Lecture topic: HISTORY OF BONE TRANSPLANTATION

Cosmos and Damian - 4^th century martyrs

Van Meekeren (1668) - dog cranium to human

Macewen (1878) - First clinical allograft

Lexter (1908) - joint transplant

Iclan (1942) - frozen bone

Hyatt (1950) - US navy tissue bank

Elosdorf (1952) - freeze drying of bone

Urist (1953) - BMP

Mankin (1971) - massive osteochondral allograf

There are several regional tissue banks in each state. They supply tissue grafts to the whole region. But the processing cost is very high. National programs such as American Red Cross distribute tissues to the region. Some cryobanks produce heart valves and cardiovascular tissues.

Most of the tissue banks have American Association of Tissue Banks(AATB) accreditation. These tissue banks are inspected and accredited by AATB. Four tissue banks in Canada under AATB. There is a network for organ procurement and transplantation. They follow a very strict selection criteria. National Bone Marrow program keeps a registry of living donors who are waiting for bone marrow donation.

Tissue banks also closely work together with organ procurement organizations. Educational programs for public are being held frequently. These include stamps, posters, TV programs etc.

	Hospital staff
	Nursing
	Social workers
	Physicians
	Surgical services
	Pathology services
	Religion
	Morticians
	Medical examiners
	Organ transplant programs
	Tissue programs
	Donor evaluation: medical charts, medical history, culture tests, serology tests

	Performs 185 000 blood collections annually between 8 fixed sites, 12 mobile coverings 13 countries in Western Washington.
	Perform 10000 random apheresis collections including matched and white cell collections.
	Perform 9000 autologous collections and 50+ directed donations.

Inventory production:

Fractionation of 185000 units of blood into components.

RBC (170 000)

FFP/RP (165 000)

Cryo (20 000)

Platelets (105 000)

Leuko-reduction of RBCs (20 000)

Labeling of components

	1970-1980: Hepatitis B viral Antigen
	1980: HIV-1 antibody, ALT, HTLV-1 antibody, HCV viral protein antibody
	1990: HIV 1/2 antibody, HIV 1 antigen, HTLV I and II, HCV-PCR, HIV-PCR

Compatiblity testing:

22 king country hospital

330 000 procedures/year

Order Processing and Distribution:

Distributes 200 000 blood components to king county hospitals and 16 regional hospitals.

Performs 175 000 processing/year.

Antibody identification

Prenatal testing

80 000 procedures/year

3000 procedures/year

Satellite Labs (3)

Bellevue

Rentorn

University district

Patient Services:

Bone Marrow Donor Program:

	National Marrow Donor Registry
	Since 1987- 46000 registered; 326 have donated.

Outpatient Transfusion Services:

Provide transfusion to 350 patient/year in king county

Therapeutic Phlebotomy

Perform 2500 procedures each year.

Therapeutic Apheresis

	Plasma exchange, peripheral blood stem cell collection
	1000 procedures perform annually.

Transfusion services

Washington, Alaska, Montana and Idaho (WAMI)

	Structural Metabolic
	Bone red cell
	Dura mater platelets
	Fascia lata marrow
	Tendon semen
	Cartilage oocyte
	Skin embryo
	Heart valve fetal tissue
	Amnion parathyroid
	Cornea islets
	Vein
	Artery

Tissue transplantation from living donors:

	Blood, semen, umbilical vein, marrow, ovum, kidney, bone, amnion, pancreas, cord blood, stem cells, liver, (require HIV retest at 6 months)
	Preserved human tissue in clinical use:
	Living Donor Neurologic death Cardiorespiratory &
	(brain death) Neurologic death
	Blood kidney cornea
	Semen heart bone
	Ovum liver skin
	Bone marrow pancreas tendon
	Bone lung fascia lata
	Amnion cartilage
	Umbilical vein heart valve
	Kidney saphenous vein
	Pancreas
	Tissue Transplantation Complications:
	Disease transmission from graft
	Risk reduced by

donor health screen, exam, tests

tissue processing, sterilization

	Graft non-function
	Due to immune rejection
	Poor function due to donor defect or tissue healing
	Bone autograft procurement complication
	anesthesia, transfusion, pain, infection, scaro-illiac joint instability, hernia of intestine through illium, nerve injury, artery injury, gain disturbance, illium fracture

* hepatitis B * CMV

* HIV * Tuberculosis

* Bacteria * Toxoplasma

* EBV * HCV

Cryopreserved nipple autograft

Choriocarcinoma with kidney, liver, heart

Renal adenocarcinoma in kidney

Bronchogenic carcinoma in heart.

