GB2622584A - Wound healing compositions - Google Patents
Wound healing compositions Download PDFInfo
- Publication number
- GB2622584A GB2622584A GB2213707.9A GB202213707A GB2622584A GB 2622584 A GB2622584 A GB 2622584A GB 202213707 A GB202213707 A GB 202213707A GB 2622584 A GB2622584 A GB 2622584A
- Authority
- GB
- United Kingdom
- Prior art keywords
- wound
- decellularized
- platelet
- tissue
- dermal tissue
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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Classifications
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- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
- A61L27/3691—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
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Abstract
A wound healing composition comprising decellularized dermal tissue and platelet-rich fibrin (PRF). A composition comprising decellularized dermal tissue and PRF for use in treatment of a chronic wound, a method of treating a wound comprising contacting the wound with the wound healing composition and a method of manufacturing a wound healing composition comprising a) providing decellularized dermal tissue and b) adding PRF to the tissue are included. The composition may be a homogenous mixture of decellularized tissue and platelet-rich fibrin. The decellularized tissue and PRF may be in between a 1:10 and 10:1 ratio. The platelet-rich fibrin may be autologous with the decellularized tissue. The decellularized tissue may be porcine and the platelet-rich fibrin may be human. The composition may further comprise growth factors, fibroblasts, keratinocytes, mesenchymal stem cells, endothelial cells and plasmids encoding genes. The wound may be a non-healing wound, diabetic wound, skin cancer resection, burn or fistulae. The composition may be injected into the wound. A worked example is given where porcine dermis tissue is decellularized by osmotic shock and cryogenically ground and the decellularized tissue is mixed with porcine platelet-rich fibrin to form a paste, which is injected into a porcine wound bed to promote healing.
Description
Intellectual Property Office Application No G1322137079 RTM Date 0 March 2023 The following terms are registered trade marks and should be read as such wherever they occur in this document: Tween Intellectual Property Office is an operating name of the Patent Office www.gov.uk/ipo Wound Healing Compositions
Technical Field of the Invention
The present invention relates to wound healing compositions comprising decellularized dermal tissue and methods of manufacturing the same. The present invention further relates to use of compositions comprising decellularized tissue in the treatment of acute and chronic cutaneous wounds, such as non-healing wounds, diabetic wounds, skin cancer resection, burns; and fistulae, such as anal and vascular fistulae.
Background
Loss of skin integrity due to acute injuries or chronic pathologies may lead to physiologic imbalance and ultimately in significant disability or even death.
Following injury, the skin is able to self-repair to an extent, but when the injury forms a large or deep wound, e.g., in third-degree burns, chronic diabetic wounds, trauma or in some genodermatoses, the skin may be unable to adequately self-repair without medical intervention.
Over the past 30 years, there have been remarkable advances in the understanding of the cellular and molecular processes involved in acute wound healing and in the pathobiology of chronic wounds. In brief, the processes of cutaneous wounds can be summarised as: tissue injury precipitates blood clotting, platelet aggregation, migration of leukocytes, including neutrophils and macrophages, to the site of injury (Clark RAF, Ghosh K, Tonnesen MG, Tissue Engineering for Cutaneous Wounds. Journal of Investigative Dermatology. Volume 127, Issue 5, May 2007, Pages 1018-1029).
The first step of wound healing is blood clotting, which is essential for complete healing. The clot is formed of fibrin and fibronectin, which provide a framework for cell migration and aggregated platelets, which release growth factors into the surrounding tissue, promoting the healing cascade The growth factors that come from the plasma stimulate the healing process by the activation of fibroblasts to produce collagen, glycosaminoglycans, and proteoglycans, essential for tissue regeneration.
In recent decades, the market for wound treatment materials has rapidly developed to incorporate various matrices of biological origin and artificial design. Such matrices are used as provisional matrices to fill a wound void and act as a framework in which host cells can grow and regenerate tissue. An advantage of biological matrices is that they retain unique features similar to the body which are essential for the tissue regeneration. However, they lack some of the essential biological compounds that are crucial for rapid homeostasis and successful complete regeneration. On the other hand, addition of exogenous healing-promoting proteins cannot only compromise/delay the approval for commercialization from governmental authorities but also create complications related to rejection It would therefore be advantageous to provide a wound healing composition which enables effective and quick tissue regeneration in the wound, and which provides a framework for host cells to colonise the wound and composition to enable rapid tissue regeneration and growth, and which ameliorates or mitigates wound contraction during healing.
It is an aim of embodiments of the present invention to provide a skin substitute or wound healing composition which overcomes or ameliorates one or more problems of the prior art.
Summary of the Invention
According to a first aspect of the invention there is provided a wound healing composition comprising decellularized dermal tissue and platelet-rich fibrin.
Platelet-rich fibrin may be referred to as "PRF" hereinafter.
The platelet-rich fibrin may be pure platelet-rich fibrin (P-PRF) or leucocyte-and platelet-rich fibrin (L-PRF).
Pure platelet-rich fibrin (P-PRF) or leucocyte-poor platelet-rich fibrin is substantially without leucocytes and with a high-density fibrin network.
Leucocyte-and platelet-rich fibrin (L-PRF) comprises leucocytes with a high-density fibrin network.
