review paper.

Biomaterials Review Assignment Snehal Ulhas Salunke
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Review Assignment
Topic- Oppenheimer Effect
Introduction:
The orthopedic hardware and prosthetic joints have been used to repair skeletal defects and replace
poorly functioning or severely painful joints. Statistics state about 140,000 total hip arthroplasties, 103,000
revisions, and 30,000 partial hip replacements were performed in the United States in 1996 (0.7% of the
U.S. population)[1] and metallic hardware is routinely used for fracture fixation as well as other orthopedic
procedures. The biomaterials used in these devices are generally considered to be nontoxic; there have
been studies that have shown some constituents to exhibit potential carcinogenic in laboratory animal
studies[2-7] and malignancies have been associated with orthopedic implants in pets[8]. In humans the
development of an orthopedic implant associated malignancy is rare, but it develops well recognized
complication. It has been observed that medical devices and prostheses implanted in connective tissue
immediately induce an initial host response to act against the foreign body. According to Hench, type of
implant-tissue response can be graded in the following ways[9], if the material is: i) Toxic, the surrounding
tissue dies. ii) Non-toxic and biologically inactive (nearly inert), a fibrous tissue of variable thickness forms.
iii) Non-toxic and biologically active (bioactive), an interfacial bond forms. iv) Non-toxic and dissolves, the
surrounding tissue replaces it. Sarcomas and carcinomas are types of malignant tumors that can affect
different types of tissue & bones. Sarcomas are derived from mesodermal (mesenchymal cells), connective
tissues and carcinomas are derived from epithelial types of cells. Sarcomas and carcinomas grow and
spread differently. The local growth of sarcomas like a ball enables resection in most instances. Carcinomas

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grow in an infiltrative manner and grow through infiltration or invasion of adjacent structures. They more
easily invade adjacent nerves, blood vessels and muscles.
In this report, the effect of biomaterials implanted in human body relating to induce or persist
sarcomas is discussed depending on surface properties of the constituents of the device.
Discussion:
First experimental evidence of body induced sarcoma was discussed by Turner in 1941 using a disc
of Bakelite [10] which was the first plastic made from synthetic components. The study examined two rats
implanted with bakelite discs; one coated with dibenzanthracene as test disc and other one uncoated disc
which was used as a control. After a period of implanting and examination, the test disc was removed and
studied to monitor the effect of hydrocarbon layer. The monitoring reported no visible changes. The disc
was not re-implanted and the rat died on its own without tumor after 11months. The control rat was killed
after 23 months and the implant was monitored. The results yielded detection of tumor around the disc.
Later an experiment by Oppenheimer et al [11], on rats reported the development of sarcomas at the site
of cellulose film wrapped around the kidney. The experiment had cellophane, which was implanted in the
body, resulting in development of sarcomas. After the cellulose film was formed around the kidney, a
portion of it was removed and implanted subcutaneously developing similar neoplasms.
An experiment performed by Brand et al. [12] verified carcinogenic potential depend on
foreign body properties such as shape/size, smoothness, hardness, porosity and electrostatic load and was
also influenced by gender and strain of the host[12]. In 1955, Northdruft concluded that chemical nature
of implants was irrelevant for the production of tumor. In 1958, Oppenheimer group strongly emphasized
importance of physical properties on the development of foreign body tumors in rodents. This was

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referred as Oppenheimer effect or even “solid-state tumorogenesis” to differentiate from chemical
carcinogenicity[13].
Tumors induced due to plastic implanted in rats are dependent on the physical properties of
the material rather than its chemical composition. One of the most important arguments in favor of the
participation of physical factors in the experiment is several plastic either lost or greatly reduced their
carcinogenicity when same amount of material is implanted in the animal in powdered form (Nothdurft,
1955; Oppenheimer et al., 1955; Oppenheimer, Oppenheimer, Stout, Danishefsky and Willhite, 1959;
Oppenheimer, Willhite, Danishefsky and Stout, 1961). James et al [13], discusses about the
characterization of cellular response to silicone implants giving rise to foreign body carcinogenesis. In this
study he concluded that the cellular response of silicone in elastomer form is because of the non-specific
foreign body reaction with the physical properties of silicone and not with the unique chemical properties.
The experiment reported by R. L. CARTER et al[14] in which the carcinogenic activity of plastic implants
was not materially impaired after shredding the material into small fragments is of interest for some
reasons. Under certain circumstances, factors other than the physical properties of the implants may be
responsible for their carcinogenic activity. The experiment consisted of making four groups, each group
having 20 rats. Polyethylene balls were cut into segments or shredded into fragments & used as the
materials for implantations. The materials were treated and sterilized with gamma irradiation and then
stored at room temperature. The implants for the groups were done in the following ways:
Group A. (Test.): Twenty animals. One segment of polyethylene (approximately 620 mg.) was
implanted subcutaneously into the right flank under ether anesthesia. Group B. (Control.): Twenty
animals. Incision made in right flank, as in Group A, but no plastic implanted. Group C. (Test.): Twenty
animals. Approximately 530 mg. shredded plastic was packed into gelatin capsules (size 000, Parke Davis

