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Functional Keratin
Applications in Wound Healing
Functional Keratin
� New Paradigm in wound healing
- Physiologic approach to wound healing
� Healing acute wounds faster
� Healing chronic wounds that have not healed with standard of care
standard of care
� Reducing pain when using Negative Pressure Wound Therapy
� Improving skin condition and quality of life in severe skin disorders.
Presentation overview
� What is keratin
� What is Functional Keratin
� Performance data overview
� Clinical applications – wound care
� Clinical applications – orthopedics
� Clinical applications – orthopedics
� IP status
� Regulatory status
� Next steps
What is keratin
� US National Library of Medicine definition
- ‘A class of fibrous proteins or scleroproteins important both as structural proteins and as keys to the study of protein conformation. The family represents the principal constituent of epidermis,
hair, nails, horny tissues, and the organic matrix of tooth enamel
� An important physical structure in a wide range of biological tissue
What is keratin
� An important biological material in cell growth and protein synthesis
Coulombe et al., Vol 441,
18 May 2006, p362-365
Omary et al.,Vol 441,
18May2006, p296-297
“K17 now becomes one of several established ‘command posts’ for the regulation of protein synthesis”
What is Functional Keratin
� Selective isolation of the different protein fractions
Intermediate filament protein
Matrix protein
What is Functional Keratin
� Maintains important functionality
� Reversibly protects Cystine
K-S-S-K
S
S
K-SH
K-S-SO3-K-SO3
-
What is Functional Keratin
� INTACT PROTEINS
• Molecular structure and cystine groups preserved
• Bioactivity maintained
• Possesses film forming properties
• Chopped up into small fractions
• Readily absorbed across biological membranes
• Protected cystine functionality preserved
� FUNCTIONAL PEPTIDES
Keratin 17
Functional KeratinTM
Keratin 17
Functional KeratinTM
Keratin 17
Functional KeratinTM
What is Functional Keratin
Functional Keratin
77% homology between wool intermediate filament protein (Functional KeratinTM) and human K-17
Keratin 17
Functional KeratinTM
Keratin 17
Functional KeratinTM
Highly versatile biopolymer
Keratin can be made into membranes, coatings, gels, wound contact layers
Performance data overview – in vitro
Test Test facility Test Test facility
In vitro
Cell growth Biocompatibility/safety
Fibroblast University of Mississippi, Lincoln University,
Cytotoxicity IS010993-5 Namsa
Keratinocyte University of Mississippi,. Lincoln University,
Irritation IS010993-10 Namsa
Endothelial cells University of Mississippi, Lincoln University.
Sensitization IS010993-10 Namsa
Lymphocytes University of Mississippi. Lincoln University
Irritation - Repeat Insult Patch Test (HRIPT)
Consumer Product Testing Co.
Lincoln University (HRIPT) Testing Co.
Other in vitro Sensitization - Kligman Toxikon Corporation
Antioxidant measurement Crop and Food Research NZ.
Material Mediated Pyrogen Assay Toxikon Corporation
Antiinflammatory, prostaglandin E2
MDS Pharma, Taiwan Reverse Mutation Assay (Ames Test)
Toxikon Corporation
Trypsin biodegradation Canesis Network NZ. Acute Oral Toxicity Toxikon Corporation
Wound fluid handling, compression test
Canesis Network NZ Acute Dermal Toxicity Toxikon Corporation
Fluid handling, inverted cup test
Canesis Network NZ Systemic toxicity Toxikon Corporation
Hemeolysis Toxikon Corporation
Performance data overview – human and animal
Wound care Orthopaedic and other
Rat – acute topical full thickness
University of Otago, NZ Sheep – long bone University of Otago,
Pig – acute topical split thickness
Vanderbilt University Sheep - subcutaneous University of Otago,
Mouse - topical Incell, USA Rat – feeding study for antioxidant effect
Hebei Yling Pharmaceutical Company
Pig Study- phase 1- Deep Partial Thickness wound study
University of Miami, Miller School of Medicine
Rat – hair growth study AgResearch NZ
Pig Study- phase 2- Deep University of Miami, Miller Gap study Flinders University of
Pig Study- phase 2- Deep Partial Thickness wound study
University of Miami, Miller School of Medicine
Gap study Flinders University of South Australia
Pig Study- phase 2-expression of indicator proteins
University of Miami, Miller School of Medicine
Athymic Rat – as DBM carrier and carrier alone (with inactivated DBM)
WuXi AppTec
Human – skin graft donor site
The Clinic of Plastic Surgery, PA.
