Transplantation Immunology

Transplantation Immunology rqd background understanding

MHC

antigen processing and presentation

MHC restriction

T cell differentiation

thymic selection

T cell activation

Chapters 4&5 Janeway

Transplantation

Tolerance

Rejection

Immunosuppression

Reading

• Pgs 644-650 : Janeway 7th Edition

• Starzl T, Zinkernagel R. Transplantation tolerance from a

historical perspective. Nature Reviews 2001;1:233-239

Transplantation

• Blood cell malignancies

• Organ failure

• Autoimmune disease

Transplantation

• Cornea

• Bone marrow

• Kidney

• Liver

• Heart

• Lungs

• Intestine

• Stem Cells

Graft Rejection: normal immune

response

• specific recipient immune response.

T-cell mediated :

New born mice do not reject grafts

Nude Mice.

rejection can be transferred by T-cells

•memory

.

Figure 5-17

Klein, J. et. al. N Engl J Med 2000;343:702-709

Location and Organization of the HLA Complex on Chromosome 6

Major Historical Events 1

Major Historical Events 2

T Cells Reject Graft/Genes Matter

• Autograft

• Syngeneic

• Allogeneic

Importance of HLA Matching

MHC polymorphisms affect TCR

interaction with the peptide–MHC

surface.

Figure 5-17

BM Transplantation/Tolerance

Classic Graft vs Host Disease

Organ Tx/Immunosuppression

MHC Restriction/T Cell Recognition

Figure 7-14

Thymic selection eliminates the most-

reactive and least-reactive TCRs.

Novel Tolerogenic Mechanisms

• Second signal (CD80/86)

• T regulatory cells

• Myeloid derived suppressor cells (MDSCs)

• NK Cells

– Kill DCs in donor organ

– Hepatic NK cells kill infiltrating T cells

1

Chapter 7

The Skeletal System:

Bone Tissue

2

INTRODUCTION

• Bone is made up of several different tissues

working together: bone tissue, cartilage, dense

connective tissue, epithelium, blood forming

tissues, adipose tissue, and nervous tissue

• Each individual bone is an organ

• Dynamic and ever-changing throughout life

• The bones, along with their cartilages, make up the

skeletal system

3

Functions of Bone

• Supporting & protecting soft tissues

• Attachment site for muscles making

movement possible

• Storage of the minerals, calcium &

phosphate -- mineral homeostasis

• Blood cell production occurs in red bone

marrow (hemopoiesis)

• Energy storage in yellow bone marrow

4

Anatomy of a Long

Bone

• diaphysis = shaft

• epiphysis = one end of a

long bone

• metaphyses are the

areas between the

epiphysis and diaphysis

and include the

epiphyseal plate in

growing bones.

• Articular cartilage over

joint surfaces acts as

friction reducer & shock

absorber

• Medullary cavity =

marrow cavity

5

Anatomy of a Long

Bone

• Endosteum = liningof marrow cavity

• Periosteum = toughmembrane coveringbone but not thecartilage

– fibrous layer =dense irregularCT

– osteogenic layer =bone cells & bloodvessels thatnourish or helpwith repairs

6

Histology of

Bone• A type of

connective tissue

as seen by widely

spaced cells

separated by

matrix

• Matrix of 25%

water, 25%

collagen fibers &

50% crystalized

mineral salts

• 4 types of cells in

bone tissue

7

Histology of Bone Tissue

• Bone (osseous) tissue consists of widely separated cells

surrounded by large amounts of matrix.

• The matrix of bone contains inorganic salts, primarily

hydroxyapatite and some calcium carbonate, and collagen

fibers.

• These and a few other salts are deposited in a framework of

collagen fibers, by a process called calcification.

– The process of calcification occurs only in the presence

of collagen fibers.

– Mineral salts confer hardness on bone while collagen

fibers give bone its great tensile strength.

8

Four Types of Bone Cells

• Osteoprogenitor (osteogenic) cells -- undifferentiated cells

– can divide to replace themselves & can become osteoblasts

– found in inner layer of periosteum and endosteum

• Osteoblasts -- form matrix & collagen fibers but can’t divide

• Osteocytes -- the principal cells of bone tissue.

– mature cells that no longer secrete matrix

• Osteoclasts -- huge cells from fused monocytes (WBC)

– serve to break down bone tissue

– function in bone resorption at surfaces such as endosteum

9

Matrix of Bone

• Inorganic mineral salts provide bone’s hardness

– hydroxyapatite (calcium phosphate) & calcium carbonate

• Organic collagen fibers provide bone’s flexibility

– their tensile strength resists being stretched or torn

• Remove minerals with acid & rubbery structure

results

• Denature collagen by heating and bones become

brittle

• Bone is not completely solid since it has small spaces

for vessels and red bone marrow

– spongy bone has many such spaces

– compact bone has very few such spaces

10

Compact Bone

• Compact bone is arranged in units called osteons

or Haversian systems

• Osteons contain blood vessels, lymphatic vessels,

nerves, and osteocytes along with the calcified

matrix.

• Osteons are aligned in the same direction along

lines of stress. These lines can slowly change as

the stresses on the bone changes.

11

Compact or

Dense Bone

• Looks like solid hard layer of bone

• Makes up the shaft of long bones and theexternal layer of all bones

• Resists stresses produced by weight andmovement

12

Histology of Compact Bone

• Osteon is concentric rings (lamellae) of calcified matrix

surrounding a vertically oriented blood vessel

• Osteocytes are found in spaces called lacunae

• Osteocytes communicate through canaliculi filled with

extracellular fluid that connect one cell to the next cell

13

Spongy Bone

• Spongy (cancellous) bone does not contain

osteons. It consists of trabeculae surrounding

many red marrow filled spaces

• It forms most of the structure of short, flat, and

irregular bones, and the epiphyses of long bones

• Spongy bone tissue is light and supports and

protects the red bone marrow

14

The Trabeculae of Spongy Bone

• Latticework of thin plates of bone called trabeculae oriented

along lines of stress

• Spaces in between these struts are filled with red marrow

where blood cells develop

No true Osteons.

15

Blood Supply of Bone

• Periosteal arteries

– supply periosteum

• Nutrient arteries

– enter through nutrient

foramen

– supplies compact bone

of diaphysis & red

marrow

• Metaphyseal & epiphyseal

arteries

– supply red marrow &

bone tissue of

epiphyses

16

BONE FORMATION

• All embryonic connective tissue begins as

mesenchyme

• Bone formation is termed osteogenesis or

ossification

• Two types of ossification occur

– Intramembranous ossification is the formation of bone

directly from fibrous connective tissue membranes

(dermis)

– Endochondral ossification is the formation of bone from

hyaline cartilage models

17

Intramembranous Bone Formation

• Intramembranous ossification forms the flat bones

of the skull and the mandible

– An ossification center forms from mesenchymal cells as

they convert to osteoblasts and lay down osteoid matrix.

– The matrix surrounds the cell and then calcifies as the

osteoblast becomes an osteocyte.

– The calcifying matrix centers join to form bridges of

trabeculae that constitute spongy bone with red marrow

between.

