Heparan sulfate analogue
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Heparan sulfate analogues are polymers engineered to mimic several properties of
heparan sulfate Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan (HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or extracellular ma ...
s. They can be constituted with a backbone of
polysaccharides Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with w ...
, such as poly glucose or glucuronatesPetit et al, Controlled sulfatation of natural anionic bacterial polysaccharides can yield agents with specific regenerating activity in vivo. Biomacromolecules 2004;5:445-52 or a polyester such as co polymers of lactic or
malic acid Malic acid is an organic compound with the molecular formula . It is a dicarboxylic acid that is made by all living organisms, contributes to the sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms ...
Jeanbat-Mimaud et al, Bioactive functionalized polymer of malic acid for bone repair and muscle regeneration. J Biomater Sci Polym Ed. 2000;11(9):979-91. to which sulfates, sulfonate or carboxyl groups are added in controlled amounts and location. They have a molecular weight that can range from a few thousand to several hundred thousand
Dalton Dalton may refer to: Science * Dalton (crater), a lunar crater * Dalton (program), chemistry software * Dalton (unit) (Da), the atomic mass unit * John Dalton, chemist, physicist and meteorologist Entertainment * Dalton (Buffyverse), minor cha ...
. Heparan sulfates can sequester
growth factor A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...
s (GFs) and
cytokines Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
in the
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
(ECM) thereby protecting them from degradation. This ensures local presence of these signaling proteins to fulfill their function in the ECM which contributes to the preservation of anatomical form and function. Heparan sulfates bind to matrix proteins on specific sites called "heparan sulfate binding sites" on ECM macromolecules like collagen, fibronectin and laminin, to form a scaffold surrounding the cells and to protect ECM proteins and growth factors from proteolytic degradation by steric hindrance. However, at any site of
inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
, so also in wound areas, heparan sulfates are degraded, mainly by
heparanase Heparanase, also known as HPSE, is an enzyme that acts both at the cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate molecules into shorter chain length oligosaccharides. Synthesis and structure The protein ...
sBarbier-Chassefière et al, Matrix therapy in regenerative medicine, a new approach to chronic wound healing. J Biomed Mater Res A. 2009 Sep 1;90(3):641-7. giving free access to protease to degrade the ECM and a subsequent loss of GFs and cytokines that disrupts the normal tissue homeostasis. Heparan sulfate analogues obtain many of the characteristics of heparan sulfates including the ability to sequester GFs and bind and protect matrix proteins.Morvan et al, An engineered biopolymer prevents mucositis induced by 5-fluorouracil in hamsters. Am J Pathol. 2004;164(2);739-46. However, heparan sulfate analogues are resistant to enzymatic degradation. This way they strengthen the healing potential of the wound bed by repositioning GFs and cytokines back into the ECM.


Heparan sulfate analogues

Several Heparan sulfate analogues (also known a
ReGeneraTing Agents, RGTA
have been developed from a poly glucose backbone. One named OTR4120 is a 85KD biopolymer and used for topical or ophthalmological application and marketed under the name CACIPLIQ20 or CACICOL20, respectively. Heparan sulfate analogues will occupy the free heparan sulfate binding sites on ECM macromolecules like collagen, fibronectin and laminin that become available following heparan sulfate degradation. In many characteristics heparan sulfate analogues are similar to the natural heparan sulfate.Barritault et al, Regenerating agents (RGTAs): a new therapeutic approach. Ann Pharm Fr. 2006 Mar;64(2):135-44. The most important difference is their resistance to enzymatic degradation. The resistance of RGTA is caused by the coupling of the subunits internal bond of the molecules. The β1-4 oxygen-linked binding of the subunits of heparan sulfate is prone to enzymatic cleavage whereas the α1-6 carbon-carbon binding of the subunits of RGTA are resistant to cleavage by all known mammalian glycanases and heparanases. This way RGTA can recreate a scaffold with the ECM proteins and will reposition GFs back into the matrix where they can re-unfold their natural action in wound repair. This way heparan sulfate analogues may contribute to chronic wound healing as will be discussed later on.


