Allometrically scaling tissue forces drive pathological foreign-body responses to implants via Rac2-activated myeloid cells.
Nature biomedical engineering
Small animals do not replicate the severity of the human foreign-body response (FBR) to implants. Here we show that the FBR can be driven by forces generated at the implant surface that, owing to allometric scaling, increase exponentially with body size. We found that the human FBR is mediated by immune-cell-specific RAC2 mechanotransduction signalling, independently of the chemistry and mechanical properties of the implant, and that a pathological FBR that is human-like at the molecular, cellular and tissue levels can be induced in mice via the application of human-tissue-scale forces through a vibrating silicone implant. FBRs to such elevated extrinsic forces in the mice were also mediated by the activation of Rac2 signalling in a subpopulation of mechanoresponsive myeloid cells, which could be substantially reduced via the pharmacological or genetic inhibition of Rac2. Our findings provide an explanation for the stark differences in FBRs observed in small animals and humans, and have implications for the design and safety of implantable devices.
View details for DOI 10.1038/s41551-023-01091-5
View details for PubMedID 37749310
View details for PubMedCentralID 2966551
- T-Line mesh as a safe and effective option for abdominal wall reinforcement with autologous breast reconstruction. Journal of plastic, reconstructive & aesthetic surgery : JPRAS 2023; 84: 273-275
Comparing the Outcomes and Complication Rates of Biologic vs Synthetic Meshes in Implant-Based Breast Reconstruction: A Systematic Review.
Annals of plastic surgery
2023; 90 (5): 516-527
This systematic review evaluates all published studies comparing biologic and synthetic meshes in implant-based breast reconstruction (IBBR), to determine which category of mesh produces the most favorable outcomes.Breast cancer is the most common cancer in women globally. Implant-based breast reconstruction is currently the most popular method of postmastectomy reconstruction, and recently, the use of surgical mesh in IBBR has become commonplace. Although there is a long-standing belief among surgeons that biologic mesh is superior to synthetic mesh in terms of surgical complications and patient outcomes, few studies exist to support this claim.A systematic search of the EMBASE, PubMed, and Cochrane databases was performed in January 2022. Primary literature studies comparing biologic and synthetic meshes within the same experimental framework were included. Study quality and bias were assessed using the validated Methodological Index for Non-Randomized Studies criteria.After duplicate removal, 109 publications were reviewed, with 12 meeting the predetermined inclusion criteria. Outcomes included common surgical complications, histological analysis, interactions with oncologic therapies, quality of life measures, and esthetic outcomes. Across all 12 studies, synthetic meshes were rated as at least equivalent to biologic meshes for every reported outcome. On average, the studies in this review tended to have moderate Methodological Index for Non-Randomized Studies scores.This systematic review offers the first comprehensive evaluation of all publications comparing biologic and synthetic meshes in IBBR. The consistent finding that synthetic meshes are at least equivalent to biologic meshes across a range of clinical outcomes offers a compelling argument in favor of prioritizing the use of synthetic meshes in IBBR.
View details for DOI 10.1097/SAP.0000000000003512
View details for PubMedID 37146317
The single-stage melolabial flap for internal lining of full thickness defects of the nasal ala.
American journal of otolaryngology
2023; 44 (3): 103804
Full-thickness defects of the nasal ala necessitate composite repair of the nasal lining, cartilage and soft tissue envelope. Repair of the nasal lining is particularly challenging due to access and geometry of this area.To evaluate the melolabial flap as a single stage operation for repair of full-thickness nasal ala defects.Retrospective study of seven adult patients with full-thickness nasal ala defects who underwent melolabial flap repair. Complications and operative technique were recorded and described.Of the seven patients who underwent melolabial flap repair, each had excellent coverage of the defect postoperatively. There were two cases of mild ipsilateral congestion, and no revision procedures performed.The melolabial flap is a versatile reconstructive option for repair of the internal lining of the nasal ala, and in our series there were no significant complications or revision procedures performed.
View details for DOI 10.1016/j.amjoto.2023.103804
View details for PubMedID 36940622
Foot Burns and Diabetes: A Systematic Review of Current Clinical Studies and Proposal of a New Treatment Algorithm.
Journal of burn care & research : official publication of the American Burn Association
This study aims to systematically identify studies that evaluate lower extremity burn injury in the diabetic population, evaluate their clinical course and patient outcomes, and present a treatment algorithm tailored to diabetic burn patients. Our systematic review of the PubMed and Web of Science databases yielded 429 unique articles. After exclusion and inclusion criteria were applied, 59 articles were selected for evaluation. In diabetic patients, thermal injury was largely a result of decreased awareness and education regarding heat therapies in the context of peripheral neuropathy. All non-case studies found that metrics such as hospital length of stay, ICU admission rates, rates of comorbidity, complication rates, scald injuries, infection rates, and cost of treatment was significantly increased in the diabetic burn population as compared to their nondiabetic counterparts. Where infection was present, microorganisms colonizing diabetic burn wounds were different than those found in the burn wounds of immunocompetent individuals. Operative intervention including split-skin graft, amputation, and debridement were more often utilized in diabetic burn patients. Foot burns in diabetic patients pose unique clinical risks to patients, and as such need to be an alternate treatment protocol to reflect their pathology. Education and training programs are crucial in the prevention of diabetic foot burns to avoid complications, protracted healing, and adverse outcomes. A unique algorithm can guide the unique treatment of this clinical entity.
View details for DOI 10.1093/jbcr/irad019
View details for PubMedID 36786194
Wireless, closed-loop, smart bandage with integrated sensors and stimulators for advanced wound care and accelerated healing.
'Smart' bandages based on multimodal wearable devices could enable real-time physiological monitoring and active intervention to promote healing of chronic wounds. However, there has been limited development in incorporation of both sensors and stimulators for the current smart bandage technologies. Additionally, while adhesive electrodes are essential for robust signal transduction, detachment of existing adhesive dressings can lead to secondary damage to delicate wound tissues without switchable adhesion. Here we overcome these issues by developing a flexible bioelectronic system consisting of wirelessly powered, closed-loop sensing and stimulation circuits with skin-interfacing hydrogel electrodes capable of on-demand adhesion and detachment. In mice, we demonstrate that our wound care system can continuously monitor skin impedance and temperature and deliver electrical stimulation in response to the wound environment. Across preclinical wound models, the treatment group healed ~25% more rapidly and with ~50% enhancement in dermal remodeling compared with control. Further, we observed activation of proregenerative genes in monocyte and macrophage cell populations, which may enhance tissue regeneration, neovascularization and dermal recovery.