PRF is differentiated from platelet-rich plasma (hereinafter "PRP"), in that autologous platelets and leukocytes (in the case of L-PRF) are present in a complex fibrin matrix in PRF, but not in 25 PRP.
It is believed that fibrin functions as bridging molecule for many types of cell-cell interactions and provides a critical provisional matrix at sites of injury, in which the cells can proliferate, organize, and carry out specialized functions. Fibrin, in particular, stimulates fibroblasts to proliferate and migrate into the wound laying down new collagen fibres essential for tissue repair.
In addition to the supportive role of fibrin toward homeostasis and fibroblast activation, it is believed that these proteins also stimulate post-wound angiogenesis. After trauma and tissue loss, the blood perfusion is severely compromised. The oxygen supply to the wound must be restored through the process of angiogenesis (formation of new blood vessels) to ensure healing and tissue regeneration, and so the addition of fibrin and/or fibrinogen to decellularized dermal tissue ensures that the wound-healing process using the wound healing compositions of the invention proceeds at a rapid pace, compared to prior art decellularized dermal tissue-based solutions.
PRF has been found to be particularly effective at ensuring optimal chronic wound healing using the compositions of the invention, in particular in reducing contraction of deep wounds such as fistulae and diabetic ulcers.wounds, and ensuring regrowth of native tissue; compared to both untreated wounds, and also surprisingly in wounds in which scaffolds which include fibrin/fibrinogen from other sources or formats are used, such as plasma containing fibrin and platelet-rich plasma. It is believed that using platelet-rich fibrin, rather than using blood plasma or platelet-rich plasma, reduces degradation, as well as ensuring that natural cooperation with other components of platelet-rich fibrin, such as electrolytes, cytokines and other blood proteins, all of which contribute to effective deep wound healing, with minimised wound contraction. It has been surprisingly found that using platelet-rich fibrin per se, containing native fibrin in a matrix, is particularly effective at ensuring optimal wound healing when the wound healing compositions of the invention are used, compared to any use of isolated fibrin/fibrinogen, blood plasma, platelet poor plasma or platelet-rich plasma.
Advantages of PRF over PRP: There is no use of harsh chemicals (such as anticoagulants or bovine thrombin) to collect the blood, allowing the natural fibrinogen (with no biochemical modification) within the blood to be converted to fibrin by thrombin in the early stages of clot formation. This creates a spongy fibrin matrix that allows for a slow release of growth factors (extremely important for wound healing as they can stimulate cells directly to produce the new matrix and new blood supply), which starts the tissue healing process. Endogenous fibrin is the main element important in the clot formation, which is the first step in the healing cascade, providing a bioactive framework for cells to migrate and repopulate the wound as well as new vessels formation, which will provide oxygen supply and nutrition to the new tissue. This protein signals to fibroblasts and other cells to migrate and repopulate the wound.
Using PRF, this process is hugely beneficial as chronic wounds usually have their initial steps in the healing cascade compromised, which is predictive of an impaired wound healing. When the "fibrin matrix" from PRP is added, it will bypass this critical initial impaired phase and expedite wound closure.
- PRF allows for a "mouldable'. scaffold (3D structure) to be formed (as opposed to PRP), which has proven to drastically reduce scar formation and wound contraction in our pre-clinical studies in pigs (see photos added in the patent description). The fibrin 3D structure is capable of counteracting the natural healing forces from the surrounding tissue, which in turn minimises considerably the contraction of the wound. The final appearance/outcome of a scar is determined in part by skin static and dynamic forces during wound healing, therefore a scaffold that has good mechano-modulatory properties and off-load high tension wounds can significantly reduce incisional scar formation and wound contraction, improving its final appearance and functionality.
The PRF product is spun at a lower speed so that the layers of the blood do not separate out as distinctly. This allows some of the white blood cells and stem cells to remain within the platelet layer that is collected for treatment. Thus, there are more healing factors within PRF than is typically seen in PRP. In addition, the lower spin speed causes less trauma to the individual cells of the blood, allowing more intact and active autologous stem cells to remain in the final PRF product.
- Slow physiological polymerisation in PRF also allows the formation of flexible three-dimensional fibrin network that supports cytokine enmeshment and cellular migration (very important in chronic wounds) Th 3-D fibrin mesh of PRF releases growth factors steadily, with a peak level following physiological healing time, which allows a more durable effect on proliferation and differentiation of cells.
The fibrin-rich of PRF is an autologous biomaterial and not an improved fibrin glue (man-made). Unlike the PRP, the fibrin matrix of PRF does not dissolve quickly after application instead, it is remodelled slowly in a similar way to a natural blood clot, allowing completion of the healing cascade in non-healing wounds.
- PRF produces a larger share of blood product (fibrin matrix) over the share of blood taken (no need to collect huge amount of patient's blood).
Instead PRP, the separation of fibrin-rich fraction requires less chemicals, less time, less manipulation of the blood, and less amount of blood taken (being, therefore, more economical); and yields more healing factors, more cells, with less trauma when compared to PRP By "decellularized" we mean that at least 95%, 96%, 97%, 98%, 99%, 99.5, 99.6%, 99.7%, 99.8%, 99.9% or substantially all cells have been removed from the tissue.
