BIODEGRADABLE IMPLANTS IN ORTHOPAEDICS PPT

implants

1. BIODEGRADABLE IMPLANTS JOURNAL CLUB BY Dr.RAM GOPAL MODERATOR – DR.V.VAMSI KRISHNA

2. INTRODUCTION A basic bio absorbable implant degrades in a biologic environment. Their breakdown products are incorporated into normal cellular physiologic and biochemical processes. These implants and degraded material are well tolerated by the host with no immunogenic or mutagenic tendency. For fracture fixation, these materials must have adequate strength and should not degrade too rapidly, so that fixation is not lost before adequate healing can occur. Ideally these implants should have mechanical characteristics equal to those of standard stainless steel implants

3. It would degrade with the healing process so that load is gradually transferred to the healing tissue. But currently available polymers do not have mechanical characteristics equal to those of metal implants.

4. Variety of implants made from different materials is commercially available. Their composition and the mode of reinforcement vary according to the operation for which they are intended. Polyglycolic acid (PGA) and Poly-L-lactic acid (PLLA) implants have been widely used, including pins, rods, screws and plates are available. Many other implants such as membranes, arthroscopic and spine surgery implants are currently in use.

5. PATHOPHYSIOLOGY Implants modify the risk of infection by bacterial adhesion, tissue integration, and immunomodulation. Bacterial adhesion to implant leads to interaction between bacteria and implant. There are numerous implant-dependent factors affecting the bacterial adherence to the surface . These include chemical composition, surface roughness and configuration, and possible surface coating. Bacterial colony accumulates over implant which secretes biofilm slim layer ( extracelluar mucopolysaccharide ), interfere with phagocytoses and antibody function of host and promotes bacterial aggregation.

6. This also provides a physiochemical barrier against both systemic and implant-released antibiotic therapy, making infections difficult to treat without implant removal. In addition to bacterial and implant properties, the modified immune response of the host plays a key role in the etiological process of foreign-body infection.

7. All implanted devices cause a foreignbody reaction. T he severity of which is dependent on numerous factors. T issue damage caused by trauma and surgery, material of the implant, and size and chemical composition of the debris particles present. The most common bacteria is coagulase negative staphylococcus .

8. To avoid second surgical intervention, the degradation of these implant materials is important. Degradation should be achieved at a rate such that partially degraded implant should maintain their mechanical integrity until the newly formed tissues have sufficient strength to replace them. Material degradation occurs by several mechanisms, including hydrolysis and enzymatic degradation Most synthetic polymers are degraded by hydrolysis of their ester linkages. On the other hand, many natural materials and some polymers, including degradable peptide sequences, are degraded by enzymatic mechanisms to oligomers and monomers.

9. The final products are excreted or used by the body. PGA and Poly dioxanone (PDS) degradation products can also be excreted by the kidneys. It is also known that PGA degradation is partially performed by enzymes such as esterase. Enzymes also seem to take part in Polylactic acid (PLA) degradation. Polymer breakage produces products that lower the regional pH and thus accelerate the procedure. The final degradation of polymer debris is done by macrophages and giant cells followed by mild local tissue reaction around absorbable implants.

10. This leads to production of a thin macrophage layer with incidentally multinucleated giant cells surrounded by a mild connective tissue capsule. ] That is responsible for many adverse effects.

11. Biodegradable materials should be biocompatible. Not only it avoids eliciting inflammatory and immunogenic responses, but also degraded materials and related chemicals should be biocompatible in terms of both the local and the systemic response. The biocompatibility of a polymer depends on both its chemical structure and the processing method that produces it. During a polymerization process, an initiator, a monomer, and sometimes a catalyst are needed. These materials often remain in preformed implants even after purification are also a particular concern for in situ forming implants. Toxicity and concentration of residual monomers or initiators should be considered when assessing biocompatibility.

12. Removal of these potentially toxic components is usually effected by prolonged rinsing in aqueous solution. Biocompatibility of the remaining material is confirmed in vitro by cytotoxicity assays. In vivo observation of the inflammatory response after implantation in animal models is also an important step before clinical application can be considered.. Under in vitro conditions, PGA is an immunologically inert substance, provoking only slight lymphocyte activation. . Clinically significant foreign-body reactions are far more rarely seen with PLA than with PGA.

