of coumarin functionalized polyurethanes

Polyurethanes consisting of tri-functional homopolymer of hexamethylene diisocyanate (tri-HDI) and polyethylene glycol (PEG) are synthesized, in which photo-reversible coumarin moieties act as pendant groups. Accordingly, the polyurethanes can be repeatedly self-healed under UV lights at room temperature by taking advantages of the photodimerization and photocleavage habits of coumarin. Molecular weight of the soft segment, PEG, is found to be closely related to the healing performance of the polyurethanes. Lower molecular weight PEG that corresponds to higher initial coumarin concentration in the polymer is critical for obtaining higher healing efficiency in the case of the first healing action. Nevertheless, it does not guarantee high reversibility of the photo-remendability during the repeated healing events. In contrast, the polyurethane with moderate molecular weight PEG has achieved balanced performance. Reaction kinetics is less important for the healing effect.

Magma fracturing and degassing associated with obsidian formation: The explosive–effusive transition

This paper explores the role of melt fracturing in degassing rhyolitic volcanic systems. The Monte Pilato–Rocche Rosse eruptions in Italy evolved from explosive to effusive in style, and H2O content in quenched glasses changed over time from relatively H2O-rich (~0.90wt.%) to H2O-poor dense obsidian (~0.10–0.20wt.%). In addition, healed fractures have been recorded in all different eruptive materials, from the glass of early-erupted tube pumice and rinds of breadcrusted obsidian pyroclasts, to the glass of late-erupted dense obsidian pyroclasts, and throughout the final effusive Rocche Rosse lava flow. These rocks show multiple fault sets, some with crenulated fault planes indicating resumption of viscous flow after faulting, complex obsidian breccias with evidence for post-brecciation folding and stretching, and centimetre- to metre-thick tuffisite preserved in pyroclasts and lava, representing collapsed foam due to fracturing of vesicle walls. These textural observations indicate that multiple fracturing and healing events occurred during both explosive and effusive eruptions. H2O content in glass decreases by as much as 0.14wt.% towards healed fractures/faults and decreases in stretched obsidian breccias towards regions of intense brecciation. A drop in pressure and increase in temperature along fractures caused diffusive H2O migration through melt towards fracture surfaces. Repetitive and pervasive fracturing and healing thereby create conditions for diffusive H2O loss into fractures and subsequent escape through permeable paths. This type of progressive magma degassing provides a potential mechanism to explain the formation of dense obsidian and the evolution from explosive to effusive eruption style.

Growth/differentiation factor‐5: pre‐clinical and clinical evaluations of periodontal regeneration and alveolar augmentation – review

Growth/differentiation factor-5 (GDF-5) plays critical roles in mesenchymal cell differentiation and stimulates human periodontal ligament cell proliferation. Potentially, GDF-5 may also play roles in wound healing including periodontal regeneration and alveolar augmentation. The objective of this review was to provide up-to-date information from pre-clinical/clinical studies evaluating GDF-5 for these indications. A comprehensive search using PubMed and Google search engines was conducted to identify reports on GDF-5 applied to periodontal and alveolar indications. Two reviewers independently screened the titles and abstracts from a total of 479 reports. Full-length articles of 17 pre-clinical and four clinical studies were selected and reviewed. Canine-, porcine- and non-human primate-based models as well as human clinical trials were used in the evaluation of GDF-5 in support of periodontal regeneration and alveolar augmentation. An absorbable collagen sponge (ACS), β-tricalcium phosphate (β-TCP) and a poly(lactic-co-glycolic) acid (PLGA) were evaluated as candidate carriers for GDF-5 using various dose and healing intervals demonstrating significantly enhanced periodontal regeneration/alveolar augmentation including cementum, periodontal ligament and alveolar bone with limited, if any, adverse effects. Growth/differentiation factor-5 supports periodontal regeneration/alveolar augmentation without aberrant healing events documented in qualified pre-clinical models and clinical pilot studies. In perspective, GDF-5 appears a promising technology for periodontal regeneration/alveolar augmentation.

