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AAOS Now

Published 3/1/2012
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Stuart B. Goodman, MD; Lynne C. Jones, PhD

Clinical Aspects of Cell Therapy in Orthopaedic Surgery

As mentioned last month, the gold standard for the treatment of abnormalities of bone healing is autogenous iliac crest bone graft. This construct contains all of the necessary elements for osteogenesis including viable osteoblasts and osteoprogenitor cells, growth factors and other important molecules, and a scaffold.

Autologous bone grafting, however, can lead to painful scars and may be associated with complications such as local infection or fracture. Furthermore, autologous bone grafts are limited in supply and often contain bone of limited quality, especially in the aged and those with chronic diseases.

Bone marrow aspirate
Cell therapy using iliac crest bone marrow aspirate was one early strategy to facilitate the union of fractures and heal bone defects without direct open exposure of the iliac bone. This approach, popularized by John F. Connolly, MD, and colleagues, was developed as a method to avoid extensive dissection and complications of open bone grafting procedures, yet obtain comparable results.

The technique evolved into a procedure in which the cellular elements of the harvested marrow were concentrated via centrifugation; the cells were then injected directly or combined with a scaffold for local delivery.

The clinical efficacy of this procedure has been extensively validated. However, the cellular component obtained by simple centrifugation is a combination of numerous cell lineages, only a minority of which has osteogenic potential. This lack of purity and specificity of the cellular pellet for bone formation has stimulated investigation into and development of other techniques and approaches.

More recently, extensive centrifugation and cell selection protocols, some of which use osteoprogenitor cell surface markers, have been developed to increase the yield of bone-forming cells using iliac crest aspiration. These techniques generally involve minimal cellular manipulation. However, the different methods to accomplish the goal of cell concentration are not equivalent, and extensive studies to assess final cell numbers, viability, and osteogenic potential are necessary to validate the various techniques and devices.

Treating fractures
Perhaps the most widely used application for marrow aspiration and concentration techniques has been in the treatment of fractures and nonunions. The technique is performed using fluoroscopy to help ensure optimal placement of the cells at the fracture or nonunion site.

Usually 30 mL or more of marrow is processed from one iliac crest. The harvesting procedure must not continue at the exact same anatomic site, because bleeding into the previously aspirated area of the iliac crest will dilute the cellular elements during repeated puncture. Thus different areas spread along the iliac wing (anterior or posterior) should be aspirated. If extensive numbers of cells are needed, both iliac crests can be harvested. This same technique can be extended to cases of spinal fusion and joint arthrodesis and for other indications.

Cell therapy for osteonecrosis
Treatment of osteonecrosis of the major joints (hip, knee, shoulder, and ankle) is another application of cell therapy. The procedure is used in “joint-preserving” operations in which the cartilage surface has not degenerated, and the underlying bone is intact or has minimal collapse.

Iliac crest marrow is first harvested and processed. After creating a channel into the osteonecrotic bone (core decompression), with or without excision of the osteonecrotic segment, concentrated cells in a carrier are injected or directly placed into the defect.

Although the literature includes reports of the success of this approach, no prospective randomized studies comparing the results of core decompression with or without the addition of a cellular pellet have been conducted.

Tissue engineering
Tissue engineering of orthopaedic mesenchymal tissues (bone, cartilage, tendon, and ligament) using progenitor cells, scaffold, and growth factors is still in its infancy. Although this article outlines some aspects of bone engineering, the principles of reconstructing large amounts of any mesenchymal-derived tissue are daunting. Not only must the new tissue function normally in a unique biologic and mechanical environment, it must undergo remodeling for ongoing repair and renewal.

Some of the earliest applications to replace smaller defects in articular cartilage entailed harvesting mature cartilage cells from one site, expanding these cells in tissue culture, then reimplanting the cells in a scaffold carrier. Recent research has attempted to formulate mature cartilage from mesenchymal stem cells or early progenitors. These in vitro and in vivo studies have had limited success for several reasons, including the following:

  • Articular cartilage is a complex, nonuniform biologic material with unique biologic and mechanical properties. The thickness and structure of articular cartilage varies within a particular joint and between different joints.
  • Because it is aneural and avascular, articular cartilage has very limited potential for repair; this makes adjacent integration of transplanted cartilage very difficult.
  • The histologic and mechanical qualities of articular cartilage are more similar to fibrocartilage than to hyaline cartilage. As such, the potential to withstand physiologic loads adequately for long periods of time is questionable. Similar challenges also apply to ligament and tendon.

The use of allogeneic cells for repair of mesenchymal tissues is even more controversial. Not only are there issues related to the efficacy of these cells, the potential immune response to these cells must also be taken into account. Finally, moral issues pertaining to the donor of the cells have to be considered.

At this point, the most proven application of cell therapy is in the regeneration of bone. Future research, however, will undoubtedly find safe and efficacious methods to restore other mesenchymal tissues.

Stuart B. Goodman, MD (Accelalox; StemCor; Tibion; Clinical Orthopaedics and Related Research; Biomaterials; The Journal of Arthroplasty; Journal of Biomedical Materials Research; Journal of Orthopaedic Research; Open Biomaterials Journal; Open Orthopaedics Journal; Orthopaedic Research Society), and Lynne C. Jones, PhD (TissueGene Inc.; Journal of Biomedical Materials Research - B; Orthopaedic Research Society; Society For Biomaterials; ARCO International; National Osteonecrosis Foundation; Rocky Mountain Bioengineering Symposium; American Institute for Medical Biological Engineering), are members of the AAOS Biological Implants Committee.

Editor’s Note: Last month, “Stem Cell Therapy in Orthopaedics” examined the basics of cell therapy; this month, authors Lynne C. Jones, PhD, and Stuart B. Goodman, MD, look at the clinical aspects of using stem cells in orthopaedic surgery. For more on this topic, see “Tissue Engineering for Meniscal Tears.”

References:

  1. Urist MR, A morphogenetic matrix for differentiation of bone tissue. Calcif Tissue Res, 1970: p. Suppl:98-101.
  2. Wagner W, Bork S, Horn P, Krunic D, Walenda T, Diehlmann A, et al. Aging and replicative senescence have related effects on human stem and progenitor cells. PLoS One, 2009. 4(6): p. e5846.
  3. Hernigou P, Beaujean F. Abnormalities in the bone marrow of the iliac crest in patients who have osteonecrosis secondary to corticosteroid therapy or alcohol abuse. J Bone Joint Surg Am, 1997. 79(7): p. 1047-53.
  4. Gangji V, Hauzeur JP, Schoutens A, Hinsenkamp M, Appelboom T, Egrise D. Abnormalities in the replicative capacity of osteoblastic cells in the proximal femur of patients with osteonecrosis of the femoral head. J Rheumatol, 2003. 30(2): p. 348-51.
  5. Breitbart AS, Grande DA, Kessler R, Ryaby JT, Fitzsimmons RJ, Grant RT. Tissue engineered bone repair of calvarial defects using cultured periosteal cells. Plast Reconstr Surg, 1998. 101(3): p. 567-74; discussion 575-6.
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  7. Xie C, Reynolds D, Awad H, Rubery PT, Pelled G, Gazit D, et al. Structural bone allograft combined with genetically engineered mesenchymal stem cells as a novel platform for bone tissue engineering. Tissue Eng, 2007. 13(3): p. 435-45.
  8. Connolly JF, Shindell R. Percutaneous marrow injection for an ununited tibia. Nebr Med J, 1986. 71(4): p. 105-7.