Lymph Node Metastases Detection Using Gd2O3@PCD as Novel Multifunctional Contrast Imaging Agent in Metabolic Magnetic Resonance Molecular Imaging.

Axillary lymph node detection is crucial to staging and prognosis of the lymph node metastatic spread in breast cancer. Currently, lymphoscintigraphy and blue dye, as the conventional methods to localize sentinel lymph nodes (SLNs), are invasive and can only be performed during surgery. This study has had a novel hybrid gadolinium oxide nanoparticle coating with Cyclodextrin-based polyester as a high-relaxivity T1 magnetic resonance molecular imaging (MRMI) contrast agent (CA). Twelve female BALB/c mice were randomly divided into three groups of four mice; each group was injected with 4T1 cells to obtain metastasis lymph nodes and diagnosed by using the 3D T1W (VIBE) MRI (Siemens 3T, Prisma). The synthesized Gd2O3@PCD nanoparticles with a suitable particle size range of 20-40 nm have had much higher longitudinal relaxivity (r 1) for Gd2O3@PCD and Gd-DOTA (Dotarem) with the values of 3.98 mM-1·s-1 ± 0.003 and 2.71 mM-1·s-1 ± 0.005, respectively. Identical MR images in coronal views were subsequently obtained to create time-intensity curves of the right axillary lymph nodes and to measure the contrast ratio (CR). The peak CR and qualitative assessment of axillary lymph nodes at five-time points were evaluated. After subcutaneous injection, the contrast ratio of axillary lymph node and tumor in mice exhibited CR peak of Gd2O3@PCD and Dotarem with the values of 2.21 ± 0.06 and 0.40 ± 0.004 for lymph node and 2.54 ± 0.04 and 1.21 ± 0.007 for the tumor, respectively. Furthermore, the lumbar-aortic lymph node is weakly visible in the original coronal image. In conclusion, the use of Gd2O3@PCD nanoparticles as novel MRMI CAs enables high resolution for the detection of lymph node metastasis in mice with the potential capability for breast cancer diagnostic imaging.

Novel FMRI-Compatible wrist robotic device for brain activation assessment during rehabilitation exercise.

Magnetic Resonance Imaging (MRI) can be applied to study the effects of rehabilitation strategies for neuroscience research. An MRI-wrist robot is designed and used as a clinical tool to examine the process of the brain plasticity changes. In this robot, the patient actuation is accomplished with two standard air cylinders, located inside the MRI chamber with two degrees of freedom (flexion-extension and ulna-radial deviation) with pneumatic air transmission, consisting of simple mechanism converting rotary motion to linear independently. A pilot study of brain image aiming at revealing more effective therapeutic strategies carried out to confirm the technical aspects of the development and validation. In a healthy subject, both wrist movement of robot and subject demonstrated brain activity in the contralateral primary somatosensory cortex. Because the robot does not move during the patient's body, a stand was designed to allow the wrist robot and patient to fit comfortably within the MRI machine. While all the parts of the robot were carefully selected with strict MRI compatibility requirements, the robot was tested by presenting some pilot imaging data with null effects on the image quality, as well. Finally, the possible further development of the robot has been introduced for a rehabilitation assessment.

Septic patients with cancer: Do prehospital antibiotics improve survival? A sub-analysis of the PHANTASi trial.

BACKGROUND: Sepsis in patients with cancer is increasingly common and associated with high mortality. To date, no studies have examined the effectiveness of prehospital antibiotics in septic patients with cancer. This study aimed without and to evaluate the effect of prehospital antibiotics in septic patients with cancer. METHODS: We conducted a post-hoc sub-analysis of the PHANTASi (PreHospital ANTibioitcs Against Sepsis) trial database: a randomised controlled trial which enrolled patients with suspected sepsis who were transported to the emergency department by ambulance. Patients in the intervention group were administered prehospital intravenous antibiotics while those in the control group received usual care. We compared patients who had cancer to those who did not. Primary outcome was 28-day mortality; among the secondary outcomes, we included in-hospital mortality and 90-day mortality. RESULTS: 357(13.4%) of the 2658 included patients had cancer in the past five years, of which, 209 (58.5%) were included in the intervention and 148 (41.5%) usual care groups; 28-day mortality was significantly higher in patients who were diagnosed with cancer in the past five years than those without cancer in the past five years: 15.2% vs. 7.1%, respectively (p < 0.001). Prehospital antibiotics in the group of patients with cancer in the last five years yielded no significant effect on survival. There were however, significantly fewer 30-day readmissions (p = 0.031) in the intervention group of cancer patients (12.2% vs 5.7%). CONCLUSION: Prehospital antibiotics did not improve overall survival. However, there was a significant reduction in 30-day readmissions.

