Possible Role of Circulating Bone Marrow Mesenchymal Progenitors in Modulating Inflammation and Promoting Wound Repair

Circulating bone marrow mesenchymal progenitors (BMMPs) are known to be potent antigen-presenting cells that migrate to damaged tissue to secrete cytokines and growth factors. An altered or dysregulated inflammatory cascade leads to a poor healing outcome. A skin model developed in our previous study was used to observe the immuno-modulatory properties of circulating BMMP cells in inflammatory chronic wounds in a scenario of low skin perfusion. BMMPs were analysed exclusively and in conjunction with recombinant tumour necrosis factor alpha (TNFα) and recombinant hepatocyte growth factor (HGF) supplementation. We analysed the expression levels of interleukin-8 (IL-8) and ecto-5′-nucleotidase (CD73), together with protein levels for IL-8, stem cell factor (SCF), and fibroblast growth factor 1 (FGF-1). The successfully isolated BMMPs were positive for both hemopoietic and mesenchymal markers and showed the ability to differentiate into adipocytes, chondrocytes, and osteocytes. Significant differences were found in IL-8 and CD73 expressions and IL-8 and SCF concentrations, for all conditions studied over the three time points taken into consideration. Our data suggests that BMMPs may modulate the inflammatory response by regulating IL-8 and CD73 and influencing IL-8 and SCF protein secretions. In conclusion, we suggest that BMMPs play a role in wound repair and that their induced application might be suitable for scenarios with a low skin perfusion.

Significance of nutrition in hemodialysis patients with peripheral arterial disease evaluated by skin perfusion pressure

Background Peripheral artery disease (PAD) is a serious complication in hemodialysis (HD) patients. Low skin perfusion pressure (SPP) is a useful marker for detecting PAD. Malnutrition is an important cause of intractable complications. We examined the relationship between low SPP and various indicators of nutritional status. Methods A total of 120 patients on maintenance HD were enrolled for SPP measurement. SPP was measured at the soles of both feet during HD, and patients were divided into low SPP (L-SPP) and normal SPP (N-SPP) groups by 50 mmHg. The following values were determined by averaging four blood samples taken before SPP measurements every 3 months for one year: hemoglobin, total protein, albumin (Alb), total cholesterol, urea nitrogen, creatinine (Cr), potassium, calcium, phosphate, intact parathyroid hormone, iron (Fe), transferrin saturation (T-SAT), and C-reactive protein (CRP). We calculated the percent Cr production rate, dialysis index (Kt/V), normalized protein catabolic rate (nPCR), geriatric nutritional risk index (GNRI), and estimated salt intake using the required formulas. In addition, the age, body mass index, and presence of diabetes mellitus (DM) were compared between both groups along with all other measurements. Data were expressed as the mean ± standard deviation or median with interquartile range as appropriate. Differences in continuous variables between the two groups were analyzed by Student’s t-test or Wilcoxon’s rank-sum test, as appropriate. Multivariate logistic analysis and receiver operating curve (ROC) analysis were performed for significant variables. The results were expressed as odds ratios with respective 95% confidence intervals (CIs). Results The enrolled patients were 82 men and 38 women, with a mean age of 66.9 ± 13.3 years and HD duration of 4.76 (2.13–12.28) years (median interquartile range). Twenty patients belonged to the L-SPP group, suggesting PAD. Comparison between the L-SPP and N-SPP groups showed significant differences in age, Cr, Fe, T-SAT, CRP, nPCR, GNRI, DM, and estimated salt intake. When the GNRI, estimated salt intake, CRP, and DM were applied as independent variables for multiple logistic regression analysis, the GNRI (odds ratio: 0.857, 95% CI 0.781–0.941, p = 0.001), CRP (2.406, 1.051–3.980, p = 0.035), and DM (9.194, 2.497–33.853, p = 0.001) were found to be significant for L-SPP, and a cutoff level of 92.1 (sensitivity 80%, specificity 72%, AUC: 0.742, 95% CI 0.626–0.858, p = 0.001) in the GNRI obtained by ROC was consistent with the risk index in the elderly presented previously. Conclusions SPP measurement is an essential tool for detecting high-risk PAD in maintenance HD, which is affected by malnutrition, DM, and inflammation. The GNRI is important for the determination of malnutrition.

