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Abstracts:
Stem Cells in Tendon/Ligament Regeneration

Awad HA, Butler DL, Boivin GP, et al. Autologous mesenchymal stem cell-mediated repair of tendon. Tissue Eng 1999; 5 (3): 267.
Abstract:
Mesenchymal Stem Cells (MSCs) were isolated from bone marrow of 18 adult New Zealand White rabbits. These cells were culture expanded, suspended in type I collagen gel, and implanted into a surgically induced defect in the donor's right patellar tendon. A cell-free collagen gel was implanted into an identical control defect in the left patellar tendon. Repair tissues were evaluated biomechanically (n=13) and histomorphometrically (n=5) at 4 weeks after surgery. Compared to their matched controls, the MSC-mediated repair tissue demonstrated significant increases of 26% (p<0.001), 18% (p<0.01), and 33% (p<0.02) in maximum stress, modulus, and strain energy density, respectively. Qualitatively, there appeared to be minor improvements in the histological appearance of some of the MSC-mediated repairs, including increased number of tenocytes and larger and more mature-looking collagen fiber bundles. Morphometrically, however, there were no significant left-right differences in nuclear aspect ratio (shape) or nuclear alignment (orientation). Therefore, delivering a large number of mesenchymal stem cells to a wound site can significantly improve its biomechanical properties by only 4 weeks but produce no visible improvement in its microstructure.

Hildebrand KA, Jia F, Woo SL-Y. Response of Donor and Recipient Cells after Transplantation of Cells to the Ligament and Tendon. Microscopy Research and Technique 2002 (58): 34.
The mechanical properties of healing ligaments and tendons are not comparable to those of normal tissue. To improve the quality of the ligament healing, therapeutic strategies include gene transfer or placement of mesenchymal stem cells at the healing site. Studies show that marker genes, growth factors, and antisense oligonucleotides can be delivered to both normal and healing ligaments and tendons by gene transfer. Cells with and without genetic modification have been successfully transplanted to ligaments and tendons and remain viable. Tendon healing can be improved using collagen gel implants seeded with autologous mesenchymal stem cells. Even though those early results are encouraging, more work is required regarding the response of the recipient site to donor cells or vectors.

Herthel DJ. Enhanced suspensory ligament healing in 100 horses by stem cell and other bone marrow components. AAEP Proceedings 2001;47;319-21.
Suspensory ligament injuries are challenging because healing is slow and reinjuries are common. Healing requires growth factors that stimulate angiogenesis, mitogenesis, and matrix formation. Bone marrow contains growth factors, cells, and fibrinogen, which facilitate healing of damaged tissues. In 100 horses with ligament damage, bone marrow seems to enhance healing.

Smith RKW, Korada M, Blunn GW, Goodship AE. Isolation and implantation of autologous equine mesenchymal stem cells from bone marrow into superficial digital flexor tendon as a potential novel treatment. Equine Vet J 2003; 35(1):99-102.
There has been considerable interest recently in the potential therapeutic benefits of mesenchymal stem cells (MSC) for tendon and ligament healing (Woo et al. 1999; Caplan and Bruder 2001; Hildebrand et al. 2002). These cells reside in small numbers in all tissues and possess multipotential capabilities of differentiating into a number of different tissues. Recent reports have shown that MSCs can be implanted into tendon and ligament tissue in experimental animals (Young et al. 1998). One source of MSCs has been bone marrow and recently Herthel (2001) reported considerable success in the use of bone marrow aspirated from the sternabrae and injected directly into damaged tendon or ligament…(see Herthel below for data)… However, injections of large volumes of bone marrow (30-50mL) might disrupt remaining intact tendon tissue, contain bone spicules and fat cells which might be deleterious to tendon healing, and contain only a small number of MSCs. (summary only)

