Endoscopic Bariatric and Metabolic Therapies: Surgical Analogues and Mechanisms of Action

Jirapinyo P, Thompson CC. Endoscopic Bariatric and Metabolic Therapies: Surgical Analogues and Mechanisms of Action. Clin Gastroenterol Hepatol. 2017;15(5):619-630. Reference: https://pubmed.ncbi.nlm.nih.gov/27989851/

This review article describes the history of bariatric endoscopy and discusses the currently available bariatric endoscopic devices and/or procedures. It also compares bariatric endoscopic procedures to their bariatric surgical analogues and discusses mechanisms of action.

Obesity is a worsening pandemic with numerous related comorbid illnesses. Conservative management including lifestyle modification and medications have limited efficacy. In contradistinction, bariatric surgery is effective, however, with substantial cost and non-negligible morbidity and mortality. As such, a small percentage of eligible patients undergo surgery. Over the past decade, endoscopic bariatric and metabolic therapies have been introduced as a less invasive option for the treatment of obesity and its related comorbid illnesses. This article reviews major endoscopic bariatric and metabolic therapies, their surgical analogues, and proposed mechanisms of action. Clinical trial data for each device also are discussed.Every reliable product review should start with an introductory paragraph. This is your chance to hook your readers right in and let them know what to expect. Are you reviewing one product or comparing a few? What is the full name of the product(s)? Share with your readers your expertise in this area; your frustration with products out in the market that haven’t met your needs; and why this review will offer them the ins and outs of the product’s benefits.

Introductions

Obesity is a rising pandemic. In 2012, more than one third of U.S. adults were obese (body mass index (BMI) ≥ 30) and more than two thirds were overweight (BMI ≥ 25).1 Similarly, there has been an increase in prevalence of obesity-related comorbidities. In 2012, approximately 210 billion dollars were spent to treat obesity related diseases in the U.S., accounting for 21% of health care expenditures.2

Sustained weight loss after lifestyle modification and pharmacotherapy is achieved in less than 5% of cases.3 Bariatric surgery is more effective and durable. However, early and late complications remain as high as 30%4, and less than 1% of eligible patients undergo surgery.5

Recently, endoscopic bariatric and metabolic therapies (EBMTs) have been developed to fill the gap between medical and surgical therapy. Similar to surgery, weight loss after EBMTs is described using total weight loss (TWL), as a percentage of total body weight. However, percentage of excess weight loss (%EWL) is still often referred to (Table 1). Recently, the American Society for Gastrointestinal Endoscopy (ASGE) and the American Society for Metabolic and Bariatric Surgery (ASMBS) defined acceptable thresholds of safety and efficacy for primary EBMTs. Specifically, a particular EBMT should have an incidence of serious adverse events of ≤ 5%, and should result in ≥ 25% EWL at 12 months, and this EWL should be ≥ 15% higher than a control group.6

Mechanisms of Bariatric Surgery

Bariatric surgery historically was classified as ‘restrictive’ (laparoscopic adjustable gastric band (LAGB) and laparoscopic sleeve gastrectomy (LSG), ‘malabsorptive’ (biliopancreatic diversion with duodenal switch (BPD-DS), or a combination of both (Roux-en-Y gastric bypass (RYGB). ‘Restrictive procedures’ rely on decreasing the stomach’s size and therefore reducing caloric intake, while ‘malabsorptive procedures’ bypass a portion of small bowel. Similarly, it was historically thought that weight loss was responsible for the improvement in metabolic comorbidities. However, there is now evidence that improvement in metabolic profile is seen within days post-operatively, prior to significant weight loss, with certain procedures. It is similarly now understood that the mechanisms of action for these procedures are more complicated than mere structural anatomical changes. Specifically, there appears to be a rapid alteration in gut hormones, which affect appetite, satiation, satiety, gut motility, and glucose and lipid homeostasis (Table 2). Additionally, changes in bile acid concentration and gut flora are thought to play a role.

Ghrelin Ghrelin is secreted from X/A-like cells in the fundus. It is the only known orexigenic (appetite stimulant) gut hormone. Its levels are highest in the fasted state, and decrease postprandially.7 It has been shown that ghrelin stimulates appetite and induces a positive energy balance that lead to weight gain. Additionally, it also stimulates gastric and duodenal contraction and opposes the effects of other gastrointestinal peptides, such as cholecystokinin, that serve as satiety signals.8

Bariatric surgeries have distinct effects on ghrelin secretion. LSG and RYGB are associated with decreased ghrelin levels, while LAGB is associated with increased ghrelin levels.9–12 As such, the association between ghrelin levels and weight loss is varied and further study is needed.

