Publications by authors named "Amy L Strong"

47 Publications

High Frequency Spectral Ultrasound Imaging Detects Early Heterotopic Ossification in Rodents.

Stem Cells Dev 2021 Apr 19. Epub 2021 Apr 19.

Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Heterotopic ossification (HO) is a devastating condition in which ectopic bone forms inappropriately in soft tissues following traumatic injuries and orthopedic surgeries as a result of aberrant mesenchymal progenitor cell (MPC) differentiation. HO leads to chronic pain, decreased range of motion, and an overall decrease in quality of life. While several treatments have shown promise in animal models, all must be given during early stages of formation. Methods for early determination of whether and where endochondral ossification/soft tissue mineralization (HO anlagen) develop are lacking. At-risk patients are not identified sufficiently early in the process of MPC differentiation and soft tissue endochondral ossification for potential treatments to be effective. Hence, a critical need exists to develop technologies capable of detecting HO anlagen soon after trauma, when treatments are most effective. In this study, we investigate high frequency spectral ultrasound imaging (SUSI) as a noninvasive strategy to identify HO anlagen at early time points after injury. We show that by determining quantitative parameters based on tissue organization and structure, SUSI identifies HO anlagen as early as 1-week postinjury in a mouse model of burn/tenotomy and 3 days postinjury in a rat model of blast/amputation. We analyze single cell RNA sequencing profiles of the MPCs responsible for HO formation and show that the early tissue changes detected by SUSI match chondrogenic and osteogenic gene expression in this population. SUSI identifies sites of soft tissue endochondral ossification at early stages of HO formation so that effective intervention can be targeted when and where it is needed following trauma-induced injury. Furthermore, we characterize the chondrogenic to osteogenic transition that occurs in the MPCs during HO formation and correlate gene expression to SUSI detection of the HO anlagen.
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http://dx.doi.org/10.1089/scd.2021.0011DOI Listing
April 2021

Novel Lineage-Tracing System to Identify Site-Specific Ectopic Bone Precursor Cells.

Stem Cell Reports 2021 Mar 18;16(3):626-640. Epub 2021 Feb 18.

Center for Organogenesis and Trauma, Department of Surgery, University of Texas Southwestern, 6000 Harry Hines Boulevard, Dallas, TX 75235, USA. Electronic address:

Heterotopic ossification (HO) is a form of pathological cell-fate change of mesenchymal stem/precursor cells (MSCs) that occurs following traumatic injury, limiting range of motion in extremities and causing pain. MSCs have been shown to differentiate to form bone; however, their lineage and aberrant processes after trauma are not well understood. Utilizing a well-established mouse HO model and inducible lineage-tracing mouse (Hoxa11-CreER;ROSA26-LSL-TdTomato), we found that Hoxa11-lineage cells represent HO progenitors specifically in the zeugopod. Bioinformatic single-cell transcriptomic and epigenomic analyses showed Hoxa11-lineage cells are regionally restricted mesenchymal cells that, after injury, gain the potential to undergo differentiation toward chondrocytes, osteoblasts, and adipocytes. This study identifies Hoxa11-lineage cells as zeugopod-specific ectopic bone progenitors and elucidates the fate specification and multipotency that mesenchymal cells acquire after injury. Furthermore, this highlights homeobox patterning genes as useful tools to trace region-specific progenitors and enable location-specific gene deletion.
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http://dx.doi.org/10.1016/j.stemcr.2021.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940250PMC
March 2021

Fat Grafting Subjectively Improves Facial Skin Elasticity and Hand Function of Scleroderma Patients.

Plast Reconstr Surg Glob Open 2021 Jan 25;9(1):e3373. Epub 2021 Jan 25.

Section of Plastic and Reconstructive Surgery, University of Michigan, Ann Arbor, Mich.

Systemic scleroderma is a chronic connective tissue disease characterized by internal organ and skin fibrosis. Unfortunately, there is a lack of efficacious treatments for cutaneous manifestations, and alternative interventions should be considered. Fat grafting has gained significant attention due to its regenerative properties and success in improving skin quality and volume deficits in fibrotic diseases. While some studies have investigated the efficacy of autologous fat grafting, we utilized the Coleman method for harvesting and processing to determine the efficacy of fat grafting to improve skin fibrosis in the hands and face of scleroderma patients without excess processing of adipose tissue. Patients with a diagnosis of scleroderma who underwent fat grafting between March 2015 and March 2019 at the University of Michigan were included. Ten female patients were identified that met inclusion criteria. The mean age at the time of surgery was 48.7 (± 17.6) years. An average of 53.2 (± 15.5) ml of fat was injected into the hands and 26.1 (± 16.4) ml into the face. Patients were treated with 1-4 rounds of grafting depending on the initial severity of skin fibrosis and volume deficiency. Fat grafting subjectively and qualitatively improved perioral skin quality, facial animation, hand range of motion, and hand pain for patients with systemic scleroderma. No complications were identified. Additional studies are necessary to determine the ideal volume, timing of treatments, and type of fat to optimize the efficacy of autologous fat grafting for the treatment of systemic scleroderma.
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http://dx.doi.org/10.1097/GOX.0000000000003373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861649PMC
January 2021

BMP Ligand Trap ALK3-Fc Attenuates Osteogenesis and Heterotopic Ossification in Blast-Related Lower Extremity Trauma.

Stem Cells Dev 2021 Jan 24;30(2):91-105. Epub 2020 Dec 24.

Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland, USA.

