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The Biology Behind BioXclude ®
The Biology Behind BioXclude®
The Biology Behind BioXclude ®


Naturally Derived Barrier Membrane
SUPERIOR BARRIER FUNCTION + INHERENT BIOLOGICAL COMPONENTS = ACCELERATED HEALING




THE AMNIOTIC SAC:
  • Barrier: The amnion-chorion membrane is the barrier between the mother and developing child. It has a unique combination of strength and flexibility that allows it to maintain its integrity while simultaneously allowing fetal movement and growth
  • Cushion: The amniotic sac effectively cushions the fetus from impacts and pressures resulting from the mother’s daily activities
  • Infection Prevention: Short, charged peptides present in the chorion layer are thought to help prevent uterine infections that would pose a significant threat to the pregnancy
  • Immunomodulation: The amniotic sac employs unique “cloaking” mechanisms to prevent the mother’s immune system from mounting a foreign body response against the child. These amnion and chorion also contain immunomodulatory cytokines that can help to temper inflammation within the uterine environment.








Dynamic Barrier Membrane
NATRUALLY TOUGH AND EXCEPTIONALLY FLEXIBLE
The amnion and chorion layers of the amniotic sac serve the critical role of creating a functional barrier between the mother and child throughout pregnancy. The amnion-chorion membrane must maintain its integrity in a highly dynamic environment. The tough but flexible properties of amnion-chorion allografts are ideally suited for dentoalveolar applications.






The amniotic sac if formed by a thin pair of membranes, the amnion and chorion, which hold a developing embryo (and later fetus) until shortly before birth. In conjunction with the placenta, the amniotic sac creates an enclosed, fluid-filled bag that protects the developing fetus from biological threats (e.g. infection, inflammation, and the mother’s immune system) as well as mechanical stresses (e.g. external pressures and impacts stemming from the mother’s movements). To accomplish this dynamic range of tasks, the amnion-chorion membrane must be both resilient and flexible.



PURION PROCESSING LEAVES BASEMENT MEMBRANES INTACT
BioXclude is created with the patented Purion process, involving a minimal manipulation of the tissue to maintain the critical layers of the amnion and chorion layers intact. As shown in the illustration below, the epithelial and intermediate spongy layers are gently removed, and the remaining layers of amnion and chorion are laminated back together. Removal of the epithelial layer exposes the basement membrane of the amnion layer to provide an ideal surface for cellular attachment and migration, a key aspect of wound healing. Removal of the spongy layer enables the efficient dehydration of the membrane, allowing the amnion-chorion laminate to be dried without loss of critical growth factors to create a shelf-stable membrane product.





BASEMENT MEMBRANE BARRIER
The basement membrane is a thin, delicate layer of protein fibers and glycosaminoglycans deposited by epithelial cells that anchors the epithelium to underlying connective tissue and maintains a functional barrier between tissues. As the natural substrate for epithelial cells, the basement membrane of BioXclude provides an ideal substrate for cellular attachment and migration. Additionally, because the basement membrane is perceived by epithelial cells as an ideal substrate, epithelial migration and proliferation will be naturally directed over the surface of the membrane, increasing wound closure rates.






Epithelial Template
BASEMENT MEMBRANES PROVIDE FOUNDATION FOR HEALING
The amnion and chorion layers are composed of a rich combination of extracellular matrix proteins. In addition to creating a dynamic barrier membrane, these proteins provide important cues that direct tissue growth and organization. When incorporated into an allograft tissue, these cues help to direct cellular migration and tissue regeneration, critical aspects of healing.




INTEGRINS LET CELLS "SEE" THEIR LOCAL ENVIRONMENT
Cells use integrins that are embedded in their outer membrane to attach to the extracellular matrix (ECM), providing a mechanism for cells to adhere to the ECM and generate force for migration. Integrins are formed as a pairing between alpha and beta subunits, with each alpha-beta combination having a specific binding affinity. Because of this, the binding of integrin pairs also provides critical information to the cell about its local environment. For example, integrin pairs that bind motifs in laminin will only be engaged when laminin is present in the ECM, allowing cells to “see” their local environment.




