Update on the Basic Science Concepts and Applications of Adipose-Derived Stem Cells in Hand and Craniofacial Surgery.

SUMMARY: Adipose-derived stem cell therapy offers plastic surgeons a novel treatment alternative for conditions with few therapeutic options. Adipose-derived stem cells are a promising treatment because of their broad differentiation potential, capacity for self-renewal, and ease of isolation. Over the past decade, plastic surgeons have attempted to harness adipose-derived stem cells' unique cellular characteristics to improve the survival of traditional fat grafting procedures, a process known as cell-assisted lipotransfer. However, the full implications of cell-assisted lipotransfer in clinical practice remain incompletely understood, stressing the urgent need to assess the scientific evidence supporting adipose-derived stem cell-based interventions. Furthermore, with the strict regulatory climate surrounding tissue explantation therapies, reviewing the safety and efficacy of these treatments will clarify their regulatory viability moving forward. In this report, the authors provide a comprehensive, up-to-date appraisal of best evidence-based practices supporting adipose-derived stem cell-derived therapies, highlighting the known mechanisms behind current clinical applications in tissue engineering and regenerative medicine specific to plastic and reconstructive surgery. The authors outline best practices for the harvest and isolation of adipose-derived stem cells and discuss why procedure standardization will elucidate the scientific bases for their broad use. Finally, the authors discuss challenges posed by U.S. Food and Drug Administration oversight of these cell-based therapies and examine the role of adipose-derived stem cell-based applications in the future of plastic surgery.

Current risk of breast implant-associated anaplastic large cell lymphoma: a systematic review of epidemiological studies.

Recent epidemiological studies have attempted to accurately determine the risk of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). However, comparisons of previously published works are difficult due to widespread variations in reporting. We systematically review the epidemiology in order to better define the current risk of BIA-ALCL. Herein, we report the global epidemiology with an emphasis on the U.S. breast implant population while simultaneously assessing the oncologic safety of smooth-surface devices. In the current manuscript, a systematic review of PubMed and other scientific databases, as well as the grey literature, was conducted for epidemiologic studies on BIA-ALCL. Using analytical and descriptive epidemiology, we estimated the cumulative incidence and incidence rate of BIA-ALCL using a standardized approach. Cumulative incidence was reported at implant and patient-specific levels. The patient-specific cumulative risk within the U.S. market ranges from 1.79 per 1,000 (1:559) to 2.82 per 1,000 (1:355) patients with a textured implant. The implant-specific risk of Allergan textured devices ranges from 1:602-871 to 1:8,500, while the risk of commercially available Mentor Siltex implants is 1:50,000. No epidemiological study or regulatory agency reported a case of BIA-ALCL occurring exclusively with a smooth device. As such, with the removal of Allergan textured breast devices, this study demonstrates substantial gaps in the epidemiological knowledge of BIA-ALCL, including the current risk of commercially available textured breast implants in the U.S. market. Although the risk of BIA-ALCL is low, surgeons should exercise extreme caution when considering the use of a textured breast device for cosmetic or reconstructive purposes.

Cellular and Molecular Mechanisms of Breast Implant-Associated Anaplastic Large Cell Lymphoma.

