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Innovations in Medical Technology

Regenerativemedicine and humantissue engineering

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Human tissue engineering and re-

generative medicine in general (e.g.

the use o smart biomaterials that

promote sel-repair o damaged tis-

sues) oer tremendous promise or

improved patient treatment, asterrecovery, improved prognosis and a

more biologically avourable situation

where the body can be stimulated to

heal itsel.

There is a huge amount o research

being undertaken worldwide in all ar-

eas mentioned in this overview (and

others) and a huge interest in the po-

tential o tissue engineering/regenera-

tive medicine.

However, there is still currently a lack

o eective regulatory ramework on aEuropean basis. Such uture legisla-

tion must be designed in such a way

that it allows research and innovation

in the eld to fourish and the prospect

o a timely return on research invest-

ment to be realised, whilst at the same

time ensuring risks to patients are

minimised and that equitable access

to treatment can be attained.

Regenerative

medic ine and humantissue engineer ing

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What are regenerative medicine and

human tissue engineering?Regenerative medicine and human tissue engineering are rapidly developing new

interdisciplinary elds in medicine. They are typically characterized by a conver-

gence o disciplines such as advanced materials science, cell biology, biochemis-

try, engineering and medicine. Regenerative medicine is a wider term that encom-

passes human tissue engineering and comprises a range o technologies that seek

to help the body repair and restore itsel. A denition currently put orward by the

US National Institutes o Health (NIH) is:

Regenerative medicine/tissue engineering is a rapidly growing multidisci-

plinary feld involving the lie, physical and engineering sciences that seeks

to develop unctional cell, tissue, and organ substitutes to repair, replace

or enhance biological unction that has been lost due to congenital abnor-

malities, injury, disease, or ageing.

A human tissue engineeredproduct is currently defned as

A product that:

F contains or consists o engineered cells ortissues; and

F is presented as having properties or, or isused in or administered to human beings

with a view to regenerating, repairing or re-

placing a human tissue.

A human tissue engineered product may con-

tain cells or tissues o human or animal origin, or

both. It may also contain additional substances, such as cellular products, biomol-

ecules, biomaterials, chemical substances, and scaolds or matrices that help to

provide a physical support to the cells/tissues.

In addition to having therapeutic applications, human tissue engineered products

can have diagnostic applications where the tissue is made in vitro and is used as a

platorm or testing drugs and other products.

Human tissue engineering includes the ollowing importantareas:

FBiomaterials: these may include novel biomaterials that can infuence, by phys-ical or chemical means, the organization, growth, and dierentiation o cells in

the process o orming the desired tissue

FCells: these may be autologous ( i.e. rom the patient him or hersel), allogeneic(rom another person), xenogeneic (animal cells), and may be stem cells or cells

that have already reached some degree o dierentiation

FBiomolecules: these may include growth actors, dierentiation actors andother key proteins

FSafety and performance issues: including characteristics o tissues, identica-tion o minimum properties required o engineered tissues, mechanical signals

regulating engineered tissues, and perormance and saety o engineered tis-

sues

FManufacturing factors: including cell expansion, three-dimensional tissue

growth, the use o bioreactors, cell and tissue storage, etc.

FOther aspects: including inormatics and data, modelling, quality assuranceand clinical data

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What are the potential benets

o regenerative medicine/human

tissue engineering?

It has been estimated that millions o people worldwide could benet rom regen-erative therapies.

Regenerative medicine products are already beginning to change medical prac-

tice today. Human tissue engineered skin and tissue engineered cartilage were

amongst the rst to be used or the treatment o chronic wounds and burns, and

joint degeneration and injury, respectively. Other regenerative techniques are be-

ing developed to repair bone, the cornea, the bladder and several other common

medical conditions.

Also under current research are treatments such as nerve regeneration or con-

ditions like Parkinsons Disease or Alzheimers Disease, pancreatic islet cells or

transplantation into the liver or diabetes treatment, and regeneration o damaged

heart tissue. An ultimate goal will be to build human tissue engineered organs on

three dimensional scaolds such as bladders, livers, hearts, and kidneys. This willentail deep and sustained multidisciplinary collaboration between previously dispa-

rate elds such as cell biology, biochemistry, materials science and immunology.

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Some regenerative medicine and

human tissue engineered treatmentsSome o the medical applications and tissue/organs to which tissue engineering

approaches are being developed include:

F severe burns

F skin ulcers

F cartilage

F bone, e.g. or acial reconstruction

F tendons

F ligaments

F blood vessels

F myocardial patches

F heart valves

F kidney

F bladder

F liver

F bioarticial pancreas

Some o these developments are urther explained in the ollowing examples.

These are just a ew o the hundreds o therapies under development worldwide

or a multitude o conditions and diseases.

Tissue engineered skinCells are already being grown on a variety o substrates or the treat-

ment o serious burns or or dicult-to-treat conditions such as dia-

betic ulcers. They can provide a biocompatible and important physi-

cal barrier to fuid loss and inection and assist in the regeneration

o the patients own skin. Treatment o diabetic ulcers in this way

oten results in much aster healing and greatly improved prognosis

or a condition that is oten impossible to treat adequately and may

sometimes result in amputation.

