Conventional biting or pulling mechanisms may cause tearing of fragile mucosal tissue. In contrast, high-speed rotary cutting mechanisms can mitigate this risk by storing energy in a pre-compressed spring and releasing it in a rapid, controlled burst, thereby driving a sharp blade to excise a relatively clean tissue sample.

Early prototypes primarily relied on thermal triggering to activate the cutting mechanism. Kong et al. used electrically heated wax to trigger a torsion spring, driving a blade 1.5 mm into tissue for superficial sampling, with the device then automatically sealing and fixing the specimen in preservative fluid^[12]. A later version added modules for tissue monitoring and capsule anchoring, using electrical heating to melt solder and release a double-layered cutting blade. However, this device still required an external power cable, limiting its applicability as a fully wireless capsule system^[13]. Le et al. subsequently integrated a shape memory alloy (SMA) wire, which contracts upon heating, into a locomoting capsule (ALICE)^[9]. A later version incorporated a thermal-fuse trigger to activate the biopsy mechanism^[14]. Although these thermally triggered systems demonstrated reliable actuation, their irreversible triggering mechanisms generally permit only a single sampling event, while the heating process can impose a substantial energy burden on the capsule battery.

To avoid electromagnetic interference, some groups used a physical wire (Bowden cable) to mechanically trigger blade release, allowing multiple independent samples to be stored in a rotating multi-slot compartment^[15,16]. This works well but sacrifices the fully wireless nature of capsule endoscopy.

Wireless magnetic triggering has become one of the most extensively investigated approaches in preclinical capsule biopsy research. In one design, interaction between two permanent magnets within the capsule was used to control blade opening and closure; however, the relatively large magnet dimensions required by this mechanism pose challenges for integration into commercially sized capsules^[17]. A widely adopted strategy employs an MTS. In this configuration, an external magnetic field displaces an internal rotating magnet relative to a fixed magnet, thereby storing magnetic potential energy; removal of the external field subsequently releases this stored energy and drives rapid blade rotation^[8]. A related design locks the blade magnetically during transit and releases it by applying a stronger external field^[10]; this required an additional robotic arm system to adjust the capsule’s orientation so that the side-mounted biopsy port aligns with the lesion^[18]. Despite their advantages in wireless actuation, current MTS-based capsule systems remain largely limited to single-shot sampling and generally produce relatively small tissue specimens.

Superficial blade biopsy may fail to reach submucosal lesions and can cause tearing of the overlying mucosa. FNA offers a potential solution to these limitations by using a small needle to penetrate deeper tissue layers, analogous to the FNA technique routinely employed during clinical endoscopic ultrasound-guided sampling.

Early needle-based capsule designs primarily relied on thermally triggered actuation. Park et al. used electrically heated SMA wire to deploy a biopsy needle^[19], whereas the SCUUP device employed a microheater to melt an adhesive bond, releasing a spring-driven gear system that enabled the acquisition of relatively large mucosal specimens suitable for downstream genetic analyses, including polymerase chain reaction (PCR)^[20]. Both approaches work reliably but are limited to a single use because thermal melting cannot be reset.

External electromagnetic actuation (EMA) has emerged as a widely investigated preclinical approach for remotely controlled needle deployment without requiring local electrical power for the actuation step. In these systems, external magnetic coils generate a magnetic field that drives an internal magnet to rotate, with the rotational motion subsequently converted into reciprocating linear motion of the biopsy needle^[21,22]. Hoang et al. further refined this concept by incorporating an automatic needle-retraction mechanism that retracts the needle during capsule locomotion, thereby reducing the risk of inadvertent mucosal injury. A front-facing camera was also integrated to provide real-time visualization and monitoring during the procedure^[21].

A major challenge is to decouple magnetic capsule locomotion from magnetic needle deployment. Several strategies have been proposed to address this issue. One approach uses a gradient magnetic field to first anchor the capsule against the intestinal wall, followed by a rotating field to independently drive needle insertion^[23]. Another employs two internal magnets, in which the anterior magnet controls the capsule steering while a second magnet, actuated by an independently controlled external magnetic field, drives the needle forward and permits automatic retraction when the field is removed^[24,25]. A third strategy uses an eccentric wheel-ratchet mechanism, in which reversing the direction of rotation of an external magnet independently controls both the anchoring legs and needle extension, substantially reducing the required internal space^[26]. The B-MASCE, a soft-bodied capsule using a concertina-like linkage structure, achieves both movement and needle guidance through axial magnetic compression, though it is currently limited to collecting cells rather than tissue cores^[27].

More advanced MEMS-integrated systems have combined needle biopsy with immediate post-procedure hemostasis. Xu et al. developed a capsule incorporating a graphene-carbon nanotube heating film that can cauterize the biopsy tract immediately after needle withdrawal, providing integrated tissue sampling and hemostatic control^[4]. Multi-chamber “roulette-style” designs with dual built-in motors can cycle through several biopsy needles and drug delivery compartments in a single procedure^[28,29]. However, further miniaturization of the internal motors while maintaining sufficient torque and reliability remains a major engineering challenge for integration into a swallowable capsule platform.

