Bioinspired Mechano‐Sensitive Macroporous Ceramic Sponge for Logical Drug and Cell Delivery

On‐demand, ultrahigh precision delivery of molecules and cells assisted by scaffold is a pivotal theme in the field of controlled release, but it remains extremely challenging for ceramic‐based macroporous scaffolds that are prevalently used in regenerative medicine. Sea sponges (Phylum Porifera), whose bodies possess hierarchical pores or channels and organic/inorganic composite structures, can delicately control water intake/circulation and therefore achieve high precision mass transportation of food, oxygen, and wastes. Inspired by leuconoid sponge, in this study, the authors design and fabricate a biomimetic macroporous ceramic composite sponge (CCS) for high precision logic delivery of molecules and cells regulated by mechanical stimulus. The CCS reveals unique on‐demand AND logic release behaviors in response to dual‐gates of moisture and pressure (or strain) and, more importantly, 1 cm3 volume of CCS achieves unprecedentedly delivery precision of ≈100 ng per cycle for hydrophobic or hydrophilic molecules and ≈1400 cells per cycle for fibroblasts, respectively.

. BPB     Movie S1. Resilience of the BPB-loaded CCS with 60 wt.% moisture content. CCS with appropriate moisture content exhibits high elasticity under the strain of < 50%.
Movie S2. BPB released by cyclic compression from CCS with > 60% moisture content.

Experimental Section
Materials: Food-grade cornstarch was purchased from Weimeisi Co., Ltd (Shanghai, China).
Hydroxyapatite (HA) was synthesized in house according to a method described elsewhere. [2] Triton X-100 was purchased from Sinopharm Chemical Reagent Co., Ltd (Shanghai, China).

Fabrication of CCS:
Cornstarch and DI water was homogeneously mixed in a beaker to obtain 10 wt% starch suspension. Different amounts of HA powders were then added into the starch suspension and mixed uniformly to form ceramic slurries. For different purposes, the solid contents of HA (the ratio of HA mass to total solid mass) varied from 71.4% to 85.9%.
The slurry was later heated to 90 o C in a water bath and a surfactant of Triton X-100 was added. The heated suspension became highly viscous gel and then was vigorously stirred by an overhead stirrer till air bubbles fully infiltrated into the suspension to obtain foam. The foam was removed from water bath, cooled down to room temperature and then set for 24 hrs.
The foam was further dried to porous composite scaffolds with wanted moisture contents, depending on different applications. Measurements of apparent density and porosity: Apparent density (ρ app ) of CCS and porous HA ceramic was calculated by its weight and volume that can be directly measured.
Theoretical density (ρ th ) of the porous composites was calculated by the densities of the HA and starch according to their proportions in the composites. The porosity (p) of CCS was thus calculated by Mechanical characterization: For uniaxial compression tests, CCS were cut into cubes with dimension of 10×10×10 mm 3 and tested on a mechanical tester (HY-1080, testing range 0~500 N with precision of 0.01 N, Hengyi company, Shanghai) operating at a crosshead speed of 1mm/min. From the stress-strain curve, the maximum stress before failure was determined as compressive strength and the linear range in the stress curve before failure was used to calculate compressive modulus. For the testing of the compressive loop of CCS, CCSs with 45% moisture content were cut into cubes with dimension of 10×10×10 mm 3 and the cubes were pressed to desired strain of CCS (1%, 3%, 5% and 10%) and then unloaded to initial position. Resilience was characterized using a CCS sample with 45% water contents using microscope. A CCS cube was pressed to designated strains (3% and 10%), and released, and this process was video-recorded by microscope. The resilience was then calculated by comparing the position of rebounding surface to its initial position. Theoretical estimation of ΔP and ε repel: In a simplified, one-end closed cylindrical pore model, the hydrophilic liquid is drawn into the pores due to capillary effect and the gas pressure in the pore is described as: Where P is the atmosphere pressure, and is capillary pressure given by Young-Laplace equation: (4) Where is the surface tension of hydrophilic liquid,θthe contact angle between water and material of cylindrical pore, and r is the radius of the cross section of pore.
Assuming change of gas pressure is due to the volume change of the pore and the gas obeys ideal gas law: Where n is moles of gas, R ideal gas constant, and T is temperature.
Assume during volume contraction the cross section of the cylinder becomes an ellipse, and the initial and changed gas pressures (P 0 and P 1, respectively) have a relationship given by ideal gas law: Where V 1 and V 2 are original and compressed volume of gas, respectively, and a and b are short and long axis of the cross-sectional ellipse, respectively.
In order to expel the liquid out of the pore, gas pressure P 1 at least needs to be equal to P, so the equation (6) rewrites as: Considering the poisson's ratio ν of CCS: Solve equations (7) and (8) to obtain: √ , (a<r) When expelling the liquid by compressing CCS, the expelling strain is thus given by, For calculation, poisson's ratio of 0.2 is measured from experiments, and surface tension of water under the experimental temperature is 7.2 ×10 -2 N/m, and the contact angle of HA was assumed equal to 10 o .