Using Cement Plugs in Soft Tissue Infection and Osteomyelitis

http://www.healio.com/orthopedics/journals/ortho/%7Bbf26d10e-c5c2-44c9-8199-5b928ff70719%7D/using-cement-plugs-in-soft-tissue-infection-and-osteomyelitis

Using Cement Plugs in Soft Tissue Infection and Osteomyelitis

Alan Y. Yan, MD; Frances D. Faro, MD; Lew C. Schon, MD

Abstract

Operative foot and ankle osteomyelitis is challenging for orthopedic surgeons because of the area’s unique anatomy, high trauma incidence, local and systemic disease effects, and often limited space. Standard treatment includes aggressive operative debridement with local and systemic antibiotic administration to control infection. Dead space management is critical yet technically demanding. The authors report a modified antibiotic cement bead therapy technique in which antibiotic sticks, minnows, and mushroom-shaped plugs are used to strike a balance between the stability of the load-bearing unit and radical removal of infection to preserve a functional foot. Three cases are presented. [Orthopedics. 2014; 37(1):32–36.]

The authors are from the Department of Orthopaedic Surgery (AYY), The Johns Hopkins University; and the Department of Orthopaedic Surgery (FDF, LCS), MedStar Union Memorial Hospital, Baltimore, Maryland.

The authors have no relevant financial relationships to disclose.

The authors thank W. Chad Hembree, MD, for providing the procedure details on the third patient for this article.

Correspondence should be addressed to: Lew C. Schon, MD, c/o Elaine P. Henze, BJ, ELS, Medical Editor and Director, Editorial Services, Department of Orthopaedic Surgery, The Johns Hopkins University/Johns Hopkins Bayview Medical Center, 4940 Eastern Ave, Baltimore, MD 21224-2780 (ehenze1@jhmi.edu).
Received: May 06, 2013
Accepted: July 25, 2013
Posted Online: January 15, 2014

Operative foot and ankle osteomyelitis is likely in part a product of this area’s unique anatomy, high trauma incidence, and local and systemic disease effects.The lower extremity’s thin soft tissue envelope is occasionally further compromised by poor vascularity from high-energy trauma, diabetes mellitus, smoking, and peripheral vascular disease.1–3 Standard treatment includes aggressive operative debridement with local and systemic antibiotic administration to control infection.2,4–7 Such debridement can be technically demanding,7 but the removal of all nonviable tissue is essential to creating a healthy tissue bed and decreasing the infectious load. However, this process creates a dead space that needs to be managed.5–7

One way to manage such space is with cement spacers that can be molded into various shapes and loaded with antibiotics. This local delivery of high concentrations directly to the tissues offers a distinct advantage over the vascular-supply–dependent delivery of high and potentially toxic levels via systemic delivery.8–13 Antibiotic cement can be molded into large blocks and spheres to fit a patient’s anatomy, providing structural integrity and preventing soft tissue contracture, or into beads strung on suture for smaller areas (eg, those in the lower extremity). This bead technique has been modified for use within the crowded anatomy of foot and ankle operative osteomyelitis. The authors have successfully used this technique for many patients, resulting in infection resolution and more preservation of normal tissue and structural stability.

Technique

Contouring the shape of the antibiotic forms creates maximum surface contact and facilitates insertion into tight spaces (Figures 12). Long “sticks” are used for penetrating sinuses, tunnels, and abandoned hardware paths; they have a large surface area for eluting the antibiotic and can be easily shortened to a custom length even after the cement hardens. After hardware removal, plugs or “mushrooms” are used in the screw holes to provide structural integrity and direct delivery of antibiotics to the bone. “Minnows” are used to help contour voids created by surgical debridement.

Figure 1:

Mushroom-shaped antibiotic cement plugs applied to screw holes after plate removal.

Figure 2:

Antibiotic cement sticks, minnows, and mushroom plugs made intraoperatively.

Institutional review board approval was waived for this study. Informed consent was obtained from the patients.

Case Reports

Patient 1: Antibiotic Mushrooms

A 20-year-old man had swelling and serous wound drainage 4 months after a left ankle fibula fracture was treated with a plate and syndesmotic tightrope device. He underwent debridement.

