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Osiris Therapeutics, Inc. Message Board

ativaloc 32 posts  |  Last Activity: May 12, 2015 4:58 PM Member since: Oct 12, 2006
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  • Reply to

    A news article just out January 2, 2015

    by ozark580 Jan 3, 2015 11:00 PM
    ativaloc ativaloc May 12, 2015 4:58 PM Flag

    Could this be the week we look back on and see the spark that set this rocket in motion?

    The longer it lingers below $18.50 the bigger the catapult to higher levels will be. Suppressing the price at these levels will turn in a large $$$$$$$ loss for many individuals an firms alike.

    There is nothing else to know, great management, great product, great gross margins.........$100.00 will be here sooner than you can say OSIRIS.

    We all have done it, when we convince ourselves that it can't go any lower ant it does then we sell, only to look back and notice we sold at the bottom.

    The difficulty comes in is when you short, the bottom is endless and the losses can be the fuse lit and rushing towards the sticks of dynamite? Or am I too quick to come to this conclusion because I'm a biased share owner.

    This August OSIRIS will celebrate eight years as a public company and has never traded above $30.00....................things are about to change for the better, get your shares while you still can and afford them. Things will never be the same.

    Sentiment: Strong Buy

  • Reply to

    A news article just out January 2, 2015

    by ozark580 Jan 3, 2015 11:00 PM
    ativaloc ativaloc May 12, 2015 10:43 AM Flag

    Close above $18.50 for three consecutive days takes us to all time highs above $30 in short order.

    Sentiment: Strong Buy

  • Reply to

    120 mil run rate

    by yappy_mutt May 11, 2015 12:26 AM
    ativaloc ativaloc May 11, 2015 12:51 AM Flag

    New job openings..............

    Job ID
    Job Title
    2015-1128 Reimbursement IT Administrator US-MD-Columbia
    2015-1127 Reimbursement Lead Associate (RLA) US-MD-Columbia

    Sentiment: Strong Buy

  • ativaloc ativaloc May 5, 2015 12:47 PM Flag

    Google this


    Sentiment: Strong Buy

  • ativaloc ativaloc May 5, 2015 12:42 PM Flag

    Materials in this supplement were reviewed and
    approved by the SAWC committee for the CME lecture.
    This supplement was not subject to WOUNDS® peer-review process.
    Supported by Osiris Therapeutics, Inc.
    Supplement to WOUNDS®
    Osiris_cover.indd 1 7/16/14 3:35 PM
    2 August 2014
    Lawrence Lavery, DPM, MPH and Dot Weir, RN, CWON, CWS
    The continued development of advanced wound therapies is quickly changing the field of wound care. With improvements
    in treatment, clinicians are able to help patients heal quicker and more easily, especially when utilizing
    cellular and acellular treatment modalities.
    We presented Advances in Wound Therapy: Understanding Differences between Cellular and Acellular Therapies in
    the Treatment of Chronic Wounds in an accredited continuing medical education presentation at the SAWC Spring/
    WHS 2014 meeting at the Gaylord Palms Hotel and Convention Center in Orlando, Florida. The following non-CME
    supplement has been adapted from that presentation.
    As we continue to emphasize multidisciplinary disease management in the treatment of high-risk patients with
    chronic wounds, facilitating an optimal wound healing environment and improving the time to healing are critical.
    Accordingly, our discussion in this supplement begins with a conceptual framework and the current tools available
    for treating chronic wounds in our field. We differentiate between cellular and acellular modalities, noting the benefits
    and risks of each based on current research.
    We then launch into a discussion about stem cells and how they are significantly altered in patients with diabetes.
    Advanced therapies can help address these issues by preserving stem cells and maintaining their functionality.
    We reviewed the landscape of various advanced wound care treatments, assessing the clinical and scientific data,
    and levels of evidence for each. We also explored various case-based scenarios involving some of these advanced
    modalities in the treatment of chronic wounds.
    We would like to thank Osiris Therapeutics for their support of this supplement. We hope that the insights generated
    through this discussion will help those of us who treat chronic wounds to achieve improved outcomes for our
    — Lawrence Lavery, DPM, MPH, and Dot Weir, RN, CWON, CWS
    The thoughts and opinions expressed in this supplement are those of the authors and not necessarily those of Osiris Therapeutics. 3
    Dr. Lavery is a consultant for Innovative Therapies, Inc. (ITI), KCI Medical, and PamLab. He is on the speaker’s
    bureau for Innovative Therapies, Inc. (ITI), KCI Medical, PamLab, and Shire Regenerative Medicine. Dr. Lavery has
    received grant/research support from GlaxoSmithKline, Integra Lifesciences, KCI Medical, MacroCure, Osiris Therapeutics,
    Smith & Nephew, and ThermoTek. He has received royalties or holds patents with Diabetica Solutions. Dr.
    Lavery is a stock shareholder with Diabetica Solutions and Prizm Medical Resources.
    Ms. Weir is on the advisory board or is a consultant for Mölnlycke Health Care, Spiracur, Smith & Nephew, Hollister,
    Organogenesis, and Central Medical Systems. She is on the speaker’s bureau for Osiris Therapeutics, Spiracur,
    Smith & Nephew, Hollister, Organogenesis, Mölnlycke Health Care, and BSN Medical.
    Lawrence Lavery, DPM, MPH, is a
    Professor in the Department of Plastic
    Surgery, as well as Director of Clinical
    Research in the Department of Plastic
    Surgery, at the University of Texas Southwestern
    Medical Center, Dallas, TX. His
    research group has published 208 peer-reviewed papers
    and has received extramural funding from the VA, NIH,
    AHRQ, American Diabetes Association, and two American
    College of Foot and Ankle Surgeons.
    He is the past chair of the American Diabetes Association
    Foot Care Council and the American Public
    Health Association Foot Section. He serves on the editorial
    board for Diabetes Care and has authored more
    than 100 peer-reviewed papers and several books. His
    areas of research interest include amputation prevention
    in high-risk diabetics, epidemiology of diabetic-related
    amputations, the use of footwear and insoles to prevent
    re-ulceration in high-risk diabetics, and fracture complications
    in diabetes.
    Dot Weir, CWON, CWS, has been a registered
    nurse for 38 years, with 34 of
    those in wound and ostomy care. She has
    practiced in all areas of healthcare as well
    as industry. She is board certified by the
    Wound, Ostomy and Continence Nurses
    Certification Board (CWON) and the American Board of
    Wound Management (CWS). She practices part-time at
    the Wound Healing Center of Osceola Regional Medical
    Center in Kissimmee, Florida as well as the Wound Care
    and Hyperbaric Medicine Center at Health Central Hospital
    in Ocoee, Florida. Ms. Weir is the Co-Chair of the Symposium
    on Advanced Wound Care (SAWC), was on the
    founding board of the Association for the Advancement of
    Wound Care (AAWC), and has held positions as treasurer
    and president. She has been a member of the WOCN
    since 1980, the FAET since 1979, and a member of the
    WHS since 2008. Ms. Weir has authored and co-authored
    many journal articles and 6 book chapters. She is on the
    faculty of the Wound Certification Prep Course, Founding
    Editor of Today’s Wound Clinic, and Co-Chair of Present
    Wounds for Nurses and Therapists, an e-learning site.
    4 August 2014
    n the diverse field of wound
    care, clinicians must be prepared
    with the necessary
    education and tools to heal
    patients. Even then, new challenges
    will be presented and
    innovative solutions found.
    Over the last few decades,
    wound care has become more
    advanced. With continually developing
    technology, the success
    rate of healing the most
    difficult wounds will greatly
    improve. In order to be successful
    in this role, clinicians
    must begin with the knowledge
    of how far wound care
    has come and how to create a
    conceptual framework.
    We have gone from simple
    disease awareness to a true focus
    on disease management as it
    relates to helping patients heal.
    We focus more on the wound
    environment and wound healing.
    Now we are really thinking
    about how we can prepare
    the wound and how it can actually
    impact cellular activity
    and wound healing. We are also
    focusing on time to healing,
    which is not only important
    from a morbidity and mortality
    standpoint, but also from a cost
    perspective. Wound healing is
    ultimately a multidisciplinary
    effort involving physicians, podiatrists,
    nurses, physical therapists,
    PAs, and other vital staff
    When we look at some of
    the products that we have to
    advance wound healing, they
    can be classified as either being
    cellular (containing living
    cells) or acellular (cells
    have been devitalized with or
    without removal from matrices).
    The sources of those can
    be biologic, coming from animals
    (equine, bovine, porcine,
    ovine, sharks, etc.), from human
    sources (cadaveric skin,
    placental tissues, neonatal foreskins),
    or from plants. Cellular
    products may also be made by
    combining cells with synthetic
    scaffolds, things that are not
    naturally present in our tissues
    but are able to coexist with our
    tissues, or they may be a composite
    of cells with both biologic
    and synthetic materials.
    The goal of most cellular skin
    substitutes is to restore some
    sort of skin barrier and to promote
    wound closure. We want
    the cells to be able to secrete
    things like collagen and other
    extracellular matrix proteins.
    Cellular skin substitutes have
    the ability to interact and respond
    with their environment,
    and then synthesize the growth
    factors and extracellular matrix
    proteins that are needed based
    on the needs of that wound.
    The cellular modalities are
    able to provide temporary
    wound coverage. They also help
    protect against losing moisture
    and provide some bacterial protection
    at least early on after application.
    These cellular products
    are not skin grafts. There
    is no vascularization and no ingrowth
    of vessels into the grafts.
    They do not integrate into the
    tissues and there is not necessarily
    any permanent persistence.
    Interestingly, a recent study
    by Hu et al looked at bilayer
    cell therapies that were placed
    on partial-thickness skin graft 5
    donor sites.1
    At the end of 10
    weeks, they did biopsies to
    look for the DNA persistence
    of the cellular product that had
    been placed on the donor sites
    and only 2 out of the 10 did
    have some residual persistence.
    Another recent case by Serena
    et al was serendipitous.2
    put a bilayered skin substitute
    on a large wound. Ten months
    later, the patient returned with
    a wound in the previously treated
    area. A biopsy of the wound
    for human leukocyte antigen
    revealed the presence of donor
    DNA from the bilayered living
    cell therapy, suggesting that
    bilayered living cell therapy in
    some cases may persist for longer
    periods in patients without
    underlying skin disease or immunosuppression.

