Current and Future Treatment of Flexor Tendon Injuries James Chang MD Chief of Plastic & Reconstructive Surgery Professor of Surgery & Orthopedic Surgery Robert A. Chase Hand Center Stanford University Medical Center

40th Anniversary 1967 ASSH Presentation: Kleinert HE, Kutz JE, Ashbell TS, Martinez E. “Primary Repair of Lacerated Flexor Tendons in No Man’s Land” Manske PR. History of Flexor Tendon Repair, Hand Clinics, 2005

Specific Problem: Zone II Flexor Tendon Laceration Current Best Treatment Based on Available Evidence Future Solutions for Current Needs

Current Best Treatment Based on Available Evidence

Future Solutions for Current Needs

Research in the past 10 years: Thought leaders Gelberman Manske Trumble Boyer Amadio Tang Strickland Mass Nagle Taras Wolfe Tomaino Tonkin Diao McGrouther Hagberg Elliot Seiler

Gelberman

Manske

Trumble

Boyer

Amadio

Tang

Strickland

Mass

Nagle

Taras

Wolfe

Tomaino

Tonkin

Diao

McGrouther

Hagberg

Elliot

Seiler

Flexor Tendon Repair: Challenges for Research Margin for error is small Many repair techniques exist Biomechanical studies may not be relevant clinically Cadaver studies: no healing Animal studies: no therapy Clinical studies limited by Differences in surgical skill Patient compliance with therapy Differences in follow-up & outcomes criteria

Margin for error is small

Many repair techniques exist

Biomechanical studies may not be relevant clinically

Cadaver studies: no healing

Animal studies: no therapy

Clinical studies limited by

Differences in surgical skill

Patient compliance with therapy

Differences in follow-up & outcomes criteria

Current Best Treatment Based on Available Evidence: Four Key Papers, Four Key Points

Point #1: 4 Strands or more are necessary for early active motion Strickland. J Hand Surg 2000; 25A:214-235 “ Development of Flexor Tendon Surgery: Twenty-five Years of Progress” Two strand repairs are at risk for rupture if early active motion is applied Four strand repairs are strong enough to withstand light active motion

Strickland. J Hand Surg 2000; 25A:214-235

“ Development of Flexor Tendon Surgery: Twenty-five Years of Progress”

Two strand repairs are at risk for rupture if early active motion is applied

Four strand repairs are strong enough to withstand light active motion

Point #2: Grasping vs. locking sutures Miller et al. J Hand Surg 2007; 32A:591-96 (Trumble) “ Flexor Tendon Repairs: The Impact of Fiberwire on Grasping and Locking Core Sutures ” Grasping repairs failed by suture pull-out in 74% Locking repairs failed by suture breakage in 99% Fiberwire suture provided significant tensile strength in locking MGH repairs Increased suture strength is only important in locking repairs

Miller et al. J Hand Surg 2007; 32A:591-96 (Trumble)

“ Flexor Tendon Repairs: The Impact of Fiberwire on Grasping and Locking Core Sutures ”

Grasping repairs failed by suture pull-out in 74%

Locking repairs failed by suture breakage in 99%

Fiberwire suture provided significant tensile strength in locking MGH repairs

Increased suture strength is only important in locking repairs

Point #3: Rehabilitation force Boyer et al. JBJS 2001; 83:891-899 (Gelberman) “ Intrasynovial Flexor Tendon Repair: An Experimental Study Comparing Low and High Levels of In vivo Force During Rehabilitation in Canines” Increasing post-op rehabilitation force from 5 to 17 N did not accelerate acrual of stiffness or strength Some motion is good (2 mm excursion); more forceful motion may not be better

Boyer et al. JBJS 2001; 83:891-899 (Gelberman)

“ Intrasynovial Flexor Tendon Repair: An Experimental Study Comparing Low and High Levels of In vivo Force During Rehabilitation in Canines”

Increasing post-op rehabilitation force from 5 to 17 N did not accelerate acrual of stiffness or strength

Some motion is good (2 mm excursion); more forceful motion may not be better

Point # 4: The Effect of Gap Gelberman. JBJS 1999; 81:975-82 “ The Effect of Gap Formation at the Repair Site on the Strength and Excursion of Intrasynovial Flexor Tendons” What happens if a significant gap forms? Repair site gap of greater than 3 mm: No increase in adhesions Weaker, with increased risk of rupture

Gelberman. JBJS 1999; 81:975-82

“ The Effect of Gap Formation at the Repair Site on the Strength and Excursion of Intrasynovial Flexor Tendons”

What happens if a significant gap forms?

