A new implantable drug delivery device is being developed in your lab. The device prototype is a very thin strip (0.1mm × 1mm × 15mm) of polymer coated on both sides with 22 milligrams of solid drug particles. To test the drug delivery profile, you "implant the device by suspending it in a homogenous model fluid that has following:

      Properties: viscosity = 0.0018 Pa.s, density = 1.32 g , temperature = 37°C. The diffusivity of the drug is estimated to be .

1. After 15 minutes, what do you expect the concentration of the drug to be at 1 mm from the device?

2. Determine how far the drug would penetrate into the fluid in 2.2 hours.

3. Clearly explain how you would determine the flux of drug at the surface of the device 10 minutes after implantation. Provide relevant assumptions, equations, and any other information that would be required for your solution.

The four types of resolution response after implantation of a device/biomaterial are

(i) extrusion,

(ii) resorption,

(iii) integration, and

(iv) encapsulation.

What type of resolution response occurs with each of the following device/biomaterial (note: in some case, more that one type of resolution is possible): a. Splinter

b. Degradable tissue engineering scaffold

c. Titanium bone screw

d. Degradable meniscal arrow (used to repair meniscal tears)

e. Breast implant

f. Artificial heart valve leaflet

g. Catheter h. Surface scar tissue (scab)

IDE Case Study

A IDE was submitted by Hyman Parts, (HP) for knee and hip replacement devices. HP informed the FDA that they had implanted a significant number of devices prior to the approval of the IDE in the hip study. These subjects did not receive informed consent nor were they aware that they had received an investigational device. HP stated that they sold these investigational devices by physician’s prescription. Based on this information the FDA decided to conduct “for cause” inspections of HP as well as the Clinical Investigators. The inspections revealed the following:

• Failure to ensure control of the investigational device.

• Failure to document and report adverse events.

• Failure to ensure the clinical investigators obtain informed consent from subjects prior to the use of the device.

• Failure to utilize IRB approved informed consent forms.

• Failure to adhere to study protocol.

Based on the inspections, the FDA took the following action:

• Issued a Warning Letter to HP.

• Issued Notices of Initiation and Disqualification Proceed in HP and Opportunity to Explain

• Letters (NIDPOE) to the Clinical Investigators

The FDA requested that no additional patients be enrolled in the study and that the HP send a patient notification letter to those who had received the device without informed consent. HP also needed to prepare a Corrective Action Plan and audit all the data from the hip study.

HP submitted a draft Audit/Corrective Action Operating Plan, however, this CAP was inadequate due to its lack of specificity in terms of actions to be taken and documentation for corrective action already made.

HP then notified the FDA that one of their hip devices that was approved in Japan not the U.S. was imported into the U.S. and implanted in 245 patients in Boston, Massachusetts and these sales were made pursuant to the physicians’ “prescriptions” as custom devices.

HP then notified the FDA that they had found similar problems as the ones documented in their hip study in their knee study

. Answer the following questions:

What are the problems that you see in this case?

What action would you take if you were representing the FDA?

What action would you take if you were representing HP?

Assume that a culture of E. coli was grown for approximately 50 generations in 15N (provided in the medium in the ammonium ion), which is a heavy isotope of nitrogen (14N). You extract the DNA from the culture, and it has a density of 1.72 gm/cm3 (water = 1.00 gm/cm3), as determined by sedimentation velocity centrifugation. From the literature, you determine that DNA containing only the common form of nitrogen, 14N, has a density of 1.70 gm/cm3. Bacteria from the 15N culture were washed in buffer and transferred to 14N medium for one generation immediately after which the DNA was extracted and its density determined. What would be the expected density of the extracted DNA?

You then heat the DNA until it completely denatured (95°C for 15 minutes), what would you expect the density of the DNA in the denatured extract to be following sedimentation velocity centrifugation? For the purposes of this question, assume that DNA has the same density regardless of whether it is single- or double-stranded.