The decellularized dermal tissue may comprise epidermis, dermis, hypodermis, basement membrane or any combination thereof, for example. In preferred embodiments the dermal tissue comprises both (at least) epidermis and dermis, and is preferably decellularized intact skin The decellularized dermal tissue may comprise decellularized mammalian dermal tissue, which in some embodiments may be selected from porcine or human dermal tissue. In some embodiments the dermal tissue may be autologous dermal tissue derived from the intended recipient. In other embodiments, the decellularized dermal tissue may be allogenic to the intended recipient, for example the decellularized dermal tissue may be porcine, intended for use in human wound healing.
In some embodiments the blood plasma is autologous material derived from the intended recipient.
In some embodiments the wound healing composition comprises both platelet-rich fibrin and 20 fibrinogen In some embodiments the wound healing composition comprises a homogeneous mixture of decellularized dermal tissue, platetlet-rich fibrin and optionally fibrinogen.
In other embodiments, the wound healing composition may comprise at least one layer of decellularized dermal tissue and at least one layer of platelet-rich fibrin.
In some embodiments there may be at least one layer of PRF between layers of decellularized dermal tissue.
In other embodiments there may be at least one layer of PRF between layers of decellularized dermal tissue, and at least one layer of PRF as an outermost layer of the wound healing composition.
In preferred embodiments the PRF is homogeneously mixed with the decellularized dermal tissue.
The PRF may be autologous with the decellularized dermal tissue (i.e., derived or taken from the same intended recipient) Autologous healing compounds such as fibrin/ fibrinogen isolated from the recipient patient and added into the new formulation can bypass the critical initial steps in the healing cascade, that is normally compromised in chronic and/or deep non-healing wounds.
The PRF is preferably substantially free of red blood cells. The PRF preferably comprises leucocytes and/or stem cells. In one embodiment the PRF comprises stem cells, preferably autologous stem cells retained in the PRF. In another embodiment the PRF comprises leucocytes, preferably autologous leucocytes retained in the PRF. In another embodiment the PRF contains autologous stem cells and leucocytes. The PRF preferably comprises growth factors.
The PRF may comprise added calcium ions, which may be in the form of calcium chloride for example. The calcium chloride may be in a concentration of between 0.1 % vol. and 2% vol. such as between 0.5 % vol. and 1.5% vol., especially around 1 % vol. For human PRF, calcium ions may not be required or present, however calcium ions may be used for any PRF in order to provide a desired degree of coagulation and consistency.
PRF can be isolated from the recipient patient and incorporated into decellularized dermal tissue to be used to speed up the healing process and avoid medical complications and multiple surgeries, which can not only be life-threatening but can also escalate the economic burden to health care.
The ratio of decellularized dermal tissue to the total amount PRF may be between 10:1 and 1:50, preferably between 10:1 and 1:25, between 5:1 and 1:10, 2:1 and 1:10 or between 1:1 and 1:10. In some embodiments the ratio is between 1:2 and 1:9 decellularized dermal tissue:PRF.
The wound healing composition may be in the form of a powder (which may be a lyophilised powder), a dry or wet paste, or a gel. In preferred embodiments the wound healing composition comprises a mouldable paste or gel, which may have a plastic consistency.
The wound healing composition may further comprise citrate, which may be in an amount from 0% to 3% wt. of the wound healing composition.
The wound healing composition may further comprise autologous cells of the intended recipient, which may be homogeneously mixed in the wound healing composition or may be present in one or more layers on one or more layers of decellularized dermal tissue and/or between layers of decellularized dermal tissue. When the autologous cells are present as a layer on or between layers of decellularized dermal tissue, the decellularized dermal tissue is preferably homogeneously mixed with the PRF.
The autologous cells may comprise any one or more of the group comprising fibroblasts, stem cells, keratinocytes and endothelial cells The wound healing composition may be used for gene therapy; or may be a carrier for plasmidencoded genes, for example VEGF, to improve angiogenesis.
In some embodiments, the wound healing composition may include one or more anti-infective or anti-inflammatory agents. In one embodiment the wound healing composition may comprise CORM -soluble carbon monoxide releasing molecule (which has anti-inflammatory action).
In other embodiments the wound healing composition may comprise an anti-infective/ antibiotic such as silver particles/ nanoparticles and/or polyhexamethylene biguanide.
In yet other embodiments the wound healing composition may include one or more further proteins, which may be a glycoprotein, such as a glycoprotein involved in ECM matrix assembly; and may be selected from the group comprising laminin, fibronectin and decorin, preferably at least fibronectin, which has been found to be particularly useful in the regeneration of dermal tissue when combined with PRF in the present wound healing compositions.
The invention provides composition which comprises a 3D structure capable of counteracting natural healing forces from the surrounding tissue, which in turn may minimise the contraction of a wound to which it is applied The final appearance/outcome of a scar is determined in part by skin static and dynamic forces during wound healing, therefore a scaffold that has good mechano-modulatory properties and off-load high tension wounds can significantly reduce incisional scar formation and wound contraction, improving its final appearance and functionality, and these properties are provided by the compositions of the invention.
