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1
P R E S E N T E D B Y : D R . S A R A N G G O T E C H A
Active Wound Coverings: Bioengineered Skin and Dermal
Substitutes.
4
Dermis
Consists of connective tissue, amorphous ground substance
composed of proteoglycans, blood vessels, nerves, lymphatics and muscles.
Dermis can be divided intoSuperficial papillary dermis superficial vascular plexusReticular dermis. Collagen Elastin Extracellular matrix
5
EXTRACELLULAR MATRIX
Extracellular matrix proteoglycans
glycosaminoglycans + core proteins
Hyaluronic dermatan keratan chondroitan heparan
Acid sulphate sulphate sulphate sulphate
6
INTRODUCTION
In the last few decades, there has been a tremendous increase in the development of new active wound coverings and bioengineered skin substitutes.
Increased understanding of wound healing and the complex interactions of cells, extracellular matrix molecules, growth factors, and various signaling molecules brought new materials that optimized wound healing and minimized scarring.
These developments overcame the biochemical difficulties of chronic wounds and the challenges of extensive wounding found with large body surface area burns.
7
INTRODUCTION
Research has shown that moist wound healing creates a more optimal healing environment and this knowledge led to the development of various occlusive synthetic dressings that improved the outcome and addressed the various issues of acute and chronic wound environments.
These new synthetic polymer dressings have improved the outcome in many situations and and slowly replaced the centuries old standard of gauze-type dressings.
9
INTRODUCTION
They can maintain an ideal moist environment, help autolytic debridement, prevent infection, and speed up granulation and epithelialization.
However they are not always able to correct the challenges of complex chronic wounds or extensive wounding of the skin with large body surface area epidermal loss.
10
INTRODUCTION
In recent years, a wide array of biologically active materials and skin substitutes has been developed.
Although an ideal skin substitute is not yet available these products address the various challenges of wound healing.
11
Properties of an ideal skin substitute
Increase healingDecrease painAre safeAre cost effectiveAre nonallergenic/-
antigenic/-toxicAre easy to apply and
removeProvide an infection barrierAre durable/resist shearing
Recreate epidermis and dermis
Provide long term/permanent wound cover
Are easy to manufacture and store
Are easy to obtain/easily available
Have a long shelf life
14
EXTRACELLULAR MATRIX MATERIALS(ECM)
Help change environment of the wound and essentially can be considered active within the wound.
Maintain ideal moist wound healing environment by absorbing excessive fluid or donating moisture.
Help dermal regeneration, absorb bacterial chemical byproducts and destruct wound enzymes (matrix metalloproteinases [MMPs]).
15
ECM (contd)
chemically binds the various metalloproteinases and inactivates them.
Protect local growth factors from degradation by MMPs and therefore growth factors can remain biologically active in the wound environment.
Dressings specifically designed for helping reduce the high levels of MMPs
composed of a mixture of collagen and oxidised regenerated cellulose or alginate fibres
16
ECM (contd)
Examples of such wound dressings are
Promogram Wound Matrix
Prisma
Fibracol plus collagen(Johnson and Johnson)
17
ECM (contd)
To aid dermal regeneration, other materials composed of collagen or hyaluronic acid from various animal sources are used in the wound
This exogenous collagen chemotactic for fibroblasts and macrophages and also provides temporary 3 dimensional scaffold to help with ingrowth of tissue
19
MATRIDERMDermal implant made of native bovine
collagen coated with elastin
This matrix results in a better reconstruction of the dermis than pure collagen matrices.
Allows the ingrowth of host fibroblasts and other cells to regenerate a dermis with properties closer to normal uninjured skin.
20
Matriderm combined with autologous grafting gave better results in terms of elasticity and vascularity than skin grafting alone.
Ryssel H, Gazyakan E, Germann G, et al. The use of matriderm in early excision and autologous skin grafting in burns- a pilot study. Burns 2008; 34: 93-7.
• Fibronectin formation of the dermis reconstructed with MatriDerm was comparable to normal uninjured skin.
