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Objective: The aim of this study was to determine the interaction of full thickness excisional wounds and tumors in vivo., Summary of Background Data: Tumors have been described as wounds that do not heal due to similarities in stromal composition. On the basis of observations of slowed tumor growth after ulceration, we hypothesized that full thickness excisional wounds would inhibit tumor progression in vivo., Methods: To determine the interaction of tumors and wounds, we developed a tumor xenograft/allograft (human head and neck squamous cell carcinoma SAS/mouse breast carcinoma 4T1) wound mouse model. We examined tumor growth with varying temporospatial placement of tumors and wounds or ischemic flap. In addition, we developed a tumor/wound parabiosis model to understand the ability of tumors and wounds to recruit circulating progenitor cells., Results: Tumor growth inhibition by full thickness excisional wounds was dose-dependent, maintained by sequential wounding, and relative to distance. This effect was recapitulated by placement of an ischemic flap directly adjacent to a xenograft tumor. Using a parabiosis model, we demonstrated that a healing wound was able to recruit significantly more circulating progenitor cells than a growing tumor. Tumor inhibition by wound was unaffected by presence of an immune response in an immunocompetent model using a mammary carcinoma. Utilizing functional proteomics, we identified 100 proteins differentially expressed in tumors and wounds., Conclusion: Full thickness excisional wounds have the ability to inhibit tumor growth in vivo. Further research may provide an exact mechanism for this remarkable finding and new advances in wound healing and tumor biology., Competing Interests: The authors have declared that no conflict of interest exists., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To investigate the effects of local doxycycline administration on skin scarring., Background: Skin scarring represents a major source of morbidity for surgical patients. Doxycycline, a tetracycline antibiotic with off-target effects on the extracellular matrix, has demonstrated antifibrotic effects in multiple organs. However, doxycycline's potential effects on skin scarring have not been explored in vivo., Methods: Female C57BL/6J mice underwent dorsal wounding following an established splinted excisional skin wounding model. Doxycycline was administered by local injection into the wound base following injury. Wounds were harvested upon complete wound closure (postoperative day 15) for histological examination and biomechanical testing of scar tissue., Results: A one-time dose of 3.90 mM doxycycline (2 mg/mL) within 12 hours of injury was found to significantly reduce scar thickness by 24.8% (P < 0.0001) without compromising tensile strength. The same effect could not be achieved by oral dosing. In doxycycline-treated scar matrices, collagen I content was significantly reduced (P = 0.0317) and fibers were favorably arranged with significantly increased fiber randomness (P = 0.0115). Common culprits of altered wound healing mechanics, including angiogenesis and inflammation, were not impacted by doxycycline treatment. However, engrailed1 profibrotic fibroblasts, responsible for scar extracellular matrix deposition, were significantly reduced with doxycycline treatment (P = 0.0005)., Conclusions: Due to the substantial improvement in skin scarring and well-established clinical safety profile, locally administered doxycycline represents a promising vulnerary agent. As such, we favor rapid translation to human patients as an antiscarring therapy.

Background: Pressure injury is seen across all healthcare settings and affects people of any age and health condition. It imposes a significant burden, with annual costs of up to $17.8 billion in the United States alone. Despite considerable resources it exhausts, the disease remains very prevalent, and the incidence is on the rise. This is in part due to aging population, growing number of nursing home residents, poorly understood biology, and dismal track record of clinical research in this field., Methods: In our Review Article, we discuss the disease pathophysiology, clinical manifestation, evidence based recommendations for risk assessment, prevention and timely management, existing challenges, and directions to improve research on the field. This article encompasses dedicated sections on the full spectrum of the pressure related pathologies including "conventional pressure ulcers", "medical device related pressure injuries", "pressure injuries in mucosal membranes", "pressure injuries in pediatric population", "pressure injury at end of life", and the "role of pressure in pathogenesis of diabetic foot ulcers".

