Tissue Eng Part A. 2010 Oct;16(10):3119-37.
Repair of full-thickness tendon injury using connective tissue progenitors efficiently
derived from human embryonic stem cells and fetal tissues.
Cohen S, Leshansky L, Zussman E, Burman M, Srouji S, Livne E, Abramov N, Itskovitz-
Sohnis and Forman Families Center for Stem Cell and Tissue Regeneration Research,
Faculty of Medicine, Technion, Haifa, Israel.
The use of stem cells for tissue engineering (TE) encourages scientists to design new
platforms in the field of regenerative and reconstructive medicine. Human embryonic stem
cells (hESC) have been proposed to be an important cell source for cell-based TE
applications as well as an exciting tool for investigating the fundamentals of human
development. Here, we describe the efficient derivation of connective tissue progenitors
(CTPs) from hESC lines and fetal tissues. The CTPs were significantly expanded and
induced to generate tendon tissues in vitro, with ultrastructural characteristics and
biomechanical properties typical of mature tendons. We describe a simple method for
engineering tendon grafts that can successfully repair injured Achilles tendons and
restore the ankle joint extension movement in mice. We also show the CTP's ability to
differentiate into bone, cartilage, and fat both in vitro and in vivo. This study offers
evidence for the possibility of using stem cell-derived engineered grafts to replace
missing tissues, and sets a basic platform for future cell-based TE applications in the
fields of orthopedics and reconstructive surgery.
PMID: 20486794 [PubMed - in process]
Int J Clin Exp Med. 2010 Sep 7;3(4):248-69.
Bone marrow and umbilical cord blood human mesenchymal stem cells: state of the art.
Malgieri A, Kantzari E, Patrizi MP, Gambardella S.
Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in all tissues, as
part of the perivascular population. As multipotent cells, MSCs can differentiate into
different tissues originating from mesoderm ranging from bone and cartilage, to cardiac
muscle. MSCs are an excellent candidate for cell therapy because they are easily
accessible, their isolation is straightforward, they can be bio-preserved with minimal loss
of potency, and they have shown no adverse reactions to allogeneic versus autologous
MSCs transplants. Therefore, MSCs are being explored to regenerate damaged tissue and
treat inflammation, resulting from cardiovascular disease and myo-cardial infarction (MI),
brain and spinal cord injury, stroke, diabetes, cartilage and bone injury, Crohn's disease
and graft versus host disease (GvHD). Most of the application and clinical trials involve
MSCs from bone marrow (BMMSCs). Transplantation of MSCs from bone marrow is
considered safe and has been widely tested in clinical trials of cardiovascular,
neurological, and immunological disease with encouraging results. There are examples of
MSCs utilization in the repair of kidney, muscle and lung. The cells were also found to
promote angiogenesis, and were used in chronic skin wound treatment. Recent studies
involve also mesenchymal stem cell transplant from umbilical cord (UCMSCt). One of
these demonstrate that UCMSCt may improve symptoms and biochemical values in
patients with severe refractory systemic lupus erythematosus (SLE), and therefore this
source of MSCs need deeper studies and require more attention. However, also if there are
79 registered clinical trial sites for evaluating MSC therapy throughout the world, it is still
a long way to go before using these cells as a routinely applied therapy in clinics.
PMID: 21072260 [PubMed - in process]
Am J Sports Med. 2010 Sep;38(9):1857-69. Epub 2010 May 27.
Repair of chronic osteochondral defects using predifferentiated mesenchymal stem cells
in an ovine model.
Zscharnack M, Hepp P, Richter R, Aigner T, Schulz R, Somerson J, Josten C, Bader A,
BACKGROUND: The use of mesenchymal stem cells (MSCs) to treat osteochondral
defects caused by sports injuries or disease is of particular interest. However, there is a
lack of studies in large-animal models examining the benefits of chondrogenic
predifferentiation in vitro for repair of chronic osteochondral defects.
HYPOTHESIS: Chondrogenic in vitro predifferentiation of autologous MSCs embedded in a
collagen I hydrogel currently in clinical trial use for matrix-associated autologous
chondrocyte transplantation facilitates the regeneration of a chronic osteochondral defect
in an ovine stifle joint.
STUDY DESIGN: Controlled laboratory study.
METHODS: The optimal predifferentiation period of ovine MSCs within the type I collagen
hydrogel in vitro was defined by assessment of several cellular and molecular biological
parameters. For the animal study, osteochondral lesions (diameter 7 mm) were created at
the medial femoral condyles of the hind legs in 10 merino sheep. To achieve a chronic
defect model, implantation of the ovine MSCs/hydrogel constructs was not performed until
6 weeks after defect creation. The 40 defects were divided into 4 treatment groups: (1)
chondrogenically predifferentiated ovine MSC/hydrogel constructs (preMSC-gels), (2)
undifferentiated ovine MSC/hydrogel constructs (unMSC-gels), (3) cell-free collagen
hydrogels (CF-gels), and (4) untreated controls (UCs). Evaluation followed after 6 months.
RESULTS: With regard to proteoglycan content, cell count, gel contraction, apoptosis,
compressive properties, and progress of chondrogenic differentiation, a differentiation
period of 14 days in vitro was considered optimal. After 6 months in vivo, the defects
treated with preMSC-gels showed significantly better histologic scores with morphologic
characteristics of hyaline cartilage such as columnarization and presence of collagen type
CONCLUSION: Matrix-associated autologous chondrocyte transplantation with
predifferentiated MSCs may be a promising approach for repair of focal, chronic
CLINICAL RELEVANCE: The results suggest an encouraging method for future treatment
of focal osteochondral defects to prevent progression to osteoarthritis.
PMID: 20508078 [PubMed - in process]
Orthopedics. 2010 Sep 7;33(9):661. doi: 10.3928/01477447-20100722-31.
Allograft alternatives: bone substitutes and beyond.
Excessive wear debris, deep infection, periprosthetic fracture, and other causes can lead
to bone loss associated with total joint replacements. When performing revisions,
surgeons are often preoccupied by the failed implant and the method of replacement, and
neglect an opportunity to replenish lost bone. Thus, when formulating a plan for revision
total joint replacement, the surgeon should consider not only the hardware that should be
used, but also ways in which lost bone could be restored. Autograft bone provides the
best source for osteoprogenitor cells, growth factors, and a scaffold. However, autograft is
limited in supply, and is generally associated with another incision, dissection, and
accompanying morbidity. Osteoconductive bone void fillers such as morselized
cancellous allograft bone, polymeric scaffolds, and biodegradable ceramics each have
their merits and deficiencies; however, all of these materials function as a scaffold only,
without the ability to induce bone formation. Osteoinductive growth factors are essential
to bone growth and remodeling; however, exogenous growth factors are expensive, are
given in large nonphysiological doses, may yield unpredictable clinical results, and may
have significant adverse effects. Demineralized bone matrix contains a scaffold and
variable amounts of several growth factors. Recently, the use of mesenchymal stem cells
and osteoprogenitors, together with a suitable scaffold carrier has gained increasing
popularity. With the addition of appropriate growth factors, this combination can provide
all the necessary components for osteogenesis. Future basic and clinical research will
define the indications and outcomes for new combination products for reconstruction of
lost bone associated with revision total joint replacement.
Copyright 2010, SLACK Incorporated.
PMID: 20839690 [PubMed - in process]
J Biomed Mater Res A. 2010 Aug 19. [Epub ahead of print]
Cartilage regeneration by bone marrow cells-seeded scaffolds.
Wegener B, Schrimpf FM, Bergschmidt P, Pietschmann MF, Utzschneider S, Milz S,
Jansson V, Müller PE.