2.2 Small Intestinal Hormones

Incretins Incretins are a class of gut hormones that include glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). GIP is secreted postprandially from K cells in the duodenum and jejunum, and GLP-1 from L cells in the terminal ileum. It has been demonstrated that an oral glucose load induces a greater release of insulin compared to intravenous glucose, a phenomenon known as the incretin effect.13 Additionally, GLP-1 suppresses glucagon secretion from pancreatic α cells, slows gastric emptying, reduces food intake and crosses the blood-brain barrier to increase satiety.14,15 To date, it has been widely believed that GIP and GLP-1 are important factors that contribute to both weight loss and improvement in glycemic control after bariatric surgery.16 Postprandial GIP secretion appears to decrease after RYGB, while postprandial GLP-1 levels appear to increase after RYGB, LAGB and LSG.9,17–19

Peptide YY (PYY) PYY is an anorectic gut hormone secreted postprandially from L cells in the distal ileum and colon. It is associated with delayed gastric and intestinal transit, the so-called “ileal break.” In addition, PYY promote satiety and inhibits food intake. PYY levels have been shown to increase after LAGB, LSG and RYGB.9

Oxyntomodulin Oxyntomodulin is co-secreted with GLP-1 from L cells in response to a meal. It inhibits gastric acid and pancreatic enzyme secretion, and delays gastric emptying.20 Additionally, it has been shown that oxyntomodulin can lead to decreased food intake, increased energy expenditure and a reduction in body weight. Oxytomodulin levels appear to increase after RYGB, although its role in inducing weight loss in other bariatric surgeries remains unclear.

2.3 Bile Acids

Bile acids, particularly secondary bile acids, have been shown to induce incretins secretion, which lead to increased insulin and decreased glucose levels.21 RYGB bypasses the foregut and accelerates the intestinal transit time. This results in an increase in BAs delivered to the distal gut and a higher ratio of secondary to primary bile acids. Increased BA concentrations have been shown to associate with higher GLP-1 and GIP levels21, which contribute to improvement in glycemic control. The role of bile acids in LAGB and LSG are less clear.

2.4 Gut Microbiota

It has been proposed that changes in intestinal flora may be associated with metabolic improvement after bariatric surgery. In obese subjects, the ratio of Firmicutes/Bacteroidaceae increase and bacterial diversity decreases. Following RYGB, this trend reverses.22 Increased prevalence of Bacteroidetes leads to increased conversion of primary to secondary bile acids via 7α-hydroxylase leading to greater GIP and GLP-1 release.23

Gastric Endoscopic Procedures

EBMTs may be divided into gastric and small-bowel interventions. Many of these were derived in part from surgical correlates and attempt to mimic their mechanisms. For gastric interventions, this is accomplished by stimulating gastric mechanical and chemical receptors, delaying gastric emptying and modulating levels of gastric orexigenic hormones.

3.1 Analogues of Vertical Banded Gastroplasty (VBG)

VBG, or stomach stapling, was developed in 1980 by Mason (Figure 1a). In this procedure, the upper stomach is stapled vertically to create a small pouch along the lesser curve. The bottom of the pouch is banded to create a one-centimeter outlet into the remaining stomach. VBG restricts the amount of food that can be consumed and delays gastric emptying. Weight loss is approximately 16±11% of baseline weight at 10 years.24 However, only 10% of patients are able to maintain this weight loss. Due to a high failure rate and incidence of long-term complications, VBG is no longer performed.

3.2 Analogues of Laparoscopic Adjustable Gastric Banding (LAGB)

LAGB is a restrictive bariatric procedure where an inflatable silicone band is placed around the upper part of the stomach with a subcutaneous port that allows adjustment (Figure 1d). It was introduced by Wilkinson in 1978, and was later placed laparoscopically for the first time by Belechew in 1993. LAGB leads to delayed bolus transit to the infra-band stomach, although it does not alter the overall gastric emptying time.30 Additionally, PYY levels increase post-LAGB, which likely contribute to satiety and early satiation. There are no changes in GLP-1 levels and thus minimal direct glycemic effects.9 Ghrelin levels increase after LAGB likely as a secondary effect of weight loss. Weight loss after LAGB is approximately 47.1±30.1 %EWL at 13 years. However, up to 84.8% of patients experienced complications31, and LAGB has recently decreased in popularity.