Initiating a regenerative response; cellular and molecular features of wound healing in the cnidarian Nematostella vectensis

BackgroundWound healing is the first stage of a series of cellular events that are necessary to initiate a regenerative response. Defective wound healing can block regeneration even in animals with a high regenerative capacity. Understanding how signals generated during wound healing promote regeneration of lost structures is highly important, considering that virtually all animals have the ability to heal but many lack the ability to regenerate missing structures. Cnidarians are the phylogenetic sister taxa to bilaterians and are highly regenerative animals. To gain a greater understanding of how early animals generate a regenerative response, we examined the cellular and molecular components involved during wound healing in the anthozoan cnidarian Nematostella vectensis.ResultsPharmacological inhibition of extracellular signal-regulated kinases (ERK) signaling blocks regeneration and wound healing in Nematostella. We characterized early and late wound healing events through genome-wide microarray analysis, quantitative PCR, and in situ hybridization to identify potential wound healing targets. We identified a number of genes directly related to the wound healing response in other animals (metalloproteinases, growth factors, transcription factors) and suggest that glycoproteins (mucins and uromodulin) play a key role in early wound healing events. This study also identified a novel cnidarian-specific gene, for a thiamine biosynthesis enzyme (vitamin B synthesis), that may have been incorporated into the genome by lateral gene transfer from bacteria and now functions during wound healing. Lastly, we suggest that ERK signaling is a shared element of the early wound response for animals with a high regenerative capacity.ConclusionsThis research describes the temporal events involved during Nematostella wound healing, and provides a foundation for comparative analysis with other regenerative and non-regenerative species. We have shown that the same genes that heal puncture wounds are also activated after oral-aboral bisection, indicating a clear link with the initiation of regenerative healing. This study demonstrates the strength of using a forward approach (microarray) to characterize a developmental phenomenon (wound healing) at a phylogenetically important crossroad of animal evolution (cnidarian-bilaterian ancestor). Accumulation of data on the early wound healing events across numerous systems may provide clues as to why some animals have limited regenerative abilities.

Neutrophil depletion in the early inflammatory phase delayed cutaneous wound healing in older rats: improvements due to the use of un-denatured camel whey protein

BackgroundWhile it is known that advanced age alters the recruitment of neutrophils during wound healing, thereby delaying the wound healing process, little is known about prolonged wound healing in advanced ages. Thus, we investigated the correlation of neutrophil recruitment with healing events, and the impact of whey protein (WP) on neutrophil activation.MethodsThe animals were allocated into wounded young group, wounded older group and wounded older rats with daily treatment of WP at a dose of 100 mg/kg of body weight.ResultsOur results pointed to a marked deficiency in the number of neutrophils in the wounds of older rats, which was accompanied with impairment of the healing process. In the group of older rats, phagocytic activity, as tested by fluorescence microscopy, declined throughout the first 24 hours after wounding. Both the neutrophil number and the phagocytic activity recovered in older rats which received WP supplementation. Interestingly, WP was found to significantly up-regulate the MIP-1α and CINC-1 mRNA expression in old rats. On the other hand, the wound size in older rats was significantly higher than that in younger ones. Blood angiogenesis was also significantly delayed in the older group as opposed to the young rats. WP, however, was found to return these indices to normal levels in the older rats. Proliferation and epidermal migration of the keratinocytes and the collagen deposition were also returned to the normal rates.ConclusionsThis data confirms the critical role of neutrophil recruitment in the early inflammatory phase of wound healing in older rats. In addition, WP protein was used to improve neutrophil function in older rats, healing events returned to a more normal profile.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2100966986117779.

