The field of healthcare is being revolutionized by the concept of artificial tissues. Tissue engineering (TE) applies the principle of biology and engineering to the development of functional substitutes for damaged tissue. It holds immense potential for replacement therapy where damaged tissues and organs such as liver, connective tissues, bone, cartilage, and muscles can be regenerated or replaced if they are beyond repair. The design of bone scaffolds has emerged as a victorious alternative to bone substitutes including autografts, allografts, and xenografts. TE of the bone and cartilage has evolved over the last few decades with the primary aim to overcome the limitations of all conventional treatments offered. The clinical applications in the field of bone and cartilage tissue engineering constitute a wide spectrum ranging from bone and cartilage regeneration, tumors, reconstructive surgeries, and arthritis treatments. The general strategy in creating a functional bone or cartilage tissue requires the incorporation of living cells into matrices or scaffolds, as structural support for cell adhesion, while influencing the fate of immature cells through bioactive molecules and/or physical cues. The key considerations to be considered while designing scaffold materials for bone and cartilage are biocompatibility, biodegradability, mechanical requirements in accordance with the tissue, architecture of the scaffolds and the fabrication technology. One of the primary goals of TE lies in developing methods to construct organs in the laboratory that can be used subsequently in medical applications. Thus, the major requirements for bone and cartilage tissue engineering are the perfect synergy between osteogenic/chondrogenic signals, suitable scaffolds, and cells (Figure 1).
- The signals constitute various biochemical cues, growth factors or bio-molecules that are essential for the differentiation into the desired lineage.
- Cells constitute osteoblasts, chondroblasts or mesenchymal stem cells (MSCs) which direct the differentiation process into the respective lineage. MSCs are quite easily available and the protocols for their extraction and culture are well documented in the literature. They can be characterized by their ability to develop into osteogenic or chondrogenic lineages in response to external stimuli and expression markers that can be supplemented.
- Lastly, scaffolds play a vital role in supportive matrix information of a tissue-engineered bone or cartilage. There is insufficient evidence to show that grafts could fully heal injuries, without causing issues like an increased inflammatory response, antigenic reactions, fixation site failure and lack of long term biocompatibility which has limited their application in treating bone and cartilage regeneration. The design of scaffolds has received a lot of attention, as it has emerged as an alternative to bone substitutes. For instance, nano-fibrous structures have multifarious applications in the nano-bioengineering domain based on their morphology and processing techniques.
Moreover, due to variations in structure within a bone (compact and spongy) and cartilage (lamellae and trabeculae), the definition of an ideal scaffold is difficult for these applications.
The key factors to consider while fabricating an ideal scaffold (Figure 2) are
(a) pore size [macro- >100 µm), micro- < 20 µm] and interconnected open porosity for in vivo tissue in-growth;
(b) Mechanical Properties: mechanical properties combined with controlled degradation kinetics,
(c) ability to survive through all the physical forces in vivo; and
(d) maintenance of a sterile environment condition for cell seeding onto the scaffold.
Three-dimensional(3D) porosity with interconnected pores is essential to facilitate cell growth, transport of nutrients and removal of metabolic wastes. Biocompatibility and bio resorption with controllable degradation rates are required to be in accordance with the cell model of interest. Conducive surface properties for cell proliferation, attachment and detachment are essential followed by commendable mechanical properties to ensure proper load transfer.
Classification of Scaffolds:
Scaffolds, in the context of musculoskeletal tissue regeneration, are temporary support structures that induce the formation of the desired lineage. They also act as carriers of drugs and other growth factors and bioactive molecules that enable osteogenesis and/or chondrogenesis to happen. To this end, scaffolds are broadly classified into three categories namely ceramics, polymers and metals (Figure 3).
Demineralized bone matrix, collagen composites, fibrin, calcium phosphate, polylactide (PLA), poly(lactide-co-glycolide)(PLGA), polylactide-polyethylene glycol(PLA-PEG), hydroxyapatite(HA), dental plaster and titanium are few of the currently approved materials used extensively for musculoskeletal tissue regeneration approaches.
Metals and ceramics pose the issue of lack of biodegradation in a biologic environment and possess limited processability and tenability.
Polymeric scaffolds, on the other hand, have gained significant attention as they can be tailored to closely mimic the extracellular matrix (ECM) of the native tissues. They are biodegradable and exhibit excellent design flexibility, which in turn relies on the material chosen, composition and the ratios of the polymers to be tailored for different applications. Polymers used in bone and cartilage TE are required to be biocompatible thus avoiding any immune responses from the host tissue. Their degradation rate can be controlled to suit the rate of tissue regeneration and degradation products are excreted through metabolic pathways.
Polymers are sub-classified into naturally-derived (eg: collagen and fibrin), and synthetic polymers (eg: poly (lactic acid) (PLA), poly (glycolic acid) (PGA), and their copolymers (PLGA)).
Natural polymers exhibit immunogenicity and do not provide flexibility over mechanical properties. In addition, batch to batch consistency, risk of pathogen infection and biodegradability are issues of concern. Synthetic polymers are reproducible in large quantities without any variations arising from different batches. They possess negligible immunogenicity and properties such as microstructure, degradation rate, and mechanical strength can be tailored according to user needs.
Various composite materials, with an optimal concoction of natural and synthetic polymers, have also been developed. Synthetic hydrogels are being explored widely for devising an injectable biodegradable scaffold system, with significant efforts focused on improving their mechanical strength.
A plethora of advancements in this arena indicates that engineered tissues to possess added clinical applicability and how it repositions itself as a viable therapeutic option for those who would benefit from the life-extending benefits of musculoskeletal tissue regeneration.
What are your thoughts on your preferred choice of cell-type, scaffold and signals for growing a bone tissue?
Stay tuned to know more about various fabrication technologies currently used for musculoskeletal tissue engineering in the next article!
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About the Author:
Dr. Chamundeswari completed her Doctorate by Research from Nanyang Technological University, Singapore; her Ph.D. work focused on developing bioactive polymeric scaffold systems for bone and cartilage tissue regeneration applications. She has interned at reputed institutions such as MIT-Harvard and National Chemical Laboratory, Pune India. She was the title winner of the Young Persons’ World Lecture Competition, in Australia (2017), and a finalist at the Falling Walls Lab Competition in Singapore (2019).
Over the last couple of years, Vidya has been actively involved in a wide spectrum of research projects ranging from designing medical devices, oral and scaffold-based drug delivery systems all the way to the extraction of bio-resins from food waste, to name a few. She is currently a Community Manager with 3DHeals, San Francisco and is passionate about applying her knowledge to drive R&D progress pertaining to healthcare and regenerative medicine.