The tympanic membrane (TM) is an exquisite structure that captures and transmits sound from the environment to the ossicular chain of the middle ear. The creation of TM grafts by multi-material three-dimensional (3D) printing may overcome limitations of current graft materials, e.g. temporalis muscle fascia, used for surgical reconstruction of the TM. TM graft scaffolds with either 8 or 16 circumferential and radial filament arrangements were fabricated by 3D printing of polydimethylsiloxane (PDMS), flex-polyactic acid (PLA) and polycaprolactone (PCL) materials followed by uniform infilling with a fibrin-collagen composite hydrogel. Digital opto-electronic holography (DOEH) and laser Doppler vibrometry (LDV) were used to measure acoustic properties including surface motions and velocity of TM grafts in response to sound. Mechanical properties were determined using dynamic mechanical analysis (DMA). Results were compared to fresh cadaveric human TMs and cadaveric temporalis fascia. Similar to the human TM, TM grafts exhibit simple surface motion patterns at lower frequencies (400 Hz), with a limited number of displacement maxima. At higher frequencies (>1000 Hz), their displacement patterns are highly organized with multiple areas of maximal displacement separated by regions of minimal displacement. By contrast, temporalis fascia exhibited asymmetric and less regular holographic patterns. Velocity across frequency sweeps (0.2-10 kHz) measured by LDV demonstrated consistent results for 3D printed grafts, while velocity for human fascia varied greatly between specimens. TM composite grafts of different scaffold print materials and varied filament count (8 or 16) displayed minimal, but measurable differences in DOEH and LDV at tested frequencies. TM graft mechanical load increased with higher filament count and is resilient over time, which differs from temporalis fascia, which loses over 70% of its load bearing properties during mechanical testing. This study demonstrates the design, fabrication and preliminary in vitro acoustic and mechanical evaluation of 3D printed TM grafts. Data illustrate the feasibility of creating TM grafts with acoustic properties that reflect sound induced motion patterns of the human TM; furthermore, 3D printed grafts have mechanical properties that demonstrate increased resistance to deformation compared to temporalis fascia.

Direct delivery of fluid to brain parenchyma is critical in both research and clinical settings. This is usually accomplished through acutely inserted cannulas. This technique, however, results in backflow and significant dispersion away from the infusion site, offering little spatial or temporal control in delivering fluid. We present an implantable, MRI-compatible, remotely controlled drug delivery system for minimally invasive interfacing with brain microstructures in freely moving animals. We show that infusions through acutely inserted needles target a region more than twofold larger than that of identical infusions through chronically implanted probes due to reflux and backflow. We characterize the dynamics of in vivo infusions using positron emission tomography techniques. Volumes as small as 167 nL of copper-64 and fludeoxyglucose labeled agents are quantified. We further demonstrate the importance of precise drug volume dosing to neural structures to elicit behavioral effects reliably. Selective modulation of the substantia nigra, a critical node in basal ganglia circuitry, via muscimol infusion induces behavioral changes in a volume-dependent manner, even when the total dose remains constant. Chronic device viability is confirmed up to 1-y implantation in rats. This technology could potentially enable precise investigation of neurological disease pathology in preclinical models, and more efficacious treatment in human patients.

Neurochemical dysregulation underlies many pathologies and can be monitored by measuring the composition of brain interstitial fluid (ISF). Existing in vivo tools for sampling ISF do not enable measuring large rare molecules, such as proteins and neuropeptides, and thus cannot generate a complete picture of the neurochemical connectome. Our micro-invasive platform, composed of a nanofluidic pump coupled to a membrane-free probe, enables sampling multiple neural biomarkers in parallel. This platform outperforms the state of the art in low-flow pumps by offering low volume control (single stroke volumes, <3 nl) and bidirectional fluid flow (<100 nl/min) with negligible dead volume (<30 nl) and has been validated in vitro, ex vivo, and in vivo in rodents. ISF samples (<1.5 μL) can be processed via liquid chromatography–tandem mass spectrometry. These label-free liquid biopsies of the brain could yield a deeper understanding of the onset, mechanism, and progression of diverse neural pathologies.

Enhanced understanding of neuropathologies has created a need for more advanced tools. Current neural implants result in extensive glial scarring and are not able to highly localize drug delivery due to their size. Smaller implants reduce surgical trauma and improve spatial resolution, but such a reduction requires improvements in device design to enable accurate and chronic implantation in subcortical structures. Flexible needle steering techniques offer improved control over implant placement, but often require complex closed‐loop control for accurate implantation. This study reports the development of steerable microinvasive neural implants (S‐MINIs) constructed from borosilicate capillaries (OD = 60 µm, ID = 20 µm) that do not require closed‐loop guidance or guide tubes. S‐MINIs reduce glial scarring 3.5‐fold compared to prior implants. Bevel steered needles are utilized for open‐loop targeting of deep‐brain structures. This study demonstrates a sinusoidal relationship between implant bevel angle and the trajectory radius of curvature both in vitro and ex vivo. This relationship allows for bevel‐tipped capillaries to be steered to a target with an average error of 0.23 mm ± 0.19 without closed‐loop control. Polished microcapillaries present a new microinvasive tool for chronic, predictable targeting of pathophysiological structures without the need for closed‐loop feedback and complex imaging.

Highlights d Multi-bolus targeting can improve coverage of irregularly shaped brain structures d Volume and position of each bolus can be computed for a given infusate and target d Rational fluidic design enables instantaneous delivery of multiple boluses d Chronic neural probes replicate computational coverage estimates with 5% error

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