Where There Is Fat There Is Fibrosis: Elucidating the Mechanisms of Creeping Fat-Driven Stricture Formation
ELSEVIER SCIENCE INC. 2021: S65
View details for Web of Science ID 000718303100105
From Chronic Wounds to Scarring: The Growing Healthcare Burden of Under- and Over-healing Wounds.
Advances in wound care
SIGNIFICANCE: Wound healing is the largest medical market without an existing small molecule/drug treatment. Both "under-healing" (chronic wounds) and "over-healing" (scarring) cause a substantial biomedical burden and lifelong consequences for patients. These problems cost tens of billions of dollars per year in the United States alone, a number expected to grow as the population ages and the prevalence of common comorbidities (e.g., diabetes) rises. However, no therapies currently exist to produce the "ideal" healing outcome: efficient wound repair via regeneration of normal tissue. Recent Advances: Ongoing research continues to illuminate possible therapeutic avenues for wound healing. By identifying underlying mechanisms of wound repair - for instance, tissue mechanics' role in fibrosis, or cell populations that modulate wound healing and scarring - novel molecular targets may be defined. This Advances in Wound Care Forum issue includes reviews of scientific literature and original research from the Hagey Laboratory for Pediatric Regenerative Medicine at Stanford and its alumni, including developing approaches for encouraging wound healing, minimizing fibrosis, and coaxing regeneration.CRITICAL ISSUES: Wound healing problems reflect an enormous and rapidly expanding clinical burden. The issues of both under- and over-healing wound outcomes will continue to expand as their underlying causes (e.g., diabetes) grow. Targeted treatments are needed to enable wound repair with functional tissue restoration and decreased scarring.FUTURE DIRECTIONS: Basic scientists will continue to refine understanding of factors driving undesirable wound outcomes. These discoveries are beginning to be translated and, in the coming years, will hopefully form the foundation for anti-scarring drugs and other wound therapeutics.
View details for DOI 10.1089/wound.2021.0039
View details for PubMedID 34521257
- JUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models. Science translational medicine 2021; 13 (609): eabb3312
Modulating cellular responses to mechanical forces to promote wound regeneration.
Advances in wound care
SIGNIFICANCE: Skin scarring poses a major biomedical burden for hundreds of millions of patients annually. However, this burden could be mitigated by therapies that promote wound regeneration, with full recovery of skin's normal adnexa, matrix ultrastructure, and mechanical strength. Recent Advances: The observation of wound regeneration in several mouse models suggests a retained capacity for postnatal mammalian skin to regenerate under the right conditions. Mechanical forces are a major contributor to skin fibrosis and a prime target for devices and therapeutics that could promote skin regeneration.CRITICAL ISSUES: Wound induced hair neogenesis, Acomys "spiny" mice, Murphy Roths Large (MRL) mice, and mice treated with mechanotransduction inhibitors all show various degrees of wound regeneration. Comparison of regenerating wounds in these models against scarring wounds reveals differences in ECM interactions and in mechanosensitive activation of key signaling pathways, including Wnt, Sonic hedgehog, Focal Adhesion Kinase, and Yes-associated protein. The advent of single cell "omics" technologies has deepened this understanding and revealed that regeneration may recapitulate development in certain contexts, though it is unknown whether these mechanisms are relevant to healing in tight-skinned animals such as humans.FUTURE DIRECTIONS: While early findings in mice are promising, comparison across model systems is needed to resolve conflicting mechanisms and to identify conserved master regulators of skin regeneration. There also remains a dire need for studies on mechanomodulation of wounds in large, tight-skinned animals such as red Duroc pigs, which better approximate human wound healing.
View details for DOI 10.1089/wound.2021.0040
View details for PubMedID 34465219
- Leveraging Mechanical Forces to Target Insulin Injection-Induced Lipohypertrophy and Fibrosis. Diabetes spectrum : a publication of the American Diabetes Association 2021; 34 (3): 308-312
Optimizing Treatment of Hand Infections: Is MRSA Coverage Always Necessary?
