Lauren Kokai - Academia.edu (original) (raw)

Papers by Lauren Kokai

Research paper thumbnail of Local Delivery of Adipose Stem Cell Promotes Allograft Survival in A Rat Hind Limb Model of Vascularized Composite Allotransplantation

Plastic & Reconstructive Surgery

Research paper thumbnail of Fat grafting in autologous breast reconstruction: applications, outcomes, safety, and complications

Plastic and Aesthetic Research

Autologous fat grafting is an important surgical technique in aesthetic and reconstructive proced... more Autologous fat grafting is an important surgical technique in aesthetic and reconstructive procedures. Fat grafting for breast reconstruction is now an established procedure for adding volume and improving cutaneous pliability; it can be used independently to replace more invasive flap procedures or implants, or as an adjunct for smaller volume supplementation. The breadth of applications in the breast necessitates diversity in technique and approach, and while there is no universally agreed-upon protocol, basic principles have guided the evolution of some commonly adopted tenets. Broadly, fat grafting outcomes are highly favorable but dependent on patient and procedure factors, requiring learned patient selection and expertise in recipient site assessment. Common complications from fat grafting, such as fat necrosis and the development of nodules, are particularly troublesome for post-oncologic patients, requiring considerable pre-surgical consultation for patient education and man...

Research paper thumbnail of Active Vitamin D3 (Calcitriol) Increases Adipose Graft Retention in a Xenograft Model

Aesthetic Surgery Journal

Background Autologous fat grafting, although broadly indicated, is limited by unsatisfactory rete... more Background Autologous fat grafting, although broadly indicated, is limited by unsatisfactory retention and often requires multiple procedures to achieve durable outcomes. Graft survival is strongly influenced by the magnitude and duration of post-engraftment ischemia. Calcitriol is a pleiotropic, safe nutrient with cell-specific influence on viability and metabolic flux. Objectives Evaluate the efficacy of activated vitamin D3 (calcitriol) in improving grafting outcomes and examine its mechanisms. Methods Lipoaspirate was collected for ex vivo culture (7 unique donors), in vitro bioenergetic analysis (6 unique donors), and in vivo transplantation (5 unique donors). Ex vivo samples were incubated for up to 2 weeks before extraction of the stromal vascular fraction (SVF) for viability or flow cytometry. SVF was collected for Seahorse (Agilent; Santa Clara, CA) analysis of metabolic activity. Human endothelial cell lines were utilized for analyses of endothelial function. In vivo, samp...

Research paper thumbnail of Comparison of Soluble and Liposome Encapsulated, Sustained Release Latanoprost for Focal Adipose Reduction

Facial Plastic Surgery & Aesthetic Medicine

Research paper thumbnail of Comparison of Clinically Relevant Adipose Preparations on Articular Chondrocyte Phenotype in a Novel In Vitro Co-Culture Model

Stem Cells and Development

Adipose therapeutics, including isolated cell fractions and tissue emulsifications, have been exp... more Adipose therapeutics, including isolated cell fractions and tissue emulsifications, have been explored for osteoarthritis (OA) treatment, however the optimal preparation method and bioactive tissue component for healing has yet to be determined. This in-vitro study compared the effects of adipose preparations on cultured knee chondrocytes. De-identified human articular chondrocytes were co-cultured with adipose preparations for 36 or 72 hours. Human adipose tissues were obtained from abdominal panniculectomy procedures and processed using three different techniques: enzymatic digestion to release stromal vascular fraction (SVF), emulsification with luer-to-luer transfer (nanofat), and processing in a bead-mill (Lipogems, Lipogems International SpA, Milan, Italy). Gene expression in both chondrocytes and adipose preparations was measured to assess cellular inflammation, catabolism, and anabolism. Results demonstrated that chondrocytes cultured with SVF consistently showed increased inflammatory and catabolic gene expression compared to control chondrocytes at both 36-and 72-hour timepoints. Alternatively, chondrocytes co-cultured with either nanofat or bead-mill processed adipose derivatives yielded minimal pro-inflammatory effects and instead increased anabolism and regeneration of cartilage extracellular matrix. Interestingly, nanofat preparations induced transient matrix anabolism while Lipogems adipose consistently demonstrated increased matrix synthesis at both study time points following co-culture. This evaluation of the regenerative potential of adipose-derived preparations as a clinical tool for knee OA treatment suggests that mechanically processed preparations may be more efficacious than an isolated SVF cell preparation.