SUMMARY: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an emerging and highly treatable cancer of the immune system that can form around textured-surface breast implants. Although the underlying cause has yet to be elucidated, an emerging theme-linking pathogenesis to a chronic inflammatory state-continues to dominate the current literature. Specifically, the combination of increasing mutation burden and chronic inflammation leads to aberrant T-cell clonal expansion. However, the impetus remains largely unknown. Proposed mechanisms include a lipopolysaccharide endotoxin response, oncogenic transformation related to viral infection, associated trauma to the breast pocket, particulate matter digestion by capsular macrophages, chronic allergic inflammation, and genetic susceptibility. The Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) pathway is a major signaling pathway that regulates a variety of intracellular growth and survival processes. Constitutive activation of JAK-STAT3 has been implicated in several malignancies, including lymphomas, and has recently been identified as a potential key mediator in BIA-ALCL. The purpose of this article is to review the cellular and molecular mechanisms of BIA-ALCL with a focus on the role of oncogenic JAK-STAT3 signaling in BIA-ALCL tumorigenesis and progression. Selected experimental work from the authors' group on aberrant JAK-STAT3 signaling in BIA-ALCL is also included. The authors discuss how an inflammatory microenvironment may facilitate malignant transformation through the JAK-STAT3 pathway-highlighting its potential mechanistic role. The authors' hope is that further investigation of this signaling pathway will reveal avenues for using JAK-STAT3 signaling as a prognostic indicator and novel therapeutic target in the case of advanced disease.

Breast Implant-Associated Anaplastic Large Cell Lymphoma: Defining Future Research Priorities.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an emerging cancer of the immune system that is exclusively associated with textured-surface breast implants. This clinical review provides an update on the diagnosis and management of BIA-ALCL with an emphasis on major advances. The epidemiology and pathophysiology of the disease are also reviewed, focusing on current paradigm shifts and highlighting current controversies related to disease classification and risk mitigation. Finally, the authors conclude by discussing medicolegal and ethical issues surrounding BIA-ALCL while establishing a future basic science and clinical research agenda that is central to improving patient safety.

Breast Implant-associated Anaplastic Large Cell Lymphoma: An Evidence-based Systematic Review.

OBJECTIVE: This evidence-based systematic review synthesizes and critically appraises current clinical recommendations and advances in the diagnosis and treatment of BIA-ALCL. This review also aims to broaden physician awareness across diverse specialties, particularly among general practitioners, breast surgeons, surgical oncologists, and other clinicians who may encounter patients with breast implants in their practice. BACKGROUND: BIA-ALCL is an emerging and treatable immune cell cancer definitively linked to textured-surface breast implants. Although the National Comprehensive Cancer Network (NCCN) consensus guidelines and other clinical recommendations have been established, the evidence supporting these guidelines has not been systematically studied. The purpose of this evidence-based systematic review is to synthesize and critically appraise current clinical guidelines and recommendations while highlighting advances in diagnosis and treatment and raising awareness for this emerging disease. METHODS: This evidence-based systematic review evaluated primary research studies focusing on the diagnosis and treatment of BIA-ALCL that were published in PubMed, Google Scholar, and other scientific databases through March 2020. RESULTS AND CONCLUSIONS: The clinical knowledge of BIA-ALCL has evolved rapidly over the last several years with major advances in diagnosis and treatment, including en bloc resection as the standard of care. Despite a limited number of high-quality clinical studies comprised mainly of Level III and Level V evidence, current evidence aligns with established NCCN consensus guidelines. When diagnosed and treated in accordance with NCCN guidelines, BIA-ALCL carries an excellent prognosis.

Epithelial TNF Receptor Signaling Promotes Mucosal Repair in Inflammatory Bowel Disease.

