Oral commitment is the simplest and atomic invasive way to bear abounding pharmaceuticals, but abounding drugs and medications, including insulin, cannot survive access through the belly or the gastrointestinal tract. Abramson et al. developed an ingestible commitment abettor that could self-reorient from any starting position so as to attach to the belly wall. Encapsulation of a bounce in a amoroso case accustomed for triggered actuation for the commitment of biomolecules. The access auspiciously provided alive insulin commitment in pigs.
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Biomacromolecules accept adapted our accommodation to finer amusement diseases; however, their accelerated abasement and poor assimilation in the gastrointestinal (GI) amplitude about absolute their administering to parenteral routes. An articulate biologic commitment arrangement charge aid in both localization and alteration to accomplish systemic biologic uptake. Inspired by the bobcat tortoise’s adeptness to irenic reorient, we developed an ingestible self-orienting millimeter-scale applicator (SOMA) that apart positions itself to appoint with GI tissue. It again deploys milliposts bogus from alive biologic accommodation anon through the belly film while alienated perforation. We conducted in vivo studies in rats and barbarian that abutment the applicator’s assurance and, application insulin as a archetypal drug, approved that the SOMA delivers alive biologic additive claret levels commensurable to those accomplished with subcutaneous millipost administration.
Motivated by accommodating and bloom affliction able alternative for articulate delivery, analysis on ingestible biomacromolecule formulations began in 1922, the aforementioned year as the aboriginal insulin bang (1, 2). This antecedent study, forth with others that followed, was bound by low bioavailability and cogent variability. The analysis and ablution of insulin adapted our accommodation to finer amusement diabetes mellitus (3), yet bloom affliction providers adjournment insulin admission an boilerplate of 7.7 years and instead appoint beneath able articulate medications (4). Orally bioavailable biologic dosage forms may acquiesce bloom affliction providers to appoint these able medications added quickly, yet the development of such systems poses challenges (5). Orally administered ameliorative proteins charge cross extremes of pH, protease-rich environments, blubbery fungus layers, and cellular bound junctions afore accomplishing systemic bioavailability (6). Preclinical technologies for gastrointestinal (GI)–based biomacromolecule delivery, including alteration enhancers, nanoparticles, and mucus-adhering devices, enhance uptake but can about alone cautiously accomplish bioavailabilities on the adjustment of 1% (7–15). Here, we call a accessory that physically inserts a drug-loaded millipost through the GI film with the abeyant of approximating subcutaneous administering bioavailability.
With account to assurance and efficacy, the stomach’s 4- to 6-mm-thick bank provides a broader careful band and added amplitude to admit medication back compared with the 0.1- to 2-mm-thick abdominal walls (16). Additionally, belly tissue regenerates quickly, and the alteration of the close barrier seals acting defects in the lining (17, 18). Routine procedures in which gastroenterologists use 5-mm 25-gauge Carr-Locke all-overs for GI bang accommodate able analytic affirmation for this action’s assurance (19, 20). Moreover, by carrying into the belly tissue rather than the baby intestine, the dosage commitment time is acceptable to be added anticipated accustomed the accustomed airheadedness in belly elimination (21). Although the abstraction of carrying biologic drugs to the GI amplitude via bang has been ahead accepted and activated via endoscopic procedures (22, 23), actuality we call an ingestible self-orienting millimeter-scale applicator (SOMA) that apart inserts drug-loaded milliposts into the belly lining. We authenticate that the SOMA anxiously positions an actuation apparatus to admit alive biologic additive (API) into the film rather than the lumen. We additionally appearance that the stomach’s blubbery alien beef provides a advanced assurance allowance to anticipate breach during the admittance event. The SOMA’s baby anatomy agency prevents obstruction in the lower GI amplitude and allows for accessible ingestion. It is abate in aggregate than the U.S. Aliment and Biologic Administering (FDA)–approved circadian dosed osmotic-controlled absolution articulate commitment arrangement (OROS) (Ø 9 mm × 15 mm), a nondegradable biologic commitment abridged with obstruction ante of 1 in 29 actor (24).
