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Tissue engineering in orthopaedics
The document summarizes recent applications of tissue engineering principles in orthopaedics. It discusses how scaffolds, signals, and cells have been combined in various tissue engineering strategies to treat fracture nonunions, osteonecrosis, and chondral/osteochondral defects. For fracture nonunions, delivering mesenchymal stem cells on an atelocollagen scaffold improved healing rates. Treating osteonecrosis with autologous mesenchymal stem cells seeded on bone grafts showed prevention of disease progression in some cases. Cell doses and scaffold properties were found to influence outcomes. Tissue engineering approaches for cartilage defects, including cell injections and composite scaffolds, demonstrated symptom improvement over baseline.
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Tissue engineering in orthopaedics
- 1. Tissue Engineering in Orthopaedics AlexanderM. Tatara, BS; Antonios G. Mikos, PhD J Bone Joint Surg Am, 2016 Jul 06; 98 (13): 1132 -1139 . http://dx.doi.org/10.2106/JBJS.16.00299 Investigation performed at the Department of Bioengineering, Rice University, Houston, Texas A Journal Club presentation at Amala Institute of Medical Sciences by Dr. Libin Thomas Manathara
- 2. Topics • Principles ofOrthopaedic Tissue Engineering • Scaffolds • Signals • Cells • Applications • Fracture Nonunion • Osteonecrosis • Chondral and Osteochondral Defects • Future Directions and Challenges 2
- 3. Tissue Enigineering • Tissueengineering is the use of a combination of cells, engineering and materials methods, and suitable biochemical and physicochemical factors to improve or replace biological tissues • Tissue engineering involves the use of a scaffold for the formation of new viable tissue for a medical purpose • The term regenerative medicine is often used synonymously with tissue engineering 3
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- 5. Principles of OrthopaedicTissue Engineering • The tissue engineering paradigm consists of scaffolds, signals, and cells • These 3 elements can be combined or used independently to attempt to generate tissues in a limitless number of arrangements 5
- 6. The orthopaedic tissueengineering paradigm. Alexander M. Tatara, and Antonios G. Mikos J Bone Joint Surg Am 2016;98:1132-1139 ©2016 by The Journal of Bone and Joint Surgery, Inc. 6
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- 8. Scaffolds • Tissue engineeringscaffolds are cytocompatible biomaterials that cells can adhere to and/or replace with extracellular matrix to produce native tissues • Scaffolds can be as simple as morselized autologous bone or as complex as injectable, thermally responsive, synthetic hydrogels capable of mineralizing in situ • morselize- To break up or divide into small portions • hydrogel- a gel in which the liquid component is water 8
- 9. Scaffolds • On thebasis of material composition, scaffolds can be divided into 3 basic classes: metals, ceramics, and polymers • Scaffolds can be further divided by their source (naturally derived versus synthetically fabricated) and ability to degrade (nonresorbable versus resorbable) 9
- 10. Overview of theclasses of scaffolds. Alexander M. Tatara, and Antonios G. Mikos J Bone Joint Surg Am 2016;98:1132-1139 ©2016 by The Journal of Bone and Joint Surgery, Inc. 10
- 11. Scaffolds • Although theyare stable, nonresorbable scaffolds and delivery systems cannot be replaced by native tissues and may elicit a chronic foreign-body reaction detrimental to tissue healing 11
- 12. Scaffolds • Naturally derivedscaffolds (such as those made from collagen, chitosan, and hyaluronan) are generally all resorbable in situ and often already possess adhesion ligands for cellular attachment • However, naturally derived scaffolds typically have a narrow range of available physical properties, such as mechanical strength and degradation rate 12
- 13. Scaffolds • Synthetic scaffoldscan be tuned to have a wide variety of properties by altering synthesis components and parameters • Not all synthetic scaffolds are biodegradable, and cell adhesion motifs may need to be added in order to promote biocompatibility 13
- 14. Scaffolds • Different scaffoldmaterials can also be combined to create composite scaffolds that have novel properties not observed in either material used alone • For orthopaedics, mechanical properties and durability are paramount to a successful device. 14
- 15. Scaffolds • While aceramic scaffold may have appropriate compressive strength in a femoral nonunion defect, its high stiffness and weak tensile properties would be inappropriate for use in a cartilage defect or repairing a rotator cuff. 15
- 16. Scaffolds • Another importantfactor to consider is the compatibility of the rate of scaffold resorption with the rate of native tissue replacement. • If a scaffold resorbs too rapidly, it may not be able to support the growth of new tissues. • If a scaffold resorbs too slowly, it may not fully integrate with surrounding tissues and may pose risks associated with chronic foreign bodies. 16