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and Co.) and implanted subcutaneously into the right flank under ether anesthesia. Group D. (Control):
Twenty animals. Empty gelatin capsule was implanted into right flank as in Group C.
Result:
Group A Group B Group C Group D
Implantation
site Tumor
Found in 7of 20 rats (one
squamous carcinoma and six
sarcomas- three spindle cell
lesions and three
pleomorphic tumours).
Latent period of induction
varied between 48 and 79
weeks with a mean of 52
weeks.
˗
Found in 5 of 20 rats (five
sarcoma-three spindle cell
lesions and two
pleomorphic lesions).
Latent period of induction
varied between 48 and 79
weeks with a mean of 52
weeks.
˗
Neoplastic
Changes
Increased amount in fibrous
tissue was detected which
enclosed the implants in a
loose capsule. The walls with
only occasional chronic
inflammatory cells and
macrophages.
˗
Connective tissues deep to
the panniculus carnosus
muscle were riddled with
small cavities which had
contained fragments of
polyethylene and these
were surrounded by a
vigorous cellular response.
˗
Other
tumors
˗
i) A spindle cell
sarcoma on the
back of a control
rat. ii) A
pleomorphic
sarcoma on the tail
of a rat
i) A fibromyxosarcoma in
the ventral body wall of a
test rat. ii) Four rats with
malignant lymphoma
i) A spindle cell
sarcoma in the chest
wall of a control rat. ii)
a phaeochromocytoma
iii) One rat with
malignant lymphoma
However, there were no differences between tumors induced by implants in either powdered or
solid form. There was often evidence of local spread but distant metastases developed in only two animals
- in the lungs of one, and in the liver of the other.
Bronchiectasis and cystic nephritis were common in the few animals in all four groups; the incidence
and severity of these changes was similar in test and control rats. Therefore we can conclude that the size
of the shredded fragments plays an important role in determining the form of the tissue response but it is

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not known to what extent other features of the particular polyethylene plastic may have contributed to
the carcinogenic activity. The larger fragments of plastic employed in the experiment clearly gave rise to a
considerable (and sustained) local response; but instead of an organized connective tissue capsule, a more
diffused reaction was found composed mainly of granulation tissue and macrophages. The material was
sterilized by irradiation before use and Carrington and Stein (1962) have shown that active free radicals
may be formed in irradiated plastics. Secondly, plastics contain many added or contaminant chemicals
(Scales, 1953; Little and Parkhouse, 1962) and it is possible that one of these may have contributed to the
overall carcinogenic activity of the test material. Whatever the full explanation, these anomalous results
are difficult to reconcile with established theories of carcinogenesis by plastics (Bischoff and Bryson, 1964).
It is almost axiomatic that fragmented plastics are not carcinogenic and that the formation of a connective
tissue capsule around implants is a pre-requisite for the development of tumors.
The shape necessary for carcinogenesis as found in foreign bodies must be in vivo as well. An easily
absorbable liquid would provide little or no chance for the conversion; however, if the liquid turns viscous,
it can produce fibrosarcoma at the site of implantation[15]. The shape also influences tumor frequency; it
is much higher in mice implanted with concave plastic discs than in those with convex ones because
concave discs evoke more intense fibroblastic reaction[16]. Moreover, tumor incidence correlates with
surface area of implants because the size of foreign bodies determines the degree of the inflammatory
reaction[16]. Tumor formation seldom occurs when a small material has been implanted, but a large
foreign body produces tumors constantly[17,18,19]. For equal area, the plate minced into small fragments
almost completely cancels its carcinogenic capacity[20, 21, 22]. Textile materials, rough-surfaced implants
and minced materials have little potential to induce tumors, whereas, if they are implanted, uninterrupted
and smoothly-surfaced, they develop tumors [16, 22-25].