Rabbit spinal fusion – as DBM carrier
University of New South Wales
Human – chronic wounds Nurse Maude clinic, Rabbit tibial defect – as DBM carrier University of New South Wales
Keraderm as an interface for NPWT
Mississippi Baptist Medical Center Jackson, MI
Case studies conducted in NZ in 2007~8
Nurse Maude, Diabetes centre and community
Wound Care Study publications
� R Kelly, F Sigurjonsson, R A Smith, A Ali, M Than, R Mcpherson, C Hammond, Keratin biopolymer dressings for wound care, Symposium on Advanced Wound Care conference proceedings, 2006.
� R Kelly, F Sigurjonsson, R A Smith, A Ali, M Than, R Mcpherson, C Hammond, Acceptability and Efficacy of Keratin-Based Dressings in the Chronic Wound, European Wound Management Association 2007 conference proceedings.
� W Thompson, S Hanneke, M Compton, L Burrage, K Butler, A keratin matrix interface in negative pressure wound therapy, Clinical Symposium on Advances in Skin and Wound Care, Las Vegas Oct 26-30, 2008.
� S Davis, R Perez, Y Rivas, J Gil, J Valdes, and R Kirsner, The effect of a keratin based dressing on the epithelialization of deep partial thickness wounds, American Academy of
dressing on the epithelialization of deep partial thickness wounds, American Academy of Dermatology meeting, March 2009 in press.
� S Cassidy, M Than, Improved healing of Epidermolysis Bullosa wounds using a novel keratin gel technology, Australian Wound Management Association conference proceedings, May 2008.
� R Perez, R Kirsner, J Gil, J Valdes, S Davis, Evaluation of the effects of two keratin formulations on wound healing and keratin gene expression in a porcine model, Symposium on Advanced Wound Care conference presentation, April 2009 in press.
Current wound care products developed
CE mark
FDA (510K) clearance
TGA approval
Soft tissue applications – acute wound healing
� Deep partial thickness wounds
� Stephen Davies, University of Miami
� Porcine model, n=40
� Keratin X = Keragel, Keratin Y = Keraderm
Acute partial thickness wound animal study
P<0.025
P<0.005
P<0.05
•test by performed the Miller School of Medicine, University of Miami, USA
Performance summary
� Keraderm
- 12% faster than polyurethane film dressings, and 26% faster than untreated controls.
� Keragel
- 7% faster than polyurethane film dressings and 21% faster than
- 7% faster than polyurethane film dressings and 21% faster than untreated controls.
� The keratin treatments did not have any adverse effects (erythema, swelling, or infection) on the healing process and enhanced epithelialization faster than positive control dressing.
Ex-vivo protein expression study
� Studied expression of keratins 6, 16, 17 at wound site in early days of healing
� KRT6A and KRT16 are associated with
� KRT6A and KRT16 are associated with keratinocytes with a more active “hyperproliferating” state.
Ex-vivo protein expression study
•test by performed the Miller School of Medicine, University of Miami, USA
conclusions
� Keragel
- Significant (p<0.05) increase in keratin gene expression (KRT6A, KRT16 and KRT17) on day 2 compared to polyurethane film and untreated controls.
� Keraderm
- Significant (p<0.05) increase in keratin gene expression (KRT16 and KRT 17) on day 4 compared to polyurethane films and untreated controls.
KRT 17) on day 4 compared to polyurethane films and untreated controls.
� Keratinocytes in the keratin treatment groups entered the activated phase sooner than in the polyurethane treated and untreated wounds.
� KRT17 analysis also suggests that the keratinocytes in the keratin treated groups entered the migratory phase two to four days sooner than untreated wounds.
Keratin Results in Strong New Skin
Functional Keratin treatmentPolyurethane treatment
in keratin treated wound, vessel rich dermis andinterdigitation of skin layers, indicative of stronger new skin.This is probably due to keratin stimulating new cell growth.
