Herbs for Optimizing Tissue Repair and Regeneration

Kerry BoneAdjunct ProfessorNew York Chiropractic College

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Integria, Standard Process and the speaker, Kerry Bone, have not evaluated the legal status of any products (except for Standard Process and MediHerb products), services or recommendations with respect to state or federal laws, including scope of practice. Integria, Standard Process and Kerry Bone do not and cannot accept responsibility for errors or omissions or for any consequences from applications of the information provided and makes no warranty, expressed or implied, with respect to the information provided.

Kerry’s recommendations for Standard Process and MediHerb product dosages are sometimes different than the doses that appear on the product labels. Please refer to the product labels or to the product descriptions found in the product catalogs or on the website for Standard Process and MediHerb dosage recommendations.

2These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure or prevent any disease.

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Kerry Bone is the co-founder and innovation driver at MediHerb, where he serves as Director of Research and Development. In 2016 MediHerb was awarded the American Botanical Council’s (ABC’s) Varro E. Tyler Award for excellence in Phytomedicinal Research.

As part of his educational role, Kerry is Principal of the Australian College of Phytotherapy and also Adjunct Professor at New York Chiropractic College, providing input into their postgraduate applied nutrition program.

Kerry is co-author of more than 30 scientific papers on herbal research. He has also written and co-written six popular textbooks on herbal medicine, including his latest, the second edition of Principles and Practice of Phytotherapy which was awarded the 2013 James A. Duke Excellence in Botanical Literature Award by the ABC.

Kerry maintains a busy herbal and naturopathic practice in Toowoomba, Queensland, where he has been in continuous service for more than 30 years.

In 2015, Kerry’s lifelong contribution to the field of herbal medicine was recognized with his receiving the prestigious Lady Cilento award from the complementary medicine industry in Australia.

Professor Kerry Bone

Introduction

As a profession we place great emphasis on assisting the body to heal itself

But herbs that promote tissue healing (other than by topical application) are scarce in our materia medica

One stand-out exception is the humble weed Gotu Kola (Centella asiatica)

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Topics

The healing process Gotu Kola the healer:

a promoter of connective tissue regeneration and regulation

Gotu Kola and circulation: veins, microcirculation and arteries

5

CC BY 3.0 Forrest and Kim Starr, 03 Aug 2002

Topics

Gotu Kola and the CNS: neuroprotective and neuroregenerative?

Combining Gotu Kola with other herbs to support healing

6CC BY 2.0, aboutmodafinil.com, 7 July 2014

Phases of Tissue Healing

The healing process is divided into three overlapping phases: Inflammatory phase Proliferative phase Remodeling or

maturational phase

7Porth CM. Pathophysiology 7th Ed. Lippincott Williams and Wilkins, Philadelphia, 2005

CC BY 2.0. HelloOJello, Dec 20 2013

Inflammatory Phase Begins at time of injury Results in vascular response leading to fluid

exudate → edema This facilitates a cellular response characterized

by infiltration of white blood cells

8Porth CM. Pathophysiology 7th Ed. Lippincott Williams and Wilkins, Philadelphia, 2005

Image: By Red_White_Blood_cells.jpg: Electron Microscopy Facility at The National Cancer Institute at Frederick (NCI-Frederick) derivative work: WhatamIdoing (Red_White_Blood_cells.jpg) [Public domain], via Wikimedia Commons

Proliferation Phase Begins several days after injury Involves generation of repair cells, most

important are the fibroblasts Fibroblasts:

connective tissue cells that synthesize and secrete collagen

9Porth CM. Pathophysiology 7th Ed. Lippincott Williams and Wilkins, Philadelphia, 2005

CC BY SA 3.0, Heiti Paves, 23 Oct 2012

Proliferation Phase

Angiogenesis: essential in the production of collagen as it:

↑ local blood flow and thus ↑ oxygen availability → enabling the fibroblasts1

Myofibroblasts (derived from fibroblasts) for wound contraction and early strength of repair2

101. Li WW et al. Adv Skin Wound Care 2005; 18(9): 501-502. PMID: 163655472. Watson T. SportEX Med 2006; 28: 8-12.

Remodeling Phase

Begins approximately 3 weeks after injury and can continue for 6 months or longer

Continued remodeling of scar tissue by the simultaneous synthesis of collagen and lysis by collagenase enzymes

Resulting in changes in the architecture of the repair to ↑ tensile strength

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Porth CM. Pathophysiology 7th Ed. Lippincott Williams and Wilkins, Philadelphia, 2005