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Porosity of the materials is influential. When implants are perforated and the holes are large, tumor
incidence is reduced.[16,19,20,22] For instance, filters with pores of 0.22 μm or larger do not induce
tumors whereas those of the same thickness with smaller pores will do. This is because the implants poorly
develop connective tissue capsules and the pore is infiltrated with phagocytes in the former[16] but the
pore sizes below 0.22 μm are surrounded by thick collagen capsules and the filter pores are not infiltrated
with phagocytes. Moreover, hydrophobic filters develop more tumors than mice implanted with
hydrophilic ones[16].
Sarcoma developing from metallic orthopedic prosthesis or hardware is an uncommon, but well
recognized complication. For the case study by Keel S B et al [26] they have reviewed 12 cases of sarcomas
arising in bone or soft tissue at the site of orthopedic hardware or a prosthetic joint. Nine patients were
male, and three were female whose ages ranged from 18 to 85 (mean 55) years at the time of diagnosis of
the malignancy. Five patients had undergone hip arthroplasty for degenerative joint disease, four had
been treated with intramedullary nail placement for fracture, two had staples placed for fixation of
osteotomy, and one had hardware placed for fracture fixation followed years later by a hip arthroplasty.
For 11 of these cases the period between the placement of hardware and diagnosis of sarcoma was ranged
to a mean period of 11 years. The patients, complaining of pain, swelling, or loosening of hardware, were
found to have a destructive bone or soft tissue mass on radiography; on further investigation two
sarcomas were located primarily in the soft tissue and 10 in bone. Eventually, seven patients developed
osteosarcoma, four malignant fibrous histiocytoma, and one a malignant peripheral nerve sheath tumor.
All of these sarcomas were reported to be high grade. The 11 patient had underwent surgical treatment &
one patient had surgical debulking combined with radiation therapy and chemotherapy. Follow-up
information was available for eight patients. Five patients died of disease 2 months to 8 years (mean 26

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months) after diagnosis. Two patients died without evidence of disease 7 and 30 months after diagnosis
and only one patient is alive without disease 6 years after diagnosis.
Therefore it was concluded that Implant-related sarcomas arise in bone or soft tissue contiguous
with the implant hardware with most tumors being high-grade malignancies and have included
pleomorphic sarcoma (malignant fibrous histiocytoma), osteosarcoma, Ewing sarcoma, angiosarcoma,
fibrosarcoma, malignant peripheral nerve-sheath tumor, synovial sarcoma, epithelioid sarcoma, epithelioid
hemangioendothelioma, chondrosarcoma and lymphoma. However, it appears to be no correlation
between the biomaterial implanted and the histologic type of sarcoma. Imaging studies of implant-related
sarcomas have demonstrated a destructive permeative mass lesion associated with the implant material.
In typical behavior, patients initially exhibit similar symptoms of pain, swelling and stiffness. So the clinical
specialist may misinterpret these findings as common inflammatory or reactive orthopedic complications,
which may lead to a delay in diagnosis and treatment.
There are few studies that have compared the carcinogenic activity of various metal compounds in
vivo [27, 28]. Additionally, it is difficult to evaluate the results of the various animal studies in order to
obtain a measure of carcinogenic potency because of differences in routes of administration, animal
species, dosages, etc. Sunderman, Jr., [28, 29] conducted a study that evaluated the carcinogenic activity
of a variety of nickel compounds in Fischer rats under well-controlled conditions. The experiment yielded
results that injecting crystalline Nickel compounds is prone to incidence of cancer, while the amorphous
are far less potent for carcinogenic activity. The phagocytosis of the metal particles was a primary
determinant of biological activity whether it be cytotoxicity or carcinogenesis [25, 30]. The Max Costa et al
[31] discussed Phagocytosis, Cellular Distribution, and Carcinogenic Activity of Particulate Nickel
Compounds in Tissue Culture. In this study Particles of crystalline Ni3S2, crystalline NiS, and crystalline

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Ni3Se2 were actively phagocytized by cultured cells as determined by light and electron microscopy.
However, particles of similar size consisting of amorphous NiS and metallic nickel were not significantly
phagocytized despite long exposure periods to high concentrations. X-ray fluorescence spectrometry
measurements of metal levels in subcellular fractions isolated from cells treated with crystalline Ni3S2,
crystalline NiS, or amorphous NiS confirmed that, amorphous NiS did not significantly enter the cells,
either as a phagocytized particle or in a solubilized form, while the other two crystalline nickel compounds
were actively taken up. Cells treated with amorphous NiS contained nickel levels generally less than 10% of
the nickel levels in whole cells and in cytoplasmic fractions, or nuclear fractions of cells treated with either
crystalline NiS or crystalline Ni3S2. The phagocytized nickel particles were always observed in the
cytoplasm with light and electron microscopy, but substantial nickel levels were measured in the nuclear
fraction. The parameter that determines carcinogenic and toxic effects of metal compounds on
mammalian cells is their potential to gain cellular entry. Following observations were made based on the
decreasing order of speed to get entry into the cells:
1. NiCI2 and NiSO4 (water soluble compounds) enter cells with relative ease, possibly following
conjugation with serum proteins or amino acids such as histidine.[32]
2. Ni(Co)4 (Lipid-soluble metal compounds) rapidly enter cells leading to considerable cytotoxic
and carcinogenic effects with comparatively low concentration.[27, 33, 34]
3. Precipitate metal compounds (insoluble) must either slowly dissolve or attach to cell surfaces or
be phagocytized to cause cellular effects.
Crystalline nickel sulfide is solubilized by some cellular process to nickel ions which subsequently can
then enter the nucleus. So solubilization may represent an activation step for the carcinogenesis of
crystalline nickel Sulfides. The results suggest that the phagocytized particulate nickel compounds were