Health related quality of life in sepsis survivors from the Prehospital Antibiotics Against Sepsis (PHANTASi) trial.

BACKGROUND: Due to the rise in incidence, the long term effect of sepsis are becoming more evident. There is increasing evidence that sepsis may result in an impaired health related quality of life. The aim of this study was to investigate whether health related quality of life is impaired in sepsis survivors and which clinical parameters are associated with the affected health related quality of life. METHODS: We analyzed 880 Short Form 36 (SF-36) questionnaires that were sent to sepsis survivors who participated in the Prehospital Antibiotics Against Sepsis (PHANTASi) trial. These questionnaires were sent by email, 28 days after discharge. Data entry and statistical analyses were performed in SPSS. The data from the general Dutch population, was obtained from the Netherlands Cancer Institute (NKI-AVL) and served as a control group. Subsequently, 567 sepsis survivors were matched to 567 controls. Non-parametric Wilcoxon signed-rank test was performed to compare these two groups. Within the group, we sought to explain the diminished health related quality of life by factor analysis. RESULTS: We found that sepsis survivors have a worse health related quality of life compared to the general Dutch population. This negative effect was more evident for the physical component than the mental component of health related quality of life. We found that health related quality of life was significantly altered by advancing age and female sex. We also found that the total length of stay (in the hospital) and (previous) comorbidity negatively affect the physical component of health related quality of life. CONCLUSION: In our study we found that health related quality of life in sepsis survivors, 28 days after discharge, is severely diminished in comparison with the general Dutch population. The physical domain is severely affected, whereas the mental domain is less influenced. The length of stay, comorbidity, advancing age and female sex all have a negative effect on the Physical Component Scale of the health related quality of life.

Dosimetry and Radioenhancement Comparison of Gold Nanoparticles in Kilovoltage and Megavoltage Radiotherapy using MAGAT Polymer Gel Dosimeter.

BACKGROUND: Numerous unique characteristics of the nanosized gold, including high atomic number, low toxicity, and high biocompatibility make it one of the most appropriate nanostructures to boost radiotherapy efficacy. Many in-vivo and in-vitro investigations have indicated that gold nanoparticles (AuNPs) can significantly increase tumor injuries in low kilovoltage radiotherapy. While deep-lying tumors require much higher energy levels with greater penetration power, and investigations carried out in megavoltage energy range show contradictory results. OBJECTIVE: In this study, we quantitatively assess and compare dose enhancement factors (DEFs) obtained through AuNPs under radiation of Cobalt-60 source (1.25MeV) versus Iridium-192 source (380 KeV) using MAGAT gel dosimeter. MATERIAL AND METHODS: MAGAT polymer gel in both pure and combined with 0.2 mM AuNPs was synthesized. In order to quantify the effect of energy on DEF, irradiation was carried out by Co-60 external radiotherapy and Ir-192 internal radiotherapy. Finally, readings of irradiated and non-irradiated gels were performed by MR imaging. RESULTS: The radiation-induced R2 (1/T2) changes of the gel tubes doped with AuNPs compared to control samples, upon irradiation of beams released by Ir-192 source showed a significant dose enhancement (15.31% ±0.30) relative to the Co-60 external radiotherapy (5.85% ±0.14). CONCLUSION: This preliminary study suggests the feasibility of using AuNPs in radiation therapy (RT), especially in low-energy sources of brachytherapy. In addition, MAGAT polymer gel, as a powerful dosimeter, could be used for 3D visualization of radiation dose distribution of AuNPs in radiotherapy.

What is the evidence for the use of biologic or biosynthetic meshes in abdominal wall reconstruction?

