Untethered shape-changing devices in the gastrointestinal tract

Abstract

Introduction:

Advances in microfabrication, automation, and computer engineering seek to revolutionize small-scale devices and machines. Emerging trends in medicine point to smart devices that emulate the motility, biosensing abilities, and intelligence of cells and pathogens that inhabit the human body. Two important characteristics of smart medical devices are the capability to be deployed in small conduits, which necessitates being untethered, and the capacity to perform mechanized functions, which requires autonomous shape-changing.

Areas covered:

We motivate the need for untethered shape-changing devices in the gastrointestinal tract for drug delivery, diagnosis, and targeted treatment. We survey existing structures and devices designed and utilized across length scales from the macro to the sub-millimeter. These devices range from triggerable pre-stressed thin film microgrippers and spring-loaded devices to shape-memory and differentially swelling structures.

Expert opinion:

Recent studies demonstrate that when fully enabled, tether-free and shape-changing devices, especially at sub-mm scales, could significantly advance the diagnosis and treatment of GI diseases ranging from cancer and inflammatory bowel disease (IBD) to irritable bowel syndrome (IBS) by improving treatment efficacy, reducing costs, and increasing medication compliance. We discuss the challenges and possibilities associated with ensuring safe, reliable, and autonomous operation of these smart devices.

1. Introduction

From the Lichtleiter to fiber-optic enabled endoscopes, tethered probes have revolutionized medicine, allowing surgical interventions to be performed through natural orifices in the gastrointestinal (GI) tract with minimal invasion [1-4] (Figure 1). Advances in miniaturization and automation have enabled the development of capsule endoscopes, analogous to untethered versions of the Lichtleiter. Capsule endoscopy is already being used in the clinic and has also been integrated with deep learning and artificial intelligence for therapeutic and diagnostic research applications [5-7]. Simultaneously, GI-based drug delivery has evolved from simple pills and tablets to increasingly complex formulations incorporating nanoparticles, microfabricated devices, and living organisms for enhanced therapeutic outcomes [8,9].

Figure 1. Motivation and trends for untethered shape-changing gastrointestinal (GI) devices.

A. Photograph of the Lichtleiter, or "light conductor," invented in 1806 by Philipp Bozzini, one of the first tethered endoscopic devices used to inspect internal cavities of the human body. Reprinted from [3] under CC BY-NC-ND 4.0. B. Image of a present-day tethered multi-functional endoscope with two flexible instrumentation arms. Adapted from [4] with permission under CC BY 4.0. Copyright © 2017, Elsevier. C. Images of untethered parasites Hookworm (duodenale) and thorny-headed worm (Phylum Acanthocephala) that live in human and fish GI tract. Images adapted from Human Parasitology, 4th Ed. and Fishdisease.net with permissions. D. Images of untethered modern-day endoscopic capsules for imaging of the GI tract. Image adapted from [7] with permission. Copyright © 2021, Elsevier.

Recent trends suggest a convergence of drug delivery systems and surgical or diagnostic devices with functionalities like motility, imaging, and sensing. Inspired by living cells and parasites, researchers have integrated shape-changing mechanisms into untethered systems to develop multifunctional devices capable of flexible locomotion, biosensing, and complex shape transformations like anchoring, gripping, suturing, and injecting, as shown in Figure 2 [10]. In this opinion, we survey opportunities and challenges in designing and implementing untethered shape-changing devices for drug delivery, diagnosis, and treatment in the GI tract.

Figure 2. Untethered shape-changing devices perform various tasks in the GI tract.

Schematic illustrating a few examples of shape-changing devices performing medical tasks in different regions of the GI tract, including the esophagus, stomach, intestine, and colon. These devices possess various functionalities, such as drug delivery, biopsy/sampling, surgical intervention, imaging, and sensing. Figure created with BioRender.com with publication license.

1.1. GI tract diseases and GI drug delivery

The GI tract participates in food digestion, nutrient absorption, waste product excretion, and immune system training to protect against pathogens that enter through the oral route [11]. GI diseases are associated with significant morbidity and mortality as well as high costs of healthcare. In the United States, GI diseases and cancers caused 255,407 deaths and resulted in healthcare expenditures totaling $119.6 billion in the year 2018 [12]. Common GI conditions include cancer, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), gastroesophageal bleeding, GI strictures, and others. The GI tract is a critical drug conduit for treating a variety of GI diseases as well as systemic conditions. Patients generally accept orally administered medications more than injectables or intravenous forms [13], thus leading to higher compliance and medication adherence.

Additionally, the enteral route is noninvasive and of lower cost, obviating the need for trained medical professionals or access to expensive medical facilities for drug administration. The enteral route is associated with fewer potential health complications, such as infections and sepsis. However, orally administered drugs are typically absorbed slowly, which is undesirable during emergencies that require rapid intervention. Moreover, the bioavailability of oral drugs, especially macromolecules and biologics, is limited by the first-pass effect in the intestine and liver and certain physiological conditions of the GI tract, such as acidic pH levels and a tight epithelial barrier. Yet, frequent dosing often leads to non-compliance and failure of chronic drug treatments. Researchers have been developing new drug formulations to overcome these limitations using methods such as chemical modification and drug carriers. More recently, dynamic drug delivery devices have emerged as novel solutions to tackle these limitations via strategies like prolonged GI retention, injection-based active delivery, and site-specific targeting [8,14].

1.2. Tethered shape-changing devices in the GI clinic

In clinical settings, shape-changing devices have played a crucial role in diagnosing, biopsying, and surgically treating GI disorders. Endoscopes are flexible tethered video-imaging probes that are advanced through the mouth or the anus for visual inspection of abnormal-appearing lesions or mucosa [15]. If such abnormalities are observed, endoscopic biopsy tools are deployed to obtain tissue samples for in-depth histological diagnoses, and endoscopic surgical tools are utilized to remove lesions. Advances in shape-changing endoscopes have enabled less invasive alternatives to surgery, such as endoscopic mucosal resection, endoscopic submucosal dissection, and resection of large polyps or cancers. Moreover, endoscopes equipped with needle catheters can be used to mark lesions, deliver drugs locally (e.g., injecting epinephrine for bleeding treatment), and place sensors for in situ monitoring (e.g., esophageal pH monitoring for GERD) [15].

These endoscopic tools are considered tethered shape-changing devices as they are introduced through natural orifices, operated via wires, and undergo shape-changing to execute specific tasks. For example, biopsy forceps have hinged jaws at their distal end that can be opened and closed by a sliding lever at the proximal end to collect tissue samples. The snare, which features a loop made of a thin metallic cable, can be used for resecting lesions, such as polyps, or for grabbing and removing foreign objects. Endoscopic clips are hinged devices passed through catheters to clip bleeding vessels or incisions in the GI tract. After actuation and closure, these clips can be detached from the cable and left in situ. Lastly, balloon dilations and stents increase in diameter upon actuation in the GI tract to treat strictures and obstructions. Such devices are tethered to external equipment through openings, thereby limiting their use.

1.3. Limitations of present-day GI devices

Endoscopic shape-changing, tethered devices have advanced minimally invasive, interventional gastroenterology. There are, however, several facets that could benefit from further development [15]. Firstly, the endoscopic shape-changing devices used in clinical practice are deployed during endoscopy, which is associated with potential health complications and high costs. An ingestible, untethered tool that can autonomously operate in the GI tract will eliminate the need for a specialized endoscopy suite, personnel, or potential anesthesia-related complications.

Secondly, existing endoscopic shape-changing devices are relatively large, which limits their precise targeting and operation, thereby increasing the likelihood of complications such as GI perforation. The large size of existing tools also limits their accessibility to small spaces in the GI tract. For example, the biliary tree is progressively smaller in diameter from the major papilla towards the liver. The small diameter of biliary ducts limits the size of endoscopic devices, resulting in the low resolution of the cholangioscope cameras. The poor imaging quality poses significant diagnostic challenges, such as differentiating between fibrotic strictures and cancer. Additionally, the lack of visual guidance and small tools restricts targeted biopsies in biliary ducts. In contrast, a smaller, untethered tool could enhance targeting precision up to cellular resolution and open access to undersized locations while reducing the likelihood of complications.

Lastly, tethered, catheter-based instruments face limitations as they are guided through an endoscope, restricting access to certain areas of the GI tract. At upper endoscopy, a standard esophagogastroduodenoscopy (EGD) can be advanced to the duodenum or, at the most, early jejunum. Longer endoscopes can be advanced through the mouth and farther than standard EGD scopes but are also limited in reach. Similarly, colonoscopes can be advanced to the ileum in a retrograde direction. Various innovations, such as an external balloon that can be anchored on the inside of the bowel, have been implemented to allow the passage of endoscopes far into the small bowel. Still, no methodology exists for routine and relatively simple exploration of the entire GI tract with clinical endoscopes. A significant portion of the GI tract cannot be examined directly with an endoscope, nor have interventions deployed. The need for direct visualization of the entire small bowel led to the development of capsule endoscopy. This video capsule is swallowed and travels through the small bowel due to motility. However, this method is restricted to capturing images and cannot perform interventions within the GI tract.