Objective: To investigate how epithelial mechanotransduction pathways impact wound repair., Background: Mechanical forces are increasingly recognized to influence tissue repair, but their role in chronic wound pathophysiology remains unknown. Studies have shown that chronic wounds exhibit high levels of matrix metalloproteinase 9 (MMP9), a key proteolytic enzyme that regulates wound remodeling. We hypothesized that epithelial mechanosensory pathways regulated by keratinocyte-specific focal adhesion kinase (FAK) control dermal remodeling via MMP9., Methods: A standard wound model was applied to keratinocyte-specific FAK knockout (KO) and control mice. Rates of wound healing were measured and tissue was obtained for histologic and molecular analyses. Transcriptional and immunoblot assays were used to assess the activation of FAK, intracellular kinases, and MMP9 in vitro. A cell suspension model was designed to validate the importance of FAK mechanosensing, p38, and MMP9 secretion in human cells. Biomechanical testing was utilized to evaluate matrix tensile properties in FAK KO and control wounds., Results: Wound healing in FAK KO mice was significantly delayed compared with controls (closure at 15 days compared with 20 days, P = 0.0003). FAK KO wounds demonstrated decreased dermal thickness and collagen density. FAK KO keratinocytes exhibited overactive p38 and MMP9 signaling in vitro, findings recapitulated in human keratinocytes via the deactivation of FAK in the cell suspension model. Functionally, FAK KO wounds were significantly weaker and more brittle than control wounds, results consistent with the histologic and molecular analyses., Conclusions: Keratinocyte FAK is highly responsive to mechanical cues and may play a critical role in matrix remodeling via regulation of p38 and MMP9. These findings suggest that aberrant epithelial mechanosensory pathways may contribute to pathologic dermal proteolysis and wound chronicity.

Objective: To test the hypothesis that the mechanical environment of cutaneous wounds can control scar formation., Background: Mechanical forces have been recognized to modulate myriad biologic processes, but the role of physical force in scar formation remains unclear. Furthermore, the therapeutic benefits of offloading cutaneous wounds with a device have not been rigorously tested., Methods: A mechanomodulating polymer device was utilized to manipulate the mechanical environment of closed cutaneous wounds in red Duroc swine. After 8 weeks, wounds subjected to different mechanical stress states underwent immunohistochemical analysis for fibrotic markers. In a phase I clinical study, 9 human patients undergoing elective abdominal surgery were treated postoperatively with a stress-shielding polymer on one side whereas the other side was treated as standard of care. Professional photographs were taken between 8 and 12 months postsurgery and evaluated using a visual analog scale by lay and professional panels. This study is registered with ClinicalTrials.gov, number NCT00766727., Results: Stress shielding of swine incisions reduced histologic scar area by 6- and 9-fold compared to control and elevated stress states, respectively (P < 0.01 for both) and dramatically decreased the histologic expression of profibrotic markers. Closure of high-tension wounds induced human-like scar formation in the red Duroc, a phenotype effectively mitigated with stress shielding of wounds. In the study on humans, stress shielding of abdominal incisions significantly improved scar appearance (P = 0.004) compared with within-patient controls., Conclusions: These results indicate that mechanical manipulation of the wound environment with a dynamic stress-shielding polymer device can significantly reduce scar formation.

Introduction: Eliminating health care disparities in the United States will require a multifaceted approach that will include increasing diversity in the health care workforce. Historically, the field of medicine, and particularly surgery, has had an incumbent that grossly misrepresents the patient population. Delineating the exact demographics of the U.S. surgical residents and faculty could provide outstanding information, yielding insight into a possible deficit that, if rectified by the medical education system, could change the face of surgery and the entire health care system., Methods: Demographic information regarding medical students, surgical residents, and surgical faculty was retrieved and analyzed from the Association of American Medical Colleges data files dating back to 1966., Results: Whites comprise 64.4% of U.S. surgical residents, whereas Asian Americans, African Americans, and Latino Americans comprise 17.2%, 4.7%, and 5.1%, respectively. Whites comprise 74.1%, of academic surgeons, whereas Asian Americans, African Americans, and Latino Americans comprise 10.8%, 2.9%, and 3.6%, respectively. African Americans and Latino Americans comprise 5.4% and 4.8% of all U.S. surgeons, but only 2.9% and 3.6% of the academic surgeons, respectively. Whites comprise 85.7% of tenured surgical professors, whereas Asian Americans, African Americans, and Latino Americans comprise 4.9%, 1.8%, and 2.7%, respectively., Conclusion: Academic surgery is exceedingly deficient of minority residents, junior faculty, and professors. Correcting this misrepresentation would facilitate establishing a more culturally and ethnically sensitive health care environment for patients who otherwise would not seek care. Additionally, with more minority academic surgeons, there will likely be a commensurate increase in investigative studies highlighting minority specific health care needs and provide additional role models and mentors for future minority surgeons.