    One of the advantages of cellular
    therapies is that they do
    have active living cells in the
    construct. These cells, such as
    keratinocytes and fibroblasts,
    do have the ability to produce
    and synthesize various types
    of mediators such as cytokines
    and growth factors. In a product
    with a combination of two
    different cell types, a certain set
    of growth factors may come
    from the keratinocytes, which
    would then stimulate the fibroblast
    and synthesize other kinds
    of growth factors or cytokines
    in that particular wound.
    Acellular matrices are usually
    human- and animal-derived
    products. They have been processed
    to devitalize cells, which
    can then be removed from
    matrices or left in them, leaving
    behind the collagen matrix
    and destroying any kind
    of pathogens by sterilization
    of the product as well as taking
    out anything that might
    cause some kind of an immune
    response. These are primarily
    collagen products that can
    be cross-linked. Cross-linking
    will stabilize them, make them
    more durable, inhibit or reduce
    the speed at which they biodegrade,
    and help prolong the
    presence in the wound. Many
    of these matrices can act as a
    biological modulator that helps
    to influence biological processes
    such as healing.
    Acellular matrices interact
    with the wound bed. They provide
    scaffolding and can act as
    a sacrificial substrate to bind
    matrix metalloproteinases. The
    metalloproteinases then break
    down the matrix rather than
    the naturally occurring collagen
    in the wound. They provide
    support, a temporary scaffold
    for cellular migration and
    attachment, and can promote
    granulation tissue formation. At
    some point, they may contain
    certain growth factors that may
    or may not be present when the
    product is put on the wound.
    The optimal response is going
    to be achieved using a matrix
    Figure 1. Placental membranes were first described
    as a treatment for wounds in 1910.
    They contain growth factors, collagen-rich
    extracellular matrix, and viable cells such
    as neonatal fibroblasts, epithelial cells, and
    mesenchymal stem cells.
    6 August 2014
    that is as close as possible to the
    tissue that it is replacing. However,
    most collagen products are
    biologically recognized, which
    means that the source is not
    typically a problem.
    We also have the human placenta,
    the use of which was
    first described in a large series
    of wounds as far back as 1910
    (Figure 1).3
    Fresh placenta is
    a combination of growth factors,
    collagen rich extracellular
    matrix, and viable cells such as
    neonatal fibroblasts, epithelial
    cells, and mesenchymal stem
    cells (Figure 2).
    When we look at the tissue
    composition, we look at the
    actual structure of the placenta
    (Figure 2). There is the amniFigure
    2. This figure shows the actual structure of the placenta’s tissue composition, including the active cells in the epithelial layer, the basement
    membrane, the compact layer, and stromal type cells.
    Trophoblast Layer
    Basement Membrane
    Stromal Layer in Chorion
    Sponge Layer
    Epithelial Cell
    Other ECM
    Stromal Layer in Amnion
    Epithelial Layer
    Basement Membrane
    Compact Layer 7
    on with active cells in the epithelial
    layer, the active basement
    membrane, the compact
    layer, and other cells, including
    stromal type cells.
    In amniotic products alone,
    there are a variety of native
    extracellular matrix proteins,
    structural ones that help to
    provide tissue integrity such
    as the various collagens as well
    as elastin. In human tissue, we
    know this allows for elasticity,
    provides an organization to the
    matrix, a reservoir for growth
    factors, and other types of molecules.
    Proteoglycans help to
    retain moisture, and glycoproteins
    promote cell migration,
    adhesion, and mediate the interactions
    between the cells
    and extracellular matrix.
    Stem cells provide matrix
    proteins, cytokines, and growth
    factors. The promise of stem
    cells is that they will be able to
    regulate things that we don’t
    even know need to be regulated.
    Stem cells should identify
    areas where there is high
    inflammation and down-regulate
    that; stimulate blood vessel
    formation; and recruit and
    support fibroblast and epithelial
    cell functions.
    In patients with diabetes, there
    are a reduced number of stem
    cells and they are less effective
    (Figure 3).4
    These patients
    have lower levels of growth
    factors and decreased numbers
    of functional stem cells. Their
    morphology is altered, growth
    is decreased, differentiation is
    decreased, and there are more
    dysfunctional cells that are senescent
    with increased apoptosis
    (Table 1).5
    As the population
    ages and obesity increases, we
    are going to have older people
    with less functional stem cells
    in their native state. Applying a
    product that will provide stem
    cells could be an advantage for
    these patients.
    The plethora of new products
    and some of the new changes
    in reimbursement have made us
    look to and learn more about
    the pathways for regulatory approval
    for some of these products.
    A lot of these products,
    collectively called human cellular-
    and tissue-based products
    or HCT/Ps, can be obtained
    from human tissue donors, processed
    and used in the exact
    same role in the recipient. It is
    tissue for tissue, skin for skin,
    tendon for tendon, bone for
    bone. The uses are regulated so
    they are intended for homologous
    use. They are expected to
    undergo minimal manipulation
    but they are strictly registered.
    Registration establishes proven
    good tissue practices and other
    procedures to prevent introduction,
    transmission, and spread of
    any kind of communicable disease
    by the modality.6
    When we look at the placental-derived
    acellular products,
    they are conceptually similar
    to the other acellular products.
    Most of them are comprised
    of dehydrated amnion and/or
    chorion membrane, and they reportedly
    retain the biologically
    active growth factors, cytokines,
    and tissue inhibitors of metalloproteinases
    1, 2, and 4.7
    also contain other soluble mediators,
    but not the mesenchymal
    stem cells (MSCs) themselves.
    The soluble mediators may be
    able to recruit host MSCs and
    8 August 2014
    provide biological extracellular
    matrix for cell ingrowth.
    When we look at the cellular
    placental products, they are
    manufactured so they do retain
    the cells. They retain the extracellular
    matrix and the growth
    factors that are naturally
    found. They also contain those
    younger healthier neonatal
    MSCs. They contain epithelial
    cells, fibroblasts, and extracellular
    matrices that provide the
    three-dimensional support that
    allows for and promotes cellular
    adhesion and migration.7
    One method of preserving
    these and having them available
    for our use is through
    cryopreservation. The majority
    of the studies on cryopreservaFigure
    3. Diabetes patients have a reduced number of stem cells and they are less effective.
    Cianfarani F, Toietta G, Di Rocco G, et al. Diabetes impairs adipose issue-derived stem cell function and efficiency in promoting wound
    healing. Wound Repair Regen. 2013;21(4):545-553.
    Stem Cell Number (x105
    ) Growth Factor Secretion
    0 Diabetic VEGF-A HGF IGF-1 Relative Amount 9
    tion pertain to ocular science
    but there is significant impact
    on the structure and function
    of placental tissues. Comparing
    fresh tissue vs. dried vs. cryopreserved,
    there are differences
    when looking at the architecture
    (Table 2 and Figure 4).8-11
    There has been an explosion
    of products in this market, including
    bioengineered tissue,
    skin substitutes, and acellular
    dermal matrix products. However,
    one question remains: are
    cellular therapies better than
    acellular therapies?
    Cellular therapies probably
    require slightly more work
    because they have to be stored
    in a freezer or delivered in a
    specific time period rather than
    being stored on a shelf for a
    longer period of time. Right
    now, there is no direct comparison
    as it is cost-prohibitive.
    Medicare is dividing these
    products into three categories
    for hospital-based clinics:
    high cost, low cost, and passthroughs.
    Depending on your
    CMS carrier, some of the
    products from each category
    will be approved for reimbursement
    (Table 3). When deciding
    which products to use, the evidence
    pyramid, ranging from
    double-blind randomized controlled
    trials to in vitro research,
    should be part of the decision.
    There are currently a large
    number of products available.
    Dermagraft (Organogenesis,
    Inc.) is a cryopreserved human
    fibroblast derived from neonatal
    foreskin. It has three randomized
    clinical studies with
    two of the studies demonstrating
    effectiveness for diabetic
    foot ulcers (DFUs) and one
    study not demonstrating effectiveness
    for venous leg ulcers
    (VLUs).12-14 The pivotal trial
    on the platelet derived growth
    factor data for diabetic foot ulcers
    took place nearly 20 years
    ago.15 Our standard of care and
    what we expect from clinical
    Cramer C, Freisinger E, Jones RK, et al. Persistent high glucose concentrations alter the
    regenerative potential of mesenchymal stem cells. Stem Cells Dev. 2010;19(12):1875-1884.
    10 August 2014
    trials has changed. Regarding
    the clinical results from the
    study by Marston et al, only
    30% of people healed in the
    12-week study with Dermagraft
    and 18% healed in the
    control group.12 These are not
    impressive results. The time to
    healing was not reported, but
    there was significant reduction
    in infection in the people
    who got Dermagraft and they
    healed faster.
    Apligraf (Organogenesis, Inc.)
    is a bilayered, epidermal and
    dermal layer product derived
    from neonatal foreskin. It is not
    cryopreserved. There are several
    high-level randomized clinical
    studies, including DFU studies
    and VLU studies, for this
    product.16-18 In a randomized
    DFU study involving 208 patients,
    56% of people healed in
    the treatment group and 38%
    healed in the control group.16
    There was faster healing time,
    but not a significant difference
    in infections. Only in the subgroup
    with osteomyelitis was
    there a difference in adverse
    events. The VLU data was also
    EpiFix (MiMedx Group, Inc.)
    is an acellular product made from
    placental tissue. It has collagen
    types IV, V, and VII. It is a product
    you can put on the shelf and
    it is not cryopreserved. There is a
    small, single-center, randomized
    clinical study on this product
    with 25 people in the treatment