- 17. Scaffolds • Scaffolds maybe osteoconductive (i.e., permit the growth of bone, such as the calcium sulfates) or osteoinductive (i.e., actively promote bone growth in a defect that otherwise would not heal, such as demineralized bone matrix). 17
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- 19. Signals • rhBMP-2 • Plateletrich plasma (PRP) • Antibiotics • Mechanical cues • Electrical cues 19
- 20. Signals • Signals areinternally or externally derived environmental factors that can influence the regeneration of tissues • As in the case of scaffolds, these signals can be further broken down into subcategories including biological, chemical, mechanical, and electrical cues 20
- 21. Signals • In orthopaedics,the most commonly utilized biological signal is rhBMP-2, a potent osteogenic growth factor • Has been approved for specific uses by US FDA 21
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- 23. Signals • However, itappears that rhBMP-2 is associated with greater risks than originally reported • There remain concerns about the use of growth factors in light of their association with malignancies such as osteosarcoma 23
- 24. Signals • Another commonsource of biological signals used in tissue engineering strategies is platelet rich plasma (PRP) and its different variants • While use of PRP is appealing because of the ease of autologous obtainment, its actual efficacy in the regeneration of musculoskeletal tissues currently remains uncertain 24
- 25. Signals • Antibiotics areanother example of chemical cues often delivered in conjunction with tissue engineering strategies • In an infected orthopaedic defect, encapsulating antibiotics for local drug delivery into the scaffold may be required to stimulate healing 25
- 26. Signals • Mechanical cueshave long been used to stimulate bone formation, such as in distraction osteogenesis • Recent studies have demonstrated that passive mechanical signals provided by scaffolds (such as substrate stiffness, roughness, and porosity) can influence the differentiation of stem cells toward specific lineages 26
- 27. Signals • Electrical cueshave been demonstrated to be important in generating functional skeletal muscle tissue as well as innervation of neotissues but have not been explored as thoroughly relative to other cellular signals for orthopaedic tissue engineering applications 27
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- 29. Cells • In orderto create living tissues, as well as integrate living engineered tissue with native host tissues, cells must be present • Cells can be recruited into an implanted scaffold by methods such as • the release of chemokines • attachment of cell ligands to the scaffold • osteoconduction • osteoinduction • scaffolds containing cells can be implanted into a defect 29
- 30. Cells • Unlike inother tissue engineering fields, there is little controversy regarding stem cell type in orthopaedic tissue engineering 30
- 31. Cells • By far,the most commonly utilized cell type is the mesenchymal stem cell (MSC) • Depending on their environment, MSCs have the ability to differentiate into • osteoblasts • chondroblasts • myoblasts • tenocytes • as well as other adult cells 31
- 32. Cells • MSCs arerelatively easy to harvest from an autologous host • The current gold standard is MSCs harvested from bone marrow aspirate • However, adipose-derived MSCs are gaining more traction in the field because of their • increased availability • lower harvesting costs • ease of expansion 32
- 33. Cells • Amniotic fluid-derivedMSCs are another intriguing source that has recently been shown to be capable of osteogenesis and chondrogenesis in small animal models • Other sources of MSCs include skin, periosteum, and umbilical cord blood 33
- 34. Cells • However, easeof collection should not be the only consideration in MSC harvesting • MSCs from different sources have different potential for differentiation and may affect the quality of tissue repair 34
- 35. Cells • Initially, itwas believed that the primary mechanism of action of implanted MSCs within an orthopaedic defect was structural • It was assumed that the implanted MSCs themselves would proliferate, differentiate, and generate the extracellular matrix required to repair the defect • However, recent studies have revealed the tremendous pleiotropic effects of MSCs 35
- 36. Cells • Beyond theirability to terminally differentiate into adult musculoskeletal cells, MSCs secrete a variety of cytokines and modulate inflammatory and immune response pathways • Because of these immunomodulatory effects, implantation of allogeneic MSCs carries minimal risk of rejection by the host and commercially available MSCs are being explored in a number of clinical trials for a multitude of autoimmune diseases 36