The Healing Process

12Scar Remodeling

Factors that Inhibit Healing

Malnutrition and micronutrient deficiency Poor blood supply, including microcirculation

issues Sustained inflammation; eg infection, trauma

etc Prescribed drugs

13CC BY 2.0, Ben Harvey, October 4 2011

Gotu Kola and TTFCA

TTFCA total triterpenic fraction of Centella asiatica (Gotu Kola)

Contains mainly asiaticoside, asiatic acid and madecassic acid

Many key pharmacological and clinical studies Can extrapolate data to whole herb extracts

provided herbal dose contains around 120 to 180 mg/day of TTFCA

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Gotu Kola andConnective Tissue

Earlier experimental studies oral administration of either Gotu Kola extract or TTFCA improved collagen synthesis and maturation of collagen improved strength of scar tissue in dermal wounds1,2

Later in vivo studies burn healing ↑3 and cartilage protective activity4

1. Vogel HG et al. Acta Therapeut 1990; 16: 2852. Suguna L et al. Indian J Exp Biol 1996; 34(12): 1208-1211. PMID: 92469123. Liu M, Dai Y, Li Y et al. Planta Med 2008; 74(8): 809-815. PMID: 184845224. Hartog A, Smit HF, van der Kraan PM et al. Exp Biol Med (Maywood) 2009; 234(6): 617-623. PMID:

19307458

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Early European Research Research in the 1980s benefit in healing

gastric and duodenal ulcers1

Early French and Italian clinical research (1960s and 1970s) good healing rates in refractory cases of:• skin and leg ulcers2

• episiotomies3

Gotu Kola: The Healer

1. Rhee JC, Choi KW. Korean J Gastroenterol 1981; 13(3): 5-402. Huriez CL. Lille Med 1972; 3(Supp 17): 574-5793. Castellani L et al. Bull Fed Soc Gynecol Obstet Lang Fr 1966; 18(2): 184-186

Bone KM, Mills SY. Principles and Practice of Phytotherapy: Modern Herbal Medicine 2nd Edition. Elsevier, UK, 2013, 664-665

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Gotu Kola: The HealerEarly European Research

• corneal wounds1

• surgical wounds2

Beneficial effects were also noted in 20 children with scleroderma in Spanish research3

and also in adults4,5

1. Marcone GJ, Esposito RJ, Dias CA. Arch Oftalmol B Aires 1962; 37: 233-239. PMID: 139328932. Cioffi L. Minerva Urol 1964; 16: 165-170. PMID: 142609093. Frati Munari AC et al. Bol Med Hosp Infant Mex 1979; 36(2): 201-214. PMID: 7581914. Sasaki S et al. Acta Derm Venereol 1972; 52(2): 141-150. PMID: 41278035. Guseva NG, Starovoitova MN, Mach ES. Ter Arkh 1998; 70(5): 58-61. PMID: 9644746 17

Image: By Flavio~ from Mazkeret Batia, Israel (Flamenco: Ilusiones; By Carmel Natan Sheli) [CC BY 2.0 (http://creativecommons.org/licenses/by/2.0)], via Wikimedia Commons

Early Indian and Egyptian Research Indian research improved healing in leprosy1,2

Egyptian research benefits in:• liver fibrosis3

• cataract surgery4

Gotu Kola: The Healer

1. Chakrabarty T, Deshmukh S. Sci Culture 1976; 42(11): 5732. Nebout M. Bull Soc Pathol Exot 1974; 67(5): 471-478. PMID: 44804673. El-Zawahry MD et al. Bull Societe Int Chirurgie 1975; 6: 573-577. PMID: 12331144. Abou Shousha ES, Khalil HA. Bull Ophthalmol Soc Egypt 1967; 60(64): 451-470.