– On the periphery the mesenchyme condenses and

develops into the periosteum.

18

Intramembranous Bone

Formation

19

Endochondral Bone Formation

• Endochondral ossification involves replacement of

cartilage by bone and forms most of the bones of

the body

• The first step in endochondral ossification is the

development of the cartilage model

20

Endochondral Bone Formation

• Development and Growth of

Cartilage Model

– mesenchymal cells form a

cartilage model

– interstitial growth in length occurs

by chondrocyte cell division and

matrix formation

– appositional growth in width occurs

by formation of new matrix on the

periphery by new chondroblasts

from the perichondrium

– cells in midregion burst and

change pH triggering calcification

and chondrocyte death

21

Endochondral Bone Formation

• Development of Primary

Ossification Center

– nutrient artery penetrates center

of cartilage model

– cells in perichondrium

differentiate into osteoblasts and

start forming bone

– osteoblasts and osteoclasts

migrate to center of cartilage

model

– osteoblasts deposit bone matrix

over calcified cartilage forming

spongy bone trabeculae

– Osteoclasts form medullary cavity

22

Endochondral Bone Formation

• Development of Secondary Ossification Center

– blood vessels enter the epiphyses around time of birth

– spongy bone is formed but no medullary cavity

– cartilage on ends of bone remains as articular cartilage

23

Bone Growth in Length

• Bones grow in length at the epiphyseal (growth) plate

• The epiphyseal plate consists of four zones:

– zone of resting cartilage

– zone of proliferating cartilage

– zone of hypertrophic cartilage

– zone of calcified cartilage

• Activity at the epiphyseal plate is the only means by which

the diaphysis can increase in length

24

Zones of Growth in

Epiphyseal Plate• Zone of resting cartilage

– anchors growth plate to bone

• Zone of proliferating cartilage

– rapid cell division (stacked

coins)

• Zone of hypertrophic cartilage

– cells enlarged & remain in

columns

• Zone of calcified cartilage

– thin zone, cells mostly dead

since matrix calcified

– osteoclasts removing matrix

– osteoblasts & capillaries move

in to create bone over calcified

cartilage

25

Bone Growth in Length

• Between ages 18 to 25, epiphyseal

plates close

– cartilage cells stop dividing and

bone replaces the cartilage

(epiphyseal line)

• Growth in length stops by age 25

26

Bone Growth in Thickness

• Only by appositional growth at the bone’s surface

• Periosteal cells differentiate into osteoblasts and form bonyridges and then a tunnel around periosteal blood vessel

• Concentric lamellae fill in the tunnel to form an osteon

27

Factors Affecting Bone Growth

• Nutrition

– adequate levels of minerals and vitamins

• calcium and phosphorus for bone growth

• vitamin C for collagen formation

• vitamins K and B12 for protein synthesis

• Sufficient levels of specific hormones

– during childhood need insulin-like growth factor

• promotes cell division at epiphyseal plate

• need hGH (growth), thyroid (T3 & T4) and insulin

– at puberty the sex hormones, estrogen and testosterone,

stimulate sudden growth and modifications of the

skeleton to create the male and female forms

28

Hormonal Abnormalities

• Oversecretion of hGH (human growth hormone)

during childhood produces giantism

• Undersecretion of hGH or thyroid hormone during

childhood produces dwarfism

• Both men or women that lack estrogen receptors

on cells grow taller than normal

– estrogen is responsible for closure of growth

plate

29

Bone Remodeling

• Remodeling is the ongoing replacement of old bone

tissue by new bone tissue

– Old bone is constantly destroyed by osteoclasts, whereas

new bone is constructed by osteoblasts

– In orthodontics teeth are moved by braces. This places

stress on bone in the sockets causing osteoclasts and

osteablasts to remodel the sockets so that the teeth can

be properly aligned

– Several hormones and calcitriol control bone growth and

bone remodeling

30

Bone Remodeling

• Ongoing since osteoclasts carve out small tunnels

and osteoblasts rebuild osteons.

– osteoclasts form leak-proof seal around cell edges

– secrete enzymes and acids beneath themselves

– release calcium and phosphorus into interstitial fluid

– osteoblasts take over bone rebuilding

• Continual redistribution of bone matrix along lines

of mechanical stress

– distal femur is fully remodeled every 4 months

31

Fracture & Repair of Bone

• A fracture is any break in a bone

• Healing is faster in bone than in cartilage due

to lack of blood vessels in cartilage

• Healing of bone is still slow process due to

vessel damage

• Clinical treatment

– closed reduction = restore pieces to normal

position by manipulation

– open reduction = realignment during surgery

32

Fractures

• Named for shape or position of fracture line

• Common types of fracture

– greenstick -- partial fracture

– impacted -- one side of fracture driven into the

interior of other side

33

Fractures

• Common types of fracture

– closed -- no break in skin

– open fracture --skin broken

– comminuted -- broken ends of bones are

fragmented

34

Fractures

• Common types of fracture

– Pott’s -- distal fracture of fibula and/or tibia

– Colles’s -- distal fracture of radius and/or ulna

– stress fracture -- microscopic fissures from

repeated strenuous activities

35

Repair of a Fracture

• Formation of fracture hematoma

– damaged blood vessels produce clot in 6-8 hours, bone cells die

– inflammation brings in phagocytic cells for clean-up duty

– new capillaries grow into damaged area

• Formation of fibrocartilagenous (soft) callus

– fibroblasts invade & lay down collagen fibers

– chondroblasts produce fibrocartilage to span the broken ends of the

bone

36

Repair of a Fracture

• Formation of bony (hard) callus

– osteoblasts secrete spongy bone that joins 2 broken ends of

bone

– lasts 3-4 months

• Bone remodeling

– compact bone replaces the spongy bone in the bony callus

– surface is remodeled back to normal shape

37

Calcium Homeostasis & Bone Tissue

• Skeleton is a reservoir of calcium & phosphate

• Calcium ions involved with many body systems

– nerve & muscle cell function

– blood clotting

– enzyme function in many biochemical reactions

• Small changes in blood levels of Ca+2 can be

deadly

– plasma level maintained 9-11 mg/100mL

– cardiac arrest if too high

– respiratory arrest if too low

38

Hormonal Influences

• Parathyroid hormone (PTH) is

secreted if Ca+2 levels fall

– osteoclast activity increased,

kidney retains Ca+2 and

produces calcitriol

• Calcitonin hormone is

secreted from parafollicular

cells in thyroid if Ca+2 blood

levels get too high

– inhibits osteoclast activity

– increases bone formation by

osteoblasts

39

EXERCISE AND BONE TISSUE

• Bone has the ability to alter its strength in response to

mechanical stress by increasing deposition of mineral salts

and production of collagen fibers

– Removal of mechanical stress leads to weakening of

bone through demineralization and collagen reduction

• reduced activity while in a cast

• astronauts in weightless environment

• bedridden person

– Weight-bearing activities, such as walking or weightlifting,

help build and retain bone mass

40

AGING AND BONE TISSUE

• Of two principal effects of aging on bone, the first is the loss

of calcium and other minerals from bone matrix, which may

result in osteoporosis.