Contracture of wounds as they heal can be a huge problem to overcome specially in children and the elderly, or in extensive burns or cancer excision. The results of the use of the compositions of the invention show that it is capable of reducing wound contraction by 10 times when compared with untreated wounds, and led to excellent cosmesis, and new tissue formed displayed the same texture and colour of the native skin.
According to a second aspect of the invention there is provided a composition comprising decellularized dermal tissue and platelet-rich fibrin for use in the treatment of wounds In preferred embodiments the wound is a chronic wound (i.e. a wound which takes a relatively long time to heal) such as pressure ulcers, venous ulcers, diabetic ulcers, ischaemic wounds, radiation wounds, fistulae or decubitus ulcers. The wound may be a closed wound or an open wound.
The wound-healing compositions may be applied by any suitable method, but it has been surprisingly found that the compositions are particularly suitable for injection directly into the wound or wound site, unlike many other wound healing compositions, and so in some embodiments the compositions are injected into the wound. In some embodiments the wound is an open wound, and the composition is injected into the wound, preferably towards the base of the wound. In some embodiments the wound is a closed wound and the composition is injected through the surrounding tissue into the wound.
The composition is particularly effective in in tunnelling wounds (contrary to compositions made with blood plasma or platelet-rich plasma) whereby a mouldable/ injectable tissue matrix (with micronized particles) can be applied with a syringe or other instrument into tunnels or extensions filling up all the possible gaps underneath the skin to encourage the cells to migrate, populate the scaffold and literally encourage the growth of new skin without the gaps that can occur with traditional skin grafting. This is important as total coverage is needed not only to provide complete healing but also to protect against infections that can occur when gaps in wounds are left uncovered. The compositions can also be used as minimally invasive treatment for fistulae. Unlike collagen plugs, the paste expands to fill and 'seal' the fistula tract, which makes it less easily expelled when defecating. For complex fistulae, the addition of adipose-derived mesenchymal stem cells in the paste could help to decrease recurrence rates.
The composition, decellularized dermal tissue, and PRY may be as described and defined here nabove.
According to a third aspect of the invention there is provided a method of manufacturing a wound healing composition, the method comprising the steps of: a) Providing decellularized dermal tissue b) Adding platelet-rich fibrin to the decellularized dermal tissue The decellularized dermal tissue may be prepared by any suitable method, including by decellularization using one or more detergents, proteases and/or nucleases, or by osmotic shock treatment. Suitable decellularization methods are those described in Garcia-Galeta et al. 2020 (Decelhtlarisecl scaffolds: just a.framework? Current knowledge and.fitntre directions; E Garcia-Gareta, Y Abdulda em, P Sawadkar, C Kyriakidis, F Lali, Karin Vicente Greco; Journal of Tissue Engineering 11, 1-18 (2020)), and W02017/174965 Step (a) may comprise subjecting the dermal tissue to a decellularization process comprising subjecting the tissue to osmotic shock. The decellularization may comprise contacting the tissue sequentially with hypotonic and hypertonic solutions (in any order) to promote cell lysis.
The dermal tissue may be immersed in the hypotonic and hypertonic solutions.
Contact, or immersion, of the dermal tissue with the hypotonic and hypertonic solutions may be repeated at least once, and preferably at least twice, three times or four times.
The hypotonic solution may comprise sodium chloride. The hypertonic solution may further comprise ethyl enediametetracetate (EDTA) and/or Tris-HCI.
The hypertonic solution may comprise between 0.5M and 2M NaC1, such as around 1M NaCl. The EDTA may be present at a concentration of between 10mNI and 100 mM, such as between 20m1V1 and 50mNI or around 25 mM. The Tris-HC1 may be present at a concentration of between 20 mM and 100 mM, such as between 25 mM and 75 mM or around 50 mM.
The hypertonic solution may comprise 1M sodium chloride, as optimally 25mM EDTA and 50mM Tris-HC1 The hypotonic solution may comprise EDTA and/or Tris-HC1 which may be present at concentrations as described for the hypertonic solution described above.
The decellularization process may comprise contacting the tissue with one or more nuclease.
The nuclease may be contacted with the tissue after the tissue is contacted with the hypotonic and hypertonic solutions. The nuclease may be a DNase or an RNase or a combination of a DNase and RNase. The decellularization process may also comprise washing the tissue, preferably in a saline solution, such as phosphate buffered saline (PBS), after each decellularization step.
After decellularization, the remaining dermal tissue scaffold comprises extracellular matrix ("ECM-), in particular collagen. The structure of the ECM is at least partially, and may be fully, preserved in the scaffold. Thus, the collagen scaffold remaining may comprise collagen fibres displaying original architecture and molecular ultrastructure of the natural tissue material from which it is desired. The natural three-dimensional structures of the fibrous tissue proteins are preferably substantially retained, through some loosening or unfolding is acceptable, without significantly affecting the structural integrity of the scaffold.
It is known that cellular components specific for the scaffold's origin and/or the place of its implantation will invoke proper constructive remodelling of the ECM only when the polymeric architecture of the fibres within the decellularized tissue remains at least partially intact. Therefore, ECM is better suited than any synthetic matrix to elicit functional regenerative remodelling, and provide a successful scaffold for tissue growth.