View details for DOI 10.1038/s41587-022-01528-3
View details for PubMedID 36424488
View details for PubMedCentralID 5350204
Characterization of Mechanoresponsive Inflammatory Cells during Wound Healing
WILEY. 2022: A22
View details for Web of Science ID 000847524300054
Epistaxis After Orthognathic Surgery: Literature Review and Three Case Studies.
Craniomaxillofacial trauma & reconstruction
2022; 15 (2): 147-163
This is a literature review with 3 case studies.Intraoperative and postoperative bleeding are the most common complications of orthognathic surgery and have the potential to become life-threatening. The rarity of severe postoperative epistaxis has resulted in limited characterization of these cases in the literature. The purpose of this study is to 1) differentiate various presentations of epistaxis following orthognathic surgery in the literature, 2) identify management approaches, and 3) to synthesize a treatment algorithm to guide future management of postoperative epistaxis.A literature search of PubMed was conducted and 28 cases from 17 studies were assessed.Bleeding within the first week may indicate isolated epistaxis, often resolved with local tamponade. Half of cases were attributed to pseudoaneurysm rupture (n = 14), with epistaxis onset ranging from postoperative day 6 to week 9. Angiography was used in most cases (n = 17), often as the primary imaging modality (n = 11). Nasal endoscopy is a less invasive and effective alternative to angiography with embolization. Proximal vessel ligation was used in 3 cases but is not preferred because collaterals may reconstitute flow through the defect and cause rebleeding. Repeat maxillary down-fracture with surgical exploration was described in 4 cases.As outlined in our management algorithm, nasal packing and tamponade should be followed by either local electrocautery or vascular imaging. Angiography with embolization is the preferred approach to diagnosis and management, whereas surgical intervention is reserved for cases of embolization failure or unavailability.
View details for DOI 10.1177/19433875211008086
View details for PubMedID 35633764
View details for PubMedCentralID PMC9133520
Disrupting mechanotransduction decreases fibrosis and contracture in split-thickness skin grafting.
Science translational medicine
2022; 14 (645): eabj9152
Burns and other traumatic injuries represent a substantial biomedical burden. The current standard of care for deep injuries is autologous split-thickness skin grafting (STSG), which frequently results in contractures, abnormal pigmentation, and loss of biomechanical function. Currently, there are no effective therapies that can prevent fibrosis and contracture after STSG. Here, we have developed a clinically relevant porcine model of STSG and comprehensively characterized porcine cell populations involved in healing with single-cell resolution. We identified an up-regulation of proinflammatory and mechanotransduction signaling pathways in standard STSGs. Blocking mechanotransduction with a small-molecule focal adhesion kinase (FAK) inhibitor promoted healing, reduced contracture, mitigated scar formation, restored collagen architecture, and ultimately improved graft biomechanical properties. Acute mechanotransduction blockade up-regulated myeloid CXCL10-mediated anti-inflammation with decreased CXCL14-mediated myeloid and fibroblast recruitment. At later time points, mechanical signaling shifted fibroblasts toward profibrotic differentiation fates, and disruption of mechanotransduction modulated mesenchymal fibroblast differentiation states to block those responses, instead driving fibroblasts toward proregenerative, adipogenic states similar to unwounded skin. We then confirmed these two diverging fibroblast transcriptional trajectories in human skin, human scar, and a three-dimensional organotypic model of human skin. Together, pharmacological blockade of mechanotransduction markedly improved large animal healing after STSG by promoting both early, anti-inflammatory and late, regenerative transcriptional programs, resulting in healed tissue similar to unwounded skin. FAK inhibition could therefore supplement the current standard of care for traumatic and burn injuries.
View details for DOI 10.1126/scitranslmed.abj9152
View details for PubMedID 35584231
Pullulan-Collagen Hydrogel Wound Dressing Promotes Dermal Remodeling and Wound Healing Compared to Commercially Available Collagen Dressings.
Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society
Biological scaffolds such as hydrogels provide an ideal, physio-mimetic of native ECM that can improve wound healing outcomes after cutaneous injury. While most studies have focused on the benefits of hydrogels in accelerating wound healing, there is minimal data directly comparing different hydrogel material compositions. In this study, we utilized a splinted excisional wound model that recapitulates human-like wound healing in mice and treated wounds with three different collagen hydrogel dressings. We assessed the feasibility of applying each dressing and performed histologic and histopathologic analysis on the explanted scar tissues to assess variations in collagen architecture and alignment, as well as tissue response. Our data indicate that the material properties of hydrogel dressings can significantly influence healing time, cellular response, and resulting architecture of healed scars. Specifically, our pullulan-collagen hydrogel dressing accelerated wound closure and promoted healed tissue with less dense, more randomly aligned, and shorter collagen fibers. Further understanding of how hydrogel properties affect the healing and resulting scar architecture of wounds may lead to novel insights and further optimization of the material properties of wound dressings. This article is protected by copyright. All rights reserved.
View details for DOI 10.1111/wrr.13012
View details for PubMedID 35384131
Surgical Applications of Materials Engineered with Antimicrobial Properties.
Bioengineering (Basel, Switzerland)
2022; 9 (4)
The infection of surgically placed implants is a problem that is both large in magnitude and that broadly affects nearly all surgical specialties. Implant-associated infections deleteriously affect patient quality-of-life and can lead to greater morbidity, mortality, and cost to the health care system. The impact of this problem has prompted extensive pre-clinical and clinical investigation into decreasing implant infection rates. More recently, antimicrobial approaches that modify or treat the implant directly have been of great interest. These approaches include antibacterial implant coatings (antifouling materials, antibiotics, metal ions, and antimicrobial peptides), antibacterial nanostructured implant surfaces, and antibiotic-releasing implants. This review provides a compendium of these approaches and the clinical applications and outcomes. In general, implant-specific modalities for reducing infections have been effective; however, most applications remain in the preclinical or early clinical stages.
View details for DOI 10.3390/bioengineering9040138
View details for PubMedID 35447700
Characterization of Mechanoresponsive Inflammatory Cells during Wound Healing
WILEY. 2022: A5
View details for Web of Science ID 000763583000021
Mechanical Signaling Mediated by IQGAP1 Promotes Pathologic Foreign Body Response
WILEY. 2022: A21
View details for Web of Science ID 000763583000050
Application of No Releasing Gel Increases Fibronectin, TGF-beta 1, and Accelerates Wound Healing in Diabetic Mice
WILEY. 2022: A8
View details for Web of Science ID 000763583000028
Pullulan-Collagen Hydrogel Wound Dressing Promotes Dermal Remodeling and Healing in an Excisional Wound Model
WILEY. 2022: A24
View details for Web of Science ID 000763583000056
Characterization of Mechanoresponsive Inflammatory Cells during Wound Healing
WILEY. 2022: A31-A32
View details for Web of Science ID 000763583000072
Galvanotactic Smart Bandage for Chronic Wound Management and Tissue Regeneration
WILEY. 2022: A36
View details for Web of Science ID 000763583000080
Foot Burns in Persons With Diabetes: Outcomes From the National Trauma Data Bank.