– very rapid in women 40-45 as estrogens levels decrease

– in males, begins after age 60

• The second principal effect of aging on the skeletal system

is a decreased rate of protein synthesis

– decrease in collagen production which gives bone its

tensile strength

– decrease in growth hormone

– bone becomes brittle & susceptible to fracture

41

Osteoporosis

• Decreased bone mass resulting in porous bones

• Those at risk

– white, thin, menopausal, smoking, drinking, female with

family history

– athletes who are not menstruating due to decreased body

fat & decreased estrogen levels

– people allergic to milk or with eating disorders whose intake

of calcium is too low

• Prevention or decrease in severity

– adequate diet, weight-bearing exercise, & estrogen

replacement therapy (for menopausal women)

– behavior when young may be most important factor

42

Disorders of Bone Ossification

• Rickets

• calcium salts are not deposited properly

• bones of growing children are soft

• bowed legs, skull, rib cage, and pelvic deformities

result

• Osteomalacia

• “adult rickets”

• new adult bone produced during remodeling fails

to ossify

• hip fractures are common

• Caused by vitamin D deficiency

hematopoietic stem cell An immature cell that can develop into all types of blood cells, including white blood cells, red blood cells, and platelets. Hematopoietic stem cells are found in the peripheral blood and the bone marrow. Also called blood stem cell.

ENLARGE

Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.

1. 1. What is Liver Transplantation? 2. 2. Liver transplantation is surgery to remove a diseased liver and

replace it with a healthy one. This kind of surgery has been done for more than 38 years. Many people have had liver transplants and now lead normal lives. When a patient receives a liver transplant, his or her entire liver is removed. It is then replaced by either a complete new liver or a portion of a healthy liver.

3. 3. What are the reasons for needing a Liver Transplant? 4. 4. Liver transplantation is needed for patients who are likely to die

because of liver failure. Many diseases can cause liver failure. The most common is cirrhosis which is the scarring and death of liver cells. Cirrhosis caused by hepatitis C is the most common reason for liver transplants.

5. 5. Other conditions that may ultimately require a liver transplant include: - Diseases of the bile ducts, including biliary atresia, primary biliary cirrhosis and primary sclorosing (PSC), which can cause liver failure if there is a backup of bile in the liver. - Some inherited diseases, such as Wilson Disease in which dangerous levels of copper build up in the body, and hemochromatosis, where the liver is overwhelmed by iron. - Primary liver cancer or cancer that affects only the liver - Alcoholism which can cause cirrhosis

6. 6. In adults, the most common reason for liver transplantation is cirrhosis. Cirrhosis: - is caused by many different types of liver injuries that destroy healthy liver cells and replace them with scar tissue. - can be caused by viruses such as hepatitis B and C, alcohol, autoimmune liver diseases, buildup of fat in the liver, and hereditary liver diseases. In children, the most common reason for liver transplantation is biliary atresia. Bile ducts: - which are tubes that carry bile out of the liver, are missing or damaged in this disease, and obstructed bile causes cirrhosis. Bile helps digest food. - Other reasons for transplantation are liver cancer, benign liver tumors, and hereditary diseases. Sometimes the cause of liver disease is not known.

7. 7. Liver transplants can help adults and children. 8. 8. What is the donor operation like? 9. 9. The donor operation is done through an incision in the upper

abdomen. If the LDLT recipient is a child, only a portion of the left part of the liver is removed from the donor: about 25% of the donor's total liver.

10. 10. If the LDLT recipient is an adult, a larger portion of the liver needs to be removed from the donor, usually the right portion of the liver: about 60% of the donor's total liver.

11. 11. The blood vessels supplying the portion of the liver to be removed are separated out, the liver itself is divided, and the portion

to be transplanted is removed. This portion is brought into a separate operating room for the recipient, where the transplant is then performed. The donor operation takes 6 to 8 hours.

12. 12. Liver Transplant Symptoms : People who have liver disease may have many of the following problems: - Jaundice - Yellowing of the skin or eyes - Itching - Dark, tea-colored urine - Gray- or clay-colored blood movements - Ascites - An abnormal buildup of fluid in the abdomen - Vomiting of blood - Tendency to bleed - Mental confusion, forgetfulness

13. 13. Where Does a Liver for a Transplant Come From? There are two types of liver transplantation options: living donor transplantation and cadaveric transplantation.

14. 14. Living donor - Living donor liver transplants are an option for some patients with end-stage liver disease. This involves removing a segment of liver from a healthy living donor and implanting it into a recipient. Both the donor and recipient liver segments will grow to normal size in a few weeks. - The donor, who may be a blood relative, spouse or friend, will have extensive medical and psychological evaluations to ensure the lowest possible risk. Blood type and body size are critical factors in determining who is an appropriate donor. - Recipients for the living donor transplantation must be active on the transplant waiting list. Their health must also be stable enough to undergo transplantation with excellent chances of success.

15. 15. Cadaver In cadaveric liver transplantation, the donor may be a victim of an accident or head injury. The donors heart is still beating, but the brain has stopped functioning. Such a person is considered legally dead, because his or her brain has permanently and irreversibly stopped working. The heart continues to beat because the donor is attached to a respirator. The respirator delivers an adequate supply of oxygen to all vital organs. At this point, the donor is in an intensive-care unit. The identity of a cadaveric donor and circumstances surrounding the person's death are kept confidential.

16. 16. Which Tests Are Required Before Getting a Liver Transplant? You will need to bring all of your previous doctor records, X-rays, liver biopsy slides and a record of medications to your pre-evaluation. To complement and to update previous tests, some or all of the following diagnostic studies are generally performed during your evaluation. If specific problems are identified, additional tests may be ordered. - Computed tomography, which uses X-rays and a computer to generate pictures of the liver, showing its size and shape. - Doppler ultrasound to determine if the blood vessels to and from your liver are open. - Echocardiogram to help evaluate your

heart. - Pulmonary function studies to determine your lungs' ability to exchange oxygen and carbon dioxide. Blood tests to determine blood type, clotting ability, and biochemical status of blood and to gauge liver function. AIDS testing and hepatitis screening are also

17. 17. What Happens When They Find a Match? When an organ has been identified for you, a transplant coordinator will contact you by telephone or by pager. Make sure that you do not eat or drink anything once you have been called to the hospital. The transplant coordinator will notify you of any additional instructions. When you arrive at the hospital, additional blood tests, an Electrocardiogram and a chest X-ray will generally be taken before the operation. You also may meet with the anesthesiologist and a surgical resident. If the donor liver is found to be acceptable you will proceed with the transplant. If not, you will be sent home to continue waiting.

18. 18. During Surgery: Liver transplant surgery takes between six and 12 hours. During the operation, doctors remove the diseased liver and replace it with the donated liver. Most patients stay in the hospital for up to three weeks after surgery. The surgeon will disconnect your diseased liver from your bile ducts and blood vessels before removing it. The blood that flows into your liver will be blocked or sent through a machine to return to the rest of your body. The surgeon will put the healthy liver in place and reconnect it to your bile ducts and blood vessels. Your blood will then flow into your new liver.

