Dental Stem Cells & their various applications

1. Regenerative Medicine & Tissue /
Organ Bioengineering
Vol - II

2. 02
Regenerative Medicine & Tissue / Organ Bioengineering
YESTERDAY
TODAY
TOMORROW
Regenerative medicine is the process of creating living, functional tissues to repair or replace tissue or organ
function lost due to age, disease, damage, or congenital defects. This field holds the promise of regenerating
damaged tissues and organs in the body by stimulating previously irreparable organs to heal themselves.
Regenerative medicine also empowers scientists to grow tissues and organs in the laboratory and safely implant
them when the body cannot heal itself. Importantly, regenerative medicine has the potential to solve the problem of
the shortage of organs available through donation compared to the number of patients that require life-saving organ
transplantation.
Successful transplantation of bone, soft tissue, and corneas occurred early in the 20th century.
Real progress in organ transplantation began in 1954 with the first successful kidney transplant.
During the 1960s, successful transplantation of pancreas/kidney, liver, isolated pancreas and heart occurred.
Transplant surgery success continued into the 1980s with successful heart-lung, single lung, double lung, living-
donor liver, and living-donor lung transplants.
The rapid development of transplant medicine along with the aging of the baby boomer generation has caused an
increased demand for tissues and organs far exceeding the available donor organs.
Tissue-engineered skin has been used for skin replacement, temporary wound cover for burns, and treatment for
diabetic leg and foot ulcers.
Tissue-engineered bladder, derived from a patient’s own cells, can be grown outside the body and successfully
transplanted.
Amaterial developed from the small intestines of pigs is increasingly used by surgeons to restore damaged tissues
and support the body’s own healing processes. Physicians rely on the material, called small intestinal submucosa
(SIS), for everything from reconstructing ligaments to treating incontinence. Today, SIS is most commonly used to
help the body close hard-to-heal wounds such as second-degree burns, chronic pressure ulcers, diabetic skin
ulcers, and deep skin lacerations.
Tissue-engineered products are used to induce bone and connective tissue growth, guide long bone regeneration,
and replace damaged knee cartilage.
Tissue-engineered vascular grafts for heart bypass surgery and cardiovascular disease treatment are at the pre-
clinical trial stage.
Stem and precursor cells are available from a wide variety of sources (e.g., embryos, gestational and adult tissues,
and reprogrammed differentiated cells). This increases the sophistication, variety and utility of engineered tissues.
Animal and small pilot human studies are currently paving the way for large scale clinical trials to treat many
intractable diseases.
By providing healthy, functional tissues and organs, regenerative medicine will improve the quality of life for
individuals.
Imagine a world where there is no donor organ shortage, where victims of spinal cord injuries can walk, and where
weakened hearts are replaced. This is the long-term promise of regenerative medicine, a rapidly developing field
with the potential to transform the treatment of human disease through the development of innovative new
therapies that offer a faster, more complete recovery with significantly fewer side effects or risk of complications.
Insulin-producing pancreatic islets could be grown in the laboratory and implanted, creating the potential for a cure
for diabetes.
Tissue-engineered heart muscle may be available to repair human hearts damaged by attack or disease.
The emerging technique of Organ Printing utilizes a standard ink jet printer modified with tissue matrix material (and
possibly also cells) replacing the ink. “Made-to-order” organs of almost any configuration could then be cast and
implanted.
Materials Science meets Regenerative Medicine as “smart” biomaterials are being made that actively participate
in, and orchestrate, the formation of functional tissue.
New approaches to revitalizing worn-out body parts include removing all of the cells from an organ, and infusing
new cells to integrate into the existing matrix and restore full functionality.

3. 03
Index
Skin and Wound Healing.... 04
Respiratory System - BioartificialTrachea.... 06
Genitourinary system - Urinary Bladder Bioengineering.... 08
Musculoskeletal System - Cartilage Regeneration.... 10
Nervous System - Cerebral Palsy.... 12
Cardivascular System.... 14
Endocrinology and Metabolism - Diabetes.... 16
DentalTissue -Tooth Bioengineering.... 18

4. 04
Skin and Wound Healing
Principles and practices for treatment of cutaneous wounds with
cultured skin substitutes
Abstract
Background:
Data Sources:
Conclusions:
Skin substitutes prepared from cultured skin cells and biopolymers may reduce requirements
for donor skin autograft, and have been shown to be effective in treatment of excised burns, burn scars, and
congenital skin lesions.
Cultured skin substitutes (CSS) generate skin phenotypes (epidermal barrier, basement
membrane) in the laboratory, and restore tissue function and systemic homeostasis. Healed skin is smooth,
soft and strong, but develops irregular degrees of pigmentation. Quantitative analysis demonstrates that CSS
closes 67 times the area of the donor skin, compared to less than 4 times for split-thickness skin autograft.
CSS reduce requirements for donor skin autograft for closure of excised, full-thickness
cutaneous wounds, and demonstrate qualitative outcome that is not different from meshed, split-thickness
autograft. These results offer reductions in morbidity and mortality for the treatment of burns and chronic
wounds, and for cutaneous reconstruction. © 2002 Excerpta Medica, Inc.All rights reserved.
Author: Boyce ST, Warden GD.
Source: Department of Surgery, University of Cincinnati, Cincinnati, Ohio 45229, USA.
Publication: Am J Surg. 2002 Apr;183(4):445-56
Skin stem cell biology is a rapidly advancing field in the life sciences. There is increasing evidence that skin
represents a larger reservoir for adult stem cells (including mesenchymal, hematopoietic and neural stem
cells) than the epidermis. Given that skin is easily accessible and immune privileged, skin stem cells will not
only provide hope for the functional repair of the skin itself but will also offer a potential source of adult stem
cells for the cell-based therapy of injuries and diseases throughout the body. This article reviews the current
status of research in this area and discusses the occurrence, plasticity and potential uses of skin stem cells.
Cell therapy is the transplantation, through local delivery or systemic infusion, of autologous or
allogeneic cells to restore the viability or function of deficient tissues. Stem cells are the best choice for cell
therapy because of their ability to self-renew and their high potential to produce differentiated cells. Awide-
variety of adult tissues contain stem and/or progenitor cells that are capable of not only generating cell types of
their tissue of origin but also of producing cell types present in other tissues. These pluripotent stem cells have
evoked significant excitement because of their potential for therapeutic applications [1–5]; however, if these
stem cells are to be used in therapeutics, it will be important that stem cell repositories are easy to access. Skin
is the largest organ in the body and is crucial in protecting against the environment. Adult skin consists of two
layers – the epidermis and the dermis – with associated appendages, such as hair follicles, sebaceous glands
and sweat glands, which are linked to the epidermis, but project deep into the dermal layer. The skin is
constantly renewed and the process of renewal necessitates the presence of adult stem cells. To date,
research has focused on the application of epidermal stem cells, which are unipotent; however, there are other
stem cells in the skin (such as mesenchymal, hematopoietic, neural stem cells, etc.) that should also be
considered. Consequently, interest in this field is increasing [6–9] and this review focuses on recent advances
in the study of skin stem cells, and their plasticity, with special reference to their potential uses in cell therapy.
Introduction:
Author: Shi C, Zhu Y, Su Y, Cheng T.
Source: Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, College of Preventive
Medicine, Third Military Medical University, 30 Gaotanyan Road, Shapingba District, Chongqing, 400038 China.
Publication: Trends Biotechnol. 2006 Jan;24(1):48-52. Epub 2005 Nov 18
Stem cells and their applications in skin-cell therapy