Van Zuijlen PP, Lamme EN, van Galen MJ, et al. Long term results of a clinical trial on dermal substitution. A light microscopy and Fourier analysis based evaluation. Burns 2002;28:151-160.
MATRIDERM
21
Matriderm also allows the clinician to simultaneously place an autologous split thickness skin graft with the same procedure, which helps minimise the need for a second operation in burn surgery.
Van Zuijlen PP, Van Trier AJ, Vloemans JF et al.
Graft survival and effectiveness of dermal subsitiution in burns and reconstrive surgery in a one stage grafting model. Plast Reconstr Surg 2000; 106: 615-23.
MATRIDERM
22OASIS WOUND MATRIX
Derived from porcine intestinal submucosa.
Indicated for various types of partial and full thickness wounds, such as burns as well as traumatic and various chronic ulcers.
This natural scaffold, which contains native ECM, and various growth factors is incorporated and absorbed into the wound base.
23OASIS WOUND MATRIX
In vivo studies have shown angiogenesis into the matrix.
Hodde JP, Ernst DM, Hiles MC. An investigation of the long term bioactivity of endogenous growth factor in OASIS Wound Matrix. J Wound Care 2005; 14: 23-5
Oasis wound matrix has been evaluated in a randomised controlled clinical trial in the treatment of venous leg ulcers, and after 12 weeks, 55% of patients were healed in the Oasis group and only 34% in the control group.
Oasis Wound Matrix Web site 2010. Available at : http://www.oasiswoundmatrix.com. Accessed May 23,2010.
25
SYNTHETIC BILAYER SUBSTITUTES
Materials that consist of a porous matrix, which contains collagen, hyaluronic acid, fibronectin, or other acellular matrix proteins, and a thin layer of silicone.
Helps protect the wound from moisture loss and infection.
Examples
26BIOBRANE
Biosynthetic skin substitute
Bilaminate membrane consisting of nylon mesh with covalently bound porcine type I collagen peptide and a thin layer of silicone.
When applied to a partial thickness or freshly excised full thickness wound, it adheres and provides a temporary skin barrier.
27BIOBRANE
As the wound heals, fibroblasts and capillaries grow under the bilayer skin substitute and regenerate tissue in the dermis.
The silicone layer functions as the epidermis, and pores in the silicone material allow some fluid to escape.
In fairly superficial wounds membrane binds to the wound and is gradually replaced by host epithelium from adnexae and wound edges.
28BIOBRANE
In full thickness wounds material stimulates granulation tissue and prepares the bed for autologous grafting, although the silicone membrane and the nylon mesh need to be removed before the procedure.
29AWBAT
Composed of a very thin, porous silicone membrane bound to a loosely knit nylon fabric, which is coated with a mixture of porcine collagen peptides.
Not covalently bound interact more quickly with fibrin in the wound and allows better acute adherence during the initial phase of wound closure.
More uniform distribution of pores in the silicone layer allows better fluid and moisture permeability and decreases the development of seromas at the wound site.
30
INTEGRA DERMAL REGENERATION TEMPLATE
Bilayer matrix that provides a scaffold for dermal regeneration and temporary wound coverage.
Dermal replacement layer consists of a porous matrix of fibres of cross linked bovine collagen and chondroitin-6-sulfate manufactured with a controlled porosity and defined degradation rate.
31
Epidermal substitute layer is made of synthetic polysiloxane polymer and functions to control moisture loss from the wound and provide protection from infection.
The collagen dermal replacement layer serves as a scaffold for the infiltration of fibroblasts and various other cells during the healing process
Over time,dermal layer of integra is degraded,replaced by host tissue,and neodermis is regenerated from template
INTEGRA DERMAL REGENERATION TEMPLATE
32
FUTURE DEVELOPMENTS AND MODIFICATIONS OF ECM MATERIALS
Delivery of antimicrobial agents, growth factors, and DNA to further enhance wound healing.
Colonisation of wound with bacteria occurs quickly formation of a bacterial biofilm chronic infections.
