Translational Studies in Wound Healing

This work explores the role of gap junctional proteins (GJP) in wound healing in two clinical settings: venous disease and epidermal grafting. Chronic wounds and ulcers are common and a feared problem particularly in the elderly, causing pain and disability. Treatment costs are estimated at £2-3 billion to the NHS with a further loss of 2 million workdays per year. Varicose veins are the major contributor to the prevalence of ulcers affecting about 0.3-0.5% of the population at any point of time. The expression of GPJ; connexins 43, 30 and 26 were explored in a cross-sectional study of patients with varicose veins at different stages of venous disease (CEAP stage). A stepwise increase in GJPs overexpression was seen corresponding to the clinical CEAP stage of the disease, supporting their role in the disease mechanism and as a biomarker of wound healing. This is also the first-time varicose veins were shown to be associated with poor wound healing. Concurrently, with the introduction of a new wound healing system for epidermal grafting, a sequential program of research was developed. Initially, a systematic review using Cochrane methodology on epidermal grafting for wound healing, and a pilot case series to evaluate the novel surgical technology. Following positive outcomes; a patient reported outcome measure and cost evaluation study was performed. Combining these data, a pilot randomised controlled trial was performed to compare efficacy of epidermal grafting to standard of care. Alongside, translational studies on GJP were undertaken to outline the cellular mechanism of action of epidermal grafts. These data led to the development of a wound healing group at UCL and subsequent engagement with the MRC UCL clinical trials team to design a novel platform trial to further assess epidermal grafting. This platform will investigate the molecular mechanism of action and explore the most appropriate use for this technology. A NIHR EME and a collaborative industry grant is in progress

Development of a Tissue-Engineered Lymphatic Graft Using Nanocomposite Polymer for the Treatment of Secondary Lymphedema

Damage of the lymphatic vessels, commonly due to surgical resection for cancer treatment, leads to secondary lymphedema. Tissue engineering approach offers a possible solution to reconstruct this damage with the use of lymphatic graft to re-establish the lymphatic flow, hence preventing lymphedema. The aim of this study is to develop a tissue-engineered lymphatic graft using nanocomposite polymer and human dermal lymphatic endothelial cells (HDLECs). A nanocomposite polymer, the polyhedral oligomeric silsequioxane-poly(carbonate-urea)urethane (POSS-PCU), which has enhanced mechanical, chemical, and physical characteristics, was used to develop the lymphatic graft. POSS-PCU has been used clinically for the world's first synthetic trachea, lacrimal duct, and is currently undergoing clinical trial for coronary artery bypass graft. Two designs and fabrication methods were used to manufacture the conduits. The fabrication method, the mechanical and physical properties, as well as the hydraulic conductivity were tested. This is followed by in vitro cell culture analysis to test the cytocompatibility of HDLEC with the polymer surface. Using the casted extrusion method, the nanocomposite lymphatic graft demonstrates desirable mechanical property and hydraulic conductivity to re-establish the lymphatic flow. The conduit has high tensile strength (casted: 74.86 ± 5.74 MPa vs. coagulated: 31.33 ± 3.71 MPa; P < 0.001), favorable kink resistance, and excellent suture retention property (casted vs. coagulated, P < 0.05). Cytocompatibility study showed that the POSS-PCU scaffold supports the attachment and growth of HDLECs. This study demonstrates the feasibility of developing a tissue-engineered lymphatic graft using the nanocomposite polymer. It displays excellent mechanical property and cytocompatibility to HDLECs, offering much promise for clinical applications and as a new treatment option for secondary lymphedema

Epidermal Graft Accelerates the Healing of Acute Wound: A Self-controlled Case Report

Wound care represents a significant socioeconomic burden, with over half of chronic wounds taking up to a year to heal. Measures to accelerate wound healing are beneficial to patients and also reduce the cost and burden of wound management. Epidermal grafting (EG) is an emerging option for autologous skin grafting in the outpatient setting to improve wound healing. Although several case series have previously reported good clinical outcome with EG, the healing rate in comparison to conservative wound management is not known. In this report, we compare the weekly healing rate of 2 separate wounds in the same patient, one treated with EG and the other with dressings. The treated wound showed accelerated healing, with the healing rate being the highest at the first 2 weeks after EG. The average healing time of the treated wound was 40% faster compared with the control wound. EG accelerates healing of acute wounds, potentially reducing the healthcare cost and surgical burden

Protocol for a systematic review of the efficacy of fat grafting and platelet-rich plasma for wound healing

