orthopaedic implant design from concept to...

Orthopaedic Implant Design from Concept to Commercialization

Hannah Dailey, PhDAssistant Professor

Mechanical Engineering & MechanicsLehigh University

Bethlehem, PA

Engineering + Human Behavior at the Frontiers of Orthopaedic Trauma Research

Bioscience in the 21st CenturyNovember 1, 2017

Overview

Part 1: Tibial Fracture Basics

• Surgical fixation

• Intramedullary (IM) nailing

• Surgical procedure

Part 2: Case Study: OrthoXel Apex IM Nailing System

• Design concept

• R&D process (transition from academia to startup company)

• Commercialization

Part 3: Frontiers in Trauma Research

• Intersection of epidemiology, engineering, clinical care, and human behavior

[1] Synthes Inc., “Expert tibial nail—technique guide.” 2006

[1]

Before Surgery After IM Nailing

Part 1: Tibial Fracture BasicsWarning: This section contains some graphic images.

Tibial Fracture

[2] tinyurl.com/m5qeu8h[3] i.imgur.com/LMe6JcF.jpg

[4] twitter.com/Slate/status/921811755629768704

Left: Tennessee Titans’ WR Marc Mariani (2012)Right: Louisville Cardinals’ Kevin Ware (2013)

Boston Celtics’ Gordon Hayward (2017)

[2]

Warning: Unedited images are graphic.

[3]

[4]

Surgical Fracture Fixation

Locking Plate and Screw Systems

IntramedullaryNails and Screws

Ilizarov Frames and Ring Fixators with Kuntscher Wires

External Fixators with Transcutaneous Pins

Plus many more hybrids and systems designed for small-extremities and specific anatomical challenges.

Secondary Fracture Healing

Newly Formed Callus

Old Cortical Bone

Medullary Canal

Secondary Healing• Formation of an external “callus”

• Evolving mixture of cartilage, fibrous tissue, and new (woven) bone

• Provides temporary structural stability

• Remodels over time

IM Nailing Surgical Procedure

[5] DePuy Synthes Trauma, Synthes GmbH, “Expert TN. Tibial Nail. Surgical Technique.” 2014

Patient Recumbent with Flexed Knee Open Medullary Canal

Nail Entry Point


Insert Guide Wire and

Progressively Ream to Get

“Chatter”

Select Nail and Attach Insertion Handle



Slide Nail into Medullary Canal Attach Aiming Arm



Freehand Distal Locking Guided Proximal Locking


IM Nailing Procedure

Remove Insertion Handle and Insert End Cap

Final Screw Configuration Options


Part 2: OrthoXel Apex IM Nailing System

Medical Device R&D from Concept to Commercialization

2010 2011 2012 2013 2014

Grant Awarded for Ovine Study

Pilot Cadaver Study Results Published [6]

[6] HL Dailey et al., “A Novel Intramedullary Nail for Micromotion Stimulation of Tibial Fractures," Clin Biomech, vol. 27, pp. 182-188, 2012.

[7] HL Dailey et al., “The Flexible Axial Stimulation (FAST) intramedullary nail provides interfragmentarymicromotion and enhanced torsional stability," Clin Biomech, vol. 28, pp. 579-585, 2013.

Cadaveric Study of Micromotion-

Enabled IM Nail

Angle-Stable FAST Nail Cadaver Results

Published [7]

Preclinical Study with MSRU/University Zurich

Proof-of-Concept Funding Awarded

(Enterprise Ireland)

PCT Filed

US/EU Patent

Applications

Pre-Spinout Development Timeline

2015

Early Concept Name: Flexible Axial Stimulation (FAST) IM Nail

Product Design Specification

Critical Analysis of Current Product

Offerings and Market Landscape

Comprehensive Review of Fracture Healing Literature

ManufacturabilityClinical AcceptanceRegulatory PathwayIntellectual Property

Marketability

What products already exist?

What should we be trying to do?

What are the constraints?

Intramedullary Nailing of Tibial Fractures

Market Landscape

[8] Medtech360 “US Market for Trauma Devices 2014”, Oct 2013.[9] tinyurl.com/SoccerBrokenLeg

[10] dopetype.wordpress.com/2009/12/15/worst-soccer-injuries/

[10]

[9]

• $146M market value (ASP $2,350)

• Delivered 62K units (20% of all IM nail procedures)

• Was growth-oriented (4.1% CAGR 2012-2022)

• Had a high three-firm concentration ratio:

85% (Stryker, DePuy Synthes, Smith & Nephew)

In 2013, the U.S. tibial IM nail market[8]:

The standard of care for fixation of midshaft tibial(shinbone) fractures is intramedullary nailing.