TNF plays an integral role in inflammatory bowel disease (IBD), as evidenced by the dramatic therapeutic responses in Crohn's disease (CD) patients induced by chimeric anti-TNF mAbs. However, treatment of CD patients with etanercept, a decoy receptor that binds soluble TNF, fails to improve disease. To explore this discrepancy, we investigated the role of TNF signaling in Wnt/ß-catenin-mediated intestinal stem cell and progenitor cell expansion in CD patients, human cells, and preclinical mouse models. We hypothesized that TNF exerts beneficial effects on intestinal epithelial cell (IEC) responses to injury. In CD patients, intestinal stem cell and progenitor cell Wnt/ß-catenin signaling correlates with inflammation status. TNF-deficient (Tnf-/-) mice exhibited increased apoptosis, less IEC proliferation, and less Wnt signaling when stimulated with anti-CD3 mAb. Bone marrow (BM) chimera mice revealed that mucosal repair depended on TNF production by BM-derived cells and TNFR expression by radioresistant IECs. Wild-type→Tnfr1/2-/- BM chimera mice with chronic dextran sodium sulfate colitis exhibited delayed ulcer healing, more mucosal inflammation, and impaired Wnt/ß-catenin signaling, consistent with the hypothesis that epithelial TNFR signaling participates in mucosal healing. The direct effect of TNF on stem cells was demonstrated by studies of TNF-induced Wnt/ß-catenin target gene expression in murine enteroids and colonoid cultures and TNF-induced ß-catenin activation in nontransformed human NCM460 cells (TOPFlash) and mice (TOP-GAL). Together, these data support the hypothesis that TNF plays a beneficial role in enhancing Wnt/ß-catenin signaling during ulcer healing in IBD. These novel findings will inform clinicians and therapeutic chemists alike as they strive to develop novel therapies for IBD patients.

Changes in skeletal muscle and tendon structure and function following genetic inactivation of myostatin in rats.

Myostatin is a negative regulator of skeletal muscle and tendon mass. Myostatin deficiency has been well studied in mice, but limited data are available on how myostatin regulates the structure and function of muscles and tendons of larger animals. We hypothesized that, in comparison to wild-type (MSTN(+/+) ) rats, rats in which zinc finger nucleases were used to genetically inactivate myostatin (MSTN(Δ/Δ) ) would exhibit an increase in muscle mass and total force production, a reduction in specific force, an accumulation of type II fibres and a decrease and stiffening of connective tissue. Overall, the muscle and tendon phenotype of myostatin-deficient rats was markedly different from that of myostatin-deficient mice, which have impaired contractility and pathological changes to fibres and their extracellular matrix. Extensor digitorum longus and soleus muscles of MSTN(Δ/Δ) rats demonstrated 20-33% increases in mass, 35-45% increases in fibre number, 20-57% increases in isometric force and no differences in specific force. The insulin-like growth factor-1 pathway was activated to a greater extent in MSTN(Δ/Δ) muscles, but no substantial differences in atrophy-related genes were observed. Tendons of MSTN(Δ/Δ) rats had a 20% reduction in peak strain, with no differences in mass, peak stress or stiffness. The general morphology and gene expression patterns were similar between tendons of both genotypes. This large rodent model of myostatin deficiency did not have the negative consequences to muscle fibres and extracellular matrix observed in mouse models, and suggests that the greatest impact of myostatin in the regulation of muscle mass may not be to induce atrophy directly, but rather to block hypertrophy signalling.

Reduced muscle fiber force production and disrupted myofibril architecture in patients with chronic rotator cuff tears.

BACKGROUND: A persistent atrophy of muscle fibers and an accumulation of fat, collectively referred to as fatty degeneration, commonly occur in patients with chronic rotator cuff tears. The etiology of fatty degeneration and function of the residual rotator cuff musculature have not been well characterized in humans. We hypothesized that muscles from patients with chronic rotator cuff tears have reduced muscle fiber force production, disordered myofibrils, and an accumulation of fat vacuoles. METHODS: The contractility of muscle fibers from biopsy specimens of supraspinatus muscles of 13 patients with chronic full-thickness posterosuperior rotator cuff tears was measured and compared with data from healthy vastus lateralis muscle fibers. Correlations between muscle fiber contractility, American Shoulder and Elbow Surgeons (ASES) scores, and tear size were analyzed. Histology and electron microscopy were also performed. RESULTS: Torn supraspinatus muscles had a 30% reduction in maximum isometric force production and a 29% reduction in normalized force compared with controls. Normalized supraspinatus fiber force positively correlated with ASES score and negatively correlated with tear size. Disordered sarcomeres were noted, along with an accumulation of lipid-laden macrophages in the extracellular matrix surrounding supraspinatus muscle fibers. CONCLUSIONS: Patients with chronic supraspinatus tears have significant reductions in muscle fiber force production. Force production also correlates with ASES scores and tear size. The structural and functional muscle dysfunction of the residual muscle fibers is independent of the additional area taken up by fibrotic tissue. This work may help establish future therapies to restore muscle function after the repair of chronically torn rotator cuff muscles.