13. In short-term studies, the biocompatibility has been acceptable with no clinical manifestations of foreign-body reactions. There are no in vitro studies investigating the cytological immune response of PLA.

14. As with other biomedical implants it would be possible to sterilize biodegradable implants without affecting their chemical or physical properties. A nd to produce and pack them on a large scale for practical and economic uses. Factors such as viscosity, curing time, and implant shape should also be optimized for injectable scaffolds to facilitate their use during complex surgical procedures .

15. These implants can also be used in fractures fixation of the glenoid fossa , radial styloid , patella and acetabulum; osteochondral fractures in the knee, tibial plateau, phalanx, calcaneus and talus; hallux valgus surgery, ankle surgery,

16. radial head fixation , distal radial fractures , hand fractures , olecranon fractures, distal femoral epiphyseal fractures, meniscal injury, anterior cruciate ligament and shoulder lesions repair

17. In addition to providing physical support, they have been employed to introduce bioactive molecules at the defect site. In one strategy, scaffolds can be used to control the release of bioactive molecules, thus accelerating the healing process. In other cases, the effectiveness of less stable drugs may be extended by encapsulating them inside a matrix.

18. Biodegradable implants provide the advantages of gradual load transfer to the healing tissue, reduced need for implant removal, and radiolucency, which facilitates postoperative radiographic evaluation and no hinderance in second surgey . They can be engineered to alter their degradation characteristics and material properties. These biodegradable implants are safe as they are made of biocompatible material hence there is no risk of metal allergic reactions as compared to metallic implants.

19. These implants degrade, they lose strength and this increases pressure over the bone, strengthening it and therefore preventing bone resorption . Resorption of these implants also makes revision surgery less complicated, as there are no permanent implants inside. So there is no need of another surgery for implant removal. Hence there is reduced trauma to soft tissue thereby decreasing the cost of surgery and reducing the risk of cross infection. As compared to metallic implants there is no longterm implant palpability hence patient compliance is much better. There is no implant temperature sensitivity so short wave diathermy and micro wave diathermy can be used after a period of time thus complying increased patient satisfaction.

20. Due to characteristic nature of these biodegradable implants there is no growth disturbances in children after surgery as biodegradable screws or rods can also be used for treating epiphyseal fractures. It facilitates fracture healing by allowing micromovements at fracture site. It can be used to control the release of bioactive molecules to accelerate the healing process. The fixation does not disturb the anatomy as depicted on radiographs as there is reduced radiographic scatter or obstruction and is compatible with magnetic resonance imaging if further evaluation of the affected joint post operatively is necessary. Bioabsorbable suture anchors are becoming alternative to metal staples and screws.

21. In this, sutures don’t have to pass through bone tunnels. Pullout strengths for bioabsorbable suture anchors are comparable to those of their metallic counterparts. Bioabsorbable suture anchor fixation has several advantages. The anchor undergoes reabsorption so no need for removal of implant as compared to metallic implants which need to removed because of osteopenia, corrosion and irritation of adjacent tissues. Improperly placed anchors may simply be drilled out rather than unscrewed or pushed through due to which stress is gradually transferred to the healing soft tissue as the anchor degrades.

22. These are more expensive, have less strength than metals. Complications with the use of these materials include tissue reactions including mild fluid accumulation, painful erythematous fluctuating papule over the implant track, the papule, if left untreated, bursts within a few days and revealed a sinus draining liquid remnants of the implant leading sterile sinus tract formation, osteolysis around the implants, synovitis when implanted intra articularly , and hypertrophic fibrous encapsulation.

23. Adverse effects such as migration of implant, growth disturbance, rigidity, radio-opacity, infection, effects on cellular level and implant removal operations, often accompany the use of these materials. Similarly improper insertion of the anchor too deep in the bone can cause suture failure. l

24. Superficial insertion of the anchor can lead to cartilage wear on the opposing articular surface. There may be pullout from bone and become an intra-articular loose body. Due to its radiolucent nature, diagnosis can be difficult to make postoperatively in a persistently painful joint.