The idea that soluble growth factors (e.g. PDGF-BB, EGF, TGF-b, BMP-2, etc.) activate cellular pathways to stimulate responses within the cell is commonly understood: a growth factor on the outside of the cell binds to a growth factor receptor, the binding of the growth factor creates a signal in the cell, that signal is propagated within the cell via signaling pathways, and changes in gene expression and cell behavior result.

It should also be recognized that the ECM activates cellular pathways to stimulate responses within the cell; however, this is a critical aspect of BioXclude’s success. When integrins bind to the complex ECM of BioXclude, signals are created in the cell that propagate by the similar mechanisms and pathways as growth factor signaling pathways. Moreover, the pathways used by growth factor and integrin signaling often converge, creating important synergies between the soluble factors and ECM present in BioXclude, effectively maximizing the healing response at the treatment site.





WHEN CELLS "SEE" MEMBRANES, THEY KNOW WHERE TO GO
Basement membranes are the natural substrate for epithelial cells. In fact, the epithelial layer is responsible for creating and maintaining the basement membrane as a critical barrier between tissue types. When tissues are damaged, local cells must use the signals available to direct wound healing and tissue repair. Re-epithelialization, a critical aspect of wound closure, requires that epithelial cells at the wound margins migrate and proliferate over the wound while simultaneously creating a new basement membrane over the wound. By placing a BioXclude, a membrane with intact basement membranes, over wounds or between distinct tissue types, cells involved in rebuilding damaged tissues are provided a template that directs their activity.




Immunomodulatory Cytokines
NATRUAL BLEND OF CYTOKINES PREVENTS DELETERIOUS INFLAMMATION
While inflammation is an important part of all wound healing processes, too much or too little inflammation can interfere with the natrual progression of tissue repair and regeneration. Exuberant inflammation within the uterine environment (in response to infection, for example) would pose a significant threat to developing child. Factors within the amnion and chorion layers of the amniotic sac work to buffer inflammatory responses and protect against dangerous levels of inflammation that would interfere with fetal growth and development. Immunomodulatory properties of amnion-chorion membranes help to prevent exuberant inflammation at treatment sites, allowing optimal healing to proceed without delay.

Although inflammation is a necessary step in the healing process, prolonged inflammation can lead to chronic conditions that prevent wound healing. Preventing excessive or prolonged inflammatory responses will also decrease post-operative patient pain.


Courtesy of MiMedx









Infection-Fighting Peptides

NATURALLY OCCURING ANTI-BACTERIAL, ANTI-FUNGAL, and ANTI-VIRAL FACTORS
In addition to protecting the developing child from an attack from the mother’s immune system, the amnion-chorion membrane actively works to fight uterine infections that would pose a significant threat to the pregnancy.

“The chorion trophoblast layer is likely to have a particularly critical role in preventing infection ascending from the vagina crossing the fetal membranes and reaching the amniotic fluid and fetus.”
- King, et al., Placenta (2007) 28, p.161-169.



The trophoblast layer of the chorion is the outermost layer of the amniotic sac membrane. In addition to providing a physical barrier to infection, the trophoblast layer is loaded with beta-defensins, potent cysteine-rich peptides that fight bacterial, fungal, and viral infections.


BETA-DEFENSINS
Beta-defensins are short (18-45 a.a.), cysteine-rich peptides found in mucosal tissues, include the respiratory tract, reproductive tract, oral cavity, and placental tissues. The peptides are active against many Gram-negative and Gram-positive bacteria, fungi, and enveloped viruses.
© Adrei Lomize / Wikimedia Commons

ACTIVE AGAINST ORAL BACTERIA
Recent studies that highlight the infection fighting capabilities of BioXclude against strains of bacteria associated with periodontal disease include:

1. Ashraf H, Font K, Powell C, and Schurr M. Antimicrobial Activity of an Amnion-Chorion Membrane to Oral Microbes. International Journal of Dentistry, 2019. 2019: p. 7. This study examined the ability of BioXclude inhibit the growth of three different strains of bacteria: Aggregatibacter actinomycetemcomitans, Streptococcus mutans, and Streptococcus oralis. Based on the observation that no colony forming units (CFUs) were recovered from BioXclude membranes after being inoculated onto the membranes and incubated for 12 and 24 hours, the authors concluded that the BioXclude membranes were bactericidal, performing as well in this study as tetracycline.