Traumatic heterotopic ossification (tHO) commonly develops in wounded service members who sustain high-energy and blast-related traumatic amputations. Currently, no safe and effective preventive measures have been identified for this patient population. Bone morphogenetic protein (BMP) signaling blockade has previously been shown to reduce ectopic bone formation in genetic models of HO. In this study, we demonstrate the efficacy of small-molecule inhibition with LDN193189 (ALK2/ALK3 inhibition), LDN212854 (ALK2-biased inhibition), and BMP ligand trap ALK3-Fc at inhibiting early and late osteogenic differentiation of tissue-resident mesenchymal progenitor cells (MPCs) harvested from mice subjected to burn/tenotomy, a well-characterized trauma-induced model of HO. Using an established rat tHO model of blast-related extremity trauma and methicillin-resistant infection, a significant decrease in ectopic bone volume was observed by micro-computed tomography imaging following treatment with LDN193189, LDN212854, and ALK3-Fc. The efficacy of LDN193189 and LDN212854 in this model was associated with weight loss (17%-19%) within the first two postoperative weeks, and in the case of LDN193189, delayed wound healing and metastatic infection was observed, while ALK3-Fc was well tolerated. At day 14 following injury, RNA-Seq and quantitative reverse transcriptase-polymerase chain reaction analysis revealed that ALK3-Fc enhanced the expression of skeletal muscle structural genes and myogenic transcriptional factors while inhibiting the expression of inflammatory genes. Tissue-resident MPCs harvested from rats treated with ALK3-Fc exhibited reduced osteogenic differentiation, proliferation, and self-renewal capacity and diminished expression of genes associated with endochondral ossification and SMAD-dependent signaling pathways. Together, these results confirm the contribution of BMP signaling in osteogenic differentiation and ectopic bone formation and that a selective ligand-trap approach such as ALK3-Fc may be an effective and tolerable prophylactic strategy for tHO.
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http://dx.doi.org/10.1089/scd.2020.0162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826435PMC
January 2021

The role of neutrophil extracellular traps and TLR signaling in skeletal muscle ischemia reperfusion injury.

FASEB J 2020 12 22;34(12):15753-15770. Epub 2020 Oct 22.

Department of Surgery, University of Michigan, Ann Arbor, MI, USA.

Ischemia reperfusion (IR) injury results in devastating skeletal muscle fibrosis. Here, we recapitulate this injury with a mouse model of hindlimb IR injury which leads to skeletal muscle fibrosis. Injury resulted in extensive immune infiltration with robust neutrophil extracellular trap (NET) formation in the skeletal muscle, however, direct targeting of NETs via the peptidylarginine deiminase 4 (PAD4) mechanism was insufficient to reduce muscle fibrosis. Circulating levels of IL-10 and TNFα were significantly elevated post injury, indicating toll-like receptor (TLR) signaling may be involved in muscle injury. Administration of hydroxychloroquine (HCQ), a small molecule inhibitor of TLR7/8/9, following injury reduced NET formation, IL-10, and TNFα levels and ultimately mitigated muscle fibrosis and improved myofiber regeneration following IR injury. HCQ treatment decreased fibroadipogenic progenitor cell proliferation and partially inhibited ERK1/2 phosphorylation in the injured tissue, suggesting it may act through a combination of TLR7/8/9 and ERK signaling mechanisms. We demonstrate that treatment with FDA-approved HCQ leads to decreased muscle fibrosis and increased myofiber regeneration following IR injury, suggesting short-term HCQ treatment may be a viable treatment to prevent muscle fibrosis in ischemia reperfusion and traumatic extremity injury.
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http://dx.doi.org/10.1096/fj.202000994RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054227PMC
December 2020

Achieving the Optimal Aesthetic Benefit While Correcting Midface Deficiency: Utilizing A High Winged Le Fort I in Cleft and Craniofacial Patients.

J Craniofac Surg 2021 Jan-Feb 01;32(1):46-50

Department of Surgery, Section of Plastic and Reconstructive Surgery.

Abstract: Craniofacial anomalies are congenital disorders that affect the cranium and facial bones, with cleft lip and palate being the most common. These anomalies are often associated with abnormal development of pharyngeal arches and can result in the development of class III malocclusion and severe maxillary retrusion. Current treatment includes orthodontic decompensation and Le Fort I osteotomy to correct the maxillomandibular relationship. However, the traditional Le Fort I (LFI) advancement does not fully address the lack of skeletal volume in the midface. The high winged Le Fort I osteotomy (HWLFI) is an excellent surgical option for simultaneous correction of the midface deficiency and malocclusion while restoring optimal esthetic convexity. A retrospective chart review was conducted to include all cleft and craniofacial patients who underwent HWLFI advancement from 2002 to 2018. Patients had a minimum of 12 months of follow-up. Patient data and complications were reviewed. Standardized facial photographs were analyzed for esthetic improvement, occlusion, and beneficial salutary effects on the midface. Forty-three patients met the inclusion criteria. The mean age at surgery was 18.9 years. The mean follow-up was 32 months. Early complications included infection (9.3%) and temporary nerve paresthesia (2.3%). Late complications included infection (6.5%), wound dehiscence (4.3%), and painful hardware (2.3%). One patient (2.3 percent) had clinically significant relapse that required surgery. Postoperatively, patients demonstrated excellent midface projection and correction of the skeletal malocclusion. The HWLFI advancement significantly improves both the malocclusion and esthetic concerns of cleft and craniofacial patients by reestablishing maximal midfacial support. Important advantages of the HWLFI are avoidance of alloplastic implant use and extensive and potentially unstable surgical procedures that increase orbital volume.
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http://dx.doi.org/10.1097/SCS.0000000000006871DOI Listing
August 2020

Immobilization after injury alters extracellular matrix and stem cell fate.

J Clin Invest 2020 10;130(10):5444-5460

Section of Plastic Surgery, Department of Surgery.