INTRODUCTION: Although many surgeons have adopted the use of biologic and biosynthetic meshes in complex abdominal wall hernia repair, others have questioned the use of these products. Criticism is addressed in several review articles on the poor standard of studies reporting on the use of biologic meshes for different abdominal wall repairs. The aim of this consensus review is to conduct an evidence-based analysis of the efficacy of biologic and biosynthetic meshes in predefined clinical situations. METHODS: A European working group, "BioMesh Study Group", composed of invited surgeons with a special interest in surgical meshes, formulated key questions, and forwarded them for processing in subgroups. In January 2016, a workshop was held in Berlin where the findings were presented, discussed, and voted on for consensus. Findings were set out in writing by the subgroups followed by consensus being reached. For the review, 114 studies and background analyses were used. RESULTS: The cumulative data regarding biologic mesh under contaminated conditions do not support the claim that it is better than synthetic mesh. Biologic mesh use should be avoided when bridging is needed. In inguinal hernia repair biologic and biosynthetic meshes do not have a clear advantage over the synthetic meshes. For prevention of incisional or parastomal hernias, there is no evidence to support the use of biologic/biosynthetic meshes. In complex abdominal wall hernia repairs (incarcerated hernia, parastomal hernia, infected mesh, open abdomen, enterocutaneous fistula, and component separation technique), biologic and biosynthetic meshes do not provide a superior alternative to synthetic meshes. CONCLUSION: The routine use of biologic and biosynthetic meshes cannot be recommended.

Relationship between neurocognitive functioning and medication management ability over the first 6 months following allogeneic stem cell transplantation.

Although neurocognitive impairment has been established as a major issue among cancer survivors, the real-world consequences of this impairment are unclear. This study investigated the relationship between neurocognitive functioning and medication management ability over time among 58 patients treated with allogeneic hematopoietic stem cell transplantation (HCT). Participants completed a neuropsychological test battery and a simulated medication management task at three time points: pre-transplant (T0), Day 100 (T1) and 6 months post transplant (T2). Neurocognitively impaired participants performed worse on the medication management task than neurocognitively normal participants at each time point, and were more likely to score in the impaired range of medication management ability post transplant (72% vs 20%, P<0.001 at T1; 67% vs 23%, P=0.013 at T2). In multivariate analyses, worse performance in executive functioning/working memory consistently predicted impaired medication management ability, even when controlling for sociodemographic and clinical confounders (odds ratio=0.89, 95% confidence interval (0.80, 0.98), P=0.023). Lower physical symptom distress also predicted impaired medication management ability, but this effect decreased over time. Self-reported cognitive problems were not correlated with medication management ability at any time point. Findings suggest that poor neurocognitive functioning, particularly in the domain of executive functioning/working memory, is associated with worse medication management ability within the first 6 months after allogeneic HCT.

Methods of abdominal wall expansion for repair of incisional herniae: a systematic review.

AIM: To systematically review the available literature regarding methods for abdominal wall expansion and compare the outcome of primary fascial closure rates. METHODS: A systematic search of Pubmed and Embase databases was conducted using the search terms "Abdominal wall hernia", "ventral hernia", "midline hernia", "Botulinum toxin", "botox", "dysport", "progressive preoperative pneumoperitoneum", and "tissue expanders". Study quality was assessed using the Methodological Index for Non-Randomised Studies. RESULTS: 21 of the 105 studies identified met the inclusion criteria. Progressive preoperative pneumoperitoneum (PPP) was performed in 269 patients across 15 studies with primary fascial closure being achieved in 226 (84%). 16 patients had a recurrence (7.2%) and the complication rate was 12% with 2 reported mortalities. There were 4 studies with 14 patients in total undergoing abdominal wall expansion using tissue expanders with a fascial closure rate of 92.9% (n = 13). A recurrence rate of 10.0% (n = 1) was reported with 1 complication and no mortalities. Follow up ranged from 3 to 36 months across the studies. There were 2 studies reporting the use of botulinum toxin with 29 patients in total. A primary fascial closure rate of 100% (n = 29) was demonstrated although a combination of techniques including component separation and Rives-Stoppa repair were used. There were no reported complications related to the use of Botulinum Toxin. However, the short-term follow up in many cases and the lack of routine radiological assessment for recurrence suggests that the recurrence rate has been underestimated. CONCLUSIONS: PPP, tissue expanders and Botulinum toxin are safe and feasible methods for abdominal wall expansion prior to incisional hernia repair. In combination with existing techniques for repair, these methods may help provide the crucial extra tissue mobility required to achieve primary closure.