Beyond the sampling mechanism itself, accurate real-time localization of the biopsy needle is critical for procedural safety, particularly when deep tissue penetration is required. Liu et al. addressed this by embedding three aligned permanent magnets within the capsule body and combining external magnetic sensors with a computational algorithm, achieving 1.83 mm positional accuracy while simultaneously tracking how far the biopsy needle has extended^[30]. This approach has not yet been tested in the complex electromagnetic environment of a clinical setting.

Forceps-based biopsy most closely replicates the tissue-acquisition technique used by clinicians during conventional endoscopy. Miniaturized forceps jaws can be opened, positioned against the target tissue, and closed to pinch off a specimen.

Several designs employ miniature electric motors to actuate the forceps mechanism. These include micro-barbed forceps driven by a stepper motor via a gear rack^[31], a three-jaw gripper incorporating a ball-screw drive to minimize mechanical backlash^[32], and a caterpillar-like colon biopsy capsule that receives power wirelessly, thereby eliminating the need for an onboard battery, to operate both a balloon anchoring system and a forceps-driving lead screw^[33]. The integration of commercially available biopsy forceps into a magnetically steered capsule has also been demonstrated, with tissue acquisition achieved through mechanical traction after the capsule reaches the target site^[34]. The main drawback of all motor-based forceps designs is that motors and drive mechanisms take up substantial space inside the capsule.

Battery-free forceps mechanisms actuated by external magnetic fields offer a potential solution to this space constraint but require precise magnetic-field control. The ALICE capsule incorporates a miniature gearbox to amplify the magnetic torque required to operate micro-forceps^[35]. However, the fabrication of such high-precision gearboxes, together with the difficulty of preventing the rotating magnetic field from inadvertently rotating the entire capsule, has thus far limited practical translation and commercialization. Simpler magnetic designs include a coaxial “magnetic switch” that separates capsule movement from biopsy activation^[36], and a passive folding tool that deploys when the capsule rotates against the intestinal wall^[37], though the cutting force of the former decreases significantly if the magnet is made smaller. Safety improvements include a fail-safe magnetic spring that automatically closes the forceps if the external magnetic field is interrupted, protecting the bowel wall from injury^[38]. A modified MTS design further deploys the forceps from the front face of the capsule, allowing the integrated camera to monitor the entire procedure without blind spots, with gravity retracting the forceps when the field is removed^[39]. However, the combined space requirements of the MTS and forceps mechanism remain considerable, and actuation delays may occur at certain magnetic-field orientations.

Other actuation strategies have also been investigated. Propeller-driven biopsy capsules actuated by an internal motor and triggered through a cam mechanism, which work well in fluid-filled bowel segments but lose propulsion in drier regions^[40,41], and a swarm of heat-activated micro-grippers deployed in large numbers to compensate for the difficulty of accurate targeting^[42], though retrieval rates are very low at around 3%. A capsule incorporating a rubber odometer wheel has also been proposed to estimate travel distance and thereby improve targeting accuracy for subsequent biopsy procedures^[43]. Nevertheless, the safety and reliability of prolonged contact between the rubber wheel and delicate GI tissue require further evaluation.

The simplest approach to gastric fluid collection is to attach an absorbent material to a retrieval string, swallow the assembly, and subsequently withdraw it. Gelatin capsules containing absorbent paper connected to a nylon thread have been used to non-invasively collect gastric fluid for the analysis of cancer biomarkers^[44]. Replacing the absorbent paper with a three-dimensional polycaprolactone (PCL) nanofiber sponge, which can absorb up to 60 times its dry weight in fluid, substantially increases the volume of fluid collected and enhances the capture of bacterial and viral particles^[45]. Wang et al. further integrated this concept with magnetically controlled capsule endoscopy, enabling the capsule to be visually navigated to the desired sampling site before fluid collection. Importantly, the retrieval string can be detached from the capsule in situ and withdrawn separately, thereby avoiding the discomfort associated with pulling a rigid capsule back through the esophagus and pharynx^[46]. The fundamental limitation of all string-based approaches is that the length and entanglement risk of the string restricts sampling to the stomach; reaching the small intestine or colon is not feasible.

To enable deeper GI sampling without a retrieval string, researchers have developed capsule coatings that dissolve or change properties in response to the local chemical environment, such as the pH of the intestinal fluid, specific enzymes, or particular bacteria.

The IMBA capsule uses a conventional enteric coating that dissolves under intestinal pH conditions, thereby releasing a spring-loaded latch that opens the capsule and allows intestinal fluid to flow in, before a piston closes and permanently seals the sample chamber^[47]. A related approach employs a 3D-printed bistable mechanical structure that snaps between two stable positions to passively seal the sample without any battery or electronics^[48]. These designs are simple and mechanically robust in bench testing, but the sampling site is wherever the coating dissolves, which the device cannot control.

