The Use of Bovine Pericardial Patches in Vascular Surgery: Where do we Draw the Line in Obtaining Informed Consent?

For a patient undergoing a carotid endarterectomy, induction with propofol, administration of heparin at the time of vessel clamping, use of a bovine pericardial patch for angioplasty, covering the wound with a hydrocolloid dressing and post-operative aspirin administration exposes the patient to animal products at every stage, from the moment they walk through the door. A number of articles have advocated obtaining informed consent when using animal products in healthcare but where should the line be drawn? METHODS: A narrative review of the literature, specifically focussing on secular and religious beliefs about the use of animal products in healthcare. Application of ethical principles and GMC guidance to formulatea discussion with regards to the use of bovine pericardium in vascular surgery. Advanced literature search carried out using Pubmed and Google Scholar databases comparing patch material used forcarotid endarterectomy. RESULTS: Disclosing the use of animal derived constituents in surgery is warranted under Beauchamp and Childress' four principals and highlighted in GMC guidance. Obtaining consent for the use of animalderived constituents at the time of surgery is something that should become a fundamental component of the written consent process and alternatives should be sought where available and practicable. CONCLUSION: This review highlights the evidence available and discusses our current standpoint from both a legal and ethical aspect.

Outcomes of Endovascular Aneurysm Repair using the Ovation Stent Graft System in Adverse Anatomy.

OBJECTIVE: The aim was the evaluation of mid-term efficacy and safety outcome measures for the Ovation (Endologix, Santa Rosa, CA, USA) stent graft system in the management of infrarenal abdominal aortic aneurysms (iAAA) with adverse anatomy. METHODS: A retrospective observational study of all patients undergoing elective iAAA repair was carried out from 2012 to 2017 using Ovation Prime or iX stent grafts with a minimum of 3 months follow-up at a single UK vascular centre. Post-operative surveillance involved computed tomography scans at 3 months and 1 year, with duplex ultrasound yearly thereafter. Outcome measures were established with retrospective analysis of pre- and post-operative imaging, and included peri-operative mortality, major adverse events, limb complications, aneurysm diameter change, and endoleak rates. All patients were within Ovation instructions for use (IFU), and assessment was made to determine whether aneurysms had anatomical features considered adverse for other commonly used stent graft platforms. RESULTS: Ovation stent grafts were implanted in 52 patients (79% male, mean age 75.7 years) with a mean aneurysm diameter of 62.5 mm (range 55-107 mm). There was 100% technical deployment success. The 30 day mortality was 0% and there was no aneurysm related mortality during follow-up (median 24 months, range 3-48 months). There were no type I or III endoleaks, but 19% developed type II endoleaks with one patient requiring re-intervention. No iliac limb occlusions were identified but one case required relining for limb kinking. All 52 cases were within the IFU for Ovation but only 12% met the IFU criteria for the Cook and Medtronic devices. CONCLUSIONS: The mid-term experience with Ovation demonstrates safe, durable treatment of iAAAs, including those with unfavourable anatomy, frequently off IFU for other commonly used devices.

Whole genome microarray data of chronic wound debridement prior to application of dermal skin substitutes.

Clinical consensus is that debridement is necessary for successful application of dermal skin substitutes (DSS) to chronic wounds. The aim here was to identify commonly expressed genes associated with wound healing in untreated acute wounds and chronic wounds treated with wound debridement followed by DSS. Cutaneous biopsies were taken at two time points from untreated acute and chronic wounds and from chronic wounds treated with DSS following debridement. Microarray analysis identified significant differences (p < 0.05) related to proliferation (HIPK2, LGR4, FGFR1, SRRT), migration (RHOC, PRPF40A, FGFR1), differentiation (TCF4, COL13A1, GNPTAB, HUWE1, FGFR1), angiogenesis (HIPK2, CASP8), extracellular matrix organization (VWA1), and apoptosis (BBC3, HIPK2, KLF11, PSME3, MSFD10, TOP2A, MLH1, CASP8, PDIA3, XAF1) when comparing untreated chronic wounds to chronic wounds treated with DSS, with similar expression levels compared to untreated acute wounds. Chronic wounds treated with debridement followed by DSS resemble untreated acute wounds at a genomic level. These novel findings, albeit with limited clinical specimen numbers, strengthen the recommendation to transform chronic into acute wounds prior to application of DSS.

Anatomic Variation of Rami Communicantes in the Upper Thoracic Sympathetic Chain: A Human Cadaveric Study.