Transoral Endoscopic Restrictive Implant System was developed as an endoscopic corollary to LAGB.

3.2.1 Transoral Endoscopic Restrictive Implant System (TERIS)

TERIS (Barosense, Redwood City, CA) is an endoscopically implanted device introduced by Biertho and colleagues in 2009 (Figure 1e). It consists of a prosthetic diaphragm placed at the gastric cardia to create a small reservoir with a 10-mm orifice. Full thickness plications are used to anchor the device. A pilot study including 13 patients reported three adverse events: one gastric perforation and two cases of pneumoperitoneum. At three months, a median EWL was 22.2%.32 The device is no longer in clinical trials.

3.3 Analogues of Laparoscopic Gastric Plication (LGP)

LGP, or gastric imbrication, is a restrictive procedure first performed by Kirk in 1968 (Figure 2a). During this procedure, the stomach is folded over and stitched to itself resulting in 75% reduction in gastric size. To date, LGP remains experimental. After LGP, ghrelin levels decrease while GIP levels increase.33 This is likely due to infolding of the highly vascular fundus, which may result in decreased perfusion and ghrelin hyposecretion. Increased GIP levels may be due to accelerated gastric emptying and/or contact with less well-digested chime. In contrast to LSG, which is associated with an increase in postprandial GLP-1, no changes in GLP-1 have been observed after LGP. Previous studies have demonstrated approximately 55% EWL at 5 years. However, up to one third of patients experienced weight regain at 12 years.34

There have been three endoscopic procedures that may mimic the effects of LGP. These are RESTORe Suturing System, Overstitch for Endoscopic Sleeve Gastroplasty and Incisionless Operating Platform for Primary Obesity Surgery Endolumenal.

3.3.1 RESTORe Suturing System (TRIM Procedure) The RESTORe System (Bard/Davol, Warwick, RI) is an updated version of the EndoCinch device (Figure 2b). It is capable of deeper tissue acquisition and suture reloading invivo. During this procedure, in addition to an anterior to posterior plication in EVG, the greater curvature is also incorporated making this procedure the first endoscopic sleeve gastroplasty (ESG) to mimic LGP. A pilot study (TRIM trial) including 18 patients showed 27.7±21.9% EWL at 12 months. No significant adverse events were seen. Twelve-month endoscopy revealed partial or complete release of plications in 13 of 18 patients.35,36

3.3.2 OverStitch for Endoscopic Sleeve Gastroplasty (ESG) The Apollo OverStitch (Apollo Endosurgery, Austin, TX) is an endoscopic suturing device that applies full-thickness sutures in a variety of patterns (Figure 2c). The system attaches to a double-channel endoscope and utilizes a curved needle driver. In April 2012, Thompson and Hawes performed the first-in-man ESG procedures in India.37 This procedure was modified to include medial interrupted reinforcing sutures based on the work of Abu Dayyeh, which reported a series of 4 patients that underwent a version of ESG using two rows of interrupted stitches.38 Procedure development continued and the final study included 77 patients across international multi-centers. In this series, patients experienced 17.4±1.2% TWL at 1 year.37 Subsequently, others have reported similar results.39–41 A multicenter trial (PROMISE trial) has recently been completed. Twenty patients were included and lost 48.2% EWL at 12 months. No serious adverse events were reported.42 Similar to LGP, ESG appears to be associated with decreased ghrelin without significant changes in GLP-1 or PYY levels. ESG has also been shown to delay gastric emptying and increase satiation.43