Wound Healing

After studying this article, the participant should be able to: 1. Describe the basic physiologic events in normal wound healing. 2. Understand the differences in healing among skin, bone, cartilage, and tendon. 3. Identify factors that may compromise or delay wound healing. 4. Describe methods for optimal closure of a wound. Understanding the physiology and pathophysiology of normal wound healing and potential impediments to its end will allow the plastic surgeon to maximize postoperative outcomes and, in some instances, avoid unnecessary surgical interventions. Continuous advancements in our understanding of this process require frequent reviews of available data to permit reliable, evidence-based recommendations for clinical application. This is the first of a two-part article summarizing the science and clinical recommendations necessary for successful wound healing.

Purinergic Signaling in Early Inflammatory Events of the Foreign Body Response: Modulating Extracellular ATP as an Enabling Technology for Engineered Implants and Tissues

Purinergic signaling is a ubiquitous and vital aspect of mammalian biology in which purines--mainly adenosine triphosphate (ATP)--are released from cells through loss of membrane integrity (cell death), exocytosis, or transport/diffusion across membrane channels, and exert paracrine or autocrine signaling effects through three subclasses of well-characterized receptors: the P1 adenosine receptors, the P2X ionotropic nucleotide receptors, and the P2Y metabotropic receptors. ATP and its metabolites are released by damaged and stressed cells in injured tissues. The early events of wound healing, hemostasis, and inflammation are highly regulated by these signals through activation of purinergic receptors on platelets and neutrophils. Recent data have demonstrated that ATP signaling is of particular importance to targeting leukocytes to sites of injury. This is particularly relevant to the subject of implanted medical devices, engineered tissues, and grafts as all these technologies elicit a wound healing response with varying degrees of encapsulation, rejection, extrusion, or destruction of the tissue or device. Here, we review the biology of purinergic signaling and focus on ATP release and response mechanisms that pertain to the early inflammatory phase of wound healing. Finally, therapeutic options are explored, including a new class of peptidomimetic drugs based on the ATP-conductive channel connexin43.

Clinical Outcomes after Treatment of Periodontal Intrabony Defects with Nanocrystalline Hydroxyapatite (Ostim) or Enamel Matrix Derivatives (Emdogain): A Randomized Controlled Clinical Trial

Introduction. Periodontitis is an inflammatory process in response to dental biofilm and leads to periodontal tissue destruction. The aim of this study was the comparison of outcomes using either an enamel matrix derivative (EMD) or a nanocrystalline hydroxyapatite (NHA) in regenerative periodontal therapy after 6 and 12 months. Methods. Using a parallel group, prospective randomized study design, we enrolled 19 patients in each group. The primary outcome was bone fill after 12 months. Attachment gain, probing pocket depth (PPD) reduction, and recession were secondary variables. Additionally, early wound healing and adverse events were assessed. Data analysis included test of noninferiority of NHA group (test) compared to EMD group (reference) in bone fill. Differences in means of secondary variables were compared by paired t-test, frequency data by exact χ 2 test. Results. Both groups showed significant bone fill, reduction of PPD, increase in recession, and gain of attachment after 6 and 12 months. No significant differences between groups were found at any time point. Adverse events were comparable between both groups with a tendency of more complaints in the NHA group. Conclusion. The clinical outcomes were similar in both groups. EMD could have some advantage compared to NHA regarding patients comfort and adverse events. The trial is registered with ClinicalTrials.gov NCT00757159.

Comparative evaluation between 20% EDTA-S & ornidazole gel as root biomodification agent asem study

Background: It should be well understood that the root surface receptiveness to clot formation & initial periodontal wound healing decides the nature of the connective tissue attachments. This study was carried out to assess the initial wound healing events after the application of 20% EDTA-S & Ornidazole gel and assess the formation of fibrin network following blood. Material& Method: Thirty multi-rooted teeth indicated for extraction due to periodontal disease were selected & divided into group A (20%EDTA-S), group B (Ornidazole gel (1% W/V)), group C (7.4pH phosphate buffer saline), group D (20%EDTA-S+ Blood), group E (Ornidazole gel+ Blood), group F (7.4pH) phosphate buffer saline+ Blood). Following root planning, the root surface was cut using diamond disc under copious irrigation. Samples from each group were subjected for root conditioning agent application by passive method. Specimens were then subjected to scanning electron microscopic study. Smear layers removal were analysed by Sampaia et al index. Results: 20%EDTA-S removed the smear layer better than ornidazole gel. Fibrin network formation was seen with specimen treated with 20% EDTA-S + Blood. Conclusion: Use of 20% EDTA-S as root conditioning agent has a beneficial effect on initial wound healing events, which are important for periodontal regenerative therapies.