Journal of burn care & research : official publication of the American Burn Association
Diabetes mellitus (DM) complicates the treatment of burn injuries. Foot burns in diabetic patients are challenging problems with unfavorable outcomes. National-scale evaluations are needed, especially with regard to limb salvage. We aim to characterize lower-extremity burns in persons with DM and evaluate the likelihood of amputation. The National Trauma Data Bank (NTDB) was queried from 2007 to 2015 extracting encounters with primary burn injuries of the feet using International Classification of Diseases (ICD) 9th edition codes. Logistic regression modeled predictors of lower-extremity amputation. Covariables included age, sex, race/ethnicity, comorbidities including DM, % burn TBSA, mechanism, and region of burn center. Poisson regression evaluated temporal incidence rate changes in DM foot burns. Of 116,796 adult burn encounters, 7963 (7%) had foot burns. Of this group, 1308 (16%) had DM. 5.6% of encounters with DM foot burns underwent amputation compared to 1.5% of non-DM encounters (P < .001). Independent predictors of lower-extremity amputation included DM (odds ratio 3.70, 95% confidence interval 2.98-4.59), alcohol use, smoking, chronic kidney disease, and burn size >20%, African-American/black race, male sex, and age >40 years (all P < .01). The incidence of DM foot burns increased over the study period with an incidence rate ratio of 1.07 (95% confidence interval 1.05-1.10, P < .001). In conclusion, DM was associated with nearly a 4-fold increase in amputation after adjusting for covariables. Furthermore, the incidence of DM foot burns is increasing. Strategies for optimizing care in persons with DM foot burns are need to improve limb salvage.
View details for DOI 10.1093/jbcr/irac021
View details for PubMedID 35395676
Reinforced Biologic Mesh Reduces Postoperative Complications Compared to Biologic Mesh after Ventral Hernia Repair.
Plastic and reconstructive surgery. Global open
2022; 10 (2): e4083
The use of biologic mesh to reinforce the abdominal wall in ventral hernia repair has been proposed as a viable alternative to synthetic mesh, particularly for high-risk patients and in contaminated settings. However, a comparison of clinical outcomes between the currently available biologic mesh types has yet to be performed.We performed a retrospective analysis of 141 patients who had undergone ventral hernia repair with biologic mesh, including noncross-linked porcine ADM (NC-PADM) (n = 51), cross-linked porcine ADM (C-PADM) (n = 17), reinforced biologic ovine rumen (RBOR) (n = 36), and bovine ADM (BADM) (n = 37) at the Stanford University Medical Center between 2002 and 2020. Postoperative donor site complications and rates of hernia recurrence were compared between patients with different biologic mesh types.Abdominal complications occurred in 47.1% of patients with NC-PADM, 52.9% of patients with C-PADM, 16.7% of patients with RBOR, and 43.2% of patients with BADM (P = 0.015). Relative risk for overall complications was higher in patients who had received NC-PADM (RR = 2.64, P = 0.0182), C-PADM (RR = 3.19, P = 0.0127), and BADM (RR = 2.11, P = 0.0773) compared with those who had received RBOR. Furthermore, relative risk for hernia recurrence was also higher in all other mesh types compared with RBOR.Our data indicate that RBOR decreases abdominal complications and recurrence rates after ventral hernia repair compared with NC-PADM, C-PADM, and BADM.
View details for DOI 10.1097/GOX.0000000000004083
View details for PubMedID 35141102
View details for PubMedCentralID PMC8820910
IQGAP1-mediated mechanical signaling promotes the foreign body response to biomedical implants.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
2022; 36 (2): e22007
The aim of this study was to further elucidate the molecular mechanisms that mediate pathologic foreign body response (FBR) to biomedical implants. The longevity of biomedical implants is limited by the FBR, which leads to implant failure and patient morbidity. Since the specific molecular mechanisms underlying fibrotic responses to biomedical implants have yet to be fully described, there are currently no targeted approaches to reduce pathologic FBR. We utilized proteomics analysis of human FBR samples to identify potential molecular targets for therapeutic inhibition of FBR. We then employed a murine model of FBR to further evaluate the role of this potential target. We performed histological and immunohistochemical analysis on the murine FBR capsule tissue, as well as single-cell RNA sequencing (scRNA-seq) on cells isolated from the capsules. We identified IQ motif containing GTPase activating protein 1 (IQGAP1) as the most promising of several targets, serving as a central molecular mediator in human and murine FBR compared to control subcutaneous tissue. IQGAP1-deficient mice displayed a significantly reduced FBR compared to wild-type mice as evidenced by lower levels of collagen deposition and maturity. Our scRNA-seq analysis revealed that decreasing IQGAP1 resulted in diminished transcription of mechanotransduction, inflammation, and fibrosis-related genes, which was confirmed on the protein level with immunofluorescent staining. The deficiency of IQGAP1 significantly attenuates FBR by deactivating downstream mechanotransduction signaling, inflammation, and fibrotic pathways. IQGAP1 may be a promising target for rational therapeutic design to mitigate pathologic FBR around biomedical implants.
View details for DOI 10.1096/fj.202101354
View details for PubMedID 35051300
Inhibiting Fibroblast Mechanotransduction Modulates Severity of Idiopathic Pulmonary Fibrosis.
Advances in wound care
OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that affects 63 in every 100,000 Americans. Its etiology remains unknown, although inflammatory pathways appear to be important. Given the dynamic environment of the lung, we examined the significance of mechanotransduction on both inflammatory and fibrotic signaling during IPF.INNOVATION: Mechanotransduction pathways have not been thoroughly examined in the context of lung disease and pharmacologic approaches for IPF do not currently target these pathways. The interplay between mechanical strain and inflammation in pulmonary fibrosis remain incompletely understood.APPROACH: In this study, we used conditional KO mice to block mechanotransduction by knocking out FAK (Focal Adhesion Kinase) expression in fibroblasts, followed by induction of pulmonary fibrosis using bleomycin. We examined both normal human and human IPF fibroblasts and used immunohistochemistry, qRT-PCR, and Western Blot to evaluate the effects of FAK inhibition (FAKI) on modulating fibrotic and inflammatory genes.RESULTS: Our data indicate that deletion of FAK in mice reduces expression of fibrotic and inflammatory genes in lungs. Similarly, mechanical straining in normal human lung fibroblasts activates inflammatory and fibrotic pathways. FAK inhibition decreases these signals but has less effect on IPF fibroblasts as compared to normal human fibroblasts.CONCLUSION: Administering FAKI at early stages of fibrosis may attenuate the FAK-mediated fibrotic response pathway in IPF, potentially mediating disease progression.