5. 05
Mesenchymal Stem Cells Enhance Wound Healing Through
Differentiation and Angiogenesis
Abstract
Although chronic wounds are common, treatment for these disabling conditions remains limited and largely
ineffective. In this study, we examined the benefit of bone marrow derived mesenchymal stem cells (BM-
MSCs) in wound healing. Using an excisional wound splinting model, we showed that injection around the
wound and application to the wound bed of green fluorescence protein (GFP) allogeneic BM-MSCs
significantly enhanced wound healing in normal and diabetic mice compared with that of allogeneic neonatal
dermal fibroblasts or vehicle control medium. Fluorescence activated cell sorting analysis of cells derived from
the wound for GFP-expressing BM-MSCs indicated engraftments of 27% at 7 days, 7.6% at 14 days, and
2.5% at 28 days of total BM-MSCs administered. BM-MSC-treated wounds exhibited significantly accelerated
wound closure, with increased re-epithelialization, cellularity, and angiogenesis. Notably, BM-MSCs, but not
CD34 bone marrow cells in the wound, expressed the keratinocyte-specific protein keratin and formed
glandular structures, suggesting a direct contribution of BM-MSCs to cutaneous regeneration. Moreover, BM-
MSCconditioned medium promoted endothelial cell tube formation. Real-time polymerase chain reaction and
Western blot analysis revealed high levels of vascular endothelial growth factor and angiopoietin-1 in BM-
MSCs and significantly greater amounts of the proteins in BM-MSC-treated wounds. Thus, our data suggest
that BM-MSCs promote wound healing through differentiation and release of proangiogenic factors.
Author: Wu Y, Chen L, Scott PG, Tredget EE.
Source: 161 HMRC, University of Alberta, 113 Street & 87 Avenue, Edmonton, Alberta T6G 2E1,
Publication: Stem Cells. 2007 Oct;25(10):2648-59. Epub 2007 Jul 5.
Abstract
The development and use of artificial skin in treating acute and chronic wounds has, over the last 30 years,
advanced from a scientific concept to a series of commercially viable products. Many important clinical
milestones have been reached and the number of artificial skin substitutes licensed for clinical use is growing,
but they have yet to replace the current ‘‘gold standard’’ of an autologous skin graft. Currently available skin
substitutes often suffer from a range of problems that include poor integration (which in many cases is a direct
result of inadequate vascularisation), scarring at the graft margins and a complete lack of differentiated
structures. The ultimate goal for skin tissue engineers is to regenerate skin such that the complete structural
and functional properties of the wounded area are restored to the levels before injury. New synthetic
biomaterials are constantly being developed that may enable control over wound repair and regeneration
mechanisms by manipulating cell adhesion, growth and differentiation and biomechanics for optimal tissue
development. In this review, the clinical developments in skin bioengineering are discussed, from conception
through to the development of clinically viable products. Central to the discussion is the development of the
next generation of skin replacement therapy, the success of which is likely to be underpinned with our
knowledge of wound repair and regeneration.
Author: Metcalfe AD, Ferguson MW.
Source: UK Centre for Tissue Engineering (UKCTE), Faculty of Life Sciences, University of Manchester, 3.239 Stopford
Building, Oxford Road, Manchester M13 9PT, UK.
Publication: Biomaterials. 2007 Dec;28(34):5100-13. Epub 2007 Aug 3.
Bioengineering skin using mechanisms of regeneration and repair

6. 06
First human transplantation of a bioengineered airway tissue
Abstract
Airway defects occurring at the anastomotic site after carinal pneumonectomy are associated with persistent
contamination between airway and pleural spaces, mediastinal spaces, or both and difficulties in the re-
expansion of and possible aspiration into the residual lung. Unfortunately, therapeutic interventions are
limited, and the outcome is often fatal.1An ideal solution would be to generate an airway segment or surface to
be implanted after achieving control of the infection and aspiration. Tissue-engineered airway is about the only
technique of the many attempts at tracheal replacement that seems to offer any real promise.2 It applies the
principles of engineering and life sciences toward the development of biologic substitutes that restore,
maintain, or improve tissue function and offers the potential to create replacement structures from
biodegradable scaffolds and autologous cells.3 We here describe the first clinical application of a tissue
engineered airway patch.
Author: Macchiarini P, Walles T, Biancosino C, Mertsching H.
Source: Department of Thoracic and Vascular Surgery, Heidehaus Hospital, Medical School Hannover, Germany.
Publication: J Thorac Cardiovasc Surg. 2004 Oct;128(4):638-41
Abstract
There are a variety of airway diseases with different clinical settings, which may extend from a surgical
approach to total organ replacement.Tissue engineering involves modifying cells or tissues in order to repair,
regenerate, or replace tissue in the body and seems to be a promising approach for airway replacement. The
successful implantation of stem-cell-based tissue-engineered trachea in a young woman with end-stage post-
tuberculosis left main bronchus collapse serves as a prototype for the airway tissue-engineered-based
approach. The trachea indeed could represent a perfect model system to investigate the translational aspects
of tissue engineering, largely due to its low-oxygen needs. This review highlights the anatomy of the airways,
the various disease conditions that cause damage to the airways, elaborates on the essential components of
the tissue-engineering approach, and discusses the success of the revolutionary trachea transplantation
approach.
Author: Kalathur M, Baiguera S, Macchiarini P.
Source: BIOAIR Lab, Department of General Thoracic and Regenerative Surgery and Intrathoracic Biotransplantation,
University Hospital Careggi, Largo Brambilla 3, 50134, Florence, Italy.
Publication: Cell Mol Life Sci. 2010 Dec;67(24):4185-96. doi: 10.1007/s00018-010-0499-z. Epub 2010 Aug 21.
Translating tissue-engineered tracheal replacement from bench to bedside
Respiratory System -
Bioartificial Trachea