Beyond triggering sampling at the desired anatomical location, preventing contamination of the collected specimen by downstream intestinal contents during subsequent transit is a critical design requirement. pH-responsive hydrogels combined with magnetic actuation allow the hydrogel trigger to be physically separated from the sample chamber itself, so that triggering is autonomous while the sample remains isolated^[7]. Sealing the sampling port with a polydimethylsiloxane (PDMS) membrane provides a self-locking physical barrier while retaining gas permeability, thereby supporting the viability of captured microorganisms^[49]. This principle has been further extended using a dual-layer pH-sensitive coating to improve targeting of the proximal colon^[50]. The principal limitation of pH-based triggering is the substantial interindividual and temporal variability in GI pH, which can be influenced by factors such as diet and intestinal transit time. Consequently, the precise anatomical location of capsule activation may remain unpredictable. Using two simultaneous triggers, both a specific pH threshold and the presence of certain bacteria, reduces this uncertainty^[51]; adding capacitive sensors that detect the local environment and communicate sampling status provides additional control^[52,53], though the battery and electronics needed for sensing take up space that would otherwise hold the sample.

Rather than collecting a discrete sample at a single point in time, osmotic pump-based capsules continuously draw small volumes of fluid throughout their transit along the GI tract. This approach enables spatially resolved sampling, allowing different portions of the collected sample to be associated with distinct intestinal locations and thereby facilitating whole-gut microbiome mapping^[54]. However, these devices cannot collect a large volume at a specific site and their spatial resolution depends on how quickly the capsule moves.

In situ sensing systems represent an adjacent but conceptually distinct technology. The Smart Capsule Bacterial Detection System (SCBDS), for example, is designed to detect metabolically active bacteria within the GI environment rather than to recover a specimen for external laboratory analysis^[55]. Although such platforms fall outside the primary definition of sampling capsules used in this review, their integration with physical sample acquisition could ultimately enable combined sampling and on-board analysis.

Capsules equipped with internal power sources and heating elements can actively aspirate large volumes of GI fluid. SMA-spring-powered scrapers can generate forces of up to 800 mN against the intestinal wall, enabling the collection of mucosal material together with the microbes attached to it^[56-58]. Du et al.’s soft capsule uses an external magnetic field for positioning and an internal heater to melt a wax seal, releasing vacuum pressure that draws in a large fluid sample without mechanically damaging the mucosa^[59]. Similarly, capsules incorporating microheaters can melt wax or metal valves to open a pre-evacuated collection chamber, enabling rapid fluid aspiration through a pressure differential. Integrated filters can exclude food particles, while preservatives help stabilize microbial DNA and RNA during collection^[60,61]. Despite their sampling efficiency, thermally actuated designs share several limitations. The heating element occupies valuable internal space, elevated temperature may pose a potential risk of thermal injury to surrounding tissues, and the additional electronic components increase system complexity, thereby constraining further miniaturization.

A particularly space-efficient approach to miniaturization is to use an external magnetic field to do all the work, eliminating the need for any internal battery or electronics.

Millimeter-scale magnetic collection devices fabricated by 3D printing can operate without any onboard electronics^[62]. Combining super-absorbent polymer pads with magnetically controlled valves has enabled multi-capsule cluster collection even in very narrow spaces such as the bile and pancreatic ducts^[63]. Magnetically driven microfluidic capsules can further enable the collection of multiple independent microbial samples from different GI locations during a single transit, with separate channels minimizing cross-contamination^[11]; A six-channel magnetically controlled design has also been proposed for sequential microbiome sampling^[64]; however, magnetic control of capsule orientation should be distinguished from the energy source required by the internal sampling mechanism. The blindly controlled magnetically actuated capsule (BCMAC) was designed to simplify clinical operation, allowing a clinician to trigger sampling by manually moving a strong external magnet over the patient’s abdomen, without requiring a robotic magnetic control system^[65]. A resonant magnetic spring design reduces the field strength required to as little as 6 mT by exploiting the resonance of an alternating magnetic field, though the resonant response can be dampened by intestinal fluid^[66]. Other spring-magnet configurations have also been developed in which deformation of a flexible internal membrane generates negative pressure for fluid aspiration^[67].

Maximizing the volume of sample collected per swallow has been a particular research focus for microbiome studies that require large amounts of material. Optimizing internal architecture has produced a chamber capacity of 290 mg (52% of the capsule’s total volume), sealed by a 2.8 N magnetic force^[68]. A dual-chamber design incorporating a distance-modulation mechanism can achieve a sampling capacity of 1,020 µL per chamber, representing one of the largest reported passive sampling volumes; however, its operation requires highly accurate real-time localization of the capsule^[69].

Beyond luminal fluid, many clinically relevant gut microorganisms reside preferentially on or within the mucosal surface. Magnetically controlled brush capsules that sweep the intestinal wall, modeled on the brush cytology used in conventional endoscopy, address this^[70,71]. A sequential dual-brush configuration incorporating a nonlinear internal spring can increase the scraping force while reducing mechanical interference between the brushing motion and capsule locomotion. Nevertheless, achieving smooth, reproducible, and predictable brush motion remains a key technical challenge.