Cells sense the extracellular environment and mechanical stimuli and translate these signals into intracellular responses through mechanotransduction, which alters cell maintenance, proliferation, and differentiation. Here we use a mouse model of trauma-induced heterotopic ossification (HO) to examine how cell-extrinsic forces impact mesenchymal progenitor cell (MPC) fate. After injury, single-cell (sc) RNA sequencing of the injury site reveals an early increase in MPC genes associated with pathways of cell adhesion and ECM-receptor interactions, and MPC trajectories to cartilage and bone. Immunostaining uncovers active mechanotransduction after injury with increased focal adhesion kinase signaling and nuclear translocation of transcriptional coactivator TAZ, inhibition of which mitigates HO. Similarly, joint immobilization decreases mechanotransductive signaling, and completely inhibits HO. Joint immobilization decreases collagen alignment and increases adipogenesis. Further, scRNA sequencing of the HO site after injury with or without immobilization identifies gene signatures in mobile MPCs correlating with osteogenesis, and signatures from immobile MPCs with adipogenesis. scATAC-seq in these same MPCs confirm that in mobile MPCs, chromatin regions around osteogenic genes are open, whereas in immobile MPCs, regions around adipogenic genes are open. Together these data suggest that joint immobilization after injury results in decreased ECM alignment, altered MPC mechanotransduction, and changes in genomic architecture favoring adipogenesis over osteogenesis, resulting in decreased formation of HO.
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http://dx.doi.org/10.1172/JCI136142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524473PMC
October 2020

Small molecule inhibition of non-canonical (TAK1-mediated) BMP signaling results in reduced chondrogenic ossification and heterotopic ossification in a rat model of blast-associated combat-related lower limb trauma.

Bone 2020 10 2;139:115517. Epub 2020 Jul 2.

Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, MD, United States of America; Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, United States of America. Electronic address:

Heterotopic ossification (HO) is defined as ectopic bone formation around joints and in soft tissues following trauma, particularly blast-related extremity injuries, thermal injuries, central nerve injuries, or orthopaedic surgeries, leading to increased pain and diminished quality of life. Current treatment options include pharmacotherapy with non-steroidal anti-inflammatory drugs, radiotherapy, and surgical excision, but these treatments have limited efficacy and have associated complication profiles. In contrast, small molecule inhibitors have been shown to have higher specificity and less systemic cytotoxicity. Previous studies have shown that bone morphogenetic protein (BMP) signaling and downstream non-canonical (SMAD-independent) BMP signaling mediated induction of TGF-β activated kinase-1 (TAK1) contributes to HO. In the current study, small molecule inhibition of TAK1, NG-25, was evaluated for its efficacy in limiting ectopic bone formation following a rat blast-associated lower limb trauma and a murine burn tenotomy injury model. A significant decrease in total HO volume in the rat blast injury model was observed by microCT imaging with no systemic complications following NG-25 therapy. Furthermore, tissue-resident mesenchymal progenitor cells (MPCs) harvested from rats treated with NG-25 demonstrated decreased proliferation, limited osteogenic differentiation capacity, and reduced gene expression of Tac1, Col10a1, Ibsp, Smad3, and Sox2 (P < 0.05). Single cell RNA-sequencing of murine cells harvested from the injury site in a burn tenotomy injury model showed increased expression of these genes in MPCs during stages of chondrogenic differentiation. Additional in vitro cell cultures of murine tissue-resident MPCs and osteochondrogenic progenitors (OCPs) treated with NG-25 demonstrated reduced chondrogenic differentiation by 10.2-fold (P < 0.001) and 133.3-fold (P < 0.001), respectively, as well as associated reduction in chondrogenic gene expression. Induction of HO in Tak1 knockout mice demonstrated a 7.1-fold (P < 0.001) and 2.7-fold reduction (P < 0.001) in chondrogenic differentiation of murine MPCs and OCPs, respectively, with reduced chondrogenic gene expression. Together, our in vivo models and in vitro cell culture studies demonstrate the importance of TAK1 signaling in chondrogenic differentiation and HO formation and suggest that small molecule inhibition of TAK1 is a promising therapy to limit the formation and progression of HO.
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http://dx.doi.org/10.1016/j.bone.2020.115517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945876PMC
October 2020

Fat Grafting for the Treatment of Scleroderma.

Plast Reconstr Surg 2019 12;144(6):1498-1507

From the Section of Plastic and Reconstructive Surgery and the Department of Biomedical Engineering, University of Michigan; and the Department of Plastic Surgery and the McGowan Institute for Regenerative Medicine, University of Pittsburgh.

Background: Scleroderma is a chronic connective tissue disease that results in fibrosis of the skin and internal organs. Although internal organ involvement corresponds with poor prognosis, systemic agents are effective at improving the effects of scleroderma on internal organs. In contrast, skin manifestations are universally present in all patients diagnosed with scleroderma, yet no systemic agents have been shown to be successful. Fat grafting has been shown to improve skin quality and improve contour irregularities and may be helpful in the treatment of patients with scleroderma.

Methods: The authors performed a thorough review of the pathophysiology of scleroderma and the current treatment options for scleroderma. The efficacy of fat grafting for the treatment of scleroderma and the mechanism by which fat grafting improves outcomes was also discussed.

Results: Scleroderma is characterized by chronic inflammation and vascular compromise that leads to fibrosis of the skin and internal organs. Fat grafting has recently been the focus of significant basic science research. It has been shown to reduce inflammation, reduce fibrosis by limiting extracellular matrix proteins and increasing collagenase activity, and provide structural support through stem cell proliferation and differentiation. The adipocytes, adipose stem cells, endothelial cells, and vascular smooth muscle cells in the processed fat likely contribute to the effectiveness of this treatment.

Conclusions: Fat grafting in scleroderma patients likely improves skin manifestations by recreating fullness, correcting contour deformities, and improving skin quality. The injected fat provides a mixture of cells that influences the recipient site, resulting in improved outcomes.
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http://dx.doi.org/10.1097/PRS.0000000000006291DOI Listing
December 2019

Discussion: Therapeutic Role of Fat Injection in the Treatment of Recalcitrant Migraine Headaches.

Plast Reconstr Surg 2019 03;143(3):886-887

From the Section of Plastic and Reconstructive Surgery, Department of Surgery, University of Michigan.

