Describes why and how knee arthritis should be treated with subchodral delivery of stem cells without potentially harmful radiation exposure

1. Bioplasty with and
without imaging
Edward G. Loniewski, DO, FACOS, FAOAO
Brighton, Michigan

2. Take Home Points
• Arthritis is a BONE and joint disease
• Bone marrow edema is a very important predictor of progression
• Subchondral injection of BMC reduces MSC migration
• Anatomic landmarks can reduce need for radiation exposure
• Bioplasty can be performed safely and effectively with and
without imaging based on known anatomic landmarks and average
distances.

3. Background- Teaching
• Michigan State University, College of Osteopathic
Medicine, Associate Clinical Professor 1997-
Present.
• Saint Joseph Mercy Health Systems- Clinical
Instructor, Family Practice Residency, 2008-2014.
• University of Michigan, Department of Orthopedics,
Alumni Instructor- 1997-2004.
• Research Reviewer, Michigan State University
College of Osteopathic Medicine Consortium of
Graduate Medical Education, 2005-Present.

4. Disclosures
• Consultant for Celling Biosciences – ART BMC™ - Austin, Tx.
2015- Present
• Consultant, Principle Investigator and Stockholder- Augmenstem™
and Plenastem™ AVM Biotechnology- Seattle Wa.- 2016- Present
• Former Consultants for:
• Biomet Biologics – GPS system
• Lilly – Forteo
• Bionicare – PEMF Knee brace

5. Why Do We Need to Even Consider the Bone ?
• Arthritis is a BONE and joint disease
• Stem cells migrate from joint injections

6. The Abnormal
Biochemical Joint
• Elevated levels of IL-1
• Tunnels form between bone
to cartilage
• Cross talk occurs and thus
loss of paracrine stability
• Stress fracture and bone
marrow lesions
• Biochemical changes lead
to Biomechanical changes.
eloniewski@gmail.com 810-923-0515

7. The Abnormal
Biomechanical Joint
• Tunneling from IL-1B release-
Stress fracture causes loss of
supportive environment
• Meniscus bulges and fails
• Mechanical axis shifts
• Chronic stress on ligaments
cause loss of stability and shear
begins
• Shear causes subluxation
• Subluxation causes loss of
motion
• Loss of motion causes loss of
function of synovial fluideloniewski@gmail.com 810-923-0515

8. Bone Marrow Lesion ( BML) is important
marker of progression
• Evidence of BML leading to
joint replacement (ref 1-3)
• T2 weighted lesion of distal
femur, proximal tibia or patella
• Reported sometimes as
subchondral edema or stress
fracture.
1. Felson DT, Chaisson CE, Hill CL, Totterman SM, Gale ME, Skinner KM, et al. The association of bone marrow lesions with pain
in knee osteoarthritis. Ann Int Med. 2001;134(7):541-9. [ Links ]
2. Sowers MF, Hayes C, Jamadar D, Capul D, Lachance L, Jannausch M, et al. Magnetic resonance-detected subchondral bone
marrow and cartilage defect characteristics associated with pain and X- ray-defined knee osteoarthritis. Osteoarthritis
Cartilage. 2003;11(6):387-93. [ Links ]
3. Roemer FW, Guermazi A, Javaid MK, Lynch JA, Niu J, Zhang Y, et al. Change in MRI-detected subchondral bone marrow
lesions is associated with cartilage loss: the MOST Study. A longitudinal multicentre study of knee osteoarthritis. Ann Rheum
Dis. 2009;68(9):1461-5.

9. Typical BML patient
• Younger female or male
• May have had recent
arthroscopy for MMT
• Progressive, persistent
pain
• Night pain
• Injections may only last
few days to few weeks.

10. Subchondral Bone Marrow Concentrate vs. Joint
Replacement
• Prospective, Randomized Trial
comparing TKA to BMC
• 30 Young Males (avg age 28) with
Bilateral AVN of the Knee
• Randomized to receive one knee with
standard total knee arthroplasty and
the other with subchondral injection of
BMC
• Followed with Knee Society Score
(KSS), MRI , Radiographs for average of
12 years (range 8-16).