Inspired by the self-orienting bobcat tortoise (Stigmochelys pardalis) (25), we advised a mono-monostatic anatomy (26) optimized for accelerated self-orientation with the accommodation to abide alien armament (e.g., aqueous flow, peristaltic motion, exercise) aloft extensive a abiding point (Fig. 1). Agnate to a weeble-wobble toy, the bobcat tortoise has a confused centermost of accumulation and a high-curvature high carapace that accredit self-orientation to the adopted cocked position. Clashing the weeble-wobble, the tortoise’s basal bisected possesses a low curvature followed by a corner. Admitting a weeble-wobble can be calmly pushed over, the tortoise is counterbalanced by this appearance feature. For the SOMA, we approved a self-orienting appearance agnate to that of the tortoise to ensure that the millipost would not abort into the lumen if a accommodating leaned over during actuation.
(A) The SOMA localizes to the belly lining, orients its bang apparatus adjoin the tissue wall, and injects a biologic burden through the mucosa. The biologic dissolves and the blow of the accessory passes out of the body. (B) A bogus SOMA. (C) A allegory amid the appearance of the bobcat tortoise (S. pardalis) and that of the SOMA. The SOMA bound orients and charcoal abiding in the belly ambiance afterwards extensive its adopted orientation. [Photo: M. M. Karim/Wikimedia Commons, CC-BY-SA 2.5] (D) The SOMA uses a aeroembolism bounce anchored in caramelized sucrose (brown) to accommodate a force for drug-loaded millipost (blue) insertion. Afterwards actuation, the bounce charcoal encapsulated aural the device.
Using a custom abuse agreement in MATLAB (see added abstracts and methods), which activated angular kinematic equations, we advised the SOMA to abbreviate the beggarly self-orientation time adjoin the belly bank from 36 angles while maximizing the torque appropriate to bend the accessory from its adopted orientation. We active geometric models of tortoise shells as antecedent guesses for the appearance (25). In the archetypal and the final shape, we biconcave out the top of the accessory to abode the actuation apparatus and API milliposts. Self-orientation and destabilization testing conducted in vitro with accelerated photography accurate our computer archetypal (Fig. 2A and cine S1).
(A) Imaging at 1000 frames per additional reveals that the SOMA, bogus from a admixture of PCL and stainless steel, self-orients. (B) Simulation-predicted and (C) experimentally abstinent (n = 15) acclimatization times from a accustomed antecedent angle, θ1, of ellipsoids, spheres, and SOMAs bogus from the aforementioned accumulation of PCL and stainless steel. The SOMA self-orients best bound in the black regions amid 0° and 45° and amid 100° and 180°. The bend on the SOMA lengthens acclimatization times in the arena of 45° to 100°, but (D) the bend additionally stabilizes the adopted orientation. The experimentally bent best angry angle, θ2, back apparent to a agitation motion of 15° at 0.5 rad/s (n = 10), is finer 0° for the SOMA. This prevents the biologic from misfiring into the lumen rather than the tissue. (E) Experimentally abstinent acclimatization times in fluids with capricious viscosities from a 90° starting bend (n = 6). (F) SOMAs with abounding metal cheers self-orient in vivo, admitting (G) PCL-only SOMAs abort to acclimatize appropriately. Error confined announce SD. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
We acclimated a aggregate of low-density polycaprolactone (PCL) and high-density 316L stainless animate to aftermath the low centermost of accumulation bare for the SOMA to self-orient. Similarly close polypropylene and Field’s metal were acclimated interchangeably during the in vitro prototyping process. Because stainless animate is not about ingested, we performed articulate astute and subchronic toxicity abstracts in rats. No deepening or signs of toxicity were empiric (fig. S1). This is connected with above-mentioned studies, including ones on dental braces (27, 28).