7. 07
Tissue engineered human tracheas for in vivo implantation
Abstract
Two years ago we performed the first clinical successful transplantation of a fully tissue engineered trachea. Despite
the clinically positive outcome, the graft production took almost 3 months, a not feasible period of time for patients with
the need of an urgent transplantation. We have then improved decellularization process and herein, for the first time,
we completely describe and characterize the obtainment of human tracheal bioactive supports. Histological and
molecular biology analysis demonstrated that all cellular components and nuclear material were removed and
quantitative PCR confirmed it. SEM analysis revealed that the decellularized matrices retained the hierarchical
structures of native trachea, and biomechanical tests showed that decellularization approach did not led to any
influence on tracheal morphological and mechanical properties. Moreover immunohistological staining showed the
preservation of angiogenic factors and angiogenic assays demonstrated that acellular human tracheal scaffolds exert
an in vitro chemoactive action and induce strong in vivo angiogenic response (CAM analysis).We are now able to
obtained, in a short and clinically useful time (approximately 3 weeks), a bioengineered trachea that is structurally and
mechanically similar to native trachea, which exert chemotactive and pro-angiogenic properties and which could be
successfully used for clinical tissue engineered airway clinical replacements.
Author: Baiguera S, Jungebluth P, Burns A, Mavilia C, Haag J, De Coppi P, Macchiarini P.
Source: BIOAIR Lab, Department of General Thoracic and Regenerative Surgery and Intrathoracic Biotransplantation University
Hospital Careggi, Largo Brambilla 3, I-50134 Florence, Italy.
Publication: Biomaterials. 2010 Dec;31(34):8931-8. doi: 10.1016/j.biomaterials.2010.08.005. Epub 2010 Aug 25.
Summary
Background:
Methods:
Findings:
Interpretation:
Funding:
The loss of a normal airway is devastating. Attempts to replace large airways have met with serious
problems. Prerequisites for a tissue-engineered replacement are a suitable matrix, cells, ideal mechanical properties,
and the absence of antigenicity. We aimed to bioengineer tubular tracheal matrices, using a tissue-engineering
protocol, and to assess the application of this technology in a patient with end-stage airway disease.
We removed cells and MHC antigens from a human donor trachea, which was then readily colonised by
epithelial cells and mesenchymal stem-cell-derived chondrocytes that had been cultured from cells taken from the
recipient (a 30-year old woman with end-stage bronchomalacia). This graft was then used to replace the recipient’s left
main bronchus.
The graft immediately provided the recipient with a functional airway, improved her quality of life, and had a
normal appearance and mechanical properties at 4 months. The patient had no anti-donor antibodies and was not on
immunosuppressive drugs.
The results show that we can produce a cellular, tissue-engineered airway with mechanical properties
that allow normal functioning, and which is free from the risks of rejection. The fi ndings suggest that autologous cells
combined with appropriate biomaterials might provide successful treatment for patients with serious clinical disorders.
Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, Fondo de Investigación Sanitaria, Spain;
Charles Courtenay-Cowlin Fund, University of Bristol; UK Arthritis Research Campaign; and the James Tudor
Foundation.
Author: Macchiarini P, Jungebluth P, Go T, Asnaghi MA, Rees LE, Cogan TA, Dodson A, Martorell J, Bellini S, Parnigotto PP, Dickinson
SC,HollanderAP, Mantero S, Conconi MT, Birchall MA.
Source: Department of GeneralThoracic Surgery, Hospital Clinic, Barcelona, Spain.
Publication: Lancet. 2008 Dec 13;372(9655):2023-30. doi: 10.1016/S0140-6736(08)61598-6. Epub 2008 Nov 18.
Clinical transplantation of a tissue-engineered airway

8. 08
Genitourinary system -
Urinary Bladder Bioengineering
Tissue engineering and stem cells: Basic principles and applications in urology
Abstract
To overcome problems of damaged urinary tract tissues and complications of current procedures, tissue engineering (TE) techniques
and stem cell (SC) research have achieved great progress. Although diversity of techniques is used, urologists should know the
basics.We carried out a literature review regarding the basic principles and applications of TE and SC technologies in the
genitourinary tract. We carried out MEDLINE/PubMed searches for English articles until March 2010 using a combination of the
following keywords: bladder, erectile dysfunction, kidney, prostate, Peyronie’s disease, stem cells, stress urinary incontinence, testis,
tissue engineering, ureter, urethra and urinary tract. Retrieved abstracts were checked, and full versions of relevant articles were
obtained. Scientists have achieved great advances in basic science research. This is obvious by the tremendous increase in the
number of publications. We divided this review in two topics; the first discusses basic science principles of TE and SC, whereas the
second part delineates current clinical applications and advances in urological literature. TE and SC applications represent an
alternative resource for treating complicated urological diseases. Despite the paucity of clinical trials, the promising results of animal
models and continuous work represents the hope of treating various urological disorders with this technology.
Author: Shokeir AA, Harraz AM, El-Din AB.
Source: Mansoura Urology and Nephrology Center, Urology Department, Mansoura, Egypt.
Publication: Int J Urol. 2010 Dec;17(12):964-73. doi: 10.1111/j.1442-2042.2010.02643.x. Epub 2010 Oct 24
Stem cell research in urology can be broadly subdivided into two fields: one that attempts to identify urological tissue-specific stem
cells; and another that tries to apply less- differentiated multipotent stem cells, such as embryonic stem cells (ESCs), to the treatment
of urological diseases. Several studies have investigated tissue-specific stem cells in the kidney, bladder, prostate, penis and testes.
The main obstacles in this field of research are the lack of reliable markers for putative tissue-specific stem cells, and the absence of a
convincing rationale to justify their use over less-differentiated stem cells, which offer more therapeutic flexibility and are usually
more-easily accessible.
In addition to tissue-specific stem cells, ESCs and some ‘adult’ multipotent stem cells have been investigated for urological
applications. These adult types include bone marrow stem cells (BMSCs), skeletal-muscle-derived stem cells (SkMSCs), adipose-
tissue-derived stem cells (ADSCs), and amniotic-fluid-derived stem cells (AFSCs). Although ESCs and BMSCs are the best studied
stem cells in most medical disciplines, SkMSCs are the only type to have reached clinical trials in urology. These trials were
conducted by Michael Chancellor’s group at the University of Pittsburgh in the US and Hannes Strasser’s group at the Medical
University of Innsbruck,Austria. However, as Nature has been reporting (AbbottA[2008] Nature 454: 922–933), questions have been
raised about the ethics and methodology of the Austrian studies. At the time of writing full details of the issues surrounding these
studies have yet to be publicly disclosed.
A wide range of studies have focused on urological applications of multipotent stem cells. ESCs, BMSCs and AFSCs have been
shown to differentiate into renal lineages and to enhance renal repair. With regard to the ureter, tissue engineering has been
attempted but studies on stem cells are still lacking. BMSCs, SkMSCs, and AFSCs have been used for bladder augmentation and
detrusor regeneration in animals. SkMSCs are the only stem cells to have been successfully tested in humans, for the treatment of
stress urinary incontinence. ESCs, BMSCs and SkMSCs have been shown to improve erectile function in animal models. Both ESCs
and BMSCs can be differentiated into sperm and, remarkably, the ESC-derived sperms have generated offspring mice. With regards
to the prostate, stem cell studies are usually focused less on the application of stem cells to treat disease, and more on understanding
so-called ‘cancer stem cells’, which are targets of therapy.
ADSC research is a relatively young field, and these cells are largely unstudied in urology. However, as a result of their high
differentiation potential and ease of isolation, ADSCs represent an exciting resource for tissue engineering and regenerative
medicine within and beyond urology.
Despite these advances, challenges abound. Many such difficulties, however, are not unique to urology. Concerns have been raised
about the ethical issues surrounding the use of ESCs, and their potential tumorigenicity. Unanswered questions also remain. Can
adult stem cells really transdifferentiate and thus replenish degenerated tissue? Or do they simply secrete growth factors that help the
host tissue to regenerate? More importantly, how translatable are the results of preclinical studies in largely healthy animal models to
clinical situations in which human patients often have considerable comorbidity? Notably, these questions might best be answered by
research in urology, rather than in other disciplines, because most urological organs are structurally simple and easily accessible. If
we recognize the potential of this technology, urological stem cell research should have a bright future.
Author: Lin CS, Lue TF.
Source: Urology Laboratory at the University of California, San Francisco, CA, USA.
Publication: Nat Clin Pract Urol. 2008 Oct;5(10):521. doi: 10.1038/ncpuro1219.
Stem cells in urology: how far have we come?