Tissue engineered c a rtil age

Degenerative joint conditions are becoming increasingly prevalent with an ageingpopulation and damage may also occur in young patients as a result o sports

injuries. Conventional treatments may include partial or total joint replacements but

it is possible, in many cases, to replace damaged cartilage with tissue engineered

cartilage ormed using the patients own chondrocytes grown on a variety o sub-

strates. This may, in the uture, avoid the need or implants or suitable patients.

Tissue engineered boneThe regeneration o skeletal bone is a major unmet clinical need, e.g. or degenera-

tive diseases and accident victims. The development o new biomimetic materials

that provide a suitable microenvironment or cell-matrix interaction and the adhe-

sion and prolieration o dierentiated osteocytes (bone cells) is the ocus o much

research. Research is centred on tissue engineering approaches or new cartilage

and bone ormation and also on how physical stresses in the body infuence tissue

development.

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Tissue engineeredper ipheral ner ves

When a peripheral nerve is severed, e.g. in an accident (a very common injury

amongst young males in particular), a gap between the severed nerve ending may

remain that is too wide to be treated by conventional microsurgery or that would

mean sacricing an existing unctional nerve in a nerve grat. There is consider-

able research under way to identiy suitable biomaterials that could provide a con-

duit to enable regeneration-promoting Schwann cells to grow in a guided manner

to bridge such injuries.

Tissue engineered corneaTissue engineering corneas is a challenge as the cornea is avascular, i.e. it has no

blood supply and receives its physiological needs rom lachrymal fuids at the ront

and rom the aqueous humor at the rear. Because o the need or donor corneasor transplant and the rejection that sometimes occurs, much research is under

way to characterise the interaction between the cells constituting the cornea and

suitable scaolds, e.g. a biocompatible but non-biodegradable hydrogen. Possible

approaches include using the patients own limbal cells (where these are still avail-

able) or donor limbal cells to colonise the substrate.

Tissue enginee red blood vesselsThe development o tissue engineered blood vessels is one o the most excit-

ing current challenges in reconstructive medicine. A variety o approaches are in

research and development using both synthetic biopolymer scaolds and biologi-cally-derived matrix materials. Both entail the incorporation o both smooth mus-

cle cells and vascular endothelial cells into a tubular scaold so as to establish a

structure analogous to that o a native artery. For blood vessels, one particularly

important characteristic is the ability to respond to changes in blood pressure in

an appropriate manner. Despite the intensive research, solutions are likely to take

a number o years to reach the market as, with bioengineered organs, a number

o dierentiated cell types and three-dimensional structures are involved which

provide considerable scientic and medical challenges.

MyocardiumThere are a number o therapies in development aimed at regenerating or repairing

the heart myocardium. These range rom well-advanced research on cell-therapy

regeneration o myocardium to earlier stage research on developing tissue engi-

neered myocardial patches.

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Human tissue engineered therapies represent a move away rom traditional med-

ical device and pharmaceutical technologies. Very oten, the tissue engineered so-

lution is geared towards an individual patient rather than a standard product being

aimed at a wide and diering population o patients. This brings a number o new

challenges or both manuacturers and regulators. For example:

F with an autologous tissue engineered treatment, the product is a one-o or aparticular patient. The ocus thereore moves rom a traditional large production

run situation to one where strict quality and risk management principles must

be applied to the process o collecting, multiplying and dierentiating cells, in-

corporating those cells with a scaold, producing a three-dimensional tissue

engineered construct and transporting and reimplanting the resulting productinto the patient within a critical timescale

F saety in sourcing cells and tissues, especially allogeneic materials

F how clinical perormance and in-vivo biological responses can best be as-sessed

F ollow-up studies with patients to monitor viability, perormance and saety othe tissue-engineered product

Some risks related to human

tissue engineering

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European Medical Technology Industry Association

2 Place des MaeursG 1150 BrusselsG BelgiumG Tel: +32 (0)2. 772.22.12 G Fax: +32 (0)2. 771.39.09

eucomed@eucomed beG Visit wwweucomed orgru

ssels,

March2007E

ucomed

design:Grabitphotosp3,

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7:I

soTis

Currently, a new Regulation is being developed at European

level on Advanced Therapy Medicinal Products (ATMPs) and

it is proposed that this should cover human tissue engineered

products as well as gene therapy and cell therapy which are

already covered under medicinal products legislation.

Eucomed is actively involved in the debate as to how to develop

this Regulation, and in the possible additional developmento other existing Directives, e.g. the Medical Device Directive

(93/42/EEC) to accommodate certain aspects related to tissue

engineering and regenerative medicine.

However this legislative process evolves, Eucomed is convinced

that a risk management-based approach is necessary that will

maximise patient saety in this important new area o medical

technology, whilst allowing scope or the rapid innovation that

is taking place throughout Europe and taking account o the

patient-specifc nature o the products.

Proposednew EU Regulat ion