The decellularized dermal tissue may be lyophilised before step b). The decellularized dermal tissue may bc in thc form of a powder, granules or paste.
The decellularized dermal tissue may comprise decellularized epidermis, dermis, hypodermis, basement membrane or any combination thereof, for example. In preferred embodiments the decellularized dermal tissue comprises both epidermis and dermis, and is preferably decellularized intact skin.
The decellularized dermal tissue may comprise decellularized mammalian dermal tissue, which in some embodiments may be selected from porcine or human dermal tissue. In some embodiments the dermal tissue may be autologous dermal tissue derived from the intended recipient. The method may therefore include obtaining a sample of dermal tissue from the intended recipient of the wound healing compositions, and decellularizing said dermal tissue.
Step b) may comprise homogeneously mixing the PRF with the decellularized dermal tissue. The PRF may be as described hereinabove for the first aspect of the invention.
The PRF may be formed by centrifugation of blood. The relative centrifugal force is chosen to ensure production of PRF, rather than PRP. For human blood, a relative centrifugal force (RCF) of between 550-800g (RAD = 85mm) (around 2400-3050 rpm), may be used, preferably for between 2-10 minutes, more preferably between 3-8 minutes. For porcine blood the RCF is preferably between 95-530g (RAD = 85mm) or between 150-480g (RAD=85mm) for between 2-10 minutes, preferably between 3-8 minutes. In preferred embodiments, centrifugation is performed only once, in order to retain maximum quantities of autologous cells, which are believed to assist with chronic wound healing. It has been surprisingly found that creating the PRF at such speeds enables an optimal product to be recovered that includes maximum quantities of fibrin, and as appropriate, leucocytes and stem cells, whilst enabling removal of red blood cells, and ensuring the correct consistency of the PRF for ease of mixing with the decellularised dermal tissue to create a mouldable and/or injectable product.
The ratio of decellularized dermal tissue to the total amount PRF may be between 10:1 and 1:10, preferably between 5:1 and 1:10, 2:1 and 1:10 or between 1:1 and 1:10. In some embodiments the ratio is between 1:2 and 1:9 decellularized dermal tissue:PRF.
The PRF is preferably obtained from the intended recipient of the wound healing composition (i.e. it is autologous PRF) and therefore preferably comprises autologous fibrin of the intended recipient.
The PRF is preferably substantially free of red blood cells. The PRF preferably comprises leucocytes and/or stem cells, and may be leucocyte-rich PRF..
In some embodiments the method may comprise adding one or more types of autologous cells of the intended recipient, which may be added before, during or after step b). The autologous cells may be as described hereinabove for the first aspect of the invention.
In some embodiments the method may comprise adding one or more proteins, anti-inflammatory agents and/or anti-infective agents, which may be independently added before, during or after step b). The proteins, anti-inflammatory agents and anti-infective agents may be as described hereinabove for the first aspect of the invention According to a fourth aspect of the invention there is provided a method of treating a wound, the method comprising contacting the wound with a wound healing composition of the first aspect of the invention.
In preferred embodiments the wound is a chronic wound (i.e., a wound that does not heal in an orderly set of stages and in a predictable amount of time the way most wounds do; wounds that do not heal within three months are often considered chronic) such as pressure ulcers, venous ulcers, diabetic ulcers, ischaemic wounds, radiation wounds, fistulae or decubitus ulcers. The wound may be a closed wound or an open wound. The wound-healing compositions may be applied by any suitable method, but it has been surprisingly found that the compositions are particularly suitable for injection directly into the wound or wound site, unlike many other wound healing compositions, and so in some embodiments the compositions are injected into the wound. In some embodiments the wound is an open wound, and the composition is injected into the wound, preferably towards the base of the wound. In some embodiments the wound is a closed wound and the composition is injected through the surrounding tissue into the wound.
The method may comprise applying a layer or coating of the wound healing composition on and/or in the wound. The method may comprise applying a layer of wound healing composition followed by a layer of any one or more of the group comprising fibroblasts, stem cells, keratinocytes and endothelial cells, and optionally a further layer of wound healing composition.
The method may comprise further applying a split thickness skin graft on top of the coating or layer of wound healing composition The split thickness skin graft may be applied on top of a layer of fibroblasts, in some embodiments
Detailed Description of the Invention
In order that the invention may be more clearly understood embodiments thereof will now be described, by way of example only
Example 1
A wound healing composition according to the invention was prepared by the following process.
PRE-containinG Dermal Paste Production I yophilised paste Fresh porcine dermis was obtained from Large-White/Landrace crossbreed pigs after euthanasia in a clean environment. Dermal sheets were decellularised using a non-enzymatic protocol consisting of the osmotic shock principle. The decellulari sati on steps employed in the process alternated between hypertonic (1M NaC1, 10mM ethylenediaminetetraacetic acid (EDTA), 50mM Tris-HCI -12h incubation) and hypotonic solutions (5mM EDTA, 10mM Tris-HC1 -12h incubation), with washing steps in between (phosphate buffered saline (PBS) containing 0.05% Tween-20, for 8 h; after each of the previous solutions). The decellularisation process took less than 2 days and was carried out under agitation (Incubator shaker, SciQuip, Shropshire, UK), with 1% antibiotic/antimycotic solution (AA; Sigma-Aldrich, Dorset, UK) to minimise bioburden.
