**4.2 Implant material**

*Animal Models in Medicine and Biology*

severity of lesions and lesion locations [50].

changes, and treatment options [59].

testing duration of 1 month [50].

used when testing in vitro.

**4.1 Implant design**

models must be clearly outlined in the future.

**4. Orthopedic in vivo implant research**

Disadvantages of this method are comparable to those in dogs, including variable

**Sheep**: This large animal model is also used to study naturally occurring OA (primary OA) with similar advantages compared to mice. For example, sheep have been successfully used to study early changes of cartilage degeneration, meniscus

**Dogs**: Dogs have been shown to be natural models to study therapeutic interventions: cranial cruciate ligament transection has been demonstrated to induce naturally occurring OA and serves as an interesting model to evaluate structural and functional benefits of treatment strategies that will give a better prediction for clinics [60]. Moreover, established canine OA models usually undergo ACL transection or partial medial meniscectomy. The major disadvantage is that dogs need large runs or plenty of exercise, otherwise resulting in mild, variable lesions. Additionally, surgical procedures must be carefully performed to avoid traumatic lesions. However, if surgical procedures are performed appropriately, OA lesions are consistent thereby allowing a relatively small number of animals per group (12–15 animals per treatment group). Another major advantage is a short screening and

Currently, there is no "gold-standardized OA model," and the most appropriate animal has to be chosen individually, depending on the research question. Moreover, extensive work is needed and advantages and disadvantages of the

In vivo studies are essential to investigate novel implant materials and cannot be fully covered by in vitro testing. Preliminary safety tests with new implant materials using in vitro models give some information on acute toxicity and cytocompatibility. Nevertheless, some studies use the term of biocompatibility when testing implant material in vitro. However, biocompatibility tests need living organisms such as animals and humans; therefore, cytocompatibility needs to be correctly

In order to test implant safety, adverse tissue reactions as well as corrosion and wear resistance need to be investigated to guarantee its long-term application in clinics. Hence, in vitro and in vivo tests are essential to evaluate new implant materials regarding cytocompatibility, biocompatibility, and mechanical stability. The development of bioresorbable metal implants is one of the major goals in orthopedic and trauma surgery. Apparently, the advantages are the unnecessity to remove the implant due to material resorption and the associated avoiding of narcosis, mandatory for the second removal surgery. Since there is an increasing number of patients with metal sensitivity to permanent implants such as titanium (Ti), and long-term complications associated with currently available metal implants cannot be foreseen to date, there is a high demand to develop novel biocompatible and bioresorbable implants with good mechanical properties to stabilize bone fractures.

To test bioresorbable orthopedic implants in animal models, the implant design and dimension is of utmost importance. Moreover, the implant number and size directly influences the number and species of animals used to test a research hypothesis. The most common implant designs used in small animal models such as mice and rats are cylindrical-shaped pins [61], whereas screws are the commonly

**32**

Conventional alloys currently used in the treatment of fractures include Ti and stainless steel, which are more rigid with desirable advantages including biocompatibility, good resistance to material corrosion, and most importantly, these alloys do not show severe toxic effects on various immune cells and can bear weight soon

**Figure 2.** *Screws (left image) and cylindrical pins (right image) are often used in orthopedic and trauma research.*

after implantation. However, Ti and stainless steel implants have a higher e-modulus (Ti: e-modulus 100–124 GPa; steel: e-modulus 200 GPa) than bone (e-modulus 6–24 GPa). Moreover, permanent implants can cause "stress-shielding" leading to loss of bone under the plate or between bone and implant, thereby increasing the risk of refractures, designated as peri-prosthetic or peri-implant fractures [29, 31]. Moreover, the FDA has already described possible metallic sensitivity or allergic reactions linked to Ti-based alloys, such as Ti-6Al-4V [66], and studies using vanadium have also shown adverse effects [67]. However, resorbable materials exhibit functional properties by supporting bone formation and in-growth on a molecular level. To date there are only few resorbable materials used in cardiac, dental and neuro-surgery and some not weight-bearing application in orthopedic surgery, but adequate materials for orthopedic and trauma surgeries need good mechanical properties. Therefore, the main focus in biomaterial research is to evolve materials and tools to develop the optimal implant for the respective bone condition under the necessity to bear weight.