Plastic and reconstructive surgery. Global open
2021; 9 (6): e3619
Multiple publications have highlighted the prevalence of methicillin resistant Staphylococcus aureus (MRSA) as a cause of hand infections. We hypothesized that these publications have shifted the empiric treatment of hand infections. The aim of this study was to identify the current standard of care, the most common causative bacteria, and factors leading to extended length of stay for hand infection patients at a suburban hospital to improve treatment and establish an optimized care protocol.Methods: Retrospective cohort analysis was conducted to identify all patients admitted for hand infections over an 8-year period. A comprehensive chart review of each patient's hospital course was completed.Results: A total of 70 patients were included. Maximum white blood cell count ≥ 12 was associated with a significantly longer hospital length of stay (9.1 days versus 5.4 days) compared to WBC values < 12 (P < 0.05). Also, 11 out of 23 (47.8%) underwent two or more incision and drainages (I&D's), compared with patients with maximum WBC < 12. Vancomycin use as an empiric antibiotic was widespread (68 patients, 97.1%), despite only 14 (20%) having MRSA positive cultures. Univariate analysis identified a significant increased likelihood for increased length of stay (P < 0.05) and rise in creatinine (P < 0.05) in patients with an initial vancomycin trough level > 20.Conclusions: This analysis of hand infection treatment in a suburban hospital demonstrates the incidence of MRSA hand infections may not be universally high across institutions. Each hospital should review its own data to optimize hand infection treatment and its associated costs.
View details for DOI 10.1097/GOX.0000000000003619
View details for PubMedID 34150420
Wnt-active Engrailed-1 Lineage-negative Fibroblasts Mediate Postnatal Skin Regeneration
WILEY. 2021: A30
View details for Web of Science ID 000650720500076
Single Cell RNA Sequencing Reveals Fibroblast Heterogeneity Across Embryonic Origins Of Skin
WILEY. 2021: A11-A12
View details for Web of Science ID 000650720500037
Novel Genetic Analysis Of MRL Mice Reveals That Complement Inhibition By Factor H Reduces Scarring
WILEY. 2021: A13
View details for Web of Science ID 000650720500040
Adipocytes In Dermal Wounds Undergo Conversion To Pro-fibrotic Fibroblasts That Contribute To Scar Formation
WILEY. 2021: A31
View details for Web of Science ID 000650720500078
Transgenic Inhibition Of Engrailed-1 Results In Endogenous Postnatal Skin Regeneration
WILEY. 2021: A14-A15
View details for Web of Science ID 000650720500043
Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring.
Science (New York, N.Y.)
2021; 372 (6540)
Skin scarring, the end result of adult wound healing, is detrimental to tissue form and function. Engrailed-1 lineage-positive fibroblasts (EPFs) are known to function in scarring, but Engrailed-1 lineage-negative fibroblasts (ENFs) remain poorly characterized. Using cell transplantation and transgenic mouse models, we identified a dermal ENF subpopulation that gives rise to postnatally derived EPFs by activating Engrailed-1 expression during adult wound healing. By studying ENF responses to substrate mechanics, we found that mechanical tension drives Engrailed-1 activation via canonical mechanotransduction signaling. Finally, we showed that blocking mechanotransduction signaling with either verteporfin, an inhibitor of Yes-associated protein (YAP), or fibroblast-specific transgenic YAP knockout prevents Engrailed-1 activation and promotes wound regeneration by ENFs, with recovery of skin appendages, ultrastructure, and mechanical strength. This finding suggests that there are two possible outcomes to postnatal wound healing: a fibrotic response (EPF-mediated) and a regenerative response (ENF-mediated).
View details for DOI 10.1126/science.aba2374
View details for PubMedID 33888614
- Discussion: Overcoming the Patent Gap: A Guide to Patenting for Plastic Surgeons. Plastic and reconstructive surgery 2021; 148 (4): 918-919
Endogenous Mechanisms of Craniomaxillofacial Repair: Toward Novel Regenerative Therapies.
Frontiers in oral health
1800; 2: 676258
In the fields of oral and craniomaxillofacial surgery, regeneration of multiple tissue types-including bone, skin, teeth, and mucosal soft tissue-is often a desired outcome. However, limited endogenous capacity for regeneration, as well as predisposition of many tissues to fibrotic healing, may prevent recovery of normal form and function for patients. Recent basic science research has advanced our understanding of molecular and cellular pathways of repair in the oral/craniofacial region and how these are influenced by local microenvironment and embryonic origin. Here, we review the current state of knowledge in oral and craniomaxillofacial tissue repair/regeneration in four key areas: bone (in the context of calvarial defects and mandibular regeneration during distraction osteogenesis); skin (in the context of cleft lip/palate surgery); oral mucosa (in the context of minimally scarring repair of mucosal injuries); and teeth (in the context of dental disease/decay). These represent four distinct healing processes and outcomes. We will discuss both divergent and conserved pathways of repair in these contexts, with an eye toward fundamental mechanisms of regeneration vs. fibrosis as well as translational research directions. Ultimately, this knowledge can be leveraged to develop new cell-based and molecular treatment strategies to encourage bone and soft tissue regeneration in oral and craniomaxillofacial surgery.