Melanoma in kidney

Hepatocarcinoma in kidney

HBV                      Rabies                  bacteria

TB                          CJD                      CMV

HIV                        yeast                     HIV

Bacteria               bacteria               HCV

HCV                        HBV

Bacteria              Toxoplasma          CJD

TB                             CMV

Yeast                       EBV

HCV                         HIV

HBV

Donor: from thoracoplasty to treat pulmonary TB

Recipient: 4 spine fusions all cases TB wound infection

Donor: 1949 transfused, normal LFT

1952 above knee amputation, age 73(vascular disease)

bone stored

Recipient: Senior medical student, Yale. Depressed fracture tibial plateau grafted, Jaundice 10week later

Donor: 34 YO, M, MVA, HCV 1.0 Neg, 2.0 Pos:

Recipient: 9 potential:

2 diceased

4 tendon and bone, AB repeat reactive PCR positive

1 AB non-reactive

2 nontraceable

Donor: 52 YO man

Nov 1984 - THR (no HIV test)

July 1986 - PCP, HIV pos, wife HIV pos

(history IV drug abuse)

Neck node biopsy - July 1984

Recipient: Woman

Nov 1984 - spine fusion for scoliosis

Day 21 - fever, diarrhea, node

July 1986 - Axillary node

Feb 1988 - PCP, AIDS, HIV pos

1985 donor

HIV-1 AB negative, PCR positive

1991 recipient

3 organs 2 cornea

2 frozen bone 1 frozen bone

1 frozen tendon 1 freeze dried tendon

28 freeze dried bone

15 FD bone untested

Disease transmission

Risk of bone

                           HIV    Hepatitis     Bacteria

Frozen                +            +                  +

Freeze dried*      -            +                  -

Air dried*             -             +                 -

Ethylene Oxide   -            -                  -

Irradiation             -            -                -

* alcohol soaked

HIV and Cornea:

No cases of transmission

HIV isolated from tears, cornea from infected person

2 HIV infected donors

	2 kidney recipients - HIV pos
	2 cornea recipients - HIV neg

Donor: 39 YO M rancher

Day 1-2 - backpain, numb, weakness arms, legs

Day 3-7 - Weakness, poor swallow and breathing intubated

Day 7 - Flaccid quadriparesis, pneumonia

Day 16 - Died

Recipient: 37 YO Female (keratoconus)

Day 30 - right headache, neck pain, right face numb

Day 32 - Dysarthria, impaired grafts, dysphagia

Day 33 - Comatose, intubated

Day 50 - Died

Rabies found in donor eyes and recipients eye, brain

Donor 55 YO man

2 Month - incoordination, poor memory, myoclonia

died with pneumonia

autopsy - CJD

Recipient: - 55 YO woman

18 month - lethargy, ataxia, nausea, progressive dementia

Impaired swallow, gain, myoclonic jerks

26 months: died, CJD

	Cornea transplant
	Intra cerebral electrodes
	Neurosurgery following CJD patient
	Recipient of hGH
	Dura transplant

25 years old man developed rapidly progressive dementia 31 month after neurosurgery (trauma).

Received Freeze dried irradiated dura (Germany)

Autopsy - CJD

Antibody ELISA assay:

HIV viral HIV Ab Goat

Lysate or + patient + Antihuman ------> colour

recombinant HRPO development

Protein

                       NAT         Antigen         Antibody

HIV 1/2          5 days     18 days          22 days

HCV               22 days     N/A              8 2 days

HBV               24 days     37 days       59 days

HTLV I/II        NA               NA              38 days

Systematic and consistent evaluation of donors (consent, screening, processing, linking, release)

The QA program defines minimum standards for donor screening.

Donor files document that standards have been met.

Inventory Control

Transfer signature

Labeling and packaging integrity.

Tracing mechanism.

