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Tag: Biomedical engineering

  • Sacrificial capillary pumps to engineer multiscalar biological forms

    Sacrificial capillary pumps to engineer multiscalar biological forms

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  • Applied body-fluid analysis by wearable devices

    Applied body-fluid analysis by wearable devices

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  • Mineralized collagen plywood contributes to bone autograft performance

    Mineralized collagen plywood contributes to bone autograft performance

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    Matrix preparation

    Collagen extraction

    Type I collagen monomers were extracted from rat tail tendons following a classical procedure. Fresh tendons were washed with phosphate-buffered saline solution and solubilized in 0.5 M acetic acid. The raw solution was centrifuged and the supernatant was selectively precipitated with 0.7 M NaCl. Precipitated type I collagen was solubilized in 0.5 M acetic acid and then desalted by dialysis against 0.5 M acetic acid. The concentrations of type I collagen solutions were assessed by hydroxyproline titration and adjusted to a final stock concentration of approximately 3 mg ml−1.

    Matrix synthesis

    All of the experiments were carried out at room temperature (19 ± 2 °C) to prevent collagen denaturation and sterility was kept throughout the procedure. The matrices were stored in distilled water at 4 °C before implantation.

    Col40 (rat model)

    The collagen solution was progressively concentrated up to 40 mg ml−1 by slow evaporation of the solvent in a safety cabinet52. Then, fibrillogenesis in vitro was performed under ammonia vapours for 24 h. This step allows the stabilization of the liquid-crystalline organization into dense fibrillar matrices53. Finally, matrices were punched with an 8-mm steel trepan and rinsed with sterile phosphate-buffered saline until neutralization of the pH.

    Col100 (rat model)

    Below the critical concentration of 40 mg ml−1, type I collagen molecules do not organize52. However, above this threshold concentration, they undergo a spontaneous transition into ordered liquid-crystalline phases owing to the lyotropic properties of acidic type I collagen solution in vitro19. After a sol–gel transition leading to collagen fibril formation, the geometries of fibrillary networks closely mimic those found in living tissues, depending on the targeted concentration (at least 80 mg ml−1 for cholesteric bone-like mesophase)53,54. The Col100 matrix was prepared using a procedure that combines injection and reverse-dialysis processes to increase the collagen concentration17. A 15 ml volume of about 1 mg ml−1 soluble acidic collagen solution (0.5 mM acetic acid) was continually injected (rate range 1 μl min−1 to 15 ml min−1) in a closed dialysis chamber (3 mm thickness and 10 mm width) for 8 days. The bottom of the chamber contained a dialysis membrane with a molecular weight cut-off of 12–14 kDa. The reverse-dialysis process was set against polyethylene glycol (35 kDa, Fluka) dissolved in 0.5 M acetic acid up to about 150 mg ml−1. The flow of the collagen solution was controlled to maintain the same pressure on each side of the dialysis membrane. After injection, dialysis was continued for 8 days, to obtain a homogeneous concentration in the samples. The pH was then increased to a range of 9–10 by ammonia gas diffusion for 4 days to induce collagen fibrillogenesis and stabilize the liquid-crystalline organization into dense fibrillar matrices29. The matrices were then removed from the dialysis chamber and washed several times in double-distilled water until neutralization. Finally, matrices were punched with an 8-mm steel trepan before implantation.

    Col (ewe model)

    The procedure matched the Col100 matrix except that: (1) the initial volume of the acid solution was 30 ml and (2) the mould dimensions were diameter 8 mm and depth 13 mm. Here the process to elaborate the materials ends with the removal of the stabilized fibrillar matrix directly from the mould that allows the shaping of the collagen construct.

    Col-CHA (ewe model)

    The Col-CHA matrix was prepared as follows: a volume of a 3 mg ml−1 soluble acidic collagen solution (0.5 mM acetic acid) was mixed with a CaCl2/NaH2PO4/NaHCO3 acidic solution (0.5 mM acetic acid). According to a previously described procedure (col/CHA in ref. 20), the procedure is consistent with the synthesis of preferentially B-type CHA, which has a formula of Ca10−x(PO4)6–x(CO3)x(OH)2–x with 0 ≤ x ≤ 2. The pH was adjusted to 2.2. The final concentration of the collagen solution was about 1 mg ml−1 and the final ionic strength was 165.9 mM. The procedure matched the Col matrix except that the initial volume of the acid solution was 30 ml.

    ColCG-CHA (ewe model)

    The procedure matched the Col-CHA matrix except that commercial acidic clinical-grade collagen was used instead of collagen extracted from rat tail tendons to avoid inflammatory response. Bovine skin type I collagen diluted in acetic acid at a concentration of 5 mg ml−1 was purchased from Symatese (reference ACI070). The use of clinical-grade collagen was chosen to eliminate any potential immunologic responses arising from variations in collagen-purification processes55, thereby enabling the evaluation of our samples as potential bone biomaterials. Although both collagen solutions exhibit lyotropic properties and the ability to form fibrils necessary to produce high-density twisted plywood collagen matrices, clinical-grade collagen demonstrates higher purity and greater thermal stability (see Extended Data Fig. 7).

    Commercially available mineral-based substitutes

    Vitoss 1.2 cc blocks (reference 2102-0013 Stryker) is composed of a porous (up to 90%) structure of β-tricalcium phosphate. The Vitoss block was shaped with a scalpel to fit the defect. Mastergraft 5cc Granules (reference 7600105, Medtronic) is composed of 80% porous resorbable ceramic granules (15% HA, 85% β-tricalcium phosphate).

    Autologous bone

    AB fragments were extracted from iliac crest. The animal’s own blood serum was kept and the fragments were subsequently used as bone filler.

    Reference human bone sample for SEM and TEM

    The bone samples observed by SEM in Fig. 1a,b and by TEM in Fig. 3c were prepared as part of a previous study56.

    Bone powder

    The organic matrix (collagen and other proteins) was removed from bone sample by immersion in dilute NaClO aqueous solution treatment to extract the mineral particles (Extended Data Fig. 1), as previously described36.

    Matrix characterization

    SEM and elemental characterizations

    Collagen matrices were fixed in 2.5% glutaraldehyde in a cacodylate solution (0.05 M). After washing in a cacodylate/saccharose buffer solution (0.05 M/0.6 M, pH 7.4), dehydration in increasing ethanol baths, matrices were dried at the carbon dioxide critical point using a Leica EM CPD300. Samples coated with a 10 nm gold layer were observed in a Hitachi S-3400N at an accelerating voltage of 10 kV.

    TEM

    Matrices were fixed in glutaraldehyde, washed and dehydrated as described for SEM and embedded in araldite. The matrices prepared without mineral (Col40, Col100 and Col) were also post-fixed with 2% osmium tetroxide for 1 h at 4 °C before dehydration. Ultrathin sections (70 nm) were obtained, stained with uranyl acetate and observed in a FEI Tecnai G2 Spirit TWIN electron microscope operating at 120 kV.

    WAXD (transmission mode)

    Small parts of the mineral matrices were cut out of the bulk sample and inserted in X-ray cylindrical borosilicate capillary tubes. The tubes were flame-sealed to keep the samples hydrated and then placed directly in the vacuum chamber beam. X-ray diffraction experiments were performed with a S-MAX 3000 RIGAKU using a monochromatic CuKα radiation. The data were collected in the 5–60° range (2θ). The sample-to-detection distance was 0.059 m. The data were analysed using FIT2D (version 18, beta) software. The 2D WAXD patterns were collected with imaging plates and then scanned with 50 μm resolution. The diameter of the cylindrical beam dimension at the specimen was 400 μm and the sample thickness was approximately 1 mm.

    Differential scanning calorimetry

    Experiments were performed on a TA Q20 apparatus. The heating rate was set at 5 °C min−1 and the temperature ranged from 25 °C to 55 °C. About 20 mg of sample was weighed and put in an aluminium pan, the reference being an empty sealed aluminium pan. Collagen purity is determined on the basis of thermal stability. Collagen solutions typically exhibit an endothermic peak around 40 °C, indicating denaturation into gelatine that occurs through the irreversible unfolding of the triple helix57.