Safety of Medical Male Circumcision in Human Immunodeficiency Virus–Infected Men in Rakai, Uganda

To assess the safety of medical male circumcision (MMC) among human immunodeficiency virus (HIV)-infected men with CD4 levels <350 cells/mm(3), CD4 counts ≥ 350 cells/mm(3), and HIV-negative men. Two hundred forty-two HIV-infected men and a sample of 262 HIV-negative consenting men aged 12 years or older who requested free MMC were enrolled in a prospective study. Blood for HIV testing and a CD4 count were collected before surgery. During weekly follow-up over 6 weeks, data were collected on wound healing and adverse events (AEs) by examination, and resumption of sex and condom use ascertained by interview. Surgery-related AEs were characterized by type, severity, management, and resolution. Chi-square and Fisher's exact tests were used to test for differences in AE proportions. Overall, only 2 of the 453 men experienced moderate AEs, a rate of 0.44 per 100 surgeries. No AE occurred among HIV-negative men, whereas the AE rate among HIV-infected men with CD4 counts ≥ 350 cells/mm(3) was 0.79 per 100 surgeries, and among men with CD4 counts <350 cells/mm(3) the rate was 1.19 per 100 surgeries (P = .214). AE rates were comparable for all characteristics (P >.05). HIV-positive men can be safely included in MMC roll out programs without necessitating presurgery CD4 counts determination.

Autogenous Options for Soft‐Tissue Management of Extraction Sockets in the Anterior Maxilla

Focused Clinical Question: How can the soft tissue be managed with autogenous options after tooth extraction in the anterior maxilla?Summary: Esthetic concerns are of unique importance in the anterior maxilla. Tooth loss usually leads to significant alterations of the soft‐ and hard‐tissue components of the ridge. These alterations may be prevented or minimized by a variety of tissue augmentation methods at different time points, ranging from tooth extraction to the placement of a restoration. Autogenous soft‐tissue options are available to achieve complete closure of socket grafting and immediate implant sites. They comprise free gingival grafts, free connective tissue grafts, pedicle palatal tissue grafts, and coronally advanced flaps. A decision tree is presented for the different hard‐ and soft‐tissue management options after tooth extraction in the anterior maxilla.Conclusions: The literature lacks comparative studies among the different soft‐tissue grafting techniques designed for soft‐tissue closure of extraction sockets. Nonetheless, full closure is recognized as an important hallmark for improved healing outcomes. Soft‐tissue augmentation and volume increase were clinically evident with the various techniques. The minimal adverse healing events and improved survival reported with the pedicle grafts tend to favor these options in socket preservation cases, whereas coronally advanced flaps are preferred in severe cases involving multiple sockets.

Temporal expression of IL-1β and IL-10 in rat skin, muscle, small bowel, and colon wounds: a correlative study