Mechanism defined

Donor screening – Medical Director

Graft processing – QA department

Transplant Record

Inventory log

Records review

Follow up communications

Tracing vs tracking

Simple to complex

Trace from donor to recipient and back

- Problem identification

Disease transmission

Other adverse outcomes

Corrected In-house

*labeling errors, culturing/micro errors, equipment problems, missing freezing curves, control rate freezer dummy problem, freeze dry tissue problems.

Major deficiencies – Inadequate QA

	Lack of comprehension.
	Conflict of interest in auditing .
	Inadequate donor screening.
	Deficiency of SOPs
	Equipment maintenance
	Improper/incomplete records
	Inadequate documentation

The policies and procedures currently in place

Organizational structure

Responsibilities of staff

Quality Assurance program.

“Process validation is the establishment of documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes”

A document or a set of document that describe the trials done to develop the process step and specifications.

Acceptance criteria not required

Provide the freedom to experiment with the process until consistent parameters are found.

Study conclusions become the specifications for the process in production.

This analytical tool is used to determine and minimize the potential weakness of the process. The development team defines the process steps and then determines possible hazards for each step. The analysis continues as each hazards can have effects on the process, the product, the product recipient or the staff performing the process. For each hazard, the upstream and down stream precautions are documented. Taking into account the effects and the precautions the team assigns a concern rating (minor, moderate or major) for each hazards.

All instruments used to measure critical process parameters are identified. The accuracy of each instrument is investigated and verified to be appropriate for use in the process. Each instrument is also verified to be in current calibration. Ex: of calibrated instruments are timers, thermometers, pipettes.

Each piece of equipment involved in the process must be validated in accordance with a quality practices SOP. Equipment validation is the establishment of documented evidence, through defined tests and challenges that a piece of equipment meets the design criteria that it will perform according to predetermined specifications.

Equipment validation is accomplished by performing an Installation Qualification (IQ) an Operational Qualification (OQ) and a Performance Qualification (PQ) on a given piece of equipment.

All the personnel involved in the process must be trained for their specific responsibilities. Training plans are created and training is documented according to a quality practice SOP.

Each material that is an input to the process should have specifications. The specifications for each material are shown to be met by performing vendor qualifications by performing quality control testing and by writing quality control and quality assurance procedures for the inspection and control of the materials.

If environment condition (temperature, relative humidity, air quality, contamination control or cleanliness) are critical to the process, then engineering controls, quality control programs, monitoring equipment or monitoring programs must be in place.

SOP specific to the process are verified to be written, approved and on file in a suitable location for personnel performing the process. The SOPs must correctly reflect the current process steps.

The process products are verified to meet the specifications for quality and safety and effectiveness. The process products are also shown to be consistent. Product testing is conducted using validated methods, calibrated instruments or certified standards to ensure that the product specifications have been met.

Validation is conducted for new or modified processes, new or modified equipment and any computer system modifications or enhancement that affect safety, purity, potency of products, accuracy of testing or distribution to patients.

Skin, fascia, tendon, bone, heart valve, surgical bone, stem cells, cord blood, islet cells.

Living Donors: 250/year - average age 64 years old

Non-living donors: 250/year - average 40 years old

* cardiovascular tissue 100

* Tendon/fascia              950

* skin                                 725

* Musculoskeletel          4550

                        Total         6325

	Hemophilia program
	Medical education/ University, Washington
	Stem cells
	Thrombo protein
	Molecular biology
	Tissue/organ transplantation

Companies:

Cerus, Amgen, Virogen, Flow/Fimbria, Haemonectics, Trans/DX

Services:

	Medical assessment and treatment
	Diagnostic testing
	Genetic counseling
	Home infusion training
	Education and counseling
	Clinical trails
	Distribution of clotting concentrates

Hemophilia A                    278

Hemophilia B                     55

Von Willebrand disease  98

Other clotting factors       41

Total                                    497

MONARC - M              KONYNE - 80

HEMOFIL- M             ALPHANINE - SD

RECOMBINATE        BeneFIX

KOGENATE                 FEIBIA

KOATE - HP             AUTOPLEX - T

ALPHANATE

HUMATE - P

THROMBATE III

NOVOSEVEN

HYATE - C

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