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Bone Regeneration through Scaffold-Free Tissue Engineering

Karthik Prabakaran
DY Patil University, School of Biotechnology and Bioinformatics

Tissue engineering is a multidisciplinary field that encompasses the practice of combining stem cells, scaffolds and signaling molecules collectively known as the tissue engineering triad to restore, construct or repair damaged tissues or whole organs. Important metabolic functions and load bearing are carried out by appendicular skeletons. In the traditional scaffold-based bone tissue engineering, implantable constructs are created with the combination of scaffolds and regenerative cells. The tubular scaffold materials for Mesenchymal stem Cells (MSCs) have been derived from natural-coral or synthetic polymers. BMP-2 (Bone Morphogenetic Protein-2) belonging to TGF-β (Tissue Growth Factor-β) family is one of the crucial signaling molecule present in humans for tissue engineering.

Using a scaffold-based implant generates the following drawbacks, which are mentioned as follows:
1. To initiate osteogenic pre-differentiation, the MSCs need to be pre-cultured for 2-3 weeks in an induction medium.
2. Only a single morphogen can be delivered.
3. The scaffold can interfere with the cell-cell communications.
4. The rate of the scaffold degradation may be faster than new tissue formation.5. Toxic byproducts can be generated by scaffold degradation.

Biomimetic engineering approaches focus on integrating and mimicking the properties of the actual biological molecules to generate bio-inspired, bio-functional materials. Templates derived from scaffold-free cartilage from self-assembled human MSCs (hMSCs) condensations have been shown to progress through in-vivo endochondral ossification. (Endochondral ossification is the process of replacement of cartilage to fully functional bone which forms a part of the skeletal framework).

TGF-β1 containing gelatin microspheres are incorporated for in situ chondrogenic priming (to enhance differentiation) and BMP-2 presenting hydroxyapatite microparticles are introduced for bony remodeling of the cartilaginous template. This strategy eliminates the need for lengthy pre-differentiation and achieves early in vivo implantation. An experiment was conducted by Herberg, S., et al. regarding the functional femoral bone defect healing. Endochondral ossification containing hMSC microparticle condensate for localized presentation of TGF-β1 + BMP-2 was done by inducing in vivo chondrogenic differentiation. It aimed to recapitulate the cellular, biochemical, and mechanical environment during early limb development.

The experiment was conducted on lab rats and the results are summarized into three categories:
i. In vitro maturation (outside the living system) was observed by microparticle mediated in situ preparation of TGF-β1 + BMP-2 to hMSC and it increased chondrogenic and osteogenic differentiation.
ii. In vivo Implantation (inside the living system) of the microparticles was done subcutaneously (beneath the skin). It increased chondrogenic and osteogenic differentiation.
iii. In vivo implantation was done orthotopically (injected into the actual site of deformation). It increased chondrogenic and osteogenic differentiation.

Thus, it is observed that instead of implanting scaffolds into a living system, we can use microparticle mediated signaling molecules to direct the cartilage to undergo differentiation and form a fully functional bone. Thus, the scaffold-free, hMSC system is of clinical significance for regeneration of long bones.

Reference (Feb-21-A1)

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