Stem cells in Orthopaedic Surgery

STEM CELLS IN ORTHOPAEDIC SURGERY


 A stem cell is an ‘immature’ or undifferentiated cell which is capable of producing an identical daughter cell.
 Stem cells must have a capacity for self-renewal giving rise to more stem cells, and the ability to differentiate into tissues of various lineages under appropriate conditions

 They may be totipotent, pluripotent or multipotent, depending on type

 Totipotent: Cells which can form all the cells and tissues that contribute to the formation of an organism

 Embryonic stem cells (ESCs) are pluripotent, which can form most, but not all cells or tissues of an organism

 Differentiation of adult stem cells is generally restricted to the tissue in which they reside. Under appropriate conditions some can differentiate into multilineages, becoming multipotent. Eg., mesenchymal stem cells (MSCs) which are found in bone marrow, skin, adipose tissue

 These cells are capable of differentiating into bone, cartilage, tendon, ligament, fat and other tissues of mesenchymal origin

 The phenomenon of transdifferentiation: Here cells from one lineage dedifferentiate, giving rise to an intermediate cell type, before redifferentiating into cells of another lineage
 MSCs as progenitor cells, injected directly into tissues to enhance the process of repair, or by using them as a vehicle for gene delivery.
 Articular cartilage is vulnerable to injury and has poor potential for repair

 Procedures directed at the recruitment of stem cells from the marrow by penetration of the subchondral bone have been widely used to treat localised cartilage defects (autologous chondrocyte implantation)

 Attempts to 'regenerate' normal articular cartilage have been introduced in clinical practice with autologous chondrocyte implantation. Lesions of osteochondritis dissecans or traumatic osteochondritis can be treated with this technique

Bone

 Trauma and some pathological conditions may lead to extensive loss of bone, which requires transplantation of bone tissue
 Mesenchymal stem cells derived from bone marrow have been used to treat segmental bone defects (Quarto et al)

 Successful tissue engineering of bone requires osteoproduction, osteoinduction, Osteoconduction and mechanical stimulation

 Bone induction to assist and enhance bone deposition and repair was introduced by Urist in 1965 and led to the isolation of the BMPs, which could stimulate osteogenic precursor MSCs to form bone.

 A number of studies have shown the potential for BMP-2, BMP-3 and BMP-4 in the healing of fractures and segmental bone defects, and in the fixation of prosthetic implants

 BMP regulates chemotaxis, mitosis and differentiation, and is fundamental in initiating fracture repair

 TGF-β and IGF may stimulate fracture repair and minimise the rate of nonunion

 In order for BMP to induce bone formation effectively, its dose must be of sufficient concentration for a sustained period.

 However, these proteins have short biological half-lives and must be maintained at therapeutic concentrations at the fracture site to be effective

Tendons and ligaments

 In rabbits tendoachilles tears and patellar tendon defects have been successfully been treated by MSC.( Young et al)
 Key to success in surgical reconstruction of the anterior cruciate ligament (ACI.) is the healing of the tendon graft to the bone.
 The normal anatomy of the insertion site of the ACL is fibrocartilaginous and consists of four distinct zones: ligament substance, unmineralised fibrocartilage, mineralised fibrocartilage and bone

 Conventional free tendon transfers are unable to restore this complex anatomy within the first six months

 By applying MSCs to tendon grafts at the tendon-bone junction results in a zone of fibrocartilage at the junction which more closely resembled that of the normal ACL (Lim et al)

Meniscus

 Tears in the avascular inner third of the meniscus have limited or no potential for repair as the reparative process cannot occur without the presence of bleeding
 Dutton et al assessed the capability of autologous seeded BMSCs to repair an avascular meniscal lesion in the pig.
 They showed that a meniscal lesion involving the inner, avascular, one-third of the meniscus benefited from the bonding capabilities of the transplant.
 This study raises the potential of cell-based therapy to repair a tear in the avascular inner third of the meniscus rather than proceeding to surgical resection.

Spine
 Degeneration of the intervertebral disc is a leading cause of back pain and morbidity
 Most commonly, fusion with or without discectomy is performed, although more recently disc replacement has received some attention
 Cell transplantation can potentially increase proteoglycan production, induce disc regeneration or slow the process of degeneration (Crevenstcn et al)
 Spinal fusion: a novel approach to create a hybrid graft by combining cultured MSCs with a ceramic scaffold (Cinotti et al)
Spinal cord
 Stem cell therapy has therapeutic potential for spinal cord injuries because of the ability of pluripotent cells to differentiate into neural tissue
 But, repair of the spinal cord is very complex. It includes restoring or enhancing local spinal reflex arcs and reconnecting regenerating axons from above.
 Gliosis may block the outgrowth of axons
 MSCs isolated in culture from the mononuclear layer of bone marrow can remyelinate demyelinated spinal cord axons after direct injection into the lesion (Akiyama et al)

Paediatric Orthopaedics
- Deformity correction in children sometimes include excision of a preexisting bony bridge and the insertion of fat, polymeric silicone or muscle as an interpositional material
 Cultured chondrocytes have been transferred into physeal defects for the correction of established growth arrest in animal models
 Attention has turned to the use of MSCs from bone marrow to repair physeal defects
 Duchenne’s Muscular dystrophy: An encouraging and pioneering experiment in mouse models of DMD demonstrated that myoblasts could be transplanted into dystrophic muscle and repaired a small proportion of damaged myofibres
 Other diseases where stem cells are being tried are Osteogenesis imperfecta and Juvenile rheumatoid arthritis.

Ref:
1. Urist MR. Bone formation by autoinduction. Science 1965;150:893-9.
2. Young RG, Butler DL, Weber W, et al. Use of mesenchymal stem cells in a collagen matrix for Achilles tendon repair. J Orthop Res 1998;16:406-13.
3. Lim JK. Hui J, Li L, et al. Enhancement of tendon graft osteointegration using mesenchymal stem cells in a rabbit model of anterior cruciate ligament reconstruction. Arthroscopy 2004;20:899-910
4. Dutton A, Hui JPP, Lee EH, Goh J. Enhancement of meniscal repair using mesenchymal stem cells in a porcine model. Procs 5th Combined Meeting of the Orthopaedic Research Societies of USA, Canada, Japan & Europe. 2004
5. Crevensten G, Walsh AJ, Ananthakrishnan D, et al. Intervertebral disc cell therapy for regeneration: mesenchymal stem cell implantation in rat intervertebral discs. Ann Biomed Eng 2004;32:430-4.
6. Cinotti G, Patti AM, Vulcano A, et al. Experimental posterolateral spinal fusion with porous ceramics and mesenchymal stem cells. J Bone Joint Surg 2004;86-B: 135-42
7. Akiyama Y, Radtke C, Honmou O, Kocsis JD. Remyelination of the spinal cord following intravenous delivery of bone marrow cells. Glia 2002;39:229-36.
8. Chen F, Hui JH, Chan WK, Lee EH. Cultured mesenchymal stem cell transfers in the treatment of partial growth arrest. J Pediatr Orthop 2003;23:425-9
9. Gussoni E, Soneoka Y, Strickland CD, et al. Dystrophin expression in the MDX mouse restored by stem cell transplantation. Nature 1999;401:390-4