19. 20. After Surgery: - You will stay in the hospital for an average of 1 to 3 weeks to be sure your new liver is working. You will take medicines to prevent rejection of your new liver and to prevent infections. Your doctor will check for bleeding, infections, and rejection. During this time you will start to learn how to take care of yourself and use your medicines to protect your new liver after you go home. - In the hospital, you will slowly start eating again. You will start with clear liquids, then switch to solid food as your new liver starts to work. - Liver transplants are performed in many centers across the country. The healthy liver is obtained from a donor who has not suffered liver injury. The healthy liver is transported in a cooled saline solution that preserves the organ for up to 8 hours. This time allows for testing to determine if the blood and tissue of the donor match the recipient. The diseased liver is removed through an incision in the upper abdomen. The new liver is put in place and attached to the patient's blood vessels and bile ducts. The operation can take up to 12 hours and may require blood transfusions.

20. 21. - Patients require hospital care for 1 to 4 weeks after liver transplant, depending on the degree of illness. After liver transplantation, patients must take immunosuppressive medications

for the rest of their lives to prevent immune rejection of the transplanted organ.

21. 22. What Complications Are Associated With Liver Transplantation? - Two of the most common complications following liver transplantation are rejection and infection.

22. 23. Rejection: Your immune system works to destroy foreign substances that invade your body. The immune system, however, cannot distinguish between your transplanted liver and unwanted invaders, such as viruses and bacteria. Therefore, your immune system may attempt to attack and destroy your new liver. This is called a rejection episode. About 70% of all liver-transplant patients have some degree of organ rejection prior to discharge. Antirejection medications are given to ward off the immune attack.

23. 24. Infection: Because antirejection drugs that suppress your immune system are needed to prevent the liver from being rejected, you are at increased risk for infections. This problem diminishes as time passes. Not all patients have problems with infections, and most infections can be treated successfully as they occur.

24. 25. What are the side effects of a liver transplant? The most common side effects are caused by the drugs that treat or prevent rejection. These side effects can include: - fluid retention - raised blood pressure - headaches - diarrhea - nausea

25. 26. Blood tests will show if the new liver is being rejected. 26. 27. Eating a healthy diet and taking the medications are part of

taking care of your new liver. 27. 28. Indications: Liver transplantation is potentially applicable to

any acute or chronic condition resulting in irreversible liver dysfunction, provided that the recipient does not have other conditions that will preclude a successful transplant. Metastatic cancer outside liver, active drug or alcohol abuse and active septic infections are absolute contraindications. This has been changing recently. Advanced age and serious heart, pulmonary or other disease may also prevent transplantation. Most liver transplants are performed for chronic liver diseases that lead to irreversible scarring of the liver.

BRIEFING NOTES ON HUMAN STEM CELLS

What are stem cells? Stem cells are cells which can generate new copies of themselves, and can turn into the more specialised

cells (e.g. red blood cells) that perform functions in the body.

There are different types of stem cells, some of which can turn into any cell in the body (pluripotent) and

some of which can only turn into certain cells in one type of tissue (tissue specific).

Adult and foetal stem cells are tissue specific: they only turn into certain types of specialised cells.

- We all have adult stem cells in many of our tissues which repair and replenish damaged cells.

Embryonic stem cells exist only briefly after fertilisation, well before the embryo becomes a foetus, and

can turn into any cells in the body. This is why they are so important scientifically.

- Scientists can create induced pluripotent stem cells (iPS cells) which act like embryonic cells.

How do we get stem cells? Human embryonic stem cells are obtained from very early stage embryos, within 5-6 days of fertilisation.

- Most embryos used in stem cell research were initially created for use in IVF and are donated by parents.

- The cells isolated from the embryo give rise to one cell line which can produce an infinite number of cells

iPS cells do not occur naturally, but any adult cell could potentially be manipulated to become an iPS cell.

- There are various different te h i ues fo ep og a i g adult cells into iPS cells, though it is not yet

known whether any iPS cells can exactly mimic embryonic cells.

Adult and foetal stem cells can be isolated from specific tissues, where they are naturally small in number.

What are stem cells used for? Stem cell research does not just focus on medical treatments that put cells into patients: all types of stem

cell are used in basic research to understand how our bodies work and develop, and to understand disease.

- Studying disease at the cellular level provides an alternative to animal based models of drug discovery

Two distinct approaches exist for using stem cells in medical treatments, both the subject of research

1. Cell replacement therapies where cells are transplanted to integrate with the od s e isti g tissue

- Not all cell replacement therapies use stem cells, some use specialised cells

2. Using stem cells for the substances they release which encourage the body to repair itself

What stem cell-based treatments exist? There are only a few widely available stem cell-based treatments all of which use adult stem cells; there

are no current stem cell-based treatments that use embryonic or iPS stem cells.

- Blood stem cells have a long history of use in treating blood disorders

- Stem cells can be used to grow sheets of skin for use in skin grafts and wound healing

Cell replacement therapies for various conditions, including eye diseases, spinal cord injuries and stroke are

in clinical trials, but are not yet available outside trials.

Stem cell treatments that encourage natural repair, making use of substances that stem cells release, are in

early development for a range of neurological conditions as well as heart disease and diabetes.

Where does the scientific community stand? The majority of scientists think research on all stem cell types, including embryonic stem cells, is necessary

because of their obvious potential for the effective treatment of all sorts of conditions.

There is not enough evidence to say whether iPS cells can completely replace embryonic stem cells, though

there is a minority of scientists who have ethical reservations about embryonic stem cells.

What are the issues around stem cells?

Ethics

Some religious groups like the Catholic Church object to using human embryonic stem cells since they view the

destruction of very early stage embryos as the destruction of a human life; likewise they object to research on

human embryos and IVF treatment. There is an argument that iPS cells could, in theory, produce human life so

they do not answer these objections. Ethi al a d legal de ates est o he a e o gai s pe so hood , though this is a not a question the science alone can answer.

Patenting life: Some groups, including Greenpeace, have objected to the patenting of stem cells on

the basis that application of intellectual property rights to anything that represents a life should not be

allowed. One possible alternative is the patenting of technologies used to carry out stem cell research.

Stem cell tourism

Dramatic claims about the pote tial of ste ells to p o ide a u e fo e e thi g ha e prompted people to

travel to countries with unregulated clinics offering stem cell treatments for a huge range of conditions.

Primarily advertised on the web, such treatments tend to use stem cells for the beneficial substances they

produce, though patients may be wilfully deceived into believing they are receiving cell replacement therapies.

Even though there are numerous legitimate clinical trials taking place for treatments which use stem cells for

their beneficial products, most advertised treatments are not properly tested.

Why have we not seen more treatments?

Regenerative medicine is a very new field compared to traditional medicine, and to some extent the science is

running ahead of the regulatory system. Testing regenerative treatments is a challenge and our ability to

develop new treatments is limited by the fact that stem cell behaviour is not yet fully understood.