11. Subchondral Bone Marrow
Concentrate vs. Joint
Replacement
• Concentrated Bone Marrow (CBM)
knee had :
• Lower rate of thrombophlebitis –
0% vs. 15% for the TKA side
• Lower rates of re-operation –
10% vs 20% for the TKA side
• Only 3 patients converted to a
total knee at 6, 8 and 12 yrs out.
• Less Invasive Total knee surgery-
on stem cell side no extended
stems were used.
• Lower rates of poor outcome
category – 1% vs 13% for TKA side
• Higher patient satisfaction – 70%
preferred the stem cell side vs.
30% TKA

12. Stem cells disappear from the synovial fluid within 30 minutes to 8
hours after injection
0
50
100
150
200
250
300
350
400
450
500
Dragongreenstainedcells
Time in Hrs
Carpus Stem Cell Retention (n=2)
0
50
100
150
200
250
300
350
400
450
500Dragongreenstainedcells
Time in Hrs
Tarsus Stem Cell Retention (n=2)
Two mares were injected with 5 to 7 million Dragon Green labeled allogeneic equine
ADSC in to both the carpus (C) and tarsus (T) joints. Synovial fluid was drawn at the
indicated times to determine stem cell retention in the synovial space by flow cytometry.
While cartilage is avascular, the
synovium is
highly vascularized, allowing stem
cell escape from the synovial
space.

13. 13
13 AVM Biotechnology LLC.
Bone Marrow Transplant was
predictive of the spleen’s role in
regenerative medicineStem cells injected into
heart via catheter
Stem cells exit from the heart and
accumulate in the spleen (red - viable)
and liver (yellow –not viable)
Scale: red highest, purple lowest
Source: Hofmann et al. Circulation 2005
Slide /

14. All stem cells & Routes lead to the spleen
Cell Type: Human Adipose MSC
Subject: Rat
Delivery: Intraocular/Striatal Injection
Indication: Biodistribution
14
Cell Type: Human Adipose MSC
Subject: Human
Delivery: IV Hand
Indication: Arthritis/Biodistribution
Cell Type: Mouse ESC
Subject: Mouse
Delivery: Kidney Subcapsule Transplant
Indication: Diabetes/Biodistribution (MRI)
M Ren et al. Sci Rep. (2014)
Haddad-Mashadrizeh A et al. Cytotherapy (2013)
Nereen Healthcare (2016)
Cell Type: Human Adipose MSC
Subject: Rat
Delivery: Tail Vein Injection
Indication: Diabetic Nephropathy
Zhang L et al. Stem Cells Dev. (2013)
Cell Type: Human Peripheral Blood HSC
Subject: Human
Delivery: IV Intracoronary
Indication: Myocardial Infarction
Kang WJ et al. J Nucl Med (2006)
Cell Type: Rat Bone Marrow MSC
Subject: Rat
Delivery: IV & IM
Indication: Acute Myocardial Infarction
Barbash Circulation (2003)
❶ ❷ ❸
❹ ❺ ❻

15. The Problem
Subchondral
injection has
favorable outcomes
• Up to 70% retention of
cells by radiotracer
• Treats the BML
• Improved clinical
outcomes
BUT Requires:
• Identifying anatomic
landmarks
• Ideal patient positioning
• C-arm for confirmation
of placement
• Extra time
• Normally general
anaesthetic or deep
sedation

16. Known Average Distances From Total Knee
Design Studies*
• Femoral Condyle Widths- M/L
• Medial: Avg: 2.6 cm
• Female- 2.43 cm
• Male- 2.8 cm
• Lateral: Avg 2.85 cm
• Female- 2.60 cm
• Male- 3.09 cm
• 2.0 cm will mean you will be
within 0.5 cm of inner edge.
• Tibial A/P Distance
• Medial A/P: Avg 5.06 cm
• Female- 4.75 cm
• Male- 5.37 cm
• Lateral A/P : Avg 4.74 cm
• Female- 4.45 cm
• Male- 5.03 cm
• 2.5 cm will mean you will be
in the central portion of the
tibia.
*Fitz W, Bliss R, Losina E. Current fit of medial and lateral unicompartmental knee
arthroplasty. Acta orthopaedica Belgica. 2013;79(2):191-196.