Systematic review of guidelines for the assessment and management of high-grade anal intraepithelial neoplasia (AIN II/III).

AIM: There is ambiguity with regard to the optimal management of anal intraepithelial neoplasia (AIN) III. The aim of this review was to assess and compare international/national society guidelines currently available in the literature on the management, treatment and surveillance of AIN III. We also aimed to assess the quality of the studies used to compile the guidelines and to clarify the terminology used in histological assessment. METHOD: An electronic search of PubMed and Embase was performed using the search terms 'anal intraepithelial neoplasia', 'AIN', 'anal cancer', 'guidelines', 'surveillance' and 'management'. Literature reviews and guidelines or practice guidelines in peer reviewed journals from 1 January 2000 to 31 December 2014 assessing the treatment, surveillance or management of patients with AIN related to human papilloma virus were included. The guidelines identified by the search were assessed for the quality of evidence behind them using the Oxford Centre for Evidence-based Medicine 2011 Levels of Evidence. RESULTS: The database search identified 5159 articles and two further guidelines were sourced from official body guidelines. After inclusion criteria were applied, 28 full-text papers were reviewed. Twenty-five of these were excluded, leaving three guidelines for inclusion in the systematic review: those published by the Association of Coloproctology of Great Britain and Ireland, the American Society of Colon and Rectal Surgeons and the Italian Society of Colorectal Surgery. No guidelines were identified on the management of AIN III from human papilloma virus associations and societies. All three guidelines agree that a high index of clinical suspicion is essential for diagnosing AIN with a disease-specific history, physical examination, digital rectal examination and anal cytology. There is interchange of terminology from high-grade AIN (HGAIN) (which incorporates AIN II/III) and AIN III in the literature leading to confusion in therapy use. Treatment varies from immunomodulation and photodynamic therapy to targeted destruction of areas of HGAIN/AIN II/III using infrared coagulation, electrocautery, cryotherapy or surgical excision but with little consensus between the guidelines. Recommendations on surveillance strategies are similarly discordant, ranging from 6-monthly physical examination to annual anoscopy ± biopsy. Over 50% of the recommendations are based on Level 3 or Level 4 evidence and many were compiled using studies that were more than 10 years old. CONCLUSION: Despite concordance regarding diagnosis, there is significant variation in the guidelines over recommendations on the treatment and surveillance of patients with HGAIN/AIN II/III. All three sets of guidelines are based on low level, outdated evidence originating from the 1980s and 1990s.

Tendon grafts: their natural history, biology and future development.

The use of tendon grafts has diminished as regimes of primary repairs and rehabilitation have improved, but they remain important in secondary reconstruction. Relatively little is known about the cellular biology of grafts, and the general perception is that they have little biological activity. The reality is that there is a wealth of cellular and molecular changes occurring with the process of engraftment that affect the quality of the repair. This review highlights the historical perspectives and modern concepts of graft take, reviews the different attachment techniques and revisits the biology of pseudosheath formation. In addition, we discuss some of the future directions in tendon reconstruction by grafting, which include surface modification, vascularized tendon transfer, allografts, biomaterials and cell-based therapies.

Patient age, remission status and HCT-CI in a combined score are prognostic for patients with AML undergoing allogeneic hematopoietic cell transplantation in CR1 and CR2.

For AML, older age, advanced disease and increased hematopoietic cell transplant comorbidity index (HCT-CI) are associated with worse prognosis following allogeneic hematopoietic cell transplantation (HCT). This single-center retrospective study investigated the influence of pre-transplant characteristics on outcomes of 387 patients undergoing allogeneic HCT for AML in CR1 and CR2. The multivariable analysis model for overall survival (OS) included age (hazard ratio (HR)=2.24 for ages 31-64 years and HR=3.23 for age ⩾65 years compared with age ⩽30 years, P=0.003), remission status (HR=1.49 for CR2 compared with CR1, P=0.005) and HCT-CI score (HR=1.47 for ⩾3 compared with <3, P=0.005). Transplant year was significantly associated with OS (P=0.001) but this did not influence the model. A weighted score was developed with age ⩽30, CR1 and HCT-CI score <3 receiving 0 points each, and CR2 and HCT-CI score ⩾3 receiving 1 point each. Ages 31-64 received 2 points, age ⩾65 received 3 points. Scores were grouped as follows: scores 0-1 (low risk, n=36), score 2 (intermediate-low risk, n=147), score 3 (intermediate-high risk, n=141) and scores 4-5 (high risk, n=63) with 3-year OS of 71%, 55%, 42% and 29% for scores 0-1, 2, 3 and 4-5, respectively (P<0.0001). The score predicted nonrelapse mortality (P=0.03) but not cumulative incidence of relapse (P=0.18). This model should be validated for the pre-HCT assessment of AML patients in CR1 and CR2.