9. 09
Tissue-engineered autologous bladders for patients
needing cystoplasty
Abstract
Background:
Methods:
Results:
Conclusions:
Patients with end-stage bladder disease can be treated with cystoplasty using gastrointestinal
segments. The presence of such segments in the urinary tract has been associated with many complications.
We explored an alternative approach using autologous engineered bladder tissues for reconstruction.
Seven patients with myelomeningocele, aged 4–19 years, with high-pressure or poorly compliant
bladders, were identifi ed as candidates for cystoplasty. A bladder biopsy was obtained from each patient.
Urothelial and muscle cells were grown in culture, and seeded on a biodegradable bladder-shaped scaff old
made of collagen, or a composite of collagen and polyglycolic acid. About 7 weeks after the biopsy, the
autologous engineered bladder constructs were used for reconstruction and implanted either with or without
an omental wrap. Serial urodynamics, cystograms, ultrasounds, bladder biopsies, and serum analyses were
done.
Follow-up range was 22–61 months (mean 46 months). Post-operatively, the mean bladder leak
point pressure decrease at capacity, and the volume and compliance increase was greatest in the composite
engineered bladders with an omental wrap (56%, 1·58-fold, and 2·79-fold, respectively). Bowel function
returned promptly after surgery. No metabolic consequences were noted, urinary calculi did not form, mucus
production was normal, and renal function was preserved. The engineered bladder biopsies showed an
adequate structural architecture and phenotype.
Engineered bladder tissues, created with autologous cells seeded on collagen-polyglycolic
acid scaff olds, and wrapped in omentum after implantation, can be used in patients who need cystoplasty.
Author:
Source: Department of Urology and Wake Forest Institute for Regenerative Medicine, Wake Forest University School of
Medicine, Winston-Salem, NC 27157, USA.
Publication: Lancet. 2006 Apr 15;367(9518):1241-6.
Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB.
Abstract
Human organ replacement is limited by a donor shortage, problems with tissue compatibility, and rejection.
Creation of an organ with autologous tissue would be advantageous. In this study, transplantable urinary
bladder neo-organs were reproducibly created in vitro from urothelial and smooth muscle cells grown in
culture from canine native bladder biopsies and seeded onto preformed bladdershaped polymers. The native
bladders were subsequently excised from canine donors and replaced with the tissue-engineered neo-
organs. In functional evaluations for up to 11 months, the bladder neo-organs demonstrated a normal capacity
to retain urine, normal elastic properties, and histologic architecture. This study demonstrates, for the first
time, that successful reconstitution of an autonomous hollow organ is possible using tissue-engineering
methods.
Author: Oberpenning F, Meng J, Yoo JJ, Atala A.
Source: Department of Urology, Children's Hospital and Harvard Medical School, Boston, MA, USA.
Publication: Nat Biotechnol. 1999 Feb;17(2):149-55.
De novo reconstitution of a functional mammalian urinary
bladder by tissue engineering

10. 10
Cartilage repair: Generations of autologous chondrocyte
transplantation
Abstract
Articular cartilage in adults has a limited capacity for self-repair after a substantial injury. Surgical therapeutic
efforts to treat cartilage defects have focused on delivering new cells capable of chondrogenesis into the
lesions. Autologous chondrocyte transplantation (ACT) is an advanced cell-based orthobiologic technology
used for the treatment of chondral defects of the knee that has been in clinical use since 1987 and has been
performed on 12,000 patients internationally. With ACT, good to excellent clinical results are seen in isolated
post-traumatic lesions of the knee joint in the younger patient, with the formation of hyaline or hyaline-like
repair tissue. In the classic ACT technique, chondrocytes are isolated from small slices of cartilage harvested
arthroscopically from a minor weight-bearing area of the injured knee. The extracellular matrix is removed by
enzymatic digestion, and the cells are then expanded in monolayer culture. Once a sufficient number of cells
has been obtained, the chondrocytes are implanted into the cartilage defect, using a periosteal patch over the
defect as a method of cell containment. The major complications are periosteal hypertrophy, delamination of
the transplant, arthrofibrosis and transplant failure. Further improvements in tissue engineering have
contributed to the next generation ofACT techniques, where cells are combined with resorbable biomaterials,
as in matrix-associated autologous chondrocyte transplantation (MACT). These biomaterials secure the cells
in the defect area and enhance their proliferation and differentiation.
Author: Marlovits S, Zeller P, Singer P, Resinger C, Vécsei V.
Source: Department of Traumatology, Center for Joint and Cartilage, Medical University of Vienna, Austria.
Publication: Eur J Radiol. 2006 Jan;57(1):24-31. Epub 2005 Sep 26.
Abstract
Injury of articular cartilage due to trauma or pathological conditions is the major cause of disability worldwide,
especially in NorthAmerica. The increasing number of patients suffering from joint-related conditions leads to
a concomitant increase in the economic burden. In this review article, we focus on strategies to repair and
replace knee joint cartilage, since knee-associated disabilities are more prevalent than any other joint.
Because of inadequacies associated with widely used approaches, the orthopedic community has an
increasing tendency to develop biological strategies, which include transplantation of autologous (i.e.,
mosaicplasty) or allogeneic osteochondral grafts, autologous chondrocytes (autologous chondrocyte
transplantation), or tissue-engineered cartilage substitutes. Tissue-engineered cartilage constructs represent
a highly promising treatment option for knee injury as they mimic the biomechanical environment of the native
cartilage and have superior integration capabilities. Currently, a wide range of tissue-engineering-based
strategies are established and investigated clinically as an alternative to the routinely used techniques (i.e.,
knee replacement and autologous chondrocyte transplantation). Tissue-engineering-based strategies
include implantation of autologous chondrocytes in combination with collagen I, collagen I=III (matrix-induced
autologous chondrocyte implantation), HYAFF 11 (Hyalograft C), and fibrin glue (Tissucol) or implantation of
minced cartilage in combination with copolymers of polyglycolic acid along with polycaprolactone (cartilage
autograft implantation system), and fibrin glue (DeNovo NT graft). Tissue-engineered cartilage replacements
show better clinical outcomes in the short term, and with advances that have been made in orthopedics they
can be introduced arthroscopically in a minimally invasive fashion. Thus, the future is bright for this innovative
approach to restore function.
Author: Ahmed TA, Hincke MT.
Source: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Publication: Tissue Eng Part B Rev. 2010 Jun;16(3):305-29. doi: 10.1089/ten.TEB.2009.0590.
Strategies for Articular Cartilage Lesion Repair and Functional Restoration
Musculoskeletal System -
Cartilage Regeneration