Incorporation of sliver, cadexomer iodine, and other antimicrobials in the ECM materials delay wound colonisation and biofilm formation.
33
ALLOGENIC ACELLULAR SUBSTITUTES
Human cadaver allograft “ GOLD STANDARD” for temporary coverage after burn wound excision.
Dermal allografts human cadaveric skin that is cryopreseved, lyophilized,and glycerolized to remove donor cellular ,infectious and antigenic materials.
Remaining structures serves as a scaffolding or template for the ingrowth of host fibroblasts and vascular tissue and helps regenerate dermal tissue.
34
ALLOGENIC ACELLULAR SUBSTITUTES
However, barrier function is not ideal, shelf life is limited, and contamination of cadaver skin and disease transmission pose risks.
Few commercially available acellular dermal substitutes Alloderm
Graftjacket
GammaGraft
35
LIVING SKIN SUBSTITUTES
ALLOGENIC CELLULAR BIOENGINEERED TISSUELiving skin substitutes Epidermal substitutes Dermal substitutes
COMPOSITE SKIN ALLOGRAFTS
AUTOLOGOUS CULTURED SKIN REPLACEMENTS
36
ALLOGENIC CELLULAR BIOENGINEERED TISSUE
EPIDERMAL SUBSTITUTES
StratagraftsLiving human skin substitute.
Consists of a dermal component that is layered with a fully stratified biologically functional allogenic epidermis generated from neonatal immortalized keratinocytes.
Pathogen free and has tensile strength and barrier function comparable to that of intact human skin, including expression of host defense peptides, which, in turn may help prevent infection.
Supp DM, Karpinski AC, Boyce ST. Expression of human beta- defensis HBD1,HBD2 And HBD3 in cultured keratinocytes and skin subsititutes. Burns 2004; 30 : 643-8
37
ALLOGENIC CELLULAR BIOENGINEERED TISSUE
StratagraftsThis material is comparable to cadaver allograft for temporary
management of skin defects.
In various studies there were no significant differences in autograft “take” between wound sites pre-treated with Stratagraft and cadaveric allograft
Schurr MJ, Foster FN, Centanni JM, et al. Phase I/II clinical evaluation of StrataGraft: a consistent, pathogen free human skin substitute. J Trauma 2009;66: 866-74.
38Dermal substitutes
Dermagraft Cryopreserved human fibroblast derived
dermal subsititute
Manufactured from newborn foreskin fibroblast cells seeded onto a bioabsorbable polyglactin mesh scaffold.
As the fibroblasts proliferate over the scaffold, they secrete various growth factors, cytokines, and ECM proteins and create a 3D human dermal substitute containing metabolically active cells
39
Dermagraft The clinician recieves the material frozen
in a pouch, and after simple thawing and rinsing procedure, it is ready to be used in the wound.
The therapeutic properties are dependent on cell viability after cryopreservation, which is about 60%.
Indicated for use and treatment of full thickness, diabetic foot ulcers lasting more than 6 weeks without muscle, tendon, joint capsule, or bone exposure, in which it has shown to improve healing.
Dermal substitutes
40
ALLOGENIC CELLULAR BIOENGINEERED TISSUEDERMAL SUBSTITUTES
TransCyte Human fibroblast- derived temporary skin substitute
consisting of a polymer silicone membrane and human neonatal fibroblast cells cultured into a nylon mesh.
They secrete various growth factors and ECM molecules, and the silicone membrane protects the wound.
The material is cryopreserved, which leaves the various growth factors and ECM molecules intact
This membrane provides a tranparent synthetic biologically active skin.
41
ALLOGENIC CELLULAR BIOENGINEERED TISSUE
DERMAL SUBSTITUTES
ICX-SKN Single layer dermal substitute comprised of collagen based
scaffolding populated with living fibroblasts.
STILL UNDERGOING CLINICAL TRIAL
42
COMPOSITE SKIN ALLOGRAFTS
Most advanced commercially available allogenic skin substitutes are bioengineered full thickness human skin.
Consist of a collagen scaffold with cultured fibroblasts and a layer of stratified cultured human keratinocytes.