Outcomes of patients with therapy-related AML/myelodysplastic syndrome (t-AML/MDS) following hematopoietic cell transplantation.

We studied outcomes of 65 consecutive patients with therapy-related AML/myelodyplastic syndrome (t-AML/MDS) who underwent allogeneic hematopoietic cell transplantation (HCT). Previously published scores of HCT-CI, CIBMTR, EBMT and Comorbidity-age index were also evaluated. Median follow-up of survivors was 72 months (range 16-204). At 2 years, overall survival (OS) was 34% (95% confidence interval (CI) 23-45). Nineteen patients (29%) had monosomal karyotype (MK). Patients with MK had an OS of 21% (95% CI 7-41) at 2 years. Abnormal adverse cytogenetics, unrelated donor, bone marrow graft and CIBMTR score were significant risk factors for OS on univariate analysis. On multivariate analysis, abnormal adverse cytogenetics (hazard ratio (HR) 2.7; 95% CI 1.02-7.2; P-value=0.02) and unrelated donor (HR 2.7; 95% CI 1.5-5.0; P-value=0.0013) were independent factors for survival. Non-relapse mortality (NRM) at 2 years was 31% (95% CI 15-47). Donor type was the only factor that was significant for NRM with matched related donors having an NRM of 20% (95% CI 0-42) whereas unrelated donors had NRM of 60% (95% CI 40-80; P-value=0.0007). In conclusion, patients with t-AML/MDS have poor OS. Unrelated donor is a significant risk factor for both higher NRM and decreased OS. Cytogenetics are predictive for OS.

Comparable outcomes post allogeneic hematopoietic cell transplant for patients with de novo or secondary acute myeloid leukemia in first remission.

Secondary AML (sAML) has a poor prognosis with conventional chemotherapy alone. Allogeneic hematopoietic cell transplantation (HCT) is beneficial for high-risk AML. Data comparing outcomes of transplants for patients with de novo and sAML are limited. We compared outcomes of patients transplanted for de novo and sAML in first complete remission and investigated the effect of age, HCT comorbidity index (HCT-CI) and karyotype in both groups. A total of 264 patients with de novo (n=180) and sAML (n=84) underwent allogeneic HCT between 1999 and 2013. Median age at transplant was 51 years (range 18-71), median follow-up of survivors was 77 months. Evaluation of all patients demonstrated no significant difference between de novo and sAML for overall survival (P=0.18), leukemia-free survival (P=0.17), cumulative incidence of relapse (P=0.51) and non-relapse mortality (P=0.42). Multivariable and propensity score analyses confirmed the comparable outcomes between de novo and sAML post transplant. Although sAML demonstrates outcomes inferior to de novo AML treated with chemotherapy alone, outcomes following allogeneic HCT are comparable between the two groups.

Risk model incorporating donor IL6 and IFNG genotype and gastrointestinal GVHD can discriminate patients at high risk of steroid refractory acute GVHD.

Steroid refractory acute GVHD (SR aGVHD) is associated with high morbidity and mortality. This study attempted to generate a risk model for SR aGVHD using 259 single nucleotide polymorphisms (SNPs) in 53 genes of recipients and donors. A total of 268 patients with aGVHD who were treated with systemic steroids were included. Patients were randomly divided into training (n=180) and validation sets (n=88). Clinical risk factors were also evaluated. In the training set, 85 (47.2%) developed SR aGVHD. Gastrointestinal involvement (P<0.0001) and donor genotypes of IL6 (rs1800797; P=6.2 × 10(-4)) and IFNG (rs2069727; P=4.4 × 10(-4)) were significant risk factors. Scores were assigned to the above risk factors. Patients were divided into low (score 0, n=74) vs high risk (scores 1-3; n=106) in risk model. Higher incidence of SR aGVHD was noted in the high risk (61.3%) vs the low-risk group (27%; P<0.0001, odds ratio (OR) 4.28). Predictive effect of risk model was replicated in the validation set (P=0.0045, OR 3.74). This risk model was associated with response to therapy, overall and GVHD-specific survival and non-relapse mortality. Our study suggested that this risk model could identify patients at high risk of SR aGVHD with donor genotype of IL6 (rs1800797) and IFNG (rs2069727) along with gastrointestinal involvement of aGVHD.

