Safety of DW-MSC infusion in patients with low clinical risk COVID-19 infection: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Due to their immunomodulatory properties, mesenchymal stem cells (MSCs) have been proposed to have therapeutic potential to improve clinical outcomes in COVID-19. However, the safety and efficacy profile of MSC infusion therapy in patients with non-severe COVID-19 infection has not been completely established; there is, in particular, a substantial void in the literature on dose-dependent studies of MSC infusion in patients with low clinical risk COVID-19 infection. METHODS: This phase 1 double-blind, placebo-controlled, randomized clinical trial examines the safety, feasibility, and tolerability of 2 doses (high and low) of DW-MSC in patients with low clinical risk COVID-19. A total of 9 patients were enrolled in this study and randomized into low-dose (TL), high-dose (TH), and placebo (C) groups. Subjects in the TL and TH groups received single intravenous infusions of 5.0 × 107 cells and 1.0 × 108 cells, respectively. The main outcome was the occurrence of treatment-emergent adverse events (TEAE) during the 28-day study period. Vital signs and various inflammatory markers were also monitored weekly during the observation period. RESULTS: There were no apparent differences in clinical characteristics between study groups (TL, TH, and C) at baseline. All patients did not show the progression of severity during the study period. During the course of the study, 6 episodes of TEAE were observed in 5 subjects; however, none of the TEAEs were severe. During the follow-up period, 8 subjects recovered and were discharged from the hospital without complications. A subject exhibited abnormal liver function biomarkers at the end of the study period. Changes in inflammatory markers throughout the clinical course were not vastly different across study groups. CONCLUSIONS: Our clinical trial has provided reliable results regarding the safety of MSCs in low clinical risk COVID-19 subjects treated with MSCs. However, further confirmation of the therapeutic efficacy aspects of MSC will require large-scale randomized controlled trials in subjects with varying severity profiles for COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04535856. Registered 2 September 2020, https://clinicaltrials.gov/ct2/show/NCT04535856.

The effect of stromal vascular fraction and Platelet-Rich Plasma combination on basic Fibroblast Growth Factor serum level during anal trauma healing in a Wistar rat model.

Introduction: Stromal Vascular Fraction (SVF) and Platelet-Rich Plasma (PRP) application play important roles in the healing process by increasing basic Fibroblast Growth Factor (bFGF) secretion. This research assesses the effect of combined SVF and PRP local injection on bFGF levels, using an anal trauma model in Wistar rats. Method: Twenty-eight adult Wistar rats were divided into three groups. Groups A and B underwent modified surgical anal trauma and repair; Group A was treated with the SVF and PRP combination local injection, while Group B was treated with only normal saline. Subsequently, we examined bFGF levels in Groups A and B on days 1, 7, and 14. Group C consisted of healthy controls sacrificed on day 0 to obtain baseline data on bFGF levels. Results: The bFGF levels were higher in Group A than in Group B on every experimental day. The Repeated Measures test shows a significant increase in bFGF levels on day 1 (p = 0.000), day 7 (p = 0.000), and day 14 (p = 0.000). This test also indicates that the local injection combination of SVF and PRP increased bFGF levels by 96.2% compared to the placebo group. Conclusion: The combination of SVF and PRP can increase bFGF levels during anal trauma healing in the Wistar rat model. Basic FGF is an important factor throughout the anal trauma healing process.

Nasal reconstruction surgery after continuous positive airway pressure delivered by prongs: A case report.

INTRODUCTION AND IMPORTANCE: Deformities resulting from nasal continuous positive airway pressure delivered using prongs can cause functional and aesthetic issues for patients. Resultant severe tissue damage to the nasal structures often requires surgical intervention and techniques continue to evolve. CASE PRESENTATION: This case report describes a 6-year-old male presenting with a full-thickness columella defect; contracture causing deformities involving the nasal tip, ala nasi, and left nasal cavity wall; missing left lateral-medial cruris cartilage; and partially missing right medial cruris cartilage. The abnormalities initially appeared when the patient was 7 days old after receiving treatment by nasal continuous positive airway pressure for 7 days. A one-stage procedure was performed as follows: left ala nasi reconstruction with skin excision followed by an ear cartilage graft; a nasal cartilage shield graft to form the nasal tip; reconstruction of the columella with a cartilage graft combined with bilateral soft tissue flaps taken from the nasal floor and mucosa vestibulum; and a full-thickness skin graft to cover the secondary defect resulting from the flaps. At 1-month post-surgery, satisfactory results were reported. CLINICAL DISCUSSION AND CONCLUSION: Our approach combining two flaps taken from the nasal floor and the inner layer of the ala nasi, a cartilage graft from the ear, and a full-thickness skin graft delivered a one-stage surgical technique that yielded satisfactory results without deformities of the donor site. However, the surgical technique should be individualized to patients. This case report adds to the literature and offers surgeons an alternative approach for managing nasal deformities.