11. 11
Increased Knee Cartilage Volume in Degenerative Joint Disease using
Percutaneously Implanted, Autologous Mesenchymal Stem Cells
Background:
Objective:
Methods:
Results:
Conclusion:
The ability to repair tissue via percutaneous means may allow interventional pain physicians to
manage a wide variety of diseases including peripheral joint injuries and osteoarthritis. This review will
highlight the developments in cellular medicine that may soon permit interventional pain management
physicians to treat a much wider variety of clinical conditions and highlight an interventional case study using
these technologies
To determine if isolated and expanded human autologous mesenchymal stem cells could
effectively regenerate cartilage and meniscal tissue when percutaneously injected into knees.
An IRB approved study with a consenting volunteer in which mesenchymal stem cells were isolated
and cultured ex-vivo from bone marrow aspiration of the iliac crest. The mesenchymal stem cells were then
percutaneously injected into the subject’s knee with MRI proven degenerative joint disease. Pre and post-
treatment subjective visual analog pain scores, physical therapy assessments, and MRIs measured clinical
and radiographic changes.
At 24 weeks post-injection, the patient had statistically significant cartilage and meniscus growth on
MRI, as well as increased range of motion and decreased modified VAS pain scores.
The described process of autologous mesenchymal stem cell culture and percutaneous
injection into a knee with symptomatic and radiographic degenerative joint disease resulted in significant
cartilage growth, decreased pain and increased joint mobility in this patient. This has significant future
implications for minimally invasive treatment of osteoarthritis and meniscal injury.
Author: Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D.
Source: Regenerative Sciences Inc (RSI), Centeno-Schultz Clinic, Westminster, CO 80020, USA.
Publication: Pain Physician. 2008 May-Jun;11(3):343-53
Abstract
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.
Author: Caplan AI.
Source: Skeletal Research Center, Department of Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
Publication: Tissue Eng. 2005 Jul-Aug;11(7-8):1198-211.
Mesenchymal Stem Cells: Cell-Based Reconstructive Therapy
in Orthopedics

12. 12
Administration of Autologous Bone Marrow-Derived
Mononuclear Cells in Children With Incurable Neurological
Disorders and Injury Is Safe and Improves Their Quality of Life
Abstract
Neurological disorders such as muscular dystrophy, cerebral palsy, and injury to the brain and spine currently
have no known definitive treatments or cures. A study was carried out on 71 children suffering from such
incurable neurological disorders and injury. They were intrathecally and intramuscularly administered
autologous bone marrow-derived mononuclear cells. Assessment after transplantation showed neurological
improvements in muscle power and a shift on assessment scales such as FIM and Brooke and Vignos scale.
Further, imaging and electrophysiological studies also showed significant changes in selective cases. On an
average follow-up of 15 ± 1 months, overall 97% muscular dystrophy cases showed subjective and functional
improvement, with 2 of them also showing changes on MRI and 3 on EMG. One hundred percent of the spinal
cord injury cases showed improvement with respect to muscle strength, urine control, spasticity, etc. Eighty-
five percent of cases of cerebral palsy cases showed improvements, out of which 75% reported improvement
in muscle tone and 50% in speech among other symptoms. Eighty-eight percent of cases of other incurable
neurological disorders such as autism, Retts Syndrome, giant axonal neuropathy, etc., also showed
improvement. No significant adverse events were noted. The results show that this treatment is safe,
efficacious, and also improves the quality of life of children with incurable neurological disorders and injury.
Author: Sharma A, Gokulchandran N, Chopra G, Kulkarni P, Lohia M, Badhe P, Jacob VC.
Source: Department of Medical Services and Clinical Research, NeuroGen Brain and Spine Institute, Surana Sethia Hospital
and Research Centre, Mumbai, India.
Publication: Cell Transplant. 2012;21 Suppl 1:S79-90. doi: 10.3727/096368912X633798
Abstract
Mesenchymal stem cells/marrow stromal cells (MSCs) present a promising tool for cell therapy, and are
currently being tested in US FDA-approved clinical trials for myocardial infarction, stroke, meniscus injury,
limb ischemia, graft-versus-host disease and autoimmune disorders. They have been extensively tested and
proven effective in preclinical studies for these and many other disorders. There is currently a great deal of
interest in the use of MSCs to treat neurodegenerative diseases, in particular for those that are fatal and
difficult to treat, such as Huntington's disease and amyotrophic lateral sclerosis. Proposed regenerative
approaches to neurological diseases using MSCs include cell therapies in which cells are delivered via
intracerebral or intrathecal injection. Upon transplantation into the brain, MSCs promote endogenous
neuronal growth, decrease apoptosis, reduce levels of free radicals, encourage synaptic connection from
damaged neurons and regulate inflammation, primarily through paracrine actions. MSCs transplanted into the
brain have been demonstrated to promote functional recovery by producing trophic factors that induce
survival and regeneration of host neurons. Therapies will capitalize on the innate trophic support from MSCs
or on augmented growth factor support, such as delivering brain-derived neurotrophic factor or glial-derived
neurotrophic factor into the brain to support injured neurons, using genetically engineered MSCs as the
delivery vehicles. Clinical trials for MSC injection into the CNS to treat traumatic brain injury and stroke are
currently ongoing. The current data in support of applying MSC-based cellular therapies to the treatment of
neurodegenerative disorders are discussed.
Author: Nanette Joyce1, Geralyn Annett1, Louisa Wirthlin1, Scott Olson1, Gerhard Bauer1, and Jan A Nolta†,1
Source: 1Department of Internal Medicine, Division of Hematology/Oncology, Stem Cell Program, University of California,
Davis, CA, USA
Publication: Regen Med. 2010 November ; 5(6): 933–946. doi:10.2217/rme.10.72.
Mesenchymal stem cells for the treatment of
neurodegenerative disease
Nervous System - Cerebral Palsy