Research paper thumbnail of QS34. Prostaglandin F2a Analog Focally Depletes Adipose Volume Without Concurrent Cytolysis

Plastic and Reconstructive Surgery - Global Open

Research paper thumbnail of 53. Wound Edge Inversion Delays Healing and Contributes to Dystrophic Scar Formation in a Mouse Model

Plastic and Reconstructive Surgery - Global Open

Research paper thumbnail of 36. Spironolactone Mitigates Fibrosis and Improves Healing of Burn Wounds

Plastic and Reconstructive Surgery - Global Open

Research paper thumbnail of QS47. Toll-like Receptor Agonism Upregulates Endothelial Populations and Supports Healing of Diabetic Wound

Plastic and Reconstructive Surgery - Global Open

Research paper thumbnail of 83. Vitamin D3 Enhances Adipose Stromal Cell Bioenergetics Capacity Andproliferation Under Hypoxic Conditions and Improves Fat Grafting Outcomes

Plastic and Reconstructive Surgery - Global Open

Research paper thumbnail of QS59. Pulsed-release Dexamethasone-loaded Microspheres Mitigate Scar Contracture and Adhesions in Composite Tissue Burn Reconstruction

Plastic and Reconstructive Surgery - Global Open

Research paper thumbnail of P30. Use of Surgical Epibole for Modeling Chronic Unresolved-Inflammation and Granulation in Murine Wounds

Plastic and Reconstructive Surgery - Global Open

Research paper thumbnail of P32. Human-Adipose Xenografts Improve Burn Wound Healing in Mice

Plastic and Reconstructive Surgery - Global Open

Research paper thumbnail of P26. Wound-Edge Inversion Results in the Reliable, Mechanical Formation of Dystrophic Scars in Mice

Plastic and Reconstructive Surgery - Global Open

Research paper thumbnail of 809 An Allogenic Fat-First Approach to Burn Reconstruction Mitigates Adhesion and Soft Tissue Deficit

Journal of Burn Care & Research, Mar 23, 2022

Introduction: Adipose and adipose-derived stem cell therapies have met success as adjunctive trea... more Introduction: Adipose and adipose-derived stem cell therapies have met success as adjunctive treatment during burn reconstruction with well described benefit in the delayed-treatment of soft-tissue deficits. While the use of allogeneic skin is well-described, adipose tissues have typically remained autologous. Allogenic fat is not commonly used in burn care, however, in large, complex burns where autologous tissue is limited adipose may not be readily available for harvest or use. Understanding the efficacy of allogeneic tissues in this setting is critical to expand our reconstructive options. Here we describe a protocol utilizing allogeneic fat as well as examine the efficacy of this approach on burn-wound contractures, adhesions, and soft-tissue deficits. Methods: Female, Yorkshire swine received 16, 4x4 cm full-thickness burns. After 48 hours, eschar was removed to fascia. Wounds were stratified to receive either A) No Reconstruction, B) Skin-Only, C) Fat-Only, D) Immediate-Skin, Delayed-Fat, or E) Immediate-Fat, Delayed-Skin. All fat utilized was allogeneic sourced from vendor-matched swine. At 8-weeks post-engraftment animals were sacrificed and all wounds were collected for photography, ultrasound, histology and serum studies. Results: Use of allogeneic fat significantly improved terminal soft-tissue thickness under both immediate and delayed administration (p< 0.05). Immediate use of allogeneic fat significantly improved tissue mobility vs. untreated and skin graft controls (p< 0.05). Contracture was most significantly affected by timing of skin graft placement, however, could be further mitigated under standard delayed-fat approached with allogeneic tissue. Conclusions: Here we demonstrate use of allogeneic fat in both traditional-delayed and a fat-first approach with significant mitigation of adhesion when applied as an initial basal layer. Both immediate and delayed allogeneic fat were sufficient to improve on soft tissue deficits.