In this review, we explore recent breakthroughs in untethered shape-changing GI devices designed to overcome the limitations of existing GI devices. We examine untethered shape-changing devices according to their size scale—an important design parameter for achieving optimal performance across diverse GI compartments characterized by distinct sizes and conditions. We then discuss the engineering design principles that enable these untethered shape-changing devices to perform unique GI tract tasks effectively. Following the discussion on shape-changing mechanisms, we provide a comprehensive summary of the recent progress made in untethered shape-changing devices, highlighting their applications in GI drug delivery, therapeutic interventions, and diagnoses. Our aim is for this review to serve as both an accessible introduction to untethered shape-changing devices for a general audience and as a practical toolbox for researchers immersed in related fields. To achieve this, we classified reviewed devices in Table 1, presenting their key information, including action sites, design principles, fabrication methods, and associated health conditions.

Table 1.

Summary of untethered shape-changing devices in the gastrointestinal tract.

Applications	GI organ	Actuation mechanism	Fabrication methodology	Diseases and health conditions	References
Extended drug release	Stomach	Bulk deformation (diffusion)	Tableting	Neuropathic pain	98-100
				Type II diabetes	101, 102
			Molding, manual assembly	Chronic diseases (e.g., malaria, type II diabetes)	103-106
		Unfolding (mechanical)	Molding, manual assembly	Parasitic worms, malaria	108
				HIV prevention	109
				Alzheimer's disease	110
				Birth control	111
			FDM 3D printing, manual assembly	Antibiotic, birth control	113
			Film casting, automated folding, encapsulation	Parkinson's disease	114, 115
		Unfolding (shape memory alloy)	Molding, manual assembly	Epilepsy, bipolar disorder, bacterial infections	84
		Folding (thermal)	Photopatterning	IBD, GI cancer	116
		Folding (shape memory alloy)	Molding, manual assembly	Tuberculosis	17
				Hepatitis C	18
		Unfolding (shape memory polymer)	Hot melt extrusion, FDM 3D printing	Gout, kidney stones, gastric and duodenal ulcers, esophagitis, Helicobacter Pylori, chronic diseases (e.g., HIV, diabetes)	89, 117
	Colon	Folding (mechanical)	Photopatterning, PVD, electroplating, coating	Pain, ulcerative colitis	40
Biologics delivery	Stomach	Uniaxial piercing (mechanical)	SLA 3D printing, manual assembly	Diabetes	28
				Transthyretin-mediated amyloidosis, homozygous familial hypercholesterolemia, cancer, Zika virus, COVID-19	128
				Diabetes, Crohn's disease, arthritis, plaque psoriasis	26
			Molding, SLA 3D printing, manual assembly	Type II diabetes	36
	Small intestine	Uniaxial piercing (chemical)	Factory manufactured (not specified)	Diabetes	129
				Acromegaly, cancer-related diarrhea	59
		Unfolding (mechanical)	Molding, PolyJet 3D printing, manual assembly	Diabetes	30
		Unfolding (mechanical)	Molding, manual assembly		39, 130
	Colon	Folding (mechanical)	Photopatterning, PVD, electroplating, coating		41
	Buccal cavity	Unfolding (mechanical)	DLP 3D Printing	Central diabetes insipidus, type II diabetes	131
Targeted delivery	Esophagus	Unfolding (mechanical)	Solvent casting, manual assembly	Esophageal diseases (e.g., eosinophilic esophagitis)	138
			Laser cutting, molding, manual assembly	IBD, eosinophilic oesophagitis	139
		Unfolding (shape memory alloy)	Molding, PolyJet 3D printing, manual assembly	Epilepsy, bipolar disorder, bacterial infections	84
	Stomach	Unfolding (magnetic)	Molding, manual assembly	Chronic diseases	154
		Unfolding (mechanical), locomotion (magnetic)	Casting, manual assembly	Button battery-induced stomach inflammation, wounds, ulcers	31
	Intestine	Unfolding (shape memory polymer)	DLP 3D printing, casting, direct laser writing, manual assembly	IBD	143
		Unfolding (mechanical)	Photopatterning, manual assembly	Asthma, chronic bronchitis, emphysema, etc.	144
		Unfolding (mechanical)	Factory manufactured (not specified)	Intestinal diseases (e.g., IBD, ulcers), systemic diseases (e.g., angina, psychotic disorders, stroke prevention)	140, 145, 149-151
		Unfolding (chemical)	Photopatterning, manual assembly	Regional GI diseases	146, 147
			Manual assembly	Hypertension, angina pectoris, arrhythmias, anxiety	148
		Unfolding (magnetic)	CNC machining, manual assembly	Lower GI tract diseases	79
		Uniaxial piercing (magnetic)	Molding, 3D printing, manual assembly	GI diseases (e.g., tumors)	153
		Uniaxial piercing (magnetic)	Molding, FDM 3D printing, manual assembly	GI diseases (e.g., angiodysplasia)	152
		Unfolding (mechanical)	Laser cutting, manual assembly	Large intestine diseases (e.g., Crohn's disease, IBD, C. difficile infection, colon cancer)	155
	Overall GI tract	Folding/ unfolding, locomotion (magnetic)	Molding, manual assembly	GI diseases (IBD or cancers) and systemic diseases	34, 76
			Electrospinning, molding, manual assembly		157
Surgical intervention	Stomach, small intestine	Folding/ unfolding (mechanical), locomotion (magnetic)	Laser cutting, molding, manual assembly	Cancer, bleeding in GI tract	162
	Intestine	Bulk deformation (diffusion), locomotion (magnetic)	Manual assembly	GI hemorrhage	163
	Colon	Shape memory alloy, locomotion (magnetic)	Manual assembly	GI lesions	164
	Stomach	Unfolding (thermal), locomotion (magnetic)	Manual assembly	Button battery-induced stomach inflammation, wounds, ulcers	31, 158
		Folding/ unfolding (mechanical), locomotion (magnetic)	Molding, manual assembly	Stomach ulcers	165
GI stenting	Esophagus, gastroduodenal region, colon	Unfolding (shape memory alloy)	Factory manufactured (not specified)	Esophageal, gastroduodenal, malignant colon obstruction	167, 171, 172
	Esophagus	Unfolding (mechanical)	Factory manufactured (not specified)	Malignant or benign esophageal strictures	167
		Bulk deformation (diffusion)	Molding, manual assembly	Benign and malignant stenoses, strictures	106
Obesity control	Stomach	Bulk deformation (diffusion)	Factory manufactured (not specified)	Obesity	178-182
			Hydrogel formulation, molding		106, 187, 188, 190
Electrical stimulation	Esophagus	Unfolding (shape memory)	Manual assembly, casting, electron-beam evaporation, laser cutting	Gastroesophageal reflux disease (GERD)	194
	Stomach	Uniaxial piercing (mechanical)	Manual assembly, SLA 3D printing, injection molding	Gastroparesis	195
Imaging	Small intestine	Folding/unfolding (magnetic)	Electrical discharge machining, 3D printing	GI diseases	199
			Laser cutting, manual assembly	GI diseases (e.g., bleeding, celiac disease, and Crohn's disease)	80
			CNC machining, 3D printing	Lower GI tract diseases	79, 201
	Stomach	Folding/unfolding (magnetic)	Microwire electrical discharge machining, molding, 3D printing	GI diseases requiring intestinal endoscopy	198
Sensing	Stomach	Bulk deformation (diffusion)	Casting, laser cutting, manual assembly	Obesity, GI tract diseases	105
		Folding/unfolding (mechanical)	FDM 3D printing	Infections, birth control	113
		Folding (shape memory alloy)	Casting, molding, manual assembly	Hepatitis C	18
		Folding/unfolding (shape memory alloy)	Nitinol programming in furnace, water jetting, CNC machining, manual assembly	GI dysmotility-related diseases (e.g., gastroesophageal reflux disease, chronic constipation)	19
		Bulk deformation (chemical)	Manual assembly	Obesity	204
	Small intestine	Folding/unfolding (magnetic)	Casting, molding, laser cutting, manual assembly	Peptic ulcers	208
		Uniaxial piercing (mechanical)	3D printing, manual assembly	Chronic diseases	205
Biopsy	Small intestine	Folding/unfolding (magnetic)	Laser cutting, manual assembly	GI diseases (e.g., bleeding, celiac disease, Crohn's disease)	80
			CNC machining, 3D printing	Lower GI tract diseases	201
	Stomach	Folding/unfolding (mechanical), locomotion (magnetic)	Photopatterning, 3D printing, molding	Diseases diagnosed using stomach tissue biopsy	47, 48
		Uniaxial piercing (magnetic), locomotion (magnetic)	3D printing, molding	Submucosal tumors, Crohn's disease	58
		Uniaxial piercing (magnetic)	3D printing	GI tract diseases	212
	Bile duct	Folding/unfolding (mechanical)	Photopatterning, thermal evaporation	Diseases diagnosed using biopsies (e.g., cancer)	44
	Intestine	Folding/unfolding (shape memory alloy, mechanical)	Milling, circuit board fabrication, manual assembly	Intestinal polyp	52
Microbiome sampling	Intestine	Folding/unfolding (diffusion)	Photopatterning, electrodeposition	Sampling in the GI tract (non-specific)	213
		Bulk deformation (diffusion)	Photopatterning	Luminal and mucus-binding microbiota-related GI diseases (IBD)	210
			SLA 3D printing, molding	Microbiota imbalance-related diseases (e.g., obesity, diabetes, neurological diseases, metabolic syndrome)	25
			SLA 3D printing, casting, molding	Metabolic diseases (e.g., obesity, IBD, colorectal cancer)	209

2. Untethered shape-changing GI devices across size scales

The network of hollow organs comprising the GI tract, including the esophagus, stomach, small intestine, large intestine, and rectum, vary in size and anatomical and physiological properties [16]. As such, shape-changing devices of appropriate size must be designed to meet the specific criteria for safe ingestion and delivery throughout the GI tract. Here, we categorize untethered shape-changing devices developed in recent years according to their size scale, ranging from tens of centimeters (large) to micrometers (small) (Figure 3).