Clinical trials: The usual model for a clinical trial is hard to apply to regenerative medicine and

benefits of cell therapies are more likely to be seen at safety testing. However, benefits seen in safety

trials should not be interpreted as eakth ough u es as the e pe i e ts a e designed to assess

safety, not to look at how effective the treatments are.

Safety and side-effects

Concerns exist over the safety of using cells that can reproduce indefinitely in medical treatments. These

concerns are addressed when treatments go through proper clinical trials, but this is not the case for

unregulated treatments (see Stem cell tourism’).

Rejection: Treatments that transplant stem cells have a risk of rejection as the body recognises

differences in the DNA of transplanted cells. Therapies have been developed that use patient-derived

adult stem cells which avoid this problem, though we are far from making these commercially viable.

Cord blood and stem cell banking

Blood from the umbilical cord, which is rich in stem cells, can be stored indefinitely for use in later life. Cord

blood can be donated to public banks, or private companies offer storage for use by the baby or his/her

relatives in later life. Storage of fat tissue (adipose cells) and dental tissue is also possible. There is some

controversy over the logic of private stem cell banking since the likelihood of the donor needing their own cells

is small, and future scientific developments may make the stored tissue obsolete.

Links/Further Information

EuroStemCell is a Europe-wide collaboration of research centres aimed at public engagement. Great resource

for information including fact sheets and FAQs spanning all topics

www.eurostemcell.org/

Wellcome Trust resources on stem cell, including succinct information on research and medical potential

http://www.wellcome.ac.uk/About-us/Policy/Spotlight-issues/Human-Fertilisation-and-Embryology-Act/Stem-

cell-basics/index.htm

Stem cell science - Hope not hype pu li atio Biotechnology and Biological Sciences Research Council

http://www.bbsrc.ac.uk/web/FILES/Publications/hope_not_hype.pdf

BioNews provides timely news and comment on embryo/stem cell research and related topics

www.bionews.org.uk

The UK Stem Cell Bank provides a repository of human embryonic, foetal and adult stem cell lines as part of the

UK governance for the use of human embryos for research

http://www.ukstemcellbank.org.uk/

Scientific Opinion Paper on Umbilical Cord Blood Banking from the Royal College of Obstetricians and

Gynaecologists

www.rcog.org.uk/womens-health/clinical-guidance/umbilical-cord-blood-banking

The International Society for Stem Cell Research (ISSCR) has become the voice of the stem cell research

community

www.isscr.org/

These Briefing Notes have been written by the Science Media Centre in consultation with a number of

scientists, science press officers and broadcast journalists. They are not intended as a comprehensive

summary on a subject, but rather a snapshot of the basics, of points of controversy and a pointer towards

sources of more detailed information. They are subject to change and will be updated as and when the

science moves on.

For more information about our Briefing Notes, please contact the Science Media Centre on 020 7611 8300

or email smc@sciencemediacentre.org.

Science Media Centre is a registered charity (no. 1140827) and a company limited by guarantee (no. 7560997).

Registered in England and Wales. Registered address: 215 Euston Road, London, NW1 2BE.

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Roles in the BodyRoles in the Body

(and fibrocartilage)

Joint Capsule

http: / /adam.about.com/encyclopedia/19089.htm

DescriptionDescription

Soft connective tissue composed of Soft connective tissue composed of

densely packed collagen fibersdensely packed collagen fibersWhiteWhiteRelatively inelastic Relatively inelastic

Mechanical properties vary with shape and Mechanical properties vary with shape and

structural organizationstructural organization

Simon, SR. Simon, SR. Orthopaedic Basic ScienceOrthopaedic Basic Science. Ohio: American Academy of Orthopaedic Surgeons; 1994.. Ohio: American Academy of Orthopaedic Surgeons; 1994.

StructureStructure

Connective tissues are characterized by Connective tissues are characterized by sparse cellularity distributed within an sparse cellularity distributed within an extracellularextracellular matrixmatrix

Cells in tendons and ligaments are Cells in tendons and ligaments are called called fibroblastsfibroblasts

ComparisonComparison

LigamentsLigaments TendonsTendons

% of collagen% of collagen LowerLower HigherHigher

% of ground % of ground substancesubstance

HigherHigher LowerLower

OrganizationOrganization More randomMore random OrganizedOrganized

OrientationOrientationWeaving Weaving patternpattern

Long axis Long axis directiondirection

Simon, SR. Simon, SR. Orthopaedic Basic ScienceOrthopaedic Basic Science. Ohio: American Academy of Orthopaedic Surgeons; 1994.. Ohio: American Academy of Orthopaedic Surgeons; 1994.

CompositionComposition

COMPONENTCOMPONENT LI GAMENTLI GAMENT TENDONTENDON

Cellular Materials:Cellular Materials:

FibroblastsFibroblasts 20%20% 20%20%

ExtracellularExtracellular::

WaterWater 6060--80%80% 6060--80%80%

SolidsSolids 2020--40%40% 2020--40%40%

CollagenCollagen 7070--80%80% Slightly higherSlightly higher

TypeType II 90%90% 9595--99%99%

TypeType I I II I I 10%10% 11--5%5%

GroundGroundsubstancesubstance

2020--30%30% Slightly lesserSlightly lesser

ElastinElastin Up to 2X collagenUp to 2X collagen ScarceScarce

StrengthStrength

LigamentLigament TendonTendon

Tensile Tensile StrengthStrength

Less than Tendon; Varies Less than Tendon; Varies 50 to 150 50 to 150 MPaMPa

Elastic Elastic ModulusModulus

MeniscofemoralMeniscofemoral (355 (355 ±± 234 234 MPaMPa

AnterolateralAnterolateral bundle of PCL (294 bundle of PCL (294 ±± 115MPa)115MPa)

Posterior bundle of PCL (150 Posterior bundle of PCL (150 ±± 69MPa)69MPa)

1,200 1,200 –– 1,800 1,800 MPaMPa

* Wide ranges of mechanical properties are largely due to locatio* Wide ranges of mechanical properties are largely due to location and agen and age

http: / / ttb.eng.wayne.edu/~ grimm/BME5370/Lect5Out.html

http: / /dahweb.engr.ucdavis.edu/dahweb/126site/chp5.pdf

Biomechanical BehaviorBiomechanical Behavior

Measured material property values vary Measured material property values vary due to:due to:

LocationLocation

Varying degrees of crimpVarying degrees of crimp

Use: Mobilization/ ImmobilizationUse: Mobilization/ Immobilization

AgingAging

PregnancyPregnancy

DiabetesDiabetes

NSAID useNSAID use

HemodialysisHemodialysis

ViscoelasticViscoelastic ResponsesResponses

Tissue response to load dependent on:Tissue response to load dependent on:Magnitude of loadMagnitude of load

Duration of loadDuration of load

Prior loadingPrior loading

Affected by movement of waterAffected by movement of waterResistance to compressive force due to water trapped Resistance to compressive force due to water trapped in in proteoglycansproteoglycans

Contributes to sustained or cyclic responses to stressContributes to sustained or cyclic responses to stress

