Allograft Anterior Cruciate Ligament Reconstruction

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					Allograft Anterior Cruciate
Ligament Reconstruction

    John F. Meyers, M.D.
Basic Science
   Allograft and Autograft
       are Dead Tissue
• Revascularization
• Act as scaffold for collagen
       Animal Studies

• Goats – slower rate of biological
  incorporation
• Dogs – mean load to failure 536
  newtons vs. 802 newtons
           Clinical

• Noyes 89% good and excellent
  results
• Shino 75 of 80 good and
  excellent results
          Advantages
• No morbidity at the donor site
• A variety of sizes and shapes are
  available
• Revision surgery
• Multiple ligament reconstructions
• Preop patellofemoral problems
       Disadvantages

• Longer incorporation time
• ? Ultimate strength
• Disease transmission
HIV Transmission From Organ
 & Tissue Transplantation :

     A Case Report and
   Comparison of Processing
          Methods
             1985

• HIV Antibody testing first
  implemented for organ and
  tissue transplantation
• Window of seronegativity
  following HIV infection
• Infected with HIV virus but not
  yet detected with available HIV
  antibody tests
            Window

• A period of 4 weeks to several
  months may pass before
  detectable levels of antibodies
  are produced
The sequential occurrence
 of HIV antigen markers &
    antibodies has been
  particularly elucidated

  Stramer, et. Al. JAMA 1989
HIV is generally believed to be
circulating in detectable levels
 within 1-2 weeks of exposure
Elisa Assay of HIV p24 Core
          Antigen

 Routine screening not yet
  advocated by american
association of tissue banks
          (AATB)
Investigational HIV Assays

• Recombinat DNA
• Viral Culture
 Harvesting of tissues may be
performed in either a sterile or
   clean non-sterile manner
       Sterile Retrieval

• Sterile surgical technique
• Secondary sterilization not
  necessary
    Non-Sterile Retrieval

• Harvest within 24 hours
• Secondary sterilization required
  –Chemical / Ethylene Oxide
  –Gamma Irradiation
  The Quality & Strength of
Irradiated Graft Material has
      been Questioned

• Haute RC, et. Al., Trans.
  Orthop. Res. Soc., 1989
  High risk behavior for HIV
transmission was not defined
 by the public health service
          until 1987
  The AATB has developed
specific guidelines for donor
  selection & exclusion as
mandated by the U.S. Public
       Health Service
 Plasma HIV Inactivation has
 been documented with heat,
ethanol, ultraviolet and gamma
           irradiation

The ability of these processes
to inactivate HIV in bone and
    soft tissue is unknown
      Sterile Retrieval :

• Tissue harvesting within 12
  hours of cessation of
  cardiopulmonary function
• If body stored at 4°C, retrieval
  may be carried out within 24
  hours
• It has been calculated that the chance
  of obtaining a soft tissue or bone
  allograft from a properly screened donor
  is less than one in one million
  Buck BE, et. Al., C.O.R.R., March 1989
• Current processing techniques probably
  further reduce this remote residual risk
       Sterile Retrieval

• Procured tissues preserved by
  either deep freezing or freeze-
  drying (Lyophilization)
Processing – Fresh Frozen

• Removes extraneous tissue
• Washing with surgical antibiotic
  irrigant
• Freezing to < 70°C
Processing – Freeze-Dried

• Washing / Freezing
• Remove moisture content to <5%
  All four vascular organs and three of
four fresh-frozen graft recipients tested
             positive for HIV

  None of the forty-two recipients of
   freeze-dried, freeze-dried ethanol
treated, or freze-dried irradiates tissue
grafts has been known to test positive
                 for HIV
Chemical Sterilization Ethylene
 Oxide – Recipient Morbidity

  • Residual ethylene chlorhydrin
  • Persistent synovial effusions
  • Cellular inflammatory
    responses
No statistical difference in strength
between fresh-frozen & freeze-dried
           allograft tissue

Trend towards decreased decreased
ultimate stress in freeze-dried group

Paulos LE, et. Al., Trans. Orthop. Res.
              Soc., 1987
           Ethanol