Research paper thumbnail of PC22. Timed-Release Dexamethasone Safely Minimizes Scar Contracture and Adhesion in Fat-First Burn Reconstruction

Plastic and Reconstructive Surgery - Global Open, 2022

Research paper thumbnail of Abstract: Oncologic Safety of Fat Grafting in Breast Reconstruction: A New Clinically Relevant Animal Model of Residual Breast Cancer

Plastic and Reconstructive Surgery Global Open, 2017

METHODS: Collagenase derived from Clostridium Histolyticum was used in a randomized, double-blind... more METHODS: Collagenase derived from Clostridium Histolyticum was used in a randomized, double-blinded, placebo controlled study on a total of 19 healthy subjects, each with two biopsy-proven lipomas of similar size (one to receive drug and one to receive placebo) at two independent investigational centers (Office of Z. Gerut and Dept. of Plastic Surgery Vanderbilt Univ. Med Ctr.). An independent pharmacist prepared the research drug and the placebo for injection and the two indiscernible preparations were randomized for injection into the two lipomas of each subject; all staff including the investigators, as well as the subject were blinded.

Research paper thumbnail of Mechanistic studies of PEG-asparaginase-induced liver injury and hepatic steatosis in mice

Acta Pharmaceutica Sinica B, 2021

PEGylated-l-asparaginase (PEG-ASNase) is a chemotherapeutic agent used to treat pediatric acute l... more PEGylated-l-asparaginase (PEG-ASNase) is a chemotherapeutic agent used to treat pediatric acute lymphoblastic leukemia (ALL). Its use is avoided in adults due to its high risk of liver injury including hepatic steatosis, with obesity and older age considered risk factors of the injury. Our study aims to elucidate the mechanism of PEG-ASNase-induced liver injury. Mice received 1500 U/kg of PEG-ASNase and were sacrificed 1, 3, 5, and 7 days after drug administration. Liver triglycerides were quantified, and plasma bilirubin, ALT, AST, and non-esterified fatty acids (NEFA) were measured. The mRNA and protein levels of genes involved in hepatic fatty acid synthesis, β-oxidation, very low-density lipoprotein (VLDL) secretion, and white adipose tissue (WAT) lipolysis were determined. Mice developed hepatic steatosis after PEG-ASNase, which associated with increases in bilirubin, ALT, and AST. The hepatic genes Ppara, Lcad/Mcad, Hadhb, Apob100, and Mttp were upregulated, and Srebp-1c and Fas were downregulated after PEG-ASNase. Increased plasma NEFA, WAT loss, and adipose tissue lipolysis were also observed after PEG-ASNase. Furthermore, we found that PEG-ASNase-induced liver injury was exacerbated in obese and aged mice, consistent with clinical studies of ASNase-induced liver injury. Our data suggest that PEG-ASNase-induced liver injury is due to drug-induced lipolysis and lipid redistribution to the liver.

Research paper thumbnail of Exploration of inflammatory biomarkers in three depots of adipose tissue in women with endometrial cancer 2

19. Chiaki Komatsu, Yolandi van der Merwe, Lin He, Maxine R. Miller, Katie A. Lucy, Huamin Tang, ... more 19. Chiaki Komatsu, Yolandi van der Merwe, Lin He, Maxine R. Miller, Katie A. Lucy, Huamin Tang, Ian Rosner, Wendy Chen, Jila Noori, Valeria Fu, Michael Steketee, Gadi Wollstein, Mario Solari, Joel S. Schuman, Kevin C. Chan, Kia M. Washington. Retinal and optic nerve viability evaluated with optical coherence tomography, manganese-enhanced MRI and electroretinography after whole eye transplantation

Research paper thumbnail of SVF Cell-Seeded Tevgs and the Removal of the in Vitro Dynamic Culture Period

INTRODUCTION Tissue engineered vascular grafts (TEVGs) seeded with autologous cells offer a treat... more INTRODUCTION Tissue engineered vascular grafts (TEVGs) seeded with autologous cells offer a treatment alternative to current coronary artery by-pass procedures1-4. Past work has demonstrated that TEVGs seeded with only a mesenchymal stem cell (MSC) population will remodel in vivo5. However, the isolation procedure of MSCs is approximately a 4-week process6; too long to be feasible in a surgical environment.