Figure 3. Untethered shape-changing devices across size scales from small (sub-millimeter) to large (>10 centimeters).

Schematic showing examples of devices across increasing size scales (left to right) along with relevant GI organs. The diameter (for adult human) is approximately 1.3-2 cm for the esophagus, 2 cm for the small intestine, 4.8 cm for the large intestine [215], and 25 cm for the stomach. Devices include (from left to right) single-cell grippers with an unfolded tip-to-tip diameter of 50 μm (adapted from [45] with permissions under hCC BY 4.0. Copyright © 2022, ACS); environmentally adaptive shape-morphing microrobots (SMMRs) in the shape of a microfish with a length of approximately 100 μm (adapted from [50] with permissions under CC BY 4.0. Copyright © 2021, ACS); theragrippers with an unfolded tip-to-tip diameter of 250 μm; microgrippers with an unfolded tip-to-tip diameter of 700 μm (adapted from [43] with permissions under CC BY 4.0. Copyright © 2009, National Academy of Sciences of the USA); ionic shape-morphing microrobotic end-effector (ISME) with an unfolded tip-to-tip length of 2.4 mm (adapted from [38] with permission under CC BY 4.0. Copyright © 2021, Springer Nature); magneto-responsive microneedle robots with a diameter of 3 mm (adapted from [35] with permissions under CC BY 4.0. Copyright © 2021, Wiley); self-orienting millimeter-scale applicator (SOMA) with a millipost length of 7 mm post (adapted from [28] with permission under CC BY 4.0. Copyright © 2019, AAAS); luminal unfolding microneedle injector (LUMI) with an unfolded tip-to-tip diameter of 2.5 cm; tough triggerable hydrogel with a length of 5 cm (adapted from [103] with permissions under CC BY 4.0. Copyright © 2017, Springer Nature); Elipse^® intragastric balloon with an inflated diameter of approximately 10 cm (adapted from [182] with permission under CC BY 4.0. Copyright © 2017, Springer Nature); shape-memory alloy with a coiled diameter of approximately 10.4 cm (adapted from [17] with permission under CC BY 4.0. Copyright © 2017, AAAS). Figure created with BioRender.com with publication license.

2.1. Macro untethered shape-changing GI devices

Macro devices with sizes greater than 10 cm can be used in larger GI organs, such as the stomach, whose width is 25 cm and distended volume ranges from 2 to 4 L in adult humans [16]. The entrance and exit to the stomach are much smaller in size. The typical diameter of the esophagus at the entrance is 2 cm, while that of the pylorus at the exit is 1.3 to 2 cm [16]. By leveraging these differences in size, macro untethered shape-changing devices can be engineered to enhance gastric residency for applications like weight management and long-term drug release [8].

Shape-memory alloys (SMAs) can transform into a preconfigured shape when subjected to a stimulus like temperature change and have been widely adopted for conventional biomedical devices. Verma et al. have reported untethered shape-changing devices for extended gastric drug delivery using superelastic nitinol wire strung with drug pills [17,18]. The SMA-based device exhibited a shape-changing from a straight wire with a diameter of 4 mm, permitting nasogastric administration, to a coil with a much larger diameter of 10.4 cm in the stomach, preventing its passage through the pylorus [17]. Such a shape-memory device was used to release drugs in the stomach over one month in vivo and was magnetically retrieved with a secondary device through the nasogastric route [17]. A modified version of the device included ethanol, temperature, and Bluetooth^® sensors for wireless communication of patient information [18]. Nickel-titanium (NiTi or nitinol) wire was also integrated with pressure sensors to increase their contact with gastric walls for improved assessment of the spatial-temporal pressure distribution [19].

Intragastric balloons (IGB), another category of macroscale untethered shape-changing devices, have been used for weight loss, GI hemorrhage treatment, and biosensing. The first iteration of IGBs required multiple endoscopies to insert the device, fill the balloon with fluid, and remove the device [20]. More recently, swallowable intragastric balloons have been introduced. The Elipse^® gastric balloon, approved for use in Europe, is swallowed as a capsule and filled with a pre-attached catheter to reach a liquid volume of 550 mL. After four months, the resorbable material sealing the balloon valve degrades, allowing the balloon to empty and pass through the GI tract naturally [21]. Although IGBs have shown promising clinical outcomes, reported cases of bowel obstruction, gastric erosions, and ulcers point to the risks associated with macroscale devices in the GI tract [20].

2.2. Centimeter-sized untethered shape-changing GI devices

Most untethered shape-changing devices have sizes below 10 cm, corresponding to the standard FDA-approved capsule size 000 (26.1 mm length, 9.9 mm diameter) [22]. These devices exhibit diverse shape-changing mechanisms, including bulk deformation, unidirectional piercing, and folding/ unfolding.

Superporous hydrogels (SPH), which can expand up to a few hundred times their weight, undergo bulk deformation. SPHs have been studied extensively for prolonged, site-specific drug release in the GI tract [23,24]. Elsewhere, a fast-absorbing hydrogel within an enterically coated capsule was used to collect intestinal fluid samples to study gut microbiota. The isotropic shape-changing behavior enabled the sealing of the sampling aperture by pushing a thin membrane against the capsule opening [25]. Soft, swellable hydrogels are an attractive alternative to stiff, non-biodegradable devices as they pose less risk of undesirable tissue penetration, but concerns about GI obstruction remain.

Devices that can pierce through the GI tissue have been developed at capsule-sized scales to improve the bioavailability of macromolecules delivered in the stomach and intestine [26,27]. Such devices include arrays of 5 mm-long microneedles that are exposed to the intestinal tissue once the outer layer is dissolved or single 7 mm-long injectors such as in the self-orienting millimeter-scale applicator (SOMA) that extend out by the actuation of compressed springs [26,28] or inflating balloons [29].

Additionally, devices can be compressed into capsule-sized forms for oral administration and unfold once they reach the target location. An example is a device called a luminal unfolding microneedle injector (LUMI) with insulin-loaded microneedle arms packaged inside a capsule with a diameter of 9 mm and a length of 30 mm. A spring was actuated as the intestinal fluid dissolved part of the capsule. It propelled the three-arm microneedle out, which expanded radially and stretched the small intestinal tissue to a diameter of approximately 40 mm [30]. Electronic modules with unfolding shape-changing abilities have also been developed for wireless communication and remote-controlled drug release. A two-arm device with a flexible element at the center allowed it to unfold to a diameter of 48 mm once the size 000 capsule dissolved in the stomach. As the material degraded over time, the arms detached, allowing the device to pass through the body naturally [28]. Untethered folding devices, such as maneuverable and ingestible origami robots, have also been used for extended drug release and remotely controlled clinical procedures [31,32].

2.3. Millimeter-sized untethered shape-changing GI devices

GI devices at the millimeter (mm) scale can also exhibit a range of shape-changing mechanisms to enhance drug delivery. These small devices can be easily loaded into capsules individually or in multiple doses for oral ingestion and actuated at the target location. To achieve omnidirectional manipulation of untethered shape-changing devices, researchers have magnetic elements into mm-sized devices for targeted drug delivery under external magnetic fields [33-35]. Notably, microneedle-based devices demonstrated active drug delivery and retention by adhering to the mucosal lining of the GI tract [35,36]. Unlike macro or cm-sized shape-changing devices that achieved prolonged retention through significant size transformations, the microneedle robots used mucoadhesive coatings, spring-based propulsion, or magnetic orientation to extend the retention time on the GI tissue without increasing the risk of obstruction [35-37]. Environmental stimuli, such as local ionic density or pH, were also used to induce shape-changing behavior of stimuli-responsive materials to carry out complex tasks like grasping and releasing a payload as demonstrated by the ionic shape-morphing microrobotic end-effectors (ISME) [38]. Shape changes were also achieved using the elastomeric properties of a 125 μm-thick self-unfolding foil (SUF) (7 x 7 mm²) made of polydimethylsiloxane (PDMS) for enhanced delivery of macromolecules as a result of the reduced proximity between the drug-loaded device and the intestinal absorptive barrier [39].