The effect of Platelet-Rich Plasma and Stromal Vascular Fraction combination on Epidermal Growth Factor serum level for anal trauma healing in the Wistar rat model.

INTRODUCTION: Stromal Vascular Fraction cells (SVFs) and Platelet Rich Plasma (PRP) are clinically proven to aid in cell regeneration and wound healing. The healing effects can be measured by the level of Epidermal Growth Factor (EGF). This study aims to investigate the effect of an SVFs and PRP combination on EGF levels in the anal trauma model. METHOD: Twenty-eight adult Wistar rats were divided into 3 groups: Group A consisted of healthy rats as a normal control group; Group B and C underwent modified anal surgical trauma and repair. Group B was treated with saline only and Group C was treated with local injection of a combination of SVFs and PRP after anal surgical repair. The EGF level was subsequently assessed on days 1, 7, and 14. RESULTS: EGF levels were generally increased in Group C compared to Group B. A one-way ANOVA test result showed significantly increased EGF levels on days 7 (p = 0.038) and 14 (p = 0.018). Based on the linear regression test results, we found that local injection of PRP and SVFs after anal repair on an anal surgical trauma model can increase the EGF level in group C by 36.9% more than that of group B. CONCLUSION: The combination of PRP and SVFs can increase the EGF level in the wound healing process of anal trauma. EGF is critical in the anal trauma healing process.

The Combination of Stromal Vascular Fraction Cells and Platelet-Rich Plasma Reduces Malondialdehyde and Nitric Oxide Levels in Deep Dermal Burn Injury.

INTRODUCTION: Thermal burns release reactive oxygen species, which cause profound systemic and local changes. Stromal vascular fraction cells (SVFs) combined with platelet-rich plasma accelerate burn wound healing. This study investigated the effect of a combination of locally injected SVFs and PRP on malondialdehyde (MDA) and nitric oxide (NO) serum and tissue levels in a deep dermal burn model in Wistar rats. METHODS: Thirty-six adult Wistar rats weighing between 150 and 250 grams were used in this study to establish a deep dermal degree burn wound model. They were randomly divided into 4 groups: locally injected the combination SVFs and PRP, the Vaseline group, the placebo group, and healthy Wistar rats (the normal control group). MDA and NO levels in blood serum and burn wound tissue were measured at 8, 24, and 48 hours. Data were analyzed with one-way ANOVA followed by multiple comparisons tests and regression tests. RESULTS: Local injection of SVFs and PRP in combination affected blood MDA, tissue MDA, blood NO and tissue NO levels, with reductions of 0.257µmol/L, 0.427 µmol/L, 21.78nmol/mg, and 23.777nmol/mg, respectively. Injection of SVFs and PRP in combination reduced tissue MDA levels by 1.282 times, NO blood levels by 2.305, and NO tissue levels by 2.377 times compared to Vaseline application. CONCLUSION: The combination of SVFs and PRP undeniably reduced the MDA and NO levels in blood and tissue compared to those in the Vaseline and placebo groups. The injection of these two preparations in combination inhibited the local and systemic stress oxidative response, as illustrated by the decreased MDA and NO levels in blood serum and tissue.

Combination of platelet rich plasma and stromal vascular fraction on the level of vascular endothelial growth factor in rat subjects experiencing deep dermal burn injury.

BACKGROUND: The healing process of burns includes coagulation, inflammation, and remodeling. Vascular endothelial growth factor (VEGF) is involved throughout this healing process. Stem cells from the platelet-rich plasma (PRP) with stromal vascular fraction (SVF) can increase concentrations of growth factors, including VEGF. This is expected to accelerate burn healing. The aim of this study was to determine the effect of a combination of PRP and SVF on VEGF levels in a rats model of deep dermal burn wound healing. MATERIALS AND METHODS: This is an experimental research study in rats using a post-test control group design with 4 groups: A) control, B) Vaseline, C) topical PRP and SVF, and D) PRP and SVF injection. Burn wounds were induced according to the modified Guo method. RESULTS: In a rats model of deep dermal wound healing, topical Vaseline significantly increased serum VEGF compared to control. Topical application and injection of stem cells also significantly increased serum VEGF compared to control and Vaseline. The VEGF concentration was significantly higher following injection of PRP and SVF, suggesting that the injection route is more effective at increasing VEGF levels compared to the topical application of stem cells. CONCLUSION: The combination of PRP and SVF, either by injection or topical application, can increase VEGF levels during the healing process from deep dermal burns.