Association between Flow-Mediated Dilation and Skin Perfusion Pressure with Peripheral Artery Disease in Hemodialysis Patients

Flow-mediated dilation (FMD) is used to noninvasively assess the health of blood vessels and it has been shown to have a similar predictive ability for cardiovascular disease to traditional risk factors. Skin perfusion pressure (SPP) refers to the blood pressure required to restore capillary or microcirculatory flow after controlled occlusion and the return of flow. SPP has been shown to be an important measurement when making clinical decisions for patients with limb ischemia and to be a predictor of the likelihood of wound healing. Peripheral artery disease is common in hemodialysis (HD) patients. However, little is known about the association between FMD or SPP and peripheral artery disease. The aim of this study was to evaluate the association between FMD and SPP with brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI) in HD patients in Taiwan, an area with a high rate of ESRD. This study was conducted at a regional hospital in southern Taiwan. ABI and baPWV values were measured using an ABI automated device. FMD and SPP were measured using ultrasound and a microvasculature blood flow monitor, respectively. Eighty patients were enrolled in this study. Compared to the patients with an ABI ≥ 0.95, those with an ABI < 0.95 had lower SPP of the feet (dorsal and plantar portions, both p < 0.001). After multivariable adjustments, low triglycerides (p = 0.033) and high calcium–phosphate product (p = 0.018) were significantly associated with low FMD. Further, low ABI (p = 0.001) and low baPWV (p = 0.036) were significantly associated with low SPP of dorsal portions. Old age (p = 0.005), low high-density lipoprotein cholesterol (p = 0.016), and low ABI (p = 0.002) were significantly associated with low SPP of plantar portions. This study demonstrated an association between FMD and SPP with peripheral artery disease in HD patients. Patients with low ABI and baPWV had a high risk of low SPP of the feet. However, there was no significant correlation between FMD and ABI or baPWV.

The Role of Cutaneous Microcirculatory Responses in Tissue Injury, Inflammation and Repair at the Foot in Diabetes

Diabetic foot syndrome is one of the most costly complications of diabetes. Damage to the soft tissue structure is one of the primary causes of diabetic foot ulcers and most of the current literature focuses on factors such as neuropathy and excessive load. Although the role of blood supply has been reported in the context of macro-circulation, soft tissue damage and its healing in the context of skin microcirculation have not been adequately investigated. Previous research suggested that certain microcirculatory responses protect the skin and their impairment may contribute to increased risk for occlusive and ischemic injuries to the foot. The purpose of this narrative review was to explore and establish the possible link between impairment in skin perfusion and the chain of events that leads to ulceration, considering the interaction with other more established ulceration factors. This review highlights some of the key skin microcirculatory functions in response to various stimuli. The microcirculatory responses observed in the form of altered skin blood flow are divided into three categories based on the type of stimuli including occlusion, pressure and temperature. Studies on the three categories were reviewed including: the microcirculatory response to occlusive ischemia or Post-Occlusive Reactive Hyperaemia (PORH); the microcirculatory response to locally applied pressure such as Pressure-Induced Vasodilation (PIV); and the interplay between microcirculation and skin temperature and the microcirculatory responses to thermal stimuli such as reduced/increased blood flow due to cooling/heating. This review highlights how microcirculatory responses protect the skin and the plantar soft tissues and their plausible dysfunction in people with diabetes. Whilst discussing the link between impairment in skin perfusion as a result of altered microcirculatory response, the review describes the chain of events that leads to ulceration. A thorough understanding of the microcirculatory function and its impaired reactive mechanisms is provided, which allows an understanding of the interaction between functional disturbances of microcirculation and other more established factors for foot ulceration.