3.3.3 Incisionless Operating Platform (IOP) for Primary Obesity Surgery Endolumenal (POSE) The IOP platform (USGI Medical, San Clemente, CA) has four working channels through which a a 4.9 mm endoscope is passed, and specialized instruments are inserted to create full-thickness plications (Figure 2d). In 2013, Espinos reported the use of this device to perform the Primary Obesity Surgery Endolumenal (POSE) procedure.44 In this procedure, 8–9 plications are placed in the gastric fundus (via retroflexion) until the fundic apex is brought down to the level of the GE junction. Subsequently, 3–4 plications are placed in the distal body. A pilot study including 45 patients showed no serious adverse events, and weight loss at 6 months was 49.4% EWL.44 A U.S. pivotal sham-controlled trial (ESSENTIAL trial) including 332 patients (221 POSE/111sham) showed that the study arm lost 4.95±7.04% EWL compared to 1.38+5.58 %EWL in the sham arm at 12 months.45

POSE has been shown to delay gastric emptying and increase ghrelin (in contrast to LGP) and PYY levels.46 Additionally, post-POSE gastric emptying time and the degree of postprandial PYY increase have been shown to be an independent predictor of weight loss after POSE.46

3.4 Other Gastric Procedures

3.4.1 Intragastric balloons (IGB) The IGB was first approved in the U.S. in 1985 with the Garren Edwards Gastric Bubble. However, it was associated with multiple adverse events including gastric mucosal damage and small bowel obstruction. A sham-controlled trial failed to demonstrate efficacy and the device was withdrawn from the market.47 In the following decades, several IGBs have demonstrated safety and efficacy, with broad adoption internationally. In the U.S., the FDA approved two IGBs in 2015—the Orbera and the Reshape Duo balloons, and more recently the Obalon balloon in September 2016.48 The Spatz Adjustable balloon (Spatz Medical, Great Neck, NY) is currently conducting its U.S. pivotal trial, while the Elipse procedureless balloon (Allurion, Natick, MA) is planning on launching its pivotal trial next year.

Orbera Intragastric Balloon The Orbera IGB (Apollo Endosurgery, Austin, TX), formerly BioEnterics Intragastric Balloon (BIB), was developed in the early 1990s. Made of silicone, the balloon is placed in the fundus and filled with 450–700 ml of saline (Figure 3a). The balloon is endoscopically implanted and removed at 6 months. Abu Dayyeh et al. demonstrated that patients who received Orbera experienced 47% delay in gastric emptying compared to baseline. Additionally, rapid baseline gastric emptying and degree of slowing in gastric emptying after therapy were associated with %TWL at 6 months on univariate and multivariate analyses.49

ReShape Duo Intragastric Balloon The ReShape IGB (Reshape, San Clemente, CA) contains 2 silicone balloons attached to each other by a flexible tube (Figure 3b). It is inserted and retrieved endoscopically at 6 months. The ReShape Duo is filled with 900 mL of saline solution (450 mL to each balloon). Each balloon has independent channels to prevent deflation of the other balloon if one leaks. A pilot study including 30 patients showed 31.8% EWL in the Reshape group compared to 18.3% in the control group.53 In a U.S. sham-controlled trial (REDUCE trial), including 326 patients, EWL was 25.1% in the Reshape arm compared to 11.3% in the sham arm.54

Obalon Intragastric Balloon The Obalon balloon (Obalon Therapeutics, Carlsbsd, CA) is a 250 ml gas-filled balloon that does not require endoscopic insertion, however, is removed endoscopically. For placement, the balloon is enclosed in a capsule that is attached to a slender tube. The capsule is swallowed under fluoroscopic visualization. Nitrogen-sulfur hexafluoride gas mixture is then used to inflate the balloon prior to removal of the tube. If the first balloon is tolerated, a second balloon can be swallowed at 4 weeks and a third balloon at 8 weeks. At 12 or 24 weeks, all balloons are removed endoscopically. A pilot study including 17 patients demonstrated that 98% of balloons were swallowed successfully. At 12 weeks, patients lost 36.2% EWL55. In a U.S. pivotal trial, including 387 subjects (n=185 in the Obalon capsule arm, n=181 in the sham capsule arm), TWL was 6.81±5.1% and 3.59±5.0% in the treatment and control groups. One case of gastric ulcer was seen48.

3.4.2 TransPyloric Shuttle The TransPyloric Shuttle (BAROnova Inc. Goleta, CA) consists of a spherical silicone bulb attached to a smaller silicone bulb by a flexible tether (Figure 3c). The device is delivered transorally via catheter and removed endoscopically. It remains in a transpyloric position with the smaller bulb entering the duodenum with peristalsis, and the larger bulb residing in the stomach intermittently occluding the pylorus. A pilot study including 20 patients reported 31.3±15.7% and 50.0±26.4% EWL at 3 and 6 months, respectively. The device was removed early in 2 patients due to persistent gastric ulceration.56 A U.S. pivotal study (ENDOBESITY II trial) is in progress.