Warning: Graphic Images

Tibial IM Nail Product Offerings

SynthesExpert Tibial Nail

with Angular-Stable Locking System (ASLS)

Stryker T2™ IM Nailing

System

Smith & Nephew TRIGEN™

META-NAIL™

Zimmer®

Natural Nail™ System

Tibial Nail

Biomet Phoenix ™ Tibial

Nail System

OrthofixCentro/Tibial

Nailing System

DePuyVersaNail®

Tibial Nailing System

DePuyBiomet

VersaNail®

Tibial Nailing System

DePuy SynthesExpert Tibial Nail

with Angular-Stable Locking System (ASLS)

2012

2015

Zimmer BiometNatural Nail

ANDVersaNail

Secondary Fracture Healing

Mechanical Environment at Fracture Site

Speed and Course of Secondary Healing

1) Inflammation 2) Soft Callus

PeriostealBridging

Cartilage

3) Callus Hardening

EndochondralOssification

IntramembranousOssification

4) Remodeling

Hematoma

Cortex

Periosteum

MedullaryCanal

Callus Resorption

Bone Union: Woven Bone

Replaced with Lamellar

Bone

Importance of Shear Stability

[1]

[11] K Kaspar et al., “Angle stable locking reduces interfragmentary movements and promotes healing in unreamed nailing. Study of a displaced osteotomymodel in sheep tibiae," J Bone Joint Surg Am, vol. 87-A, pp. 2028-2037, 2003.

• Sheep received transverse osteotomies of tibia with a 3 mm interfragmentary gap[11]

• Comparison of standard unreamed IM nailing to an angle-stable configuration with threaded screw holes to prevent torsional shear

Standard Locking

Angle-Stable Locking • Angle-stable locking produced:

• Higher postmortem callus torsional stiffness

• Greater mineralised bone area (black)

• Complete bridging of osteotomy gap (arrows)

Products with Torsional Stability Focus

Expert TibialNail with

expandable bio-

resorbablesleeves for “enhanced fixation”.

Threaded screw holes

and polyethylene

bushings reduce angular

instability.

DePuy Synthes®

Angular-Stable Locking System (ASLS)

Smith & Nephew TRIGEN™

META-NAIL™

Biomet®

Phoenix™ Nail System

Internal setscrew locks the proximal oblique

screws and 5.0mm of fracture

compression.

Zimmer®

Natural Nail™ System

StabiliZe technology

links nail and screws to control rotation.

These systems produce highly-rigid constructs.Is more rigidity better?

6 Different Fixators Stiffness Map and Healing Results

[12] D Epari et al., “Timely Fracture-Healing Requires Optimization of Axial Fixation Stability," J Bone Joint Surg Am, vol. 89-A, pp. 1575-1585, 2007.

• Angle-stable nail better than standard nail

• ASTN not as good as fixator with lower stiffness

Optimizing Construct Stiffness

Micromotion Animal Studies

• Delayed callus formation• Lower fracture stiffness

• Proliferative external callus• Higher fracture stiffness

Rigid Fixation

P.O. 10 Weeks

Micromotion

P.O. 10 Weeks

Osteotomized sheep were treated with controlled axial micromotion via an ex-fix. Post-mortem bending stiffness showed that:

• Large gaps delay healing

• For well-reduced fractures (gaps ≤ 3 mm), micromotiondistances of:

0.2, 0.5, and 1 mm

increase callus stiffness compared to rigid fixation[12-14]

[13] L Claes et al., "Influence of Size and Stability of the Osteotomy Gap on the Success of Fracture Healing," J. Orthop. Res., vol. 15, pp. 577-584, 1997.

[14] LE Claes et al., "Effects of Mechanical Factors on the Fracture Healing Process," Clin. Orthop. and Relat. R., vol. 355S, pp. S132-S147, 1998.

[15] J Kenwright and AE Goodship, "Controlled Mechanical Stimulation in the Treatment of Tibial Fractures," Clin. Orthop. Relat. R., vol. 241, pp. 36-47, 1989. (Radiograph Images)

Micromotion Clinical Trials

[5]

• Stimulates development of proliferative callus

• Significantly reduces healing time

For a wide range of fracture types, micromotion:

[15] J Kenwright and AE Goodship, "Controlled Mechanical Stimulation in the Treatment of Tibial Fractures," Clin. Orthop. Relat. R., vol. 241, pp. 36-47, 1989.

[16] J Kenwright et al., "Axial Movement and Tibial Fractures," J. Bone Joint Surg. Br., vol. 73-B, pp. 654-659, 1991.

