Classically, an implanted medical device is expected to be stable, or to interact with the body in a very controlled, limited manner. In contrast, absorbable implantable devices are designed for gradual, significant decomposition. The idea is not new. A century ago, a researcher at the University of Pennsylvania1 described a technique involving the use of ivory rather than steel as a temporary support for fractures. Steel had to be removed; ivory was absorbed as the bone grew. Some combination devices, including drug-eluting devices, are also resorbed. The field has grown, albeit slowly, and terms such as absorbable, resorbable, bioabsorbable, and biodegradable have come to be used somewhat interchangeably.
More interest
Steve Coulter, senior associate at Fallbrook Engineering in Chicago, explains that in contrast with the past 20 years, “in the past year, we have had several inquiries about bioabsorbable materials.” As recently as 2005, fewer than 50 device-related patents referred to absorbable materials (Figure 1, below). There are signs of increased interest. In 2011, the number of such patents had grown to over 300. At a recent medical device forum2, resorbable materials were a recurrent topic of discussion by presenters, conference participants, and suppliers of material.
Figure 1. A recent sharp increase in patents referencing absorbable materials has focused interest in materials and process management. Image: Foster Corp.
While many materials could be used in absorbable devices, much of the interest has centered around polymers, primarily esters. They are broadly divided into surface erosion and bulk erosion polymers.3 Bulk erosion polymers are digested hydrolytically and enzymatically. In contrast, the interior of surface erosion polymers is sufficiently hydrophobic to maintain the desired structure.
Challenges
How should absorbable materials be used? How should they be monitored and controlled? “A little is good; a lot may be dangerous,” asserts Bob Baier, executive director at Industry/University Center for Biosurfaces, University at Buffalo, The State University of New York. “Esters hydrolyze; they break down to acids. If a great deal of absorbable material is present, the acids produced by products of hydrolysis can digest the very bone that is to be repaired.”
Baier adds that “in evaluating overall performance of the device, it is critical to emphasize that in vitro studies cannot possibly replicate in vivo conditions.”4 Baier notes that in vitro, monocytes are observed to differentiate to macrophages. In contrast, in vivo, resorbable biomaterials act as “contact cytokines;” they produce a “foreign body” response. Monocytes develop into osteoclasts rather than macrophages. Baier explains that “the natural function of osteoclasts is to ‘eat’ the adjacent bone. Acid formation from hydrolysis leads to even more rapid breakdown of bone. In vitro studies alone would not convey the clinical outcome. It is important to design in vivo testing so as to both maximize the information needed for a good clinical outcome and to minimize the amount of tests performed in animals.” An ASTM/FDA workshop on the subject of in vivo and in vitro testing of absorbable materials is likely to generate additional clarification, guidance, documents, and standards.5
Biodegradable bone screws for orthopedic repair. Photo: Foster Corp.
Such standards and guidance documents are likely to encompass far more than testing in biological systems. Evaluating the performance of absorbable materials and assuring good manufacturing processes must, of necessity, involve a confluence of many areas of specialization, including chemistry, engineering, materials science, surface chemistry, taxonomy, molecular biology, biochemistry – and even critical cleaning. Multiple approaches to validation are needed, because a resorbable material is an inherently dynamic situation. Coulter cautions against attempts by manufacturers to use master files alone to qualify a device containing absorbables. It’s useless to do that, explains Coulter. “You must also actually build the device, including sterilization. You must look at the impact of sterilization; you must look at leachables, volatiles, and processing aids.”
The details
The synthesis and fabrication of device materials must be spelled out. Requiring in vitro testing without understanding the inherent variability of materials of construction is likely to provide a false sense of security. Determination of expected, achievable, and acceptable batch to batch variability is crucial because, particularly with polymers, variability among lots can be significant.
Resorbable suture for tissue fixation. Photo: Foster Corp.
Lawrence Acquarulo, CEO at Foster Corp. in Putnam, Conn., outlines a number of concerns with polymers. “We perform site inspections of our suppliers; we use analytical testing like FTIR to verify purity of the as-received polymer. We are very concerned with viscosity because that is reflective of molecular weight; molecular weight controls the degradation path. Our processing may involve additives and modification, so we again characterize the product. Then, because the material is degraded by moisture, we control drying and packaging to assure that the product does not become degraded. We use GMP and guidance documents, but the important thing is having the correct interpretation for our application.”
Defining acceptability
Qualitatively and quantitatively, enterprises using bioabsorbable materials must determine the chemical and physical attributes that are most important to success of the device. We may be setting standards for more properties, but are those the correct properties? Have we sufficiently defined the properties, both qualitatively and quantitatively, in an encompassing manner?
Maintaining the appropriate environment during manufacturing is essential, and, in the case of bioabsorbable materials, the controlled environment must include management of moisture. It is likely that airborne molecular contamination (AMC) will be of increased concern. In terms of the cleaning process, manufacturers will need to understand, define, and control critical cleaning. This means more process understanding. For example, ultrasonic cleaning may also have work-hardening attributes. Overall, given the inherent costs, regulatory requirements, and legal issues, growth of absorbable devices is likely to be favorably influenced by critical cleaning and by strategically-implemented controlled environments.
References
1. P.B. Magnuson. Holding Fractures with Absorbable Material—Ivory Plates and Screws, a New Method, JAMA. 1913;61(17):1514-1516.
2. MedDevice Forum, San Diego, Sept. 19–20, 2012.
3. Coulter, S. and R. Meyst. “Bioresorbable Materials for Medical Devices – A (Still) Emerging Field,” MD&M East, Philadelphia. May 21, 2012.
4. Baier, R.E. and A. E. Meyer.“Transactions, Biomaterials in Regenerative Medicine: The Advent of Combination Products,” Society for Biomaterials, Philadelphia. Oct. 16-18, 2004.
5. ASTM-FDA Workshop on Absorbable Medical Devices: “Lessons Learned from Correlations of Bench Testing and Clinical Performance,” scheduled Nov. 28, 2012, Silver Springs, Md.
Barbara Kanegsberg and Ed Kanegsberg (the Cleaning Lady and the Rocket Scientist), are independent consultants in critical and precision cleaning, surface preparation, and contamination control. They are the editors of The Handbook for Critical Cleaning, Second Ed., CRC Press. Contact: info@bfksolutions.com
This article appeared in the January 2013 issue of Controlled Environments.