    Polarized light microscopy

    The materials were placed, without any treatment, between a glass slide and a coverslip. Observations were made using a transmission Zeiss Axio Imager A2 POL. The microscope was equipped with the standard accessories for examination of birefringent samples under polarized light (that is, crossed polars) and an Axiocam CCD camera.

    SDS-PAGE

    Sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) of type I collagen extracted from rat tail tendons and bovine dermis (clinical grade) was performed, using an acrylamide (10%)/bis-acrylamide (30%) gel in the presence of tris-HCl 1.5 M (pH 8.8), SDS, EDTA, glycerol and 2-mercaptoethanol. Migration was checked by adding bromophenol blue to the samples (0.05%). The separated protein bands were identified by comparison with a standard molecular mixture marker (Sigma-Aldrich) including the α chain of type I collagen (125.103 KDa).

    Mechanical characterization

    The local Young’s modulus E of the Col40, Col100 and Col-CHA matrices was estimated at room temperature (22 °C) through microindentation (Piuma Nanoindenter, Optics 11 Life). To this aim, the Col40 and Col100 matrices were used as is (see Fig. 2c), whereas the Col-CHA matrix shown in Fig. 3e was cut into a piece of thickness about 1 mm. These matrices were immersed in their conservation medium at the bottom of a small Petri dish and their upper surface was indented using a spherical glass probe of radius R attached to a cantilever of calibrated stiffness k, with R = 105 µm and k = 0.45 N m−1 for Col40 and R = 51 µm and k = 0.26 N m−1 for Col100 and Col-CHA. Depending on the sample, these indentation tests involved forces ranging from 0.15 µN to 1.2 µN and penetration depths of 0.5–12 µm at the end of the loading phase, and to contact radii of 5–30 µm between the probe and the matrix. For each sample, about 200 independent indentations spaced by 50–200 µm were performed and each force–depth curve was fitted by a Hertzian contact model, yielding the effective Young’s modulus Eeff at the locus of the indent. The local Young’s modulus E was then computed through E = Eeff(1 − ν2), assuming a Poisson ratio ν of 0.5 for all samples. The statistical analysis of the Young’s modulus data was performed using MATLAB (release R2018b) software.

    Implantations

    Rat calvaria critical-size defect

    The study was reviewed and approved by the Animal Care Committee of the University Paris Descartes (no. P2.JLS.174.10) The 30 8-week-old (220–240 g) male Wistar rats used in the study were housed in individual cages at stable conditions in the animal facility of the Laboratoire Pathologies, Imagerie et Biothérapies Orofaciales, Université Paris Cité. The surgical procedures were performed as described previously24,25,58. After anaesthesia with an intraperitoneal injection of 100 mg per kg body weight of ketamine and 10 mg per kg body weight of xylazine hydrochloride (Centravet Alfort), the cranial area was shaved, disinfected and the skin was incised in the sagittal direction. The periosteum was then incised in the same direction and elevated to expose the underlying calvaria. An 8-mm defect was created in the centre of the calvaria using a steel trephine mounted on a low-speed dental handpiece, under sterile saline irrigation. The defects were randomly filled with dense collagen matrices, either twisted plywood organized fibrils (100 mg ml−1; Col100, n = 10) or randomly dispersed fibrils (40 mg ml−1; Col40, n = 10) or left empty (controls n = 8). The skin flap was then replaced and secured with interrupted sutures. After 10 weeks, rats were anaesthetized as previously and euthanized using exsanguination. The skulls were removed and fixed in 70% ethanol. Three animals were excluded from further analysis: in the control group, one animal died and another had an incomplete defect created during the surgical procedure; in the Col100 group, one animal had its underlying dura mater and mid-sagittal sinus damaged, thus introducing a technical bias.

    Radiomorphometric analysis (rat)

    The skulls were radiographed (exposure 13 kV, 12 mA, 15 min) in a microradiography unit (model Sigma 2060, CGR) with X-ray film (Kodak Professional Films). Morphometry was performed at a constant magnification with a semi-automatic image analyser coupling the microscope to a video camera and a computer. The percentage of bone-defect closure, corresponding to the percentage of radiopacity in skull defect, was calculated as the following ratio: area of radiopaque formation in the defect/area of the defect created by trephination × 100 using ImageJ software (v1.52a).

    µCT

    µCT was performed in IMOSAR, Laboratoire de Biologie, Bioingénierie et Bioimagerie Ostéo-articulaires (B3OA), UMR CNRS 7052 INSERM U1271, Université de Paris. Representative samples were scanned using a desktop micro-X-ray computed tomography (Micro-CT SkyScan 1172, Bruker), source voltage 59 kV, source current 100 μA, image pixel size 17.77 μm. Each sample was rotated 180° with a rotation step of 0.7°, exposure time 90 ms. 3D reconstruction and analysis were made with NRecon SkyScan software 1.7.1.6 (Bruker).

    Statistical analysis

    Given the high variability of the in vivo response and the related small sample size, the Kruskal–Wallis test (α = 0.05, no correction, multiple comparison using the Mann–Whitney test) was used to assess overall differences between groups owing to its robustness in handling nonparametric data, whereas independent two-sided pairwise comparisons using the Mann–Whitney U test were performed to detect any potential trends or variations between specific groups. The results were discussed following two levels of significance. Differences were considered strictly significant if P < 0.05, whereas a P < 0.10 indicates a trend in the data. The statistical tests conducted in this study are indicated in the figure legends as follows: *P < 0.05 and **P < 0.10. Data are given as mean ± s.d.

    Histomorphometric analysis (rat)

    After dehydration, the explants were embedded without demineralization in methyl methacrylate (Merck). 4-μm-thick sections were cut in the frontal plane with a Polycut E microtome (LEICA) in the central part of the defect. Sections were stained with toluidine blue, von Kossa or processed for enzyme histochemistry (Extended Data). Morphometry was performed at a constant magnification with a semi-automatic image analyser coupling the microscope to a video camera and a computer. TRAP sections were used to count the number of osteoclasts by millimetre based on 1/10th of the section. The von Kossa staining was used to quantify the percentage of mineralized tissue in the defect, calculated as the following ratio: area of matrix-related mineralized tissue/area of the defect × 100.

    Enzyme histochemistry (rat)

    ALP activity was revealed with naphthol AS-TR phosphate (Sigma-Aldrich) and diazoted Fast Blue RR (Sigma-Aldrich). TRAP was detected using Fast Red TR Salt (Sigma-Aldrich) and naphthol AS-TR phosphate (Sigma-Aldrich).

    SEM characterization of histological sections

    Unstained bone histological thin sections were coated with 10 nm of carbon and imaged with a Hitachi S-3400N scanning electron microscope with an accelerating voltage of 10 kV. Energy-dispersive X-ray spectroscopy was performed using an Oxford Instruments X-Max detector (20 mm2). Using SEM to characterize histological sections is useful to visualize the in situ mineralization in which the fibrillar collagen matrix disappears in favour of mineral aggregates59,60.

    Ewe critical-size defect surgical procedure

    Two studies were conducted on ewe. Both studies were reviewed and approved by the IMM Recherche’s Institutional Animal Care and Use Committee before the initiation of this study. The Animal Care and Use Committee of the IMM Recherche is registered at the CNREEA under the Ethics Committee no. 37. The animal research centre (IMM Recherche) received an agreement (no. 75-14-01) by the Direction Départementale de la Protection des Populations. The studies were also performed in compliance with the Principles of Laboratory Animal Care, formulated by the National Society for Medical Research, and the Guide for the Care and Use of Laboratory Animals, by the Institute for Laboratory Animal Resources (published by the National Academies Press), as amended by the Animal Welfare Act of 1970 (P.L. 91-579) and the 1976 amendments to the Animal Welfare were followed. The surgical procedures were performed as described in ref. 39. This model for bone-defect reconstruction differs from the healing process of larger load-bearing defects, which often necessitate a further specific procedure, such as fixation plate61. A total of eight hole defects (diameter 8 mm, depth 13 mm) per animal (two animals for a total of 16 for ewe study no. 1 and six animals for a total of 48 for ewe study no. 2) were created with a drill into the distal and proximal metaphysis of the humerus and femur. After washing the bone cavity with saline solution, the holes were randomly left empty to heal or fill with the different materials (ewe study no. 1: Col and Col-CHA, n = 5 each; ewe study no. 2: ColCG-CHA n = 12, VO, MG and AB, n = 5 each). Then, the wound was covered with the adjacent tissues and the skin was stapled. Two months after surgery, the sheep were euthanized and both femoral and humeral bones were collected, freed from all overlying tissues and the drill holes were identified. Bone samples were cut perpendicular to the original drill hole.