After the final wash dermal sheets were, under sterile conditions, washed 4 times with sterile PBS in order to remove any remaining antibiotics/ antimycotics.
Acellular dermal samples were cut into small pieces (0 5x0 5cm) and placed in sterile cryomil tubes (approximately 2g per tube). Cryogenic gridding was performed using a cryomil machine (Spex SamplePrep Cryomill, Stanmore, UK) which was set using a single operating cycle at an impaction rate of 15 cps, with a run time of 2 minutes. The tubes were loaded and unloaded under a classified laminar flow hood in order to maintain sterility.
The resulting milled dermal scaffolds (i.e. extracellular matrices -ECM) were placed into sterile glass flasks and freeze-dried overnight using Christ Alpha 1-2 LO plus' freeze dryer/Iyophiliser, to preserve temperature-sensitive materials while lyophilising.
Dried ECM particles can be gamma irradiated and kept in a sterile glass flask.
Isolation of autologous platelet-rich fibrin Materials 20 mL sterile syringe.
0.22 pm pore-sized filter. Plastic tubes for blood. Conventional centrifuge.
Solutions: - Sodium citrate solution at 3.8% in water (wt/vol): 0.38 g of sodium citrate dihydrate "302600, Sigma Aldrich, MW = 294.10 g/mol) in 10 mL of distilled water.
- Calcium chloride solution at 10% in PBS (wt/vol): 1.0 g of calcium chloride (#C5670, Sigma Aldrich, MW = 110.98 g/mol) in 10 mL of PBS pH 7.4 (#79382, Sigma Aldrich, 1 20 tablet/200 mL, pH=7.4).
* all solutions are sterile filtered using a 0.22 pm pore-sized filter into a sterile 50 mL tube, using a 20 mL syringe.
Methods * Add 200 pL 3.8% sodium citrate and keep to a sterile 15 mL plastic tube. In other embodiments the concentration of sodium citrate can be adjusted, for example between 0% citrate (i.e. citrate-free) and 200u1 of 5% sodium citrate.
* Collect 9 mL of whole porcine blood and gently transfer to this tube * Centrifuge at 95-480 g (RAD/mm = 85), 8 min, at room temperature (i.e. around 1000 to around 2250 rpm) * The resultant material comprises a topmost layer consisting of platelet poor plasma, a PRF in the middle, and red blood cells (RBC) at the bottom. The PRF forms as a leucocyte-and fibrin-rich component.
* The PRF component is removed from the test tube After removal, the RBC layer attached to the PRF is separated * The PRF is transferred to a separate tube, then 10 RL of a 10% calcium chloride solution in PBS per millilitre of plasma may be added (final calcium chloride concentration in the plasma should be 1%). If a certain degree of coagulation is required the amount of calcium chloride can be adjusted, for example from 0% to around 2-3% final calcium chloride concentration. For human fibrin, calcium chloride is not required.
* Mix gently and incubate for 1 hour at 37°C, In other embodiments mixing can be done for between 1-90 minutes at a temperature of 15-40°C, such as room temperature or at around 37°C.
Production of fibrin-rich dermal paste -wound healing composition of the invention * After the th incubation, the dry dermal powder was assembled into the PRF in different proportions: 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8 1:9 dermal lyophilised paste: PRF, depending on the desired outcome * The sample was kept at room temperature or at 4°C for 5 min * After this period, a gelatinous but mouldable fibrin-rich paste was formed * This paste can be injected into a wound or moulded into the shape of the wound and applied into the wound bed. In alternative embodiments the paste can be applied directly into the wound and moulded in sin, or in vivo to cover the contour of the wound bed of any size or shape.
Wound healing in pigs All experiments were approved by a local ethical review committee and carried out under UK Home Office approval and according to the Animals Scientific Procedures Act (1986). Female Large White pigs, with an initial weight of approx. 50 kg were used for this study. On arrival, pigs were placed into individual pens and allowed to acclimatise for 14 days before initiation of any experiments. Animals were pre-medicated with an intramuscular injection of 1 mg/kg of xylazine (Bayer, Newbury, UK) and 5 mg/kg of ketamine (Pharmacia Animal Health Ltd., Corby, UK), and anaesthetized with 2-5% isofluorane (Baxter Healthcare Ltd., Thetford, UK) in oxygen:nitrous oxide mix-ture (50:50). After clipping and shaving the designated area, each animal was washed with chlorhexidine gluconate 0.5% w/v in 70% (v/v) DEB (Adams Healthcare, Leeds, UK), followed by Pov done-Iod ne USP 10% (w/w) in water (Adams Healthcare, Leeds, UK) A. Chronic wound experimental model Under aseptic techniques, full-thickness, circular wounds, 2 cm in diameter (six per animal), were created between scapula and iliac fossa on the dorsal area of 4 animals. Using sharp dissection with a scalpel (blade 11) full-thickness skin was removed encompassing the epidermis, dermis, subcutaneous fat and superficial fascia. Bleeding was kept to a minimum using pressure and dry gauze. The wound edges were approximately 2.5 cm to allow polytetrafluoroethylene (PTFE) chambers (custom designed in house, with 2cm diameter) to be inserted under the skin and stitched in place with 2.0 prolene sutures (Ethicon Ltd, Livingston, UK). These chambers were inserted to restrict wound contraction and to prevent healing by epithelialization from the wound margins.