View details for DOI 10.1089/wound.2021.0077
View details for PubMedID 34544267
- Epistaxis After Orthognathic Surgery: Literature Review and Three Case Studies CRANIOMAXILLOFACIAL TRAUMA & RECONSTRUCTION 2021
- Risk Factors for Wound Complications After Soft Tissue Sarcoma Resection ANNALS OF PLASTIC SURGERY 2021; 86 (3S): S336-S341
The Impact of Plastic Surgery Volume on Inpatient Burn Outcomes.
Plastic and reconstructive surgery
2021; 148 (6): 1001e-1006e
Acute burn care involves multiple types of physicians. Plastic surgery offers the full spectrum of acute burn care and reconstructive surgery. The authors hypothesize that access to plastic surgery will be associated with improved inpatient outcomes in the treatment of acute burns.Acute burn encounters with known percentage total body surface area were extracted from the National Inpatient Sample from 2012 to 2014 based on International Classification of Diseases, Ninth Edition, codes. Plastic surgery volume per facility was determined based on procedure codes for flaps, breast reconstruction, and complex hand reconstruction. Outcomes included odds of receiving a flap, patient safety indicators, and mortality. Regression models included the following variables: age, percentage total body surface area, gender, inhalation injury, comorbidities, hospital size, and urban/teaching status of hospital.The weighted sample included 99,510 burn admissions with a mean percentage total body surface area of 15.5 percent. The weighted median plastic surgery volume by facility was 245 cases per year. Compared with the lowest quartile, the upper three quartiles of plastic surgery volume were associated with increased likelihood of undergoing flap procedures (p < 0.03). The top quartile of plastic surgery volume was also associated with decreased odds of patient safety indicator events (p < 0.001). Plastic surgery facility volume was not significantly associated with a difference in the likelihood of inpatient death.Burn encounters treated at high-volume plastic surgery facilities were more likely to undergo flap operations. High-volume plastic surgery centers were also associated with a lower likelihood of inpatient complications. Therefore, where feasible, acute burn patients should be triaged to high-volume centers.Therapeutic, III.
View details for DOI 10.1097/PRS.0000000000008573
View details for PubMedID 34847127
First reported case of Wohlfahrtiimonas chitiniclastica infection in California JAAD Case Reports
Journal of the American Academy of Dermatology Case Reports
View details for DOI 10.1016/j.jdcr.2021.09.022
Risk Factors for Wound Complications After Soft Tissue Sarcoma Resection.
Annals of plastic surgery
Soft tissue sarcomas are a heterogenous group of malignant tumors that represent approximately 1% of adult malignancies. Although these tumors occur throughout the body, the majority involved the lower extremity. Management may involve amputation but more commonly often includes wide local resection by an oncologic surgeon and involvement of a plastic surgeon for reconstruction of larger and more complex defects. Postoperative wound complications are challenging for the surgeon and patient but also impact management of adjuvant chemotherapy and radiation therapy. To explore risk factors for wound complications, we reviewed our single-institution experience of lower-extremity soft tissue sarcomas from April 2009 to September 2016. We identified 127 patients for retrospective review and analysis. The proportion of patients with wound complications in the cohort was 43.3%. Most notably, compared with patients without wound complications, patients with wound complications had a higher proportion of immediate reconstruction (34.5% vs 15.3%; P = 0.05) and a marginally higher proportion who received neoadjuvant radiation (30.9% vs 16.7%; P = 0.06).
View details for DOI 10.1097/SAP.0000000000002592
View details for PubMedID 33234885
Supercharged Free Transverse Rectus Abdominis Myocutaneous Flap: An Autologous Reconstructive Option for the Thin Breast Reconstruction Patient
2020; 12 (6): e8776
The free transverse rectus abdominis myocutaneous (fTRAM) flap is a frequently used option for autologous breast reconstruction, typically based on deep inferior epigastric vessels anastomosed to either the axillary or internal mammary systems. The distal portion of the fTRAM flap is routinely discarded prior to anastomosis, due to tenuous blood supply in the vascular territory most distal to the pedicle. This becomes problematic in cases that require use of the entire flap, such as in thin patients with large soft-tissue defects. We report a case where an additional "supercharged" venous microsurgical anastomosis was successfully performed to minimize adverse events while utilizing the entire fTRAM flap.
View details for DOI 10.7759/cureus.8776
View details for Web of Science ID 000542976100021
View details for PubMedID 32742826
View details for PubMedCentralID PMC7384455
- Improvements in Cleft Lip Aesthetics with the Fisher Repair Compared to the Mohler Repair PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN 2020; 8 (6)
Improvements in Cleft Lip Aesthetics with the Fisher Repair Compared to the Mohler Repair.
Plastic and reconstructive surgery. Global open
2020; 8 (6): e2919
The extended Mohler rotation-advancement repair and the Fisher anatomic subunit repair are commonly used for the surgical correction of unilateral cleft lip. The rotation-advancement repair was the initial technique of choice by the senior surgeon. However, due to recurring suboptimal aesthetic results, the senior surgeon transitioned to the anatomic subunit repair. This study was performed to compare the outcomes of the rotation-advancement repair and the anatomic subunit repair.A retrospective study of all consecutive patients undergoing unilateral cleft lip repair by the senior author between 2009 and 2016 was conducted. Demographic data, the presence of scar shortening/contraction, hypertrophy, widening, and revision rates were recorded.There were 68 patients identified for inclusion. Thirty-four patients had a rotation-advancement repair and 35 had an anatomic subunit repair. Twelve patients (36%) with the rotation-advancement repair and 1 patient (2.9%) with the subunit repair required anterior lip revision (P < 0.001). Conversely, 2 patients (6.1%) with the rotation-advancement repair and 13 patients (37.1%) with the subunit repair required minor debulking of excess red vermilion fullness (P < 0.005).Transitioning from the rotation-advancement repair to the anatomic subunit repair has resulted in improved lip aesthetics with decreased incidence of scar contracture, hypertrophy, and widening as evidenced by a decrease in the revision rate for these suboptimal scars. However, the rate of debulking procedures of the red vermilion did increase early in the adoption of the anatomic subunit repair, requiring minor modifications in the technique.
