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Xenotransplantation
in Orthopaedic Surgery
Abstract
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,
Table 1
Select Xenobased Implants Currently Available for Orthopaedic Surgery
Applications
Product Composition
Product
(Manufacturer)
Porcine
HAp
TCP
Bovine
Indications
Collagraft
(Neucoll,
Campbell, CA)
CuffPatch
(Arthrotek,
Warsaw, IN)
Soft-tissue repair
reinforcement5
Bio-Gide
(Geistlich
Biomaterials,
Wolhousen,
Switzerland)
Autologous
chondrocyte
transplantation6,7
Bio-Oss
(Geistlich
Biomaterials)
Bone grafting6,7
Healos
(DePuy Spine,
Raynham, MA)
Bone grafting8
ZCR-Permaol
(Zimmer,
Warsaw, IN)
Restore (DePuy,
Warsaw, IN)
Soft-tissue repair9
Soft-tissue repair10
Research on
Xenotransplantation
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
infectivity.3,15
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
5
Guidelines for
Industry Production
and Clinical Use of
Xenotransplantation
Table 2
Two Current Xenograft Sources and the Risk Analysis of Disease
Transmission
Zoonotic
Disease
Bovine-derived
products
BSE
Porcine-derived
products
PERVs
Xenograft
Potential Public
Health Risks in
Xenotransplantation
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
6
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
benefits.14
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
(http://www.fda.gov) 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.
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
Discussion
References
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.
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