B. Full-thickness skin wounds model fbr assessment of 'wound contraction Full thickness circular wounds were created using marked tattoo circles as a reference, by using sharp dissection, and skin was removed encompassing the epidermis, dermis, subcutaneous fat and superficial fascia. The diameter of the wound defect was -3 cm in diameter. Bleeding was kept to a minimum using pressure and dry gauze. And dermal paste (either using decellularized dermal paste with added PRF, as made by Example I, or using decellularized paste without added PRE as a control) was added onto the wound bed.
The fascia over the skeletal muscle acted as the wound bed, and 0.7m1 of wound healing composition, in the form of the mouldable paste produced in Example 1 was injected from syringes onto the wound bed and smoothed to create a uniform surface. In other embodiments the wound healing composition may be applied in a layer of at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5 or up to 2m1 of wound healing composition.
If required in some embodiments, such as when treating open wounds, either a split-thickness skin graft (STSG) can be applied to the surface of the paste or autologous cells such as fibroblasts can be added. In the wounds where fibroblasts are applied to the paste, half of the paste (0.35m1) can be loaded into the wound bed first, then some cells (2.5x105 per cm2 resuspended in 100u1 of PBS) and subsequently applied to the surface, which can be covered with the second half of paste; however, the wound-healing compositions of the invention regenerate skin effectively without addition of STSG or autologous cells, and so these steps are optional Keratinocytes (2.5x105 per cm2 re-suspended in 100u1 ofPBS) were also applied in designated wounds on the surface of the dermal paste.
Each wound (in both experimental in vivo tests) was dressed with pre-cut sheets of Tefiacleart (or any commercially available wound dressing) followed by Jelonet. Over the top of the Jelonet, chambers were packed with saline-moist sterile swabs, and the chamber structure above the skin was wrapped with providone-iodine-soaked swabs. The final dressing applied to all chambers was made with orthopaedic wool (VelbandTM) Mefix® and Elastplast® adhesive tape. Finally, custom-made plastic rigid jackets were applied and secured in place with Velcro straps to protect the experimental wounds from abrasion and accidental displacement.
Once a week the animals were anaesthetised as described above and the dressings were changed for identical fresh dressings. At every dressing change, wounds were assessed for bleeding, microbial contamination, pathologic wound discharge, or any other complications.
The wounds were excised after 28 days (in the chronic wound experimental model), and 56 days (in the wound contraction model), under general anaesthesia. Specimens were processed and stained accordingly for further histological evaluation.
Results Autologous PRF, assembled into the decellularized dermal matrix in a powder format creates a fibrin-rich wound healing composition (a fibrin rich dermal paste) of the invention. When added at sites of tissue damage, in particular full thickness skin wounds the fibrin-rich dermal paste stimulated neovascular ingrowth and a significant number of infiltrated cells, indicating complete engraftment of the fibrin-rich dermal paste The neo epithelium formed after 28 days of implantation, indicating full skin regeneration. The wounds showed small blood vessels and cell infiltration into the matrix after 28 days of implantation, which confirms effective wound healing has occurred. Collagen was assembled and arranged in large collagen bundles in the newly formed skin demonstrating the same thickness and disposition comparable to control/native skin. This is of particular importance as the orientation of collagen fibres can profoundly influence the directed migration of cells, possibly by potentiating growth factor receptor signalling or by mechanically reinforcing cell migration which has a positive impact in tissue remodelling Known skin replacements have major limitations including wound contraction, scars, and poor integration with the host tissue due to lack in the main proteins that are essential for cell growth.
The present invention provides decellularized dermal tissue (especially using osmotic shock decellularization that does not use harsh chemicals and enzymatic digestion which allows preservation of most native proteins in the matrix) in which the preserved extracellular matrix (ECM) proteins in the dermal component are associated with autologous fibrin(isolated from plasma), which provide the essential elements that give chemical and biological healing properties to the scaffold which will speed up the wound closure and guide the migration of fibroblasts to the scaffold, whilst preventing or mitigating wound contraction. Once in the PRF, fibroblasts undergo phenotypic changes characterised by increased collagen production promoting tissue remodelling.
A comparison was made amongst the wounds that were either left to heal naturally, treated with decellularized dermal tissue paste alone or the PRF-containing wound healing composition of Example 1, all compared with non-wounded skin over 56 days. All wounds were outlined with a tattoo to illustrate the extent of the wound and the subsequent degree of contraction during healing. The composition and three-dimensional shape conferred by addition of fibrin-fibrinogen complex to the acellular dermal paste drastically reduced wound contraction and scar formation after creation of full-thickness wounds (where epidermis, dermis and hypodermis were surgically removed) in a porcine in vivo model that was followed up to 56 days. Addition of PRF-rich dermal paste of Example 1 into wounds showed that the tattoo line (used to outline the wounds at day zero and follow up the skin contraction around the wounds) kept the exact same shape and size when compared to control tattoo, indicating 0% contraction of the newly formed skin. Non-treated wounds showed around 80% contraction compared to the wounds treated with the fibrin-rich paste. And wounds whereby decellularized paste with no PRF was added showed about 50% wound contraction.