They lack appendageal structures, vasculature, and rete ridges, the histology resembles normal skin.
43OrCel
Consists of a layer of cultured neonatal keratinocytes and a bovine collagen sponge with cultured neonatal fibroblasts.
Cryopreserved- thus needing to be thawed and rinsed before placement into the wound
44APLIGRAF
Composite bilayer product that consists of a layer of bovine type I collagen gel with cultured neonatal fibroblasts for its epidermal component and a cornified epidermal layer of neonatal keratinocytes
Approved by FDA for chronic venous ulcers lasting more than a month that have not responded to standard care and for full thickness diabetic neuropathic foot ulcers lasting more than 3 weeks without exposed tendon, muscle, capsule or bone.
45APLIGRAF
Patients treated with Apligraf experienced faster healing and decreased complication rate, thereby needing less medical follow up.
Falanga V, Margolis D, Alvarez O, et al. Rapid healing of venous ulcers and lack of clinical rejection with an allogenic cultured human skin equivalent. Arch Dermatol 1998; 134: 293-300.
Median time for ulcer closure was 61 days for the Apligraf patients compared with 181 days for the control group.
Veves A, Falanga V, Armstrong DG, et al. Graftskin, a human
skin equivalent , is effective in the management of noninfected neuropathic diabetic ulcers: a prospective randomized mulitcenter clinical trial. Diabetes Care 2001; 24: 290-5.
46
AUTOLOGOUS CULTURED SKIN REPLACEMENTS
EPICEL Cultured epithelial autografts.
First commercially available autologous bioengineered epidermal product available in the United States.
Indicated for use in patients who have deep dermal or full thicknes burns covering more than 30% of body surface area.
47
Limitations of cultured epthelial autografts:
Quite fragile
Susceptible to sheer injury and degradation by infection
Can vary greatly from less than 20% to 100% depending on the wound bed and clinical technique.
Time taken for culturing process is about 3 weeks, which poses challenges with patients clinical care and temporary skin coverage issues.
Although these grafts ultimately induce formation of a normal-appearing dermis, this process takes several years, so currently used in conjunction with a dermal substitute.
48
AUTOLOGOUS CULTURED SKIN REPLACEMENTS
CELL SPRAY: Cultured epithelial autograft suspension that is applied onto a
clean wound bed using an aerosol applicator.
A small split thickness donor biopsy is needed to start the process, and within about 5 days, viable preconfluent keratinocyte suspension can be produced.
These cells proliferate and migrate in the wound bed; provide an even, confluent epidermal cell cover ; promote healing; and optimize scar quality.
49AUTOLOGOUS CULTURED SKIN REPLACEMENTS
The Aerosolized method of application is much simpler, particularly in complex contour areas that are typically difficult to graft.
Also because keratinocytes retain the properties of the donor site, replacing skin with cell suspension from a matched donor site helps optimize outcome.
50AUTOLOGOUS CULTURED SKIN REPLACEMENTS
Epidex Cultured epidermal skin equivalent that is grown from hair follicle
outer root sheeth stem cells.
After a small amount of hair is plucked, the outer root sheath cells are grown in a coculture process designed to result in the formation of fully differentiated epidermis, mounted on silicone disks to facilitate handling.
These disks are then applied onto the wound surface.
51
AUTOLOGOUS CULTURED SKIN REPLACEMENTS
The rapidly dividing epidermal cells expand to cover the lesion
The culturing process takes several weeks but has the advantage that no skin biopsy is required.
52
AUTOLOGOUS CULTURED SKIN REPLACEMENTS
LASERSKIN
Epidermal autograft of cultured keratinocytes on a microperforated esterified hyaluronic acid.
Has been used alone and in combination with autologous fibroblasts cultured on hyaluronic acid matrix making it the first full thickness skin replacement.
53
FUTURE DIRECTIONS
Future research and development in the area of bioengineered skin substitutes is most likely to focus on:
Modifying culturing techniques
Delivering growth factors
DNA and microRNA
Improving full thickness autologous skin substitutes