Challenges in Breast Evaluation: Breast Asymmetry, Macromastia, and the Surgically Altered Breast.

Many breast conditions that warrant referral to a plastic surgeon may first be identified in a routine gynecologic or primary care setting. These range from asymmetric anomalies and macromastia to sequelae of previous aesthetic and reconstructive procedures. The purpose of this reference article is to provide an overview of common breast deformities and discuss their unique challenges in evaluation.

Connexin 43-Based Therapeutics for Dermal Wound Healing.

The most ubiquitous gap junction protein within the body, connexin 43 (Cx43), is a target of interest for modulating the dermal wound healing response. Observational studies found associations between Cx43 at the wound edge and poor healing response, and subsequent studies utilizing local knockdown of Cx43 found improvements in wound closure rate and final scar appearance. Further preclinical work conducted using Cx43-based peptide therapeutics, including alpha connexin carboxyl terminus 1 (αCT1), a peptide mimetic of the Cx43 carboxyl terminus, reported similar improvements in wound healing and scar formation. Clinical trials and further study into the mode of action have since been conducted on αCT1, and Phase III testing for treatment of diabetic foot ulcers is currently underway. Therapeutics targeting connexin activity show promise in beneficially modulating the human body's natural healing response for improved patient outcomes across a variety of injuries.

Axillary Lymphadenectomy and Wound Complications in Implant-Based Breast Reconstruction.

BACKGROUND: The most common method of breast reconstruction in the United States today is implant-based reconstruction. However, reported complication rates are high, from 30% to 50%. Thus, it is important for reconstructive surgeons to identify factors associated with or contributing to wound complications after breast reconstruction. This study sought to identify associations between axillary lymph node dissection and postoperative wound complications in implant-based breast reconstruction. METHODS: A retrospective chart review was performed of subjects undergoing breast oncologic and reconstructive surgery by a single breast surgeon and reconstructive surgeon, respectively, from 2013 to 2016. Medical records were reviewed of 273 subjects with 338 reconstructed breasts. Data were recorded on the extent of axillary node dissection and subsequent wound complications including seroma requiring percutaneous drainage, seroma requiring open drainage, wound dehiscence requiring local wound care, wound dehiscence requiring operative revision, implant exposure, and implant loss. RESULTS: Analysis of the data demonstrated an increase in complication rates with extent of axillary lymph node dissection; however, these rates did not reach statistical significance. Statistically significant associations, however, were identified between wound complication rates and other known risk factors including increasing age and body mass index, as well as smoking status. CONCLUSIONS: Although an association between increasing complication rates and the extent of lymph node dissection has previously been reported, this study failed to demonstrate a statistically significant association with logistic regression analysis.

Evidence-Based Practice in Liposuction.

BACKGROUND: The goal of this study is to examine the existing peer reviewed literature comparing modern adjunctive techniques in liposuction including laser-assisted liposuction (LAL) and ultrasound-assisted liposuction (UAL) to standard suction-assisted liposuction (SAL). We intend to interpret these findings into a literature-based clinical application to influence practice patterns. METHODS: A literature review was conducted using a keyword search in PubMed. Keyword search items included liposuction, lipoplasty, suction assisted liposuction, ultrasound assisted liposuction, laser assisted liposuction, tumescent, liposuction comparison, liposuction review, and combinations therein. Exclusion criteria included articles with a primary focus on histologic effects of energy devices, primary animal models, primary opinion papers with no reference to available data, and industry-sponsored publications. Inclusion criteria included articles with direct comparison of liposuction modalities, randomized or blinded studies, and studies with objective outcomes. RESULTS: Twenty-five articles that met the inclusion criteria comparing SAL to UAL or LAL out of 9972 articles identified were obtained. The selected literature was assigned into 3 categories: evidence demonstrating an advantage of 1 modality (SAL, UAL, or LAL) over another, evidence that showed no benefit of 1 modality over another, and evidence that demonstrated risks of complications of 1 modality over another. CONCLUSIONS: The benefits of UAL and LAL over SAL include the following: (1) UAL over SAL in the treatment of gynecomastia, (2) LAL and UAL over SAL with decreased hemoglobin/hematocrit in high-volume lipoaspirates, and (3) LAL over SAL with skin tightening in select areas specifically the submental area. Otherwise, the literature demonstrates equivocal results among the described techniques with no clear benefit to set one apart from the other. There appears to be no demonstrable added benefit to the addition of either UAL or LAL that would urge a change in practice patterns outside the exceptions listed.

