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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
IM Nailing Surgical Procedure
Insert Guide Wire and
Progressively Ream to Get
“Chatter”
Select Nail and Attach Insertion Handle
[5] DePuy Synthes Trauma, Synthes GmbH, “Expert TN. Tibial Nail. Surgical Technique.” 2014
IM Nailing Surgical Procedure
Slide Nail into Medullary Canal Attach Aiming Arm
[5] DePuy Synthes Trauma, Synthes GmbH, “Expert TN. Tibial Nail. Surgical Technique.” 2014
IM Nailing Surgical Procedure
Freehand Distal Locking Guided Proximal Locking
[5] DePuy Synthes Trauma, Synthes GmbH, “Expert TN. Tibial Nail. Surgical Technique.” 2014
IM Nailing Procedure
Remove Insertion Handle and Insert End Cap
Final Screw Configuration Options
[5] DePuy Synthes Trauma, Synthes GmbH, “Expert TN. Tibial Nail. Surgical Technique.” 2014
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
Fracture Healing Simulations
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
Fracture Healing Simulations
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
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