13. 13
Therapeutic Potential of Umbilical Cord Mesenchymal Stromal
Cells Transplantation for Cerebral Palsy: A Case Report
Abstract
Cerebral palsy is the most common motor disability in childhood. In current paper, we first report our clinical
data regarding administration of umbilical cord mesenchymal stem cells (MSCs) transplantation in treatment
of cerebral palsy. A 5-year-old girl with cerebral palsy was treated with multiple times of intravenous and
intrathecal administration of MSCs derived from her young sister and was followed up for
28months.Thegrossmotor dysfunction was improved.Other benefits included enhanced immunity, increased
physical strength, and adjusted speech and comprehension. Temporary low-grade fever was the only side
effect during the treatment. MSCs may be a safe and effective therapy to improve symptoms in children with
cerebral palsy.
Author: Wang L, Ji H, Zhou J, Xie J, Zhong Z, Li M, Bai W, Li N, Zhang Z, Wang X, Zhu D, Liu Y, Wu M.
Source: Cell Therapy Center, 323 Hospital of People's Liberation Army, Xi'an 710054, China.
Publication: Case Rep Transplant. 2013;2013:146347. doi: 10.1155/2013/146347. Epub 2013 Mar 3.
Abstract
Background:
Methods:
Results:
Conclusion:
Stem cell therapy is a promising treatment for cerebral palsy, which refers to a category of brain
diseases that are associated with chronic motor disability in children. Autologous MSCs may be a better cell
source and have been studied for the treatment of cerebral palsy because of their functions in tissue repair and
the regulation of immunological processes.
To assess neural stem cell–like (NSC-like) cells derived from autologous marrow mesenchymal
stem cells as a novel treatment for patients with moderate-to-severe cerebral palsy, a total of 60 cerebral palsy
patients were enrolled in this open-label, non-randomised, observer-blinded controlled clinical study with a 6-
months follow-up. For the transplantation group, a total of 30 cerebral palsy patients received an autologous
NSC-like cells transplantation (1-2 × 107 cells into the subarachnoid cavity) and rehabilitation treatments
whereas 30 patients in the control group only received rehabilitation treatment.
We recorded the gross motor function measurement scores, language quotients, and adverse
events up to 6 months post-treatment. The gross motor function measurement scores in the transplantation
group were significantly higher at month 3 (the score increase was 42.6, 95% CI: 9.8–75.3, P=.011) and month
6 (the score increase was 58.6, 95% CI: 25.8–91.4, P=.001) post-treatment compared with the baseline
scores. The increase in the Gross Motor Function Measurement scores in the control group was not
significant. The increases in the language quotients at months 1, 3, and 6 post-treatment were not statistically
significant when compared with the baseline quotients in both groups.All the 60 patients survived, and none of
the patients experienced serious adverse events or complications.
Our results indicated that NSC-like cells are safe and effective for the treatment of motor deficits
related to cerebral palsy. Further randomised clinical trials are necessary to establish the efficacy of this
procedure.
Author: Chen G, Wang Y, Xu Z, Fang F, Xu R, Wang Y, Hu X, Fan L, Liu H.
Source: Division of Pediatrics, Zhejiang General Hospital of Armed Police Forces, 16 South Lake Road, Jiaxing City 314000,
China.
Publication: J Transl Med. 2013 Jan 26;11:21. doi: 10.1186/1479-5876-11-21.
Neural stem cell-like cells derived from autologous bone mesenchymal
stem cells for the treatment of patients with cerebral palsy

14. 14
Abstract
Coronary heart disease and chronic heart failure are common and have an increasing frequency. Although
interventional and conventional drug therapy may delay ventricular remodelling, there is no basic therapeutic
regime available for preventing or even reversing this process. Chronic coronary artery disease and heart
failure impairs quality of life and are associated with subsequent worsening of the cardiac pump function.
Numerous studies within the past few years have been demonstrated, that the intracoronary stem cell therapy
has to be considered as a safe therapeutic procedure in heart disease, when destroyed and/or compromised
heart muscle must be regenerated. This kind of cell therapy with autologous bone marrow cells is completely
justified ethically, except for the small numbers of patients with direct or indirect bone marrow disease (e.g.
myeloma, leukaemic infiltration) in whom there would be lesions of mononuclear cells. Several preclinical as
well as clinical trials have shown that transplantation of autologous bone marrow cells or precursor cells
improved cardiac function after myocardial infarction and in chronic coronary heart disease. The age of
infarction seems to be irrelevant to regenerative potency of stem cells, since stem cells therapy in old
infarctions (many years old) is almost equally effective in comparison to previous infarcts. Further indications
are non-ischemic cardiomyopathy (dilative cardiomyopathy) and heart failure due to hypertensive heart
disease.
Author: B. E. Strauer, M. Brehm and C. M. Schannwell
Source: Department of Cardiology, Pneumology and Vascular Medicine, Heinrich-Heine-University Düsseldorf, Düsseldorf,
Germany
Publication: Cell Prolif. 2008, 41 (Suppl. 1), 126–145
The therapeutic potential of stem cells in heart disease
Cardivascular System
Abstract
Coronary heart disease and chronic heart failure are common and have an increasing frequency. Although
interventional and conventional drug therapy may delay ventricular remodelling, there is no basic therapeutic
regime available for preventing or even reversing this process. Chronic coronary artery disease and heart
failure impairs quality of life and are associated with subsequent worsening of the cardiac pump function.
Numerous studies within the past few years have been demonstrated, that the intracoronary stem cell therapy
has to be considered as a safe therapeutic procedure in heart disease, when destroyed and/or compromised
heart muscle must be regenerated. This kind of cell therapy with autologous bone marrow cells is completely
justified ethically, except for the small numbers of patients with direct or indirect bone marrow disease (e.g.
myeloma, leukaemic infiltration) in whom there would be lesions of mononuclear cells. Several preclinical as
well as clinical trials have shown that transplantation of autologous bone marrow cells or precursor cells
improved cardiac function after myocardial infarction and in chronic coronary heart disease. The age of
infarction seems to be irrelevant to regenerative potency of stem cells, since stem cells therapy in old
infarctions (many years old) is almost equally effective in comparison to previous infarcts. Further indications
are non-ischemic cardiomyopathy (dilative cardiomyopathy) and heart failure due to hypertensive heart
disease.
Author:
CW, Süselbeck T, Werner N, Haase J, Neuzner J, Germing A, Mark B, Assmus B, Tonn T, Dimmeler S, Zeiher AM; REPAIR-AMI
Investigators.
Source: J. W. Goethe Universität Frankfurt, Med. Klinik III, Abt. Kardiologie, Theodor-Stern-Kai 7, 60590 Frankfurt a. M.,
Germany.
Publication: Eur Heart J. 2006 Dec;27(23):2775-83. Epub 2006 Nov 10
Schächinger V, Erbs S, Elsässer A, Haberbosch W, Hambrecht R, Hölschermann H, Yu J, Corti R, Mathey DG, Hamm
Improved clinical outcome after intracoronary administration of bone-
marrow-derived progenitor cells in acute myocardial infarction: final
1-year results of the REPAIR-AMI trial