Different approaches exist for the treatment of small articular cartilage defects. Several
studies show comparable results for autologous chondrocyte implantation (ACI) and
microfracture. Unfortunately, the fibrocartilage resulting from microfracture has neither
the structure nor the mechanical properties of hyaline cartilage, even though the adult
mesenchymal stem cells, which immigrate into the defect, are supposed to differentiate
into chondrocytes. This study was performed to examine the capacity of a resorbable
implant made from polylactide-co-glycolide acid (PGLA)-fleece combined with autologous
bone marrow cells fixed with a fibrin/thrombin-clot in the weight-bearing area of the
femoral condyle of mature sheep. For this study, six defects were treated with either the
PGLA-implant alone or with a combination of the implant with added fibrin glue or were
left untreated to serve as controls. The animals were sacrificed after 12 weeks; the
operated knees were removed and examined by measuring the covering of the defect with
cartilaginous tissue and according to the score of O'Driscoll. Additional criteria such as
immunolabeling for collagen II and aggrecan were included. Results showed that no
improvement of the tissue quantity or quality could be achieved by increasing the cell load
of the implant with cells fixed by fibrin glue. (c) 2010 Wiley Periodicals, Inc. J Biomed
Mater Res Part A, 2010.
PMID: 20725984 [PubMed - as supplied by publisher]
Stem Cell Res Ther. 2010 Jun 29;1(2):19.
Clinical and preclinical translation of cell-based therapies using adipose tissue-derived
Gimble JM, Guilak F, Bunnell BA
ABSTRACT : Adipose tissue is now recognized as an accessible, abundant, and reliable
site for the isolation of adult stem cells suitable for tissue engineering and regenerative
medicine applications. The past decade has witnessed an explosion of preclinical data
relating to the isolation, characterization, cryopreservation, differentiation, and
transplantation of freshly isolated stromal vascular fraction cells and adherent, culture-
expanded, adipose-derived stromal/stem cells in vitro and in animal models. This body of
work has provided evidence supporting clinical translational applications of adipose-
derived cells in safety and efficacy trials. The present article reviews the case reports and
phase I-III clinical evidence using autologous adipose-derived cells that have been
published, to date, in the fields of gastroenterology, neurology, orthopedics,
reconstructive surgery, and related clinical disciplines. Future directions and challenges
facing the field are discussed and evaluated.
PMID: 20587076 [PubMed - in process]
Arthroscopy. 2009 Dec;25(12):1435-41. Epub 2009 Nov 6.
Augmentation of degenerated human cartilage in vitro using magnetically labeled
mesenchymal stem cells and an external magnetic device.
Kobayashi T, Ochi M, Yanada S, Ishikawa M, Adachi N, Deie M, Arihiro K.
Department of Orthopaedic Surgery, Hiroshima University, Hiroshima, Japan.
PURPOSE: The purpose of this study was to investigate whether it is possible to
regenerate degenerated human cartilage in vitro by use of magnetically labeled
mesenchymal stem cells (MSCs) and an external magnetic device.
METHODS: MSCs from human bone marrow were cultured and magnetically labeled.
Degenerated human cartilage was obtained during total knee arthroplasty. The
osteochondral fragments were attached to the sidewall of tissue culture flasks, and
magnetically labeled MSCs were injected into the flasks. By use of an external magnetic
device, a magnetic force was applied for 6 hours to the direction of the cartilage, and then
the degenerated cartilage was cultured in chondrogenic differentiation medium for 3
weeks. In the control group a magnetic force was not applied. The specimens were
RESULTS: A cell layer was formed on the degenerated cartilage as shown by H&E
staining. The cell layer was also stained in toluidine blue and safranin O and with anti-
collagen type II immunostaining, indicating that the cell layer contained an extracellular
matrix. In the control group a cell layer was not observed on the cartilage.
CONCLUSIONS: We were able to show that our system could deliver MSCs onto
degenerated human cartilage and then form an extracellular matrix on the degenerated
cartilage in vitro.
CLINICAL RELEVANCE: Our novel cell delivery system using magnetic force may lead
toward a new treatment option for osteoarthritis.
PMID: 19962071 [PubMed - indexed for MEDLINE]
Expert Opin Biol Ther. 2009 Nov;9(11):1399-405.
Stem cell therapy for cartilage regeneration in osteoarthritis.
Koelling S, Miosge N.
Georg August University, Tissue Regeneration Work Group, Department of
Prosthodontics, Abteilung Prothetik im Zentrum ZMK, Robert-Koch-Str. 40, Goettingen, D-
Enhancing the regeneration potential of hyaline cartilage tissue remains a great challenge.
During embryonic development, some of the cells of the inner cell mass will turn into the
mesoderm. This will be the founder of the mesenchymal cells in connective tissues of
adult life, such as bone, tendon, muscle, and cartilage. Some of these embryonic
mesenchymal cells are believed not to differentiate, but reside in each of the tissues.
These are now collectively described as adult mesenchymal stem cells, which are thought
to be capable of repairing injured tissue. We will briefly summarize the current knowledge
about stem cell-related cells in cartilage tissue and carefully discuss the potential of the
cell population we described recently as a starting-point for a regenerative therapy for
osteoarthritis. We found that repair tissue from human articular cartilage during the late
stages of osteoarthritis harbors a unique progenitor cell population, termed chondrogenic
progenitor cells (CPC). These exhibit stem cell characteristics combined with a high
chondrogenic potential. They offer new insights into the biology of progenitor cells and
may be relevant in the development of novel therapeutic approaches for a cell-based
therapy for late stages of osteoarthritis.
PMID: 19793003 [PubMed - indexed for MEDLINE]
Tissue Eng Part A. 2009 Jul;15(7):1543-51.
Combination of transforming growth factor-beta2 and bone morphogenetic protein 7
enhances chondrogenesis from adipose tissue-derived mesenchymal stem cells.
Kim HJ, Im GI
In this study, the authors examined combinations of growth factors that induce effective
chondrogenesis from adipose tissue-derived mesenchymal stem cells (MSCs). Human
MSCs were isolated from bone marrow (BMMSCs) and adipose tissue (ATMSCs) and
characterized according to flow cytometry for CD34, CD45, CD73, and CD166.
Chondrogenesis was induced by culturing ATMSCs in pellets without growth factors
(negative control) and with 5 ng/mL of transforming growth factor beta 2 (TGF-beta(2)), 100
ng/mL of bone morphogenetic protein (BMP)-2, 100 ng/mL of BMP-6, 100 ng/mL of BMP-7,
5 ng/mL of TGF-beta(2) and 100 ng/mL of BMP-2, 5 ng/mL of TGF-beta(2) and 100 ng/mL of
BMP-6, and 5 ng/mL of TGF-beta(2) and 100 ng/mL of BMP-7. BMMSCs cultured under the
same condition with 5 ng/mL of TGF-beta(2) were used as positive controls. Flow
cytometry showed that ATMSCs and BMMSCs had similar surface marker profiles. After 4
weeks of in vitro culture, glycosaminoglycan assays, real-time reverse transcriptase
polymerase chain reaction, and histological findings demonstrated that the combination of
5 ng/mL of TGF-beta(2) and 100 ng/mL of BMP-7 most effectively induced chondrogenesis
from ATMSCs. The findings of this study suggest that the combination of TGF-beta(2) and
BMP-7 potently enhances chondrogenesis from ATMSCs and can be used to overcome the
inferior chondrogenic potential of ATMSCs in cartilage tissue engineering.
PMID: 19072523 [PubMed - indexed for MEDLINE]
Physiol Res. 2010;59(4):605-14. Epub 2009 Nov 20.
Quality of newly formed cartilaginous tissue in defects of articular surface after
transplantation of mesenchymal stem cells in a composite scaffold based on collagen I
with chitosan micro- and nanofibres.