Target and function

Heparan sulfate analogues are thought to display identical properties as heparan sulfate with exception of being stable in a proteolytic and glycolytic environment like a
wound A wound is a rapid onset of injury that involves laceration, lacerated or puncture wound, punctured skin (an ''open'' wound), or a bruise, contusion (a ''closed'' wound) from blunt force physical trauma, trauma or compression. In pathology, a '' ...
. Because heparan sulfate is broken down in chronic wounds by heparanase, the analogues only bind at sites where natural heparan sulfate is absent. Also the function of the heparan sulfate analogues is the same as heparan sulfate: structuring the ECM scaffold and protecting a variety of protein ligands such as ECM proteins growth factors and cytokines. By positioning and holding them in place, in a reconstituted organization mimicking that of before the wound, the tissue can then use these different proteins properly and spatially displayed for inducing cell migration, proliferation and differentiation. This results in improved tissue repair and sometimes a real regeneration process.Blanquaert et al, Heparan like molecules induce the repair of skul defects. Bone 1995;17(6):499-506.


Wound repair

Normal
wound repair Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue. In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier agains ...
consists of three different phases:
hemostasis In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. This involves coagulation, whi ...
and
inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
, proliferation and tissue remodeling. In disturbed wound healing, these stages cannot be completed often resulting in a reduced anatomical and functional outcome.Lazarus et al, Definitions and guidelines for assessment of wounds and evaluation of healing. Wound Repair Regen. 1994 Jul;2(3):165-70. Multiple factors determine the average healing time of the different phases. These factors can be classified into local factors such as
infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...
and
ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...
, and systemic factors such as age, stress,
Diabetes Mellitus Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
and smoking.Guo et al, Factors affecting wound healing. J Dent Res. 2010 Mar;89(3):219-29. Epub 2010 Feb 5. Review. In chronic wounds, factors as mentioned above, make it impossible for the tissue to regenerate properly. After injury, the extracellular matrix, and thereby also the heparan sulfate is broken down by different local
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s, produced by
macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
such as, heparanases, serine proteases and
metalloproteinase A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myogen ...
s (MMPs).Henry et al, Inflammatory mediators in wound healing. Surg Clin North Am. 2003 Jun;83(3):483-507. Review. Heparan sulfate analogues replace the broken heparan sulfate at the wound site and bind to the free heparan sulfate binding sites of the extracellular matrix. Heparan sulfate is slightly negatively charged and so it can bind the positively charged units of the proteins and secure the ECM scaffold. That ensures a supply of the different protein ligands at the wound site.


Clinical use

Regenerative medicine Regenerative medicine deals with the "process of replacing, engineering or regenerating human or animal cells, tissues or organs to restore or establish normal function". This field holds the promise of engineering damaged tissues and organs by st ...
is the "process of replacing or regenerating human cells, tissues or organs to restore or establish normal function."Regenerative Medicine, 2008, 3(1), 1–5 7/ref> Heparan sulfate analogues are one of the early examples of regenerative medicine that reached daily clinical use. Multiple articles of animal wound models demonstrated vast effects on improving wound healing heparan sulfate analogues.Tong et al, Stimulated neovascularization, inflammation resolution and collagen maturation in healing rat cutaneous wounds by a heparan sulfate glycosaminoglycan mimetic, OTR4120. Wound Repair Regen. 2009 Nov-Dec;17(6):840-52.Tong et al, RGTA OTR 4120, a heparan sulfate proteoglycan mimetic, increases wound breaking strength and vasodilatory capability in healing rat full-thickness excisional wounds. Wound Repair Regen. 2008 Mar-Apr;16(2):294-9.Tong et al, Heparan sulfate glycosaminoglycan mimetic improves pressure ulcer healing in a rat model of cutaneous ischemia-reperfusion injury. Wound Repair Regen. 2011 Jul;19(4):505-14. These findings formed a rationale for its clinical application. The first clinical studies also show a significant improvement in wound healing.Groah et al, Regenerating matrix-based therapy for chronic wound healing: a prospective within-subject pilot study. Int Wound J. 2011 Feb;8(1):85-95. Different cases have shown improvement and better wound healing over time and persistent ulcer healing after usage of heparan sulfate analogues. Even though several studies show that heparan sulfate analogues contribute to the wound healing, more research in the form of a
Randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical te ...
is needed to obtain conclusive evidence.


See also

*
Heparan sulfate Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan (HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or extracellular ma ...
*
Wound healing Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue. In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier again ...
*
Regenerative medicine Regenerative medicine deals with the "process of replacing, engineering or regenerating human or animal cells, tissues or organs to restore or establish normal function". This field holds the promise of engineering damaged tissues and organs by st ...


References

{{reflist * * * * Glycosaminoglycans