15. 15
Abstract
Over the past decade, use of autologous bone marrow-derived mononuclear cells (BMCs) has proven to be
safe in phase-I/II studies in patients with myocardial infarction (MI). Taken as a whole, results support a
modest yet significant improvement in cardiac function in cell-treated patients. Skeletal myoblasts, adipose-
derived stem cells, and bone marrow-derived mesenchymal stem cells (MSCs) have also been tested in
clinical studies. MSCs expand rapidly in vitro and have a potential for multilineage differentiation. However,
their regenerative capacity decreases with aging, limiting efficacy in old patients. Allogeneic MSCs offer
several advantages over autologous BMCs; however, immune rejection of allogeneic cells remains a key
issue. As human MSCs do not express the human leukocyte antigen (HLA) class II under normal conditions,
and because they modulate T-cell-mediated responses, it has been proposed that allogeneic MSCs may
escape immunosurveillance. However, recent data suggest that allogeneic MSCs may switch immune states
in vivo to express HLA class II, present alloantigen and induce immune rejection. Allogeneic MSCs, unlike
syngeneic ones, were eliminated from rat hearts by 5 weeks, with a loss of functional benefit.Allogeneic MSCs
have also been tested in initial clinical studies in cardiology patients. Intravenous allogeneic MSC infusion has
proven to be safe in a phase-I trial in patients with acute MI. Endoventricular allogeneic MSC injection has
been associated with reduced adverse cardiac events in a phase-II trial in patients with chronic heart failure.
The long-term safety and efficacy of allogeneic MSCs for cardiac repair remain to be established. Ongoing
phase-II trials are addressing these issues.
Author:
Source: Fondazione Cardiocentro Ticino, Lugano, Switzerland.
Publication: Swiss Med Wkly. 2011 May 23;141:w13209. doi: 10.4414/smw.2011.13209.
Vassalli G, Moccetti T.
Cardiac repair with allogeneic mesenchymal stem
cells after myocardial infarction
Human bone marrow-derived adult stem cells for post-myocardial
infarction cardiac repair: current status and future directions
Abstract
Stem cell-based cell therapy has emerged as a potentially therapeutic option for patients with acute
myocardial infarction (AMI) and heart failure. With the completion of a number of trials using bone marrow
(BM) -derived adult stem cells, critical examination of the overall clinical benefits, limitations and potential side
effects of this revolutionary treatment will pave the way for future clinical research. At present, clinical trials
have been conducted almost exclusively using BM stem cells. The primary endpoints of these trials are mainly
safety and feasibility, with secondary endpoints in the efficacy of post-myocardial infarction (MI) cardiac repair.
Intervention with BM-derived cells was mainly carried out by endogenously-mobilised BM cells with
granulocyte-colony stimulating factor, and more frequently, by intracoronary infusion or direct intramyocardial
injection of autologous BM cells. While these studies have been proven safe and feasible without notable side
effects, mixed outcomes in terms of clinical benefits have been reported. The major clinical benefits observed
are improved cardiac contractile function and suppressed left ventricular negative remodelling, including
reduced infarct size and improved cardiac perfusion of infarct zone. Moderate and transient clinical benefits
have been mostly observed in studies with intracoronary infusion or direct intramyocardial injection of BM
cells. These effects are widely considered to be indirect effects of implanted cells in association with paracrine
factors, cell fusion, passive ventricular remodelling, or the responses of endogenous cardiac stem cells. In
contrast, evidence of cardiac regeneration characterised by differentiation of implanted stem cells into
cardiomyocytes and other cardiac cell lineages, is weak or lacking. To elucidate a clear risk-benefit of this
exciting therapy, future studies on the mechanisms of cardiac cell therapy will need to focus on confirming the
ideal cell types in relation to dosage and timing for post- MI cardiac repair, developing more effective cell
delivery techniques, and devising innovative cell tracking modalities that could unveil the fates of implanted
cells such as survival, engraftment and functionality.
Author:
Source: Research and Development Unit, National Heart Centre, 9 Hospital Drive, Blk C, #03-2, Singapore.
Publication: Singapore Med J. 2009 Oct;50(10):935-42.
Wei HM, Wong P, Hsu LF, Shim W.

16. 16
Abstract
Stem cell therapy is one of the most promising treatments for the near future. It is expected that this kind of
therapy can ameliorate or even reverse some diseases. With regard to type 1 diabetes, studies analyzing the
therapeutic effects of stem cells in humans began in 2003 in the Hospital das Clínicas of the Faculty of
Medicine of Ribeirão Preto - SP USP, Brazil, and since then other centers in different countries started to
randomize patients in their clinical trials. Herein we summarize recent data about beta cell regeneration,
different ways of immune intervention and what is being employed in type 1 diabetic patients with regard to
stem cell repertoire to promote regeneration and/or preservation of beta cell mass. The Diabetes Control and
Complications Trial (DCCT) was a 7-year longitudinal study that demonstrated the importance of the intensive
insulin therapy when compared to conventional treatment in the development of chronic complications in
patients with type 1 diabetes mellitus (T1DM). This study also demonstrated another important issue: there is
a reverse relationship between C-peptide levels (endogenous indicator of insulin secretion) chronic
complications - that is, the higher the C-peptide levels, the lower the incidence of nephropathy, retinopathy and
hypoglycemia. From such data, beta cell preservation has become an additional target in the management of
T1DM [1].
Author: Couri CE, Voltarelli JC.
Source: Department of Internal Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP,
Publication: Diabetol Metab Syndr. 2009 Oct 16;1(1):19. doi: 10.1186/1758-5996-1-19.
Stem cell therapy for type 1 diabetes mellitus: a review of
recent clinical trials
Endocrinology and Metabolism -
Diabetes
Abstract
Mesenchymal stem cells (MSCs) can be derived from adult bone marrow, fat and several foetal tissues. In
vitro, MSCs have the capacity to differentiate into multiple mesodermal and non-mesodermal cell lineages.
Besides, MSCs possess immunosuppressive effects by modulating the immune function of the major cell
populations involved in alloantigen recognition and elimination. The intriguing biology of MSCs makes them
strong candidates for cell-based therapy against various human diseases. Type 1 diabetes is caused by a
cellmediated autoimmune destruction of pancreatic -cells. While insulin replacement remains the cornerstone
treatment for type 1 diabetes, the transplantation of pancreatic islets of Langerhans provides a cure for this
disorder.And yet, islet transplantation is limited by the lack of donor pancreas. Generation of insulin-producing
cells (IPCs) from MSCs represents an attractive alternative. On the one hand, MSCs from pancreas, bone
marrow, adipose tissue, umbilical cord blood and cord tissue have the potential to differentiate into IPCs by
genetic modification and/or defined culture conditions in vitro. On the other hand, MSCs are able to serve as a
cellular vehicle for the expression of human insulin gene. Moreover, protein transduction technology could
offer a novel approach for generating IPCs from stem cells including MSCs. In this review, we first summarize
the current knowledge on the biological characterization of MSCs. Next, we consider MSCs as surrogate -cell
source for islet transplantation, and present some basic requirements for these replacement cells. Finally,
MSCs-mediated therapeutic neovascularization in type 1 diabetes is discussed.
Author:
Source: State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences &
Peking Union Medical College, Tianjin, PR China.
Publication: J Cell Mol Med. 2008 Aug;12(4):1155-68. doi: 10.1111/j.1582-4934.2008.00288.x. Epub 2008 Feb 24.
Liu M, Han ZC.
Mesenchymal stem cells:
biology and clinical potential in type 1 diabetes therapy

17. 17
Pancreatic Stem/Progenitor Cells for the Treatment of Diabetes
Abstract
Patients with type 1 diabetes, and most patients with type 2 diabetes, have associated hyperglycemia due to
the absence or reduction of insulin production by pancreatic β-cells. Surgical resection of the pancreas may
also cause insulindependent diabetes depending on the size of the remaining pancreas. Insulin therapy has
greatly improved the quality of life of diabetic patients, but this method is inaccurate and requires lifelong
treatment that only mitigates the symptoms.The successes achieved over the last few decades by the
transplantation of whole pancreas and isolated islets suggest that diabetes can be cured by the replenishment
of deficient β-cells. These observations are proof-of-principle and have intensified interest in treating diabetes
by cell transplantation, and by the use of stem cells. Pancreatic stem/progenitor cells could be one of the
sources for the treatment of diabetes. Islet neogenesis, the budding of new islets from pancreatic
stem/progenitor cells located in or near pancreatic ducts, has long been assumed to be an active process in
the postnatal pancreas. Several in vitro studies have shown that insulin-producing cells can be generated from
adult pancreatic ductal tissues. Acinar cells may also be a potential source for differentiation into insulin-
producing cells. This review describes recent progress on pancreatic stem/progenitor cell research for the
treatment of diabetes.
Author: Noguchi H.
Source: Regenerative Research IsletTransplant Program, Baylor Research Institute, 1400 8thAvenue, Fort Worth,TX 76104,
Publication: Rev Diabet Stud. 2010 Summer;7(2):105-11. doi: 10.1900/RDS.2010.7.105. Epub 2010Aug 10