After dissection, the screws securing the plate were removed. A tunnel from the superficial tissue extending deep was found with 3 to 4 mL of purulent material.The hardware was removed. The bone plate interface and screw holes were debrided with a curette. All wounds were copiously irrigated and closed primarily. A packet of cement was mixed with tobramycin (2.4 g) and vancomycin (2.0 g) until tacky and fashioned into small mushrooms (Figure 2), which were inserted into the screw holes. Because the cement was still slightly pliable, it formed to the bone hole, leaving a flat disk shape on the outside of the bone. Biplanar fluoroscopy confirmed removal of all hardware (Figure 3) and indicated syndesmosis widening, but no additional fixation was undertaken, given the infected tissue bed. The patient was allowed to bear weight as tolerated postoperatively. The patient had excellent infection resolution and no recurrence 3 years postoperatively.

Figure 3:

Intraoperative biplanar fluoroscopic image confirming plate removal and mushroom plug placement.

Patient 2: Antibiotic Sticks

A 54-year-old man had a history of morbid obesity, ankylosing spondylitis, and peripheral neuropathy. He had had severe right forefoot deformity, hallux valgus, and laterally deviated and clawed second through fifth toes and had undergone reconstructive surgery elsewhere, with subsequent recurrent deformity and ulcerations on the plantar aspect of the second metatarsal. One month after revision surgery, he jammed his right second toe, pushing the pin in farther. He presented 1 day later with edema, blistering, erythema of the foot, and purulent pin site drainage.

He underwent a second-toe amputation at the metatarsophalangeal joint, where purulence and necrotic tissue were debrided. After copious irrigation, cement sticks and plugs fashioned with vancomycin and tobramycin were placed in and around the second metatarsal (Figures 46). Two stitches were lightly applied to secure the sticks and plugs in place, allowing fluid egress.

Figure 4:

Placement of antibiotic cement sticks in a surrounded fashion.

Figure 5:

Toe site packed with antibiotics with the plugs placed over the tip after debridement.

Figure 6:

Mushroom antibiotic plugs applied. (©2012 Alan Yan. Used with permission.)

One week later, the patient had clean soft tissue and markedly decreased swelling. He returned to the operating room for suture and spacer removal.Minimal devitalized tissue was noted and debrided with curette and scalpel.New antibiotic cement sticks and plugs were placed, and the wound was closed with 3-0 nylon horizontal mattress and simple sutures. The wound was covered and placed into a bulky dressing. The patient was restricted to heel weight bearing only for 2 weeks. The patient had infection resolution at 1 week and no recurrence at 4 years.

Patient 3: Antibiotic Minnows

A 47-year-old man had a chronic draining sinus after open debridement elsewhere for plantar fasciitis of the right foot (Figure 7). Aggressive debridement was performed, and a large medial portion of the plantar fascia was excised and sent for culture (Figure 8). The bone was not involved. The wound was copiously irrigated. A packet of cement containing tobramycin (2.4 g) was mixed with vancomycin (2.0 g). Several minnow spacers (Figure 9) were placed, the “heads” deep to fill the void from the debridement and the “tails” wrapped around the medial aspect of the calcaneus. The wound was closed with 2-0 nylon simple, deep stitches. The patient was kept nonweight bearing for 6 weeks. The wound healed uneventfully, and the drainage stopped.Intraoperative cultures showed no growth. The patient was treated with a 7-day course of oral cephalosporin for the first week postoperatively. The spacers were removed 8 weeks postoperatively. The patient healed with some delay. There was no recurrence at 1 year.

Figure 7:

A 47-year-old man with a chronic draining sinus after open debridement of plantar fasciitis.

Figure 8:

Intraoperative image showing a large medial portion of the plantar fascia was excised and sent for culture. The bone was not involved in the infection.

Figure 9:

A pack of antibiotic cement containing 2.4 g of tobramycin was mixed with 2 g of vancomycin. Several minnow-shaped cement spacers were fashioned for insertion into the wound.