    Faxitron X-ray radiographic imaging

    Bone samples were imaged with a cabinet X-ray system to screen, track and evaluate structural, bone density and bone distribution changes using a Faxitron system. Transversal slices of bones taken from the implant sites were submitted to X-ray analysis using Faxitron SR v1.5.

    Scanner imaging

    Bone samples were submitted to computed tomography scan analysis to investigate 3D reconstruction of the implants sites using a 256 Slice GE Revolution CT Scanner and observed with RadiAnt DICOM Viewer 2022.1.1.

    Radiological image analysis

    ImageJ software (v1.52a) was used to blindly analyse radiographic images from the rat experiment and Faxitron X-ray and scanner images from the first ewe experiment. First, each image was converted to greyscale and a grey-level threshold was set to discriminate radiopaque and non-radiopaque areas. Then, an area corresponding to the original defect size was set. Pixels with grey level above the threshold, corresponding to radiopaque bone, were counted and divided by the total amount of pixels in the selected area to obtain a bone-filling percentage. For scanner, as full depth acquisition was performed, several relevant images were analysed and the result was expressed as a mean to represent the bone filling of the entire depth of the defect.

    Bone histological preparation (ewe)

    Samples were fixed in 4% paraformaldehyde solution, dehydrated with increasing ethanol baths and immersed for a week in a solution of butyl methacrylate, methyl benzoate, polyethylene glycol and benzoyl peroxide resin. Polymerization was triggered by the addition of N,N-dimethyl-toluidine and the samples were placed at −20 °C for 48 h. Serial thin sections (4–8 μm) were cut using tungsten carbide knives. Thereafter, the resin was removed using 2-ethoxyethyl acetate and the sections were rehydrated. The sections were then stained for the identification of tissue components in light microscopy analysis, scanned and observed using NDP.view2.8.24.

    Histochemical staining

    GT (haematoxylin, fuchsine, light green)

    The sections were immersed in haematoxylin Weigert solution. After washing, the sections were stained with Ponceau fuchsine. Non-specific staining areas were washed with a 1% phosphomolybdic acid solution. Subsequently, the sections were stained with a light-green solution. After a washing step, the sections were dehydrated with ethanol (increasing gradient) and xylene solutions and then mounted with a resin mounting liquid. Using GT, mineralized bone is stained in green, osteoid in red/orange, nuclei in blue and cytoplasm in light red.

    von Kossa/Van Gieson staining

    Sections were preincubated with 1% silver nitrate solution under ultraviolet light. Then, the non-specific staining patches were washed with 5% sodium thiosulfate solution. The sections were counterstained with Van Gieson picrofuscine. After a washing step, the sections were dehydrated with ethanol (increasing gradient) and xylene solutions and then mounted with resin mounting fluid. After von Kossa staining, calcium deposits are highlighted in brown-black, osteoid in red and other tissue in yellow.

    Haematoxylin–eosin

    Sections were immersed in haematoxylin solution. Then, they were rinsed and stained with a 1% eosin solution. After a washing step, the sections were dehydrated with ethanol (increasing gradient) and xylene solutions and then mounted with resin mounting fluid. After HE staining, nuclei are stained purple, cytoplasm pink and collagen pink-red.

    Histomorphometry

    On the basis of GT and von Kossa-stained histological sections, image analysis (ImageJ2 software v2.0.0) allowed measurement of (1) the amount of mineralized newly formed bone into the defect (mineralized bone surface/total surface) after exclusion of residual biomaterials and (2) the amount of osteoid tissue into the defect (osteoid surface/total surface).

    Reporting summary

    Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

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  • Cephalopod-inspired jetting devices for gastrointestinal drug delivery

    Cephalopod-inspired jetting devices for gastrointestinal drug delivery

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    Jet physics and theoretical model

    To study the influence of jetting parameters (ampule pressure, jet diameter and jet velocity) on tissue deposition, a theoretical model was derived (Extended Data Fig. 1a and Supplementary Methods  1). The jetting apparatus used to investigate jet delivery into ex vivo tissue is described and characterized in Extended Data Fig. 1b–g. The main components of this apparatus were a handheld jetting device for generating jets, and a piezoelectric force transducer (9215 A with 5165A4KH10 LabAmp amplifier; Kistler Instrument) and software (Network Setup Wizard; Kistler Instrument) for measuring jetting impingement force (at 200 kHz sampling frequency). Based on previous literature and theory, variation of nozzle diameter and ampule pressure has the highest impact on penetration in soft tissue20,21,22. A subset of 4 exemplary jetting force profiles with a 257 µm nozzle is shown in Extended Data Fig. 1c. From these force profiles the experimental period of the jetting event, T (Extended Data Fig. 1d), the experimental steady-state jetting force, Fj,exp (Extended Data Fig. 1e), and the experimental steady-state jetting power, Pj (Extended Data Fig. 1f) were extracted. An expanded set of results, including all nozzle–pressure permutations, is shown in Extended Data Fig. 2a–g and the procedure is described in Supplementary Methods  2 and 3.

    To examine the effect of fluid viscosity on jet performance the ampule pressure and diameter were fixed and viscosity was measured23,24,25 between 1 and 219 cPa. The system pressure factor dropped significantly—from a mean of 0.82 to a mean of 0.40 (Extended Data Fig. 2h), while no significant changes were observed for the CT contrast fluid (Extended Data Fig. 2i,j).

    Porcine tissue excision and processing methods

    Female Yorkshire pigs, 3–5 months old and weighing 35–70 kg were used. After euthanasia (procedure described below), a midline incision allowed access to the abdominal cavity. Stainless steel pean forceps were placed at the oral and aboral part of the organ of interest. The organ was then separated from the omentum and removed from the carcass with a scalpel. Precautions were taken to ensure that the tunica serosa and other important tissue layers were kept intact. After excision, the tissue was placed in a plastic bag kept on ice and shipped to the laboratory where ex vivo injections were performed on the same day.

    Bulk sections of tissue ranging from 10 to 35 cm in length (depending on the organ) were extracted from the organs with Mayo scissors and placed into beakers filled with phosphate buffer solution (PBS), pH 7.4. For both the cheek and oesophagus, tissue from the entire organ was used. For the stomach, only tissue from the antrum/lower corpus was used. For the small intestine, only jejunal tissue at least 20 cm from the pylorus was used. For the colon and rectum, distal sections were used. An image of a bulk section of rectal tissue is shown in Extended Data Fig. 3b.

    Smaller sections of tissue (approximately 4 × 4 cm, the final sample size) were extracted from the bulk with scissors. These samples were further cleaned in a separate wash beaker with PBS to remove any remaining chyme or debris. Finally, immediately before injection, the tissue samples were placed on a piece of foam in a 6.5 × 4.7 cm plastic dish. In total, the time between euthanasia of the animal and injection experiments was 2–3 h.

    Ex vivo jet injection study with porcine tissue

    Prior to each set of ex vivo experiments, the polycarbonate ampules were lubricated to improve sliding of the plunger. To accomplish this, the ampules were dipped in a mixture of 5% hexamethyldisiloxane, 95% deionized water solution, then left to dry overnight. Before each injection, the ampule was filled with 232 µl of an aqueous mixture containing 30% micro-CT contrast agent (Iomeron 350 mg ml−1; Bracco), 1% green tissue dye (WAK-HM-G-1/60, WAK-Chemie Medical) and 69% deionized water. The ampule was then mounted onto the handheld jetting device and the input pressure of the device was adjusted to the desired level with a digital pressure regulator. An example image of the device positioned for injection is depicted in Extended Data Fig. 3c,d. Finally, the triggering sleeve was actuated, causing the jetting injection event. Between two and eight replicates were performed for each pair of pressure-diameter inputs, with certain sets of shots performed on the same tissue sample (space permitting). All experimental points can be found in Supplementary Table 3.