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http://dx.doi.org/10.1097/PRS.0000000000005356DOI Listing
March 2019

Concise Review: Using Fat to Fight Disease: A Systematic Review of Nonhomologous Adipose-Derived Stromal/Stem Cell Therapies.

Stem Cells 2018 09 16;36(9):1311-1328. Epub 2018 Jul 16.

Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.

The objective of this Review is to describe the safety and efficacy of adipose stem/stromal cells (ASC) and stromal vascular fraction (SVF) in treating common diseases and the next steps in research that must occur prior to clinical use. Pubmed, Ovid Medline, Embase, Web of Science, and the Cochrane Library were searched for articles about use of SVF or ASC for disease therapy published between 2012 and 2017. One meta-analysis, 2 randomized controlled trials, and 16 case series were included, representing 844 human patients. Sixty-nine studies were performed in preclinical models of disease. ASCs improved symptoms, fistula healing, remission, and recurrence rates in severe cases of inflammatory bowel disease. In osteoarthritis, ASC and SVF improved symptom-related, functional, radiographic, and histological scores. ASC and SVF were also shown to improve clinical outcomes in ischemic stroke, multiple sclerosis, myocardial ischemia, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, chronic liver failure, glioblastoma, acute kidney injury, and chronic skin wounds. These effects were primarily paracrine in nature and mediated through reduction of inflammation and promotion of tissue repair. In the majority of human studies, autologous ASC and SVF from liposuction procedures were used, minimizing the risk to recipients. Very few serious, treatment-related adverse events were reported. The main adverse event was postprocedural pain. SVF and ASC are promising therapies for a variety of human diseases, particularly for patients with severe cases refractory to current medical treatments. Further randomized controlled trials must be performed to elaborate potential safety and efficacy prior to clinical use. Stem Cells 2018;36:1311-1328.
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http://dx.doi.org/10.1002/stem.2847DOI Listing
September 2018

Gauze Impregnated With Quaternary Ammonium Salt Reduces Bacterial Colonization of Surgical Drains After Breast Reconstruction.

Ann Plast Surg 2018 06;80(6S Suppl 6):S426-S430

From the Division of Plastic Surgery, Department of Surgery, Tulane University School of Medicine, New Orleans, LA.

Surgical site infection after breast reconstruction is associated with increased length of hospital stay, readmission rates, cost, morbidity, and mortality. Identifying methods to reduce surgical site infection without the use of antibiotics may be beneficial at reducing antimicrobial resistance, reserving the use of antibiotics for more severe cases. Quaternary ammonium salts have previously been shown to be a safe and effective antimicrobial agent in the setting of in vitro and in vivo animal experiments. A retrospective study was conducted to investigate the antimicrobial properties of a quaternary ammonium salt, 3-trimethoxysilyl propyldimethyloctadecyl ammonium chloride (QAS-3PAC; Bio-spear), at reducing surgical drain site colonization and infection after breast reconstruction (deep inferior epigastric perforator flap reconstruction or tissue expander placement). Twenty patients were enrolled, with 14 surgical drains covered with nonimpregnated gauze and 17 surgical drains covered with QAS-3PAC impregnated gauze, for the purposes of investigating bacterial colonization. Antibiotic sensitivity analysis was also conducted when bacterial cultures were positive. The overall incidence of bacterial colonization of surgical drains was lower in the treatment group compared with the control group (17.6% vs 64.3%, respectively; P = 0.008). QAS-3PAC impregnated gauze reduced the incidence of bacterial colonization of surgical drains during the first (0.0% vs 33.3%) and second (33.3% vs 87.5%; P = 0.04) postoperative week. Furthermore, no enhanced antibiotic resistance was noted on drains treated with QAS-3PAC impregnated gauze. The results of this study suggest that QAS-3PAC impregnated gauze applied over surgical drains may be an effective method for reducing the incidence of bacterial colonization.
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http://dx.doi.org/10.1097/SAP.0000000000001420DOI Listing
June 2018

Peripheral Neuropathy and Nerve Compression Syndromes in Burns.

Clin Plast Surg 2017 Oct 21;44(4):793-803. Epub 2017 Jul 21.

Section of Plastic and Reconstructive Surgery, Department of Surgery, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA; Burn Wound and Regenerative Medicine Laboratory, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA. Electronic address:

Peripheral neuropathy and nerve compression syndromes lead to substantial morbidity following burn injury. Patients present with pain, paresthesias, or weakness along a specific nerve distribution or experience generalized peripheral neuropathy. The symptoms manifest at various times from within one week of hospitalization to many months after wound closure. Peripheral neuropathy may be caused by vascular occlusion of vasa nervorum, inflammation, neurotoxin production leading to apoptosis, and direct destruction of nerves from the burn injury. This article discusses the natural history, diagnosis, current treatments, and future directions for potential interventions for peripheral neuropathy and nerve compression syndromes related to burn injury.
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http://dx.doi.org/10.1016/j.cps.2017.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5674779PMC
October 2017

Glycinol enhances osteogenic differentiation and attenuates the effects of age on mesenchymal stem cells.

Regen Med 2017 07 18;12(5):513-524. Epub 2017 Jul 18.

Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA, USA.

Aim: Phytoestrogens, such as glycinol, have recently gained significant attention as an alternative therapy for osteoporosis due to their structural similarity to estradiol and their bone-generating potential.

Methods: The osteogenic effects of glycinol were investigated in human bone marrow mesenchymal stem cells (BMSCs) derived from older (>50 years old) and younger subjects (<25 years old).

Results: BMSCs isolated from older donors demonstrated reduced osteogenesis. 17β-estradiol and glycinol exposure rescued the age-related reduction in osteogenic differentiation of BMSCs. These results correlated with the induction of osteogenic genes and estrogen receptor-α (ER-α) following glycinol treatment. ER antagonist studies further support that glycinol promotes osteogenesis through ER signaling.