Hyperspectral Imaging to Study Dynamic Skin Perfusion after Injection of Articaine-4% with and without Epinephrine—Clinical Implications on Local Vasoconstriction

This study aimed to investigate the dynamic skin perfusion via hyperspectral imaging (HSI) after application of Articaine-4% ± epinephrine as well as epinephrine only. After the subcutaneous injection of (A100) Articaine-4% with epinephrine 1:100,000, (A200) Articaine-4% with epinephrine 1:200,000, (Aw/o) Articaine-4% without epinephrine, and (EPI200) epinephrine 1:200,000, into the flexor side of the forearm in a split-arm design, dynamic skin perfusion measurement was performed over 120 min by determining tissue oxygen saturation (StO2) using HSI. After injection, all groups experienced a reactive hyperaemia. With A200, it took about three min for StO2 to drop below baseline. For Aw/o and EPI200, perfusion reduction when compared to baseline was seen at 30 min with vasoconstriction >120 min. A100 caused vasodilation with hyperaemia >60 min. After three minutes, the perfusion pattern differed significantly (p < 0.001) between all groups except Aw/o and EPI200. The vasoactive effect of epinephrine-containing local anaesthetics can be visualised and dynamically quantified via StO2 using HSI. Aw/o + epinephrine 1:100,000 and 1:200,000 leads to perfusion reduction and tissue ischaemia after 30 min, which lasts over 120 min with no significant difference between both formulations. When using Aw/o containing epinephrine in terms of haemostasis for surgical procedures, a prolonged waiting time before incision of 30 or more min can be recommended.

Novel leukocyte-depleted platelet-rich plasma-based skin equivalent as an in vitro model of chronic wounds: a preliminary study

Background Chronic leg ulcerations are associated with Haemoglobin disorders, Type2 Diabetes Mellitus, and long-term venous insufficiency, where poor perfusion and altered metabolism develop into a chronic inflammation that impairs wound closure. Skin equivalent organotypic cultures can be engineered in vitro to study skin biology and wound closure by modelling the specific cellular components of the skin. This study aimed to develop a novel bioactive platelet-rich plasma (PRP) leukocyte depleted scaffold to facilitate the study of common clinical skin wounds in patients with poor chronic skin perfusion and low leukocyte infiltration. A scratch assay was performed on the skin model to mimic two skin wound conditions, an untreated condition and a condition treated with recombinant tumour necrotic factor (rTNF) to imitate the stimulation of an inflammatory state. Gene expression of IL8 and TGFA was analysed in both conditions. Statistical analysis was done through ANOVA and paired student t-test. P < 0.05 was considered significant. Results A skin model that consisted of a leukocyte-depleted, platelet-rich plasma scaffold was setup with embedded fibroblasts as dermal equivalents and seeded keratinocytes as multi-layered epidermis. Gene expression levels of IL8 and TGFA were significantly different between the control and scratched conditions (p < 0.001 and p < 0.01 respectively), as well as between the control and treated conditions (p < 0.01 and p < 0.001 respectively). The scratch assay induced IL8 upregulation after 3 h (p < 0.05) which continued to increase up to day 1 (p < 0.05). On the other hand, the administration of TNF led to the downregulation of IL8 (p < 0.01), followed by an upregulation on day 2. IL8 gene expression decreased in the scratched condition after day 1 as the natural healing process took place and was lower than in the treated condition on day 8 (p < 0.05). Both untreated and treated conditions showed a downregulation of TGFA 3 h after scratch when compared with the control condition (p < 0.01). Administration of rTNF showed significant downregulation of TGFA after 24 h when compared with the control (p < 0.01) and treated conditions (p < 0.05). Conclusion This study suggests that a leukocyte-depleted PRP-based skin equivalent can be a useful model for the in vitro study of chronic skin wounds related to poor skin perfusion.

Transverse upper abdominal scars in DIEP flaps: pushing the limit of donor site abdominal skin perfusion

We present two immediate breast reconstruction cases utilising deep inferior epigastric perforator (DIEP) flaps in the presence of upper transverse abdominal scars and their outcomes. The available evidence in relation to its impact on abdominal skin perfusion and published clinical experience is reviewed.