Patient-reported outcomes and health-related quality of life in prostate cancer treated with a single fraction of high dose rate brachytherapy combined with hypofractionated external beam radiotherapy.

AIMS: High dose rate (HDR) brachytherapy offers a highly conformal approach to radiotherapy delivery, enabling dose escalation. We report our experience using a combined HDR boost and external beam radiotherapy (EBRT) approach and its associated toxicity and effect on quality of life. MATERIALS AND METHODS: Patients with intermediate- or high-risk prostate cancer were treated with a single fraction HDR boost and EBRT between July 2008 and March 2010. Patient-reported toxicity data were collected at baseline and regular intervals after radiotherapy using International Prostate Symptom Score and Late Effects in Normal Tissues-Subjective, Objective, Management and Analytic scales (LENT-SOMA) questionnaires; health-related quality of life data were captured by the Expanded Prostate Cancer Index Composite (EPIC) questionnaire. RESULTS: Ninety-five patients received an HDR boost of 12.5 Gy followed by EBRT delivered as 37.5 Gy in 15 fractions over 3 weeks. The International Prostate Symptom Score peaked 6 weeks after radiotherapy (median value: 9). The LENT-SOMA bladder/urethra mean baseline score was 0.35 and peaked 6 weeks after radiotherapy (mean = 0.59). Difficulties with urinary flow and frequency were the most common reported symptoms. LENT-SOMA rectum/bowel mean scores at baseline were 0.24 and peaked after 6 months (mean = 0.37). Bowel urgency was the most common reported toxicity. EPIC urinary scores returned to baseline values at 6 months and bowel median scores recovered after 24 months. There were no statistically significant associations between patient or dosimetric parameters and patient-reported outcomes. CONCLUSION: A combined HDR boost and hypofractionated EBRT regimen offers a well-tolerated method of dose escalation with acceptable levels of patient-reported toxicity.

Allogeneic hematopoietic cell transplantation for myelofibrosis using fludarabine-, intravenous busulfan- and low-dose TBI-based conditioning.

Graft failure is one of the major barriers to the success of allogeneic hematopoietic cell transplantation (HCT) in myelofibrosis (MF). We report our institutional experience with 27 MF patients who underwent HCT using fludarabine-, intravenous BU- and low-dose total body irradiation (FBT)-based reduced-intensity (n=20) or full-intensity (n=7) conditioning regimens. Eight patients had prior exposure to JAK1/2 inhibitor therapy; six patients received JAK1/2 inhibitors leading on to HCT and two patients received transplant at the failure of JAK1/2 inhibitor therapy. No adverse impact of JAK1/2 inhibitor therapy was observed on early post-transplant outcomes. All evaluable patients had neutrophil recovery, and no primary graft failure was observed. Cumulative incidence of grades II-IV acute GVHD at day 100 was 48% (95% confidence interval (CI), 29-67%) and chronic GVHD at 2 years was 66% (95% CI, 49-84%). Cumulative incidences of nonrelapse mortality (NRM), relapse and probability of OS at 2 years were: 43% (95% CI, 12-74%), 10% (95% CI, 0-39%) and 56% (95% CI, 28-77%), respectively. FBT-based conditioning regimen has a favorable impact on engraftment; however, further efforts are required to reduce NRM.

The cellular biology of tendon grafting.

We investigated the cellular biology of tendon grafting in a mouse model using green fluorescent protein mismatch grafting and quantitative immunohistochemistry of molecular markers for inflammation, proliferation, collagen synthesis, cell death, and myofibroblast/pericyte expression. We provide a detailed analysis of the healing characteristics during the phases of inflammation, synthesis, and remodelling. Our findings indicated that survival of the cells in the grafted tendon was finite. Syngenic and autologous grafts provoked a similar cellular reaction and all grafts healed. Cells in the graft contributed significantly to collagen synthesis and do have a role in healing.