Objective: We examined the transcriptional response to serum stimulation as an in vitro model of wound healing in keloid fibroblasts to identify molecular mechanisms leading to their aberrant growth., Summary Background Data: Keloids are proliferative dermal growths representing a pathologic wound healing response. Although several groups have shown increased expression of profibrotic factors in keloids, there is little known about why they are expressed at higher levels than normal., Methods: Fibroblasts derived from keloids and normal scar were subjected to serum stimulation as an in vitro model to mimic a component of the wound microenvironment to examine differential gene expression in keloid derived fibroblasts versus normal human fibroblasts. A promoter analysis was performed to identify specific enhancers involved in mediating the differential response of connective tissue growth factor (CTGF, CCN2). Point mutations in the enhancers were performed to confirm their role. Finally, we examined activation of transcription factors known to bind the targeted enhancers., Results: Transcription of CCN2 after serum stimulation was significantly higher in keloid versus normal fibroblasts. Promoter analysis demonstrates the fragment from -625/-140 conferred increased serum responsiveness. Mutational analysis showed an AP-1 and SMAD binding site were both necessary for serum responsiveness. Preventing activation of either transcriptional complex will block CCN2 transcription. Additional experiments suggest that a single complex that includes components of the AP-1 and SMAD binding complexes is responsible for transactivation in response to serum. The key difference between keloid and normal fibroblasts appears to be the degree of activation of c-Jun., Conclusions: We suggest that altered responsiveness to cellular stress, based upon current data using serum stimulation and past data on response to mechanical strain, is a key defect leading to keloid formation.

Objective: To reveal, on a cellular and molecular level, how skeletal regeneration of a corticotomy is enhanced when using laser-plasma mediated ablation compared with conventional mechanical tissue removal., Summary Background Data: Osteotomies are well-known for their most detrimental side effect: thermal damage. This thermal and mechanical trauma to adjacent bone tissue can result in the untoward consequences of cell death and eventually in a delay in healing., Methods: Murine tibial corticotomies were performed using a conventional saw and a Ti:Sapphire plasma-generated laser that removes tissue with minimal thermal damage. Our analyses began 24 hours after injury and proceeded to postsurgical day 6. We investigated aspects of wound repair ranging from vascularization, inflammation, cell proliferation, differentiation, and bone remodeling., Results: Histology of mouse corticotomy sites uncovered a significant difference in the onset of bone healing; whereas laser corticotomies showed abundant bone matrix deposition at postsurgical day 6, saw corticotomies only exhibited undifferentiated tissue. Our analyses uncovered that cutting bone with a saw caused denaturation of the collagen matrix due to thermal effects. This denatured collagen represented an unfavorable scaffold for subsequent osteoblast attachment, which in turn impeded deposition of a new bony matrix. The matrix degradation induced a prolonged inflammatory reaction at the cut edge to create a surface favorable for osteochondroprogenitor cell attachment. Laser corticotomies were absent of collagen denaturation, therefore osteochondroprogenitor cell attachment was enabled shortly after surgery., Conclusion: In summary, these data demonstrate that corticotomies performed with Ti:Sapphire lasers are associated with a reduced initial inflammatory response at the injury site leading to accelerated osteochondroprogenitor cell migration, attachment, differentiation, and eventually matrix deposition.

Objective: To describe the field of surgical innovation from a historical perspective, applying new findings from research in technology innovation., Background: While surgical innovation has a rich tradition, as a field of study it is embryonic. Only a handful of academic centers of surgical innovation exist, all of which have arisen within the last 5 years. To this point, the field has not been well defined, nor have future options to promote surgical innovation been thoroughly explored. It is clear that surgical innovation is fundamental to surgical progress and has significant health policy implications. A process of systematically evaluating and promoting innovation in surgery may be critical in the evolving practice of medicine., Methods: A review of the academic literature in technology innovation was undertaken. Articles and books were identified through technical, medical, and business sources. Luminaries in surgical innovation were interviewed to develop further relevance to surgical history. The concepts in technology innovation were then applied to innovation in surgery, using the historical example of surgical endoscopy as a representative area, which encompasses millennia of learning and spans multiple specialties of care., Results: The history of surgery is comprised largely of individual, widely respected surgeon innovators. While respecting individual accomplishments, surgeons as a group have at times hindered critical innovation to the detriment of our profession and patients. As a clinical discipline, surgery relies on a tradition of research and attracting the brightest young minds. Innovation in surgery to date has been impressive, but inconsistently supported., Conclusion: A body of knowledge on technology innovation has been developed over the last decade but has largely not been applied to surgery. New surgical innovation centers are working to define the field and identify critical aspects of surgical innovation promotion. It is our responsibility as a profession to work to understand innovation in surgery, discover, translate, and commercialize advances to address major clinical problems, and to support the future of our profession consistently and rationally.