Conclusion: The results from these studies support investigating glycinol as a potential preventive or treatment for osteoporosis.
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http://dx.doi.org/10.2217/rme-2016-0148DOI Listing
July 2017

Stem Cells and Tissue Engineering: Regeneration of the Skin and Its Contents.

Clin Plast Surg 2017 Jul 22;44(3):635-650. Epub 2017 Apr 22.

Division of Plastic Surgery, Department of Surgery, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA; Burn Wound and Regenerative Medicine Laboratory, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA. Electronic address:

In this review, the authors discuss the stages of skin wound healing, the role of stem cells in accelerating skin wound healing, and the mechanism by which these stem cells may reconstitute the skin in the context of tissue engineering.
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http://dx.doi.org/10.1016/j.cps.2017.02.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513194PMC
July 2017

Laser direct-write based fabrication of a spatially-defined, biomimetic construct as a potential model for breast cancer cell invasion into adipose tissue.

Biofabrication 2017 05 11;9(2):025013. Epub 2017 May 11.

Bioinnovation Program, Tulane University, New Orleans, LA, United States of America.

Epithelial-adipose interaction is an integral step in breast cancer cell invasion and progression towards lethal metastatic disease. Understanding the physiological contribution of obesity, a major contributor to breast cancer risk and negative prognosis in post-menopausal patients, on cancer cell invasion requires detailed co-culture constructs that reflect mammary microarchitecture. Using laser direct-write, a laser-based CAD/CAM bioprinting technique, we have demonstrated the ability to construct breast cancer cell-laden hydrogel microbeads into spatially defined patterns in hydrogel matrices containing differentiated adipocytes. Z-stack imaging confirmed the three-dimensional nature of the constructs, as well as incorporation of cancer cell-laden microbeads into the adipose matrix. Preliminary data was gathered to support the construct as a potential model for breast cancer cell invasion into adipose tissue. MCF-7 and MDA-MB-231 breast cancer cell invasion was tracked over 2 weeks in an optically transparent hydrogel scaffold in the presence of differentiated adipocytes obtained from normal weight or obese patient tissue. Our model successfully integrates adipocytes and gives us the potential to study cellular and tissue-level interactions towards the early detection of cancer cell invasion into adipose tissue.
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http://dx.doi.org/10.1088/1758-5090/aa6badDOI Listing
May 2017

Osteoinductive effects of glyceollins on adult mesenchymal stromal/stem cells from adipose tissue and bone marrow.

Phytomedicine 2017 Apr 14;27:39-51. Epub 2017 Feb 14.

Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA, USA; Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA; Division of Regenerative Medicine, Tulane National Primate Research Center, Tulane University, Covington, LA USA. Electronic address:

Background: While current therapies for osteoporosis focus on reducing bone resorption, the development of therapies to regenerate bone may also be beneficial. Promising anabolic therapy candidates include phytoestrogens, such as daidzein, which effectively induce osteogenesis of adipose-derived stromal cells (ASCs) and bone marrow stromal cells (BMSCs).

Purpose: To investigate the effects of glyceollins, structural derivatives of daidzein, on osteogenesis of ASCs and BMSCs.

Study Design: Herein, the osteoinductive effects of glyceollin I and glyceollin II were assessed and compared to estradiol in ASCs and BMSCs. The mechanism by which glyceollin II induces osteogenesis was further examined.

Methods: The ability of glyceollins to promote osteogenesis of ASCs and BMSCs was evaluated in adherent and scaffold cultures. Relative deposition of calcium was analyzed using Alizarin Red staining, Bichinchoninic acid Protein Assay, and Alamar Blue Assay. To further explore the mechanism by which glyceollin II exerts its osteoinductive effects, docking studies of glyceollin II, RNA isolation, cDNA synthesis, and quantitative RT-PCR (qPCR) were performed.

Results: In adherent cultures, ASCs and BMSCs treated with estradiol, glyceollin I, or glyceollin II demonstrated increased calcium deposition relative to vehicle-treated cells. During evaluation on PLGA scaffolds seeded with ASCs and BMSCs, glyceollin II was the most efficacious in inducing ASC and BMSC osteogenesis compared to estradiol and glyceollin I. Dose-response analysis in ASCs and BMSCs revealed that glyceollin II has the highest potency at 10nM in adherent cultures and 1µM in tissue scaffold cultures. At all doses, osteoinductive effects were attenuated by fulvestrant, suggesting that glyceollin II acts at least in part through estrogen receptor-mediated pathways to induce osteogenesis. Analysis of gene expression demonstrated that, similar to estradiol, glyceollin II induces upregulation of genes involved in osteogenic differentiation.

Conclusion: The ability of glyceollin II to induce osteogenic differentiation in ASCs and BMSCs indicates that glyceollins hold the potential for the development of pharmacological interventions to improve clinical outcomes of patients with osteoporosis.
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http://dx.doi.org/10.1016/j.phymed.2017.02.003DOI Listing
April 2017

The Effects of Endocrine Disruptors on Adipogenesis and Osteogenesis in Mesenchymal Stem Cells: A Review.

Front Endocrinol (Lausanne) 2016 9;7:171. Epub 2017 Jan 9.

Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA, USA; Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA.