    groups (13 EpiFix, 12 control).19
    It has the best results that have ever
    been reported in any DFU study
    TABLE 2. Cryopreservation Maintains Structure and Functionality of Placental Tissues
    Structural and Functional Characteristics Fresh Dried Cryopreserved
    Tissue Architecture
    and ECM
    Tissue thickness 85-90 mM 45 mM 90mM
    Tissue degeneration Not observed Vacuolar
    degeneration Not observed
    Basement membrane
    ECMs Intact Degraded Intact
    Growth Factor and
    Cytokine Release After
    120 Hours
    TIMPs, TGFs, CTGF,
    IL-1ra, etc Not reported Not detectable Sustain
    Epithelial Cell
    Number of supported
    cultures Not reported 30% 100%
    Outgrowth area after day
    18 Not reported 10-20 mm2 100 mm2
    Niknejad H, Deihim T, Solati-Hashjin M, Peirovi H. The effects of preservation procedures on amniotic membrane’s ability to serve as a substrate
    for cultivation of endothelial cells. Cryobiology. 2011;63(3):145-151. von Versen-Höynck F, Syring C, Bachmann S, Möller DE. The influence of
    different preservation and sterilisation steps on the histological properties of amnion allografts--light and scanning electron microscopic studies. Cell
    Tissue Bank. 2004;5(1):45-56. Rodríguez-Ares MT, López-Valladares MJ, Touriño R, et al. Effects of lyophilization on human amniotic membrane.
    Acta Ophthalmol. 2009;87(4):396-403. Thomasen H, Pauklin M, Steuhl KP, Meller D. Comparison of cryopreserved and air-dried human amniotic
    membrane for ophthalmologic applications. Graefes Arch Clin Exp Ophthalmol. 2009;247(12):1691-1700. 11
    for the treatment group
    and probably the worst
    for the control group
    but the study is underpowered.
    There was a
    significant reduction in
    the time to healing. No
    infections were reported
    in the treatment group
    whereas 17% of the control
    group had infections.
    Grafix (Osiris Therapeutics,
    Inc.) is a cryopreserved
    product derived
    from placental tissues
    in planned C-sections.
    This product has a single-blind
    clinical study
    that is currently still in
    review and a case series
    that was published last
    December.20 In the phase 4 clinical
    study, 62% of people healed in
    the treatment group, 21% in the
    control group, with significantly
    faster healing and fewer adverse
    events in the treatment group.
    Graftjacket (KCI Medical) is
    an acelluar regenerative tissue
    matrix. Reyzelman et al did a
    randomized, multicenter study
    comparing Graftjacket to moist
    wound healing for diabetic foot
    ulcers.21 It is a little bit unusual
    because there is a big difference
    in randomization in the two
    treatment arms. A noncompliant
    patient was removed from the
    study. According to the results,
    70% healed, but if you put the
    noncompliant patient back in the
    study, 68% healed in the treatment
    group. In the control arm,
    46% healed, which is still significant.
    The P value is .048. There
    was a significant difference in the
    time to healing if you take out
    the noncompliant patients.
    Oasis (Smith & Nephew,
    Inc.) is an acellular product
    and there are several small, randomized
    clinical studies.22-25
    One of the most vital studies
    is a VLU study that shows a
    significant increase in healing
    with people who are treated
    with the Oasis product.22 The
    Figure 4. When comparing cryopreserved tissue to dried tissue, there are definite differences in the architecture
    of the tissues.
    H and E staining
    (1/2 thickness
    of cryo AM)
    Rodríguez-Ares MT, López-Valladares MJ, Touriño R, et al. Effects of lyophilization on human amniotic
    membrane. Acta Ophthalmol. 2009;87(4):396-403.
    Col IV staining in the
    basement membrane
    Col IV
    Col IV
    12 August 2014
    time to healing is not reported.
    There is not a significant
    reduction in infections in this
    group. The DFU studies that
    involved separate comparisons
    of Oasis to Regranex (Smith &
    Nephew, Inc.) and Dermagraft
    found no significant differences
    in the proportion of people
    who healed.23,25
    There are a lot of randomized
    clinical studies for using
    Integra (Integra LifeSciences)
    for burns, but not so much in
    the diabetic foot. There is one
    small descriptive clinical study
    with 11 patients that suggests
    64% wound healing.26 No infections
    were reported but this
    is a very small retrospective
    clinical experience.
    Theraskin (Soluble Systems,
    LLC) is a human skin allograft
    with dermis and epidermis. It
    has some retrospective case series
    data in a large number of
    VLUs and DFUs with a high
    proportion of wounds that
    healed. They don’t report healing
    time or adverse events.27
    Looking at the products that
    have randomized clinical studies
    and those that have high quality
    DFU studies that are powered in
    a reasonable way and report the
    evidence, there are just a few of
    products that are commercially
    available. In the DFU space,
    Dermagraft, Apligraf, Grafix and
    Graftjacket have higher-level,
    randomized clinical studies. In
    the VLU space, Apligraf and Oasis
    have supportive randomized
    controlled trials.
    We have now changed the
    way we do clinical studies after
    looking at these cellular products
    in this space and their healing.
    Offloading is much better
    and more studies are requiring
    debridement on a regular basis
    as opposed to improvised
    debridement by the clinician.
    Perhaps the quality of what we
    do in the control arm is better
    but if you look at the data, these
    studies report 21% healing,
    18%, 38%, and 46% in the control
    arms of these studies (Table
    4).12,16,20,21 The time to closure
    is faster in the three studies that
    report it (Grafix, Apligraf and
    Graftjacket) and there are fewer
    TABLE 3. Medicare Payment Changes: CTPs*
    “High Cost CTPs” “Low Cost CTPs” CTPs with Pass-Through
    Status in 2014
    • Apligraf
    • Dermagraft
    • Alloderm
    • Graftjacket
    • Primatrix
    • Hmatrix
    • Integuply
    • Arthroflex
    • Dermaspan
    • TranZgraft
    • Oasis
    • Integra
    • EZ Derm
    • MatriStem
    • Unite Biomatrix
    • AlloSkin
    • Hyalomatrix
    • TenSIX
    • Surgiment
    • Repriza
    • Grafix
    • EpiFix
    • DermACELL
    • Talymed
    • Theraskin
    *As of April 2014 13
    adverse events but not in the
    Graftjacket group. The odds
    ratio in the likelihood that the
    wounds would heal is the highest
    in the Grafix group. There is
    about a sixfold increased likelihood
    that people would heal in
    the Grafix study and the other
    studies range from a 2 to 2.4
    odds ratio (Table 4).12,16,20,21
    What makes a wound really
    chronic? The literature states
    that 90 days is supposedly what
    defines a wound as chronic. It
    is unlikely that clinicians will
    wait 90 days to determine that
    a wound is chronic after debridement,
    wound preparation,
    compression, and offloading.
    When we look at what makes a
    wound chronic, is it time driven?
    Has the wound been there
    because it has been open for a
    long time? There are a lot of
    bacteria and proteases because
    of an extremely hostile environment.
    Due to the proteases
    and the hostility of the environment,
    we have growth factors
    and matrix proteins that
    are breaking down. We know
    that the cell surface receptors
    are going to be altered in
    one such wound environment.
    These types of wounds also
    get stuck in a chronically inflamed
    state. There is cellular
    senescence and there are those
    wounds that simply have not
    had adequate treatment. In this
    case, could the chronicity also
    be patient driven?
    There are studies that have
    suggested prognostic indicators
    for time to healing. In regard to
    VLUs, Gelfand et al and Phillips
    et al found that if there is
    not a 40% reduction in the venous
    leg group by week 4, it is
    unlikely that the wound is going
    to achieve complete closure
    TABLE 4. High Quality DFU RCTs
    N = 97
    N = 245
    N = 208
    N = 86
    Healed (%) 62 vs 21* 30 vs 18* 56 vs 38* 68 vs 46*
    Time to Closure
    (days) 42 vs 70* Not stated 65 vs 90* 40 vs 48
    Adverse Events (%) 18 vs 36* 19 vs 32* 22 vs 32 Not stated
    Odds Ratio 6.04
    Marston WA, Hanft J, Norwood P, Pollak R; for the Dermagraft Diabetic Foot Ulcer Study Group. The efficacy and safety of Dermagraft in improving
    the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care. 2003;26(6):1701-1705. Veves A, Falanga
    V, Armstrong DG, Sabolinski ML; for the Apligraf Diabetic Foot Ulcer Study. Graftskin, a human skin equivalent, is effective in the management of
    noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care. 2001;24(2):290-295. Lavery LA,
    Kirsner RS, Serena T. The Wound Care Pipeline: Ongoing Trials. Symposium on Advanced Wound Care Fall. Las Vegas, NV. September 27-29,
    2013. Reyzelman A, Crews RT, Moore JC, et al. Clinical effectiveness of an acellular dermal regenerative tissue matrix compared to standard
    wound management in healing diabetic foot ulcers: a prospective, randomised, multicentre study. Int Wound J. 2009;6(3):196-208.
    14 August 2014
    by 24 weeks.28,29 For diabetic
    foot ulcers, Sheehan et al found
    that if there is not a 50% reduction
    in the wound size by
    4 weeks, then it is unlikely to
    achieve complete healing by
    12 weeks (Figure 5).30 Keeping
    that in mind, it should give
    us the impetus to consider advanced
    wound care modalities
    as early as possible.
    The other things to consider
    about patient selection with
    more advanced wounds are the
    type, history, and duration of the
    wounds. We cannot forget about
    atypical wounds or traumatic
    wounds. For example, if a patient
    has a large avulsive injury
    on the leg and he or she comes
    in with hemosiderin staining,
    there is a bigger picture that we
    need to address before expecting
    the wound to heal.
    Case Report 1
    A 34-year-old male patient
    with a past medical history of
    diabetes, ischemic cardiomyopathy,
    and ventricular tachycardia
    presented with an infected
    AICD device. His ventricular
    or cardiac device became infected
    and required removal.
    He was on several different
    medications for these ailments.
    The patient was required to
    wear a life vest to monitor his
    heart and react in the event that
    something went wrong until
    the wound healed. At his initial
    visit, we applied a cellular amnion
    product pre-debridement.
    The wound closed at day 21 so
    the patient could have another
    surgery and have a new device
    implanted (Figure 6).
    Case Report 2
    In this case, a 42-year-old
    male patient with a history of
    recurrent diabetic foot ulcers,
    right great toe amputation, hypertension,
    hyperlipidemia, type
    Figure 5. Studies on VLUs and DFUs showed prognostic indicators for time to healing.