Cytokines play a major role in coordinated wound healing events. We hypothesized that rapid intestinal healing is due to an early upregulation of the pro-inflammatory cytokine interleukin-1β (IL-1β), followed by increases in the expression of the anti-inflammatory cytokine IL-10. We characterized the time course of IL-1β and IL-10 release at four wounds (skin, muscle, small bowel, and colonic anastomosis) after surgery on 38 juvenile male Sprague-Dawley rats. The tissue samples of each site were harvested at 0 (control), 1, 3, 5, 7, and 14 days postoperatively (n=6-8 per group) and analyzed by enzyme-linked immunosorbent assay kits for IL-1β and IL-10. IL-1β expression peaked at days 5 and 7 in small bowel and colonic wounds when compared to skin or muscle. Similarly, IL-10 showed high expression in these time points in small bowel and colonic wounds. However, IL-10 showed the same expression in all time points in muscle and skin tissues except at day 1. The high expression in IL-1β and IL-10 levels in small bowel and colon might explain the accelerated healing process in these wounds in comparison to skin and muscle tissues. Additional studies are required to determine whether IL-1β and IL-10 expression is the major factor defining site-specific differences in healing rates in different tissues. Understanding cytokine action in the wound healing process could lead to novel and effective therapeutic strategies.

Numerical investigation into blood clotting at the bone-dental implant interface in the presence of an electrical stimulus

The insertion of a dental implant activates a sequence of wound healing events ending with bone formation and implant osseointegration. This sequence starts with the blood coagulation process and the formation of a fibrin network that detains spilt blood. Fibrin formation can be simplified as the kinetic reaction between thrombin and fibrinogen preceding the conversion of fibrinogen into fibrin. Based on experimental observations of the electrical properties of these molecules, we present a hypothesis for the mechanism of a static electrical stimulus in controlling the formation of the blood clot. Specifically, the electrical stimulus increases the fibrin network formation in such a way that a preferential region of higher fibrin density is obtained. This hypothesis is validated by means of a numerical model for the blood clot formation at the bone-dental implant interface. Numerical results compare favorably to experimental observations for blood clotting with and without the static electrical stimulus. It is concluded that the density of the fibrin network depends on the strength of the static electrical stimulus, and that the blood clot formation has a preferential direction of formation in the presence of the electrical signal.

First-in-Human Evaluation of a Bioabsorbable Polymer–Coated Sirolimus-Eluting Stent: Imaging and Clinical Results of the DESSOLVE I Trial (DES With Sirolimus and a Bioabsorbable Polymer for the Treatment of Patients With De Novo Lesion in the Native Coronary Arteries)

This first-in-human multicenter study sought to examine prospectively the safety and efficacy of a new, cobalt chromium thin-strut, coronary absorbable polymer-coated, sirolimus-eluting stent. Bioabsorbable polymers on drug-eluting stents may lower the long-term risks of inflammation, delayed healing, and adverse events. We enrolled patients with symptomatic coronary artery disease with stable or unstable angina pectoris and >50% diameter stenosis, amenable to coverage with a ≤23-mm long stent in a vessel 2.5 to 3.5 mm in diameter. All patients received dual antiplatelet therapy after implantation. Patients, in groups of 10, underwent repeat angiography, intravascular ultrasound, and optical coherence tomography at 4, 6, or 8 months, and all patients were seen or contacted at 18 months of follow-up. The median (range) in-stent late lumen loss (LLL) was 0.03 mm (-0.22 to 0.21 mm), 0.10 mm (-0.03 to 1.2 mm), and 0.08 mm (-0.01 to 0.28 mm), at 4, 6, and 8 months, respectively. At 18 months, the median in-stent LLL was 0.08 mm (-0.30 to 0.46 mm). On optical coherence tomography, the proportion of uncovered stent struts decreased from a median of 7.3% (range 0.4% to 46.3%) at 4 months to 0% (range: 0% to 3.4%) at 18 months. The percentage of neointimal volume obstruction by intravascular ultrasound increased from a median of 5.3% to 9.1% between 4 and 6 months and remained nearly unchanged thereafter through 18 months of follow-up. The only recorded major adverse cardiac event was a myocardial infarction. At 18 months of follow-up, this absorbable polymer-coated, cobalt chromium sirolimus-eluting stent was associated with a low and stable in-stent LLL, complete strut coverage, and no stent thrombosis. (First-In-Human Trial of the MiStent Drug-Eluting Stent [DES] in Coronary Artery Disease [DESSOLVE-I]; NCT01247428).