View details for DOI 10.1097/GOX.0000000000002919
View details for PubMedID 32766066
View details for PubMedCentralID PMC7339201
Ischemia and reperfusion injury in superficial inferior epigastric artery-based vascularized lymph node flaps
2020; 15 (1): e0227599
Vascularized lymph node transfer (VLNT) is a promising treatment modality for lymphedema; however, how lymphatic tissue responds to ischemia has not been well defined. This study investigates the cellular changes that occur in lymph nodes in response to ischemia and reperfusion. Lymph node containing superficial epigastric artery-based groin flaps were isolated in Prox-1 EGFP rats which permits real time identification of lymphatic tissue by green fluorescence during flap dissection. Flaps were subjected to ischemia for either 1, 2, 4, or 8 hours, by temporarily occluding the vascular pedicle. Flaps were harvested after 0 hours, 24 hours, or 5 days of reperfusion. Using EGFP signal guidance, lymph nodes were isolated from the flaps and tissue morphology, cell apoptosis, and inflammatory cytokines were quantified and analyzed via histology, immunostaining, and rtPCR. There was a significant increase in collagen deposition and tissue fibrosis in lymph nodes after 4 and 8 hours of ischemia compared to 1 and 2 hours, as assessed by picrosirius red staining. Cell apoptosis significantly increased after 4 hours of ischemia in all harvest times. In tissue subject to 4 hours of ischemia, longer reperfusion periods were associated with increased rates of CD3+ and CD45+ cell apoptosis. rtPCR analysis demonstrated significantly increased expression of CXCL1/GRO-α with 2 hours of ischemia and increased PECAM-1 and TNF-α expression with 1 hour of ischemia. Significant cell death and changes in tissue morphology do not occur until after 4 hours of ischemia; however, analysis of inflammatory biomarkers suggests that ischemia reperfusion injury can occur with as little as 2 hours of ischemia.
View details for DOI 10.1371/journal.pone.0227599
View details for Web of Science ID 000534350000099
View details for PubMedID 31923917
View details for PubMedCentralID PMC6954070
Timing of Flap Surgery in Acute Burn Patients Does Not Affect Complications.
Journal of burn care & research : official publication of the American Burn Association
Pedicled and free flaps are occasionally necessary to reconstruct complex wounds in acute burn patients. Flap coverage has classically been delayed for concern of progressive tissue necrosis and flap failure. We aim to investigate flap complications in primary burn care leveraging national US data.Acute burn patients with known % total body surface area(TBSA) were extracted from the Nationwide/National Inpatient Sample from 2002-2014 based on International Classification of Disease (ICD) Codes 9th edition. Variables included age, gender, race, Elixhauser index, %TBSA, mechanism, inhalation injury, and location of burn. Flap complication was defined by ICD-9 procedure code 86.75, return to OR for flap revision. Multivariable analysis evaluated predictors of flap compromise using stepwise logistic regression with backwards elimination.The weighted sample included 306,924 encounters of which 526 received a flap (0.17%). 7.8% of flap encounters sustained electric injury compared to 2.7% of non-flap encounters (OR 3.76, 95% CI 1.95-7.24, p<0.001). The mean hospital day of flap procedure was 10.1 (SD 10.7) days. Flap complications occurred in 6.4% of cases. The timing of flap coverage was not associated with complications. The only independent predictor of flap complication was electrical injury (OR 40.49, 95% OR 2.98-550.64, p=0.005).Electrical injury was an independent predictor of flap complications compared to other mechanisms. Flap timing was not associated with return to surgery for complications. This suggests that the use of flaps is safe in acute burn care to achieve burn wound closure with an understanding that electrical injuries may warrant particular consideration to avoid failure.
View details for DOI 10.1093/jbcr/iraa096
View details for PubMedID 32582915
Pelvic/Perineal Reconstruction: Time to Consider the Anterolateral Thigh Flap as a First-line Option?
Plastic and reconstructive surgery. Global open
2020; 8 (4): e2733
Abdominoperineal resection (APR) and pelvic exenteration continue to be common procedures for the treatment of colorectal malignancy. The workhorse flap for reconstruction in these instances has been the vertical rectus abdominis myocutaneous flap. The associated donor site morbidity, however, cannot be ignored. Here, we provide a review of the literature and present the senior author's (A.M.) experience using the pedicled anterolateral thigh (ALT) flap for reconstruction of soft tissue defects following APR and pelvic exenteration.Patients who underwent pelvic/perineal reconstruction with pedicled ALT flaps between 2017 and 2019 were included in the study. Parameters of interest included age, gender, body mass index, comorbidities, history of radiation, extent of ablative surgery, and postoperative complication rate.A total of 23 patients (16 men and 7 women) with a median age and body mass index of 66 years (inter-quartile range [IQR]: 49-71 years) and 24.9 kg/m2 (IQR: 24.2-26.7 kg/m2) were included in the study, respectively. Thirteen (56.5%) patients presented with rectal cancer, 5 (21.7%) with anal squamous cell carcinoma (SCC), 4 (17.4%) with Crohn's disease, and 1 (4.3%) with Paget's disease. Nineteen patients (82.6%) received neoadjuvant radiation. Nine (39.1%) patients experienced 11 complications (2 major and 9 minor). The most common complication was partial perineal wound dehiscence (N = 6 [26.1%]). Stable soft tissue coverage was achieved in all but one patient.The ALT flap allows for stable soft tissue coverage following APR and pelvic exenteration without being associated with abdominal donor site morbidity. Consideration to its use as a first-line reconstructive option should be given in pelvic/perineal reconstruction.
View details for DOI 10.1097/GOX.0000000000002733
View details for PubMedID 32440406
View details for PubMedCentralID PMC7209827
Prevalence of Ganglion Cyst Formation After Wrist Arthroscopy: A Retrospective Longitudinal Analysis of 2420 Patients.
Hand (New York, N.Y.)
