Recent advances in therapies utilizing superabsorbent hydrogel technology for weight management: A review

Abstract Long‐term therapeutic benefit of treatments for weight management in patients with overweight (also termed preobesity) or obesity may be limited by variable safety, tolerability, and efficacy profiles, and patient adherence to treatment regimens. There is a medical need for nonsystemic treatments that promote weight loss in patients with overweight or early obesity. This report reviews four different approaches of utilizing superabsorbent hydrogel technology for weight management at varying stages of preclinical and clinical development. The first is a nonsystemic, oral superabsorbent hydrogel created from naturally derived building blocks used in foods (cellulose‐based), designed to mix homogenously with and change the properties of the ingested meal throughout the gastrointestinal tract (stomach and small intestine). This is the first‐in‐class to be cleared by the Food and Drug Administration (FDA) to aid in weight‐management for adults with BMI of 25–40 kg/m2 in conjunction with diet and exercise. In contrast, the other three approaches in development utilize superabsorbent hydrogel technologies to support an intragastric balloon‐like structure, solely occupying space in the stomach and displacing the meal: (1) a pufferfish‐inspired device; (2) Epitomee, a pH‐sensitive self‐expanding hydrogel device; and (3) a light‐degradable hydrogel used to control balloon deflation. These new approaches that utilize superabsorbent hydrogel technology offer a wide range of clinical applicability and have the potential to broaden the weight management treatment landscape. Over time, increasing the number of patients treated with superabsorbent hydrogel technologies will provide important information on long‐term efficacy and safety.

weight, 4 others will have comorbidities including prediabetes and diabetes or will be in the process of gaining weight over their adult years on their way to obesity. 5 Close to 39% of deaths and 36% of disability-adjusted life years related to higher BMI occur in people with overweight, not obesity. 6 While results from some studies have shown no association between abnormal weight gain or overweight status and greater morbidity and mortality, 7 data from the Framingham study demonstrated that nonsmoking women who are aged 40 years with overweight lose 3.3 years of life, and nonsmoking men who are aged 40 years with overweight lose 3.1 years of life compared with age-matched individuals who are at normal weight. 8 Obesity-related diseases/comorbidities are associated with loss of between 0.2 and 11.7 years of life, depending on an individual's sex, race, BMI classification, age, and heightened risk of mortality. 9 In some people with overweight, continued progressive weight gain may lead to further health risks and eventually obesity; this holds true for older populations with obesity-related diseases, where a loss of lean body mass or muscle mass can be outpaced by a gain in fat mass. 5,10,11 In the elderly population, a BMI in the overweight range may falsely indicate lower risk.
The long-term therapeutic benefit of current treatment options (behavioral, nutrition, and lifestyle approaches; pharmacotherapy in conjunction with comprehensive lifestyle management; procedural medical devices, [e.g., intragastric balloon such as the TransPyloric Shuttle]; noninvasive endoscopic procedures; and bariatric surgeries [e.g., Roux-en-Y gastric bypass]) is limited by variable efficacy, safety, and tolerability profiles and patient adherence. [12][13][14][15][16][17] Long-term weight loss maintenance is difficult to achieve and maintain with lifestyle modification alone. 18,19 There are multiple barriers to effective long-term weight management care, 20 including patients' lack of access to healthcare for weight management, 21,22 clinical inertia that prevents providers from offering care, 23-25 the costs of treatment, patients' inability to comply with a weight management plan, and the problem of long-term efficacy of current weight-loss treatment options. [26][27][28] The worldwide surge in obesity prevalence dictates the need to increase the availability of therapeutic strategies that alter the course of the disease. [29][30][31] Interestingly, the prevalence of overweight is actually declining as obesity develops in more people at a greater rate. 27 There is a medical need for therapies that result in clinically meaningful weight loss with favorable safety profile, that will allow patients to be treated earlier while they are at a lower BMI with the hope of preventing or delaying the onset of complications related to overweight and obesity.
Interest is developing around the utilization of superabsorbent hydrogel technologies as a nonsystemic, biodegradable approach for weight management, with the idea that achievable weight loss and maintenance in individuals in the overweight range can prevent development of greater levels of obesity and attendant comorbidities. [32][33][34] The following is a review of the emerging science and description of several approaches utilizing superabsorbent hydrogel technologies at varying stages of preclinical and clinical development.