BACKGROUND: Hyperhidrosis is secondary to over activation of the sympathetic nervous system and surgical sympathectomy is the treatment of choice when other modalities have failed. This study investigated anatomic variation in the upper thoracic sympathetic chain and associated rami communicantes among cadaveric specimens. It considers the implications of these findings on surgical techniques to treat hyperhidrosis. METHODS: The upper 4 thoracic sympathetic ganglia, intercostal nerves, and connecting rami were dissected, measured and mapped in 40 sides of 20 adult human cadavers. Ganglia location was recorded. The incidence, orientation, and distance travelled by rami communicantes was compared across different ganglionic levels and between sides. RESULTS: The percentage of ganglia located below their associated intercostal space was 6.25% with stellate ganglions present in 70% of specimens and Kuntz fibers noted in 40%. There was a stepwise reduction in incidence of rami from superior to inferior placed ganglia. The number of rami identified across all levels was significantly greater on the right (P = 0.03). The horizontal distance between the sympathetic chain and union of the rami on the intercostal nerves was significantly greater on the right across all levels (P = 0.04). CONCLUSIONS: There was substantial variation in the rami communicantes across the upper 4 ganglia and between right and left sides. Consideration of this variation should be given when planning surgical sympathectomy for hyperhidrosis particularly to avoid symptom recurrence.

Noninvasive device readouts validated by immunohistochemical analysis enable objective quantitative assessment of acute wound healing in human skin.

Objective evaluation of cutaneous wounds through use of noninvasive devices has important implications for diagnosis, monitoring treatment efficacy, progression and may lead to development of improved theranostic treatment strategies. However, there is a lack of validation in the use of certain devices in wound repair, where objective measurements taken by noninvasive devices have been corroborated by immunohistochemical analysis. Thus, data from three acute wound-healing studies in healthy volunteers using three noninvasive objective devices were further evaluated by immunohistochemistry. One hundred ten participants had 5-mm diameter skin biopsies to their arms. Spectrophotometric intracutaneous analysis (SIAscopy), full-field laser perfusion imaging, and three-dimensional imaging provided quantitative measurements of melanin, hemoglobin, collagen, blood flow, and wound size; all of which were validated by immunohistochemistry. Full-field laser perfusion imaging showed blood flow increased to D7 and decreased by 40% to D14. SIAscopy showed that hemoglobin increased to D7 and reduced to D14. CD31 analysis corroborated this by showing a 76% increase in blood vessel density to D7 and a reduction by 14% to D14. Three-dimensional imaging showed that wound surface area reduced by 50% from day 7 to day 14. Alpha-smooth muscle Actin (Alpha-SMA) staining supported these trends by showing increased levels by 72% from D0 to D14 (corresponding to wound contraction). Collagen, measured by SIAscopy, decreased to D7 and increased to D14, which was validated by collagen III analysis. Additionally, collagen I increased by 14% from D0 to D14. SIAscopy measurements for melanin showed an increase at D7 and a slight reduction to D14, while melanogenesis increased by 46.7% from D0 to D14. These findings show the utility of noninvasive objective devices in the quantitative evaluation of wound-healing parameters in human skin as corroborated by immunohistochemistry. This may contribute to the development of prognostic parameters for assessment of response to wound therapy.

Skin substitute-assisted repair shows reduced dermal fibrosis in acute human wounds validated simultaneously by histology and optical coherence tomography.

Skin substitutes are heterogeneous biomaterials designed to accelerate wound healing through provision of replacement extracellular matrix. Despite growing evidence for their use in chronic wounds, the role of skin substitutes in acute wound management and their influence on fibrogenesis remains unclear. Skin substitute characteristics including biocompatibility, porosity, and elasticity strongly influence cellular behavior during wound healing. Thus, we hypothesize that structural and biomechanical variation between biomaterials may induce differential scar formation after cutaneous injury. The following human prospective cohort study was designed to investigate this premise. Four 5-mm full thickness punch biopsies were harvested from 50 volunteers. In all cases, site 1 healed by secondary intention, site 2 was treated with collagen-GAG scaffold (CG), and decellularised dermis (DCD) was applied to site 3 while tissue extracted from site 4 was replaced (autograft). Healing tissue was assessed weekly with optical coherence tomography (OCT), before being excised on days 7, 14, 21, or 28 depending on study group allocation for later histological and immunohistochemical evaluation. Extracted RNA was used in microarray analysis and polymerase chain reaction of highlighted genes. Autograft treatment resulted in minimal fibrosis confirmed immunohistochemically and with OCT through significantly lower collagen I levels (p = 0.047 and 0.03) and reduced mean grayscale values (p = 0.038 and 0.015), respectively. DCD developed intermediate scar formation with partial rete ridge reformation and reduced fasiculonodular fibrosis. It was uniquely associated with late up-regulation of matrix metalloproteinases 1 and 3, oncostatin M, and interleukin-10 (p = 0.007, 0.04, 0.019, 0.019). Regenerated dermis was significantly thicker in DCD and autografts 28 days post-injury compared with control and CG samples (p = 0.003 and < 0.0001). In conclusion, variable fibrotic outcomes were observed in skin substitute-treated wounds with reduced scarring in autograft and DCD samples compared with controls. OCT enabled concurrent assessment of wound morphology and quantification of dermal fibrosis.