Endocrine-disrupting chemicals (EDCs) are prevalent in the environment, and epidemiologic studies have suggested that human exposure is linked to chronic diseases, such as obesity and diabetes. experiments have further demonstrated that EDCs promote changes in mesenchymal stem cells (MSCs), leading to increases in adipogenic differentiation, decreases in osteogenic differentiation, activation of pro-inflammatory cytokines, increases in oxidative stress, and epigenetic changes. Studies have also shown alteration in trophic factor production, differentiation ability, and immunomodulatory capacity of MSCs, which have significant implications to the current studies exploring MSCs for tissue engineering and regenerative medicine applications and the treatment of inflammatory conditions. Thus, the consideration of the effects of EDCs on MSCs is vital when determining potential therapeutic uses of MSCs, as increased exposure to EDCs may cause MSCs to be less effective therapeutically. This review focuses on the adipogenic and osteogenic differentiation effects of EDCs as these are most relevant to the therapeutic uses of MSCs in tissue engineering, regenerative medicine, and inflammatory conditions. This review will highlight the effects of EDCs, including organophosphates, plasticizers, industrial surfactants, coolants, and lubricants, on MSC biology.
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http://dx.doi.org/10.3389/fendo.2016.00171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220052PMC
January 2017

Obesity Enhances the Conversion of Adipose-Derived Stromal/Stem Cells into Carcinoma-Associated Fibroblast Leading to Cancer Cell Proliferation and Progression to an Invasive Phenotype.

Stem Cells Int 2017 17;2017:9216502. Epub 2017 Dec 17.

Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA, USA.

Obesity is associated with enhanced tumor growth and progression. Within the adipose tissue are adipose-derived stromal/stem cells (ASCs) that have been shown to convert into carcinoma-associated fibroblast (CAFs) in the presence of tumor-derived factors. However, the impact of obesity on the ASCs and on the conversion of ASCs into CAFs has not been demonstrated. In the current study, ASCs isolated from lean donors (BMI < 25; lnASCs) were compared with ASCs isolated from obese donors (BMI > 30, obASCs). The contribution of tumor-derived factors on the conversion of ASCs to CAFs was investigated. Following exposure to cancer cells, obASCs expressed higher levels of CAF markers, including NG2, alpha-SMA, VEGF, FAP, and FSP, compared to lnASCs. To investigate the crosstalk between ASCs and breast cancer cells, MCF7 cells were serially cocultured with lnASCs or obASCs. After coculture with lnASCs and obASCs, MCF7 cells demonstrated enhanced proliferation and expressed an invasive phenotype morphologically, with more pronounced effects following exposure to obASCs. Long-term exposure to obASCs also enhanced the expression of protumorgenic factors. Together, these results suggest that obesity alters ASCs to favor their rapid conversion into CAFs, which in turn enhances the proliferative rate, the phenotype, and gene expression profile of breast cancer cells.
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http://dx.doi.org/10.1155/2017/9216502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748106PMC
December 2017

Adipose Stromal Vascular Fraction-Mediated Improvements at Late-Stage Disease in a Murine Model of Multiple Sclerosis.

Stem Cells 2017 02 9;35(2):532-544. Epub 2016 Nov 9.

Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.

Multiple sclerosis (MS) is a common neurodegenerative disease and remains an unmet clinical challenge. In MS, an autoimmune response leads to immune cell infiltration, inflammation, demyelination, and lesions in central nervous system (CNS) tissues resulting in tremors, fatigue, and progressive loss of motor function. These pathologic hallmarks are effectively reproduced in the murine experimental autoimmune encephalomyelitis (EAE) model. The stromal vascular fraction (SVF) of adipose tissue is composed of adipose-derived stromal/stem cells (ASC), adipocytes, and various leukocytes. The SVF can be culture expanded to generate ASC lines. Clinical trials continue to demonstrate the safety and efficacy of ASC therapies for treating several diseases. However, little is known about the effectiveness of the SVF for neurodegenerative diseases, such as MS. At late-stage disease, EAE mice show severe motor impairment. The goal for these studies was to test the effectiveness of SVF cells and ASC in EAE mice after the onset of neuropathology. The clinical scoring, behavior, motor function, and histopathologic analyses revealed significant improvements in EAE mice treated with the SVF or ASC. Moreover, SVF treatment mediated more robust improvements to CNS pathology than ASC treatment based on significant modulations of inflammatory factors. The most pronounced changes following SVF treatment were the high levels of interleukin-10 in the peripheral blood, lymphoid and CNS tissues along with the induction of regulatory T cells in the lymph nodes which indicate potent immunomodulatory effects. The data indicate SVF cells effectively ameliorated the EAE immunopathogenesis and supports the potential use of SVF for treating MS. Stem Cells 2017;35:532-544.
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http://dx.doi.org/10.1002/stem.2516DOI Listing
February 2017

Local Wound Care for Primary Cleft Lip Repair: Treatment and Outcomes With use of Topical Hydrogen Peroxide.

Wounds 2015 Dec;27(12):319-26

Oregon Health & Science University, Portland, OR.

Objectives: This study highlights and validates a peroxide-based wound healing strategy for treatment of surgically closed facial wounds in a pediatric population. The authors identified pediatric patients undergoing primary cleft lip repair as a specific population to evaluate the outcomes of such a protocol. Through analysis of defined outcome measures, a reliable and reproducible protocol for postoperative wound care following primary cleft lip repair with favorable results is described.

Methods: This retrospective study analyzes wound healing outcomes in pediatric patients undergoing primary cleft lip repair from 2006 to 2011 at a tertiary academic center. The wound healing protocol was used in both primary unilateral and bilateral repairs. One hundred fortysix patients between the ages of 0 and 4 years underwent primary cleft lip repair and cleft rhinoplasty by a single, fellowship-trained craniofacial surgeon. Postoperatively, wounds were treated with half-strength hydrogen peroxide and bacitracin, as well as scar massage. Incisional dehiscence, hypertrophic scar formation, discoloration, infection, and reoperation were studied. Outcomes were evaluated in light of parent compliance, demographics, preoperative nasoalveolar molding (PNAM), and diagnosis.

Results: The authors identified 146 patients for inclusion in this study. There was no wound or incisional dehiscence. One hundred twenty-four patients demonstrated favorable cosmetic outcome. Only 3 (2%) of patients who developed suboptimal outcomes underwent secondary surgical revision (> 1 year after surgery). Demographic differences were not statistically significant, and PNAM treatment did not influence outcomes.