Most commercially available skin replacements in different formulations (i.e., sheet, gels, pastes, powders, pads, etc) have mainly collagen in their formulation. Collagen-based biomaterials typically possess non-adherent qualities meaning they won't firmly attach to the wound bed. Wounds that are already hard to heal due to underlying pathology require immediate adherence of the biomaterial with prompt start of the healing cascade to allow complete healing and decrease the chance of microorganism growth Conversely, the fibrin-rich (and fibrin and fibrinogen-rich) dermal wound healing compositions of the invention are formed of naturally occurring proteins present in the human skin, and have the property of adhering into the wound bed and cover an extensive variety of wound sizes and depths, from small acute wounds to spreading chronic injuries, further proving its ability to bypass the critical initial steps in the healing cascade, that is normally compromised in chronic non-healing wounds Fibrin markedly affects the extent and stability of new capillaries formation into the wound.
The wound healing compositions of the invention provide a three-dimensional fibrin-rich skin replacement which results in a favourable matrix for the outgrowth of endothelial cells in capillary-like tubular stmctures that enable oxygenation and nutrition to the new formed tissue.
Moreover, the long-term shape stability conferred by PRF to the wound healing composition of Example 1 enables an exact, flat accommodation of the scaffold to the wound bed that will promote seamless scar formation In scarred tissue, the collagen fibres are often more densely packed and differently aligned compared to the collagen found in unwounded skin, and this can be particularly disabling for patients with severe trauma or extensive burns. After implantation, the wound healing composition described in Example 1 above induced tissue regeneration, and the collagen deposition occurred in an organised manner similar to normal skin.
The wound healing compositions of the invention also provide a unique natural skin substitute which has huge potential to expedite closure of large chronic wounds, as its adhesive and mouldable natural features will immobilise the tissue scaffolds and prevent shearing and formation of hematomaiseroma. 'This can drastically decrease the need for several surgical procedures involving wound debridement and multiple grafting, which will significantly reduce the co-morbidities and patient distress with a consequent economic impact on the health care system.
Lastly, the wound healing compositions of the invention have huge positive implications to the healthcare not only in the developed world, but also in poorer countries where healthcare is less developed. Its manufacturing process uses inexpensive materials and allows for longer shelf-life as it does not need refrigerated storage. Being of xenogeneic or autologous origin this scaffold is remarkably beneficial as it does not rely on organ donation and does not require high surgical skills to deliver it.
The above embodiment is/embodiments are described by way of example only. Many variations are possible without departing from the scope of the invention as defined in the appended claims.
Claims (15)
- CLAIMS1. A wound healing composition comprising decellularized dermal tissue and platelet-rich fibrin.
- 2. A wound healing composition as claimed in claim 1 comprising a homogeneous mixture of decellularized dermal tissue and platelet-rich fibrin.
- A wound healing composition as claimed in claim 1 or 2, wherein the platelet-rich fibrin is autologous with the decellularized dermal tissue 4.
- A wound healing composition as claimed in claim 1 or 2, wherein the decellularized dermal tissue is decellularized porcine dermal tissue and the platelet-rich fibrin is human platelet rich fibrin.
- A wound healing composition as claimed in any preceding claim, wherein the ratio of decellularized dermal tissue to the total amount platelet-rich fibrin is between 10:1 and 1:10, preferably between 1:2 and 1:9 decellularized dermal tissue: platelet-rich fibrin.
- A wound healing composition as claimed in any preceding claim further comprising one or more of the group comprising growth factors, fibroblasts, keratinocytes, mesenchymal stem cells, endothelial cells and plasm ids encoding genes.
- 7. A composition comprising decellularized dermal tissue and platelet-rich fibrin, for use in the treatment of a chronic wound.
- 8. A composition for use in the treatment of a wound as claimed in claim 7, wherein the wound is selected from the group comprising non-healing wounds diabetic wounds, skin cancer resection, burns and fistulae.
- 9. A composition for use as claimed in claim 8 wherein the composition is injected into the wound, preferably using a syringe.
- 10. A method of manufacturing a wound healing composition, the method comprising the steps of: a) Providing decellularized dermal tissue; and b) Adding platelet-rich fibrin to the decellularized dermal tissue.
- 11. A method as claimed in claim 10, wherein step b) comprises homogenously mixing the platelet-rich fibrin with the decellularized dermal tissue.
- 12. A method as claimed in claim 10 or 11, wherein the ratio of decellularized dermal tissue to the total amount platelet-rich fibrin is between 10:1 and 1.10, preferably between 1:2 and 1:9 decellularized dermal tissue: platelet-rich fibrin.
- 13. A method as claimed in any one of claims 10 to 12, wherein the method further comprises adding one or more of the group comprising growth factors, fibroblasts, keratinocytes, mesenchymal stem cells, endothelial cells and plasm ids encoding genes to the decellularized dermal tissue.
- 14. A method as claimed in claim 13, wherein the fibroblasts are added after step b).
- 15. A method of treating a wound, the method comprising contacting the wound with a wound healing composition as claimed in any one of claims 1 to 6.
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