BACKGROUND: The use of fat grafting as a reconstructive surgical option is becoming much more common. Adipose-derived stem cells found in fat grafts are believed to facilitate wound healing via differentiation into fibroblasts and keratinocytes and the release of pro-healing growth factors. Several small studies have shown a positive effect of fat grafting in healing of wounds of a variety of aetiologies. When fat is combined with autologous platelet-rich plasma (PRP), there may be enhanced healing effects. This may be due to the pro-angiogenic and anti-inflammatory effects of PRP. We aim to synthesise the current evidence on combination fat grafting and PRP for wound healing to establish the efficacy of this technique. METHODS/DESIGN: We will conduct a comprehensive literature search in the MEDLINE, EMBASE, CENTRAL, Science Citation Index, and Google Scholar databases (up to July 2017) to identify studies on fat grafting and PRP for wound healing. All primary studies and systematic reviews of these studies will be included, except case reports and case series with fewer than three patients, to evaluate the outcome of fat grafting and PRP on wound healing either on its own or when compared to other studies. Primary outcome measures are expected to be the proportion of total wounds healed at 12 weeks and the average wound healing time (time for 100% re-epithelialisation). Expected secondary outcome measures are the proportion of wounds achieving 50% wound healing, the type of wound benefitting most from fat grafting, economic evaluation, health-related quality of life, and adverse events. Subgroup analysis will be performed for the proportions of wounds healed based on wound aetiology. DISCUSSION: This review will provide robust evidence of the efficacy of fat grafting and PRP for wound healing. This is an emerging technique, and this review is expected to guide clinical practice and ongoing research aimed at improving wound care. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016049881

Protocol for a systematic review of the efficacy of epidermal grafting for wound healing

BACKGROUND: Autologous skin grafting is an important modality for wound coverage; however, it can result in donor site morbidity. Epidermal grafting is an emerging option to overcome this challenge. Furthermore, it can be done in an outpatient setting with minimal or no pain. To date, the evidence on the efficacy of this technique for wound healing has yet to be outlined. We aim to synthesise the current evidence on epidermal grafting for wound healing to establish the efficacy of this technique. METHODS/DESIGN: We will conduct a comprehensive search in the MEDLINE, EMBASE, and CENTRAL databases (up to May 2016) to identify studies on epidermal grafting for wound healing. We will include any primary studies (excluding case reports or case series lesser than three patients) or systematic reviews of such studies to assess the outcome of epidermal grafting for wound healing either on its own or compared to other methods. The expected primary outcome measures are the efficacy of epidermal grafting for wound healing (measured by the proportion of wounds healed at 6 weeks) and the mean wound-healing time (time for complete re-epithelialisation). Secondary outcome measures are the mean donor site-healing time, need for anaesthesia, costs associated with resource use, health-related quality of life, and proportion of patients with adverse event. Subgroup analysis will be performed for the proportions of wounds healed based on wound aetiology. DISCUSSION: This is a timely systematic review, and the finding of this systematic review is expected to guide research and clinical practice aimed at improving wound care. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016033051

The CelluTome epidermal graft-harvesting system: a patient-reported outcome measure and cost evaluation study

Conventional split skin grafts (SSG) require anaesthesia, specialist equipment and can have high donor site (DS) morbidity. The CelluTome epidermal graft-harvesting device is a novel alternative, providing pain-free epidermal skin grafts (ESG) in the outpatient setting, with projected minimal DS trauma and improved patient satisfaction. This study aimed to compare ESG with SSG by evaluating patient-related outcome measures (PROMs) and the cost implications of both. Twenty patients answered a graft satisfaction questionnaire that evaluated: donor/graft site noticeability, aesthetic concerns, adverse problems and patient satisfaction. Cost/patient was calculated based on total operative expenses and five clinic follow-ups. In 100% of the ESG cases, there were no DS noticeability or adverse problems compared to 25% in the SSG group. Complete satisfaction with DS appearance was observed in 100% of the ESG cases (50% SSG). Noticeability, adverse problems and overall satisfaction were significantly better in ESG cases (P < 0.05). Graft site parameters were comparable with similar healing outcomes. The cost per patient for ESG was £431 and £1489 for SSG, with an annual saving of £126 960 based on 10 grafts/month. For the right patient, CelluTome provides comparable wound healing, with reduced DS morbidity and higher patient satisfaction

Systematic review of the efficacy of fat grafting and platelet-rich plasma for wound healing

Adipose‐derived stem cells found in fat grafts may have significant healing properties. When fat is combined with autologous platelet‐rich plasma (PRP), there may be enhanced healing effects due to the pro‐angiogenic and anti‐inflammatory effects of PRP. This study aimed to evaluate the current evidence on fat grafting in combination with PRP for wound healing to establish the efficacy of this technique. A comprehensive search in the MEDLINE, EMBASE, CENTRAL, Science Citation Index, and Google Scholar databases (to March 2017) was conducted to identify studies on fat grafting and PRP for wound healing. Case series of less than 3 cases and studies only describing harvest technique were excluded. The database identified 571 articles, of which 3 articles that used a combination of fat and PRP for wound healing (1 RCT and 2 case series) were included in this review. A total of 69 wounds in 64 patients were treated with an average wound size of 36.32cm2. Of these, 67% of wounds achieved complete healing. When reported, the mean time to healing was 7.5 weeks for those who underwent a single treatment. There were no significant complications in any patients. The combination of fat grafting and PRP may achieve adequate wound healing with relatively quick wound healing time compared with standard wound management options. However, evidence is extremely limited, and further studies are required to evaluate its efficacy for wound healing