Clinical Case Series Venous UlcersClinical Case Series Venous Ulcers
Venous UlcersVenous Ulcers
�� Purpose: to observe the performance and user Purpose: to observe the performance and user
�� Purpose: to observe the performance and user Purpose: to observe the performance and user
acceptability of the products in venous ulcersacceptability of the products in venous ulcers
Clinical Case Series Venous UlcersClinical Case Series Venous Ulcers
� Patient Population
� 22 patients
� Mean Age: 74 years old
(range 42 – 91 years old)
� Mean Ulcer Duration: 5.2 years
(range 3 months to 22 years)
Clinical Case Series Venous UlcersClinical Case Series Venous Ulcers
7 patients were treated with Keraderm7 patients were treated with Keraderm
6 patients were treated with the Kerafoam6 patients were treated with the Kerafoam
9 patients were treated with the Keragel9 patients were treated with the Keragel
Treatment period 8 Treatment period 8 --12 weeks12 weeks
Clinical Case Series Venous UlcersClinical Case Series Venous Ulcers
Dressing Dressing
Type Type
NN Patient Patient
Preference Preference
Nurse Nurse
Preference Preference
AllAll 2222 91%91% 86%86%
KeragelKeragel 99 82%82% 73%73%
KeragelKeragel 99 82%82% 73%73%
KerasorbKerasorb 66 96%96% 86%86%
KeradermKeraderm 77 82%82% 73%73%
Clinical Case Series Venous UlcersClinical Case Series Venous Ulcers
�� Margolis (Am. J. Medicine 2000) has Margolis (Am. J. Medicine 2000) has established that >5cmestablished that >5cm22 venous leg ulcers venous leg ulcers present for >6 months have a 13% healing rate. present for >6 months have a 13% healing rate.
�� In this case series 50% of this wound type In this case series 50% of this wound type achieved a clinical healing outcome when achieved a clinical healing outcome when
achieved a clinical healing outcome when achieved a clinical healing outcome when treated with treated with Functional Keratin Functional Keratin dressings. dressings.
�� In addition, 77% of patients improved during the In addition, 77% of patients improved during the treatment periodtreatment period
Clinical Case Series Venous UlcersClinical Case Series Venous Ulcers
* Data from Nurse Maude wound clinic, Christchurch, New Zealand
Chronic venous ulcer of 50 weeks duration prior to Functional Keratin treatment
DAY 0 (26/04 06) DAY 99 (2/08 06)
Clinical Case Series Venous UlcersClinical Case Series Venous Ulcers
* Data from Nurse Maude wound clinic, Christchurch, New Zealand
Chronic venous ulcer of 26 weeks duration prior to Functional Keratin treatment
DAY 0 (18/04/06) DAY 78 (11/07/06)
Clinical Case Series Venous UlcersClinical Case Series Venous Ulcers
Day 0 (27/4/06) Day 40 (6/6/06)Chronic ulcer > 2 years duration prior to Functional Keratin treatment
ConclusionsConclusions
�� Patients preferred all 3 keratin dressings to their Patients preferred all 3 keratin dressings to their existing dressingsexisting dressings
�� Nurses preferred all 3 keratin dressings to their Nurses preferred all 3 keratin dressings to their existing dressings existing dressings
�� Long duration wounds exhibited substantial Long duration wounds exhibited substantial improvement in healing rateimprovement in healing rate
Other wound healing indications
� Negative Pressure Wound Therapy (NPWT)
� $1.5B product – limited by pain on dressing change
� Market opportunity if problem solved?
� Market opportunity if problem solved?
Acute wounds – in combination with NPWT
� To evaluate the efficacy of a keratin matrix interface between the wound surface and the synthetic sponge in stage III and IV wounds receiving NPWT.
� Case series included five pressure ulcers, two venous stasis ulcers, one ischemic ulcer, and one post-operative wound. Six of the wounds were sensate and three were insensate.
Acute wounds – clinical cases using NPWT
� Outcomes
- Pain relief
• 6/6 of sensate wounds reported substantial pain reduction at dressing change, avoiding the “velcro” effect common with NPWT treatment.
“velcro” effect common with NPWT treatment.
- Wound healing rate
• No decrease in wound healing rate. Improved wound healing rate in superficial wound cases.
Skin conditions – Epidermolysis Bullosa
� Genetic disease characterised by extremely fragile skin and recurrent blister formation
� EB simplex – frequent blister formation on the feet
� EB dystrophic – extensive blister formation and skin disruption over the body
R foot before Treatment
Skin conditions – EB simplex
R foot after one month’s Treatment
Outcome
Reduced pain
Reduced recurrence of blisters
Increased hours of work
Improved quality of life
Skin conditions – EB dystrophic
Before keragel
Blistering consistent for 10 years
After 9 months of keragel.