PMID: 5602933 18

Image CC BY 2.0, Don Cochrane, April 11 2008

Gotu Kola andKeloid Scarring

Oral TTFCA for elevated scars and keloids, including post burn keloids

139 patients, dose 60-90 mg/day 82% benefited from the extract after 2-18 months, either relief of symptoms or disappearance of inflammation

Bosse JP et al. Ann Plast Surg 1979; 3(2): 13-21. PMID: 396846

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Image: CC BY 2.0, Michael Rodger, 26 June 2011

Gotu Kola and Veins

A 4-week, dose-finding study: normal volunteers (180 mg/day) and patients with chronic venous insufficiency (CVI, doses 0, 90 and 180 mg/day)

Changes in capillary flow and ankle edema Dose-response effect observed, (no change in

the placebo group and normal volunteers) Objective changes correlated with symptom

improvements (next slide)

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De Sanctis MT et al. Angiology 2001; 52(Suppl 2): S55-S59. PMID: 11666125

Gotu Kola and CVIAverage score obtained by considering four major symptoms*Groups Before After Treatment

A 7.7 ± 1.5 4.6 ± 1.1†B 7.8 ± 6.2 6.2 ± 1.7†C 7.7 ± 1.2 7.6 ± 1.3 ns

A = 180 mg/day, B = 90 mg/day, C = placebo* (1) swelling sensation, (2) restless lower extremities, (3) pain and cramps and (4) tiredness. The analog scale ranged from 1 to 10

† p<0.05ns: not significant

21De Sanctis, MT et al. Angiology 2001; 52(Suppl 2): S55-S59. PMID: 11666125

Why Veins?

Varicose veins and CVI long regarded as disorders of valvular incompetence

Recent evidence: changes in the vein wall precede incompetence

Varicosities often observed below competent valves and occur before valvular incompetence

Defects in extracellular matrix (ECM) and collagen composition in vein wall thought to be part of this process

Lim CS, Davies AH. Br J Surg 2009; 96(11): 1231-1242. PMID: 19847861Naoum JJ, Hunter GC. Vascular 2007; 15(5): 242-249. PMID: 17976322

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Veins and TTFCA

Review of Gotu Kola actives: Act on fibroblasts in the vein wall; improve the

synthesis of collagen and stimulate collagen remodeling

May decrease endothelial cell damage Improve microcirculation, decrease edema and

improve lymphatic drainage

Incandela L, Cesarone MR, Cacchio M et al. Angiology 2001; 52(suppl 2): S9-S13. PMID: 11666128

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Microcirculation and Health

Compromised microcirculation Heart attack, stroke, CVI Insulin resistance Liver and kidney disease Neurological disorders Osteoarthritis Retinal diseases Poor healing/tissue damage

24Image: By Artwork by Holly Fischer [CC BY 3.0 (http://creativecommons.org/licenses/by/3.0)], via Wikimedia Commons

Smoking and Microcirculation

Passive smoking1

Smoking affects healing capacity2

Carbon monoxideis thought to play role3

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1. Henriksson P, Lu Q, Diczfalusy U, et al. Microcirculation 2014; 21(7): 587-592. PMID: 24698527

2. Balaji SM. Indian J Dent Res 2008; 19(4): 344-348. PMID: 190754403. Leone A, Landini L. Curr Vasc Pharmacol 2013; 11(4): 524-530. PMID: 22022776

Anesthesia and Wound Repair in Aging

Surgical wound repair in elderly Surgery disrupts microvasculature of aged skin Most anesthetics affect microcirculation

26Bentov I, Reed MJ. Anesthesiology 2014; 120(3): 760-772. PMID: 24195972

Image: By CMSRC (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

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Gotu Kola andMicrocirculation

Two controlled trials investigated the activity of TTFCA in patients with microvascular damage due to diabetes

Largest trial:100 patients with or without neuropathy; extract versus placebo over 12 months and also in 40 healthy controls1

Extract significantly more effective at improving microcirculatory measures and edema

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1. Incandela L, Belcaro G, Cesarone MR et al. Angiology 2001; 52(Suppl 2): S27-S31. PMID: 11666119

Gotu Kola andMicrocirculation

Smaller trial: 50 patients compared TTFCA to placebo or no treatment for 6 months

Significant improvements in measures linked to microscopic vascular damage, including capillary permeability

29Cesarone MR, Incandela L, De Sanctis MT et al. Angiology 2001; 52(Suppl 1-2): S49-S54. PMID: 11666124

Stages of Arterial Plaque Development

Endothelial and microcirculatory (vasa vasorum damage)

Inflammation Lipid accumulation

and calcification Unstable plaque

formation/resolution

30Image: CC BY 3.0, Bruce Blaus, 28 May 2014

Vulnerable Plaque

Unstable or vulnerable plaque: atherosclerotic plaque at a high short-term risk of rupture

Rupture can result in a massive aggregation of platelets (known as a thrombus): can block the artery