2. Palanker ND, Lee C-T, Weltman RL, Tribble GD, van der Hoeven R, Hong J, and Wang B. Antimicrobial Efficacy Assessment of Human Derived Composite Amnion-Chorion Membrane. Scientific reports, 2019. 9(1): p. 15600. Using three novel assays to directly evaluate the antimicrobial efficacy of BioXclude, this study was able to observe that BioXclude acted to kill Streptococcus gordonii Challis, a Gram-positive bacterium and one of the initial colonizers in the oral cavity.






Active Growth Factors
NATUALLY BALANCED FOR GROWTH AND DEVELOPMENT
As the child grows, the amnion-chorion membrane, itself, must grow. This requires active cellular proliferation and tissue generation, which is directed by growth factors in the tissue. High levels of growth factors are needed to keep the amnion-chorion growing at an appropriate rate throughout pregnancy. When released from the amnion-chorion allograft, these factors have been shown to activate cells in vitro, indicating that their presence in these membranes will activate tissue growth and development when placed into surgical treatment sites.

Over 200 soluble factors have been identified in dehydrated amnion-chorion allografts (MiMedx Primer, 2015), including key regulators of wound healing and tissue repair:


226 PRESERVED GROWTH FACTORS,
CYTOKINES, AND CHEMOKINES IN BIOXCLUDE


Angiostatin
Galectin-7
TIMP-2
IL-1 F10
IGFBP-2
FLRG
IGFBP-6
Pentraxin 3
Resistin
CA9
OSM
TRAIL
Thrombos
WISIP-1
S100A8
RGM-B
Marapsin
PGRP-S
Thrombo
aFGF
FABP2
OPG
Trappin-2
Dkk-4
Lipocalin-2
Cystatin C
FGF-9
IL-1ra
Leptin
MCSF
Cripto-1
GASP-1
TFPI
GRO
GDNF
PIGF
Eotaxin-2
IGFBP-3
Thyroglobulin
OPN
Furin
DKK-1
GROa
PF4
BMP-5
Granulysin
Galectin-1
DAN
IL-21
Clusterin
MIF
GDF-15
CEA
MIP-1a
CXCL16
CNTF
TPO
Procalcitonin
sFRP-3
FGF-19
PDGF-AA
MCP-1
Kallikrein 5
PARC
FGF-21
VEGF
IP-10
NT-3
IL-18
IL-8
IL-1 F8
VEGF-D
I-309
Eotaxin
ACE-2
NSE
PAI-1
IL-1 F5
IL-1 F7
Gas 1
CRP
HGF
6Ckine
EG-VEGF
Cystatin B
CHI3L1
IL-17C
SP-D
uPA
ANG-4
Shh-N
TSH
Renin
NT-4
GASP-2
ANGPTL3
FGF-6
NAP-2
BDNF
ST2
IL-34
BAFF
EGF
GH
IGF-I
BTC
TGFb3
MIP-d
CK beta 8-1
IL-12p40
Adiponectin
TSP-1
Angioten
Serpin A4
Midkine
TGFb1
IL-1 F6
Dkk-3
IL-1 F9
Obsteoactivin
DcR3
Fractalkine
LAP(TGFb1)
IGF-2
DLL1
PDGF-88
Angiogenin
Cystatin A
BMP-7
MBL
Cystatin E M
NOV
Eotaxin-3
PDGF-AB
IL-33
SDF-1b
IL-6
BMP-9
LIGHT
TNFb
IL-1a
NRG1-b1
FGF-7
IL-32 alpha
IL-7
HB-EGF
Pref-1
Follistati
gp130
RBP4
hCGb
Legumain
Prolactin
bIG-H3
RANTES
WIF-1
Galectin-3
Follistatin
APRIL
Insulin
IL-24
CF XIV
ULBP-1
Chemerin
CSa
MIG
IL-23
IL-17B
VEGF-C
IL-6sR
MIP-1b
ENA-78
IL-20
TGFb2
Lymphotactin
AgRP
TNFa
I-TAC
Fit-3L
Il-1b
G-CSF
IL-2
Fetuin A
ANGPTL4
IGFBP-5
Adipsin
TIMP-1
LRIG3
IGFBP-1
BMP-2
HAI-2
CXCL14
IGFBP-4
FSH
TRANCE
TWEAK
Galectin-9
ADAMTS
ANG-2
MCP-2
IL-27
HCC-1
Kallikrein 14
bFGF
ANG-1
IL-16
IL-11
BLC
IL-17E
TIMP-4
IL-3
Galecin-2
SCF
GCP-2
GM-CSF
Activin A
IL-15
IL-4
Courtesy of MiMedx