Inhibition of 5-LOX, COX-1, and COX-2 increases tendon healing and reduces muscle fibrosis and lipid accumulation after rotator cuff repair.

BACKGROUND: The repair and restoration of function after chronic rotator cuff tears are often complicated by muscle atrophy, fibrosis, and fatty degeneration of the diseased muscle. The inflammatory response has been implicated in the development of fatty degeneration after cuff injuries. Licofelone is a novel anti-inflammatory drug that inhibits 5-lipoxygenase (5-LOX), as well as cyclooxygenase (COX)-1 and COX-2 enzymes, which play important roles in inducing inflammation after injuries. While previous studies have demonstrated that nonsteroidal anti-inflammatory drugs and selective inhibitors of COX-2 (coxibs) may prevent the proper healing of muscles and tendons, studies about bone and cartilage have demonstrated that drugs that inhibit 5-LOX concurrently with COX-1 and COX-2 may enhance tissue regeneration. HYPOTHESIS: After the repair of a chronic rotator cuff tear in rats, licofelone would increase the load to failure of repaired tendons and increase the force production of muscle fibers. STUDY DESIGN: Controlled laboratory study. METHODS: Rats underwent supraspinatus release followed by repair 28 days later. After repair, rats began a treatment regimen of either licofelone or a vehicle for 14 days, at which time animals were euthanized. Supraspinatus muscles and tendons were then subjected to contractile, mechanical, histological, and biochemical analyses. RESULTS: Compared with controls, licofelone-treated rats had a grossly apparent decrease in inflammation and increased fibrocartilage formation at the enthesis, along with a 62% increase in the maximum load to failure and a 51% increase in peak stress to failure. Licofelone resulted in a marked reduction in fibrosis and lipid content in supraspinatus muscles as well as reduced expression of several genes involved in fatty infiltration. Despite the decline in fibrosis and fat accumulation, muscle fiber specific force production was reduced by 23%. CONCLUSION: The postoperative treatment of cuff repair with licofelone may reduce fatty degeneration and enhance the development of a stable bone-tendon interface, although decreases in muscle fiber specific force production were observed, and force production in fact declined. CLINICAL RELEVANCE: This study demonstrates that the inhibition of 5-LOX, COX-1, and COX-2 modulates the healing process of repaired rotator cuff tendons. Although further studies are necessary, the treatment of patients with licofelone after cuff repair may improve the development of a stable enthesis and enhance postoperative outcomes.

Aging-associated exacerbation in fatty degeneration and infiltration after rotator cuff tear.

BACKGROUND: Rotator cuff tears are one of the most common musculoskeletal complaints and a substantial source of morbidity in elderly patients. Chronic cuff tears are associated with muscle atrophy and an infiltration of fat to the area, a condition known as "fatty degeneration." To improve the treatment of cuff tears in elderly patients, a greater understanding of the changes in the contractile properties of muscle fibers and the molecular regulation of fatty degeneration is essential. METHODS: Using a full-thickness, massive supraspinatus and infraspinatus tear model in elderly rats, we measured fiber contractility and determined changes in fiber type distribution that develop 30 days after tear. We also measured the expression of messenger RNA and micro-RNA transcripts involved in muscle atrophy, lipid accumulation, and matrix synthesis. We hypothesized that a decrease in specific force of muscle fibers, an accumulation of type IIb fibers, and an upregulation in atrophic, fibrogenic, and inflammatory gene expression would occur in torn cuff muscles. RESULTS: Thirty days after the tear, we observed a reduction in muscle fiber force and an induction of RNA molecules that regulate atrophy, fibrosis, lipid accumulation, inflammation, and macrophage recruitment. A marked accumulation of advanced glycation end products and a significant accretion of macrophages in areas of fat accumulation were observed. CONCLUSIONS: The extent of degenerative changes in old rats was greater than that observed in adults. In addition, we identified that the ectopic fat accumulation that occurs in chronic cuff tears does not occur by activation of canonical intramyocellular lipid storage and synthesis pathways.