• Commonly used to remove lipid
• Often in preparation of
  demineralized freeze-dried
  bone
            Ethanol

• Proven viral inactivator
• 70% ETOH & 0.5% Sodium
  Hypochlorite both completely
  inactivate HIV within one minute
  Allografts & Autografts undergo a
   similar course of incorporation

Allograft incorporation may lag behind
      Autograft in animal model

  Arnoczky SP, et. Al., JBJS 86, 68A
           Incorporation

•   Necrosis
•   Revascularization
•   Cellular proliferation
•   Remodeling
    Tissue Preservation

• Vascular Organs
 –Rapid cooling with eurocollins
 –Transplanted within 24 hours
• Musculoskeletal Tissues
 –Sterile harvest, deep frozen to –
  80°C
  Musculoskeletal Tissue
     “Fresh Frozen”
• 2 femoral heads, 1 proximal femur,
  1 bone-patellar tendon-bone graft
• Tx: Thawed, clensed of extraneous
  soft tissue, treated with bacitracin &
  polymixin B, refrozen to –80°C
   HIV Transmission via
Allograft Organs & Tissues

       A Case Report
                Donor
•   22 y.o. Male
•   C.O.D.: GSW to Head
•   Multi-Organ & Tissue Donor
•   Recovered in 1985
•   No overt risk factors identified
•   Negative autopsy
Organs & Tissues Recovered

• Vascular Organs
• Corneas
• Musculoskeletal Tissue
        Seralogic Assays

•   HIV antibody X 2 – Negative
•   HBsAg – Negative
•   HBcAb – Negative
•   Anti-HAV – Negative
•   STS – Negative
LifeNet Tissue Distributed
• 4 Frozen (“Fresh Frozen”)
  Musculoskeletal Grafts
• 4 Freeze Dried Soft Tissue Grafts
• 6 Freeze Dried Irradiated Soft
  Tissue Grafts
• 38 Freeze Dried Bone Grafts
LifeNet Tissue Distributed

• First tissue distributed
  November, 1985
• Last tissue distributed July,
  1986
Potential Patients Affected

• 4 Organ Transplants
• 2 Cornea Transplants
• 52 Musculoskeletal Grafts
  Distributed
         Chronology of Events
•   Telephone call from hospital 4/18/91
•   Investigation of organ recipients 4/24/91
•   Letter from State Dept. Healts 4/26/91
•   Began preliminary recall 5/6/91
      Chronology of Events
•   FDA/CDC notification 5/7/91
•   Meeting with FDA/CDC 5/14/91
•   Look back procedure began 5/16/91
•   Media coverage began 5/17/91
Laboratory Investigation of
          Donor
• Lymphoid Tissue
  – Proviral DNA by PCR – Positive
  – HIV antigen – Positive
  – HIV Reverse Transcriptase – Positive
  Processing / Prevention

• Organs
 –Perfused with crystalloid
 –Cold Storage
 –Transplanted within 24 hours
 Processing / Preservation

• Corneas
 –Preserved in Dextrose-
  Electryolyte-Gentamicin
 –Transplanted within 48 hours
Processing / Presesrvation

• Frozen Musculoskeletal Tissue
 –Thawed
 –Treated with antibiotics
 –Refrozen to –80°C
 Processing / Preservation

• Freeze Dried Soft Tissue
 –Thawed
 –Treated with antibiotics
 –Refrozen to – 80°C
 –Lyophilized to <5% H2O
 Processing / Preservation
• Freeze Dried Bone
  – Thawed
  – Treated with antibiotics
  – Cleaned in Ultrasound / 30% Ethanol
  – Pulsating water lavage
  – Treated with 100% Ethanol
  – Refrozen to – 80°C
  – Lyophilized to <5% H2O H2O
 Processing / Preservation
• Freeze Dried, Irradiated Soft Tissue
  – Thawed
  – Treated with antibiotics
  – Refrozen to – 80°C
  – Lyophilized to <5% H2O
  – Irradiated (3.0-3.4 Mrad, Co 60)
           Organ Recipients
       Date 1st Tested Positive   Date of Death
K              7/24/86              12/25/86