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more cytotoxic as determined by reduction of cell-plating efficiency and induced more morphological
transformations than did the particulate nickel compounds which were not phagocytized. The mechanisms
by which unphagocytized water-insoluble metal compounds such as metallic nickel and amorphous NiS
exert biological effects are unclear, but they could involve occasional particle entry by phaogcytosis;
alternatively, their effects may depend upon the slow generation of nickel ions by extracellular dissolution
[32, 35-37]. The effect of the addition of manganese dust together with Ni3S2 to cultured cells also
observed. With equal weight amounts of manganese dust and Ni3S2, the uptake was inhibited by 40 to
50%. So manganese dust inhibited Ni3S2 induction of morphological transformation and also reduced the
phagocytosis of Ni3S2 particles. Manganese dust has been shown to inhibit the incidence of Ni3S2-induced
rhabdomyosarcomas if administered at the same injection site as that for Ni3S2 [38].
The sarcoma model to study preneoplastic changes developed by Kirkpatrick et. Al [5] in which
preneoplastic lesions can be readily identified and also reproducibly induced which provides the molecular
biologist with defined stages in the development of mesenchymal malignancy, with which the multistage
tumorigenesis hypothesis can be tested, analogous to the well-known adenoma-carcinoma sequence. In
1983, Rachko and Brand used subcutaneous implantation of a copolymer of vinyl chloride acetate in two
mouse strains to induce sarcomas[39]. They described 6 cases of preneoplasia derived from the peri-
implant tissue taken at 4, 6, 9, and 16 months postimplantation. Using their mouse model, Brand and
colleagues established a hypothetical model to describe the stages of foreign body tumorigenesis[40].
Their proposed sequence involved an initial phase of proliferation with the acute foreign body
inflammatory reaction, followed by capsule fibrosis, quiescence of phagocytic activity, and, finally, direct
contact between material and clonal preneoplastic cells. There was no indication that the initial acquisition

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of neoplastic potential and the determination of specific tumor characteristics are based on direct physical
or chemical reaction between cells and the foreign body. These etiological key events occur presumably in
mesenchymal stem cells associated with the microvasculature no later than during the acute stage of
foreign body reaction and certainly long before clonal descendants of these cells are first found in contact
with the foreign body surface. In fact, there is no reason to assume that cells with neoplastic
determination may be present in normal tissue prior to the introduction of a foreign body and that the
foreign body would only create the conditions required for stepwise preneoplastic maturation.
Although the materials composing these implants are relatively biologically inert they may induce a
variety of tissue responses [41]. Animal studies analyzing the biological effects of the components of
prosthetic joints revealed carcinogenic properties of beryllium, cadmium, chromium, cobalt, iron, lead,
nickel, selenium, zinc, and titanium [2-4, 7, 42]. Some authors state that the placement of an implant may
induce osteonecrosis, which in itself is a risk factor for the development of a sarcoma [43, 44].
Furthermore, a Finnish study of 31,651 patients who received polyethylene and metal hip prosthesis
reported no associated sarcomas [45]. However, the fact that malignancies have arisen in close proximity
to metallic implants is strong evidence that there may be an important relationship. Chromosomal
aberrations have been reported in the marrow adjacent to hip arthroplasties [46]. In other anatomic sites,
such as the lung, metal foreign bodies have also been associated with the development of malignancy [47].
An animal model for the development of sarcomas in rats that have been implanted with various
biomaterials has shown that up to 67% of implant sites developed either a sarcoma or a reaction that they
termed “proliferative, probably preneoplastic”[5]. There was no correlation between the morphology of
the sarcoma and the type of biomaterial that was implanted.

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Conclusion:
However, it is very difficult to determine the cause and effect relation between the biomaterial
implant and development of cancer. This study infers that the development of sarcomas or carcinogenesis
is due to foreign body reactions occurring with the body. Different parameters other than physical
properties of the implant are responsible to induce sarcoma. An envelope is formed around the implant
showing the foreign body reactions. The cause-and-effect relation between development of cancer and
materials used in the making the implants, still remains as a mystery. Further, study discussed that
addition of Manganese to Ni3S2 compounds reduces phagocytosis & inhibit sarcoma.
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