2.4. Submillimeter-sized untethered shape-changing GI devices

State-of-the-art wafer scale microfabrication techniques have made it possible to create sub-mm sized untethered shape-changing devices. Such minuscule devices significantly reduce the risk of GI obstruction and perforation. While they can easily traverse the GI tract and exit the body naturally or undergo complete degradation, it is essential to incorporate shape-changing mechanisms for enhanced, extended, or targeted biomedical applications. For example, Ghosh et al. developed microinjectors of sizes ranging from 250 μm to 1.5 mm that could penetrate and fold into the colonic walls for extended drug release and biologics injection [40]. By delivering several hundreds of microscale devices in a capsule-sized dose, these untethered shape-changing devices made of micropatterned metal bilayers and a thermoresponsive polymer achieved a drug bioavailability greater than the drug alone and comparable to intravenously injected doses [40,41]. Additionally, the incorporation of magnetic materials enabled the remote control of 700 μm-sized grippers in the GI tract under external magnetic resonance fields [42]. Microgrippers of much smaller sizes (10-50 μm) have been created with various materials, including bioresorbable films. These shape-changing devices have been used to capture and manipulate single cells, biopsy tissue from hard-to-reach areas such as the bile duct, and fasten microscale transponders [43-48].

Magnetic microrobots have also demonstrated significant potential for micromanipulation and on-demand drug delivery. In particular, a magnetically driven micromotor approximately 5-6 μm in length was used to transport drug-loaded microparticles at speeds up to 10 μm/s for cancer cell treatment. Due to the flexible silver segment, the micromotor could deform in a chiral manner to produce propulsion [49]. Magnetic microrobots composed of pH-responsive hydrogels have also been fabricated by 4D laser printing, wherein a shape-morphing microfish 10-100 μm in size was magnetically guided to a target location and actuated by the environmental pH to load and release a drug for cancer cell treatment [50].

3. Engineering design principles for untethered shape-changing GI devices

The absence of a tether presents significant engineering design challenges since tethers often transmit the power (e.g., electrical, hydraulic) needed to effect shape changes or other functionalities in biomedical devices. To elicit untethered shape-changing behavior, one needs alternative power sources, either in the form of batteries or triggered changes in material properties. The silver oxide battery, used in the PillCam^™ capsule endoscope for powering image transmission, has sufficient energy density to power tiny sensors or mechanisms [51]. However, small batteries often lack the energy required to power multifunctional shape-changing devices. Kong et al.have reported that a similar battery supplied sufficient energy to power their shape-changing module for the biopsy trial [52]. However, incorporating other functionalities like imaging and data transmission would necessitate additional tethered powering. Hence, alternative untethered power sources like diffusion [53] and chemical reactions [54] have been explored for multifunctional shape-changing devices. Such shape-changing mechanisms can be classified into three major categories: bulk deformation, uniaxial piercing, and folding/ unfolding.

3.1. Bulk deformation

Diffusion, chemical reactions, or photothermal effects can drive bulk shape changes. The diffusion of intestinal fluid into the pores of an interconnected polymer network of SPH can induce isotropic expansion up to a few hundred times the original dried mass or volume in as quickly as less than a minute (Figure 4A) [53]. Such bulk deformations are attractive for retentive sensors, microbiome sampling, and weight management. On-demand and targeted drug delivery is vital for reducing the systemic toxicity of certain drugs, such as those used for cancer treatment. Untethered, targeted drug delivery can be achieved with polymers that disintegrate or de-swell in response to optical triggers like near-infrared (NIR) irradiation. These drug-loaded thermally degradable polymers with nanoparticles of ideal absorption spectrum can release the drug at a specific time and location when subjected to a concentration of NIR energy that disintegrates the polymer [55]. Alternatively, a combination of temperature-responsive hydrogels, such as poly-n-isopropylacrylamide, and magnetic nanoparticles can enable a microrobot to reach a specific location and de-swell in response to external NIR irradiation for targeted drug delivery [56].

Figure 4. Three major design principles of GI shape-changing devices.

A. Bulk deformation caused by (i). expansion of porous hydrogel upon intestinal fluid intake, (ii). filling of balloons by gas produced from chemical reactions, or (iii). disintegration or de-swelling triggered by light; B. uniaxial piercing caused by (i). release of a compressed spring paired with a needle, (ii). inflation of a pouch attached with microneedles, or (iii). movement of a needle attached to a magnet in an external magnetic field; C. folding and unfolding driven by (i). residual stress in a bilayer, (ii). a magnetic torsional spring, (iii). differential thermal expansion in a bilayer, or (iv). shape memory effect. Figure created with BioRender.com with publication license.

IGBs, another shape-changing device that undergoes isotropic bulk deformation, can expand by inserting fluid via endoscopy [20] or self-actuate by gas-producing chemical reactions. Do et al. designed a soft capsule containing a thin, biocompatible balloon that inflates by the CO₂ gas produced from a reaction between sodium bicarbonate and citric acid, obviating the need for conventional tools such as catheters or endoscopes to insert and remove the IGB [57]. However, potential safety concerns regarding gas release in the GI tract, variability in gas release kinetics, and its impact on drug absorption efficiency must be considered when designing such devices.

3.2. Uniaxial piercing

Devices can achieve untethered uniaxial piercing by generating sufficient force to penetrate the GI tissue via mechanical, chemical, or magnetic actuation. The SOMA demonstrates the uniaxial piercing of a drug-loaded post based on the stored energy of a compressed macroscale spring held in place by a dissolvable material [28,58]. Apart from mechanically triggered actuation, inflatable designs based on gas-producing chemical reactions have also been used to drive drug-loaded needle arrays into the intestinal wall, as illustrated in Figure 4B [29]. These devices can deliver large doses of macromolecules like monoclonal antibodies; however, obstruction of the GI pathway and peristalsis dysfunction from such macro devices are significant concerns [59]. Alternatively, a magnetically actuated needle offers better spatiotemporal control for avoiding such potential obstruction. Son et al. created a wireless capsule endoscope (WCE) with a fine needle that could be oriented and actuated under external magnetic fields to collect biopsy samples deep in the stomach tissue [58]. By designing a Sarrus linkage-based soft robot that compresses when the magnetic force overcomes the resistive flexural force of the linkage, the needle could be actuated in the target location and retracted by the spring force of the linkage. In another battery-free capsule endoscope, a rotating magnetic field was applied to extrude and retract a biopsy punch needle via a screw mechanism [60]. Nevertheless, functions such as anchoring and gripping for extended GI retention demand more complex shape changes such as folding/ unfolding.

3.3. Folding/ unfolding

Devices that undergo folding/ unfolding can perform elaborate locomotion, such as walking, rolling, swimming, and gripping, to accomplish tasks that require precise spatial control [61-64]. Folding/ unfolding is primarily achieved through the deformation or rotation of links between stiffer segments via mechanical, magnetic, or thermal actuation. By implementing bilayer and trilayer designs consisting of various materials, including stimuli-responsive gels and pre-stressed thin films, researchers have created folding/ unfolding devices with varying degrees of complexity [31,40,65,66]. Breger et al. employed a thermally and magnetically responsive bilayer design consisting of poly(N-isopropylacrylamide-co-acrylic acid) and poly(propylene fumarate) to make self-folding grippers based on differential swelling [67]. Bending forces can also be generated by the residual stress from thermally deposited materials when combined with another material in a mechanically actuated bilayer design, as demonstrated in μ-grippers and microinjectors, which can generate μ-N range forces [40].

Forward and reverse engineering can accomplish more intricate folding/ unfolding designs using edge-unfolding algorithms and curved fold designs [68-71]. Miyashita et al. designed an accordion-shaped robot that could fit inside a swallowable capsule and unfold to a size five times greater than its folded state at the target location to perform tasks like recovering swallowed batteries [31]. Another study demonstrated using a kirigami pattern known as the Kresling pattern to steer magnetic microrobots via a combination of contraction and bending motions [34]. The design incorporated a Kresling-dipole configuration with four magnetic plates made of silicone embedded with hard magnetic particles. These plates have predetermined magnetization that generates a distributed torque to the Kresling crawler under an applied magnetic field for controlled locomotion.

Magnetically actuated folding/ unfolding and complex shape manipulations have been achieved with soft polymer sheets with magnetic particles fixed inside [33,72-76]. A magnetic torsional spring system consisting of two axially arranged, diametrically magnetized permanent ring magnetic blocks is another driving mechanism used in untethered capsules [77]. When an external magnetic field is applied, the ring magnets orient themselves to that field, bringing the pair’s poles to the same side. This reorientation results in repulsion between the ring magnets and, as a result, axial displacement, as shown in Figure 4C. The resulting movement can open and close a capsule for localized drug delivery [78], operate a scissor-like structure for anchoring [79,80], and enable tissue collection when fitted with a circular razor or biopsy forceps [81,82].