    Sentiment: Strong Buy

  • ativaloc ativaloc May 4, 2015 1:00 PM Flag

    Meet Dr. Lawrence Lavery
    Wound Care Specialist

    A board-certified podiatrist, Lawrence Lavery, D.P.M., M.P.H., is an internationally recognized expert in diabetic foot complications, including diabetic foot ulcers, soft tissue and bone infections, Charcot arthropathy, and prevention strategies. As a leading member of the team that established UT Southwestern’s Wound Care Clinic, he’s been at the forefront of expanding options for patients in North Texas.

    Dr. Lavery currently is a member of the International Working Group on the Diabetic Foot, including both the diabetic foot infection and diabetic foot prevention study groups. He is past chair of the American Diabetes Association Foot Care Counsel and the American Public Health Association’s Foot Section.

    We apply comprehensive solutions focused on helping patients recover. For some patients, this means salvaging a limb using advanced techniques based on the newest research available in wound care.”
    By combining groundbreaking research with scientific treatment options, he’s able to offer novel, evidenced-based treatments. His expertise includes the full range of wound care options – including stem cell-based wound therapy, bioengineered tissue, electrical stimulation, and negative pressure wound therapy.

    “One of the most important advantages I can offer patients is access to a full spectrum of therapies based on scientific evidence,” Dr. Lavery says.

    “We use the proven treatments that might be considered old school, as well as many of the most innovative treatments in the world. And because we collaborate with industry to study new technologies, we often have new treatments that are not available at other centers,” he adds.

    He says seeing patients at UT Southwestern’s Wound Care Clinic offers another distinct advantage because there he has a close working relationship with world-class vascular surgeons and vascular testing. He notes that, for many people with diabetic foot wounds, optimizing the blood flow to the foot is the difference between healing or losing their leg.

    Dr. Lavery says great progress has been accomplished with science-based strategies to save limbs. However, he stresses patients should seek care sooner rather than later because early treatment can be key to improving their chances of recovery and preventing an amputation.

    As director of research for UT Southwestern’s Department of Plastic Surgery, Dr. Lavery leads a team that’s focused on improving treatment and prevention of diabetic foot complications. Dr. Lavery’s groundbreaking work has received research funding from the National Institute of Health (NIH), Veterans Administration (VA), American Diabetes Association, Agency for Health Quality Research, Qatar National Research Foundation, American College of Foot and Ankle Surgeons, American Podiatric Medical Association, and private industry. This includes studies funded by the National Institutes of Health (NIH), such as identifying biomarkers in diabetic patients to diagnose and monitor foot infections and to help doctors understand why some people heal and some don’t.

    Dr. Lavery brings a unique perspective to treating wounds and understands foot and ankle complications on a personal level. Dr. Lavery’s father was born with a clubfoot, and his great grandfather lost both legs to disease. So he uses that experience to relate to patients and help them understand the disease process and their treatment options.

    Sentiment: Strong Buy

  • ativaloc ativaloc May 4, 2015 12:58 PM Flag

    Biography for Dr. Lawrence Lavery
    Osiris Therapeutics will also be exhibiting at the Symposium on Advanced Wound Care meeting at booth 741. The event runs from April 30 through May 3, 2015 at the Henry B. Gonzalez Convention Center in San Antonio, Texas. In addition, Dr. Lawrence Lavery will host an oral presentation at the Osiris booth, entitled "A Cryopreserved, Viable Human Amniotic Membrane in Advanced Wound Care: Scientific Background and Clinical Outcomes," on Thursday, April 30, 2015 at 7:00 p.m. and on Friday, May 1, 2015 at 1:00 p.m.

    Lawrence Lavery, D.P.M., MPH., is a board-certified podiatrist and Professor of Plastic Surgery, Orthopaedic Surgery, and Physical Medicine & Rehabilitation at UT Southwestern. He also is medical director of UT Southwestern’s Comprehensive Wound Care Center and director of the amputation prevention program at Parkland Memorial Hospital.

    Dr. Lavery completed undergraduate studies at Indiana University and then earned his medical degree from the Dr. William Scholl College of Podiatric Medicine in Chicago. He completed a residency in podiatric medicine and surgery at the University of Texas Health Science Center in San Antonio, where he also earned a Master’s in Public Health.

    Prior to joining UT Southwestern in 2010, Dr. Lavery held academic appointments at the Texas A&M Health Science Center College of Medicine in Temple; the University of Texas Health Science Center in San Antonio; and Loyola University Medical Center in the Chicago area. He has also served as a staff podiatrist at VA hospitals in San Antonio and Illinois.

    Dr. Lavery is a member of the American Podiatric Medical Association, American Diabetes Association, and Texas Podiatric Medical Association. He has been invited to lecture on podiatric medicine, diabetic ulcers, and wound care at medical conferences around the world and has published a dozen book chapters and more than 150 research articles on these topics.

    He has served on the editorial board for Diabetes Care, and the International Diabetes Monitor, and was editor-in-chief of Foot and Ankle Quarterly and deputy editor of the Journal of Foot and Ankle Surgery.

    Dr. Lavery enjoys hunting quail and training hunting dogs. He also likes family activities such as kayaking, snorkeling, hiking, rock climbing and cooking.

    Sentiment: Strong Buy

  • Reply to

    well what do you know

    by moveonup210 Apr 22, 2015 11:18 AM
    ativaloc ativaloc Apr 22, 2015 2:48 PM Flag

    Stryker is capitalizing on its stronger market position by acquiring MAKO while its rivals are lagging. Stryker's last big purchase was that of Chinese medical equipment maker Trauson Holdings earlier this year for $764 million in cash. Prior to that, it purchased Israeli medical equipment company Surpass Medical for $135 million.

    While the Trauson acquisition is expected to be have a neutral impact on Stryker's adjusted full-year earnings, the MAKO purchase is expected to dilute Stryker's adjusted earnings per year by $0.10 to $0.12 per share in the first year. The company expects the deal to become earnings accretive by the third year.

    Although MAKO is a large acquisition, Stryker has the cash to support it. The company finished last quarter with $4.7 billion in cash and equivalents and $2.8 billion in debt.

    Breaking down Stryker's core businesses to find opportunities
    To understand why Stryker purchased MAKO, we should take a look at the growth and weight of Stryker's three business segments.

    Business Segment
    Second-Quarter Revenue

    Percentage of Total Revenue

    Growth (YOY)


    (implants for the hip, knee, foot, and extremities)

    $979 million




    (surgical equipment, power tools, cameras, endoscopy)

    $819 million



    Neurotechnology and Spine

    (spinal implants)

    $414 million



    Source: Stryker 2Q2013 report.

    Stryker's previous acquisition of Surpass Medical added a flow diversion stent to treat brain aneurysms to its MedSurg segment, and its purchase of Trauson boosted revenue growth at its Neurotechnology and Spine business.

    Although MAKO also sells regular joint-specific implants, which will complement Stryker's reconstructive segment, the bulk of the company's revenue comes from its RIO system, a robotic surgical arm that allows a surgeon to treat patient-specific osteoarthritic diseases with minimally invasive procedures. MAKO also recently introduced a new robotic arm, the MAKOplasty Total Hip Arthroplasty, to aid in hip replacement procedures.

    Source: Company website.

    The appeal of robotic surgery
    Over the past several years, robot-guided surgical procedures have gained mainstream acceptance thanks to Intuitive Surgical's (NASDAQ: ISRG ) da Vinci surgical system. The da Vinci was used for nearly 400,000 minimally invasive surgeries in the United States last year, and costs $1.45 million per unit and over $100,000 more in annual service costs. MAKO's RIO Robotic Arm, by comparison, costs nearly $1 million.

    Despite the rise of the robot surgeons in the United States, robot-assisted procedures only represent a small sliver of the global market. Only 2% of worldwide surgeries last year were performed with robot-assisted procedures, according to MedCity News' Amy Siegel.

    This indicates massive untapped growth potential in emerging markets like China, India, and Latin America. Therefore, robotic surgery could grow substantially to become Stryker's fourth pillar of growth.

    Stryker could send the sharks to China
    China's state-owned hospitals have a strong interest in robotic surgery, opening the doors to companies like Intuitive Surgical, which started selling the da Vinci to Chinese hospitals in 2007.

    By acquiring Trauson, Stryker already has one foot in the door. Stryker's sells its cheaper Trauson orthopedic implants in less affluent parts of the country while selling its more expensive namesake implants in richer urban areas.

    Therefore, Stryker's presence in China could provide the framework to launch MAKO's RIO system into the country, which has one of the world's fastest growing elderly populations. There are currently 194 million people over the age of 60 in China -- a figure that is expected to more than double by 2050.

    That's a lot of knees, hips, and spines that will need surgery and implants, which could boost Stryker's top-line growth for decades to come.

    A Foolish final thought
    Stryker clearly has ambitious plans for the future. With the acquisition of MAKO, Stryker gains a line of premium surgical products that complement its core business of implants and surgical equipment worldwide.

    With Trauson and MAKO now under its umbrella, Stryker is well positioned to profit from an aging global population and rising demand for less-invasive procedures. These positive catalysts could help it outgrow rivals like Zimmer Holdings and Smith & Nephew in the long run.

    Leo Sun has no position in any stocks mentioned. The Motley Fool recommends Intuitive Surgical and MAKO Surgical. The Motley Fool owns shares of Intuitive Surgical and Zimmer Holdings. Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy.

    Sentiment: Strong Buy

  • Reply to

    well what do you know

    by moveonup210 Apr 22, 2015 11:18 AM
    ativaloc ativaloc Apr 22, 2015 2:44 PM Flag

    Stryker Orthopaedics – ShapeMatch Cutting Guide: Class 1 Recall

    [Posted 04/18/2013]

    AUDIENCE: Surgery, Risk Manager

    ISSUE: FDA notified healthcare professionals of a Class 1 recall for this product due to a software defect that results in wider cutting ranges. The parameters of the manufactured cutting guides may not meet the surgeon’s pre-operative planning parameters entered via the web application. Additionally, Stryker Orthopaedics determined that another software defect resulted in the displayed parameters (e.g. depth of resection, angle of cut) not matching the cutting guides produced. This may result in serious adverse health consequences including joint instability, fracture,need for revision surgery and chronic pain and limitations of mobility.

    The FDA has received a total of 44 reports (41 malfunctions and 3 temporary medically reversible injuries) of incidents related to the ShapeMatch Cutting Guides.

    BACKGROUND: The ShapeMatch Cutting Guides are single-use, disposable, cutting guides. They are intended to be used as surgical instrumentation to assist in the positioning of total knee replacement (arthroplasty) components intraoperatively and in guiding the marking of bone before cutting. In November 2012, Stryker Orthopaedics e-mailed field locations, registered surgeons and imaging centers of the problem and to immediately stop prescribing, planning or performing operative or imaging procedures with the ShapeMatch Cutting Guides until further notice.

    In January 2013, a Product Notification was issued to all branches, agencies, surgeons and risk managers at affected hospitals informing them of the problem and risk mitigation factors. On April 10, 2013, Stryker issued an Urgent Medical Device Recall.

    RECOMMENDATION: The ShapeMatch Cutting Guides have not been available on the market since November 2012. Stryker is recommending patients who had knee replacement surgery in which ShapeMatch Cutting Guides were used and who are experiencing symptoms to contact their surgeon. If symptom-free, the patient should continue to follow-up with the surgeon as scheduled.

    Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

    Sentiment: Strong Buy

  • Reply to

    well what do you know

    by moveonup210 Apr 22, 2015 11:18 AM
    ativaloc ativaloc Apr 22, 2015 2:40 PM Flag

    Mr. Kevin A. Lobo has been Chief Executive Officer of Stryker Corporation since October 1, 2012 and has been its President since 2012. Mr. Lobo served as the President of Stryker since October 1, 2012. He served as the President of Orthovita Inc. since June 27, 2011. He is the Group President of Orthopaedics at Stryker Corporation since June 10, 2011. He served as the President of Ethicon Endo-Surgery, a division of Johnson & Johnson, from June 2009 to April 2011, as President of Ethicon Endo-Surgery from July 2006 to May 2009 and President of Johnson & Johnson Medical Products from October 2005 to July 2006. He served as President of J&J Medical Products Canada and at McNeil as the Vice President of Finance for Consumer and Specialty Pharmaceuticals and Ortho Women's Health & Urology. He also worked for Rhone-Poulenc in North America and Europe, as well as Kraft and KPMG in Canada. Mr. Lobo served as a Vice President of Finance. He has been the Chairman of Stryker Corporation since July 22, 2014. He has been a Director of Stryker Corporation since October 1, 2012 and Parker-Hannifin Corporation since August 1, 2013. Mr. Lobo received his Bachelors degree in Commerce from McGill University and his MBA from the University of Toronto.

  • ativaloc ativaloc Apr 9, 2015 8:52 PM Flag

    Always a fun and informative day, I plan to be in attendance and ask a few questions. By then we should be above $18.50 on our way to $56.

    Sentiment: Strong Buy

  • Reply to

    dyax may see 35 dollares on friday.

    by dkatakmo Apr 8, 2015 5:02 PM
    ativaloc ativaloc Apr 8, 2015 11:11 PM Flag

    Hong Kong shares rocket higher in sharpest rally since 2007

    Sentiment: Hold

  • BioFlash

    Burlington biotech Dyax is now worth more than the maker of Sam Adams

    Apr 8, 2015, 2:02pm EDT Updated: Apr 8, 2015, 2:36pm EDT

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    Gustav Christensen Dyax
    Enlarge Photo

    Gustav Christensen, CEO of Dyax Corp.

    Don SeiffertBioFlash Editor-
    Boston Business Journal
    Email | Twitter
    With promising results of a single early-stage trial last week, a 124-employee Burlington biotech working on a drug for a disease few people have ever heard of has suddenly become worth more on the stock market than the state’s best-known beer maker.

    It’s a testament to both the strength of the current biotech industry and, conversely, fears that the industry is being widely overvalued, that with a current market capitalization of $4.1 billion, Dyax Corp. (Nasdaq: DYAX) is now among the top 50 most highly-valued companies in Massachusetts. Its ranking of No. 49 places it slightly below the 12,000-employee diagnostics firm, Alere (NYSE: ALR), but above the 1,325-employee Boston Beer Co., maker of Sam Adams beer.

    Among local biotech companies, Dyax — which has one drug on the market called Kalbitor which brought in $68 million in revenue last year — has become the fourth most valuable biotech in the state as of this afternoon, trailing internationally-known companies like Biogen, Vertex and Alnylam.

    The stock surge which caused the sudden prominence for a company little-known outside the industry came last week, when the company reported results of a 37-patient trial of a longer-lasting form of Kalbitor which showed promise in preventing attacks of a rare swelling disease called hereditary angioedema, or HAE. The company has said it hopes to begin a late-stage trial of the drug, pending meetings with the Food and Drug Administration, which could have results as soon as next year. Those results could form the basis of an application for a drug which analysts at Leerink Partners estimate could bring in $1.8 billion in revenue by 2029.

    The value of that drug in the eyes of a potential buyer (Shire has been mentioned as a possible acquirer since it already has a similar drug on the market) is likely what’s fueling a 78 percent stock increase since the close of the day on March 31, the day before the trial data was announced, to $30.33 as of 12:30 today. Today, Dyax took advantage of its highest stock price in 15 years to raise $200 million in a secondary stock offering, boosting its cash more than 10-fold since it reported having $19.4 million at the end of last year.

    Sentiment: Strong Buy

  • ativaloc ativaloc Mar 31, 2015 10:40 PM Flag

    Shorts need to pay attention, look here DYAX

    OSIR soon too follow frog slowly simmering

    Difference is OSIR is making moola, can't change that.

    Sentiment: Strong Buy

  • Reply to

    Great report! Next stop.... 20!!!

    by irwin_campbell Feb 24, 2015 7:55 AM
    ativaloc ativaloc Mar 31, 2015 4:32 PM Flag

    hbc you nailed it. Sell or hold?

  • Reply to

    How many 52 week highs will OSIRIS have in 2015?

    by ativaloc Feb 25, 2015 12:47 PM
    ativaloc ativaloc Mar 19, 2015 11:36 AM Flag

    We know the CASH is coming. $20,000,000.00 $15 from Meso & $5 from Stryke what better place to invest with insider info? Yep, no brainer.

    I bet you're wonderin' how I knew
    'Bout your plans to make me blue
    With some other guy you knew before
    Between the two of us guys
    You know I loved you more
    It took me by surprise I must say
    When I found out yesterday
    Don't you know that I heard it through the grapevine
    Not much longer would you be mine
    Oh I heard it through the grapevine
    Oh I'm just about to lose my mind

    Honey, honey yeah.
    I heard it through the grapevine
    Not much longer would you be mine baby

    I know a man ain't supposed to cry
    But these tears I can't hold inside
    Losin' you would end my life you see
    'Cause you mean that much to me
    You could have told me yourself
    That you loved some one else
    Instead I heard it through the grapevine
    Not much longer would you be mine
    Oh, I heard it through the grapevine
    And I'm just about to lose my mind

    Honey, honey yeah
    I heard it through the grapevine
    Not much longer would you be mine, baby

    People say believe half of what you see
    Son and none of what you hear
    But I can't help but be confused
    If it's true please tell me dear
    Do you plan to let me go
    For the other guy you loved before?

    Don't you know I heard it through the grapevine
    Not much longer would you be mine, baby yeah
    I heard it through the grapevine
    I'm just about to love my mind
    Honey, honey, yeah
    I heard it through the grapevine,
    Not much longer would you be mine, baby yeah

    Honey, honey, yeah
    I heard it through the grapevine,
    Not much longer would you be mine, baby yeah yeah
    I heard it through the grapevine,
    Not much longer would you be mine, baby yeah yeah

    Sentiment: Strong Buy

  • These last few years of waiting will be the last of shorts manipulation and best for holding tight. its been a long time in coming. Yes there are millions if not billions at stake on both sides. Peter has come from billion to millions and soon back to billions again. The fight will be well fought and win we will.
    In August 2017 we will celebrate our 10th anniversary being a public Co. and in December of the same year we will be celebrating our 25 anniversary closing out the year with the share price trading well over $100 a share.

    Only Two catalyst exist for the shorts to exit with little pain, one is the overall market correction and the other will come from OSIRIS themselves of an event I wish not to share now but it will be brief and have a long positive outcome.

    End of 2015 we will all see what we envisioned a few years ago but with a twist ''Osiris Therapeutics: An Old Stem Cell Biotech Coming Of Age'' (google it seeking alpha article) Bio-Surgery rules the day today and days to come, but one day soon we will reunite and rule the STEM CELL WORLD once again.

    Arthrex, Stryker, Grafix and no other than Dr. Hansjörg Wyss who was last heard saying " deliver on its potential ''

    Disney World would make a great place in 2017 to celebrate 25 stem cell years.

    Just Saying.........

    Sentiment: Strong Buy

  • Reply to

    Any near term catalysts???

    by locatedmyballs Mar 16, 2015 12:37 PM
    ativaloc ativaloc Mar 17, 2015 8:10 AM Flag

    Little ghost, you're listening,
    Unlike most you don't miss a thing,
    You see the truth.
    I walk the halls invisibly,
    I climb the walls, no one sees me,
    No one but you.

    You've always loved the strange birds
    Now I want to fly into your world
    I want to be heard
    My wounded wing's still beating,
    You've always loved the stranger inside
    Me, ugly pretty.

    Oh oh, no no no, oh...

    Oh little ghost, you see the pain
    But together we can make something beautiful.
    So take my hand and perfectly,
    We fill the gaps, you and me make three,
    I was meant for you, and you for me.

    You've always loved the strange birds
    Now I want to fly into your world
    I want to be heard
    My wounded wing's still beating,
    You've always loved the stranger inside
    Me, ugly pretty.

    Oh oh, no no no, oh...

    You've always loved the strange birds
    Now I want to fly into your world
    I want to be heard
    My wounded wing's still beating,
    You've always loved the stranger inside
    Me, ugly pretty.

    Sentiment: Strong Buy

  • Reply to

    Any near term catalysts???

    by locatedmyballs Mar 16, 2015 12:37 PM
    ativaloc ativaloc Mar 17, 2015 8:03 AM Flag

    Prochymal is currently in clinical trials for the treatment of moderate to severe Crohn's disease, a painful, disabling inflammatory disease that often requires surgery. Osiris is currently conducting a multi-center trial to evaluate the safety and efficacy of Prochymal for Crohn's disease.
    In previous studies in gastrointestinal graft versus host disease (GvHD), Prochymal has been shown to reduce inflammation and promote crypt regeneration in the damaged intestine. Below is an endoscopic view and corresponding histology in a patient with severe gastrointestinal GvHD before (left) and nine days following Prochymal treatment (right). At the time of Prochymal infusion, this patient was unresponsive to all other modes of intervention. Nine days after treatment with Prochymal, there is a decrease in intestinal inflammation and ulceration as well as corresponding crypt regeneration as depicted by the arrows.