A Multicenter Randomized Controlled Trial Evaluating a Cx43-Mimetic Peptide in Cutaneous Scarring.

The transmembrane protein Cx43 has key roles in fibrogenic processes including inflammatory signaling and extracellular matrix composition. aCT1 is a Cx43 mimetic peptide that in preclinical studies accelerated wound closure, decreased inflammation and granulation tissue area, and normalized mechanical properties after cutaneous injury. We evaluated the efficacy and safety of aCT1 in the reduction of scar formation in human incisional wounds. In a prospective, multicenter, within-participant controlled trial, patients with bilateral incisional wounds (≥10 mm) after laparoscopic surgery were randomized to receive acute treatment (immediately after wounding and 24 hours later) with an aCT1 gel formulation plus conventional standard of care protocols, involving moisture-retentive occlusive dressing, or standard of care alone. The primary efficacy endpoint was average scarring score using visual analog scales evaluating incision appearance and healing progress over 9 months. There was no significant difference in scar appearance between aCT1- or control-treated incisions after 1 month. At month 9, aCT1-treated incisions showed a 47% improvement in scar scores over controls (Vancouver Scar Scale; P = 0.0045), a significantly higher Global Assessment Scale score (P = 0.0009), and improvements in scar pigmentation, thickness, surface roughness, and mechanical suppleness. Adverse events were similar in both groups. aCT1 has potential to improve scarring outcome after surgery.

Cell-populated collagen lattice contraction model for the investigation of fibroblast collagen interactions.

The fibroblast-populated collagen lattice (FPCL) was intended to act as the dermal component for "skin-equivalent" or artificial skin developed for skin grafting burn patients. The "skin-equivalent" was clinically unsuccessful as a skin graft, but today it is successfully used as a dressing for the management of chronic wounds. The FPCL has, however, become an instrument for investigating cell-connective tissue interactions within a three-dimensional matrix. Through the capacity of cell compaction of collagen fibrils, the FPCL undergoes a reduction in volume referred to as lattice contraction. Lattice contraction proceeds by cell-generated forces that reduce the water mass between collagen fibers, generating a closer relationship between collagen fibers. The compaction of collagen fibers is responsible for the reduction in the FPCL volume. Cell-generated forces through the linkage of collagen fibers with fibroblast's cytoskeletal actin-rich microfilament structures are responsible for the completion of the collagen matrix compaction. The type of culture dish used to cast FPCL as well as the cell number will dictate the mechanism for compacting collagen matrices. Fibroblasts, at moderate density, cast as an FPCL within a petri dish and released from the surface of the dish soon after casting compact collagen fibers through cell tractional forces. Fibroblasts at moderate density cast as an FPCL within a tissue culture dish and not released for 4 days upon release show rapid lattice contraction through a mechanism of cell contraction forces. Fibroblasts at high density cast in an FPCL within a petri dish, released from the surface of the dish soon after casting, compact a collagen lattice very rapidly through forces related to cell elongation. The advantage of the FPCL contraction model is the study of cells in the three-dimensional environment, which is similar to the environment from which these cells were isolated. In this chapter methods are described for manufacturing collagen lattices, which assess the three forces involved in compacting and/or organizing collagen fibrils into thicker collagen fibers. The clinical relevance of the FPCL contraction model is related to advancing our understanding of wound contraction and scar contracture.

Complex abdominal wall reconstruction: an outcomes review.