Other functional devices, such as untethered shape-changing stents and endoclips, are generally driven by the physiologically or Joule heating-triggered shape-memory effect [17,52,83-85] (Figure 4C). Among various SMAs, nitinol is the most widely used material owing to its biocompatibility and fatigue resistance [86]. Like spring-based actuation, the bent/folded shape could be kept inside a dissolvable material for more controlled deployment [87]. Also, thermoresponsive shape-memory polymers (SMP), such as poly(vinyl alcohol) (PVA) and dried agarose gel, have been utilized, including in bilayers for controlled folding [88,89]. For instance, Ubold et al. reported a PVA SMP device prepared in a helix-shape with a diameter of 36 mm, then temporarily bent to a 7 mm diameter capsule for ingestion [89]. Upon reaching the stomach, it unfolds to its original shape for retention.

By applying the design principles discussed above, researchers have created various untethered shape-changing devices tailored for specific applications within the GI tract. In the upcoming sections, we will explore the applications of these devices in three key areas: drug delivery, therapeutic intervention, and diagnosis.

4. Drug delivery devices

Orally administered drugs constitute over 62% of FDA-approved pharmaceutical products [90]. Due to the noninvasive and convenient nature of oral delivery, it remains the most popular drug administration method with unrivaled patient compliance and accessibility compared to injection-based methods, which require costly hospital-based infusions [8,91]. Traditional oral administration, however, is limited by short drug retention, low bioavailability, and non-site-specific release [9,91]. Untethered shape-changing devices present a promising solution for tackling these challenges as they can achieve active delivery for systemic absorption.

4.1. Extended drug release

Long-term pain management, birth control, and chronic diseases, such as diabetes, arthritis, HIV, and malaria, often require one or multiple doses of medication daily due to the drugs’ short half-time. However, clinical research shows that around 50% of patients fail to adhere to their chronic medication regimens, leading to treatment failures that account for approximately 125,000 deaths in the United States each year [13,92,93]. Developing extended-release drug formulations would increase patient compliance by reducing dosing frequency and improve therapeutic outcomes by prolonging steady-state pharmacokinetics. No marketed oral medication has achieved GI retention longer than 24 hours due to GI emptying [94,95]. Here, we discuss novel shape-changing devices capable of extended drug release for treating chronic diseases and infections, birth control, and more (Figure 5A) [16,96].

Figure 5. Untethered shape-changing drug delivery devices.

A. Extended drug release devices: (i). Photos of ingestible hydrogel device swelling to 100 times its original volume (top) and a plot showing the device residing in a pig’s stomach for 29 days (bottom). Adapted from [105] with permission under CC BY 4.0. Copyright © 2019, Springer Nature. (ii). Photos of star-shaped capsule devices before (top left) and after unfolding (top right) that reside in pig stomach and release ivermectin for 14 days. Adapted from [108] with permission under CC BY 4.0. Copyright © 2016, AAAS. (iii). Photos of theragrippers on rat colon tissue (left top), a micro-CT image of a theragripper latched into rat colon tissue (left bottom), which releases ketorolac in rat colon for 24 hours (right). Adapted from [40] with permission under CC BY 4.0. Copyright © 2020, AAAS. (iv). Photo of shape memory alloy (SMA) string devices with drug beads (left top). X-ray image of an SMA device in a pig and a plot showing the device's extended release of doxycycline hyclate for 28 days (right). Adapted from [17] with permission under CC BY 4.0. Copyright © 2019, AAAS. B. Biologics delivery devices: (i). Schematic of a self-orienting millimeter-scale applicator (SOMA) (left top), micro-CT image of a SOMA injected a millpost into pig stomach tissue (left bottom), and a plot showing insulin delivery bioavailability using SOMA and controls (right). Adapted from [28] with permission under CC BY 4.0. Copyright © 2019, AAAS. (ii). Photos of self-unfolding foil (SUF) encapsulated in a capsule (left top) and after unfolded (left bottom), and a plot showing SUF delivered nisin in pig models with two times higher AUC than pure drug and permeation enhancer (right). Adapted from [130] with permission. Copyright © 2023, Elsevier. (iii). Schematics showing bi-directional self-folding microinjectors penetrate colonic tissue (left) and a plot showing microinjectors deliver insulin with bioavailability in line with intravenous injection (right). Adapted from [41] with permission. Copyright © 2022, ACS. C. Targeted delivery devices: (i). Schematic showing EsoCap that unrolls and adheres to the esophagus for drug delivery. Adapted from [138] with permission. Copyright © 2020, Elsevier. (ii). Schematic showing a capsule with thermomechanical soft actuator for targeted delivery of anchoring drug deposits to the GI tract. Adapted from [143] with permission. Copyright © 2023, Wiley. (iii). Photos of a nanofiber-based millirobot (Fibot) that moves and anchors on GI tissue by magnetic field for drug delivery. Adapted from [157] with permission. Copyright © 2022, Elsevier. (iv). Schematic showing a soft robotic origami crawler that crawls on the gastric wall and delivers model drug dye to the target. Adapted from [34] with permission under CC BY 4.0. Copyright © 2022, AAAS.

The first group of extended-release, gastric-resident devices are hydrogels and balloons that dramatically increase volume to withstand gastric clearance through the pylorus. Acuform^® is a swellable polymer pill that expands in the stomach and is retained for 6 - 10 hours [97]. Several drug formulations have been incorporated with Acuform^® for extended release of drugs on the market. For example, Gralise^® achieved the extended release of Gabapentin, used for treating neuropathic pain, and reduced the necessary dosing frequency from three times daily to once daily [98-100]. Similarly, Glumetza^® enables the delivery of Metformin to treat type II diabetes with a once-daily dosing schedule [101,102]. Although biocompatible hydrogels are widely used in intragastric devices, they must be carefully designed to prevent breakage during gastric motility. To improve the mechanical properties, researchers have developed intragastric devices with tough double network (DN) hydrogels, which have been shown to stay intact for up to 16 days in animal experiments [103,104]. One example is the puffer fish-inspired device, composed of superabsorbent hydrogel particles encapsulated in a tough hydrogel membrane. The device demonstrated its capacity to swell 100 times its volume in 10 minutes and remained in pigs’ stomachs for up to 29 days [105]. After extended release, hydrogel devices usually degrade by themselves or by chemical triggers. Light-triggerable materials can facilitate on-demand hydrogel degradation and drug release with high temporal resolution [106]. In addition to hydrogel-based devices, inflatable balloons have also been used for extended drug release in the GI tract [107].

A second group of untethered extended-release devices displays folding and unfolding shape changes. A typical design packs the self-unfolding device into a capsule-sized form for ingestion. Upon reaching the actuation site, the device unfolds to a larger geometry to avoid gastric emptying. For example, the star-shaped device with a flexible elastomer at the center is attached to drug-loaded rigid arms that unfold once the capsule dissolves in the stomach for prolonged retention. Each arm was made of smaller segments connected by enteric linkers that dissolved in the intestine, allowing the device to disassemble into small pieces to prevent obstruction. This device extended the release of ivermectin, a parasitic worm treatment drug, at its therapeutic dosage to 14 days in pig experiments [108]. The same group reported similar devices that were used to release drugs for HIV prevention [109], Alzheimer's disease [110], and birth control [111], reducing the daily dosing to weekly and even monthly. Early phase I clinical studies have been conducted to validate the therapeutic performance of these devices on humans [96]. Besides the star-shaped, circle-shaped [112], cubic-shaped [84], and Y-shaped [113] devices, gastric extended-release devices consisting of similar arm-and-linker designs have been reported. Of note, the Accordion Pill^®, which encapsulates a folded drug sheet like an accordion, unfolds and retains in the stomach for eight hours, is conducting phase III clinical trials to extend-release drugs for Parkinson's disease with better pharmacokinetics [114,115]. The presence of gaps in such devices allows food passing, lowering the risk of obstruction, but the linkers may break by gastric peristalsis, shortening their service life.

Theragrippers have been used to enable self-latching for extended release of an FDA-approved nonsteroidal anti-inflammatory drug (NSAID) in the GI tract [40]. They resided in the colon of animals for up to 24 hours, significantly increasing the drug’s half-life sixfold. Aside from these metal theragrippers, polymer or gel-based theragrippers composed of stimuli-responsive hydrogel hinges have been loaded with drugs such as mesalamine and doxorubicin and delivered to the porcine stomach in vivo [116].

The last group of extended-release devices uses shape-memory materials to achieve gastric residency. The PVA SMA devices release allopurinol for 24 hours during in vitro dissolution. The filament is 3D printable, allowing complex geometrical fabrication [89,117]. SMA-based string devices discussed previously can house and release drugs up to tens of grams due to their long length [17]. Animal experiments showcased the extended release of 10 g of doxycycline hyclate for tuberculosis treatment for 28 days and hepatitis C virus treatments for up to one month in pig models [18]. Nevertheless, challenges persist due to the complex and uncomfortable nature of the device administration and retrieval process.

