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Advances in Therapeutics and Diagnostics

in Orthopaedic Surgery

Cato T. Laurencin, MD, PhD

Saadiq F. El-Amin, MD, PhD

Dr. Laurencin is University Professor, the

Lillian T. Pratt Distinguished Professor,
and Chair, Department of Orthopaedic
Surgery, The University of Virginia,
Charlottesville, VA. Dr. El-Amin is
Orthopaedic Surgical Resident,
Academic Orthopaedic Training
Program, Department of Orthopaedic
Surgery, The University of Virginia.
None of the following authors or a
member of their immediate families has
received anything of value from or owns
stock in a commercial company or
institution related directly or indirectly to
the subject of this article: Dr. Laurencin
and Dr. El-Amin.
Reprint request: Dr. Laurencin,
Department of Orthopaedic Surgery,
The University of Virginia, Suite 330,
400 Ray C. Hunt Drive, Charlottesville,
VA 22903.
J Am Acad Orthop Surg 2008;16:4-8
Copyright 2008 by the American
Academy of Orthopaedic Surgeons.

We define xenotransplantation as including any procedure that
involves the transplantation, implantation, or infusion into a
human recipient of cells, tissues, or organs from a nonhuman
animal source or of human body fluids, cells, tissues, or organs that
have had ex vivo contact with nonhuman animal cells, tissues, or
organs. The current FDA definition of xenotransplantation relates
to procedures involving live, nonhuman materials. The proposed
use of xenotransplanted tissues for treatment of a wide variety of
human diseases is increasing. In orthopaedic surgery, a number of
xeno-based products for treatment of musculoskeletal conditions
have been cleared by the FDA. Commercially available products
include those used as alternatives for bone, cartilage, and softtissue repair. Most xenografts are from bovine- or porcine-derived
sources. Studies internationally have demonstrated a low relative
risk of disease transmission, although there is concern regarding
the potential for transmission into humans of agents not
considered pathogenic or not detected in animals.

e define xenotransplantation
as including any procedure
that involves the transplantation,
implantation, or infusion into a human recipient of either (a) cells, tissues, or organs from a nonhuman animal source or (b) human body
fluids, cells, tissues, or organs that
have had ex vivo contact with nonhuman animal cells, tissues, or organs.1 The current US Food and
Drug Administration (FDA) definition of xenotransplantation relates
to procedures involving live, nonhuman materials.2 Interest is growing
in the use of xenotransplantation
procedures in orthopaedic surgery.
Controversies surround the use of
xenotransplantation procedures and
efforts made to address safety issues
regarding their use.
The advantages of xenografts include their relative abundant supply,

ease of use, and potentially favorable

clinical performance. A primary concern regarding xenotransplantation
products is risk of disease transmission, such as bacterial, viral, and
prion transmission when using xenograft tissue.3 The possibility of immune response also is a safety issue.
Several products have already been
cleared by the FDA for use in orthopaedic surgery. Many have been
cleared as surgical meshes for tissue
regeneration and are labeled as devices by the FDA4-10 (Table 1). Before
being made available by suppliers,
xenograft materials are assessed for
potential disease-causing viruses
and microorganisms. Viral inactivation validation assessments of the
manufacturers manufacturing process are part of the review process.
Postmarket surveillance consists
largely of medical device adverse

Journal of the American Academy of Orthopaedic Surgeons

Cato T. Laurencin, MD, PhD, and Saadiq F. El-Amin, MD, PhD

event reporting (MDR) submissions

and surveillance for relevant disease
detection information, as outlined
by the guidance provided by the
Center for Devices and Radiological
Health (CDRH) of the FDA regarding surgical mesh and dura substitute.11,12
For example, when collagen or
another animal-derived material is a
device component, the FDAs device
application for its use also should
identify the following: (1) The species and tissue from which the animal material was derived, including
the specific type of collagen or other
material used. (2) How the health of
the herd is maintained and monitored. Is the herd closed? Is the animal material of bovine origin and, if
so, is there certification that the
herd is from a country free of bovine
spongiform encephalopathy (BSE)?
(3) How the health of each animal is
maintained and monitored. What is
the age of the animal at sacrifice?
What tests are performed to determine that the material is accessible
for further processing or is pooled
with material from other animals?13
If the product contains synthetic
(eg, polymeric, metallic) components,
then the application should identify
the concentration in the final device
of any component (eg, organic solvents, heavy metals, cross-linking reagents) that is potentially toxic, carcinogenic, or immunogenic.
For device manufacturers, the
application should contain information about all reagents and processing steps used in device manufacturing. Information similar to
that for devices (for example reagent
source, purity), and/or Material Safety Data Sheet (MSDS) information
can be very helpful in evaluating the
substantial equivalence of proposed
and legally marketed devices. Also,
information must be provided regarding sterilization and methods for
inactivating bacteria, yeast, and
fungi and must be validated by the
company.14 Development strategies
at present focus on improving disVolume 16, Number 1, January 2008

Table 1
Select Xenobased Implants Currently Available for Orthopaedic Surgery
Product Composition






Long bone fracture

and bony void filler4

Campbell, CA)
Warsaw, IN)

Soft-tissue repair




Bone grafting6,7

(DePuy Spine,
Raynham, MA)

Bone grafting8

Warsaw, IN)

Restore (DePuy,
Warsaw, IN)

Soft-tissue repair9

Soft-tissue repair10

Product composition as reported by the manufacturer

Bovine = bovine-derived products, HAp = hydroxyapatite, Porcine = porcine-derived
products, TCP = tricalcium phosphate

ease detection and prevention techniques.