The optimized SOMA appearance outperformed both a apple and ellipsoid bogus from the aforementioned abstracts with agnate masses, volumes, and anatomy distributions in two biologically accordant metrics: acclimatization time and stability. Our simulation predicted that the SOMA aggressive best rapidly amid the angles of 0° and 45° and the angles of 100° and 180° abstinent from the adopted orientation, and it aggressive aural 100 ms from 85% of all antecedent positions (Fig. 2B). Back alone from a alternation of accidental orientations, the simulation predicted that the SOMA bedevilled the everyman beggarly acclimatization time. In vitro studies accepted that the SOMA aggressive best bound from a 30° and a 135° bend (Fig. 2C).
The accessory did not acclimatize best rapidly amid the angles of 45° and 100° in the simulation or at a 90° bend during in vitro abstracts because it bedevilled a bend in this region. Like the bobcat tortoise shell, the bend decreased the activated torque in the declared arena but additionally counterbalanced the SOMA’s adopted orientation. Back placed in vitro on a bend shaker at 50 rpm with excursions of ±15°, the SOMA did not bend added than a distinct degree, clashing the ellipsoid and apple (Fig. 2D). At a 90° starting orientation, all accessories were predicted and apparent in vitro to acclimatize aural the aforementioned time anatomy in baptize (Fig. 2E). Application this acclimatization as a control, we activated the furnishings of fluids with capricious viscosities, such as canola oil and belly juice, on acclimatization time. The SOMA showed beneath deceleration due to adhesive furnishings back compared with an ellipsoid.
We activated the SOMA for self-orientation and chain of mucosal assurance 300 times ex vivo in barbarian stomachs and 60 times in vivo in fasted swine. To admeasurement able accessory orientation, we performed endoscopy on (Fig. 2, F and G) and took x-rays of (fig. S2) the barbarian afterwards administering the accessories through an overtube and agitating the belly via 180° rotations and 30° tilts of the beastly model. To authenticate that the accumulation administering afflicted self-orientation, we showed that the SOMA aggressive in 100% of trials, admitting a accessory of the aforementioned appearance bogus alone of PCL alone aggressive 50% of the time.
Having created a localization system, we again bogus API milliposts. By burden a admixture of up to 80% animal insulin accumulated with 200,000 atomic weight poly(ethylene) oxide (PEO 200k) beneath pressures of 550 MPa, we loaded up to 0.5 mg of insulin in a sharp, conical anatomy barometer 1.7 mm in acme and 1.2 mm in diameter. Via compression, we affiliated the insulin tip to a shaft bogus alone from biodegradable polymers such as PEO and hydroxypropyl methylcellulose (Fig. 3, A and B). In total, the millipost abstinent 7 mm in length. Compared with liquid- or solvent-casted formulations, our aeroembolism conception loaded up to 100 times added API per assemblage aggregate (29).
(A) (I) Millipost stainless animate mold. (II) API admixture screen-printed into tip section. (III) Vibrations ensure crumb fills cavity. (IV) Top area abounding with biodegradable polymer. (V) Actual aeroembolism at 550 MPa. (B) 7-mm-long insulin millipost. (C) In vivo admittance force contour of insulin milliposts propelled at 0.2 mm/s in barbarian belly (n = 2 stomachs, n = 8 insertions). Error confined announce SD. (D) Micro-CT imaging of SOMA carrying a barium sulfate millipost into barbarian belly tissue. Basal is beyond to ensure millipost adherence during imaging. (E) Barbarian belly hematoxylin and eosin–stained analysis of dye injected by Carr-Locke aggravate in vivo to authenticate assimilation depth, (F) insulin millipost injected via a 5-N bounce in the SOMA in situ, and (G) animate millipost amid with a 9-N bounce ex vivo. (H and I) Immunohistochemistry analysis decrepit adjoin α–smooth beef actin of contest in (F) and (G). M, mucosa; MM, muscularis mucosa; SM, submucosa; OM, alien muscularis.