Necas A, Plánka L, Srnec R, Crha M, Hlucilová J, Klíma J, Starý D, Kren L, Amler E, Vojtová
L, Jancár J, Gál P
The aim of this study was to evaluate macroscopically, histologically and
immunohistochemically the quality of newly formed tissue in iatrogenic defects of
articular cartilage of the femur condyle in miniature pigs treated with the clinically used
method of microfractures in comparison with the transplantation of a combination of a
composite scaffold with allogeneic mesenchymal stem cells (MSCs) or the composite
scaffold alone. The newly formed cartilaginous tissue filling the defects of articular
cartilage after transplantation of the scaffold with MSCs (Group A) had in 60 % of cases a
macroscopically smooth surface. In all lesions after the transplantation of the scaffold
alone (Group B) or after the method of microfractures (Group C), erosions/fissures or
osteophytes were found on the surface. The results of histological and
immunohistochemical examination using the modified scoring system according to
O'Driscoll were as follows: 14.7+/-3.82 points after transplantations of the scaffold with
MSCs (Group A); 5.3+/-2.88 points after transplantations of the scaffold alone (Group B);
and 5.2+/-0.64 points after treatment with microfractures (Group C). The O'Driscoll score in
animals of Group A was significantly higher than in animals of Group B or Group C
(p<0.0005 both). No significant difference was found in the O'Driscoll score between
Groups B and C. The treatment of iatrogenic lesions of the articular cartilage surface on
the condyles of femur in miniature pigs using transplantation of MSCs in the composite
scaffold led to the filling of defects by a tissue of the appearance of hyaline cartilage.
Lesions treated by implantation of the scaffold alone or by the method of microfractures
were filled with fibrous cartilage with worse macroscopic, histological and
PMID: 19929138 [PubMed - in process]
Arthroscopy. 2009 Dec;25(12):1391-400. Epub 2009 Sep 17.
Articular cartilage regeneration with autologous marrow aspirate and hyaluronic Acid: an
experimental study in a goat model.
Saw KY, Hussin P, Loke SC, Azam M, Chen HC, Tay YG, Low S, Wallin KL, Ragavanaidu K.
Kuala Lumpur Sports Medicine Centre, Kuala Lumpur, Malaysia. email@example.com
PURPOSE: The purpose of the study was to determine whether postoperative intra-
articular injections of autologous marrow aspirate (MA) and hyaluronic acid (HA) after
subchondral drilling resulted in better cartilage repair as assessed histologically by Gill
METHODS: In a goat model we created a 4-mm full-thickness articular cartilage defect in
the stifle joint (equivalent to 1.6 cm in the human knee) and conducted subchondral
drilling. The animals were divided into 3 groups: group A (control), no injections; group B
(HA), weekly injection of 1 mL of sodium hyaluronate for 3 weeks; and group C (HA + MA),
similar to group B but with 2 mL of autologous MA in addition to HA. MA was obtained by
bone marrow aspiration, centrifuged, and divided into aliquots for cryopreservation.
Fifteen animals were equally divided between the groups and sacrificed 24 weeks after
surgery, when the joint was harvested, examined macroscopically and histologically.
RESULTS: Of the 15 animals, 2 from group A had died of non-surgery-related
complications and 1 from group C was excluded because of a joint infection. In group A
the repair constituted mainly scar tissue, whereas in group B there was less scar tissue,
with small amounts of proteoglycan and type II collagen at the osteochondral junction. In
contrast, repair cartilage from group C animals showed almost complete coverage of the
defect with evidence of hyaline cartilage regeneration. Histology assessed by Gill scoring
was significantly better in group C with 1-way analysis of variance yielding an F statistic of
10.611 with a P value of .004, which was highly significant.
CONCLUSIONS: Postoperative intra-articular injections of autologous MA in combination
with HA after subchondral drilling resulted in better cartilage repair as assessed
histologically by Gill scoring in a goat model.
CLINICAL RELEVANCE: After arthroscopic subchondral drilling, this novel technique may
result in better articular cartilage regeneration.
PMID: 19962065 [PubMed - indexed for MEDLINE]
Med Sport Sci. 2009;54:150-65. Epub 2009 Aug 17.
Innovative strategies for treatment of soft tissue injuries in human and animal athletes.
Hoffmann A, Gross G
Our aim is to review the recent progress in the management of musculoskeletal disorders.
We will cover novel therapeutic approaches based on growth factors, gene therapy and
cells, including stem cells, which may be combined with each other as appropriate. We
focus mainly on the treatment of soft tissue injuries - muscle, cartilage, and
tendon/ligament for both human and animal athletes. The need for innovative strategies
results from the fact that despite all efforts, the current strategies for cartilage and
tendon/ligament still result in the formation of functionally and biomechanically inferior
tissues after injury (a phenomenon called 'repair' as opposed to proper 'regeneration'),
whereas the outcome for muscle is more favorable. Innovative approaches are urgently
needed not only to enhance the outcome of conservative or surgical procedures but also
to speed up the healing process from the very long disabling periods, which is of special
relevance for athletes.
2009 S. Karger AG, Basel
PMID: 19696513 [PubMed - indexed for MEDLINE]
Nat Rev Rheumatol. 2009 Jul;5(7):392-9.
Mesenchymal stem cells: innovative therapeutic tools for rheumatic diseases.
Djouad F, Bouffi C, Ghannam S, Noël D, Jorgensen C.
Inserm, U844, Montpellier, France.
Mesenchymal stem cells (MSCs), or multipotent mesenchymal stromal cells as they are
also known, have been identified in bone marrow as well as in other tissues of the joint,
including adipose, synovium, periosteum, perichondrium, and cartilage. These cells are
characterized by their phenotype and their ability to differentiate into three lineages:
chondrocytes, osteoblasts and adipocytes. Importantly, MSCs also potently modulate
immune responses, exhibit healing capacities, improve angiogenesis and prevent fibrosis.
These properties might be explained at least in part by the trophic effects of MSCs through
the secretion of a number of cytokines and growth factors. However, the mechanisms
involved in the differentiation potential of MSCs, and their immunomodulatory and
paracrine properties, are currently being extensively studied. These unique properties of
MSCs confer on them the potential to be used for therapeutic applications in rheumatic
diseases, including rheumatoid arthritis, osteoarthritis, genetic bone and cartilage
disorders as well as bone metastasis.
PMID: 19568253 [PubMed - indexed for MEDLINE]
Z Rheumatol. 2009 May;68(3):228-33.
[Mesenchymal stem cells in arthritis]
[Article in German]
David JP, Zwerina J, Schett G.
Medizinische Klinik 3, Rheumatologie und Immunologie, Universitätsklinikum Erlangen,
Krankenhausstr. 12, 91054, Erlangen, Deutschland. firstname.lastname@example.org
While one of the major achievements of the 20th century was prolonging life expectancy in
developed countries, the main challenge of the 21st century is to improve the quality of life
of the aging population. Aging is associated with a progressive reduction of organ system
function. Therefore, regenerative medicine will be one of the major developing fields of
medicine. This new medical field does not only apply to aging but also to all degenerative
diseases, such as arthritis and degenerative joint disease, which lead to progressive
degeneration of mesenchymal tissues such as bone and cartilage. The discovery of
pluripotent mesenchymal stem cells (MSCs) offers a promising alternative to surgery for
non-invasive regenerative therapies of mesenchymal tissues. This review focuses on the
characterization and potential application of MSCs in the regeneration of damaged joints.
PMID: 19384551 [PubMed - indexed for MEDLINE]
Z Rheumatol. 2009 May;68(3):234-8.
[Regenerative potential of human adult precursor cells: cell therapy--an option for treating
[Article in German]
Dehne T, Tschirschmann M, Lauster R, Sittinger M.