| THERAPIES UTILIZING SUPERABSORBENT HYDROGEL TECHNOLOGY FOR WEIGHT MANAGEMENT
A superabsorbent hydrogel is a cross-linked polyelectrolyte polymer that is capable of absorbing and retaining large quantities of fluid/ water (up to more than 1 L/g of dry material without losing its threedimensional [3-D] structure under moderate compression). 35 Superabsorbent hydrogels appear as a fine white powder-like sand or tiny granule-like sugar in a dry state and transform into 3-D structures filled with water once fully hydrated. Hydrogels can be classified based on their natural or synthetic origins, type of cross-linking (chemical or physical), physical appearance (sphere, matrix, or film), and electrical charge (nonionic, ionic, etc.). 36 According to the required application, hydrogels can be tailored to absorb more or less water, to be more or less rigid/firm, and to be responsive to external stimuli such as the ambient temperature, pH, light, ionic strength, or electric field. 36 Because of their tissue-like softness and heightened biocompatibility, hydrogels are widely utilized in biomedical applications, including enhanced drug delivery systems, tissue engineering, and wound healing, in addition to weight loss therapies. 34,37,38

| FDA-CLEARED ORAL SUPERABSORBENT HYDROGEL FOR WEIGHT MANAGEMENT
Plenity ® (Gelesis, Inc.) is a novel, orally administered, nonsystemic, superabsorbent hydrogel, and the first in its class to be cleared by the Food and Drug Administration (FDA) to aid in weight management for adults with a BMI of 25-40 kg/m 2 in conjunction with diet and exercise. [39][40][41] Each capsule contains thousands of dry, oral superabsorbent hydrogel (OSH) particles, and each particle is approximately the size of a grain of salt (100-1000 μm). The OSH particles are made up of carboxymethylcellulose (a derivative of cellulose, the main substance in plant cell walls) cross-linked with citric acid, both of which are food grade and generally recognized as safe ( Figure 1A).
To our knowledge, OSH is the first and only superabsorbent hydrogel therapy produced using solely nonsynthetic, naturally derived building blocks. Additionally, OSH is a hydrogel that reacts to its environment.
OSH is intended to be taken as three capsules (0.75 g each) with 500 ml of water, 20-30 min before lunch and dinner. 39 In the stomach, the capsules disintegrate and release thousands of OSH particles ( Figure 2A). Each particle responds to changes in gastrointestinal pH and ionic milieu and quickly expands by absorbing water.
Individual, fully hydrated beads (each approximately 2 mm in diameter) do not cluster or form a large mass but rather mix homogenously with food to change the texture, rheologic behavior, and sensory characteristics of the meal. 42  viscosity, and firmness of the content) through the small intestine. 39 The stomach and gastrointestinal tract are highly regulated organs with complex neural and hormonal control mechanisms. 43 The external muscle layers of the gastrointestinal tract are sensitive to stretch (sensing an increase in volume) and tension (sensing an increase in firmness) and this mechanical effect may result in activation of the vagus nerve which in term could trigger signals of satiety and satiation. 44,45 The OSH particle remnants are not digested, metabolized, or absorbed during intestinal transit, have no nutritional value, and are naturally degraded and eliminated from the body in the feces. 39 OSH is considered an encapsulated medical device and is regulated by the FDA as such because its primary function is achieved through mechanical modes of action and its effects are nonsystemic in nature. 34,46 Once fully hydrated, OSH exhibits rheologic behavior that is markedly different from dietary fiber supplements; OSH forms a solid, while dietary fibers (e.g., glucomannan, guar gum, and psyllium) are viscous liquids ( Figure 1B). 42 While water adheres to the surface of dietary fibers, which have a linear, non-cross-linked structure, the cross-linked polymers that make up OSH trap water in a 3-D sphere of more rigid, elastic solid beads. OSH (solid, form filled with water) more closely resembles natural fiber-rich vegetables (e.g., cucumber and mixed green salad) than dietary fiber ( Figure 1C).
While dietary fibers may increase the viscosity/thickness of the meal, OSH, like natural fiber-rich vegetables, exhibits combined properties of increased viscosity, and firmness/elasticity and therefore changes the mechanical properties of the meal.
The higher the degree of cross-linking, the lower the swelling capacity (i.e., fluid absorption capacity) and the higher the elasticity (i.e., ability of a material to maintain its normal shape after being compressed) of the hydrogel. Results from a study of gastrointestinal digestion using an in vitro model demonstrated that the viscoelastic properties of OSH were comparable to those of masticated cucumber and mixed green salad (i.e., natural fiber-rich vegetables) and were orders of magnitude higher to common processed dietary fiber supplements (e.g., glucomannan, guar gum, and psyllium) ( Figure 1D). 42 These data provide further insight into the mechanisms underlying the weight-loss outcomes in patients treated with OSH technology (detailed below).
As reported by Greenway et al., 34  About 6 of 10 patients (59%) taking OSH achieved significant and clinically meaningful weight loss (5% or more), and 27% of patients lost 10% or more of their total body weight (∼30 pounds).
Comparatively, 42% and 15% of patients on placebo had ≥5% and ≥10% weight loss, respectively. In a post hoc analysis, early weight loss predicted long-term effectiveness of OSH (i.e., 3% or more weight loss at 8 weeks was predictive of weight loss of 5% or more after 6 months). No weight loss plateau was observed during the 6-month GLOW study, and weight loss was sustained during the 24-week follow-up period. 34 The overall incidence of adverse events (AEs) was no different than placebo. The most common treatment-related AEs reported in patients taking OSH were gastrointestinal related (i.e., diarrhea, abdominal distension, infrequent bowel movements, and flatulence). OSH does not affect the absorption of vitamins and minerals after 24 weeks of administration, 34 and the effect of OSH on metformin absorption is the same as that of a typical meal. 47