Phalangectomy combination double-pedicled digital artery flap for second-toe macrodactyly reconstruction: A case report.

INTRODUCTION: Pedal macrodactyly is a rare form of congenital deformity in which the toes and underlying structures are enlarged. The goal of most macrodactyly reconstruction surgeries is to reconstruct the affected toes to resemble the normal size such that the patient is able to wear shoes of the same size. CASE PRESENTATION: We report a three-year-old female patient presenting with an enlargement of the right foot index and middle toes. The anomaly was noticed at two months of age and grew progressively. X-ray imaging revealed enlarged bones and soft-tissue hypertrophy proximal to the distal phalanx of the second and third digits. There was no history of other systemic or syndromic diseases. The patient underwent phalangectomy surgery involving reduction of the fibrofatty tissue, double-pedicle medial and lateral digital artery flap. Satisfactory results were noted at evaluation two months of after surgery. CONCLUSION: Macrodactyly reduction surgeries are generally composed of several kinds of surgical techniques to provide the best results. The management of macrodactyly depends on the surgeon's experience while considering the most suitable surgical technique to be performed in each case. Therefore, it was deemed necessary to report this case and its surgical technique. We hope that this case report will enrich the existing literature and be useful for the management of macrodactyly cases.

Bartsocas-Papas syndrome: The first case report of severe autosomal recessive form from Indonesia.

INTRODUCTION: Bartsocas-Papas syndrome (BPS) is an autosomal recessive form of Popliteal Pterygium syndrome (PPS). It is a very rare disease characterized by congenital craniofacial anomalies, popliteal webbing, and genitourinary and musculoskeletal anomalies. Almost all of the cases were reported in dead intrauterine pregnancies. PRESENTATION OF CASE: We present a 10-month-old boy with bilateral complete cleft lip and palate, abnormal scalp hair, an absence of both upper eyelids, choanal atresia, syndactyly of the third and fourth fingers of the right hand, agenesis fingers on the left hand, bilateral popliteal pterygia, bilateral talipes equinovarus, agenesis of the toes of both lower extremities, intercrural webbing, an absence of testis, and scrotal anomaly. Multistage surgical correction was performed for the multiple congenital malformations. CONCLUSION: We report the first case of BPS from Indonesia. Gradual management should be performed according to the patient's age and available facilities.

Effects of hyperbaric oxygen therapy on the healing of thermal burns and its relationship with ICAM-1: A case-control study.

BACKGROUND: The damaging effects of thermal burns need to be managed holistically in order to create a suitable environment for wound healing. The purpose of our study was to investigate the effects of hyperbaric oxygen therapy (HBOT) on the healing of thermal burns and its relationship with intercellular adhesion molecule 1 (ICAM-1). METHODS: Twenty patients with thermal burns were randomly divided into two groups: the group to receive HBOT and the control group. Levels of the ICAM-1 mRNA gene and ICAM-1 serum along with the degree of wound epithelialization were examined before and after treatment. Laboratory and physical findings between the groups were compared. RESULTS: In the HBOT group compared with the control group, thermal wound complications were significantly reduced (p = .006), while length of stay in hospital was substantially reduced (p = .001). ICAM-1 serum levels strongly correlated with ICAM-1 mRNA gene expression (R 2 = 0.909, p < .001). The expression of the ICAM-1 mRNA gene (12.32 ± 1.31 vs. 10.79 ± 1.38) and ICAM-1 serum level (231.46 ± 37.20 vs. 158.23 ± 68.30) in patients with at least a 50% burn area exceeded those of patients with a smaller burn area. HBOT significantly decreased (p < .05) the expression of the ICAM-1 mRNA gene and ICAM-1 serum level (p = .004). The number of HBOT sessions strongly correlated with ICAM-1 serum level (p = .043) but poorly correlated with ICAM-1 mRNA gene expression (p = .22). The expression of the gene, however, strongly correlated with ICAM-1 serum level (r = -0.988, p < .001). CONCLUSION: HBOT can reduce thermal wound complications, length of stay in hospitals due to thermal burns, ICAM-1 mRNA gene expression, and ICAM-1 serum level.

Combination of platelet-rich plasma and stromal vascular fraction on the level of transforming growth factor-ß in rat subjects experiencing deep dermal burn injury.