Elevation in circulating biomarkers of cartilage damage and inflammation in athletes with femoroacetabular impingement.

BACKGROUND: Femoroacetabular impingement (FAI) is one of the most common causes of early cartilage and labral damage in the nondysplastic hip. Biomarkers of cartilage degradation and inflammation are associated with osteoarthritis. It was not known whether patients with FAI have elevated levels of biomarkers of cartilage degradation and inflammation. HYPOTHESIS: Compared with athletes without FAI, athletes with FAI would have elevated levels of the inflammatory C-reactive protein (CRP) and cartilage oligomeric matrix protein (COMP), a cartilage degradation marker. STUDY DESIGN: Controlled laboratory study. METHODS: Male athletes with radiographically confirmed FAI (n = 10) were compared with male athletes with radiographically normal hips with no evidence of FAI or hip dysplasia (n = 19). Plasma levels of COMP and CRP were measured, and subjects also completed the Short Form-12 (SF-12) and Hip Disability and Osteoarthritis Outcome Score (HOOS) surveys. RESULTS: Compared with controls, athletes with FAI had a 24% increase in COMP levels and a 276% increase in CRP levels as well as a 22% decrease in SF-12 physical component scores and decreases in all of the HOOS subscale scores. CONCLUSION: Athletes with FAI demonstrate early biochemical signs of increased cartilage turnover and systemic inflammation. CLINICAL RELEVANCE: Chondral injury secondary to the repetitive microtrauma of FAI might be reliably detected with biomarkers. In the future, these biomarkers might be used as screening tools to identify at-risk patients and assess the efficacy of therapeutic interventions such as hip preservation surgery in altering the natural history and progression to osteoarthritis.

Changes in circulating biomarkers of muscle atrophy, inflammation, and cartilage turnover in patients undergoing anterior cruciate ligament reconstruction and rehabilitation.

BACKGROUND: After anterior cruciate ligament (ACL) reconstruction, there is significant atrophy of the quadriceps muscles that can limit full recovery and place athletes at risk for recurrent injuries with return to play. The cause of this muscle atrophy is not fully understood. HYPOTHESIS: Circulating levels of proatrophy, proinflammatory, and cartilage turnover cytokines and biomarkers would increase after ACL reconstruction. STUDY DESIGN: Descriptive laboratory study. METHODS: Patients (N = 18; mean age, 28 ± 2.4 years) underwent surgical reconstruction of the ACL after a noncontact athletic injury. Circulating levels of biomarkers were measured along with Short Form-12, International Knee Documentation Committee, and objective knee strength measures preoperatively and at 6 postoperative visits. Differences were tested using repeated-measures 1-way analysis of variance. RESULTS: Myostatin, TGF-ß, and C-reactive protein levels were significantly increased in the early postoperative period and returned to baseline. Cartilage oligomeric matrix protein levels decreased immediately after surgery and then returned to baseline. CCL2, CCL3, CCL4, CCL5, EGF, FGF-2, IGF-1, IL-10, IL-1α, IL-1ß, IL-1ra, IL-6, myoglobin, and TNF-α were not different over the course of the study. CONCLUSION: An increase in potent atrophy-inducing cytokines and corresponding changes in knee strength and functional scores were observed after ACL reconstruction. CLINICAL RELEVANCE: Although further studies are necessary, the therapeutic inhibition of myostatin may help prevent the muscle atrophy that occurs after ACL reconstruction and provide an accelerated return of patients to sport.