Research paper thumbnail of Local Delivery of Adipose Stem Cell Promotes Allograft Survival in A Rat Hind Limb Model of Vascularized Composite Allotransplantation

Plastic & Reconstructive Surgery

Research paper thumbnail of Fat grafting in autologous breast reconstruction: applications, outcomes, safety, and complications

Plastic and Aesthetic Research

Autologous fat grafting is an important surgical technique in aesthetic and reconstructive proced... more Autologous fat grafting is an important surgical technique in aesthetic and reconstructive procedures. Fat grafting for breast reconstruction is now an established procedure for adding volume and improving cutaneous pliability; it can be used independently to replace more invasive flap procedures or implants, or as an adjunct for smaller volume supplementation. The breadth of applications in the breast necessitates diversity in technique and approach, and while there is no universally agreed-upon protocol, basic principles have guided the evolution of some commonly adopted tenets. Broadly, fat grafting outcomes are highly favorable but dependent on patient and procedure factors, requiring learned patient selection and expertise in recipient site assessment. Common complications from fat grafting, such as fat necrosis and the development of nodules, are particularly troublesome for post-oncologic patients, requiring considerable pre-surgical consultation for patient education and man...

Research paper thumbnail of Active Vitamin D3 (Calcitriol) Increases Adipose Graft Retention in a Xenograft Model

Aesthetic Surgery Journal

Background Autologous fat grafting, although broadly indicated, is limited by unsatisfactory rete... more Background Autologous fat grafting, although broadly indicated, is limited by unsatisfactory retention and often requires multiple procedures to achieve durable outcomes. Graft survival is strongly influenced by the magnitude and duration of post-engraftment ischemia. Calcitriol is a pleiotropic, safe nutrient with cell-specific influence on viability and metabolic flux. Objectives Evaluate the efficacy of activated vitamin D3 (calcitriol) in improving grafting outcomes and examine its mechanisms. Methods Lipoaspirate was collected for ex vivo culture (7 unique donors), in vitro bioenergetic analysis (6 unique donors), and in vivo transplantation (5 unique donors). Ex vivo samples were incubated for up to 2 weeks before extraction of the stromal vascular fraction (SVF) for viability or flow cytometry. SVF was collected for Seahorse (Agilent; Santa Clara, CA) analysis of metabolic activity. Human endothelial cell lines were utilized for analyses of endothelial function. In vivo, samp...

Research paper thumbnail of Comparison of Soluble and Liposome Encapsulated, Sustained Release Latanoprost for Focal Adipose Reduction

Facial Plastic Surgery & Aesthetic Medicine

Research paper thumbnail of Comparison of Clinically Relevant Adipose Preparations on Articular Chondrocyte Phenotype in a Novel In Vitro Co-Culture Model

Stem Cells and Development

Adipose therapeutics, including isolated cell fractions and tissue emulsifications, have been exp... more Adipose therapeutics, including isolated cell fractions and tissue emulsifications, have been explored for osteoarthritis (OA) treatment, however the optimal preparation method and bioactive tissue component for healing has yet to be determined. This in-vitro study compared the effects of adipose preparations on cultured knee chondrocytes. De-identified human articular chondrocytes were co-cultured with adipose preparations for 36 or 72 hours. Human adipose tissues were obtained from abdominal panniculectomy procedures and processed using three different techniques: enzymatic digestion to release stromal vascular fraction (SVF), emulsification with luer-to-luer transfer (nanofat), and processing in a bead-mill (Lipogems, Lipogems International SpA, Milan, Italy). Gene expression in both chondrocytes and adipose preparations was measured to assess cellular inflammation, catabolism, and anabolism. Results demonstrated that chondrocytes cultured with SVF consistently showed increased inflammatory and catabolic gene expression compared to control chondrocytes at both 36-and 72-hour timepoints. Alternatively, chondrocytes co-cultured with either nanofat or bead-mill processed adipose derivatives yielded minimal pro-inflammatory effects and instead increased anabolism and regeneration of cartilage extracellular matrix. Interestingly, nanofat preparations induced transient matrix anabolism while Lipogems adipose consistently demonstrated increased matrix synthesis at both study time points following co-culture. This evaluation of the regenerative potential of adipose-derived preparations as a clinical tool for knee OA treatment suggests that mechanically processed preparations may be more efficacious than an isolated SVF cell preparation.