Labor für Tissue Engineering, Medizinische Klinik mit Schwerpunkt Rheumatologie und
Klinische Immunologie, Charité-Universitätsmedizin Berlin, Tucholskystr. 2, 10117, Berlin,
Cell-based therapeutical approaches are already in clinical use and are attracting growing
interest for the treatment of joint defects. Mesenchymal stem and precursor cells (MSC)
cover a wide range of properties that are useful for the regeneration process of bone and
cartilage defects. The following article is an overview of the regenerative potential of MSC
and discusses how the properties of these cells can be used for the development of new
strategies in regenerative medicine.
PMID: 19384550 [PubMed - indexed for MEDLINE]
Tissue Eng Part C Methods. 2009 Mar;15(1):87-94.
Characterization of equine adipose tissue-derived progenitor cells before and after
Mambelli LI, Santos EJ, Frazão PJ, Chaparro MB, Kerkis A, Zoppa AL, Kerkis I.
Laboratory of Genetics, Butantan Institute, Sao Paulo, Brazil.
In horses, stem cell therapies are a promising tool to the treatment of many injuries, which
are common consequences of athletic endeavor, resulting in high morbidity and often
compromising the performance. In spite of many advantages, the isolation of stem cells
similar to human, from equine adipose tissue, occurred only recently. The aim of this
study was to isolate equine adipose tissue-derived progenitor cells (eAT-PC), to
characterize their proliferative potential, and to study their differentiation capacity before
and after cryopreservation. The cells, isolated from horse adipose tissue, presented
similar fibroblast-like cell morphology in vitro. Their proliferation rate was evaluated
during 63 days (23 passages) before and after cryopreservation. After the induction of
osteogenic differentiation, von Kossa staining and positive immunostaining studies
revealed the formation of calcified extracellular matrix confirming the osteogenic potential
of these cells. Adipogenic differentiation was induced using two protocols: routine and
other one developed by us, while our protocol requires a shorter time (Oil Red O staining
revealed significant accumulation of lipid droplets after 7 days). Chondrogenic
differentiation was observed after 21 days of induced pellet culture, as evidenced by
histological (toluidine blue) and immunohistochemistry studies. Our data demonstrate that
eAT-PC can be easily isolated and successfully expanded in vitro while presenting
significant proliferating rate. These cells can be maintained undifferentiated in vitro and
can efficiently undergo differentiation at least into mesodermal derivates. These eAT-PC
properties were preserved even after cryopreservation. Our findings classify eAT-PC as a
promising type of progenitor cells that can be applied in different cell therapies in equines.
PMID: 19196122 [PubMed - indexed for MEDLINE]
Histol Histopathol. 2009 Mar;24(3):347-66.
Mesenchymal stem cells in connective tissue engineering and regenerative medicine:
applications in cartilage repair and osteoarthritis therapy.
Mobasheri A, Csaki C, Clutterbuck AL, Rahmanzadeh M, Shakibaei M.
Division of Veterinary Medicine, School of Veterinary Medicine and Science, University of
Nottingham, Sutton Bonington Campus, Loughborough, United Kingdom.
Defects of load-bearing connective tissues such as articular cartilage, often result from
trauma, degenerative or age-related disease. Osteoarthritis (OA) presents a major clinical
challenge to clinicians due to the limited inherent repair capacity of articular cartilage.
Articular cartilage defects are increasingly common among the elderly population causing
pain, reduced joint function and significant disability among affected patients. The poor
capacity for self-repair of chondral defects has resulted in the development of a large
variety of treatment approaches including Autologous Chondrocyte Transplantation
(ACT), microfracture and mosaicplasty methods. In ACT, a cartilage biopsy is taken from
the patient and articular chondrocytes are isolated. The cells are then expanded after
several passages in vitro and used to fill the cartilage defect. Since its introduction, ACT
has become a widely applied surgical method with good to excellent clinical outcomes.
More recently, classical ACT has been combined with tissue engineering and implantable
scaffolds for improved results. However, there are still major problems associated with the
ACT technique which relate mainly to chondrocyte de-differentiation during the expansion
phase in monolayer culture and the poor integration of the implants into the surrounding
cartilage tissue. Novel approaches using mesenchymal stem cells (MSCs) as an
alternative cell source to patient derived chondrocytes are currently on trial. MSCs have
shown significant potential for chondrogenesis in animal models. This review article
discusses the potential of MSCs in tissue engineering and regenerative medicine and
highlights their potential for cartilage repair and cell-based therapies for osteoarthritis and
a range of related osteoarticular disorders.
PMID: 19130405 [PubMed - indexed for MEDLINE]
Arthritis Res Ther. 2008;10(5):223. Epub 2008 Oct 10.
Mesenchymal stem cells in arthritic diseases.
Chen FH, Tuan RS.
Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis, and
Musculoskeletal and Skin Diseases, National Institutes of Health, 50 South Dr, Bethesda,
MD 20892, USA. email@example.com
Mesenchymal stem cells (MSCs), the nonhematopoietic progenitor cells found in various
adult tissues, are characterized by their ease of isolation and their rapid growth in vitro
while maintaining their differentiation potential, allowing for extensive culture expansion
to obtain large quantities suitable for therapeutic use. These properties make MSCs an
ideal candidate cell type as building blocks for tissue engineering efforts to regenerate
replacement tissues and repair damaged structures as encountered in various arthritic
conditions. Osteoarthritis (OA) is the most common arthritic condition and, like
rheumatoid arthritis (RA), presents an inflammatory environment with immunological
involvement and this has been an enduring obstacle that can potentially limit the use of
cartilage tissue engineering. Recent advances in our understanding of the functions of
MSCs have shown that MSCs also possess potent immunosuppression and anti-
inflammation effects. In addition, through secretion of various soluble factors, MSCs can
influence the local tissue environment and exert protective effects with an end result of
effectively stimulating regeneration in situ. This function of MSCs can be exploited for
their therapeutic application in degenerative joint diseases such as RA and OA. This
review surveys the advances made in the past decade which have led to our current
understanding of stem cell biology as relevant to diseases of the joint. The potential
involvement of MSCs in the pathophysiology of degenerative joint diseases will also be
discussed. Specifically, we will explore the potential of MSC-based cell therapy of OA and
RA by means of functional replacement of damaged cartilage via tissue engineering as
well as their anti-inflammatory and immunosuppressive activities.
PMID: 18947375 [PubMed - indexed for MEDLINE]
J Artif Organs. 2008 Jun;31(6):480-9
Mesenchymal stem cell-based repair of articular cartilage with polyglycolic acid-
hydroxyapatite biphasic scaffold.
.Zhou XZ, Leung VY, Dong QR, Cheung KM, Chan D, Lu WW:
This study investigates the capacity of a composite scaffold composed of polyglycolic
acid-hydroxyapatite (PGA-HA) and autologous mesenchymal stem cells (MSCs) to
promote repair of osteochondral defects. MSCs from culture-expanded rabbits were
seeded onto a PGA and HA scaffold. After a 72-hour co-culture period, the cell-adhered
PGA and HA were joined together, forming an MSCs-PGA-HA composite. Full-thickness
cartilage defects in the intercondylar fossa of the femur were then implanted with the
MSC-PGA-HA composite, the PGA-HA scaffold only, or they were left empty (n=20).
Animals were sacrificed 16 or 32 weeks after surgery and the gross appearance of the
defects was evaluated. The specimens were examined histologically for morphologic
features, and stained immunohistochemically for type 2 collagen. Specimens of the MSCs-
PGA-HA composite implantation group demonstrated hyaline cartilage and a complete
subchondral bone formation. At 16 weeks post-implantation, significant integration of the
newly formed tissue with surrounding normal cartilage and subchondral bone was
observed when compared to the two control groups. At 32 weeks, no sign of progressive
degeneration of the newly formed tissue was found. A significant difference in histological
grading score was found compared with the control groups. The novel MSCs-seeded,
PGA-HA biphasic graft facilitated both articular cartilage and subchondral bone
regeneration in an animal model and might serve as a new approach for clinical
PMID: 18609500 [PubMed - indexed for MEDLINE]
Expert Opin Biol Ther. 2008 Mar;8(3):255-68.