Rotator cuff tear reduces muscle fiber specific force production and induces macrophage accumulation and autophagy.

Full-thickness tears to the rotator cuff can cause severe pain and disability. Untreated tears progress in size and are associated with muscle atrophy and an infiltration of fat to the area, a condition known as "fatty degeneration." To improve the treatment of rotator cuff tears, a greater understanding of the changes in the contractile properties of muscle fibers and the molecular regulation of fatty degeneration is essential. Using a rat model of rotator cuff injury, we measured the force generating capacity of individual muscle fibers and determined changes in muscle fiber type distribution that develop after a full thickness rotator cuff tear. We also measured the expression of mRNA and miRNA transcripts involved in muscle atrophy, lipid accumulation, and matrix synthesis. We hypothesized that a decrease in specific force of rotator cuff muscle fibers, an accumulation of type IIb fibers, and an upregulation in fibrogenic, adipogenic, and inflammatory gene expression occur in torn rotator cuff muscles. Thirty days following rotator cuff tear, we observed a reduction in muscle fiber force production, an induction of fibrogenic, adipogenic, and autophagocytic mRNA and miRNA molecules, and a dramatic accumulation of macrophages in areas of fat accumulation.

Mechanical loading and TGF-ß change the expression of multiple miRNAs in tendon fibroblasts.

Tendons link skeletal muscles to bones and are important components of the musculoskeletal system. There has been much interest in the role of microRNA (miRNA) in the regulation of musculoskeletal tissues to mechanical loading, inactivity, and disease, but it was unknown whether miRNA is involved in the adaptation of tendons to mechanical loading. We hypothesized that mechanical loading and transforming growth factor-ß (TGF-ß) treatment would regulate the expression of several miRNA molecules with known roles in cell proliferation and extracellular matrix synthesis. To test our hypothesis, we subjected untrained adult rats to a single session of mechanical loading and measured the expression of several miRNA transcripts in Achilles tendons. Additionally, as TGF-ß is known to be an important regulator of tendon growth and adaptation, we treated primary tendon fibroblasts with TGF-ß and measured miRNA expression. Both mechanical loading and TGF-ß treatment modulated the expression of several miRNAs that regulate cell proliferation and extracellular matrix synthesis. We also identified mechanosensitive miRNAs that may bind to the 3'-untranslated region of the basic helix-loop-helix transcription factor scleraxis, which is a master regulator of limb tendon development. The results from this study provide novel insight into the mechanobiology of tendons and indicate that miRNA could play an important role in the adaptation of tendons to growth stimuli.

Physiological loading of tendons induces scleraxis expression in epitenon fibroblasts.

Scleraxis is a basic helix-loop-helix transcription factor that plays a central role in promoting fibroblast proliferation and matrix synthesis during the embryonic development of tendons. Mice with a targeted inactivation of scleraxis (Scx(-/-)) fail to properly form limb tendons, but the role that scleraxis has in regulating the growth and adaptation of tendons of adult organisms is unknown. To determine if scleraxis expression changes in response to a physiological growth stimulus to tendons, we subjected adult mice that express green fluorescent protein (GFP) under the control of the scleraxis promoter (ScxGFP) to a 6-week-treadmill training program designed to induce adaptive growth in Achilles tendons. Age matched sedentary ScxGFP mice were used as controls. Scleraxis expression was sparsely observed in the epitenon region of sedentary mice, but in response to treadmill training, scleraxis was robustly expressed in fibroblasts that appeared to be emerging from the epitenon and migrating into the superficial regions of tendon fascicles. Treadmill training also led to an increase in scleraxis, tenomodulin, and type I collagen gene expression as measured by qPCR. These results suggest that in addition to regulating the embryonic formation of limb tendons, scleraxis also appears to play an important role in the adaptation of adult tendons to physiological loading.