Dorsal wrist ganglion cysts arise from the leakage of synovial fluid through tears in the scapholunate ligament and/or dorsal wrist capsule. An analogous disruption of the dorsal capsule is created with routine portal placement during wrist arthroscopy. We hypothesized that wrist arthroscopy would predispose to wrist ganglions.Using the Truven MarketScan Outpatient Services Database from 2015 to 2016, patients who underwent wrist arthroscopy and developed an ipsilateral wrist ganglion were identified. Exclusion criteria included ganglion diagnosis preceding arthroscopy and bilateral pathology. Postoperative ganglion diagnosis was modeled with logistic regression. Predictor variables included age, gender, comorbidities, and arthroscopic procedure.In all, 2420 patients underwent wrist arthroscopy. Thirty (1.24%) were diagnosed with an ipsilateral wrist ganglion at a mean time of 4.0 months (standard deviation: 2.4, range: 0.2-9.0). Significant predictors of ganglion diagnosis included female gender (odds ratio [OR]: 4.0, P < .01) and triangular fibrocartilage complex and/or joint debridement (OR: 0.13, P < .01). By comparison, among all 24,718,751 outpatients who had not undergone wrist arthroscopy, 39,832 patients had a diagnosis of a wrist ganglion cyst (0.16%).Wrist arthroscopy is associated with a postoperative rate of ganglion cyst formation that is nearly 8 times the rate in the general population. Additional studies are needed to investigate techniques that minimize the risk of this complication.
View details for DOI 10.1177/1558944720939203
View details for PubMedID 32935572
Evidenced-Based Practice Among Trainees: A Survey on Facial Trauma Wound Management.
Journal of surgical education
Assess whether facial trauma wound care and antibiotic use recommendations are guided by evidence-based practice (EBP) or practice patterns, and investigate strategies to improve EBP adoption among surgical trainees.We conducted a survey of all trainees who manage facial trauma (general surgery, emergency medicine, plastic surgery, otolaryngology) to assess clinical knowledge and sources of treatment recommendations. Clinical questions were based on Oxford Center for Evidence-Based Medicine Level 1 or 2 evidence. We measured internal validity of questions using Cronbach's α. Results were weight-adjusted for nonresponse and then analyzed using Welch t test and descriptive statistics.Stanford Hospital and Clinics, a Level I trauma center.Response rate was 50.3% overall (78/155). For recommendations on facial trauma wound and antibiotic use, nonspecialty junior residents most frequently relied on their own senior or specialty residents (79.1%); nonspecialty senior residents relied on specialty residents (67.9%). Specialty junior residents most often relied on their own senior residents (51.0%), the majority of whom made recommendations based on their own knowledge (73.2%). Questions assessing EBP knowledge had Cronbach's α of 0.98; response accuracy was similar between specialty and nonspecialty residents (54.6% vs 55.5%, p = 0.96). When provided recommendations that conflict with EBP, both nonspecialty and specialty residents more frequently followed recommendations rather than EBP; junior residents reported doing so to avoid conflict with superiors. Total 92.6% of surveyed residents felt cross-departmental EBP guidelines would improve patient care.Facial trauma wound care and antibiotic recommendations disseminate down seniority and from craniofacial specialty to nonspecialty residents, yet knowledge of EBP among senior specialty and nonspecialty residents was weak. EBP may be difficult to adopt in the absence of consensus society guidelines. To address this gap, we published a review of EBP for facial trauma and plan to update our trauma manual with cross-departmental guidelines to facilitate EBP adoption among trainees.
View details for DOI 10.1016/j.jsurg.2020.03.015
View details for PubMedID 32461098
Small Peptide Modulation of Fibroblast Growth Factor Receptor 3-Dependent Postnatal Lymphangiogenesis
LYMPHATIC RESEARCH AND BIOLOGY
2019; 17 (1): 19–29
The fibroblast growth factor receptor (FGFR) family includes transmembrane receptors involved in a wide range of developmental and postdevelopmental biologic processes as well as a wide range of human diseases. In particular, FGFR3 has been implicated in the mechanism by which 9-cis retinoic acid (9-cisRA) induces lymphangiogenesis and improves lymphedema. The purpose of this study was to validate the efficacy of a novel small peptide FGFR3 inhibitor, peptide P3 (VSPPLTLGQLLS), and to elucidate the role of FGFR3 in 9-cisRA-induced lymphangiogenesis using this peptide.Peptide P3 effectively inhibited FGFR3 phosphorylation. In vitro, peptide P3-mediated FGFR3 inhibition did not decrease lymphatic endothelial cell (LEC) proliferation, migration, or tubule formation. However, peptide P3-mediated FGFR3 inhibition did block 9-cisRA-stimulated LEC proliferation, migration, and tubule formation. In vivo, peptide P3-mediated FGFR3 inhibition was sufficient to inhibit 9-cisRA-induced tracheal lymphangiogenesis.FGFR3 does not appear to be essential to nonpromoted LEC proliferation, migration, and tubule formation. However, FGFR3 may play a key role in LEC proliferation, migration, tubule formation, and postnatal in vivo lymphangiogenesis when pharmacologically induced by 9-cisRA. P3 may have the potential to be used as a precise regulatory control element for 9-cisRA-mediated lymphangiogenesis.
View details for DOI 10.1089/lrb.2018.0035
View details for Web of Science ID 000463399400003
View details for PubMedID 30648916
View details for PubMedCentralID PMC6388710
Complex Reconstruction of the Knee with a Free Vertical Rectus Abdominis Flap after Periprosthetic Soft Tissue Necrosis
2019; 11 (1): e3969
Periprosthetic joint infection (PJI) is limb threatening and difficult to treat. Although a two-stage re-implantation is accepted as the standard of care for PJI, extensive debridement, numerous surgeries, or liquifactive necrosis from the infection can result in a tissue defect. With a large tissue defect, soft tissue coverage is required to protect the prosthesis, fill any dead space, and obtain a satisfactory wound closure. With defects too large for local or regional flap coverage, free tissue transfer is the best option. We present a case in which soft tissue coverage with both medial and lateral gastrocnemius muscle flaps was not sufficient; free tissue transfer was necessary for both wound closure and creation of an adequate soft tissue envelope for the future placement of a prosthesis. Regardless of the complicated surgical history and extensive soft tissue damage, limb function was restored and the patient regained his independence.