View details for DOI 10.3389/froh.2021.676258
View details for PubMedID 35048022
Prrx1 Fibroblasts Represent a Pro-fibrotic Lineage in the Mouse Ventral Dermis.
2020; 33 (6): 108356
Fibroblast heterogeneity has been shown within the unwounded mouse dorsal dermis, with fibroblast subpopulations being identified according to anatomical location and embryonic lineage. Using lineage tracing, we demonstrate that paired related homeobox 1 (Prrx1)-expressing fibroblasts are responsible for acute and chronic fibroses in the ventral dermis. Single-cell transcriptomics further corroborated the inherent fibrotic characteristics of Prrx1 fibroblasts during wound repair. In summary, we identify and characterize a fibroblast subpopulation in the mouse ventral dermis with intrinsic scar-forming potential.
View details for DOI 10.1016/j.celrep.2020.108356
View details for PubMedID 33176144
Peripheral Motor Neuron Activity Influences over Local Sarcoma Progression
ELSEVIER SCIENCE INC. 2020: S230–S231
View details for Web of Science ID 000582792300421
Detection, Scoring, and Classification of Solid Organ Fibroses with Machine Learning Analysis
ELSEVIER SCIENCE INC. 2020: S222
View details for Web of Science ID 000582792300403
A Surgical Model for Investigating the Role of Creeping Fat in Intestinal Fibrosis
ELSEVIER SCIENCE INC. 2020: S50–S51
View details for Web of Science ID 000582792300070
Elucidating Molecular Drivers of Wound Regeneration in MRL Mice Via Novel Transcriptomic Analyses
ELSEVIER SCIENCE INC. 2020: S225
View details for Web of Science ID 000582792300410
Fibroblast Heterogeneity in Wound Healing: Hurdles to Clinical Translation.
Trends in molecular medicine
Recent work has revealed that fibroblasts are remarkably heterogeneous cells, but the appropriate lens through which to study this variation (lineage, phenotype, and plasticity) and its relevance to human biology remain unclear. In this opinion article, we comment on recent breakthroughs in our understanding of fibroblast heterogeneity during skin wound healing, and on open questions that must be addressed to clinically translate these findings in order to minimize scarring in patients. We emphasize the need for experimental models of wound healing that better approximate human biology, as well as comparison of scarring and regenerative phenotypes to uncover master regulators of fibrosis.
View details for DOI 10.1016/j.molmed.2020.07.008
View details for PubMedID 32800679
- Rewriting the Future: Promises and Limits of Germline Gene Editing in Craniofacial Surgery. The Journal of craniofacial surgery 2020
- Doxycycline Reduces Scar Thickness and Improves Collagen Architecture ANNALS OF SURGERY 2020; 272 (1): 183–93
Harnessing novel gene expression analyses to identify drivers of regenerative ear wound healing in MRL mice
WILEY. 2020: S25
View details for Web of Science ID 000548418300052
- Fibroblast Heterogeneity in and Its Implications for Plastic and Reconstructive Surgery: A Basic Science Review PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN 2020; 8 (6)
"Tissues in a Dish": A Review of Organoids in Plastic Surgery.
Plastic and reconstructive surgery. Global open
2020; 8 (4): e2787
Organoids are in vitro miniaturized organ models-or, colloquially, "organs in a dish." These 3-dimensional, multicellular structures are classically derived from pluripotent or multipotent stem cells. When guided by tissue-specific molecular factors, these cells exhibit self-organizing abilities that allow them to accurately recapitulate the architecture and function of the organ of interest. Organoid technology is a rapidly expanding field that endows researchers with an unprecedented ability to recreate, study, and manipulate complex biologic processes in vitro. When compared with standard 2- and 3-dimensional culture systems, which rely on co-culturing pre-established cell types, organoids provide a more biomimetic model with which to study the intercellular interactions necessary for in vivo organ function and architecture. Organoids have the potential to impact all avenues of medicine, including those fields most relevant to plastic and reconstructive surgery such as wound healing, oncology, craniofacial reconstruction, and burn care. In addition to their ability to serve as a novel tool for studying human-specific disease, organoids may be used for tissue engineering with the goal of developing biomimetic soft-tissue substitutes, which would be especially valuable to the plastic surgeon. Although organoids hold great promise for the field of plastic surgery, technical challenges in creating vascularized, multilineage organoids must be overcome to allow for the integration of this technology in clinical practice. This review provides a brief history of the organoid, highlights its potential clinical applications, discusses certain limitations, and examines the impact that this technology may have on the field of plastic and reconstructive surgery.