Types of ResponseTypes of ResponseCreepCreep

StressStress--RelaxationRelaxation

HysteresisHysteresishttp: / /www.tendinosis.org/ injury.html

CreepCreep

Time dependent elongation of Time dependent elongation of a tissue when subjected to a a tissue when subjected to a constant stressconstant stress

Example:Example:

Tendons: in an isometric Tendons: in an isometric contraction, the tendon will contraction, the tendon will lengthen slightly and more lengthen slightly and more muscle fibers will be recruited in muscle fibers will be recruited in order to maintain the position of order to maintain the position of the limbthe limb

Ligaments: joints will loosen Ligaments: joints will loosen with time, decreasing the with time, decreasing the possibility of injurypossibility of injury

http: / / ttb.eng.wayne.edu/~ grimm/ME518/L5A3.html

http: / /www.orthoteers.co.uk/Nrujp~ ij33lm/Orthconntiss.htm

StressStress--RelaxationRelaxation

Time dependent decrease in Time dependent decrease in applied stress required to applied stress required to maintain a constant elongationmaintain a constant elongation

Example:Example:

Tendons: in an isotonic Tendons: in an isotonic contraction, the stress will contraction, the stress will decrease with timedecrease with time

Ligaments: joints will loosen Ligaments: joints will loosen with time, decreasing the with time, decreasing the possibility of injurypossibility of injury

http: / / ttb.eng.wayne.edu/~ grimm/ME518/L5A3.html

http: / /www.orthoteers.co.uk/Nrujp~ ij33lm/Orthconntiss.htm

HysteresisHysteresis

Energy lost within the tissue between Energy lost within the tissue between loading and unloadingloading and unloading

Response of tissue becomes more repeatableResponse of tissue becomes more repeatable

Subsequent use of same force results in Subsequent use of same force results in greater deformationgreater deformation

Ligaments

silver.neep.wisc.edu/ ~ lakes/ linksLec3.html

Anterior Cruciate Posterior Cruciate Ligament

Ligament

Lateral CollateralMedial Collateral LigamentLigament

Anterior View of KneeAnterior View of Knee

Posterior View of KneePosterior View of Knee

Posterior View: Right knee in extension

www.ma.psu.edu/ ~ pt/ re nee384/ anatomy.htm

Lateral meniscus

Anterior cruciate ligament

Medial meniscus

Posterior cruciate ligament

Click for more detail

Superior View of KneeSuperior View of Knee

Posterior cruciate ligament

Medial meniscus

Lateral meniscus

Anterior cruciate ligament

StructureStructure

No molecular bonds between No molecular bonds between fasciclesfascicles

Free to slide relative to each Free to slide relative to each otherother

Orientations:Orientations:

Branching & InterwovenBranching & InterwovenSpirally wound: Ex ACLSpirally wound: Ex ACL

ParallelParallelDirect connection between Direct connection between bones: Ex Collateral bones: Ex Collateral LigamentsLigaments

Smaller diameter fibers than in Smaller diameter fibers than in tendonstendons

http: / /dahweb.engr.ucdavis.edu/dahweb/126site/chp4.pdf http: / / silver.neep.wisc.edu/~ lakes/BME601Fr.html

Simon, SR. Simon, SR. Orthopaedic Basic ScienceOrthopaedic Basic Science. Ohio: American Academy of Orthopaedic Surgeons; 1994.. Ohio: American Academy of Orthopaedic Surgeons; 1994.

CrimpingCrimpingOrientation of collagen in ligamentsOrientation of collagen in ligamentsAllows elongation of fibers before tensile stresses are experienAllows elongation of fibers before tensile stresses are experiencedced

FunctionsFunctions

Transmit loadTransmit load from bone to bonefrom bone to bone

Hold the skeleton togetherHold the skeleton together

Flexible but plasticFlexible but plastic

Provide stability at jointsProvide stability at jointsMaintain joint congruency Maintain joint congruency

Limit freedom of movementLimit freedom of movementPrevent excessive motion by being a static restraintPrevent excessive motion by being a static restraintOccasionally act as a positional bend/strain sensorOccasionally act as a positional bend/strain sensor

Mediate motions between opposing Mediate motions between opposing fibrocartilagefibrocartilage surfacessurfaces

Degrees of FreedomDegrees of Freedom

Potentially 6 degrees of freedom in all jointsPotentially 6 degrees of freedom in all joints33--plane rotationplane rotation

oo FlexionFlexion--extensionextension

oo AbductionAbduction--adductionadduction

oo InternalInternal--externalexternal

3 3 --plane translationplane translationoo MedialMedial-- laterallateral

oo CompressionCompression--distraction distraction

oo AnteriorAnterior--posteriorposterior

Primary Restraint*Primary Restraint*

Knee FlexKnee Flex Maximal StretchMaximal Stretch@Knee flexion @Knee flexion

of (of ( °° ))

Anterior CruciateAnterior Cruciateanterior anterior tibialtibialtranslationtranslation

30 30 -- 4545

Posterior CruciatePosterior Cruciateanterior anterior tibialtibialtranslationtranslation

9090

Medial CollateralMedial CollateralValgusValgus forces forces

internal tibia rotationinternal tibia rotation

00

1010--6060

Lateral CollateralLateral Collateral varusvarus forcesforces 00

* No peer* No peer--reviewed documentation to support this informationreviewed documentation to support this information

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Tensile Response CurveTensile Response Curve

Region 1Region 1““ToeToe””

Crimp: low stiffness; change in slope as Crimp: low stiffness; change in slope as collegencollegen fibers fibers straighten; ligaments become more stiff as more fibers straighten; ligaments become more stiff as more fibers are recruitedare recruited

Region 2Region 2Linear Region: slope = stiffness/Elastic Modulus Linear Region: slope = stiffness/Elastic Modulus

Elastic: higher stiffnessElastic: higher stiffness

Region 3Region 3Less linear behavior; deformation is permanent Less linear behavior; deformation is permanent (tearing, stretch); Area of (tearing, stretch); Area of MicrofailureMicrofailure;;Ultimate Load: where failure occurs (N)Ultimate Load: where failure occurs (N)

Region 3aRegion 3aEnergy absorbed to failure: area under the curve Energy absorbed to failure: area under the curve ((NmmNmm))

Region 4Region 4 Ligament rupturesLigament ruptures

Region 5Region 5Ligament may appear intact; Fibers to slide under low Ligament may appear intact; Fibers to slide under low loadsloads

Stress Vs. StrainStress Vs. StrainMore relevant method of expressing Force vs. More relevant method of expressing Force vs. Deformation behaviorDeformation behavior

Region descriptions same as Force vs. Deformation curveRegion descriptions same as Force vs. Deformation curve

Stress (N/mmStress (N/mm22) = load per cross) = load per cross--sectional area of sectional area of samplesample

Strain = percentage change in lengthStrain = percentage change in length

InjuriesInjuriesOccur most frequently during athletic activitiesOccur most frequently during athletic activities

Knee injuriesKnee injuriesACLACL

Partial or complete tear of ligament caused by quick changes in Partial or complete tear of ligament caused by quick changes in direction, direction, slowing down while running, landing a jump, direct contactslowing down while running, landing a jump, direct contact