18. 18
Bioengineered Dental Tissues Grown in the Rat Jaw
Abstract
Our long-term objective is to develop methods to form, in the jaw, bioengineered replacement teeth that exhibit
physical properties and functions similar to those of natural teeth. Our results show that cultured rat tooth bud cells,
seeded onto biodegradable scaffolds, implanted into the jaws of adult rat hosts and grown for 12 weeks, formed small,
organized, bioengineered tooth crowns, containing dentin, enamel, pulp, and periodontal ligament tissues, similar to
identical cell-seeded scaffolds implanted and grown in the omentum. Radiographic, histological, and immunohisto -
chemical analyses showed that bioengineered teeth consisted of organized dentin, enamel, and pulp tissues. This
study advances practical applications for dental tissue engineering by demonstrating that bioengineered tooth tissues
can be regenerated at the site of previously lost teeth, and supports the use of tissue engineering strategies in humans,
to regenerate previously lost and/or missing teeth. The results presented in this report support the feasibility of
bioengineered replacement tooth formation in the jaw.
Author:
Source: University Federal of São Paulo, Department of Plastic Surgery, São Paulo, Brazil.
Publication: J Dent Res. 2008 Aug;87(8):745-50.
Duailibi SE, Duailibi MT, Zhang W, Asrican R, Vacanti JP, Yelick PC.
Abstract
Background:
Objective:
Methods:
Results:
Conclusion:
With today’s 21st century technological advancements, it is expected that individuals will either retain
their natural teeth or obtain functional tooth replacements throughout their entire life. Modern dental therapies for the
replacement of missing teeth largely utilize partial or complete dentures and titanium implants capped with prosthetic
crowns. Although these prostheses serve a purpose, they are not equivalent, neither in function nor aesthetics, to
natural teeth. Recent progress in dental tissue engineering has lent significant credibility to the concept that biological
replacement teeth therapies may soon be available to replace missing teeth.
In this review, we summarize the emerging concepts of whole-tooth replacement strategies, using
postnatal dental stem cells (DSCs) and dental tissue engineering approaches.
We provide a thorough and extensive review of the literature.
Current approaches to achieve clinically relevant biological replacement tooth therapies rely on the
cultivation of DSCs capable of relaying odontogenic induction signals, through dental epithelial-mesenchymal cell
interactions. DSC expansion and differentiation can be achieved by programming progenitor stem cells to adopt
dental lineages, using instructive, bioengineered scaffold materials. Periodontal ligament regeneration in particular
has demonstrated significant progress recently, despite the somewhat unpredictable clinical outcomes, with regard to
its capacity to augment conventional metallic dental implants and as an important component for whole-tooth tissue
engineering. Following recent advances made in DSC and tissue engineering research, various research groups are
in the midst of performing ‘proof of principle’ experiments for whole-tooth regeneration, with associated functional
periodontal tissues. This mini-review focuses on recent and promising developments in the fields of pulp and
periodontal tissue DSCs that are of particular relevance for dental tissue and whole-tooth regeneration.
Continued advances in the derivation of useable DSC populations and optimally designed scaffold
materials unequivocally support the feasibility of dental tissue and whole-tooth tissue engineering.
Author:
Source: Department of Oral and Maxillofacial Pathology, Division of Craniofacial and Molecular Genetics, Tufts University, Boston,
Mass., USA.
Publication: Gerontology. 2011;57(1):85-94. doi: 10.1159/000314530. Epub 2010 May 6.
Yen AH, Yelick PC.
Dental Tissue Regeneration – A Mini-Review
Dental Tissue - Tooth Bioengineering

19. 19
Adult Human Gingival Epithelial Cells as a Source for Whole-
tooth Bioengineering
Abstract
Teeth develop from interactions between embryonic oral epithelium and neural-crest-derived mesenchyme.
These cells can be separated into singlecell populations and recombined to form normal teeth, providing a
basis for bioengineering new teeth if suitable, non-embryonic cell sources can be identified. We show here
that cells can be isolated from adult human gingival tissue that can be expanded in vitro and, when combined
with mouse embryonic tooth mesenchyme cells, form teeth. Teeth with developing roots can be produced from
this cell combination following transplantation into renal capsules. These bioengineered teeth contain dentin
and enamel with ameloblast-like cells and rests of Malassez of human origin.
Abstract
Proper rehabilitation of craniofacial defects is challenging because of the complexity of the anatomy and the
component tissue types. The ability to simultaneously coordinate the regeneration of multiple tissues would
make reconstruction more efficient and might reduce morbidity and improve outcomes. The craniofacial
complex is unique because of the presence of teeth, in addition to skin, bone, cartilage, muscle, vascular, and
neural tissues since teeth naturally grow in coordination with the craniofacial skeleton, our group developed an
autologous, tooth–bone hybrid model to facilitate repair of mandibular defects in the Yucatan minipig. The
hybrid tooth–bone construct was prepared by combining tooth bud cell-seeded scaffolds with autologous iliac
crest bone marrow derived stem cell-seeded scaffolds, which were transplanted back into surgically created
mandibular defects in the same minipig. The constructs were harvested after 12 and 20 weeks of growth. The
resulting bone/tooth constructs were evaluated by X-ray, ultra high-resolution volume computed tomography
(VCT), histological, immunohistochemical analyses, and transmission electron microscopy (TEM). The
observed formation of small tooth-like structures consisting of organized dentin, enamel, pulp, cementum,
periodontal ligament, and surrounded by regenerated alveolar bone, suggests the feasibility for regeneration
of teeth and associated alveolar bone, in a single procedure. This model provides an accessible method for
future clinical applications in humans.
Author:
Source: Division of Craniofacial and Molecular Genetics, Department of Oral and Maxillofacial Pathology, Tufts University,
136 Harrison Avenue, Room M824, Boston, MA 02111, USA.
Publication: Methods. 2009 Feb;47(2):122-8. doi: 10.1016/j.ymeth.2008.09.004. Epub 2008 Oct 7.
Zhang W, Abukawa H, Troulis MJ, Kaban LB, Vacanti JP, Yelick PC.
Tissue engineered hybrid tooth–bone constructs
Author: Angelova Volponi A, Kawasaki M, Sharpe PT.
Source: Department of Craniofacial Development and Stem Cell Biology, Dental Institute, King's College London, Tower Wing
Guy's Hospital, London Bridge, London SE1 9RT, UK.
Publication: J Dent Res. 2013Apr;92(4):329-34. doi: 10.1177/0022034513481041. Epub 2013 Mar 4.

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