| Encapsulated gastric space-filling devices utilizing superabsorbent hydrogel technologies in development
Based on the defense mechanism of pufferfish that quickly inhale large amounts of water to inflate, Liu et al. 33  demonstrating that ED treatment combined with lifestyle modification led to 3.7%-4.5% total body weight loss after 3 months. In addition to reductions in BMI and waist circumference, 31% of the total population and 42% of study completers achieved 5% or more total body weight loss after 3 months of treatment with ED. In this study, patients swallowed one ED capsule with two cups of water twice per day approximately 30 min prior to lunch or dinner and were instructed to follow a hypocaloric diet. ED was highly tolerable with a favorable safety profile. The most commonly reported AEs were headache, viral infection, abdominal discomfort, bloating, nausea, constipation, and flatulence. 32 Results from an endoscopic examination revealed mild, asymptomatic gastric/duodenal erythema without erosions or need for medical intervention in five of 26 patients (19%). 32 A prospective, randomized, double-blind, placebo-controlled, multicenter, pivotal, adaptive study of the effect of ED on body weight  The rheologic properties and mechanosensory effects of OSH differs from gastric space filling devices. OSH elasticity is similar to vegetables (2 kPa); instead of forming one large sphere, the individual OSH beads mix homogeneously with the meal (Figure 2A) in clinically meaningful weight loss, and given its favorable safety and tolerability profile, there appears to be limited increased risk associated with the use of OSH to support weight management.

PUFFERFISH-INSPIRED HYDROGEL DEVICE
Therefore, OSH opens the possibility to treat patients earlier while at a lower BMI.