Discussion

Operative infection control is facilitated by a thorough debridement and microbial-specific antibiotic administration,12 but the surgical management of osteomyelitis is challenging. A suboptimal technique can result in recalcitrant chronic infection.7,14

Antibiotics can be delivered systemically or locally. Effective systemic application requires a high serum level, which can cause systemic side effects.11,15 However, an effective local delivery system incorporated surgically can provide the needed concentration of antibiotics while minimizing systemic toxicity.16

Antibiotic-loaded bone cement represents the gold standard for local antibiotic delivery16 and provides for dead space management.8 This concept is based on the pioneering work of Buchholz and Engelbrecht in the 1970s.4,12,17 In 1979, Klemm18 extended the indications for antibiotic bone cement by developing gentamicin-polymethylmethacrylate bead chains for chronic osteomyelitis surgery. He reported that 91.4% of 128 patients with chronic osteomyelitis treated with this technique had complete infection subsidence.18

The local delivery system works primarily via elution and some passive diffusion,12,19 affording high local concentrations, low serum levels, and no system toxicity.11–13,20 It also reduces systemic complications, compliance issues, and intravenous access problems12 and may address systemic antibiotics’ poor bone penetration, especially in devascularized bone.8 Local delivery also provides antibiotics independent of vascular support,8 an advantage in foot and ankle infection, where peripheral vascular condition is often compromised by systemic diseases.

Some studies have shown that the local deposit of antibiotics is a safe and useful method and provides favorable results for osteomyelitis and open fractures.11,21 However, Level I evidence is still limited.12

The original principles of osteomyelitis surgery included an atraumatic approach and removal of all necrotic or nonviable material with reconstruction in mind.6,7 However, management of the ensuing dead space is a key factor for a successful outcome.7,14 When serial debridement is indicated or inadequate local tissues require additional surgeries for closure, antibiotic-impregnated beads or spacers are implanted to inhibit and kill remaining pathogens13 and to preserve useful dead space for maintaining working length, facilitating closure, and preparing for later clean reconstruction.7,22

Because antibiotic spacers are intended for subsequent removal, generally after soft tissues have completely recovered (3 to 4 weeks, or 10 to 14 days if they are within the medullary canal), the second stage of surgery includes bead or spacer removal, repeat irrigation and debridement, and exchange for bone graft or a bone graft substitute.7 The longest recommended removal time is 4 to 6 weeks after implantation; removal thereafter can be incomplete or difficult because of fibrous tissue or callus enclosure.23

Although the current literature still has limited clinical data on foot and ankle infection treated with local antibiotic-loaded cement, complications related to the use of antibiotic beads for bone infection are uncommon.8,11,21

Conclusion

This technique modifies existing antibiotic bead therapy for the often-limited space in foot and ankle surgery and deep sinuses that are difficult to reach. It is designed to strike a balance between the stability of the load-bearing unit and radical removal of infection to preserve a functional foot. The sticks, minnows, and mushroom-shaped plugs are easy to place and retrieve. The mushroom-shaped plugs are most useful in the screw holes and local defects created by surgery or disease process. The sticks can be placed around the crowded locus in foot and ankle anatomy. The minnows are a hybrid shape that fills a long narrow tunnel and a larger zone of dead space. In the authors’ experience, the technique is a useful adjunct for infections in the foot and ankle.