BACKGROUND: Complex abdominal wall reconstruction (AWR) remains challenging. Techniques for repair are numerous and include primary fascial approximation, separation of components (SOC), and use of various biologic and synthetic meshes. Given the vast expanse of available techniques and lack of consistent algorithms, an analysis of outcomes in AWR is presented. METHODS: A retrospective review was performed of complex AWRs performed by 2 surgeons at a single institution from July 2008 to October of 2011. Outcome differences for hernia repairs specifically addressing SOC with an acellular dermis inlay (retrorectus), underlay, or overlay mesh, as well as interposition biologic mesh placement were included. RESULTS: A total of 66 patients were identified. The average body mass index in this population was 35.5 kg/m. The average age was 53.7 years, with 62% females and 38% males. The overall rate of tobacco use history was 48%. Twenty-eight percent were diabetic. The overall hernia recurrence rate was 16%. Patients having SOC with inlay (retrorectus) mesh had a hernia recurrence rate of 9%. Hernia recurrence in those with SOC and biologic mesh reinforcement as an underlay or onlay was 12%; in those without mesh reinforcement, 22%; and for those with a biologic mesh interposition, 40%. CONCLUSIONS: The results of this review show that hernia recurrence rates are decreased with primary fascial repair. Further reduction occurs when biologic mesh reinforcement is used. The lowest recurrence rates were seen in the group with SOC and a porcine biologic mesh inlay. Abdominal wall reconstruction is challenging and with continued outcomes review a refined algorithm can be achieved. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic: III.

Capsular contracture after breast reconstruction: collagen fiber orientation and organization.

BACKGROUND: Breast implant capsular contracture is a common complication of implant-based breast reconstruction. To develop nonsurgical interventions to combat breast capsular contractures, a clearer understanding of the process is required. Comparing breast implant-related capsular contracture to the fibrotic scarring process, the hypothesis is that these processes differ with regard to the compaction of collagen fibers within the connective tissue matrix. METHODS: Morphologic differences in the connective tissue matrix by light, polarized light, and fluorescence microscopy documents these differences. Discarded Baker grade II and III periimplant capsules harvested during routine breast reconstructive operations were used for the evaluation. RESULTS: Within severe breast capsule contractures, light microscopy revealed the absence of mast cells, whereas polarized light microcopy showed that collagen fiber bundles were consolidated into thick cable-like structures. In less severe breast capsules, mast cells were present, whereas thick cable-like collagen structures were absent. By fluorescence microscopy, fibroblast populations associated with severe contractures were oriented perpendicular to the long axis, suggesting a spiral orientation in the compaction of these cable-like structures. These findings were absent in less severe contractures. CONCLUSIONS: To the authors' knowledge, these histologic findings in breast implant capsules are unreported and unique when compared with other fibrotic contractures. Elucidating the biological mechanisms involved in the reorganization of collagen fiber bundles that lead to implant-related capsular contracture is a critical step for developing strategies to treat and control breast capsule contractures.

Technique for seroma drainage in implant-based breast reconstruction.

Seromas are a common complication associated with breast reconstructive surgery. In expander based breast reconstructions, a seroma can pose a particularly difficult problem related to final tissue envelope shape as well as an increase in the risk of infection and possible tissue necrosis. Unfortunately, the literature describes few non-image related techniques to drain a seroma with a breast implant in place. We present a technique to drain a seroma associated with expander based breast reconstruction in conjunction with expander inflation, minimizing the risk of expander puncture, utilizing the same equipment necessary for expander inflation in the office. The benefit to this technique is that diagnostic and therapeutic imaging is not necessary and the risk of expander damage is minimized.

Pedicled rectus femoris flap for coverage of complex open pelvic fractures.

Complex open pelvic fractures are highly morbid injuries. Distant soft tissue transfer is often necessary for reconstruction. We report two cases of traumatic open pelvic fractures in which a pedicled rectus femoris flap was used for soft tissue coverage. Two patients presented with complex open pelvic fractures resulting from blunt trauma. In both patients a pedicled rectus femoris flap was used to reconstruct the full thickness soft tissue defect. Both patients had complete soft tissue coverage of the anterior pelvic defect allowing definitive pelvic fracture fixation. No significant donor site morbidity was associated with either patient post operatively. The well described pedicled rectus femoris flap's reliable anatomy, ease of harvest, and versatility as well as acceptable donor site morbidity makes this flap ideal for the reconstruction of complex open anterior pelvic fractures with full thickness soft tissue defects when other local flaps or free tissue transfer is not an option.

Rat mast cells enhance fibroblast proliferation and fibroblast-populated collagen lattice contraction through gap junctional intercellular communications.

