Cell-Instructive Mineralized Microenvironment Regulates Osteogenesis: A Growing SYMBIOSIS of Cell Biology and Biomaterials Engineering in Bone Tissue Regeneration

Abstract

One of the objectives of bone tissue engineering is to produce scaffolds that are biocompatible, osteoinductive, and mechanically equivalent to the natural extracellular matrix of bone in terms of structure and function. Reconstructing the osteoconductive bone microenvironment into a scaffold can attract native mesenchymal stem cells and differentiate them into osteoblasts at the defect site. The symbiotic relationship between cell biology and biomaterial engineering could result in composite polymers containing the necessary signals to recreate tissue- and organ-specific differentiation. In the current work, drawing inspiration from the natural stem cell niche to govern stem cell fate, the cell-instructive hydrogel platforms were constructed by engineering the mineralized microenvironment. This work employed two different hydroxyapatite delivery strategies to create a mineralized microenvironment in an alginate–PEGDA interpenetrating network (IPN) hydrogel. The first approach involved coating of nano-hydroxyapatite (nHAp) on poly(lactide-co-glycolide) microspheres and then encapsulating the coated microspheres in an IPN hydrogel for a sustained release of nHAp, whereas the second approach involved directly loading nHAp into the IPN hydrogel. This study demonstrate that both direct encapsulation and a sustained release approach showed enhanced osteogenesis in target-encapsulated cells; however, direct loading of nHAp into the IPN hydrogel increased the mechanical strength and swelling ratio of the scaffold by 4.6-fold and 1.14-fold, respectively. In addition, the biochemical and molecular studies revealed improved osteoinductive and osteoconductive potential of encapsulated target cells. Being less expensive and simple to perform, this approach could be beneficial in clinical settings.

The symbiotic effect of osteoinductive extracellular vesicles and mineralized microenvironment on osteogenesis

“…The IPN is a cutting-edge approach that aids in enhancing the mechanical strength of natural polymeric hydrogels by integrating mechanically more robust synthetic polymer in addition to the natural network. [6][7][8][9][10] For the current study, IPN was prepared by combining alginate, a natural polymer, with PEGDA, a synthetic polymer. 6 The capacity of alginate to retain and release EVs over time has previously been demonstrated.…”

“…A biomineralized microenvironment was created by direct encapsulation of nHAp in the IPN of alginate-PEGDA. 6 Hydroxyapatite powder is mixed in an alginate precursor solution and collected in one syringe.…”

“…Therefore, in the current investigation, we used the previously standardized IPN of alginate and polyethylene glycol diacrylate (PEGDA) to enhance the mechanical strength of alginate up to 3.34-fold. 6,10 Alginate, PEGDA, and hydroxyapatite were employed in the study because they are FDA-approved materials with several potential uses in BTE. The IPN of these two polymers, created using a unique synthesis process, is the novel aspect of the materials used in the current investigations.…”

“…Furthermore, we were able to improve the osteoinductive and osteoconductive capabilities of the scaffold by directly encapsulating nHAp in such an IPN. 6 Thus, in the current study, we chose to use the same mineralized IPN microenvironment together with cell-free EVs to boost its osteoinductive and osteoconductive capabilities.…”

“…The IPN of these two polymers, created using a unique synthesis process, is the novel aspect of the materials used in the current investigations. 6,10 Combining natural (alginate) and synthetic (PEGDA) materials results in a product with a moderate cell affinity and greater mechanical strength and is hence used in the current investigation. 6 Our previous study found that IPN comprising alginate (natural network) and PEGDA (synthetic network) greatly enhanced the mechanical strength of alginate.…”