References
Ansari MA, Shukla VK. Foot infections. Int J Low Extrem Wounds. 2005; 4(2):74–87. doi:10.1177/1534734605277312 [CrossRef]
Malizos KN, Gougoulias NE, Dailiana ZH, Varitimidis S, Bargiotas KA, Paridis D. Ankle and foot osteomyelitis: treatment protocol and clinical results. Injury. 2010; 41(3):285–293. doi:10.1016/j.injury.2009.09.010[CrossRef]
Verhelle N, Van Zele D, Liboutton L, Heymans O. How to deal with bone exposure and osteomyelitis: an overview. Acta Orthop Belg. 2003; 69(6):481–494.
Buchholz HW, Engelbrecht H. [Depot effects of various antibiotics mixed with Palacos resins]. Chirurg. 1970; 41(11):511–515.
Cierny G III, DiPasquale D. Treatment of chronic infection. J Am Acad Orthop Surg. 2006; 14(10):S105–S110.
Cierny G III, Mader JT, Penninck JJ. A clinical staging system for adult osteomyelitis. Clin Orthop Relat Res. 2003; 414:7–24. doi:10.1097/01.blo.0000088564.81746.62 [CrossRef]
Tetsworth K, Cierny G III, . Osteomyelitis debridement techniques. Clin Orthop Relat Res. 1999; 360:87–96. doi:10.1097/00003086-199903000-00011 [CrossRef]
Decoster TA, Bozorgnia S. Antibiotic beads. J Am Acad Orthop Surg. 2008; 16(11):674–678.
Elson RA, Jephcott AE, McGechie DB, Verettas D. Antibiotic-loaded acrylic cement. J Bone Joint Surg Br. 1977; 59(2):200–205.
Hanssen AD. Local antibiotic delivery vehicles in the treatment of musculoskeletal infection. Clin Orthop Relat Res. 2005; 437:91–96.doi:10.1097/01.blo.0000175713.30506.77 [CrossRef]
Wahlig H, Dingeldein E, Bergmann R, Reuss K. The release of gentamicin from polymethylmethacrylate beads: an experimental and pharmacokinetic study. J Bone Joint Surg Br. 1978; 60(2):270–275.
Zalavras CG, Patzakis MJ, Holtom P. Local antibiotic therapy in the treatment of open fractures and osteomyelitis. Clin Orthop Relat Res. 2004; 427:86–93. doi:10.1097/01.blo.0000143571.18892.8d [CrossRef]
Adams K, Couch L, Cierny G, Calhoun J, Mader JT. In vitro and in vivo evaluation of antibiotic diffusion from antibiotic-impregnated polymethylmethacrylate beads. Clin Orthop Relat Res. 1992; 278:244–252.
Lazzarini L, Mader JT, Calhoun JH. Osteomyelitis in long bones. J Bone Joint Surg Am. 2004; 86(10):2305–2318.
Schentag JJ, Lasezkay G, Plaut ME, Jusko WJ, Cumbo TJ. Comparative tissue accumulation of gentamicin and tobramycin in patients. J Antimicrob Chemother. 1978; 4(Suppl A):23–30. doi:10.1093/jac/4.suppl_A.23 [CrossRef]
Nelson CL. The current status of material used for depot delivery of drugs.Clin Orthop Relat Res. 2004; 427:72–78.doi:10.1097/01.blo.0000143741.92384.18 [CrossRef]
Buchholz HW, Elson RA, Engelbrecht E, Lodenkamper H, Rottger J, Siegel A. Management of deep infection of total hip replacement. J Bone Joint Surg Br.1981; 63(3):342–353.
Klemm VK. [Gentamicin-PMMA-beads in treating bone and soft tissue infections (author’s transl)]. Zentralbl Chir. 1979; 104(14):934–942.
Baker AS, Greenham LW. Release of gentamicin from acrylic bone cement: elution and diffusion studies. J Bone Joint Surg Am. 1988; 70(10):1551–1557.
Holtom PD, Warren CA, Greene NW, et al. Relation of surface area to in vitro elution characteristics of vancomycin-impregnated polymethylmethacrylate spacers. Am J Orthop (Belle Mead NJ). 1998; 27(3):207–210.
Walenkamp GHIM, Vree TB, van Rens TJG. Gentamicin-PMMA beads: pharmacokinetic and nephrotoxicological study. Clin Orthop Relat Res. 1986; 205:171–183.
Cierny G III, . Chronic osteomyelitis: results of treatment. Instr Course Lect.1990; 39:495–508.
Salvati EA, Callaghan JJ, Brause BD, Klein RF, Small RD. Reimplantation in infection: elution of gentamicin from cement and beads. Clin Orthop Relat Res. 1986; 207:83–93.

Meniscal Transplant Surgery

http://orthoinfo.aaos.org/topic.cfm?topic=a00381

Meniscal Transplant Surgery
The meniscus is a C-shaped cushion of cartilage in the knee joint. When people talk about torn cartilage in the knee, they are usually referring to torn meniscus.
If a meniscus is so badly damaged it cannot be repaired, it may need to be removed or trimmed out. Without the meniscus cushion, persistent knee pain and arthritis can develop.
For many older patients with this condition, a knee joint replacement might be the right option. But active people younger than 55 may be eligible for an alternative treatment: meniscal transplant surgery.
A meniscal transplant replaces the damaged meniscus with donor cartilage.
Meniscal transplants are not right for everyone. If you already have arthritis in your knee, a meniscal transplant may not help you. But for a select group of people, meniscal transplants can offer significant pain relief.
Anatomy
Three bones meet to form your knee joint: your thighbone (femur), shinbone (tibia), and kneecap (patella). Your patella sits in front of the joint to provide some protection.