Conclusion: These data validate the use of halfstrength hydrogen peroxide and bacitracin as part of a wound healing strategy in pediatric incisional wounds. The use of hydrogen peroxide produced comparable outcomes to previously published studies utilizing other wound healing strategies and, therefore, these study findings support the further use of this regimen for this particular population.
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December 2015

Refinements in the Techniques of 2-Stage Breast Reconstruction.

Ann Plast Surg 2016 Jun;76 Suppl 4:S304-11

From the *Tulane University School of Medicine, †Division of Plastic and Reconstructive Surgery, Tulane University School of Medicine, New Orleans; ‡Private Practice, Metairie, LA.

Background: Two-stage breast reconstruction with tissue expanders is one of the most common plastic surgery procedures. Acellular dermal matrix (ADM) has become popular for its ability to improve expansion parameters and aesthetics, albeit with a higher complication profile. We present data that support redefining 2-stage reconstruction to include tissue expanders regardless of final reconstructive modality to act as a bridge. Furthermore, we show that cooperation with the ablative surgeon and technical refinements support ADM omission from the first stage of reconstruction.

Methods: We retrospectively reviewed charts from the senior author's (D.A.J.) private practice over a 10-year follow-up period. Inclusion criteria included all women over 18 years who underwent mastectomy and had a tissue expander placed immediately or in a delayed fashion and successfully completed tissue expansion and are finished with the second stage of reconstruction or awaiting second stage of reconstruction. Demographic data, tissue expander filling data, final reconstruction, aesthetic outcome, and complications were tabulated.

Results: A total of 118 women (165 breasts) met inclusion criteria. There were no statistically significant differences in initial fill volume (P = 0.094), number of visits until final expansion (P = 0.677), or final fill volume (P = 0.985) between the ADM and non-ADM cohorts. In addition, non-ADM patients had superior aesthetic scores with respect to defects other than scarring (P = 0.015), projection (P = 0.013), and inframammary fold quality (P = 0.009). Fifteen percent of women decided to change desired final reconstruction modality during the tissue expansion phase.

Conclusions: This reconstructive algorithm emphasizes surgical cooperation between the ablative and reconstructive surgeon, improved technique, and patient education. This focus translates into maintained tissue expansion, aesthetically pleasing results, and allows for the omission of ADM from reconstruction.
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http://dx.doi.org/10.1097/SAP.0000000000000763DOI Listing
June 2016

Obesity inhibits the osteogenic differentiation of human adipose-derived stem cells.

J Transl Med 2016 Jan 27;14:27. Epub 2016 Jan 27.

Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA.

Background: Craniomaxillofacial defects secondary to trauma, tumor resection, or congenital malformations are frequent unmet challenges, due to suboptimal alloplastic options and limited autologous tissues such as bone. Significant advances have been made in the application of adipose-derived stem/stromal cells (ASCs) in the pre-clinical and clinical settings as a cell source for tissue engineering approaches. To fully realize the translational potential of ASCs, the identification of optimal donors for ASCs will ensure the successful implementation of these cells for tissue engineering approaches. In the current study, the impact of obesity on the osteogenic differentiation of ASCs was investigated.

Methods: ASCs isolated from lean donors (body mass index <25; lnASCs) and obese donors (body mass index >30; obASCs) were induced with osteogenic differentiation medium as monolayers in an estrogen-depleted culture system and on three-dimensional scaffolds. Critical size calvarial defects were generated in male nude mice and treated with scaffolds implanted with lnASCs or obASCs.

Results: lnASCs demonstrated enhanced osteogenic differentiation in monolayer culture system, on three-dimensional scaffolds, and for the treatment of calvarial defects, whereas obASCs were unable to induce similar levels of osteogenic differentiation in vitro and in vivo. Gene expression analysis of lnASCs and obASCs during osteogenic differentiation demonstrated higher levels of osteogenic genes in lnASCs compared to obASCs.

Conclusion: Collectively, these results indicate that obesity reduces the osteogenic differentiation capacity of ASCs such that they may have a limited suitability as a cell source for tissue engineering.
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http://dx.doi.org/10.1186/s12967-016-0776-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4730660PMC
January 2016

Human Adipose Stromal/Stem Cells from Obese Donors Show Reduced Efficacy in Halting Disease Progression in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis.

Stem Cells 2016 Mar 2;34(3):614-26. Epub 2016 Feb 2.

Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.

Multiple sclerosis is an autoimmune disease that affects the white matter of the central nervous system and involves inflammation and demyelination. The recent advances in our understanding of adipose-derived stromal/stem cells (ASCs) and the utilization of these cells in clinical settings to treat diseases have made it essential to identify the most effective ASCs for therapy. Studies have not yet investigated the impact of obesity on the therapeutic efficacy of ASCs. Obesity is characterized by adipocyte hyperplasia and hypertrophy and can extend to metabolic and endocrine dysfunction. Investigating the impact obesity has on ASC biology will determine whether these cells are suitable for use in regenerative medicine. The therapeutic efficacy of ASCs isolated from lean subjects (body mass index [BMI] < 25; lnASCs) and obese subjects (BMI > 30; obASCs) were determined in murine experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Compared with the EAE disease-modifying effects of lnASCs, obASCs consistently failed to alleviate clinical symptoms or inhibit inflammation in the central nervous system. When activated, obASCs expressed higher mRNA levels of several pro-inflammatory cytokines compared with lnASCs. Additionally, conditioned media (CM) collected from the obASCs markedly enhanced the proliferation and differentiation of T cells; whereas, CM from lnASC did not. These results indicate that obesity reduces, or eliminates, the anti-inflammatory effects of human ASCs such that they may not be a suitable cell source for the treatment of autoimmune diseases. The data suggest that donor demographics may be particularly important when identifying suitable stem cells for treatment.
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http://dx.doi.org/10.1002/stem.2272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4803617PMC
March 2016

Analysis of the Pro- and Anti-Inflammatory Cytokines Secreted by Adult Stem Cells during Differentiation.