Epidermal grafting for wound healing: a review on the harvesting systems, the ultrastructure of the graft and the mechanism of wound healing

Epidermal grafting for wound healing involves the transfer of the epidermis from a healthy location to cover a wound. The structural difference of the epidermal graft in comparison to the split-thickness skin graft and full-thickness skin graft contributes to the mechanism of effect. While skin grafting is an epidermal transfer, little is known about the precise mechanism of wound healing by epidermal graft. This paper aims to explore the evolution of the epidermal graft harvesting system over the last five decades, the structural advantages of epidermal graft for wound healing and the current hypotheses on the mechanism of wound healing by epidermal graft. Three mechanisms are proposed: keratinocyte activation, growth factor secretion and reepithelialisation from the wound edge. We evaluate and explain how these processes work and integrate to promote wound healing based on the current in vivo and in vitro evidence. We also review the ongoing clinical trials evaluating the efficacy of epidermal graft for wound healing. The epidermal graft is a promising alternative to the more invasive conventional surgical techniques as it is simple, less expensive and reduces the surgical burden for patients in need of wound coverage

Deep inferior epigastric perforator (DIEP) flap: Impact of drain free donor abdominal site on long term patient outcomes and duration of inpatient stay

Background: The deep inferior epigastric perforator (DIEP) flap is widely regarded as the Gold Standard in autologous breast reconstruction. Although drain-free abdominoplasty is performed in many centres, there is a paucity of evidence comparing outcomes when applied to DIEP breast reconstruction. Method: A retrospective review of patients who underwent DIEP breast reconstruction without abdominal drain insertion at Royal Free Hospital between Jan 2012-Nov 2016 was undertaken. Results were compared to previously published data from our centre on patients undergoing DIEP breast reconstruction with abdominal drains between Jan 2011-Jul 2012. Results: Thirty-five patients underwent abdominal drain-free reconstruction (GroupA). Of 74 patients who previously underwent reconstruction with abdominal drains, 33 patients underwent drain removal by postoperative day (POD)3 regardless of output (GroupB) and 41 underwent drain removal after POD3 following instructions on drainage volume/24 h (GroupC). There was no significant difference in the length of stay between patients in Group A and B (3.6 vs. 3.9 days; p = 0.204). Length of stay in Group C was significantly higher than Group A and B (p = 0.001, p = 0.001). There were no statistically significant differences in total (11.43% vs. 12.12% vs 17.07%, p = 0.780) or specific complications: Seroma: 2.86% vs. 0% vs. 4.88% (p = 0.774); Wound dehiscence: 8.57% vs. 9.09% vs. 4.88% (p = 0.728); Haematoma: 0% vs. 3.00% vs. 7.32% (p = 0.316) between Groups A, B and C, respectively. Conclusion: Our data suggests that drain-free abdominal closure in DIEP reconstruction can be safely achieved without increased postoperative complications. These conclusions support existing evidence on the use of a drain-free approach in cosmetic abdominoplasty

Radiation-induced fibrosis in breast cancer: A protocol for an observational cross-sectional pilot study for personalised risk estimation and objective assessment

Introduction: About 30% of patients request breast reconstruction following surgery for breast cancer, but radiation therapy negatively influences the outcome. Post-reconstruction radiotherapy is associated with more complications, including more severe capsular contracture and inferior cosmetic results. In general, less fibrosis is seen if autologous reconstruction is performed after radiotherapy, so surgeons will often delay reconstruction until after radiotherapy is complete. Drawbacks to this approach include additional surgery, recuperation, cost, and an extended reconstructive process. Randomised clinical trials are required to determine the best approach. Methods and analysis: The aim of this cross-sectional pilot study is to see if it is feasible to recruit women, and gather the required data. This information will be used to design a subsequent, larger study whose aim is to identify factors that increase the risk of radiation-induced fibrosis, and use these to develop a personalised risk-prediction tool, to enable the clinician and patient to have a more informed discussion when treatment for breast cancer is being discussed. Identification of the risk factors will also enable the development of methods to minimise the risk, which would have applications in other medical conditions where fibrosis is a problem. In addition, the project will develop objective methods of assessing fibrosis, and will determine the psychological and economic impacts that fibrosis has affected individuals. A better understanding of the long-term effects of radiotherapy on normal tissues such as the heart and lungs may also have applications in other medical conditions where fibrosis is a problem. Ethics and dissemination: The study has been submitted for ethical approval (REC reference). Findings will be made available to patients and clinicians through presentations at national and international meetings, peer-reviewed publications, social media and patient support groups