Normal knee anatomy
The ends of your thighbone and shinbone are covered with articular cartilage. This slippery substance helps your knee bones glide smoothly across each other as you bend or straighten your leg.
Two wedge-shaped pieces of meniscal cartilage act as “shock absorbers” between your thighbone and shinbone. Different from articular cartilage, the meniscus is tough and rubbery to help cushion and stabilize the joint. Each knee has two menisci, one on each side of the joint.
Description
If your meniscus is severely damaged or has been removed, it is likely that the articular cartilage protecting your knee will begin to wear. As this cartilage wears away, it becomes frayed and rough. Moving the bones along this exposed surface is painful. This condition is osteoarthritis.
The goal of meniscal transplant surgery is to replace the meniscus cushion before the articular cartilage is damaged. The donor cartilage supports and stabilizes the knee joint. This relieves knee pain. The hope is that the transplant will also delay the development of arthritis, but long-term results are not yet available.

Allograft Preparation

Healthy cartilage tissue is taken from a cadaver (human donor) and frozen. This tissue is called an allograft. It is sized, tested, and stored. Correct sizing is one of the most important factors in the success of the transplant. Later, the allograft will be matched by size to a candidate for the procedure.

Allograft Safety

A screening process is done before selecting a possible donor. Someone who knows the donor well is interviewed to help identify risk factors that would prevent the use of the donor tissue.

Once selected, the donor tissue undergoes many tests. The safety of the tissue is monitored by the American Association of Tissue Banks and the United States Food and Drug Administration. The tissue is tested for viruses like those that cause HIV/AIDS, West Nile virus, hepatitis B and C, as well as for bacteria.

Patient Eligibility
Although meniscal transplants have been performed for more than 20 years, the procedure is still relatively uncommon. This is largely due to the strict criteria patients must meet to be considered for the procedure.
Most people with severe meniscal problems have also developed arthritis in the knee. If the articular cartilage has worn away too much, a meniscal transplant will not be helpful.
The criteria for meniscal transplant include:
  • Younger than 55 years and physically active
  • Missing more than half of a meniscus as a result of previous surgery or injury, or a meniscus tear that cannot be repaired
  • Persistent activity-related pain
  • Knee with stable ligaments and normal alignment
  • No or minimal knee arthritis
  • Not obese
Surgery
Meniscal transplant surgery is an arthroscopic procedure. It can be performed on an outpatient or inpatient basis. Whether or not you will need to stay overnight at the hospital will depend on your medical needs.

Procedure

Knee arthroscopy is one of the most commonly performed surgical procedures. In it, a miniature camera is inserted through a small incision. This provides a clear view of the inside of the knee. Your orthopaedic surgeon inserts miniature surgical instruments through other small incisions to do the procedure.

Typically, a 2- to 4-inch incision is made in the knee with a few other small “poke” holes. The new meniscal tissue is anchored into the shinbone to stabilize the transplant. More stitches are placed into the meniscal transplant to sew it into place.

Surgical Complications

The risk of complications from meniscal transplant surgery is very slight. Stiffness, reoperation, and incomplete healing are the most common complications.

Other risks include bleeding, infection, and nerve or blood vessel injury.
The risk of getting an infection from donor tissue is small, but it has happened. You are twice as likely to be struck by lightning (1 in 800,000 chance) than to contract HIV from a meniscal transplant (1 in 1.6 million chance).

Rehabilitation

Immobilization. You will need to wear a knee brace and use crutches for the first 4 to 6 weeks after surgery. This gives the transplanted tissue time to become firmly attached to the bone.

Physical therapy. Once the initial pain and swelling has settled down, physical therapy can begin. Specific exercises can restore range of motion and strength.
A therapy program focuses first on flexibility. Gentle stretches will improve your range of motion. As healing progresses, strengthening exercises will gradually be added to your program.
Return to daily activities. Most patients are not able to return to work for at least 2 weeks. Many patients with active jobs require 2 to 3 months of rehabilitation before they resume their jobs. Your doctor will discuss with you when it is safe to return to work, as well as any sports activity. Full release is typically given 6 to 12 months after surgery.