    Sentiment: Strong Buy

  • Reply to

    Any near term catalysts???

    by locatedmyballs Mar 16, 2015 12:37 PM
    ativaloc ativaloc Mar 17, 2015 3:50 AM Flag

    Journal ListHHS Author ManuscriptsPMC3766369
    Logo of nihpa
    Crit Rev Biomed Eng. Author manuscript; available in PMC 2013 Sep 7.
    Published in final edited form as:
    Crit Rev Biomed Eng. 2012; 40(5): 363–408.
    PMCID: PMC3766369
    NIHMSID: NIHMS449335
    Bone Tissue Engineering: Recent Advances and Challenges
    Ami R. Amini,1,2 Cato T. Laurencin,1,2,3,5 and Syam P. Nukavarapu1,2,4,5,*
    Author information ► Copyright and License information ►
    The publisher's final edited version of this article is available at Crit Rev Biomed Eng
    See other articles in PMC that cite the published article.
    Go to:
    The worldwide incidence of bone disorders and conditions has trended steeply upward and is expected to double by 2020, especially in populations where aging is coupled with increased obesity and poor physical activity. Engineered bone tissue has been viewed as a potential alternative to the conventional use of bone grafts, due to their limitless supply and no disease transmission. However, bone tissue engineering practices have not proceeded to clinical practice due to several limitations or challenges. Bone tissue engineering aims to induce new functional bone regeneration via the synergistic combination of biomaterials, cells, and factor therapy. In this review, we discuss the fundamentals of bone tissue engineering, highlighting the current state of this field. Further, we review the recent advances of biomaterial and cell-based research, as well as approaches used to enhance bone regeneration. Specifically, we discuss widely investigated biomaterial scaffolds, micro- and nano-structural properties of these scaffolds, and the incorporation of biomimetic properties and/or growth factors. In addition, we examine various cellular approaches, including the use of mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), adult stem cells, induced pluripotent stem cells (iPSCs), and platelet-rich plasma (PRP), and their clinical application strengths and limitations. We conclude by overviewing the challenges that face the bone tissue engineering field, such as the lack of sufficient vascularization at the defect site, and the research aimed at functional bone tissue engineering. These challenges will drive future research in the field.

    Keywords: bone tissue engineering stem cells, scaffolds, vascularization, immunomodulation, cell homing, clinical challenges
    Go to:
    Bone grafts are utilized in a wide array of clinical settings to augment bone repair and regeneration. Bone defect repair using the tissue engineering approach is perceived as a better approach because the repair process may proceed with the patient’s own tissue by the time the regeneration is complete.1–3 Currently, the United States, as well as other countries worldwide, is experiencing an exceedingly high demand for functional bone grafts. Annually in the United States, more than half a million patients receive bone defect repairs, with a cost greater than $2.5 billion. This figure is expected to double by 2020 in the United States and globally due to a variety of factors, including the growing neeeds of the baby-boomer population and increased life expectancy.4

    Extensive studies have reported the considerable shortcomings, limitations, and complications of current clinical treatments for bone repair and regeneration; these include autologous and allogeneic transplantations using autografts and allografts.4–10 To date, autografts serve as the gold standard for bone grafts because they are histocompatible and non-immunogenic, and they offer all of the imperative properties required of a bone graft material. Specifically, autografts possess the essential components to achieve osteoinduction (i.e., bone morphogenetic proteins (BMPs) and other growth factors), osteogenesis (i.e., osteoprogenitor cells) and osteoconduction (i.e., three-dimensional and porous matrix). However, autografts involve harvesting bone from the patient’s iliac crest, and thus, requires a second operation at the site of tissue harvest.11 Autologous bone transplants are very expensive procedures, and they may result in significant donor site injury and morbidity, deformity, scarring and they are associated with surgical risks as well: bleeding, inflammation, infection, and chronic pain.12–14 Autografts, further, may be a null treatment option in cases where the defect site requires larger volumes of bone than is feasible or available. Allografts represent the second most common bone-grafting technique; they involve transplanting donor bone tissue, often from a cadaver. Allogeneic bone is also likely histocompatible, and is available in various forms, including demineralized bone matrix (DBM), morcellised and cancellous chips, cortico-cancel-lous and cortical grafts, and osteochondral and whole-bone segments, depending on the host-site requirements. In comparison to autografts, allografts are associated with risks of immunoreactions and transmission of infections. They have reduced osteoinductive properties and no cellular component, because donor grafts are devitalized via irradiation or freeze-drying processing.15–17 Although less than autografts, allogenic grafts come with substantial cost issues. Furthermore, the bone grafting market is experiencing an obvious unmet supply and great demand; there is currently a shortage in allograft bone graft ma-terial.18 Other commonly used bone repair techniques may involve distraction osteogenesis, bone cement fillers, and bone morphogenic proteins. Although the previously mentioned clinical interventions have been shown to improve repair of bone, none possess all of the ideal characteristics: high osteoinductive and angiogenic potentials, biological safety, low patient morbidity, no size restrictions, ready access to surgeons, long shelf life, and reasonable cost.

    The field of bone tissue engineering (BTE) was initiated nearly three decades ago. Interest and progress in the BTE field has seen tremendous growth over the years, with an exponentially increasing number of studies and reviews published on the PubMed database since the mid-1980s (Fig. 1). The field of BTE focuses on alternative treatment options that will ideally eliminate the previously described issues of current clinically used treatments (i.e., donor site morbidity, limited availability, immune rejection, and pathogen transfer). BTE requires the collaborative efforts of scientists, engineers, and surgeons to achieve this ultimate goal of creating bone grafts that enhance bone repair and regeneration.19 The classic BTE paradigm highlights several key players: (1) a biocompatible scaffold that closely mimics the natural bone extracellular matrix niche, (2) osteo-genic cells to lay down the bone tissue matrix, (3) morphogenic signals that help to direct the cells to the phenotypically desirable type, and (4) sufficient vascularization to meet the growing tissue nutrient supply and clearance needs. Specifically, upon implantation, the construct may influence the host by releasing osteogenic and/or vasculo-genic growth factors (i.e., growth factor-releasing scaffold, scaffold with growth factor analogs, or seeding with platelet-enriched plasma), or by housing cells that are genetically engineered to or naturally release growth factors (Fig. 2). In turn, accelerated cell homing, vascularization, and bone regeneration of the defect site results. Although much progress has been made, many crucial hurdles remain to be cleared on the way to BTE becoming a true clinical reality. The following review critically considers advances and obstacles for functional BTE.

    FIGURE 1
    FIGURE 1
    (A) Published articles on BTE since mid-1980s on PubMed.
    FIGURE 2
    FIGURE 2
    Schematic illustration of bone tissue engineering paradigm. Factors from the implanted graft at the defect site that influence the host response may include growth factors (or their analogs, or from platelet-enriched plasma), and cells (genetically modified ...
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    Bone tissue engineering (BTE) is based on the understanding of bone structure, bone mechanics, and tissue formation as it aims to induce new functional bone tissues. In other words, to successfully regenerate or repair bone, knowledge of the bone biology and its development is quite essential.

    Bone possesses the ability to perform a wide array functions, and bone responds to a variety of metabolic, physical and endocrine stimuli. Bones (1) represent the foundation for our bodily locomotion, (2) provide load-bearing capacity to our skeleton and protection to our internal organs, (3) house the biological elements required for hematopoiesis, (4) trap dangerous metals (i.e., lead), and (5) maintain the homeo-stasis of key electrolytes via calcium and phosphate ion storage. In addition, bone is engaged in a constant cycle of resorption and renewal, undergoing continual chemical exchange and structural remodeling due to both internal mediators and external mechanical demands. Bone has been previously, and most appropriately, referred to as the ultimate smart material for its scar-less regenerative capacity. Functional bone tissue engineering requires the newly restored bone to be fully integrated with the neighboring host bone, and importantly, to perform the previously mentioned functions of native bone.

    Bone is a highly dynamic and diverse tissue, both structurally and functionally. Macroscopic structure and mechanical properties of the more than 200 bones in the human skeletal system are largely influenced by distinct loading conditions. Skeletal structures range from long (i.e., tibia, ul-nar, etc.) to short (i.e., phalanges, etc.), flat (i.e., skull, sternum, etc.), and irregular (i.e., pelvic, vertebrae, etc.). Bone functions range from locomotion to vital organ protection. Bone tissue may also either take on a compact (i.e., cortical bone) or trabecular (i.e., cancellous bone) pattern arrangement, ranging in mechanical strength and modulus. Despite these complex features and forms, it has relative simplicity in terms of its microscopic, hierarchical architecture. Specifically, bone extracellular matrix (ECM) is composed of both a non-mineralized organic component (predominantly type-1 collagen) and a mineralized inorganic component (composed of 4-nm-thick plate-like carbonated apatite mineralites). The nano-composite structure (tough and flexible collagen fibers reinforced by hydroxyapatite crystals) is integral to the requisite compressive strength and high fracture toughness of bone.

    A. Bone Development

    Bone formation occurs via two very distinct pathways, intramembraneous and endochondral. In either case, mesenchymal cellular condensation first occurs and serves as a template for subsequent bone formation. Intramembraneous bone formation involves mesenchymal progenitor cells differentiating directly into osteoblasts and the subsequent development of parts of the mandible, clavicle, and many cranial bones. Most bones in the body (i.e., all long bones and vertebrae), however, are formed through endochondral bone formation. This process involves mesenchymal progenitor cells first differentiating into chondrocytes, which are responsible for depositing a cartilaginous template that is later mineralized and replaced by bone.

    Although distinct differences in the bone composition and structure occur via endo-chondral and intramembranous ossification, several molecular regulators are shared.20,21 For instance, several key molecules, including Indian Hedgehog (Ihh), parathyroid hormone related peptide (PTHrP), bone morphogenetic proteins (BMPs), vascular endothelial growth factor (VEGF) and fibroblastic growth factors (FGFs), are critical regulators in both processes.22 In en-dochondral ossification, BMPs are responsible for the initiation of mesenchymal condensations, and Ihh and PTHrP form a critical feedback loop that mediate the balance between chondrocyte proliferation and hypertrophy and regulate the thickness of the growth plate. Likewise, during intramembranous bone formation, these key players are required to induce uncommitted mensenchymal progenitor cells along the osteogenic pathway as pre-osteoblasts, which co-express chondrocytic and osteoblastic markers simultaneously. Furthermore, in both processes, bone remodeling is required for the maintenance of all normal healthy bone, which involves a balance between osteoclastic bone resorption and osteoblastic bone formation.23

    1. Bone Defect Repair
    Interestingly, upon fracture, bone is repaired by a process that recapitulates many of the events of both intramembraneous and endochondral bone formation, and it uniquely heals without the formation of scar tissue.24,25 Initially, hema-toma formation is accompanied by an inflammatory response, and the recruitment of many of the signaling molecules involved in the regulation of new bone formation (i.e., ILs, TNF-α, FGFs, BMPs, PDGF, VEGF, etc.). At the cortex and periosteum, intramembranous bone formation immediately occurs. The external soft tissues stabilize the fracture by the formation of a callus, which subsequently undergoes chondrogenesis, and then a process highly similar to endochondral ossiflcation. More specifically, after the callus forms, chondrocyte proliferation decreases as the tissues begin to mature (i.e., hypertrophy) and calcify the matrix. In-growing blood vessels carry chondroclasts, which are responsible for resorbing the calcified cartilage and osteoblastic progenitors, which begin the process of new bone formation. The mechanical continuity of the cortex is achieved via subsequent remodeling of the newly formed bone.