INTRODUCTION: The combination of stromal vascular fraction (SVF) and platelet-rich plasma (PRP) is effective at increasing the concentration of growth factors including transforming growth factor-ß (TGF-ß). The increase in this growth factor is expected to accelerate the healing of burns. This study aims to determine the effect of giving a combination of SVFs and PRP on TGF-ß levels in the healing process of deep dermal burns. METHODS: This was an experimental study in 64 rats using a post-test control group design consisting of 1 group of SVFs and PRP combination injection treatment group, 1 group given a topical combination of SVFs and PRP, 1 group given Vaseline, and 1 control group. RESULTS: There was a significant difference in TGF-ß levels between the deep dermal burns group that was given a combination of SVFs and PRP injection and topical, the Vaseline group, and the control group with p-value <0.05. CONCLUSION: The combination of SVFs and PRP increases the level of TGF-ß in the healing process of deep dermal burns.

Concentration of PDGF-AB, BB and TGF-ß1 as valuable human serum parameters in adipose-derived stem cell proliferation.

INTRODUCTION: Human serum (HS) has attributes similar to fetal bovine serum (FBS) in the proliferation and differentiation of human adipose-derived stem cells (hASCs) when compared in vitro. The purpose of this study was to determine what types of HS, with respect to the concentrations of endogenous growth factors, could be made available for hASC proliferation. METHODS: HS was collected from 2 groups of healthy donor (freshly isolated HS [n=9], and HS preserved for 4 years [n=7]). All sera were isolated with a Cellaid HS isolation device (JMS Co., Ltd, Hiroshima, Japan) and then classified into 3 groups based on the concentrations (high, middle, and low) of platelet-derived growth factor (PDGF)-AB, PDGF-BB, and transforming growth factor-beta 1 (TGF-ß1) by means of enzyme-linked immunoassay screening. The hASCs were isolated from subcutaneous fat using a collagenase enzymatic digestion process and were cultured in control media, each supplemented with HS from a different group. Cell numbers were counted on days 2, 4, 7, and 14, and the relationship between cell proliferation and the level of each growth factor was investigated. RESULTS: The proliferation of hASCs correlated with the concentration of each growth factor. The cut-off points for PDGF-AB, PDGF-BB, and TGF-ß1 in HS [necessary for hASC proliferation when compared with FBS] were 10 ng/mL, 1.5 ng/mL, and 15 ng/mL, respectively. There was no correlation between the storage period of HS and the proliferation potential of hASCs. CONCLUSIONS: These results suggest that the effectiveness of HS on hASC proliferation depends on the concentrations of endogenous PDGFs. In addition, the Cellaid device used in this study allows the simultaneous release of several growth factors from platelets, and our results have shown that it can be used to collect HS for future hASC-based therapies.

Accelerated and safe proliferation of human adipose-derived stem cells in medium supplemented with human serum.

Adipose-derived stem cells (ASCs) are a promising cell source and are being investigated for a variety of therapeutic applications. However, standard expansion protocols use fetal bovine serum (FBS) as a growth factor supplement, which is a potential source of undesirable xenogeneic pathogens. For clinical safety, autologous human serum (HS) would be more appropriate. This study compared FBS-supplemented and HS-supplemented media for their enhancement of the proliferation and differentiation potential of human ASCs (hASCs). HS was obtained from the blood of 8 healthy volunteers using collection devices specially designed to derive growth factors from platelets. Growth factors in HS or FBS were measured with enzyme-linked immunosorbent assays. The hASCs were isolated with an established protocol from discarded human fat tissues obtained during a medical procedure and cultured in a medium supplemented with either 10% HS or 10% FBS. The hASCs were collected at several time points for the proliferation assays. The capacity for differentiation into the osteogenic, chondrogenic and adipogenic lineages was assessed qualitatively with the histochemical stains von Kossa, Alcian blue, and Oil red O, respectively, and quantitatively with the qualitative reverse transcriptase polymerase chain reaction. Differences in cell surface marker expression between the HS-supplemented and FBS-supplemented cultures were examined with flow cytometric analysis. Proliferation assays showed that the growth of hASCs was more rapid in HS-supplemented medium than in FBS-supplemented medium. All cells grown in each medium expressed similar patterns of cell surface markers. The ASCs cultured in the HS-supplemented medium proliferated more rapidly than those cultured in the FBS-supplemented medium and retained their differentiation capacity and immunophenotype. These results support the establishment of a safe and rapid expansion protocol with autologous serum for cell-based therapies, such as tissue engineering and regenerative medicine, using hASCs.