Research paper thumbnail of QS34. Prostaglandin F2a Analog Focally Depletes Adipose Volume Without Concurrent Cytolysis

Plastic and Reconstructive Surgery - Global Open

Research paper thumbnail of 53. Wound Edge Inversion Delays Healing and Contributes to Dystrophic Scar Formation in a Mouse Model

Plastic and Reconstructive Surgery - Global Open

Research paper thumbnail of 36. Spironolactone Mitigates Fibrosis and Improves Healing of Burn Wounds

Plastic and Reconstructive Surgery - Global Open

Research paper thumbnail of QS47. Toll-like Receptor Agonism Upregulates Endothelial Populations and Supports Healing of Diabetic Wound

Plastic and Reconstructive Surgery - Global Open

Research paper thumbnail of 83. Vitamin D3 Enhances Adipose Stromal Cell Bioenergetics Capacity Andproliferation Under Hypoxic Conditions and Improves Fat Grafting Outcomes

Plastic and Reconstructive Surgery - Global Open

Research paper thumbnail of QS59. Pulsed-release Dexamethasone-loaded Microspheres Mitigate Scar Contracture and Adhesions in Composite Tissue Burn Reconstruction

Plastic and Reconstructive Surgery - Global Open

Research paper thumbnail of P30. Use of Surgical Epibole for Modeling Chronic Unresolved-Inflammation and Granulation in Murine Wounds

Plastic and Reconstructive Surgery - Global Open

Research paper thumbnail of P32. Human-Adipose Xenografts Improve Burn Wound Healing in Mice

Plastic and Reconstructive Surgery - Global Open

Research paper thumbnail of P26. Wound-Edge Inversion Results in the Reliable, Mechanical Formation of Dystrophic Scars in Mice

Plastic and Reconstructive Surgery - Global Open

Research paper thumbnail of 809 An Allogenic Fat-First Approach to Burn Reconstruction Mitigates Adhesion and Soft Tissue Deficit

Journal of Burn Care & Research, Mar 23, 2022

Introduction: Adipose and adipose-derived stem cell therapies have met success as adjunctive trea... more Introduction: Adipose and adipose-derived stem cell therapies have met success as adjunctive treatment during burn reconstruction with well described benefit in the delayed-treatment of soft-tissue deficits. While the use of allogeneic skin is well-described, adipose tissues have typically remained autologous. Allogenic fat is not commonly used in burn care, however, in large, complex burns where autologous tissue is limited adipose may not be readily available for harvest or use. Understanding the efficacy of allogeneic tissues in this setting is critical to expand our reconstructive options. Here we describe a protocol utilizing allogeneic fat as well as examine the efficacy of this approach on burn-wound contractures, adhesions, and soft-tissue deficits. Methods: Female, Yorkshire swine received 16, 4x4 cm full-thickness burns. After 48 hours, eschar was removed to fascia. Wounds were stratified to receive either A) No Reconstruction, B) Skin-Only, C) Fat-Only, D) Immediate-Skin, Delayed-Fat, or E) Immediate-Fat, Delayed-Skin. All fat utilized was allogeneic sourced from vendor-matched swine. At 8-weeks post-engraftment animals were sacrificed and all wounds were collected for photography, ultrasound, histology and serum studies. Results: Use of allogeneic fat significantly improved terminal soft-tissue thickness under both immediate and delayed administration (p< 0.05). Immediate use of allogeneic fat significantly improved tissue mobility vs. untreated and skin graft controls (p< 0.05). Contracture was most significantly affected by timing of skin graft placement, however, could be further mitigated under standard delayed-fat approached with allogeneic tissue. Conclusions: Here we demonstrate use of allogeneic fat in both traditional-delayed and a fat-first approach with significant mitigation of adhesion when applied as an initial basal layer. Both immediate and delayed allogeneic fat were sufficient to improve on soft tissue deficits.