Repair site gap of greater than 3 mm:

No increase in adhesions

Weaker, with increased risk of rupture

Flexor tendon repair: what we know in 2007 Core suture: 3-0 or 4-0 Epitendinous suture Gaps significantly weaken the repair Locking techniques prevent pullout and reduce gapping Some early active motion is beneficial 4 strands or more will allow early active motion

Core suture: 3-0 or 4-0

Epitendinous suture

Gaps significantly weaken the repair

Locking techniques prevent pullout and reduce gapping

Some early active motion is beneficial

4 strands or more will allow early active motion

The “Optimal” Repair Technique Should incorporate the concepts of multi-strand repair with early motion Surgeons are still influenced by their training and anecdotal experience Michael Tonkin: “One’s chosen repair technique should be simple to learn, with the goal of being able to be performed safely by all trainees”

Should incorporate the concepts of multi-strand repair with early motion

Surgeons are still influenced by their training and anecdotal experience

Michael Tonkin: “One’s chosen repair technique should be simple to learn, with the goal of being able to be performed safely by all trainees”

Great strides have been made in suture techniques and post-operative rehabilitation. What now?!?

Flexor Tendon Repair: Future Solutions for Current Needs 2007 ASSH Papers: Biomolecular Strategies

Four Current Needs Increase early strength of repair Decrease adhesion formation Shortage of tendon material in mutilating injuries True outcomes data for best methods of repair and rehabilitation

Increase early strength of repair

Decrease adhesion formation

Shortage of tendon material in mutilating injuries

True outcomes data for best methods of repair and rehabilitation

Strategies to increase early strength of repair focus on delivery of growth factors or stem cells to the repair site Gelberman et al. - Sustained delivery of PDGF-BB with a bioactive fibrin-based delivery system Tang et al. - Delivery of bFGF gene with adenoviral vectors Lou et al. - Delivery of BMP-12 with adenoviral vectors Chong et al. - Mesenchymal stem cells in a fibrin carrier Yao et al. - Mesenchymal stem cell-coated sutures

Strategies to increase early strength of repair focus on delivery of growth factors or stem cells to the repair site

Gelberman et al. - Sustained delivery of PDGF-BB with a bioactive fibrin-based delivery system

Tang et al. - Delivery of bFGF gene with adenoviral vectors

Lou et al. - Delivery of BMP-12 with adenoviral vectors

Chong et al. - Mesenchymal stem cells in a fibrin carrier

Yao et al. - Mesenchymal stem cell-coated sutures

Strategies to decrease adhesion formation focus creating an interface or blocking known factors that cause fibrosis Amadio, An et al. - Surface modification with hyaluronic acid Khan et al. - 5-Fluorouracil Chang et al. - Inhibitors of TGF-Beta

Strategies to decrease adhesion formation focus creating an interface or blocking known factors that cause fibrosis

Amadio, An et al. - Surface modification with hyaluronic acid

Khan et al. - 5-Fluorouracil

Chang et al. - Inhibitors of TGF-Beta

Transforming Growth Factor - Beta Family of growth factors - 3 isoforms Expressed in cells active in wound healing Implicated in the pathogenesis of fibrosis Inflammation Excessive collagen deposition Natural inhibitors of TGF-Beta Decorin: 40,000 MW naturally occurring proteoglycan in extracellular matrix Mannose-6-phosphate (M-6-P): Naturally occurring 6 carbon sugar

Family of growth factors - 3 isoforms

Expressed in cells active in wound healing

Implicated in the pathogenesis of fibrosis

Inflammation

Excessive collagen deposition

Natural inhibitors of TGF-Beta

Decorin: 40,000 MW naturally occurring proteoglycan in extracellular matrix

Mannose-6-phosphate (M-6-P): Naturally occurring 6 carbon sugar

In Situ Hybridization Control: IL-2 mRNA TGF-  1 mRNA

Rabbit Postoperative Range of Motion

Rabbit Postoperative Breaking Strength

Anti-TGF-Beta Therapy Rabbit model of flexor tendon repair Intra-operative addition of M6P significantly improved post-operative range of motion without decreasing strength of repair Bates SJ, Morrow E, Zhang AY, Pham H, Longaker MT, Chang J. Mannose-6-Phosphate, An Inhibitor of TGF-Beta, Improves Flexor Tendon Repair. Journal of Bone and Joint Surgery (Am), 88:2465-72, 2006.

Rabbit model of flexor tendon repair

Intra-operative addition of M6P significantly improved post-operative range of motion without decreasing strength of repair

Bates SJ, Morrow E, Zhang AY, Pham H, Longaker MT, Chang J.

Mannose-6-Phosphate, An Inhibitor of TGF-Beta, Improves Flexor

Tendon Repair. Journal of Bone and Joint Surgery (Am), 88:2465-72, 2006.