17. Previous studies of blind placement of
intraosseous IV
• 90% successful blind insertion
during cardiac arrest. *
• After just one hour of training
success increased to 84% on
first attempt and 97% after
second. **
*Santos D1, Carron PN, Yersin B, Pasquier M. EZ-IO(®) intraosseous device implementation in a pre-hospital emergency service: A
prospective study and review of the literature. Resuscitation. 2013 Apr;84(4):440-5. doi: 10.1016/j.resuscitation.2012.11.006. Epub
2012 Nov 14.
** Gazin N1, Auger H, Jabre P, Jaulin C, Lecarpentier E, Bertrand C, Margenet A, Combes X.
Efficacy and safety of the EZ-IO™ intraosseous device: Out-of-hospital implementation of a management algorithm for difficult
vascular access. Resuscitation. 2011 Jan;82(1):126-9. doi: 10.1016/j.resuscitation.2010.09.008. Epub 2010 Oct 14.

18. Injection of bone marrow
arthrogram shows wide displacement of BMA
Courtesy of Philippe Hernigou, M.D.
• Bone Marrow is
flowable to
distances over
4 cm away.
• “The bone is a
sponge.” P.
Hernigou
• Anatomic
placement is
not necessary.

19. Core decompression
alone
Autologous bone
marrow injection
Courtesy of Philippe Hernigou, M.D.

20. Effects of Radiation on Stem Cells
• Pregnant women maximum allowable radiation
• 0.4 mGy
• Normal exposure of c-arm cases-
• Avg exposure- 2.0 mGy-m²*
• Effect of Radiation on cells-
• 0.1 mGy resulted in temp stunned growth for 2 weeks. **
• 0.4 mGy resulted in temp damage.***
• 100 mGy causes altered gene expression on progenitor cells. ****
*Lee Y-S, Lee H-K, Cho J-H, Kim H-G. Analysis of radiation risk to patients from intra-operative use of the mobile X-ray system (C-arm). Journal
of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences. 2015;20(1):7-12.
** Fujishiro A, Miura Y, Iwasa M, et al. Effects of acute exposure to low-dose radiation on the characteristics of human bone marrow
mesenchymal stromal/stem cells. Inflammation and Regeneration. 2017;37:19. doi:10.1186/s41232-017-0049-2.
** Wilson KD, Sun N, Huang M, et al. Effects of Ionizing Radiation on Self Renewal and Pluripotency of Human Embryonic Stem Cells. Cancer
research. 2010;70(13):5539-5548. doi:10.1158/0008-5472.CAN-09-4238.
***Katsura, Mari et al, The Effects of Chronic Low Dose Radiation on Human Neural Progenitor Cells; Scientific Reports 6, 2017

21. Can we accurately perform a blind effective
Bioplasty without radiation exposure?
• Use known anatomic landmarks as
entry points
• Distance away from neuro-vascular
structures
• Use stop points of 2 and 2.5 cm
• Use of external guide

22. Sample
trajectories
of different
entry points

23. Axial view
shows
placement of
Subchondral
injection
options

24. Epicondyle entry point
• Benefits:
• Easily palpable landmark
• Truly extra-capsular
• Easy to anesthetize
• No vital structures near
• Many patients with varus
deformity have MCL pain and
easy to inject around MCL after
local given to this area.

25. Medial femoral ridge entry point
• Allows more vertical entry
point to avoid backflow.
• Easier to line up with C-arm to
center of condyle
• Potential to exit posterior
• Avoids any potential damage
to origin of MCL.