25. The use of PGA is now limited, since materials and copolymers with better degradation properties. As per Bostman et al and Tuompo et al, a total of 2037 and 1879 patients respectively were included in study, adverse reaction ranged from 2.8% to 60%in a series of paediatric fractures and wrist fractures respectively. Tissue reactions included fluid accumulation, sinus formation and osteolysis that was apparent 2 to 17 months postoperatively. PLLA has a low degradation rate because of this, adverse reaction tend to appear late, even 4-5 years postoperatively. This renders many studies weak regarding the presentation of true adverse reaction rate in procedures where PLLA implants have been used, since the follow-up of these studies is shorter than the complete absorption time of the material.

26. . A review of the first clinical trials where PLLA implants were used presents 14 series that were performed from 1990 to 1996. A wide variety of reaction rates was reported, from no adverse reactions to swelling in 47% of the patients. Advances in material science, such as self-reinforcement technique and elimination of factors that were considered responsible for reaction . Enantiomeric isomers of PLA were mixed to develop a material less crystallic and more hydrophilic than PLLA, in order to accelerate the degradation process and avoid late tissue reactions. Latjai et al used P(L/D)LA-PGA copolymer screws in ACL reconstruction procedures. No material-related tissue reactions were reported in the mean follow-up time of 5.2 years in the 28 patients that were included in the study.

27. Clearly, future work in the area of orthopaedic biomaterials should be focused on the reduction of the foreign-body response. Reducing the crystallinity of the polymer or controlling the pH in the degrading implants may help reduce the incidence of the foreign-body response.

28. INTRODUCTION Bone is one of the most important components of the human body, and functions in a supportive and protective role. Damage to bone may result from external impact, or from diseases such as tuberculosis or tumor invasion. It is estimated that more than 3 million individuals in China develop bone complications such as fractures, or diseases such as tuberculosis or tumors annually . Non-degradable metal implants have good mechanical properties and can achieve early stable fxation , so have often been used for treatment. However, the elastic modulus of the implants is far greater than that of human bone , which often leads to stress shielding and subsequent osteoporosis, osteolysis and secondary fractures .

29. The need for a second fracture surgery to remove the implants is complex and carries the risk of surgical complications, increased physical pain and fnancial burden for patients . To avoid these issues there has been a surge in availability of degradable orthopedic implants over the past two decades. These implants have good biocompatibility, bone conduction and biodegradability, and have gradually gained acceptance by most clinicians and patients. To date, biodegradable implant materials used domestically and internationally are mainly polymers and magnesium alloys.

30. Polymer implants have good mechanical features, physical properties and biodegradability, as well as having an elastic modulus similar to human bone. Therefore, they are often used to treat human fractures. P olymer implants can efectively prevent stress shielding and the need for a second operation to remove the implant. Common orthopedic polymer implants used clinically include polylactide (PLA), poly-l/dl- lactide (PLDLA) and poly-l-lactic

31. PLA has been used as an internal fixator for more than 30 years, and can effectively cure cancellous bone fractures. PLA was the first degradable implant to be used as bone and cartilage tissue engineering scaffold materials . . Zeng et  al.compared the ability of different materials to fix maxillofacial fractures after initial curative effects. Postoperatively, PLA micro plate treatment was better than steel wire or titanium plates .

32. Treatment of mandibular fractures with PLDLA and poly (dl- lactide ) (PDLLA) screws and plates, can promote bone healing based on biomechanical principles. However, PDLLA has high crystallinity , and slow degradation and absorption rates. Thus, it is unlikely that it would assist with fracture healing, and it may increase the incidence of infammatory reactions. PLDLA due to the addition of amorphous PLDLA in PLLA, lessens the crystallinity of PDLLA, and increases molecular chain mobility. This can result in greater hydrophilicity , leading to accelerated degradation

33. . Compared to PDLLA, PLDLA has a higher mechanical strength, which improves fracture fxation safety . When PLDLA implants were used to treat mandibular fractures, PLDLA screws provided the same fixation strength as titanium screws and patients recovered well . In addition, only 16 of 281 patients with facial fractures treated with PLDLA screws had complications, supporting satisfactory treatment overall . Tiihonen et al. attempted to use PLDLA implants to treat patients with soft tissue and bone defects. In these patients, PLDLA implants relieved pain but did not enable them to return to their preoperative state. Therefore, patients with soft tissue and bone defects should not be treated with PLDLA implants.