Role of mesenchymal stem cells in regenerative medicine: application to bone and
Granero-Molto F, Weis JA, Longobardi L, Spagnoli A.
University of North Carolina at Chapel Hill, Division of Endocrinology, Department of
Pediatrics, 3341 Medical Biomolecular Research Building, 103 Mason Farm Road Campus
Box: 7039, Chapel Hill North Carolina 27599-7239, USA.
BACKGROUND: Mesenchymal stem cells (MSC) are multipotent cells with the ability to
differentiate into mesenchyme-derived cells including osteoblasts and chondrocytes.
OBJECTIVE: To provide an overview and expert opinion on the in vivo ability of MSC to
home into tissues, their regenerative properties and potential applications for cell-based
therapies to treat bone and cartilage disorders.
METHODS: Data sources including the PubMed database, abstract booklets and
conference proceedings were searched for publications pertinent to MSC and their
properties with emphasis on the in vivo studies and clinical use in cartilage and bone
regeneration and repair. The search included the most current information possible.
CONCLUSION: MSC can migrate to injured tissues and some of their reparative properties
are mediated by paracrine mechanisms including their immunomodulatory actions. MSC
possess a critical potential in regenerative medicine for the treatment of skeletal diseases,
such as osteoarthritis or fracture healing failure, where treatments are partially effective or
PMID: 18294098 [PubMed - indexed for MEDLINE]
Biotechnol Appl Biochem. 2008 Mar;49(Pt 3):185-94.
Interactive effects of growth factors and three-dimensional scaffolds on multipotent
mesenchymal stromal cells.
Heckmann L, Fiedler J, Mattes T, Dauner M, Brenner RE
The creation of tissue-engineered constructs with autologous cells is a central goal in
regenerative medicine. With respect to ligament replacement, we have evaluated the
influences of matrix and growth factors on hMSCs (human mesenchymal stromal cells).
hMSCs were seeded in two different 3D (three-dimensional) systems consisting of either a
collagen type I gel or a synthetic PLA [poly-(L-lactic acid)] scaffold. After cultivation for 14
days with rhTGFbeta1 (recombinant human transforming growth factor beta1), rhPDGF-BB
(recombinant human platelet-derived growth factor homodimer of B-chain) or rhBMP13
(recombinant human bone morphogenetic protein 13), we assessed the proliferation
potential, mRNA expression and protein expression of various matrix-interacting and
matrix-degrading molecules by quantitative real-time RT (reverse transcriptase)-PCR,
immunohistochemistry and gelatin zymography in comparison with unstimulated cells.
Cellular reactions to the type of scaffold or soluble factors could be found in the
expression of tenascin-C as well as integrin subunits alpha1, alpha3 and beta1. Collagen
type X expression was induced by 3D culture and stimulated by rhTGFbeta1 on PLA. The
expression of MMP-1 (matrix metalloproteinase 1) tended to increase, and MMP-13 was
induced in the collagen culture system. The activation of MMP-2 was stimulated by the
cultivation of MSCs within the collagenous matrix. These results demonstrated that
various interactive effects of growth factors and scaffolds influence the cell-biological
behaviour of MSCs. It is important to take these complex interactions, which partly differ
from differentiated cells, into account in further tissue-engineering approaches.
PMID: 17640172 [PubMed - indexed for MEDLINE]
Orthopedics. 2008 Sep;31(9):855-6; discussion 856.
Mesenchymal stem cells and fracture healing.
PMID: 18814592 [PubMed - indexed for MEDLINE]
Clin Sports Med. 2008 Jan;27(1):231-9, x-xi.
International Olympic Committee consensus statement: molecular basis of connective
tissue and muscle injuries in sport.
Ljungqvist A, Schwellnus MP, Bachl N, Collins M, Cook J, Khan KM, Maffulli N, Pitsiladis Y,
Riley G, Golspink G, Venter D, Derman EW, Engebretsen L, Volpi P.
International Olympic Committee Medical Commission, Lausanne, Switzerland.
Tendon and ligament injures cause significant loss of performance in sport and decreased
functional capacity in the workplace. Many of these injures remain difficult to treat, and
many individuals have long-term pain and discomfort. Animal studies of growth factor and
cell-based therapies have shown promising results, but these treatments also can be
misused to enhance athletic performance. The International Olympic Committee (IOC) now
has high-level scientific advisors who can advise the IOC as to the use and abuse of these
PMID: 18206577 [PubMed - indexed for MEDLINE]
J Cell Physiol. 2007 Nov;213(2):341-7.
Adult mesenchymal stem cells for tissue engineering versus regenerative medicine.
Skeletal Research Center, Department of Biology, Case Western Reserve University,
Cleveland, Ohio, USA. firstname.lastname@example.org
Adult mesenchymal stem cells (MSCs) can be isolated from bone marrow or marrow
aspirates and because they are culture-dish adherent, they can be expanded in culture
while maintaining their multipotency. The MSCs have been used in preclinical models for
tissue engineering of bone, cartilage, muscle, marrow stroma, tendon, fat, and other
connective tissues. These tissue-engineered materials show considerable promise for use
in rebuilding damaged or diseased mesenchymal tissues. Unanticipated is the realization
that the MSCs secrete a large spectrum of bioactive molecules. These molecules are
immunosuppressive, especially for T-cells and, thus, allogeneic MSCs can be considered
for therapeutic use. In this context, the secreted bioactive molecules provide a
regenerative microenvironment for a variety of injured adult tissues to limit the area of
damage and to mount a self-regulated regenerative response. This regenerative
microenvironment is referred to as trophic activity and, therefore, MSCs appear to be
valuable mediators for tissue repair and regeneration. The natural titers of MSCs that are
drawn to sites of tissue injury can be augmented by allogeneic MSCs delivered via the
bloodstream. Indeed, human clinical trials are now under way to use allogeneic MSCs for
treatment of myocardial infarcts, graft-versus-host disease, Crohn's Disease, cartilage and
meniscus repair, stroke, and spinal cord injury. This review summarizes the biological
basis for the in vivo functioning of MSCs through development and aging.
PMID: 17620285 [PubMed - indexed for MEDLINE]
Vet Ther. 2007 Winter;8(4):272-84.
Effect of adipose-derived mesenchymal stem and regenerative cells on lameness in dogs
with chronic osteoarthritis of the coxofemoral joints: a randomized, double-blinded,
multicenter, controlled trial.
Black LL, Gaynor J, Gahring D, Adams C, Aron D, Harman S, Gingerich DA, Harman R.
Vet-Stem, Inc., Poway, CA 92064, USA. LBlack@vet-stem.com
Autologous stem cell therapy in the field of regenerative veterinary medicine involves
harvesting tissue, such as fat, from the patient, isolating the stem and regenerative cells,
and administering the cells back to the patient. Autologous adipose-derived stem cell
therapy has been commercially available since 2003, and the current study evaluated such
therapy in dogs with chronic osteoarthritis of the hip. Dogs treated with adipose-derived
stem cell therapy had significantly improved scores for lameness and the compiled scores
for lameness, pain, and range of motion compared with control dogs. This is the first
randomized, blinded, placebo-controlled clinical trial reporting on the effectiveness of
stem cell therapy in dogs.
PMID: 18183546 [PubMed - indexed for MEDLINE]
J Orthop Res. 2007 Oct;25(10):1261-8.
Regenerative medicine in orthopaedic surgery.