Research on
Zoonoses are diseases and/or infections that are naturally transmissible
from animals to humans. Theoretically, these diseases are considered to
be possible even in decellularized
xenografts. A class of infectious
agents of concern are prions, which
are infectious proteins that may be
associated with bovine-derived tissues. However, no current data have
demonstrated prion transmission in
current xenografts.3 Based on exper-

imental models, it has been suggested that degree of infectivity decreases such that infectivity of the
central nervous system is predominant, whereas the spleen and lymph
node are moderately susceptible. Organs such as bone, skin, or skeletal
muscles do not harbor any detectable
The immune response to tendon
xenografts has been studied in rabbit
models.16,17 Bovine fibroblasts, extracellular proteoglycans, and glycoproteins all have elicited immune responses. However, these minimal
immune responses are similar to the
response elicited by collagen matrices. Cellular elements within the

Xenotransplantation in Orthopaedic Surgery

Guidelines for
Industry Production
and Clinical Use of

Table 2
Two Current Xenograft Sources and the Risk Analysis of Disease

Risk Analysis of Cross-Species

Disease Transmission





PhRMA risk analysis revealed an

incidence of infection from ABM
of 1:1 1018
German Ministry of Health
model revealed ABM to be 30
orders of magnitude (ie, 1,010
times) safer than a product of
acceptable safety19
No evidence of PERV
transmission in clinical trials
A retrospective assessment of 160
patients receiving porcine tissues
throughout the world showed
no evidence of PERV infection20


ABM = anorganic bone material, BSE = bovine spongiform encephalopathy, PERVs =

porcine endogenous retroviruses, PhRMA = Pharmaceutical Research and
Manufacturers of America

grafted tissue elicit the greatest immune response. The extracellular

matrix components induce a B-cell/
antibody response. One study has
identified a T-helper type 2 (Th2)
lymphocyte response to extracellular matrix components.18

Potential Public
Health Risks in
Most xenografts are from bovine- or
porcine-derived sources (Table 2).The
bovine-derived products could be of
concern because of the possible
transfer of bovine spongiform encephalopathy (BSE), while porcinederived products could be of concern
due to porcine endogenous retroviruses (PERVs). Studies internationally have reported the relative risk of
disease transmission of BSE to be
rather low and report no evidence of
viral transmission of PERVs in xenotransplants.21 However, concern still
focuses on the transmission of organisms that may become pathogenic
in immunosuppressed or immunocompromised individuals. Xenografts
have the potential for transmission

into humans of infectious or pathogenic agents that may not be considered pathogenic or detectable in the
animal source. A further concern is
the risk of recombination or reassortment of various infectious agents
with nonpathogenic or endogenous
human infectious agents to form new
pathogenic entities. Some think that
the process of allowing donor animals to be used, obtaining consent
from those who are seriously ill, and
requiring life-long monitoring of patients and third parties is sufficiently
burdensome to outweigh potential
Because of the lack of international regulation, the potential benefits of xenotransplantation may be
annulled as a result of the increased
risk of negative outcomes as well as
because of xenotourism. (Xenotourism is traveling to another country
for a xenotransplantation, typically
for treatment not available domestically.) Oversight is the key to public
safety. International collaboration
and coordination is needed to both
prevent and maintain surveillance
for potential infections that could result from xenotransplants.15

To date, little research has been published regarding the proper use of
xenotransplants. However, the Center for Biologics Evaluation and Research (CBER) of the FDA has published the Guidance for Industry
regarding use of xenotransplantation
products in humans.2 The Guidance focuses on the regulation of
live materials; however, we believe
it has utility in the assessment of all
xenotransplantation products.
The Guidance notes that animals
should not be imported from any
country or region where transmissible spongiform encephalopathy is
known to be present.2 Also, xenotransplantation guidelines should be
followed by manufacturers during
the development of cellular-based tissue products. Microbiologic testing
of xenotransplantation products
should be performed, including assays to detect pathogens and viruses.
The FDA should be notified immediately when a possible xenogeneic infection is suspected or when the
causative infectious agent is identified. Regularly monitoring the Federal Register (http://www.gpoaccess.
gov/fr/index.html) and FDA News
( may be helpful
in understanding reporting requirements.
Informed consent should be obtained in all instances and must cover the risks of using xenotransplantation devices. Also, the physician is
responsible for providing recipients
with updated information, especially when that information is relevant
to the patients clinical course.
Future plans by the FDA have included discussions centered around
the development of a computerized
national xenotransplantation database to assist in data monitoring and
tracking recipients for public health
service needs.