BACKGROUND: Mast cells' association with fibrosis is known, but the mechanics of that association are unclear. The hypothesis is that mast cells promote fibroblast profibrotic activities through heterocellular gap junctional intercellular communications. Casting populated collagen lattices with both human mastocytoma cell line (HMC-1), an established mast cell line, and fibroblasts enhances lattice contraction via gap junctional intercellular communications. Unfortunately, in monolayer culture, HMC-1 cells and fibroblasts do not form heterocellular gap junctional intercellular communications. Freshly isolated rat peritoneal mast cells, however, establish these communications with fibroblasts in monolayer culture. Isolated rat peritoneal mast cells, however, survive only 7 days. Establishing a rat mast cell line that grows in the same medium as fibroblasts advances the study of mast cell-fibroblast interactions. HMC-1 cells thrive without supplements, suggesting that they release the factor(s) necessary for their viability. Spent HMC-1 medium may contain the factor(s) that generate a viable rat mast cell line. METHODS: Rat peritoneal-isolated mast cells grew in culture medium containing spent HMC-1 medium for 4 weeks. At 4 weeks, rat mast cells (RMC-1) were successfully maintained in Dulbecco's Modified Eagle Medium with 10% serum. RESULTS: RMC-1 cells formed heterocellular gap junctional intercellular communications with fibroblasts, enhancing both fibroblast proliferation and co-cultured RMC-1/fibroblast/populated collagen lattice contraction. Enhanced fibroblast proliferation and lattice contraction failed to occur by including RMC-1 cells unable to establish gap junctional intercellular communications with fibroblasts, but cell proliferation was not affected by including degranulated RMC-1 cells. CONCLUSION: Heterocellular gap junctional intercellular communications with mast cells increase in fibroblast proliferation and fibroblast PCL contraction, two hypertrophic scar fibroblast activities.

Plastic surgery within the Veterans Affairs Medical System: proposed modified indications for operative procedures.

Many plastic surgery procedures span the divide between aesthetic ("cosmetic") and reconstructive surgery. However, definitions and guidelines may be inconsistent, which may decrease patients' access to legitimate procedures. The article aims to assist Veterans' Health Administration-affiliated plastic surgeons in continuing to provide optimal care to the Nation's Veterans and family members, and should be regarded as an open discussion.

Soft-tissue defects and exposed hardware: a review of indications for soft-tissue reconstruction and hardware preservation.

BACKGROUND: Traditionally, management of exposed hardware has included irrigation and débridement, intravenous antibiotics, and likely removal of the hardware. Increasingly, the goal of wound closure without hardware removal using plastic surgical techniques of soft-tissue reconstruction has been emphasized. Identification of parameters for retaining exposed hardware may assist surgeons with management decisions and outcomes. METHODS: A current literature review was performed to identify parameters with prognostic relevance for management of exposed hardware before soft-tissue reconstruction. RESULTS: The following parameters were identified as important for the potential salvage of exposed hardware with soft-tissue coverage: hardware location, infection, duration of exposure, and presence of hardware loosening. CONCLUSIONS: Management of exposed hardware has included the removal of the hardware. However, if certain criteria are met--specifically, stable hardware, time of exposure less than 2 weeks, lack of infection, and location of hardware--salvage of the hardware with plastic surgical soft-tissue coverage may be a therapeutic option.

Metabolic and functional characterization of human adipose-derived stem cells in tissue engineering.

BACKGROUND: The use of adipose-derived stem cells for tissue engineering involves exposing them to metabolically adverse conditions. This study examines the metabolism, proliferation, and differentiation of adipose-derived stem cells under various conditions. METHODS: Adipose-derived stem cells were cultured in 16 media conditions containing 0.6, 2.4, 4.3, or 6.1 mM glucose; 0.1, 2.5, 4.1, or 6.1 mM glutamine; and then grown in either 0.1% or 20% oxygen. Conditioned media were collected and assayed for glucose, lactate, and pyruvate. Cell proliferation and cell death were measured at several time points. Osteogenic differentiation was analyzed by alizarin red staining/quantification and alkaline phosphatase activity, measured weekly over 4 weeks. RESULTS: Adipose-derived stem cells remained metabolically active in all nutrient and oxygen conditions tested. Glucose consumption and lactate production increased under hypoxic conditions, but pyruvate consumption was jointly dependent on oxygen and glucose concentration. The 20% oxygen environment produced greater proliferation and cell death compared with the hypoxic environment. Osteogenic differentiation of adipose-derived stem cells was observed only when glucose and/or oxygen concentrations were physiologically normal to high. CONCLUSIONS: Adipose-derived stem cells are an excellent source of multipotent cells and are capable of advancing current tissue engineering methodologies. These data show that adipose-derived stem cells remain viable under adverse conditions of low glucose, glutamine, and oxygen concentrations. However, there are variable levels of differentiation in the various culture conditions, which could lead to challenges in de novo osteogenesis and other forms of tissue engineering. Therefore, these results should be used in developing specific strategies to ensure successful application of adipose-derived stem cells in bone engineering and similar applications.

