PEG/HA Hybrid Hydrogels for Biologically and Mechanically Tailorable Bone Marrow Organoids

Abstract

Bone marrow (BM) organoids provide powerful tools to study the vital interplay between the BM microenvironment and resident cells. Current biomaterials, however, are limited in terms of versatility for independently studying the biochemical and biophysical properties that regulate BM function. Here, a transglutaminase (TG) crosslinked system that seamlessly incorporates poly(ethylene glycol) (PEG) and hyaluronic acid (HA) into hybrid hydrogels for the formation of BM analogues is presented. By combining features of PEG and HA, these novel biomaterials are tunable to optimize their physical and biological properties for BM organoid formation. Utility of the TG-PEG/HA hybrid hydrogels to maintain, expand, or differentiate human bone marrow-derived stromal cells and human hematopoietic stem and progenitor cells in vitro is demonstrated. Even more compelling, TG-PEG/HA hybrid hydrogels are superior to currently used natural biomaterials in forming humanized BM organoids in a xenograft model. Hybrid hydrogels in comparison to pure PEG or pure HA afford the ideal attributes of both regarding material handling, structural integrity, and minimizing macrophage infiltration in vivo. The engineered humanized BM organoids presented here may be effective tools for the study of this intricate organ.

Recent advances in chemically defined and tunable hydrogel platforms for organoid culture

“…Developing a highly controlled microenvironment for studying the cellular dynamics in the bone marrow is challenging. In this regard, bone marrow organoids were formed in a tunable and defined PEG-HA composite hydrogels [92]. Hydrogels were hydrolytically sensitive to MMP peptide and were conjugated with RGD motif.…”

Bioprinting of Cartilaginous Auricular Constructs Utilizing an Enzymatically Crosslinkable Bioink

“…[ 12 ] This platform allows for the design of biomaterial systems mimicking the biomolecular characteristics of native tissue in either natural or synthetic hydrogels. [ 12b,13 ] Modulation of natural features, such as bioactive peptides, [ 13b ] signaling molecules, [ 14 ] proteolytic sequences and adhesive ligands, [ 15 ] as well as modular architectures linking different hydrogel systems such as polyethylene glycol (PEG), chondroitin sulfate, [ 14b ] gelatin, [ 16 ] hyaluronan, [ 17 ] and heparin [ 18 ] are thus possible. The innate biocompatibility of many enzymatic crosslinking processes [ 19 ] further overcomes concerns regarding cytotoxicity of chemical crosslinking processes such as in the case of photopolymerization where exposure to UV‐radiation and free radicals can be detrimental to cell viability.…”

Biomaterials for protein delivery for complex tissue healing responses

“…Hydrogels have been extensively investigated for tissue regeneration applications due to their innate hydrophilic characteristic, which makes them suitable delivery vehicles for cells and proteins. 16,17 Hydrogels are 3D networks consisting of various natural and/or synthetic polymers, including alginate, 18 gelatin, 19 hyaluronic acid, 20 polyethylene glycol (PEG), 21 and devitalized or decellularized ECM. 22 Synthetic polymer hydrogels are highly reproducible and can be extensively functionalized for modular addition of proteins, cells, and other bioactive ligands; however, since synthetic polymers are typically biologically inert, multiple functional groups may be required to achieve a desired biological response.…”