34. In 1966, PLLA sutures were frst used as an implant in animals and were found to be non-toxic and to degrade gradually . Eppley et  al.retrospectively analyzed the clinical curative efects of craniofacial reconstruction with poly-l-lactic- polyglycolic implants. The results showed that postoperative implants can stabilize the affected area, while having low propensity for foreign body reactions and good patient recovery . In anterior cruciate ligament (ACL) injury there is a change in metalloproteinase (MMPs) secretion by cartilage tissue, synovial membrane and the intra-articular ligament that increases matrix metalloproteinase-2 in synovial fuid , thus hindering self-healing of the ligament [20]. If not treated in time, it may lead to premature degeneration of the knee .

35. Animal experiments showed that use of PLLA/hydroxyapatite (HA)/αFe2O3 and PLLA–PEG/HA for ACL reconstruction can meet biomechanical requirements . Arama et al. used PLLA–HA screws and titanium screws for ACL reconstruction, and observed no statistical diferences in their mechanical properties. However, patients treated with PLLA–HA screws were less likely to experience surgical complications, and did not have bone tunnel enlargement. Robinson et al further proved that PLLA–HA screws for ACL reconstruction can reduce the probability of bone tunnel enlargement. The weakest part of the ACL reconstruction is the tibia fxation of grafts.

36. Use of PLLA–HA screws for grafting was associated with reduced implant degradation postoperatively. They were also associated with good mobilization recovery for the patient . The ankle is composed of the talus, and the lower ends of the tibia and fbula , and is commonly injured orthopedically. Approximately 187 of every 100,000 individuals experience a fractured ankle every year . Rangdal et  al.followed 16 patients whose ankle fractures were treated using PLLA screws.

37. One patient developed localized pain and swelling at 14 weeks after surgery, but responded well to antimicrobial treatment. The remaining patients recovered favorably. It has also been reported that use of PLLA screws to repair meniscus injuries can efectively reduce the risk of neurovascular damage . Anterior cervical decompression with PLLA screw fxation for bone grafting can successfully treat cervical spondylosis . The screws were absorbed as predicted, grafts fused well with adjacent vertebrae, and only a few complications ensued [29].

38. Wendelstein et  al.conducted a three-year follow-up investigation of 34 patients with lesser toe deformities treated with PLLA. Of these patients, 84.6% healed well following surgery, while three had misaligned toes and two had recurrent deformity .

39. Use of a degradable poly (l-lactic acid)/poly (glycolic acid) screw to treat patients with osteochondritis dissecans was associated with adequate stability to area postoperatively without development of infammatory reactions like recurrent effusion, warmth or erythema during screw degradation . Park et al used poly (lactic-co-glycolic acid) screws and plates to treat rabbit mandibles, and reported that all fractured sites had new bone formation without infammation at 8 and 10 weeks postoperatively. Wang et al. retrospectively analyzed the clinical efficacy and complication rate of degradable INION [synthesized from PLLA, PLDLA, polyglycolic acid (PGA) and trimethylene carbonate (TMC)] screws and metal screws, which were all used to treat elderly patients with tibial plateau fractures complicated by osteoporosis.

40. The observation group had biodegradable screw fxation plus external fixation treatment, while the control group was treated with metal cancellous bone screw fixation and external fixation . Degradable screws not only promoted fracture healing and reduced pain postoperatively, but also shortened the time for fracture healing and for disappearance of the fracture. However, it is essential to prevent infection during fracture treatment .

41. A principle of magnesium alloy as an orthopedic implant is that magnesium is an essential element for the human body. The total body content of magnesium is 21–25 g, with 53% contained in bones, 27% in muscle, 19% in soft tissue, 0.5% in erythrocytes and 0.3% in serum. Further advantages of magnesium alloy include the ability of magnesium to promote new bone formation and bone metabolism. It also has an elastic modulus that is close to that of human bone , so it avoids the efects of stress shielding.

42. Magnesium alloy has favorable properties like biocompatibility, osteoconductivity and biodegradability, which avoids secondary operational implant removal. Magnesium is also abundant in nature. Collectively, these features mean that it is often used to treat fractures. Commonly used magnesium alloys include high-purity magnesium alloy, MgCa0.8 alloy, MgYREZr alloy and AZ series alloy.