Calmodulin-myosin light chain kinase inhibition changes fibroblast-populated collagen lattice contraction, cell migration, focal adhesion formation, and wound contraction.

Wound healing requires fibroblast migration, synthesis of new extracellular matrix, and organization of that matrix, all of which depend upon myosin ATPase activation and subsequent cytoplasmic actin-myosin contraction. Myosin ATPase activity is optimized by phosphorylation of myosin light chain at serine 19. Several different signaling pathways can perform that phosphorylation, the focus here is calcium saturated calmodulin dependent -myosin light chain kinase (CaM-MLCK). It is proposed that CaM-MLCK phosphorylation of myosin light chain and subsequent myosin ATPase activation affects granulation tissue fibroblast behavior and contributes to wound contraction. Myosin ATPase activity generates actin-myosin contraction within fibroblasts. Myosin ATPase activity is involved in ATP-induced cell contraction, the generation of focal adhesions, fibroblast migration, fibroblast populated collagen lattice (FPCL) contraction, and wound contraction. The MLCK inhibitors ML-9 and ML-7 inhibited ATP-induced cell contraction, fibroblast migration, FA formation, and FPCL contraction. The calmodulin inhibitors W7 and fluphenazine blocked rat open wound contraction. In addition, fluphenazine delayed re-epithelialization. These findings support the idea that fibroblast CaM-MLCK activity is essential for tissue repair. We speculate that inhibition of CaM-MLCK may reduce or prevent detrimental fibrotic contracture.

Mast cells promote fibroblast populated collagen lattice contraction through gap junction intercellular communication.

The release of mast cell granules is commonly associated with inflammation and fibrosis. However, does direct communication between mast cells and fibroblasts through gap junction intercellular communication (GJIC) occur? Fibroblast populated collagen lattice (FPCL) cast with mast cells show enhanced lattice contraction. Do released granules or GJIC between mast cells and fibroblasts promote enhanced lattice contraction? Mast cells preloaded with a fluorescent dye that readily passes through gap junctions were cast in FPCL. Dye passed from mast cells into fibroblasts within these cocultured mast cell-FPCLs. Fatty acid amide hydrolase inhibitor blocks the breakdown of oleamide, which is a potent endogenous inhibitor of GJIC. GJIC was blocked for 3 days when mast cells were pulsed for 3 hours with fatty acid amide hydrolase inhibitor. Mast cells pretreated with fatty acid amide hydrolase inhibitor cast in cocultured mast cell-FPCLs failed to enhance cocultured lattice contraction. Mast cell-FPCLs made with mouse fibroblasts unable to generate GJIC failed to show enhanced lattice contraction. Degranulated mast cells were equal to intact mast cells at enhancing cocultured mast cell-FPCL contraction. The supernatant from degranulated mast cells had no effect upon FPCL contraction. Therefore, enhanced mast cell-FPCL contraction appears to be independent of mast cell granules, but dependent upon GJIC between fibroblasts and mast cells. We speculate that mast cell-fibroblast GJIC may play a role in fibrosis.

Systemic vanadate ingestion modulates rat tendon repair.