26. Medial Ridge of
Condyle entry
point

27. Lateral view of Medial epicondyle entry point
• Center of MEDIAL epicondyle
• Center of femoral condyle
• Avoids posterior exit
• Keeps entry point outside of
capsule.

28. Patella can
act as central
guide for
injections
without
imaging

29. Medial
femoral
ridge entry
point

30. Depth of
epicondyle
entry point
guided by
medial edge
of patella
Easy to set depth of needle insertion from
epicondyle to medial patellar line.

31. Ideal location of
tibial
Subchondroplasty
is 0.5 patellar
length from
inferior pole of
patella

32. Locating the tibial Subchondroplasty site
• 0.5 patellar height
distance and 10 degree
posterior slope is
normally the ideal spot for
entry .

33. Patellar
centering device
Fits around the patella
Fit proximal end first .
Adjusts distance to proximal tibia
based on size of patella
Smaller patella moves needle more
proximal
Should be at 1.5 patellar width

34. Lateral view
Centerline of patella
can fit outrigger for
placement to
epicondyle
Out rigger angled 10
degrees posterior to
mimic slope of tibia.

35. Anterior view
Avoids any placement into vital
structures
Stop placed at 25 mm to avoid
posterior penetration
Rests easily on anterior knee with
adjustable legs

36. Patellar stop
Distance
Line from medial or
lateral edge of patella
acts as stop distance for
epicondyle entry
Will provide delivery
to center of condyle

37. Option #1- slip over sleeve with
aiming portals
• Slips over the knee
• Cut out areas give physician a target to aim
through.
• Provides very visible landmarks to prevent
misplacement of injection.
• Allows patients to take brace home and use after
the procedure with your name on the brace!

38. Option #2- for the larger
patient
• Wrap around design
for larger knees and
patients.
• Direct visualization
of the patella
• May require some
modifications with
patellar web to
highlight patellar
edges

39. Sample Case- Quick Aspiration Pearl
• Anterior approach
• 3 cm posterior to ASIS
• 10 ml syringe –
• Fast pull from 0 to 10 ml
• See ”Champagne Foam”
• Let go to hear “pop”-
• 1 ml – 2ml fill
• Rotate 90º and repeat.
• Stop at 4 ml
• Advance needle 0.75 to 1 cm and
repeat

40. Fast Pull Pays off
Without Pre-
conditioning and
slow pull
Day#14
With Pre-
conditioning &
Fast Pull Day#10

41. Sample Case - Anatomic Landmarks
Find center of patella and
move to find epicondyle Readjust by finding joint line

42. Case Sample- Medial Femur Blind Insertion
Place in 2.0 to 2.5 cm (2
lines) C-arm confirmation
Aspirate damaged marrow – create
negative pressure with 10 cc syringe

43. Slow and Low for Bioplasty – Under 100
mm/hg
Larger 20 cc syringe with
very light hand
100 mg/hg= Not more pressure
than squeezing grape

44. Importance of slow push
• Intra-osseous IV infusion
• Normally placed with 100- 300
mg/hg pressure
• “Slow and low is the way to
go!”
• https://youtu.be/oLl4jTON7xU

45. Medial Tibia
• Insert 1.5 patella widths or 2
cm distal to joint line.
• 2 to 2.5 cm into tibia

46. Patellar Subchondroplasty
• Small 15 g interosseous needle
• Less traumatic for patella
• Easy blind insertion
• “Macaron Technique”
• Slow push of 2 cc

47. Bioplasty
Summary
Arthritis is a BONE
and joint disease
BML need to be
treated
Stem Cells Migrate
Subcondral
injections provide
reliable superior
results
Radiation may
cause temporary
damage to MSC
Anatomic
landmarks provide
safe entry for
intraosseous BMC
Validation studies
to come

48. One Final Thought
Thank You
and…
May God &
Your Neighbor
Bless Your
Hands!