- 37. Cells • From aproduct development and regulatory standpoint, acellular strategies present advantages over cell-containing products, which carry a potential risk of rejection or disease transmission, have heterogeneous cell populations, etc • For example, it is clear that rhBMP-2 combined with a collagen scaffold has ample regenerative capacity for spinal fusion without the addition of any exogenous MSCs • However, for complex diseases such as osteonecrosis, the pleiotropic and immunomodulatory capacities of MSCs may be required for treatment 37
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- 39. Orthopaedic Tissue Engineering Elements Appliedin Recent Clinical Experiences
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- 42. Fracture Nonunion • Whilethere is currently no standardized definition, fracture nonunion has been defined by the FDA and others as incomplete healing at 9 months after injury and the absence of healing progression over the following 3 consecutive months • Despite advances in surgical techniques, fracture nonunions continue to present clinical challenges • As disrupted vascularity is one of the major contributors to nonunion, strategies to enhance angiogenesis, including delivery of hematopoietic stem cells, are being explored 42
- 43. Fracture Nonunion • Inone study, autologous bone marrow-derived hematopoietic stem cells were delivered on an atelocollagen scaffold into tibial and femoral nonunion defects in 7 patients • This combination of cells and scaffold resulted in fracture-healing in 5 (71%) of 7 patients at 12 weeks • While there was no control arm, the threshold of healing achieved was 18% (2 of 11 patients) 43
- 44. Atellocollagen • Collagen isa major connective tissue protein that plays an important role in the extracellular matrix in animals. • As such, collagen possesses good biocompatibility with animal body tissues. 44
- 45. Atellocollagen • Atelocollagen isa type of soluble collagen produced from tropocollagen, the collagen molecule that makes up collagen fibrils, via the elimination of the telopeptide moieties, which are considered to account for most of collagen's antigenicity. • Thus, atelocollagen is considered to have little immunogenicity, which makes it a safe biomaterial. • It is widely used for implantable medical and plastic surgical products 45
- 46. Fracture Nonunion • Ina retrospective review of 52 patients treated for forearm nonunion defects at a single center, patients were categorized as being treated with a single tissue engineering element (MSCs, a scaffold, or BMP, i.e., “monotherapy”) or with all 3 elements of the tissue engineering paradigm (“polytherapy”) • With a minimum follow-up time of 1 year, patients receiving all 3 elements had significantly improved radiographic healing, clinical success criteria, and rapidity of healing compared with patients treated with monotherapy 46
- 47. Fracture Nonunion • Whilethat study lends support to the synergistic nature of combining cells, scaffolds, and signals to treat severe orthopaedic defects, a randomized prospective study would have provided stronger evidence by minimizing bias 47
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- 49. Osteonecrosis • Given theirnecrotic nature, the lesions associated with osteonecrosis have poor innate regenerative capacity with few or no viable MSCs • In addition, it has been reported that, in corticosteroid-induced osteonecrosis, there is a global decrease in available MSCs • In theory, MSC therapy may be promising, given the immunomodulatory properties of MSCs as well as their ability to secrete angiogenic growth factors and recruit local vasculature 49
- 50. Osteonecrosis • In arecent clinical study of 5 femoral heads in 4 patients, autologous bone marrow-derived MSCs were seeded onto morselized allogeneic bone as scaffold and were implanted in the defect after core decompression 50
- 51. Osteonecrosis • Unfortunately, inthe patient who received treatment bilaterally, disease progressed in both femoral heads, leading to bilateral total hip replacement (after 13 and 19 months, respectively) • Microcomputed tomography revealed that the treated zone was greater in opacity than trabecular bone • The tissue in the treated zone was histologically and mechanically indistinguishable from the patient’s healthy trabecular bone 51
- 52. Osteonecrosis • The other3 patients had no more disease progression after treatment (22 to 44 months of follow-up) • As the authors noted, “Further clinical trials are necessary, including comparison to concurrent therapies” 52
- 53. Osteonecrosis • In asimilar study in which cells and scaffolds were utilized in disease treatment, 10 patients with osteonecrosis were treated with vascularized bone grafts augmented with autologous bone marrow- derived MSCs seeded on a β-tricalcium phosphate scaffold 53