K              3/27/87              6/15/88

H             6/18/86*              8/17/86

L                N/A                11/16/85


*EIA+;WB
      Look Back Results
       Organ Recipients
• Heart recipient seropositive at
  death
• Kidney recipients seropositive at
  death
• Liver recipient HIV ab negative but
  Ag positive
  Musculoskeletal Tissue
      Freeze Dried
• Tx/Bone: thawed, clensed, 30%
  ETOH, water lavage, 100% ETOH,
  bacitracin & polymixin B, freeze-
  dried over 5 day cycle
• Tx/Soft Tissue: Similar processing
  without ETOH 2 Fascia Lata, 1
  achilles, 1 bisected bone-pt-bone
 Soft Tissue / Preservation
• Dura Mater – Similar processing
  with freeze-drying followed by 3
  Mrads gamma irradiation
• Corneas – preserved by K-Sol
  solution & hypothermia,
  transplanted within 48 hours
• Graft material distributed to
  hospitals from 11/85 to 7/86
Hospital Notification and Look
                Back
 • Instituted by tissue bank and
   assisted by CDC
 • Determine existance of unused
   grafts
 • Identify & test recipients of
   tissues
 Donor Medical & Clinical
        Review
• 2 Serum specemins HIV antibody
  negative at two different labs
• Fluid I/O reviewed with no evidence of
  significant hemodilution
• No associated infection with PPF lots
• Family interview revealed no HIV risk
• 2 Female sexual contacts HIV antibody
  neg.
Donor Medical / Labaratory
             Review
• Archived donor serum not
  available
• Cryopreserved Lymphocyte
  Preparation located at
  transplant center
Organ Recipient Investigation

 • All four have died, and were
   HIV antibody and antigen
   negative pre-transplantation
Organ Recipient Investigation
 • The heart and one kidney
   recipients died from causes
   suspicious for HIV infection
 • The other kidney recipient died
   from underlying kidney diseases
 • All three were HIV antibody positive
   post-transplantation
Organ Recipient Investigation
 • Liver recipient died 24 days post
   transplantation from surgical
   complications
 • Not tested for HIV prior to death
 • Stored serum HIV antigen positive
   3 days post-transplantation
 • No HIV antibody found in stored
   serum by time of death.
      Look Back Results
     Fresh Frozen Tissues
• 2 Femoral Heads
  – Recipients tested positive for HIV antibody at 2
    years
• Bone-Patella Tendon-Bone
  – Was used in ACL reconstruction fever, rash,
    pharyngitis 3 weeks post transplantation HIV
    antibody positive look back
• Proximal Femoral Allograft
  – Revision hip surgery tested neg. 6 years post-
    transplantation at look back
       Look Back Results
Freeze-Dried, Ethanol Treated Bone Graft Recipients

• 25 of 37 potential tested HIV antibody
  neg.
• Two grafts unused
• Two died of unrelated causes
• Two ID’d but not located
• One ID’d not tested
• Five grafts disposition unknown
• No HIV infection documented
      Look Back Results
      Freeze-Dried Soft Tissue Recipients

• The 3 recipients of 4 grafts tested
  negative for HIV antibody at look
  back
• One patient received two grafts,
  fascia lata and Achilles Tendon
• All grafts used for knee
  reconstruction
           Look Back
• Freeze-Dried, irradiated Dura
  Mater graft recipients
  –3 of 6 have been located and
   tested negative for HIV antibody
• Corneal Recipients
  –Both tested negative for HIV
   antibody at look back
          Discussion
• CDC & tissue bank have concluded
  that the donor had recently been
  infected with HIV
• Was in the window period of
  negative seroconversion and
  positive infectivity
• HIV antigen testing was not done
• Evidence suggests the early HIV
  infection may be the most infectious
  period
• High levels of viremia in plasma and
  peripheral WBCs exist during this period
• Antigen level correlates with viremia

 Daar ES, et. Al., NEJM, April, 1991
   Marc A. Asselmeier, M.D.
     Richard B. Caspari
    Scott Bottenfield, R.N.