* Bending stiffness of 15Nm/deg

Clinical Union* [16]

Micromotion

17.9 weeksIndependent Weight-Bearing [15]

22.3 weeks

13.4 weeks 18.1 weeks(N = 38) (N = 35)(p=0.004)

vs. Rigid Fixation

(N = 29) (N = 38)(p=0.0005)

Micromotion reduced healing time by approximately 4.5 weeks

Technology Objective

The aim of the Flexible Axial Stimulation (FAST) Intramedullary Nail is to produce controlled

axial interfragmentary micromotionwhile maintaining high torsional stability to

produce the optimum mechanical environment for accelerated fracture healing.

Product Design Specification

Critical Analysis of Current Product

Offerings and Market Landscape

Comprehensive Review of Long Bone

Fracture Healing Literature

ManufacturabilityClinical AcceptanceRegulatory PathwayIntellectual Property

Marketability

Complex and Multifaceted Design Specification

Can we find a simple and elegant solution to satisfy the complex design requirements and achieve maximum clinical benefit?

Design Constraints/Considerations

Regulatory Pathway

• Reduce number of components• Minimize incremental cost• Employ standard machining techniques

Design for Manufacturability

Intellectual Property

Protection

Clinical Acceptance

• Accepted materials (no biocompatibility issues)• Risk analysis/dFMEA/uFMEA (consider device and user failures)• Line of sight to FDA 510(k) substantial equivalence claim

• Broad IP footprint • Inventive step and non-obviousness• Provisional, PCT, and country-specific filings

• No added time or complexity in operating theatre• Accommodate a guide wire• Backward-compatible with fully-static fixation• Minimize risk bone on-growth (internal features only)

Marketability• Unique selling points (device)• Cost pressures (US vs. EU)

FAST Nail Concept

Insert slides telescopically inside proximal cannulus and

ensures axial micromotion

Short slot controls micromotion

Machined features prevent rotation and ensure

proximal torsional stability

Micromotion and torsional stability derived from a proximal stem insert

Design Objective

Generating axial micromotion at the fracture site requires relative movement between proximal and

distal locking screws.

How much force is

required to induce

movement?

Image credit: [5] DePuy Synthes Trauma, Synthes GmbH, “Expert TN. Tibial Nail. Surgical Technique.” 2014

Mechanical Testing

[6] HL Dailey et al., “A Novel Intra-medullary Nail for MicromotionStimulation of Tibial Fractures," Clinical Biomechanics, vol. 27, pp. 182-188, 2012.

• Proximal/distal extremities embedded in PMMA

• Measured forces required to induce micromotion

Micromotion Plateau Force Data

Box plots show median, range, and upper/lower quartiles (N=7 samples)

DISTRACTION COMPRESSION-8

-6

-4

-2

0

2

4

6

8

Mic

rom

oti

on

Fo

rce

[kg

f]

4.5 kgf

Weight of hanging shank and foot:

FFoot = 0.06 x BW

= 4.5 kgf

Weight of the hanging foot alone is sufficient to cause micromotionwithout requiring full

weight-bearing.

Image of Cadaveric

Tissue

`

Synthetic Bone

Multiaxial Construct Testing

Axial tension/compression, torsion, shear, and four-point bending tests were carried out on implanted prototypes

with enhanced torsional stability features.

Measurements were repeated for explanted prototypes mounted in

composite tubes (Sawbones).

Embalmed Cadaveric Specimens

[7] HL Dailey et al., “The Flexible Axial Stimulation (FAST) intramedullary nail provides interfragmentary micromotion and enhanced torsional stability," Clin Biomech, vol. 28, pp. 579-585, 2013.

Images of Cadaveric Tissue

Preclinical Study

Results• Continuation to commercialization

stage was viable

Veterinary Research Partner• Musculoskeletal Research Unit (MSRU)

at University of Zurich

Funding• Grant from Irish Health Research Board

for a large-animal study

Translation to Startup Company

Before After

FAST Tibial Nail

Objectives: Research

PublicationsVisibility

Apex Nailing System (Product Family)

Objectives: Capitalization

Regulatory ClearancesProduct Launch

Timeline to Product Launch

2014 2015 2016

CE Mark certification: Initiate distribution of

approved product, start post-market clinical evaluation

Proven Concept

Idea

2017

Fundraising and Company Growth (Hiring)OEM Supplier Selection and Quality Management Activities

DFM (Implants and Instruments)IP Management

Regulatory Submissions

Rebranding

2018+

Femoral Nailing System

Enhanced Web Presence

Images courtesy: www.orthoxel.net

Part 3: Frontiers in Orthopaedic Trauma Research

Innovation at the Intersection of Epidemiology, Engineering, Clinical Care, and Human Behavior

Challenges in Fracture Care

Gordon Hayward, post-op recovery 2017twitter.com/YahooSports/status/923667897716695041

robynmhayward | Instagram

Most of the time…• Right implant + experienced surgeon +

active weight bearing = good healing

But sometimes things go wrong...• Fracture nonunion

• Who and why?