Single-stage application of a novel decellularized dermis for treatment-resistant lower limb ulcers: positive outcomes assessed by SIAscopy, laser perfusion, and 3D imaging, with sequential timed histological analysis.

We present results of an original clinical study investigating efficacy of a decellularized dermal skin substitute (DCD) as part of a one-stage therapeutic strategy for recalcitrant leg ulcers. Twenty patients with treatment-resistant ulcers underwent hydrosurgical debridement, after which DCD was applied and covered with negative pressure dressings for 1 week. Participants were reviewed on seven occasions over 6 months. 3D photography, full-field laser perfusion imaging, spectrophotometric intracutaneous analysis, and sequential biopsies were used to monitor healing. Mean ulcer duration and surface area prior to DCD placement were 4.76 years (range 0.25-40 years) and 13.11 cm(2) (range 1.06-40.75 cm(2)), respectively. Seventy percent of ulcers were venous. Surface area decreased in all patients after treatment (range 23-100%). Mean reduction was 87% after 6 months, and 60% of patients healed completely. Wound bed hemoglobin flux increased significantly 6 weeks after treatment (p = 0.005). Histological and immunohistochemical analysis confirmed progressive DCD integration with colonization by host fibroblasts, lymphocytes, and neutrophils, resulting in fibroplasia, reepithelialisation, and angiogenesis, with correlating raised CD31, collagen I, and collagen III levels. Subgroup analysis showed differing cellular behavior depending on wound duration, with delayed angiogenesis, reduced collagen deposition, and smaller reductions in surface area in ulcers present for over 1 year. The stain intensities of immunohistochemical markers including fibronectin, collagen, and CD31 differed depending on depth from the wound surface and presence of intact epithelium. DCD safely produced significant improvement in treatment-resistant leg ulcers. With no requirement for hospital admission, anesthetic, or autogenic skin grafting, this treatment could be administered in hospital and community settings.

The role of skin substitutes in the management of chronic cutaneous wounds.

Chronic wounds, including diabetic and venous ulcers, represent disruption of normal healing processes resulting in a pathological state of nonhealing cutaneous inflammation. They place an increasingly significant economic burden on healthcare providers as their prevalence is rising in keeping with an aging population. Current treatment modalities are slow acting and resource intensive. Bioengineered skin substitutes from autogenic, allogenic, or xenogenic sources have emerged as a new and alternative therapeutic option. A range of such products is licensed for clinical use, which differ in terms of structure and cellular content. Placed directly onto a prepared wound bed, skin substitutes may stimulate or accelerate healing by promoting revascularization, cellular migration, and repopulation of wound fields through provision of an appropriate scaffold material to facilitate these processes. Products containing fetal or autologous cells also benefit from early release of bioactive molecules including growth factors and cytokines. To date, limited numbers of randomized controlled trials studying skin substitutes have been published but evidence from case series and case-control studies is encouraging. This review discusses chronic wound biology, the influence that skin substitutes can exert on this environment, the products currently available, and examines the evidence for their use in chronic wound management.

Chemokines in Wound Healing and as Potential Therapeutic Targets for Reducing Cutaneous Scarring.

Significance: Cutaneous scarring is an almost inevitable end point of adult human wound healing. It is associated with significant morbidity, both physical and psychological. Pathological scarring, including hypertrophic and keloid scars, can be particularly debilitating. Manipulation of the chemokine system may lead to effective therapies for problematic lesions. Recent Advances: Rapid advancement in the understanding of chemokines and their receptors has led to exciting developments in the world of therapeutics. Modulation of their function has led to clinically effective treatments for conditions as diverse as human immunodeficiency virus and inflammatory bowel disease. Potential methods of targeting chemokines include monoclonal antibodies, small-molecule antagonists, interference with glycosaminoglycan binding and the use of synthetic truncated chemokines. Early work has shown promising results on scar development and appearance when the chemokine system is manipulated. Critical Issues: Chemokines are implicated in all stages of wound healing leading to the development of a cutaneous scar. An understanding of entirely regenerative wound healing in the developing fetus and how the expression of chemokines and their receptors change during the transition to the adult phenotype is central to addressing pathological scarring in adults. Future Directions: As our understanding of chemokine/receptor interactions and scar formation evolves it has become apparent that effective therapies will need to mirror the complexities in these diverse biological processes. It is likely that sophisticated treatments that sequentially influence multiple ligand/receptor interactions throughout all stages of wound healing will be required to deliver viable treatment options.