43. High-purity magnesium avoids second phase and microgalvanic corrosion and is, therefore, nontoxic. It also has a low degradation rate. Various tests (impregnation, cytotoxicity and biological activity) showed that high-purity magnesium screws possess uniform corrosion behavior. This can improve cell activity and the genes that are related to osteogenic diferentiation such as alkaline phosphatase, osteopontin (OPN), human bone marrow mesenchymal stem cells and RUNX2.

44. All of these genes contribute to mRNA expression . Animal experiments showed that high-purity magnesium screws had good osseointegration properties, which increased bone mass and density. Thus, in addition to not compromising fracture site healing, it also promoted new bone formation . By increasing anti-bending bone performance, the bone can nearly recover to the pre-fracture state . High purity magnesium can also stimulate expression of bone morphogenetic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF) to promote reconstruction of the ACL .

45. In addition, use of vascularized bone grafts with high-purity magnesium screws after fixation can significantly improve hip joint function in osteonecrosis patients . Implanting MgCa0.8 screws into rabbit tibia was well tolerated and had good biocompatibility postoperatively. However, it degraded fast, which potentially contributed to its lack of mechanical properties (Fig. 6) [40]. Thomann et al. [41] implanted MgCa0.8 implants coated with MgF2 into the tibia bone marrow cavity of New Zealand white rabbits.

46. The implants were well tolerated in vivo and had slower degradation postoperatively. Compared with uncoated implants, coated implants were stronger at 6 months after surgery. Adam et al. [42] further proved that use of MgCa0.8 implants was non-toxic to animal

47. Due to presence of the element, rare earth (RE), MgYREZr has a high yield, tensile strength and elongation along with other favorable mechanical properties. RE also stabilizes the corrosion layer. Additionally, reasonable heat treatment of MgYREZr alloy can reduce its degradation rate . In 2013, Syntellix Company used the MgYREZr screw to treat hallux valgus, with good therapeutic effect. Indeed, MgYREZr alloy was the world’s frst certifed biodegradable magnesium alloy bone implant product, and became available commercially in Europe . Diekmann et al implanted MgYREZr alloy screws and titanium screws into the left tibia of rabbits to experiment with ACL reconstruction.

48. The results of micro-computer tomography (µCT) scans showed that obvious bubbles appeared 4 weeks after implantation, but these decreased in number by 24 weeks. All magnesium screws had bonded well with tendons at 24 weeks postoperatively, and had good synostosis ability . Histological evaluation showed that neither infammation nor tendon necrosis occurred. Further, blood concentration of Y and Zr were both within the normal range.

49. Some patients who had acute scaphoid fractures treated with MgYREZr compression screws showed severe osteolysis and cyst phenomenon after surgery. None of the patients’ fracture sites were fxated at 6 months postoperatively. Therefore, such patients should not be treated with MgYREZr compression screws .

50. Witte et al. [47] conducted in vitro and in vivo experiments using two magnesium alloy implants. This group found that the implant corrosion rate in vivo was four orders of magnitude less than observed in vitro. Thus, this study showed that the conclusions drawn from in vitro corrosion tests of magnesium alloys cannot be used to predict the in vivo corrosion rate . Three months after removal of magnesium alloy screws that had been diferences between groups (Table 10). Tensile experiments showed that anti-pull-out and tensile strengths of magnesium alloy intramedullary nail were better than PLLA intramedullary nail (Table 11). The animal experiments showed that use of fuoride to coat the magnesium alloy screw not only enhanced the biocompatibility and corrosion resistance of the screw, but also stimulated new bone formation (Fig. 8) [50].

51. Yan et al used the three-point bending experiment and further proved that AZ31B magnesium alloy implants containing fuoride on the surface, had mechanical properties that met bone implantation requirements in terms of the degradation process. One study reported improved biocompatibility when magnesium alloy (AZ31) porous scafolds with MgF2 surface-coating were used to repair the New Zealand white rabbit femoral condylar bone defect, compared with a magnesium alloy stent without surface coating. Additionally, surface-coated scafolds induced more bone formation in vivo .

52. Biodegradable implants have good biocompatibility, osteoconductivity and biodegradability in their application for fracture treatment. However complications may occur in some patients with these implants, as summarized in Table 12. The research showed that composites should not only function as a delivery vehicle but also provide a proper framework to achieve appropriate bone formation .