4.2. Biologics delivery

In the last few decades, biological drugs or biologics, including peptides, proteins, antibodies, and nucleic acids, have shown remarkable therapeutic effects for cancer, autoimmune, and chronic diseases, such as diabetes, Crohn’s disease, rheumatoid arthritis, and psoriasis [118,119]. Yet, most biologics require injection or intravenous infusion-based administration as oral administration results in poor systemic absorption due to degradation in the stomach by the acidic environment and digestive enzymes. Moreover, biologics show poor absorption across the GI epithelium and mucosa. To increase the bioavailability of biologics, researchers have used permeation enhancers (PE), mucoadhesive devices, and nanoparticles [120-123].

In recent years, mechanical penetration or disruption of the GI mucosa has been suggested to increase bioavailability. Shape-changing devices (Figure 5B), especially those with the capacity to pierce through mucosal tissue, can help in this regard [124-127]. For example, SOMA delivered insulin with comparable bioavailability to subcutaneous millipost injection, resulting in hypoglycemia in pigs [28]. SOMA also delivered lyophilized mRNA nanoparticles and facilitated animal protein translation, indicating its potential for nucleic acid therapeutics and vaccines, such as the COVID-19 vaccine [128]. Another variation called liquid-injecting SOMA (L-SOMA) can deliver larger doses of biologics in liquid form, using a second spring to drive the liquid drug out after the needle is inserted into the submucosal space [26]. In swine studies, the L-SOMA has been shown to inject up to 80 microliters of liquid drugs, including insulin, GLP-1 analog, and adalimumab. Instead of injecting a single needle, a dynamic omnidirectional adhesive microneedle system (DOAMS) can shoot out tablets with microneedles on both sides from a spring-powered capsule. The mucoadhesive microneedle tablets were pushed to penetrate the gastric wall and effectively delivered semaglutide for type 2 diabetes treatment on swine models [36]. As an alternative to springs, RaniPill^™ (RP) uses a self-inflating balloon to power the drug-loaded microsyringe for the intestinal wall drug injection. The RP is encapsulated by an Eudragit coating, which dissolves in the intestine and then exposes the reaction valve to intestinal fluid, generating CO₂ to inflate the balloon. Animal experiments on pigs showed that RP delivers insulin with bioavailability similar to subcutaneous injection [129]. Clinical trials in human volunteers demonstrated that RP can dose octreotide at therapeutic levels in line with intravenous administration [59].

Alternatively, several ingestible devices undergo unfolding shape changes for enhanced delivery of biologics. For example, LUMI can deliver insulin with 10% of the systemic bioavailability compared to the subcutaneous injections in pig models [30]. Unfolding devices also deliver biologics by bringing the biologic drugs near the GI epithelium for better drug adsorption. The SUF, which contains hexagonal cavities filled with biologics and penetration enhancers (PEs) coated with Eudragit, unfolds and contacts the intestinal wall at proximity. The SUF reported increased insulin bioavailability by 12-fold in rats and increased nisin bioavailability by 4-fold in pigs compared to controls of only drugs and PEs [39,130].

Shape-changing devices that undergo folding motion can also be engineered for biologics delivery. Bi-directionally self-folding microinjectors have shown that they can penetrate the intestinal mucosa to deliver insulin [41]. Bidirectional folding is an attractive mechanism that obviates the need for a specific orientation in the GI tract, which can be challenging to control. Microinjectors were shown to deliver insulin in rats with similar bioavailability compared to intravenous injection.

Most recently, a shape-changing device that mechanically stretches the GI mucosa has also been reported to enhance the adsorption of peptides through the GI tract. Luo et al. have reported an octopus-inspired buccal-stretching patch that delivers desmopressin or semaglutide with improved bioavailability in beagle dogs by stretching and thinning the buccal mucosa when the suction cap expands and sticks on tissue [131].

4.3. Targeted drug delivery

By leveraging the differences in the size, absorptive area, transit time, pH, and permeability of different GI compartments, especially the esophagus and colon, it is possible to deliver drugs locally or optimize systemic drug absorption (Figure 5C) [8,14,132]. Esophageal disorders include GERD, eosinophilic esophagitis, Barrett’s esophagus, and esophageal cancer [133,134]. However, the esophagus is hard to target due to its fast transit time, which is as short as a few seconds. Bowel diseases such as ulcerative colitis, Crohn’s disease, amebiasis, and colonic cancer require local treatments [135,136]. In clinics, these diseases are generally treated by systemic therapy. However, systemic delivery significantly increases the risk of adverse effects and toxicity in non-target organs, especially at high doses or prolonged dosing. Therefore, there is a need for localized drug delivery methods to eliminate systemic side effects and improve therapeutic outcomes [137].

Existing esophagus local delivery methods use viscous drug solution to slow the passage or direct endoscopic drug injection. For example, the EsoCap-system encapsulates a rolled-up polymeric film loaded with dyes such as fluorescein sodium in a capsule. The researchers report unrolling and local adherence to the esophagus wall in humans [138]. Babaee et al. described a kirigami-inspired stent for local drug delivery of steroidal budesonide microparticles in the esophagus or intestine [139]. Another flower-like device deposited budesonide microneedles in pigs’ esophagi using SMA-powered unfolding [84].

To overcome challenges with biochemical variability between patients that could result in false triggering of drug release, researchers have also developed smart capsules that can be triggered on-demand using either electrical or magnetic signals [140-142]. For example, Levy et al. described a WCE with a thermomechanical actuator capable of on-demand delivery, verified with model drug FD&C blue #1 dye such as in agarose phantoms and ex vivo intestinal tissue [143]. Similar smart on-demand drug release capsules have been equipped with electrically triggered drug release components such as compressed elastomer [144]spring (Enterion^™) [145]microthruster [146,147], gas-producing cell [148] and piston pump (IntelliCap^®) [149]. Of note, IntelliCap^® and Enterion^™ have been tested on humans for early-phase clinical tests to deliver diltiazem, ziprasidone, and edoxaban [149-151]. In addition to electrical triggering, magnetically actuated smart capsules have been shown to release model drug dyes in ex vivo tissue or phantom by anchor and release drugs [79], push microneedle patches [152] or needle into tissue [153], break or activate drug reservoirs at the target [154,155].

Soft robots, primarily magnetically controlled ones, are particularly well-suited for navigating the complex and dynamic GI environment for targeted delivery due to their flexibility over rigid counterparts [156]. Tan et al. reported a nanofiber-based millirobot (Fibot) consisting of a magnetic multi-legged array and nanofiber body. The Fibot was able to move along the rabbit’s GI tract and was anchored on targeted sites controlled by an external magnetic field. Fibot released drugs in multi-step using pH-responsive drug carriers [157]. Similar planar magnetic soft robots that can crawl on tissue and carry drug cargo have been reported elsewhere [76]. Origami-inspired soft robots incorporated with magnets could move across GI tissue and then deliver the drug [31,34,158]. Other than magnetic-assisted targeting, soft robots may use the GI tract's temperature, pH, and enzyme differences to actuate shape-changing behavior and targeted delivery [38,159,160].

5. Therapeutic untethered shape-changing GI devices

Various untethered shape-changing devices have been utilized for therapeutics, including surgical intervention, stenting, obesity control, and electrical stimulation (Figure 6A).

Figure 6. Untethered shape-changing therapeutic and diagnostic devices.

A. Therapeutic devices: (i). Photograph of a pangolin-inspired shape-changing microrobot that moves on an intestinal wall controlled by a low-frequency magnetic field. The microrobot produces heat under a high-frequency magnetic field for mitigating bleeding and tumor hyperthermia. Adapted from [162] with permission under CC BY 4.0. Copyright © 2023, Springer Nature. (ii). Photograph of a wireless capsule endoscope treating a GI hemorrhage by balloon tamponade-induced hemostasis using a gas-inflated balloon. Adapted from [163] with permission. Copyright © 2017, IEEE. (iii). Photograph of Elipse^® balloon before inflation (left) and after inflation (right) for bariatric obesity control. Adapted from [182] with permission under CC BY 4.0. Copyright © 2017, Springer Nature. (iv). Photograph of a WallFlex^® duodenal stent for palliative treatment of malignant gastric outlet obstruction. Adapted from [172] with permission. Copyright © 2009, Elsevier. (v). Photograph of a self-orienting injection and electrostimulation (STIMS) that injects electrode probes into the gastric wall and treats gastric motility disorders. Adapted from [195] with permission under CC BY 4.0. Copyright © 2020, AAAS. B. Diagnostic devices: (i). Photo of magnetic anchoring endoscope capsule for site-specific imaging. Adapted from [80] with permission. Copyright © 2019, IEEE. (ii). Photo of a 3D-printed capsule with a Y-shaped unfolding arm for gastric retentive temperature sensing. Adapted from [113] with permission. Copyright © 2019, Wiley. (iii). Photos of wireless miniature soft robots that change shapes to sense pH and viscoelasticity of GI tissues. Adapted from [208] with permission under CC BY 4.0. Copyright © 2023, AAAS. (iv). Photos of magnetically actuated soft capsule endoscope for fine-needle biopsy, needle retracted (top), and needle exposed (bottom). Adapted from [58] with permission. Copyright © 2017, IEEE. (v). Photo of a self-folding biopsy μ-gripper gripping a piece of stained bile duct tissue. Adapted from [44] with permission. Copyright © 2013, Wiley.