3. Strategies to replace tendon material in mutilating injuries Goal of Tissue Engineering: Produce construct similar to intrasynovial flexor tendon Scaffold: Acellularized intrasynovial tendon Seeding Cells: Epitenon & Endotenon Fibroblasts Mesenchymal stem cells Zhang A, Chang J. Tissue Engineering of Flexor Tendons, in Clinics in Plastic Surgery, 30: 565:72, 2003.

Goal of Tissue Engineering:

Produce construct similar to intrasynovial flexor tendon

Scaffold:

Acellularized intrasynovial tendon

Seeding Cells:

Epitenon & Endotenon

Fibroblasts

Mesenchymal stem cells

Zhang A, Chang J. Tissue Engineering of Flexor Tendons, in Clinics in Plastic Surgery, 30: 565:72, 2003.

Normal Intrasynovial Tendon

Acellularization Protocol: Freeze/Thaw, Trypsin & Triton X-100 Tendons are completely acellularized

Acellular Tendon Control: 3 weeks post-implantation Disordered collagen Inflammatory cell infiltration

Seeded Constructs: 3 weeks post-implantation Normal collagen architecture Tenocytes repopulated

Different cell lines can be used for flexor tendon tissue engineering Bone Marrow Derived MSC Adipoderived MSC Tenocytes Sheath Fibroblasts

Similar collagen I & III synthesis Collagen I Immunohistochemistry Bone Marrow Derived MSC Adipoderived MSC Tenocytes Sheath Fibroblasts

Cell Proliferation Can be Increased with a Cell Bioreactor (Intermittent Cyclic Strain)

Intermittent Cyclic Strain Optimizes Total Collagen I Production

Cyclic Strain Causes Cytoskeletal Alignment Control Cyclic Strain 200x 200x

The Next Step: Tendon Bioreactor

Clinical Relevance Flexor tendon losses Biopsy from patient Intrasynovial tendon from hand or foot Adipoderived stem cells Expand autologous cells in culture Banked allogenic acellularized scaffolds Seed acellularized scaffolds to create constructs Reconstruct flexor tendon losses

Flexor tendon losses

Biopsy from patient

Intrasynovial tendon from hand or foot

Adipoderived stem cells

Expand autologous cells in culture

Banked allogenic acellularized scaffolds

Seed acellularized scaffolds to create constructs

Reconstruct flexor tendon losses

Tissue Engineered Flexor Tendon Seeded construct prior to reimplantation

4. True outcomes data for best method of repair and rehabilitation Tang JB. Clinical outcomes associated with flexor tendon repair. Hand Clin 2005, 21:199-210.

Controversies that persist Suture repair technique? Grasp vs. lock? Fiberwire? Suture caliber? 4 - 6 - 8 strand repair? Repair FDS and FDP? Repair sheath? Sacrifice A4 pulley? Rehabilitation method?

Suture repair technique?

Grasp vs. lock?

Fiberwire?

Suture caliber?

4 - 6 - 8 strand repair?

Repair FDS and FDP?

Repair sheath?

Sacrifice A4 pulley?

Rehabilitation method?

Repair types in the Stanford program Epi Last 4 Strand Locking 4-0FW Curtin Epi 1st/last 4 Strand Grasping 3-0FW Gutow Epi Last 2 Strand Grasping 3-0 Nguyen Epi 1st 4 Strand Grasping 4-0Pro Maser Epi Last 4 Strand Grasping 4-0FW Buncke Epi Last 4 Strand Locking 4-0FW C. Lee Epi 1st 4 Strand Grasping 4-0Pro Press Epi Last 4 Strand Locking 3-0 G. Lee Epi Last 4 Strand Locking 4-0FW Yao Epi 1st 4 Strand Locking 3-0Ethi Chang Epi Last 2 Strand Locking 4-0 Ladd Epi 1st 4 Strand Grasping 4-0 Hentz

The Problem Different injuries Different repairs Different post-op regimens One Cochrane review on postoperative therapy: inconclusive No multicenter trial Ideal topic for the new ASSH Clinical Trials and Outcomes Committee

Different injuries

Different repairs

Different post-op regimens

One Cochrane review on postoperative therapy: inconclusive

No multicenter trial

Ideal topic for the new ASSH Clinical Trials and Outcomes Committee

A Plea for Support of Research Basic science research for modulating flexor tendon repair and reconstruction Clinical research for establishing a true multi-center trial on outcomes of Zone II flexor tendon repair Flexor tendon repair - All hand surgeons face this clinical problem Hand surgeons are the only group who care to advance this field

Basic science research for modulating flexor tendon repair and reconstruction

Clinical research for establishing a true multi-center trial on outcomes of Zone II flexor tendon repair

Flexor tendon repair -

All hand surgeons face this clinical problem

Hand surgeons are the only group who care to advance this field