    Computed tomography scanning (Phoenix Nanotom M micro-CT; GE Inspection Technologies) was used to evaluate each sample. The stage and detector were positioned at travel distances of 130 mm and 300 mm from the X-ray source, respectively. Background detector calibrations were performed before each scan series. Scans were performed at a tube voltage of 100 kV, radiation intensity of 100 μA and a target scan time of 6 min.

    All scans were performed 10–15 min after injection. After each scan, the tissue samples were placed in plastic histology cartridges (Extended Data Fig. 3e) and stored in 10% formalin solution. Although it was not possible to maintain the original structure of the depot with this storage method due to diffusion and dissolution, the use of green tissue dye in the payload fluid dye enabled us to later identify the tissue layer(s) in which the depot resided. The entire injection and scanning procedure is depicted in Extended Data Fig. 3a.

    Volumetric diffusion, standoff distance and jetting angle ex vivo studies

    Using the methods described above, we also performed a set of studies to determine the impact of volumetric diffusion within tissue, standoff between nozzle and tissue, and angle of incidence between the jet and tissue on delivery characteristics.

    To evaluate the effect of diffusion on the apparent volume of fluid in tissue after injection we performed a set of calibration experiments and found that the apparent volume of fluid in tissue increased at a rate of 0.5 ± 0.1% per min (95% confidence interval). Results from this diffusion study are shown in Extended Data Fig. 3g. GraphPad Prism (GraphPad Software) was used to calculate the linear rate of change of volume with 95% confidence (the intercept was set at 0, 0). Furthermore, the upper error boundary from this analysis was used to make conservative corrections to VDE estimates in subsequent analyses. Photos and diagrams showing the injection, scanning and segmentation processes are shown in Extended Data Fig. 3b–f. Additional scans from jejunal and stomach tissue are shown in Extended Data Fig. 4b–e. Next, each set of injections was semantically categorized as luminal, submucosal or intraperitoneal based on where most of the micro-CT scanned fluid resided on average.

    The results of the nozzle-to-tissue standoff and angle study are shown in Extended Data Fig. 3h,i. For the angle study, a constant standoff of 5 mm was chosen.

    Histological imaging of samples from ex vivo injection studies

    Tissue samples were fixed in 10% formalin solution for a minimum of 24 h. They were then processed in an ASP300S fully enclosed tissue processor (Leica Biosystems), embedded in paraffin wax and cut on a microtome in 4 µm thick sections. From there, sections were mounted on glass slides and stained with haematoxylin and eosin. Finally, the slides were scanned on a NanoZoomer S60 Digital Slide scanner (Hamamatsu Photonics) at 40×. Results from this process can be seen in Fig. 2b and Extended Data Fig. 5.

    Processing of volumetric data from ex vivo injection studies

    Acquisition, processing and reconstruction of images were performed with Phoenix Datos|x (GE Measurement & Control). Examples of processed scans are shown in Fig. 3a and Extended Data Fig. 4b–e. Once the scanning and reconstruction was complete, a segmentation of regions of the contrast fluid that were on top of, beneath and contained inside the tissue was performed. A simplified representation of the segmentation process is shown in Extended Data Fig. 3f. A standard Student’s t-distribution was used to determine 95% confidence intervals for the submucosal volume and VDE. Statistical analysis was applied only after all other quantitative analyses—including segmentation and diffusion correction—were complete. Further details on the processing of volumetric data are provided in Supplementary Methods  4.

    Axial endoscopic device prototype MiDeAxEndo

    The MiDeAxEndo prototype can deploy a therapeutic dose via the working channel of an endoscope. A schematic of all its components is shown in Extended Data Fig. 6a. The MiDeAxEndo system consists of a nitrogen pressure tank, a pressure controller, an air-tight 18 ml polycarbonate drug reservoir with an internal plunger separating pressurized gas from the drug product, a high-speed valve operated by a microcontroller and 2.8 m of polyether-ether-ketone (PEEK) tubing capped with a computer numerical control (CNC) machined PEEK adapter and stainless steel nozzle. Polytetrafluoroethylene (PTFE) sealing tape was used at all junctions to ensure air-tight connections. The stainless steel nozzle was assessed to have a 254 µm diameter with scanning electron microscopy. Jetting is conducted by loading the reservoir and tubing with the drug product, applying the desired pressure, and then opening the high-speed valve to initiate jetting. Operating valve times were characterized for each jetting pressure such that 200 µl was ejected. In Fig. 4a,b, valve times were 120 ms, 97 ms, 77 ms, 75 ms and 50 ms for the 3.5 bar, 5.0 bar, 9.4 bar, 11.3 bar and 24.5 bar jetting pressures, respectively.

    Radial endoscopic device prototype MiDeRadEndo

    In this study, a spring-loaded drug delivery device with a radially oriented jetting nozzle was utilized (Extended Data Fig. 6b). Activation of the device was achieved through a pneumatic tube, which also served as a tether for holding the device in place. The pneumatic tube was threaded through the endoscopic working channel for simultaneous delivery and positioning. The device, capable of ejecting a drug volume of 188 µl, was designed with an inflatable bag, featuring a diameter of 32 mm, to ensure optimal device-tissue proximity. Further details on the operation, design and assembly of MiDeRadEndo are provided in Supplementary Methods 5.

    Autonomous intestinal device prototype MiDeRadAuto

    The devices were used with the minor assistance from an endoscope. It is triggered via a dissolvable ‘polymer pellet’ that holds a detent pin captive. When the polymer pellet dissolves, the detent pin is released, allowing the spring to pressurize the ampule. The device is placed directly into the duodenum with an endoscope and allowed to trigger and pass without further assistance.

    The nominal ampule volume and diameter for MiDeRadAuto are 200 µl and 6 mm, respectively. The stainless steel spring used in the device has an initial force of 70 N, resulting in corrected ampule pressures of 14 ± 1.5 bar (n = 48). The nozzles are oriented radially, and its diameter is 240 ± 10 µm (95% confidence, n = 8). The overall footprint of the device is depicted in Extended Data Fig. 6c–h. The device is made of machined polyoxymethylene (POM), PEEK and common metals. The piston seals are made from NBR-70. A photo of this device is shown in Fig. 1h and a section view is shown in Fig. 4f. Diagrams of MiDeRadAuto before and after assembly are shown in Extended Data Fig. 6c–h, and each of the assembly steps are described in Supplementary Methods  6.

    Autonomous gastric device prototype MiDeAxAuto

    The autonomous axial prototype (MiDeAxAuto) can deploy a therapeutic dose to the stomach via direct oral ingestion. The device relies on a sugar plug-based triggering mechanism which passively degrades in the stomach. The sugar plug is located directly in front of the nozzle orifice, so the payload fluid—which is constantly pressurized—cannot escape from the chamber. To prevent the payload fluid from degrading the sugar plug, the plug is separated from the orifice exit by a thin polymeric burst membrane. Thus, when the sugar plug dissolves enough so that it can no longer support the pressure exerted by the payload fluid, the burst membrane ruptures and the payload exits the device as a columnar jet. A diagram of the triggering mechanism is shown in Extended Data Fig. 9a.

    As the stomach is a cavernous organ, we needed to implement an axial localization mechanism to align the jet. To achieve this, we drew inspiration from the methods used by Abramson et al.4 in their self-orientating system. MiDeAxAuto is 10.8 mm in diameter and 11.8 mm in height, with a centre of mass 3.5 mm above the bottom face. The diameter of the nozzle orifice is 298 ± 10 µm (95% confidence, n = 3). The nominal ampule volume and diameter are 80 µl and 7.9 mm, respectively. These ampule dimensions, combined with the pressure requirements for delivery in the stomach, mandated use of a relatively strong spring. We found that any sufficiently strong coil or disk spring’s mass interfered with the device’s self-orientation properties, so we decided to use compressed CO2 at its saturation pressure of 60 bar instead. Assuming a pressure factor of 70%, we deemed the aforementioned nozzle diameter to be most appropriate per our heat map results in Fig. 3c.