5.1. Surgical intervention

Endoscopic tools that enable image-guided minimally invasive surgery can be used to treat GI conditions such as gastric ulcers, GI lesions, bleeding, perforation, and tumors. However, the region the endoscope can access is limited, and the insertion causes discomfort to patients. The development of untethered shape-changing devices offers opportunities to perform surgical interventions, such as wound patching, plugging, and hemorrhage cessation, autonomously throughout the entire GI tract with minimal invasion [161]. Magnetically actuated robots have demonstrated noninvasive, controlled heating for medical procedures, such as devitalization, coagulation, and cutting. Soon et al. developed a soft robot to locate the wound site by demagnetization-induced rolling and tumbling under a low-frequency magnetic field and generate heat to mitigate bleeding under a high-frequency magnetic field [162]. The robot demonstrated its capacity for on-demand drug release and hyperthermia by destroying simulated tumor spheroids in a porcine small intestine under a radiofrequency field. The unique pangolin-inspired design, consisting of overlapping metal scales bonded to a magnetic polymer, allowed the robot to achieve both flexibility for unobstructed locomotion and efficient heat generation. A WCE also showed the possibility of treating GI hemorrhage by balloon tamponade-induced hemostasis [163]. The device, consisting of three sections in a silicone balloon, reached a precalculated pressure level by a gas-producing chemical reaction. In vivo studies in porcine models revealed that the WCE could achieve hemostasis within 5 min. Valdastri et al. demonstrated that hemostasis could also be achieved by placing surgical clips on GI lesions [164]. A swallowable, wireless endoscopic capsule with a nitinol surgical clip was magnetically steered to the lesion in a porcine model and successfully actuated upon a wirelessly transmitted command. However, using non-degradable materials raises concerns about the compatibility of untethered shape-changing devices for surgical procedures. A biodegradable accordion-shaped robot demonstrated its capacity for treating button battery-induced stomach inflammation with minimal clinical intervention and onboard electronics [31,158]. In the first phase, an ice-encapsulated magnetic device is guided to the swallowed battery to remove the battery under an external magnetic field. Another ice-encapsulated origami device is swallowed and guided to the gastric inflammation site by electromagnetic actuation in the subsequent phase. The device releases its drug cargo in minutes as the ice melts, depending on the temperature. Another untethered origami device demonstrated its capacity to treat gastric ulcers. Du Plessis d’Argentre et al. designed a swallowable pill made of agarose hydrogel that could be magnetically guided to the ulcer and unfolded to approximately 10 times its initial size for patching a 5 cm-wide ulcer [165].

5.2. GI stenting

GI stents are deployed via endoscopy to alleviate GI tract obstructions caused by esophageal benign strictures, esophageal cancer, gastric cancer, periampullary cancer, or others to maintain the GI luminal patency, therefore maintaining regular nutrition intake and improving patients’ life quality. In the past, GI stents were rigid cylinders, which resulted in very low treatment effectiveness and accompanied by stent migration, reflux of gastric contents to the esophagus, and many complications [166]. Novel shape-changing devices such as flexible and self-expandable metal/plastic stents have been investigated to treat esophageal and gastroduodenal obstructions/strictures [167]. For example, a self-expandable metal stent of stainless steel, nitinol, and Elgiloy demonstrated improved flexibility. Because of nitinol's excellent shape-memory properties and flexibility, it exerted substantial radial forces to maintain the stent patency and position. Several types of self-expandable metal stents are available in clinical endoscopy practices based on surface coating: uncovered, partially covered, or fully covered self-expandable metal stents [167]. Self-expandable plastic stents made of polyester and silicone showed treatment effects similar to self-expandable metal but with a higher risk of migration [168]. Current innovation trends focus on addressing issues of stent migration and gastric contents reflux. A one-way valve attached to the distal stents was applied to self-expandable stents to prevent refluxing. However, clinical trials showed improvement in refluxing occurrence but resulted in frequent migration, which led to a decline in the application [169]. Stents with anti-migration properties have been designed, featuring elements like metal mesh, wider diameters with flare, full double-layered coverage as well as antimigration rings on the outer surface and others, but clinical data on their enhanced antimigration performance is lacking [170]. Instead, a higher rate of recurrent obstructions and complications with these new antimigration stents were reported in some studies [171,172]. These upper GI stent design advancements have improved patient options, but challenges remain in addressing migration and reflux symptoms.

5.3. Obesity control

Obesity, with a prevalence of over 40% in the US alone, is a significant risk factor for chronic diseases like type 2 diabetes and cardiovascular disease [173]. Besides lifestyle changes, including diet and exercise, bariatric surgery can be utilized for weight loss by reducing the stomach volume. This procedure, however, is relatively expensive and invasive [174,175]. In contrast, GI shape-changing devices characterized by dramatic volumetric transformations offer a less invasive and reversible method for restricting gastric volume and slowing down gastric emptying [176,177]. A popular type of such device is IGB, a silicone balloon that can be filled with liquid or gas. IGBs have been widely used clinically since 1991. Early FDA-approved IGBs such as Orbera^® and Spatz3^® require an endoscope or a catheter for placement and retraction. Another device, Obalon^®, is swallowable but still needs endoscopic removal [178-181]. A more recent and entirely untethered IGB, Elipse^® is equipped with a self-deflating valve that can self-empty after four months of ingestion. These marketed IGBs are reported to result in a 10–12% body weight loss after the treatment period [182]. Besides these commercial IGB devices, several gas-inflated mechanisms are being explored in research laboratories, including those controlled by magnetic fields [57,183,184] or wireless communication circuits [185,186]. Apart from balloons, superabsorbent hydrogels have been used for obesity control as well [187,188]. Plenity^® is an FDA-approved pill loaded with hydrogel particles that disperse inside the stomach and can swell to 100 times to restrict gastric volume [189,190]. Apart from isotropic swelling, we anticipate that alternate mechanisms of anisotropic, triggered, and transient untethered shape-changing devices can also be utilized for obesity control.

5.4. Electrical stimulation

Electrical stimulation can effectively modulate GI motility, presenting a promising alternative to medicine for treating GI dysmotility. Clinical use of implantable stimulation devices is established for gastroparesis and obesity treatment [191-193]. The usage of untethered shape-changing devices for electrostimulation offers future promise. Recently, Zhang et al. presented an untethered E-stent consisting of a superelastic nitinol stent and a liquid metal elastic antenna and circuit with a microneedle to deliver an electric pulse across the mucosa [194]. The stent self-expands to adapt to esophageal contour after deployment, then harvests energy wirelessly by antenna for electrostimulation. In experiments with a porcine model, the researchers report that continuous electrical stimulation via this stent notably boosts lower esophageal sphincter pressure, presenting a potential surgery-free therapy for the GI tract. A self-orienting injection and electrostimulation (STIMS) device has been developed elsewhere. Instead of a drug needle in the SOMA, when triggered, the STIMS ejects hooked electrode probes into the gastric wall to immobilize the device [195]. These probes are connected to an electronic unit that sends electrical pulses to the tissue, resulting in acute muscular contractions in pigs, for potential treatment of gastric motility disorders.

6. Diagnostic devices

Various untethered shape-changing devices have been utilized for diagnostics, including imaging, sensing, biopsy, and sampling (Figure 6B).

6.1. Imaging

GI endoscopy is the first screening line for GI diseases, especially for cancers. However, the invasiveness and cost of using tethered endoscopes can limit their accessibility [196]. Due to advances in automation and miniaturization, several untethered ingestible capsule endoscopes have emerged, such as the PillCam^®, Bravo^®, and OMOM^® Capsules [5,197]. These capsules rely on peristalsis to move through the GI tract, but this mechanism can impede local site-specific imaging. To address this challenge, electrically or magnetically triggered shape-changing devices capable of anchoring onto the GI tissue have been integrated with capsule endoscopes to resist peristalsis, enabling some extent of localization. For example, Kong et al. introduced a capsule robot capable of prolonged imaging with four extendable legs driven by SMA springs [52]. Upon arrival at the target location, a wirelessly controlled electric heater warms up the SMA spring, and the legs push against the intestinal wall to enhance the friction for anchoring the imaging capsule. Alternatively, magnetic forces can push the device against the GI wall for anchoring, as demonstrated by Yim et al.[198]. Several other magnetically actuated endoscope capsules with unconventional designs, such as quadrupedal holders [199], scissor-like extenders [80], and elastic rubber legs [200], have been used for GI anchoring. These shape-changing endoscope capsules are often incorporated with biopsy or drug delivery components for imaging-guided drug release and biopsy [52,79,198,201].

