Cell-laden colloidal gels for bottom-up tissue engineering

Huanan Wang

The demand for restoration or regeneration of tissues that become dysfunctional due to disease or injury prompted the emergence of tissue engineering, which has led to a paradigm shift for design and fabrication of natural-like functional tissues and complex organs for regenerative medicine. Tissue engineering combines a biomimetic matrix (scaffold) with variable cells and bioactive signals, in which three-dimensional (3D) scaffolds play an important role to not only provide initial structural support for cells, but also to stimulate cell proliferation and differentiation, and ultimately the regeneration of functional tissues. However, traditional “top-down” strategy using bulk scaffolds with inherently heterogeneous and poorly controlled structural and functional properties are often not competent to offer appropriate microenvironment for cells. These challenges encouraged the smart design of novel generation of biomaterials, which are increasingly accepted as biomimetic scaffolds to provide cells with a variety of physicochemical and biological cues that instruct cell growth and function.

Figure 1. Schematic illustration of the micro-architecture of cellular construct resulting from self-assembly of individual cells and functionalized gelatin microspheres (A). Cohesive cell-microsphere interaction (B) can be formed between the choline phosphate groups grated on the microsphere surface and phospholipid (DPPC) bilayer of cell membrane (C).

  In that respect, colloidal gels, a novel class of hydrogels that allow for a “bottom-up” approach for the design of biomaterials, have recently attracted increasing attention for fabrication of scaffolds containing complex structural and functional properties. In contrast to conventional bulk scaffolds, colloidal gels typically employ biopolymer particles in micro- or nanoscale as building blocks to assemble into shape-specific scaffolds of larger length-scales. Due to the small size of particulate building blocks, colloidal gels exhibit properties superior to bulk scaffolds in many aspects, i.e. accurate control over the properties of particulate sub-units and thereby the final macroscopic construct, strong capacity for incorporation and controlled delivery of biomolecules, physically crosslinking particulate network resulting from interparticle attractions (e.g. electrostatic, hydrophobic interactions), and injectability/moldability that facilitates application of the gels using minimally invasive surgery.

Cells as blocks to build-up human tissues

Colloidal gels, a novel class of hydrogels that allow for a “bottom-up” approach for the design of biomaterials by employing biopolymer particles as building blocks, have recently emerged as an intriguing concept in regenerative medicine. These gels exhibit properties superior to traditional bulk scaffolds, including i) accurate control over scaffold’s properties, ii) strong capacity for controlled delivery of biomolecules, iii) physically crosslinking particulate network, and iv) injectability. Importantly, the micro-architecture of colloidal gels is in line with the construction of human tissues that can be regarded as hierarchically organized cellular constructs, characterized by a complex microstructure based on assembly of building blocks made of cells and extracellular matrix. Inspired by this concept, the current research proposal aims to develop a class of innovative, biomimetic colloidal gels by employing mesenchymal stem cells and gelatin microspheres as building blocks, to create 3D cellular constructs with complex structure and tissue-specific function. Strong cell-microsphere binding will be introduced by surface-decorating gelatin microspheres with cell-adhesion sequences that possess strong affinity to cell membrane, thereby inducing self-assembly and gel formation based on MSCs and gelatin microspheres. Such cellular structures show great potential for engineering 3D tissue constructs that can steer cell fate and induce tissue regeneration.

Movie: http://youtu.be/o8sp87nNKfI