This article is more than 5 years old. Information may no longer be current.
Current tissue engineering strategies in orthopaedics show promise
Click Here to Manage Email Alerts
Editor’s note: In this article from the FORTE organization, Pinar Yilgor Huri, PhD, discusses the future of tissue engineering in orthopaedic surgery and successes to date in this area. Look for more articles from FORTE members in future issues of Orthopaedics Today Europe.
Orthopaedic surgery is probably top on the list of medical fields using biomaterials in routine clinical applications. Indeed, it is reported the orthopaedic biomaterials market is projected to reach $3.9 billion by 2021 in the United States and 376 million by 2019 in Europe. These biomaterials include metals, ceramics, polymers and some biological components, and they have been in clinical use for decades. Although great improvement has occurred in the orthopaedic biomaterials field since its inception, making the treatment options better and more feasible, material scientists have learned along the way that the more we mimic the natural tissue structure, the easier it is to reach the regeneration outcomes.
Based on this, tissue engineering has emerged as an alternative strategy to generate viable tissue substitutes in the lab. It is important to understand, however, what tissue engineering is and the possible ways in which it can impact the future of orthopaedic surgery.
Focus on biological substitutes
Tissue engineering is an interdisciplinary research field that generates biological substitutes to restore, replace or support tissue and/or organ function using principles of engineering and life sciences. The major goal of tissue engineering is to produce personalized, autologous grafts in the lab to hopefully overcome problems associated with the use of autografts, such as donor shortage and donor site morbidity. First introduced in 1993 by Langer and Vacanti, the concept of tissue engineering evolved fairly rapidly, and today engineered skin, cornea, trachea and cartilage substitutes find clinical applications. At the same time, challenges remain concerning the engineering of more functional and more sophisticated systems.
The tissue engineering strategy consists of three basic elements: appropriate cell sources, bioactive agents to regulate cell function and scaffolds to serve as 3-D temporal guides and mechanical support on which the tissue can grow and organize.
To produce an engineered graft, cells are isolated from the patient and multiplied in vitro. They are seeded on biocompatible and biodegradable scaffolds that are produced to meet the structural and mechanical constraints of a defect site. Bioactive agents — usually growth factors that regulate the proliferation and differentiation of resident and transplanted cells — are combined with the scaffold, and what is a functional viable tissue substitute is then transplanted to the defect site.
Stems cells support cell renewal
Primary cells or stem cells can be used as cell sources in tissue engineering. Although the ideal approach is to use the primary autologous cells isolated from the non-defected site of the target tissue, there can be problems in the isolation and multiplication of primary cells, such as the isolation of primary osteoblasts from bone tissue. In such cases, stem cells offer various advantages over the use of primary cells.
Stem cells have the capacity of cell renewal and differentiation along multiple lineages. They can be of embryonic or adult tissue origin. One of the most recent advances in stem cell technology is the generation of induced pluripotent stem cells (iPSCs). The iPSCs are formed by transfection of terminally differentiated adult cells with genes that encode the embryonic transcription factors so that a mature cell can be reprogrammed to become pluripotent. This discovery was recognized the with Nobel Prize in 2012 and holds great promise for the future of cell therapy and tissue engineering approaches. However, there still are issues that need to be resolved before iPSCs can be used in therapeutic applications.
Scaffolds are important components of tissue engineering strategy. The roles of scaffolds in engineered tissues are analogous to the functions of extracellular matrix (ECM) in native tissues. The best design of a tissue-engineered scaffold is undoubtedly the ECM of the target tissue in its native state. Although it is not easy to mimic the exact structure and function of the ECM, due to its unique properties such as multiple functioning, complex composition and dynamic nature, many tissue engineering scaffold designs were inspired from the ECM and attempt to mimic the 3-D microenvironment of the native tissue.
Scaffolds need multipurpose design
Scaffolds made of biodegradable materials are designed to degrade gradually in the body and will be replaced eventually by newly formed tissues. The design of the scaffold and selection of the appropriate biomaterial to be used are critical in the development of engineered tissues. Scaffolds should be designed appropriately so they provide sufficient pore volume for vascularization and new tissue formation, have sufficient porosity and interconnected pores to enable efficient nutrient, oxygen and metabolite diffusion without significantly compromising the mechanical stability of the scaffold, and have degradation rates that match those of the new matrix production by the developing tissue.
They should also provide support for cells to attach, grow and differentiate during in vitro culture and upon implantation. Scaffolds also may include biological cues, such as cell adhesion ligands to enhance attachment, or physical cues, such as topography, to influence cell morphology and alignment.
Growth factors are generally used in a tissue engineering strategy to control the functionality of the engineered graft. The direct injection of growth factors into the defect site is not a feasible approach because it leads to loss of function, rapid clearance from the administration site and requires application of high doses to be effective. Therefore, incorporation of growth factors into scaffolds is a better strategy.