View details for DOI 10.7759/cureus.3969
View details for Web of Science ID 000461526100001
View details for PubMedID 30956921
View details for PubMedCentralID PMC6438685
Risk Factors Associated with Reconstructive Complications Following Sacrectomy
PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN
2018; 6 (11): e2002
Sacral pathology requiring partial or total sacrectomy is rare, and reconstructing the ensuing defects requires careful decision-making to minimize morbidity. The purpose of this study was to review the experience of a single institution with reconstructing large sacral defects, to identify risk factors for suboptimal outcomes.A retrospective chart review was conducted of all patients who underwent sacrectomy over a 10-year period. Univariate analysis of differences in risk factors between patients with and without various postoperative complications was performed. Multivariate logistic regression was used to identify predictive variables.Twenty-eight patients were identified. The most common diagnosis leading to sacrectomy was chordoma (39%). Total sacrectomy was performed on 4 patients, whereas 24 patients underwent partial resection. Reconstructive modalities included 15 gluteal advancement flaps, 4 pedicled rectus abdominis myocutaneous flaps, and 9 paraspinous muscle or other flap types. There was an overall complication rate of 57.1% (n = 12) and a 28.6% (n = 8) incidence of major complications. There were significantly more flap-related complications in patients who underwent total sacrectomy (P = 0.02). Large defect size resulted in significantly more unplanned returns to the operating room (P < 0.01).Consistent with other published series', the overall complication rate exceeded 50%. Defect volume and sacrectomy type were the strongest predictors of postoperative complications and return to the operating room, while reconstructive strategy showed limited power to predict patient outcomes. We recommend that patients anticipated to have large sacral defects should be appropriately counseled regarding the incidence of wound complications, regardless of reconstructive approach.
View details for DOI 10.1097/GOX.0000000000002002
View details for Web of Science ID 000453901600028
View details for PubMedID 30881800
View details for PubMedCentralID PMC6414132
Human Acellular Dermis as Spacer for Small-Joint Arthroplasty: Analysis of Revascularization in a Rabbit Trapeziectomy Model
PLASTIC AND RECONSTRUCTIVE SURGERY
2018; 142 (3): 679–86
Carpometacarpal joint osteoarthritis affects 8 to 12 percent of the general population. Surgical management provides symptomatic relief for 78 percent of patients who fail conservative therapy, but little consensus exists regarding which surgical procedure provides superior patient outcomes. Recent human trials substituted exogenous acellular dermal matrices in the bone space, but there are no quantitative histologic data on the outcome of acellular dermal matrices in this environment. The authors aimed to quantify the revascularization and recellularization of acellular dermal matrices in the joint space using a rabbit model.Bilateral lunate carpal bones were surgically removed in New Zealand rabbits. Acellular dermal matrix and autologous tissue were implanted in place of the lunate of the right and left wrists, respectively. Acellular dermal matrix was also implanted subcutaneously as a nonjoint control. Histologic and immunofluorescence analysis was performed after collection at 0, 6, and 12 weeks.Quantitative analysis of anti-α-smooth muscle actin and CD31 immunofluorescence revealed a sequential and comparable increase of vascular lumens in joint space and subcutaneous acellular dermal matrices. In contrast, autologous tissue implanted in the joint space did not have a similar increase in α-smooth muscle actin-positive or CD31-positive lumens. Semiquantitative analysis revealed increased cellularity in both autologous and acellular dermal matrix wrist implants at each time point, whereas average cellularity of subcutaneous acellular dermal matrix peaked at 6 weeks and regressed by 12 weeks. Trichrome and Sirius red staining revealed abundant collagen at all time points.The trapeziectomy joint space supports both cellular and vascular ingrowth into human acellular dermal matrix.
View details for DOI 10.1097/PRS.0000000000004629
View details for Web of Science ID 000442857300053
View details for PubMedID 29878993
Local Administration of Interleukin-1 Receptor Antagonist Improves Diabetic Wound Healing
ANNALS OF PLASTIC SURGERY
2018; 80: S317–S321
Impaired healing of the skin is a notable cause of patient morbidity and mortality. In diabetic individuals, dysregulated inflammation contributes to delayed wound healing. Specific immunomodulatory agents may have a role in the treatment of diabetic wounds. One of these molecules is interleukin-1 receptor antagonist (Anakinra; Amgen Corp.). Although interleukin-1 receptor antagonist (Anakinra; Amgen Corp.) is approved by the Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis and neonatal-onset multisystem inflammatory disease, little is known about the local use this drug in cutaneous wound healing. Therefore, the aim of this study is to determine the effect of locally administered interleukin-1 receptor antagonist on delayed wound healing, specifically, in a diabetic mouse model. Two 6-mm full-thickness wounds were created on the dorsa of diabetic (db/db) mice and stented. One-hour postwounding, wound margins were subcutaneously injected with either (1) low-dose interleukin-1 receptor antagonist in a gelatin-transglutaminase gel vehicle or (2) the gel vehicle only. Wounds were imaged on days 0, 7, 14, and 21 postwounding, and wound area was determined. Wound biopsies were collected on day 21 and immunohistochemically stained for neutrophil and macrophage infiltration. Wounds treated with interleukin-1 receptor antagonist had significantly smaller wound area than nontreated wounds on day 7 and day 14 postwounding. Treated wounds also showed significantly less neutrophil and macrophage infiltration. These findings support the hypothesis that interleukin-1 receptor antagonist may have an important role in cutaneous wound healing, possibly by promoting successful resolution of acute inflammation and hence accelerating wound closure. Thereby, administration of IL-1Ra may be useful in the treatment of nonhealing wounds.
View details for DOI 10.1097/SAP.0000000000001417
View details for Web of Science ID 000473114300019
View details for PubMedID 29553981
View details for PubMedCentralID PMC5929157
Porcine Mesothelium-Wrapped Diced Cartilage Grafts for Nasal Reconstruction
TISSUE ENGINEERING PART A
2018; 24 (7-8): 672–81
Fascia-wrapped diced cartilage grafts have become a useful tool in modern rhinoplasty surgery. Unfortunately, fascial harvest is associated with donor site morbidity; therefore, a nonautologous alternative to fascia would be ideal. Decellularized porcine mesothelium (PM), Meso BioMatrix™, is an acellular scaffold that could potentially fill this need. To determine if PM could serve as an acceptable alternative, we histologically compared diced cartilage grafts wrapped in fascia versus PM.Human rib cartilage and temporoparietal fascia were obtained under an IRB-approved protocol. Cartilage was diced into 0.5 mm pieces and implanted in subcutaneous pockets in nude rats. Implanted materials included cartilage alone, cartilage wrapped in fascia, cartilage wrapped in PM, fascia alone, or PM alone. Specimens were harvested at 8 weeks and stained with hematoxylin and eosin, Masson's trichrome, Safranin-O, and Verhoeff's stain to assess cartilage viability, architecture, and regenerative potential.Unwrapped diced cartilage showed the highest cartilage viability, but was associated with loss of contour and dispersion of the cartilage pieces. Meso BioMatrix-wrapped grafts maintained contour and cartilage pieces had not dispersed; however, there was a significantly lower number of nucleated lacunae and a greater amount of basophilia than both fascia-wrapped cartilage and unwrapped cartilage. There was no significant difference in cartilage resorption between fascia-wrapped cartilage and Meso BioMatrix-wrapped cartilage or in the proteoglycan or collagen content between all groups.Off-the-shelf decellularized PM was associated with lower cartilage viability than unprocessed fascial allograft. No cartilage piece dispersion, fibrosis, resorption, or a foreign body reaction to Meso BioMatrix was observed. PM, although not equivalent to autologous tissue, may be utilized to achieve acceptable clinical results and be a viable alternative that limits donor side morbidity. This experimental study supports further clinical investigation of this material in rhinoplasty procedures.