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Vulnerable Plaque

Only plaque with very thin fibrous cap at risk of rupture

Are essentially unstable because of a deficiency of connective tissue

Also referred to now as thin-cap fibroatheroma (TCFA) or high-risk plaque

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Hansson GK, Libby P, Tabas I. J Intern Med 2015; 278(5): 483-93. PMID: 26260307

Plaque is a Wound

Arterial plaque is a wound on the blood vessel wall

Vulnerable plaque: not healing appropriately, like an ulcer or abscess

Even in presence of widespread arterial disease, rarely more than a few plaques appear to be at risk of rupture at any given moment1

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1. Thim T, Hagensen MK, Bentzon JF et al. J Intern Med 2008; 263(5): 506-516. PMID: 18410594

Stabilizing Plaque

If vulnerable plaque is a wound that has not healed properly, promoting healing should help

In two early placebo-controlled clinical trials, Gotu Kola (Centella) actives stabilized low-density carotid1 and femoral plaques2

1. Cesarone MR, Belcaro G, Nicolaides AN et al. Angiology 2001; 52(Suppl 2): S19-S25. PMID: 11666118

2. Incandela L, Belcaro G, Nicolaides AN et al. Angiology 2001; 52(Suppl 2): S69 S73. PMID: 11666127

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Stabilizing Plaque

The dose used in both trials was 180 mg/day of Gout Kola (Centella) triterpenoids for 12 months

Clinical outcome was assessed by significant and marked increases in the echogenicity of plaques compared to placebo

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Gotu Kola: 2015 Trial 391 low risk, asymptomatic people followed

over 4 years Carotid and femoral plaques assessed Group 1 (controls): education, exercise and diet Group 2: pine bark OPCs (100 mg/day) Group 3: pine bark OPCs (100 mg/day) and

Gotu Kola (100 mg/day)

36Image: CC BY 3.0, Jean-Pol Grandmont, 11 May 2008

Gotu Kola: 2015 Trial

Plaque characteristics assessed by ultrasound Plaques became more dense in both treatment

groups (2 and 3) Anginal events < 3% in treatment groups (2

and 3) versus 6.25% in control (1) Other ischemic events lower in treatment

groups

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Belcaro G, Dugall M, Ippolito E et al. Minerva Cardioangiol 2015. [Epub ahead of print] PMID: 26505327.

Gotu Kola and the Brain Thai clinical research: Gotu Kola improved

memory and accuracy in both short-term (1 hour) and long-term (60 days) studies

Long-term use alsolifted reaction times and recognition skills

Gotu Kola also boosted calmness and mood

Doses used were 250 to 750 mg/day of an extract containing 5% triterpenes

Wattanathorn J et al. J Ethnopharmacol 2008; 116(2): 325-332. PMID: 1819135538

Gotu Kola and the BrainNeuroprotective and Neuroregenerative? Gotu Kola extract accelerated nerve regeneration

after oral doses in rats (300–330 mg/kg/day) and contained multiple active fractions that increased neurite elongation in vitro1

Anticonvulsant activity in vivo (200 mg extract/kg/day)2 and a neuroprotective effect in a model of parkinsonism (300 mg extract/kg/day)3

1. Soumyanath A, Zhong YP, Gold SA et al. J Pharm Pharmacol 2005; 57(9): 1221-1229. PMID: 16105244

2. Visweswari G, Prasad KS, Chetan PS et al. Epilepsy Behav 2010; 17(3): 332-335. PMID: 20144879

3. Haleagrahara N, Ponnusamy K. J Toxicol Sci 2010; 35(1): 41-47. PMID: 2011862339

Gotu Kola andAnti-aging Effects

Gotu Kola extract: 250, 500 and 750 mg/day significantly improved physical strength and fitness measured by the 30-second chair stand test in 80 healthy older volunteers (average age around 65 years)

Two higher doses also improved the physical subscale of a quality of life scale (SF-36)

Was a placebo-controlled, randomized, double blind trial

Mato L, Wattanathorn J, Muchimapura S et al. Evid Based Complement Alternat Med. 2011; 2011: 579467. PMID: 19880441

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Ginkgo: Role in Tissue Healing

Activities associated with Ginkgo that support tissue healing: Anti-PAF, as platelet

activating factor (PAF) is associated with inflammation

Improved circulation in arteries, veins and capillaries, especially the microcirculation

Nrf2 based antioxidant: ↓ oxidative stress associated with damaged tissues

Smith JV, Luo Y. Appl Microbiol Biotechnol 2004; 64(4): 465-472. PMID: 14740187 41