3.4.3 Full Sense Device The Full Sense Device (Baker, Foote, Kemmeter, Walburn [BFKW] LLC, Grand Rapids, MI) is a temporary, reversible device that is deployed and removed endoscopically. It is a modified fully-covered stent with an esophageal component and a gastric disk component (Figure 3d). It is designed to induce satiety and fullness in the absence of food by applying pressure on the distal esophagus and gastric cardia. The device is currently being studied in Europe.

3.4.4 Aspiration Therapy The AspireAssist (Aspire Bariatrics, King of Prussia, PA) is a unique percutaneous gastrostomy tube (PEG) that allows removal of a portion of an ingested meal approximately 20–30 minutes after consumption. Tube placement is similar to that of a standard PEG. Two weeks after insertion, the external portion of the tube is shortened and attached to a skin port (Figure 3e). An external device is connected to the skin port to perform aspiration after meals. A pilot study including 18 patients showed a 49.0±7.7% EWL in the AspireAssist group compared to 14.9±12.2% EWL in the control group.57 In a U.S. pivotal study (PATHWAY trial), including 171 patients, %EWL in the AspireAssist arm was 31.5±26.7 compared to 9.8±15.5 in the control arm at 1 year. Serious adverse events were reported in 3.6% of patients in the treatment arm. No evidence of increased food intake or development of abnormal eating behaviors was found.58 In June 2016, the device was approved by the FDA for long-term implantation.

3.4.5 Botulinum Toxin injection Botulinum toxin A (BTX-A) is a selective acetylcholine inhibitor which blocks smooth and striated muscle contraction. Because vagus-mediated antral contractions are important for food propulsion into the duodenum, it has been hypothesized that antral BTX-A injection may lead to weight loss by delaying gastric emptying and inducing satiety. In 2006, Albani performed the first proof-of-concept work, which prompted subsequent studies with mixed results. In a meta-analysis including 8 studies, regression showed that wide area injections including the fundus or body rather than the antrum alone and multiple injections (>10) were associated with weight loss.59 However, BTX-A injection remains controversial and more studies are needed.

Small Bowel Endoscopic Procedures

The proximal small bowel plays an important role in glucose homeostasis. Also known as the incretin effect, oral glucose intake leads to amplification of insulin secretion compared to intravenous infusion. This effect is understood to be due to gut hormones as detailed above. In addition to their effect on glucose homeostasis, these gut hormones also affect satiety and gastrointestinal motility. Therefore, small bowel EBMTs may contribute to weight loss as well as diabetes improvement.

RYGB was developed by Mason and Ito in 1967 (Figure 4a). Since then, the procedure has undergone several technical modifications and has been a preferred bariatric procedure for the past several decades. During RYGB, the stomach is divided into a 20–30 mL pouch and a larger remnant stomach. The pouch is connected to the jejunal Roux limb, bypassing the gastric remnant, duodenum and proximal jejunum. RYGB patients experienced 27±12% TWL and had decreased mortality rate compared to control subjects at 15 years.24 In addition, RYGB patients had resolution of diabetes (A1c level of 6%) more commonly than those who received medical treatment (38% versus 5%, respectively).60 After RYGB, ghrelin level decreases, while GLP-1, PYY, oxyntomodulin and CCK levels increase.9,11

4.2 Analogue of Variant Biliopancreatic Diversion-Duodenal Switch (BPD-DS) Biliopancreatic diversion (BPD) was first described by Scopinaro in 1979. It consists of a horizontal gastrectomy, which leaves an upper stomach that is connected to the distal 250 cm small intestine. Bile and pancreatic enzymes travel down the excluded small intestine (including the duodenum, jejunum and proximal ileum) and mix with the nutrients in the common limb. BPD-DS is a variant of BPD where sleeve gastrectomy (SG) is performed instead of horizontal gastrectomy. The small intestine is divided at the duodenum and a duodeno-ileal anastomosis is performed (duodenal switch). These procedures are performed in small numbers in the U.S.

