An Injectable Meta‐Biomaterial: From Design and Simulation to In Vivo Shaping and Tissue Induction

Abstract

metamaterials. Although typical metamaterials are produced in crystal-like repetitive structures, [3][4][5][6] this is not an absolute requirement, as for instance acoustical negative index materials have been realized as soft metafluids. [7] Here, we develop an injectable metamaterial specifically designed to provide dynamic tissue mechanical matching. Indeed, tissues have strongly non-linear elastic responses, [8] yet it remains a challenge to match more than a given single mechanical parameter. [9] We use here metamaterial design to provide, for the first time, dynamic matching of effective shear modulus over a wide range of deformation amplitudes in a biocompatible injectable. Our aim here is to apply the metamaterial development to soft tissue reconstruction in nearly arbitrary shapes, yet naturally following local tissue movement and mechanics.Disease, trauma, surgery, and aging can indeed result in loss of soft tissue, producing major medical demand for tissue reconstruction. [10,11] Reconstructive procedures should be minimally invasive to decrease patient burden and surgical complications. [12] Ideally, this is addressed by injectability through thin needles. [10] To match patient-specific defect geometries, surgeons desire in situ shapeability, [13] and most importantly, shape-and volume-stability following the procedure. Therefore, an ideal material-based A novel type of injectable biomaterial with an elastic softening transition is described. The material enables in vivo shaping, followed by induction of 3D stable vascularized tissue. The synthesis of the injectable meta-biomaterial is instructed by extensive numerical simulation as a suspension of irregularly fragmented, highly porous sponge-like microgels. The irregular particle shape dramatically enhances yield strain for in vivo stability against deformation. Porosity of the particles, along with friction between internal surfaces, provides the elastic softening transition. This emergent metamaterial property enables the material to reversibly change stiffness during deformation, allowing native tissue properties to be matched over a wide range of deformation amplitudes. After subcutaneous injection in mice, predetermined shapes can be sculpted manually. The 3D shape is maintained during excellent host tissue integration, with induction of vascular connective tissue that persists to the end of one-year follow-up. The geometrical design is compatible with many hydrogel materials, including cell-adhesion motives for cell transplantation. The injectable meta-biomaterial therefore provides new perspectives in soft tissue engineering and regenerative medicine.

The Role of Interstitial Fluid Pressure in Cerebral Porous Biomaterial Integration

“…We based the synthesis of our porous biomaterial on cryogelation of carboxymethylcellulose, followed by forceful fragmentation of the bulk material to obtain irregular and porous particles as described previously [ 25 , 55 ]. Briefly, a reactive premix was prepared by adding 13.65 g of carboxylmethylcellulose (Aqualon TM , 90.5 KDa, DS: 0.84, Ashland, Wilmington, DE, USA, ref 891158), 6.30 g of PIPES buffer (1,4-Piperazinediethanesulfonic acid, Sigma-Aldrich, St. Louis, MO, USA, P6757), 486 mg of adipic acid dihydrazide (ADH, Sigma, Kawasaki, Japan, A0638) and NaOH pellets (1.2 g, Carlo Erba, Val-de-Reuil, Germany, 480507) and the total volume was adjusted to 1000 mL with deionized water.…”

“…Porous biomaterials were thawed and washed with deionized water and PBS and then fragmented [ 25 ]. The bulk material was roughly cut using a razor blade and filled into a 10 mL syringe and then passed sequentially through 18 G, 20 G and 22 G needles.…”

“…Covalent modification with collagen I followed established protocols [ 25 ]. Briefly, the biomaterial was dried on a filtration unit (TPP, Switzerland, 191060), washed and incubated in an acetic acid buffer 0.5 M (pH = 4).…”

“…However, in a desired regenerative course, endogenous stem cells and possibly transplanted stem cells are thought to then ensure de novo tissue formation and functional maturation [ 23 ]. In addition, 3D tissue ingrowth from the surrounding environment occurs as well, providing vascularization, but also stromal and possibly functional components [ 24 , 25 ]. Vascular support is of particular importance in the context of neuronal transplantation for which cells are metabolically demanding and thus requires a rapid access to oxygen and nutrients upon transplantation [ 26 ].…”

“…In order to satisfy the known high metabolic and gas exchange demands of neural tissue, we implement the device using an air–liquid interface geometry [ 50 , 54 ]. We use this setup to investigate in vitro the role of the IFP on the biointegration of an established highly porous and biocompatible carboxylmethylcellulose (CMC) biomaterial scaffolds [ 25 , 55 ] with metabolically demanding neuro-organoids.…”