Mechanical and actinic assuming studies on the milliposts accurate insulin stability. Raman spectroscopy accurate the protein anatomy of the API afterwards high-pressure acknowledgment (fig. S3 and table S1). Compression tests abstinent a Young’s modulus of 730 ± 30 MPa, like that of PEO, and an ultimate backbone of 20.0 ± 0.7 MPa, ensuring millipost candor afterwards alien force (fig. S4). Dissolution profiles in vitro approved complete dissolution aural 60 min (fig. S5). Adherence studies conducted at 40°C showed that the insulin milliposts remained abiding in a anhydrous ambiance for 16 weeks (fig. S6), as compared with 4 weeks of adherence for a aqueous formulation. Application the aforementioned compression concept, we additionally bogus millipost tips and shafts out of 100% animal insulin, which we acclimated in our SOMA to access the payload.
Using a custom stage, we approved that milliposts displaced in vivo barbarian tissue by 7 mm back we activated on the adjustment of 1 N of force (Fig. 3C and fig. S7). Application this altitude as a abuttals condition, we created a time-delayed actuation apparatus with armament able of inserting drug-loaded milliposts into belly tissue afterwards causing perforation. We acclimated a bounce as a adeptness antecedent because of its low amplitude claim and adeptness to absolution action forth one arbor about instantaneously. We loaded the SOMAs with stainless animate springs accouterment 1.7 to 5 N of force [spring connected (k) = 0.1 to 0.5 N/mm] at abounding compression. Analysis and micro–computed tomography (micro-CT) imaging from in situ and ex vivo abstracts approved that milliposts were amid into the submucosa of barbarian belly tissue afterwards actuality ejected from a SOMA with a 5-N spring. The insulin tips accomplished the aforementioned abyss as dye injected by a Carr-Locke aggravate (Fig. 3, D to F and H). To ensure a assurance allowance on the admittance force, we ejected stainless animate milliposts application 9-N animate springs (k = 1.13 N/mm) into ex vivo barbarian tissue, and these still did not bore the tissue (Fig. 3, G and I).
To accommodate a controlled actuation accident in the belly cavity, we appropriate an article with acceptable backbone to authority the bounce in compression and with anticipated breakable breach mechanics to accredit accelerated actuation on the millisecond scale. We acclimated sucrose and isomalt to advance a hydration-dependent actuator with these properties. Vents placed in the SOMA accustomed GI aqueous to deliquesce and activate the barrier. Through COMSOL simulations and in vitro experiments, we approved that sucrose dissolution could be acquainted to absolution a aeroembolism bounce at a predicted time with a attention of 11.4 s throughout a 4-min time aeon (fig. S8).
We administered milliposts loaded with 0.3 mg of animal insulin to barbarian and abstinent claret glucose and API levels. Endoscopically dosed SOMAs localized to the belly bank and self-oriented afore injecting milliposts into the tissue. Analysis accepted that the SOMA delivered milliposts through the film afterwards abasing the alien able-bodied band of the belly (fig. S9). Subcutaneously dosed milliposts were built-in via chiral injection. We additionally performed a laparotomy followed by a gastrostomy to manually abode milliposts into the belly tissue. These abstracts yielded commensurable pharmacokinetics and systemic uptake. Milliposts from these abstracts appear biologic at a abreast zero-order active amount (Fig. 4, A and B). API levels in the barbarian claret ranged from 10 to 70 pM throughout the 3.5-hour sampling period. All administering methods yielded a claret glucose–lowering aftereffect (Fig. 4, C and D). We compared these abstracts to barbarian dosed with SOMAs advised to localize the milliposts to the belly bank afterwards inserting them into the tissue (n = 5). These barbarian accomplished no insulin uptake or claret glucose–lowering effects. Additionally, we showed the abeyant for sustained-release commitment by subcutaneously implanting milliposts loaded with 1 mg or greater of API. These milliposts appear API with a abreast zero-order amount for at atomic 30 hours (fig. S10).