    The question remains: What is the optimal method for bone regeneration? Should BTE focus more on bone development processes or on bone defect repair? In the opinion of the authors, BTE should not exclusively focus on one or the other, but both. In situations requiring bone regeneration, the initial events always involve he-matoma formation and an early inflammatory response, which is largely responsible for the recruitment of host cells and release of critical signaling molecules. From there, emulation of some aspects of normal bone tissue development and remodeling may hold the key to the future success of BTE. Seminal developmental biology principles that may help the future success of BTE include the following:

    The use of pluri- or multipotent stem cells
    The identification of critical genes, growth factors, and signal transduction cascades that mediate bone formation
    The physical process of bone formation
    Complex interactions between epithelium and mesenchyme within the underlying connective tissue
    The understanding of mesenchyme encoding tissue-specific patterns
    The understanding that normal tissue healing involves progressive remodeling and restructuring of pre-existing tissue structures
    The importance of the tissue microenviron-ment’s physical properties (i.e., “mechanother-apy”) (8) Angiogenesis and neo-vascularization of the newly formed bone tissue
    Incorporation of developmental biology insights will critically impact future tissue engineering approaches. For instance, future approaches may include appropriate extracellular matrix molecules or adhesive ligands that target stem cells mediating earlier stages of tissue remodeling and regeneration.26 And for the promotion of angiogenesis, BTE will aim to develop scaffolds that incorporate growth factors and possess the necessary porosity for vascular ingrowth.27 Furthermore, engineering featuring micro- and nano- meter surface topography of these scaffolds is critical for directing cellular adhesion, spreading, and proliferation. On a broader scale, for successful bone tissue engineering, it is critical to develop a scaffold that is inspired by the natural processes of developmental biology and promotes tissue remodeling, rather than simply supporting final tissue form and function.

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    Although bone is a highly vascularized tissue and has the ability to regenerate, beyond a critical point, clinical intervention measures are required. It is the hope that BTE will be the future treatment of choice, as it will likely eliminate many of the pitfalls of current treatments. In this section, we discuss the status and key issues for BTE components (i.e., biomaterials, cells, signaling molecules, and vascularization).

    A. Biomaterials

    1. Osteoinductive Materials
    Osteoinductive or “smart” biomaterials have the ability to induce ectopic bone formation by instructing its surrounding in vivo environment to form bone.28–30 Although the biological mechanisms of this phenomenon have not been fully elucidated, it is well recognized that these materials hold great potential for bone tissue regeneration. An array of biomaterial families have demonstrated having osteoinductive properties, including natural and synthetic ceramics (i.e., hydroxyapatite (HA) and variouscalcium phosphate compositions, and their composites (i.e., HA/ poly(lactic-co-glycolic acid) (PLGA). A number of studies have illustrated osteoinduc-tion by calcium phosphate (CaP)-based bioma-terials in various physical forms.31 Specifically, osteoinductivity has been demonstrated with CaP-based biomaterials in the form of sintered ceramics,32–36 cements,37,38 coatings,39,40 and coral-derived ceramics41–43 in a variety of animal models. Other ceramics, such as alumina ceramic and porous bioglass, have also been recently identi-fied as being osteoconductive.44 In addition, polymer/ceramic composites, such as PLGA/ HA, have been shown to be osteoinductive and to induce bone formation ectopically.45–50 However, it is critical to note that other material properties play a critical role in osteoinduction, aside from the chemical composition of the biomaterial, which may include porosity of the biomaterial implant and its surface properties, such as nano/micro topography. To some extent, the level of osteoinductivity also depends on the species used for the study (i.e., interspecies variation). Two main theories have been proposed to explain the observed osteoinductivity. The first is based on the biomaterial surface features that absorb and present osteoinductive factors to the surrounding cells. The second hypothesis is that the calcium phosphate–based materials release calcium and phosphate ions, which later influence stem cell differentiation into bone cells. No conclusive evidence exists for either of these hypotheses.29

    2. Hybrid Materials
    A number of synthetic and natural polymers, as well as ceramics have been developed and identified as biomaterials for BTE. Biomaterials for bone-scaffolding applications have to possess certain physical, chemical, and biological properties. Although great strides have been made, it is difficult for any biomaterial to satisfy all of the listed requirements. Recent efforts have been aimed, however, in the direction of developing hybrid biomaterials. These are nothing but the combination of two or more biomaterials, with enhanced functionalities, in the form of either co-polymers, polymer–polymer blends, or polymer–ceramic composites. These are considered an advanced class of biomaterials that are more optimal for bone scaffolding applications.

    a. Co-polymers
    Co-polymers are defined as being derived from two or more monomeric species. For example, poly (lactide-co-glycolide) (PLGA) co-polymer systems are derived from poly lactide, which displays a glass transition temperature (Tg) above room temperature with an unreasonably long degradation time, and polyglycolide, which displays Tg below room temperature and a shorter degradation time. The development of the PLGA co-polymer system allowed for the tuning of Tg and degradation based on the need. Similarly, other co-polymer systems have been developed, such as PLGA-PCL, PLGA co-polymerized with PLL, and PLA- co-polymerized PCL.54 In addition, DegraPol™ is another example of a co-polymer that was originally synthesized for bone regeneration.55

    b. Polymer–polymer blends
    Polymer blends involve a mixture of two polymers. By choosing polymers with required intermolecular or Van der Walls interactions, it is possible to design a miscible blend system with enhanced properties. PLGA blends with polyphosphazenes are a prime example. It is known that PLGA biomaterials produce acidic byproducts upon degradation, and this has been a major problem, because the long-term tissue exposure to acidic products may result in tissue necrosis and implant failure. On the other hand, polyphosphazenes release neutral or basic products in degradation.56 Therefore, PLGA has been blended with a wide variety of polyphosphazenes to achieve novel biomaterials with near-neutral degradation products.57–62

    c. Polymer-ceramic composites
    Composite materials represent attractive candidates for BTE applications because bone is, in fact, a composite material composed of a mix of inorganic hydroxyapatite crystals (HA) and organic collagen fibers.63 Furthermore, polymer-ceramic composites capitalize the advantages of each of its components (i.e., biodegradable polymer and ceramic materials), and have demonstrated success in bone regeneration that exceeds the results when these materials are used separately.64

    Composites of HA and various polymers, including poly(lactic acid) (PLA),65 PLGA,66 gelatin,67 chitosan,68,69 and collagen70 have been successfully fabricated and have demonstrated enhanced bone formation in vitro and/or in vivo. These materials are considered to be biomimetic and to stimulate the formation, precipitation, and deposition of calcium phosphate from simulated body fluid (SBF), resulting in enhanced bone-matrix interface strength.62 Furthermore, Ma et al. demonstrated porous poly(L-lactic acid) (PLLA)/HA composite scaffolds to have superior osteoconductivity properties and to promote enhanced osteoblastic cell survival, proliferation, and expression of bone-specific markers (i.e., a bone sialoprotein and osteocalcin) in comparison to pure PLLA scaffolds during 6 weeks of in vitro cultivation.71

    Upon implantation, the addition of HA to natural polymer scaffolds has been shown to improve the bioactivity and mechanical properties compared to polymer control scaffolds72 and to potentially reduce adverse effects associated with the degradation of some synthetic polymers.73 For instance, Higashi et al. observed accelerated and increased bone formation with composite PLA/HA scaffolds in a rat femur defect model, in comparison to pure PLA scaffolds.74 Overall, polymer/HA composites demonstrate osteoconductivity superior to their pure polymer counterparts.

    3. Advanced Hydrogels
    Hydrogels, due to their unique biocompatibility and desirable physical characteristics, have long been used as materials for tissue engineering. Hydrogels not only serve as matrices for tissue engineering and regenerative medicine but also are capable of mimicking extracellular matrix topography and delivering required bioactive agents that promote tissue regeneration.75,76 From the naturally derived collagen and gelatin gels to the synthetic poly(ethylene glycol) materials, poly(vinyl alcohol)-based hydrogel systems have been utilized for bone tissue engineering.76,77

    Recently, self-assembling peptides have gained attention for forming scaffolds, as they are completely biological, biocompatible, and biodegradable.78,79 Self-assembling systems aim to mimic the natural extracellular matrix, and peptides, which may be readily synthesized chemically and biologically, conveniently serve as the starting material. For example, self-assembling RAD16-I (i.e., PuraMatrix™, Cambridge, MA) can form an injectable nanofiber network or hydrogel upon implantation. In other words, RAD16-I peptides may be injected, and via interactions with body fluids, they will gel and adopt the physical geometry of the tissue defect. Further, self-assembling RAD16-I, as well as other peptides such as P11-4, have been shown to support osteogenesis both in vitro and in vivo.80–83 For instance, Misawa et al. observed bony bridge formation after the injection of RAD16-I into small (i.e., 3 mm) bone defects of mice calvaria. Lastly, these self-assem-bling nano-featured biomaterials have been sown to be non-immunogenic and biodegradable, safely breaking down into amino acids that may be readily and easily cleared in vivo. Thus, SAPs represent a novel class of biomaterials that offers a promising option for BTE applications.

    4. Immuno-modulatory Biomaterials
    Immunobioengineering aims to design materials that have the ability to modulate or manipulate the immune system in a favorable manner for enhanced bone repair and regeneration.84 Typically, the host’s immune reaction to an implant begins with the initial acute response to the surgical injury and innate recognition of the foreign material, which is subsequently followed by adaptive immunity mediated chronic inflammation in response specific recognition of antigens. Novel strategies in immunobioengineering are highlighting the importance of incorporating rational control and modulation, and importantly not elimination, of host inflammation into the design of tissue engineering strategies methods. A list of immunomodulating biomate-rial strategies are presented in Table 1.