Symptoms include delayed pain and swellingSymptoms include delayed pain and swelling

PCLPCLSprain of ligament due to overstretching, impact to the front ofSprain of ligament due to overstretching, impact to the front of the knee, the knee, misstepmisstep

MCLMCL

DiagnosisDiagnosisPress gently at knee cap to feel for fluid at the jointPress gently at knee cap to feel for fluid at the joint

XX--rayray

MRIMRI

http: / /http: / / orthoinfo.aaos.org/ fact/ thr_report.cfm?Thread_IDorthoinfo.aaos.org/ fact/ thr_report.cfm?Thread_ID= 157&topcategory= Knee= 157&topcategory= Knee

http: / /hcd2.bupa.co.uk/ fact_sheets/mosby_factsheets/Knee_ligamenhttp: / /hcd2.bupa.co.uk/ fact_sheets/mosby_factsheets/Knee_ligament_injuries.htmlt_injuries.html

HealingHealing

RICERICERest, Ice, Compression, ElevationRest, Ice, Compression, Elevation

Physical therapyPhysical therapyStrengthening exercisesStrengthening exercises

Range of motion testsRange of motion tests

BracesBraces

CrutchesCrutches

SurgerySurgery

http: / /http: / / orthoinfo.aaos.org/ fact/ thr_report.cfm?Thread_IDorthoinfo.aaos.org/ fact/ thr_report.cfm?Thread_ID= 157&topcategory= Knee= 157&topcategory= Knee

http: / /hcd2.bupa.co.uk/ fact_sheets/mosby_factsheets/Knee_ligamenhttp: / /hcd2.bupa.co.uk/ fact_sheets/mosby_factsheets/Knee_ligament_injuries.htmlt_injuries.html

http:/ /12.31.13.115/hwdb/ images/hwstd/medical/orthoped/n5550876.jpg

StructureStructure

Long cylindrical structures Long cylindrical structures Tightly packed longitudinally running collagen Tightly packed longitudinally running collagen fibersfibers

Nuclei and sparse cytoplasm of fibrocytes Nuclei and sparse cytoplasm of fibrocytes compressed almost flat between them compressed almost flat between them

Relatively avascularRelatively avascular

Slow to heal from trauma injuriesSlow to heal from trauma injuries

http: / /adam.about.com/encyclopedia/19089.htmhttp: / /adam.about.com/encyclopedia/19089.htm

AttachmentAttachment

Each muscle has two tendons:Each muscle has two tendons:

Proximal:Proximal: MyotendinousMyotendinous JunctionJunction (MTJ)(MTJ)The point of union with a muscle: origin The point of union with a muscle: origin

Distal:Distal: OsteotendinousOsteotendinous JunctionJunction (OTJ)(OTJ)The point of union with a bone: insertionThe point of union with a bone: insertion

FunctionFunction

Force transmission between muscle and boneForce transmission between muscle and boneSustain high tensile stressesSustain high tensile stresses

Conserve substantial muscular energy during Conserve substantial muscular energy during locomotionlocomotion

Energy storage capacityEnergy storage capacity

Enables the muscle belly to be at a convenient Enables the muscle belly to be at a convenient

distance from joint distance from joint

Satisfies kinematic and damping requirementsSatisfies kinematic and damping requirements

FunctionFunctionWithstand tensile forces while retaining Withstand tensile forces while retaining flexibilityflexibility

StructureStructure

Orientations:Orientations:

Parallel to direction of tensile forceParallel to direction of tensile force

Larger collagen fibers than in ligamentsLarger collagen fibers than in ligaments

Structure of TendonsStructure of Tendons

Collagen Fibers

In Vitro Tensile TestIn Vitro Tensile Test

Tissue is elongated to failureTissue is elongated to failurePrescribed ratePrescribed rate

Changes in force are recordedChanges in force are recorded

The force is plotted against timeThe force is plotted against time

Time axis is proportional to elongationTime axis is proportional to elongation

Constant strain rate Constant strain rate

Response to Tensile ForcesResponse to Tensile Forces

Highest tensile strength of any soft tissueHighest tensile strength of any soft tissue

Schematic loadSchematic load--elongation curve with 3 distinct elongation curve with 3 distinct regions of response to tensile loading:regions of response to tensile loading:

Mechanical BehaviorMechanical Behavior

Energy absorbed to failure: area under the curve

Mechanical BehaviorMechanical BehaviorRegion 1: Region 1: ““ToeToe”” RegionRegion

Collagen fibers straighten (less prominent than in ligaments Collagen fibers straighten (less prominent than in ligaments because fibers begin more aligned); Continued elongation stiffenbecause fibers begin more aligned); Continued elongation stiffens s tissuetissue

Region 2:Region 2:

Linear Linear ResponseResponse

Region 3Region 3

Region 4:Region 4:

Macroscopic Macroscopic FailureFailure

Slope represents stiffness; Micro failure occurs at the end;Slope represents stiffness; Micro failure occurs at the end;

Elastic recovery at stresses less than 4%Elastic recovery at stresses less than 4%

Corresponds to strains of 3Corresponds to strains of 3--8%8%

CrosslinksCrosslinks fail; Collagen fibers slide past one another; irreversible fail; Collagen fibers slide past one another; irreversible changes such as tearing or permanent stretching occurschanges such as tearing or permanent stretching occurs

Tensile failure of the fibersTensile failure of the fibers

Shear failure between the fibersShear failure between the fibers

Once maximum load is surpassedOnce maximum load is surpassed

Complete failure occurs rapidlyComplete failure occurs rapidly

Fibers recoil and blossomFibers recoil and blossom

Tangled bud at ruptured endTangled bud at ruptured end

Loses Load supporting abilityLoses Load supporting ability

Mechanical Properties (ContMechanical Properties (Cont’’d)d)

Greater crossGreater cross--sectional areasectional areaLarger loads can be applied prior to failureLarger loads can be applied prior to failure

Increased tissue strengthIncreased tissue strength

Increased StiffnessIncreased Stiffness

Longer tissue fibersLonger tissue fibersGreater fiber elongation before failureGreater fiber elongation before failure

Decreased tissue stiffnessDecreased tissue stiffness

Unaltered tissue strengthUnaltered tissue strength

InjuriesInjuries

OveruseOveruse

Spontaneous RuptureSpontaneous Rupture

DislocationDislocation

Thermal InjuriesThermal Injuries

Other InjuriesOther Injuries

HealingHealing

RegenerationRegenerationNew tissue identical to normal tissueNew tissue identical to normal tissue

StructurallyStructurallyFunctionallyFunctionally

Soft tissue injury healingSoft tissue injury healing

Scar repairScar repairRepair by connective tissueRepair by connective tissue

Inferior structural propertiesInferior structural propertiesInferior functional propertiesInferior functional properties

Or by their combinationOr by their combination

Healing ProcessHealing Process

Inflammation phase Inflammation phase From the first day of injury to the fourth From the first day of injury to the fourth through seventh daythrough seventh day