A variant of these procedures involving just the duodenal switch with no SG (DS-SG) has been described in clinical research studies in Laval, Canada (Figure 4e).66 Patients who underwent DS-SG alone were compared to those who received SG alone, and the combination. At 1 year, the DS-SG group experienced 39±13 %EWL compared to 47±19 %EWL in the SG group. However, SG patients had significant weight regain and experienced only 12±35 %EWL compared to 45±19 %EWL in the DS-SG group at 5 years. HbA1c decreased by 10% and 19% in the SG and DS-SG groups, respectively. This data suggests a more durable weight loss effect for distal small bowel anastomosis as well as better glycemic control. A surgical procedure that is structurally different but may be mechanistically similar to BPD is the ileal transposition. First described by De Paula in 1999, the procedure involves resecting a 10–20 cm portion of the distal ileum and then transposing it into the proximal jejunum. This results in early delivery of food chyme to the ileum, while the total length of the small bowel remains unaffected. Compared to a sham procedure, ileal transposition has been shown to lead to greater weight loss and reduced food intake in rats.67 Additionally, GLP-1 and PYY increased after ileal transposition.67,68

The Incisionless Anastomotic System (IAS) is used to create an enteral diversion that is functionally similar to the variant DS procedure and mechanistically similar to ileal transposition. 4.2.1 Incisionless Anastomotic System (IAS) IAS (GI Windows, Boston, MA) creates an anastomosis via incisionless magnetic compression. This technology has many applications including a bariatric dual-path enteral diversion procedure. During this procedure, enteroscopy and colonoscopy are performed simultaneously. The IAS self-assembling magnets are deployed from the working channel of each endoscope forming magnetic octagons in the jejunum and ileum. After a week, a compression anastomosis is completely formed and the coupled magnets spontaneously pass (Figure 4f). The first inhuman study including 10 patients showed 14.6% [0.3%–41.8%] TWL at 1 year. HbA1c decreased from 6.6±1.8% to 5.4±0.5%.69 Postprandial GLP-1 increased at 2 months, however, longer term results are needed to draw further conclusion.

4.3 Other Small Bowel Procedures

4.3.1 SatiSphere SatiSphere (Endosphere, Columbus, OH) consists of a nitinol memory wire with two pigtals at each end, and several polyethylenterephtalat spheres along the wire. It is implanted endoscopically into the duodenum and takes a C-shape configuration. In a randomized pilot study, including 31 patients, the study arm experienced 18.4% EWL compared to 4.4% in the control arm. Additionally, the device was associated with delayed glucose absorption, insulin secretion and altered GLP-1 kinetics.70 Device migration occurred in 10 of 21 study arm patients, with two necessitating emergent surgery. European study is currently ongoing

Conclusion

EBMTs have the potential to transform the treatment of obesity, which remains a growing pandemic. In this paper, primary EBMTs are reviewed as a more effective option than lifestyle modification and medical therapy, with lower invasiveness and greater accessibility than bariatric surgery. In addition to primary intervention, EBMTs also have various applications including preventive therapy, bridging therapy, cosmetic therapy, and revision of bariatric surgery. Understanding the mechanisms of actions of each EBMT, and studying their surgical correlates which have a longer track record, may provide us with information to better personalize therapy. Additionally, combining devices with different mechanisms of action, and using drug-device combinations, may enhance the effectiveness of these procedures. Furthermore, as obesity is a chronic disease, these less invasive and reversible options may allow sequential therapy to more optimally manage this condition in the long-term.

Footnotes

Pichamol Jirapinyo MD

No Conflict of Interest

Christopher C. Thompson, MD, MHES, FACG, FASGE

Conflict of Interest Disclosures

Boston Scientific – Consultant (Consulting fees)

Covidien– Consultant (Consulting Fees)/Endoluminal Advisory Board Member

USGI Medical – Consultant (Consulting Fees)/Advisory Board Member (Consulting fees)/Research Support (Research Grant)

Valentx – Consultant (Consulting Fees)

Olympus – Lab Support (Lab supplies/equipment), Consultant

Apollo Endosurgery – Consultant/Research Support (Consulting fees/Research Grants)

GI Windows – Ownership interest

Aspire Bariatrics – Research Grant

Fractyl – Consultant/Advisory Board Member

GI Dynamics – Expert reviewer

Spatz – Research Grant

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