Corsi KA, Schwarz EM, Mooney DJ, Huard J:
Stem Cell Research Center, Children's Hospital of Pittsburgh, 4100 Rangos Research
Center, 3460 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA.
Regenerative medicine holds great promise for orthopaedic surgery. As surgeons
continue to face challenges regarding the healing of diseased or injured musculoskeletal
tissues, regenerative medicine aims to develop novel therapies that will replace, repair, or
promote tissue regeneration. This review article will provide an overview of the different
research areas involved in regenerative medicine, such as stem cells, bioinductive factors,
and scaffolds. The potential use of stem cells for orthopaedic tissue engineering will be
addressed by presenting the current progress with skeletal muscle-derived stem cells. As
well, the development of a revascularized massive allograft will be described and will
serve as a prototypic model of orthopaedic tissue engineering. Lastly, we will describe
current approaches used to design cell instructive materials and how they can be used to
promote and regulate the formation of bony tissue.
PMID: 17551972 [PubMed - indexed for MEDLINE]
Acta Pharmacol Sin. 2007 May;28(5):663-71.
Neocartilage formation from predifferentiated human adipose derived stem cells in vivo.
Department of Orthopedics, Peking University, Third Hospital, Beijing 100083, China.
Jin XB, Sun YS, Zhang K, Wang J, Ju XD, Lou SQ
AIM: To examine the chondrogenic potential of human adipose derived stem cells (hASC)
induced by human transforming growth factor beta2 (hTGF beta2) in vitro, and to
investigate if predifferentiated hASC can produce neocartilage in vivo.
METHODS: hASC were isolated from subcutaneous adipose tissue and cultured in pellets
with the addition of hTGF beta2. Chondrogenic differentiation was assayed by RT-PCR,
Western blotting, toluidine blue staining, and immunohistochemistry staining for collagen
type II. For the in vivo study, intact induced cell pellets or the released cells embedded in
alginate gel with different concentrations were implanted subcutaneously in nude mice.
Specimens were harvested at different time points and carried with histological and
immunohistochemistry examination to evaluate the cartilage formation.
RESULTS: RT-PCR analysis revealed that hASC produced aggrecan and collagen type II
after 7 d of induction and continued throughout the culture period. This was also
demonstrated by the Western blot analysis, positive staining of toluidine blue, and
immunohistochemistry for collagen type II. After reseeding in the monolayer, the cells
isolated from the pellets displayed a polygonal morphology compared with the primary
spindle shape. hASC were released from the induced cell pellets when embedded in
alginate gel (implanted cell concentration=5X10(6) /mL or higher). They produced
neocartilage after 12 weeks in vivo culture; however, intact induced cell pellets implanted
subcutaneously rapidly lost their differentiated phenotype.
CONCLUSION: Chondrogenesis of hASC in vitro can be induced by combining pellet
culture and hTGF beta2 treatment. Predifferentiated hASC embedded in alginate gel have
the ability of producing neocartilage in vivo.
PMID: 17439723 [PubMed - indexed for MEDLINE]
Acta Orthop Traumatol Turc. 2007;41 Suppl 2:153-9.
[The future of treatment for chondral and osteochondral lesions]
[Article in Turkish]
Cirpar M, Korkusuz F.
Kirikkale Universitesi Tip Fakültesi Ortopedi ve Travmatoloji Anabilim Dali, Kirikkale,
The population of patients with symptomatic focal or generalized cartilage lesions is
growing due to prolongation of life expectancy and to increasing frequency of sports
injuries. Cartilage tissue lesions which were defined as untreatable in the past have now
become treatable thanks to advances in basic scientific research. With the development of
technologies regarding biomaterial, cell and local regulators, and with the introduction of
new surgical techniques, it is estimated that, in the near future, clinical applications of
cartilage tissue engineering will also receive particular attention in our country. Currently,
all alternatives used in the treatment of cartilage lesions have merits and demerits,
including arthroscopic debridement and lavage, mesenchymal stem cell stimulation,
osteochondral replacement techniques, and autologous chondrocyte transplantation.
Preliminary results of experimental cartilage tissue engineering are encouraging for the
replacement of disrupted tissue with that having mechanical properties of hyaline
cartilage. Clinical applications of cartilage tissue engineering include bioabsorbable
scaffolds as extracellular collagen, hyaluronic acid matrices, and genetically engineered
PMID: 18180597 [PubMed - indexed for MEDLINE]
Tissue Eng. 2007 Jun;13(6):1135-50.
Review: gene- and stem cell-based therapeutics for bone regeneration and repair.
Kimelman N, Pelled G, Helm GA, Huard J, Schwarz EM, Gazit D
Skeletal Biotech Lab, The Hebrew University of Jerusalem-Hadassah Medical Campus, Ein
Kerem, Jerusalem, Israel.
Many clinical conditions require regeneration or implantation of bone. This is one focus
shared by neurosurgery and orthopedics. Current therapeutic options (bone grafting and
protein-based therapy) do not provide satisfying solutions to the problem of massive bone
defects. In the past few years, gene- and stem cell-based therapy has been extensively
studied to achieve a viable alternative to current solutions offered by modern medicine for
bone-loss repair. The use of adult stem cells for bone regeneration has gained much
focus. This unique population of multipotential cells has been isolated from various
sources, including bone marrow, adipose, and muscle tissues. Genetic engineering of
adult stem cells with potent osteogenic genes has led to fracture repair and rapid bone
formation in vivo. It is hypothesized that these genetically modified cells exert both an
autocrine and a paracrine effects on host stem cells, leading to an enhanced osteogenic
effect. The use of direct gene delivery has also shown much promise for in vivo bone
repair. Several viral and nonviral methods have been used to achieve substantial bone
tissue formation in various sites in animal models. To advance these platforms to the
clinical setting, it will be mandatory to overcome specific hurdles, such as control over
transgene expression, viral vector toxicity, and prolonged culture periods of therapeutic
stem cells. This review covers a prospect of cell and gene therapy for bone repair as well
as some very recent advancements in stem cell isolation, genetic engineering, and
exogenous control of transgene expression.
PMID: 17516852 [PubMed - indexed for MEDLINE]
Regen Med. 2006 Jul;1(4):549-61.
Applications of gene therapy and adult stem cells in bone bioengineering.
Kimelman N, Pelled G, Gazit Z, Gazit D
The Hebrew University of Jerusalem, Skeletal Biotechnology Laboratory, Hadassah
Medical Campus, Ein Kerem, PO Box 12272, Jerusalem, 91120, Israel.
Bone tissue engineering is an emerging field, that could become a main therapeutic
strategy in orthopedics in coming years. While bone has regenerative abilities that enable
the self repair and regeneration of fractures, there are extreme situations in which the
extent of bone loss is too large for complete regeneration to occur. In order to achieve
bone regeneration, osteogenic genes (mainly from the bone morphogenetic protein family)
can be delivered either directly into the target tissue, or by using adult stem cells, which
are later implanted into the target site. Engineered adult stem cells combined with
biodegradable polymeric scaffolds can be implanted into target sites, with or without ex
vivo culture period. Several important factors influence the success of bone engineering
approaches including: choice of cell and scaffold, the vector used in order to deliver the
osteogenic gene, and the osteogenic gene itself. Cutting-edge imaging technologies,
bioinformatics-based analysis of gene expression and exogenous regulation of transgene
expression are among the tools that are being used to optimize and control bone
formation in vivo. In this review we have attempted to provide an overview of the main
factors that should be considered when utilizing adult stem cells and gene therapy
strategies to regenerate bone defects or to promote new bone formation in vivo.
PMID: 17465849 [PubMed - indexed for MEDLINE]
Indian J Med Sci. 2006 Apr;60(4):162-9.
Stem cells in orthopedics: current concepts and possible future applications.