Research paper thumbnail of PC22. Timed-Release Dexamethasone Safely Minimizes Scar Contracture and Adhesion in Fat-First Burn Reconstruction

Plastic and Reconstructive Surgery - Global Open, 2022

Research paper thumbnail of Abstract: Oncologic Safety of Fat Grafting in Breast Reconstruction: A New Clinically Relevant Animal Model of Residual Breast Cancer

Plastic and Reconstructive Surgery Global Open, 2017

METHODS: Collagenase derived from Clostridium Histolyticum was used in a randomized, double-blind... more METHODS: Collagenase derived from Clostridium Histolyticum was used in a randomized, double-blinded, placebo controlled study on a total of 19 healthy subjects, each with two biopsy-proven lipomas of similar size (one to receive drug and one to receive placebo) at two independent investigational centers (Office of Z. Gerut and Dept. of Plastic Surgery Vanderbilt Univ. Med Ctr.). An independent pharmacist prepared the research drug and the placebo for injection and the two indiscernible preparations were randomized for injection into the two lipomas of each subject; all staff including the investigators, as well as the subject were blinded.

Research paper thumbnail of Mechanistic studies of PEG-asparaginase-induced liver injury and hepatic steatosis in mice

Acta Pharmaceutica Sinica B, 2021

PEGylated-l-asparaginase (PEG-ASNase) is a chemotherapeutic agent used to treat pediatric acute l... more PEGylated-l-asparaginase (PEG-ASNase) is a chemotherapeutic agent used to treat pediatric acute lymphoblastic leukemia (ALL). Its use is avoided in adults due to its high risk of liver injury including hepatic steatosis, with obesity and older age considered risk factors of the injury. Our study aims to elucidate the mechanism of PEG-ASNase-induced liver injury. Mice received 1500 U/kg of PEG-ASNase and were sacrificed 1, 3, 5, and 7 days after drug administration. Liver triglycerides were quantified, and plasma bilirubin, ALT, AST, and non-esterified fatty acids (NEFA) were measured. The mRNA and protein levels of genes involved in hepatic fatty acid synthesis, β-oxidation, very low-density lipoprotein (VLDL) secretion, and white adipose tissue (WAT) lipolysis were determined. Mice developed hepatic steatosis after PEG-ASNase, which associated with increases in bilirubin, ALT, and AST. The hepatic genes Ppara, Lcad/Mcad, Hadhb, Apob100, and Mttp were upregulated, and Srebp-1c and Fas were downregulated after PEG-ASNase. Increased plasma NEFA, WAT loss, and adipose tissue lipolysis were also observed after PEG-ASNase. Furthermore, we found that PEG-ASNase-induced liver injury was exacerbated in obese and aged mice, consistent with clinical studies of ASNase-induced liver injury. Our data suggest that PEG-ASNase-induced liver injury is due to drug-induced lipolysis and lipid redistribution to the liver.

Research paper thumbnail of Exploration of inflammatory biomarkers in three depots of adipose tissue in women with endometrial cancer 2

19. Chiaki Komatsu, Yolandi van der Merwe, Lin He, Maxine R. Miller, Katie A. Lucy, Huamin Tang, ... more 19. Chiaki Komatsu, Yolandi van der Merwe, Lin He, Maxine R. Miller, Katie A. Lucy, Huamin Tang, Ian Rosner, Wendy Chen, Jila Noori, Valeria Fu, Michael Steketee, Gadi Wollstein, Mario Solari, Joel S. Schuman, Kevin C. Chan, Kia M. Washington. Retinal and optic nerve viability evaluated with optical coherence tomography, manganese-enhanced MRI and electroretinography after whole eye transplantation

Research paper thumbnail of SVF Cell-Seeded Tevgs and the Removal of the in Vitro Dynamic Culture Period

INTRODUCTION Tissue engineered vascular grafts (TEVGs) seeded with autologous cells offer a treat... more INTRODUCTION Tissue engineered vascular grafts (TEVGs) seeded with autologous cells offer a treatment alternative to current coronary artery by-pass procedures1-4. Past work has demonstrated that TEVGs seeded with only a mesenchymal stem cell (MSC) population will remodel in vivo5. However, the isolation procedure of MSCs is approximately a 4-week process6; too long to be feasible in a surgical environment.