View details for DOI 10.1097/GOX.0000000000002787
View details for PubMedID 32440447
View details for PubMedCentralID PMC7209840
Fibroblast Heterogeneity in and Its Implications for Plastic and Reconstructive Surgery: A Basic Science Review.
Plastic and reconstructive surgery. Global open
2020; 8 (6): e2927
Fibroblasts' integral role in tissue development, maintenance, and disease represents a fast-growing field of basic science research. Although fibroblasts were long thought to be a homogeneous cell population, recent research has illuminated the unforeseen complexity of these cells, giving rise to the rapidly expanding research field of "fibroblast heterogeneity." Fibroblasts play a critical role in states of tissue fibrosis such as skin scarring, which affects hundreds of millions of patients annually and causes severe aesthetic, developmental, and functional morbidity. Beyond scarring, major organ fibrosis is an enormous public health concern responsible for nearly half of all deaths in the United States. Because fibrosis is a conserved response to tissue damage in all organs, the study of fibroblasts throughout the body may help us to understand their role in the conditions most relevant to plastic and reconstructive surgery-for instance, skin scarring (eg, from burns, traumatic lacerations, or surgical incisions), "pathological" scarring (hypertrophic scars, keloids), and capsular contracture. Here, we present a basic science review of fibroblast heterogeneity in wound healing, cancer, organ fibrosis, and human dermal architecture. The field of fibroblast heterogeneity is young, and many of the insights discussed have yet to be translated clinically. However, plastic surgeons stand in a unique position to bridge these discoveries into clinical realities. We hope this information can spur readers to consider both what questions in plastic surgery can be studied from the lens of fibroblast heterogeneity, and how these preclinical insights can be translated to improving care of our patients.
View details for DOI 10.1097/GOX.0000000000002927
View details for PubMedID 32766071
View details for PubMedCentralID PMC7339369
Understanding the impact of fibroblast heterogeneity on skin fibrosis.
Disease models & mechanisms
2020; 13 (6)
Tissue fibrosis is the deposition of excessive extracellular matrix and can occur as part of the body's natural wound healing process upon injury, or as a consequence of diseases such as systemic sclerosis. Skin fibrosis contributes to significant morbidity due to the prevalence of injuries resulting from trauma and burn. Fibroblasts, the principal cells of the dermis, synthesize extracellular matrix to maintain the skin during homeostasis and also play a pivotal role in all stages of wound healing. Although it was previously believed that fibroblasts are homogeneous and mostly quiescent cells, it has become increasingly recognized that numerous fibroblast subtypes with unique functions and morphologies exist. This Review provides an overview of fibroblast heterogeneity in the mammalian dermis. We explain how fibroblast identity relates to their developmental origin, anatomical site and precise location within the skin tissue architecture in both human and mouse dermis. We discuss current evidence for the varied functionality of fibroblasts within the dermis and the relationships between fibroblast subtypes, and explain the current understanding of how fibroblast subpopulations may be controlled through transcriptional regulatory networks and paracrine communications. We consider how fibroblast heterogeneity can influence wound healing and fibrosis, and how insight into fibroblast heterogeneity could lead to novel therapeutic developments and targets for skin fibrosis. Finally, we contemplate how future studies should be shaped to implement knowledge of fibroblast heterogeneity into clinical practice in order to lessen the burden of skin fibrosis.
View details for DOI 10.1242/dmm.044164
View details for PubMedID 32541065
Intrinsic Chromatin State and Extrinsic Wound-Related Cues Can Coordinate to Activate Fibroblasts for Scarring
ELSEVIER SCIENCE INC. 2019: S223–S224
View details for Web of Science ID 000492740900428
Regenerative Skin Healing Through Targeted Modulation of Engrailed1-Negative Fibroblasts
ELSEVIER SCIENCE INC. 2019: S228
View details for Web of Science ID 000492740900437
Quality of Randomized Controlled Trials for Surgical Treatment of Carpal Tunnel Syndrome: A Systematic Review.