• Clues from epidemiological models

Other Challenges• Opioid abuse

• Obesity

• Human behavior

Nonunion Epidemiology

0%

10%

20%

30%

40%

50%

18-

29

30s

40s

50s

60s

70s

80+

Age

Fre

qu

en

cy

Male

FemaleTibial Fractures

• Injuries most common in young men and often result from risk-taking behaviors (motorcycles, sports)[17]

Nonunion• Fracture does not unite after primary

surgery and requires additional intervention to stimulate healing (exchange nailing, bone grafting)

• Complex, multifactorial problem

• New data: nonunion is more frequent in middle adulthood, particularly among women, but why?

[17] HL Dailey et al., “Tibial Fracture Nonunion and Time to Healing Following Intramedullary Nailing: Risk Factors Based on a Single-Centre Review of 1003 Patients,” J Orthop. Trauma. In review, 2017

0%

5%

10%

15%

20%

25%

18

-29

30s

40s

50s

60s

70s

80

+

No

nu

nio

n R

ate

MalesFemalesAll

Fracture Pattern Risks

Nonunion Risk Theory #1• Nonunion risk may depend on fracture pattern

Nonunion Risk Theory #1 Model Test• Nonunion risk is driven in part by fracture pattern (AO/OTA Classification)

42-A Simple Fractures

A1 Spiral A2 Oblique A3 Transverse

42-B Wedge Fractures

B1 Spiral Wedge B2 Bending Wedge

B3 Fragmented Wedge

42-C Complex Fractures

C1 Spiral C2 Segmental C3 Irregular

Use computational simulations to compare the healing process using simple

rules for mechanical stimulation.

Fracture Healing Simulations

tissue destruction

cart

ilage

connective tissue

bone

bone resorpti

on

Hydrostatic (Volumetric) Strain, 𝜀𝐻𝑦𝑑𝑟𝑜

Distortional (Shear) Strain, 𝜀𝐷𝑖𝑠𝑡

Connective Tissue

Bone CartilageEndochondral Ossification

Chondrogenesis

Resorption or Destruction

Intramembranous Ossification (compression

without destructive

shear)

(moderate hydrostatic strain with moderate

shear strain)

(moderate to high hydrostatic strain and low to moderate shear)

(strains too low or too high)

Mechanoregulation model: mechanical strain-based rules govern tissue differentiation in the healing zone


Simulation methods: ANSYS + MATLAB with Fuzzy Logic Toolbox, loading conditions based on partial weight bearing on IM nail.

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20

No

rmal

ized

To

rsio

nal

Rig

idit

y,

Rto

r/R

tor,i

nta

ct[-

]

Iteration Number

B2

A1A2A3

C2B1

C3

B3

Key Results: • Fracture pattern has a mechanical influence on healing

• Models with floating bone fragments (B3, C3) healed most slowly

Callus Element Stiffness, E [MPa]

0.5 Min 4,000 Max

Step 1 Step 20


Required Elements for Healing

BIOLOGY

Metabolic Factors

Vascularity

Mechanoregulation

SURGERY

Choice of Implant

Accuracy of Reduction

Soft Tissue Injury Management

STIMULUS???

= PATIENT

Pain (Tolerance and Management)

Weight Bearing (Body Mass and Assertiveness)

Compliance

Nonunion Risk Theory #2• Nonunion risk may depend on patient behavior

Future Directions in Clinical Research

Future Study Design: • Observational studies designed to measure behavior (weight bearing) and

quantify the healing response

® Tekscan, Inc.

red = callus region at 12 weeks post-op

Image-Based Structural Modeling

Structural Strain

High

Low

CT-Derived Finite-Element Meshes ANSYS Structural Analysis Results

Scale [mm]

30

20

10

0

The largest callus isn’t always the strongest. Structure and mechanical properties both matter and x-rays can’t provide this information.

Future Directions in Clinical Research

Observational Hypothesis Testing • More early weight bearing is

associated with faster healing

• Higher levels of reported pain are associated with less weight bearing and slower healing

Future Interventional Trials • Use behavioral interventions to help

patients achieve optimal early activity levels, especially in the critical early weeks when pain levels are highest

• Use personal data tracking to help manage pain and activity levels

® Tekscan, Inc.

Contact

Acknowledgements & Contact

Hannah Dailey, PhDAssistant Professor

Mechanical Engineering & MechanicsPackard Lab, Room 556

[email protected]

Sources of Funding Collaborators and Support

Health Research BoardCharles DalyPat O’Connor

Prof. James Harty, FRCSI Prof. Michael Maher, FRCSIDr. John Galbraith, MRCSI

Prof. Dr. med. vet. Brigitte von Rechenberg, ECVS

orthopaedic implant design from concept to...

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