Stem Cells Int 2015 2;2015:412467. Epub 2015 Aug 2.

Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA ; Departments of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA.

Adipose-derived stromal/stem cells (ASCs) are adult stem cells that have the potential to differentiate into mesenchymal lineage cells. The abundance of ASCs in adipose tissue and easy accessibility with relatively little donor site morbidity make them attractive candidate cells for tissue engineering and regenerative medicine. However, the underlying inflammatory process that occurs during ASC differentiation into adipocytes and osteoblast has not been extensively investigated. ASCs cultured in osteogenic and adipogenic differentiation medium were characterized by oil red o staining and alizarin red staining, respectively. ASCs undergoing osteogenic and adipogenic differentiation were isolated on days 7, 14, and 21 and assessed by qRT-PCR for the expression of pro- and anti-inflammatory cytokines. ASCs undergoing osteogenic differentiation expressed a distinct panel of cytokines that differed from the cytokine profile of ASCs undergoing adipogenic differentiation at each of the time points analyzed. Mapping the cytokine expression profile during ASC differentiation will provide insight into the role of inflammation in this process and identify potential targets that may aid in enhancing osteogenic or adipogenic differentiation for the purposes of tissue engineering and regenerative medicine.
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http://dx.doi.org/10.1155/2015/412467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537750PMC
August 2015

Leptin produced by obese adipose stromal/stem cells enhances proliferation and metastasis of estrogen receptor positive breast cancers.

Breast Cancer Res 2015 Aug 19;17:112. Epub 2015 Aug 19.

Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-99, New Orleans, LA, 70112, USA.

Introduction: The steady increase in the incidence of obesity among adults has been paralleled with higher levels of obesity-associated breast cancer. While recent studies have suggested that adipose stromal/stem cells (ASCs) isolated from obese women enhance tumorigenicity, the mechanism(s) by which this occurs remains undefined. Evidence suggests that increased adiposity results in increased leptin secretion from adipose tissue, which has been shown to increased cancer cell proliferation. Previously, our group demonstrated that ASCs isolated from obese women (obASCs) also express higher levels of leptin relative to ASCs isolated from lean women (lnASCs) and that this obASC-derived leptin may account for enhanced breast cancer cell growth. The current study investigates the impact of inhibiting leptin expression in lnASCs and obASCs on breast cancer cell (BCC) growth and progression.

Methods: Estrogen receptor positive (ER+) BCCs were co-cultured with leptin shRNA lnASCs or leptin shRNA obASCs and changes in the proliferation, migration, invasion, and gene expression of BCCs were investigated. To assess the direct impact of leptin inhibition in obASCs on BCC proliferation, MCF7 cells were injected alone or mixed with control shRNA obASCs or leptin shRNA obASCs into SCID/beige mice.

Results: ER+ BCCs were responsive to obASCs during direct co-culture, whereas lnASCs were unable to increase ER(+) BCC growth. shRNA silencing of leptin in obASCs negated the enhanced proliferative effects of obASC on BCCs following direct co-culture. BCCs co-cultured with obASCs demonstrated enhanced expression of epithelial-to-mesenchymal transition (EMT) and metastasis genes (SERPINE1, MMP-2, and IL-6), while BCCs co-cultured with leptin shRNA obASCs did not display similar levels of gene induction. Knockdown of leptin significantly reduced tumor volume and decreased the number of metastatic lesions to the lung and liver. These results correlated with reduced expression of both SERPINE1 and MMP-2 in tumors formed with MCF7 cells mixed with leptin shRNA obASCs, when compared to tumors formed with MCF7 cells mixed with control shRNA obASCs.

Conclusion: This study provides mechanistic insight as to how obesity enhances the proliferation and metastasis of breast cancer cells; specifically, obASC-derived leptin contributes to the aggressiveness of breast cancer in obese women.
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http://dx.doi.org/10.1186/s13058-015-0622-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4541745PMC
August 2015

The Current State of Fat Grafting: A Review of Harvesting, Processing, and Injection Techniques.

Plast Reconstr Surg 2015 Oct;136(4):897-912

New Orleans, La.; Ann Arbor, Mich.; Pittsburgh, Pa.; and New York, N.Y. From the Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine; the Department of Surgery, Division of Plastic Surgery, and the Burn Wound and Regenerative Medicine Laboratory, University of Michigan; the Department of Plastic Surgery, University of Pittsburgh Medical Center; and the Department of Plastic Surgery, New York University Langone Medical Center.

Background: Interest in and acceptance of autologous fat grafting for use in contour abnormalities, breast reconstruction, and cosmetic procedures have increased. However, there are many procedural variations that alter the effectiveness of the procedure and may account for the unpredictable resorption rates observed.

Methods: The authors highlighted studies investigating the effects of harvesting procedures, processing techniques, and reinjection methods on the survival of fat grafts. This review focused on the impact different techniques have on outcomes observed in the following: in vitro analyses, in vivo animal experiments, and human studies.

Results: This systemic review revealed the current state of the literature. There was no significant difference in the outcomes of grafted fat obtained from different donor sites, different donor-site preparations, harvest technique, fat harvesting cannula size, or centrifugation speed, when tumescent solution was used. Gauze rolling was found to enhance the volume of grafted fat, and no significant difference in retention was observed following centrifugation, filtration, or sedimentation in animal experiments. In contrast, clinical studies in patients found more favorable outcomes with fat processed by centrifugation compared with sedimentation. In addition, higher retention was observed with slower reinjection speed and when introduced into less mobile areas.

Conclusions: There has been a substantial increase in research interest to identify methodologies for optimizing fat graft survival. Despite some differences in harvest and implantation technique in the laboratory, these findings have not translated into a universal protocol for fat grafting. Therefore, additional human studies are necessary to aid in the development of a universal protocol for clinical practice.
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http://dx.doi.org/10.1097/PRS.0000000000001590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833505PMC
October 2015