Plastic and reconstructive surgery
2019; 143 (3): 791–99
BACKGROUND: Randomized controlled trials are considered the gold standard in evidence-based medicine. The authors conducted a systematic review to evaluate the quantity, quality, and trends of randomized controlled trials that assess surgical treatment of carpal tunnel syndrome.METHODS: The authors identified randomized controlled trials comparing two or more surgical interventions for carpal tunnel syndrome in PubMed, Cochrane, Scopus, Google Scholar, and Clinicaltrials.gov. Two independent reviewers evaluated articles for inclusion, extracted data, and assessed randomized controlled trial quality using the Jadad score.RESULTS: Of 2253 identified studies, 58 met full inclusion criteria. They were published between 1985 and 2015, with a significant increase over time (p = 0.003). They were most frequently published in Journal of Hand Surgery (European Volume) [n = 15 (25.9 percent)]. Most randomized controlled trials were single-center studies [n = 54 (93.1 percent)] conducted in the United Kingdom [n = 13 (22.4 percent)] or the United States [n = 10 (17.2 percent)], with a mean study size of 80.1 ± 55.5 patients. Funding source was unknown in 62.1 percent (n = 36). Three-quarters [n = 44 (75.9 percent)] of randomized controlled trials did not define the primary outcome measure(s). Less than 30 percent (n = 17) of randomized controlled trials conducted a power analysis. Only four studies with patients reported lost to follow-up provided an explanation for each patient. Six randomized controlled trials (10.3 percent) conducted intention-to-treat analysis. The mean Jadad score was 2.14 ± 1.26, with no significant improvement over time (p = 0.245).CONCLUSIONS: Despite the significant increase in the number of randomized controlled trials published studying surgical treatment of carpal tunnel syndrome over time, a mean Jadad score of 2.14 with no change over time indicates a need for improvement in quality. Proper study design is key to avoiding introduction of bias and ensuring the validity of conclusions drawn.
View details for PubMedID 30822284
- Quality of Randomized Controlled Trials for Surgical Treatment of Carpal Tunnel Syndrome: A Systematic Review PLASTIC AND RECONSTRUCTIVE SURGERY 2019; 143 (3): 791-799
The Spectrum of Scarring in Craniofacial Wound Repair.
Frontiers in physiology
2019; 10: 322
Fibrosis is intimately linked to wound healing and is one of the largest causes of wound-related morbidity. While scar formation is the normal and inevitable outcome of adult mammalian cutaneous wound healing, scarring varies widely between different anatomical sites. The spectrum of craniofacial wound healing spans a particularly diverse range of outcomes. While most craniofacial wounds heal by scarring, which can be functionally and aesthetically devastating, healing of the oral mucosa represents a rare example of nearly scarless postnatal healing in humans. In this review, we describe the typical wound healing process in both skin and the oral cavity. We present clinical correlates and current therapies and discuss the current state of research into mechanisms of scarless healing, toward the ultimate goal of achieving scarless adult skin healing.
View details for PubMedID 30984020
Doxycycline Reduces Scar Thickness and Improves Collagen Architecture.
Annals of surgery
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.
View details for PubMedID 30585822
- Quality of surgical randomized controlled trials in hand surgery: a systematic review JOURNAL OF HAND SURGERY-EUROPEAN VOLUME 2018; 43 (8): 801-807
Fibroblasts and wound healing: an update.
View details for PubMedID 30062921
- Fibroblasts and wound healing: an update REGENERATIVE MEDICINE 2018; 13 (5): 491–95
Quality of surgical randomized controlled trials in hand surgery: a systematic review.
The Journal of hand surgery, European volume
We assessed the quantity, quality and trends of randomized controlled trials comparing hand surgical interventions. Study characteristics were collected for 125 randomized controlled trials comparing hand surgical interventions. The Jadad scale (0-5), which assesses methodological quality of trials, was calculated. Logistic regressions were conducted to determine associations with the Jadad score. The studies were published between 1981 and 2015, with an increase over time, most often in Journal of Hand Surgery (European). Mean study size was 68 patients. Mean Jadad score was 2.1, without improvement over time. Thirty percent conducted a power analysis and 8% an intention-to-treat analysis. Studies conducted in the United Kingdom and with smaller sample sizes, power analysis and intention-to-treat analysis were associated with a higher Jadad score. The quantity of trials has increased over time while methodological quality has remained low, indicating a need to improve quality of trials in hand surgery literature.
View details for PubMedID 29896997