Orthopaedic Research of Virginia
• Human Immunodeficiency Virus
  (HIV) infection via vascular
  organ & tissue transplantation is
  well documented.
• Majority of early transmissions
  occurred before antibody
  testing
              1984

• Original case HIV transmission
  through allograft bone
  transplantation
• Sterile harvest of femoral head
  from ? THA patient
             1984

• Femoral head frozen & used
  during spine fusion
• Both donor & recipient later
  documented HIV positive
• A rapid enzyme linked
  immnosorbent assay (Elisa/EIA)
  to detect antibodies against
  viral envelope protiens
• Positive Elisa results may be
  verified by western blot analysis
  to eliminate false positive Elisa
  Assays
• Anyone with HIV antibodies in
  their serum is infected with HIV
  & harbors it in a transmissable
  form in their blood, body fluids
  & tissues
         Since 1985

• 3 Reports of organ
  transplantation associated HIV
  transmission from seronegative
  donors
          Since 1985

• Hemodilution
• Urgent transplantation prior to
  HIV antibody results
• Prior negative testing
• The need and efficacy of the
  routine use of the HIV antigen test
  continues to be questioned
• The U.S. Public Health Service
  Work Group on organ and tissue
  transplantation is now considering
  HIV antigen testing as a required
  serologic assay
Reason for Non-Transmission
           of HIV
• Processing / Nature of tissue itself
• Virus is known to concentrate in WBCs
• Freeze-dried grafts were relatively
  hypocellular in comparison to fresh-
  frozen grafts
• Combination may reduce viral burden to
  zero or a level which is subinfectious
• Freeze-Dried Tissue Grf=afts in
  use since 1951
• AATB Estimates over One
  Million Freeze-Dried Tissue
  Grafts have been used
                Conclusion
To assure safety of tissue and organ transplantation

   • Careful screening of prospective
     donors
   • Adhering to existing AATB
     guidelines
   • Continued processing and
     serologic research
   • Know practices of local tissue bank
• Antigen testing would thus
  narrow this “window” of
  infectivity & non-detection
           Includes

• HIV Core & Regulatory Protein
  Analysis
• Culturing for detection of
  reverse transcriptase activity
• Proviral DNA by the polymerase
  chain reaction (PCR)
            1985

• Donor
 –Heart, liver, kidneys
  Medical Center Transplant Team
 –Femora, tibias, fascia lata,
  Achilles & patellar tendons
  AATB certified tissue bank
          April 1991

• Tissue bank notified that
  recipient of femoral head from
  donor had seroconverted to HIV
  antibody positive as early as
  1987
  Donor Laboratory Review
         Cryopreserved Lymphocytes
          HIV Infection Documented

• Detection HIV reverse transcriptase
• HIV p24 Antigen
• HIV Provial DNA by Polymerase Chain
  Reaction (PCR)
• To date there have been no
  known cases of HIV or other
  viral transmission through
  freeze-dried tissue grafts
Know the source of your graft
 • Negative
 • Freeze-dried tissue
 • HIV antibody test 3-6 month
   window
 • HIV antigen test 2 week window
 • Polymerase chain reaction – tests
   for viral DNA closes window
      Look Back Results
             Frozen Tissue


• Femoral head recipients seropositive
• Patellar tendon recipient seropositive
• Proximal femur recipient seronegative
      Take Home Lessons
• Confirms “window” of seronegativity and
  infection
• Frozen grafts capable of transmitting HIV
• “Processed” grafts did not transmit HIV
• Importance of OPO/TB communication
• Importance of adequate recipient tracking
             Fall Out
• Safety-Driven Tissue Banking
  System
• Better HIV testing
• HIV inactivation research
• Potential decrease in elective
  surgery use
• Regulatory
         Regulatory
• PHS Workshop
• “Fast Track” ?
• Better Recipient Tracking
  Systems
• Better Coordination Between
  Agencies