Journal of the American Academy of Orthopaedic Surgeons

Cato T. Laurencin, MD, PhD, and Saadiq F. El-Amin, MD, PhD

Commercially Available
Xenografts in
Orthopaedic Surgery
Several commercial manufacturers
produce xenograft-based products
cleared by the FDA. These products
are used for musculoskeletal repair,
such as surgical meshes for rotator
cuff or Achilles tendon repair21 (Table 1).
As an example, the Restore Orthobiologic Implant (DePuy) is a resorbable scaffold derived from porcine
small intestine submucosa. The Restore implant has been reported to be
used for reinforcement of soft tissues
involving the supraspinatus tendon
repaired by sutures or anchors during
rotator cuff repair. However, one
study has shown that the Restore implant should not be used to repair
massive rotator cuff tears because of
the implants inability to reproduce
the native anatomy and lack of muscle contraction required to induce remodeling and regeneration.16
The CuffPatch Soft-Tissue Reinforcement (Arthrotek) is a resorbable
matrix composed of porcine collagen
(Table 1). CuffPatch is intended for
use as an implantation device during
rotator cuff surgery.5 Its application
is limited to the supraspinatus to reinforce soft tissues repaired by suture or suture anchors.
Healos Bone Graft replacement
(DePuy Spine) is an osteoconductive
matrix composed of cross-linked bovine type I collagen fibers fully coated
with hydroxyapatite (Table 1). The
company states that, when combined
with autogenous bone marrow aspirate, Healos provides an environment
for osteoprogenitor cell attachment,
proliferation, and differentiation.
Bio-Oss (Geistlich Biomaterials) is
an osteoconductive bone graft substitute composed of natural hydroxyapatite crystals obtained from deproteinized bovine bone (Table 1).10
Bio-Oss demonstrates similarity to
human bone and is used for bone regeneration applications. Orthoss (Geistlich Biomaterials) is a similar
Volume 16, Number 1, January 2008

bovine-derived bone graft product

used as an alternative bone replacement material. Combined with autogenous bone or bone marrow aspirate, Orthoss provides additional
osteogenic potential.
Bio-Gide (Geistlich Biomaterials)
is a resorbable membrane composed
of porcine type I and III collagen.6
The bilayer structure consists of a
compact, smooth, cell-occlusive layer and a loose, porous layer that
favors cell invasion. Bio-Gide is indicated for use in guided bone regeneration and wound healing.
Collagraft Strip (also called NeuGraft Strip; NeuColl) is a bone graft
substitute consisting of a combination of type I bovine dermal fibrillar
collagen, hydroxyapatite, and tricalcium phosphate.4 Collagraft provides an osteoconductive environment for new bone formation. The
addition of autogenous bone marrow
provides Collagraft with osteoinductive and osteogenic properties, allowing for its use in acute long bone
fractures, traumatic osseous defects,
and bony voids.

able. In general, the strength of

many xenografts is similar to that of
autografts, although the authors of
some studies have suggested that
xenografts may be limited in their
ability to reapproximate the native
Future research must include a
thorough understanding of the longterm immunologic responses to
xenografts for use in orthopaedic
applications. Additionally, new strategies for disease detection and prevention must be developed to eliminate theoretic risk. We believe that
xenotransplantation products should
follow the Guidance for Industry established by CBER, even those that do
not contain cells. In addition, physicians must take it upon themselves
to promptly report to the FDA all suspected xenogeneic infection or unidentified, non-xenogeneic causative
infectious agents. Xenografts have a
clinical role to play in medicine and,
in particular, orthopaedic surgery. Future studies and research must continue to ensure the safety and clinical efficacy of these products.



Commercially available xenografts

are used as alternatives for bone,
cartilage, and soft-tissue repair in
orthopaedic procedures with varied indications. Materials involving
xenografts vary from collagen components derived from bovine and
porcine sources to deproteinized
bone that can be combined with
polymers, ceramics, and autogenous
tissues. Xenografts offer several
promising alternatives for regenerative and reparative applications involving both clinical applications
and orthopaedic basic research.
There are a number of obvious concerns in the use of xenograft materials, including theoretic transmission
of pathogens, viruses, and the elicited immunologic response in patients. The xenografts currently
available in orthopaedic surgery
have been proved to be safe and reli-

Evidence-based Medicine: Reference 21 is a level IV study (case series). References 2, 3, 12, and 20 are
level V studies (expert opinion).
Citation numbers printed in bold
type indicate references published
within the past 5 years.

Sykes M, dApice A, Sandrin M, IXA

Ethics Committee: Position paper of
the Ethics Committee of the International Xenotransplantation Association. Xenotransplantation 2003;10:
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Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans. Available
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3. Dormont D: How to limit the spread
of Creutzfeldt-Jakob disease. Infect

Xenotransplantation in Orthopaedic Surgery








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Available at: http://www.jnjgateway.

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Journal of the American Academy of Orthopaedic Surgeons