    In order to both maintain self-orientation and safely contain the gas pressure, we chose to machine the bottom piece of the MiDeAxAuto from brass and its top piece from 7075 aluminium. The piston is made from POM, the seals from silicone rubber and the burst-film from 25 µm thick fluorinated ethylene propylene (FEP). A photo of this device is shown in Fig. 1i and a section view is shown in Fig. 4i. Diagrams of MiDeAxAuto before and after assembly are shown in Extended Data Fig. 7, and each of the assembly steps are described in Supplementary Methods  7.

    Force profile studies with MiDeRadAuto and MiDeAxAuto

    The aim of the force profile studies was to determine whether the devices we had fabricated produced sufficiently strong jets to deliver therapeutics. A Kistler 9215 A piezoelectric force transducer was again used to measure jetting force. Because MiDeAxEndo and MiDeRadAuto have identical ampules, springs and nozzles, we decided that it was only necessary to test the latter of the two devices. Diagrams of setups for force profile testing of MiDeRadAuto and MiDeAxAuto devices and their associated results are shown in Extended Data Fig. 8. Further details are provided in Supplementary Methods  8.

    Formulation of therapeutic payloads

    For the MiDeAxEndo and MiDeRadAuto studies—including controls—we used an insulin payload solution (pH 7.4) with the following concentrations: 244.2 µM insulin analogue (Novo Nordisk), 8.05 mM sodium phosphate dibasic, 1.96 mM potassium dihydrogen phosphate and 140 mM sodium chloride. This solution (200 µl) was added to the device, resulting in an insulin dose of 0.28 mg (8 U). For the siRNA, a payload solution with a concentration of 170 mg ml−1 in 10 mM phosphate buffer at pH 7.4 was used. The solutions were stored at 4 °C until they were used.

    For the MiDeAxAuto studies—including controls—we used an insulin payload solution (7 < pH < 8) which was tailored based on the animal’s weight. To make this solution, between 10 and 20 mg of human insulin powder (Novo Nordisk) was weighed, and the exact mass noted. The insulin was then added into a 2 ml vial, followed (successively) by the following excipients: 600 µl 0.1 M sodium hydroxide, 0.5 mg PF68 (Sigma-Aldrich), 12.6 mg HEPES (Sigma-Aldrich), 300 µl 0.1 M hydrochloric acid and 100 µl deionized water. This solution was then diluted with deionized water in a separate vial based on the weight of the animal (35–80 kg) and payload volume of the device (80 µl) to achieve a dose of 0.25 U kg−1.

    In vivo pharmacokinetic exposure studies

    All in vivo pharmacokinetic studies were performed either at MIT or Novo Nordisk’s animal facilities by trained veterinary technicians and complied with relevant ethical regulations on animal research. Our procedures were reviewed and approved by review boards at each respective site (Committee on Animal Care at MIT and the Animal Experiment Inspectorate, Ministry of Justice, Denmark). For MiDeAxAuto, MiDeRadAuto and MiDeAxEndo (exclusively small intestine delivery) studies, female LYD (crossbred Landrace, Yorkshire and Duroc) pigs (body weight 50–70 kg; Novo Nordisk) and female Yorkshire pigs (body weight 35–80 kg; Tufts University, USA) were used, and for the gastric MiDeAxEndo study, female Beagle dogs, from 10 months old and weighing 8–13 kg were used. Pigs were placed on a liquid diet up to two days before each study and fasted overnight with the aim of reducing the amount of chyme and food debris in the gastrointestinal tract.

    On the day of the study, anaesthesia was induced either with propofol intravenously (5 ml and supplemented as needed) or with a mixture of Telazol (tiletamine/zolazepam; 4–6 mg kg−1) and xylazine (2–4 mg kg−1) intramuscularly. Immediately after sedation, animals were transferred to an operating room where they were intubated and immediately provided with isoflurane (1.5–3% mixture with oxygen). The isoflurane was used throughout the entire duration of the study to maintain anaesthetization. During the study, vital signs were continuously monitored and noted at least every 15 min. Vital signs included breathing rate, end tidal CO2, oxygen saturation (SpO2) level in blood and pulse rate. The maximum period of anaesthetization was 4 h for non-terminal procedures and 8 h for terminal procedures. Whether a study was terminal was decided in advance and depended on external factors such as the age and weight of the animal.

    During studies in which a device was deployed, a 100 cm over-tube (McMaster-Carr Tygon PVC tubing, 5/8 inch internal diameter, 13/16 inch outer diameter) was inserted into the oesophagus. This over-tube made it easier to transfer devices to and from the target location. The over-tube was removed immediately after device deployment was completed. For subcutaneous control studies, we used a 1 ml syringe with a hypodermic needle to administer the same dose as with the jet device to the subcutis on the animal’s belly or neck. For intraluminal or intragastric control studies, we used a Carr–Locke needle and endoscope to administer the same dose to the target organ.

    Blood sampling was performed via a central line placed either in the ear (for non-terminal studies) or the femoral vein (for terminal studies). Though sampling frequency and duration varied depending on the test site and type of study, in general, samples were extracted at least every 15 min for the first 2 h and then at least every hour for up to 8 h. In the case of non-terminal studies, blood samples were drawn from the ear-catheter after the animal was recovered. Each blood sample was extracted from the catheter with a 3 ml syringe, then stored on ice in tubes pre-coated with EDTA. After collection, samples were centrifuged for 10 min at 1,500g. From there, 500–600 µl of plasma from each sample was extracted with pipettes and deposited into 750 µl Micronic tubes (Micronic). Plasma from each time point was stored in up to three separate aliquots at −80 °C until bioanalysis was performed.

    In the case of terminal studies, pigs were euthanised with 80–100 mg kg−1 pentobarbital sodium intravenously or via an intra-cardiac injection. In all cases—before euthanasia—full anaesthetization was verified by the absence of pain-responsive reflexes (for example through a limb withdrawal test).

    For the inactive GLP1 analogue tablet control study, 8 healthy male Beagle dogs (2.8–3.5 years old, 9.9–14.5 kg) were fasted overnight for ≥18 h, before receiving a single tablet orally the next morning along with 10 ml of tap water. Tablets contained 2.65 mg active pharmaceutical ingredient, 101 mg sodium N-[8-(2-hydroxybenzoyl) aminocaprylate] (SNAC), 66.7 mg nicotinamide, and 0.8 mg magnesium stearate. To reduce inter-individual variance among dogs, all dogs received a subcutaneous glucagon injection (3.2 nmol kg−1) 10 min prior to the tablet administration. Approximately 0.8 ml of whole blood was drawn into EDTA-coated tubes at the time points 5, 10, 15, 20, 30, 45 min, and 1, 1.5, 2, 4, 7, and 10 h, respectively, including one baseline sample immediately before dosing. 100 μl plasma from each sample was transferred into Micronic tubes and subsequently centrifuged at 4,000 rpm for 4 min at 4 °C.

    In vivo deployment of MiDeAxEndo, MiDeRadEndo and MiDeRadAuto

    All three devices were assembled and filled with the therapeutic payload within 10 min of deployment. The MiDeAxEndo device was then threaded through the endoscope’s channel and inserted into the over-tube. To reach the small intestine, the endoscope was further inserted into the pylorus and advanced 10–20 cm into the small intestines. During in vivo endoscopic operations, the jetting nozzle of the MiDeAxEndo device was positioned orthogonal to the tissue and secured in place by activating the elevator on the endoscope (to prevent MiDeAxEndo from recoil during the jetting event). At this point, the device was triggered and blood sample collection was initiated. After jetting, MiDeAxEndo was held in place for 10 s, then removed to allow for optical observation of the delivery site. The device was then withdrawn from the animal, disassembled, cleaned with isopropyl alcohol or soapy water and stored for future use. Results from MiDeAxEndo studies can be found in Fig. 4a,b for small intestine and stomach depositions, respectively.

    The MiDeRadEndo was attached to the front of the endoscope via a rigid pneumatic tube which was fed through the working channel of the endoscope and allowed the operator to extend and retract the device as needed. As with MiDeAxEndo, an over-tube was used to reach the small intestine. To secure the device in place and establish its proximity to the tissue, the attached bag was inflated via a pneumatic tube threaded through the second working channel. A pressure of 25 mbar was applied for inflation. After optical confirmation of successful inflation, the device was activated to deliver the intended drug dosage, followed by deflation of the bag using negative pressure and retraction of the device.