    TABLE 1
    TABLE 1
    Immunomodulation Strategies for Biomaterials
    Several specific strategies have been proposed in immunobioengineering, namely selection of appropriate material type, biomaterial surface modulate (i.e., surface treatments, surface topography), and incorporation of artificial extracellular matrix and/or bioactive molecules. Although traditionally it has been accepted that the implants should be immune-inert, it is proving to be more beneficial to design materials that allow for enhanced cell-specific responses that encourage accelerated wound healing and bone tissue regeneration (i.e., increased boneforming cell activity, and decreased NK cell activity and T and B cell-mediated immunity). One of these strategies is to design biomateri-als of ECM similar composition and structure. For instance, Smith et al. demonstrated blends of polydioxanon and collagen or elastin to have immunomodulating effects by decreasing the activity of natural killer cells, as well as T- and B-cell proliferation.85 In addition, in immuno-modulating biomaterials, the biomaterial surfaces may be modified to become more immuno-compatible. The biomaterial surface is the first most critical factor for host acute immune response upon implantation, since the surface chemistry is responsible for the type, intensity, and conformation of serum proteins that are absorbed. The biomaterial surface should limit macrophage adhesion and activation as well as their fusion into foreign body giant cells (FBGCs). For instance, hydrophilic surfaces are associated with low-integrin binding sites and, therefore, decreased dendritic cell maturation and macrophage spreading, and increased macrophage apoptosis.86,87 Biomaterial surface topography, and micro/nano-scale architecture play a significant role in modulating and activating the immune system. Cao et al. demonstrated decreased capsule formation and increased tissue regeneration in scaffolds with aligned fiber topography compared to scaffolds with randomly aligned fibers.88 Biomaterial surface treatments may also be employed to shield the biomaterial from protein absorption (i.e., coating with mic-roparticle hydrogels, surfactant polymers, etc.), or to deliver bioactive molecules (i.e., growth factors, anti-inflammatory drugs).88

    Specific immunobioengineering studies have investigated the effects of pharmacologic modulation of the inflammatory response on bone regeneration in vivo; they involve cytokine-specific agents, corticosteroids, prostaglandins, non-ste-roidal anti-inflammatory drugs, and selective prostaglandin agonists.89 For instance, pro-inflam-matory synthetic thrombin peptide TP508, which activates the same signaling pathways stimulated by TNF-α, IL-1, and other pro-inflammatory cy-tokines during fracture healing, has been shown to have anabolic effects and to enhance in vivo bone regeneration.90 In a rat model, a single injection of TP508 into a femoral fracture resulted in increased strength of the healed bone, vascularization of fracture site, and accelerated fracture repair and regeneration.91 Furthermore, studies have reported similar effects on bone healing in rabbits, with the controlled release of TP508 from various biodegradable scaffolds (i.e., PLGA microspheres and poly(propylene fumarate) scaffolds).92,93

    Selective prostaglandin agonists represent another interesting immunomodulating target for enhanced bone regeneration. Previously, prostaglandins have been avoided as a therapeutic agent for bone repair, due to the risk of well-recognized side effects, including severe systemic inflammation. However, the main effects of prostaglandins on bone have been recently identified to occur selectively via two prosta-glandin receptors (i.e., Prostaglandin E2 type 2 (EP2) and EP4 receptors); thus, the systemic side effects may be avoided. Several studies have demonstrated the positive effects of selective EP2 or EP4 receptor agonists on bone fracture healing in various animal models.94,95 In dogs, healing of critical-size long-bone segmental defects in the radius and tibia was accelerated and significantly enhanced with EP2 agonists encapsulated in a PLGA carrier.95

    Although these results are extremely promising thus far, further studies are needed to investigate more immunomodulating targets. Most importantly, strategies to integrate inflammatory modulation into tissue engineering strategies to enhance bone regeneration are needed.

    B. Biodegradable Scaffolds

    1. Scaffold Mechanical Integrity, Structure, and Mechanotransduction
    A key feature of BTE scaffolds is to provide temporary mechanical integrity at the defect site until the bone tissue is repaired or regenerated, and normal biomechanical function is restored. For the bone tissue engineering scaffold to be “functional” immediately upon implantation, its biomechanical properties must match the physical demand of the healthy surrounding bone.96 In addition, the mechanical strength of the scaffold affects the mechanotransduction of the adherent bone cells on the scaffold, which plays a critical role in the bone repair and remodeling processes. It has been proposed that, generally, the structural biomechanics of the BTE scaffold is related to the osteoconductive properties of the scaffold, while mechanotrans-duction is related to its potential osteoinduc-tive properties.97 Biomechanical stimuli of cells due to the scaffold deformation largely influences osteoinduction (i.e., bone ingrowth from the host). Therefore, as suggested by Sikavitsas et al., a mechanotransduction strategy may be used to control the function of bone cells in vivo by designing a scaffold with mechanical properties that allow ‘osteoinductive fluid flow’ in the scaffold. By combining three-dimensional imaging, flow modeling, and numerical simulation of scaffold physical properties, threshold permeability (k = 1/32[var phi]r2 where r is the hydraulic radius and [var phi] is equivalent to the required cut-off radius) may be determined. Specifically, it was verified that a threshold permeability of ∼3 × 10−11 m2 of a porous bone graft implant was necessary for inducing vascularization and mineralization in an implant.98,99

    The BTE biomechanical paradigm has been well described in a step-wise fashion, where each step holds the mechanical aspects of the scaffold central to insure the safety of the surgical procedure using a BTE scaffold (Fig. 3).97 The first step, which involves the bone mechanical properties and loading conditions, is analogous to the primary fixation of the scaffold. At this point, the BTE scaffold should not induce a stress-shielding effect, which will result in peri-scaffold bone resorption as seen in metallic joint implants. Also, the elastic property of the BTE scaffold should not exceed that of bone, to maintain a proper mechanical stimulation on the peri-scaffold bone, which depends on the loading conditions. The second step involves interface biomechanics and may be identified as the secondary fixa-tion. Here, the mechanical properties of the BTE scaffold may be adapted to generate interface scaffold-bone mechanotransduction, which has been shown to influence tissue differentiation and osteointegration of the scaffold.100 The third step, which may be termed ‘final fixation,’ involves scaffold evolution, in which the ingrowing bone offers support to the mechanical load as the BTE scaffold degrades. Thus, each step revolves around mechanical aspects, which induces a biological reaction in and around the BTE scaffold via mechanotransduction. It has been suggested that the separation between these steps may be represent an engineering approach in the mechanical design of bone scaffolds. Ideally, if mechanical considerations can be used to confer osteoinductivity to a BTE scaffold, the dependency on osteogenic factors and bioreactors may be reduced. This might eventually lead to the development of an off-the-shelf product.101

    FIGURE 3
    FIGURE 3
    Illustration of a three-step biomechanical paradigm in BTE. In the first step, upon implantation, it is critical that the mechanical properties of the BTE scaffold should closely match that of the surrounding host bone tissue and loading conditions to ...
    Mechanical properties of human bone vary tremendously according to location and function (i.e., load or non-load bearing). Again, the restorative scaffold’s mechanical properties should be modulated or tailored to match the demands of the defect site, to decrease or avoid complications such as stress shielding, implant-related osteopenia, and subsequent re-fracture.102 The scaffold’s material composition largely influences its mechanical properties. Dense ceramics (HA, calcium triphosphate) possess elastic moduli and compressive strength similar to human cortical bone; however, they are brittle and display slow degradation rates (Fig. 4).103 On the other hand, biodegradable polymer scaffolds display human cancellous bone compatible mechanics with tunable degradation. For this reason, the development of polymer-ceramic composite BTE scaffolds is becoming increasingly attractive: scaffold properties can be tailored to the particular mechanical and physiologic demands of the host tissue by effectively controlling volume fraction, morphology, and arrangement of the inorganic particulate phase in the polymer matrix. For example, widely investigated composites for BTE involve the incorporation of bioceramic and bioglass particles, carbon nanotubes (CNTs), or magnesium metallic or alloy particles.104–107 These inorganic inclusions positively affect the mechanical properties leading to reinforcement of the scaffold structure104 compared with non-composite polymer scaffolds. The enhancement of mechanical properties depends strongly on the inclusion shape and size distribution, as well as on the quality of the inclusion distribution in the matrix and on the strength of the inclusion–matrix interface. Although the composite strategy is promising, the scaffold mechanical properties are nowhere close to demonstrating the human cortical bone mechanical properties. On the other hand, composite scaffolds display enhanced functionality. In a study conducted in our lab on composite CNT/PLGA microsphere scaffolds, we observed increased biomimetic biomineralization of the composite scaffolds after a 14-day incubation in simulated body fluid (SBF) in vitro, in comparison to PLGA polymer scaffolds (Fig. 5). The increased bio-mineralization may be attributed to the CNTs present in the composite scaffold. The increased mechanical strength of the composite scaffolds can be attributed to the increased CNTs at the joining microsphere–microsphere areas. Thus, by forming composites with CNTs, the overall mechanical and biomimetic properties of a polymer scaffold may be effectively enhanced.104

    FIGURE 4
    FIGURE 4
    Elastic modulus versus compressive strength values of various BTE biomaterial classes compared to human bone. Adapted from Rezwan et al. (103).
    FIGURE 5
    FIGURE 5
    SEM images of (A) PLGA (50/50) microsphere scaffolds, and (B) composite carbon nanotube/PLGA (50:50) microsphere scaffolds after 14 days in simulated body fluid. Crystalization is seen the joining areas of mi-crospheres in only composite CNT/PLGA scaffolds. ...
    Recently, biodegradable metals gained attention as the new generation biomaterials. They offer good mechanical properties, and therefore may be potent biomaterial options to make scaffolds with cortical bone–like mechanical properties. Particularly, magnesium metal has attracted attention because it has density and mechanical strength similar to cortical bone.108–110 Moreover, magnesium is present in small quantities in our bones. One particular disadvantage of magnesium is its rapid and uncontrolled degradation. Although this problem can be partially addressed by alloying magnesium with other metals such as zinc and aluminum, further investigations to develop and characterize magnesium-based scaffold systems for BTE are needed.111

    2. Scaffold Porosity
    Microporosity is a critical element of the osteoconductive properties of scaffold material and the resultant bone tissue ingrowth and vascularization. Scaffold pore structure (i.e., pore size, volume, and interconnectedness) is an essential consideration for proper cell growth, cell migration, nutrient flow, vascularization, and better spatial organization for cell growth and ECM production.112,113 Although some ambiguity remains surrounding the optimal porosity and pore size for a three-dimensional bone scaffold, studies suggest that scaffolds currently designed with small pore sizes (i.e.,

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