Grape Seed Grape Seed extract from the seeds of red or

white grapes Contains a range of

polyphenols, mostly oligomeric procyanidins (OPCs)

OPCs have a number of key actions related to tissue healing

Gabetta B et al. Fitoterapia 2000; 71(2): 162-175. PMID: 10727813 42

Image: By Philmarin (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

Grape Seed and Collagen In vitro and in vivo studies demonstrate that Grape Seed extract: Supports connective tissue, by protecting

collagen and elastin within the microvessel wall1

Stabilizes connective tissue by facilitating the formation of collagen microfibrils and collagen crosslinking2

Protects vascular endothelium during ischemia2

1. Robert AM et al. Biomed Pharmacother 2006; 60(3): 113-120. PMID: 165463472. Morgan M, Andrews C. Nutritional Perspective 2007; 26: 1-3.

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Grape Seed and Microcirculation

Several clinical trials using doses 100-150 mg/day OPCs have demonstrated benefits for capillary resistance and capillary permeability

For example, 100 mg/day OPCs to elderly patients with capillary fragility

Very good results were achieved in 67%, good in 17% and moderate in 13%

Treatment with 150 mg/day of OPCs stabilized retinopathic lesions in 80% of patients

Morgan M, Andrews C. Nutritional Perspective 2007; 26: 1-3 44

Grape Seed and CVI

Various clinical trials on patients with CVI and/or oxidative stress: Grape Seed extract (100-150 mg/day): ↓ edema repaired capillary damage increased peripheral circulation

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Morgan M, Andrews C. Nutritional Perspective 2007; 26: 1-3Image: By Nini00 (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

Grape Seed and CVI 80% of patients with CVI

had a significant ↓ in lower limb swellingafter 10 days of OPC treatment (100 mg/day)1

Compared to placebo and diosmin (a flavonoid),

150 mg/day OPCs ↓ the functional problems associated with impaired venous back flow2

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1. Costantini A et al. Minerva Cardioangiol 1999; 47(1-2): 39-46. PMID: 103569402. Morgan M, Andrews C. Nutritional Perspective 2007; 26: 1-3

Image: CC BY 2.0, Karolina van Schrojenstein Lantman, 06 July 2002

Herbal Synergy

Healing involves development of new circulation followed by laying down of new connective tissue and endothelium

Ginkgo will support microvascular development and circulation, as will Grape Seed extract

Grape Seed extract has also been shown to support and strengthen connective tissue

Gotu Kola stimulates connective tissue production

Morgan M. A Phytotherapist’s Perspective No. 52 April 2007. Available via www.mediherb.com

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Vein Health

Key Herbs Horsechestnut Butcher’s Broom Gotu Kola Ginkgo Grape Seed Bilberry 5-Point Microcirculation Phytonutrient Protocol

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Image: By Solipsist (Own work) [CC BY-SA 2.0 (http://creativecommons.org/licenses/by-sa/2.0)], via Wikimedia Commons

Eye Vascular Health

Key Herbs Bilberry Gotu Kola Ginkgo Grape Seed 5-Point

Microcirculation Phytonutrient Protocol

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Arterial Health

Key Herbs Ginkgo Gotu Kola Grape Seed Turmeric

and other Nrf2 herbs 5-Point

Microcirculation Phytonutrient Protocol

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Joint Tissue Health

Boswellia Turmeric Gotu Kola Ginkgo Grape Seed 5-Point

Microcirculation Phytonutrient Protocol

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Image: http://www.gnu.org/copyleft/fdl.html, JM Garg, 02 Feb 1910

Post-Surgery

Milk Thistle Echinacea root Gotu Kola Ginkgo Grape Seed 5-Point

Microcirculation Phytonutrient Protocol

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Image: By Zeynel Cebeci (Own work) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons

Nourishing Tissue Microvascular integrity - Grape Seed extract,

Bilberry, Gotu Kola

Microvascular flow - Ginkgo, beets, Ginger, Garlic

Endothelial function - Green Tea, cocoa, Garlic,

Blood quality - Ginger, Turmeric, Garlic, omega-3 fatty acids

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The 5-Point Microcirculation

Phytonutrient Protocol1. Boost dietary nitrate - beets2. Increase cocoa intake3. Increase berry

anthocyanin intake4. Raw crushed garlic:

½ to 1 clove/day5. Increase herbs

and spices:green tea, turmeric and ginger

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Thank You and Questions

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