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BIOCOMPATIBILITY OF DENTAL AGENTS: A SERIES OF VI FACTOIDS
PART-I: DENTAL BIOCOMPATIBILITY – A HISTORICAL PERSPECTIVE PART-II: WHICH CAME FIRST? – IN VITRO OR IN VIVO BIOCOMPATIBILITY ANALYSIS PART-III: IN VIVO BIOCOMPATIBILITY ANALYSIS PART-IV: IN VITRO BIOCOMPATIBILITY ANALYSIS PART-V: WHICH BIOCOMPATIBILITY TEST IS MOST IMPORTANT ? PART-VI: A BACTERIOMETIC SEAL IS THE REAL DEAL
PART-V: WHICH BIOCOMPATIBILITY TEST IS MOST IMPORTANT ? Now that you’ve read FACTOIDS #I thru #IV, you may think that the answer is simple. But, if you’ve followed the chronological comparison of in vitro versus in vivo testing, you may realize that no simple answer has yet presented itself—a proper scientific answer for biocompatibility testing is simply not easily reported by a simple yes or no response. A number of in vivo animal & human usage studies (Kakahashi 1968, Brännström 1968, Bergenholtz 1978, Cox et al 1982,1984,1987, 1992) each demonstrated— beyond a doubt—that certain bacteria & their toxins can easily infiltrate into enamel lamella & restorative channels & rapidly penetrate down to the EDJ. From this point, the bacteria & toxins can easily spread along the EDJ interface, where they penetrate into & through the dentine tubules. From this point, they may initiate a low-grade irritation response to the odontoblast cells, whereby these cells may respond by depositing a thin layer of reactionary dentine. However, if the insult persists as a chronic effect, the primary odontoblasts may die—whereby certain undifferentiated cells of the pulp stroma may respond to form new odontoblastoid cells that then deposit a new layer of reparative dentine directly adjacent to the secondary dentine. However, if the bacterial insult is persistent, it may easily cause pulp inflammation & regional pulp necrosis (Van Hassell). Such dynamic factors of microleakage & bacteria are extremely difficult to control & even more so, they are difficult to simulate within in vitro bench top tests—the ISO committee is still waiting for such well controlled & in vitro tests to be repeated by ―certified research laboratories‖. Lets now consider some additional research publications to allow you to make the decision for yourself: 1) In vivo research data in dog teeth were first published in the 1936 Brit Dent Jour by Dr. Manley of Birmingham, England. He reported that the 1
Charles F. Cox, DMD, PhD Director, Research & Developm ent Phoenix Dental Inc. Fenton, Michigan H3PO4 component of silicate cement was the toxic factor to vital canine dental pulps. 2) It was 2-decades later that in vitro tissue culture tests were first published on silver-tin dental amalgam by Dr. Kawahara & colleagues from Osaka University in 1955. 3) In 1968, Dr. Brännström demonstrated in controlled human studies, that silicate cement was non-toxic to vital pulp cells—bacteria were the causative agents for inflammation through microleakage along the restorative interface. 4) In 1977—after years of personal efforts with colleagues—Dr. William Cotton organized the 1st IADR PBG Symposium in Copenhagen, which strongly advocated for the creation of harmonized biocompatibility standards—he was 1
biocompatibility testing. 5) After years of meetings the ISO committee published their 1st Book of Harmonized Biocompatibility testing standards in 1999. 6) In 2009, the ISO committee published revised testing standards that serve as suggested standards, which may be chosen for evaluation by the ―developing group‖ for biocompatibility validation. ARE TOXIC AGENTS PRESENT IN TODAYS DENTAL RESTORATIVE AGENTS? Today, the fact remains. There are certain agents that are minor & major components of restorative dental systems that range from irritational, mutagenic, carcinogenic & toxic to vital human tissues. For instance, research publications report that the toxic chemistry of formalin (OSHA Tech guide 2006), aldehydes (O’Brien et al. 2005), glutaraldehyde (Sano et al. 2005), formocresol (Block 2010), phenol (Conning 1970), hydroxy ethyl methacrylates (HEMA), (Mathias et al. 2006), bis-phenyl-A (BPA) (FDA 2010), & ketones (Breeze 1984); are known irritants that range from mild-totoxic within the International Medical & Dental profession (Autian 1972, 1974). Isn’t, it somewhat curious that due to that rather infamous grandfather clause that still lingers in the dental industry since the 1950’s era, that the dental profession is still able to continue to employ many of these irritational & toxic agents as a minor component of ―newly developed‖ dental products. And, in addition to the various chemicals, certain metals (nickel, cadmium, zinc, copper) that are commonly found in many cosmetics also are known to cause initial sensitizing reactions to humans. In 1999, Yamanaka reported more intense irritational reactions to human dentine & vital pulp tissues! Again, even with the current continued ISO acceptance of these grandfathered, yet known irritating dental products, many worldwide dental agencies continue to permit the clinical use of these agents—even though some are classified as 2