Proliferative phase Proliferative phase From the seventh through twentyFrom the seventh through twenty--first dayfirst day

Maturation or remodeling phase Maturation or remodeling phase From three weeks to one year From three weeks to one year

The End

Anterior Cruciate LigamentAnterior Cruciate Ligament

ACL: LocationACL: Location

ACL: FlexionACL: Flexion

AA-- AA’’ –– AnteromedialAnteromedial bandbandBB-- BB’’ –– I ntermediate componentI ntermediate componentCC-- CC’’ –– PosterolateralPosterolateral aspect of ligamentaspect of ligament

ACLACL

Located between the femur and tibia at the Located between the femur and tibia at the center of the kneecenter of the knee

Origin from lateral femoral condyleOrigin from lateral femoral condyleInsert into the surface of tibial plateauInsert into the surface of tibial plateauIntracapsularIntracapsularExtrasynovialExtrasynovial

Consists of two bundlesConsists of two bundlesAnteromedialAnteromedialPosterolateralPosterolateral

Blood supply originates primarily from femoral Blood supply originates primarily from femoral sideside

http: / /www.amershamhealth.com/medcyclopaedia/medical/ volume% 20I I I% 201/CRUCIATE% 20LIGAMENT.ASP

Posterior Cruciate Ligament:Posterior Cruciate Ligament:

LocationLocation

PCL: FlexionPCL: Flexion

AA-- AA’’ –– Small bandSmall bandBB-- BB’’ –– Bulk of the ligamentBulk of the ligamentCC-- CC’’ –– Anterior Anterior meniscofemoralmeniscofemoral ligamentligament

PCLPCLLocationLocation

Origin: Medial femoral condyleOrigin: Medial femoral condyle

Insert: Posterior cortical surface of tibia in the sagittal Insert: Posterior cortical surface of tibia in the sagittal midlinemidline

Intimately associated with posterior capsuleIntimately associated with posterior capsuleCovered by SynoviumCovered by Synovium

Less susceptible to vascular injury than ACLLess susceptible to vascular injury than ACL

Blood supply comes from middle geniculate Blood supply comes from middle geniculate arteryartery

Spiral shape permits tibiofemoral rotationSpiral shape permits tibiofemoral rotation

Medial Collateral LigamentMedial Collateral Ligament

MCLMCL

Primary stabilizer of the medial aspectPrimary stabilizer of the medial aspect

LocationLocationOrigin: Medial femoral Origin: Medial femoral condylecondyle at the at the adductor tubercleadductor tubercle

Fans out in anterior and posterior directionsFans out in anterior and posterior directions

Insert: Medial side of tibiaInsert: Medial side of tibia

Has both superficial and deep layerHas both superficial and deep layer

Visually appears like a sailboatVisually appears like a sailboat

MCL (ContMCL (Cont’’d)d)

Deep LayerDeep LayerOriginates at adductor tubercleOriginates at adductor tubercle

Separates distallySeparates distally

Above the joint line Above the joint line Inserts into the medial meniscusInserts into the medial meniscus

Holds the fibro cartilage in placeHolds the fibro cartilage in place

Along the inferior meniscal margin Along the inferior meniscal margin Blends into superficial layerBlends into superficial layer

Inserts into the medial tibial diaphysisInserts into the medial tibial diaphysis

Has generous blood supplyHas generous blood supply

Lateral Collateral LigamentLateral Collateral Ligament

Ligament of HumphreyLigament of Humphrey

Ligament of Ligament of WrisbergWrisberg

Other InjuriesOther Injuries

Tendon AvulsionsTendon AvulsionsTendon StrainsTendon StrainsPartial Tendon rupturesPartial Tendon rupturesLacerationsLacerationsTendon divisionTendon divisionForeign bodies in TendonsForeign bodies in TendonsBite Injuries and Bite Injuries and AcupuntureAcupunture induced induced complicationscomplications

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Joint Rotations

Knee Translations

FibrocartilageFibrocartilage

Fibrocartilage Fibrocartilage (n.)(n.) A kind of A kind of cartilage with a cartilage with a fibrous matrix and fibrous matrix and approaching fibrous approaching fibrous connective tissue in connective tissue in structure structure

http: / /www.kumc.edu/ instruction/medicine/anatomy/histoweb/cart/ cart12.htm

http: / /www.brainydictionary.com/words/ fi/ fibrocartilage164589.html

FibroblastsFibroblasts

Any cell or corpuscle from which connective Any cell or corpuscle from which connective tissue is developedtissue is developed

Oriented longitudinally with respect to tissueOriented longitudinally with respect to tissueOvoid or spindle shapedOvoid or spindle shaped

http: / /www.digitalnaturopath.com/cond/C136641.html

FibroblastsFibroblasts

Secrete and absorb matrix Secrete and absorb matrix elementselements

Components: Components: CollagenCollagenProteoglycansProteoglycansElastinElastin (recoil) (recoil) FibronectinFibronectin (cell(cell-- toto--cell cell

adhesion and migration)adhesion and migration)

Joint CapsuleJoint CapsuleFluid sac at joints that holds joints togetherFluid sac at joints that holds joints together

Creates skeletal system for Creates skeletal system for synovialsynovial membranemembraneLigaments or tendons thicken the exteriorLigaments or tendons thicken the exteriorProtects cartilage, muscles, connective tissueProtects cartilage, muscles, connective tissue

Difficult to identify ligaments and tendons from capsule Difficult to identify ligaments and tendons from capsule in the bodyin the body

http://physicaltherapy.about.com/cs/disabilities/l/aa111700f.htmhttp://web1.tch.harvard.edu/cfapps/A2ZtopicDisplay.cfm?Topic=Anatomy%20of%20a%20Joint

CollagenCollagen

Different Types: Different Types: I> > > I I I> > V,VI ,X,XI II> > > I I I> > V,VI ,X,XI I

Collagen Type I is Collagen Type I is fibrillarfibrillarMade up of three Made up of three polypeptide chainspolypeptide chains

22αα11

11αα22

Chains are leftChains are left --handed handed helixes but are wound helixes but are wound together in a righttogether in a right --handed handed helixhelix

http: / /www.accessexcellence.org/RC/VL/GG/collagen_Elastin.htmlhttp: / / en.wikipedia.org/wiki/Collagen

CollagenCollagen

Hydrogen bonds form Hydrogen bonds form between between glycinesglycines(( interchaininterchain) and ) and prolinesprolinesand and hydroxyprolineshydroxyprolines(( interchaininterchain))

CrossCross-- links between links between collagen molecules collagen molecules ““headhead--toto--tailtail”” and staggered in and staggered in parallelparallel

CollagenCollagen

Hydrogen bonds and Hydrogen bonds and crosscross-- links contribute links contribute to the stability of to the stability of each molecule and each molecule and aggregation at the aggregation at the fibril levelfibril level

Result: Structures Result: Structures extremely resistant extremely resistant to tensile forcesto tensile forces

http: / /www.orthoteers.co.uk/Nrujp~ ij33lm/Orthconntiss.htm

Additional PicturesAdditional Pictures