6.2. Sensing

Biosensing and real-time analysis of physiological signals, including temperature, motility, pH, and chemical analytes, can provide a more accurate and detailed assessment of GI pathology and health [202,203]. Ingestible devices, such as smart capsules with different sensors, can be non-invasive alternatives to traditional GI sensors requiring surgical implantation [7,161]. Incorporating shape-changing designs into ingestible devices can aid in collecting signals from localized site-specific regions.

As discussed earlier, retentive devices for continuous sensing often use similar shape-changing principles for GI resident drug delivery devices [204]. For example, swellable hydrogel gastric devices can be equipped with sensors for long-term temperature monitoring, as demonstrated for up to 29 days in live pigs [105]. A capsule with a Y-shaped unfolding arm measured the real-time temperature in the pig's stomach for 17 days [113]. SMA strings that coiled up in the stomach with alcohol sensors can reside in swine for a month [18]. For intestinal retentive sensing, Xie et al. reported a capsule that deploys a detachable biosensing unit with a suction hole and needles on the small intestine wall for up to 40 hours in swine [205]. Elsewhere, deformable magnetic hydrogels with the potential to carry biosensing electronics are localized by magnetic fields at specific sites in the intestines for 7 days in mice [206].

Proximity sensors change their shape to bring sensors closer to the gastric wall, such as to measure gastric motility, but many of these devices are still wired. [19,207] In this regard, Wang et al. reported an untethered magnetically controlled bioadhesive soft robotic crawler that could measure the viscoelasticity and pH of ex vivo animal tissues [208].

6.3. Biopsy and sampling

Many microorganisms reside in the approximately 9 m-long human gut and play essential roles in the human body’s metabolism, digestion, absorption, and physiology [209]. Conventional biome sampling approaches (e.g., fecal sampling) cannot provide site-specific microbiome information, and tethered surgical sampling techniques (e.g., gastroscopy, colonoscopy) are relatively invasive, causing discomfort to patients and incurring high costs. In contrast, untethered shape-changing capsules can provide a non-surgical method to collect biome samples. For example, Waimin et al. and Chen et al. designed capsules containing a fast-absorbing hydrogel that collected GI fluids containing samples of the microbial flora [25,209,210]. Also, Rehan et al. demonstrated active control of a wirelessly triggered device based on a two-way SMA spring actuation mechanism for microbiome sampling [211].

Pill-shaped robots have demonstrated the capacity to reach a target site under an external electromagnetic actuation system, often guided by an onboard camera. They then spring out and retract their biopsy needle for tissue sampling [58,212]. Zhang et al. described controlled tissue collection by implementing an anchoring module for localization in their device [201]. Rather than attaching traditional biopsy needles or forceps to larger capsules, Gultepe et al. showed that deploying a multitude of tiny star-shaped microgrippers (tip-to-tip ranging from 300 μm to 1.5 mm) could excise tissues from hard-to-reach places and organs [44]. As demonstrated via a Monte Carlo simulation, sampling tissue from large organs, such as the intestine, with many micro shape-changing devices rather than one large device could reduce GI obstruction or perforation while enhancing sampling efficiency. Additionally, small devices can be easily loaded in capsules, as demonstrated with the magnetic capsule [48], or deployed locally using pneumatic probes [47]. In a recent study, Zheng et al. designed an environmentally adaptive variation of star-shaped grippers to collect tissues using ionically- or pH-triggered swelling and shrinkage [213].

7. Conclusion

Emerging evidence suggests a growing trend in using untethered shape-changing devices within the GI tract. Shape-morphing behavior, such as bulk deformation, uniaxial piercing, and folding/ unfolding has been shown to enhance device capabilities for drug delivery, surgical intervention, and diagnostics. In this opinion, we explored the potential impact of untethered, shape-changing devices on the future of GI-based drug delivery. Recent advancements include gastric retentive devices that can release drugs for up to a month, injecting devices that can overcome the mucosal barrier to deliver biologics with bioavailabilities paralleling that of intravenous and subcutaneous injections, and targeted drug delivery devices that can deliver precise doses of the drug to the affected area. Moreover, untethered, shape-changing devices are pushing the boundaries of diagnostic and therapeutic technologies like biopsy, sampling, sensing, stenting, surgical intervention, and electrical stimulation by providing access to hard-to-reach sites and less invasive alternatives to surgery. Some of these devices, such as the Orbera^®, Acuform^®, and Obalon^®, have already undergone clinical translation, contributing significantly to improved patient outcomes and healthcare delivery.

Given that the development of untethered shape-changing devices is still in its infancy, several challenges must be addressed before these devices become widely available. We anticipate the future untethered, shape-changing devices to be composed of soft, biodegradable materials that can generate sufficient force for intricate, controlled shape changes needed in advanced drug delivery devices and remote surgical procedures. Furthermore, multimodal systems with miniaturized onboard electronics capable of real-time diagnosis, automated drug release, and continuous monitoring are poised to revolutionize GI-based treatments. The concept of a swallowable doctor may be realized by implementing closed-loop systems with intelligent shape-changing mechanisms. By enhancing drug delivery, performing intricate surgical tasks, and offering minimally invasive treatments, untethered shape-changing devices have the potential to transform healthcare delivery and patient outcomes.

Expert Opinion

Looking ahead, we foresee the development of various untethered shape-changing devices in the GI tract, ranging from retentive devices with expandable structures, sampling/ biopsy devices with self-actuating grippers or graspers, and injectors with piercing components. However, as with many small machines, these devices face power-coupling, remote-guidance, and localization challenges. In the case of ingestible devices, these challenges are exacerbated by concerns regarding toxicity and safety. Below, we outline a few significant engineering challenges and potential solutions to address these issues.

1. How do we build small-sized, untethered shape-changing devices? Significant advances in photo, e-beam, nanoimprint lithography, and 3D printing offer solutions, but challenges remain in multimaterial and multiscale integration.

2. How do we design untethered shape-changing devices for a specific function? The shape-changing design principles must be carefully chosen based on the purpose of the devices. While designing, factors such as the device size and operating duration are critical to consider. For example, larger macroscale devices have risks associated with blockage and perforation, but smaller devices, such as microinjectors, face issues such as food waste blockage and low mechanical integrity. Also, the devices’ duration of operation, manufacturing and operational complexity must be considered since defects and malfunctions can lead to medical complications.

3. What materials do we use to build untethered shape-changing devices? For example, stimuli-responsive materials can power shape-changing in an untethered manner. Using soft, biocompatible materials can enhance the biocompatibility of the devices, but it misses the mechanical rigidity required to perform tasks such as piercing cutting. Developing novel and composite materials is necessary for advanced GI shape-changing devices.

4. How can we deploy, move, localize, and retrieve untethered shape-changing devices without a tether? Here, we can look at solutions that leverage current endoscopes, pills, and capsules. Besides utilizing natural body modes of transit such as swallowing, peristalsis, and excretion, external wireless (magnetic, acoustic) guidance approaches are being explored.

5. Without tethers or wires, how do we power small devices? Apart from small-scale batteries, as discussed, one can leverage changes in material properties such as differential swelling, shape memory effects, and loaded pre-stressed thin films or springs.

6. For localized drug delivery and treatments, how do we trigger actuation at the desired site? Much like targeted drug delivery, one could incorporate disease-specific antibodies. Alternatively, such devices could be activated using image guidance and external fields (e.g., radiofrequency, acoustic). At small size scales, there are significant challenges with power coupling to electrically small antennas, and 3D antenna designs may be need to be explored for wireless communication if one or two-way information transfer is required [214].

7. How do we translate untethered shape-changing GI devices from research to clinics? While several devices have been tested and approved for clinical use, most untethered shape-changing GI devices are still in their prototypical phase. They have been primarily tested in organ phantoms and ex vivo tissues, quite unlike the realistic GI environment in vivo, which is dynamic and challenging to visualize. Also, many in vivo studies have been performed merely in animal models with relatively empty or clean GI tracts (e.g., fasting or cleared), which may not be the case for real-world dosing where chyme could reduce functionality. Moreover, many magnetic or electronic control systems cannot be readily adapted to use on humans in the clinic due to safety or scaling issues.

8. Finally, how do we ensure patient safety? Safety considerations should be prioritized when designing and engineering these devices to avoid complications. One notes that the GI tract is one of the easiest anatomical places for the first use of such devices due to its relatively easy access and natural excretion. In the future, to enhance safety and access other organ systems, one may need to develop untethered shape-changing devices using bioresorbable or biodegradable materials.

Article Highlights.

• Current trends, such as capsule endoscopy and active matter therapeutics, point to the convergence of surgical and diagnostic tools with drug delivery devices.

• Shape-changing devices can emulate the autonomy and mechanical features of GI-resident organisms.

• Evidence shows that shape-changing and self-latching microdevices, such as theragrippers, can enhance the efficacy of extended drug delivery.

• The untethered shape-changing devices capable of tissue penetration improve the bioavailability of macromolecules and biologics via the GI tract.

• Untethered devices can access hard-to-reach conduits and operate in large numbers for localized treatments.

• Multimodal shape-changing devices capable of performing surgical or diagnostic functions (e.g., imaging, sensing, sampling, and patching) and drug delivery are gaining attention.