Acute cutaneous wounds treated with human decellularised dermis show enhanced angiogenesis during healing.

BACKGROUND: The influence of skin substitutes upon angiogenesis during wound healing is unclear. OBJECTIVES: To compare the angiogenic response in acute cutaneous human wounds treated with autogenic, allogenic and xenogenic skin substitutes to those left to heal by secondary intention. METHODS: On day 0, four 5mm full-thickness punch biopsies were harvested from fifty healthy volunteers (sites 1-4). In all cases, site 1 healed by secondary intention (control), site 2 was treated with collagen-GAG scaffold (CG), cadaveric decellularised dermis (DCD) was applied to site 3, whilst excised tissue was re-inserted into site 4 (autograft). Depending on study group allocation, healing tissue from sites 1-4 was excised on day 7, 14, 21 or 28. All specimens were bisected, with half used in histological and immunohistochemical evaluation whilst extracted RNA from the remainder enabled whole genome microarrays and qRT-PCR of highlighted angiogenesis-related genes. All wounds were serially imaged over 6 weeks using laser-doppler imaging and spectrophotometric intracutaneous analysis. RESULTS: Inherent structural differences between skin substitutes influenced the distribution and organisation of capillary networks within regenerating dermis. Haemoglobin flux (p = 0.0035), oxyhaemoglobin concentration (p = 0.0005), and vessel number derived from CD31-based immunohistochemistry (p = 0.046) were significantly greater in DCD wounds at later time points. This correlated with time-matched increases in mRNA expression of membrane-type 6 matrix metalloproteinase (MT6-MMP) (p = 0.021) and prokineticin 2 (PROK2) (p = 0.004). CONCLUSION: Corroborating evidence from invasive and non-invasive modalities demonstrated that treatment with DCD resulted in increased angiogenesis after wounding. Significantly elevated mRNA expression of pro-angiogenic PROK2 and extracellular matrix protease MT6-MMP seen only in the DCD group may contribute to observed responses.

Current understanding of molecular and cellular mechanisms in fibroplasia and angiogenesis during acute wound healing.

Cutaneous wound healing ultimately functions to facilitate barrier restoration following injury-induced loss of skin integrity. It is an evolutionarily conserved, multi-cellular, multi-molecular process involving co-ordinated inter-play between complex signalling networks. Cellular proliferation is recognised as the third stage of this sequence. Within this phase, fibroplasia and angiogenesis are co-dependent processes which must be successfully completed in order to form an evolving extracellular matrix and granulation tissue. The resultant structures guide cellular infiltration, differentiation and secretory profile within the wound environment and consequently have major influence on the success or failure of wound healing. This review integrates in vitro, animal and human in vivo studies, to provide up to date descriptions of molecular and cellular interactions involved in fibroplasia and angiogenesis. Significant molecular networks include adhesion molecules, proteinases, cytokines and chemokines as well as a plethora of growth factors. These signals are produced by, and affect behaviour of, cells including fibroblasts, fibrocytes, keratinocytes, endothelial cells and inflammatory cells resulting in significant cellular phenotypic and functional plasticity, as well as controlling composition and remodelling of structural proteins including collagen and fibronectin. The interdependent relationship between angiogenesis and fibroplasia relies on dynamic reciprocity between cellular components, matrix proteins and bioactive molecules. Unbalanced regulation of any one component can have significant consequences resulting in delayed healing, chronic wounds or abnormal scar formation. Greater understanding of angiogenic and fibroplastic mechanisms underlying chronic wound pathogenesis has identified novel therapeutic targets and enabled development of improved treatment strategies including topical growth factors and skin substitutes.

Gunshot bullet embolus with pellet migration from the left brachiocephalic vein to the right ventricle: a case report.

We report the case of a 16 year old male who was the victim of a drive by shooting sustaining the rare but recognised complication of cardiovascular bullet embolism. He was seen as a trauma call in the emergency department and CT scanning revealed 70 shotgun pellets scattered throughout left sided sub-cutaneous tissues of the head and neck, and more significantly a single pellet within the right atrium. It is believed to have got there via injury to the left brachiocephalic vein which was demonstrated by extravasation of contrast on the CT scan. He remained stable throughout admission and the injury was managed conservatively. Serial scanning showed the pellet had subsequently migrated into the right ventricle where it has remained since, presumably having become epithelialised. This case report highlights the importance of repeated scanning for the possibility of projectile migration within the cardiovascular system in similar cases of penetrating injury.