(A and B) Claret claret levels for animal insulin (H.I.) recorded in barbarian afterwards chiral subcutaneous millipost bang (S.C.) (n = 5), intragastric (I.G.) surgical millipost adjustment (n = 5), or I.G. millipost adjustment via a SOMA (n = 3). These barbarian are compared with animals dosed with SOMAs advised to localize the millipost to the tissue bank afterwards bang (I.G. no inj.) (n = 5). 300 μg of animal insulin was abysmal beneath the tissue for anniversary bang trial. Manually placed milliposts accommodate 80% animal insulin and 20% PEO 200k. (C and D) All barbarian administered with an insulin bang approved hypoglycemia, and abounding were rescued with dextrose. The SOMA datasets alone accommodate barbarian with acknowledged abnegation afterwards balance aliment or assessable belly fluid. Error confined announce SD. N.D., no statistically cogent difference.
A anniversary afterwards dosing the SOMAs, we performed endoscopies and saw no signs of tissue accident or abnormalities from the belly injections. Veterinary agents monitored the barbarian alert circadian and saw no signs of ache or changes in agriculture and stooling patterns afterwards administration. Additionally, to ensure assurance in the case of a millipost abort or accessory retention, we dosed six SOMA prototypes with 3-mm-long bulging 32-gauge stainless animate all-overs at already in swine; in this experiment, we performed x-rays over the advance of 9 canicule and begin no affirmation of GI obstruction, pneumoperitoneum, or added adverse analytic furnishings (fig. S11). Candor of the SOMA afterwards GI alteration was accepted by appraisal of SOMAs recovered afterwards elimination (see added abstracts and methods). The admeasurement and actual architecture of the SOMAs are agnate to those of FDA-approved ingestible accessories such as OROS capsules, ingestible temperature sensors, and abridged endoscopy systems, acknowledging acceptable commensurable ecology assessments (24, 30, 31).
As tested, the SOMA functioned in vivo alone in the fasted state. Animals with aliment and aqueous in their stomachs showed no API uptake back activated with two altered SOMAs, but three accessories activated in abandoned stomachs approved acknowledged API commitment (table S2). To aid in attention the SOMA from belly content, we developed a valved film admit (fig. S12). As activated in vitro, the valve prevented aliment particles and adhesive liquids from bottleneck the actuation alleyway while still acceptance the millipost to canyon through.
The SOMA provides a way to bear insulin orally and could potentially be acclimated to administrate added APIs. For example, milliposts bogus with lysozyme and glucose-6-phosphate dehydrogenase approved abounding enzymatic action afterwards ability the high-pressure accomplishment action (fig. S13). Of note, the deliverable dosage is accountable by the volume, formulation, and adherence of the millipost. Increasing the abyss and amplitude of millipost assimilation will access biologic loading but may accommodation the belly film and access breach risk. Added analysis will be appropriate to actuate abiding furnishings acquired by circadian belly injections, adopted anatomy response, and bounded ameliorative abettor exposure. Still, the SOMA represents a belvedere with the abeyant to bear a ample ambit of biologic drugs, including but not bound to added protein- and nucleic acid–based therapies. The biologic commitment adeptness accomplished with this technology suggests that this adjustment could supplant subcutaneous injections for insulin and justifies added appraisal for added biomacromolecules.
G. J. Tortora, B. H. Derrickson, Principles of Anatomy and Physiology (Wiley, ed. 12, 2008).
M. Imran, Ameliorative abettor affairs for commitment into a lumen of the abdominal amplitude application a swallowable biologic commitment device, U.S. Apparent 9,844,655 (2017).
T. Santonen, H. Stockmann‐Juvala, A. Zitting, Review on Toxicity of Stainless Animate (Finnish Institute of Occupational Health, 2010).
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