    The MiDeRadAuto device was gripped with endoscopic forceps and inserted into the intestine directly. The MiDeRadAuto device was then released from the endoscope, the endoscope retracted from the animal and the animal went through emergence from anaesthesia. Once the animal was fully awake the device actuated autonomously. X-rays were recorded 4 h after dosing to inspect the device’s spring and thereby determine whether it had triggered. All devices (n = 7) successfully activated in the small intestine. The above study was executed successfully seven times with MiDeRadAuto and an insulin analogue payload. Results from the MiDeRadAuto studies can be found in Fig. 4g.

    To establish that there is no systemic exposure when peptides are delivered to the lumen of the small intestine (no disruption to the mucosal barrier) a negative control was performed. Eight female LYD pigs weighing 50–70 kg were anaesthetized according to the same anaesthetic protocol listed above. Once under deep and stable anaesthesia, an endoscope was navigated to the proximal small intestine of each animal. When in location, a primed tubing was fed through the working channel of the endoscope and 50 nmol (200 µl of 250 µM solution) of an insulin analogue was delivered to the lumen via a syringe attached to the primed tubing. The tubing was primed with the liquid insulin solution for 30 min before the procedure to mitigate any leeching of insulin into the tubing material during dosing. Thereafter the tubing was flushed with fresh insulin before each dosing. After dosing, the animals were recovered, and blood samples were taken for the next 4 h. The samples confirmed that there was no plasma exposure for each of the eight animals.

    In vivo deployment of MiDeAxAuto

    MiDeAxAuto devices were filled and pressurized within 10 min of deployment. The device was then dropped into the over-tube and advanced into the stomach with an endoscope. Once inside the stomach, the endoscope was used to monitor the device. An endoscopic image of a MiDeAxAuto in the stomach is shown in Fig. 4k. The device was continuously monitored until triggering occurred, at which point the time was marked and blood sampling was initiated. When triggering occurs, the device visibly jumps (because of recoil). After triggering, the device was retrieved with a Roth Net Standard Retriever (Steris). The device was then disassembled, and actuation of the piston was confirmed through inspection. Finally, the device parts were cleaned with isopropyl alcohol and stored for future use. The above study was executed successfully three times with MiDeAxAuto. Results from the MiDeAxAuto studies can be found in Fig. 4j.

    For negative control studies with the MiDeAxAuto, we repeated the original procedure and dosage, except instead of using CO2 for pressurization, we used a weak spring (which generated pressures no more than 0.5 bar). All the above control studies were successfully executed three times.

    Bioanalysis of blood samples

    Blood samples from animal experiments were analysed for human insulin or insulin analogue in plasma using an AlphaLISA assay (Perkin Elmer), for the GLP1 analogue in plasma using LC-MS and for siRNA in plasma using the Meso Scale Discovery platform. Further details are provided in Supplementary Methods 14 for the human insulin and insulin analogue assay and in Supplementary Methods  15 for the siRNA quantification.

    Reporting summary

    Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

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  • Task-agnostic exoskeleton control via biological joint moment estimation

    Task-agnostic exoskeleton control via biological joint moment estimation

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  • Bioelastic state recovery for haptic sensory substitution

    Bioelastic state recovery for haptic sensory substitution

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    3D printer assembly

    Version 1

    The DIP system components were mounted on two orthogonal optical breadboards to ensure precise alignment of the vertical and horizontal components (Supplementary Information section 1 and Supplementary Fig. 2a). Cross-sectional images were captured using a high-power projection module (LRS-WQ, Visitech) with a resolution of 2,560 × 1,600 pixels and a pixel size of 15.1 μm. The projection module and print head were positioned in the z direction using a 100 mm linear stage (MOX-02-100, Optics Focus) affixed to the vertical breadboard. The position of the air–liquid interface was controlled by a 50 ml syringe connected to the print head with a silicone tube and pressurized using a 50 mm linear stage (MOX-02-50, Optics Focus). Two further linear stages (MOX-02-100, Optics Focus) enabled precise positioning of the cuvette or well plate for sequential or multi-step printing. Motion control was managed using a commercially available 3D printer control board (BIGTREETECH, SKR 3) with a custom DB9 breakout board. Orthogonal videos of the printing process were captured with a 4K CCD camera (AmScope, HD408) equipped with a 16 mm lens (Raspberry Pi, RPI-16MM-LENS).

    Version 2

    A second system iteration was developed for in situ imaging, with modifications to allow the printing container to move relative to a stationary probe (Supplementary Fig. 3). The system incorporated a custom CoreXY motion system and a NEMA 23 ball-screw linear stage to translate the entire CoreXY stage relative to the stationary print head. In situ imaging was facilitated by a blue reflective dichroic mirror (35-519, Edmund Optics) and a 50:50 beam splitter for illumination (43-359, Edmund Optics). Illumination was provided either coaxially or with a custom well-plate holder with a red collimated backlight. To maintain physiological temperatures and sterility during printing, the motion components and print head were enclosed within a custom heated chamber. Sterility was maintained by continuous HEPA filtration during printing, surface sanitization with 70% ethanol and sterilization with UV-C before use.

    Print head

    In this study, the size of the print head was tailored contingent upon the desired dimensions of the resin container. For almost all configurations, we used axisymmetric cylindrical print heads to simplify the computation of the interface shape, although other (arbitrarily shaped) print-head boundary contours were feasible as demonstrated. For more complex print-head topologies resulting in complex interface shapes, numerical methods such as Surface Evolver54 or SE-FIT55 can be used. Here, we used print heads ranging from 30 to 5 mm. An object’s extent in the x and y directions was limited by the projector’s total field of view at the focal plane. Additionally, an object’s height was limited by the length of the print head, which was intrinsically coupled to the projection focal length and the ratio of the container volume to the volume displaced by the print head. For our set-up, the total submergible print-head length was approximately 70 mm. Note that much taller structures are conceptually feasible by submerging the projection and illumination optics or by increasing the working distance of the projection system. The print head was fabricated using a commercial 3D printing system (Form 3+, Formlabs). The print heads have an SM2 threaded insert, which allows us to quickly interchange print heads in version 2 of the system. A glass window was clamped between a gasket and the top of the print head to maintain an airtight enclosed volume while facilitating the transmission of light down its centre (Supplementary Fig. 1a,b). The print head also included an internal channel to enable gas to be delivered into the print-head cavity through the syringe system and acoustic modulation device. This port was used to either maintain or modulate the shape of the air–liquid interface during printing.

    Acoustic modulation device

    Acoustic modulation of the air–liquid interface was achieved by direct volume manipulation of the air volume within the print head. Conceptually, the approach was straightforward. The set-up consisted of a 3 inch 15 W voice coil driver (Techbrands, AS3034) affixed to an enclosed 3D printed manifold containing an inlet and outlet port (Fig. 3a and Supplementary Information section 2 and Supplementary Fig. 1c,d). The voice coil was driven by a commercially available amplifier (Adafruit, MAX9744) using the supplied auxiliary port, with specified waveforms sent by the MATLAB GUI. The frequency ranged between 1 and 500 Hz when possible, with fixed or transient frequency or amplitude switching. By specifying a waveform for each degree of freedom, it was straightforward to synchronize the acoustic modulation with the remainder of the motion, optical and pressure control (Fig. 1c).

    Material composition and preparation

    PEGDA materials

    Various concentrations of PEGDA were used in this study, ranging from 10% to 100% w/v. For each formulation, we followed the same protocol. The required weight fraction of PEGDA Mn 700 (455008, Sigma) was dissolved in the corresponding volume fraction of 40 °C deionized water (excluding 100% w/v) and thoroughly mixed for 10 min. Subsequently, 0.035 w/w% of tartrazine (T0388, Sigma) and 0.25% w/w of LAP (900889, Sigma) were added to the mixture and stirred until complete dissolution. The materials were then stored in light-safe Falcon tubes until required.