Watanabe N, Woo SL-Y, Papageorgiou C, Celechovsky C, Takai S. Fate of Donor Bone Marrow Cells in Medial Collateral Ligament after Simulated Autologous Transplantation. Microscopy Research and Technique 2002 (58): 39.
A potential strategy to enhance ligament healing by transplantation of mesenchymal stem cells (MSCs), which are demonstrated to differentiate into fibroblast-like cells in vitro, is presented. The objective of this study was to follow transplanted nucleated cells from bone marrow, which contain MSCs, in the healing medial collateral ligament (MCL) over time, and to examine their phenotype and survivability. It was hypothesized that MSCs in nucleated cells from bone marrow would differentiate into fibroblast-like cells in the healing ligament following adaptation to the environment. The transplantation model employed in this study eliminates the immune response to a donor by the recipient using a transgenic rat (donor), which does not produce foreign protein from transgenes, and its wild-type rat (recipient) in order to simulate autologous transplantation. The MCL of the wild-type rat was ruptured, where 1 x 10(6) nucleated cells of bone marrow from the transgenic rat were injected. The transgenes in transplanted nucleated cells were detected throughout the healing MCL for 28 days by in situ hybridization. At 3 days, many donor cells were evident in the injury site and fascial pocket, and some were found in the midsubstance. Morphologically, transplanted cells with elongated nuclei were found at the ruptured edge of the midsubstance and surface of the unruptured site after 3 days. At 28 days, these cells continued to survive in the healing MCL. Their shapes were similar to those of surrounding recipient MCL fibroblasts. Thus, transplanted cells might differentiate into fibroblasts. Therefore, it was demonstrated that there is a potential for nucleated cells from bone marrow to serve as a vehicle for therapeutic molecules as well as to be a source in enhancing healing of ligaments.

Vulliet RP, McDonald MH, Galuppo LD, et al. The use of stem cells to repair damaged tendons (02-12). Research Preview, Orthopedics/Performance. Center for Equine Health, University of California, Davis 2002-2003.
Study Objectives: (1)Optimize conditions for growth and differentiation for equine bone marrow stem cells. (2) Test the safety of equine stem cells administered in normal tendons. (3) Investigate the effects of bone marrow stem cells in damaged equine tendons. Anticipated Benefits to the Equine Industry: This project will employ stem cell technology to investigate if the collagen-synthesizing cells will help repair damaged tendons. Previous studies have documented that stem cells increase rabbit tendon strength when compared to non-injected tendons. Researchers anticipate that the horse tendon will show a similar response and will show a demonstrable improvement both histologically and ultrasonically.

Young RG, Butler DL, Weber W, Caplan AI, Gordon SL, Fink DJ. Use of Mesenchymal Stem Cells in a Collagen Matrix for Achilles Tendon Repair. J Ortho Res 1998 (16): 406.
This investigation tested the hypothesis that delivering mesenchymal stem cell-seeded implants to a tendon gap model results in significantly improved repair biomechanics. Cultured, autologous, marrow-derived mesenchymal stem cells were suspended in a collagen gel delivery vehicle.: the cell-gel composite was subsequently contracted onto a pretensioned suture. The resulting tissue prosthesis was then implanted into a 1_cm_long gap defect in the rabbit Achilles tendon. Identical procedures were performed on the contralateral tendon, but only the suture material was implanted. The tendon-implant constructs were evaluated 4,8, and 12 weeks later by biomechanical and histological criteria. Significantly greater load-related structural and material properties wee seen at all time intervals in the mesenchymal stem cell-treated tendons than in the contralateral, treated control repairs (p<0.5), which contained suture alone with natural cell recruitment. The values were typically twice those for the control tissues at each time interval. Load-related material properties for the treated tissues also increased significantly over time (p<0.05). The treated tissues had a significantly larger cross-sectional area (p<0.05), and their collagen fibers appeared to be better aligned than those in the matched controls. The results indicate that delivering mesenchymal stem cell-contracted, organized collagen implants to large tendon defects can significantly improve the biomechanics, structure, and probably the function of the tendon after injury.


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