Outcome
Many factors contribute to the success of a meniscal transplant. These include:
  • The condition of the knee at the time of surgery
  • Correct sizing of the transplant
  • The technique of placing the tissue
  • Commitment to rehabilitation
The research studies that have been done on meniscal transplants are not perfect. Overall, between 21% and 55% of transplants fail within 10 years. Meniscal transplants on the outside (lateral) part of the knee are more successful than those on the inside (medial) of the knee.
Synthetic (artificial) meniscal tissue has been tried, but there is conflicting information at this time.
Meniscal transplants can be quite helpful, but are not a good option for every patient. For patients who are carefully and correctly selected, meniscal transplant surgery can provide significant benefits.
Last reviewed: February 2009
Co-developed by the American Orthopaedic Society for Sports Medicine

Resultado clínico-radiológico del tratamiento quirúrgico de las fracturas intra-articulares del calcáneo

http://new.medigraphic.com/cgi-bin/resumenMainOrto.cgi?IDREVISTA=9&IDARTICULO=1100&IDPUBLICACION=118

Acta Ortopédica Mexicana

Netzahualcóyotl BJPF, Gutiérrez MI, Makkozzay PTH
Resultado clínico-radiológico del tratamiento quirúrgico de las fracturas intra-articulares del calcáneo
Acta Ortop Mex 2004; 18 (1)
Idioma: Español
Referencias bibliográficas: 22
Paginas: 21-24
Archivo PDF: 52.68 Kb.
RESUMEN
Objetivo: Evaluar los resultados clínico-radiológicos de las fracturas intra-articulares del calcáneo bajo tratamiento quirúrgico abierto. Material y métodos: Se realizó un estudio transversal analítico de 21 pacientes de cualquier edad, sexo y ocupación con fractura intra-articular de calcáneo unilateral bajo tratamiento quirúrgico abierto mediante placa tercio de caña, de reconstrucción o especial para calcáneo y se les citó para realizar una evaluación funcional y radiológica (en busca de cambios artrósicos) del pie y tobillo involucrados. Se realizó estadística descriptiva e inferencial para las variables del estudio. La edad promedio de los pacientes fue de 62± 19 (de 16 a 80 años), el sexo predominante fue el masculino con 81%, el calcáneo afectado que predominó fue el derecho con 52%; con un seguimiento promedio de 17 ± 4.6 meses.Resultados: Consolidación radiológica de la fractura de 10 ± 2 meses, la placa especial para calcáneo mostró mejoría estadísticamente significativa respecto de la tercio de caña y reconstrucción (p = 0.0001) no así en la evaluación radiográfica (p = 0.31). Se confirma que la placa especial para calcáneo tiene ventajas funcionalmente significativas respecto de la tercio de caña y reconstrucción para las fracturas intra-articulares del calcáneo.


Palabras clave: fracturas, calcáneo.

Manifestaciones óseas en enfermedad de Gaucher entre pacientes mexicanos

http://new.medigraphic.com/cgi-bin/resumenMainOrto.cgi?IDREVISTA=9&IDARTICULO=26281&IDPUBLICACION=2681

Acta Ortopédica Mexicana

Blass PJ
Manifestaciones óseas en enfermedad de Gaucher entre pacientes mexicanos
Acta Ortop Mex 2010; 24 (5)
Idioma: Español
Referencias bibliográficas: 11
Paginas: 351-358
Archivo PDF: 409.31 Kb.
RESUMEN
La enfermedad de Gaucher (EG) es la más común entre las enfermedades por depósito lisosomal (EDL) definidas a la fecha. Posee una tasa de incidencia bastante baja a nivel mundial, pero su perfil de afectación orgánica es perturbador ya que se traduce en una morbimortalidad importante, así como en elevados costos de atención y pobre calidad de vida. Es una patología genética recesiva y autosómica asociada con la insuficiencia de la enzima glucocerebrosidasa. El depósito de sustrato produce deterioro orgánico considerable en esqueleto, hígado, riñones, pulmones, bazo, cerebro y médula ósea. Este informe presenta varios casos clínicos de pacientes mexicanos, caracterizados por el daño óseo con el objetivo de difundir los hallazgos y evoluciones típicas de la enfermedad entre los ortopedistas. Se discuten las particularidades de los pacientes, así como su respuesta al tratamiento con terapia de reemplazo enzimático (TRE) y los resultados en su seguimiento clínico, con los recursos terapéuticos actualizados.


Palabras clave: enfermedades por almacenamiento lisosomal, hueso, tratamiento, enzimas, México.