    HDDA material

    A solution of 500 mg of phenylbis(2,4,6-trimethylbenzoyl) phosphine oxide (511447, Sigma) and 50 g of 1,6-hexanediol diacrylate (246816, Sigma) was prepared by warming the mixture to 40 °C and stirring for 30 min. To control the resolution in the z direction, the photo-absorber Sudan I (103624, Sigma) was added in various quantities ranging from 0 to 0.04% w/w. The materials were then stored in light-safe Falcon tubes until required.

    GelMA material

    GelMA was synthesized following a previously reported protocol56, yielding a degree of substitution of 93% (confirmed by nuclear magnetic resonance). A 10% w/v GelMA solution was prepared by dissolving 1 g of GelMA in 10 ml of cell culture media (Freestyle 293 Expression Medium, Thermofisher) preheated to 37 °C. After complete dissolution of the GelMA, 3.5 mg of tartrazine and 25 mg of LAP were added to the solution, which was maintained at 37 °C until complete dissolution. The mixture was sterilized by passing it through a 0.22 µm sterile filter within a biosafety cabinet and subsequently stored in refrigerated light-safe Falcon tubes until required.

    Alginate material

    Norbornene-functionalized sodium alginate was synthesized based on a previously reported protocol57. In short, 10 g of sodium alginate were dissolved in 500 ml of 0.1 M 2-(N-morpholino) ethane-sulfonic acid buffer (145224-94-8, Research Organics) and fixed to pH 5.0. Then, 9.67 g of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide•HCl, 2.90 g of N-hydroxysuccinimide and 3.11 ml of 5-norbornene-2-methylamine were added. The pH was fixed at 7.5 with 1 M NaOH. The reaction was carried out at room temperature for 20 h. The mixture was dialysed against water for 5 d before lyophilization. The degree of norbornene functionalization was determined to be 16.2% by 1H nuclear magnetic resonance. A 7% w/v sodium alginate solution was prepared by dissolving 1 g of the sodium alginate in 14.29 ml of phosphate-buffered saline solution. Next, 5 mg of tartrazine, 36 mg of LAP and 122.7 µl of 2,2′-(ethylenedioxy)diethanethiol were dissolved in 5.59 ml of phosphate-buffered saline, added to the sodium alginate solution and mixed until it was homogeneous. The pH was adjusted with 1 M NaOH until the solution was visibly opaque.

    Diurethane dimethacrylate (UDMA) support material

    A solution of 50 mg of phenylbis(2,4,6-trimethylbenzoyl) phosphine oxide (511447, Sigma) and 5 g of diurethane dimethacrylate (436909, Sigma) was prepared by warming the mixture to 45 °C and stirring for 30 min. To remove trapped air bubbles, the mixture was transferred to a light-safe Falcon tube and centrifuged at 4,000 rpm for 10 min to remove residual air bubbles.

    Cell printing

    Human embryonic kidney 293-F cells (Freestyle 293-F, Thermo Fisher) were used in a preliminary determination of the cell viability of the DIP 3D printing system. In this work, a cell solution with 7.2 million cells per millilitre was used for both the model of the kidney and the cell-viability measurements. To determine cell viability, a thin 500 µm wall (5 mm × 0.5 mm × 10 mm) was printed to minimize the effect of cell death due to insufficient media diffusion, which was imaged using a live/dead viability/toxicity kit (L3224, Invitrogen). Three structures were printed (n = 3), and measurements were taken after 24 h to determine the preliminary viability of the technique. Cell viability was determined at three locations for each sample (s = 3), with the total viability being an average of all collection points (Supplementary Fig. 18).

    To create the cell-loaded bioink, the GelMA solution was warmed to 37 °C followed by the resuspension of cells into the solution. The solution was passed through a cell strainer (0877123, Thermo Fisher) and stored in a water bath at 37 °C when not in use. The printing process involved pipetting approximately 3 ml of the GelMA ink into a single well of a 12-well plate and lowering the print head into the well. During each print, acoustic modulation (50 Hz, P = 0.3) was used to homogenize the suspension and mitigate cell settling. As the printed wall had a high aspect ratio and low contact area, a relatively slow print velocity of Vz = 150 µm s−1 was used to mitigate unwanted detachment. This resulted in an object creation time of approximately 30 s.

    Data preprocessing, printing and postprocessing

    Three-dimensional design models of Bowman’s capsule, a tri-helix structure and a Kelvin cell were created using nTop. Tricuspid, heart and buckyball models were downloaded from Thingiverse.com. For each geometry, the STL file was extracted and sliced using Chitubox into a stack of PNG images. As the frame rate of the HDMI signal was limited to 120 frames per second (fps), we commonly used projection frame rates that matched the acoustic driving frequencies to minimize motion blurring. The object was discretized into a voxel array according to the desired linear print speed and frame rate. The layer height (Lh) was determined as \({L}_{{\rm{h}}}={v}_{z}/f\), where vz is the linear print speed and f is the acoustic excitation frequency, which matched the projection frequency. The image stack was further corrected using the convex-slicing algorithm to produce a secondary optimized image stack, with the sequence being sent to the projector over HDMI using Psychtoolbox-3 (ref. 58). The print sequence started by moving the print head to a defined distance above the print surface (or high-density material). The interface was then automatically brought coplanar with the image plane contingent on the selected print head. The MATLAB GUI was operated by first sending a signal to turn on the LED module and subsequently controlling the location of the air–liquid interface by modulating the pressure, acoustic driving and translation location. The optical power of the projection module was automatically set depending on the selected print velocity using the parameter space matrix. For prints made with HDDA, the printed structures were removed from the print volume and washed with isopropyl alcohol. For soft structures made from PEGDA and GelMA, the excess material was gently removed using a pipette (and recycled if PEGDA) and resuspended in deionized water or cell culture media to remove unpolymerized material. If required, the structures were fluidically detached from the bottom of the container and stored in an appropriate solution.

    Convex-slicing algorithm

    The developed convex-slicing algorithm aims to correct for geometrical discretization differences between a traditionally flat construction surface and the curved surface used in this work. A detailed explanation of the convex-slicing process is given in the Supplementary Information. However, the main components will be briefly restated here. First, the general shape of the interface was determined by the Young–Laplace equation, \(\Delta p=-\,\gamma \nabla \cdot \widehat{n}\), which describes the Laplace pressure difference (\(\Delta p\)) sustained across a gas–liquid boundary dependent on the material surface tension (\(\gamma \)) and surface normal (\(\hat{n}\)). Here, we used axisymmetric print containers such that \(\hat{n}\) can easily be found by substituting the general expressions for principal curvatures. The capillary length \(l=\sqrt{\gamma /\rho g}\), where γ is the material surface tension, ρ is the material density and g is the acceleration due to gravity, was used to normalize the radial and vertical coordinates of the interface as \(x=r/l\) and \(y=z/l\). The resulting ordinary differential equation for the interface shape was \(\frac{{y}^{{\prime\prime} }}{{(1+{({y}^{{\prime} })}^{2})}^{3/2}}+\frac{{y}^{{\prime} }}{x{(1+{({y}^{{\prime} })}^{2})}^{1/2}}-y=0\).

    This equation can be readily solved using numerical integration with appropriate boundary conditions (Supplementary Information section 4). However, using this method would require numerical integration for the steady-state case, and moreover, we would need to solve each intermediate state during compression with the associated boundary conditions. We, instead, opted to approximate the solution using cubic Bézier curves for the steady-state case and approximating the compressed profiles by geometrically deforming the Bézier curve while ensuring volume equivalency (Supplementary Information section 7). This is computationally faster given the large number of intermediate surfaces within the transient region. To convert the 2D Bézier solution into a 3D surface, the half-profile was revolved about the print head’s central z axis (Supplementary Information section 5). This produced a sequence of surfaces starting at the compressed state and transitioning to the steady-state interface profile. The corresponding convex projection(s) were determined by minimizing the Euclidean distance between the Cartesian voxel grid and the surface arrays (Supplementary Information section 6). Reconstruction accuracy was validated by ‘replaying’ the projections over an empty voxel array and computing the Jaccard index between the reconstructed voxel array and the input voxel array (Supplementary Information sections 8 and 9).