Bagaria V, Patil N, Sapre V, Chadda A, Singrakia M.
Department of Orthopedics, CIIMS HOSPITAL, 88/2, Bajaj Nagar, Nagpur - 440 010, India.
Stem cells are the cells that have the ability to divide for indefinite periods in culture and
to give rise to specialized cells. Sources of these cells include embryo, umbilical cord and
certain sites in adults such as the central nervous system [CNS] and bone marrow. Its use
hold promise of wide spread applications particularly in areas of spinal cord injury,
difficult non-unions, critical bone defects, spinal fusions, augmentation of ligament
reconstructions, cartilage repair and degenerative disc disorders. This review article
contains current information derived from Medline searches on the use in various
orthopedic subspecialties. Some issues remain at the forefront of the controversy
involving stem cell research - legislation, ethics and public opinion, cost and
concentration methods. As is true with any new technology, the enthusiasm for this
technology that has potential to influence virtually every orthopedic case management,
must be balanced by subjecting it to stringent clinical and basic research investigations.
PMID: 16679634 [PubMed - indexed for MEDLINE]
Br J Sports Med. 2005 Sep;39(9):582-4.
Harnessing the stem cell for the treatment of tendon injuries: heralding a new dawn?
Smith RK, Webbon PM:
PMID: 16118291 [PubMed - indexed for MEDLINE]
Tissue Eng. 2005 Jul-Aug;11(7-8):1198-211.
Review: mesenchymal stem cells: cell-based reconstructive therapy in orthopedics.
Skeletal Research Center, Department of Biology, Case Western Reserve University,
Cleveland, OH 44106, USA. email@example.com
Adult stem cells provide replacement and repair descendants for normal turnover or
injured tissues. These cells have been isolated and expanded in culture, and their use for
therapeutic strategies requires technologies not yet perfected. In the 1970s, the embryonic
chick limb bud mesenchymal cell culture system provided data on the differentiation of
cartilage, bone, and muscle. In the 1980s, we used this limb bud cell system as an assay
for the purification of inductive factors in bone. In the 1990s, we used the expertise gained
with embryonic mesenchymal progenitor cells in culture to develop the technology for
isolating, expanding, and preserving the stem cell capacity of adult bone marrow-derived
mesenchymal stem cells (MSCs). The 1990s brought us into the new field of tissue
engineering, where we used MSCs with site-specific delivery vehicles to repair cartilage,
bone, tendon, marrow stroma, muscle, and other connective tissues. In the beginning of
the 21st century, we have made substantial advances: the most important is the
development of a cell-coating technology, called painting, that allows us to introduce
informational proteins to the outer surface of cells. These paints can serve as targeting
addresses to specifically dock MSCs or other reparative cells to unique tissue addresses.
The scientific and clinical challenge remains: to perfect cell-based tissue-engineering
protocols to utilize the body's own rejuvenation capabilities by managing surgical
implantations of scaffolds, bioactive factors, and reparative cells to regenerate damaged
or diseased skeletal tissues.
PMID: 16144456 [PubMed - indexed for MEDLINE]
J Musculoskelet Neuronal Interact. 2005 Oct-Dec;5(4):367-8.
Summary--Cell therapies for orthopedic applications.
Center for Musculoskeletal Research, University of Rochester, School of Medicine and
Dentistry, Rochester, NY, USA. firstname.lastname@example.org
PMID: 16340141 [PubMed - indexed for MEDLINE]
Pathol Biol (Paris). 2005 Apr;53(3):142-8.
[Therapeutic application of mesenchymal stem cells in orthopaedics] [Article in French]
Potier E, Petite H
Laboratoire de recherches orthopédiques, CNRS UMR 7052, Faculté de médecine
Lariboisière-Saint-Louis, 10, avenue de Verdun, 75010 Paris, France.
Stem cell therapy of skeletal tissues involves the transplantation of stem cells to the
tissues that have been damaged by injury or disease. Although these cells can be derived
from embryos, the preferred source of skeletal stem cells is the bone marrow as it
contains adult stem cells that can be easily driven towards a bone phenotype. More
recently, cells with similar potentialities have also been derived from adipose tissue,
muscle, or blood. A biomaterial (ceramics or polymers) is often required as a scaffold to
promote cell adhesion, proliferation and differentiation as well as encourage vascular
invasion and ultimately new bone formation. The first clinical studies are encouraging and
suggests that stem cell therapy could be a prime method for bone reconstruction.
PMID: 15781372 [PubMed - indexed for MEDLINE]
Mesenchymal stem cell-based cartilage tissue engineering: cells, scaffold and biology.
Song L, Baksh D, Tuan RS:
Cartilage Biology and Orthopedics Branch, National Institute of Arthritis, and
Musculoskeletal and Skin Diseases, Department of Health and Human Services, NIH,
Bethesda, MD 20892-8022, USA.
Cartilage repair and regeneration by stem cell-based tissue engineering could be of
enormous therapeutic and economic potential benefit for an aging population. However, to
use stem cells effectively, their natural environment must be understood in order to
expand them in vitro without compromising their multilineage potential and their specific
differentiation program. Collaboration between diverse academic disciplines and between
research and regulatory government agencies and industry is crucial before cell-based
cartilage tissue engineering can achieve its full therapeutic potential.
PMID: 15773023 [PubMed - indexed for MEDLINE]
Med J Aust. 2004 Mar 1;180(5 Suppl):S35-8.
Orthopaedic tissue engineering: from laboratory to the clinic.
Department of Anatomy and Cell Biology, Monash University, Wellington Road, Clayton,
VIC 3800, Australia. Barry.Oakes@med.monash.edu.au
Tissue engineering involves the use of cells (either adult, mesenchymal or embryonic
stem cells) coupled with biological or artificial matrices or scaffolds which guide the cells
during repair or regeneration of the tissue. Recently discovered and isolated growth
factors can promote either adult or stem-cell growth and differentiation along selected
pathways to re-form and repair skeletal tissues in adults. Bone repair enhancement and
replacement is now possible with the use of tissue-engineering technologies. It is now
possible to repair articular cartilage using the patient's own articular chondrocytes
retrieved during arthroscopy, and expanded in vitro. Clinical results of this technique are
PMID: 14984362 [PubMed - indexed for MEDLINE]
J Musculoskelet Neuronal Interact. 2002 Jun;2(4):309-20.
Adult mesenchymal stem cells: potential for muscle and tendon regeneration and use in
Pittenger M, Vanguri P, Simonetti D, Young R.
Osiris Therapeutics, Inc., Baltimore, Maryland 21231, USA. email@example.com
The expansion potential and plasticity of stem cells, adult or embryonic, offer great
promise for their use in medical therapies. Recent provocative data suggest that the
differentiation potential of adult stem cells may extend to lineages beyond those usually
associated with the germ layer of origin. In this review, we describe recent developments
related to adult stem cell research and in particular, in the arena of mesenchymal stem cell
(MSC) research. Research demonstrates that transduced MSCs injected into skeletal
muscle can persist and express secreted gene products. The ability of the MSC to
differentiate into cardiomyocytes has been reported and their ability to engraft and modify
the pathology in infarcted animal models is of great interest. Research using MSCs in
tendon repair provides information on the effects of physical forces on phenotype and
gene expression. In turn, MSCs produce changes in their matrix environment in response
to those biomechanical forces. Recent data support the potential of MSCs to repair
tendon, ligament, meniscus and other connective tissues. Therapeutic applications of
adult stem cells are approaching clinical use in several fields, furthering the possibility to
regenerate damaged and diseased tissue.
PMID: 15758422 [PubMed]
Bosch U, Krettek C: Tissue engineering of tendons and ligaments. A new challenge.