Charles F. Cox, DMD, PhD Director, Research & Developm ent Phoenix Dental Inc. Fenton, Michigan germicidal (glutaraldehyde, Sano 2005). In addition, studies have documented that high concentrations of alcohols, aldehydes & acetone may rapidly dehydrate & denature vital cells, collagen fibers & other proteins especially when improperly placed by the clinician. Today, there still remains on the commercial dental marketplace, endodontic & pædiatric restorative agents that contain lead, formaldehyde & glutaraldehyde, which are known irritants & are potentially toxic, not only to the patient but more importantly to all office personnel who work in the clinic environment on a daily basis. WE NOW POSE AN APPARENT QUESTION: CAN IN VITRO RESEARCHERS WHO OFTEN REPRESENT VARIOUS COMPANIES INTERESTS—HAVE IT BOTH WAYS ? SHOULD THEY BE ABLE TO CHOOSE THEIR OWN FAVORITE TEST ? As we’ve reached this point, we can now understand that the ISO–10993-5-2009 committee in vitro tests recommendations are only suggestions. They only serve as the first biocompatibility ―test gate‖, especially when a new dental restorative product or device is developed for use in the oral cavity. Once the developing group has passed their own personally chosen in vitro biocompatibility test—they can then move to the next in vivo biocompatibility-testing gate—again an animal system of their choice. Animal tests involve the surgical placement of the agent into the connective tissues of the tissues of rats or rabbits for certain periods of time along with positive & negative control agents such as ZnOE, silicate or ZnPh cements for evaluation of their histological responses. Still, we are now confronted by the fact that initial in vitro tests are not completely reliable to define a possible false positive or a false-negative test outcome. For instance, if you challenge those same in vitro research laboratories who adhere to their ―own suggested‖ in vitro test & then ask them if they have routinely employed a known toxic control agent e.g. glutaraldehyde in their system, they often respond that they do not concern themselves with such a control test—especially since those agent (glutaraldehyde, phenol, acetone, HEMA) have long been grandfathered as legally acceptable restorative dental agents. If you ask those same in vitro researchers who sit on today’s Pulp Biology committees that discuss & define testing models & then challenge them with the critical issue of bacterial infection use in their own in vitro system, they quickly respond they ―are only required to follow the suggested BS EN
Charles F. Cox, DMD, PhD Director, Research & Developm ent Phoenix Dental Inc. Fenton, Michigan ISO–10993-5 standards‖—some of these same people sit on committees to define standards. Isn’t it ironic that these researchers can continue to have it both ways? IS THERE AN IDEAL IN VITRO BIOCOMPATIBILITY TEST ALTERNATIVE TO USING LIVE ANIMALS? Well, I’ve presented—what I consider to be important concerns about biocompatibility testing. So let me present a possible solution to what I see as a testing conundrum. As we think about an ideal ISO in vitro biocompatibility test, the research person/group needs to demonstrate a proficiency of understanding of enamel, dentine, cementum & pulp substrates of the tooth. More importantly, they need to consider the dynamic dimension of the oral bacterial biofilm & their toxins, which easily penetrate from the tooth surface & into the vital pulp. Today, there appears to be greater research focus on mechanical bond strength testing of new restorative agents when submitted for the intended clinical use. Nakabayashi (1992, 1997) determined that the general breaking (cohesive) capacity of ―normal‖ human dentine is approximately 21-megapascals (MPa), whereas the general breaking capacity of normal human enamel is approximately 52-MPa (Shimada 1992). In addition, (Craig & Peyton 1956) verified that mineralized substrates have regional morphological extremes of density—demonstrated by their indentation tests. Ten Cate’s text (2002) has eloquently demonstrated that enamel, dentine & pulp tissues are variable substrates in their developmental, aging, physiological & morphological dimensions—today’s researchers should be responsible to be knowledgeable about all tooth substrates before they begin their research studies. WHERE MIGHT THE RESEARCH ISSUES NOW GO ? As one searches the www to identify published in vivo & in vitro studies of new dental materials—it is obvious that in vitro publications far exceed all other tests. Personal experience reflects that a well defined & controlled ISO in vivo usage primate study takes several years from inception to completion as well as requiring a strong funding base. In contrast, an in vitro study is much less time consuming & much less expensive. As future ISO committees move towards harmonization of biocompatibility testing, they should consider to move beyond bond strength testing & to explore the development of tests that will to merge the more important biological issue of a bacteriometic restorative seal—from both a biological as well as mechanical ―sealed‖ perspective. ESSENTIALLY-THE SEAL IS THE DEAL !
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