Biomimetic-engineered bone graft
As an example, our approach to generate biomimetic-engineered bone grafts was to incorporate bone morphogenetic protein-2 (BMP-2) and bone morphogenetic protein-7 (BMP-7) into 3-D-printed poly(-caprolatone) (PCL) scaffolds to mimic their natural spatiotemporal release profiles. For this, we encapsulated BMP-2 and BMP-7 within biodegradable polylactic-co-glycolic acid (PLGA) and poly3-hydroxybutyrate-co-3-hydroxyvalerate nanocapsules and we then released the two BMPs from these nanocapsules 2 days and 10 days later, respectively, which mimicked the timing of their natural bioavailability. Then these nanocapsules were incorporated on 3-D printed scaffolds and again released from the 3-D constructs with spatiotemporal control.
From this work we showed these growth factor-releasing constructs enhance osteogenic differentiation of mesenchymal stem cells and the regeneration of rabbit iliac crest defects in in vitro and in vivo studies.
Matrix-induced autologous chondrocyte implantation is a good example of the application of tissue engineering strategy in the clinic. Primary chondrocytes are isolated from the patient, multiplied in vitro and seeded on 3-D biodegradable scaffolds. After in vitro maturation of the construct, the scaffold is transplanted to the defect site. This procedure is one of the most widespread tissue engineering techniques used in the clinic. Studies are ongoing into better engineered and better functioning cartilage grafts.
Tissue-engineered ligaments
There are numerous studies at different stages, i.e., preclinical, animal model or clinical, that aim to generate engineered skeletal muscle, tendon and ligament grafts, as well as bone and cartilage. For example, the main advantages of tissue-engineered ligaments include minimal patient morbidity, simpler surgical technique, reliable fixation methods, rapid return to pre-injury function, minimal risk for infection or disease transmission, biodegradation at a rate that provides adequate mechanical stability and supporting host tissue ingrowth. Natural and synthetic materials in the form of gels, membranes or 3-D scaffolds have also been widely used for ligament replacement. Collagen, silk, hyaluronic acid, ECM bioscaffolds, such as porcine small intestine submucosa and urinary bladder membrane, as well as polyhydroxyalkanoates (PHA), such as poly-hydroxybutyrate, poly-3-hydroxybutyrate-co-hydrovalerate and poly-3-hydroxy-10-undecenoate, are examples of potential natural replacements. Dacron polyester, polyglycolic acid, polyL-lactic acid, PLGA, polyethylene oxide and polyurethane urea are examples of synthetic materials. Collagen was one of the first natural scaffold materials to be used in ligament reconstruction as it is the natural component of the native tissue and has great ability to support ligament fibroblast growth under static tension. However, collagen scaffold alone was found to be ineffective to enhance suture repair of the ACL. Fibroblast-seeded collagen scaffolds, in other studies, were more effective in ligament regeneration.
Tissue engineering led to the production of the cartilage grafts that are now being successfully applied in the clinic. Moreover, there are numerous studies ongoing to produce better engineered bone, cartilage, muscle, tendon and ligament grafts, but there is a way to go in the engineering of clinically applicable substitutes for tissues that require higher-level functionality. Clinician-scientist coordination is critical for achieving such a goal. Along with a multidisciplinary approach, the interdisciplinary contributions of biologists, chemists, biomaterial scientists and tissue engineers are needed to meet patient demand in this area.
- References:
- Bellincampi LD, et al. J Orthop Res. 1998;16:414-420.
- Fleming BC, et al. J Orthop Res. 2010;doi:10.1002/jor.21071.
- iData Research Report. European market for orthopedic biomaterials; April 9, 2013.
- iData Research Report. US orthopedic biomaterials market is projected to reach $3.88 billion by 2021; December 4, 2014.
- Langer R, et al. Science. 1993;260:920-926
- Takahashi K, et al. Cell. 2007;131(5):861-72.
- Vunjak-Novakovic G, et al. Annu Rev Biomed Eng. 2004;6:131-156.
- Yilgor HP, et al. J Biomed Mater. 2013;doi:10.1088/1748-6041/8/4/045009.
- Yilgor P, et al. Biomaterials. 2009;doi:10.1016/j.biomaterials.
- Yilgor P, et al. J Biomed Mater Res. 2010;93A:528-536.
- Yilgor P, et al. J Mater Sci Mater Med. 2010;doi:10.1007/s10856-010-4150-1.
- Yilgor P, et al. J Tissue Eng Regen Med. 2013;doi:10.1002/term.1456.
- For more information:
- Pinar Yilgor Huri, PhD, can be reached at Ankara University Department of Biomedical Engineering and BIOMATEN Center of Excellence in Biomaterials and Tissue Engineering, Ankara Turkey; email: pyilgor@yahoo.com.
Disclosure: Yilgor reports no relevant financial disclosures.