Unfallchirurg. 2002 Feb;105(2):88-94
Injuries to ligaments and tendons heal by formation of inferior repair tissue. This may result
in severe joint dysfunction. Because of an increased occurrence of sports-related injuries,
musculoskeletal disorders may become one of the major burden of health care. Tissue
engineering offers the potential to improve the quality of ligament and tendon tissues during
the healing process and may provide a more effective approach to the treatment of injuries
to ligaments and tendons than traditional methods. Application of growth factors, gene
transfer techniques, cell therapy and cell-matrix composites have shown to affect the
process of ligament and tendon healing. The benefits of using mesenchymal stem cells on a
three dimensional biological matrix have been shown recently. Tissue engineering will also
include mechanical manipulation of tissue environments to accelerate cell differentiation and
to improve matrix formation. Fibroblast-seeded polymer scaffolds could be useful in
ligament and tendon replacement in which autogenous fibroblasts would be obtained
through biopsy, cultured and seeded onto a scaffold.
PMID: 11968548 [PubMed - indexed for MEDLINE]
Clin Sports Med. 2001 Apr;20(2):403-16, viii.
Treatment of osteochondral injuries. Genetic engineering.
Martinek V, Fu FH, Lee CW, Huard J.sss
Department of Orthopaedic Surgery, University of Pittsburgh, Pennsylvania, USA.
Articular cartilage injuries are commonly encountered problems in sports medicine and
orthopaedics. The treatment of chondral and osteochondral lesions, which possess only a
very limited potential for healing, still represents a great challenge to clinicians and to
scientists. Experimental investigations reported over the last 20 years have shown that a
variety of methods, including implantation of periosteum, perichondrium, artificial
matrices, growth factors, and transplanted cells, can stimulate formation of new cartilage.
Genetic engineering--a combination of gene transfer techniques and tissue engineering--
will facilitate new approaches to the treatment of articular cartilage injuries.
PMID: 11398365 [PubMed - indexed for MEDLINE]
Tissue Eng. 2003 Aug;9(4):733-44.
Cell-based therapy in the repair of osteochondral defects: a novel use for adipose tissue.
Nathan S, Das De S, Thambyah A, Fen C, Goh J, Lee EH
Department of Orthopedics, National University Hospital, National University of Singapore,
Mesenchymal stem cells are currently procured from periosteum and bone marrow. The
procurement of stem cells from these sources is tedious and gives a low yield of cells.
This study was aimed at circumventing these problems and allowing for a method that
would be more acceptable in the clinical setting. Tissue for transplantation was harvested
from a single New Zealand White rabbit. Cells were more readily obtained from adipose
tissue than from bone marrow or periosteum. The present method also provided a better
yield of cells through culture. In vitro studies were performed to assess the differentiation
potential of these cells. Successful in vitro transformation into alternative mesenchymal
cell lines including cardiomyocytes revealed these cells to have wide differentiation
potential. Further characterization morphologically, immunohistochemically, and via gene
transfection showed features consistent with mesenchymal stem cells. Cultured cells were
then transplanted into defects created in the left medial femoral condyle. The femora were
harvested at various intervals and the repair tissue was assessed. Gross osteochondral
defect reconstitution and histological grading was superior to periosteum-derived stem
cell repair and repair by native mechanisms. Biomechanically, the repair tissue
approximated intact cartilage and was superior to osteochondral autografts and repair by
PMID: 13678450 [PubMed - indexed for MEDLINE]
Mol Biol Cell. 2002 Dec;13(12):4279-95.
Human adipose tissue is a source of multipotent stem cells.
Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK,
Benhaim P, Hedrick MH:
Department of Surgery and Orthopedics, Regenerative Bioengineering and Repair
Laboratory, UCLA School of Medicine, Los Angeles, California 90095, USA.
Much of the work conducted on adult stem cells has focused on mesenchymal stem cells
(MSCs) found within the bone marrow stroma. Adipose tissue, like bone marrow, is
derived from the embryonic mesenchyme and contains a stroma that is easily isolated.
Preliminary studies have recently identified a putative stem cell population within the
adipose stromal compartment. This cell population, termed processed lipoaspirate (PLA)
cells, can be isolated from human lipoaspirates and, like MSCs, differentiate toward the
osteogenic, adipogenic, myogenic, and chondrogenic lineages. To confirm whether
adipose tissue contains stem cells, the PLA population and multiple clonal isolates were
analyzed using several molecular and biochemical approaches. PLA cells expressed
multiple CD marker antigens similar to those observed on MSCs. Mesodermal lineage
induction of PLA cells and clones resulted in the expression of multiple lineage-specific
genes and proteins. Furthermore, biochemical analysis also confirmed lineage-specific
activity. In addition to mesodermal capacity, PLA cells and clones differentiated into
putative neurogenic cells, exhibiting a neuronal-like morphology and expressing several
proteins consistent with the neuronal phenotype. Finally, PLA cells exhibited unique
characteristics distinct from those seen in MSCs, including differences in CD marker
profile and gene expression.
PMID: 12475952 [PubMed - indexed for MEDLINE]
J Am Acad Orthop Surg. 2002 Jan-Feb;10(1):6-15.
Gene therapy and tissue engineering in orthopaedic surgery.
Musgrave DS, Fu FH, Huard J
Department of Orthopaedic Surgery, University of Pittsburgh Medical Center, Pittsburgh,
A new biologic era of orthopaedic surgery has been initiated by basic scientific advances
that have resulted in the development of gene therapy and tissue engineering approaches
for treating musculoskeletal disorders. The terminology, fundamental concepts, and
current research in this burgeoning field must be understood by practicing orthopaedic
surgeons. Different gene therapy approaches, multiple gene vectors, a multitude of
cytokines, a growing list of potential scaffolds, and putative stem cells are being studied.
Gene therapy and tissue engineering applications for bone healing, articular disorders,
intervertebral disk pathology, and skeletal muscle injuries are being explored. Innovative
methodologies that ensure patient safety can potentially lead to many new treatment
strategies for musculoskeletal conditions.
PMID: 11809046 [PubMed - indexed for MEDLINE]
Tissue Eng. 1999 Aug;5(4):327-37.
Meniscus regeneration in a rabbit partial meniscectomy model.
Walsh CJ, Goodman D, Caplan AI, Goldberg VM.
The Departments of Biology and Orthopaedics, Case Western Reserve University and
University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.
Meniscectomy is known to be associated with osteoarthrosis of the knee. The purpose of
this study was to compare the natural and augmented repair of menisci in the knees of
New Zealand White rabbits. To create a partial defect in the medial meniscus, we used an
experimental model that has been well characterized and extensively used in the study of
osteoarthrosis and articular cartilage repair. The defect was left untreated or treated with
one of the following: a periosteal autograft, a type I collagen sponge, or the same sponge
loaded with autologous, bone marrow-derived, cultured mesenchymal stem cells. The
natural repair was always incomplete and degenerative changes within these joints were
progressive. The periosteal autograft underwent differentiation into a bone and hyaline
cartilage composite that was ineffectual as a meniscus and accelerated the degenerative
changes in those joints when compared to natural repair controls. There was evidence of a
consistent sequence of events in the transformation of the periosteal grafts to a core of
cartilage that underwent endochondral ossification. In the last two groups, the collagen
sponge functioned as a scaffold that resulted in more abundant repair tissue. The collagen
sponge alone supported a largely fibrous repair process. The cultured mesenchymal stem
cells were observed to augment the repair process in some specimens to include
fibrocartilage histologically similar to normal meniscus. Degenerative changes were
present in both of these groups, which indicates that the biomechanical function of the
meniscus was not restored, or an irreversible osteoarthrosis cascade was initiated during Download full-text
the repair period. Based on these preliminary studies, further investigation of cell-based
meniscus regeneration appears to be warranted.
PMID: 10477855 [PubMed - indexed for MEDLINE]