Objective: This study investigated the influence of the fetal environment on the healing characteristics of adult skin., Summary Background Data: The remarkable ability of the fetus to heal without scarring is poorly understood. The unique qualities of fetal wound healing may be caused by the fetal environment, the fetal tissues, or a combination of both. There are numerous differences between the prenatal and postnatal environments that may play a role in the unique fetal response to injury., Methods: Full-thickness adult sheep skin was transplanted onto the backs of 60-day-gestation fetal lambs (term, 145 days of gestation). The adult skin grafts were thus perfused by fetal blood and bathed in amniotic fluid. Previous work has demonstrated that, before midgestation, fetal lambs do not reject allogenic skin grafts. Forty days later (100 days of gestation), incisional wounds were made on both the adult skin graft and the adjacent fetal skin. The wounds were harvested 14 days postwounding and analyzed by both light microscopy and immunohistochemical testing using antibodies to collagen types I, III, and VI., Results: The wounds in the adult skin grafts healed with scar formation. This observation contrasts strongly with the scarless healing of the incisional fetal skin wounds., Conclusions: This study suggests that scarless fetal skin healing properties are intrinsic to fetal skin and are not primarily the result of the fetal environment.

Objective: This study determined how scar formation develops in a non-human primate model of fetal skin repair., Summary Background Data: A transition from healing scarlessly to healing with scar formation characterizes skin repair in rat and sheep fetuses. New knowledge of the regulatory processes occurring in the fetal wound at the initial stages of scar formation may provide insights into the early mechanisms of scar formation., Methods: Full-thickness wounds were made in fetal rhesus monkey lips from 75 through 114 days gestation (n = 6, term = 165 days). Wounds were harvested at 14 days postwounding and processed for histology (hematoxylin & eosin, Masson's trichrome) as well as immunohistochemistry (human type I or type III collagen)., Results: Wounds healed with complete restoration of normal tissue architecture in the 75-day gestation fetus. However in the 85-100 day gestation fetuses, wounds healed with an absence of hair follicles and sebaceous glands, but the dermal collagen pattern remained reticular and similar to that in unwounded dermis. At 107 days, a thin scar was present in the wound, thereby demonstrating a transition to scar formation between 100 and 107 days gestation (early 3rd trimester) in the non-human primate., Conclusions: In the non-human primate fetus, a transition from scarless repair to adult-type repair with scar formation occurs in the early third trimester. These data provide insight into the transition process; the ontogeny of scar formation is characterized initially by wounds healing without the presence of epidermal appendages but with a normal reticular dermal collagen pattern, which we term the "transition wound."

The purpose of this report is to call attention to the fetal wound healing process as a blueprint for ideal tissue repair. Wound healing in the fetus is fundamentally different from healing in the adult. Fetal tissue repair occurs rapidly and in the absence of scar formation. Because scarring and fibrosis dominate some diseases in every area of medicine, an understanding of fetal wound healing should help develop therapeutic strategies to avert the devastating consequences of excessive scar formation.

Midgestation fetal wound healing is characterized by healing without fibrosis or scar formation. The mechanisms that underlie this remarkable process are mediated in part through a fetal wound extracellular matrix rich in hyaluronic acid. In this study a newly developed assay was used to determine the hyaluronic acid levels in fetal and adult wound fluid. Adult wound fluid had a rapid increase in hyaluronic acid, which peaked at 3 days and decreased to 0 by 7 days. In contrast levels of hyaluronic acid in fetal wound fluid increased rapidly and remained significantly elevated for 3 weeks. This prolonged presence of hyaluronic acid in the matrix of fetal wounds creates a 'permissive' wound environment that promotes fetal fibroblast movement and proliferation and inhibits cytodifferentiation. Such a matrix environment promotes healing by regeneration rather than by scarring. This observation has therapeutic implications. The prolonged application of hyaluronic acid or hyaluronate protein complexes to wounds in children or adults may modulate healing in a manner that makes the wounds more fetal-like.

Recent clinical and experimental evidence suggests that the fetus responds to injury in a fashion fundamentally different from that of the adult. Our initial experience with human open fetal surgery reinforces experimental observations that the fetal wounds heal without the scarring, inflammation, and contraction that often accompany adult wounds. In this study we examine fetal wound fluid in an attempt to elucidate the control mechanisms that endow the fetus with unique healing properties. The extracellular matrix of fetal wounds is rich in hyaluronic acid, a glycosaminoglycan found in high concentrations whenever there is tissue proliferation, regeneration, and repair. We establish that wound fluid from the fetus contains high levels of hyaluronic acid-stimulating activity that may underlie the elevated deposition of hyaluronic acid in the fetal wound matrix. In contrast there was no hyaluronic acid-stimulating activity present in adult wound fluid. Hyaluronic acid, in turn, fosters an extracellular environment permissive for cell motility and proliferation that may account for the unique properties observed in fetal wound healing.