The chronic ingestion of vanadate prevents the appearance of myofibroblasts within granulation tissue of full excision wounds in rats, yet these wounds close at an optimal rate. Myofibroblasts are reported in the repair of transected tendons. Here we investigate tendon repair in the absence of myofibroblasts. Vanadate in saline drinking water was given to rats in the experimental group, while rats in the control group received saline alone. The Achilles tendon of the left leg of each rat was transected and suture repaired. On day 10, both repaired tendons and uninjured tendons from the right leg were harvested and processed for histology. By immunohistology the repaired tendons of control rats had myofibroblasts (fibroblasts with alpha smooth muscle actin positive stress fibers), while myofibroblasts were absent in healing tendons from vanadate-treated rats. By transmission electron microscopy and polarized light optics, repaired tendons of control rats demonstrated thin, loosely packed, immature collagen fiber bundles. Collagen fiber bundles from healing tendons of the vanadate-treated group were thicker, uniformly packed, and more mature. The chronic ingestion of vanadate promotes the more rapid organization of collagen fiber bundles of healing transected tendons in the absence of myofibroblasts.

Topical vanadate optimizes collagen organization within granulation tissue.

Systemic ingestion of vanadate, a nonspecific inhibitor of tyrosine phosphatases, doubles wound breaking strength, enhances the packing of collagen fibers, and prevents the appearance of myofibroblasts in granulation tissue. Will the local application of vanadate mimic the systemic effects? Pairs of polyvinyl alcohol sponges, each with a central reservoir and attached injection port, were subcutaneously implanted in rats. Daily, one implant received 0.2 ml of saline and the other received 0.2 ml of 0.03 mM vanadate in saline. On day 7, harvested sponges had equivalent wet weights. The vanadate-treated sponges had fibroblasts separated by connective tissue, with a more intense birefringence of the collagen fibers. Transmission electron microscopy showed collagen more uniformly packed in the vanadate treated sponges where collagen fibers were equally spaced and had equal diameters. By immunohistology, myofibroblasts, defined by the expression of alpha-smooth muscle actin within stress fibers, were absent in vanadate-treated granulation tissue. The expression of alpha-smooth muscle actin was restricted to smooth muscle cells of blood vessels. Controls had densely packed alpha-smooth muscle actin staining myofibroblasts, weak birefringence, and randomly spaced collagen fibers with irregular diameters. We conclude that the local application of vanadate prevents the appearance of myofibroblasts and optimizes the organization of collagen fibers in developing granulation tissue.

Dupuytren's disease: physiologic changes in nodule and cord fibroblasts through aging in vitro.

The pathogenesis of the fibrotic disease Dupuytren's contracture remains unclear. The disease process includes two structurally distinct fibrotic elements, the nodule and the cord. It has been proposed that as the disease progresses, nodules develop into cords. To corroborate that hypothesis, the authors took advantage of cultured fibroblast differences found between gap junction intercellular communication and fibroblast-populated collagen lattice contraction. Paired fibroblast cell lines of nodules and cords derived from four patients with Dupuytren's disease were maintained in culture for at least eight passages. The presence of gap junction intercellular communication in nodule- and cord-derived fibroblasts was documented and reported as a coupling index. The contraction of free-floating nodule- or cord-derived collagen lattices was also documented and reported. Early passage (passage 4) cord-derived fibroblasts showed a significant increase in coupling index compared with passage 4 nodule-derived fibroblasts (4.0 +/- 0.4 versus 2.5 +/- 0.3, respectively), where p < or = 0.01. However, late passage (passage 8) nodule- and cord-derived fibroblasts were equivalent in their coupling index (4.1 +/- 0.4 versus 4.4 +/- 0.4, respectively). Early passage nodule-derived fibroblast-populated collagen lattices contracted by 64 percent, whereas late passage nodule-derived lattices showed less contraction, at only 40 percent. Early and late passage cord-derived lattices contracted 46 and 37 percent, respectively. All nodule- and cord-derived cell lines were statistically equivalent at lattice contraction by passage 8. These in vitro studies support the hypothesis that fibroblasts derived from Dupuytren's contracture nodules change their phenotype after undergoing repeated cell passage, acquiring a cord-like fibroblast phenotype. Dupuytren's nodules represent the early, active form of fibrosis in which cells are more proliferative, better at fibroblast-populated collagen lattice contraction, and display less gap junction intercellular communication. The speculation is that alterations in gap junction intercellular communication may be involved in the progression of Dupuytren's nodules to cords as the disease progresses.