- 54. Osteonecrosis • At 2years of follow-up, 9 patients had completed the protocol and 7 had no further disease progression • In the 2 patients who had disease progression, the authors postulated that “an imbalance between bone resorption and formation” may have contributed to the cystic lesions observed in their femoral heads 1 year after surgery 54
- 55. Osteonecrosis • Given thedegradation rate of β-tricalcium phosphate (weeks to months) and the low innate regenerative potential of the femoral head in osteonecrosis, a mismatch in the rate of scaffold degradation and native tissue regeneration may have resulted in collapse of the lesion • While a prospective randomized study is required for conclusive evidence on treatment superiority, these studies in sum demonstrate how selection of scaffold properties may impact the clinical outcome 55
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- 57. Chondral and OsteochondralDefects • Cell monotherapy for the treatment of cartilage defects is more common than in other orthopaedic pathologies • Despite the popularity of these monotherapies, the optimal amount of MSCs required for efficacy is unclear 57
- 58. Chondral and OsteochondralDefects • In a recent study, autologous adipose-derived MSCs in 3 different doses were injected without scaffold or exogenous signals into osteoarthritic knees in 18 patients • While no patient experienced treatment-related adverse events, the effects of dose are more difficult to ascertain as the low and medium dosage groups had only 3 patients each • However, patients in the high dosage group demonstrated significantly improved clinical, radiographic, and arthroscopic measurements compared with baseline, and these improvements were not reflected in the low and medium dosage groups 58
- 59. Chondral and OsteochondralDefects • Increasing in complexity, allogeneic chondrocytes that have been genetically modified to express transforming growth factor-beta 1 (TGF-β1) by retroviral modification ex vivo were injected at 2 different concentrations in 27 patients with osteoarthritis • While the 2 groups did not show significant differences in healing compared with one another, both groups demonstrated significantly improved clinical scores (including reduced pain and stiffness and increased physical function) compared with baseline values 59
- 60. Chondral and OsteochondralDefects • This recent work demonstrates that cells can be programmed to deliver signals themselves to mitigate disease in human patients, rather than requiring exogenous delivery of the signals through non- living vehicles such as collagen sponges or microparticles 60
- 61. Chondral and OsteochondralDefects • A composite scaffold, constructed using collagen and hydroxyapatite nanoparticles in a gradient-based fashion, was implemented in 27 patients • Again, patients showed significant improvement compared with baseline values at both 2 and 5 years following treatment, which is historically not the case with osteochondral defects 61
- 62. Chondral and OsteochondralDefects • While this improvement could be due to the gradient-based nature of the acellular scaffold, without a nongradient-based control, it is difficult to draw any definitive conclusions regarding the effects of acellular gradient-based scaffolds on the treatment of osteochondral defects in human disease 62
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- 64. Future Directions andChallenges • Although the future for orthopaedic tissue engineering is bright, there is much work to be done • While the small number of clinical studies reviewed in the present work may not necessarily be a representative sample of the field as a whole, they demonstrate that small patient numbers, lack of randomization, and absence of control groups consisting of current clinical treatment standards can make it difficult to determine the efficacy of the various elements of the tissue engineering paradigm in orthopaedics 64
- 65. Future Directions andChallenges • New manufacturing techniques, such as the advent of high-resolution bioprinting are allowing for the rapid creation of personalized devices to an extent that was not previously possible • Infections, which often plagued implantation of foreign materials like scaffolds, are being mitigated by advances in anti-infective strategies such as biofilm-repulsing surfaces and antibiotic-delivering materials 65
- 66. Future Directions andChallenges • Synthetic biology and genetic engineering techniques are being utilized to reprogram cells to optimize healing • Ultimately, products such as INFUSE (Medtronic) and Carticel have demonstrated that the field of orthopaedics is willing to adopt tissue engineering strategies into clinical practice 66
- 67. Future Directions andChallenges • In the past, the benchmark for successful treatment of conditions such as osteoarthritis was lack of disease progression • With the new therapies inspired by tissue engineering, the new benchmark may be the absence of disease 67
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