View details for DOI 10.1089/ten.tea.2017.0119
View details for Web of Science ID 000419439400001
View details for PubMedID 28922982
Development and Characterization of A Novel Prox1-EGFP Lymphatic and Schlemm's Canal Reporter Rat
2017; 7: 5577
The lymphatic system plays a key role in tissue fluid homeostasis, immune cell trafficking, and fat absorption. We previously reported a bacterial artificial chromosome (BAC)-based lymphatic reporter mouse, where EGFP is expressed under the regulation of the Prox1 promoter. This reporter line has been widely used to conveniently visualize lymphatic vessels and other Prox1-expressing tissues such as Schlemm's canal. However, mice have a number of experimental limitations due to small body size. By comparison, laboratory rats are larger in size and more closely model the metabolic, physiological, and surgical aspects of humans. Here, we report development of a novel lymphatic reporter rat using the mouse Prox1-EGFP BAC. Despite the species mismatch, the mouse Prox1-EGFP BAC enabled a reliable expression of EGFP in Prox1-expressing cells of the transgenic rats and allowed a convenient visualization of all lymphatic vessels, including those in the central nervous system, and Schlemm's canal. To demonstrate the utility of this new reporter rat, we studied the contractile properties and valvular functions of mesenteric lymphatics, developed a surgical model for vascularized lymph node transplantation, and confirmed Prox1 expression in venous valves. Together, Prox1-EGFP rat model will contribute to the advancement of lymphatic research as a valuable experimental resource.
View details for DOI 10.1038/s41598-017-06031-3
View details for Web of Science ID 000405675400057
View details for PubMedID 28717161
View details for PubMedCentralID PMC5514086
Topical Fibronectin Improves Wound Healing of Irradiated Skin
2017; 7: 3876
Wound healing is significantly delayed in irradiated skin. To better understand global changes in protein expression after radiation, we utilized a reverse phase protein array (RPPA) to identify significant changes in paired samples of normal and irradiated human skin. Of the 210 proteins studied, fibronectin was the most significantly and consistently downregulated in radiation-damaged skin. Using a murine model, we confirmed that radiation leads to decreased fibronectin expression in the skin as well as delayed wound healing. Topically applied fibronectin was found to significantly improve wound healing in irradiated skin and was associated with decreased inflammatory infiltrate and increased angiogenesis. Fibronectin treatment may be a useful adjunctive modality in the treatment of non-healing radiation wounds.
View details for DOI 10.1038/s41598-017-03614-y
View details for Web of Science ID 000403643900029
View details for PubMedID 28634413
View details for PubMedCentralID PMC5478660
Surgical applications of three-dimensional printing: a review of the current literature & how to get started
ANNALS OF TRANSLATIONAL MEDICINE
2016; 4 (23): 456
Three dimensional (3D) printing involves a number of additive manufacturing techniques that are used to build structures from the ground up. This technology has been adapted to a wide range of surgical applications at an impressive rate. It has been used to print patient-specific anatomic models, implants, prosthetics, external fixators, splints, surgical instrumentation, and surgical cutting guides. The profound utility of this technology in surgery explains the exponential growth. It is important to learn how 3D printing has been used in surgery and how to potentially apply this technology. PubMed was searched for studies that addressed the clinical application of 3D printing in all surgical fields, yielding 442 results. Data was manually extracted from the 168 included studies. We found an exponential increase in studies addressing surgical applications for 3D printing since 2011, with the largest growth in craniofacial, oromaxillofacial, and cardiothoracic specialties. The pertinent considerations for getting started with 3D printing were identified and are discussed, including, software, printing techniques, printing materials, sterilization of printing materials, and cost and time requirements. Also, the diverse and increasing applications of 3D printing were recorded and are discussed. There is large array of potential applications for 3D printing. Decreasing cost and increasing ease of use are making this technology more available. Incorporating 3D printing into a surgical practice can be a rewarding process that yields impressive results.
View details for DOI 10.21037/atm.2016.12.18
View details for Web of Science ID 000392653700005
View details for PubMedID 28090512
View details for PubMedCentralID PMC5220021
Prevention of Postsurgical Lymphedema by 9-cis Retinoic Acid
ANNALS OF SURGERY
2016; 264 (2): 353–61
To determine the effect of 9-cis retinoic acid (9-cis RA) on postsurgical lymphedema.9-cis RA promotes lymphangiogenesis in vitro and in vivo and has promise as a therapeutic agent to limit the development of postsurgical lymphedema.Lymphedema was induced in the right hind limb after a single fraction of 20 Gy radiation, popliteal lymphadenectomy, and lymphatic vessel ablation. Postoperatively, mice were randomly divided in to 2 groups that received daily intraperitoneal injections of either (1) an oil-based vehicle solution (control) or (2) 0.08 mg/kg of 9-cis RA dissolved in a vehicle solution. Outcome measures included paw thickness, lymphatic drainage, and lymphatic vessel density as measured by podoplanin immunohistochemistry and whole mount skin analysis.Using our combined injury protocol, postsurgical lymphedema was observed 89% of the time. 9-cis RA-treated animals had less early postsurgical edema and significantly less paw lymphedema compared with vehicle-treated animals at all time-points (P < 0.001). 9-cis RA-treated animals had significantly faster lymphatic drainage as measured by indocyanine green clearance and increased lymphatic vessel density as measured by podoplanin immunohistochemistry (P < 0.001) and whole mount skin analysis (P < 0.05).We have developed a highly reproducible model of secondary lymphedema and have demonstrated that 9-cis RA significantly prevents postsurgical lymphedema. Treatment with 9-cis RA is associated with increased lymphatic clearance and lymphangiogenesis. Because 9-cis RA (alitretinoin) is already approved for clinical use by the US Food and Drug Administration for other conditions, it has the potential to be repurposed as a preventative agent for postsurgical lymphedema in humans.
View details for DOI 10.1097/SLA.0000000000001525
View details for Web of Science ID 000380504400032
View details for PubMedID 26655920