    Optical modelling

    To determine our theoretical optical model (Supplementary Information section 10), we employed a similar approach to Behroodi et al.59, who modelled the in-plane resolution as the spatial convolution of the point spread function (\({\rm{PSF}}(x,y)\)) and the micro-mirror spatial arrangement (\(f(x,y)\)), where \(f\left(x,y\right)\ast {\rm{PSF}}\left(x,y\right)={\int }_{-\infty }^{\infty }{\int }_{-\infty }^{\infty }f({\tau }_{1},{\tau }_{2})\,\cdot \,{\rm{PSF}}\left(x-{\tau }_{1},y-{\tau }_{2}\right)\,{\rm{d}}{\tau }_{1}\,{\rm{d}}{\tau }_{2}\), and τ1 and τ2 represent spatial shifts, summed over all possible displacements, during convolution. To determine the effective delivered energy and depth of cure across the meniscus, a ray incident on the meniscus was decomposed into reflective and transmissive components, described by a transmissive efficiency η, dependent on the relative angle and refractive index mismatch \(\eta ({n}_{1},{n}_{2},\hat{{\bf{u}}},\hat{{\bf{n}}})\). Here, n1 and n2 represent the refractive index of the air and liquid, respectively, and \(\hat{{\bf{u}}}\) is the normal vector at a given point on the meniscus’s surface. The energy intensity along the transmissive vector \({\gamma }_{z}\) was approximated as a material-dependent Beer–Lambert decay \({\mathcal{H}}({{\boldsymbol{\gamma }}}_{x},{{\boldsymbol{\gamma }}}_{y},{{\boldsymbol{\gamma }}}_{z})\,=\,\eta ({n}_{1},{n}_{2},\hat{{\bf{u}}},\hat{{\bf{n}}})\cdot \hat{{\bf{E}}}\,\exp \left(\frac{-{{\boldsymbol{\gamma }}}_{z}}{{\varepsilon }_{{\rm{d}}}\left[D\right]+{\varepsilon }_{{\rm{i}}}\left[S\right]}\right)\) (Supplementary Information section 11), where, εd and εi are molar absorption coefficients of the photoinitiator and the light absorber, respectively, and D and S are the concentrations of the photoinitiator and light absorber of the photopolymer resin, respectively. As the interface is curved, the effective resolution is spatially dependent on the local height of the meniscus relative to the focal plane. For each pixel at the focal plane, we mapped its local coordinate to the corresponding coordinate on the meniscus surface, resulting in a contour map of the effective pixel size across the interface. This map was used to theoretically predict the accurate area fraction the contingent on print head’s size and material properties (Supplementary Information section 12).

    Acoustically driven flow

    Analytical solution

    To understand the formation of acoustically driven capillary-gravity waves, we used many established analytical approaches that describe the induced velocity and secondary streaming effects32 created by the meniscus (Supplementary Information sections 13–15). This analysis, therefore, establishes the velocity scaling laws for capillary-gravity waves dependent on the dominance of capillary- or gravity-driven effects. The dispersion relation for capillary waves, \({\omega }^{2}=\frac{\gamma }{\rho }{k}^{3}+{gk}\), relates the wave frequency (ω) to the wavenumber (k). We, therefore, show that \({(\lambda /{l}_{{\rm{cap}}})}^{2}\) is a unitless quantity that relates the dominance of surface tension and acoustic parameters on the flow magnitude (Supplementary Information section 14). Here, lcap denotes the capillary length of the material. Thus, the flow velocity U scales as \(U\propto \frac{{h}_{0}^{2}\rho g\phi }{\lambda \mu }\) for \((\lambda /{l}_{{\rm{cap}}}) > 1\) and \(U\propto \frac{{h}_{0}^{2}\gamma \phi }{{\lambda }^{3}\mu }\) for \((\lambda /{l}_{{\rm{cap}}}) < 1\), where, h0, ϕ and μ represent the surface perturbation, wave amplitude and viscosity, respectively. Supplementary Fig. 19 shows the effect of material and acoustic parameters on velocity scaling.

    Experimental investigation

    PIV was employed to understand the 3D flow field produced below the air–liquid boundary under acoustic excitation. A high-speed camera (Kron Technologies, Chronos 1.4 Camera) was used to capture footage of 20–50 µm poly(methyl methacrylate) particles during excitation, both normal and orthogonal to the air–liquid boundary. Particle tracing and velocity reconstruction were performed on the captured video sequences using PIVLab (ref. 60) for MATLAB. The exact parameters and methodology used can be found in Supplementary Information section 18. The velocity profiles for top-down and side are shown in Fig. 3c–e and Supplementary Figs. 8 and 9.

    Interface restabilization

    To determine the transient interface restabilization in the bulk flow, high-speed photography under a uniform backlight was captured at 5,000 fps (Supplementary Fig. 7). Restabilization was determined by segmenting the meniscus edge and tracking the minimum y pixel location of the video stream during excitation and subsequent stabilization. The interface settling time was determined by applying an exponential criterion set at 1/e2 of the starting amplitude.

    Image analysis of the material influx rate

    The material influx rate with and without acoustic excitation was determined by filling a glass cuvette with materials doped with black dye to prevent light transmission. The cuvette was placed on top of a red backlight, such that when the air–liquid boundary formed against the base of the cuvette, the transmitted light was observed by a CCD (Supplementary Information section 19). The material influx rate was measured by raising the air–liquid boundary with and without acoustic excitation and tracking the influx of dyed material, which occluded the backlight transmission (Fig. 3f and Supplementary Information section 20 and Supplementary Fig. 11).

    Print parameter space

    To identify the ideal parameter space for DIP, a range of print speed and optical dose combinations were tested using three materials: PEGDA, GelMA and HDDA. For each combination, triplicate (n = 3) structures with dimensions of 5 × 5 × 15 mm3 were printed, with successful outcomes being defined by the presence of a sharply delineated structure and a smooth surface finish. Structures that did not meet these requirements, either because they were only partially resolved or because no structure had been produced, were removed from the parameter map. Generally, the print-speed parameter space was not only constrained by the optical dosage but also by the rate at which new material can ‘wet’ the interface. Inadequate wetting typically caused the interface to fluidically ‘pin’ to the underlying structure as the polymerization rate exceeded the mass transport of new material.

    Microscopy

    Micro computed tomography

    Micro computed tomography images were acquired using a Phoenix Nanotom M scanner (Waygate Technologies, voxel size of 10 µm3, 90 kV tube voltage, 200 µA tube current and 8 min scan time). For hydrogel samples, the structures were briefly dried with tissue paper and mounted into a Falcon tube for imaging. For hard materials such as HDDA, the structures were placed on a plastic cap to provide good contrast between the printed structure and the supporting medium. An STL surface mesh was extracted and imported into Keyshot 11 (Keyshot, Luxion) to render the final micro computed tomography representation.

    Fluorescence microscopy

    Fluorescence microscopy images were captured using a Zeiss Axio Observer Z1 (Zeiss) using either a ×4 or a ×10 objective. For constructs that were larger than the objective’s field of view, the images were stitched within the Zeiss Zen software to create a large-format image. Once the fluorescence images were acquired, cell-counting was performed on each live/dead image pair using a custom MATLAB script.

    Scanning electron microscopy

    Scanning electron microscope images were acquired on a FlexSEM 1000 (Hitachi High Technologies). Printed structures on glass slides were mounted directly on the microscope stage with no further sample preparation. The samples did not have a conductive coating applied. The electron microscope was operated in variable-pressure mode at 50 Pa. Images were acquired with a 15 keV beam using the ultra-variable detector. To cover the field of view needed for the large structures, the working distance was typically 40–50 mm, and several images were collected in a tiled manner and stitched together in postprocessing.

    Helium-ion microscopy images

    Helium-ion microscopy images were acquired with a Zeiss NanoFab using a helium source. During imaging, the flood gun was used to actively neutralize the surface, thus removing the need for a conductive coating. All structures were imaged using an accelerating voltage of 30 kV, a beam current of between 1 and 2 pA, and a field of view of 1,100 µm. Structures were printed directly onto a silanized glass slide and were mounted on the stage using the integrated mounting clips. To facilitate the capture of structures larger than the field of view, several images were taken and later stitched using ImageJ/Fiji.

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