Courtesy of MiMedx

Purion processing maximizes the growth factor content in each allograft, delivering 20 times the growth factor load over amnion-only products produced with standard processing methods.


Courtesy of MiMedx







ACCELERATED HEALING
First and foremost, BioXclude is a superior barrier membrane. Its tough but flexible physical properties make it an ideal membrane product for use in a wide range of dentoalveolar surgical procedures. It can be easily placed at surgical sites that include tight spaces and irregular surfaces, providing a continuous seal over wounds of all shapes and sizes. Because the epithelial layer of the amnion has been removed, there is no need to worry about the membrane’s orientation at the surgical site: the extracellular matrix on either side of the membrane provides an adhesive surface that can be securely tacked to both soft and hard tissues. Once secured in place, BioXclude flexible matrix can withstand physical forces that are inherent to oral cavities without losing its integrity and, subsequently, barrier function.

Once in place, the complex extracellular matrix of BioXclude membranes provides an ideal substrate for cellular attachment, movement, and proliferation. Specifically, the laminin-rich basement membrane layers of BioXclude are a natural substrate for epithelial cells found in gingival tissue. When these cells encounter the BioXclude membrane, they will naturally grow across the surface, effectively re-epithelializing the membrane and closing the wound. In addition to accelerating wound closure, the presence of the basement membrane template provided by the BioXclude membrane prevents epithelial layers from invading deep into wound voids (e.g. extractions sockets) where they would interfere with bone formation.

Preventing active or ongoing infections in wounds is critical to the progression of wound healing. If infections are present, the body is forced to direct its energy at fighting the infection, leading to destructive inflammatory processes that accompany the immune system’s infection fighting response. Inflammation is a natural stage of acute wound healing processes, but when inflammation persists, as would occur if there is an active infection, wound healing will be delayed. The presence of infection-fighting peptides found in BioXclude are thought to prevent the re-establishment of infections within the surgical site, allowing wound healing activities to progress without delay. Additionally, immunomodulatory cytokines that are naturally present in amnion-chorion membranes, can temper inflammatory processes that would otherwise delay the progression of wound healing. Together, the infection-fighting peptides and immunomodulatory cytokines found in BioXclude likely help to prevent the establishment of conditions that will slow natural wound healing responses, effectively accelerating the establishment of new tissues and wound closure.

BioXclude also has a reservoir of growth factors that are known to play critical roles in wound healing processes. To date, over 200 growth factors have been identified in BioXclude that are known to play active roles in cellular proliferation and migration, stem cell recruitment, and matrix deposition. These factors, when released from rehydrated, Purion-processed amnion-chorion membranes have been shown to remain active, eliciting growth responses in cultured cells.

Ultimately, BioXclude’s naturally derived amnion-chorion membrane provides a multifactorial approach to accelerating wound healing, creating a unique product in this market.