Outcome
After 3 months, collar dressing no longer required. Increased time and focus at school
Reduced tendancy to blister
Dramatic quality of life improvement
Clinical conclusions
� Healing acute wounds faster
� Healing chronic wounds that have not healed with standard of care
� Reducing pain when using Negative Pressure
� Reducing pain when using Negative Pressure Wound Therapy
� Improving skin condition and quality of life in severe skin disorders.
Intellectual Property
� Based on world leading keratin and fibre science.
� Aggressive patenting strategy in place
� Substantial patent portfolio
- Provides sustainable competitive advantage
- underpins technology licensing opportunities
- underpins technology licensing opportunities
- Underpins key multinational supply agreements
- Creates opportunities for future strategic collaborations
Issued US patents – similar ww coverage
1 7,501,485 Bioactive keratin peptides
2 7,465,321 The Production of Biopolymer Film, Fibre, Foam and Adhesive Material From Soluble S-Sulfonated Keratin Derivatives
3 7,297,342 Orthopedic Materials Derived from Keratin
4 7,001,988 Methods for controlling peptide solubility, chemically modified peptides, and stable solvent systems for producing same
5 7,001,987 Hydrogel with controllable mechanical, chemical, and biological properties and method for making same
6 6,989,437 Methods for producing, films comprising, and methods for using heterogeneous crosslinked protein networks
7 6,914,126 Methods for producing, films comprising, and methods for using heterogenous crosslinked protein networks
8 6,849,092 Implantable prosthetic or tissue expanding device
9 6,783,546 Implantable prosthetic or tissue expanding device
9 6,783,546 Implantable prosthetic or tissue expanding device
10 6,649,740 Hydratable form of keratin for use as a soil amendment
11 6,544,548 Keratin-based powders and hydrogel for pharmaceutical applications
12 6,461,628 Non-woven keratin cell scaffold
13 6,432,435 Keratin-based tissue engineering scaffold
14 6,379,690 Keratin-based hydrogel for biomedical applications and method of production
15 6,371,984 Implantable prosthetic or tissue expanding device
16 6,316,598 Water absorbent keratin and gel formed therefrom
17 6,274,163 Keratinous protein material for wound healing applications and method
18 6,274,155 Nonwoven sheet and film containing water absorbent keratin
19 6,270,793 Absorbent keratin wound dressing
20 6,270,791 Soluble keratin peptide
Issued US patents and pending applications21 6,165,496 Keratin-based sheet material for biomedical applications and method of production
22 6,159,496 Keratin-based hydrogel for biomedical applications and method of production
23 6,159,495 Porous and bulk keratin bio-polymers
24 6,124,265 Method of making and cross-linking keratin-based films and sheets
25 6,110,487 Method of making porous keratin scaffolds and products of same
26 5,948,432 Keratin-based sheet material for biomedical applications and method of production
27 5,932,552 Keratin-based hydrogel for biomedical applications and method of production
28 5,358,935 Nonantigenic keratinous protein material
Pending applications
1 10/583,445 Wound care products containing keratin
1 10/583,445 Wound care products containing keratin
2 10/572,593 Composite materials containing keratin
3 11/987,939 Bone Void Fillers and Method of Making the Same
4 12/000,292 Porous Keratin Construct and Method of Making the Same
5 12/127,694 Porous Keratin Constructs, Wound Healing Assemblies and Methods Using the Same
6 09/899,372 Soluble keratin peptide
7 11/047,474 Implantable prosthetic or tissue expanding device
8 10/715,337 Hydratable form of keratin for use as a soil amendment
9 11/945,614 Keratin-based powders and hydrogel for pharmaceutical applications
10 10/352,786 Bioactive keratin peptides
11 11/570,402 New and gentle process for conversion of cystine keratin-containing materials to lanthionine
12 10/626,907 Bioactive coating for medical devices
13 11/920,456 Hydratable keratin compositions
Regulatory status
� FDA (510K) clearance
� Manufacturing and design to ISO 13485
� CE mark issued
� Australian TGA approval
� Australian TGA approval
� Established device manufacturing in certified facilities
summary
� Isolated keratin and maintained form and function.
� Versatile biopolymer with a range of physical forms
� Established new paradigm in wound care
- Physiologic healing
- Chronic, acute, skin disorder
� Potential substantial advance in orthopedics
� Biomaterials platform with multiple potential applications.
� FDA clearance and certified manufacturing in place
� IP portfolio strong foundation for partnership