53. Degradable implants can effectively avoid stress shielding, and have good biocompatibility, osteoconductivity and biodegradable properties. They also enable avoidance of a second surgical procedure to remove the implant. However, some shortcomings exist in the clinical application of these implants. A small number of patients treated with biodegradable screws may develop bone surface infections , bone tunnel enlargement , cysts , screw movement , a rapid degradation rate or other complications. Commonly used magnesium alloy and polymer implants also have these problems

54. . One survey found that patients who smoked tobacco and those with diabetes or immunodefciency had a longer bone healing time. Too fast a degradation of the implant will compromise its mechanical properties, resulting in failure of the surgical intervention. Use of PLLA screws to conduct ACL reconstruction is advantageous compared with surgical steel or titanium screws [11, 14]. However, some patients will develop cyst phenomenon, which may result from a foreign body reaction caused by screw damage [18, 26], tibial tunnel caused by synovial joint fuid leakage [57], failure of the implant to match the diameter of the bone tunnel, placement of the implant in the eccentric position of the bone tunnel [58] or uneven torsional force on the screw [59].

55. In addition, ACL repair and the regenerative process are not independent. In both of these processes, all tissues within the joint cavity play an important role. This is especially so early in the time course of ACL injury, where regulation of the intra-articular environment is of great importance for the ligament’s repair.

56. Use of magnesium alloy implants for fracture treatment also has some shortcomings. Too rapid a degradation of the magnesium alloy implant leads to insufcient mechanical properties and poor bone healing around the fracture [61]. During implant degradation a considerable quantity of degradation products attach to the fracture and slow healing. Further, the corrosion resistance of magnesium alloy is poor, with fast corrosion producing a large amount of harmful hydrogen. Additionally, if the magnesium ion content in the body exceeds normal physiological levels, it may lead to respiratory diseases, muscle paralysis, hypotension and other symptoms of hypomagnesaemia .

57. . The reactive pathways for magnesium alloy implants in the body are shown as follows: Excessive corrosion of magnesium alloy limits its clinical application. Argo et al. found that adding Sr to the Mg–Al alloy reduces its corrosion rate. Addition of Sr to Mg–Zn– Ca screws can improve mechanical properties, and enhance and regulate corrosion resistance . Use of Sr as an orthopedic implant element has advantages. Sr is a trace element necessary for the human body, with 99% existing in bone . Sr can stimulate bone growth, increase bone mass and reduce the incidence of fractures .

58. These advantages have prompted us to focus our research on the relationship of Sr with mechanical and corrosion properties, and biocompatibility with magnesium alloys. In addition, coating the screw surface with Sr can efectively reduce the degradation rate . In addition to the clinical and biochemical applications mentioned previously, the numerical simulation method represented by fnite element has been used widely to predict the behavior of biodegradable vascular stents .

59. For the degradable screws and plates mentioned in this article, the numerical simulation method can be used to predict the control of factors such as degradation rate, boundary load and boundary constraints. This can optimize the structural design of the screw, and the clinical and surgical plan. Therefore, with efective promotion of computer hardware and calculation methods, numerical simulation will be widely applied to the study of biodegradable implants in orthopedic fractures.

60. The use of magnesium alloy or polymer implants to treat fractures results in good therapeutic effect. However, degradable implants have some drawbacks. Their degradation rate is too fast, which can lead to rapid loss of initial strength. It remains unclear how the degradation rate can be controlled to align with the growth rate of bone.

61. Therefore, future research needs to focus on how to slow the degradation rate, as well as identifying strategies to enhance abrasion and corrosion resistance. Additional investigations should be undertaken to develop other non-toxic, and degradable implants containing multiple nutrients. As science progresses, further improvement to the mechanical properties and biological performance of degradable implants is necessary. Development of more efficient biodegradable implants would have a very promising future in the treatment of orthopedic fractures.

62. When patients with syndesmosis injury were treated with PLA screws, there was sufficient fatigue and failure strength to repair the syndesmosis injury postoperatively [11]. Zhao et al. [12] used PLA screws and titanium alloy lag screws in patients with ankle fractures, and observed no significant difference in treatment effect or healing time compared with the metal group (Tables 5 and 6). Patients treated with PLA screws had good outcomes. The callus grew well, the fracture ends accorded well, there was no delayed union or nonunion of bones, and ankle function restored effectively.

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